Radixact - Carpeta de Producto

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CONTENIDO CONTENIDO R A D I X A C T 5 ¿QUÉ ES EL SISTEMA RADIXACT?

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D E L E C C I E N T Í F I C A 8 A B O C A D O S A L A I N N O VA C I Ó N

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C O N S U LT O R Í A I N T E G R A L

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APLICACIONES CLÍNICAS

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SERVICIO TÉCNICO ESPECIALIZADO

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¿POR QUÉ ELEGIRLO?

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S O B R E A C C U R AY Y R A D I X A C T

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P I L A R E S F U N D A M E N TA L E S

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AMIGABLE CON EL USUARIO

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P R E C I S I Ó N S I N C O M PA R A C I Ó N

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VERDADERA EXACTITUD

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COMPONENTES DEL SISTEMA

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¿ Q U É P A C I E N T E S S E P U E D E N T R ATA R ?

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C A R A C T E R Í S T I C A S D E L T R ATA M I E N T O

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DISEÑO DEL BÚNKER

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CASOS DE ÉXITO 67 ENTRENAMIENTO

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C O M P A R AT I VA

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BIBLIOGRAFÍA

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PUBLICACIONES CIENTÍFICAS

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Esta carpeta fue generada por el equipo de consultores de DeLeC Científica. 2021.

DeLeC Científica Uruguaya - Representante Regional Exclusivo Fco. García Cortina 2357 – Piso 1. Montevideo - Uruguay Tel: (+598) 2711 4466 DeLeC Científica Argentina – Agente Comercial Local Aráoz 821 -C1414DPQ - Buenos Aires – Argentina.

Tel: (+54-11) 4775 5844

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A lo largo de la historia, las patologías oncológicas han representado uno de los desafíos más importantes a los que se enfrenta la medicina y la industria asociada, a nivel mundial.

Con la premisa de lograr controlar estas enfermedades con el mínimo impacto negativo sobre la calidad de vida de los pacientes, las instituciones han destinado cuantiosos recursos a la investigación y el tratamiento oncológico en todas las áreas clínicas involucradas: la cirugía, la quimioterapia y la radioterapia (RT).

En el ámbito de la RT, donde la eficiencia, la exactitud y la precisión juegan un papel fundamental, se han logrado numerosos avances con el desarrollo de soluciones tecnológicas realmente innovadoras.

La complejidad del proceso radioterapéutico es tal que ha obligado al desarrollo de diferentes tecnologías y softwares especializados en cada una de las modalidades y etapas que lo constituyen, de modo que en conjunto se complementan y permiten garantizar la ejecución de procedimientos óptimos y seguros para el mayor número de patologías oncológicas posible. Así, para cada modalidad: RT externa, braquiterapia y RT intraoperatoria, se han logrado grandes avances tecnológicos que se han traducido en el desarrollo de equipos y sistemas versátiles que permiten abandonar la RT convencional y adentrarse a la RT moderna, con todos los beneficios que esto conlleva para los pacientes.

En DeLeC Científica S.A., vamos de la mano de los avances del siglo XXI y nos preocupamos por seleccionar las tecnologías más destacadas que ofrecen soluciones reales a todos los pacientes oncológicos candidatos a radioterapia: • TomoTherapy / Radixact: el único sistema para radioterapia y radiocirugía helicoidal. Aplica a cualquier tipo de tumor, especialmente en los casos más complejos, como las metástasis múltiples y masas tumorales extensas; • CyberKnife: el único sistema de radiocirugía robótica con precisión submilimétrica. Aplica a masas tumorales pequeñas en cualquier parte del cuerpo (intra y extracraneal), especialmente aquellas ubicadas en órganos con movimiento; • RayStation: el mejor software de planificación de tratamientos que integra en una misma plataforma aceleradores de cualquier casa comercial;

• Xoft: primer sistema de braquiterapia electrónica que garantiza excelentes distribuciones de dosis sin el uso de material radioactivo.

• Liac HWL: sistema más eficiente para radioterapia intraoperatoria con electrones, con la que se logra aumentar significativamente el control local en un gran número de patologías oncológicas.

En este documento les presentamos con detalle el sistema Radixact. Se trata del equipo de radioterapia más completo y actualizado del mercado. Su geometría y diseño helicoidal fueron pensados para maximizar las posibilidades de ofrecer tratamientos seguros y eficaces con un nivel de precisión sub-milimétrico.

Radixact combina un acelerador lineal y un sistema de tomografía que permite verificar continuamente la posición de los órganos involucrados previo a la entrega de la dosis.

Es el equipo que cubre el mayor campo de trabajo gracias a su geometría helicoidal, lo que es fundamental para pacientes que ameriten irradiación de volúmenes tumorales extensos o tratamientos de irradiación corporal total (TBI).

Los softwares de planificación de tratamientos y operación del equipo son intuitivos y de fácil manejo, aprovechan al máximo la fidelidad de la tecnología y minimizan los posibles errores humanos al garantizar flujos de trabajo rápidos y dinámicos.

Además, posee ventajas que aceleran la logística para las instituciones. Al ser un acelerador monoenergético (6MV) y poseer una barrera de protección contra la radiación en su interior, se minimizan los requerimientos del búnker, pudiendo incluso adecuarse a las instalaciones de las viejas bombas de cobalto. Además, viene pre-comisionado de fábrica, lo que permite reducir el proceso de puesta en marcha del equipo a 30 días.

En DeLeC Científica S.A. estamos seguros que el Radixact es el equipo más seguro, eficiente y versátil para la entrega de tratamientos de radioterapia externa en tumores grandes y pequeños. Es un paso hacia el futuro en la lucha contra el cáncer para la comunidad médica y científica, y nuestra recomendación más enfática en la decisión de brindar un servicio de radioterapia con el nivel más alto de excelencia.

MSc Miguel Yanez Director de División Radioterapia y Radiocirugía DeLeC Científica

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RADIOTERAPIA HELICOIDAL DE ALTA PRECISIÓN

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¿Qué es el sistema Radixact?

El sistema Radixact es la renovación del TomoTherapy, primera y única plataforma para radioterapia helicoidal, que integra la planificación del tratamiento, la verificación de la posición del paciente, la administración de la dosis y el monitoreo del haz de radiación durante la entrega.

Usa un revolucionario colimador multiláminas binario con el cual es posible modular la intensidad de un haz de radiación de entrega helicoidal, rotatorio y continuo. El haz es generado en un acelerador lineal instalado en un gantry de morfología anular, obteniendo altos índices de conformabilidad en el blanco, distribuciones de dosis homogéneas y altos gradientes dosimétricos, optimizando el rango terapéutico.

El sistema proporciona imágenes volumétricas de TAC de las estructuras de interés inmediatamente antes del tratamiento, permitiendo en tiempo real verificar la posición del paciente, y con esto la localización del blanco y de los órganos en riesgo. También permite adaptar la planificación de la radioterapia de acuerdo a las posibles modificaciones que ocurren durante el periodo del tratamiento en la morfología, tamaño y movilidad del tumor.

Radixact contempla en una única unidad funcional, tratamiento e imagen con un diseño que le permite ejecutar con la más alta eficiencia y precisión la verdadera radioterapia de intensidad modulada (IMRT) guiada por imagen tomográfica.

Precisión y robustez en los tratamientos oncológicos.

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DeLeC Científica, abocados a la innovación

En DeLeC Científica hicimos de la innovación tecnológica el combustible para impulsar la modernización de los sistemas de salud y la calidad de los servicios médicos.

Trabajamos acercando las innovaciones tecnológicas más destacadas del siglo XXI a los hospitales y clínicas de la región, desde la consultoría, la comercialización y el desarrollo de programas médicos integrales que permiten garantizar servicios médicos de excelencia.

Nuestra firma comercializa la mayoría de sus productos en Argentina, Uruguay, Paraguay y Bolivia, y cuenta con representaciones que alcanzan Chile, Perú, Ecuador y Brasil.

Misión Nos hemos propuesto hacer foco en lo especial y proveer soluciones a problemas de los que nadie se ha ocupado. Por eso aportamos equipamiento y asesoramiento para hacer factibles y seguros los nuevos paradigmas en el ámbito de la salud, como son los tratamientos personalizados, con mayor seguridad y una experiencia más confortable para los pacientes.

Nos interesan los procesos y sus resultados. Por eso trabajamos junto a nuestros partners desde el diseño de sus propuestas, con consultorías especializadas, asesoramiento y asistencia técnica oficial, garantizando la ejecución de proyectos exitosos.

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Consultoría integral

Nuestra experiencia en el ámbito de la innovación tecnológica en salud nos dice que, tan importante como el equipamiento son las etapas de formación, la comprensión de la tecnología, el acompañamiento clínico, el asesoramiento y los objetivos que orientan la práctica.

Por eso en DeLeC Científica acompañamos a las instituciones desde el desarrollo de los proyectos, el diseño de nuevas áreas o servicios de salud, el asesoramiento en la adquisición de nuevas tecnologías, el seguimiento clínico con especialistas en radioterapia, los requerimientos normativos y legales, la diagramación logística, el mantenimiento y el monitoreo del uso.

Un asesoramiento adecuado es clave para:

Obtener planificaciones que permitan optimizar el tiempo de los proyectos,

Implementar know how para conseguir mejores resultados,

Aplicar estrategias para retorno de la inversión,

Visualizar un camino de crecimiento con fundamentos sólidos y desarrollo de valor.

Con el fin de asesorar, tomando como referencia los máximos estándares de calidad, los consultores de DeLeC nos actualizamos de acuerdo a los programas de formación de las firmas que representamos y participamos de forma activa en la agenda más relevante de la innovación tecnológica médica a nivel global.

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Acompañamiento desde Aplicaciones Clínicas

DeLeC Científica se destaca por ser la única em-

Nuestro personal de Aplicaciones Clínicas brindará

presa capaz de proveer un servicio de aplicaciones

capacitación y entrenamiento a los equipos de salud,

clínicas completo, que va desde la etapa de consul-

con orientaciones prácticas y teóricas para aprove-

toría hasta la docencia post instalación de manera

char al máximo la potencialidad de la tecnología.

continua. Este equipo conformado por especialistas con una amplia experiencia clínica en radioterapia, capacitados por fábrica y con actualizaciones permanentes, asisten a las instituciones en el diseño de programas médicos de excelencia que mejoran de forma exponencial los flujos de trabajos asocia-

Con este programa de acompañamientos, brindamos a nuestros partners la seguridad de estar alineados con las mejores prácticas de cada especialidad, favoreciendo una mayor seguridad tanto para los usuarios como para los pacientes.

dos a la práctica de la radioterapia.

De esta forma, las tecnologías seleccionadas se logran implementar con los mejores resultados, favoreciendo una práctica médica integral que seguramente superará los objetivos clínicos y económicos de los proyectos.

El acompañamiento a nuestros clientes no conoce distancias. Implementamos plataformas, videoconferencias y aplicamos un cronograma de visitas para anticiparnos a las necesidades de consultas y actualización.

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Servicio técnico especializado

Todos nuestros proyectos de consultoría están respaldados por la dirección de Servicio Técnico. El área se compone de ingenieros biomédicos y bio-ingenieros capacitados por las fábricas para brindar asistencia local de alta performance.

Trabaje seguro con equipamiento único en el mundo, contando con un grupo de especialistas que le garantizará continuidad de servicio y respaldo los 365 días del año.

Ofrecemos un servicio técnico de alta performance, alineado tanto a las exigencias y estándares de las marcas con las que trabajamos, como a los requerimientos de nuestros clientes.

El equipo técnico asiste en la interpretación de los requerimientos previos (condiciones eléctricas, infraestructura, etc.), se ocupa de la instalación, cuando el equipo lo requiere, y luego monitorea el funcionamiento y el uso para garantizar el desempeño óptimo de la tecnología.

Nuestros ingenieros deben cumplir con un cronograma de formación y capacitación anual, en las casas matrices de las firmas que representamos. Por lo tanto, desde DeLeC Cientíífica ofrecemos una asistencia de instalación y posventa certificada por fábrica.

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Servicio oficial de instalaciones

Staff

Ofrecemos el servicio de instalación oficial de los

• División de Radioterapia y Radiocirugía: Desarrolla proyec-

equipos de las firmas que representamos en Ar-

tos llave en mano para el tratamiento de tumores malignos y

gentina, Uruguay, Paraguay, Bolivia y Chile. Nues-

benignos, previendo todas las dimensiones vinculadas: consul-

tro servicio cumple con todos los procesos reco-

toría, docencia, comercialización, servicio de Aplicaciones Clí-

mendados por la fábrica.

nicas pos-venta completo. Brinda servicio docente a los usua-

Contar con el certificado y la habilitación de servicio

rios para asegurar su correcta utilización y las buenas prácticas.

La firma cuenta con seis áreas:

oficial garantiza a nuestros clientes seguridad y calidad a lo largo del proceso de instalación de los siste-

• División de Sistemas Médicos: Provee la mejor tecnología de

mas, contemplando los más altos estándares a nivel

punta para cubrir necesidades de equipamiento de diagnósti-

mundial. La formación constante en fábrica de nues-

co. Busca optimizar resultados clínicos y mejorar la calidad de

tros ingenieros se traslada en mejoras continuas en

la experiencia vivida por los pacientes.

los procesos de instalación. El Servicio Técnico de instalaciones combina la mejor tecnología disponible

• División de Simulación Clínica: Pone a disposición de la co-

en la actualidad, respaldo y experiencia.

munidad médica un catálogo de simuladores que abarca desde soluciones sencillas hasta las más completas que existen en el mercado. Esta versatilidad nos permite ofrecer proyectos a medida y escalables.

• División de Ingeniería y Servicio Técnico: Lleva a cabo todas las acciones de logística necesarias para la importación de las distintas tecnologías. Asegura que el funcionamiento de los equipos instalados sea igual que el de origen, en fábrica. Controla y monitorea el funcionamiento de la base de instalada, con mantenimiento preventivo y correctivo, y actualización continua.

• División de Comunicación y RSE: Genera contenidos para favorecer el conocimiento de las innovaciones tecnológicas que representamos. Asimismo, promovemos eventos de divulgación, demostraciones y acciones para conectar con nuestra audiencia.

• División de Administración, Personal y Finanzas: Optimiza los resultados económicos de la empresa, cuidando que haya una distribución equitativa de los recursos entre los proveedores, clientes, personal, accionistas, bancos/inversores y el fisco. Su objetivo principal es velar por una gestión eficiente y ecuánime al momento de crear valor económico produciendo, al mismo tiempo, valor social.

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Tecnología

Representamos exclusivamente equipos que son seguros y están debidamente certificados y aprobados por los organismos internacionales de control -FDA y CE- y también los nacionales -ANMAT y ARN-. Además, brindamos un soporte pre y post venta de excelencia para garantizar la funcionalidad una vez instalados.

Nuestro diferencial es que no sólo proveemos equipos, sino que desarrollamos programas médicos de excelencia, acompañando al cliente desde la etapa embrionaria del proyecto hasta su optimización operativa.

Trabajamos codo a codo con las instituciones, haciendo transferencia de tecnología desde el servicio técnico, el acompañamiento clínico, la comunicación y la consultoría integral. Así logramos que las inversiones en equipamiento, se conviertan en mejoras en la calidad de vida de los pacientes.

Nuestro lema es ganar cuando el cliente también gana, cumplir con lo prometido y hacerlo a tiempo.

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Potenciamos desde la comunicación

En DeLeC no hablamos de clientes sino de partners. Nuestro modelo de innovación y comunicación nos vincula a todas las organizaciones e instituciones que integran la comunidad médica regional. En este marco, brindamos soporte de comunicación y marketing a nuestros parterns. Sabemos que toda innovación tecnológica, para ser capitalizada debidamente, requiere un trabajo de divulgación y comunicación.

Por eso nuestro equipo en Argentina y Uruguay genera materiales atractivos de todos los sistemas y equipos que representamos. Desarrollamos eventos propios, workshops, webinars con finalidades formativas y de divulgación. Son abiertos y de fácil acceso.

Potenciamos los proyectos a través de diferentes estrategias de comunicación:

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Marketing digital

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SEO y datos

•

Contenidos originales

• Videos

•

Ciclos temáticos

•

Eventos y conferencias

•

Proyectos con instituciones

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Nuestros representados

A Subsidiary of Samsung Electronics Co. , Ltd

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Sobre Accuray y Radixact

Accuray es una compañía especializada en radio-on-

der en el campo de radiocirugía, adquirió TomoThe-

cología, que desarrolla, fabrica y ofrece sistemas de

rapy Inc. con el fin de colocarse como una compañía

innovación tecnológica que proporcionan las mejores

de excelencia en el campo de la radioterapia. Duran-

soluciones de tratamiento para pacientes oncológicos

te el período de 2011 a 2016 Accuray se dedicó a

en el ámbito de la radioterapia y de la radiocirugía.

perfeccionar el sistema TomoTherapy de manera de

A partir de 1997, la empresa TomoTherapy Inc. en Wisconsin, emprendió el desarrollo de un sistema que combina la Radioterapia de Intensidad Modula-

incorporar la mejor tecnología en sus equipos, de este esfuerzo surgió una nueva generación del sistema TomoTherapy, el Radixact.

da (IMRT, por sus siglas en inglés) con la capacidad

El sistema Radixact está diseñado para permitir a

de obtener imágenes de tomografía computarizada a

los médicos brindar de manera más eficiente y efec-

partir de haces de megavoltaje (MVCT), con el fin de

tiva tratamientos de radiación mucho más prec isos

garantizar una precisión inigualable en cada fracción

a más pacientes en una amplia variedad de cán-

del tratamiento. A mediados de 2003 fue aprobado

ceres, desde los más comunes hasta los más com-

por la Administración de Alimentos y Medicamentos

plejos. El gantry del Radixact combina imágenes de

(FDA, por sus siglas en inglés) y obtuvo la Conformi-

TC con IMRT a fin de proporcionar tratamientos de

dad Europea (CE), durante la existencia de la empresa

radiación más sofisticados, con mayor velocidad y

TomoTherapy Inc. se vendieron más de 300 unidades

precisión, reduciendo la exposición a la radiación del

en todo el mundo. A principios del 2011 Accuray, lí-

tejido sano circundante.

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Pilares fundamentales

INTEGRACIÓN COMPLETA Ofrece un proceso de tratamiento totalmente integrado para la terapia del cáncer.

Incorpora un software muy fácil de usar para la planificación del tratamiento, el control de calidad, y la configuración y administración del tratamiento. Debido a que todos los pacientes y la información del plan se almacena en un solo lugar, el riesgo de errores de transferencia de datos se reduce al mínimo.

LÍDER EN LA INDUSTRIA Brinda una modalidad de tratamiento helicoidal (continua 360˚) en la cual se utilizan decenas de miles de beamlets estrechos, los cuales son dirigidos al tumor con el fin de optimizar la dosis total al mismo.

PRECISIÓN VERDADERA El sistema Radixact viene integrado con la tecnología CTrue™ y ClearRT™, las cuales permiten a los médicos adquirir imágenes TC todos los días para cada paciente. Éstas últimas desempeñan un rol fundamental en el posicionamiento del paciente, en el análisis dosimétrico y en la modificación del tratamiento en cualquier momento de la terapia.

CTRUE™ Permite a los médicos comparar el volumen tumoral original a partir de imágenes precisas y reconstrucciones en 3D. Luego, pueden determinar rápidamente si se requieren ajustes para asegurarse de que la dosis prescripta en el tumor se administre con precisión durante todo el tratamiento.

ClearRTTM Es un sistema integrado que permite la adquisición de tomografía helicoidal (haz en abanico) de kV de alta fidelidad, comparable a una tomografía de diagnóstico.

Dichas imágenes se pueden utilizar para la configuración diaria del paciente, para evaluar si la adaptación del plan sería beneficiosa y potencialmente para crear un plan de tratamiento adaptado.

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Pilares fundamentales

SYNCHRONY® Es un sistema, que empleando inteligencia artificial (AI), es capaz de seguir, en tiempo real, el movimiento del tumor y ajustar el haz de tratamiento automáticamente a esos cambios de posición para poder entregar la dosis continuamente durante todo el recorrido del tumor de manera precisa. Esto permite reducir los márgenes de tratamiento, escalar la dosis, y realizar hipofraccionamiento.

PLANIFICACIÓN ADAPTATIVA El software PreciseART™ permite lograr una verdadera radioterapia adaptativa. Mediante el uso de las imágenes 3D utilizadas para el posicionamiento diario del paciente, los médicos son capaces de visualizar la dosis que realmente se entregará al paciente ese día.

ADMINISTRACIÓN DE LA DOSIS ADAPTABLE Permite el análisis cuantitativo, dosimétrico y la modificación del tratamiento de un paciente, durante el curso del mismo, ajustándolo a los cambios en la anatomía y el tamaño del tumor. Como resultado, los pacientes pueden estar seguros de que están recibiendo la dosis prescrita.

ASEGURAMIENTO DE LA CALIDAD INTEGRADO La aplicación TomoQuality Assurance (TQA™) simplifica la recopilación y el análisis de la información del rendimiento del sistema, ofrece información de tendencias y de los parámetros que permitirán a los físicos controlar el rendimiento del equipo.

TRATAMIENTOS EFICACES Brinda dos modalidades de tratamiento: TomoDirect (opción de entrega no rotativa), la cual se basa en ángulos discretos, con las capacidades de la radioterapia 3D conformada; TomoHelical, que permite la rotación alrededor del cuerpo y multiplica la cantidad de posiciones del gantry.

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Planifique el tratamiento desde un software poderoso e intuitivo.

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Amigable con el usuario

Con sus equipos de radioterapia y radiocirugía, Accuray logró un cambio fundamental en las salas de terapia radiante: hacer las cosas mejor, en menos tiempo. En este paso, el sistema de planificación Presicion cumple un rol determinante: facilita la actividad de los equipos interdisciplinarios, optimiza los planes de tratamiento y reduce errores.

El sistema de planificación incorpora: 1. Software de planificación del tratamiento fácil de utilizar. Los controles de calidad, el posicionamiento del paciente y la administración del tratamiento se efectúan con una única base de datos centralizada. El fácil uso del software de planificación permite al personal de la unidad tratar a más pacientes y dedicarle mayor tiempo a cada uno de ellos. Las capacidades clave incluyen fusión de imágenes multimodalidad con deformación patentada, un conjunto de opciones de contorneado, y herramientas de comparación y suma del plan.

2. La planificación de los tratamientos está centralizada en un solo lugar, el iDMs. Es posible conectar múltiples sistemas de entrega de tratamiento Accuray y administrar toda la planificación del tratamiento desde un único punto de control.

CONFIDENCE IN CONNECTIVITY

Customer Backup

RaySta n® System

™ Accuray Precision Treatment Planning System

Gateway

Internet / Accuray Service

iDMS ™

Treatment Planning CT

Data Management System Oncology Informa on System

Delivery Analysis

® TomoTherapy Treatment Delivery System

DATA ENCRYPTION

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™ Radixact Treatment Delivery System

CyberKnife® Treatment Delivery System

SECURE FIREWALL

Precisión sin comparación

Los aceleradores lineales de otras casas comerciales no pueden realizar una radioterapia helicoidal, limitando sus opciones de tratamiento a un tamaño de campo cuadrado, haciendo que tratamientos extensos sean divididos en varios isocentros para cubrir la región a tratar y poniendo en riesgo la efectividad del tratamiento mediante flujos de trabajos complicados.

El sistema de tratamiento Radixact emite radiación continua desde todos los ángulos alrededor del paciente.

Implementa un verdadera innovación en su MLC de forma binaria, un diseño específico que permite brindar un mejor tratamiento de IMRT (Zaleska et al. 2017; Hsu et al. 2017). El modo TomoHelical permite la irradiación continua alrededor de los 360º del paciente a medida que la camilla avanza hacia dentro del equipo lo que permite entregar un tratamiento en forma helicoidal único.

Con esta modalidad se pueden tratar volúmenes tumorales muy grandes en una única y sencilla configuración, posibilitando tratar cualquier región del paciente dentro de un volumen cilíndrico de 80 cm de diámetro transversal y 135 cm de largo.

Otro modo de tratamiento es el TomoDirect™ que nos permite realizar, a través de diferentes ángulos de gantry fijos, una entrega de dosis de forma más directa. En ambos casos, los volúmenes reales de tratamiento son variables dependiendo de la posición de la camilla y la configuración del ancho de campo (Saw et al. 2018).

La precisión del tratamiento se logra gracias a las decenas de miles de beamlets que surgen como resultado de una optimización del plan dirigiendo el 100% de la dosis al tumor. Cabe destacar que un beamlet corresponde a la radiación emitida a través de una hoja abierta del sistema de MLC (patentado con el acelerador) en un ángulo dado y durante una determinada rotación.

Entrega tratamiento de forma helicoidal abarcando un campo de 135 cm.

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Verdadera exactitud

La tomografía computada es una herramienta funda-

En cada fracción del tratamiento, el equipo brinda

mental en el diagnóstico del cáncer, así como en la

la posibilidad de visualizar la anatomía en los pla-

delimitación de objetivos, los órganos de riesgo y la

nos axiales, coronales, sagitales y correlacionar estas

generación de la planificación del tratamiento. Con el

imágenes con las adquiridas mediante un tomógra-

sistema CTrue el papel de la TC se amplía aún más.

fo convencional. Mediante el registro automatizado de imágenes se pueden determinar rápidamente los ajustes necesarios y realizar de manera precisa el corrimiento on-line de la camilla para ubicarla en la posición óptima del tratamiento.

La tecnología MVCT tiene como resultado una uniformidad igual a la de una tomografía convencional (kVCT) manteniendo una consistencia en los valores de las unidades Hounsfield obteniendo mapas de densidad precisos.

Planificación de Radixact

Un haz de MV permite proporcionar imágenes de TC confiables independientemente del tamaño y

El sistema de tratamiento viene integrado con la

forma del paciente, e incluso con la presencia de

tecnología CTrue que permite a los médicos adquirir

materiales de alto número atómico, los cuales pro-

imágenes de TC todos los días para cada paciente.

ducen artefactos que distorsionan las imágenes de

Éstas pueden ser utilizadas con fines de posiciona-

tomografía de kV convencional. Otra ventaja es que

miento, permitiendo un análisis cuantitativo, dosi-

la dosis proporcionada para adquirir la imagen es

métrico y la modificación del tratamiento en cual-

baja. Cabe aclarar que las imágenes no son compa-

quier momento durante el curso del mismo (Ramsey

tibles en calidad con las de kVCT, pero pueden ser

et al. 2006; Kim et al. 2018).

utilizadas para el cálculo de dosis teniendo en cuen-

Para el posicionamiento de los pacientes las imágenes de CTrue desempeñan un papel fundamental.

Ellas son tomografías realizadas con el mismo acelerador lineal, pero con una energía de 3.5 MV (MVCT), entregando una dosis adicional de solamente entre 1 y 2 cGy (Ding et al. 2018).

24

ta las heterogeneidades (Hu et al. 2017). Esto abre la puerta a la replanificación dosimétrica y por ende a la planificación adaptativa.

El objetivo central es mostrar los efectos dosimétricos que se producen debido a los desajustes en el posicionamiento y los cambios de la anatomía.

Existen diversos factores que deforman las estructuras anatómicas antes de llevar a cabo el tratamiento, como son, la pérdida de peso, la contención de líquidos, el movimiento de la respiración, entre otros. El software PreciseART™ permite hacer un seguimiento de este tipo de cambios.

La opción de terapia radiante PreciseART amplía las posibilidades de radioterapia adaptativa, brindando un nivel completamente nuevo de integración de sistemas y automatización del flujo de trabajo. PreciseART les permite a los médicos monitorear a cada paciente y adaptar de manera eficiente los planes, ayudando a ofrecer tratamientos más precisos a más pacientes.

El procesamiento automatizado de imágenes diarias permite a los médicos supervisar a todos los pacientes y establecer niveles de acción específicos del protocolo para marcar los casos para su revisión y posible adaptación al plan.

25

El sistema posee una única base de datos que alma-

• Genera informes definidos por el usuario.

cena la información de la planificación y la entrega de

• Marca fracciones con estructura(s) que exceden la

dosis, lo que hace sencillo identificar los puntos “ca-

dosis definida por el usuario o la tolerancia al volu-

lientes” y “fríos”, haciendo más fácil la actualización

men de dosis.

de la planificación.

• Registro y revisión de la dosis diaria, la dosis acumu-

La automatización de procesos clave permite a los

lada, las diferencias de dosis y los datos de tendencias.

médicos supervisar a todos los pacientes e identificar

• Compara fracciones y muestra contornos originales

de inmediato a los candidatos para volver a planificar.

y deformados en una imagen fusionada.

• Evalúa la deformación con herramientas de control

Características: • Deforma los VOI de planificación en la imagen diaria.

• Calcula la dosis en la imagen diaria.

• Deforma y acumula dosis diarias en la planificación de tratamiento .

Imagen de planificación de tratamiento para Radixact.

26

de calidad incorporadas.

27

MLC Binario

LINAC

Anillo de 85 cm Magnetrón Cadena de RF pre-calibrada Soporte de camilla

Detector de imágenes y Beam Stop

Control de temperatura

Diagrama de todos los componentes de un equipo Radixact.

Acelerador lineal Opera con fotones de 6MV generados en el Linac integrado en el gantry. Opuestamente al Linac se encuentran los detectores de Xenón que permiten la adquisición de imágenes TC y facilitan las tareas de control de calidad.

Inmediatamente después del sistema detector se encuentra el Beam Stop que detiene la radiación directa y dispersa en un 50% proveyendo un auto-blindaje que disminuye los requerimientos de construcción del bunker.

Integrated Shielding Linear Accelerator (Linac)

Target Primary Collimator

Jaw Collimator

Vista lateral de los componentes del sistema de colimación.

28

Gantry Posee la capacidad de generar un movimiento con-

Características:

tinuo, rotatorio, del acelerador lineal en 360° mien-

• La velocidad de rotación para el tratamiento va

tras la camilla de tratamiento avanza hacia dentro del

desde 1 a 5.08 RPM y para adquisición de imágenes

Gantry produciendo una entrega de dosis de manera

es de 10 RPM.

helicoidal. Reproduce los tratamientos con una pre-

• La rotación completa de gantry se divide en 51 pro-

cisión de décimas de milímetros optimizando la dosi-

yecciones, donde cada una cubre un segmento de ≈ 7º

metría y la planificación. Tanto para la TC como para

con apertura máxima del colimador.

el tratamiento existe una conjunción entre el movi-

• Si existiese un error en la rotación al realizar la fusión

miento de mesa y el gantry (PITCH), el cual puede ser

de la imagen de MVCT con la TAC de referencia, éste

modificado según la patología y la sección a irradiar

se corrige variando gradualmente el punto de inicio de

(van Gestel et al. 2015).

irradiación a través del gantry.

El diseño helicoidal permite entregar tratamientos con mayor precisión, en menor tiempo.

29

Sistema de colimación Multi-Leaf Es un sistema multi-lámina acoplado al sistema de colimación que se mueve junto con el acelerador lineal, generando un haz modulado rotatorio. Junto a este sistema se encuentra el sistema de colimación primario compuesto por mandíbulas dinámicas que permiten la obtención de campos rectangulares de tamaños 1x40.

2,5x40 y 5x50 cm a nivel del isocentro.

Está compuesto por 64 láminas que se interponen

A diferencia de los aceleradores lineales convenciona-

en el haz de radiación mediante un sistema binario

les, donde los movimientos de MLC son realizados me-

de apertura/cierre definiendo pequeños haces indi-

diante motores, el Radixact es el único equipo del mer-

viduales. Las dimensiones de los haces son mínimas,

cado que ofrece un movimiento neumático del MLC de

en el caso más pequeño de 6x10 mm2, correspon-

elevada precisión, velocidad y exactitud.

diendo a la anchura de la lámina y a la apertura mínima del colimador. La velocidad de apertura/cierre de las láminas es de aproximadamente 250 cm/s.

30

Sistema de obtención de imágenes El Radixact permite obtener imágenes de TC para la

El sistema de detección se encuentra en la salida del

verificación de la posición, forma del tumor y tejido

haz de radiación que genera una imagen CT con fo-

sano adyacente con respecto a la TC de planificación.

tones de 3,5 MV. El sistema de adquisición de imáge-

Gracias a ello, es posible disminuir al máximo erro-

nes tiene una geometría de haz de abanico helicoidal

res en el posicionamiento del paciente en cada una

como el de una tomografía de diagnóstico denomi-

de las sesiones, aumentando el control tumoral y por

nada MVCT.

ende la vida del paciente.

Características de las imágenes MVCT: • La uniformidad es comparable con la CT de diagnóstico mientras que el ruido es mayor.

• Las unidades Hounsfield MVCT son consistentes, adecuados para el cálculo dosimétrico.

• La resolución espacial para una imagen de 512x512 es de aproximadamente 1.5 mm • La dosis es de aproximadamente 1.1 cGy para un ancho de slice de 5 mm y pitch de 1. La dosis decrece con la disminución del pitch.

• La energía es de 3.5 MV, dado que se genera mediante un spot mucho más pequeño con un mejoramiento en la penumbra y la resolución de contraste.

Cabe destacar que la calidad de la imagen es aceptable para la alineación del paciente y para la delineación y marcación de tejidos blandos.

31

32

Cone Beam CT vs MVCT El sistema de imágenes del Radixact es superior en ciertos aspectos a los sistemas convencionales. A continuación, ofrecemos dos imágenes comparativas que ilustran la calidad de imagen del sistema MVCT de Radixact.

Tomografía (CBCT)

Radixact (MVCT)

En las siguientes figuras podemos observar algunos cortes de la secuencia de tomografías para un estudio de próstata en la cual el paciente posee prótesis. También es posible observar su correspondiente reconstrucción en 3D.

33

33

El sistema permite comparar las tomografías de planificación, realizada en un tomógrafo convencional de kilovoltaje, y la tomografía de verificación MVCT realizada directamente en el sistema Radixact de manera de asegurar que el tratamiento sea efectivo. La tomografía de megavoltaje permite obtener una imagen clara bien definida aún en los casos donde los artefactos por piezas metálicas complican la visualización de la imagen.

Tomografía (CT)

Radixact (MVCT)

34

El planificador nos permite realizar una correlación manual o automática entre las imágenes de MVCT y de planificación para los planos transversales, sagitales y coronales. Una vez conseguida la óptima alineación de todas las proyecciones, el planificador obtiene las correcciones de los parámetros que se deben modificar en la camilla. Luego de eso, la misma se desplazará, de manera on-line, para ubicarse en las coordenadas precisas.

Imagen de planificación de tratamiento para Radixact.

Dosimetría La innovación que propone Radixact es realizar una

determinar, de manera precisa, si las curvas de isodo-

dosimetría antes del tratamiento sobre las imágenes

sis abarcan completamente las estructuras blanco y si

de MVCT o kVCT, obteniendo grandes beneficios

se minimiza la dosis para los órganos de riesgo. Con

para el aumento del control tumoral. En las siguien-

esta verificación previa se optimiza sustancialmente

tes figuras se pueden visualizar diferentes tipos de

el tratamiento y se reducen los efectos no deseados.

patologías y sus correspondientes dosimetrías para

35

Dosimetría en Planificación

Dosimetría en Verificación

36

Capacite a su equipo con los flujos de trabajo y los programas de tratamientos con radioterapia más adaptables del mercado.

Precision permite centralizar la actividad de todos los sistemas de terapias radiantes de Accuray.

AUMENTA LA EFICIENCIA DE LA PLANIFICACIÓN Genere y adapte planes de tratamiento personalizados y precisos en menos tiempo.

MEJORA LOS RESULTADOS DEL PACIENTE MEJORA LA SATISFACCIÓN DEL PERSONAL Automatice los flujos de trabajo y proporcione herramientas de planificación de tratamientos de última generación.

Ofrezca planes de tratamiento más personalizados y precisos para más pacientes.

Planifique para todos los tipos de casos Sistemas Radixact y TomoTherapy Entrega de tratamiento TomoHelical Entrega de tratamiento TomoDirect 3DCRT planificado hacia adelante

Sistema CyberKnife SRS intracraneal sin marco Seguimiento pulmonar sin fiduciarios con compensación dinámica de movimiento SBRT SRT IMRT

37

Sistema de planificación El sistema de planificación Precision diseñado por Accuray específicamente para su sistema de terapia radiante, es la herramienta que fortalece al equipo de trabajo con potencia de planificación y flujo de trabajo.

Es un sistema de planificación que incluye capacidades de registro y fusión de imágenes de diferentes tipos, herramientas de contorneo de estructuras avanzadas, opciones de comparación, suma y verificación de planes de tratamiento para asegurar la mejor optimización de la dosis en la enfermedad restringiendo al máximo la dosis recibida en los órganos a riesgo.

38

Modalidades de tratamiento a. TomoDirect

b. TomoHelical

El sistema ofrece una modalidad de tratamiento

El modo de administración TomoHelical proporciona

con gantry fijo.

la entrega de tratamiento IMRT en un patrón helicoi-

El modo de entrega TomoDirect proporciona tratamiento 3DCRT a través de un modo de entrega no giratorio de ángulo discreto. TomoDirect permite la creación de planes de tratamiento que incluyen entre 2 y 12 ángulos.

Durante la administración del tratamiento, los haces se administran secuencialmente con la camilla pasando a través del gantry a una velocidad adecuada

dal continuo (360°). El modo TomoHelical es adecuado para la mayoría de situaciones clínicas, donde la entrega rotacional y la modulación del haz mejoran la conformación y uniformidad de la dosis.

El usuario puede crear un plan de tratamiento donde puede definir los objetivos y las restricciones de dosis para las estructuras blanco y de riesgo, el nivel de modulación para el plan, así como el de fraccionamiento.

para cada haz.

Los modos de mandíbula fija y opcionalmente el de mandíbula dinámica (TomoEDGE) están disponibles para TomoDirect. Con TomoEDGE, el ancho del campo varía durante la entrega para disminuir el ancho del gradiente de dosis fuera del objetivo.

TomoDirect Entrega el mejor tratamiento modulado para cáncer de mama desde ángulos fijos.

39

Durante la administración del tratamiento, el acelera-

sistemas de tratamiento de radiación, y proporciona

dor lineal completa múltiples rotaciones de 360 gra-

distribuciones de dosis uniformes y altamente con-

dos alrededor del paciente, mientras que la camilla

formadas, al tiempo que minimiza la dosis a las es-

pasa a través del orificio central del gantry. La admi-

tructuras normales circundantes.

nistración continua de dosis altas permite tiempos de tratamientos más cortos que la mayoría de los demás

TomoHelical Se pueden tratar objetivos de hasta 135 cm de longitud, sin necesidad de reposicionar al paciente y sin unión de campo.

40

X5

CONFIGURATIONS Configuraciones de Radixact Radixact ® Treatment Delivery System

Linac Dose Output TomoHelical TomoDirect

Standard Delivery Mode (60 cm)

™

™

Delivery Mode (60 cm, 9 beam angles)

Fixed 2.5 & 5 cm beam widths Advanced Precision Treatment Delivery Mode including:

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X7

1000 MU/min

850 MU/min

850 MU/min

O

X5

• • •

• • •

TomoEDGE

™

Dynamic Jaws

• •

Synchrony ® Motion Synchronization

• •

CTrue ™ IR (Iterative Reconstruction)

Remote Registration Review

iDMS Primary Server

2 Full Licenses

1 License for 60 days

1 License for 60 days

iLink ™ Remote Diagnostic System

OIS Connect

®

Licensed Accuray Precision

®

TPS including:

Image Fusion, Deformable Image Registration, Standard and Forward Planning, VOLO ™ Plan Optimization, Plan Review & Approval, Plan Comparison & Summation, Plan Transfer

Head & Neck, Brain, and Male Pelvis AutoSegmentation ™ Packages

PreciseART ® Adaptive Radiation Therapy and Precise RTX ® Re-Treatment

iDMS Storage Vault

iDMS Report Administration

Standard and Advanced TQA

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™

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•

™

– STANDARD FEATURE

– OPTIONAL FEATURE

OPTIONAL FEATURES

MU/min

• MD Suite Physician Contouring and Plan Review Workstation • PlanTouch ® iPad Plan Review • Power Conditioner and UPS • RIT Software Products • Beam Measurement and QA Package • TomoElectrometer with Beam Data Software • TomoElectrometer • Detector Data DICOM Export • Deformable Image Registration • Accuray Precision

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(perpetual license for one concurrent user) • Accuray Alliance service offerings

cense 0 days

41

42

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La radioterapia helicoidal que ofrecen en igual cali-

Debido a la posibilidad de tratar blancos de hasta una

dad TomoTherapy y su nueva configuración, Radixact,

longitud de 135 cm. con Radixact, el problema de las

es la tecnología más avanzada y confiable para el tra-

uniones de campo se reduce y, por lo tanto, se evi-

tamiento del cáncer haciendo uso de las radiaciones

ta la subdosificación por brechas en los campos o la

ionizantes. La diversidad de casos que se pueden tra-

sobredosis debido a la superposición de estos. Esta

tar con este sistema es tan amplia que prácticamente

capacidad permite desarrollar planificaciones ópti-

ninguna lesión oncológica está fuera del alcance de

mas para casos poco frecuentes como el Total Skin,

tratamiento usando el TomoTherapy o Radixact. Esto

Meduloblastomas o TBI.

involucra desde los casos más simples hasta los más complicados, todos bajo la misma estructura de flujo de trabajo que hace que la experiencia del paciente sea más cómoda al tener unos tiempos de tratamiento sumamente bajos. En este capítulo se presentan consideraciones sobre las capacidades de ambos equipos para el tratamiento de todo tipo de tumores.

Versatilidad y precisión en todo el cuerpo Radixact ha demostrado ser el sistema más versátil entre los aceleradores modernos. Se puede emplear para tratar tumores benignos o malignos en todas las localizaciones, como lo demuestra la literatura existente.

Y aún más. Este sistema de administración de trata-

Su capacidad de entrega personalizada en sincronía con el movimiento del objetivo para cada tratamiento logra adaptar la posición del haz a la ubicación del tumor de manera precisa y exacta en todo momento durante la administración del tratamiento. Esto permite entregar una dosis continua e ininterrumpida con márgenes estrechos y gradientes de dosis pronunciados, así los médicos tienen la libertad de elegir el esquema de fraccionamiento que mejor se adapte a las necesidades clínicas de sus pacientes, sabiendo que la eficacia y la eficiencia de su tratamiento se mantendrán sin obstáculos.

Radioterapia helicoidal en la contención del COVID

mientos aumenta las indicaciones de radioterapia pre-

La radioterapia helicoidal se está utilizando en el mar-

cisa para una amplia variedad de pacientes oncológicos

co de las terapias para enfrentar el COVID-19 con

como ningún otro sistema disponible en el mercado.

resultados promisorios y fundamentales en el marco

Gracias a su diseño y características únicas proporciona una flexibilidad sin precedentes, favorable para un gran número de aplicaciones.

Radioterapia para lesiones extensas La tomoterapia es especialmente adecuada para la irradiación de volúmenes extensos en un solo procedimiento de irradiación, como, por ejemplo: • irradiación craneoespinal, • volúmenes linfáticos de cabeza y cuello, • cáncer de mama y sarcomas, • linfomas, • leucemias.

44

de la contención de la pandemia. Aunque la mayoría de los pacientes con COVID-19 son asintomáticos, pueden ocurrir complicaciones como neumonía grave, insuficiencia respiratoria o síndrome de dificultad respiratoria aguda, que a menudo conducen a resultados fatales para los pacientes. La mayoría de las veces, los pacientes con dichas complicaciones requieren el ingreso en la unidad de cuidados intensivos y el apoyo de un ventilador mecánico (VMI), servicios que por su especificidad y recursos son muy limitados. Como demuestra el estudio de Elena Moreno-Olmedo et al., publicado en 2020, la aplicación de muy bajas dosis (ultra-LDRT) en pacientes con CO-

VID-19 podría desempeñar un papel en la reducción de la respuesta inflamatoria pulmonar, reducir el riesgo de requerir VMI y aliviar los síntomas potencialmente mortales, lo que ayuda a reducir la mortalidad sin secuelas significativas a largo plazo.

Eficacia probada La investigación clínica respalda el uso de la tecnología TomoTherapy utilizada en el sistema Radixact para el tratamiento de tumores cerebrales. A continuación, se enumeran los estudios clave que respaldan el uso de la tecnología.

CÁNCER DE CEREBRO

Para lesiones metastásicas

Los tumores cerebrales pueden afectar diferentes

Un análisis retrospectivo evaluó el uso de radiocirugía

sentidos y / o memoria según su ubicación. Por eso,

estereotáctica (SRS) administrada con TomoTherapy

cuando es necesario tratar los tejidos y estructuras

helicoidal como tratamiento exclusivo para pacientes

complejos, delicados y vitales del cerebro, la preci-

con una y tres metástasis cerebrales. El estudio encon-

sión es importante.

tró que el tratamiento no invasivo fue muy bien to-

Los avances tecnológicos de la actualidad brindan

lerado y proporciona resultados clínicos alentadores.1

mejores opciones para las personas diagnosticadas

Un estudio retrospectivo de pacientes con metásta-

con tumores cerebrales, lo que ayuda a garantizar

sis cerebrales grandes que no se pudieron extirpar

que reciban el tratamiento más eficaz para su afec-

quirúrgicamente encontró que la radioterapia este-

ción médica particular. La radioterapia puede ser una

reotáctica hipofraccionada (SRT) administrada me-

opción de tratamiento y puede usarse para tratar los

diante tomoterapia helicoidal “puede considerarse

dos tipos principales de tumores cerebrales:

un tratamiento seguro para metástasis cerebrales

• Tumores cerebrales primarios: tumores que comienzan en el cerebro.

• Tumores cerebrales metastásicos o secundarios: tumores que comienzan en otra parte del cuerpo y luego se diseminan al cerebro.

mayores de 2 cm dada la baja tasa de radionecrosis asociada con esta método.”2 Un estudio prospectivo evaluó el uso de SRT administrado con tomoterapia helicoidal en cuatro sesiones para tratar metástasis únicas o múltiples. Los investigadores del estudio encontraron que el proto-

El sistema Radixact es el único equipo en el mundo

colo de tratamiento resultó en un excelente control

capaz de administrar radiación helicoidal, entregando

del tumor con una toxicidad mínima.3

el 100% de la dosis al tumor protegiendo al máximo las estructuras sanas. En caso de tratar múltiples lesiones cerebrales, el Radixact es capaz de restringir la dosis que recibe el cerebro sano disminuyendo la toxicidad por radiación. Además, la verificación diaria de la posición del paciente a través de la imagen TC permite garantizar la precisión del tratamiento.

45

Para tumores primarios: Múltiples estudios que evalúan la viabilidad del uso de la tomoterapia helicoidal para la irradiación del eje

cuello proporcionando una alternativa eficaz cuando la cirugía no es posible o cuando el tumor no se puede extirpar por completo.

craneoespinal (meduloblastomas) han demostrado el interés de los médicos por esta técnica y sus beneficios en el tratamiento de este tipo de tumores.4, 5, 6 Un estudio comparó los planes de tratamiento desarrollados para la tomoterapia helicoidal y los sistemas de radioterapia convencional para tratar a pacientes con glioblastoma multiforme (GM) cuyos tumores se encontraban cerca de órganos críticos. Los autores concluyeron que “los planes de tomoterapia eran superiores a los planes de aceleradores lineales desde el punto de vista de la conservación de órganos en riesgo”.8 Por último, un estudio de planificación del tratamiento que evaluó la tomoterapia helicoidal, IMRT y 3D-CRT, mostró que, para los pacientes con glioblastoma multiforme, la tomoterapia helicoidal proporcionó una mejor cobertura del objetivo que la IMRT y mejoró la preservación de los órganos en riesgo en comparación con la IMRT y la 3D-CRT.⁹

CÁNCER DE CABEZA Y CUELLO Los cánceres de cabeza y cuello pueden afectar la

Un estudio de una sola institución de 72 pacientes con varias etapas de carcinoma nasofaríngeo (NPC) tratados con el método de administración TomoHelical encontró que la tasa de control local de cinco años fue del 97 por ciento, lo que demuestra un excelente control de la enfermedad a largo plazo. El estudio también mostró que los tratamientos con TomoHelical produjeron una toxicidad aguda y tardía generalmente leve.⁹

capacidad en los pacientes para comunicarse y co-

Otro estudio prospectivo multiinstitucional evaluó los

mer, causar dolor y afectar negativamente su bien-

beneficios clínicos de la IMRT administrada con el modo

estar emocional. Por eso, cuando es necesario tra-

TomoHelical en comparación con la terapia de arco vo-

tar tumores de la cabeza y el cuello, la precisión es

lumétrico modulado (VMAT) para 166 pacientes con

importante. El sistema Radixact proporciona una

cáncer de cabeza y cuello. La tasa de control local y la

opción no quirúrgica diseñada para maximizar la

tasa de supervivencia específica del cáncer fueron sig-

radiación administrada al tumor mientras minimiza

nificativamente mejores en el grupo de pacientes con

la dosis a los tejidos sanos, como los del cerebro, la

tomoterapia que en el grupo de pacientes con VMAT.

médula espinal, las glándulas salivales y parótidas,

El tratamiento con TomoHelical también permitió la ad-

protegiendo las funciones relacionadas y preser-

ministración de dosis de radiación significativamente

vando su calidad de vida. Radixact se puede utilizar

reducidas fuera del tumor, lo que condujo a una mejor

para tratar todo el espectro de tumores de cabeza y

función salival que con VMAT.10

46

CÁNCER DE MAMA El sistema Radixact está diseñado para ayudar a mejorar los resultados clínicos, mientras se minimiza el riesgo de efectos secundarios, para mejorar la calidad de vida de los pacientes, tanto durante el tratamiento como después de este.

Sus dos modos de administración de tratamiento, TomoHelical y TomoDirect, ofrecen ventajas únicas en el tratamiento del cáncer de mama, incluida la capacidad de administrar una dosis de radiación precisa a cualquier tumor o lecho tumoral, durante cada sesión de tratamiento, mientras minimiza la dosis a los órganos y tejidos sanos cercanos. Esto es especialmente importante para las mujeres diagnosticadas con cáncer en la mama izquierda, donde el tumor puede estar cerca de órganos críticos como el corazón.

Un estudio realizado utilizando la modalidad TomoDirect demostró una administración uniforme de la dosis de radiación para toda la mama, con una dosis mínima a los órganos en riesgo cercanos. Los pacientes experimentaron una toxicidad leve y ninguna recidiva local en un seguimiento medio de 12 meses. La estética (preservación de la apariencia normal de la mama) fue buena / excelente en el 91 por ciento de los pacientes tratados.17 De forma similar, el análisis de 30 pacientes que usaron TomoHelical para la irradiación del cáncer de mama en estadio III encontró que los tratamientos se toleraron muy bien, con efectos secundarios agudos o moderadamente tardíos mínimos. Las pruebas cardíacas y respiratorias no mostraron evidencia de anomalías significativas relacionadas con el tratamiento. No se registró ninguna recidiva local del cáncer al finalizar el estudio.18 Otro estudio retrospectivo en un mismo centro con 136 pacientes con cáncer de mama invasivo encontró que la radioterapia hipofraccionada administrada con TomoTherapy fue muy bien tolerada con toxicidades agudas y tardías mínimas. Además, esta modalidad de tratamiento proporcionó una excelente supervivencia libre de falla locorregional a tres años, lo que significa que no hubo recurrencia local o regional o progresión del tumor, o muerte por cáncer de mama, tres años después del tratamiento.19

La opción más precisa para tratar el cáncer, protegiendo el tejido sano El sistema Radixact se puede utilizar para tratar el espectro completo de cánceres de mama, desde tumores de rutina hasta tumores complejos, aquellos ubicados en áreas de difícil acceso y tumores recurrentes. Varios estudios realizados utilizando radioterapia helicoidal han mostrado buenos resultados en el tratamiento de esta patología.

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CÁNCER DE ESÓFAGO

Otro estudio que evaluó la quimiorradioterapia con-

El sistema Radixact permite la administración pre-

en radioterapia conformada 3D en pacientes diag-

cisa de IG-IMRT, un tipo avanzado de IMRT, para el

nosticados con carcinoma de células escamosas de

tratamiento del cáncer de esófago en varias etapas,

esófago torácico avanzado (estadio IIIA-IIIC) encon-

incluida la enfermedad recurrente. El uso de IG-

tró que la CCRT basada en IMRT resultó en tasas de

IMRT es una solución efectiva para esta enferme-

supervivencia más altas.22

currente basada en IMRT (CCRT) y la CCRT basada

dad tan difícil de tratar con cualquier otra terapia, porque cuando se detecta se suele presentar en un estadio avanzado.

CÁNCER DE PULMÓN Uno de los mayores desafíos en el tratamiento del cáncer de pulmón sigue siendo tratar eficazmente la lesión, al tiempo que se minimiza la dosis a los numerosos tejidos sensibles y órganos vitales que rodean los pulmones.

Un tratamiento clínicamente probado para el cáncer de esófago Un estudio, desarollado en una sola institución, encontró que la supervivencia general mejoró significativamente con el tratamiento de IMRT. Ese estudio comparó 1) IMRT y quimioterapia con radioterapia conformada 3D y 2) quimioterapia en pacientes con

La radioterapia helicoidal proporciona la flexibilidad

cáncer de esófago localmente avanzado.20

para adaptar la radioterapia a la anatomía de cual-

Un estudio retrospectivo que evaluó una pequeña cantidad de pacientes con cáncer de esófago localmente avanzado encontró que la IMRT y la IG-IMRT pueden proporcionar dosis curativas de radiación con niveles aceptables de toxicidad, incluso en personas con afecciones preexistentes.21

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quier paciente con cáncer de pulmón. TomoTherapy es la opción no quirúrgica para el tratamiento del cáncer de pulmón diseñada para maximizar la radiación administrada al tumor y minimizar la dosis a los tejidos sanos. Esta precisión ayuda a mejorar la eficacia del tratamiento del cáncer, al tiempo que reduce el riesgo de efectos secundarios.

Radixact cuenta con la capacidad de rastrear la posi-

Cáncer de pulmón de células no pequeñas en esta-

ción de los tumores en movimiento en tiempo real a

dio temprano (CPCNP): La SBRT de pulmón con la

través del sistema Synchrony.

tecnología TomoTherapy ofrece un buen control local

Cuando el paciente respira, el torso se mueve. Esto significa que un tumor de pulmón, o cualquier objetivo dentro o cerca de los pulmones, se moverá continuamente durante la administración del tratamiento.

A diferencia de cualquier otro dispositivo de radiación convencional, el sistema Radixact con Synchrony utiliza la única tecnología capaz de sincronizar el haz de

y supervivencia con baja toxicidad en el tratamiento del cáncer de pulmón de células no pequeñas en estadio temprano.23 Cáncer de pulmón médicamente inoperable: la SBRT de pulmón con la tecnología TomoTherapy proporciona una alternativa segura y eficaz cuando la cirugía no es posible.24

tratamiento con el movimiento del tumor en tiempo

Mesotelioma: IMRT con la tecnología TomoTherapy

real, de manera que la radiación se entregue conti-

ofrece un excelente control local- regional y super-

nuamente sobre el tumor sin irradiar tejido sano in-

vivencia en el tratamiento del mesotelioma pleural

cesariamente. Esto ayuda a garantizar que la dosis de

maligno (MPM).25

radiación se administre al objetivo, lo que maximiza la efectividad del tratamiento y minimiza la dosis a los tejidos circundantes para reducir la incidencia de efectos secundarios.

Oligometástasis: la SBRT con la tecnología TomoTherapy ofrece un control local adecuado con baja morbilidad aguda en el tratamiento de oligometástasis, incluidas las metástasis múltiples.26

A diferencia de otras opciones de radioterapia convencional en 4D, el sistema Radixact guiado con Syncrhony no requiere dispositivos para restringir la respiración de paciente. Al contrario, puede relajarse y respirar normalmente.

CÁNCER DE CUELLO DE ÚTERO Radixact es uno de los sistemas avanzados más integrados para el tratamiento integral del cáncer

Un tratamiento clínicamente probado para el cán-

disponibles en la actualidad. Este sistema permite la

cer de pulmón

administración precisa de IG-IMRT, un tipo avanza-

Radixact System es el equipo mejor preparado para el tratamiento del cáncer en la actualidad, lo que permite la administración precisa de tratamientos simples

do de IMRT, para el tratamiento del cáncer de cuello uterino. El uso de esta tecnología, así como IMRT, está respaldado por estudios clínicos publicados.

a complejos para todo el espectro de pacientes con

Un análisis de múltiples estudios independientes (me-

cáncer de pulmón, desde los primeros estadios del

tanálisis) encontró que los pacientes con cáncer de

cáncer de pulmón de células no pequeñas (CPCNP)

cuello uterino tratados con radioterapia de intensidad

hasta el tratamiento posoperatorio del mesotelioma.

modulada (IMRT) experimentaron una reducción sig-

Los resultados positivos que se obtienen con el uso de la radioterapia helicoidal se encuentra respaldada por estudios clínicos publicados, algunos de los cuales se muestran a continuación:

nificativa de las toxicidades gastrointestinales agudas y genitourinarias y la toxicidad crónica , que los pacientes en el grupo de control tratado con radioterapia conformada tridimensional (3DCRT) o 2DCRT.12 Un estudio evaluó el uso de la tomoterapia para ad49

ministrar IMRT pélvica completa en pacientes con

Esto quiere decir que que la radiación no afectó sig-

cáncer de cuello uterino localmente avanzado. Los

nificativamente los órganos sanos ni la vida normal

planes de tratamiento con tomoterapia se compara-

del paciente.

ron con los creados para la radioterapia pélvica completa convencional (WPRT). El estudio encontró que el tratamiento con TomoTherapy es una opción viable. Además, los planes de tratamiento de TomoTherapy redujeron con éxito la dosis de radiación que se administraría al recto, la vejiga y los intestinos, en comparación con los planes WPRT convencionales.13

CÁNCER DE PRÓSTATA La evidencia clínica respalda el uso del sistema de tomoterapia para el tratamiento de pacientes con cáncer de próstata de todos los grupos de riesgo, y la evidencia preliminar sugiere excelentes resultados clínicos. Los regímenes de tratamiento descritos en los estudios refuerzan los beneficios de las capacidades únicas de las plataformas TomoTherapy y Radixact.

Tratamiento del cáncer de próstata moderadamente hipofraccionado Varios estudios demuestran que la radioterapia helicoidal es excelente para el tratamiento con hipofraccionamiento moderado de grandes volúmenes blanco que incluyen la próstata y los ganglios linfáticos pélvicos. El consenso clínico indica que determinados niveles de hipofraccionamiento son apropiados para el tratamiento eficaz de los cánceres de próstata.27, 28, 29

La radioterapia helicoidal es la mejor opción para pacientes con cáncer de cuello uterino ya que logra los niveles más bajos de toxicidad en órganos sanos, lo que permite mejorar la calidad de vida después del tratamiento.14 Los resultados de un estudio aleatorizado diseñado para comparar la perspectiva de los pacientes con cáncer de cuello uterino y de endometrio sobre la toxicidad aguda y la calidad de vida durante el tratamiento con radiación pélvica estándar o IMRT, encontraron que la IMRT tuvo un impacto menor en la función intestinal y urinaria durante el tratamiento.

