Liac - Carpeta de Producto by deleccientifica

CONTENIDO

CONTENIDO LIAC LIAC, DE SIT DELEC CIENTÍFICA

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A B O C A D O S A L A I N N O VA C I Ó N

C O N S U LT O R Í A I N T E G R A L

APLICACIONES CLÍNICAS

SERVICIO TÉCNICO ESPECIALIZADO

IOeRT

R A D I O T E R A P I A I N T R A O P E R AT O R I A CON ELECTRONES (IOeRT)

SOBRE SIT Y LIAC

L I A C , E L M E J O R A C E L E R A D O R C O M PA C TO 2 3 CARACTERÍSTICAS DE LIAC

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

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

BIBLIOGRAFÍA

PUBLICACIONES CIENTÍFICAS 47

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

LIAC

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 hardwares 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 posibles. 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, 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: • 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 • 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. En este documento les presentamos con detalle a LIAC HWL, el equipo más destacado que permite llevar a cabo la modalidad de tratamiento radiante más exacta disponible en la actualidad: la radioterapia intraoperatoria con electrones (IOeRT). La IOeRT consiste en entregar una dosis única de radiación con electrones durante la intervención quirúrgica en un tumor no resecado o en el lecho quirúrgico, mientras que los tejidos normales sin afectación tumoral son desplazados del haz de radiación. LIAC HWL fue diseñado para garantizar procedimientos de IOeRT rápidos y seguros tanto para el paciente como para el personal médico. Este novedoso equipo es un acelerador lineal móvil miniaturizado, de fácil manipulación y traslado. Gracias a su amplio rango de tamaños de campo, energías y tasas de dosis, es posible tratar eficazmente diferentes tamaños de tejidos tumorales y a diferentes profundidades. Los requerimientos para su puesta en marcha son mínimos debido a sus características de autoblindaje y diseño: compacto y liviano (570 Kg), por lo tanto, no son necesarios cambios estructurales significativos, ni en los quirófanos, ni en los ascensores de los centros hospitalarios. En DeLeC Científica estamos seguros que el LIAC HWL es el equipo más seguro, eficiente y versátil para la entrega de tratamientos de radioterapia intraoperatoria. 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 en quirófanos con el nivel más alto de excelencia.

MSc. Katiuska Coello Sub Directora de Aplicaciones Clínicas y Ventas DeLeC Científica Argentina S.A.

LIAC

ACELERADOR LINEAL AUTOBLINDADO Y MÓVIL PARA RADIOTERAPIA INTRAOPERATORIA

LIAC

Liac, de Sit

Liac es el más avanzado de los aceleradores de electrones para IOeRT y el punto de referencia en el mercado mundial. Gracias a su pequeña dimensión y a su poco peso, une un moderno equipamiento de irradiación a la mejor movilidad. Un concentrado de altísima tecnología exaltada por diseños que potencian la ergonomía y la facilidad de utilización del sistema. Tiene un peso liviano (< 600 kg) por lo que puede ser utilizado en todo tipo de pisos sin necesidad de refuerzo o cambios estructurales; gracias a su tamaño reducido puede ser transportado con alta capacidad de maniobra en todo tipo de ascensores como los destinados para la movilización de camillas en los centros hospitalarios. Su implementación es segura en cualquier tipo de quirófano con un nivel de complejidad mínimo para su habilitación, evitando además el alto costo de blindar una sala de cirugía con hasta 100 toneladas de concreto o plomo. El equipo cuenta con un sistema de alimentación eléctrica que proporciona estabilidad a corto y largo plazo, para ofrecer mayor seguridad durante los tratamientos. Con estas capacidades, LIAC logró integrarse de forma inmediata a los quirófanos y servicios de terapia radiante, para ofrecer la IOeRT más precisa y segura, con mínimos requisitos de instalación.

Debido a que es un equipo móvil, los médicos podrán moverlo a control remoto entre diferentes salas quirúrgicas.

LIAC

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

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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.

LIAC

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.

LIAC

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.

LIAC

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.

LIAC

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.

LIAC

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.