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Ultra-hipofraccionamiento para el cáncer de próstata En este caso, la evidencia clínica respalda el uso de

la tecnología para el hipofraccionamiento extremo.

Sociedad Estadounidense del Cáncer y varias organi-

En un estudio clínico, los pacientes que recibieron

zaciones profesionales de la salud, la radioterapia de

tratamiento “ultrahipofraccionado” con TomoTherapy

intensidad modulada (IMRT) es el tipo preferido de tra-

vieron tasas de recaída a 5 años comparables a una

tamiento con EBRT.

combinación de radioterapia tradicional y braquiterapia; sin embargo, con una toxicidad significativamente menor y un curso general de tratamiento más corto.

Un tratamiento clínicamente probado para el cáncer anal El sistema Radixact es uno de los sistemas avanzados más integrados para el tratamiento integral del cán-

CÁNCER DE ANO Los pacientes con cánceres de ano están logrando resultados exitosos a través de tratamientos avanzados que combinan quimioterapia y radioterapia.

Debido a que los cánceres anales se encuentran

cer disponibles en la actualidad. El sistema Radixact permite la administración precisa de IG-IMRT, un tipo avanzado de IMRT, para el tratamiento del cáncer anal. El uso de la tecnología de radioterapia helicoidal, así como la IMRT, está respaldado por estudios clínicos publicados.31, 32

muy cerca del resto del tracto digestivo, la vejiga

Los estudios encontraron que los pacientes con

y los órganos reproductivos, la precisión es funda-

cáncer anal que recibieron IG-IMRT con un refuer-

mental para reducir el riesgo de efectos secundarios

zo de radiación simultáneo, utilizando tomoterapia

a corto y largo plazo. La precisión en la administra-

helicoidal, experimentaron bajas toxicidades agudas

ción de la dosis de radiación también es necesaria

o tardías relacionadas con el tratamiento y un buen

para ayudar a controlar la enfermedad.

control local del cáncer, al tiempo que brindan una

La radioterapia de haz externo (EBRT) es la forma más común de tratar los cánceres anales en estadio I (con invasión de la membrana basal) a estadio III. Según la

opción de tratamiento más eficiente y conveniente para los pacientes. Este enfoque de tratamiento con radiación, con o sin quimioterapia, permitió a los médicos reducir los márgenes alrededor del tumor que recibe radiación, lo que resultó en una reducción significativa en ciertas tasas de toxicidad sin afectar los resultados del tratamiento.

Un análisis que involucró a pacientes con cáncer anal encontró que el tratamiento con IMRT y la radiación de refuerzo integrada simultánea mostró excelentes resultados a largo plazo y con efectos secundarios bien tolerados por los pacientes.33 La comparación que generaron Fredman E.T., Abdel-Wahab M., Kumar AMS entre pacientes que recibieron IMRT o radioterapia conformada 3D, en combinación con quimioterapia, mostró que la IMRT,

51

como parte del protocolo de tratamiento, resultó en

imagenes que permite realizar una radioterapia pre-

una cantidad significativamente menor de incontinen-

cisa guiada por imágenes y de intensidad modulada

cia, dolor y fatiga, así como significativamente menos

(IG -IMRT) de múltiples rotaciones de 360 grados

toxicidades crónicas posteriores al tratamiento, en

alrededor de su cuerpo, lo que brinda una opción al-

comparación con la terapia conformada 3D.34

tamente precisa, personalizada y no invasiva para el tratamiento del cáncer de recto avanzado.

CÁNCER DE RECTO El primer paso para tratar el cáncer de recto localmente avanzado suele ser la radioterapia y la qui-

Una opción más precisa: tratar el cáncer. Minimizar el daño al tejido sano

mioterapia, cuando el paciente está lo suficien-

La radioterapia es un tratamiento comprobado para

temente sano para ambos. Las innovaciones en

el cáncer de recto localmente avanzado y general-

radioterapia ayudan a garantizar que los pacientes

mente se usa antes de la cirugía, con o sin quimio-

reciban el tratamiento más eficaz para su afección

terapia, para reducir el tamaño del tumor, con el ob-

médica particular.

jetivo final de curar la enfermedad. Sin embargo, la

El sistema Radixact/TomoTherapy es el único equipo el mundo que es capaz de administrar radiación helicoidal, y a su vez tiene integrado un sistema de

radiación administrada a los órganos circundantes, como el intestino y la vejiga, puede provocar efectos secundarios que cambian la vida lo que hace que sea de vital importancia que la radiación se administre con extrema precisión y precisión.

El sistema Radixact porciona un mayor control de la radiación para que se adapte con precisión al tumor y ayude a minimizar el daño a los tejidos sanos.

El resultado es un tratamiento de radioterapia que maximiza la efectividad al tiempo que ayuda a preservar la función gastrointestinal y genitourinaria, lo que puede conducir a una mejor calidad de vida para los pacientes tanto durante como después del tratamiento.

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Radixact incorpora una camilla que ingresa al grantry mientras el acelerador lineal gira a su alrededor.

Este diseño, único en Radixact, permite ofrecer tratamientos más eficaces y en un menor tiempo.

OTRAS INDICACIONES Micosis Fungoides La micosis fungoides es una enfermedad que afecta la piel y es familia de los linfomas no hodgkinianos.

La micosis fungoides es la expresión más frecuente del linfoma cutáneo de células T y se presenta como una afectación de la piel en la que aparecen brotes

Pre Tratamiento

Post Tratamiento

de lesiones planas, en forma de placas delgadas o pequeños tumores en todo el cuerpo. Esta enfermedad tiende a diseminarse a los ganglios linfáticos y otros órganos. Entre los tratamientos comunes para esta enfermedad está la irradiación con electrones a cuerpo entero. Sin embargo, con el sistema Radixact existe una manera de tratar esta enfermedad con fotones dirigidos a la piel. Existe evidencia científica de los protocolos utilizados con este sistema para tratar dicha enfermedad (Sarfehnia et al 2013).

Leucemia Linfoblástica Una de las técnicas utilizadas para tratar la leucemia linfoblástica aguda es la Irradiación Corporal Total o TBI por sus siglas en inglés. La finalidad de este tratamiento es inmuno- suprimir al paciente para hacerle implante de médula ósea. Con el sistema Radixact es posible realizar este tipo de tratamiento de manera muy efectiva. La definición de los volúmenes de irradiación y restricción es un proceso muy importante

Meduloblastoma Este tipo de tumor es intracraneal maligno y se origina en el cerebelo. Usualmente crece desde la parte más central del cerebelo produciendo a menudo hidrocefalia secundaria. Este tipo de tumor tiene tendencia a extenderse a través del sistema nervioso central e invadir meninges. El tratamiento radiante para estos casos generalmente se realiza mediante una irradiación craneo-espinal por lo que dicho plan de tratamiento es complicado de hacer y entregar con un acelerador lineal convencional. El sistema Radixact ofrece una solución muy eficiente para tratar estos casos debido a su modalidad de tratamiento helicoidal.

con el cual se garantiza la dosis en el sistema de plani-

La ventaja en estos casos es evitar la superposición

ficación. Existen trabajos que evidencian esta técnica.

de campos que se genera con aceleradores lineales

Carcinoma de células escamosas El carcinoma de células escamosas suele desarrollarse en zonas de piel expuestas al sol, pero también puede hacerlo en cualquier otra parte del cuerpo, como la lengua o la mucosa bucal. Puede formarse en piel de aspecto normal o en piel dañada (aunque haya sido muchos años antes) por la exposición al sol (queratosis actínica). Con Radixact es posible tratar estas afecciones de manera muy efectiva.

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convencionales. A continuación, se presenta una figura comparando la planificación con TomoTherapy (A) y con un acelerador lineal convencional (B).

Al abarcar campos de 135 cm es el equipo ideal para tratamientos de columna.

Planificación con Radixact

Otra ventaja que ofrece el Radixact en este caso que

El confort del paciente es algo que se viene buscan-

es la ubicación del paciente en máquina. El paciente

do con el desarrollo de nuevas técnicas de radiote-

se ubica sólo una vez, se verifica diariamente con la

rapia ya que está directamente relacionado con la

tomografía de posicionamiento y se trata todo el vo-

precisión del tratamiento. Un paciente que se sienta

lumen de irradiación con un solo plan. Mientras que

cómodo le resultará más fácil recibir el tratamiento

con un acelerador lineal convencional este tipo de

que si se sintiese incómodo, y esto se relaciona con

tratamiento involucra 3 isocentros diferentes y ade-

el posicionamiento diario y el tiempo que transcurre

más está el riesgo de superponer los campos produ-

durante el tratamiento.

ciendo una superposición de dosis en las uniones.

En conclusión, existe evidencia científica que cualquier tipo de cáncer puede ser tratado con esta tecnología, desde el más simple hasta el más complicado, con una efectividad extraordinaria. La modalidad helicoidal trae múltiples ventajas en cuanto a distribución de dosis, longitud de tratamiento y tiempo de tratamiento, lo que hace que esta tecnología sea realmente innovadora.

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Tabla región/patologías del Radixact

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LOCALIZACIÓN

PAT O LO G Í A S

INTRACRANEAL

MALFORMACIONES ARTEREOVENOSAS MÚLTIPLES METÁSTASIS TUMORES PRIMARIOS DE CUALQUIER TAMAÑO

CABEZA Y CUELLO

TUM O RE S P RI M ARI O S P EQ UE ÑO S TUM O RE S P RI M ARI O S G RAND E S RE I RRAD I ACI O NE S & BO O S T

PULMÓN

TUM O RE S P RI M ARI O S P EQ UE ÑO S TUM O RE S P RI M ARI O S G RAND E S M E TÁS TAS I S

MAMA

M AM A CO M P LE TA PARED COSTAL MAMA BILATERAL

COLUMNA

TUM O RE S BE NI G NO S MALFORMACIONES ARTEREOVENOSAS METÁSTASIS

HÍGADO

P RI M ARI O S I NO P E RABLE S M E TÁS TAS I S

PÁ N C R E A S

TUM O RE S I NO P E RABLE S BO O S T P RE / P O S T O P E RATO RI O

RIÑONES

TUM O RE S I NO P E RABLE S M E TÁS TAS I S

GINECOLÓGICO

CUE LLO UTE RI NO E ND O M E TRI O M E TÁS TAS I S

P E LV I S

VE JI GA CANAL ANAL

P R Ó S TATA

PRIMARIOS RIESGO BAJO / INTERMEDIO RECURRE NCI AS

SUPERFICIAL

LE S I O NE S E N P I E L CARCI NO M A BASAL Q UE LO I D E S

OTRAS

TBI TM I SARCO M AS

RECTO M E TÁS TAS I S

CRANEOESPINAL OLIGOMETÁSTASIS

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Mundialmente reconocido como el mejor en tratamientos pediátricos.

Ultra preciso y versátil, para todo tipo de tumores.

Reducción de efectos secundarios.

Preservación de tejidos sanos.

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SEGURIDAD

EFICACIA Y EFECTIVIDAD

La toxicidad asociada a Radixact y los efectos adversos su-

Radixact es una tecnología efectiva para el tratamien-

fridos por el paciente son menores que con radioterapia

to del cáncer. Según los estudios realizados, en compa-

convencional. Esto se debe a que la tomoterapia adminis-

ración con la radioterapia convencional, se obtiene una

tra la dosis con gran precisión sobre el tumor, evitando los

irradiación de alta precisión y mejores indicadores do-

tejidos sanos circundantes, reduciendo el riesgo de infra y

simétricos, mayor conformidad y homogeneidad en la

sobre dosificaciones. El tratamiento es indoloro y no resulta

distribución con mayores gradientes de dosis. Al poder

incómodo para el paciente.

administrar dosis superiores sobre el tumor, existe mayor eficacia terapéutica en cuanto a destrucción de tejido

UTILIDAD CLÍNICA

tumoral, mayor control local de la enfermedad y menor riesgo de recidiva tumoral, sin incrementar la toxicidad.

Radixact contribuye a mejorar la calidad de vida de los pacientes, con un incremento de los controles de calidad realizados previo a la administración del tratamiento en comparación a otras formas de radioterapia. Es posible ver una reducción de la morbilidad y un aumento del control de la enfermedad y de la esperanza de vida. Otra ventaja es la reducción del tiempo global de tratamiento.

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DeLeC y Accuray prestarán asesoría a los profesionales de la institución en la evaluación de las instalaciones y en la interpretación de las especificaciones técnicas para la construcción del búnker, con el fin de que la institución proceda a una adecuada instalación y operación del equipo.

En términos generales el servicio de asesoría consistirá en: Prestar asesoría, por parte de ingenieros de DeLeC y Accuray Inc. a los profesionales que designe la institución, en: la evaluación de las actuales instalaciones; en el visto bueno formal a los planos presentados para la obra de construcción del búnker, en forma previa su inicio; en la definición de las especificaciones técnicas para el diseño del búnker; y, en la realización de visitas inspectivas de carácter formal a la obra de construcción del búnker.

A continuación, se relaciona un documento orientativo de las disposiciones genéricas que debe tener un búnker para el sistema Radixact. Cada caso concreto se tratará de forma puntual y detallada teniendo en cuenta las características particulares de cada proyecto.

Compacto, autoblindado y potente. Optimiza los espacios del búnker.

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Dimensiones del BÚNKER

A: 275 cm. B: 602 cm. C: 463 cm

Gracias a su exclusivo blindaje primario, podría permitir la reducción de los espesores de las paredes hasta 105 cm.

Radixact X7 instalado en Hospital de Clínicas, La Paz, Bolivia.

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Centro Oncológico Sunchales

A principios del 2019 concluyó la instalación del

cionales, con evaluaciones y calificaciones que se

equipo para radioterapia y radiocirugía ThomoThera-

aplican en todo el mundo, actualizaciones periódicas

py, de Accuray. Lo adquirió la Fundación ATILRA para

y controles de calidad estrictos que garantizan el ni-

el Centro Oncológico Sunchales, ubicado en la ciu-

vel de prestación.

dad de Sunchales, provincia de Santa Fe. El equipo de bioingenieros y físicos de DeLeC Científica participó del asesoramiento y la provisión del equipo. El Radixact es la nueva versión del TomoTherapy, en la que Accuray mejoró el rendimiento del gantry, lo que permite realizar intervenciones más rápidas. Además, el software permite facilitar la utilización de los operadores y reducir los errores.

Con la compra del equipo, ATILRA obtuvo un entrenamiento dirigido a los Físicos Nucleares y Técnicos

Foto: equipo de Servicio Técnico de DeLeC

en Radioterapia, siguiendo una planificación que consiste en tres etapas:

COS Atilra superó los 500 pacientes tratados con To-

i) fábrica de Accuray en Estados Unidos; ii) Centro

moTherapy, demostrando que es posible ofrecer te-

Médico instalado en Sudamérica y

rapias radiantes de máxima calidad en las provincias.

iii) por último el entrenamiento final in situ en el Centro Oncológico Sunchales. Los entrenamientos son impartidos por expertos y bajo estándares interna-

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Las clínicas más prestigiosas de Argentina hacen derivaciones a la ciudad de Sunchales para garantizar tratamientos seguros con TomoTherapy

69

Tecnología de punta en las provincias Se trata de un hito significativo para la región de Santa Fe y alrededores ya que el ThomoTerapy es un equipo fundamental en el tratamiento de todas las patologías de cáncer a través de la radiocirugía y la radioterapia. La ciudad de Sunchales es de fácil acceso para los ciudadanos de Santa Fe, Córdoba, Rosario, Buenos Aires y se proyecta como un enclave de vanguardia en el ámbito de la salud en el país.

Con la inauguración del Centro Oncológico Sunchales, ATILRA busca ampliar las alternativas de tratamiento contra el cáncer y además impulsar proyectos de formación e investigación, junto con Universidades nacionales y de otros países. La tecnología de Accuray es una pieza importante para mejorar la calidad de vida de la población e impulsar el desarrollo local.

70

Hospital de Clínicas, SEDES, La Paz (Bolivia)

Otro caso notable de incorporación de nueva tecno-

desde fábrica, se ajustó al búnker existente. Esta

logía para radioterapia y radiocirugía es el de SEDES.

ventaja acortó los tiempos del proceso de insta-

El Hospital de Clínicas de La Paz, Bolivia, adquirió un

lación y puesta en marcha. Se ganó la licitación y

equipo Radixact X7 para su área de terapia radiante.

en diciembre de 2018 llegó el Radixact a La Paz.

Para incorporar el equipo, SEDES llamó a licitación pública. Entre los requisitos técnicos estaban la reutilización del búnker existente en el edificio y la presentación de estudios o certificaciones, por parte del proveedor, asegurando el funcionamiento a 3600 mts sobre el nivel del mar, altura en la que se encuentra la ciudad.

La instalación del mismo la llevó adelante un grupo de ingenieros y técnicos liderados por DeLeC Científica S.A. Se trabajó respetando los protocolos previstos para la contención del COVID19, se superaron las adversidades que implicó la crisis social y política en Bolivia en 2019, y a comienzos del 2020 se inauguró el nuevo servicio de Radioterapia y Radiocirugía del Hospital de Clínicas SEDES, de La Paz.

En la actualidad, el staff de físicos y médicos continúan con entrenamientos en Bolivia y en otros centros de referencia de Accuray.

Este proceso significa un paso notable para la calidad DeLeC Científica S.A., a través del Grupo Co-

de los tratamientos que brinda el sistema público de sa-

sin, su representante oficial en Bolivia, se pre-

lud boliviano, y responde a una demanda de años de la

sentó a la convocatoria con una propuesta supe-

comunidad de pacientes oncológicos de este país con

radora. Gracias a que el equipo viene blindado

la tecnología del mundo en radioterapia y radiocirugía.

71

Radixact X7 en el Hospital de Clínicas de La Paz, Bolivia

73

El usuario final de TomoTherapy/Radixact podrá acceder a un plan de capacitación integral compuesto por: i.

Cursos en fábrica.

ii.

Curso en una institución a definir con experiencia en el sistema y equipo en funcionamiento.

iii.

Curso en la institución de destino una vez instalado el equipo.

iv.

Capacitación brindada por personal de Aplicaciones Clínicas de DeLeC.

Cursos ofrecidos para el Sistema Radixact

74

i.

Cursos en fábrica

El usuario deberá determinar el número de asistentes que enviará a cada curso. El personal de DeLeC los asistirá para la inscripción. Se debe considerar que previo a la instalación, al menos un físico debe tener

Objetivo: Este curso provee una visión general de la operación clínica con instrucciones en profundidad de los procedimientos para los test de aceptación (ATP), procedimientos de comisionamiento y herramientas prácticas de rutina para QA.

el curso en fábrica finalizado y es recomendable que

Detalles: El programa del curso combina formación

también tenga completo el curso on-site en un sitio

teórica y conceptual con ejercicios prácticos para

donde ya se encuentra un equipo en funcionamiento.

preparar al Físico en el desarrollo del ATP, así como

Los cursos en fábrica son tres. En la siguiente tabla se enuncian y se indica además quién debería realizarlos. Al menos 1 Físico y 1 Técnico deben realizar estos cursos.

también en las actividades de QA de rutina. Incluye una introducción a la Planificación del Tratamiento con prácticas aplicadas sobre el Sistema de Tratamiento Radixact. La finalización de este curso prepara al Físico para ejecutar las actividades de comisio-

Se encuentran incluidos en la oferta los entrena-

namiento y pruebas necesarias para asegurar que el

mientos en fábrica para 1 médico,1 fisico médico y

sistema está listo para uso clínico.

1 tecnólogo.

Nota: Para los Físicos que diseñan planes clínicos de tratamiento se les recomienda alistarse en el curso separado de Planificación de Tratamiento.

A. Curso para Físicos

Audiencia: Físicos Médicos responsables de ejecutar el comisionamiento y las tareas de control de calidad del Sistema de tratamiento Radixact.

75

B. Curso para Operaciones de Entrega de Tratamiento

Audiencia: Todos los operadores del Sistema Radixact.

porcionar un contexto clínico para las habilidades que se enseñan.

Las fechas se definirán entre el usuario final y Accuray y/o DeLeC. La capacitación se dicta únicamente en

Objetivo: Este curso enseña las habilidades requeri-

idioma inglés. En caso de que el personal del cliente

das para la entrega de tratamientos y el desarrollo de

no tenga un buen dominio del idioma inglés, Accuray

tareas básicas de mantenimiento de datos.

hará los arreglos necesarios para que haya un intér-

Detalles: El curso de tres días combina formación conceptual y teórica sobre entrega de tratamientos con ejercicios prácticos en laboratorio para permitir que los asistentes puedan realizar todos los pasos específicos en el proceso de tratamiento con Radixact.

Los asistentes tendrán la posibilidad de aplicar las habilidades adquiridas en un contexto práctico basado en la resolución de problemas, que los preparará para la operación del sistema en el escenario clínico.

C. Planificación de Tratamiento

Audiencia: Dosimetristas, Físicos Médicos y personal clínico responsable del desarrollo y optimización de los planes de tratamiento clínico utilizando la estación de planificación de Radixact.

Objetivo: Este curso incluye una descripción completa de las herramientas y capacidades de la planificación TomoHelical ™ y TomoDirect ™ usando IMRT y 3DCRT. Detalles: El programa del curso combina formación conceptual y teórica con ejercicios prácticos en laboratorio que permitirá a los asistentes el desarrollo y aplicación de actividades prácticas. La formación va desde los fundamentos básicos a las técnicas de planificación más avanzadas. Se abordan aspectos y consideraciones únicos para planificar los tratamientos del sistema Radixact. Se presta atención a las diferentes aplicaciones clínicas, incluidos los tratamientos intracraneales y extracraneales, para pro-

76

prete disponible para la capacitación correspondiente; dichos intérpretes deberán estar capacitados para realizar interpretación simultánea y estar familiarizados con la terminología involucrada. El cliente notificará con anticipación a Accuray si son necesarios los servicios de traducción. El cliente será responsable de todos los gastos de interpretación y traducción.

ii. Curso en institución con experiencia en el sistema y equipo en funcionamiento

iii. Curso en la institución una vez instalado el sistema

Además de los cursos en fábrica para físicos y téc-

La última etapa de entrenamiento se coordinará para

nicos, se realizará en fecha e institución a coordinar

ser realizada al finalizar la instalación del equipo en

con el personal del usuario final y Accuray, el entre-

el Hospital.

namiento en un sitio donde ya se encuentra instalado un equipo.

iv.

Capacitación personalizada permanente brindada por personal de Aplicaciones Clínicas Una vez finalizados los tres cursos anteriores mandatorios de Accuray, el personal de Aplicaciones Clínicas y Docencia de DeLeC Científica proveerá capacitaciones de forma permanente a la totalidad de los profesionales del servicio.

Allí se sugiere la participación del personal médico radioterapeuta, físico y/o dosimetrista y técnico del servicio. Se encuentran incluidos en la oferta los entrenamientos en fábrica para 1 médico,1 fisico médico y 1 tecnólogo.

77

78

79

Radixact vs Synergy Comparativa técnica

CARACTERÍSTICAS TÉCNICAS

RADIXACT

SYNERGY

Caracterís cas de los haces de tratamiento ENERGÍAS DE FOTONES

6 MV

4, 6, 8, 10, 15 y 18 MV 4 MV: 30 - 230(MU/min)

TA S A D E D Ó S I S

850, 1000(MU/min)

4 MV: 30 - 230(MU/min) 6[1] - 10 MV: 30 - 500(MU/min) 15 y 18 MV: 40 - 600(MU/min)

APERTURA MÁX. DE CAMPO

5 x 40 cm[2]

40 x 40 cm

ENERGÍAS DE ELECTRONES

no posee electrones

4, 6, 8, 9, 10, 12, 15, 18 y 20 MeV

TA S A

-

37.5 - 600(MU/min)[3]

DE DOSIS

Caracterís cas mecánicas del gantry PRECISIÓN GANTRY

R OTA C I Ó N

±0.1o 1 - 5 RPM para tratamiento

V E LO C I D A D R O TA C I Ó N GANTRY

de imágenes

D I S TA N C I A F U E N T E ISOCENTRO

85 cm

DESPLAZAMIENTO DEL ISOCENTRO MECÁNICO

<0.25 mm

R A N G O D E R O TA C I O N GANTRY

±0.5o 0 - 1 RPM

100 cm

DEL

)

)

o

o

CUÑA FÍSICA

-

Motorizadas (40x30 cm, 0-60o)

CÁMARA MONITORA

Cámara ionización sellada

Cámara ionización abierta

REFRIGERACION GANTRY

Sistema de refrigeración por

Sistema externo de refrigeración

DEL

Caracterís cas

mecánicas

y dosimétricas

CANTIDAD DE LÁMINAS

del

MLC

160 (permite interdigitación)

ANCHO LÁMINA ISOCENTRO

0.625 cm

0.5 cm

APERTURA MÁXIMA CAMPO

hasta 135 cm de largo

40 x 40 cm

250 cm/s

hasta 6.5 cm/s

TRANSMISIÓN ENTRE LÁMINAS MÁXIMA VELOCIDAD LÁMINA MECANISMO DE DESPLAZAMIENTO

80

Electrónico

CARACTERÍSTICAS TÉCNICAS

RADIXACT

SYNERGY

ENERGÍA DEL HAZ

kV[4]

MV y kV

CONFIGURACIÓN DEL DETECTOR

Detector plano

Detector plano silicio amorfo(a-Si)

M AT R I Z D E I M A G E N

512 x 512

1024 x 1024

GEOMETRÍA DEL HAZ

MVCT / kVCT (haz de abanico)

kVCT (haz cónico)

UNIFORMIDAD DE LA IMAGEN

Dentro de las 25 HU (MVCT)

Dentro de las 2 HU

CONFIGURACIÓN DEL DETECTOR

Arreglo cámaras ionización de xenon (MVCT) / panel plano (kVCT)

Detector plano silicio amorfo(a-Si)

R E S O LU C I Ó N E S PAC I A L

1.6 mm (MVCT)

> 10 lp/cm

M AT R I Z D E I M A G E N

512 x 512

1024 x 1024

GUÍA POR IMÁGENES

Diaria (corregistro MVCT/CT)

RESOLUCIÓN DEL CONTRASTE

Camilla P E S O M Á X I M O S O P O R TA D O

200 kg

200 kg

[1] Se pueden lograr 600 MU/min bajo demanda.

[3] Opcionalmente, puede ser habilitado el modo de alta tasa de dosis de electrones (HDRE, por sus siglas en ingles), [4] Disponible solo con sistema Synchrony, para el rastreo de tumores en movimiento.

81

Comparativa clínica

DESCRIPCIÓN

MODALIDADES T R ATA M I E N T O

RADIXACT

DE

SYNERGY

3DCRT, IMRT, Helicoidal, SRS,

SISTEMA DE PLANIFICACIÓN MOSAIQ

OIS SISTEMA DE MANEJO MOVIMIENTO

DEL

T R ATA M I E N T O S E N LOCALIZACIONES MÁXIMA LONGITUD DEL C A M P O T R ATA M I E N T O

Synchrony

Response

Si

Si

135 cm

40 cm

Procedimientos especiales

Técnica a distancia extendida, I R R A D I A C I Ó N TO TA L

DE tratamiento aproximado 1 hora

Técnica de irradiación con electrones a distancia extendida, planicación de posiciones correctas del tratamiento, se necesita comisionar la energía de los

MICOSIS FUNGOIDES

campo y a distancia extendida, se deben colocar protecciones de plomo

Un solo plan para tratar con técnica helicoidal

82

Separación de tratamiento en 3 planes: plan para el craneo y cervical, plan empleando 3DCRT, IMRT, VMAT o combinación de éstas técnicas

Radixact vs TrueBeam Comparativa técnica

CARACTERÍSTICAS TÉCNICAS

ENERGÍAS DE FOTONES

RADIXACT

6 MV

4, 6, 8, 10, 15 y 20 MV [1] 6 - 10 MV [2] 15 y 20 MV [3]

TA S A D E D Ó S I S APERTURA MÁX. DE CAMPO

5 x 40 cm[4]

40 x 40 cm

ENERGÍAS DE ELECTRONES

PRECISIÓN GANTRY

R OTA C I Ó N

4, 6, 8, 9, 10, 12, 15, 18 y 20 MeV

± 0.1o

V E LO C I D A D R O TA C I Ó N GANTRY

85 cm

DESPLAZAMIENTO DEL ISOCENTRO MECÁNICO

< 0.25 mm

R A N G O D E R OTA C I O N GANTRY

± 0.3o

1 - 5 RPM para tratamiento

D I S TA N C I A F U E N T E ISOCENTRO

REFRIGERACION GANTRY

TRUEBEAM

DEL

0 - 1 RPM

100 cm

)

o

Rango de 370o

)

o

DEL

CANTIDAD DE LÁMINAS

120

APERTURA MÁXIMA CAMPO

34 x 40 cm

FUGA MÁXIMA ENTRE LÁMINAS MÁXIMA VELOCIDAD LÁMINA MECANISMO DE DESPLAZAMIENTO

83

CARACTERÍSTICAS TÉCNICAS

ENERGÍA DEL HAZ

RADIXACT

kV[5]

TRUEBEAM

MV y kV

UNIFORMIDAD DE LA IMAGEN CONFIGURACIÓN DEL DETECTOR M AT R I Z D E I M A G E N

512 x 512

GEOMETRÍA DEL HAZ UNIFORMIDAD DE LA IMAGEN CONFIGURACIÓN DEL DETECTOR

de xenon

RESOLUCIÓN DE CONTRASTE M AT R I Z D E I M A G E N GUÍA POR IMÁGENES

84

512 x 512

512 x 512

Comparativa clínica

DESCRIPCIÓN

MODALIDADES T R ATA M I E N T O

RADIXACT

DE

SBRT

TRUEBEAM

3DCRT, IMRT, VMAT, SRS, SBRT

SISTEMA DE PLANIFICACIÓN ARIA

OIS SISTEMA DE MANEJO MOVIMIENTO

DEL

RPM

T R ATA M I E N T O S E N LOCALIZACIONES HABITUALES

Si

Si

MÁXIMA LONGITUD DEL C A M P O T R ATA M I E N T O

135 cm

40 cm

I R R A D I A C I Ó N TO TA L

DE

MICOSIS FUNGOIDES

MEDULOBLASTOMAS

85

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16. Klopp A.H., Yeung A.R., Deshmukh S. et al. Patient-Reported Toxicity During Pelvic Intensity-Modulated Radiation Therapy: NRG Oncology-RTOG 1203. J Clin Oncol. 2018 Aug 20;36(24):2538-2544.

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Bibliografía DING (2018) Image guidance doses delivered during radiotherapy: Quantification, managment and reduction: Report of the AAPM Therapy Physics Committee Task Group 180. 2018 ZALESKA (2017) Influence of optimizing protocol choice on the integral dose value in prostate radiotherapy planning by dynamic techniques - Pilot study.

HSU (2017) Dosimetric comparison of different treatment modalities for stereotactic radiotherapy.

SHELLEY (2017) Delivered dose can be a better predictor of rectal toxicity than planned dose in prostate radiotherapy.

NAGAI (2017) Intensity-modulated radiotherapy using two statics ports of TomoTherapy for breast cancer after conservative surgery : dosimetric comparison with other treatment methods and 3-year clinical results.

WADASADAWALA (2015) Use of TomoTherapy in treatment of synchronous bilateral breast cancer: dosimetric comparison study.

VAN GESTEL (2015) Fast Helical TomoTherapy in a head and neck cancer planning study: is time priceless?

SAW (2018) 3D treatment planning on helical tomotherapy delivery system HU (2017) A feasibility study on the use of tomotherapy megavoltage computed tomography images for palliative patient treatment planning.

RAMSEY (2006) A technique for adaptive image-guided helical tomotherapy for lung cancer.

KIM (2018) Assesment of inter- and intra-fractional volume of bladder and body contor by mega-voltage computed tomography in helical tomotherapy for pelvic malignancy.

PEÑAGARÍCANO (2011) Clinical feasibility of TBI with helical TomoTherapy.

ZHANG (2014) Dosimetric comparison of craniospinal irradiation using different TomoTherapy techniques.

RONG (2011) Dosimetric and clinical review of helical tomotherapy SARFEHNIA (2013) A novel approach to total skin irradiation using helical tomotherapy

90

91

Índice 1. Image guidance doses delivered during radiotherapy.

94

2. Dosimetric comparison of different treatment modalities for stereotactic radiotherapy.

110

3. A feasibility study on the use of TomoTherapy megavoltage computed Tomograpy images for palliative Patient tratment planning.

121

4. Assessment of inter and intra-fractional volume of bladder and body contour by mega-voltage computed tomography in helical tomotherapy for pelvic malignancy.

139

5. Intensity-modulated radiotherapy using two static port of TomoTherapy for breast cancer after conservative surgery: dosimetric comparison with other treatment methods and 3-years clinical results.

145

6. Patient dose from kilovoltage radiographs durin motion-synchronized treatments on Radixact.

5153

7. Clinical Imprementation and Initial Experience of Real-Time Motion Tracking With Jaws and Multileaf Collimator During Helical Tomotherapy Delivery.

161

8. Organ sparing total marrow irradiation compared to total body irradiation prior to allogeneic stem cell transplantation.

9. 3D treatment planning on helical TomoTherapy.

171 186

10. Delivered dose can be a better predictor of rectal toxicity than planned dose in prostate radiotherapy.

195

11. Helical tomotherapy for prostate cancer radiation therapy: An audit of early toxicity and quality of life.

201

12. Influence of optimizing protocol choice on the integral dose value in prostate radiotherapy planning by dynamic techniques.

13. A novel approach to total skin irradiation using helical TomoTherapy.

207 212

14. COVID-19 pneumonia treated with ultra-low doses of radiotherapy (Ultra-COVID study): a single institution report of two cases.

92

219

A continuación se pone a disposición una selección de publicaciones científicas que avalan las características y beneficios del sistema Radixact, de Accuray.

En la selección de estos papers se dio prioridad a los contenidos más recientes y pertinentes, teniendo en cuenta la presentación que se ofrece en la carpeta Radixact confeccionada por DeLeC Científica.

Si el lector desea ampliar la información científica sobre los usos del Radixact puede consultar a los sitios www.delec.com.ar, o bien al correo: comunicaciones@ delec.com.ar.

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Image guidance doses delivered during radiotherapy

Image guidance doses delivered during radiotherapy: Quantification, management, and reduction: Report of the AAPM Therapy Physics Committee Task Group 180 George X. Dinga)

Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA

Parham Alaei University of Minnesota, Minneapolis, MN 55455, USA

Bruce Curran Virginia Commonwealth University, Richmond, VA 23284, USA

Ryan Flynn University of Iowa, Iowa City, IA 52242, USA

Michael Gossman Tri-State Regional Cancer Center, Ashland, KY 41101, USA

T. Rock Mackie University of Wisconsin, Madison, WI 53715, USA

Moyed Miften University of Colorado, Aurora, CO 80045, USA

Richard Morin Mayo Clinic, Jacksonville, FL 32224, USA

X. George Xu Rensselaer Polytechnic Institute, Troy, NY 12180, USA

Timothy C. Zhu University of Pennsylvania, Philadelphia, PA 19104, USA

(Received 18 July 2017; revised 10 January 2018; accepted for publication 10 January 2018; published xx xxxx xxxx) Background: With radiotherapy having entered the era of image guidance, or image-guided radiation therapy (IGRT), imaging procedures are routinely performed for patient positioning and target localization. The imaging dose delivered may result in excessive dose to sensitive organs and potentially increase the chance of secondary cancers and, therefore, needs to be managed.

Aims: This task group was charged with: a) providing an overview on imaging dose, including megavoltage electronic portal imaging (MV EPI), kilovoltage digital radiography (kV DR), Tomotherapy MV-CT, megavoltage cone-beam CT (MV-CBCT) and kilovoltage cone-beam CT (kVCBCT), and b) providing general guidelines for commissioning dose calculation methods and managing imaging dose to patients.

Materials & Methods: We briefly review the dose to radiotherapy (RT) patients resulting from different image guidance procedures and list typical organ doses resulting from MV and kV image acquisition procedures.

Results: We provide recommendations for managing the imaging dose, including different methods for its calculation, and techniques for reducing it. The recommended threshold beyond which imaging dose should be considered in the treatment planning process is 5% of the therapeutic target dose.

Discussion: Although the imaging dose resulting from current kV acquisition procedures is generally below this threshold, the ALARA principle should always be applied in practice. Medical physicists should make radiation oncologists aware of the imaging doses delivered to patients under their care.

Conclusion: Balancing ALARA with the requirement for effective target localization requires that imaging dose be managed based on the consideration of weighing risks and benefits to the patient. © 2018 American Association of Physicists in Medicine [https://doi.org/10.1002/mp.12824] Key words: IGRT, image dose management, image dose reduction techniques, image guidance doses, recommended dose threshold

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TABLE OF CONTENTS 1. INTRODUCTION 2. OVERVIEW OF DOSE RESULTING FROM IMAGE GUIDANCE PROCEDURES 2.A. Megavoltage beam imaging 2.B. Kilovoltage beam imaging 3. DOSE CALCULATION ALGORITHMS FOR KV AND MV IMAGING DOSE 3.A. Monte Carlo-based methods 3.B. Model-based methods 4. KILOVOLTAGE IMAGING BEAM DOSIMETRY 4.A. Input data for kV x-ray beam characterization 4.B. Output of a kV imager 4.C. In vivo dosimetry 5. METHODS OF ACCOUNTING FOR IMAGING DOSE 5.A. Patient-specific imaging dose calculations 5.B. Nonpatient-specific imaging dose estimations 6. RECOMMENDATIONS 6.A. General recommendations 6.B. Imaging dose output and consistency checks 6.C. Accounting for imaging dose to RT patients 6.D. Available techniques to reduce imaging dose to patients 7. ACKNOWLEDGMENTS

1. INTRODUCTION Image-guided radiation therapy (IGRT) has rapidly been adopted as the standard of care to improve the geometric accuracy of patient positioning during radiotherapy.1–6 IGRT can significantly reduce target positioning errors, therefore, enabling highly conformal treatments. The acquired images during treatment delivery can be used for monitoring patient and target geometry changes, potential adaptive planning,7–9 or margin reduction.10 During the course of IGRT, the image guidance procedure is typically performed for each treatment fraction. The patient may occasionally be imaged more than once during any fraction in order to ensure that the patient’s position is correct, and to reposition if necessary. Since these imaging procedures deliver additional radiation dose to patients, understanding the magnitude of this dose has become increasingly important in order to minimize its risk.

While the commonly adopted radiation protection safety philosophy of As Low As Reasonably Achievable (ALARA) is also applicable for imaging dose, minimizing imaging doses by employing reasonable methods should not compromise target localization. Currently, imaging dose is not accounted for in RT treatment planning,11 and the purpose of this report is to provide imaging dose data and develop guidelines for clinicians to make informed decisions regarding the risk and benefits of x-ray image guidance.

The report of AAPM TG-751 provided dose estimates for a variety of image guidance techniques and recommended strategies for minimizing imaging dose while improving treatment delivery. TG-75 also identified the need to manage imaging dose for the large number of current and emerging

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imaging techniques in RT. These techniques include CT; 4DCT; diagnostic x-ray imaging; in-room CT; dual radiographic x-ray imaging; fluoroscopy; and portal imaging, either using film or an electronic portal imaging device (EPID), in various modes.

This report is intended to complement the AAPM TG-75 report.1 It contains updated dose data resulting from current image acquisition procedures and modalities and addresses current issues in estimating and accounting for imaging dose during treatment planning when required. It also addresses how to minimize dose due to imaging procedures, and provides recommendations for incorporating suggestions made in AAPM TG-751 and ICRP-102.12 This report also offers guidelines for commissioning imaging beams in order to provide patient-specific imaging dose calculations when needed.

The imaging dose referred to in this report is absorbed dose to medium (e.g., dose to bone or dose to soft tissue), which differs from the effective dose metric used in TG-75.

Effective dose, as defined by the ICRP,13 is based on an estimate of biological effect integrated over the entire patient body, requiring a detailed knowledge of the radiation energy spectrum and irradiation geometry. Most treatment planning systems (TPSs) are not capable of calculating and displaying kV energy range dose distributions without special research tools, nor are they capable of converting calculated absorbed dose to effective dose and displaying the results. Thus, in order to avoid this additional level of complexity, absorbed dose is used in this report rather than effective dose.

The magnitude of imaging dose is dependent on many factors, including the frequency of imaging and the technique used. For a single treatment fraction, two or more planar images or one or more volumetric acquisitions may be acquired. In the case of the Brainlab AG (Feldkirchen, GERMANY) ExacTrac14,15 or Accuray, Inc. (Sunnyvale, CA) CyberKnife systems,16,17 the number of planar image acquisitions per session can potentially be well over 80, even for none of the SRS/SBRT treatments, as frequent imaging is typical for monitoring patient position. Each of these imaging procedures deliver additional radiation dose to normal tissue.1,18–25 Depending on the imaging protocols and techniques used there are large variations in the imaging dose delivered to the patient.

In general, MV imaging delivers higher doses than kV imaging.26 With the exception of MV volumetric imaging, a single image acquisition can deliver a dose of 0.1–5.0 cGy to the patient depending on the imaging modality. However, even with demonstrated progress in dose reduction,21,25,27–41 the kV-CBCT procedure employed for pelvic imaging can add a cumulative dose of 1–3% of the prescription dose during the course of treatment. Since the photoelectric effect is the dominant photon interaction process for kV imaging, the imaging dose to bony structures is a factor of 2–4 greater than that to soft tissue.20,21,29 For an MV-CBCT image acquisition, the imaging dose can be greater than 10 cGy, depending on the imaging site and clinical protocol.23,42–45 With all imaging procedures, the imaged volume is generally larger than the treatment volume, and tissues and organs outside the

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therapeutic beams are exposed to imaging radiation. These imaging doses to organs outside the treatment volume also need to be managed, as they may present an increased risk, especially in the case of pediatric patients.

In this report, we review a variety of methods for determining x-ray imaging dose. For kV-CBCT imaging dose, these include experimental phantom measurements,19,38,46,47 in vivo measurements on patients,48 and Monte Carlo (MC) calculations.21,22,25–27,29,30,40,49–52 Commercially available treatment planning systems with user modifications, as well as mathematical models,39 have been used to calculate the MV-CBCT42,45 and kV-CBCT53,54 dose. Measurements have been used to estimate doses from 2D kV radiographs,32,38 kV-CBCT,21,27–41 MV portal images,26,32,38 MV23,42,44 55,56 and MVCT. CBCT, In radiation therapy the prescribed therapeutic dose represents the minimum dose to part or all of the planning target volume. In developing strategies for managing the imaging dose, this task group considers 5% of the therapeutic target dose to be the threshold beyond which imaging dose should be accounted for in the treatment planning process. Dische et al.57 stated that there was evidence from published clinical data and a suggestion from an analysis of the Continuous Hyperfractionated, Accelerated Radiotherapy (CHART) pilot study data58 that dose variations as small as 5% may lead to real variations in both tumor response and the risk of morbidity.59 Many studies on accuracy requirements in radiotherapy have recommended an accuracy level of 5% in the delivery and determination of dose to tumors and normal tissue.60–65 Hence, the choice of a 5% threshold is based on considerations of clinical relevance, accuracy of dose calculation and delivery, dose tolerances for critical organs, and feasibility in clinical practice. Data currently available in the literature, and quoted throughout this report, for patient populations undergoing IGRT indicate that imaging dose is generally less than 5% of the therapeutic target dose,26,32,66,67 except for some imaging procedures that use MV beams, particularly MV-CBCT.42 Balancing ALARA principles with the requirement for effective target localization, however, requires the imaging dose to be managed on the consideration of weighing risks and benefits to the patient.

2. OVERVIEW OF DOSE RESULTING FROM IMAGE GUIDANCE PROCEDURES 2.A. Megavoltage beam imaging Megavoltage imaging modalities capture projection images using either electronic portal imaging devices (EPIDs) [Fig. 1(a)] or, in the case of MVCT in the Tomotherapy HiArt Radixact system (Accuray Inc., Sunnyvale, CA),55,68,69 a single-row CT detector. A typical pair of orthogonal 6 MV portal images acquired using an EPID results in a dose distribution like the one shown in Fig. 1(b), and organ doses of 1– 5 cGy (Tables Ia–Ic) while the imaging dose from a 2.5-MV image beam70 is about 50% of that from a 6-MV beam.

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Volumetric MV-CBCT images are reconstructed using projections acquired with the EPID and result in a greater dose than a pair of orthogonal MV portal images. Reported doses per monitor unit for MV-CBCT delivered to regions and organs typically considered are listed in Table Id.45 Monitor unit values ranging from 2 to 15 have been reported in the literature.42–45,71 Typically the head and neck region is imaged with lower monitor unit protocols (2–5 MU) than the thoracic or pelvic regions, which may be imaged at up to 15 MU. Figure 2 shows an MV-CBCT dose distribution for a pelvic patient imaged at 15 MU for reference.

The Siemens kView system provides the option to improve MV-CBCT image quality per unit dose by generating the imaging beam with a low Z (carbon) electron target and a 4.2-MeV electron beam, increasing the percentage of kilovoltage photons in the imaging beam considerably relative to MV-CBCT acquired with a conventional 6-MV beam generated with a tungsten target.72 With the kView system it is possible to obtain the same contrast-to-noise ratio as conventional MV-CBCT at about one-third the imaging dose.73 Organ-specific kView CBCT doses reported by Beltran74 and Dzierma et al.75 ranged from 0.6 cGy to 1.2 cGy/ MU. Image doses from kView based MV-CBCT per monitor unit are generally less than those of conventional 6-MV beams.44,73–80 Table Ie shows measured Tomo MVCT doses at the center of a 30-cm water phantom. Doses range from 0.8 to 2.5 cGy and depend on the acquisition mode.

2.B. Kilovoltage beam imaging Current kV imaging devices are generally integrated into linear accelerators and are capable of acquiring both 2D radiographs and 3D volumetric kV-CBCT images.8,81–83 Examples of kV-CBCT scanners integrated into a Varian Medical Systems, Inc. (Palo Alto, CA) On Board Imaging (OBI) system and an Elekta (Stockholm, Sweden) X-Ray Volume Imaging (XVI) system are shown in Fig. 3. Using MC methods to simulate an earlier version of the kV-CBCT scanner on the Varian OBI system (Varian OBI 1.3), Ding et al. reported21 the imaging doses received by patients from kV-CBCT scans of different treatment sites, including head and neck, chest, and abdomen. The imaging doses resulting from a single kV-CBCT procedure were 1–9 cGy to soft tissues and 6–29 cGy to bones and depended on the patient size and the site of the scan.21 Since the introduction of kV imaging systems, progress has been made by the vendors to reduce the imaging dose29 while maintaining or improving image quality. Examples of these efforts include better reconstruction techniques, improved software implementation, and the use of lower beam energies (100 and 110 kVp, in addition to the standard 125 kVp x rays), where beam energy is optimized for the size of the patient and the atomic number of the structures being imaged.85 Newer kV-CBCT acquisition techniques, which utilize 200 degree scans (instead of 370 degree ones), were introduced to reduce the imaging dose to patients for head and pelvis scans.29

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(a)

(b)

FIG. 1. (a) Conventional electronic portal imaging device (EPID) and (b) typical dose distributions and organ dose-volume histograms (DVHs) resulting from an orthogonal pair of 6 MV portal images (2 MU per image). Reproduced from Ding and Munro.26 TABLE IA. Typical organ doses for the head and neck treatment site with MV EPID portal imaging. D50 is minimum dose delivered to 50% of the organ volume (from Reference [26] for 6 MV beam and Reference [70] for 2.5 MV beam). These are for a typical pair of orthogonal setup fields (2 MU/field for 6 MV and 1 MU for 2.5 MV).

TABLE IB. Typical organ doses for the chest treatment site with MV EPID portal imaging (from References [26] and [70]) for a typical pair of orthogonal setup fields (2 MU/field for 6 MV and 1 MU for 2.5 MV).

Chest D50 range (cGy)

Brain D50 range (cGy) Organ

6 MV

2.5 MV

Brain

2.0–5.0

1.0–2.0

Brainstem

3.0–4.0

1.0–2.0

Chiasm

3.0–5.0

1.2–2.0

Eyes

3.0–5.0

1.3–2.0

Optic Nerves

3.0–5.0

1.0–2.0

Pituitary

2.0–5.0

1.0–2.0

This not only reduces CBCT acquisition times, but results in a nonuniform exposure of the patient with the potential to avoid irradiating superficial critical structures.29 These

Organ

6 MV

Aorta

2.0–4.0

1.0–2.0

Lungs

1.0–4.5

0.5–2.0

Esophagus

2.5–3.5

–

Kidney Heart

2.0–3.0 3.0–4.5

– 1.0–1.5

Liver

1.0–4.5

Spinal Cord

2.0–3.0

2.5 MV

0.5–1.0

improvements have reduced imaging dose by more than an order of magnitude in some cases. Figures 4–6 compare dose distributions between kV-CBCT scanners on newer

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TABLE IC. Typical organ doses for the pelvis treatment site with MV EPID portal imaging (from Reference [26] and [70]) for a typical pair of orthogonal setup fields (2 MU/field for 6 MV and 1 MU for 2.5 MV).

5 TABLE IE. Tomo MVCT dose at the center of a 30-cm water phantom and its dependency on acquisition protocols.

MVCT in Tomo

Pelvis

Acquisition mode D50 range (cGy)

Dose (cGy)

Fine pitch (4 mm couch travel/rotation)

2.5 cGy

Organ

6 MV

2.5 MV

Normal pitch (8 mm couch travel/rotation)

1.2 cGy

Bladder

2.0–3.5

1.0–1.5

Coarse pitch (12 mm couch travel/rotation)

0.8 cGy

Bowel

2.0–4.0

1.0–1.5

Femoral heads

2.5–3.5

0.8–1.5

Prostate

3.5–3.5

0.9–1.1

Rectum

2.0–4.0

0.8–1.0

TABLE ID. MV-CBCT doses per monitor unit using a 6 MV treatment beam with an acquisition arc of 200 degrees, starting at 270 degrees and stopping at 110 degrees (from Reference [45]).

Location Cranium Total-brain

Isocenter dose (cGy/MU) 0.88 0.01

Left lens Left eye 0.81 0.06

Total lung Heart

1.13 0.03

1.18 0.01

1.13 0.01 0.85 0.06 0.80 0.06

Soft Tissue 0.75 0.04

1.18 0.01

1.25 0.03

1.15 0.06 1.11 0.04 1.15 0.05

0.80 0.08

0.61 0.08

0.86 0.15

0.80 0.14

0.95 0.09

0.61 0.09

Varian OBI systems (OBI 1.4/1.5) and on a previous version of the Varian OBI system (OBI 1.3).26,29 When two orthogonal planar kV images are sufficient for an image guidance task, 2D radiographs are often used. The doses resulting from 2D kV imaging, investigated using multiple methods,26,32,38 have been shown to be much lower compared to those from volumetric kV-CBCT26 procedures.

Figure 7 shows typical dose distributions resulting from a pair of orthogonal planar images in head, thorax, and pelvis scans.26 Similar lower doses, on the order of 0.1 cGy, were reported for fixed double x-ray tube systems that use projected images for patient localization, such as the Brainlab ExacTrac 14,15 and the Accuray CyberKnife.16,17

1.19 0.01

1.16 0.01

0.59 0.10

0.86 0.15

Vertebral bodies

Femoral heads

1.16 0.01

0.83 0.06

Spinal canal

Pelvis

0.90 0.01

1.16 0.01

Right eye Left lung Right lung

Maximum organ dose (cGy/MU)

1.15 0.03

Right lens

Thorax

Average organ dose (cGy/MU)

From Edward Chao, Accuray Incorporated and T. Rock Mackie, UW, Madison, WI.

1.10 0.06

1.25 0.03 1.25 0.01

3. DOSE CALCULATION ALGORITHMS FOR KV AND MV IMAGING DOSE 3.A. Monte Carlo-based methods Monte Carlo (MC) techniques for simulating dosimetry problems have evolved considerably over the last three decades86 and are regarded as the gold standard in dose calculations. The development of a special purpose MC code, BEAM,87,88 made it practical to simulate megavoltage and kilovoltage beams. With many improvements in both accuracy and computational efficiency,87,89 MC techniques have been used to characterize therapeutic megavoltage beams from linear accelerators and kilovoltage photon beams from x-ray units.21,25,51,84,86,88,90–92 Given these capabilities, MC simulations have been used to calculate realistic imaging dose distributions in patients resulting from different x-ray imaging systems.21,22,25,27,29,30,40,49–51 These studies provide detailed information about patient organ dose resulting from different image guidance procedures. Although a number of commercial treatment planning systems incorporate MC calculations for MV beams, none currently allow MC calculations for kV beams.

3.B. Model-based methods

FIG. 2. Dose distribution resulting from an MV-CBCT localization procedure of a prostate cancer patient using a 15 MU imaging protocol with a 6 MV beam. Reproduced from Miften et al.42 It is worth noting that the asymmetric dose distribution is because the scan is acquired with a gantry rotation of 200 degrees.

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Model-based dose calculation algorithms were developed for accurate MV beam dose calculations and are commonly implemented in commercial treatment planning systems.93 When an imaging procedure uses MV beams, these algorithms are capable of accurately calculating the imaging dose.

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(b)

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“wedge” to mimic the isodose tilt of a half fan/half-bow tie imaging beam in the treatment planning system. Further work in this area has demonstrated that this could also be achieved by inserting a compensator in the beam.99 The same commercial TPS has also been used to model kV beams from Elekta XVI and Siemens kVision imaging systems.100,101 In general, use of these algorithms produces dose distributions of sufficient accuracy, except in and around bony structures.

A proposed correction method, the Medium-Dependent Correction (MDC) approach,102 accounts for atomic number dependency when computing kV dose distributions and can potentially increase the accuracy of kV imaging dose calculations to an acceptable 10–20%.94,95 With additional improvements in commercial TPSs, therefore, it may become feasible to use the same model-based algorithms to calculate doses from both an MV therapeutic beam and a kV imaging beam.

4. KILOVOLTAGE IMAGING BEAM DOSIMETRY Unlike MV imaging beams that can be easily added to treatment plans for dose calculation purposes, kV imaging beams generally require commissioning in treatment planning systems.

As indicated above, current commercial treatment planning systems do not accommodate the addition of kV imaging beams in routine clinical practice. Considering that kV imaging dose calculation in treatment planning systems may become possible in the future, however, guidance is provided in Sections 4.A and 4.B to address kV imaging beam data acquisition.

4.A. Input data for kV x-ray beam characterization

FIG. 3. kV image devices integrated into linear accelerators: (a) Varian OBI system on a Varian Trilogy treatment unit, Reproduced from Ding at el.84; (b) Elekta XVI on an Elekta Synergy treatment unit.

Morin et al.43 and Miften et al.42 calculated the imaging dose from MV-CBCT using two different treatment planning systems and reported dose calculation accuracy of better than 3%. The dose from the Siemens’ kView system has been computed using a commercial treatment planning system44,76 by implementing the kView beam spectrum given by Faddegon et al.72 in the TPS. It is feasible to use model-based dose calculation algorithms to perform dose calculations for kV-range beams, but there are inherent inaccuracies in the approach. Commercially available model-based algorithms underestimate dose to bone by up to 300%94,95 when used for kV beams due to the fact that they do not account for photoelectric effect.21,93,96,97 Alaei et al. demonstrated the feasibility of modifying an existing MV model-based dose calculation algorithm in a commercial TPS to calculate kV-CBCT dose.53 This required the addition of low-energy deposition kernels98 which accounted for the density effect of bone but not the photoelectric effect. In addition, unlike MV beams, modeling kV beams in a planning system requires beam data for the respective kV system, a topic which is further discussed in Section 5. In reference 51, Alaei et al. used a

Characterizing kV imaging beams in a planning system requires collecting beam data, including depth-dose curves, cross-profiles, and the absolute dose resulting from an image acquisition procedure. There are inherent challenges in collecting data for kV imaging beams due to the low radiation dose rate and the strong dependence on the medium in which the measurements are made.

To overcome these challenges, experimentally validated MC-simulated beam data can be used.53,84,103 Caution should be taken when using the beam data generated from MC simulations, as they will depend on the simulation parameters.

4.B. Output of a kV imager The beam output should be collected by the clinical physicist using a proper detector calibration and data collection protocol. Although a method for determining kV absorbed dose with a calibrated ionization chamber based on x-ray beam specifiers, such as half-value layer (HVL) and kVp, is available from dosimetry protocols,104–106 the calibration conditions recommended in these dosimetry protocols are often not applicable to imaging acquisition procedures, especially when the x-ray source is moving during the scan.

It is known that water is the most suitable medium for kV x-ray beam measurements. However, plastic phantom materials are more convenient. A method to determine the output

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(a)

(b)

(d) 100 90

80

70 60

Left eye

50

Bone

Right eye

Brain

40

Body

30 20

Spinal cord

70 60

Brain

50 40

Bone

Right eye

30

Body

20

10 0

Standard Dose Head: OBI 1.4

90

Spinal cord

% volume

% volume

80

(e) 100

Head Scan: OBI 1.3

10 0

5

10 dose /cGy

15

20

(c)

0

% volume

7

Left eye 0.0

0.5

1.0 dose /cGy

1.5

2.0

(f) 100 90 80 70 60 50 40 30 20 10 0

Head OBI 1.4

Left eye Right eye Spinal cord

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

dose /cGy

FIG. 4. Typical doses for a head scan shown in color wash along with dose-volume histograms (DVHs) for radiosensitive organs for the Varian OBI 1.3 (a,d); for the OBI 1.4 during a Standard-Dose Head scan (b,e), where the x-ray source is positioned below the patient; and for the OBI 1.4 during a head scan with the xray source positioned above the patient (c,f—dashed lines). The solid lines in (f) are reproduced from (e) and show the quantitative effect of rotating the x-ray source from the back to the front of the patient. Note that the abscissa in (d) is 10 times larger than in (e). Reproduced from Ding et al.29 (Scanning parameters are listed Table IId).

resulting from a specific image acquisition procedure has been described103 where the effect of using different plastic phantom materials in the kV energy range is investigated.

This study includes two water equivalents, Plastic Water – Low Energy Range (PW-LR–CIRS, Inc., Norfolk, VA) and Solid Water (Gammex, Inc., Middleton, WI), along with the less water-equivalent polymethyl methacrylate (PMMA).

Caution should be used when interpreting the measured data from solid water-equivalent and PMMA phantoms to determine the output of a kV beam, as the uncertainties can be significant (8–20%).103 The considerations for a suitable phantom include phantom size relative to x-ray field size, beam attenuation by the phantom, and availability.

For cases where fluoroscopy mode is used instead of radiography mode for acquiring 2D kV planar images, the imaging dose is proportional to the x-ray exposure times for the selected imaging protocol parameters (kVp and mA), and doses can be estimated based on the product of dose rate and scan time for the kV beam. The output of a kV beam can be obtained in air or in a phantom as recommended in the AAPM dosimetry protocol for kV beams.106 When measured in air, the beam output is insensitive to the field size used. When measured in a phantom, the beam output is affected by the phantom scatter, which depends on the field size. If the beam cannot be delivered in static mode, rotational absorbed dose can be measured utilizing a cylindrical chamber placed at the isocenter.

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4.C. In vivo dosimetry If patient-specific imaging dose verification is desired, in vivo patient dose measurements can be performed using available detectors such as diodes, thermoluminescent dosimeters (TLDs), or optically stimulated luminescent dosimeters (OSLDs).48,107,108 Dosimeters, such as diodes, that are intended for use in MV beam in vivo measurements are not suitable for kV beams as they include inherent buildup. In addition, their response to kV radiation is significantly different from MV beams. Dosimeters that are used for kV beams should be calibrated for the beam energy used.48 In vivo measurements using detectors placed on the patient’s skin may be used to estimate organ dose once detector response has been scaled by the known dose distribution inside the patient.48 There have been many publications discussing the use of TLDs, OSLDs, MOSFETs, and other detectors in kV beams.48,109–112 5. METHODS OF ACCOUNTING FOR IMAGING DOSE Many different methods have been used to calculate the imaging dose delivered to RT patients.1,11,18,19,21–23,25,51 When there is reasonable expectation that the imaging dose will exceed 5% of the total prescribed dose, two methods can

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(a)

(b)

(d)

100 90

Pelvis: Full scan length

100

Left femur head

90

60 50

Body

40 30

Rectum

20 0

0

1

2

dose /cGy

3

60

4

3 Left femur head

Body

Righ femur head

50 40 20

Prostate

10

70

30

Bladder

Dose profiles in axial direction

Pelvis: 5 cm scan length

80

Righ femur head

70

% volume

% volume

80

(e)

Bladder

Rectum

10 Prostate 0 0 1

2

dose /cGy

3

4

dose /cGy

(c)

Standard scan length (17 cm) Scan length set to 10 cm Scan length set to 5 cm

2

1

0

-10

-5

0

5

10

z-axis /cm

FIG. 5. The effect of reducing the scanned length: (a) Dose distributions shown in colorwash for default Pelvis scan length (16 cm); (b) reduced Pelvis scan length (5 cm); (c, d) Corresponding dose-volume histograms for the specific organs resulting from respective scans; (e) Dose profiles in the inferior–superior direction along the line AB shown in Figure (a,b) across the irradiated volume for 16 cm (standard scan length), 10 cm, and 5 cm, respectively. The direction of z-axis is from inferior to superior in (e). The peak at the right in (e) represents the dose as the line AB crosses into the sacral vertebral body (bone). Note that reducing the scan length of the CBCT scan reduces both the maximum dose and the volume that is exposed to radiation. Reproduced from Ding et al.29 (Scanning parameters are listed Table IId).

be used to manage it: patient-specific dose calculations and nonpatient-specific dose estimations.

5.A. Patient-specific imaging dose calculations Patient-specific imaging dose calculations are based on patient CT images67,113 and provide individualized organ doses, since the dose resulting from image guidance procedures will vary depending on the patient size as well as image location.21,54,67 In order to perform patient-specific imaging dose calculations in a treatment planning system, the beams used for imaging procedures must be characterized as part of the commissioning process.

The process of characterizing MV imaging beams in a treatment planning system is straightforward in cases where

the imaging beam is the same as the therapeutic beam, allowing imaging dose to be calculated according to the monitor units and field sizes used in image acquisition.

Imaging dose can then be added to therapeutic dose directly during treatment planning. Moreover, if the total number of imaging procedures is known at the planning stage, the imaging dose can be accounted for when optimizing patient treatment plans for total dose to the target and OARs. Miften et al. demonstrated this approach42 by showing optimized IMRT plans with and without MV-CBCT included in the process. This, along with the lack of MC simulations or model-based algorithms capable of handling kV beams in commercial TPSs,53 currently precludes patient-specific imaging dose calculations for any other than therapeutic MV beams.

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(a)

(b)

(d)

100

Low Dose Thorax: OBI 1.4

% volume

90

100

80

80

70

70

Bone

60 50

Heart Left lung Right lung Spinal cord

40 30

Body

20

Bone

60

Heart Left lung Right lung Spinal cord

50 40 30

Body

20 10

10 0

Chest: OBI 1.3

90

% volume

(c)

9

0

1

2

3

4

5

dose /cGy

0

0

5

10

15

20

25

dose /cGy

FIG. 6. Axial, frontal, and sagittal views showing dose distributions resulting from (a) OBI 1.4 low-dose thorax scan and (b) OBI 1.3 scan. The corresponding dose-volume histograms for different organs are shown for the low-dose scan (c) and the OBI 1.3 scan (d). Note that the horizontal scales in (c) and (d) differ by a factor of 5. Reproduced from Ding et al.29 (Scanning parameters are listed Table IId).

5.B. Nonpatient-specific imaging dose estimations Given the small magnitude of imaging dose relative to therapeutic dose,26,113 it may be adequate to use simpler approaches that provide reasonable estimates of the imaging dose. It has been shown Ref. [54,67] that interpatient variation and geometry dependence are small in most cases and that dose estimates could be provided in the form of simple look-up tables, which may be accurate enough to estimate the dose from repeat imaging procedures. Such tabulated values67,113 can provide clinicians with adequate estimates of Medical Physics, 0 (0), xxxx

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imaging dose to organs. Tables IIa, IIb, IIc, IId, IIe, and IIIa, IIIb, IIIc list representative organ doses resulting from kVCBCT scans in the Varian OBI and Elekta XVI systems for different treatment sites and scan protocols. Note that bow tie filters used in the kV-CBCT acquisition not only improve image quality but also significantly reduce imaging dose.26 These tabulated values, when scaled by the mAs used for image acquisition, are sufficient to estimate imaging dose to within 20%67 and can assist the clinician in: (a) determining if the imaging doses are expected to be close to the 5% threshold, (b) choosing a suitable IGRT protocol, and (c)

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Ding et al.: Image Guidance Doses to Radiotherapy Patients

10

(a)

(b)

(c)

FIG. 7. Imaging dose from a pair of orthogonal planar kV images for (a) head, (b) chest, and (c) pelvis images using the Varian OBI system.26 (Parameters for kV radiographs for specified acquisition techniques are listed in Table IId).

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TABLE IIA. Organ doses for the head and neck and brain treatment sites from Varian OBI v1.4 using Standard Head kV-CBCT scan. D50 and D10 are minimum dose delivered to 50% and 10% of the organ volume, respectively.

(From Reference [67] and kV-CBCT scan parameters for Varian OBI 1.4 shown in Table IId).

11 TABLE IID. Parameters for kV-CBCT-specified acquisition techniques in Varian OBI 1.4 (from Reference [26]).

kV-CBCT Standard head, brain

Standard head, head and neck

Organ

D50 range (cGy)

D50 range (cGy)

Brain

0.21–0.33

0.27–0.40

Brain

0.15–0.22

0.16–0.23

Brainstem

0.19–0.30

0.22–0.32

Larynx

0.21–00.29

0.25–0.33

Chiasm Eyes

0.08–0.26 0.03–0.31

0.09–0.26 0.04–0.35

Oral cavity Parotids

0.13–0.26 0.26–0.42

0.20–0.31 0.31–0.48

Optic Nerves

0.05–0.27

0.05–0.27

Spinal cord

0.16–0.25

0.19–0.32

Pituitary

0.07–0.24

0.08–0.25

Thyroid

0.07–0.23

0.11–0.32

Spinal Cord Skin

0.26–0.33

0.29–0.34

Esophagus

0.07–0.16

0.14–0.26

0.19–0.41

0.39–0.63

Skin

0.18–0.27

0.34–0.44

Bones

0.45–1.11

1.13–1.67

Bones

0.25–0.65

0.64–1.07

D10 range (cGy)

Organ

D10 range (cGy)

TABLE IIB. Organ doses for the chest treatment site from Varian OBI v1.4 using the low-dose thorax kV-CBCT scan (from Reference [114] and kVCBCT scan parameters for Varian OBI 1.4 shown in Table IId).

Low-dose thorax

Name

Bow tie filter

(kV)

(mAs)

Gantry rotation (degrees)

OBI

Standard-dose head

Full fan

100

145

200

OBI

Low-dose head

Full fan

100

72

200

OBI

High-quality head

Full fan

100

720

200

OBI OBI

Pelvis Pelvis spot light

Half fan Full fan

125 125

700 720

360 200

OBI

Low-dose thorax

Half fan

110

262

360

TrueBeam TrueBeam

Head Pelvis

Full fan Half fan

100 125

147 1056

200 360

TrueBeam

Spotlight

Full fan

125

733

200

TrueBeam

Thorax

Half fan

125

264

360

TABLE IIE. Parameters for kV radiographs for specified acquisition techniques in Varian OBI 1.4.

Name

(kV)

(mAs)

Head-AP Head-Lat

100 70

8 5

Organ

D50 range (cGy)

D10 range (cGy)

Aorta

0.42–0.58

0.44–0.63

Lungs Small bowel

0.30–0.61 0.33–0.54

0.43–0.72 0.39–0.61

Thorax-AP

75

5

Thorax-Lat

95

40

Esophagus

0.29–0.60

0.35–0.74

Pelvis-AP-Med

75

10

0.49–0.59

Pelvis-Lat-Med

105

80

Kidney

0.43–0.54

Heart

0.31–0.55

0.41–0.63

Liver

0.31–0.51

0.38–0.61

Spinal cord

0.32–0.57

0.35–0.78

Spleen

0.32–0.52

0.36–0.60

Stomach Trachea

0.28–0.57 0.36–0.71

0.31–0.62 0.47–1.04

Skin

0.46–0.57

0.64–0.89

Bones

1.06–1.74

1.47–2.25

The clinical default OBI blades are set to X1 = X2 = 13.3 cm and Y1 = Y2 = 10.3 cm in all acquisition techniques. All six techniques were modeled with and without a full fan bow tie filter.

TABLE IIIA. Organ doses for the head and neck treatment site from Elekta XVI kV-CBCT scan using S cassettes, 100 kVp, 0.1 mAs/acquisition, 360 acquisitions, 345–190 degree (IEC) rotation (from Reference [54]).

Head and neck Organ

TABLE IIC. Organ doses for the pelvis treatment site from Varian OBI v1.4 using Pelvis kV-CBCT scan. (From Reference [114] and kV-CBCT scan parameters for Varian OBI 1.4 shown in Table IId).

Pelvis scan, prostate isocenter Organ

D50 range (cGy)

D10 range (cGy)

D50 range (cGy)

Brainstem

0.06–0.08

Rt eye Lt eye

0.08–0.09 0.13–0.13

Rt parotid

0.05–0.06

Lt parotid

0.16–0.17

Rt cochlea

0.04–0.05

Bladder

1.36–2.20

1.72–2.69

Lt cochlea

0.09–0.12

Bowel

1.54–1.91

2.04–2.65

Oral cavity

0.09–0.11

Femoral heads

2.40–3.60

3.22–4.88

Prostate

1.19–1.79

1.33–1.89

Rectum

1.51–1.99

1.70–2.22

Skin Bone

1.80–1.96 2.93–3.96

2.26–2.92 4.61–5.72

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accounting for the organ dose resulting from a specific image acquisition procedure over the course of treatment.

Until kV dose calculations become available in commercial treatment planning systems, using estimated organ dose

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TABLE IIIB. Organ doses for the pelvis treatment site from Elekta XVI kVCBCT scan using an M cassette without a bow tie filter, 120 kVp, 1.0 mAs/ acquisition, 650 acquisitions, full 360 degree rotation (from Reference [54]).

Pelvis Organ

D50 range (cGy)

Bladder

0.9–2.0

Rectum Small bowel

1.1–1.9 1.0–1.8

TABLE IIIC. Organ doses for the pelvis treatment site from Elekta XVI kVCBCT scan using an M cassette with bow tie filter, 120 kVp, 1.6 mAs/acquisition, 650 acquisitions, full 360 degree rotation (from Reference [54]).

Pelvis Organ

D50 range (cGy)

Bladder

1.1–2.5

Rectum Small Bowel

1.3–2.4 1.1–2.3

tables from various imaging procedures may be an acceptable option given the expected low-dose level.

6. RECOMMENDATIONS Unlike diagnostic imaging procedures, IGRT image acqusitions are more frequent, repeated on a daily basis, and include a volume that is larger than the treated one. Proper management of imaging dose in IGRT includes adherence to ALARA principles by minimizing the dose as much as possible and accounting for it when necessary.

6.A. General recommendations (a) Create local imaging protocols, including imaging modality, technique, and frequency, that are suitable for the imaging requirements of the clinic.26 Consulting with a diagnostic imaging physicist may be helpful in this process. (b) Develop protocols that are specific for pediatric patients.29,40 (c) Communicate the imaging dose associated with IGRT protocols by site (head, thorax, abdomen, pelvis) to radiation oncologists. This enables informed decision-making for selecting imaging protocols and ensures the clinicians are aware of the imaging doses being delivered to their patients.

6.B. Imaging dose output and consistency checks (a) The anticipated imaging dose for each image acquisition procedure, with specified protocol parameters, should be measured in air or in-phantom, according to the AAPM dosimetry protocols for kV and MV beams, to confirm

12

that measured dose is within the manufacturer-stated specifications at the time of acceptance of the image device. Image acquisition procedures should include both those at MV and kV energies. The phantom and detectors used should be appropriate for the beam energy. Phantom sizes should be large enough to provide full x-ray scattering. (b) Consistency checks should be performed annually and after each system upgrade, and the recommendations from AAPM quality assurance reports, such as those from AAPM Task Group 142,115 should be used. Checks for imaging dose consistency in air can also be performed using commercially available tools for measuring beam parameters (i.e., kVp, mAs, etc.) that uniquely define the specific procedure. (c) If patient-specific imaging dose verification is desired for a particular patient, in vivo patient dose measurements should be performed with suitable detectors. The limited accuracy of patient-specific measurements should be taken into account in the review of the measured data.

6.C. Accounting for imaging dose to RT patients It is recommended that imaging dose be considered part of the total dose at the treatment planning stage if the dose from repeated imaging procedures is expected to exceed 5% of the prescribed target dose. Patient organ doses can be calculated or estimated by using either patient-specific or nonpatient-specific methods. Facilitation of patient-specific imaging dose calculations may require implementation of new algorithms for MV and kV beams in commercial treatment planning systems.

It is acceptable for the uncertainties of calculated imaging doses to reach 20%, because imaging dose is generally only a few percent of the prescribed target dose. As a result, the uncertainty of the summed dose (therapeutic + imaging) will still be at a level of 2–3%.

6.D. Available techniques to reduce imaging dose to patients Depending on the imaging modality, a variety of techniques are available to reduce the imaging dose to organs at risk, as recommended by AAPM TG-751 and AAPM TG179.116 ALARA should always be the guiding principle applied in practice. At the time of this report, the following techniques are recommended: (a) Reduce the imaging field size as much as possible. This will reduce the volume of irradiated tissue surrounding the target. Reducing the cranial-caudal extent of kVCBCT scans can also significantly reduce the integral as well as scattered dose in the volume.29 (b) During patient setup for MV portal images, minimize the imaging field size without removing reference

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structures needed for patient alignment. For images acquired for documenting delivery, select “image during treatment” to avoid adding additional dose to the patient. (c) For Tomotherapy units, select MVCT scan pitch parameters that balance imaging dose with clinical need (i.e. patient positioning or adaptive planning). The imaging dose differs significantly when different pitch parameters are selected (Table Ie).56 (d) For MV-CBCT, select a patient-specific MV imaging protocol and restrict the imaging field of view (FOV).

The imaging dose can be reduced if bony anatomy rather than soft tissue is used for treatment localization.78 Note that the degree of dose reduction possible will depend upon the image quality requirements of the clinicians. (e) When deciding between 2D radiographs or 3D volumetric images, consider the image requirements. As ALARA is the guiding principle, consider 2D if two planar orthogonal kV images are sufficient for the task.

The organ doses from image guidance can be reduced by a factor of 10 using 2D kV imaging compared to 3D kV-CBCT.26 (f) Optimize imaging parameters (e.g., kVp, mAs) and select appropriate manufacturer-provided default clinical protocols (pelvis, abdomen, thorax, head and neck) for different normal adult body sites. In the case of pediatric patients with a small body size, default low-dose protocols for a head and neck kV-CBCT scan can be used to image a pelvic site. This reduces imaging dose by a factor of 2–3 without compromising the image quality.29 (g) The kV-CBCT scan protocols that use partial rotation provide the opportunity to selectively avoid irradiating superficial organs. Partial rotation during a head scan can be used to dramatically reduce the dose to the eyes.29 The technique can also be applied to reduce dose to the bladder or rectum for kV-CBCT scans. (h) Since the beam exit dose is only a few percent of the entry dose for kV x rays, the beam directions used for orthogonal planar images can be selected to minimize dose to critical organs.26 For a fixed orthogonal pair, consider not only 0 and 90 but also 180 and 90, 0 and 270, and 180 and 270 beam angles to minimize dose to organs at risk. (i) Consider the use of full bow tie filters when acquiring planar kV images. Bow tie filters can significantly reduce skin dose and dose to organs at risk. Always use the appropriate bow tie filter for kV-CBCT acquisition when manual placement of the filter is required, since failure to employ the filter increases the imaging dose by factors of 2–4.26 ACKNOWLEDGMENTS The members of this task group thank Greg Sharp (TISC Lead Reviewer), Ping Xia (TPC Lead Reviewer), Jeffrey Medical Physics, 0 (0), xxxx

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Siebers (External Lead Reviewer), Jeff Colvin, and Sonja Dieterich for their very helpful comments and suggestions.

We thank Gig Mageras and Debra Brinkmann for their helpful guidance over the years in which this report was developed. We also thank the referees for their very helpful and constructive comments. We wish to acknowledge the support from AAPM TPC leadership and extend our thanks to the science editor for the professional proof reading of this report. Finally, we want to thank our consultants: Walter Bosch, Jun Deng, Choonsik Lee, Peter Munro and Ying Xiao for their invaluable contributions to this report. a)

Author to whom correspondence should be addressed. Electronic mail: george.ding@vanderbilt.edu.

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Hsu et al. Radiation Oncology (2017) 12:155 DOI 10.1186/s13014-017-0890-0

Dosimetric comparison of different treatment modalities for stereotactic radiotherapy

RESEARCH

Open Access

Dosimetric comparison of different treatment modalities for stereotactic radiotherapy Shih-Ming Hsu1,2,3*, Yuan-Chun Lai1,4,5, Chien-Chung Jeng4 and Chia-Ying Tseng1,2 Abstract Background: The modalities for performing stereotactic radiotherapy (SRT) on the brain include the cone-based linear accelerator (linac), the flattening filter-free (FFF) volumetric modulated arc therapy (VMAT) linac, and tomotherapy. In this study, the cone-based linac, FFF-VMAT linac, and tomotherapy modalities were evaluated by measuring the differences in doses delivered during brain SRT and experimentally assessing the accuracy of the output radiation doses through clinical measurements.

Methods: We employed a homemade acrylic dosimetry phantom representing the head, within which a thermoluminescent dosimeter (TLD) and radiochromic EBT3 film were installed. Using the conformity/gradient index (CGI) and Paddick methods, the quality of the doses delivered by the various SRT modalities was evaluated. The quality indicators included the uniformity, conformity, and gradient indices. TLDs and EBT3 films were used to experimentally assess the accuracy of the SRT dose output.

Results: The dose homogeneity indices of all the treatment modalities were lower than 1.25. The cone-based linac had the best conformity for all tumors, regardless of the tumor location and size, followed by the FFF-VMAT linac; tomography was the worst-performing treatment modality in this regard. The cone-based linac had the best gradient, regardless of the tumor location and size, whereas the FFF-VMAT linac had a better gradient than tomotherapy for a large tumor diameter (28 mm). The TLD and EBT3 measurements of the dose at the center of tumors indicated that the average difference between the measurements and the calculated dose was generally less than 4%. When the 3% 3-mm gamma passing rate metric was used, the average passing rates of all three treatment modalities exceeded 98%.

Conclusions: Regarding the dose, the cone-based linac had the best conformity and steepest dose gradient for tumors of different sizes and distances from the brainstem. The results of this study suggest that SRT should be performed using the cone-based linac on tumors that require treatment plans with a steep dose gradient, even as the tumor is slightly irregular, we should also consider using a high dose gradient of the cone base to treat and protect the normal tissue. If normal tissues require special protection exist at positions that are superior or inferior to the tumor, we can consider using tomotherapy or Cone base with couch at 0° for treatment.

Keywords: Linac, Stereotactic radiotherapy, Tomotherapy, Treatment planning systems, VMAT

* Correspondence: smhsu@ym.edu.tw 1 Medical Physics and Radiation Measurements Laboratory, National Yang-Ming University, Taipei, Taiwan, ROC 2 Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, No. 155, Sec. 2, Li-Nong St., Beitou District, Taipei 112, Taiwan, ROC Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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Background Stereotactic radiosurgery (SRS) can be used to treat arteriovenous malformation, glioblastoma multiforme, and various metastasized tumors in the brain. Because lesions that are treated using SRS tend to be very small, and the method in which the doses are delivered differs from the traditional multi-fractionated dose-delivery mode, the required radiation in SRS is usually delivered in a single dose. In stereotactic radiotherapy (SRT), the required dose is fractionated into multiple doses. Because each of the doses in a single SRT or SRS treatment is extremely large, a high accuracy is necessary for the treatments, as well as a very steep dose gradient, to ensure the tumor is given a sufficiently high dose while the surrounding normal tissues are protected and left unharmed [1]. In recent years, advancements in linear accelerator (linac) based technologies, including developments in image-guidance systems, multileaf collimators (MLCs), and volumetric-modulated arc therapy (VMAT), have led to linac-based treatments that can achieve a high accuracy, steep gradients, and a high level of conformity [2–9].

Traditionally, the Gamma Knife has been the primary tool for performing brain SRS or SRT. However, the sites without this facility instead utilize tomotherapy and MLC or cone-based linac devices to perform SRT therapy. Tomotherapy has a linac mounted on a ring gantry, and a binary MLC is used to adjust the dose of the photon-beam irradiation in sync with the forward motion of the treatment couch, resulting in a helical and tomographic form of intensity modulated radiotherapy (TomoHelical IMRT). Linear accelerators may use either an MLC or a cone to shape and limit the field of radiation. Recent developments in flattening filter-free (FFF) high-dose models have led to a further reduction in the probability of patient movement, thus reducing the effects caused by patient movement. This has enabled the FFF-VMAT linac treatment modality to become a viable tool for performing SRT. Different treatment modalities have different output dose characteristics, which may affect the radiation doses received by normal tissues surrounding the tumor [10–12]. Therefore, the main goal of this study is to compare the SRT treatment doses of the cone-based linac, FFF-VMAT linac, and tomotherapy treatment modalities and evaluate the differences between doses calculated according to treatment planning systems and measured radiation doses.

Methods Design of dosimetry phantom

A homemade acrylic phantom of the head was created according to computed-tomography (CT) images of patients. EBT3 radiochromic films (Ashland, USA) and the cubic thermoluminescent dosimeters (Thermo,

Page 2 of 11

USA) were installed within the coronal slices to measure the distribution of the radiation doses. In the region where the tumor was located the slices were 2 mm thick; the thickness of the remaining slices was 5 mm, as shown in Fig. 1.

Treatment planning

CT (LightSpeed GE, USA) was applied to obtain images of the phantom, and the thickness of each CT slice was 1.25 mm. The images were sent to a tomotherapy treatment planning system (TomoTherapy Planning Station Hi-ART® version 4.3.2 Accuray, USA) and a Pinnacle treatment planning system (Pinnacle3® Version 9.8 Philips, USA). The TomoTherapy system designed all the planning related to tomotherapy, and the Pinnacle system designed all the planning for the cone-based and FFF-VMAT linacs. All necessary beam data were entered into the Pinnacle system, and commission tests were completed for this system. A structure with a diameter of 3 cm was placed on the CT images to simulate the location of the brainstem. To match the size of the collimating cone, spherical tumors 8, 18, and 28 mm in diameter were placed at distances of 1 and 6 mm from the borders of the brainstem, as shown in Fig. 2. The use of spherical tumors is expected to exclude the effects of tumor shapes in order to purely assess the differences in different modalities.

Different treatment plans were designed by the treatment planning systems according to the size of the tumors. To exclude the effects of the beam angle, all the cone-based linac and FFF-VMAT linac plans used the arc-therapy method and the same beam angles, as shown in Fig. 3. The beam angles were as follows: counterclockwise from 179° to 345° with a collimator angle of 0° and a couch angle of 0°, counter-clockwise from 210° to 180° with a collimator angle of 10° and a couch angle of 0°, counter-clockwise from 179° to 0° with a collimator angle of 330° and a couch angle of 330°, counterclockwise from 179° to 0° with a collimator angle of 310° and a couch angle of 300°, counter-clockwise from 179° to 0° with a collimator angle of 260° and a couch angle of 270°, and clockwise from 180° to 0° with a collimator angle of 250° and a couch angle of 60°.

The accelerator used for the cone-based linac was a 6MV Elekta Synergy (Sweden) photon. Cone diameters of 10, 20, and 30 mm were used. The accelerator used for the FFF-VMAT linac was a 6-MV FFF Elekta Axesse (Sweden) photon beam and was used in conjunction with a 5 mm wide Elekta Agility high-speed MLC. The following parameters were used for the TomoTherapy system (Accuray, USA): modulation factor of 3.0, field width of 1 cm, pitch of 0.086.

All treatment planning were planned by the same planner. In all treatment plans, a dose of 600 cGy was

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Fig. 1 Homemade acrylic dosimetry phantom of the head: (a) coronal slices and fixing rods, (b) head phantom formed from all of the coronal slices, and (c) head phantom fixed by a mask

delivered to the tumors, and the conditions were optimized to maintain 98% dose coverage on the tumor, with the maximum tumor dose not exceeding 125% to minimize the doses incident on the brainstem and normal brain tissue. Maximum dose constrain of brainstem for tumor away from brainstem 1 mm and 6 mm were limited to 500 cGy and 200 cGy, respectively and D1% of these were limited to 150 cGy and 100 cGy, respectively.

Auxiliary ROIs such as “Ring” structure were also used to decrease the dose of normal tissue during planning.

The three-dimensional (3D) dose grid of the three axes of the Pinnacle system was set to 1 mm and that of the tomotherapy system was set to “fine”.

Analytic indicators of dose quality

The homogeneity index (HI) [13], conformity/gradient index (CGI), and Paddick indices were used to compare the quality of the treatment plans. The HI was used to describe the homogeneity of the dose within the tumor.

The HI is defined as HI ¼ MD=PD;

ð1Þ

where MD is the maximum dose within the tumor, and PD is the 100% prescription dose. The HI of a perfect

treatment plan is 1; if the 80% isodose curve is selected as the prescription dose, then the HI becomes 1.25 instead.

The CGI is a holistic index that consists of the conformity index (CGIc) and the gradient index (CGIg) [14].

The CGI is defined as

CGI ¼ CGI C þ CGI g =2

ð2Þ

The CGIc is used to describe the relationship between the volume of the tumor and the volume covered by the dose. The CGIc is defined as CGI C ¼

TV PIV

� 100

ð3Þ

PIV is the volume covered by the 100% prescription dose curve, and TV is the volume of the tumor.

CGIc = 100 corresponds to perfect conformity of the treatment planning. .

The CGIg is the effective difference in radius between the volumes covered by the 50% and 100% doses; it is used to evaluate the decrement of the dose in the highdose region (50% and above) and is defined as follows:

Fig. 2 CT images of the homemade acrylic dosimetry phantom of the head: (a) transverse view, (b) sagittal view, (c) coronal view (Red, the simulated brainstem; Green, tumor of 8 mm diameter and 1 mm away from brainstem; Blue, tumor of 8 mm diameter and 6 mm away from brainstem; Pink, tumor of 18 mm diameter and 1 mm away from brainstem; Dark-green, tumor of 18 mm diameter and 6 mm away from brainstem; Yellow-green, tumor of 28 mm diameter and 1 mm away from brainstem; Orange, tumor of 28 mm diameter and 6 mm away from brainstem.)

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represents the degree to which a tumor is covered by a specified isodose curve. For a perfect treatment plan, CIPaddick = 1.

The GIPaddick describes the decrement of the dose in the high-dose region (50% and above) and is defined as

GI Paddick ¼ V 50% V 100

where V50% is the volume covered by 50% of the prescription dose, and V100% is the volume covered by 100% of the prescription dose. The GIPaddick can represent the degree to which normal tissues outside the tumor are protected. A perfect treatment plan must have a value of the GIPaddick that approaches 1.

Fig. 3 All the beam angles used by the Pinnacle treatment planning system

� �� � �� CGI g ¼ 100− 100 � Reff ;50%Rx −Reff ;Rx −0:3cm

Radiation dose measurements

ð4Þ

Reff , Rx refers to the effective radius of the volume covered by the 100% prescription dose curve, and Reff , 50 % Rx is the effective radius of the volume covered by the 50% prescription dose curve, with Reff defined as rffiffiffiffiffiffiffi 3 3V ð5Þ Reff ¼ 4π V is the volume covered by the required dose. This 3 mm in distance between Reff , 50 % Rx and Reff , Rx gradient was obtained empirically from clinical radiosurgery planning cases, and corresponds to the possible gradient with linac radiosurgery when using multiple noncoplanar arcs. As CGIg more than 100, it corresponds to less gradient than an optimum 3 mm empirically..

The Paddick indices are clinically used to describe the conformity [15] and gradient [16] of the treatment plan.

The Paddick indices include the conformity index (CIPaddick) and the gradient index (GIPaddick). As the CGIc is unable to present the degree of tumor-volume coverage for a specified prescription dose curve, the CIPaddick complements the CGIc by describing the volume covered by the prescription dose as well as the relationship between the tumor volume covered by the prescription dose and the overall volume of the tumor.

The CIPaddick is defined as CIPaddick ¼

ðTV PIV Þ2 TV � PIV

ð7Þ

ð6Þ

where PIV refers to the volume covered by the 100% prescription dose curve, TV is the tumor volume, and TVPIV is the tumor volume covered by PIV. This index

In this work, cubic TLD-100 dosimeters and EBT3 films were used to measure the radiation dose [17–22], with the dose at each tumor location measured three times.

Each cone-based linac and FFF-VMAT linac measurement was accompanied by alignment using the six degree-of-freedom image-guided cone-beam CT of the accelerator. MVCT was used to align the tomotherapy measurements to correct for 3D position shifts and rollangle deviations in the rotating gantry. FILM QATM Version 2.2 was used to evaluate the profile changes in the right–left (R–L) and superior–inferior (S–I) directions, and gamma evaluation was used to determine the differences between the calculated dose of the treatment plan and the two-dimensional planar dose measured by the EBT3 films. Because SRT treatments characteristically require a high level of positional accuracy and a steep gradient, the 3% 3-mm and 5% 1-mm criteria were chosen as the gamma passing rate metrics for assessing the differences in the planar doses.

Statistical analysis

The Mann–Whitney test (Statistical Package for the Social Sciences, IBM Corporation, New York, USA) was used to assess the statistical significance of the gamma analysis results for the different techniques.

Results Dose-quality analysis

The results of the cone-based linac, FFF-VMAT linac, and tomotherapy dose-quality analyses are shown in Table 1. The average HI values of the cone-based linac, the FFF-VMAT linac, and tomotherapy were 1.20 ± 0.03, 1.21 ± 0.03, and 1.23 ± 0.02, respectively. As it was strictly specified that the maximum dose on the tumors did not exceed the 125% of the prescription dose during the creation of the treatment plans, none of the average HIs of the treatment plans exceeded 1.25. The lowest HI

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Table 1 HI, CGI, and Paddick indices calculated by the treatment planning system using the cone-based linac, FFF-VMAT linac, and tomotherapy treatment modalities Tumor Diameter

8 mm

18 mm

Distance 1 mm from brainstem Modality

6 mm

28 mm

1 mm

6 mm

1 mm

6 mm

Cone- FFF- Tomo Cone- FFF- Tomo Cone- FFF- Tomo Cone- FFF- Tomo Cone- FFF- Tomo Cone- FFF- Tomo based VMAT based VMAT based VMAT based VMAT based VMAT based VMAT

HI

1.24

1.25

1.20

CGIc

84.59

48.89

47.96 86.25

1.23

1.25

1.23

67.93

46.79 92.02

1.20

1.19

1.25

75.66

69.75 95.35

1.20

1.17

1.24

73.99

67.76 98.99

1.17

1.23

1.21

95.44

86.04 99.84

1.16

1.19

1.23

92.27

86.68

CGIg

103.25 66.45

74.39 103.15 74.30

75.96 88.43

60.53

60.61 89.33

59.71

62.68 74.02

52.79

48.02 75.26

61.62

50.49

CGI

93.92

57.67

61.18 94.71

71.11

61.38 90.23

68.10

65.18 92.34

66.85

62.22 86.50

74.11

67.03 87.55

76.95

68.58

CIPaddick

0.82

0.48

0.47

0.84

0.66

0.45

0.90

0.73

0.68

0.92

0.72

0.66

0.94

0.92

0.84

0.95

0.88

0.81

GI Paddick

4.23

10.97

9.07

4.28

10.58

8.57

3.02

4.90

4.83

3.00

4.93

4.62

2.73

3.67

4.14

2.69

3.21

3.90

(1.16) was observed when the cone-based linac was used to treat 28 mm diameter tumors that were located 6 mm from the brainstem.

The average CGI values for the cone-based linac, the FFF-VMAT linac, and tomotherapy were 90.88 ± 3.37, 69.13 ± 6.74, and 64.26 ± 3.13, respectively. In general, the FFF-VMAT linac had higher CGI values than tomotherapy except for tumors with small distance from the brainstem. The average CGIc values for the conebased linac, the FFF-VMAT linac, and tomotherapy were 92.84 ± 6.41, 75.70 ± 17.01, and 67.50 ± 17.48, respectively. For all distances from the brainstem and tumor diameters, the cone-based linac exhibited the highest CGIc values, followed by the FFF-VMAT linac, and finally tomotherapy.

The average CGIg values for the cone-based linac, the FFF-VMAT linac, and tomotherapy were 88.91 ± 12.78, 62.57 ± 7.23, and 62.03 ± 11.65, respectively. The FFF-VMAT linac had higher CGIg values than tomotherapy for large-diameter tumors (28 mm), with ratios of 52.79: 48.02 and 61.62: 50.49 for distances of 1 and 6 mm from the brainstem, respectively. The average CIPaddick for the cone-based linac, the FFF-VMAT linac, and tomotherapy were 0.90 ± 0.05, 0.73 ± 0.16, and 0.65 ± 0.16, respectively.

Regardless of the tumor diameter and distance from the brainstem, the cone-based linac exhibited the best CIPaddick values, followed by the FFF-VMAT linac, and finally tomotherapy. The GIPaddick value of the FFF-VMAT linac for large-diameter tumors (28 mm) was better than that of tomotherapy, with ratios of 3.67: 4.14 and 3.21: 3.90 for distances of 1 and 6 mm from the brainstem. However, tomotherapy had better GIPaddick values than the FFF-VMAT linac for smaller-diameter tumors (8 mm), with ratios of 9.07: 10.97 and 8.57: 10.58 for distances of 1 and 6 mm from the brainstem, respectively.

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Dose measurements

The dose-linearity curves of TLD and EBT3 (0–800 cGy) are shown in Fig. 4. The radiation doses at the center of the tumors within the phantom were clinically measured and compared with the dose calculated in the treatment plan; the differences are shown in Table 2. The TLD and EBT3 dose measurements indicated that the average differences between the output doses of the cone-based linac, the FFF-VMAT linac, and tomotherapy and the calculated doses of the treatment plans were generally lower than 4%. The largest observed difference was −3.68% (−4.52% to −3.27%) for the cone-based linac and was measured using the EBT3 film.

Figure 5 shows the dose profile measured using EBT3 films for tumors locaed 1 mm from the brainstem in the R–L and S–I directions. The results of the measurement using the EBT3 film are generally consistent with calculations of the treatment plan. The average dose profile widths of the 50% and 30% doses relative to the dose at the center of the tumor for tumors of various sizes are shown in Fig. 6. The 30% profile widths of the FFFVMAT linac were smaller than those of tomotherapy for all tumor volumes because the gantry rotated in a coplanar fashion, synchronized with the movement of the treatment couch, during the tomotherapy treatments to enable irradiation of the tumor. Because the R–L direction lies within the beam pathway, the distribution of low-intensity doses in the R–L direction was broadened.

The gamma passing rates of the three treatment modalities under two different gamma passing criteria are shown in Fig. 7. When the 3% 3-mm criteria was used as the passing metric, the passing rates for the conebased linac, the FFF-VMAT linac, and tomotherapy were 99.28 ± 1.36%, 98.71 ± 1.39%, and 99.98 ± 0.18%, respectively. Among these, tomotherapy had the highest passing rate (p < 0.05), and there was no statistically significant difference between the passing rates for the

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Fig. 4 Dose-linearity curves for 6 MV: (a) TLD and (b) EBT3

cone-based and FFF-VMAT linacs (p = 0.235). Considering that SRT treatments characteristically require a high level of positional accuracy and steep dose gradients, the treatment modalities were also evaluated using the 5% 1-mm criteria as the passing metric. In this case, the passing rates for the cone-based linac, the FFF-VMAT linac, and tomotherapy were 97.73 ± 2.42%, 93.53 ± 3.82%, and 98.19 ± 2.09%, respectively. Among these, the FFF-VMAT linac had the lowest passing rate (p < 0.01), and there was no significant difference between the passing rates for the cone-based linac and tomotherapy (p = 0.46).

The gamma evaluation maps of 28 mm diameter tumors located 1 mm from the brainstem using the 3% 3mm and 5% 1-mm criteria were analyzed, as shown in Fig. 8. Here, changing the passing metric caused an increase in the failed areas in regions with steep doses at the borders of the tumor for the cone-based and FFFVMAT linac modalities. The cone-based linac and tomotherapy retained a gamma passing rate of 95% and above, whereas the passing rate of the FFF-VMAT linac decreased below 95%.

Discussion The result of this study show that the average HI for the cone-based linac was lower than those for the FFFVMAT linac and tomotherapy because of the radiation of the cone-based linac was homogeneous. As a result of no dose-intensity control within the radiation field of

cone-based linac, there were no significant changes for a cone treatment at a distance difference of only 5 mm distance to brainstem.

Because the radiation field of the cone-based linac was similar to the size of the tumors, this modality yielded the highest CGIc and CIPaddick. Unlike the cone-based linac, tomotherapy uses a constant jaw size, leading to a “ramp-up” effect, which causes normal tissues surrounding the tumor in the S–I direction to receive a higher dose [23].

The use of a cone in the cone-based linac minimized the dose divergence, resulting in the cone-based linac having the best CGIg and GIPaddick among the three treatment modalities. When the tumor volume was very small, the jaw used in tomotherapy limited the dispersion range of the low-dose region, causing the CGIg to be higher than that for the FFF-VMAT linac. As the tumor volume increased, the dose on the brainstem increased.

The research of Yip et al. [12] indicated that, regardless of the conformity and gradient, the cone-based linac performed better than tomotherapy for tumors with a regular shape; this finding is consistent with our results.

However, Soisson et al. [24] reported that excellent levels of tumor conformity were achieved using tomotherapy.

Nevertheless, we obtained a similar result with respect to the overall evaluation of the CGI. Soisson et al. did not provide a detailed comparison between the doses of the FFF-VMAT linac and tomotherapy for SRT, whereas

Table 2 Average difference in the dose at the center of tumors between the calculated doses from the treatment planning system and the doses measured using TLD and EBT3 for the cone-based linac, the FFF-VMAT linac, and tomotherapy Dosimeter

Cone-based linac

FFF-VMAT linac

Tomotherapy

TLD (%)

−1.38 (−4.08 to 0.81)

−1.34 (−4.96 to 4.04)

1.05 (−2.10 to 3.65)

EBT3 (%)

−3.68 (−4.52 to −3.27)

−1.75 (−4.70 to 2.52)

−1.02 (−3.72 to 0.58)

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Fig. 5 Differences of EBT3-measured and treatment plan-calculated profiles (normalized to the dose of tumor center) in the R–L and S–I directions for tumors located 1 mm from the brainstem with diameters of (a) 8 mm, (b) 18 mm, and (c) 28 mm

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Fig. 6 Average dose profile widths of doses that are 50% and 30% of the dose at the center of the tumor, measured using EBT3 films, in the (a) R–L direction and (b) S–I direction

we showed that, regardless of the tumor size and distance from the brainstem, the conformity of the FFFVMAT linac was always better than that of tomotherapy.

The FFF-VMAT linac also had a steeper gradient than tomotherapy for larger tumors, whereas tomotherapy exhibited a steeper gradient for smaller tumors.

It will result in the dose accumulation to the borders of 18 mm and 28 mm diameter PTV located 1 mm from brainstem if we try to lower the dose of brainstem for FFF-VMAT linac and tomotherapy with intensity modulated field. In this situation, if we take into account the tumor coverage, it may increase the dose closed to the borders of PTV. For cone-based linac without intensity modulated field, the dose in the PTV will be more uniform and the dose of brainstem will be reduced because of high dose gradient. According to the AAPM TG-142

report, a deviation of 1 mm is allowed in the rotational center of the couch and gantry of the linear accelerator used for SRS or SRT, and the repeatability of the MLC is required [25]. These deviations could have affected the gamma analysis results for regions with a steep dose gradient. O’Connor et al. [26] reported that errors in the position of the MLC significantly affected the results of gamma analysis; for example, with the 3% 1-mm criteria as the gamma analysis passing metric, a 0.8 mm deviation in the position of the MLC reduced the gamma passing rates of square-field rotating beams with field sizes of 16 and 40 mm by 5.7% and 4.5%, respectively. In the continuous delivery of VMAT, the position of MLC at each control point must match the gantry’s speed and dose rate, and the MLC position in this continuous process will also be affected by gravity and the speed of

Fig. 7 Gamma passing rates of the three treatment modalities under two different gamma passing criteria: Criteria 1: 3% 3-mm and Criteria 2: 5% 1-mm

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Fig. 8 Gamma-evaluation maps of the three different treatment modalities evaluated using two different gamma passing criteria (the red circle indicates the area of the 28 mm tumor that is located 1 mm from the brainstem): (a) 3% 3-mm and (b) 5% 1-mm

MLC. Since the setting of MLC’s tolerance table in machine’s setting is 1 mm, it means that the machine will keep delivery as the MLC position error is less than 1 mm at each control point in the process of delivery, and that the 1 mm tolerance may affect the measurement results, especially in the small field and high-dose gradient regions [27, 28]. Therefore the more mechanical error variable, the more likely to affect the Gamma pass rate.

The treatment time of each technique is also the focus of our concern. In our study, the longest treatment time required for the cone-based linac, FFF-VMAT linac and Tomotherapy were 830, 679 and 728 s, respectively. The above time did not include the time of image registration and confirmation. For cone-based linac and FFF-VMAT linac techniques using the non-coplanar angles, the number of beams that need to rotate the angle of the couch which can affects the time required for treatment.

Conclusion As a result of the use of spherical tumors, we could not be affected by the shape of the tumor and clearly understand the differences of the dose characteristics between three modalities. Among the three treatment modalities studied, the cone-based linac had the best conformity

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and dose gradient for tumors of all sizes and locations.

According to our results, if a critical organ, such as the brainstem, is located near the tumor and the situation requires a steep dose gradient, the cone-based linac should be used for SRT therapy. Since the steep dose gradient of the cone-based linac is obvious, we should also consider using a high dose gradient of the cone base to treat slightly irregular tumor and protect the critical organs or normal brain. The dose conformity of the FFF-VMAT linac for tumors of all sizes and positions was better than that of tomotherapy. The dose gradient of the FFF-VMAT linac for large tumors (28 mm in diameter) was better than that of tomotherapy, whereas tomotherapy had a better dose gradient than the FFFVMAT linac for small tumors (8 mm in diameter). The cone-based linac had the smallest 50% and 30% dose profile widths in the R–L and S–I directions among the three modalities, with the exception of the 30% dose profile width for 28 mm tumors in the S–I direction, where tomotherapy and the cone-based linac produced similar results. On one hand, the 30% dose profile widths of the FFF-VMAT linac in the R–L direction for all tumor volumes were smaller than those of tomotherapy. Therefore, for protecting normal tissues located superior and inferior to the tumor, we can consider using

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tomotherapy or Cone base with couch at 0 ° for treatment. The TLD and EBT3 measurement results indicate that all three SRT treatment modalities achieved accurate doses. However, the FFF-VMAT and cone-based linacs may have produced dose deviations in regions with steep gradients on the borders of the tumor because of the effects of mechanical factors.

Abbreviations 3D: Three-dimensional; CGI: Conformity/gradient index; CGIc: Conformity index; CGIg: Gradient index; CIPaddick: Paddick conformity index; CT: Computed-tomography; FFF: Flattening filter-free; GIPaddick: Paddick gradient index; HI: Homogeneity index; Linac: Linear accelerator; MLCs: Multileaf collimators; R–L: Right–left; S–I: Superior–inferior; SRS: Stereotactic radiosurgery; SRT: Stereotactic radiotherapy; TLD: Thermoluminescent dosimeter; VMAT: Volumetric modulated arc therapy

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Acknowledgements Not applicable.

10.

Funding This study was supported in part by the Ministry of Science and Technology of Taiwan (MOST 104-2314-B-010-040-MY3 and MOST 106-NU-E-010-001-NU).

11.

Availability of data and materials All data generated or analysed during this study are included in this published article.

Authors’ contributions SMH and YCL designed the project. SMH,YCL, CCJ and CYT contributed to acquisition of data and data analysis. SMH,YCL and CCJ contributed to methodology of the process. SMH was the Senior Author who oversaw the project. All authors read and approved the final manuscript.

Ethics approval and consent to participate Not applicable.

Consent for publication Not applicable.

Competing interests The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Author details 1 Medical Physics and Radiation Measurements Laboratory, National Yang-Ming University, Taipei, Taiwan, ROC. 2Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, No. 155, Sec. 2, Li-Nong St., Beitou District, Taipei 112, Taiwan, ROC. 3Biophotonics and Molecular Imaging Research Center, National Yang-Ming University, Taipei, Taiwan, ROC. 4Department of Physics, National Chung Hsing University, Taichung, Taiwan, ROC. 5Department of Radiation Oncology, Changhua Christian Hospital, Changhua, Taiwan, ROC.

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Received: 20 April 2017 Accepted: 7 September 2017 23.

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Shaw E, Scott C, Souhami L, Dinapoli R, Bahary JP, Kline R, et al. Radiosurgery for the treatment of previously irradiated recurrent primary brain tumors and brain metastases: Initial report of Radiation Therapy Oncology Group Protocol 90-05. Int J Radiat Oncol Biol Phys. 1996;34:647–54.

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A Feasibility Study on the Use of TomoTherapy Megavoltage Computed Tomography Images for Palliative Patient Treatment Planning

A feasibility study on the use of TomoTherapy megavoltage computed Tomograpy images for palliative Patient tratment planning

J Med Phys. 2017 Jul-Sep; 42(3): 163–170. doi: 10.4103/jmp.JMP_32_17: 10.4103/jmp.JMP_32_17

PMCID: PMC5618464 PMID: 28974863

A Feasibility Study on the Use of TomoTherapy Megavoltage Computed Tomography Images for Palliative Patient Treatment Planning Yunfei Hu,1 Mikel Byrne,2 Ben Archibald-Heeren,2 Matthew Squires,1 Amy Teh,1,2 Kylie Seiffert,1 Sonja Cheers,1 and Yang Wang2 1Radiation Oncology Centres, Gosford, NSW, Australia 2Radiation Oncology Centres, Wahroonga, NSW, Australia

Address for correspondence: Dr. Yunfei Hu, ROC Gosford, 41 William St., Gosford 2250, NSW, Australia. Email: yunfei.hu@roc.team Received 2017 Mar 1; Revised 2017 Jun 12; Accepted 2017 Jun 14.

Copyright : © 2017 Journal of Medical Physics This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercialShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

Abstract Dedicated rapid access palliative radiation therapy improves patients’ access to care, allowing more timely treatment which would positively impact on quality of life. The TomoTherapy (Accuray, Sunnyvale, CA) system provides megavoltage (MV) fan-beam computed tomography (FBCT) as the image guidance technique, and a module called “statRT” that allows the use of these MV FBCT images for direct planning.

The possibility of using this imaging modality for palliative radiotherapy treatment planning is assessed against accepted planning CT standards by performing tests following AAPM TG 66 and an end-to-end measurement. Results have shown that MV FBCT images acquired by TomoTherapy are of sufficient quality for the purpose of target delineation and dose calculation for palliative treatments. Large image noise and extended scan acquisition time are the two main drawbacks, so this imaging modality should only be used for palliative treatments at areas with well-known, easily distinguishable, and relatively immobile targets such as spine and whole brain.

Keywords: Imaging, megavoltage computed tomography, palliative radiotherapy, TomoTherapy

INTRODUCTION Most cancer patients will require radiation therapy at some stage during their disease. Among all radiation treatments, 30%–50% of treatments are palliative.[1,2] For palliative treatments, radiation therapy is a locally effective tool, with little to no systemic side effects and mostly mild acute side effects.

Furthermore, radiotherapy is important for oncological emergency procedures, such as treatment of obstructions, tumor bleeding, and spinal cord compression.[1] Dedicated rapid access palliative radiation therapy improves patients’ access to care and quality of life.[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618464/?report=printable

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TomoTherapy is a ring gantry-based radiotherapy treatment system that is also capable of producing highquality megavoltage fan-beam computed tomography (MV FBCT) images for setup verification.

TomoTherapy have created a module called “statRT (Accuray, Sunnyvale, CA)” that allows these MV CT images to be used for treatment planning. This module has the benefit of allowing simulation, treatment planning, and treatment to be carried out in a single-visit taking <1 h in total,[4] which in turn minimizes the time to treatment and movement required by patients, which is particularly beneficial for urgent palliative patients who are typically in considerable pain. In fact if patient-specific quality assurance (QA) is performed using calculation based methods, and sufficient time is available on the machine, the simulation, and treatment can actually be performed in a single setup rather than move the patient off the bed for the time required for planning[4] and later put him/her back on the bed. Thus far, research has focused on whether the statRT functionality gives comparable plans to the conventional planning method.

[4,5,6] However, relatively little research has systematically verified the image quality of MV CT images against accepted planning CT standards (AAPM TG 66),[7] particularly since the significant changes to the image reconstruction algorithm introduced in the TomoTherapy HDA system (H series v2.0, Accuray, Sunnyvale, CA).

The MV CT on TomoTherapy is a spiral CT using 3.5 MV X-rays from the therapeutic linear accelerator and detected with a xenon gas ion chamber array. The MV CT uses a 512 × 512 matrix in a field of view (FOV) of 40 cm resulting in a pixel resolution of 0.78 mm. Fine, normal or coarse slice thicknesses can be selected, which correspond to a couch travel speed of 4, 8, and 12 mm per rotation during imaging.[8] Depending on the selected slice thickness, a reconstruction interval of 1 or 2 mm for fine slices, 2 or 4 mm for normal slices, or 3 or 6 mm for coarse slices can be selected. Time required for one rotation during the CT scan is 10 s.[9] Compared to MV cone beam CT (MV CBCT), MV FBCT uses a thin fan-beam instead of a wide cone beam and acquires images slice by slice. It provides the advantage that scattered X-rays do not contribute as significantly as in MV CBCT and thus results in better image quality.[10] It has been reported that there is a linear relationship between MV FBCT Hounsfield Unit (HU) and the electron density (ED) of materials imaged on TomoTherapy and that the MV CT HU are quite stable, such that the dosimetric end-points vary by <2.0% with various MV CT acquisition parameters.[11,12] The typical imaging dose to patient per acquisition is about 1–2 cGy when a normal pitch with a 2 mm reconstruction interval is selected.[13] Some clinics use TomoTherapy MV CT directly for planning when high-atomic number materials, such as dental fillings or bilateral hip replacement are in the proximity of the PTV which can cause severe imaging artifacts in kV CT scans.[9,10] The aim of this study is to assess the quality of the MV CT images provided by TomoTherapy against accepted planning CT standards to see if MV CT can be used directly for planning with the statRT module, so that radiotherapy patients’ simulation, planning, and first-day treatment can be completed all in one visit on the TomoTherapy Unit, allowing the patients to have accurate, and yet rapid-access palliative radiotherapy treatment to improve their quality of life.

MATERIALS

AND

METHODS

A well-established CT simulation process should be able to provide spatial information for patient positioning and immobilization as well as anatomical information for contouring and dose calculation. If TomoTherapy MV FBCT was to be used for dose calculation, then it can be argued that the same scope of QA tests that apply to a kV CT scanner should be applied to TomoTherapy. AAPM TG 66[7] has a recommended list for CT QA. As for TomoTherapy, the imaging system and the treatment delivery system share the same gantry and laser systems. Some of the listed check items are already included in the linear accelerator's regular QA programs, such as QA on couch motion and gantry rotation. Apart from these tests, the following QA measures were added to test TomoTherapy's capacity for radiation therapy planning. Those QA tests were also repeated on the kV CT scanner currently used for clinical planning to provide a reference for comparison. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618464/?report=printable

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In this study, all kV CT scans were acquired on a GE Discovery PET-CT scanner (GE Healthcare, Little Chalfont, United Kingdom) with 120 kV X-ray at 440 mA and a reconstruction interval of 2.5 mm at a large FOV. All MV CT scans were acquired on TomoTherapy HDA v2.0 with 3.5 MV X-ray and normal slice thickness and a reconstruction interval of 2.0 mm at an FOV of 40 cm.

Alignment of wall lasers with respect to the imaging plane TomoTherapy does not have a gantry laser system and only uses a wall-mounted laser system. Its alignment and orientation with respect to the imaging plane must be checked. In this test, the TomoTherapy phantom, or “cheese” phantom, was used. The geometric center of the phantom was aligned to the lasers and then scanned using the MV CT system. The position of the scanned center of the phantom was then compared to the imaging center as indicated by the software to ensure laser-imaging coincidence.

Geometric accuracy The geometric accuracy of the system was tested by checking the distance between two known points on a phantom. In this test, the CATPHAN 500 imaging phantom (The Phantom Laboratory, Greenwich, New York, USA), whose three dimensions were physically measured, was used. The phantom was scanned on both kV CT and MV CT, with the three dimensions of the scanned phantom measured and compared to the physically measured values. The difference was expected to be within 1.0 mm.[14] Field uniformity and image noise The field uniformity and image noise were assessed by measuring the CT numbers of a region of homogenous material using the uniformity section of the CATPHAN. The imaging uniformity section in CATPHAN was cast from a uniform material. The material's CT number was designed to be within 2% of water density at standard scanning protocols. After the phantom was scanned, a cylindrical structure of 5 cm radius and 2 cm length was created at the center of the uniformity module, whose average, minimum, and maximum HU values were then provided by the radiotherapy planning system (RTPS). Using the range rule of thumb, the standard deviation (SD) of the structure can then be estimated from the minimum and the maximum HU as: SD ≈ (Maximum – Minimum)/4 The average and the SD HU were then used to assess the field uniformity and the noise of both systems.

The SD was estimated because it was not given by the RTPS and would take the authors too long to manually collect enough sample data to calculate it.

Spatial resolution The spatial resolution of both imaging systems was assessed using the image resolution section in CATPHAN. This section of the CATPHAN contained a 1 through 21 line-pair per centimeter highresolution test gauge and two impulse sources which were cast into a uniform material. The number of visible pairs of lines was recorded for each imaging system to compare the resolution.

Electron/mass density to computed tomography number conversion and computed tomography number constancy TomoTherapy treatment planning system (TPS) converts CT number to mass density (MD) to calculate dose. A CT-ED phantom with density plugs of known physical densities was used to generate CT-MD tables for both systems. The resultant CT-MD curves for both imaging systems were compared to see if a linear relationship can be established between the CT number (in HU) and the MD (g/cm3) for dose calculation. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618464/?report=printable

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After the calibration curves were established, to ensure that the CT-MD calibration stayed valid for dose calculations, a simplified QA program, utilizing the TomoTherapy phantom, or the “cheese” phantom, was implemented. The cheese phantom, with a lung and a bone insert replacing the water inserts, was scanned on a regular basis. After scanning, the density of the lung, bone, and water inserts was recorded in the planning system and compared to the baseline data, whose difference was expected to be within 2.0%. The results for this constancy check would not be listed in this study.

End-to-end measurement and calculation constancy An end-to-end measurement provides a direct method to quantify the potential errors in the procedure. The end-to-end measurement should be designed such that it simulates real treatment. For this reason, the authors performed end-to-end tests in the Computerized Imaging Reference Systems (CIRS) upper thorax phantom, as it provides multiple measurement positions and areas of inhomogeneity. A calibrated farmer chamber was used for chamber measurement.

The CIRS thorax phantom was established according to the same setup used for Australian Clinical Dosimetry Service level III audits[15] as shown in Figures 1 and 2. The CIRS phantom was scanned both with the kV CT and the MV CT and saved as different QA phantoms in the TomoTherapy planning system for future calculations.

Araki reported that when a thin-walled cylindrical chamber was used for measurements in a heterogeneous phantom that includes solid water, lung, and bone plastic materials, for a 6 MV photon beam on a conventional linear accelerator, the perturbation factor introduced by the chamber due to the replacement of the air cavity, nonwater equivalence of the chamber wall, and the stem and nonair equivalence of the central electrode could be up to 2% and 3.5% for lung and bone, respectively, depending on the field size.

[16] This effect can be more significant for TomoTherapy because of the lack of electron equilibrium from the small segmented fields in TomoTherapy helical delivery mode. As a result, to reduce the chamber perturbation in the bone measurements, a water insert with chamber cavity was inserted in the bone cavity instead of the bone insert both in the measurement and in the TPS calculation. This is the same method applied in ARPANSA level III audits.[15] A total of three complex TomoTherapy helical plans were chosen whose 50% isodose distributions covered several chamber cavities so that multiple measurements at different points were possible. These plans were copied and recalculated on both the MV CT and the kV CT scanned CIRS phantom. Although scanned by different CT modalities, the exact same isocenter position was used when recalculating the plan.

As is shown in Figure 2, 10 measurement points were available in the phantom. Points 1–5 sit in a homogeneous water density. Points 6–9 sit in a homogeneous lung density. Point 10 sits in a water density but is surrounded by a bone ring representing spine. Due to its large cavity, the farmer chamber was deemed unsuitable for measurement at areas with high-dose gradient. For this reason, with each plan, only some points were chosen as chamber measurement points depending on where the dose distribution was relatively homogeneous.

The reading was converted to dose after corrections were applied. This dose reading was then compared to the predicted point doses calculated on the kV CT and the MV CT phantom.

As a routine check of the dose calculation constancy, a plan was recalculated on an MV CT utilizing the adaptive planning module provided by TomoTherapy. The cheese phantom was scanned on the MV CT, and a predesigned QA plan was then recomputed on the MV scan in the adaptive module, whose resultant dose distributions were compared to the original plan computed on the same phantom scanned by the kV

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CT. The difference was expected to be within 2.0%. This test was relatively simple and provided neither inhomogeneity calculations nor direct detector measurement, but was efficient in quickly checking the dose calculation constancy of the MV CT. Its results were not listed in this study.

RESULTS Alignment of wall lasers with respect to the imaging plane Table 1 lists the results of this part of the test.

Geometric accuracy Table 2 lists the results of this part of the test.

Field uniformity and image noise Table 3 lists the result for this part of the test.

Figures 3 and 4 show the screen capture of the CATPHAN uniformity section from both imaging systems.

Spatial resolution Table 4 lists the result for this part of the test.

Figures 5 and 6 show the screen capture of the CATPHAN image resolution section from both imaging systems.

Electron/mass density to CT number conversion Table 5 shows the results of CT-MD tables generated from the CT-ED phantom for kV CT and MV CT. Figure 7 shows the CT-MD curve for both imaging systems.

End-to-end measurements Table 6 lists the results for the end-to-end measurements.

DISCUSSIONS Alignment of wall lasers with respect to the imaging plane From Table 1, it is noted that TomoTherapy's laser system aligns well with the MV CT imaging system to within 1.0 mm. As such the laser system can be used as guidance for patient positioning during the initial image acquisition. This alignment is checked on a regular basis.

Geometric accuracy From Table 2, it is noted that the detected dimensions from both imaging systems are within 1.0 mm of the physical dimensions. It indicated that geometric dimensions can be determined accurately from both imaging systems. The difference from the MV CT system was slightly higher but was of no statistical significance given the image pixel size, as the P value, when calculated by the N-1 Chi-square test,[17] is more than 0.05 (0.0586). No obvious geometric distortions were observed from both image sets.

Field uniformity and image noise

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From the result in this section, it is noted that the average MD read from the kV CT was 1.007 g/cm3, and from MV CT was 0.995 g/cm3, converted from the average CT number calculated by the RTPS using the CT-MD table established in the MD to CT number conversion test. Both results were within ±1.0% of the expected MD of water (1.0 g.cm3). However, from the SD values as well as screen captures from Figures 4 and 5, it was noted that MV CT has a much larger noise compared to kV CT. MV CT tends to have a worse signal-to-noise ratio compared to kV CT for two main reasons: 1. In the MV CT range where Compton scattering dominates, most of the scattered photons produced travel forward at a small angle deviation from the incident photon and will likely be absorbed by the detector as noise. In contrast in kV CT range where the photoelectric effect is dominant, the photons are fully absorbed, and the ejected electrons are usually emitted at 90° to the incident photon and thus ignored by the detector;[18] and 2. The absorbed dose per photon emitted is much higher for MV than for kV and therefore to limit the imaging dose fewer photons are used in MV FBCT[14] compared to kV CT. Large image noise could make both automatic and manual anatomy delineation difficult. Intra-imaging motion from the patient would further increase the noise level.

Spatial resolution From the results in this section, it is noted that the image resolution provided by MV CT is poorer compared to that from a conventional CT scanner. The poor spatial resolution alone would not reduce accuracy in dose calculation, but it would introduce difficulties in the delineation of targets and critical structures. As nowadays volume-based optimization is widely used in many commercial radiation planning systems such as the TomoTherapy planning station, accurate identification, and delineation of both the targets and the organs-at-risk are critical for optimal plan outcome. They are also important in the evaluation of the plan quality. The poor spatial resolution would consequently be likely to downgrade the plan accuracy and the plan quality, especially for those plans that use volume-based optimization.

Electron/mass density to computed tomography number conversion From Figure 8, it was noted that for both kV CT and MV CT, the relationship between CT number and MD is linear, making it possible to establish a CT-MD curve for both scans to achieve dose calculation.

Both curves are similar for materials with density equal to or lower than water (1.0 g/cm3), but for materials with density higher than water, the difference between the curves is significant. Compared to kV CT, the part of the curve beyond water density from MV CT is sharper. This indicates that the MV CTs would have a poorer contrast compared to kV CT, as the CT number difference for materials of different densities is smaller and thus more difficult to distinguish visually. This is because in the MeV photon energy range used in MV FBCT, Compton scattering effect is predominant in attenuating the beams, which is almost independent of the atomic number Z of the material. In contrast, in the keV range used in kV CT, the predominant interaction is the photoelectric effect, whose attenuation is highly dependent on the atomic number Z of the material. As a result, while both kV and MV CT depend on electron densities, kV CT tends to display sharper contrast in the visualization of materials with differing atomic numbers. At the same time, this also means MV CT produces less artifact and image distortion when high atomic number material is present within the scan.[10] Note that this effect was not specifically due to materials having a density greater than water, but rather was because materials with density greater than water tend to have greater atomic number.

End-to-end measurements

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The average absolute difference for calculations based on kV CT images was 1.76%, with an absolute SD of ±1.30%. The average absolute difference for calculations based on MV CT images was 1.78%, with an absolute SD of ±0.87%. These results agree with what was reported in the previous studies.[11,12] From all the above results, it was noted that the largest problem with the MV FBCT was the large noise compared to kV CT, which resulted in uncertainties in target delineation. The noise could have larger impact on patients due to more complicated geometries and patient motion. MV CT also demonstrated a poorer spatial resolution and less contrast for materials of MD more than water, both of which would make accurate target delineation more difficult. As inverse planning optimization is fully based on structures, inaccuracy in target delineation can potentially degrade the plan quality. As a result, users should be cautious with the use of TomoTherapy MV CT as the primary image set in plans that use inverse planning technique.

The results also indicate that for TomoTherapy MV CT an accurate CT-MD curve can be established for dose calculation and point doses calculated on both MV CT and kV CT agree well with the measured values, despite its relatively poor image quality due to high noise, low contrast, and low spatial resolution.

The imaging system also provides accurate geometric measurements. As a consequence, the imaging system can be used for direct dose calculation in forward planning for areas with well-known structures, as long as proper commissioning tests are performed and proper QA systems are maintained.

As such one suitable application of TomoTherapy MV CT is palliative radiation therapy treatment planning, where structure delineation is primarily determined from bony anatomy, and larger margins can be justified. All test results have indicated that adequate geometric and dosimetric information can be provided by the MV CT alone for these types of treatment. The use of TomoTherapy MV CT for palliative planning allows patients to gain rapid access to palliative radiation therapy with minimal patient movement required. Consequently, patients’ access to quality care and an improved quality of life is made possible.[3,19] The other advantage provided using TomoTherapy MV CT in conjunction with a TomoTherapy linear accelerator for palliative treatment is that as in this procedure; the patient is both scanned and treated on the same TomoTherapy couch, the accuracy in reproducing the patient's position from scanning to treatment delivery can be greatly improved.

MV CT produces less artifact and image distortion when high atomic number material is present within the scan.[10] As such it provides a significant advantage over kV CT for patients with high atomic number implants such as metal dental fillings or hip prosthesis. One example is given below, where the patient not only requires treatment around the lower lip but also has titanium dental fillings. The patient was scanned with both kV CT and MV CT, displayed in Figure 8. It is noted that there is no image artifact on the MV CT scan, but considerable streaking appears on the kV CT scan. The presence of artifacts requires density overrides to the areas affected by the artifact and also reduces the accuracy of structure delineation. For this reason, for patients with high atomic number implants, TomoTherapy MV CT can be acquired and used as the secondary image set, which can be fused to the kV CT images to aid target delineation, if not used directly as the primary image set for planning.

One potential source of error that was not analyzed by the described tests was the imaging artifact caused by patient's intrafractional motion. Since the MVFB CT acquisition on TomoTherapy takes much longer than a kV CT, patient motion becomes a significant problem. One example is shown below in Figure 9, where the artifact caused by patient's respiratory motion can be clearly observed. Although palliative treatments are most likely prescribed to patients with bone metastases, brain metastases, and spinal cord compression[1] which are relatively motionless anatomical sites compared to others such as lung and liver, the motion effect can still be significant with extended imaging acquisition time. This is more of a problem during initial image acquisition, as during treatment delivery patient motion can be accounted for by adding proper margin or overshoot in planning to account for organ motion.[20]

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CONCLUSION The study assessed whether TomoTherapy MV FBCT images have comparable image qualities to conventional kV CT images and can be used directly for radiotherapy planning. Despite its long image acquisition time and relatively large noise, the authors concluded that TomoTherapy MV CT images provide adequate information for the delineation and planning of palliative radiotherapy patients whose treatment sites are relatively immobile and well-distinguishable. As such, it can be used together with the statRT module provided by TomoTherapy for the simulation, planning, and treatment of palliative radiotherapy patients.

Compared to a conventional radiotherapy treatment workflow that involves the use of a separate CT scanner and a treatment unit, using TomoTherapy as both the imaging unit and the treatment unit for palliative radiotherapy patients provides the following advantages: 1. Rapid access to treatment. Using the statRT software, the time to treatment has been reported as under 1 h.[4] Our test run results also support this timing. In contrast, the conventional planning workflow usually requires at least 1-day turnaround. As studies have shown that dedicated rapid access palliative radiation therapy improves patients’ access to care,[3] the quick access to radiation therapy, and the rapid workflow will potentially improve these patients’ quality of life significantly; 2. Better reproducibility in patient positioning from simulation to treatment, as the patient is simulated and treated on the same unit. The turnaround time from simulation to treatment is also greatly reduced; and 3. For less-mobile palliative patients, it is possible to allow the patient to stay on the TomoTherapy couch from simulation until treatment, which minimizes the chance of doing damage to the patients and reduces reduced potential aggravating morbidity pain during bed transfer. The pretreatment QA for these patients can be performed with QA programs that are based on calculations and do not require direct dose measurements.

As a result, it is feasible to use the TomoTherapy unit for the simulation, planning, and treatment of palliative radiotherapy patients. Once TomoTherapy planning is available in an open-source planning system, the workflow can be further optimized through the implementation of scripting and automation in steps such as image transfers, contouring, plan setup and plan check, so that the turnaround time for the patient can be further reduced, thus further improving patient quality of life.

Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

REFERENCES 1. van Oorschot B, Rades D, Schulze W, Beckmann G, Feyer P. Palliative radiotherapy – New approaches.

Semin Oncol. 2011;38:443–9. [PubMed: 21600376] 2. Mackillop WJ, Kong W. Estimating the need for palliative radiation therapy: A benchmarking approach.

Int J Radiat Oncol Biol Phys. 2016;94:51–9. [PubMed: 26700702] 3. Dennis K, Linden K, Balboni T, Chow E. Rapid access palliative radiation therapy programs: An efficient model of care. Future Oncol. 2015;11:2417–26. [PubMed: 26271002] 4. Rong Y, Yadav P, Paliwal B, Shang L, Welsh JS. A planning study for palliative spine treatment using StatRT and megavoltage CT simulation. J Appl Clin Med Phys. 2010;12:3348. [PubMed: 21330983] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618464/?report=printable

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5. McIntosh A, Dunlap N, Sheng K, Geezey C, Turner B, Blackhall L, et al. Helical tomotherapy-based STAT RT: Dosimetric evaluation for clinical implementation of a rapid radiation palliation program. Med Dosim. 2010;35:280–6. [PubMed: 19944589] 6. Dunlap N, McIntosh A, Sheng K, Yang W, Turner B, Shoushtari A, et al. Helical tomotherapy-based STAT stereotactic body radiation therapy: Dosimetric evaluation for a real-time SBRT treatment planning and delivery program. Med Dosim. 2010;35:312–9. [PubMed: 21055611] 7. Mutic S, Palta JR, Butker EK, Das IJ, Huq MS, Loo LN, et al. Quality assurance for computedtomography simulators and the computed-tomography-simulation process: Report of the AAPM Radiation Therapy Committee Task Group No 66. Med Phys. 2003;30:2762–92. [PubMed: 14596315] 8. TomoTherapy Incorporated. MVCT imaging with J1 TomoImage beam. Application Note for the Tomotherapy Hiart Treatment System. TomoTherapy Incorporated. 2010 9. Sterzing F, Kalz J, Sroka-Perez G, Schubert K, Bischof M, Roder F, et al. Megavoltage CT in helical tomotherapy – Clinical advantages and limitations of special physical characteristics. Technol Cancer Res Treat. 2009;8:343–52. [PubMed: 19754210] 10. Yang C, Liu T, Jennelle RL, Ryu JK, Vijayakumar S, Purdy JA, et al. Utility of megavoltage fan-beam CT for treatment planning in a head-and-neck cancer patient with extensive dental fillings undergoing helical tomotherapy. Med Dosim. 2010;35:108–14. [PubMed: 19931022] 11. Meeks SL, Harmon JF, Jr, Langen KM, Willoughby TR, Wagner TH, Kupelian PA. Performance characterization of megavoltage computed tomography imaging on a helical tomotherapy unit. Med Phys.

2005;32:2673–81. [PubMed: 16193798] 12. Langen KM, Meeks SL, Poole DO, Wagner TH, Willoughby TR, Kupelian PA, et al. The use of megavoltage CT (MVCT) images for dose recomputations. Phys Med Biol. 2005;50:4259–76. [PubMed: 16148392] 13. Held M, Cremers F, Sneed PK, Braunstein S, Fogh SE, Nakamura J, et al. Assessment of image quality and dose calculation accuracy on kV CBCT, MV CBCT, and MV CT images for urgent palliative radiotherapy treatments. J Appl Clin Med Phys. 2016;17:279–90. [PMCID: PMC5874969] [PubMed: 27074487] 14. Ruchala KJ, Olivera GH, Schloesser EA, Mackie TR. Megavoltage CT on a tomotherapy system. Phys Med Biol. 1999;44:2597–621. [PubMed: 10533931] 15. Australian Clinical Dosimetry Service. Instructions for the ACDS level III audit: Wedged and Asymmetric fields with Inhomogeneities for Lung treatments (WAIL) Int ACDS Rep. 2014 16. Araki F. Monte Carlo-based correction factors for ion chamber dosimetry in heterogeneous phantoms for megavoltage photon beams. Phys Med Biol. 2012;57:7615–27. [PubMed: 23103477] 17. Karl P. On the criterion that a given system of deviations from the probable in the case of a correlated system of variables is such that it can be reasonably supposed to have arisen from random sampling. Philos Mag Ser. 5 19;0;50:157–75.

18. Khan FM. The Physics of Radiation Therapy. 3rd ed. Baltimore: Williams & Wilkins; 2003. p. 67.

19. Yeo R, Campbell T, Fairchild A. Is weekend radiation therapy always justified. J Med Imaging Radiat Sci. 2012;43:3–24.

20. Squires M, Hu Y, Byrne M, Archibald-Heeren B, Cheers S, Bosco B, et al. Static beam tomotherapy as an optimisation method in whole-breast radiation therapy (WBRT) J Med Radiat Sci. 2017;6:1–9.

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Figures and Tables

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Figure 1

CIRS thorax phantom setup on TomoTherapy for megavoltage computed tomography scan

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Figure 2

A computed tomography slice of the CIRS upper thorax phantom used in the end to end measurements. The numbers correspond to the measurement positions in the phantom

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Table 1 Laser alignment test results

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Table 2 Geometric accuracy test results

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Table 3 Field uniformity and image noise test results

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kV computed tomography uniformity scan results 25/1/2019

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Figure 4

Megavoltage computed tomography uniformity scan results

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Table 4 Spatial resolution test results

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Figure 5

Open in a separate window kV computed tomography image resolution scan results

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Figure 6

Megavoltage computed tomography image resolution scan results

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Table 5 Mass density to computed tomography number conversion results

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Figure 7

Open in a separate window Computed tomography-mass density curves for GE kV computed tomography and TomoTherapy megavoltage computed tomography. At areas beyond water (mass density >1.0 g/cm3) megavoltage computed tomography showed a much sharper curve

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Table 6 End-to-end point dose measurement results

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Figure 8

On the left: Megavoltage computed tomography scan of a patient with titanium dental implant. On the right: kV computed tomography scan of the same patient. Imaging artifact caused by the implant is more obvious. If the kV scan is used solely for planning, a density override would be required for those areas affected by artifact, thus slowing down the workflow

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Figure 9

Lateral and longitudinal image artifact caused by patient's motion during imaging acquisition Articles from Journal of Medical Physics are provided here courtesy of Wolters Kluwer -- Medknow Publications

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Assessment of inter and intra-fractional volume of bladder and body contour by megavoltage computed tomography in helical tomotherapy for pelvic malignancy

Original Article Radiat Oncol J 2018;36(3):235-240 https://doi.org/10.3857/roj.2018.00185 pISSN 2234-1900 · eISSN 2234-3156

Assessment of inter- and intra-fractional volume of bladder and body contour by mega-voltage computed tomography in helical tomotherapy for pelvic malignancy Sunghyun Kim, MD, Sei Hwan You, MD, Young Ju Eum, BA, RTT Department of Radiation Oncology, Yonsei University Wonju College of Medicine, Wonju, Korea

Purpose: We describe the daily bladder volume change observed by mega-voltage computed tomography (MVCT) during pelvic radiotherapy with potential predictors of increased bladder volume variations.

Materials and Methods: For 41 patients who received pelvic area irradiation, the volumes of bladder and pelvic body contour were measured twice a day with pre- and post-irradiation MVCT from the 1st to the 10th fraction. The median prescription dose was 20 Gy (range, 18 to 30 Gy) up to a 10th fraction. The upper and lower margin of MVCT scanning was consistent during the daily treatments. The median age was 69 years (range, 33 to 86 years) and 10 patients (24.4%) were treated postoperatively.

Results: Overall bladder volume on planning computed tomography was 139.7 ± 92.8 mL. Generally, post-irradiation bladder volume (POSTBV) was larger than pre-irradiation bladder volume (PREBV) (p < 0.001). The mean PREBV and POSTBV was reduced after 10 fraction treatments by 21.3% (p = 0.028) and 25.4% (p = 0.007), respectively. The MVCT-scanned body contour volumes had a tendency to decrease as the treatment sessions progressed (p = 0.043 at the 8th fraction and p = 0.044 at the 10th fraction).

There was a statistically significant correlation between bladder filling time and PREBV (p = 0.001).

Conclusion: Daily MVCT-based bladder volume assessment was feasible both intra- and inter-fractionally.

Keywords: Mega-voltage computed tomography, Radiotherapy, Pelvic neoplasms, Urinary bladder

Introduction Urinary bladder filling is a beneficial process for sparing the small intestine during radiotherapy (RT) to the pelvic area.

The achievement of consistent daily bladder expansion is one of the significant issues. Bladder volume changes can affect radiation dose distribution to the bladder itself and adjacent pelvic organs. Significant volume changes can compromise sophisticated planning data such as intensity-modulated radiotherapy (IMRT) [1-3]. Thus, the bladder volume needs

to be kept consistent throughout all of the fractionated treatment sessions.

Many attempts to assess bladder volume during RT have been conducted. Ultrasonography, which is one of the useful tools for bladder volume measurement, has its restrictions in accurate set-up and consistent daily bladder volume measurements because it is a separate process during RT [4-9].

An alternative method to compensate for this problem can be a mega-voltage computed tomography (MVCT) system, which is actively used for volumetric set-up error correction during

Received 11 April 2018, Revised 22 June 2018, Accepted 31 July 2018.

Correspondence: Sei Hwan You, MD, Department of Radiation Oncology, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju 26426, Korea. Tel: +82-33-741-1518, Fax: +82-33-741-1519, E-mail: ys3259@yonsei.ac.kr This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

www.e-roj.org 235

Copyright © 2018. The Korean Society for Radiation Oncology

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Bladder volume change in tomotherapy tomotherapy. Despite a relatively low resolution, it is effective in improving treatment accuracy by combining a scanning system with RT. Due to mega-volt energy beam characteristics, bony landmark-dependent images are the main references for error correction. However, MVCT scanning has been applied without a definite protocol. In a typical example, the scanning range is usually different for each treatment session. In addition, soft tissues such as the urinary bladder are not used so actively in set-up process. Especially, the urinary bladder needs to be utilized for set-up because the anatomic boundary is detectable on MVCT images as seen in previous pelvic tomotherapy studies [10-14].

Most assessments of bladder volume are based upon an intentional filling method, which is associated with practical limitations such as lack of objectivity and unpredictable urination timing. Thus, the validity of bladder filling requires more detailed assessment in the era of IMRT. In this study, we intended to quantify the daily bladder volume changes during the initial course of RT for pelvic malignancy using MVCT images and to assess the feasible set-up techniques with systematic MVCT application.

Materials and Methods 1. Patient characteristics Between October 2014 and January 2016, 52 consecutive patients with pelvic irradiation indication were enrolled after patient approval for this prospective study. Among them, 11 patients were excluded because of treatment interruption or poor MVCT image quality and 41 patients were finally analysed. All patients received helical tomotherapy using the Hi-Art System (TomoTherapy Inc., Madison, WI, USA). None had severe urinary dysfunction initially. Their median age was 69 years (range, 33 to 86 years). Their diagnoses were prostate cancer, rectal cancer, cervix cancer, bladder cancer, and other pelvic area tumours. This study was approved by the Institutional Review Board of Yonsei University Wonju College of Medicine (No. YWMR-14-7-024).

All patients underwent simulation with supine position using computed tomography (CT) of a 3–5 mm slice thickness including the pelvis and lower abdomen. Then target delineation was drawn using Pinnacle v7.6 radiotherapy planning systems (Philips, Cleveland, OH, USA) and was optimized to reflect each disease status. RT was planned as three-dimensional RT or IMRT. Ten patients (24.4%) were treated with postoperative RT. IMRT with a helical mode was applied to 13 patients (31.7%) and the others were irradiated https://doi.org/10.3857/roj.2018.00185

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by a three-dimensional conformal method with a direct mode.

MVCT analysis was performed for the initial 10 consecutive fractions of each RT course regardless of the total prescription dose focusing on the bladder volume and its dose distribution.

Patient characteristics related to clinical factors are displayed in Table 1.

Table 1. Patients’ characteristics (n = 41) Characteristic Age (yr) Median (range) Sex Male Female Diagnosis Prostate cancer Rectal cancer Cervix cancer Bladder cancer Others Postoperative radiotherapy Yes No Endorectal balloon insertion Yes No Radiotherapy technique Three-dimensional conformal Intensity-modulated

Value 66.3 ± 12.4 69 (33–86) 31 (75.6) 10 (24.4) 14 (34.1) 21 (51.2) 3 (7.3) 1 (2.4) 2 (4.9) 10 (24.4) 31 (75.6) 14 (34.1) 27 (65.9) 28 (68.3) 13 (31.7)

Values are presented as mean ± standard deviation or number (%).

2. Bladder dosimetry on MVCT images All patients were irradiated in a supine position with natural bladder filling. Patients with prostate cancer were treated with urination for 1–1.5 hours before treatment but were not strictly enforced, and no other bladder filling training was given to other patients. The MVCT scan was performed right before and after the daily irradiation. The pre-irradiation MVCT scan (PRESCAN) image was matched with the planning CT image based upon the three-dimensional bony structure followed by shifting the couch to the optimal position. After irradiation, a post-irradiation MVCT scan (POSTSCAN) was taken in the same position, in which the original reference point was maintained. Basically, the MVCT scan range was set from the sacral promontory level to the lower margin of the ischium and it was partially modified according to bladder www.e-roj.org

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Sunghyun Kim, et al volume extent. This scan range was maintained consistently from the 1st fraction to the 10th fraction for each patient’s RT course for both PRESCAN and POSTSCAN. The pelvic body outline volume (POV), which includes pelvic organs, skeletal, and soft tissue, was also calculated by contouring the outermost skin area on MVCT image slices for a consistent scan range from the 1st fraction to the 10th fraction for each patient’s RT course. This was also done by one radiation oncologist using the Hi-Art System for both PRESCAN and POSTSCAN and the method of volume measurement was the same as for bladder volume.

Bladder volume at the planning CT was measured on a kilovoltage CT image of 3–5 mm thickness as a routine planning process. During the RT course, it was calculated by contouring the bladder wall on every 6-mm slice of the MVCT images.

This was performed by one radiation oncologist using a HiArt System and the volume was measured by an operating planning process from the 1st fraction to the 10th fraction for each patient’s RT course for both PRESCAN and POSTSCAN (Fig. 1). We analysed the inter-fractional variability in daily bladder volumes according to the prescription dose to the clinical target volume (CTV) and bladder dose distribution from the 1st fraction to the 10th fraction. In addition, the intra-fractional variability was assessed by comparing PRESCAN data with POSTSCAN data for each RT fraction. Planning CT-based dosimetric parameters for the initial 10 fractions are shown in Table 2.

3. Clinical factors We assessed the correlations between bladder volume change and potential clinical predictors such as urinary ascorbic acid, urinary white blood cells, and urinary red blood cells along with surgical intervention, bladder filling sensation, bladder filling time, and time gap between PRESCAN and POSTSCAN. The bladder filling time was defined as the interval from the last urination to the PRESCAN time point for each fraction.

4. Statistical analysis A paired t-test was used for comparison of the PRESCAN and POSTSCAN data. Surgical intervention was analyzed by independent t-test, the correlations between other clinical factors and bladder volume changes were evaluated by the Pearson correlation method. Statistical significance was defined at the p < 0.05 level. The SPSS version 20.0 (IBM, Armonk, NY, USA) program was used for analysis.

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Fig. 1. An example of a mega-voltage computed tomography image and bladder contouring.

Table 2. Planning CT-based dosimetric parameters in terms of consecutive 10 fractions Parameter

Value 20.0 (18.0–30.0) 105.9 (24.9–354.5) 139.7

Prescription dose (Gy) Bladder volume (mL) Mean Bladder dose (Gy) Mean Max Min

14.9 (5.6–19.3) 20.3 (14.4–28.4) 7.0 (0.4–17.9)

Values are presented as median (range).

CT, computed tomography.

Results All planned bladder volume data were acquired successfully.

The median prescription dose to the CTV was 20 Gy (range, 18 to 30 Gy) for the initial 10 fractions. The mean bladder volume on planning CT was 139.7 ± 92.8 mL and its mean, maximum, and minimum doses were 14.7 ± 3.0 Gy, 20.8 ± 2.9 Gy, and 8.2 ± 3.6 Gy, respectively, up to the 10th fraction. The mean bladder filling time was 75.3 ± 44.8 minutes (range, 4 to 210 minutes). It took an average of 13.6 ± 4.8 minutes (range, 9 to 41 minutes) from PRESCAN to POSTSCAN. The bladder filling sensation was categorized into three stages of the patients’ subjective estimation for the overall treatment sessions, full, moderate, and empty comprised 10.4%, 53.7%, and 35.8%, respectively.

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2. Radiation influence on other clinical factors Mean POV values with standard deviation before and after irradiation from the 1st to the 10th fraction are displayed in Fig. 4. Unlike bladder volume (PREBV and POSTBV) change patterns, the intra-fractional POV changes were not remarkable. POSTSCAN volume showed a restrictive decrease tendency at the 8th (p = 0.043) and 10th (p = 0.044) treatment session compared with PRESCAN volume. These volume change patterns had a strong tendency towards a correlation with pre-irradiation surgery at some treatment sessions (p = 0.057 at the 3rd fraction, p = 0.069 at the 6th fraction). For the cystitis assessment, only the planning maximum dose was moderately correlated with an increase in urine white blood cell numbers after the 10th fraction (Pearson r = 0.49, p = 0.011). As age increased, PREBV was found to be statistically significantly reduced, but the correlation was very weak (Pearson r = -0.138, p = 0.005). The other potential clinical predictors such as urinary ascorbic acid, urinary red blood cells, surgical intervention, ERB, and time gap between PRESCAN and POSTSCAN did not show a significant relationship with the change pattern of bladder volume or POV. There was no statistically significant difference in PREBV between prostate cancer (118.23 ± 75.22 mL) and rectal cancer (116.80 ± 60.09 mL). In the case of other diseases, statistical significance could not be assessed because the number of the patients was too small.

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300

Before irradiation After irradiation

Bladder volume (mL)

250 200 150 100 50 0

0

1

2

3

4 5 6 7 Daily fraction number

8

9

10

Fig. 2. Mean values of bladder volume with standard deviation before and after irradiation from the 1st to the 10th fraction.

PRESCAN bladder volume (mL)

1. MVCT bladder volume The mean PRESCAN bladder volume (PREBV) from the 1st to the 10th fraction was 140.4 ± 90.2 mL (1st fraction), 111.9 ± 59.2 mL (2nd fraction), 126.1 ± 65.0 mL (3rd fraction), 124.5 ± 78.6 mL (4th fraction), 131.8 ± 75.4 mL (5th fraction), 112.6 ± 65.6 mL (6th fraction), 118.1 ± 72.7 mL (7th fraction), 107.6 ± 61.1 mL (8th fraction), 112.1 ± 77.4 mL (9th fraction), and 110.5 ± 63.8 mL (10th fraction), respectively. A mean PREBV reduction of 21.3% was observed between the 1st and the 10th fraction (p = 0.028). A significant mean POSTSCAN bladder volume (POSTBV) reduction was also found between the 1st and the 10th fraction (25.4%, p = 0.007) (Fig. 2). For all treatment sessions, the POSTBV was larger than PREBV (p < 0.001). Pre-irradiation surgery, irradiation technique, and bladder dosimetric parameters were not related to bladder volume changes. There was a weak relationship only between bladder filling sensation and bladder filling time (Pearson r = 0.282, p = 0.001) (Fig. 3).

400 350 300 250 200 150 100 50 0

0

50

100 150 Bladder filling time (min)

200

250

Fig. 3. Correlation of PRESCAN bladder volume and bladder filling time (Pearson r = 0.282, p = 0.001).

Discussion and Conclusion The main objective of this study was to assess inter- and intra-fractional bladder volume during RT to the pelvic area.

Generally, MVCT was a useful option for bladder volume assessment as well as set-up error correction. Intra-fractional bladder volume changes were found to be different for each treatment. These data suggest that the current bladder filling system should be improved and more careful approaches are needed in IMRT. For the patients in our study, the natural bladder filling method was applied without strict urination training for full bladder. Our protocol for consistent bladder www.e-roj.org

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Before irradiation After irradiation

Scanned body contour volume (mL)

11,000 10,000 9,000 8,000 7,000 6,000 5,000

1

2

3

4 5 6 7 Daily fraction number

8

9

10

Fig. 4. Mean values of scanned pelvic body outline volume with standard deviation before and after irradiation from the 1st to the 10th fraction.

volume was based upon non-stressful urination with supine position to avoid the setup instability caused by respiratory movements. Also, elderly patients, which composed a large amount of groups in prostate cancer and rectal cancer in our study, usually had problems in urination control. Thus, despite our less strict regulation, our protocol seems to be efficient for the treatment of prostate cancer, bladder cancer, and rectal cancer, which may be supported by our MVCT results.

When using ultrasound-based measurements, patients must have their bladder volume measured separately from the RT session, which results in anatomic inconsistency. In contrast, MVCT can be a good monitoring tool because the bladder volume changes can be easily detected as an extension of the radiation treatment without a separate set-up process.

Due to its relatively low resolution, MVCT application has been usually confined to bony structure comparisons in setup error corrections. However, in most cases in our study, the bladder border was easily identified on MVCT except for a few patients with unstable bowel status. Unlike ultrasonograms, MVCT could provide information on its anatomic relationship to surrounding organs as well as volumetric values of the bladder. In addition, MVCT of a consistent scan range through all treatment sessions resulted in the same volume variation pattern as that of ultrasonography in previous studies [47,10,15]. Thus, the MVCT-mediated approach in our study appears to be valid.

At present, due to large inter-fractional variation, it is 239

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difficult to find a suitable protocol that ensures consistent bladder volumes [5,7,10]. Actually, intra-fractional volume increase is an inevitable problem. However, dosimetric and clinical effects might not be large considering the modern irradiation process in pelvic area RT except bladder cancer.

Rather, other clinical factors such as urination pattern, cystitis, or adjacent tissue effect may be more influential than the bladder volume itself. On the other hand, inter-fractional variation can be an issue to pay attention to because of its clinical effects and the possibility for improvement. Despite many unknown variables, regular volume reduction is observed as the treatment session progresses [4-7,10,15,16]. Our study also revealed a bladder volume decline even in the early phase of the treatment course, which can be explained by a low dose effect or tissue susceptibility including cystitis or fibrosis [17,18].

A similar decline of inter-fractional POV might not be overlooked considering the correlation with bladder volume change. Despite an intra-fractional bladder volume increase, the corresponding intra-fractional POV had a tendency to decrease paradoxically, which was contrary to existing concepts. From these results, we can guess the possibility of a physiological response to surrounding tissue elasticity changes. This point should be discussed with along with a more systematic approach in future studies.

Subjective patient assessments or biofeedback has its limitations in controlling bladder volume consistently [6].

In our study, self-assessment for voiding and bladder filling sensation was partly reliable. However, it is not sufficient for precisely controlling bladder volume. For these reasons, a more systematic bladder filling method should be devised in the era of adaptive RT, especially for the pelvic area considering the need for whole pelvic tissue stability as well as bladder volume consistency for accurate dose delivery. Other limitations of this study might be the absence of principle identification of bladder volume decreases and the insufficient resolution of the MVCT image. Improvement of these design aspects is desirable in the future. Nevertheless, our results can be meaningful in that the method of maintaining a constant MVCT scan range was applied, demonstrating the feasibility of the standardized volumetric set-up method.

In conclusion, daily MVCT-mediated bladder and body contour volume assessment was feasible both intra- and interfractionally. We expect that MVCT can be used to evaluate the bladder volume easily and accurately, and it will be of some help for better RT.

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Conflict of Interest No potential conflict of interest relevant to this article was reported.

Acknowledgments This study was supported by a grant from the Korea Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (No. HI10C0051 [A100054]).

References 1. Nairz O, Merz F, Deutschmann H, et al. A strategy for the use of image-guided radiotherapy (IGRT) on linear accelerators and its impact on treatment margins for prostate cancer patients. Strahlenther Onkol 2008;184:663-7.

2. Tsai CL, Wu JK, Wang CW, Hsu FM, Lai MK, Cheng JC. Using cone-beam computed tomography to evaluate the impact of bladder filling status on target position in prostate radiotherapy. Strahlenther Onkol 2009;185:588-95.

3. Moiseenko V, Liu M, Kristensen S, Gelowitz G, Berthelet E. Effect of bladder filling on doses to prostate and organs at risk: a treatment planning study. J Appl Clin Med Phys 2006;8:55-68.

4. Chang JS, Yoon HI, Cha HJ, et al. Bladder filling variations during concurrent chemotherapy and pelvic radiotherapy in rectal cancer patients: early experience of bladder volume assessment using ultrasound scanner. Radiat Oncol J 2013;31:41-7.

5. Ahmad R, Hoogeman MS, Quint S, Mens JW, de Pree I, Heijmen BJ. Inter-fraction bladder filling variations and time trends for cervical cancer patients assessed with a portable 3-dimensional ultrasound bladder scanner. Radiother Oncol 2008;89:172-9.

6. Stam MR, van Lin EN, van der Vight LP, Kaanders JH, Visser AG. Bladder filling variation during radiation treatment of prostate cancer: can the use of a bladder ultrasound scanner and biofeedback optimize bladder filling? Int J Radiat Oncol Biol Phys 2006;65:371-7.

7. O'Doherty UM, McNair HA, Norman AR, et al. Variability of bladder filling in patients receiving radical radiotherapy to the prostate. Radiother Oncol 2006;79:335-40.

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8. Hynds S, McGarry CK, Mitchell DM, et al. Assessing the daily consistency of bladder filling using an ultrasonic Bladderscan device in men receiving radical conformal radiotherapy for prostate cancer. Br J Radiol 2011;84:813-8.

9. Orio PF 3rd, Merrick GS, Allen ZA, et al. cExternal beam radiation results in minimal changes in post void residual urine volumes during the treatment of clinically localized prostate cancer. Radiat Oncol 2009;4:26.

10. Nakamura N, Shikama N, Takahashi O, et al. Variability in bladder volumes of full bladders in definitive radiotherapy for cases of localized prostate cancer. Strahlenther Onkol 2010;186:637-42.

11. Kalz J, Sterzing F, Schubert K, Sroka-Perez G, Debus J, Herfarth K. Dosimetric comparison of image guidance by megavoltage computed tomography versus bone alignment for prostate cancer radiotherapy. Strahlenther Onkol 2009;185:241-7.

12. Fiorino C, Di Muzio N, Broggi S, et al. Evidence of limited motion of the prostate by carefully emptying the rectum as assessed by daily MVCT image guidance with helical tomotherapy. Int J Radiat Oncol Biol Phys 2008;71:611-7.

13. Yeung TP, Yartsev S, Rodrigues G, Bauman G. Evaluation of image-guidance strategies with helical tomotherapy for localised prostate cancer. J Med Imaging Radiat Oncol 2011;55:220-8.

14. Kupelian PA, Langen KM, Zeidan OA, et al. Daily variations in delivered doses in patients treated with radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 2006;66:876-82.

15. Fiorino C, Foppiano F, Franzone P, et al. Rectal and bladder motion during conformal radiotherapy after radical prostatectomy. Radiother Oncol 2005;74:187-95.

16. Lebesque JV, Bruce AM, Kroes AP, Touw A, Shouman RT, van Herk M. Variation in volumes, dose-volume histograms, and estimated normal tissue complication probabilities of rectum and bladder during conformal radiotherapy of T3 prostate cancer. Int J Radiat Oncol Biol Phys 1995;33:1109-19.

17. Verit A, Yeni E, Unal D, Kafali H, Ozturk A, Ozardali I. Idiopathic retroperitoneal fibrosis mimicking a pelvic tumor: a case of pericystitis plastica. Yonsei Med J 2003;44:548-50.

18. Pinkawa M, Asadpour B, Gagel B, Piroth MD, Holy R, Eble MJ. Prostate position variability and dose-volume histograms in radiotherapy for prostate cancer with full and empty bladder.

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Intensity-modulated radiotherapy using two static port of TomoTherapy for breast cancer after conservative surgery: dosimetric comparison with other treatment methods and 3-years clinical results

Journal of Radiation Research, 2017, pp. 1–8 doi: 10.1093/jrr/rrw132 Regular Paper

Intensity-modulated radiotherapy using two static ports of tomotherapy for breast cancer after conservative surgery: dosimetric comparison with other treatment methods and 3-year clinical results Aiko Nagai1,2,*, Yuta Shibamoto2, Masanori Yoshida1, Koji Inoda3 and Yuzo Kikuchi1 1

Radiation Therapy Center, Fukui Saiseikai Hospital, 7-1, Funabashi, Wadanaka-cho, Fukui 918-8503, Japan Department of Radiology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan 3 Department of Radiological Technology, Fukui Saiseikai Hospital, 7-1, Funabashi, Wadanaka-cho, Fukui 918-8503, Japan *Corresponding author: Department of Radiology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. Tel: +81-52-853-8276; Fax: +81-52-852-5244; E-mail: love_child317@hotmail.com Received July 5, 2016; Revised October 23, 2016; Editorial Decision December 18, 2016

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ABSTRACT This study investigated the differences in dose–volume parameters for the breast and normal tissues during TomoDirectTM (TD) intensity-modulated radiation therapy (IMRT), TD-3D conformal radiotherapy (3DCRT) and 3DCRT plans, all using two beams, and analyzed treatment outcomes of two-beam TD-IMRT for breast cancer after breast-conserving surgery. Between August 2011 and January 2015, 152 patients were treated using two-beam TD-IMRT with 50 Gy/25 fractions. Among them, 20 patients with left-sided breast cancer were randomly chosen, and two-beam TD-IMRT, TD-3DCRT and 3DCRT plans were created for each patient. The homogeneity and conformity indices and various dose–volume parameters for the planning target volume and OARs were evaluated. Clinical outcomes were evaluated at 3 years. Toxicities were evaluated using the Common Terminology Criteria for Adverse Events version 4.0. TD-IMRT and TD-3DCRT showed better whole-breast coverage than 3DCRT (P < 0.001). Most of the mean values of dosimetric endpoints for OARs were better in TD-IMRT than in TD-3DCRT and 3DCRT. Overall survival rates were 97.7% and local control rates were 99.1% at 3 years. Regional control and distant metastasis control rates at 3 years were 98.6% and 96.8%, respectively. Twenty-four of the 152 patients had Grade 2 or higher acute radiation dermatitis. Four patients (4/146 = 2.7%) had Grade 2 radiation pneumonitis. There were no late adverse events of Grade 2 or higher. Two-beam TD-IMRT appeared to yield better dose distribution for whole-breast external-beam radiation therapy than TD-3DCRT and two-beam 3DCRT. The treatment appeared to provide low skin toxicity and acceptable tumor control.

KEYWORDS:

breast cancer, intensity-modulated radiation therapy, tomotherapy, Tomo-Direct, static

tomotherapy

IN TR ODU CT IO N Adjuvant whole-breast external-beam radiation therapy (WBRT) is an essential part of the current standard approach for early-stage breast cancer, because it yields excellent long-term local control and survival [1]. However, conventional 3D-conformal radiotherapy (3DCRT) for breast cancer occasionally causes treatment-related

complications (e.g. dermatitis, pneumonitis, cardiac injuries). The severity of both acute and late dermatitis is associated with increased breast dose inhomogeneity and resultant hot spots [2].

With conventional breast radiotherapy, a portion of the breast tissue receives 110% of the prescription dose, occasionally up to 120% [2]. Intensity-modulated radiation therapy (IMRT) has been shown

© The Author 2017. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial reuse, please contact journals.permissions@oup.com

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2 • A. Nagai et al. to improve breast dose homogeneity by decreasing hot spots and doses to normal tissues (e.g. the lung and heart) [3]. Breast IMRT is a developing area of active research, and several publications have shown feasibility, dosimetric superiority over 3DCRT [4], decreased acute side effects compared with conventional WBRT [5], and the potential for fewer late complications [6]. In particular, two Phase III studies have shown a reduction in skin toxicity by using IMRT [7, 8]. However, the use of IMRT for breast cancer has not yet become popular in Japan.

Tomotherapy (TomoTherapy, Accuray, Madison, WI, USA) delivers IMRT with a high target-dose homogeneity, minimized doses to surrounding organs at risk [9], and a precise set-up using the onboard megavoltage (MV) computed tomography (CT) system enabling on-line image-guided radiotherapy (IGRT) [10].

TomoDirectTM (TD) is a fixed beam treatment method, allowing planning and delivery of static beams past binary multileaf collimators (MLCs) for fluence modulation [11, 12]. Recently, some clinical data on the use of helical tomotherapy (HT) and TD-IMRT in breast cancer have been reported [13–15]. TD-IMRT plans can decrease the dose for the contralateral lung and breast compared with HT plans. However, the previous reports only paid attention to dermatitis. In addition, there have been no reports that have compared the dosimetric parameters between two-beam TD-IMRT, two-beam TD-3DCRT and two-beam 3DCRT. In Japan, breast cancer patients are usually treated with two opposed tangential fields. Since our institution has no conventional linear accelerator (linac), we have used tomotherapy for all patients.

Therefore, in this study, we investigated the differences in dose–volume parameters for the breast and normal tissues during TomoDirectTM (TD) intensity-modulated radiation therapy (IMRT), TD-3D conformal radiotherapy (3DCRT) and 3DCRT plans, all using two beams, and analyzed treatment outcomes of two-beam TD-IMRT for breast cancer after breast-conserving surgery.

M A T E R I A L S A ND M ET H O D S

Patient characteristics

Between August 2011 and January 2015, a total of 152 patients were treated at Fukui Saiseikai Hospital using TD-IMRT. All patients who underwent TD-IMRT were conventionally treated (2 Gy/day, 5 fractions/week) with two tangential fields using 6-MV photon beams to a total dose of 50 Gy/25 fractions. Our center had two tomotherapy machines but no linac. Written informed consent was obtained before treatment from all patients. Patient and tumor characteristics are shown in Table 1. Patient age ranged from 31 to 79 years (median, 52 years). All patients had a performance status score of 0. Concurrent chemotherapy was not used. We randomly chose 20 patients with left-sided breast cancer from the 152 patients for planning comparison of TD-IMRT, TD-3DCRT and 3DCRT. The Fukui Saiseikai Hospital Review Board approved this study (No. 2016-003).

CT simulation, planning target volume and organ at risk definition and contouring Our methods of tomotherapy have previously been described in detail [16]. All patients were immobilized in a supine position with a

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customized Blue BAG Cushion (Medical Intelligence, Schwabmuenchen, Germany) for simulation and treatment. Planning CT images were acquired with the ActivionTM 16 (Toshiba Medical Systems Corporation, Tochigi, Japan) and obtained from the midneck to the bottom of the lung with a 3-mm slice thickness under shallow breathing. All target volumes and normal structures were contoured on the Pinnacle3 workstation version 9.2 (Philips Medical Systems, Madison, WI, USA). The target for breast irradiation was determined by referring to preoperative sagittal CT and positron emission tomography (PET)-CT images. The planning target volume (PTV) for WBRT covered the superior border at the base of the manubriosternal joint and the inferior border at 1 cm below the inframammary line; the medial border was usually the midline of the sternum, and the lateral border was the midaxillary line, excluding the outermost 2 mm from the superficial skin surface. Delineated organs at risk (OARs) were the ipsilateral, contralateral and bilateral lungs, heart, contralateral breasts, and skin. The skin was defined as the volume with a depth of 2 mm from the external surface, and was automatically outlined.

Treatment plan comparison between TD-IMRT, TD-3DCRT and 3DCRT TD-IMRT and TD-3DCRT plans for 20 patients with left-sided breast cancer were created and optimized with the TomoTherapy version 5.0.5.18 treatment planning station (Accuray, Inc, Madison, WI, USA) using a convolution/superposition dose calculation algorithm. The planning parameters used for both plans were as follows: a field width of 2.51 cm, a pitch of 0.251, a modulation factor of 1.15–1.85, and a fine calculation grid (1.96 mm × 1.96 mm × slice thickness) for both optimization and calculation. The same beam angles were selected for both plans in order to minimize doses to the OARs. To account for possible breath-related target movements, 2 MLC leaves were opened on the anterior edge of each beam. The TD-3DCRT plans were made selecting the normal tissue homogeneity option and setting the tissue compensation to low, in order to allow for a more significant comparison with TD-IMRT plans.

Details of the inverse planning algorithm used, the optimization method, and several parameters associated with the optimization in the tomotherapy planning station have been described previously [17]. A prescription dose of 50 Gy in 25 fractions to 50% of the PTV was chosen.

The 3DCRT plans for 20 patients with left-sided breast cancer were created with the Pinnacle3 workstation using two open tangential 6-MV photon beams from a Varian Clinac 2100 C/D (Varian Medical System, Palo Alto, CA). Beam angles were chosen such that the edges matched those of the corresponding TD treatment beams. Adequate wedges were selected from 15, 30 and 45 degrees for the breast tissues. Final dose calculation employed a beam modeling based on the collapsed cone convolution/superposition. A prescription dose of 50 Gy in 25 fractions to the isocenter of the PTV was chosen.

Verification of treatment planning system calculations We compared the dose profiles calculated using each planning system with the dose profiles for beam modeling and actually measured doses in order to validate the accuracy of the treatment planning

TomoDirect for breast cancer

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3

Table 1. Patient characteristics Characteristic

Number of patients (%)

Total number of patients

152

Age (years), median [range]

52 [31–79]

Follow-up (months), median [range]

33 [1–53]

Laterality

Right/Left

76 (50)/76 (50)

Clinical stage

0/I/II/III

37 (24.4)/83 (54.6)/28 (18.4)/4 (2.6)

Histology Ductal/Lobular/Mucinous/Scirrhous

147 (96.7)/2 (1.3)/2 (1.3)/1 (0.7)

Estrogen receptor

Positive/Negative

32 (21.1)/120 (78.9)

Progesterone receptor

Positive/Negative

107 (70.4)/45 (29.6)

HER2

Positive/Negative

61 (40.1)/91 (59.9)

Ki-67

≥20%/<20%/Unknown

101 (66.4)/45 (29.6)/6 (4.0)

Neoadjuvant chemotherapy

Yes/No

52 (34.2)/100 (65.8)

Concurrent chemotherapy

Yes/No

0 (0)/152 (100)

Adjuvant chemotherapy

Yes/No

5 (3.3)/147 (96.7)

Neoadjuvant hormonotherapy

Yes/No

72 (47.4)/80 (52.6)

Concurrent hormonotherapy

Yes/No

84 (55.3)/68 (44.7)

Adjuvant hormonotherapy

Yes/No

92 (60.5)/60 (39.5)

Neoadjuvant molecularly targeted therapy

Yes/No

22 (14.5)/130 (85.5)

Concurrent molecularly targeted therapy

Yes/No

23 (15.1)/129 (84.9)

Adjuvant molecularly targeted therapy

Yes/No

24 (15.8)/128 (84.2)

HER2 = human epidermal growth factor receptor type 2.

systems. The dosimetric quality indices for beam profiles differ considerably between the Varian linac on Pinnacle3 and TomoTherapy, since the latter has no flattening filter. For beam model verification of the Varian machine with a flattening filter, W50 (radiological width on a 50% dose level) and P80–20 (penumbra, defined as the distance between 80 and 20% dose levels) were used. On the other hand, full width at quarter maximum (FWQM) was used to check consistency between the beam model and the beam measurement for tomotherapy.

Planning evaluation Dosimetric comparisons of the treatment plans were performed based on the following parameters extracted from dose–volume histograms (DVHs): homogeneity index (HI); conformity index (CI); maximum dose for the PTV (Dmax); dose received by 95% of the PTV (D95%); dose received by 2% of PTV (D2%); V5 Gy, V10 Gy, V20 Gy and mean lung dose (MLD) for the bilateral, ipsilateral and contralateral lungs; V10 Gy, V25 Gy, V30 Gy, V35 Gy and mean heart dose (MHD) for the heart; mean dose for the

contralateral breast; and maximum dose for the skin. Furthermore, we divided the patients into a large PTV (above-median) group and a small PTV (below-median) group (n = 10 for each). The median PTV for all patients was 575.1 cm3. The median PTV was 685.7 cm3 (range: 586.1–1055.5) in the large PTV group and 456.2 cm3 (361.8–564.1) in the small PTV group (P = 0.002 by unpaired ttest). Maximum dose for the skin in the large and small PTV groups was compared between TD-IMRT, TD-3DCRT and 3DCRT. The HI was defined as the ratio of the maximum dose in the PTV (Dmax) and the prescription dose in the PTV (Drx): HI = Dmax/ Drx. The CI, as proposed by ICRU 62 [18], was defined as the ratio of the treated volume within the prescription isodose surface (VTV) to the PTV (VPTV): CI = VTV/VPTV.

Evaluation of clinical outcome In principle, physical examination and a blood test were performed at every follow-up visit, and CT, chest radiography, mammography and/or ultrasonography was performed whenever necessary until death. PET-CT and magnetic resonance imaging

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4 • A. Nagai et al. were performed when history, physical examination, CT scan, and/or tumor marker assessment yielded suspicious findings.

Toxicity was assessed according to the Common Terminology Criteria for Adverse Events version 4.0. Acute dermatitis and overall survival (OS) were evaluated for all 152 patients, and late dermatitis, pneumonitis, local control (LC) and regional control (RC) were evaluated for 146 patients with at least 6 months of follow-up. Cardiac injuries were evaluated for 74 patients with left-sided breast cancer followed for at least 12 months, and distant metastasis control (DMC) rates were evaluated for 126 patients who had been evaluated with follow-up CT, PET-CT and/or abdominal ultrasonography.

Statistical analysis Comparisons of dose–volume parameters of the PTV and OARs among the three plans for 20 patients were carried out using the factorial analysis of variance (ANOVA), followed by the Tukey– Kramer post hoc test. OS, LC, RC and DMC rates were calculated using the Kaplan–Meier method from the start of IMRT. A twosided P-value of ≤0.05 was considered to reflect statistical significance. These univariate analyses were carried out using Prism (Graph Pad Institute Inc., San Diego, CA, USA).

TD-IMRT and TD-3DCRT. The PTV homogeneity of TD-IMRT and TD-3DCRT plans was better than that of the 3DCRT plan (P < 0.0001). Most of the mean values of OAR dosimetric endpoints were significantly better in TD-IMRT than in TD-3DCRT and 3DCRT. TD-IMRT provided lower values of ipsilateral lung V5 Gy and V10 Gy, bilateral lung V5 Gy and V10 Gy, and contralateral MLD than 3DCRT (P = <0.0001, 0.0091, <0.0001, 0.017 and 0.037, respectively). MHD and heart V10 Gy, V25 Gy, V30 Gy and V35Gy for TD-IMRT were significantly lower than those of TD-3DCRT (P = 0.0012, 0.0029, 0.0004, 0.0002 and 0.0003, respectively). Mean dose for the contralateral breast tissue was lower in TD-IMRT than in TD-3DCRT (P = 0.0018). Maximum dose for the skin was lower in 3DCRT than in TD-IMRT and TD3DCRT (P = 0.0055). In the small PTV group, the maximum dose for the skin was smaller in 3DCRT (mean ± SD: 48.4 ± 1.5 Gy) than in TD-IMRT (50.2 ± 0.5 Gy) and TD-3DCRT (50.2 ± 0.6 Gy; P = 0.0007). On the other hand, there were no significant differences in the large PTV group between the three plans (50.5 ± 0.3 Gy for TD-IMRT, 50.7 ± 0.4 Gy for TD-3DCRT, and 50.0 ± 2.1 Gy for 3DCRT; P = 0.53).

RESULTS

Verification of treatment planning system calculations W50, P80–20 and FWQM values are shown in Table 2. The difference in W50 between measured values and values calculated from the treatment planning systems in Pinnacle3 was 1.4 mm, which satisfied the <2 mm criteria [19]. In the same way, the difference in P80–20 was 0.5 mm, which satisfied the 3 mm criteria of distance to agreement [20]. For tomotherapy, the gamma-index of 2%/1 mm was 0.271, which satisfied the <1 criteria [21].

Treatment plan analysis for 20 patients with left-sided breast cancer PTV and OAR isodose distributions for a typical left-sided breast plan are illustrated in Fig. 1. The mean values ( ± SD) of the PTV and OAR dosimetric parameters of TD-IMRT, TD-3DCRT and 3DCRT plans are listed in Table 3. TD-IMRT and TD3DCRT showed better whole-breast coverage than 3DCRT; D95% was more than 95% in all TD-IMRT and TD-3DCRT plans (P < 0.0001). PTV Dmax and D2% were significantly lower for the TD-IMRT and TD-3DCRT plans than 3DCRT (both P < 0.0001), and no significant difference was observed between

Fig. 1. Isodose distribution for a left-sided breast cancer planned with TomoDirect (TD) intensity-modulated radiation therapy (IMRT) (A), TD-3D conformal radiotherapy (3DCRT) (B) and 3DCRT (C). The pink line in (A) to (C) indicates the planning target volume.

Table 2. Verification of treatment planning system calculations for Pinnacle3 and TomoTherapy

W50 (mm) P80–20 (mm) FWQM (mm)

Measured value

Calculated value on Pinnacle3

Calculated value on TomoTherapy workstation

101.8

100.4

–

6.6

6.1

–

410.7

–

411.2

W50 = radiological width on a 50% dose level, P80–20 = penumbra defined as distance between 80 and 20% dose levels, FWQM = full width at quarter maximum.

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TomoDirect for breast cancer

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5

Table 3. Dose parameter comparison among TD-IMRT, TD-3DCRT and 3DCRT plans for 20 left-sided breast cancer patients Parameters

TD-IMRT

TD-3DCRT

3DCRT

P-value

Dmax (%)

106 ± 1.0

105 ± 1.0

113 ± 4.3

<0.0001

D95 (%)

95.4 ± 0.3

96.0 ± 0.6

89.5 ± 2.5

<0.0001

D2 (%)

103 ± 0.7

102 ± 0.5

109 ± 2.4

<0.0001

HI

1.8 ± 0.4

1.3 ± 0.1

4.3 ± 1.5

<0.0001

CI

0.5 ± 0.0

0.5 ± 0.0

0.6 ± 0.1

<0.0001

V5 Gy (%)

5.8 ± 1.3

6.6 ± 1.4

9.3 ± 2.7

<0.0001

V10 Gy (%)

4.4 ± 1.1

5.2 ± 1.2

6.0 ± 2.4

0.017

V20 Gy (%)

3.3 ± 0.9

4.0 ± 1.0

4.0 ± 2.1

0.17

MLD (Gy)

2.1 ± 0.7

2.3 ± 0.5

2.5 ± 1.0

0.22

Right lung

MLD (Gy)

0.2 ± 0.0

0.2 ± 0.0

0.3 ± 0.1

0.037

Left lung

V5 Gy (%)

12.8 ± 3.2

14.8 ± 2.8

20.9 ± 6.1

<0.0001

V10 Gy (%)

9.7 ± 2.6

11.6 ± 2.4

13.5 ± 5.3

0.0091

V20 Gy (%)

7.2 ± 2.2

9.1 ± 2.1

9.1 ± 4.6

0.11

MLD (Gy)

4.1 ± 0.9

4.9 ± 1.0

5.0 ± 2.0

0.11

V10 Gy (%)

4.1 ± 2.4

7.9 ± 3.8

5.7 ± 3.4

0.0029

V25 Gy (%)

2.0 ± 1.5

5.3 ± 3.1

3.0 ± 2.5

0.0004

V30 Gy (%)

1.6 ± 1.3

4.7 ± 2.8

2.5 ± 2.2

0.0002

V35 Gy (%)

1.2 ± 1.1

4.0 ± 2.6

2.1 ± 2.0

0.0003

MHD (Gy)

2.2 ± 0.9

3.8 ± 1.6

3.5 ± 1.4

0.0012

Dmax (Gy)

46.7 ± 4.7

48.5 ± 1.2

47.1 ± 2.8

Right breast tissue

Dmean (Gy)

0.4 ± 0.1

0.4 ± 0.1

0.5 ± 0.2

0.0018

Skin

Dmax (Gy)

50.4 ± 0.5

50.5 ± 0.5

49.3 ± 2.0

0.0055

PTV

Bilateral lung

Heart

0.18

3DCRT = 3D-conformal radiotherapy, IMRT = intensity-modulated radiation therapy, TD = TomoDirect, PTV = planning target volume, HI = homogenity index, CI = conformity index, MLD = mean lung dose, MHD = mean heart dose. P-values from the factorial analysis of variance (ANOVA) followed by the Tukey–Kramer post hoc test. Data presented as mean ± standard deviation.

Clinical outcome The median follow-up was 38 months for all patients (range, 1–58 months). The OS, LC, RC and DMC rates at 3 years were 97.7%, 99.1%, 98.6% and 96.8%, respectively. OS rates for Stage 0, I, II and III patients at 3 years were 100%, 100%, 91.4% and 100%, respectively (Fig. 2). LC rates were 100%, 98.4%, 100% and 100% at 3 years for Stage 0, I, II and III, respectively (Fig. 3). RC rates at 3 years were 100%, 98.7%, 100% and 100%, for Stage 0, I, II and III, respectively (data not shown). DMC rates at 3 years were 100%, 97.3%, 95.8% and 75% for Stage 0, I, II and III, respectively (data not shown).

Twenty-four of the 152 (15.8%) patients had ≥Grade 2 acute radiation dermatitis. Grade 3 acute radiation dermatitis was seen in

4 of the 152 (2.6%) patients. Most patients (84.2%) had Grade 1 acute dermatitis. There was no late radiation dermatitis of Grade 2 or higher. Two of the 146 patients had Grade 2 radiation pneumonitis (1.4%). There were no acute or late adverse cardiac events of Grade 2 or higher.

DISCUSSION In this study, dose homogeneity of PTVs in TD-IMRT and TD3DCRT plans were better than in 3DCRT plans (both P < 0.001), and most of the mean values of the OAR dose parameters were better in TD-IMRT than in TD-3DCRT and 3DCRT. The maximum dose for the skin in 20 patients was lower in 3DCRT than in TDIMRT and TD-3DCRT, but there were no significant differences in

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Fig. 2. Curves for overall survival (OS) according to clinical stages for all 152 patients.

Fig. 3. Curves for local control (LC) according to clinical stages for 146 patients. the large PTV group between the three plans. It has been reported that a larger breast size is associated with more severe dermatitis [22, 23], so the results of our study would indicate that the use of TD-IMRT might not increase the incidence of severe dermatitis. In a 3DCRT study using a 50-Gy dose, Grade 2 or higher acute dermatitis was seen in 22% [24]; that study used both 4 and 6 MV X rays, so it is not appropriate to compare the results with those obtained in our study that used 6 MV X rays only. Nevertheless, the incidence of Grade 2 or higher dermatitis of 15.8% in our study may be an acceptable level. Regarding late toxicity, palpable breast induration and negative changes in telangiectasia were reported to be reduced with breast IMRT compared with 3DCRT [25], while there was no late dermatitis in this study. TD-IMRT could also decrease bilateral V5 Gy and V10 Gy, ipsilateral V5 Gy and V10 Gy of the lung, and contralateral MLD, while bilateral MLD and V20 Gy could not be reduced. In the clinical study, the frequency of Grade 2 or higher pneumonitis (1.38%) was nearly equal to or possibly slightly higher than that in 3DCRT studies (0.9–1.28%) [19, 26]. The lung toxicity of TD-IMRT should be further investigated in future studies. Concerning doses for the heart, TD-IMRT was superior to TD-3DCRT regarding V10 Gy, V25 Gy, V30 Gy and V35 Gy. There was no pericarditis in this study, but a previous

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study showed that pericarditis occurred in 3 of 831 patients (0.4%) [27]. A clinical study on IMRT showed a low rate of local relapse with mild acute/late effects [28]. Short follow-up is a limitation of our study, but the clinical outcomes obtained so far are comparable with those of the previous studies. From the above considerations, it seems that TD-IMRT provides more appropriate dose distribution for WBRT than the other two plans.

Moreover, TD-IMRT has two other advantages for breast irradiation. First, TD-IMRT is an image-guided IMRT delivery using a fixed gantry; in that respect it is thus suitable for clinical use [9].

Daily MVCT assures set-up accuracy, and it can detect changes in the skin surface and occurrence of pneumonitis during treatment, so we can make a more accurate re-plan and cope with acute adverse events immediately.

As a second advantage, compared with 3DCRT in our study TD-IMRT provided adequate target coverage of the whole breast, with a reduction of the high doses to the target and of the low doses to the contralateral tissues. The low-dose effect to the contralateral tissues is known to lead to an increased rate of radiationinduced secondary malignancies; women <40 years of age who received a radiation dose of >1.0 Gy to the contralateral breast had an elevated, long-term risk of developing a second primary contralateral breast cancer [29]. In this study, the dose to the contralateral breast was lower in TD-IMRT than in 3DCRT, but the Dmean was <1.0 Gy in both treatments, so the influence on the incidence of secondary breast cancer may be small. Regarding the dose of the MVCT, the mean dose delivered to the contralateral breast was ~26.8 cGy in 25 fractions in a previous study [30], so the influence of the MVCT dose on the contralateral breast appears to be small.

However, it should be noted that daily MVCT increases MLD and MHD. On the other hand, breast TD-IMRT has three issues that need to be improved. One is the high cost of breast IMRT, so breast IMRT is not necessarily recommended for all patients [31]. In Japan, however, the cost of two-beam IMRT is equal to that of twobeam 3DCRT, so patients there receiving two-beam therapy could benefit from IMRT in terms of clinical outcome at no additional cost. Second, the current version of tomotherapy cannot use respiration gating or deliver treatment under breath holding. It is expected that this issue will be solved in the future version of tomotherapy. Third, breast hypofractionated radiotherapy over a shorter number of treatment days (15–16 fractions) is reported to have an advantage, with equivalent or even improved outcomes and acute/late toxicities compared with conventionally fractionated radiotherapy [17, 32, 33]. However, breast hypofractionated IMRT is not as frequently employed in Japan as it is in the rest of the world. By using TD-IMRT, the daily doses to OARs could be reduced, so the adverse effects caused by using a higher dose per fraction may be alleviated. Hypofractionated IMRT using TD may be a promising topic of future investigation.

CONCLUSION The two-beam TD-IMRT plan appeared to yield better dose distribution for WBRT than TD-3DCRT or two-beam 3DCRT. Our preliminary results for TD-IMRT suggest that the skin and other

TomoDirect for breast cancer toxicities and tumor control are acceptable, and further studies are warranted.

A C KN O W L ED G EM E NT S The authors are grateful to Dr Yoshio Kasahara, Dr Kojiro Horita, Dr Masayo Kimura, Dr Yoshiko Sudo, Yuichi Nushimo, Shinji Himeji, Naoki Nakajima, Tadashi Nakabayashi and Fuyumi Kobayashi for their valuable help in this research.

CONFLICT OF INTEREST The authors declare that there are no conflicts of interest.

R EF E RE N CE S 1. Clarke M, Collins R, Darby S, et al. Early Breast Cancer Trialists Collaborative Group. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomized trials. Lancet 2005;366:2087–106.

2. Buchholz TA, Gurgoze E, Brice WS, et al. Dosimetric analysis of intact breast irradiation in off-axis planes. Int J Radiat Oncol Biol Phys 1997;39:261–7.

3. Kestin LL, Sharpe MB, Frazier RC, et al. Intensity modulation to improve dose uniformity with tangential breast radiotherapy: initial clinical experience. Int J Radiat Oncol Biol Phys 2000;48: 1559–68.

4. Hong L, Hunt M, Chui C, et al. Intensity-modulated tangential beam irradiation of the intact breast. Int J Radiat Oncol Biol Phys 1999;44:1155–64.

5. Harsolia A, Kestin L, Grills I, et al. Intensity-modulated radiotherapy results in significant decrease in clinical toxicities compared with conventional wedge-based breast radiotherapy. Int J Radiat Oncol Biol Phys 2007;68:1375–80.

6. McDonald MW, Godette KD, Butker EK, et al. Long-term outcomes of IMRT for breast cancer: a single-institution cohort analysis. Int J Radiat Oncol Biol Phys 2008;72:1031–40.

7. Pignol JP, Olivotto I, Rakovitch E, et al. A multicenter randomized trial of breast intensity-modulated radiation therapy to reduce acute radiation dermatitis. J Clin Oncol 2008;26:2085–92.

8. Mukesh MB, Barnett GC, Wilkinson JS, et al. Randomized controlled trial of intensity-modulated radiotherapy for early breast cancer: 5-year results confirm superior overall cosmesis. J Clin Oncol 2013;31:4488–95.

9. Coon AB, Dickler A, Kirk MC, et al. TomoTherapy and multifield intensity-modulated radiotherapy planning reduce cardiac doses in left-sided breast cancer patients with unfavorable cardiac anatomy. Int J Radiat Oncol Biol Phys 2010;78:104–10.

10. Beavis AW. Is Tomotherapy the future of IMRT? Br J Radiol 2004;77:285–95.

11. Franco P, Catuzzo P, Cante D, et al. TomoDirect: an efficient means to deliver radiation at static angles with tomotherapy.

Tumori 2011;97:498–502.

12. Murai T, Shibamoto Y, Manabe Y, et al. Intensity-modulated radiation therapy using static ports of tomotherapy (TomoDirect): comparison with the TomoHelical mode. Radiat Oncol 2013; 8:68.

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13. Cendales R, Schiappacasse L, Schnitman F, et al. Helical tomotherapy in patients with breast cancer and complex treatment volumes. Clin Transl Oncol 2011;13:268–74.

14. Franco P, Zeverino M, Migliaccio F, et al. Intensity-modulated adjuvant whole breast radiation delivered with static angle tomotherapy (TomoDirect): a prospective case series. J Cancer Res Clin Oncol 2013;139:1927–36.

15. Zhang F, Wang Y, Xu W, et al. Dosimetric evaluation of different intensity-modulated radiotherapy techniques for breast cancer after conservative surgery. Technol Cancer Res Treat 2015; 14:515–23.

16. Nagai A, Shibamoto Y, Yoshida M, et al. Safety and efficacy of intensity-modulated stereotactic body radiotherapy using helical tomotherapy for lung cancer and lung metastasis. Biomed Res Int 2014;2014:473173.

17. Sugie C, Manabe Y, Hayashi A, et al. Efficacy of the dynamic jaw mode in helical tomotherapy with static ports for breast cancer. Technol Cancer Res Treat 2015;14:459–65.

18. International Commission on Radiation Units and Measurements. Prescribing, recording, and reporting photon beam therapy (Supplement to ICRU Report 50). ICRU Report 62. ICRU, Bethesda, MD, 1999.

19. Mijnheer B, Olszewska A, Fiorino C, et al. Accuracy requirements and tolerance levels. ESTRO Booklet No. 7: Quality Assurance of Treatment Planning Systems. Practical Examples for Non-IMRT Photon Beams. Brussels: ESTRO, 2004, 11–20.

20. Smilowitz JB, Das IJ, Feygelman V, et al. AAPM Medical Physics Practice Guideline 5.a. Commissioning and QA of treatment planning dose calculations—megavoltage photon and electron beams. J Appl Clin Med Phys 2015;16:5768.

21. TomoTherapy Service Instructions. Installation Dosimetric Verification Guide (T-PSC-HB0004). Accuray, Inc. 2013.

Internal document. (22 September 2016, date last accessed).

22. De Langhe S, Mulliez T, Veldeman L, et al. Factors modifying the risk for developing acute skin toxicity after whole-breast intensity modulated radiotherapy. BMC Cancer 2014;14:711.

23. Fernando IN, Ford HT, Powles TJ, et al. Factors affecting acute skin toxicity in patients having breast irradiation after conservative surgery: a prospective study of treatment practice at the Royal Marsden Hospital. Clin Oncol (R Coll Radiol) 1996;8: 226–33.

24. Osako T, Oguchi M, Kumada M, et al. Acute radiation dermatitis and pneumonitis in Japanese breast cancer patients with whole breast hypofractionated radiotherapy compared to conventional radiotherapy. Jpn J Clin Oncol 2008;38:334–8.

25. Barnett GC, Wilkinson JS, Moody A, et al. Randomized controlled trial of forward-planned intensity modulated radiotherapy for early breast cancer: interim results at 2 years. Int J Radiat Oncol Biol Phys 2012;82:715–23.

26. Nozaki M, Kagami Y, Mitsumori M, et al. A multicenter investigation of late adverse events in Japanese women treated with breast-conserving surgery plus conventional fractionated wholebreast radiation therapy. Jpn J Clin Oncol 2012;42:522–7.

27. Pierce SM, Recht A, Lingos TI, et al. Long-term radiation complications following conservative surgery (CS) and radiation

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28. Keller LM, Sopka DM, Li T, et al. Five-year results of whole breast intensity modulated radiation therapy for the treatment of early stage breast cancer: the Fox Chase Cancer Center Experience. Int J Radiat Oncol Biol Phys 2012;84:881–7.

29. Stovall M, Smith SA, Langholz BM, et al. Dose to the contralateral breast from radiotherapy and risk of second primary breast cancer in the WECARE study. Int J Radiat Oncol Biol Phys 2008;72:1021–30.

30. Shah AP, Langen KM, Ruchala KJ, et al. Patient dose from megavoltage computed tomography imaging. Int J Radiat Oncol Biol Phys 2008;70:1579–87.

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31. Medscape. ASTRO: 5 Radiation Oncology Practices Should Stop. www.medscape.com/viewarticle/811528 (23 September 2013, date last accessed).

32. Haviland JS, Owen JR, Dewar JA et al. The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol 2013;14:1086–94.

33. Chan EK, Woods R, McBride ML, et al. Adjuvant hypofractionated versus conventional whole breast radiation therapy for early-stage breast cancer: long-term hospital-related morbidity from cardiac causes. Int J Radiat Oncol Biol Phys 2014;15;88: 786–92.

Patient dose from kilovoltage radiographs durin motion-synchronized treatments on Radixact

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Technical Note: Patient dose from kilovoltage radiographs during motionsynchronized treatments on Radixact® William S. Ferrisa)

and Wesley S. Culberson

Department of Medical Physics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA

(Received 9 June 2020; revised 27 August 2020; accepted for publication 27 August 2020; published 14 October 2020) Purpose: Synchrony is a motion management system available on the Radixact linear accelerator that utilizes kilovoltage (kV) radiographs to track target motion and synchronize the delivery of radiation with the motion. Proper management of this imaging dose requires accurate quantification. The purpose of this work was to use Monte Carlo (MC) simulations to quantify organ-specific patient doses from these images for various patient anatomies.

Methods: Point doses in water were measured per TG-61 for three beam qualities commonly used on the Radixact. The point doses were used to benchmark a model of the imaging system built using the Monte Carlo N-Particle (MCNP) transport code. Patient computed tomography (CT) datasets were obtained for 5 patients and 100 planar images were simulated for each patient. Patient dose was calculated using energy deposition mesh tallies.

Results: The MCNP model was able to accurately reproduce the measured point doses, with a median dose difference of less than 1%. The median dose (D50%) to soft tissue from 100 radiographs among the 5 patient cases ranged from 2.0 to 4.6 mGy. The max dose (D1%) to soft tissue ranged from 6.2 to 31.0 mGy and the max dose to bony structures ranged from 20.2 to 71.7 mGy. These doses can be scaled to estimate total patient dose throughout many fractions.

Conclusions: Patient dose is largely dependent on imaging protocol, patient size, and treatment parameters such as fractionation and gantry period. Organ doses from 100 radiographs (an approximate number for one fraction) on the Radixact are slightly less than the doses from Tomo MVCT setup images. Careful selection of clinical protocols and planning parameters can be used to minimize risk from these images. © 2020 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine. [https://doi.org/10.1002/mp.14461] Key words: intrafraction imaging dose, Radixact, tomotherapy 1. INTRODUCTION Active intrafraction motion management during radiotherapy often relies on kilovoltage (kV) imaging, magnetic resonance imaging (MRI), or radiofrequency tracking to determine the location of the target in real time.1 Kilovoltage image tracking techniques deposit dose to the patient in addition to the dose from the therapy itself. The American Association of Physicists in Medicine (AAPM) Task Group 180 (TG-180) reported on management of imaging doses in radiation therapy, and recommends that imaging dose be considered in the treatment planning process if the dose will likely exceed 5% of the therapeutic dose.2 Appropriate management of this imaging dose requires accurate quantification.

The Radixact linear accelerator (Accuray, Inc., Sunnyvale, CA) contains an optional motion management system called Synchrony®, which uses kV imaging during treatment to monitor the location of the target and synchronize the delivery of radiation with the motion of the target. A description of target tracking and motion of the jaws and multileaf collimator (MLC) during treatment has been provided in the works of Schnarr et al. and Chen et al.3,4 Radiographs are acquired at two to six imaging angles every gantry rotation and are chosen by the operator. Synchrony can be used to manage both respiratory and nonrespiratory, or quasi-static 5772

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motion,3 both of which require the use of kV radiographs during treatment.

Due to the recent release of Radixact Synchrony, there is limited literature on doses from kV radiographs acquired during these treatments. Accuray provides skin exposures at isocenter, which must be corrected for varying patient size and position and do not reflect dose at depth. Chen et al. measured the weighted computed tomography dose index (CTDIw) for 100 radiographs of the large thorax protocol on Radixact to be 8.4 mGy.4 This value provides a magnitude of expected doses to water, but it does not consider patient anatomy, imaging protocol, or dose to materials other than water such as bone. The purpose of this work is to use measurements and simulations to quantify volumetric, organ-specific patient doses for various disease sites that may commonly be treated using Radixact Synchrony.

2. MATERIALS AND METHODS A photograph of the kV imaging system mounted on the Radixact is shown in Fig. 1. The kV tube is manufactured by Siemens (Siemens AG, Munich, Germany) and is capable of tube potentials between 40 and 150 kVp. The kV tube is mounted 90° from the megavoltage (MV) source and is positioned such that the anode/cathode axis is parallel to the

0094-2405/2020/47(11)/5772/7

© 2020 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications oradaptations are made.

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TABLE I. Default preset imaging protocols available for Synchrony treatments on Radixact.

FIG. 1. Photograph of a Radixact at UW-Madison with the cover removed, showing the kV tube and flat panel kV detector. The MV source-to-axis distance (SAD) is 85 cm, the kV SAD is 57.5 cm, and the kV source to imager distance is 113.5 cm. The MV source is hidden in the picture by the couch.

[Color figure can be viewed at wileyonlinelibrary.com]

direction of table travel. The beam is statically collimated to irradiate just inside the detector’s usable pixels, which projects to approximately 20 × 20 cm2 at isocenter. The beam qualities investigated in this work were 100, 120, and 140 kVp, which are the beam qualities used in the preset imaging protocols that come default on the Radixact, shown in Table I. The imaging protocol is the same for every angle used in the Synchrony treatment, that is, images at different angles cannot be set to different parameters.

2.A. Beam data measurements The recommendations of the AAPM TG-61 were followed for measurement of kV point doses in water.5 TG-61 specifies beam quality in terms of half-value layer (HVL), which were measured for each beam quality in millimeters of aluminum and millimeters of copper using an A12 ionization chamber (Standard Imaging, Middleton, WI). The filters were 99.9% pure and the thicknesses were specified to the nearest 0.001 mm. Narrow-beam geometry was obtained for the HVL measurements by addition of a lead diaphragm.

Point doses at depth in a water tank were determined using the TG-61 in-water method, described by Eq. (1).5 The ion chamber was moved to each position at depth or off-axis with the water tank software and three measurements were acquired at each position. During each measurement, the couch and gantry were static, the kV imager was at zero degrees (pointing toward the floor), and the MV beam was off. The measured charge was fully corrected per TG-61 including a shutter correction. Air-kerma calibration coefficients were obtained for the A12 chamber from the University of Wisconsin Accredited Dosimetry Calibration Laboratory (ADCL) for medium-filtered beam qualities. The HVLs of the calibrated beam qualities bracketed the HVLs of the three Radixact beam qualities of interest and logarithmic

Imaging protocol

mAs

kVp

XS thorax/pelvis

1

100

S thorax

0.8

120

S pelvis/ M thorax

1

120

M pelvis

1.25

120

L thorax

1.6

120

L pelvis XL thorax/pelvis

2 4

120 140

interpolation was used to obtain the air-kerma calibration for each beam quality. The overall correction factor, PQ,chamb , and the ratio of mean mass energy-absorption coefficient for water-to-air were obtained from the tables in TG-61 for the A12 chamber using the measured HVL of each beam. Field size correction factors were not used as these corrections are less than 1% for field sizes larger than the reference field size.5 Point doses were acquired for one source-to-surface distance (SSD) for an inline profile, a crossline profile, and a depth-dose profile. w μen (1) Dw ¼ M � N k � PQ,chamb � ρ air water 2.B. Monte carlo modeling The Monte Carlo N-Particle (MCNP) transport code version 6.2 was used for all simulations in this work.6 The simulation geometry is shown in Fig. 2. A point source of photons was used for the starting particles for all simulations, which was set at depth in the anode to approximate the heel effect. The spectrum for each beam quality was obtained using the MATLAB code Spektr.7 Beam hardening due to the inherent filtration, the mirror, and the monitor chamber were accounted for in the spectra of the starting particles using Spektr.

Energy deposition tallies were used for all tallies in this work. The tally results were converted to a dose in mGy/mAs using the following equation,

0 mGy D mGy MeV ¼ X MC � Meas mAs , (2) DMC MeV mAs g � s:p: X 0 MC g�s:p: where D0Meas is the measured dose at the reference point in mGy/mAs, X 0MC is the simulated tally value at the reference point in MeV/g per source particle, and X MC is the simulated tally value in the conditions of interest. Doses to water at the measurement points were calculated for the purpose of benchmarking the MCNP model.

2.C. Patient dose calculations Five patient computed tomography (CT) datasets were acquired to be used for this imaging dose study. The disease

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FIG. 2. Geometry of the MCNP simulations showing the kV tube shell (a), the tungsten anode (b), the 1 mm aluminum and 0.5 mm copper filters (c), the static tungsten collimator (d), and the 1.6 mm polycarbonate bore material (e). The anode–cathode axis is parallel to the direction of table travel.

[Color figure can be viewed at wileyonlinelibrary.com]

sites included in this work were lung (x2) and pancreas, which are likely candidates for respiratory Synchrony, and endothelium and prostate, which are likely candidates for nonrespiratory Synchrony motion management. All doses are provided for a single fraction and a standard number of radiographs per fraction (100). The imaging protocol for each patient was chosen based on patient size and disease site. The planning target volume (PTV) ranged from 2 to 146 cc among the five patients. Four or five imaging angles per gantry rotation were simulated in this work. Soft tissue was defined as all tissue excluding bone. The skin was defined as a 5 mm rind around the body. The CT datasets were aligned such that the target was centrally located in the bore (within the geometric restrictions of the bore). Couch travel was modeled by simulating the source at multiple superior/inferior locations for each gantry angle. The extent of superior/inferior point source locations was equal to the couch travel distance during treatment. The voxel size was 2.5 × 2.5 mm2 or smaller in the axial plane and 3 mm or smaller in the superior/inferior direction. The carbon fiber couch of the Radixact was included in the simulations. Each voxel in the original CT image was assigned a physical density using a measured HU-to-density calibration phantom8 and a material such as air, lung, adipose, muscle, cartilage, and bone based on the physical density. Equation (2) was used to convert the tally values into dose for each voxel. The dose calculation grid overlapped the CT grid.

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uncertainty (k = 1) of the measured reference doses were estimated to be 4% based on the uncertainty of the measurements (<0.5%) and the 3.6% uncertainty reported in TG-61 for in-water point doses at the reference depth.5 The standard uncertainty of nonreference-condition point doses (such as off-axis or depths not at 2 cm) was estimated to be 5%. The A12 ion chamber was observed to have a small energy dependence in the range of interest, as the air-kerma coefficients varied <0.2% between tube potentials of 100 and 140 kVp. Figure 3 shows a comparison of the measured and simulated point doses for each energy. The median and maximum global dose difference between the measured and simulated data were 0.6% and 6.0%, respectively.

Organ dose statistics are shown for each patient in Table III and example CT datasets and dose distributions for two of the patient cases are shown in Fig. 4. Doses are for 100 total images to approximate the number of images that may be delivered in one fraction. Simulation uncertainty in the MCNP 3D mesh dose was summarized for each patient case using the value umed,10%, the median simulation uncertainty of voxels above 10% of the maximum dose. This value was 10% or less for all cases. The mesh doses are scaled by the reference dose measurements, whose uncertainty was estimated to be 4%. Therefore, the total uncertainty of voxel dose calculation in the patient geometries is estimated to have a median value of less than 11%, which is much less than the acceptable uncertainty of 20% stated in the TG-180 report.2 4. DISCUSSION The MCNP model reproduced the measured point-dose data within a median difference of 0.8%. The asymmetric profile in the inline direction from the heel effect is reproduced (Fig. 3) by simulating the point source at depth in the anode, which allows for modeling changes in output and spectrum as a function of superior/inferior position. The accuracy of the model in reproducing the measured data was far better than the accuracy tolerance of �20% stated in TG180 for imaging dose calculations during radiotherapy.2 The calculated doses to water in this work approximately agree with the work of Chen et al., who reported that the CTDIw for 100 radiographs of the large thorax protocol (120 kVp, 1.6 mAs) was 8.4 mGy.4 The point dose at isocenter for the large lung case using the large thorax imaging protocol in this work was 6.8 mGy. However, this work indicates TABLE II. Parameters used for calculation of TG-61 point-doses in-water for three beam qualities commonly used on the Radixact.

Tube potential (kVp)

Measured HVL (mm Cu, mm Al)

N k (Gy/C)

100

0.50, 9.07

4.412E7

120

0.63, 10.17

4.408E7

3. RESULTS

140

0.77, 11.01

4.406E7

The parameters used to determine point doses in water using the TG-61 protocol are shown in Table II. The standard

The conditions for the measured reference dose (D0Meas ) were open field (20 × 20 cm2 at iso), 55 cm source-to-point distance (SPD), and 2 cm depth.

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D0Meas (mGy/mAs) 0.120 � 0.005

0.216 � 0.009

0.336 � 0.013

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FIG. 3. Measured (A12) and simulated (MCNP) point-dose data in water for open-field radiographs (20 × 20 cm2). Error bars indicate standard error (k = 1). The standard error of all simulated points was less than 0.5%. The heel effect can be observed in the inline direction via the asymmetric profile. The gray lines indicate the location of the reference point, at 2 cm depth and 55 cm from the source along the central axis. [Color figure can be viewed at wileyonlinelibrary.com]

that doses to soft tissue may be much higher than ~7–8 mGy, such as a max dose (D1%) of 31.0 mGy for the endothelium patient imaged with the XL pelvis protocol. In addition, maximum doses to bony structures ranged from 20.2 to 71.7 mGy. The data in this work suggest that patient dose is highly dependent on imaging protocol. The reference point dose was proportional to kVp3.1 when fit with the data in Table II. Dose at this point increases by a factor of 1.76 from 100 to 120 kVp and by a factor of 2.84 from 100 to 140 kVp. Patient dose also scales linearly with mAs, therefore patient dose can increase by a factor of 5 among the mAs protocol considered in this work. The values reported in this work can be scaled using the observed trends (Dose / kVp3:1 � mAs) to approximate doses when the clinical imaging protocol differs from the protocol used in this work.

Imaging protocol in this work was chosen based on the patient size and disease site alone. The imaging angles were

chosen to be approximately evenly spaced for this study. During a patient treatment, imaging protocol and angles can be chosen to optimize image quality and ensure visibility of the target. If angles are chosen such that they are unevenly spaced, this will result in a change in the hot and cold spots at the overlap of the beams. However, the user is prevented from choosing angles that are too close together and doses near the isocenter will likely not be largely changed since all imaging angles are centered on isocenter. The effect of varying imaging angles on patient dose was outside the scope of this work.

Patient anatomy and geometric setup also has a large effect on patient dose. The maximum dose (D1%) to soft tissue ranged from 6.2 to 31.0 mGy among the five cases, which is a difference of a factor of 5. Even when scaled for kVp output using the fitted power law and to equal mAs, the maximum dose to soft tissue still varied by more than a factor of 2

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TABLE III. Simulated patient dose in mGy from 100 radiographs.

Patient Large lung L thorax

Small lung XS Thorax

Prostate M Pelvis

Endothelium XL Pelvis

Pancreas L Pelvis

umed,10%T (%)

Diso

10

6.8

8

9

4.1

6.8

Volume

Dave

D50%

Heart

6.8

6.9

8.5

10.1

Lungs

7.4

7.3

11.4

15.1

Ribs

12.7

8.9

33.4

47.7

Skin

3.8

1.5

11.4

16.3

Soft tissue

4.6

3.5

10.1

15.0

Spinal cord

6.6

6.4

10.0

32.2

10

10.9

6.9

D1%

Heart

3.2

3.2

4.4

5.3

Lungs

3.2

3.1

4.8

6.2

Ribs

6.4

4.7

15.0

20.2

Skin

1.7

1.1

4.2

6.6

Soft tissue

2.2

2.0

4.4

6.2

Spinal cord

1.8

1.6

3.3

6.0

Bladder

7.2

6.9

9.2

10.7

11.9

12.6

19.1

26.0

Prostate

5.4

5.4

6.1

6.8

Rectum

6.0

6.1

7.3

8.2

Skin

2.9

1.8

6.9

10.2

3.1 11.4

2.6 11.4

6.6 13.5

9.7 15.3 46.5

Pubic bone

9

D10%

Soft tissue Bladder Femurs

11.1

6.8

29.9

Pubic bone

29.8

25.4

52.0

71.7

Rectum

12.8

12.6

16.5

20.5 35.9

Skin

6.1

1.8

21.6

Soft tissue

7.3

4.6

18.4

31.0

Liver

8.3

8.3

10.6

13.3

4.4 10.4

3.7 10.5

8.4 12.2

11.9 13.6

Lungs Pancreas Skin

3.9

1.5

11.7

18.2

Soft tissue

4.5

3.0

10.6

15.5

Spinal cord

5.9

5.9

9.7

16.7

Doses may be scaled to approximate dose from multiple fractions or varying number of total images. The imaging protocol used in the simulation is indicated in italics. The median simulation uncertainty of voxels above 10% of the maximum dose is denoted umed,10%T.

among the five cases. The scaled maximum dose to soft tissue was lowest for the largest patients, since the individual fields are attenuated before overlapping. This can be observed in Fig. IV which displays dose distributions for a large and a small patient.

The attenuation of the couch used in this study was explored by simulating dose to a homogenous water phantom from a posterior to anterior beam with and without the couch. The average dose to a 10 × 10 × 0.5 cm3 volume on the surface of the water closest to the couch decreased by 5% and the dose to a point at 2 cm depth from the couch decreased by 8% when the couch was added. Therefore, skin entrance dose is expected to decrease by ~5% when imaging through the couch.

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In addition to patient anatomy and imaging protocol, total patient dose will be highly dependent on treatment parameters. The number of images throughout a patient’s treatment is a function of total treatment time and the number of active gantry rotations, since images are acquired every gantry rotation. Highly modulated treatments are more likely to have a tight pitch, leading to more gantry rotations per treatment and thus more total images. Treatments with a large number of fractions will likely have more total images since images must be acquired prior to starting the treatment to build the model of the target motion. In addition, the number of images per fraction might increase substantially if the treatment is paused regularly due to inaccurate target motion modeling, as new images must be acquired to resume the treatment each time the treatment is paused with the MV beam off.

Table IV compares the range of imaging doses in this work to imaging doses from other image-guidance procedures used in radiotherapy from the TG-180 report.2 These data suggest that dose from 100 radiographs on the Radixact is expected to be slightly less than that from typical kVCBCT scans or a Tomo MVCT setup scan.

Cumulative dose from kV images throughout many Synchrony fractions can be estimated by scaling the per fraction values provided in this work by the total number of images acquired throughout treatment. In an initial study with 13 Synchrony treatment plans with various fractionation schemes, the number of images per fraction ranged from 50 to 206, and the total number of images over all fractions ranged from 310 to 1920, with an average of 810 images.9 When scaled to 2000 total images, the largest dose to any structure in Table III would be 1.4 Gy (D1% to the pubic bone for the endothelium patient). This value is slightly less than 5% of a typical therapeutic dose of 30, or 1.5 Gy. Therefore, it is expected that most cases will not exceed 5% of the therapeutic dose from these images alone, as 2000 images is an upper estimate and most therapeutic doses are greater than 30 Gy. However, these images will be combined with other routine imaging techniques and care should be used to reduce imaging dose from these procedures as choice of treatment parameters has a large effect on total number of images.

5. CONCLUSIONS Monte Carlo simulations were used to calculate volumetric patient dose from 100 images on the Radixact with tube potentials between 100 and 140 kVp. Patient median doses to soft tissue and bony structures ranged from 2.0 to 4.6 mGy and 4.7 to 25.4 mGy, respectively. These doses are lower than that from other imaging procedures such as kV-CBCT or Tomo MVCT scans. Total patient dose will depend on imaging protocol, fractionation, and parameters such as number of gantry rotations, therefore careful planning can reduce imaging doses.

The values in this work can be used by healthcare professionals to quantify patient imaging dose for typical treatment sites and manage risk from these procedures.

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FIG. 4. Example computed tomography (CT) axial slices through isocenter and dose distributions in mGy resulting from 100 radiographs on the Radixact for two patient cases. Four imaging angles were used for the cases in this example. The target was placed at the geometric isocenter. The red line on the CT slice displays the AP location of the coronal dose distribution in this figure. Organ-specific dose statistics are provided for each patient case in Table III. [Color figure can be viewed at wileyonlinelibrary.com] TABLE IV. Comparison of imaging doses from 100 planar radiographs on the Radixact to doses from other imaging procedures.2 Procedure

Description

Dose range (mGy)

Soft tissue organs; median dose Soft tissue organs; median dose

1.6–12.6a 9.0–20.0

Varian pelvis kV-CBCT

Soft tissue organs; median dose

11.9–19.9

Tomo MVCT setup scan

Isocenter of 30 cm water phantom

8.0–25.0c

Radixact 100 radiographs Elekta pelvis kV-CBCT b

Analysis is limited to soft tissue organs and excludes the skin and the “soft tissue” contour. a Range from five patient cases in this work. b M cassette, no bow-tie filter, 120 kVp, 1 mAs/acquisition, 650 acquisitions. c Range corresponds to the range of available pitches (coarse, normal, fine).

ACKNOWLEDGMENTS The authors thank the students and staff of the UWMRRC for their continued support, the UWRCL and UWADCL customers whose calibrations help support ongoing student research at the UWMRRC. CONFLICT OF INTEREST The authors have no conflict of interest to disclose. a)

Author to whom correspondence should be addressed. Electronic mail: williamferris0@gmail.com; Telephone: (402) 889-3894.

REFERENCES 1. Keall PJ, Mageras GS, Balter JM, Emery RS, Forster KM, Jiang SB. The management of respiratory motion in radiation oncology report of AAPM Task Group 76. Med Phys. 2006;33:3874–3900.

2. Ding GX, Alaei P, Curran B, et al. Image guidance doses delivered during radiotherapy: quantification, management, and reduction: report of the AAPM therapy physics committee task group 180. Med Phys. 2018;45: e84–e99.

3. Schnarr E, Beneke M, Casey D, et al. Feasibility of real-time motion management with helical tomotherapy. Med Phys. 2018;45:1329–1337.

4. Chen GP, Tai A, Keiper TD, Lim S, Li XA. Technical note: comprehensive performance tests of the first clinical real-time motion tracking and compensation system using MLC and jaws. Med Phys.

2020;47:2814–2825.

5. Ma CM, Coffey CW, DeWerd LA, et al. AAPM protocol for 40–300 kV x-ray beam dosimetry in radiotherapy and radiobiology. Med Phys.

2001;28:868–893.

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6. Werner CJ. MCNP6.2 Release Notes. Los Alamos National Laboratory report LA-UR-18-20808; 2018.

7. Siewerdsen JH, Waese AM, Moseley DJ, Richard S, Jaffray DA. Spektr: a computational tool for x-ray spectral analysis and imaging system optimization. Med Phys. 2004;31:3057–3067.

8. Constantinou C, Harrington JC, DeWerd LA. An electron density calibration phantom for CT-based treatment planning computers. Med Phys.

1992;19:325–327.

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9. Ferris WS, Kissick MW, Bayouth JE, Culberson WS, Smilowitz JB. Evaluation of radixact motion synchrony for 3D respiratory motion: modeling accuracy and dosimetric fidelity. J Appl Clin Med Phys. 2020;21:96–106. https://doi.org/10.1002/acm2.12978.

Clinical Imprementation and Initial Experience of Real-Time Motion Tracking With Jaws and Practical Radiation Oncology® (2021) xx, e1-e10

Multileaf Collimator During Helical Tomotherapy Delivery www.practicalradonc.org

Clinical Investigation

Clinical Implementation and Initial Experience of Real-Time Motion Tracking With Jaws and Multileaf Collimator During Helical Tomotherapy Delivery Guang-Pei Chen, PhD,* An Tai, PhD, Lindsay Puckett, MD, Elizabeth Gore, MD, Sara Lim, PhD, Timothy Keiper, PhD, Candice Johnstone, MD, Monica Shukla, MD, Colleen Lawton, MD and X. Allen Li, PhD Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin Received 21 October 2020; revised 28 January 2021; accepted 29 January 2021

Abstract Purpose: This work reports the clinical implementation of a real-time motion tracking and correction system using dynamic multileaf collimator and jaws during helical tomotherapy delivery (Synchrony on Radixact; Accuray, Inc).

Methods and Materials: The first clinical Synchrony on Radixact system was recently installed and tested at our institution. Various clinical workflows, including fiducial implantation, computed tomography simulation, treatment planning, delivery quality assurance, treatment simulation, and delivery, for both fiducial-free and fiducial-based motion tracking methods were developed. Treatment planning and delivery data from initial patients, including dosimetric benefits, real-time target detection, model building, motion tracking accuracy, delivery smoothness, and extra dose from real-time radiographic imaging, were analyzed.

Results: The Synchrony on Radixact system was tested to be within its performance specifications and has been used to treat 10 lung (fiducial-free) and 5 prostate (fiducial-based) patients with cancer so far in our clinic. The success of these treatments, especially for fiducial-free tracking, depends on multiple factors, including careful selection of the patient, appropriate setting of system parameters, appropriate positioning of the patient and skin markers, and use of treatment simulation. For the lung tumor cases, difficulties in model building, due primarily to the changes of target detectability or respiration patterns, were observed, which led to important system upgrades, including the addition of a treatment delivery simulation capability. Motion tracking metrics for all treated patients were within specifications, for example, (1) delivery quality assurance passing rates >95%; (2) extra dose from radiograph <0.5% of the prescription dose; and (3) average Potential Diff, measured D, and Rigid Body were within 6.5, 2.9, and 3.9 mm, respectively.

Conclusions: Practical workflows for the use of the first clinical motion tracking and correction system in helical tomotherapy delivery have been developed, and the system has now been successfully implemented in our clinic for treating patients with lung and prostate cancer.

2021 The Authors. Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Sources of support: This work had no specific funding.

Disclosures: The authors’ institution received grants from Accuray, Inc, during the conduct of the study. L.P. received travel support from Accuray, Inc. X.A.L. received grants from Elekta AB, grants from Manteia Med, and grants from Siemens outside the submitted work.

Research data are stored in an institutional repository and will be shared upon request to the corresponding author. * Corresponding author: Guang-Pei Chen, PhD; E-mail: gpchen@mcw.edu https://doi.org/10.1016/j.prro.2021.01.010 1879-8500/ 2021 The Authors. Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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Introduction Intrafraction organ motion can be significant during radiation therapy (RT) for tumors in thorax, abdomen, and pelvis, and is a major issue affecting RT delivery accuracy.1-4 Tumor motion management, including clinical approaches as simple as planning target volume (PTV) expansion, motion compression, or breath hold to more sophisticated techniques such as gating and tracking, has been investigated for decades.5-8 In 2019, a real time motion tracking and compensation technique using dynamic multileaf collimator (MLC) and jaws (Synchrony on Radixact; Accuray, Inc) was introduced for tomotherapy delivery.9 The first commercially available Synchrony on Radixact system was installed in our institution recently.10 The system can be used for both respiratory (with and without fiducials) and nonrespiratory (with fiducials) motion tracking. The fiducial-free tracking is attractive in lung tumor treatment, for example, stereotactic body RT, for possible PTV margin reduction.11 It also avoids the costs and risks associated with surgically inserted fiducial markers. Neither fiducial-free nor fiducial-based tracking, which have been previously used in RT, have been demonstrated with helical delivery.12 We have previously reported our comprehensive commissioning tests for this helical-based system.10 In this work, we report our clinical implementation of this technology focusing on our learning curve, practical workflows, and patient selection criteria. Our initial experience gained in using the system for treating patients with lung and prostate cancer is also included.

Methods and Materials Compliance with ethical standards All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

Technical description of the Synchrony system Technical details of the Synchrony on Radixact system have been reported elsewhere.10,13,14 A brief description of the system is provided. The hardware of the system consists of a kV x-ray source and a detector panel mounted with a 90 offset from the MV beam and a camera mounted on the ceiling to capture motion of a set of light-emitting diodes (LEDs) placed on the patient’s skin and treatment couch. By tracking the LEDs on the

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patient while simultaneously acquiring 2-dimensional (2D) kV x-ray radiographic images that detect tumor location, a model is built that correlates the external surface motion with respiratory tumor motion. For nonrespiratory tracking, a position model is built using radiographic images only. During the irradiation, the tumor motion is predicted based on the updated model at each newly acquired radiographic image and is compensated by dynamic MLC shifting and jaw sweeping. The success of model building is critical and is manipulated by adjusting radiographic image protocols (kVp and mAs) and angles, LED placement, fiducial selection if applicable, and thresholds of various system parameters.15 Such parameters include model quality, represented by a statistical prediction of the 3D distance error when the model is used (Potential Diff), predicted and measured target position difference on a plane at target centroid and parallel to the radiographic image (Measured D), maximum fiducial pair distance difference between detection and planning (Rigid Body), and predicted target motion in 3D (Target Offset). The radiation delivery can be paused manually or automatically when a parameter exceeds its threshold within a certain amount of time (Autopause Delay) or the target moves outside hardware tracking range (Target Outside of Jaw Range). During clinical implementation, the Synchrony system hardware and software were upgraded multiple times to add functionalities and to improve performance based on the feedback from our initial experience. Adaptive modeling off (allowing treatment to progress using the last good model) and treatment delivery simulation (allowing operators to carry out the entire Synchrony tracking without turning on the MV treatment beams) are among these additional functionalities.

Overview of clinical implementation The first clinical Synchrony on Radixact system was installed in our clinic in June 2019. Extensive commissioning and quality assurance (QA) tests were performed to ensure geometric and dosimetric accuracy of the motion tracking before implementing the technology in the clinic.10 To implement the technology in the clinic, we first performed a series of end-to-end tests of the entire Synchrony motion tracking process using a motion phantom with realistic motion signals. A workflow as shown in Figure 1 was designed based on the tests. A step-by-step checklist for each tracking mode was developed for the clinical team, including radiation oncologists, physicists, dosimetrists, and radiation therapists, to follow. As an example, Table 1 shows the checklist for the fiducial-free respiratory motion tracking treatment.

To successfully use the Synchrony system, particularly for fiducial-free tracking, suitable patients need to be

Practical Radiation Oncology: --- 2021

Figure 1

Implementation of real-time tracking for Radixact

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Workflow for Synchrony tumor tracking treatment process.

selected carefully in consideration of (1) the size of the kV panel (20 20 cm2 projected at the isocenter) on which the target needs to be visible for the whole

treatment; (2) the jaw swing range ( 20.0 and 12.5 mm for the 10 and 25 mm jaw widths, respectively); and (3) model building reliability, which depends on multiple

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Table 1

Practical Radiation Oncology: --- 2021

Checklist for the nonfiducial RSM treatment

Category

Item

Morning warmup Setup

kV included?

Load/set up patient as usual (free breathing) Light-emitting diodes (LED) placement

IGRT Prepare

Acquire images

Build model (RSM only)

Treat/resume

End of treatment PostTx

As usual kV protocol and mAs Potential Diff (mm) Measured D (mm) Target offset (mm) If more than 1 fiducial, rigid body (mm) Target outside jaw range threshold (% of time) Tracking range (mm) Auto pause delay (sec) Sensitivity Adaptive modeling Used fiducial identifiers Angles () used Assess images and parameters Adjustment when treatment cannot be started

Stability (1-3 on patient, 4 on couch) Visibility ( 2 of 1-3; and 4) Thorax (L) 120 kVp 1.6 mAs 10 5 20.0 1.5 10 40 60 Low On 0, 55, 120, 188, 240, 308

Select/deselect/change angle Turn off certain images Change thresholds Select/deselect/drag fiducials Select/deselect LEDs If cannot go through, troubleshooting, consult with phy/MC for stopping Synchrony treatment Assess images and parameters Adjustment when model building fails Adjust LED positions Select/deselect/change angle Turn off certain images Change thresholds Reset model If cannot go through, troubleshooting, consult with physicist/physician for stopping Synchrony treatment Adaptive modeling On If system pauses automatically Acquire images and/or build model again Pause if it is needed to Select/deselect/change angle Select/deselect LEDs Select/deselect/drag fiducials Change thresholds Stop if it is needed to Reposition LEDS Acquire another CTrue image If the next patient is not RSM tx, unplug and clean the LEDs Unload patient as usual QA PreciseArt Document Billing

Abbreviations: IGRT Z image guided radiation therapy; QA Z quality assurance; RSM Z respiratory motion tracking.

Applicable lists for each patient depend on tracking mode being used; nonapplicable items are grayed out. Items in green boxes are specific to an individual patient/fraction that need to be determined before treatment.

factors, for example, visibility of the tracking target and regularity of the breathing pattern. Based on the phantom tests, we included the following considerations in the patient selection criteria: (1) target location (eg, lung tumor not attached to mediastinum and chest wall) and size (eg, within a sphere of 8 cm diameter or smaller, but a diameter >~2 cm is recommended); (2) contrast of the

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target on x-ray images (eg, computed tomography [CT] number); (3) respiratory motion pattern (not extremely irregular, eg, hyperventilation, frequent respiratory rate, rapid change of amplitude, phase, and baseline, etc); (4) motion range (eg, 2 to 20 mm in longitudinal direction) and rigidity if multiple targets exist; (5) separation and motion rigidity with target if fiducials are used; and

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(5) patient health (both physical and mental for a patient to tolerate possible long on-table time) and possible metal implants that could obstruct target detection.

Six weeks after the installation, we started using the system for patients with lung tumor with fiducial-free respiratory tracking mode and for patients with prostate cancer with fiducial- tracking mode. The workflow, checklists, and patient selection criteria were iteratively refined and updated based on the experience gained from the clinical use on the patients. Described are details in each key step in using the Synchrony system on patients.

non-Synchrony treatment as a backup in case the Synchrony plan could not be delivered. In the Synchrony plan for a patient with a lung tumor the gross tumor volume (GTV) was delineated on the midP images, whereas in the non-Synchrony, the GTV was delineated based on the exhale phase CT together with 4D positron emission tomography, when available, and the internal target volume was created to enclose the GTV motions in the 10 phases.

The organs at risk were segmented from the midP images.

The PTV was created from the GTV with a 5-mm expansion for the Synchrony plan, whereas the PTV for the non-Synchrony plan was the internal target volume plus 5-mm margin. For the prostate cancer cases with fiducial tracking, no special consideration was taken in PTV and organs at risk delineation due to the use of Synchrony.

The Synchrony plan was generated using a Precision workstation (Accuray, Inc), similar to a regular tomotherapy plan, with a few exceptions: (1) the jaw width was selected based on the target motion range and delivery efficiency; (2) for fiducial tracking, the fiducials were identified as tracking targets; (3) for fiducial-free tracking, tracking target volume (TTV), for example, solid tumor, was contoured with the soft tissue window level preset; (4) 2 to 6 radiograph angles were selected based on the visibility of the tracking target on the digitally reconstructed radiographs; (5) the patient might have been positioned with a lateral offset if a laterally off-centered target was to be treated; (6) the pitches and modulation factors might have been chosen to compromise the plan quality, gantry rotation speed, and total treatment time; and (7) a simulation plan, similar to the Synchrony plan but without the MV (treatment) beam, was generated for the treatment delivery simulation described in the following sections.

Fiducial implantation For prostate cancer treatment, 4 fiducials of 0.8 � 3.0 mm cylindrical gold markers (2021-1-2; Best Medical International, Inc, Springfield, VA) were implanted in urology with the patient under short-duration local anesthesia. The fiducials were placed using ultrasound guidance, with each at the left and right of the base and apex of the prostate, respectively. Images were taken before, at regular intervals during, and following the procedure to check for fiducial positioning and the absence of immediate complications. An interval of 1 to 2 weeks was planned to allow the fiducials to stabilize before the RT planning CT was acquired.

CT simulation and treatment planning A conventional CT was acquired for each patient with prostate cancer and a 4DCT was acquired for each patient with lung tumor using a CT simulator (Drive; Siemens).

The 4DCT was acquired with the patient free breathing and the breathing pattern recorded using a pressure sensor under an abdominal belt (Anzai Medical Co, Ltd, Japan).

The CT images were reconstructed with 2-mm slice thickness using an iterative metal artifact reduction algorithm (Siemens) for patients with fiducials or other implanted metal objects or using a filtered back projection algorithm otherwise. For a 4DCT set, 10 respiratory phase sets were generated based on amplitude-sorting or phasesorting if breathing signal was cut off due to large diaphragm motion. The images were processed and a timeaveraged middle position (midP) CT was created using the 10 sets of phase images in MIM software (v6.8.6; MIM Software Inc, Cleveland, OH).16 A middle phase image set can be used if lung tumor density in midP is low due to inaccurate deformable registration. The respirationinduced tumor motion was measured based on the maximum edge motion of the tumor at all phases along the longitudinal (SI), vertical (AP), and lateral directions.

For patient-specific QA purpose, the continuous breathing signal was used to generate patient-specific motion trace with the measured mean breathing period and amplitude set based on the assessed tumor motion in each direction.

For each case treated, both Synchrony and conventional (non-Synchrony) plans were created with the

Patient-specific delivery QA Each Synchrony plan was delivered to a 3D phantom (ArcCheck; Sun Nuclear, Melbourne, FL, or Delta4 Phantomþ; ScandiDos, Uppsala, Sweden) with the Synchrony on Radixact system. The phantom was placed on a motion platform (CIRS; Norfolk, VA, or Hexamotion; ScandiDos) driven by an irregular motion trace for a patient with prostate cancer or the patient-specific breathing trace recorded during the 4DCT scan with LEDs placed on the motion platform surrogate (CIRS) or directly on the phantom itself (Hexamotion) for a patient with a lung tumor. Tracking targets used were inserts with embedded high-density block (fiducial-free tracking) or fiducials (fiducial tracking). The delivered dose was measured in the phantom and was compared with that from calculation.10 Dose agreement was analyzed using gamma analysis with the criteria of 3%, 3 mm, and 5% threshold.

In addition, each non-Synchrony plan was measured per our institutional standard.

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Treatment simulation and delivery In our implementation, we schedule the first session as a delivery simulation to evaluate reliability of the model building and smoothness of the entire delivery process.

This allows us to verify that the patient could be successfully treated with Synchrony. With a successful simulation, the Synchrony treatment proceeds. Otherwise, the non-Synchrony plan will be carried out.

On each day with Synchrony simulation or treatment, a daily QA procedure was performed to verify appropriateness and consistency of the motion tracking functionality and the geometry and dosimetry accuracy. At the simulation or each fraction of treatment, the checklist with predetermined patient-specific parameters was followed by the clinical team. The patient, under free breathing for the whole treatment, was set up as usual, except that the LEDs were placed on both the couch and on the patient for respiratory tracking. The patient was repositioned by aligning the motion-averaged target from the daily image to the target in the midP planning image with the standard megavoltage CT (MVCT)-based image guided RT process. The Synchrony procedure was carried out with these steps: (1) acquiring pretreatment x-ray radiographs at preselected angles from the plan to initiate target detection and motion model building based on the real-time radiographs and LED signals, (2) adjusting various tracking parameters if necessary (mostly in the simulation session) to account for a variety of patient specific issues (eg, unexpected motion change, difficulty in target detection, low model confidence, lack of enough good-quality radiographs), (3) initiating beam on while the jaws and MLCs were tracking the target motion, and (4) closely observing patient treatment and taking necessary action (pause treatment, take more images to re-establish model with MV beam off, resume treatment, etc) while the target was tracked, with motion model updated at each newly acquired radiograph image at preselected angles.

Postdelivery evaluation To evaluate the correctness of the treatment delivery, we analyzed the treatment data stored in the system during the delivery after each treatment fraction using an inhouse software tool. These data included: (1) target detection confidence and rate of successful detection; (2) model- building confidence, percentage of beam-on radiograph images (model building difficulty would lead to more images acquired initially and additional images acquired after interruption, both with MV beam off), and frequency of treatment interruption; and (3) tracking goodness as measured by average Potential Diff, Measured D, Rigid Body effectively used in compensation, and target position difference between current and updated models. Identified possible correlation with the successful tracking was used to adjust relevant parameters for the remaining treatment.

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To evaluate dosimetry accuracy after each fraction, we reconstructed the dose delivered on the daily MVCT using PreciseArt (Accuray, Inc). The dose volume parameters were evaluated and compared with their planning goals. When the Synchrony plan was not completely delivered, the reconstructed dose was used as a bias dose to create a new plan for the remaining treatment.

Results We have treated 10 patients with lung tumor and 5 patients with prostate cancer using Synchrony on Radixact. There was a steep learning curve in this initial period. The system (hardware and/or software) was upgraded 2 times to improve its performance with additional functionalities during the period. Based on our clinical implementation and the initial clinical experience, we observed that the success of Synchrony treatments relied on (1) careful selection of suitable patients, (2) optimal patient and LED positioning, (3) appropriate setting of tracking parameters, and (4) use of treatment simulation. In fact, the simulation tool was used for 3 potential patients and 2 of these patients were determined not suitable for Synchrony treatment due to substantial variation of the breathing pattern or patient health condition.

Fiducial-free tracking All 10 patients with lung tumors were treated with stereotactic body RT with doses of 54 or 45 Gy in 3 fractions or 50 Gy in 5 fractions. The total tumor motion ranged from 4.6 to 31.1 mm (median 6.4 mm). The Synchrony plan beam on times were between 504.1 and 1020.9 seconds (median 599.8 seconds). Comparing to the corresponding non-Synchrony plans, the Synchrony plans led to reductions of PTV volume, lung V5, V20, and mean dose by 26.4% 13.3%, 10.5% 16.8%, 16.0% 8.7%, and 12.0% 7.4%, respectively. Figure 2 compares dose-volume histograms and dose distributions of Synchrony and non-Synchrony plans for a representative case. For the cases treated, the average plan delivery QA passing rate was 99.2% 1.0% with the minimum of 97.4%, all above the 95% passing criteria.

Various x-ray radiograph protocols, for example, 120 kVp and 2.0 mAs, 120 kVp and 1.6 mAs, and 140 kVp and 3.2 mAs, were used depending on patient body size, target visibility, and model building smoothness. Number of image angles per rotation ranged from 3 to 6 (median 4), and the average time between images ranged from 5.3 to 13.9 seconds (median 7.5 s). As an example, the radiographic image is compared with the corresponding digitally reconstructed radiographs for 1 of the cases treated in Figure 3. For the 10 patients with lung cancer,

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Compared with non-Synchrony plan, the Synchrony plan led to a reduction of 19.6% (115 cc) and 27.2% (30 cc) of lung V5 and V20, respectively. In (B), the Synchrony and non-Synchrony PTV difference is demonstrated in a sagittal view. The patient had biggest tumor motion in longitudinal direction and vertical next. The isodose lines shown are from the Synchrony plan on the left and non-Synchrony plan on the right.

the threshold setting ranges for Potential Diff, Measured D, and Target Offset were 5 to 10, 4 to 6, and 15 to 40 mm, respectively, depending on target motion range.

In the early stage of this clinical implementation with unupgraded system, treatment might be interrupted primarily due to the unsuccessful model building during the delivery. The frequency of such interruptions (pauses) depended on multiple factors including (1) change of target detection capability on radiographs due to the obstacle of patient anatomy and/or implanted metal objects with patient traveling during helical delivery, (2) substantial change of the breathing pattern and LED signals, (3) tight Synchrony parameters, and (4) patient overall health condition. For 3 patients treated before the

upgrade, some planned Synchrony treatment fractions were aborted because the large number of pauses resulted in the treatment being too long to be delivered within our scheduled treatment slot (60 min). When a Synchrony fraction delivery was aborted, the remaining fraction dose was delivered with or without Synchrony at another fraction. For a non-Synchrony completion delivery, PreciseART was able to be used to reconstruct the delivered dose that was used as the bias dose for the nonSynchrony plan. When there was no pause or a low number of pauses, the Synchrony deliveries were smooth, with delivery times comparable with those of non-Synchrony deliveries (as low as 22 min from door to door).

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Figure 3 A typical radiograph image (A) and digitally reconstructed radiographs (DRRs) (B) for a patient with lung cancer. The cyan X indicates the predicted target position, and the purple þ indicates the found target position. The target offset calculated for this radiograph was 6.9 mm. Average target motions for this patient were �1.8, �4.1, and �2.6 mm in lateral, longitudinal, and vertical, respectively. (A color version of this figure is available at https://doi.org/10.1016/j.prro.2021.01.010.)

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Figure 4 (A)Variation of successful target detection rate with tracking target volume (TTV). (B)Variation of model confidence with TTV volume. (C) Variation of percentage of beam-on radiograph image (BORI) with TTV volume (primary vertical axis), and variation of average number of BORI per Gy dose (NBORI/Gy) with TTV volume (secondary vertical axis). (D) Variation of treatment interruption frequency with average light-emitting diodes (LED) amplitude. One of the 10 patients was not included due to unavailable raw data for analysis. Patients with successful target detection rate lower than 80% were not included in (D).

Successful target detection based on real-time radiograph depended on multiple factors, as shown in Figure 4.

The successful target detection rate was found to be not definitely lower with a smaller TTV (Fig 4A). The model building confidence and percentage of beam-on radiograph image showed the trend of being lower with a

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smaller TTV, as shown in Figure 4B and 4C, respectively.

The average number of beam-on radiograph images per unit dose for each patient is also shown in Figure 4C. In general, number of beam-on radiograph images per unit dose is bigger with larger irradiated volume but the jaw width and pitch used also play a role, as indicated by the

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Figure 5 (A) Variation of average fiducial detection rates and total number of acquired images with treatment fraction for a patient with prostate cancer. (B) Variation of average Potential Diff, Rigid Body, Target Offset, and model confidence with treatment fraction for the patient. Error bars are from the daily standard deviations.

outlier in the plot, for which the delivery had too many rotations due to a small jaw width (1 cm) combined with a small pitch (0.1) being used in the plan. It was also observed that the model building experienced a smaller number of interruptions with LED signal amplitude exceeding a certain threshold (eg, 5 mm) when patients with low successful target detection rate (eg, 80%) were excluded (Fig 4D). For this reason, we normally placed LEDs on stable locations on the abdomen or chest where relatively large motion was observed. For all patients with lung tumor treated, the patient’s average Potential Diff and Measured D ranged from 2.9 to 6.5 mm (median, 3.9 mm) and from 1.5 to 2.9 mm (median, 1.8 mm), respectively. The Potential Diff was found to be strongly correlated with the root means square (RMS) offset error (Potential Diff z 1.5 RMS offset error) based on phantom tests.

The imaging dose from the real-time radiographs was low. For the cases treated, the maximum average number of radiograph images (including those with MV beam off) per unit Gy RT dose was 45.3/Gy (typically below 10/ Gy), which leads to an imaging dose of approximately 0.5% of the prescription dose.10,17

Fiducial tracking Plans with a prescription of either 70 Gy in 28 fractions (4 patients) or 75.6 Gy in 42 fractions (1 patient) were generated for both Synchrony and non-Synchrony (a backup) delivery for the prostate cancer cases with beam on time range of 149.5 to 372.0 seconds (median, 315.1 seconds). The Synchrony treatment deliveries were smooth. All 4 fiducials for each patient were identified in plan generation with CT numbers >5000.

The minimum fiducial separation from all patients was 14.0 mm. The number of radiograph image angles picked was 4 to 6 (median, 6). The average time

between images ranged from 3.7 to 6.9 seconds (median, 4.2 seconds). The radiograph protocol with 120 kVp and 1.6 mAs was used. Thresholds of several key parameters were 6, 16, and 10 mm for Potential Diff, Target Offset, and Rigid Body, respectively. All 4 fiducials were detected confidently 94.0% of the time for the first patient and >99.5% of the time for other patients. There was a slight difficulty in detecting fiducial 4 for the first patient on some days because this fiducial was close to the rectum wall (Fig 5A). The average model confidence for each patient was 0.96 to 1.00 (median, 0.99). The overall percentage of beam-on radiograph image was 85.3% to 94.9% (median, 88.6%). The maximum number of radiograph images per unit dose among all patients was 38.9/Gy, which is equivalent to approximately 0.3% of the planned dose.10,17 The maximum values of patient overall average of Potential Diff, Rigid Body, and Target Offset were 1.4 3.3, 3.9 1.7, and 4.8 2.7 mm, respectively. The variations of their daily averages are shown in Figure 5B for the first patient. The intrafraction motion of the prostate varied between different fractions and moved up to 8 mm but was typically 2 to 5 mm within ~6 min primarily in SI and AP directions. This motion is consistent with those observed with ultrasound systems.3,18 The average difference between target positions predicted by the existing and updated models was small; for example, such values for a typical patient were 0.0 0.4, 0.0 0.4, and 0.0 0.6 mm in lateral, AP, and SI directions, respectively, indicating that the target tracking metrics were within specifications.

Discussion Intrafraction motion remains a key challenge in radiation therapy. With a steep learning curve, we have

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successfully implemented the Synchrony on Radixact system to manage intrafraction motion in our clinic. The capability of motion tracking and compensation with Synchrony on Radixact combined with high dose conformity with the helical delivery19 can lead to minimized PTV volume, improving normal tissue sparing. As shown in this work, successful use of the Synchrony on Radixact system requires special considerations, including careful selection of suitable patients (eg, general health condition, tumor size and location, motion pattern, feasibility for fiducial implantation) and effective use of the technology (eg, informative treatment simulation, appropriate tracking parameters, and robust workflow).

The motion tracking accuracy and dose delivery accuracy were demonstrated adequately,10,14; however, it is still desirable to reconstruct the delivered dose based on actual information (eg, delivered sinogram, real-time motion incorporated images). The current dose reconstruction with PreciseART is based on planned sinogram on pretreatment MVCT, not accounting for actual delivered information such as intrafraction motion, variation in motion tracking, and so forth. Due to the nature of helical delivery, incomplete fractional Synchrony treatment should be avoided, as the subsequent delivery may not be able to fully account for the variations of motion and anatomy. As shown in this study, continuing technology advancements and user group clinical experience will flatten the learning curve and improve the applicability of the system for patient treatments.

Conclusions Performance of the first clinical motion tracking and correction system (Synchrony on Radixact) for helical tomotherapy delivery has been tested within specifications. Practical workflows, including patient selection technical criteria, treatment planning, patient specific QA, treatment simulation and delivery, and posttreatment evaluation, were developed. The system has now been successfully implemented in our clinic for treating selected patients with lung and prostate cancers. Despite the steep learning curve we experienced in the initial phases of clinical implementation, the dosimetry benefits of using the motion tracking and compensation are now achievable for our patients.

Acknowledgments We thank Kevin Sonnemann, CMD, for planning support; Sarah McDonald, RTT, for treatment support; and Rick Vaden, CMD, Nancy Schauer, CMD, Jeremy Heil, MS, and Andrea Cox, PhD for technical support.

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2. Suramo I, Päivänsalo M, Myllylä V. Cranio-caudal movements of the liver, pancreas and kidneys in respiration. Acta Radiol Diagn (Stockh). 1984;25:129-131.

3. Sihono DSK, Ehmann M, Heitmann S, et al. Determination of intrafraction prostate motion during external beam radiation therapy with a transperineal 4-dimensional ultrasound real-time tracking system. Int J Radiat Oncol Biol Phys. 2018;101:136-143.

4. Keall PJ, Mageras GS, Balter JM, et al. The management of respiratory motion in radiation oncology report of AAPM Task Group 76. Med Phys. 2006;33:3874-3900.

5. Mah D, Hanley J, Rosenzweig KE, et al. Technical aspects of the deep inspiration breath hold technique in the treatment of thoracic cancer. Int J Radiat Oncol Biol Phys. 2000;48:1175-1185.

6. Wong JW, Sharpe MB, Jaffray DA, et al. The use of active breathing control (ABC) to reduce margin for breathing motion. Int J Radiat Oncol Biol Phys. 1999;44:911-919.

7. Berbeco RI, Nishioka S, Shirato H, et al. Residual motion of lung tumours in gated radiotherapy with external respiratory surrogates.

Phys Med Biol. 2005;50:3655-3667.

8. Paganelli C, Seregni M, Fattori G, et al. Magnetic resonance imaging-guided versus surrogate-based motion tracking in liver radiation therapy: A prospective comparative study. Int J Radiat Oncol Biol Phys. 2015;91:840-848.

9. PRNewswire.com. Chicago, IL: Cision Ltd. Available at: https:// www.prnewswire.com/news-releases/accuray-launches-synchronymotion-tracking-and-correction-technology-for-the-radixact-sys tem-300836858.html. Accessed July 1, 2019.

10. Chen GP, Tai A, Keiper TD, et al. Technical Note: Comprehensive performance tests of the first clinical real-time motion tracking and compensation system using MLC and jaws. Med Phys. 2020;47: 2814-2825.

11. AAPM. The MArkerless Lung Target Tracking CHallenge (MATCH). Available at: https://www.aapm.org/GrandChallenge/ MATCH/default.asp. Accessed September 1, 2020.

12. Kilby W, Dooley J, Kuduvalli G, et al. The CyberKnife robotic radiosurgery system in 2010. Technol Cancer Res Treat. 2010;9: 433-452.

13. Schnarr E, Beneke M, Casey D, et al. Feasibility of real-time motion management with helical tomotherapy. Med Phys. 2018;45:13291337.

14. Ferris WS, Kissick MW, Bayouth JE, et al. Evaluation of radixact motion synchrony for 3D respiratory motion: Modeling accuracy and dosimetric fidelity. J Appl Clin Med Phys. https://doi.org/10.1 002/acm2.12978.

15. Accuray training document 1064193.A. In: Synchrony Real-Time Motion Tracking and Correction on the Radixact Treatment Delivery System. Sunnyvale, CA: Accuray Inc; 2019.

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Organ sparing total marrow irradiation compared to total body irradiation prior to allogeneic stem cell transplantation

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Received: 22 March 2021 Revised: 1 June 2021 Accepted: 7 June 2021 DOI: 10.1111/ejh.13675

ORIGINAL ARTICLE

Organ sparing total marrow irradiation compared to total body irradiation prior to allogeneic stem cell transplantation André Haraldsson 1,2 | Stina Wichert 3 | Per E. Engström 1 | Stig Lenhoff 3 | Dominik Turkiewicz 4 | Sarah Warsi3,5 | Silke Engelholm 3 | Sven Bäck 1,2 | Jacob Engellau 1,3 1 Radiation Physics, Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden 2

Department of medical radiation physics, Clinical Sciences, Lund university, Lund, Sweden 3

Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden 4

Abstract Objectives: Total body irradiation (TBI) is commonly used prior to hematopoietic stem cell transplantation (HSCT) in myeloablative conditioning regimens. However, TBI may be replaced by total marrow irradiation (TMI) at centres with access to Helical TomoTherapy, a modality that has the advantage of delivering intensity-modulated radiotherapy to long targets such as the entire bone marrow compartment. Toxicity after organ sparing TMI prior to HSCT has not previously been reported compared to

Department of Pediatric Oncology and Hematology, Skåne University Hospital, Lund, Sweden

TBI or with regard to engraftment data.

5

Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden

ceived organ sparing TMI prior to HSCT and compared this cohort to retrospective

Correspondence André Haraldsson, Radiation Physics, Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden.

Email: andre.haraldsson@med.lu.se

67.5% for all patients treated with TMI and 80.5% for patients with matched unrelated

Methods: We conducted a prospective observational study on 37 patients that redata on 33 patients that received TBI prior to HSCT. Results: The 1-year graft-versus-host disease-free, relapse-free survival (GRFS) was donor and treated with TMI, which was a significant difference from historical data on TBI patients with a hazard ratio of 0.45 (P = .03) and 0.24 (P < .01). Engraftment with a platelet count over 20 [K/µL] and 50 [K/µL] was significantly shorter for the TMI group, and neutrophil recovery was satisfactory in both treatment cohorts.

There was generally a low occurrence of other treatment-related toxicities.

Conclusions: Despite small cohorts, some significant differences were found; TMI as part of the myeloablative conditioning yields a high 1-year GRFS, fast and robust engraftment, and low occurrence of acute toxicity.

KEYWORDS

ALL, HSCST, TBI, TMI, Tomotherapy

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2021 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd. Eur J Haematol. 2021;00:1–15.

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1 | I NTRO D U C TI O N Total body irradiation (TBI) is used in myeloablative conditioning regimes prior to hematopoietic stem cell transplantation (HSCT), primarily to younger patients with high-risk haematological malignancies.1,2 The rationale of TBI is shown by lower relapse rate and improved overall survival (OS) when radiotherapy combined with chemotherapy is compared to chemotherapy alone.1-3 However, the standard radiotherapy treatment with whole-body anterior-posterior irradi4

ation is toxic, especially in combination with chemotherapy, and may cause significant side effects to several organs such as lungs, kidneys, bowel and liver. Increased toxicity has previously haltered attempted dose escalation, a lower relapse rate with higher radio5

therapy dose has not affected the overall survival. A consensus on TBI technique and fractionation 6,7 has been lacking, which hampers comparisons between centres.

Helical Tomotherapy (HT; Accuray, CA, USA) is a radiotherapy

Summary of significance • This is the first reported comparison between two specific radiotherapy techniques with regard to haematological recovery and toxicity, where the newer technique irradiates less to the tissue surrounding the bone marrow as compared to the older radiotherapy technique.

• From our data, we conclude that the newer targeted radiotherapy is not worse than the older total body irradiation, and more patients survive without complications associated with side effects from either radiation or the transplantation.

• Patients irradiated prior to hematopoietic stem cell transplantation should be considered for the newer, more targeted radiotherapy, and could potentially reduce adverse events associated with the treatment.

treatment modality capable of delivering intensity-modulated treatments to complex and long targets like the bone marrow, generally referred to as total marrow irradiation (TMI). HT allows precise treat-

cyclosporine and methotrexate were used as standard GvHD proph-

ment and imaging of targets up to about 135 cm length without any

ylaxis. In addition, in both cohorts, patients with a matched unre-

field junctions, and with the built-in imaging, it delivers precise radio-

lated donor (MUD) all received Thymoglobuline, an anti-thymocyte

8,9

This provides for the opportunity to deliver bone marrow

globulin (ATG) in the conditioning, 4 mg/kg if the HLA match was

targeted radiotherapy while sparing other organs, which may affect

≥8/8 and 6 mg/kg if the HLA match was 7/8. The date of the last

recovery, toxicity and outcome.

follow-up is the 20th of August 2020. The study was approved by

therapy.

Toxicity after organ sparing TMI prior to HSCT has previously 10,11

been reported,

the Regional Ethical Review Board in Lund, Sweden (2013/149 and

and dose escalation trials have been con-

2017/132). Signed informed consent according to local guidelines,

ducted12,13 as well as reduced intensity studies,14 but has thus far

the guidelines of the European Blood and Marrow Transplantation

not been compared to standard TBI treatment with patients from the

Group (EBMT), and the Declaration of Helsinki was obtained in all

same clinic nor reported with regard to graft-versus-host disease-

patients prior to treatment to register patients demographics, diag-

free, relapse-free survival (GRFS) or engraftment. In this paper, we

nosis, transplant characteristics, outcome and length of follow-up.

compare prospectively observed patients that received TMI with

The data were then retrieved from our institution's local transplant

retrospective data on a similar patient cohort receiving the same

registry and supplemented in case of missing data by reviewing the

fractionated TBI during the 5-year period that preceded the intro-

patient's clinical charts.

duction of the new TMI irradiation technology, with other treatment standards unchanged.

2 | M ATE R I A L S A N D M E TH O DS 2.1 | Patient characteristic

2.2 | Radiotherapy treatment Our method for TMI has previously been described in detail,15 but is summarised in this section. The patients were irradiated with 2 Gy/ fraction twice daily, to a total dose of 12 Gy unless stated otherwise.

The treatment was performed with a TomoTherapy HD that delivers

In this study, all patients at our JACIE accredited transplant centre

radiation at a maximum of 860 cGy/min at 1.5 cm depth in a helical

in Lund (Sweden) receiving TMI-based myeloablative conditioning

fashion. All patients were immobilised, scanned and treated in two

prior to HSCT were consecutively included since the introduction of

positions due to the maximum treatment length of 140 cm on the

the treatment modality in October 2014. For comparison, we used

TomoTherapy, and the upper body treated head-first followed by

retrospective data on all patients that have received TBI as part of

the lower body treated feet-first at every fraction. For all patients,

a myeloablative conditioning regimen during the previous 5-year

the clinical target volume included the skeletal structures and the

period, between July 2009 until August 2014. Patients receiving a

spleen. For patients with acute lymphoblastic leukaemia (ALL) the

haploidentical alfa/beta T–cell-depleted transplant were excluded.

CNS and for male children, testicles were included. A 5-10 mm mar-

The stem cell source was for all adult patients’ peripheral blood stem

gin, depending on immobilisation of body site, was added as a plan-

cells (PBSC) and for children's bone marrow (BM). For all patients,

ning margin to account for movement and geometrical uncertainties

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called planning target volume (PTV). Dose to organs at risk was mini-

non-relapse death as a competing risk. GRFS events were defined

mised without compromising dose to this PTV.

as the first occurrence from severe (grade >II) acute GVHD, severe

Patients receiving TBI were treated immobilised in a side posi16

chronic GVHD, relapse or death from any cause. Patients’ that did

with lead blocks to

not reach the specific time point was censored. For GVHD, compet-

shield the lungs. The absorbed dose rate at the dose maximum depth

ing risk included treating deaths, relapse and graft failure. For time to

of 1.5 cm was approximately 30 cGy/min.

engraftment, patient with relapse or death was censored. The sub-

tion at 4.5 m distance from the radiation source

distribution hazard model28 was used for the analysis of outcomes with competing events.

2.3 | Evaluation of toxicity and outcome

All tests were two-sided and considered significant at P < .05, using 95% confidence intervals. All statistical analyses were per-

Follow-up included overall survival (OS), 1-year GvHD-free/

formed with Python 3.629 or R.30

relapse-free survival (GRFS),17 1-year transplant-related mortal-

The following variables were included in the analysis: recipient

ity (TRM), engraftment data, acute toxicities, scoring of acute and

age, disease, disease status at HSCT, donor type, in vivo T-cell de-

chronic graft-versus-host disease (GvHD) and relapse rate (RR).

pletion, GVHD prophylaxis, Karnofsky performance score (KPS) for

Where GRFS was defined as the fraction of patients that survived

adult patients, donor-recipient sex match and year of transplant. All

with no adverse event described in depth in the original article.

clinical variables were tested first for the affirmation of the propor-

For late effect complications, the median time of follow-up for the

tional hazard assumption.

TMI cohort is slightly over one year, but we report on pulmonary and renal function tests before and at 3, 6 and 12 months, respectively, after HSCT.18 Engraftment was defined according to EBMT criteria: the first of three consecutive days with neutrophil count

3 | R E S U LT S

≥0.5 × 109/L and ≥1.0 × 109/L, and platelet count ≥20 × 109/L and

3.1 | Patient characteristics

mainly scored according to the modified Glucksberg criteria.19 The

A total of 37 TMI patients and 33 TBI patients were analysed.

TMI cohort was additionally scored according to the MAGIC crite-

Patient characteristics were very similar with respect to age, gender,

ria. 20 For the assessment of chronic GvHD, we have used stand-

diagnosis distribution, stem cell source and CD34 cell doses for the

ard NIH criteria. 21,22 Glomerular filtration rate has previously been

cohorts, Tables 1 and 2. Median follow-up (range) was 13 (2-70) and

used to estimate the radiation and chemotherapy-related renal tox-

72 (2-134) months for the TMI and TBI groups, respectively. There

icity in TBI23 and was calculated from the pre- and post-treatment

were more patients in the TMI cohort that had a disease of second

S-creatinine. Idiopathic pneumonia syndrome (IPS) was defined as

complete remission (CR2) or worse. Dose distribution to the target

lung symptoms, dyspnoea and hypoxia, with radiological evidence

was similar for the cohorts, two patients in the TMI group received

of widespread alveolar injury, in which infectious aetiologies, as well

reduced 10 Gy in 5 fractions, and one received 8 Gy on four frac-

≥50 × 109/L (without transfusion), respectively. Acute GvHD was

as cardiac and renal dysfunction, has been excluded. 24 Function

tions. Two patients from the TBI group received 10 Gy in 5 fractions.

pulmonary test constituted of FEV1 (Forced Expiratory Volume in

For the TMI patients, the dose was kept to a minimum in the kidneys,

one second). The probability for complications was calculated using

heart, bowel bag and liver, Figure 1. Generally, lower to (surround-

normal tissue complication probability (NTCP),

25,26

a widely used

ing) normal tissue. Also, with TMI a larger portion of the bone mar-

logistic model for estimating the probability of radiation-induced

row received closer to a prescribed dose, that is better homogeneity.

toxicity in radiotherapy. Radiation toxicity scoring was done according to the common Radiation Therapy Oncology Group (RTOG) criteria. 27

3.2 | Survival

2.4 | Statistical analysis

treatment types was 67.5% for TMI and 39.4% for TBI patients

The 1-year GRFS (no GRFS-related event at 1 year) for the two (HR = 0.45, 95% CI: 0.21- 0.93, P = .027), Figure 2A. When only con-

Hypothesis testing was performed using Mann-Whitney U test

sidering patients with MUD, the GRFS at 1 year was 80.5% for TMI

for continuous variables, and chi-squared or Fisher's exact test for

and 42.3% for TBI patients, respectively (HR = 0.24, 95% CI: 0.09-

categorical variables. Covariates and significance for toxicities and

0.67, P = .003), Figure 2B. More patients in the group that received

recovery where time to event existed was tested using Cox's propor-

TMI as radiotherapy survived without any adverse events such as

tional model. Kaplan-Meier was used to assess the non-parametric

graft-versus-host disease compared to historical data on TBI pa-

survival on group level for overall survival, and the log-rank test

tients. A total of 27 patients treated with TMI had a follow-up time

was used to compare the survival distribution between the two pa-

longer than 1 year, and 33 patients treated with TBI. Several vari-

tient groups. The probability of relapse was calculated using non-

ables were tested univariate and GRFS was additionally modelled

relapse death and TRM as competing risk and TRM using relapse and

with multivariate logistic regression, Table 3, where radiotherapy

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TA B L E 1 [Patient characteristics]: Thymoglobuline, an anti-thymocyte globulin (ATG), was used for all patients with matched unrelated donor (MUD). Diagnosis included was: B-Acute Lymphoblastic Leukaemia (B-ALL), T-Acute Lymphoblastic Leukaemia (T-ALL), Mixed Phenotype Acute Leukaemia (MPAL), Acute Myeloid Leukaemia (AML), Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN), Chronic Myeloid Leukaemia (CML), MyeloProliferative Neoplasms (MPN), Multiple Myeloma (MM), Non-Hodgkin's Lymphoma (NHL), Myelodysplastic Syndrome (MDS). Stem cell sources included bone marrow (BM) or peripheral blood stem cells (PBSC). Human leukocyte antigens (HLA) for a matched unrelated donor (MUD) was compared as perfect match (8/8) versus less than 8/8. Similar, the number of patients in first complete remission (CR1) was compared to second complete remission (CR2) and partial remission (PR) or worse. Finally, the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) was available for all adult patients in both cohorts, 31 of the TMI patients and 29 of the TBI patients. *Cyclophosphamide 60 mg/kg day −6 and day −5, Etoposide 60 mg/kg day-5 (maximum dose of 3600 mg) Patient characteristics

TMI (N = 37)

TBI (N = 33)

Median age (range) /years

29 (5-57)

28 (10-53)

19 (51%)

19 (58%)

HCT-CI Score 0 Score 1

3 (8%)

4 (12%)

Score 2

7 (19%)

6 (18%)

Score 3

1 (3%)

0 (0%)

Missing

7 (19%)

4 (12%)

Female

15

12

Male

22

21

B-ALL

18

12

T-ALL

3

5

Gender

Diagnosis

MPAL

2

0

AML (incl. BPDCN)

2

7

CML

3

1

MPN

1

1

MM

3

0

NHL

5

4

MDS

0

3

Stem cell source BM

7

4

PBSC

30

29

6.0 (σ = 1.2)

6.0 (σ = 1.1)

CD34 cell dose, median [×10 6/kg] Transplantation type MUD

29

26

MRD

8

7

Donor age, median (range)

27 (16-55)

32 (15-55)

MUD HLA match 7/8

4

7

CR1

16

20

>CR1 (or MDS)

21

13

Stage at tx

Chemotherapy* Cyclophosphamide

21

29

Etoposide

16

4

technique was a significant contributing factor. There was no signifi-

3.3 | Engraftment

cant difference in OS between the radiotherapy treatment types at 12 months (P = .509), TRM P = .239 or relapse P = .309. However,

The engraftment time for patients with peripheral blood stem cells

the cohorts are small, and the follow-up too short to assess long-

(PBSCs) as stem cell source was generally satisfactory for both TMI

term effects, and they are included merely for reference.

and TBI. The median (range) was 14 days (11-124) for TMI and 16 days

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TA B L E 2 [Disease characteristics]: Disease characteristics with radiotherapy type (RT), diagnosis, subclassification, disease stage at Tx, HCT-CI score for adults, age at Tx and Disease Risk Index (DRI) according to CIBMTR HCT- CI score

DRI (Disease Risk Index CIBMTR)

Age at Tx

RT

Diagnosis

Subclassification

Disease stage at Tx

TMI

MPN

8p11-syndrome (t(8;13)) with T lymphoblastic lymphoma

PR1 (FISH positive for FGFR-1 -rearrangement)

2

Intermediate

49

CML

Ph+, p210, with lymphoid blast crisis

CP2, no CHR (complete hematologic response) b

1

Low

45

ALL

Pre-B-ALL

CR2

NA

NA

14

ALL

Ph+, p210

CR1

0

Intermediate

35

ALL

Pre-B-ALL, t(12;21)

CR2 (CNS relapse)

NA

NA

12

Myeloma

IgG st IIIA, ISS stage II

PR2a

0

Intermediate

18

ALL

Pre-B-ALL, non responder day 29.

CR1

1

Intermediate

22

ALL

Pre-B-ALL, Ph+, p190

CR1

3

Intermediate

50

MPAL

MPAL (dominant pre-B-ALL clone)

CR1

0

NA

23

ALL

T-ALL, del(9p)

CR2

0

High

27

ALL

Pre-B-ALL

CR2

0

High

19

AML

Blastic plasmacytoid dendritic cell neoplasm

CR1

0

Intermediate

20

ALL

Pre-B-ALL

CR1

2

Intermediate

45

ALL

B-ALL

CR2

0

High

21

ALL

T-ALL/LBL, bulky disease

CR1

0

Intermediate

30

ALL

B-ALL Ph-like SFPQ-ABL1 fusion gene

CR1

0

Intermediate

30

ALL

Pre-B-ALL, Ph+p190

CR3

NA

NA

10

NHL

FL, FLIPPI 3A

VGPR3

0

Intermediate

47

ALL

B-ALL

CR2 (CNS and BM relapse)

0

High

29

ALL

Pre-B-ALL, complex karyotype, LiFraumeni mosaicism

CR1

0

Intermediate

35

Myeloma

IgA, ISS 3, t(4;14)

CR2 a

2

Intermediate

42

ALL

Pre-B-ALL

CR2 (CNS and BM relapse)

NA

NA

8

NHL

hepatosplenic T cells lymphoma (gamma/delta)

CR1

0

Intermediate

44

CML

Ph+, p210, with lymphoid blast crisis

CP2, Ph+ 96%b

2

Low

30

CML

Ph+, p210, with lymphoid blast crisis

CP2 with MMR (major molecular response)b

2

Low

20

ALL

Pre-B-ALL

CR2

NA

NA

13

a

Myeloma

RRMM with del(17p), PR3 on 6th line of therapy with VTD-PACE

PR3

2

High

43

NHL

hepatosplenic T cells lymphoma (gamma/delta)

CR1

NA

NA

9

NHL

DLBCL

PR3

2

Intermediate

52

AML

MLL-rearrangement, complex karyotype, extensive extramedullary disease

CR1

0

High

23

ALL

B-ALL

CR1

1

Intermediate

57

NHL

Waldenstrom macroglobulinemia

CR3

0

Low

55

ALL

T-ALL, bulky disease

CR1

0

Intermediate

20

(Continues)

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TA B L E 2 (Continued)

RT

Diagnosis

Subclassification

ALL

Ph+, p190

MPAL

TBI

Disease stage at Tx

HCT- CI score

DRI (Disease Risk Index CIBMTR)

Age at Tx

CR1

0

Intermediate

33

CR1

0

NA

20

ALL

Pre-B-ALL

CR2

0

High

33

ALL

Pre-B-ALL, ABL2-translocation

CR2 (CNS and BM relapse)

NA

NA

5

ALL

Pre-B-ALL, t(1;22)

CR1

NA

NA

15

MDS

RAEB-2 (10% blasts), normal karyotype

cytological remission

0

Intermediate

19

ALL

pre-B-ALL, Ph+, p190

CR1

0

Intermediate

32

AML

trisomy 13, FLT3 neg, NPM1 neg.

CR1

0

Intermediate

50

AML

M4. Inversion 16

CR2

0

Low

45

AML

Ph+, p210

CR1

0

Intermediate

53

ALL

T-ALL, t(7;11)

CR1

NA

NA

10

AML

normal karyotype, FLT3-ITD+, NPM1+

CR1

0

Intermediate

37

AML

normal karyotype, FLT3-ITD+, NPM+

CR1

2

Intermediate

50

ALL

T-ALL

CR1

0

Intermediate

24

MPN

sAML post-PV, trisomy 13, FLT3-ITD+,NPM1+

CR1

0

Intermediate

39

MDS

RAEB-2 (14% blasts), t(3;3)

PR (reduction of blasts to 6%-7%)

1

Intermediate

26

AML

FLT3-ITD+, NPM1 neg

CR1

0

Intermediate

31

ALL

Pre-B, t(8;14), not Burkitt

CR2

1

High

38

ALL

Pre-B, trisomy 21

CR1

NA

NA

10

ALL

Pre-B, t(4;11), MLL+

CR1

0

Intermediate

29

NHL

T lymphoblastic lymphoma (LBL)

CR2

0

Intermediate

28

AML

FLT3 neg, NPM1+.

CR2

1

Intermediate

47

MDS

RAEB-2/AML (20% blasts), complex monosomal karyotype, including −5 och −7

cytological remission

2

High

51

ALL

T-ALL + minor clone with pre-B-ALL and CNS involvement

CR1

NA

NA

10

NHL

Lymphoplasmacytic lymphoma, stage IV

PR1

0

Low

44

ALL

Pre-B-ALL

CR1

2

Intermediate

27

CML

Ph+, p210, with lymphoid blast crisis

CP2 with MMR (major molecular response) b

1

Low

22

ALL

Pre-B-ALL

CR2

0

High

24

NHL

T lymphoblastic lymphoma (LBL)

CR2

2

Intermediate

46

ALL

T-ALL, t(1;1), del(9), extramedullary bulky disease

CR1

0

Intermediate

24

ALL

Pre-B-ALL

CR2

2

High

28

ALL

MLL-rearrangement, t(4;11), XXY

CR1

0

Intermediate

24

ALL

Pre-B-ALL

CR1

0

Intermediate

42

ALL

Pre-B-ALL, t(4;11)

CR1

2

Intermediate

28

(Continues)

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TA B L E 2 (Continued)

RT

a

DRI (Disease Risk Index CIBMTR)

Age at Tx

Diagnosis

Subclassification

Disease stage at Tx

HCT- CI score

ALL

T-ALL, t(8;22) with fusion bcr/FGFR1

CR1

0

Intermediate

42

ALL

Pre-B-ALL

CR1

0

Intermediate

26

NHL

Sezarys syndrome with lymphadenopathy and bone marrow involvement

PR 1

0

Intermediate

25

According to IMWG response criteria for multiple myeloma [56].

b

CML response according to ELN (European Leukaemia Net) criteria [57].

F I G U R E 1 [Example dose distribution for the two radiotherapy types] Reconstructed dose distribution for total body irradiation (left/middle upper) and planned dose distribution for total marrow irradiation (right/middle lower) for the same patient and prescribed dose. The dose for TBI was reconstructed using delivered monitor units and reconstructed blocks from saved data. Absorbed dose is presented in Gy

(11-52) for TBI for a thrombocyte count of 20 [K/µL] (P < .01), and me-

Three months after transplantation, all but two patients in the

dian (range) of 16 days (12-144) and 19 days (12-136), respectively, for

TMI cohort and three patients in the TBI cohort showed complete T-

a count over 50[K/µL] (P < .01). Similar for neutrophil recovery with

lymphocytic and myeloid chimerism in peripheral blood. Two patients

absolute neutrophil count (ANC) over 0.5 [K/µL] and PBSC as stem

in the TMI cohort had mixed T-lymphocytic chimerism with 10%-15%

cell source, the median (range) was 18 (12-26) days and 18 (12-31)

and 6%, respectively, of their recipient cells. Both patients are alive

for TMI and TBI, respectively. Similar, for an ANC over 1.0 [K/µL], the

and disease-free 53 and 16 months after transplantation. Three pa-

median (ranges) was 20 (13-29) days and 19 (12-39) for TMI and TBI,

tients in the TBI cohort with mixed chimerism had progressive dis-

respectively. Similar for bone marrow (BM) as stem cell source, the

ease four, five and eight months, respectively, post-transplant.

time to engraftment for the TMI and TBI patients was 26 days (14-33) versus 29 days (20-176), 30 days(17-76) versus 72.5 days (23-226), 18 days (12-29) versus 25.5 days (19-29) and 21 days (13-33) versus

3.4 | Graft-versus-host disease

26 days (19-34) for a thrombocyte count of 20 [K/µL], thrombocyte count of 50 [K/µL], ANC over 0.5 [K/µL] and ANC over 1.0 [K/µL].

The incidence of acute GvHD scored >II according to the modified

Engraftment with a platelet count over 20 [K/µL] and 50 [K/µL]

Glucksberg criteria was 4 for the TMI cohort (N = 37) and 6 for the

was significantly shorter for the TMI group for patients with PBSCs

TBI cohort (N = 33), Table 3. Using standard NIH criteria for chronic

as a stem cell source (P = .01, P = .03) Figure 3, but not for patients

GvHD, there were 3 moderate-to-severe incidents for the TMI co-

with BM as stem cell source (P = .25, P = .25). With a subdistribution

hort (N = 36) and 8 for the TBI cohort (N = 32), Table 3. Only con-

hazard model, the difference between radiotherapy treatment types

sidering patients with MUD, the incidence was 0/28 and 5/25 for

was significant for time to platelet count over 20 [K/µL], Table 4.

TMI and TBI. Further, with multiple regression analysis, moderate-

Further, time to engraftment was modelled as a dependent variable

to-severe chronic GvHD was modelled as dependent where trans-

with a neutrophil count over 1.0 [K/µL] and a thrombocyte count

plantation was significant as independent variables, Table 3. Similar,

over 20 [K/µL], Table 4, where the difference was significantly im-

acute GVHD with grade >II was analysed with multiple regression,

pacted by radiotherapy type and stem cell source for time to platelet

Table 3. Similar results were obtained with Cox's regression, where

recovery, but no such correlation was seen for time to neutrophil

donor age (P < .01) and CMV serostatus status (P < .01) were signifi-

count.

cant factors influencing acute GVHD but radiotherapy type (P = .29)

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F I G U R E 2 [Kaplan-Maier plot for graft-versus-host disease-free survival].

GRFS over time presented for all patients (top) and for patients transplanted from MUD (bottom). Hazard ratio (HR) was calculated using Cox's proportional model, with radiotherapy treatment type as independent variable and significance testing with the log-rank test

178

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TA B L E 3 [Graft-versus-host disease-free/relapse-free survival and graft-versus-host disease]: Regression for GRFS, acute GvHD and chronic GvHD, presented with hazard ratio (HR), confidence intervals (CI) and significance. The variables were Radiotherapy treatment type, total marrow or total body irradiation, Cytomegalovirus (CMV) serostatus (D-/R-), type of donor, matched unrelated (MUD) or matched related (MRD), if the donor was over 40, Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI). Numbers in bold was found significant P < .05. Multivariate analysis with all the corresponding dependent variables listed under the independent variable, four dependents for GRFS and acute GvHD, and three dependents for chronic GvHD, with independent variables in bold Univariable

Multivariable

(N)

HR (95% CI)

P

HR (95% CI)

P

TMI (37)

0.45 (0.21- 0.93)

.03

0.39 (0.18- 0.84)

.02

2.29 (1.09- 4.79)

.03

2.08 (0.98- 4.38)

.05

1.78 (0.88-3.63)

.11

2.30 (1.10- 4.79)

.03

0.55 (0.16-1.92)

.35

0.49 (0.08-1.62)

.25

1.70 (0.43-6.61)

.45

4.29 (0.68-27.06)

.12

2.68 (0.76-9.09)

.13

7.25 (1.47-35.59)

.01

cont.

1.06 (1.02-1.13)

.01

1.08 (1.04-1.12)

<.01

TMI (37)

0.35 (0.10-1.30)

.11

0.33 (0.09-1.18)

.08

4.54 (1.43-14.37)

.01

4.99 (1.44-17.35)

.01

0.80 (0.18-3.52)

.76

1.66 (0.35-7.97)

.52

GRFS (1 year) Radiation treatment type

TBI (33) Transplantation type

MRD (15) MUD (55)

Disease stage

>CR1 (32) CR1 (38)

Acute GvHD Radiation treatment type

TMI (37) TBI (33)

Transplantation type

MRD (15) MUD (55)

CMV serostatus status

D-/R- (15) <D-/R- (55)

Donor age Chronic GvHD Radiation treatment type

TBI (33) Transplantation type

MRD (15) MUD (55)

CMV serostatus status

D-/R- (15) < D-/R- (55)

and transplantation type (P = .13) did not. Most notable, the pattern

3.5 | Radiation-induced normal tissue toxicity

of acute GvHD differed between the two cohorts with more cases of lower GI involvement for patients receiving TBI, 4 with stage >2

The probability of radiation-induced normal tissue complication

in the TBI cohort, versus 2 with stage >2 in the TMI cohort. Hence, a

(NTCP) grade over stage II, as graded according to RTOG criteria,

regression for lower GI acute GVHD stage >2 as the dependent vari-

was calculated for TMI and TBI, respectively. Estimated glomeru-

able was performed but none of the independent variables was sig-

lar filtration (eGFR) was lower after radiotherapy for the TBI group

nificant. Twelve patients in the TMI cohort fulfilled the new MAGIC

than for the TMI group, the difference was significant (P = .020)

criteria for mild acute GVHD with upper GI involvement stage 1,

but too small to be clinically relevant, Table 5. With linear regres-

whereas only two were biopsy-verified with a typical histologic pic-

sion to predict eGFR, no significant regression equation was found

ture, thereby fulfilling the older modified Glucksberg criteria for this

(P = .186, N = 44), where a few patients lacked follow-up serum

diagnosis.31 In the TBI cohort, only one patient was diagnosed with

creatine.

acute GVHD with upper gastrointestinal (GI) involvement according

There was only one incident of IPS in each cohort, a grade 4 event

to older criteria. In an attempt to retrospectively re-evaluate the TBI

from the TMI cohort versus a grade 5 event from the TBI group ac-

cohort according to the modern MAGIC criteria, at least five more

cording to CTCAE v.5. Both patients were older, 45 and 47 years re-

patients would have been scored with mild upper GI acute GVHD.

spectively, the TMI patient diagnosed with CML in a second chronic

There was one case of acute severe liver GvHD stage 4 in the TBI

phase and the TBI patient with AML in second complete remission.

cohort, compared to one case with milder stage 2 liver engagement

There was no incident of hepatic sinusoidal obstruction syndrome

of acute GVHD in the TMI cohort.

(HSOS) in either cohort.

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F I G U R E 3 [Time to engraftment]. Cumulative time to engraftment comparing radiotherapy treatment type. Time to engraftment according to EBMT criteria plotted for patients transplanted from peripheral stem cells (PBSCs)

4 | D I S CU S S I O N

except for the radiotherapy technique. The TMI cohort had more patients in second complete remission or worse. One factor that

The GRFS was significantly better for patients treated with TMI

could attribute to increased GRFS was the year of treatment, where

prior to HSCT than for patients irradiated with TBI when consider-

the TMI cohort was treated more recently. GRFS has been shown

ing matched unrelated donors. The difference remained significant

to increase to some extent over time and Holtan et al17 stratified a

when modelled with multivariate logistic regression. This result

number of variables related to HSCT and found in multivariate logis-

strengthens the impression that conditioning with TMI generally re-

tic regression that the period of treatment was significant with an RR

sults in a lower occurrence of toxicity, treatment-related mortality

of 0.8. This can be compared to the HR of a GRFS-related adverse

and GvHD. The treatment groups were very similar with regards to

event for our two cohorts of 0.24 in our study when considering

HCT-CI score, age, donor age, diagnosis, infused CD34+ cell count,

only patients transplanted from a matched unrelated donor. Thus,

and patients were given the same GvH prophylaxis and treatment

post-treatment care and other factors that have improved over time

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TA B L E 4 [Engraftment data for days to platelet count over 20 K/µL and days to neutrophils over 1.0 K/µL]: The variables were radiotherapy treatment type, total marrow or total body irradiation, stem cell source bone marrow or PBSCs and donor age over or under 40. Numbers in bold was found significant P < .05.

Independent variables in bold using all the dependent variables listed for multivariable regression. Higher hazard ratio (HR) should be interpreted in favour of faster engraftment

Univariable N

HR (95% CI)

Multivariable Pvalue

HR (95% CI)

Pvalue

Days to platelets >20 [K/µL] Radiation treatment type

TMI (37)

1.61 (1.02-2.55)

.04

2.04 (1.28-3.23)

<.01

TBI (33) Infused cell count CD34+

70

1.30 (1.10-1.53)

<.01

1.28 (1.02-1.61)

.03

Stem cell source

PBSC (59)

2.01 (1.33-3.05)

.01

2.12 (1.24-3.63)

<.01

0.98 (0.96-1.01)

.14

0.97 (0.95- 0.99)

.03

1.29 (0.79-2.09)

.31

1.20 (0.72-1.98)

.49

BM (11) Donor age

70

Days to neutrophils >1.0 [K/µL] Radiation treatment type

TMI (37) TBI (33)

Infused cell count CD34+

70

0.95 (0.78-1.15)

.59

0.83 (0.63-1.07)

.15

Stem cell source

PBSC (59)

1.60 (0.83-3.10)

.16

2.46 (1.04-5.80)

.04

0.99(0.97-1.02)

.66

0.98 (0.96-1.01)

.19

BM (11) Donor age

TA B L E 5 [Outcome data] The median follow-up for the TMI cohort is 12 months and for TBI patients 60 months. Estimated glomerular filtration rate (eGFR), median difference between the pre-transplant measurement versus 12 months after HSCT. Acute graft-versus-host-disease (aGvHD) patients with symptoms over grade II and which organ, with some patients experiencing symptoms in several organs. Abbreviations: Idiopathic Pneumonia Syndrome (IPS) and Hepatic Sinusoidal Obstruction Syndrome (HSOS) and aGvHD according to the modified Glucksberg criteria (MG). FEV1 is presented as the difference versus pre-treatment FEV1. *Number of patients with chronic graft-versus-host disease for patients alive at day 100. †Significant difference (p = .02). **number of patients with aGvHD with the number of incidence at each site

70

TMI (N = 37)

TBI (N = 33)

0

0

IPS incidence <Grade 4 Grade 4

1 (3%)

0

Grade 5

0

1 (3%)

eGFR difference (σ) [mL/min/1.73 m2]

−8.6 (13.7)†

−9.8 (16.7)†

FEV1 3 mo difference, median (σ) [L]

0.0 (0.3)

0.0 (0.4)

FEV1 6 mo difference, median (σ) [L]

0.1 (0.4)

0.1 (0.7)

VOD incidence

0 (0%)

0 (0%)

cGvHD*, moderate to severe

3 (9%) (N = 35)

8 (25%) (N = 32)

AGvHD > grade 2**

4 (8%)

6 (18%)

Skin

3

3

Lower GI

2

4

Liver

0

1

could, to some extent, explain the improved GRFS. However, the dif-

such a risk. Kim et al32 investigated patterns of relapse following

ference we present is more prominent than shown in other publica-

TMI prior to HSCT and found no evidence of increased extramedul-

tions attributed to the difference in time of treatment.

lary relapse related to total marrow or total lymph node irradiation

Limiting the dose to organs at risk and to a higher degree tar-

compared to published results of regimens with TBI, nor did they

get the bone marrow with TMI will subsequently lower the dose

find any increased risk of relapse in part of the patients irradiated

to circulating blood. There have been speculations that circulating

with over 10 Gy versus under 10 Gy. Similar, Stein et al33 found no

leukemic cells could increase the risk of relapse when decreasing

higher risk of extramedullary relapse with TMI as a radiotherapy

the dose to non-stem cell sites. The follow-up is too short to assess

technique prior to HSCT when compared to similar studies with TBI.

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HARALDSSON et AL.

In addition, in a review of literature by Kogut et al,34 including 246

incidence of radiotherapy-related early toxicity in the TMI cohort

patients, no risk of extramedullary relapse was found for patients

may be expected to also yield a lower risk of late side effects. This

that did not receive TBI.

will be reported in later studies with longer follow-up for this group.

Engraftment was significantly faster in the TMI group when mea-

The incidence of chronic GvHD was lower in patients who re-

sured by platelet count and with a lower incidence of both acute and

ceived TMI prior to SCT than the control group that received TBI, but

chronic GvHD. This has previously only been found in pre-clinical

the difference was not found significant. The prevalence of GvHD

trials,35,36 where both a dose distribution and dose rate have been

has been found to correlate with dose distribution36 in preclinical tri-

found to correlate with engraftment. Hui et al36 hypothesise that in

als. The prevalence of moderate-to-severe GvHD of 9% was similar

TMI, compared to TBI, the reduced radiation dose to the non-skeletal

to other studies for TMI46 in general, and more notable thus far no

organs results in a chemokine stromal-derived factor-1 (SDF-1) gra-

patients that were transplanted from MUD have developed severe

dient facilitating donor stem cells engraftment in the bone marrow

or moderate chronic GvHD. The incidence of acute GVHD was, simi-

niche. This could explain the shorter engraftment times in our TMI

lar to chronic GVHD, lower in the TMI group as compared to the TBI

cohort, though the engraftment time was adequate in the TBI group.

group but not statistically significant. One hypothesis for the lower

Another factor that could affect the engraftment time is the radio-

incidence is that TMI, compared to standard TBI, reduces the extent

therapy dose rate. Increased dose rate has long been linked directly

of damage to intestinal epithelial cells, a potential trigger of allore-

In this study, the local dose rate, that is the instanta-

active T-cell reactions.47,48 This is important, since the early onset of

neous dose rate, was increased 30 times in TMI compared to TBI.

acute GvHD has been found to correlate with an increased risk of

The global dose rate, the fraction dose divided by the total treat-

extensive chronic GvHD and TRM.49,50

to cell kill.

37

ment delivery time, was on the other hand decreased. We suggest

Total marrow irradiation and TBI prior to HSCT have been stud-

the local, but not the global, dose rate to influence cell kill and thus

ied in randomised trials. Paix et al51 reviewed the current literature

toxicity, but this subject is partly uncharted in a clinical setting for

in 2018. They concluded that Phase I and II trials have demonstrated

TBI and TMI. In addition, there is a difference in dose coverage to

the feasibility and tolerance of TMI and that the dose to organs at risk

the bone marrow of the ribs, in the lung shielded area between the

could be reduced. High-dose TBI of up to 14 Gy has been compared to

two techniques. The effect is negligible when considering the total

standard regimen.38 The authors found that the reduced relapse risk

volume but may affect the cell kill from the radiotherapy treatment

with higher doses was hampered by increased non-relapse mortality

in that volume. Finally, differences and advances in care for HSCT

(NRM) and found no significant difference in OS. Dose escalation with

patients have improved38 and could contribute to the increased re-

TMI has been investigated from 12 Gy up to 15 Gy13 for patients with

covery. Which of these effects impacts the treatment, and to what

ALL. The authors concluded that dose escalation was feasible and that

extent, should be attributed to further studies.

the doses were well tolerated. The authors concluded that research

The large difference in the mean dose and probability of compli-

should focus on strategies to reduce TBI toxicity since radiotherapy

cation to kidneys as calculated by NTCP did not translate to a large

clearly benefits disease control. TMI irradiation has also been investi-

difference in renal dysfunction. Renal dysfunction after TBI and SCT

gated in patients with relapsed ALL33 with doses of up to 20 Gy and had

has previously been reported for children,

39,40

where 44.4% had im-

a relatively low occurrence of severe acute GVHD but many patients

paired renal function or elevated creatinine levels at follow-up, and

exhibited severe cGVHD, and with a 1-year OS of 55.5%. Further,

for adults41 where 5 out of 29 and 4 out of 64 adult patients in the

Stein et al33 concluded that TMI is feasible and was encouraged by the

respective study had elevated levels. Pulmonary toxicity has previ-

preliminary clinical response. Treatment and dose escalation with TMI

ously been found to correlate with radiotherapy, cyclophosphamide,

prior to HSCT has been studied for a number of diseases such as mul-

the addition of busulphan42 and dose rate 43,44 in total body irradi-

tiple myeloma and ALL11,12,14 where the key takeaway was that TMI

ation using similar radiotherapy fractionation as the current study.

was found feasible, and CR rate was found encouraging. Jensen et al14

The fractionation of 12 Gy TBI in 6 fractions was found to induce

reported outcome and toxicity and compared transplant-related tox-

an IPS incidence of 6%-7% with lung shielding, which correlates well

icity and mortality from other studies52-55 with FLU/MEL condition-

with this study. Since dose rate has been found to correlate with pul-

ing combined with TMI regimens and concluded that their patient's

monary toxicity, there was an a priori concern that a switch to TMI

outcome compared favourably to those reported with chemotherapy-

on TomoTherapy could increase the pulmonary toxicity. However,

based conditioning alone. The lower toxicity in our study strengthens

the occurrence of IPS was low in both study groups. Hence, no

the perception that dose escalation using TMI is feasible, and patients

correlation could be found caused by increased local dose rate. A

previously ineligible for full-dose treatment could be eligible for radio-

much larger cohort would be required to rule out any difference.

therapy thanks to organ-sparing radiotherapy.

The incidence of IPS that occurred was both in older patients, which

This study compared two similar cohorts from the same clinic

actualise questions of reducing the prescribed radiation dose to pa-

that received similar treatment in all regards except radiotherapy

tients past their forties, similar to what has been recommended pre-

and time of treatment. The same GvH prophylaxis was used for both

viously.45 For the TMI cohort, the follow-up time is yet too short to

cohorts. Despite the large similarities in treatment, changes in care

evaluate late toxicity. However, as early toxicity following radiother-

can to some extent influence the result of the comparison and we

apy is related to an increased risk of developing late toxicity, the low

interpret the result with caution.

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HARALDSSON et AL.

5 | C o n c l u s i o n Our early results indicate that organ-sparing radiotherapy with TMI

8.

as part of the myeloablative conditioning translates to a low occurrence of toxicity, a robust and fast engraftment, and a low degree of GvHD. GRFS was significantly higher with TMI compared to condi-

9.

tioning with TBI. The low number of adverse events for patients that received TMI prior to HSCT at our one-year follow-up shows promising results and that organ sparing TMI warrants further studies and

10.

further follow-up to assess long-term effects and survival.

AC K N OW L E D G E M E N T

11.

The authors want to sincerely thank Dr Susann Ullén (Clinical Studies Sweden—Forum South, Skane University Hospital, Lund, Sweden) for input and discussion regarding the statistical methodology and presentation.

12.

C O N FL I C T O F I N T E R E S T Department of the corresponding author has an ongoing research agreement with Accuray Inc, which includes funding.

13.

DATA AVA I L A B I L I T Y S TAT E M E N T The data that support the findings of this study are available on request from the corresponding author.

14.

ORCID André Haraldsson

https://orcid.org/0000-0002-1694-3738

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How to cite this article: Haraldsson A, Wichert S, Engström PE, et al. Organ sparing total marrow irradiation compared to total body irradiation prior to allogeneic stem cell transplantation. Eur J Haematol. 2021;00:1–15. https://doi. org/10.1111/ejh.13675

S U P P O R T I N G I N FO R M AT I O N Additional supporting information may be found online in the Supporting Information section.

185

3D treatment planning on helical TomoTherapy

ARTICLE IN PRESS Medical Dosimetry ■■ (2018) ■■–■■

Medical Dosimetry j o u r n a l h o m e p a g e : w w w. m e d d o s . o r g

Dosimetry Contribution:

3D treatment planning on helical tomotherapy delivery system Cheng B. Saw, PhD,a Leah Katz, MD,b Carol Gillette, CMD,b and Lawrence Koutcher, MDb Northeast Radiation Oncology Centers (NROC), Dunmore, PA 18512; and bHudson Valley Radiation Oncology Associates, Cortlandt Manor, NY 10567

a

A R T I C L E

I N F O

Article history:

Received 18 February 2018 Accepted 19 February 2018 Keywords: Intensity-modulated radiation

therapy Radiosurgery Stereotactic body radiation therapy Stereotactic ablative radiation therapy Tomotherapy

A B S T R A C T

The helical tomotherapy is a technologically advanced radiation dose delivery system designed to perform intensity-modulated radiation therapy (IMRT). It is mechanistically unique, based on a small 6-MV linear accelerator mounted on a ring gantry that rotates around the patient while the patient moves through a bore, ultimately yielding a helical path of radiation dose delivery. The helical pattern of dose delivery differentiated tomotherapy from other contemporary radiation therapy systems at the time of its inception. The accompanying 3-dimensional (3D) treatment planning system has been developed to solely support this specific type of dose delivery system. The treatment planning system has 2 modules identified as TomoHelical and TomoDirect to perform IMRT and conformal radiation therapy, respectively. The focus of this work within the scope of this special issue on 3D treatment planning systems is to assess the use of planning tools to generate treatment plans for helical tomotherapy. Clinical examples are used throughout to demonstrate the quality and differences of various clinical scenarios planned with tomotherapy. © 2018 American Association of Medical Dosimetrists.

Introduction The helical tomotherapy system offers an integrated approach to radiation therapy, combining imaging and treatment delivery to precisely target a wide variety of pathology. 1 From the historical point of view, helical tomotherapy was conceived to optimally implement intensity-modulated radiation therapy (IMRT) treatment technique in the clinic.2 At that time, the concerns of the radiation oncology community were the ability to deliver a very

Reprint requests to Cheng B Saw, PhD, Northeast Radiation Oncology Centers, 1110 Meade Street, Dunmore, PA 18512.

E-mail: cheng.saw@aol.com

targeted dose, maximally spare surrounding sensitive structures, concurrent verification of beam shape and patient position, and of course, patient safety, which entail preventing patient collision with the dynamic therapy treatment unit.

The solution to these priorities and concerns was the introduction of the commercial helical tomotherapy delivery system by Tomotherapy, Inc. (Madison, WI) in 2003.3 Although helical tomotherapy was initially designed with IMRT intent, it has evolved to include 3-dimensional (3D) conformal radiation therapy. The design of helical tomotherapy is unique compared with other contemporary radiation therapy machines, and its accompanying treatment planning system has been developed specifically to support and enhance the helical tomotherapy treatment delivery capabilities. The focus of this work within the scope of this special

https://doi.org/10.1016/j.meddos.2018.02.012 0958-3947/Copyright © 2018 American Association of Medical Dosimetrists

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C.B. Saw et al. / Medical Dosimetry ■■ (2018) ■■–■■

issue on 3D treatment planning is to assess the current use of the helical tomotherapy system, as well as explore the exciting future it holds.

Table 1 Helical tomotherapy nomenclature Delivery mode option

Parameters

TomoHelical

Methods and Materials The helical tomotherapy delivery system consists of a small 6-MV linear accelerator mounted on a ring gantry that rotates isocentrically around the patient. As the patient moves through the bore, a helical path of radiation dose delivery is produced, as seen in Fig. 1. Although it looks like a helical computed tomography (CT) scanner on the outside, the beam intensity is modulated using an internal binary collimator.

The specially designed binary collimator has 2 banks, and each bank has 64 leaves with a beamlet size of 0.626 cm, giving a total field width of 40 cm. The binary collimator is computer controlled with the leaves sliding in and out of the slit aperture to provide temporal beam modulation. The jaw settings create a beam width of either 1.0, 2.5, or 5.0 cm.

Helical tomotherapy now allows movable jaws to optimize treatment planning, which is a significant improvement from the older, fixed jaw model.4 The helical tomotherapy unit also encompasses megavoltage CT imaging to provide imageguided radiation therapy capability for accurate patient setup.

As a technologically advanced dose delivery system, helical tomotherapy system has the network connectivity for the seamless transfer of electronic data. After the patient is immobilized and simulated, the CT image dataset on the patient is transferred to a contouring station. The initial stage of contouring typically involves image fusion with diagnostic imaging, and more commonly with positron emission tomography or magnetic resonance imaging for enhanced tumor visualization. After the image fusion, target volumes and organs at risk are delineated by the radiation oncologist, whereas pseudostructures, such as rings around the

Fig. 1. Helical tomotherapy unit. (Color version of figure is available online.)

Plan mode

IMRT/3DCRT

Field width

5.0 cm 2.5 cm

Jaw mode

1.0 cm Static/dynamic

Modulating factor Pitch Dose constraints and penalties TomoDirect Plan mode Field width

Jaw mode Gantry angles

IMRT/3DCRT 5.0 cm 2.5 cm 1.0 cm Static/dynamic 2-12

3DCRT, 3D conformal radiation therapy.

target volumes are drawn by the dosimetrist to aid in performing inverse planning.

The CT image and structure dataset are exported to the TomoHD treatment planning system (version 5.1.1.6). Initially, the origin and the laser system are identified and placed on the CT image dataset, the CT couch is then replaced with the helical tomotherapy couch, and the prescribed dose is assigned to the target volume at a defined percent level with a set number of fractions. Lastly, constraints are placed on organs at risk and pseudostructures. At this juncture, the treatment planning system provides 2 delivery mode options to choose, the TomoHelical or the TomoDirect.

TomoHelical treatment technique offers the helical mode of radiation dose delivery for the IMRT treatment method.

The dose delivery involves multiple rotations as the patient translates or moves through the bore of the system and the continuous high dose rate allows for shorter treatment times.

Besides the dose prescription, there are 3 important machine parameters that must be manually entered: field width, pitch, and the modulation factor. The field width options are 5.0, 2.5, and 1.0 cm, and the selected parameter depends on the length of the target volume, the shape of the target volume, and the anticipated treatment time. Generally, the larger field width is used for longer target volumes in the inferior to superior direction in the effort to reduce treatment time. The pitch refers to the relationship of the distance the couch travels per rotation to the field width. The modulation factor refers to the maximum leaf opening time to the average leaf opening time of all the nonzero leaf opening times. These various relationships must be matched for a prescribed dose to avoid regular intervals of hot spots that would otherwise be present, known as the “zebra” effect. The input parameters are listed in Table 1. Inverse-planning dose algorithm is used to generate the IMRT treatment plan. At this

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time, the dose constraints and their respective penalties are assigned to both the target volume and structure constraints. Treatment planning is then initiated, and the iterative process of optimization is performed. After a certain number of iterations, the penalties are adjusted interactively to “push” or modify the dose patterns. The interactive adjustment is made by first hitting the pause button to halt the dose algorithm calculation, adjusting the parameters, and then continue. The decision to make the change can be deduced from the isodose pattern, which is updated regularly on the screen. After a certain number of iterations, the isodose pattern plateaus, indicating that the dose algorithm calculation reaches a cost minimum or near a minimum. The process is repeated until an acceptable plan is obtained. The acceptability of the treatment plan is evaluated to ensure that the plan meets the target conformity requirements and normal tissue dose-volume constraints.

TomoDirect treatment technique offers the discrete angle, nonrotational option for 3D conformal radiation therapy.

TomoDirect permits the use of 2 to 12 user defined beam angles directed at the target, and the leaves of the multileaf collimation system extend or retract to enable the field to conform to the projected target volume. The delivery involves the movement of the leaves of the multileaf collimation system as the patient translates or moves into the radiation therapy machine.

The delivery quality assurance is an essential component of the dose delivery systems. It involves the measurements of the patient treatment fluence directed at a phantom and compared against the dose distribution generated by the treatment planning. At our institution, this is performed on the Delta4 3D phantom for physical measurements.5 The dose planes can be exported to the vendor’s software for isodose distribution comparison with the measurements. In addition, an absolute point dose measurement in the “Cheese” or delivery quality assurance TomoPhantom can also be taken.

Results Figure 2 shows an axial view of a TomoTherapy IMRT head and neck case. As pictured, isodose lines, targets, and organs at risk appear as they would within the helical tomotherapy treatment planning system. The major planes are typically used in this treatment planning system for evaluation, and the plane of interest can be rotated into the largest window to better examine the plan’s isodose pattern and volume conformality. As seen in Fig. 2, the axial view is displayed.

The isodose levels can be displayed in isodose lines or dose color wash, as seen in Fig. 2A and B, respectively. The choice of isodose line display vs dose color wash depends on the radiation oncologist’s preference and the clinical site, as some anatomical sites and disease contexts lend themselves better

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to 1 display over another. The color wash display is particularly useful for head and neck plan evaluation, as there are often several dose levels used. Figure 3 shows the dosevolume histogram for this head and neck case, and the specific values can be directly obtained by placing the cursor over the organs at risk of interest line.

The use of IMRT in general has become the standard of care for most head and neck patients, as the sparing of parotid structures and avoidance of xerostomia have been found to be superior. In that vein, the use of TomoTherapy for head and neck patients has allowed for dose intensification to gross tumor and areas at high risk of microscopic spread while sparing adjacent, normal tissue structures. The intrinsic complexity of head and neck anatomy and the relatively small areas over which sharp dose gradients are needed, lends itself very well to the dose modulating capabilities of TomoTherapy. Additionally, as many radiosensitive head and neck tumors recede, TomoTherapy’s integrated imaging system allows for radiation oncologists to know when they need to resimulate and replan, and be assured on a daily basis that the patient are setting up correctly. Although there is yet to be a prospective randomized control trial evaluating TomoTherapy vs other IMRT treatment planning systems, retrospective series have shown excellent local control rates and toxicity profiles with TomoTherapy. Modern day radiation oncologists regard TomoTherapy IMRT planning for complex head and neck plans as an excellent option.

Figure 4 shows a prone breast treatment plan indicating that the bore hole is sufficiently large to accommodate this widely used type of treatment technique. Breast tangents are dosimetrically mimicked through the use of the TomoDirect treatment planning modality, which takes advantage of autoselection and adjustment of width and length based on the drawn target volume.

Prone breast positioning allows for maximal lung sparing and in some women with specific anatomy, the heart and left anterior descending artery as well. TomoTherapy treatment planning is able to integrate this setup into its broad list of capabilities, and although it has been criticized in the past for spreading more low dose across a larger volume on normal tissue for prone positioning, its ability to maximally avoid heart and lungs still makes it an excellent modality for these women.

By its operational principles, helical tomotherapy is well suited to perform focal radiation, either in the form of stereotactic radiosurgery (SRS) or stereotactic body radiation therapy (SBRT).6-8 Focal irradiation broadly refers to treatment technique where multiple beams are directed at a small, discrete target to deliver a very high dose with sharp dose fall off. Helical tomotherapy delivers radiation systematically from all directions, in complete rotations, satisfying the dosimetric criteria of focal irradiation. Because of the increased

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Fig. 2. (A) A bilateral neck treatment plan in which isodose lines are displayed for a head and neck patient using TomoHelical delivery mode. (B) Same plan as in A but in color wash display. (Color version of figure is available online.)

number of degrees of freedom offered by TomoTherapy, an extremely conformal isodose pattern is produced.

TomoTherapy’s capabilities are very well suited to lung SBRT, which has been shown to have a far superior local control rate compared with the traditionally fractionated external beam radiation, and is an excellent option for medically

inoperable patients. As such, the use of SBRT has grown over the past decade and continues to be widely used. SBRT allows for excellent normal structure sparing, such as ribs, chest wall, esophagus, heart, skin, and spinal cord.

The ability of TomoTherapy to avoid normal structures and spread out surface skin dose makes it an excellent modality

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Fig. 3. The DVH for the head and neck treatment plan in Fig. 2. DVH, dose-volume histogram. (Color version of figure is available online.)

to provide SBRT.9 Figure 5 illustrated a posterior pleural lesion targeted by SBRT using TomoTherapy IMRT treatment planning. Note the excellent dose optimization around the adjacent spinal cord. Lastly, SBRT for centrally located lung tumors have often been excluded, for fear of tracheal/ bronchial toxicity; however, through TomoTherapy, many of these lesions may be safely treated. In this way, TomoTherapy helps expand treatment options for many lung cancer

patients. To summarize, the innate conformal delivery exhibited by TomoTherapy IMRT, meticulous setup using TomoTherapy’s onboard megavoltage CT system, and evolving respiratory gating techniques will only continue to render TomoTherapy an excellent delivery system for lung SBRT. In addition to SBRT, SRS in the treatment of brain metastases has become increasingly popular. SRS offers patients an excellent treatment alternative to whole brain radiation,

Fig. 4. TomoDirect treatment plan for prone whole-breast irradiation. (Color version of figure is available online.)

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Fig. 5. A peripheral lung lesion is targeted by SBRT using TomoTherapy IMRT. Note the excellent spinal cord sparing with this treatment planning approach. (Color version of figure is available online.)

which results in significant cognitive decline. In addition, it is far less invasive than surgical resection. TomoTherapy is compatible with SRS, as it is fast, achieves excellent conformity indices, spares normal brain tissue, is steady given the

ring gantry system, and requires no additional hardware. A typical treatment plan is shown in Fig. 6.

The vast utility and capabilities of TomoTherapy include prostate cancer treatment, both for definitive prostate/

Fig. 6. Axial view of the SRS plan for the treatment of brain metastases. Note the excellent dose fall off for each treated lesion. (Color version of figure is available online.)

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Fig. 7. An axial view of a TomoTherapy treatment plan for the treatment of prostate cancer. (Color version of figure is available online.)

seminal vesicle treatment only, (see Fig. 7) as well as prostate/ seminal vesicle plus pelvic lymph node treatment for patients with more advanced disease (see Fig. 7). The treatment of pelvic lymph nodes and prostate illustrates one of the strengths of TomoTherapy, as the target volume is an extensive planning target volume (PTV) in the superior to inferior axis. Note the isodose pattern made concave contours sparing the bladder and rectum (Fig. 8). Additionally, TomoTherapy allows for the treatment of prostate bed status post radical prostatectomy. Given the intrinsic movement of the prostate caused by bladder and rectum filling, the ability to image the patient directly before each treatment assures that the desired target always remains within the treated PTV while avoiding unwanted dose to the bladder and rectum.

Discussion Patients undergoing radiation therapy on the helical tomotherapy machine follows the procedures for the IMRT treatments: (1) immobilization and CT simulation, (2) treatment planning, (3) plan verification, (4) patient setup and target localization, and (5) dose delivery. This is the typical workflow of a modern radiation oncology facility. As a uniquely design dose delivery system on a ring gantry, the

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tight tolerances for IMRT are consistent with the requirements for focal irradiation.10,11 There is no additional hardware needed to perform SRS and SBRT using this dose delivery system. Also, the same image-guidance system is used for both focal irradiation and IMRT. The workflow of IMRT can be implemented for SRS and SBRT on the helical tomotherapy unlike being performed using medical linear accelerators or those done in the past, which require resources and quality assurance to ensure patient physical safety. It is also not a whole day event, which is typically associated with SRS procedure.

Helical tomotherapy offers some unique benefits as a dose delivery system. This includes the ability to treat multiple lesions in a session, which accelerates the treatment compared with other treatment modalities.12 By its very nature of rotational and translational dose delivery, the system is highly efficient in the treatment of extended length, for example, in total body irradiation.13 With the numerous degrees of freedom (beam angles), the treatment plan can yield a highly conformal treatment plan, in particular to irregular targets as illustrated in these examples.

TomoTherapy Radixact is the latest dose delivery system offered by Accuray, Inc. (Sunnyvale, CA)14 The machine output is higher, at 1000 MU per minute. The gantry rotation is also faster, at 10 revolutions per minute for imaging acquisition.

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Fig. 8. Axial view of a pelvic lymph node plus prostate treatment. Note the rectal and bladder sparing. (Color version of figure is available online.)

There is an available integrated data management system serving as a central management of data storage and processing for multiple dose delivery systems. The system allows for remote review and sign-off of reports and DICOM (Digital Imaging and Communications in Medicine) import/export and interfaces with other oncology information system. The treatment planning system, Accuray Precision, offers (1) the ability to plan for multiple Radixact dose delivery systems, (2) remote view and approval of plans, (3) autosegmentation, and (4) multimodality image support. It also has PreciseART adaptive radiation therapy and PreciseXRT option.

Conclusions The helical tomotherapy system offers an integrated approach to radiation therapy, combining imaging and treatment delivery to precisely target a wide variety of cancers. The treatment planning system provides the option of 2 dose delivery modes, the TomoHelical and the TomoDirect. These 2 dose delivery modes enable TomoTherapy to treat a wide array of tumors, including advanced techniques such as SRS and SBRT. By its operational principles, helical tomotherapy is also effective in the treatment of extended fields, as with total body irradiation or in treating 2 PTVs far from each other.

References 1. Accuray Incorporated. Tomotherapy products. Available at: http:// www.tomotherapy.com/. Accessed March 18, 2018.

2. Mackie, T.R.; Holmes, T.; Swerdloff, S.; et al. Tomotherapy: A new concept for the delivery of dynamic conformal radiotherapy. Med. Phys. 20:1709–19; 1993.

3. Mackie, T.R. History of tomotherapy. Phys. Med. Biol. 51:R427–53; 2006.

4. Rudofsky, L.; Aynsley, E.; Beck, S.; et al. Lung and liver SBRT using helical tomotherapy—a dosimetric comparison of fixed jaw and dynamic jaw delivery. J. Appl. Clin. Med. Phys. 15:114–21; 2014.

5. Scandidos. Delta4 family products. Available at: http:// delta4family.com/. Accessed March 18, 2018.

6. Saw, C.B.; Gillette, C.; Peters, C.A.; et al. Clinical implementation of radiosurgery using helical tomotherapy unit. Med. Dosim. 2018. in press.

7. Chi, A.; Jang, S.Y.; Welsh, J.S.; et al. Feasibility of helical tomotherapy in stereotactic body radiation therapy for centrally located early stage non-small-cell lung cancer or lung metastases. Int. J. Radiat. Oncol.

Biol. Phys. 81:856–62; 2011.

8. Sterzing, F.; Hauswald, H.; Uhl, M.; et al. Spinal cord sparing reirradiation with helical tomotherapy. Cancer 116:3961–8; 2010.

9. Hoppe, B.S.; Laser, B.; Kowalski, A.V.; et al. Acute skin toxicity following stereotactic body radiation therapy for stage I non-smallcell lung cancer. Who’s at risk? Int. J. Radiat. Oncol. Biol. Phys.

72:1283–6; 2008.

10. Langen, K.M.; Papanikolaou, N.; Balog, J.; et al. QA for helical tomotherapy: Report of the AAPM Task Group 148. Med. Phys.

37:4817–53; 2010.

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11. Benedict, S.H.; Yenice, K.M.; Followill, D.; et al. Stereotactic body radiation therapy: The report of AAPM Task Group 101. Med. Phys.

37:4078–101; 2010.

12. Saw, C.B.; Battin, F.; McKeague, J.; et al. Dose planning management of patients undergoing salvage whole brain radiation therapy after radiosurgery. Med. Dosim. 41:277–80; 2016.

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13. Gruen, A.; Ebell, W.; Wlodarczyk, W.; et al. Total body irradiation (TBI) using helical tomotherapy in children and young adults undergoing stem cell transplantation. Radiat. Oncol. 8:92; 2013.

14. Accuray Incorporated. Radixact products. Available at: http:// www.accuray.com/product/radixact. Accessed March 18, 2018.

Delivered dose can be a better predictor of rectal toxicity than planned dose in prostate radiotherapy Radiotherapy and Oncology xxx (2017) xxx–xxx

Contents lists available at ScienceDirect

Radiotherapy and Oncology journal homepage: www.thegreenjournal.com

Original article

Delivered dose can be a better predictor of rectal toxicity than planned dose in prostate radiotherapy L.E.A. Shelley a,b,c,⇑, J.E. Scaife a,d, M. Romanchikova a,b, K. Harrison a,f, J.R. Forman a,e, A.M. Bates a,d, D.J. Noble a,d, R. Jena a,d, M.A. Parker a,f, M.P.F. Sutcliffe a,c, S.J. Thomas a,b, N.G. Burnet a,d a Cambridge University Hospitals NHS Foundation Trust, Department of Oncology; b Department of Medical Physics and Clinical Engineering, Cambridge University Hospitals NHS Foundation Trust; c Department of Engineering, University of Cambridge; d Department of Oncology, University of Cambridge; e Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust; and f Cavendish Laboratory, University of Cambridge, United Kingdom

a r t i c l e

i n f o

Article history: Received 13 December 2016 Received in revised form 3 April 2017 Accepted 5 April 2017 Available online xxxx Keywords: Rectal toxicity VoxTox Dose–surface maps Delivered dose Prostate radiotherapy

a b s t r a c t Background and purpose: For the first time, delivered dose to the rectum has been calculated and accumulated throughout the course of prostate radiotherapy using megavoltage computed tomography (MVCT) image guidance scans. Dosimetric parameters were linked with toxicity to test the hypothesis that delivered dose is a stronger predictor of toxicity than planned dose.

Material and methods: Dose–surface maps (DSMs) of the rectal wall were automatically generated from daily MVCT scans for 109 patients within the VoxTox research programme. Accumulated-DSMs, representing total delivered dose, and planned-DSMs, from planning CT data, were parametrised using Equivalent Uniform Dose (EUD) and ‘DSM dose-width’, the lateral dimension of an ellipse fitted to a discrete isodose cluster. Associations with 6 toxicity endpoints were assessed using receiver operator characteristic curve analysis.

Results: For rectal bleeding, the area under the curve (AUC) was greater for accumulated dose than planned dose for DSM dose-widths up to 70 Gy. Accumulated 65 Gy DSM dose-width produced the strongest spatial correlation (AUC 0.664), while accumulated EUD generated the largest AUC overall (0.682).

For proctitis, accumulated EUD was the only reportable predictor (AUC 0.673). Accumulated EUD was systematically lower than planned EUD. Conclusions: Dosimetric parameters extracted from accumulated DSMs have demonstrated stronger correlations with rectal bleeding and proctitis, than planned DSMs. 2017 The Authors. Published by Elsevier Ireland Ltd. Radiotherapy and Oncology xxx (2017) xxx–xxx This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

In prostate radiotherapy, the correlation between dose to rectum and toxicity has been the focus of many research studies [1– 7]. The rectum is one of the dose-limiting organs when planning intensity-modulated radiotherapy (IMRT) to the prostate due to the risk of radiation-induced adverse effects. Modern systems for inverse IMRT treatment planning iteratively seek to achieve an optimal plan, delivering maximal dose to the tumour volume and minimal dose to healthy organs. Current normal tissue complication probability (NTCP) models and conventional treatment planning constraints are based upon dose–volume histogram (DVH) data to minimise the risk of toxicity. With ever improving disease control [8,9] and survival rates [10], post-treatment quality of life becomes an increasingly significant consideration during treatment planning, alongside target coverage. ⇑ Corresponding author at: Cancer Research UK VoxTox Research Group, Cambridge University Hospitals NHS Foundation Trust, Department of Oncology, Addenbrooke’s Hospital, Cambridge CB2 0QQ, United Kingdom.

E-mail address: ls698@cam.ac.uk (L.E.A. Shelley).

The DVH-based approach to radiotherapy treatment planning has been criticised for lacking in spatial dose consideration [2]. Consequently, accumulation of DVHs is not dosimetrically representative and results in false overestimations of dose. A review by Landoni et al. [11] emphasises the need to assess associations between spatial dose patterns and late toxicity [12], particularly as results may reveal inhomogeneous intra-organ radiosensitivities.

Several groups have explored alternative approaches for parametrisation of dose distributions in order to establish links with toxicity. Methods have included dose–surface histograms [1,5,13,14], dose–surface maps [1,5,15], dose–line histograms [14], principal component-based pattern analysis [16], and voxelbased approaches for identifying rectal subregions [2,6,7]. These studies have been limited in their analysis by the availability of planned dose data only, based on a single anatomical snapshot in time.

A common recommendation in the literature has been the need to establish dose-toxicity models based on delivered dose [17].

However, this has proven technically challenging to date due to

http://dx.doi.org/10.1016/j.radonc.2017.04.008 0167-8140/ 2017 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Please cite this article in press as: Shelley LEA et al. Delivered dose can be a better predictor of rectal toxicity than planned dose in prostate radiotherapy.

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Correlating delivered dose with toxicity

hardware and software limitations. These challenges have been addressed within the VoxTox Research Programme [18] where contours generated from on-treatment megavoltage computed tomography (MVCT) image guidance scans are used to calculate daily delivered dose. This approach has made it possible to account for the effect of interfractional anatomical variation. Total delivered dose can be estimated by accumulating daily delivered dose throughout the course of radiotherapy. Studies by the VoxTox group have demonstrated that the rectum moves more than previously predicted based on estimates from prostate motion [19], and that planned dose is not equal to delivered dose [20].

The dose–surface map (DSM) approach has been implemented within this study as a solution enabling meaningful accumulation and conservation of geometric information, an advantage over the DVH methodology. The concept of accumulating DSMs to estimate total delivered dose has been applied previously for the bladder [13]. By extracting spatial parameters from DSMs of delivered dose, and linking with the archive of patient follow-up data available within VoxTox, it was hypothesised that stronger correlations could be established with late toxicity than previously achievable using planned dose alone. Ultimately, improved dose-toxicity modelling based on delivered dose could facilitate real-time in silico prediction of NTCP within the clinical pathway.

Material and methods VoxTox study design & patient information The VoxTox research programme is an observational study linking radiation dose to toxicity outcomes [18,20]. It received approval from the National Research Ethics Service (NRES) Committee East of England (13/EE/0008) in February 2013 and is part of the UK Clinical Research Network Study Portfolio (UK CRN ID 13716).

One hundred and nine prostate cancer patients were selected from the discovery cohort of the VoxTox research programme [18]. This cohort (Table 1) comprised patients treated prior to the formal collection of baseline data, but for whom prospective follow-up data of at least 2 years were available (median 4 years).

Early VoxTox patients were selected based on expected benefit from IMRT rather than conventional 3D conformal radiotherapy.

Patients in this study were included on the basis of availability of pre-existing toxicity status from clinical notes, or no reported toxicity, and was limited to those prescribed IMRT to a dose of 74 Gy in 37 fractions, the standard of care in the UK at the time [21]. VoxTox patients are treated with TomoTherapy (Accuray, Sunnyvale, CA). Manual contouring of the anatomy on the kilovoltage computed tomography (kVCT) planning scan was performed according to local procedures [19], adapted from clinical trials. Daily MVCT image guidance scans were acquired immediately prior to treatment delivery for the purposes of online target localisation [22].

Following our department protocol, scans were inspected for rectal dilation and if deemed excessive, remedial action was taken prior to delivery of radiation therapy [23].

Dose–surface map construction & dose accumulation Within the VoxTox research programme, MVCT scans are multifunctional; primarily for the purpose of routine image guidance, they also provide a platform for calculation of delivered dose.

The rectum was identified on each MVCT image series using an in-house autocontouring system based on a customised ChanVese segmentation algorithm [24]. Delivered dose was independently calculated using a locally implemented ray-tracing algorithm [25,26] and the rectal contour-of-the-day, accounting for inter-fraction motion. Automation and integration of dose calcula-

Table 1 Baseline characteristics for the 109 VoxTox participants. Prescribed dose to the prostate was 74 Gy in 37 fractions over 7.5 weeks. All patients were treated with androgen deprivation therapy. IBD = inflammatory bowel disease, IQR = interquartile range, PSA = prostate-specific antigen, SD = standard deviation.

Clinical data for VoxTox patients (n = 109) Age, years Median (IQR) Range

68 (64–71) 51–80

T stage, n (%) T1A/T1B/T1C/T1X T2A/T2B/T2C/T2X T3A/T3B/T3X T4 Not known

24 (22%) 34 (31%) 45 (41%) 0 6 (6%)

Gleason score, n (%) 66 7 P8 Not known

23 (21%) 44 (40%) 39 (36%) 3 (3%)

PSA (ng/ml) Median (IQR) Mean (SD) Not known

11 (7–20) 20 (30) 3 (3%)

Clinical history Diabetes Hypertension IBD or diverticular disease Previous pelvic surgery Haemorrhoids past 12 months Any previous TURP Not known

10 (9%) 35 (32%) 7 (6%) 7 (6%) 3 (3%) 9 (8%) 9 (8%)

tion and contouring systems were essential for large-scale processing of the 4142 scans in this study.

Planned and daily DSMs were generated based on algorithms described by Buettner et al. [1] and Murray et al. [15]. The rectal wall was considered the structure of interest, and was treated as a tubular surface rather than a volume. Contours were virtually ‘cut’ along the superior–inferior axis and ‘unfolded’ to a twodimensional plane. The ‘cutting point’ was identified as the point on the contour surface directly posterior to the centre of mass of the rectal outline, on each CT slice [20].

The height of the planned-DSM was defined by the number of slices of the manually contoured rectum on the kV planning scan (slice thickness 3 mm). The circumference of the rectal contour on each slice was normalised such that the unfolded width of the planned-DSM was equal to the height. Daily delivered DSMs calculated from the image-guidance MVCT scans (slice thickness 6 mm) were normalised to the same width as the planned-DSM but were restricted in height by the field of view (FOV), resulting in a shorter DSM, as shown in Fig. 1.

Rectal DSMs were calculated for each treatment fraction, and corrected for daily couch shifts. For the purposes of dose accumulation, any ‘missing’ dose data cropped by the restricted FOV superiorly or inferiorly were substituted from the planned-DSM [20] in order to maintain common dimensions between final accumulated-DSM and planned-DSM. The final accumulated-DSM was resampled to match the 3 mm resolution of the plannedDSM, producing an easily comparable and interpretable spatial representation of total delivered dose to the rectal wall throughout the course of prostate radiotherapy [25] (illustrated in Fig. 1).

The use of planned-DSM data as a surrogate beyond the boundaries of the MVCT FOV was considered an acceptable estimate under the assumption that the relative anatomical motion of the rectum becomes more confined by surrounding musculature as the distance from the prostate increases [20]. However, this could have reduced potential differences between planned and accumulated dose, and was a limitation of the analysis.

Please cite this article in press as: Shelley LEA et al. Delivered dose can be a better predictor of rectal toxicity than planned dose in prostate radiotherapy.

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Fig. 1. Generation of planned, daily and accumulated dose surface maps.

Dose parameters & clinical endpoints Dose was parametrised from DSMs using two methods implemented in MATLAB (MathWorks , Natick, MA): 1. Calculation of Equivalent Uniform Dose (EUD) 2. Fitting of DSM ‘dose-widths’ to discrete isodose clusters EUD reduces the dose information extracted from the DSMs to a single generalised value which allows comparison between inhomogeneous dose distributions [27]. An ‘a’ value of 11.11 was used in the EUD calculation [28]. Spatial dose information was generated by reproducing Buettner’s ellipse-fitting method [1], reporting the most significant dose quantifier, the lateral extent, termed here the ‘DSM dose-width’.

For a given isodose level, a binary image was created from the DSM by assigning a pixel value of 1 to doses greater than or equal to the nominated isodose, with lower doses assigned a value of 0.

An ellipse was then fitted to the largest central cluster. The maximum lateral extent of the ellipse was projected onto the DSM axis, accounting for any rotation with respect to the DSM coordinate system. The resulting DSM dose-width, expressed as a the percentage of total normalised DSM width, allowed parametrisation of the geometrical dose distribution which would have been masked using a DVH approach.

For each patient, EUD and DSM dose-widths for isodose levels of 30, 40, 50, 60, 65, and 70 Gy were calculated from planned-DSM and accumulated-DSM. Doses less than 30 Gy were not included as DSM dose-width results became dominated by extrapolated values greater than 100%, indicating that the entire rectal circumference was receiving less than or equal to the selected isodose level. This was identified as a limitation of the ellipse fitting method when seeking to analyse low dose toxicity correlations. Doses greater than 70 Gy were also excluded from toxicity analyses due to the increasing frequency of 0% DSM dose-widths, indicating that doses greater than or equal to the selected isodose level were not received by the rectal wall. Only 49/109 patients recorded a non-zero result from accumulated DSM at 74 Gy, reducing to 10/109 at 75 Gy, compared with 106/109 and 64/109 respectively from planned-DSM. It was identified that a 0% DSM result could conceal information leading to misinterpretation of data when performing AUC calculations so results at these isodose levels were not reported. Despite these restriction, the dose levels included within this study incorporate the 39–61 Gy range at which Buettner [1] determined significant correlations between lateral extent and toxicity.

Study specific clinical reporting forms were developed for robust collection of toxicity data, and raw data were used to populate recognised systems, including: Common Terminology Criteria for Adverse Events (CTCAE) v4.03 [29], Late Effects of Normal Tissues/Subjective, Objective, Management, Analytic (LENT SOMA) scores [30]; Radiation Therapy Oncology Group (RTOG) grading system [31]; University of California, Los Angeles, Prostate Cancer Index (UCLA-PCI) questionnaire [32]. Receiver Operator Characteristic (ROC) curves (Fig. 2) were generated using SPSS (IBM 23.0.0.2) to evaluate the link between dosimetric parameters extracted from planned and accumulated DSMs, and the six most prevalent clinical endpoints, listed in Table 2.

The mean area under the curve (AUC), with associated upper and lower 95% confidence intervals (CIs), was calculated for each ROC curve as a measure of the level of association between dosimetric parameter and toxicity. An ideal correlation would have an AUC of 1. Results were reported for dosimetric parameters with AUC P 0.6 and lower 95% CI P 0.5, considered statistically significant by Gulliford et al. [33].

Results Rectal bleeding Twenty-eight patients reported rectal bleeding CTCAE PGrade 1, which was equivalent to PGrade 2 (LENT SOMA). The AUC was greater for all accumulated DSM dose-widths than planned DSM dose-widths up to 70 Gy (Table 3). At 30, 40 and 60 Gy, the lower 95% CI boundaries for the planned DSM dose-widths extended below 0.5, but remained above this threshold for the corresponding accumulated DSM dose-widths (Fig. 3a). The strongest spatial predictor of rectal bleeding was accumulated 65 Gy DSM dose-width (AUC 0.664), and the largest difference between planned and accumulated DSM dose widths was at 60 Gy (AUC difference 0.035).

Overall, for both planned and accumulated DSMs, the AUC was greater for EUD than from respective DSM dose-widths, with the strongest predictor of rectal bleeding being accumulated-EUD (AUC 0.682).

Proctitis The RTOG definition of proctitis considers urgency and frequency of bowel movements, as well as the presence of rectal mucous/blood. Eighteen patients reported RTOG proctitis PGrade

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Correlating delivered dose with toxicity Table 2 Clinical endpoints, scoring systems and incidence rates of the 6 most frequently reported toxicities within the patient sample (*Data were missing for 4 patients so sample size was reduced accordingly).

Clinical Endpoint

Scoring System

Incidence % (n)

Rectal Bleeding PGrade 1 (Rectal Bleeding PGrade 2) Proctitis PGrade 2

CTCAE [29] (LENT SOMA [30]) RTOG [31]/ Gulliford [35] LENT SOMA [30] CTCAE [29]/ LENT SOMA [30] UCLA-PCI [32] UCLA-PCI [32]

25.7 (28/109)

Sphincter Control PGrade 1 Rectal Pain PGrade 1 Bowel bother PGrade 1 Bowel bother PGrade 2

16.5 (18/109) 10.1 (11/109) 15.6 (17/109) 30.7 (32/105*) 11.5 (12/105*)

Table 3 Mean Area Under the Curve (AUC) for planned and accumulated DSM dose-widths and EUD corresponding to rectal bleeding PGrade 2 (LENT SOMA) and PGrade 1 (CTCAE), n = 28/109. The greater AUC of each parameter has been presented in bold.

Dose Level (Gy)

Mean AUC (Planned)

Mean AUC (Accumulated)

30 40 50 60 65 70

0.606 0.603 0.627 0.608 0.635 0.659

0.629 0.621 0.635 0.643 0.664 0.642

EUD

0.673

0.682

at 50, 60, 65 and 70 Gy, and were equivalent at 40 Gy. At 30 Gy, the AUC of planned DSM dose-width was slightly higher than the accumulated AUC (0.004 difference).

Remaining clinical endpoints For the remaining clinical endpoints (LENT SOMA sphincter control PGrade 1; CTCAE/LENT SOMA subjective rectal pain PGrade 1; UCLA-PCI ‘‘Overall, how big a problem have your bowel habits been for you during the last 4 weeks?”, bowel bother PGrade 1 and PGrade 2), EUD and DSM dose-widths had little discriminatory power from planned-DSM or accumulated-DSM. No dosimetric parameter was found to have AUC P 0.6 and lower 95% CI P 0.5. Results have been included as supplementary data.

Equivalent uniform dose EUD produced the greatest AUCs for rectal bleeding and proctitis, indicating a stronger association than the spatial parameters investigated. In both cases, accumulated-EUD generated a higher AUC than planned-EUD. For all patients, EUD of accumulatedDSM was lower than that of planned-DSM (mean difference 2.2 Gy, standard error 0.3 Gy, range [ 0.3, 7.1] Gy).

Discussion

Fig. 2. Receiver operator characteristic curves for (a) rectal bleeding with 65 Gy DSM dose-widths, (b) rectal bleeding with EUD, and (c) proctitis with EUD.

2. Accumulated-EUD (AUC 0.673) was the only dosimetric parameter with AUC P 0.6 and lower 95% CI P 0.5 (Fig. 3b). Accumulated DSM dose-widths had greater AUC than planned DSM dose-widths

Radiation dose received by the rectal wall during prostate radiotherapy was calculated and accumulated using DSMs. Geometric aspects of dose distribution - information not distinguishable from DVHs – were parametrised using DSM dose-widths.

EUD was calculated to compare planned and accumulated DSMs using a single metric. Extracted dosimetric parameters were evaluated against six clinical endpoints reported by patients within the VoxTox research programme. Previous dose-toxicity investigations in the literature have been limited to planned dose only. This study has demonstrated, for the first time, that delivered dose can

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L.E.A. Shelley et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx

Fig. 3. High-low plots of mean AUC and 95% confidence intervals for (a) Rectal Bleeding and (b) Proctitis, where results were considered significant if mean AUC P0.6 and lower 95% CI P0.5.

be a stronger predictor of toxicity in the case of rectal bleeding and proctitis in prostate radiotherapy.

Toxicity rates reported in the literature have been variable. The rate of bowel toxicity PGrade 2 (CTCAE), 5 year cumulative incidence, amongst VoxTox prostate patients was 17%. This falls within the bowel toxicity PGrade 2 (RTOG) range of 13.7–24.9% for IMRT over the same timeframe, reported by Dearnaley et al. [9] and Wortel et al. [34], respectively. The rates of incidence indicate that toxicity remains an important clinical issue.

5

Many associations were found between DSM dose-widths with rectal bleeding. Accumulated DSMs generated greater AUCs than planned DSMs for 5 DSM dose-width levels up to 70 Gy. The strongest correlation between rectal bleeding and any spatial parameter was the 65 Gy DSM dose-width from accumulated dose (AUC 0.664). At 30, 40 and 60 Gy, accumulated DSM dose-widths produced AUC P 0.6 and lower 95% CI P 0.5, where corresponding planned DSM dose-widths did not. These thresholds were considered indicative of significance following the methods of Gulliford et al. [33]. The greatest difference between planned and accumulated AUCs was observed at the 60 Gy DSM dose-width. Overall, the results compared well with the findings of Buettner et al. [1] who reported the most significant correlation with rectal bleeding to be the 61 Gy lateral extent (AUC 0.66), derived from planned dose data.

Accumulated EUD was found to have the strongest correlation overall with rectal bleeding (AUC 0.682), and was the only predictor of proctitis (AUC 0.673).

For all patients, accumulated-EUD was systematically lower than planned-EUD. A contributory factor was possibly the inherent blurring of high dose regions during accumulation. Upon visual inspection of daily DSMs, the differences in size, shape and position of the high dose region due to anatomical variation was clearly visible (for example, shown in deep red in Fig. 1). During accumulation, high doses were superimposed in overlap regions, but reduced where isodose edges differed, due to averaging over the full course of radiotherapy. This affected the maximum dose of the accumulated-DSM, on which EUD calculation was heavily weighted.

The dose-blurring effect could also have been responsible for the increased frequency of 0% DSM dose-width results at high dose levels from accumulated-DSMs with respect to plannedDSMs. At 70 Gy, 4/109 patients recorded a 0% accumulated DSM dose-width (including 1 patient experiencing toxicity), whereas all corresponding planned DSM dose-widths had non-zero results. Furthermore, dose levels could not be considered independent variables, as a low 70 Gy DSM dose-width was likely to be associated with a low 65 Gy DSM dose-width, and a cooler plan overall. These issues were not accounted for within the scope of this study.

The generally lower reported values for EUD and DSM dosewidths from accumulated dose compared with planned dose should not be interpreted as delivered treatment erring on the ’safe side’ in terms of dose to rectum. Where current NTCP models are based on planned dose, the presented results suggest that the same magnitude of risk would be associated with a systematically lower delivered dose.

The findings show that the difference in dose between patients with and without rectal toxicity is greater from delivered dose than planned dose. This indicates that dosimetric parameters from accumulated-DSMs could provide new information to improve understanding of the relationship between dose and toxicity. The single parameter EUD was a superior predictor of rectal bleeding and proctitis than spatial dose quantifiers. However, DSM-dose widths produced several strong correlations with rectal bleeding, and for 5/6 dose levels, accumulated dose generated AUC values greater than planned dose.

The ability to preserve and accumulate spatial dose information throughout treatment is a novel process requiring careful consideration of data interpretation and parametrisation. Future work may involve exploring alternative methods for geometrical quantification of spatial dose distributions in order to determine stronger correlations with toxicity. Analysis of delivered dose to the rectal wall could facilitate the identification of inhomogeneous intraorgan radiosensitivities, allowing shape-based dose constraints to be derived. Spatial considerations could complement current DVH-based approaches to treatment planning.

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Correlating delivered dose with toxicity

Through novel characterisation of delivered dose, beyond the limitations of the static planned DVH, the aim is to determine those parameters strongly associated with rectal toxicity which could be incorporated into multivariate NTCP models. Emerging dose quantifiers could be integrated into planning constraints, as well as being prospectively monitored throughout treatment.

Delivered dose can be accumulated in ’real-time’ and analysed with each fraction, allowing on-treatment toxicity risk assessment.

Towards the end of the course of treatment, if toxicity prediction was found to be lower than planned, the decision could be made to increase the total delivered dose to the target. The potential scope for further individualisation and adaptation of treatment could ultimately reduce rates of toxicity incidence and improve clinical outcomes.

Conclusion Parametrisation of delivered dose to the rectal wall during prostate radiotherapy has revealed stronger correlations with rectal bleeding and proctitis than achievable from planned dose.

New information from accumulated delivered dose could lead to improved dose-toxicity modelling in the future, with the aim of reducing post-treatment toxicity.

Conflict of interest The authors declare no conflicts of interest.

Acknowledgements The authors would like to thank the patients who participated in the study, the referring physicians, and VoxTox Research Facilitator, Michael Simmons. LEAS is supported by the University of Cambridge W D Armstrong Trust Fund; AMB, MRR and KH are supported by the VoxTox Programme Grant, which is funded by Cancer Research UK (CRUK); JES was supported by a CRUK Clinical Research Fellowship; DJN is supported by a CRUK Clinical Research Fellowship; NGB is Principle Investigator of the CRUK VoxTox Programme and is supported by the NIHR Cambridge Biomedical Research Centre.

Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.radonc.2017.04.

008.

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Helical tomotherapy for prostate cancer radiation

Original Article

therapy: An audit of early toxicity and quality of life

Helical tomotherapy for prostate cancer radiation therapy: An audit of early toxicity and quality of life ABSTRACT Background: Radiation plays a major role in the management of localized prostate cancer (CaP). There are limited studies reporting the quality of life (QOL) and toxicity with CaP tomotherapy.

Materials and Methods: This is a single‑institutional prospective observational study evaluating the acute toxicity and QOL of patients with CaP receiving tomotherapy from May 2018 to October 2019. Toxicity assessed using radiation therapy oncology group toxicity grading. QOL assessed using International Prostate Symptom Score (IPSS) and QOL score.

Results: A total number of 74 patients received radiation therapy (RT), of which 25 had postoperative RT and 49 had radical RT. The median age was 71 years. During RT, 8 (10.8%) had Grade 2 gastrointestinal (GI) and 4 (5.4%) had Grade 2 genito urinary (GU) toxicities. At 3 months, 1 (1.4%) had Grade 2 GI, 1 (1.4%) had Grade 2 GU, and 1 (1.4%) had Grade 3 GU toxicities. At 6 months, 1 patient had Grade 2 GU and no Grade 2 GI toxicity noted. In postoperative RT Group, 2 (8%) Grade 2 GI and 1 (1.4%) Grade 2 genitourinary toxicity reported during radiation. At 3 months, 1 (1.4%) Grade 2 GI, 1 (1.4%) G2 GU, and 1 (1.4%) G3 GU toxicities noted. At 6 months, no ≥ Grade 2 noted. In radical RT group, during radiation 6 (12.2%) Grade 2 GI and 3 (6.1%) Grade 2 GU recorded. At 3 and 6 months, no ≥ Grade 2 GI/GU toxicity was recorded. No Grade 3/Grade 4 observed in radical RT group. One patient in radical RT and one in postoperative RT had severe IPSS symptom score. Results are comparable to reported studies.

Conclusion: Our initial clinical experience with helical tomotherapy in CaP confirms lower rate of toxicities and no significant worsening of QOL with RT. KEY WORDS: Helical tomotherapy, image guided radiotherapy, prostate cancer, quality of life, toxicity

INTRODUCTION Tomotherapy is an intensity‑modulated rotational radiation therapy (RT) technique using photon fan beam designed for image guided radiotherapy (IGRT).[1‑5] In helical tomotherapy, the couch and gantry are in continuous motion and described as a helical trajectory. Thus, it permits high tailored dose distributions with excellent coverage and integrates the image guidance for patients setup verification. [6,7] The additional benefit of helical tomotherapy is incorporated with adaptive planning software which determines the changes in external or internal anatomy and can modify the radiation treatment plans if necessary.

Prostate cancer (CaP) RT plays a major role in the management of localized CaP. In our center, IGRT for CaP is delivered either using volumetric arc therapy or helical tomotherapy. Majority of prostate cases

are treated with helical tomotherapy. There are limited study reporting the quality of life (QOL) and toxicity pattern with different RT techniques and studies pertaining to tomotherapy are even less.

Beena Kunheri, J. S. Lakshmi, Greeshma C. Ravindran1, Haridas, Vishal Marwaha2 Departments of Radiation Oncology, 1 Biostatistics and 2 Amrita School of Medicine, AIMS, Amrita Vishwa Vidyapeetham, Kochi, India For correspondence: Prof. Beena Kunheri, Department of Radiation Oncology, Amrita School of Medicine, AIMS, Amrita Vishwa Vidyapeetham, Kochi ‑ 682 041, Kerala, India.

E‑mail: beenakunheri@yahoo. co.in

In the present study, we prospectively evaluated the acute, early delayed toxicity and QOL of patient undergoing postoperative RT (RP + RT) or radical RT for localized CaP using helical tomotherapy.

MATERIALS AND METHODS This is a single institutional study evaluating the acute, early late toxicities and QOL of patient

Submitted: 08‑Sep‑2020 Revised: 20‑Dec‑2020 Accepted: 03‑Jan‑2021 Published: 11‑Jun‑2021 Access this article online

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Cite this article as: Kunheri B, Lakshmi JS, Ravindran GC, Haridas, Marwaha V. Helical tomotherapy for prostate cancer radiation therapy: An audit of early toxicity and quality of life. J Can Res Ther 2021;17:366‑71.

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Kunheri, et al.: An audit of helical tomotherapy acute toxicity outcome in prostate cancer

receiving RT for localized CaP using helical tomotherapy from May 2018 to October 2019.

Patients with age ≤85 years, with histologically confirmed nonmetastatic CaP were included in this study. Intermediate and high Risk patients received hormonal treatment as per institutional protocol. Informed consent was taken and those willing to participate in this study were given QOL questionnaires.

Simulation and planning All patients underwent computed tomography (CT) simulation with bladder and rectal protocol (moderately filled bladder and empty rectum) in supine position with appropriate immobilization devices (head rest, knee rest, etc.,) and were treated with helical tomotherapy according to the standard institutional protocol.

Radiation dose Postoperative radiation dose was 60–66 Gy/30–33 fractions and in patients with gross residual disease or local relapse dose escalation was done up to 70 Gy. In radical RT intermediate risk, patients received 60 Gy in 20 fractions to prostate alone.

High risk patients were treated with 70 Gy in 28 fractions to primary and pelvic nodal region received 50.4 Gy/28 fractions (SIB‑simultaneous integrated boost).

Toxicity and quality of life assessment Toxicity assessed weekly during RT and then at 3 and 6 months following RT using RT Oncology Group toxicity grading.[8] QOL assessed pre‑RT, on the last day of treatment and at 3 and 6 months following RT. QoL assessment done using International Prostate Symptom Score (IPSS) and QOL score.[9] All patients will be followed up long term for any new toxicity and will be recorded. Compliance assessed based on treatment breaks and completion of proposed treatment. After completion, patients were reviewed every 3 months for 1st year and then every 4 months for next 1 year and thereafter every 6 months for subsequent 3 years and then annually after 5th year. This is an interim report, analyzing acute and early delayed toxicity as well as QOL. Acute toxicity is during radiation and within 3 months of treatment, early delayed toxicity is from 3 months to 6 months of treatment. Late toxicity is the toxicity after 6 months and late toxicity was not analyzed for this report.

Ethical issues Informed consent was obtained from all patients participating in this study.

This study was approved by the Institutional Review Board.

Statistical details Statistical analysis was done using IBM SPSS 20.0 (SPSS Inc., Chicago, USA). For all continuous variables, results shown as mean ± standard deviation, and for categorical variables as percentage. To test the statistical significance of difference

between the two groups Chi‑square test was applied. To test the statistical significance of difference in mean QOL score between the two groups, Student’s t‑test was applied. P < 0.05 was considered as statistically significant.

RESULTS The data of 74 patients were analyzed.

Patient characteristics The median age was 71 years (range 51–82 years). Based on D’Amico risk stratification; 2 (2.7%) patients were low risk, 10 (13.5%) were intermediate and 62 (83.8%) were high risk.

Patient characteristics are shown in Table 1.

Toxicity pattern During RT, majority of the toxicity was reported at week 3 of RT. Thirty (40.5%) had Grade 1 and 8 (10.8%) had Grade 2 gastrointestinal (GI) toxicities. Regarding genitourinary (GU) toxicities 43 (58.1%) had Grade 1 and 4 (5.4%) had grade 2.

At first follow‑up (3 months), 1 (1.4%) had Grade 1, 1 (1.4%) had Grade 2 GI toxicity and none had Grade —. Regarding GU toxicity 11 (14.9%) had Grade 1 and each 1 (1.4%) patient had Grade 2/3. At 6 months, only 2 (2.7%) had Grade 1 GI, 4 (5.4%) had Grade 1 GU and 1 (1.4%) had Grade 3 GU toxicities. Overall no Grade 3 or 4 GI toxicity and no grade 4 GU toxicity were observed. Figure 1 shows the overall toxicity pattern in my cohort.

Of the 74 patient, 25 (33.8%) patients received postoperative RT and 49 (66.2%) received Radical RT. On subgroup analysis Table 1: Patients characteristics Characteristics

n (%)

RP+RT group Radical RT group Age (years) Range Median age

25 (33.8) 49 (66.2)

Characteristics Stage I II A II B II C III A III B III C IV A Risk stratification Low Intermediate High Adjuvant RT Salvage RT Radiation dose EQD2: ≤66 EQD2: >66 Hypofractionation

RP+RT group, n (%)

Radical group, n (%)

0 (0.0) 0 (0.0) 0 (0.0) 4 (16) 0 (0.0) 11 (44) 3 (12) 7 (28)

1 (2) 1 (2) 9 (18.4) 6 (12.2) 11 (22.4) 7 (14.3) 2 (4.9) 12 (24.5)

0 (0.0) 3 (12) 22 (88) 14 (56) 11 (44)

2 (4.1) 7 (14.3) 40 (81.6) NA NA

13 (52) 12 (48) NA

NA NA 49 (100)

RP=Radical prostatectomy, RT=Radiation therapy, NA=Not available, EQD2: equivalent dose in 2Gy

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with regards to postoperative RT patients, 12 (48%) had Grade 1 and 2 (8%) had Grade 2 GI toxicities. Regarding GU toxicity 19 (76%) had Grade 1 and 1 (4%) had Grade 2. At 3 months, 1 (4.5%) patient had Grade 2 GI and each 1 (4.5%) had Grade 2/3 had GU toxicity. At 6 months, no Grade 2 toxicity was recorded. Figure 2 shows the toxicity pattern in adjuvant/ salvage RT patients. With regards to radical RT, during RT 18 patients (36.7%) had Grade 1 and 6 (12.2%) had Grade 2 GI toxicity. With regards to GU toxicity 24 (49%) had Grade 1 and 3 (6.1%) patients had Grade 2. At 3 months and 6 months, no Grade 2 GI toxicity was recorded. Overall, no grade 3 or 4 GI and GU toxicity were observed. Figure 3 shows the toxicity pattern in radical RT patients.

modalities of treatment are combined. After the advent of modern RT techniques (IGRT) and following advancement in surgical techniques, there is a significant reduction in the toxicities compared to conventional methods. Beck et al.[10] in 2017, analyzed the toxicity pattern of 69 patients receiving adjuvant/salvage RT using Tomotherapy technique, reported 10.1%(n = 7) GU and 5.8% (n = 4) GI acute toxicities. Similarly, Linsay et al.[11] in 2017, evaluated the toxicity pattern of 313 patients receiving adjuvant RT using helical tomotherapy

Quality of life QOL assessment done at baseline (before starting RT), at RT completion, at 3 months and at 6 months. IPSS symptom score and IPSS QOL scale were used for assessment. For analysis, IPSS QOL scale categorization done as good and average to severe. “Good” includes delighted, pleased, and mostly satisfied. “Average” includes mixed and “Poor” includes mostly dissatisfied, unhappy, and terrible.

International Prostate Symptom Score symptom score No severe symptoms were noted at baseline. One (1.4%) patient had severe symptom score at the time of RT completion and 3 months. No severe symptoms noted at 6 months. On subgroup analysis, in postoperative patients, one patient had severe symptom at RT completion and at 3 months whereas in radical RT patients no severe symptom score noted at RT completion, at 3 months and at 6 months.

Figure 1: Overall toxicity pattern in prostate patients in helical tomotherapy

International Prostate Symptom Score quality of life score One patient in the radical RT arm had poor QOL at RT completion. No poor QOL score noted at 3 months and at 6 months.

IPSS symptom and QOL score is shown in Tables 2 and 3.

DISCUSSION Helical tomotherapy is an advanced form of IGRT delivery system with onboard imaging and capability of adaptive planning.[6,7] Our clinical experience with moderate hypofractionation in carcinoma prostate patients using helical tomotherapy show low rate of toxicity with no marked deterioration in QOL. With the benefit of image guidance and adaptive planning software in tomotherapy, lower and acceptable rate of toxicities were achievable which translates into better QOL. This study reports the acute toxicity and QOL. Late toxicity will be reported later after adequate follow‑up.

Acute toxicity As mentioned in the literature, the most common toxicities are GI and GU in CaP patients. Patients receiving postoperative RT are expected to have more toxicities as two radical 368

Figure 2: Toxicity pattern in postoperative radiation therapy patients in helical tomotherapy

Figure 3: Toxicity pattern in radical radiation therapy patients in helical tomotherapy

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Table 2: Overall international prostate symptom score symptom score and quality of life score IPSS symptom score No Mild Moderate Severe IPSS QOL score Good Average Poor

Pre-RT (%)

RT completion (%)

3 months (%)

6 months (%)

10 (13.5) 31 (41.9) 27 (36.5) 6 (8.1)

10 (13.5) 50 (67.6) 13 (17.6) 1 (1.4)

17 (23) 53 (71.6) 0 (0.0) 1 (1.4)

22 (29.7) 48 (64.9) 1 (1.4) 0 (0.0)

31 (41.9) 35 (47.3) 8 (10.8)

48 (64.9) 25 (33.8) 1 (1.4)

61 (82.4) 10 (13.5) 0 (0.0)

64 (86.5) 7 (9.5) 0 (0.0)

IPSS=International prostate symptom score, QOL=Quality of life, RT=Radiation therapy

Table 3: International prostate symptom score symptom score and quality of life score of postoperative radiation therapy and radical radiation therapy patients Pre-RT (%)

RT completion (%)

3 months (%)

6 months (%)

Postoperative RT group IPSS symptom score No Mild Moderate Severe IPSS QOL score Good Average Poor Radical RT group IPSS symptom score No Mild Moderate Severe IPSS QOL score Good Average Poor

5 (20) 16 (64) 4 (16) 0 (0.0)

4 (16) 17 (68) 3 (12) 1 (4)

8 (36.4) 13 (59.1) 0 (0.0) 1 (4.5)

10 (45.5) 11 (50) 1 (4.5) 0 (0.0)

17 (68) 7 (28) 1 (4)

20 (80) 5 (20) 0 (0.0)

20 (90.9) 2 (9.1) 0 (0.0)

20 (90.9) 2 (9.1) 0 (0.0)

5 (10.2) 15 (30.6) 23 (46.9) 6 (12.2)

6 (12.2) 33 (67.3) 10 (20.4) 0 (0.0)

9 (18.4) 40 (81.6) 0 (0.0) 0 (0.0)

12 (24.5) 37 (75.5) 0 (0.0) 0 (0.0)

14 (28.6) 28 (57.1) 7 (14.3)

28 (57.1) 20 (40.8) 1 (2)

41 (83.7) 8 (16.3) 0 (0.0)

44 (89.8) 5 (10.2) 0 (0.0)

IPSS=International prostate symptom score, QOL=Quality of life, RT=Radiation therapy

reported 25% (n = 77) Grade 2 GU and 33% (n = 103) Grade 2/1% (n = 1) Grade 3 GI acute toxicities. The literature on hypofractionated postoperative helical tomotherapy in CaP

by Cuccia et al.[12‑15] report the various helical tomotherapy fractionation schemes. Acute GI and GU toxicities were reported. These include: For GU Grade 1 in 46% (n = 35) and Grade 2 in 4% (n = 3). For GI toxicities, Grade 1 in 36% (n = 75) and Grade 2 in 18% (n = 14). In the present study, we observed low rate of acute and early delayed toxicity. During RT, 8% patients had Grade 2 GI and 4% had Grade 2 GU toxicity. At 3 months, 4.5% had Grade 3 GI and 4.5% grade 2 GU and 4.5% had Grade 3 GU toxicities. At 6 months, no Grade 2, 3, or 4 toxicities were recorded. Low rates of toxicities observed in the present study could be due to advanced techniques such as Helical Tomotherapy and minimally invasive surgery, robotic‑assisted radical prostatectomy. We also used a tighter margin of 0.5 cm from CTV to PTV, which is considered minimum recommended when daily online image guidance adopted.[16] Table 4 shows the CaP studies and related toxicity pattern following image‑guided RT. Due to the increasing workload and logistic issues in a country like India, it becomes important to reduce treatment time

whenever possible. CaP with low α/β value is one tumor that can be treated using hypofractionation. Long‑term follow‑up results of hypofractionated studies such as conventional versus hypofractionated high‑dose intensity‑modulated radiotherapy for CaP ‑CHHIP (60 Gy in 20 fractions)[19] and Cleveland clinic[20] dose schedules (70 Gy in 28 fractions) did show improved control rates with acceptable toxicity. CHHIP trial used IMRT to compare conventional versus hypofractionation in 3162 men. They reported 38% Grade 2 or more GI and 49% Grade 2 or more GU acute toxicities. At 18 weeks, they noted decreasing trend; 3% GI and 5%GU toxicities were reported. Cleveland clinic data on hypofractionation ((70 Gy in 28 fractions) with IGRT reported 40% Grade 1 and 9% Grade 2 GI toxicity. GU toxicities were 48% Grade 1, 18% Grade 2, and 1% Grade 3. Barra et al.[21] in 2014, reported 36% Grade 1, 13% Grade 2, 4% Grade 3 GU toxicities and 6% Grade 1, 4% Grade 2 GI toxicities using helical tomotherapy in CaP patients receiving radical radiotherapy. In this study, we observed 12.2% Grade 2 GI and 6.1% Grade 2 GU toxicity. At 3 months and 6 months, no Grade 2 or more GI/GU toxicity was recorded. The low rates of toxicity could be attributed to the high conformality achieved in our plans thereby limiting the dose to the organs at risk (OARs). We need further follow‑up and larger cohort to confirm the absolute benefit and outcome.

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Table 4: Prostate studies reporting acute and late toxicities Technique Postoperative RT study Beck et al.[10] Jensen et al.[11]

Tomotherapy Tomotherapy

Cuccia et al.[12]

Tomotherapy

Berlin et al.[17]

IMRT

Goenka et al.[18]

IMRT

Current study

Tomotherapy

Radical RT study CHHIP[19] Cleaveland clinic[20]

IMRT IMRT

GI toxicities

GU toxicities

Acute

Late

Acute

Late

5.8% G2: 33% G3: 1% G1: 36% G2: 18% G2: 16% G3: 0% G2: 8% G3: 0% G2: 8% G3: 0%

No G2 or higher G2: 16% G3: 2% G2: 6.6%

10.1% G2: 25% G3: 0% G1: 46% G2: 4% G2: 19% G3: 0% G2: 13%

G2: 2.9% G2: 37% G3: 10% ≥G2: 5.3%

G2: 4% G3: 0%

NR

≥G2: 38% G2: 9%

≥G2: 49% G2: 18% G3: 1%

≥G2: 11.7% G2: 5.1% G3: 0.1%

G2: 13% G3: 4% G2: 6.1%

G2: 4%

G2: 12% G3: 0% G2: 2% G3: 1.4% NR

Barra et al.[21]

Tomotherapy

G2: 4%

≥G2: 11.9% G2: 3.1% G3: 1.3% G4: 0.1% No G2 or higher

Current study

Tomotherapy

G2: 12.2%

NR

G2: 13% G3: 0% G2: 17%

NR

GI=Gastro-intestinal, GU=Genito-urinary, RT=Radiation therapy, IMRT=Intensity Modulated Radiation Therapy, NR: Not reported

Quality of life assessment QOL is an important hallmark in CaP management, especially considering that men are likely to survive for a considerable number of years after treatment. The CaP Outcomes Study on QOL[22] examined 1,655 men in 1994–1995 and who underwent either radical prostatectomy (1,164 men) or radiotherapy (491 men). The study found that those undergoing surgery were significantly more likely to have urinary incontinence and erectile dysfunction (ED) at 2 and 5 years. However, bowel urgency at 2 and 5 years were significantly more in those undergoing radiotherapy. Notably, when the follow‑up duration was extended to 15 years, the burden of urinary incontinence, ED, and bowel urgency were comparable between the treatment modalities. A systematic review and meta‑analysis by Chen et al.[23] reported a pooled analysis of total 6 studies containing 4423 patients. They analyzed the QOL between RP and RT patients and concluded that RP was associated with worse urinary and sexual domain score than EBRT. In contrast, EBRT group had lower bowel domain score than RP group. Pervez et al.[24] reported the QOL outcome of CaP patients treated with tomotherapy in 2012. The study found that bowel functions were affected maximum than urinary symptoms. Bowel symptoms scores declined at 1 and 6 months compared to baseline whereas overall urinary scores at baseline with those at 1 month and 6 months showed improvement. In the present study, we observed improvement in both IPSS symptom score and QOL score on completion of RT, at 3 months and at 6 months compared to baseline in the radical RT group. On subgroup analysis, radical RT patients had better QOL as compared to postoperative RT patients on follow‑up. In the postoperative RT group, one patient had severe IPSS score during RT whereas no patient had severe score in the radical RT arm. The improvement in QOL noticed for radical RT patients compared to base line could be due to 370

the bulky local disease responding to treatment. The subjective nature of questionnaires and attitude of the patients toward their QOL and the timing does affect the response to the questionnaire.

Limitation This is a short‑term study analyzing acute toxicity and health‑related QOL issues. Longer follow‑up is needed to evaluate the late effects, outcome, and long‑term bearing on QOL. CONCLUSION Our clinical experience with helical tomotherapy in CaP RT confirms lower rate of toxicities and no deterioration in QOL as compared with studies in literature.[13‑15,25,26] The use of IGRT and highly conformal treatment lowers the toxicity rates in both radical RT and postoperative RT as it allows more uniform coverage of target, while minimizing OARs doses improving the therapeutic ratio.

Acknowledgment We would like to thank all the staff of the Department of Radiation oncology, Medical Oncology, Uro‑oncology.

Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

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Outcomes and toxicity of 313 prostate cancer patients receiving helical tomotherapy after radical prostatectomy. Adv Radiat Oncol 2017;2:597‑607.

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Berlin A, Cho E, Kong V, Howell KJ, Lao B, Craig T, et al. Phase 2 trial of guideline‑based postoperative image guided intensity modulated radiation therapy for prostate cancer: Toxicity, biochemical, and patient‑reported health‑related quality‑of‑life outcomes. Pract Radiat Oncol 2015;5:e473‑82.

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Influence of optimizing protocol choice on the integral dose value in prostate radiotherapy planning by reports of practical oncology and radiotherapy 2 2 ( 2 0 1 7 ) 415–419 dynamic techniques Available online at www.sciencedirect.com

ScienceDirect journal homepage: http://www.elsevier.com/locate/rpor

Technical note

Influence of optimizing protocol choice on the integral dose value in prostate radiotherapy planning by dynamic techniques – Pilot study Anna Zaleska a,b,∗ , Krzysztof Bogaczyk c , Tomasz Piotrowski a,d a

Department of Medical Physics, Greater Poland Cancer Centre, Poznan, Poland Faculty of Physics, University of Warsaw, Warsaw, Poland c Fryderic Chopin State Clinical Hospital, Rzeszow, Poland d Department of Electroradiology, University of Medical Sciences, Poznan, Poland b

a r t i c l e

i n f o

a b s t r a c t

Article history:

Aim: The purpose of this study was to compare the values of integral dose, calculated for

Received 17 September 2016

treatment plans of dynamic radiotherapy techniques prepared with two different optimiza-

Received in revised form

tion protocols.

27 December 2016

Background: Delivering radiation by IMRT, VMAT and also HT techniques has an influence on

Accepted 19 April 2017

the low dose deposition of large areas of the patient body. Delivery of low dose can induce

Available online 17 August 2017

injury of healthy cells. In this situation, a good solution would be to reduce the area, which receives a low dose, but with appropriate dose level for the target volume.

Keywords:

Materials and methods: To calculate integral dose values of plans structures, we used 90

Integral dose

external beam radiotherapy plans prepared for three techniques (intensity modulated

Prostate

radiotherapy, volumetric modulated arc therapy and helical tomotherapy). One technique

IMRT

includes three different geometry combinations. 45 plans were prepared with classic opti-

VMAT

mization protocol and 45 with rings optimization protocol which should reduce the low

HT

doses in the normal tissue.

Results: Differences in values of the integral dose depend on the geometry and technique of irradiation, as well as optimization protocol used in preparing treatment plans. The application of the rings optimization caused the value of normal tissue integral dose (NTID) to decrease.

Conclusion: It is possible to limit the area of low dose irradiation and reduce NTID in dynamic techniques with the same clinical constraints for OAR and PTV volumes by using an optimization protocol other than the classic one. © 2017 Greater Poland Cancer Centre. Published by Elsevier Sp. z o.o. All rights reserved.

1.

Introduction

In recent years, techniques using beam intensity modulation, Corresponding author. Tel.: +48 785 617 141. both intensity modulated radiotherapy (IMRT), volumetric E-mail address: anna.zaleska@o2.pl (A. Zaleska). http://dx.doi.org/10.1016/j.rpor.2017.04.003 1507-1367/© 2017 Greater Poland Cancer Centre. Published by Elsevier Sp. z o.o. All rights reserved. ∗

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modulated arc therapy (VMAT) and helical tomotherapy (HT), have become frequently used in clinical practice. One can say that in some locations, on account of dose distribution conformality to the target area, better dose reduction in organs at risk or shorter therapy sessions, IMRT techniques substitute conventional three dimensional conformal radiotherapy (3DCRT).1–3 Despite significant advantages, there is a problem associated with the use of both IMRT, VMAT and HT as they have the dose bath effect.4 Dose bath effect or low radiation dose in normal tissue area is clearly observable when low isodose on CT scans are compared between the 3DCRT and IMRT techniques as is dose reduction in the organ at risk (OAR) volume for IMRT techniques plans towards 3DCRT. Integral dose (ID) is defined as a product of mean dose and tissue volume for contemplated organs or structure (1).5 ID = Dmean of structure × Vstructure

(1)

In the case of normal tissue, the term normal tissue integral dose (NTID) is used, defined as a difference between ID deposited in the body (in healthy tissue) and ID deposited in the clinical target volume (CTV) (2).

NTID = IDnormal tissue − IDCTV

(2)

In prostate location, both the bladder and the rectal wall are in close proximity or they have a common part with the planning target volume. It is very important in the case of prostate cancer therapy, on account of patients’ quality of life and side effects, to reduce high dose to the bladder and rectal wall,6,7 but integral dose reduction in these organs would also be beneficial.

According to As Low As Reasonably Achievable rule, it would also be ideal to reduce as much as possible dose delivered to healthy tissue.

Value of Integral Dose for given organs depends on many factors, including the beam energy, density of surrounding tissue, dose calculating algorithm, margin size,5,8–10 but, primarily, on the choice of radiation technique.

In prostate cancer therapy, in dynamic techniques, ID and low isodose location may be different depending on the number of beams for IMRT, number of arcs for VMAT, and the pitch factor for HT. Another factor, determining the value of ID may be the choice of an optimization process.

In this pilot study, we report the use of two optimization processes for planning of the same patient to explore their influence over the value of the integral dose in the volume of healthy tissue and OAR.

2.

Materials and methods

To prepare plans, five prostate cancer patients were selected.

The patients had been previously treated with external beam radiotherapy. CTV was defined between 28 and 51 cm3 (entire prostate – without nodes and seminal vesicles). CTV with 1 cm margin (unsymmetrical to the rectum site 0.7 cm) creating PTV extent 120–160 cm3 . Common part PTV and rectum did not exceed 15% of the volume of the rectum and the common part

208

of the PTV and bladder did not exceed 25% of the volume of the bladder.

The criterion for patients selection, besides PTV and CTV volumes, was organs at risk volume. Bladder filling was defined between 150 and 250 cm3 , rectum volume between 65 and 90 cm3 , femoral heads between 60 and 80 cm3 . Organs at risk and CTV contouring was performed by the same doctor.

To determine normal tissue volume, which ranged from 17 to 25 l, two limits were used: the upper one – between third and fourth lumbar vertebrae, and the lower one – three CT scans below the biggest ring.

To optimize data collection, five auxiliary structures were created: body ID volume (normal tissue volume defined earlier), a sphere with a margin of 1 mm around the PTV, created to make a high dose gradient between the target and healthy tissue volumes during the optimization process (used in IMRT and VMAT) and three rings. First ring of 2 cm around PTV, second of 2 cm around the first one and third of 2 cm around the second one. Ring structures were used to plan optimization by reducing the dose to healthy tissue.

IMRT plan was made with the following geometry: 5 beams (0, 60, 110, 250, 300 deg), 7 beams (0, 50, 100, 150, 210, 260, 310 deg), 9 beams (0, 40, 70, 110, 150, 210, 250, 290, 320 deg).

VMAT plans have been prepared with 1 arc (160–200 deg), 2 arcs (170–190 and 160–200 deg) and 3 arcs (181–179 deg and two previous combinations) geometry.

Tomotherapy plans were prepared using three pitch factors: 0.215; 0.287 and 0.430. Parameters used in HT plans were the Modulation Factor (MF) = 2.6; Field Width (FW) = 1.0 cm and pitch factors defined earlier.

For all 5 patients, unified optimization protocols were used for planning. Structures weight during the optimization were identical for IMRT and VMAT, and different for HT, because another treatment planning system was used for HT. Criteria of clinical constraints for OARs and PTV in all techniques were the same.

For one patient, 18 plans were prepared (6 IMRT, 6 VMAT, 6 HT plans) – 9 with normal optimization (only one auxiliary structure – 1 mm around PTV for IMRT and VMAT and without this structure for HT) and 9 with rings optimization.

Dose calculation algorithm in IMRT and VMAT optimization was AAA version 10.0.28 in the Eclipse treatment planning system by Varian, in Tomtherapy CCC version 4.3 in TomoTherapy Planning System by Accuracy.

6 MV X-ray beam was used in all prepared plans, and for IMRT and VMAT FF beam with Millennium 120 Leaf MLC. To calculate integral dose values for each patient, Aoyama formula was used, and the difference between normal tissue and CTV integral dose to calculate NTID.

3.

Results

Differences in values of integral dose between techniques are not great, but we can point to lower ID in some of these groups and to some trends (Fig. 1).

In the bladder, integral doses are similar for IMRT and HT techniques. For VMAT technique in this structure, they are slightly higher.

reports of practical oncology and radiotherapy 2 2 ( 2 0 1 7 ) 415–419

417

Fig. 1 – Mean integral dose values (point) with standard error (frame) of organs at risk and normal tissue (NTID) for all five patients. 5, 7, 9 = numbers of beams; 1, 2, 3 = numbers of arcs; 0.215, 0.287, 0.430 = pitch factor; Ropt = rings optimization.

Rectum integral doses are the lowest for IMRT techniques and the highest for VMAT and HT. Lowest integral doses for the femoral heads are for HT, then for VMAT and for IMRT. Only in 7-beam IMRT plans, values are similar to HT and VMAT techniques, in 5- and 9-beam plans, values of integral dose are higher.

NTIDs in VMAT, HT and 9-beam IMRT plans are similar, but higher in VMAT and 9-beam IMRT than HT in context of the value. Quite a high value of NTID can be seen in 5-beam IMRT plans, and a little bit lower in 7-beam plans.

A trend to decrease ID value can be observed in the rectum with the number of beams and arcs increasing in IMRT and

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reports of practical oncology and radiotherapy 2 2 ( 2 0 1 7 ) 415–419

Table 1 – Mean ID values of normal and rings (Ropt) optimization, for all 5 patients.

Technique and geometry

IMRT

VMAT

HT

5/5 Ropt 7/7 Ropt 9/9 Ropt 1/1 Ropt 2/2 Ropt 3/3 Ropt 0.215/0.215 Ropt 0.287/0.287 Ropt 0.430/0.430 Ropt

Mean [Gy × l] Rectum

Bladder

Left femoral heads

Right femoral heads

2.76/2.60 2.72/2.63 2.66/2.56 2.93/2.92 2.84/2.80 2.73/2.72 2.94/3.00 3.02/3.05 3.08/3.02

4.78/4.73 4.72/4.64 4.58/4.55 5.16/4.93 4.83/4.79 5.02/4.88 4.40/4.44 4.49/4.51 4.62/4.45

1.23/1.16 0.89/0.84 1.20/1.22 0.91/0.88 0.95/0.93 1.04/1.00 0.79/0.77 0.78/0.75 0.79/0.74

1.36/1.30 1.04/0.98 1.27/1.26 0.90/0.88 1.05/0.97 1.13/1.09 0.83/0.80 0.82/0.78 0.83/0.76

VMAT techniques. The same can be seen in the bladder. In HT we have a poorly visible rising trend of integral doses with the increasing of the pitch factor value.

In the femoral heads, a trend can be observed for the ID value to grow with the increasing number of arches in the VMAT technique, but in HT they are at the same level. The drop of ID value in 7-beam IMRT plans is strongly dependent on the plans geometry in the IMRT techniques. If the femoral heads are not directly in the axis of the beam, the ID value will be lower.

A noticeable decrease in the value of the integral dose always occurs after rings optimization for every structure (Table 1).

The differences between the mean values of the integral dose before and after rings optimization is well noticeable in the case of NTID, except for 0.215 and 0.430 pitch factor optimization of HT. Isolated cases of ring structures properly worked are also found in the OARs, for the bladder in the 0.430 pitch plans and for the rectum in 5- and 9-beam plans.

The greater differences in the context of one technique are visible in the IMRT, particularly in the femoral heads and normal tissue dose value, but they are not observed in VMAT and HT. All analyses were prepared in Statistica 12 by StatSoft.

Discussion

Value of integral dose is closely linked with the volume which was calculated. To compare doses in a given location, we should know the volume of analyzed organs and the presented group should be uniform by volume.

Other influencing factors are clinical constraints, priorities and weights used during the optimization process. They may affect the organs at risk, integral dose values and, indirectly, also the normal tissue integral dose value (NTID).

Compared with Ślosarek et al. paper, in our patient group differences between the planning techniques used in the NTID value are not so large, with the smallest one for HT. In our pilot study, we observed a decrease in the dose to OARs and normal tissue in the dose volume histograms and in the isodose distribution of the CT scans, but we did not observe statistical significance for all test volumes, techniques, geometries and factors. All we can say is that there are clear trends.

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133.5/126.3 119.5/112.0 124.8/119.6 122.2/116.2 122.9/115.7 123.4/117.8 118.0/114.7 118.6/113.6 118.0/112.0

One of possible reasons for the lack of statistical significance is the size of the patient group, which is small at the moment. In the future, the authors plan to increase patients group.

As D’Suoza and Aoyama showed, the total energy deposited in the patient during radiation is dependent on the treatment planning parameters.

Our study showed that planning parameters include not only the choice of planning geometry and planning technique, but also the choice of an optimization process, especially in the context of normal tissues.

In view of our and previous results, it is clear that the choice of a planning geometry and optimization process has an impact on the values of integral doses in organs at risk and NTID values. The most extreme example of this is the comparison of the values of ID for the femoral heads in IMRT plans, another may be the rectum ID values (when more beams or arcs are used in this area, the dose can be distributed more sparingly).

Probably due to the different algorithms used in the treatment planning systems in IMRT and VMAT, integral dose in all types of structures was smaller after rings optimization, and in HT it was not always smaller.

5.

4.

Normal tissue (NTID)

Conclusion

A general tendency can be observed for integral dose value to decrease in all structures after rings optimization. Better effect of rings optimization is noticeable in the IMRT and VMAT techniques. It is possible to satisfactorily reduce NTID without detriment to the PTV and OARs by the use of rings optimization.

Conflict of interest None declared.

Financial disclosure The study was funded by Greater Poland Cancer Centre, research task number 10/2015(102).

reports of practical oncology and radiotherapy 2 2 ( 2 0 1 7 ) 415–419

references

1. Ost P, Speleers B, De Meerleer G, et al. Volumetric Arc Therapy and Intensity-Modulated radiotherapy for primary prostate radiotherapy with simultaneous integrated boost to intraprostatic lesion with 6 and 18 MV: a planning comparison study. Int J Radiat Oncol Biol Phys 2011;79(3):920–6.

2. Marnitz S, Wlodarczyk W, Neumann O, et al. Which technique for radiation is most beneficial for patients with locally advanced cervical cancer? Intensity modulated proton therapy versus intensity modulated photon treatment, helical tomotherapy and volumetric arc therapy for primary radiation – an intraindividual comparison. Radiat Oncol 2015;10:91.

3. Skórska M, Piotrowski T. Empirical estimation of beam-on time for prostate cancer patients treated on Tomotherapy.

Rep Pract Oncol Radiother 2013;18(4):201–8.

4. Davidson MT, Blake SJ, Batchelar DL, Cheung P, Mah K. Assessing the role of volumetric modulated arc therapy (VMAT) relative to IMRT and helical tomotherapy in the management of localized, locally advanced, and post-operative prostate cancer. Int J Radiat Oncol Biol Phys 2011;80(5):1550–8.

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5. Aoyama H, Westerly DC, Mackie TR, et al. Integral radiation dose to normal structures with conformal external beam radiation. Int J Radiat Oncol Biol Phys 2006;64(3):962–7.

6. Fuentes-Raspall R, Inoriza JM, Rosello-Serrano A, Auñón-Sanz C, Garcia-Martin P, Oliu-Isern G. Late rectal and bladder toxicity following radiation therapy for prostate cancer: predictive factors and treatment results. Rep Pract Oncol Radiother 2013;18(5):298–303.

7. Polkinghorn WR, Zelefsky MJ. Improving outcomes in high-risk prostate cancer with radiotherapy. Rep Pract Oncol Radiother 2013;18(6):333–7.

8. D’Souza WD, Rosen II. Nontumor integral dose variation in conventional radiotherapy treatment planning. Med Phys 2003;30(8):2065–71.

9. D’Arienzo M, Masciullo SG, de Sanctis V, Osti MF, Chiacchiararelli L, Enrici RM. Integral dose and radiation-induced secondary malignancies: comparison between stereotactic body radiation therapy and three-dimensional conformal radiotherapy. Int J Environ Res Public Health 2012;9(11):4223–40. ˛ 10. Ślosarek K, Osewski W, Grzadziel A, et al. Integral dose: comparison between four techniques for prostate radiotherapy. Rep Pract Oncol Radiother 2014;20(2): 99–103.

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A novel approach to total skin irradiation using helical TomoTherapy

Practical Radiation Oncology (2013) xx, xxx–xxx

www.practicalradonc.org

Original Report

A novel approach to total skin irradiation using helical TomoTherapy Arman Sarfehnia PhD a,⁎, Emily Poon PhD a , Stephen D. Davis PhD a , Adam Fleming MD b , David Mitchell MD b , Carolyn R. Freeman MD c a

Department of Medical Physics, McGill University Health Centre, Montreal, Quebec, Canada Department of Hematology/Oncology, McGill University Health Centre, Montreal, Quebec, Canada c Department of Radiation Oncology, McGill University Health Centre, Montreal, Quebec, Canada b

Received 21 August 2013; revised 7 October 2013; accepted 9 October 2013

Abstract Purpose: To describe our experience with a novel technique for total skin irradiation using helical TomoTherapy (Accuray, Sunnyvale, CA).

Methods and materials: An infant with refractory acute myelogenous leukemia with extensive cutaneous involvement was given total skin irradiation using inverse-planned helical tomotherapy.

Quality assurance tests to determine the deliverability of the technique and the accuracy of dose estimation at the superficial skin level were devised and performed. Daily megavoltage imaging, tomotherapy plan adaptive evaluation, in vivo skin dose measurements, and cumulative dose summation were tools employed to assess the quality of treatment and positioning reproducibility on a daily basis.

Results: The quality assurance checks showed that tomotherapy can indeed be used for total skin irradiation in cases where conventional electron treatment delivery is not possible. However, the overestimation of absorbed dose near surface by the treatment planning software must be quantified and taken into account using in-phantom and in vivo dosimetry techniques with appropriate detectors. Daily imaging allows for superior positioning, while daily plan adaptive and dose summations based on the plan adaptive calculations allow for evaluation of the treatment delivery.

Conclusions: An infant has been treated successfully using helical TomoTherapy for total skin irradiation prior to allogeneic stem cell transplant. The course of treatment was uncomplicated and the patient is doing well more than 15 months following therapy.

Crown Copyright © 2013 Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. All rights reserved.

Introduction Conflicts of interest: None. ⁎ Corresponding author. McGill University Health Centre, Department of Radiation, Oncology, Rm L5-112, 1650 Cedar Ave, Montreal, Canada, QC H3G 1A4.

E-mail address: asarfehnia@medphys.mcgill.ca (A. Sarfehnia).

Total skin irradiation is normally performed at our institution using a rotational technique with the patient standing on a rotating platform at an extended source-tosurface distance. 1-3 A high-dose-rate 6 MeV electron beam is used with a custom-built flattening filter to ensure

1879-8500/$ – see front matter. Crown Copyright © 2013 Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. All rights reserved.

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a degraded beam that is relatively uniform in the central 80% of the large patient field size. Our requirement for uniformity is ± 10%, although our most recent in-air measurements have shown ± 3% uniformity.

The decision to use total skin irradiation as part of the preparatory regimen for a stem cell transplant for an infant with refractory acute myelogenous leukemia (AML) with extensive cutaneous involvement therefore posed a challenge. Our solution was to develop a technique using intensity modulated image guided radiation therapy using 6 MV photons on a helical TomoTherapy (Accuray, Sunnyvale, CA) unit. To the best of our knowledge, such an approach has not been previously described in the literature.

Methods and materials Our patient The patient presented to hospital at 10 months of age with fever, respiratory congestion, and an extensive nodular skin rash. He was found to be mildly anemic, with severe neutropenia. He had no previous medical history except for recurrent upper respiratory tract infections. His skin surface was extensively covered with a variety of lesions, from superficial scaly patches to thicker erythematous nodules, with relative sparing of the scalp.

On physical examination and imaging, there was no evidence of lymphadenopathy or organomegaly.

Biopsy of a nodular skin lesion was positive for a leukemic infiltrate and a bone marrow biopsy showed acute myeloid leukemia (French-American-British [FAB] classification M5, acute monocytic leukemia). His cerebrospinal fluid showed many mononuclear cells and it was not possible to rule out central nervous system involvement by leukemia. He was admitted and treated with intensive chemotherapy as per the current Children’s Oncology Group protocol (AAML1031) with cytarabine, daunorubicin, etoposide, mitoxantrone, and bortezomib. Based on an excellent marrow response at the end of induction cycle 1, he was stratified as low-risk and received a total of 4 chemotherapy cycles as per protocol. His skin lesions markedly improved and disappeared during the treatment phase. However, skin nodules reappeared within 2 weeks of completing his treatment and a skin biopsy performed approximately 1 month after chemotherapy was positive for leukemia cells. Bone marrow biopsy showed 6% blast cells.

His cerebrospinal fluid was negative.

He was admitted for reinduction chemotherapy (“FLAG”; fludarabine, cytarabine, and filgrastim). 4 The skin lesions continued to progress over the following month, covering his entire body surface. The decision was made to treat him with stem cell transplantation using his brother’s stored umbilical cord blood as a stem cell source. Due to the refractory skin disease, it was decided to use a conditioning regimen that

Practical Radiation Oncology: Month 2013

included radiation therapy, to be given in 3 phases: first, total skin irradiation with a total dose of 14 Gy given in 7 daily fractions (2 Gy per fraction), then craniospinal radiation therapy with a single dose of 1.8 Gy, and then finally total body irradiation (TBI), with a total dose of 10 Gy given in 5 fractions (a single fraction on the first day of treatment and then twice daily on each of the following 2 days).

Total skin irradiation technique Planning The patient underwent computed tomography (CT) simulation under anesthesia in the supine position immobilized in a full body Vac-Lok cushion (Civco, Kalona, IA) along with a thermoplastic head mask. The whole skin surface was contoured and the planning target volume (PTV) was defined as a 3 mm rim of skin and subcutaneous tissue. Due to technical difficulties with accurate and reproducible placement of bolus, we chose not to use any bolus for treatment. Instead, we relied on in vivo film dosimetry for accurate surface dose measurement.

Optimization was performed using TomoTherapy, version 4.0.4 software. A field width of 5.0 cm, a pitch of 0.287, and modulation factor of 2.5 were used. Four concentric rings of 5-mm width each were drawn inside the larger PTV ring. These acted as optimizing structures and were used to force the dose to drop at an acceptable rate (Fig 1). The maximum doses for the rings were set at 17.9, 17.0, 16.7, and 16.0 Gy. Complete blocks at the center of the brain, abdominal, and thoracic cavity were also used to further minimize beams traversing through the patient and force the TomoTherapy to deliver tangential beams along the outer contour for the most optimal solution.

Delivery TomoTherapy-based total skin therapy relies heavily on appropriate positioning of the patient as well as motion management. Accuracy in positioning was accomplished through the use of the couch-indexed Vac-Lok cushion and head mask. Daily full body megavoltage imaging using MVCT scans were performed to ensure appropriate positioning and monitor any weight changes or deviations of the body contour from the original kVCT.

Verification techniques Prior to patient treatment To evaluate the accuracy of surface dose estimation by the treatment planning system (TPS), a planned dose of 2 Gy was delivered along the 3-mm rim of a cylindrical phantom. Several pieces of radiochromic film (GafChromic EBT3; Ashland, Inc, Covington, KY) film were taped onto the phantom during the delivery. The measured dose

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Total skin irradiation using helical TomoTherapy

3

Figure 1 (A) The planning target volume (PTV; red) and consecutive rings of optimizing structure to reduce the dose from surface toward the center. (B) The final dose–volume histogram achieved for the PTV and the consecutive rings. (For color version, see online at www.practicalradonc.org).

at these points was compared against the TPS-calculated dose.

Two delivery quality assurance tests were done with solid water phantoms to verify treatment deliverability and accuracy. The proposed treatment was first delivered onto a slab phantom in which a piece of radiochromic film and an ionization chamber were inserted. As such, we ensured deliverability of the proposed plan, as well as the accuracy of the dose distribution along a coronal plane and the reference dose at a single point.

modulated treatment plan was created that enabled delivery of prescription dose to the body surface with relatively sharp drop off of dose at depth. Figure 2 shows the calculated dose distribution by the TomoTherapy treatment planning software in the 3 orthogonal planes.

During patient treatment TomoTherapy planned adaptive was performed daily for the entire duration of the treatment to determine accuracy of delivery and differences between delivered and intended dose distributions. Dose summation based on the plan adaptive distributions allowed for an evaluation of the total delivered dose following the completion of treatment delivery.

Skin dose measurements using radiochromic films were performed on days 1, 2, 3, and 7. The films were distributed over the patient’s body, with several film pieces (1 cm 2 in size) placed below the mask and between the patient’s skin and Vac-Lok cushion or underneath the anesthesia tubing. These were to determine if there were hot or cold spots in regions where high density equipment was in contact with the skin.

Results Total skin irradiation technique Based on the technique described in the previous section and shown in Fig 1, an inverse planned intensity

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Figure 2 The dose distribution in the transverse (top), coronal (middle), and sagittal (bottom) planes.

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Figure 3

Practical Radiation Oncology: Month 2013

Dose–volume histogram for some major organs at risk. (PTV, planning target volume.)

Figure 3 shows the standard cumulative dose–volume histogram (DVH) for the major organs at risk, and Table 1 gives the maximum, minimum, and average doses received by these structures. Figure 3 shows the overall dose distribution in 3 planes. All constraints were well within limits.

Under anesthesia, patient motion was minimized and dominated by patient breathing. We evaluated this motion and deemed it acceptable for the level of required uniformity (ie, an allowed ± 10% variation in dose around the prescription dose).

The patient tolerated radiation therapy well with only mild erythema over most of the skin surface and a more pronounced reaction around the mouth, genitals,

and buttocks, with mild dry desquamation. He went on to complete the transplant conditioning regimen with chemotherapy as planned. His course following stem cell rescue was relatively uncomplicated and he has no evidence of leukemia or graft versus host disease now 15 months post transplant. He has moderate to severe eczema, confirmed by multiple skin biopsies that have ruled out leukemia and graft versus host disease. Of note, the patient’s stem cell donor (his sibling) has suffered from moderate eczema since early infancy.

The patient also has clinical skin findings consistent with Gianotti-Crosti syndrome (infantile papular acrodermatitis). These rashes have been successfully managed with antihistamines and steroid or emollient topical treatments.

Table 1 Maximum, minimum, and average doses for selected organs. Dose values shown in Gy

Verification techniques

Organ

Maximum dose

Minimum dose

Average dose

PTV Spinal cord Brainstem Optic nerve (L) Globe (L) Globe (R) Liver Trachea Heart Lung (L) Lung (R)

16.2 1.6 1.4 2.8 15.2 14.5 12.7 8.3 6.9 9.6 9.2

9.6 0.9 0.6 0.9 2.5 2.3 0.7 0.9 0.8 0.8 0.8

14.7 1.1 0.8 1.4 7.0 6.9 2.2 2.6 0.7 1.6 1.6

Dose profiles along a coronal plane as measured by the radiochromic film agreed with the TPS calculation. The ionization chamber measurement in a medium dose, low dose gradient region was found to be 5.9% higher than expected. Dose–volume averaging effect of the ionization chamber may have played a part in the slightly larger than expected discrepancy.

The radiochromic film measurement showed that the TPS overestimated the skin dose by up to a maximum of 25%. From our previous experience with TomoTherapy and based on literature, 5 the overestimation of the surface dose by the TPS did not come as a surprise and was simply taken into consideration in the dose prescription.

L, left; PTV, planning target volume; R, right.

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Total skin irradiation using helical TomoTherapy

5

Figure 4 Differences in dose–volume histogram (DVH) and isodose lines between delivered (dashed) and calculated (solid) plans. All organs at risk agree well to within uncertainty. The planning target volume coverage is compromised partially due to difficulty with patient positioning. (A, anterior; L, left; P, posterior; R, right; ROI, regions of interest.)

In general, the in vivo film dosimetry confirmed our delivery quality assurance measurements. Our results showed that the TomoTherapy planning station overestimates the skin dose. Overall, we measured about 20 cGy lower for a calculated 200 cGy dose deposited close to the skin (ie, a 10% overestimation of the dose by the treatment planning software). Neither the thermoplastic mask nor the anesthesia tubing affected the skin dose distribution significantly and we did not observe any hot spots. Agreement between measurement and calculation in these regions was within 5%.

Figure 4 shows the dose distribution and the DVH for a slice through the abdomen for summed daily delivered doses. This was performed following completion of the entire treatment, and compared with the planned distribution and DVH (ie, initial intent).

Discussion Using the TomoTherapy unit for total skin irradiation was an elegant solution to a difficult clinical problem. We were able to achieve good coverage of the PTV and good sparing of organs at risk including and most especially the lungs and kidneys. We accounted for the relatively higher dose at depth in the arms by omitting the arms from the PTV for the last 2 days of treatment. We accounted for the total body contribution (~ 2 Gy, including the dose from daily MVCT verification imaging) by reducing the TBI dose from our standard 12 Gy in 6 twice-daily fractions to 10 Gy in 5 fractions and then compensated for the lower

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TBI dose by adding a single fraction of 2 Gy to the craniospinal axis.

Problems encountered included reproducibility between CT images and the treatment MVCT, and day-today setup during the 7 days of treatment, with, for example, changes in the abdominal girth that is not surprising in such a young child. One and sometimes 2 full body scans (0.25 cGy per scan) were necessary each day for positioning purposes. Although the DVHs of most organs at risk looked similar to those predicted by the TPS, summation of daily plan adaptives showed that the PTV coverage was not as conformal. Instead of 95% coverage of the target volume by the 14 Gy isodose as intended, the final distribution displays 95% coverage by the 13 Gy isodose line. Finally, a maximum underdosage of 13% to the skin surface was observed. However, for most areas we measured 3%-5% underdosage which we judged acceptable.

Given the degree of difficulty in measurements and accurate positioning of the child, as well as in the spatial registration of the measured and TPS calculated dose, the agreement between the dose delivery and TPS calculated dose distribution was also deemed acceptable, and in practice was not associated with unacceptable toxicity.

References 1. Podgorsak EB, Pla C, Pla M, Lefebvre PY, Heese R. Physics aspects of a rotational total skin electron irradiation. Med Phys. 1983;10: 159-168.

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2. Freeman CR, Suissa S, Shenouda G, et al. Clinical experience with a single field rotational total skin electron irradiation technique for cutaneous T-cell lymphoma. Radiother Oncol. 1992;24:155-162.

3. Reynard EP, Evans MD, Devic S, et al. Rotational total skin electron irradiation (RTWEI) with a linear accelerator. J Appl Clin Med Phys.

2008;9:123-134.

Practical Radiation Oncology: Month 2013 4. McCarthy AJ, Pitcher LA, Hann IM, Oakhill A. FLAG (fludarabine, high dose cytarabine, and G-CSF) for refractory and high risk relapsed acute leukemia in children. Med Pediatr Oncol. 1999;32:411-415.

5. Ramsey CR, Seibert RM, Robison B, Mitchell M. Helical tomotherapy superficial dose measurements. Med Phys. 2007;34: 3286-3293.

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Strahlenther Onkol https://doi.org/10.1007/s00066-020-01743-4

COVID-19 pneumonia treated with ultra-low doses of radiotherapy (Ultra-COVID study): a single institution report of two cases.

ORIGINAL ARTICLE

COVID-19 pneumonia treated with ultra-low doses of radiotherapy (ULTRA-COVID study): a single institution report of two cases Elena Moreno-Olmedo1 · Vladimir Suárez-Gironzini1 · Manuel Pérez2 · Teresa Filigheddu2 · Cristina Mínguez3 · Alba Sanjuan-Sanjuan4 · José A. González5 · Daniel Rivas6 · Luis Gorospe7 · Luis Larrea8 · Escarlata López1 Received: 22 July 2020 / Accepted: 31 December 2020 © Springer-Verlag GmbH, DE part of Springer Nature 2021

Abstract Introduction Since the outbreak of coronavirus disease 2019 (COVID-19) pandemic, healthcare systems have focused their efforts into finding a treatment to avoid the fatal outcomes of severe acute respiratory syndrome due to coronavirus-2 (SARS-CoV-2). Benefits and risks of systemic treatments remain unclear, with multiple clinical trials still ongoing. Radiotherapy could play a role in reducing the inflammatory response in the lungs and relieve life-threatening symptoms.

Methods We designed a prospective study of Ultra-Low Doses of Therapy with Radiation Applied to COVID-19 (ULTRA-COVID) for patients who suffer pneumonia, are not candidates for invasive mechanical ventilation and show no improvement with medical therapy.

Results We present the preliminary results of two patients diagnosed with COVID-19 pneumonia treated with ULTRA-COVID. After one radiotherapy session, significant clinical response and a good radiological response was observed in both cases, resulting in both patients being discharged from hospital in less than 2 weeks after radiation treatment.

Conclusion Preliminary clinical and radiological results suggest a potential benefit of treating COVID-19 pneumonia with ULTRA-COVID. ClinicalTrials.gov Identifier: NCT04394182

Keywords COVID-19 pneumonitis · SARS-CoV-2 · Radiation · Cytokine storm · Inflamatory response

Introduction Elena Moreno-Olmedo, M.D.

escarlata.lopez@genesiscare.es 1

Department of Radiation Oncology, La Milagrosa Hospital, GenesisCare, Madrid, Spain

2

Department of Internal Medicine, La Milagrosa Hospital, Madrid, Spain

3

Department of Radiophysics, La Milagrosa Hospital, GenesisCare, Madrid, Spain

4

Oral and Maxillofacial Surgeon, Universtiy Hospital Reina Sofía, Córdoba, Spain

5

Department of Radiation Oncology, GenesisCare, Seville, Spain

6

Department of Radiation Oncology, GenesisCare, Málaga, Spain

7

Department of Radiodiagnosis, La Milagrosa Hospital, Madrid, Spain

8

Department of Radiation Oncology, Vithas Valencia Consuelo Hospital, Valencia, Spain

The onslaught of coronavirus disease 2019 (COVID-19) has challenged healthcare infrastructures worldwide. In this evolving situation and with still many unanswered questions about the optimal therapeutic approach, healthcare systems worldwide have struggled with a rise of critically ill patients [1].

Although the majority of COVID-19 patients are asymptomatic, complications such as severe pneumonia, respiratory failure, or acute respiratory distress syndrome (ARDS) can occur, often leading to fatal outcomes for patients. Most of the time, these cases require intensive care unit (ICU) admission and invasive mechanical ventilator (IMV) support [2].

In the case of these critically ill patients, the host response against the virus appears to be mediated by a ‘cytokine storm or release syndrome (CRS)’, leading to a macrophage-mediated inflammatory mechanism (inflammatory M1-phenotype) [3] and ARDS, in the form of

K

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Strahlenther Onkol https://doi.org/10.1007/s00066-020-01743-4

ORIGINAL ARTICLE

COVID-19 pneumonia treated with ultra-low doses of radiotherapy (ULTRA-COVID study): a single institution report of two cases Elena Moreno-Olmedo1 · Vladimir Suárez-Gironzini1 · Manuel Pérez2 · Teresa Filigheddu2 · Cristina Mínguez3 · Alba Sanjuan-Sanjuan4 · José A. González5 · Daniel Rivas6 · Luis Gorospe7 · Luis Larrea8 · Escarlata López1 Received: 22 July 2020 / Accepted: 31 December 2020 © Springer-Verlag GmbH, DE part of Springer Nature 2021

Abstract Introduction Since the outbreak of coronavirus disease 2019 (COVID-19) pandemic, healthcare systems have focused their efforts into finding a treatment to avoid the fatal outcomes of severe acute respiratory syndrome due to coronavirus-2 (SARS-CoV-2). Benefits and risks of systemic treatments remain unclear, with multiple clinical trials still ongoing. Radiotherapy could play a role in reducing the inflammatory response in the lungs and relieve life-threatening symptoms.

Methods We designed a prospective study of Ultra-Low Doses of Therapy with Radiation Applied to COVID-19 (ULTRA-COVID) for patients who suffer pneumonia, are not candidates for invasive mechanical ventilation and show no improvement with medical therapy.

Results We present the preliminary results of two patients diagnosed with COVID-19 pneumonia treated with ULTRA-COVID. After one radiotherapy session, significant clinical response and a good radiological response was observed in both cases, resulting in both patients being discharged from hospital in less than 2 weeks after radiation treatment.

Conclusion Preliminary clinical and radiological results suggest a potential benefit of treating COVID-19 pneumonia with ULTRA-COVID. ClinicalTrials.gov Identifier: NCT04394182

Keywords COVID-19 pneumonitis · SARS-CoV-2 · Radiation · Cytokine storm · Inflamatory response

Introduction Elena Moreno-Olmedo, M.D.

escarlata.lopez@genesiscare.es 1

Department of Radiation Oncology, La Milagrosa Hospital, GenesisCare, Madrid, Spain

2

Department of Internal Medicine, La Milagrosa Hospital, Madrid, Spain

3

Department of Radiophysics, La Milagrosa Hospital, GenesisCare, Madrid, Spain

4

Oral and Maxillofacial Surgeon, Universtiy Hospital Reina Sofía, Córdoba, Spain

5

Department of Radiation Oncology, GenesisCare, Seville, Spain

6

Department of Radiation Oncology, GenesisCare, Málaga, Spain

7

Department of Radiodiagnosis, La Milagrosa Hospital, Madrid, Spain

8

Department of Radiation Oncology, Vithas Valencia Consuelo Hospital, Valencia, Spain

The onslaught of coronavirus disease 2019 (COVID-19) has challenged healthcare infrastructures worldwide. In this evolving situation and with still many unanswered questions about the optimal therapeutic approach, healthcare systems worldwide have struggled with a rise of critically ill patients [1].

Although the majority of COVID-19 patients are asymptomatic, complications such as severe pneumonia, respiratory failure, or acute respiratory distress syndrome (ARDS) can occur, often leading to fatal outcomes for patients. Most of the time, these cases require intensive care unit (ICU) admission and invasive mechanical ventilator (IMV) support [2].

In the case of these critically ill patients, the host response against the virus appears to be mediated by a ‘cytokine storm or release syndrome (CRS)’, leading to a macrophage-mediated inflammatory mechanism (inflammatory M1-phenotype) [3] and ARDS, in the form of

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bilateral pneumonitis. In order to prevent patient progression to the critical state, it has been proposed that the CRS can be safely treated with a single course of ultra-low dose of radiotherapy (ultra-LDRT) < 1 Gy [2, 4] which could alleviate symptoms of respiratory distress quickly, helping to reduce mortality without significant long-term sequelae [5].

As Confucius said: “Study the past if you would define the future” and indeed the past may hold the key answer to support the application of ultra-low dose of radiotherapy for these patients. The use of a single ultra-LDRT to treat pneumonia was reported in the early 1900s in 15 studies, involving 863 patients. It showed 80–85% rates of inflammatory relief success and an overall mortality reduction from 30% to 10% [6]. The established role of radiotherapy in nonmalignant inflammatory conditions [7] due to its antiinflammatory properties such as decreasing levels of proinflammatory cells including cytokines and macrophages (polarizing them toward an anti-inflammatory M2-like phenotype) has been practically explored in our study [8–10].

We have hypothesized that ultra-LDRT applied to COVID-19 patients (ULTRA-COVID) could play a role in reducing the pulmonary inflammatory response, counteracting the CRS, reducing the risk of requiring IMV and relieving life-threatening symptoms [4].

Given the need to rapidly communicate information on the global clinical effort against COVID-19, we would like to share this report that describes patient eligibility criteria, treatment course parameters and clinical outcomes of our first two patients with COVID-19 pneumonia treated with ultra-LDRT.

Methods After approval by a local ethics committee, a prospective study was designed and initiated at La Milagrosa Hospital (Madrid, Spain) to treat COVID-19 patients with ultraLDRT. The main purpose of the study was to establish the efficacy of LDRT, as an anti-inflammatory treatment in patients with COVID-19 pneumonia and with a poor response to medical treatment who would otherwise be eligible for IMV, but because of other comorbidities they were not ICU candidates. Given the extremely unusual clinical situation and poor disease prognosis if left untreated, the study has been designed without a control arm.

We identified eligible patients after reviewing their medical records for their biographical data and medical history. The Charlson Comorbidity Index (CCI; > or < 6 score) [11] was then calculated for each patient. The diagnosis of COVID-19 was proven by polymerase chain reaction (PCR) on nasal and oral swabs and a blood gas analysis was used

to calculate the Pa02/Fi02 ratio (> or < 300 mm Hg). We measured the oxygen saturation status (> or < 93%) and the ventilatory support with oxygen therapy (from nasal cannula [NC], increasing to Ventimask [VMK], and finally VMK with reservoir). In addition, blood analysis was done for inflammatory and immunological parameters, including total lymphocyte count, IL-6 levels, D-dimer, ferritin and lactate dehydrogenase (LDH) levels, C-reactive protein (CRP) and fibrinogen [12, 13].

All patients underwent a baseline thoracic computerized tomography (CT) scan, which was used to evaluate lung involvement using the Total Severity Score (TSS) [14]. This score ranged from 0 to 20 according to the sum of the percentage of involvement of each of the 5 lung lobes, which were scored from 0 to 4 points. The same senior thoracic radiologist estimated the lung involvement as mild (TSS 0–5), moderate (TSS 6–15), or severe (TSS > 15). Patients with worsening TSS score during admission of > 5 were considered eligible for the ultra-LDRT study.

Those patients should have a baseline performance status ≤ 3 on the Eastern Cooperative Oncology Group (ECOG) scale [15] and a life expectancy of > 1 month at the time of hospital admission for COVID-19 pneumonia. Patients who had previous thoracic radiotherapy and/or chemotherapy history were also included in the study. All patients provided assigned written consent, stating that they understood the purpose of the treatment and the risk that such treatment may not work.

Treatment protocol Ultra-LDRT was administered using 6 MV photon beams through a Tomotherapy Hi-Art Accuray® (Accuray, Madison, WI, USA) linear accelerator and following institutional safety procedures. A clean patient access circuit from ward to the radiotherapy unit and back was established and both patients were treated last on the day. The treatment protocol team included: 1 radiation oncologist, 1 internal medicine doctor, 1 radiation physicist, 3 radiographers and 1 cleaning staff member. All of them were provided with appropriate personal protective equipment (PPE PSH 310 Bio®) to reflect the high-risk exposure. The two patients were transferred through one specific internal hospital elevator. In order to reduce staff exposure in the radiotherapy unit, a fasttrack process was designed including simulation, contouring, dosimetry and treatment in one go.

The simulation images were acquired by megavoltage CT (MVCT) in the Tomotherapy®. Immobilization was done in supine position with thorax board and with arms support SIHO®. Three radiopaque marks were placed on the patient skin. The contouring was made in Pinnacle3 v.9.10 Philips® (Philips Radiation Oncology Systems, Fitchburg, WI, USA) station and dosimetry in Tomotherapy Hi-Art

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Planning Station 5.1.1.6 Accuray® (Accuray, Madison, WI, USA). The planning target volume (PTV) was defined as both whole lungs extended 1 cm isotropically. No dose constraints were applied to surrounding organs. Regarding the target coverage, the 90% of PTV should receive 100% of the prescription dose and the maximum hotspots dose should be < 110%.

Verification imaging was carried out using a MVCT limited to the central third of the thorax, to correct for any error. Total single dose administered was 0.8 Gy in a 3 min session.

At the end of treatment and in order to guarantee asepsis the next oncological day, a complete surface decontamination was performed using locally established decontamination procedures.

Response evaluation The radiological response was assessed using TSS change on CT imaging, which was evaluated in two separate occasions, 7 days and 4 weeks after the treatment finished.

Radiological improvement was defined as mild (TSS decrease < 3 points), moderate (TSS decrease 3–5 points), or high (TSS decrease > 5 points) from the baseline CT.

The clinical response was evaluated by repeat pulseoximetry, blood gas analysis and lab analysis as above, at days 2, 5, 7, and at 4 weeks after ultra-LDRT. Two months later, oxygen levels and pulse-oximetry were evaluated again. A Sp02 > 93%, a reduction of oxygen therapy support, a Pa02/Fi02 > 300 mm Hg and the achievement of normal range value in one or more of the inflammatory and immunological parameters on blood analysis, was considered as clinical improvement.

Radiotherapy toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE v5.0) scale [16].

Case reports After establishing our protocol, 4 patients with COVID-19 pneumonia were candidates for ultra-LDRT. One refused to participate and another died before receiving the treatment.

The other two participants met the study inclusion criteria and are discussed below.

Patients’ clinical characteristics are summarized in Table 1.

Table 1 Patients’ characteristics Variables

Patient 1

Patient 2

Gender Ethnic Age Smoking history Medical history

Male South-American 80 No Hypertension Right lower limb amputation due to myxofibrosarcoma in remission 2 No

Female Caucasian 65 No Asthma Lumbar stenosis Uterine polypectomy 2 No

No

No

12 April 2020

12 March 2020

15 April 2020

19 March 2020

Dyspnea, cough, mild fever and chest pain 3 37.5 153/80 92 70% Rhythm without murmurs Crackles predominantly in bilateral lower 2/3

Dry cough, fever, asthenia and dysgeusia 2 38.5 120/70 100 87% Tachycardia heart rhythm without murmurs Decrease in vesicular murmur.

Crackles predominantly bibasal and left

CCI Previous thoracic RT Chemotherapy history Onset symptoms date Admitted hospital date Onset symptoms ECOG at admission Temperature (°C) BP (mmHg) Heart rate (bpm) Oxygen saturation Cardiac auscultation Pulmonary auscultation

CCI Charlson Comorbidity Index, ECOG Eastern Cooperative Oncology Group, °C degrees Celsius, BP Blood Pressure, mm Hg millimeters of mercury, bpm beats per minute

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Fig. 1 CT scan evaluation. Axial and coronal reconstructions of computed tomography (CT) scans for patient 1: a Baseline, b first follow-up 7 days after radiotherapy (RT), c second follow-up at month 1. Patient 2: d Baseline, e first follow-up 7 days after RT, f second follow-up at month 1

Patient 1

An 80-year-old man presented to the emergency department with a 3-day history of dyspnea, cough and chest pain.

He showed 70% Sp02 and tachypnea. Pulmonary auscultation revealed crackles on lower two-thirds of both lungs.

During hospitalization the patient needed increasing ventilatory support (50% reservoir, 15 L of flow) and SpO2

was around 87% at best. The baseline CT thorax showed bilateral pneumonia and extensive bilateral ground-glass opacities corresponding to an acute inflammatory stage and ARDS (Fig. 1a).

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Patient 2

A 65-year-old woman presented to the emergency department with persistent cough, fever, asthenia and dysgeusia, leading to her being admitted. During hospitalization, radiological studies showed pneumomediastinum, making her ineligible for IMV. After 5 weeks of admission and several desaturation episodes, her respiratory status evolved and she needed support with VMK 40%. The CT scan ruled out the possibility of pulmonary embolism and showed moderate bilateral pneumonia, bronchiectasis, and subpleural bands suggesting an advanced inflammation phase (Fig. 1d).

The medical therapy administrated to both patients consisted of lopinavir/ritonavir (Kaletra®) 100/400 mg/12 h for 7 days after admission; hydroxychloroquine (Dolquine

azithromycin 500 mg/24 h for 3 days; piperazillin/tazobactam 4 g/0.5 g administered every 6 h for 5 days in patient 1 and for 14 days in patient 2 (neither patient required readjustment due to impaired kidney function), prophylactic doses of low-molecular-weight heparins (Enoxaparin 40 mg/24 h), corticosteroids (methylprednisolone-Urbason®-250 mg × 3 boluses) and tocilizumab (600 mg single dose). Despite this pharmacotherapy, prone position and oxygen support, the respiratory status and high inflammatory parameters of both patients continued to worsen. At this point, their enrollment in the ULTRACOVID study was decided and a single ultra-LDRT was administered in both patients on April 23, 2020.

Table 2 Results Patient 1 Pre-RT (Baseline)

Day 2

Blood test D-Dimer 4.11 1.7 (mg/dl) IL-6 (pg/ml) 112.2 67.1 Hb (g/dl) 15.8 15.0 CRP (mg/dl) 0.4 0.10 Ferritin (ng/ml) 747 685 Lymphocytes 760 750 (cells/μl and %) (8%) (14%) LDH (UI/l) 457 350 Fibrinogen 598 443 (mg/dl) Radiological assessment (CT scan) CT TSS 16 RUL TSS 4 RML TSS 3 RLL TSS 3 LUL TSS 3 LLL TSS 3 CT subjective Severe Oxygen status Support

Sp02 Fi02 COVID-19 status PCR

VMK 40% (10L) 90% 272 +

NC 2L 94% 327

Day 5

Day 7

Patient 2 Month 1 Pre-RT (Baseline)

Day 2

Day 5

Day 7

Month 1

1.13

0.80

0.27

1

0.44

0.42

0.41

0.30

40.1 15.6 0.00 721 760 (14.4%) 341 458

39.8 15.9 0.10 775 670 (13.7%) 346 395

7.76 15.0 0.14 367 1509 (30%) 396 325

46 12 1 916 740 (27.5%) 727 492.00

20 10.7 0.10 647 1310 (30.5%) 567 516

12.1 9.9 0.30 545 760 (22.6%) 607 419

6.2 9.9 0.10 469 1100 (24.6%) 523 557

4.19 12.9 0.02 185 700 (6.6%) 672 260

11 3 2 2 2 2 Moderate

9 3 2 2 1 1 Moderate

10 1 1 3 2 3 Moderate

9 1 1 2 2 3 Moderate

7 1 1 2 1 2 Mild-Moderate

None

None

VMK40% (10L)

Part time NC 2L

95% 400

95–97% 432

91% 268

Patient demand (NC 2L) 97% 395

Part time NC 94% 350

+

+

VMK 35% (8L) 92% 270

VMK 30% (6L) 92% 330

94% 337 +

RT Radiotherapy; Normal range values: IL-6 (Interleukin-6) < 7 pg/ml, D-Dimer < 0.5 mg/l; Hb (Hemoglobin) males 14–18 and females 12–16; CRP (C-Reactive Protein) < 0.500 mg/dl; Ferritin: males 22–322 ng/ml and females 10–291 ng/ml; LDH (Lactate dehydrogenase) 208–378 UI/l, Fibrinogen 200–400 mg/dl, Lymphocytes 45% CT Computed Tomography, RUL Right upper lobe, RML Right middle lobe, RLL Right lower lobe, LUL Left upper lobe, LLL Left lower lobe, TSS Total Severity Score. 1 = 0–25%; 2 = 26–50%; 3 = 51–75%; 4 = 76–100%, VMK Venturi Mask (Ventimask), NC Nasal Cannula, 02-Sat Oxygen Saturation, PCR Polymerase Chain reaction

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Results Clinical status Respiratory status improved rapidly in both patients.

Patient 1 showed an improvement on his Sp02 and Pa02/Fi02 (> 300) two days after the treatment. Supplemental oxygen with 2 L NC was discontinued at day five, he was discharged on day eight after ULTRA-COVID with 95% Sp02 values on air, and his condition remained stable 1 and 2 months later.

Patient 2 showed a slower recovery, achieving less need of oxygen support at 2, 5 and 7 days after the treatment, intermittently requiring 2 L NC 1 month after and, dropping oxygen support two months after treatment. Pa02/Fi02 was > 300 mm Hg at day 5 and she was discharged 14 days after ultra-LDRT. Both patients reported improvement of symptoms such as asthenia and dyspnea after 48 h of treatment. In addition,

the inflammatory parameters showed a decline, followed by some fluctuation and eventual stabilization. We want to highlight in particular the decrease in IL-6 (CRS). The viral status results by PCR 1 month after treatment were positive in patient 1 and negative in patient 2.

No significant or acute adverse events were observed, even after a 2-month follow-up period.

Radiological status ULTRA-COVID intervention showed an improvement of the TSS score in both patients after the first scan, with greater improvement in patient 1 (Table 2).

The first CT scan at 7 days in patient 1 showed fibrotic subpleural bands and bronchial and vascular retraction was also present (Fig. 1b). The second scan at 4 weeks showed fewer consolidation areas, although moderate lung involvement persisted (Fig. 1c).

Table 3 Low-dose radiotherapy trials applied to COVID-19 patients. Source: ClinicalTrials.gov [19] Trial

Institution/Location

Dose

RESCUE119 Phase 1 and 2 RESCUE119 Phase 3 COLOR-19

Emory University Hospital Midtown/Winship Cancer Institute, Atlanta, GA, USA

Single fraction of whole lung low-dose radiation therapya

Emory University Hospital Midtown/Winship Cancer Institute, Atlanta, GA, USA

Single fraction of whole lung low-dose radiation therapya

Radiation Oncology Department, ASST SpedaliCivili, Brescia, Brescia, Italy Imam Hossein Hospital Tehran, Iran, Islamic Republic of Iran Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center, Columbus, OH, USA Ohio State University Comprehensive Cancer Center, USA

Single fraction whole lung radiotherapy of 0.7 Gy

NCT04390412 VENTED

NCT04466683

NCT04394793 NCT04393948 NCT04534790 NCT04493294 IPACOVID

LOWRADCov19 COVRTE-19 ULTRACOVID

All India Institute of Medical Sciences, New Delhi, India Brigham and Women’s Hospital, Boston, MA, USA Social Secure Institute of Radiation Oncology, Cantonal hospital Graubuenden, Chur, Switzerland Hospital Sant Joan de Reus, Tarragona, Spain, Hospital Del Mar, Barcelona, Spain, Hospital Universitario, Madrid, Sanchinarro Madrid, Spain Servicio de Oncología Radioterápica. Hospital Clínico San Carlos Madrid, Spain Hospital Provincial de Castellon, Castellón De La Plana, Castellon, Spain Hospital La Milagrosa, GenesisCare, Madrid, Spain, Hospital Vithas Valencia Consuelo, Valencia, Spain

0.5 Gy radiation to both lungs; may be another fraction of 0.5 Gy (maximum 1 Gy in two fractions at least 72 h apart) Single dose of 0.8 Gy to the bilateral lungs

Low radiation arm: A single dose of 0.35 Gy to whole thorax; high radiation arm: A single dose of 1 Gy to whole thorax; selection of best radiotherapy dose-arm after 20 patients Single 0.7 Gy to lungs 1 Gy single lung radiation; 1 cGy bilateral lung radiation Radiotherapy 1 Gy to whole lung Low dose whole lung radiotherapya Bilateral low-dose lung irradiation: 0.5 Gy in a single fraction. Optionally, additional 0.5 Gy fraction 48 h later Low-dose radiotherapya Low-dose lung radiation (0.5–1.0 Gy) Single 0.8 Gy including both whole-lungs extended 1 cm isometric in all directions

COVID 19 Coronavirus 19 disease a Dose not specified

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The first CT scan in patient 2 showed the resolution of the pneumomediastinum, but there was fibrosis and loss of volume, with fewer consolidation areas. The second CT scan at 4 weeks showed minimum fibrosis.

In both cases, we observed an improvement from moderate to mild–moderate TSS pattern (Fig. 1e, f).

Discussion Experimental therapies have been used since the outbreak of the COVID-19 pandemic and expert societies advocated for enrolling patients into clinical studies when possible, as no standard treatment exists so far.

In this scenario, ULTRA-COVID has followed the most up-to-date evidence based on national and international guidelines; however we are facing a constantly changing situation. Indeed, some drugs used in our study (hydroxychloroquine, lopinavir/ritonavir and azithromycin) are no longer used routinely given the results of recent studies and others have taken center stage such as remdesivir.

Regarding tocilizumab [17], the only potential supportive treatment for COVID-19, the scientific community is waiting for more robust studies. In this scenario of uncertainty, the interactions bias can occur towards a beneficial or detrimental effect, although none of our patients presented side effects or clinical improvement associated with the administered pharmacotherapy.

RT is a cost-effective non-toxic treatment available in most hospitals [18]. The radiobiological basis is not well known, but literature suggests that the ultra-LDRT would modulate the overreacting immune-landscape [8–10]. The design of clinical trials to investigate RT effectiveness in COVID-19 pneumonia has been justified by the RT community and ongoing trials exist ([19]; Table 3). Despite these ongoing trials, patient recruitment is still challenging.

With the ULTRA-COVID study we wanted to analyze the anti-inflammatory effect of ultra-LDRT and its potential use to mitigate this pandemic. We support the potential activity of ultra-LDRT by presenting clinical recovery of two patients with COVID-19 pneumonia and with a poor response to standard medical therapy, who would otherwise have no other treatment than IMV, but for which they were not candidates. To our knowledge, this is the first study to demonstrate the positive outcomes of a single 0.8 Gy of helicoidal-RT for COVID-19 pneumonia treatment, which combined clinical, imaging and laboratory outcomes over time.

We agree that the timing of the irradiation in relation to disease progression is likely to influence treatment outcomes. However, it is still unclear what the best timing for ultra-LDRT administration is. It is important to distinguish between the dominant viral phase versus the host

inflammatory-cytokines-mediated response and literature supports low-dose irradiation in the early progressive stage rather than the chronic disease stage [20]. In our study, the faster recovery and the greater radiological improvement in the case of patient 1 who presented at an earlier disease stage as opposed to patient 2, whose disease stage was advanced, suggests that the earlier we apply the ultra-LDRT in the acute inflammation host phase, the better the clinical response. This hypothesis needs to be validated through a larger clinical trial.

We argue that the ultra-LDRT target is the cytokine storm and it is important that decisions about ICU escalation are made early in the patient disease journey, so that eligible patients for ultra-LDRT are identified early [19, 20].

The optimal timing for LDRT appears to be between 7 and 12 days from onset of symptoms [3].

The use of RT could stop the progression of the disease to an advance stage; and this could help curb death rates, now 3.4% on average and higher among elderly and ICU patients [21]. The optimal dose of RT is unknown with evidence supporting 0.5–1 Gy [2, 4, 5]. The average prescription doses of the ongoing trials are 0.35 and 1 Gy in a single dose and; optionally, an additional 0.5 Gy fraction 48 h later in some of them (Table 3).

We decided to apply 0.8 Gy in a single session for three main reasons: (1) available literature for pneumonia treatment supports dose 0.5–1.25 range [6], (2) the aggressiveness of the virus encouraged us to dose escalate above 0.5 Gy and (3) this is the minimum effective dose of gantry rotation period of Tomotherapy devices.

The strengths of our study are our rigorous inclusion criteria and the combination of clinical, radiological and laboratory result during follow-up. We observed a better clinical than radiological response and an improvement in inflammatory blood markers, which overall constitute a success to this treatment.

Although LDRT may increase the effectiveness of antiviral immune responses, it does not decrease the viability of virus directly [20]. It could be the reason why the PCR of patient 1 was positive 4 weeks later.

The main concerns about the RT use in non-neoplasic disease is its carcinogenesis and cardiovascular toxicity risk. Regarding carcinogenesis, evidence to support this risk is scarce when low-doses are used (0.1–4/1000 to < 1/10,000) [22–26]. Our patients were older and suffered from a life-threatening illness which makes the risk less important.

In addition, no cardiovascular event or other side effects are expected in the future due to the ultra-LDRT (0.8 Gy).

The usual dose constraints established to avoid cardiotoxicity in a standard oncological treatment such as keeping the heart mean dose < 4 Gy (RTOG 1005) means that the ul-

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tra-LDRT is safe for the heart. Nevertheless, a larger study sample and a longer follow-up period is necessary.

Our main study weakness was the small number of patients recruited. This can be explained by the fact that COVID-19 pneumonia cases started to decline at the time of the study and as we were heading to summer which made patient recruitment difficult. A larger study is needed to validate our study results.

We also consider the possible lead time bias as our study weakness, due to the different disease phase in which patients were included.

Despite these limitations, the preliminary results on our first two patients suggest a good response to RT and encourage us to continue.

Researchers at Emory University have also shared the preliminary results of day 7 analysis of their phase I/II trial (RESCUE1-19). Five patients were treated with a single dose of 1.5 Gy. They have also supported that LDRT appears to be safe without any acute toxicities noted and have shown early promise of efficacy [27].

This report highlights the importance of identifying those patients who could benefit from LDRT in order to decrease the worsening of the disease, especially in those patients who are not candidates for IMV. Further studies could demonstrate the effectiveness of LDRT, considering it as an alternative co-treatment with pharmacotherapy (or even as a sole treatment). This could be of a great importance in countries with limited or no access to expensive drugs or ICUs and it could even become standard of care in COVID-19 management. Additionally, we support that it could have a positive therapeutic impact on other viral pneumonia epidemics in which CRS has been observed [28].

Conclusion Preliminary clinical and radiological results suggest a potential benefit of treating SARS-CoV-2 (Severe acute respiratory syndrome due to coronavirus 2) pneumonia with ultra-LDRT during the acute inflammatory phase with a positive impact on the disease’s evolution and patient recovery.

Acknowledgements We thank patients and their families involved in the study, as well as all members of workforce who participated.

Compliance with ethical guidelines Conflict of interest E. Moreno-Olmedo, V. Suárez-Gironzini, M. Pérez, T. Filigheddu., C. Mínguez, A. Sanjuan-Sanjuan, J.A. González, D. Rivas, L. Gorospe, L. Larrea and E. López declare that they have no competing interests.

Ethical standards All procedures performed in studies involving human participants or on human tissue were in accordance with the ethical standards of the institutional and/or national research committee and with the 1975 Helsinki declaration and its later amendments or comparable ethical standards. Approved by the HM Hospitales Group Ethics Committee (CEIm) on April 21, 2020. CEIm code 20.4.1597GHM. Patients signed consent was obtained after verbal information on the procedure, objective and secondary effects of the treatment.

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