LIAC

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:

•

Marketing digital

•

SEO y datos

•

Contenidos originales

• Videos

•

Ciclos temáticos

•

Eventos y conferencias

•

Proyectos con instituciones

LIAC

Nuestros representados

A Subsidiary of Samsung Electronics Co. , Ltd

LIAC

IOeRT

Radioterapia intraoperatoria con electrones (IOeRT)

La IOeRT consiste en la administración directa de una dosis única de radiación con electrones sobre el tejido tumoral residual o el lecho tumoral, durante la intervención quirúrgica oncológica. Gracias a LIAC®, hoy es posible utilizar en los quirófanos haces de electrones de alta energía que aseguran una distribución de dosis de radiación homogénea sobre la región de interés, en tiempos extremadamente cortos. La IOeRT, adoptada en todo el mundo, resulta eficaz y segura para el control local de la neoplasia, reduciendo la posibilidad de recrecimiento del tumor, lo cual se traduce en una nueva esperanza para pacientes con cáncer.

Características principales Mayor control local. Disminución de efectos secundarios. Reducción -en caso de boost- y eliminación -en casos de dosis única- de la radioterapia externa. Radiación de manera inmediata Intraoperatoria inhibiendo la reproducción de las células neoplásicas. Precisión basada en la visualización directa del blanco. Significativa reducción de la dosis al tejido sano.

LIAC

La IOeRT resulta una excelente opción para el tratamiento de muchos tumores malignos, siendo usada como único tratamiento o en combinación con radioterapia de haces externos (EBRT). Esta modalidad de tratamiento radiante posee características clínicas y beneficios para el paciente que tiene una notoria diferencia con los tratamientos convencionales para las patologías tumorales. Características clínicas • A diferencia de la EBRT, la IOeRT se realiza en una irradiación única y directamente sobre el lecho quirúrgico luego de la resección y antes de cerrar al paciente. • Debido a que los tejidos sanos circundantes a la lesión se pueden desplazar y proteger quirúrgicamente, es posible alcanzar una dosis total al lecho tumoral significativamente mayor a aquella alcanzada únicamente con EBRT. • Es un procedimiento rápido y sencillo que puede ser realizado por los profesionales adecuados en pocos minutos y sin necesidad de mover al paciente de la mesa quirúrgica. • Se trata de un procedimiento de radioterapia “guiada por el oncólogo”. Beneficios para el paciente •Reducción del ciclo completo de RT a un único día, o disminución considerable del número de sesiones de EBRT para los casos de tratamiento combinado; dos minutos de irradiación con IOeRT pueden eliminar de 1 a 2 semanas de EBRT. • Mayor control local del tumor con menor toxicidad debido a la irradiación directa sobre el tejido tumoral y a la disminución del daño en los tejidos sanos circundantes. • Aumento notorio en la sobrevida a largo plazo. • Brinda mejores resultados cosméticos. Beneficios para la sociedad • Reducción del costo social asociado a la necesidad del cuidado y disminución de la productividad del paciente. Beneficios para la instalación médica • Reducción significativa en las listas de espera de los centros de radioterapia.

LIAC

Sobre SIT y Liac

SIT – Sordina IORT Technologies S.p.A. es una empresa que

emisiones de radiofrecuencia y los altos voltajes. Semejantes

nace de la fusión de dos compañías italianas, Sordina S.p.A.

competencias también están singularmente a disposición de

fundada en 1878 especializada en la producción y venta de

empresas e investigaciones nacionales e internacionales. Se

dispositivos médicos, y New Radiant Technology S.p.A. es-

estudian y se proyectan cuidadosamente los ciclos de fabri-

pecializada en aparatos emisores de radiación. Con la expe-

cación de las máquinas y de erogación de los servicios para

riencia de quien ha logrado crear la primera mesa operatoria,

optimizar tanto los tiempos de fabricación, como el costo de

el primer esterilizador y el primer acelerador lineal móvil en

los materiales utilizados. La sociedad ha proyectado y cons-

la historia, SIT ahora es líder mundial y pionero en la pro-

truido diferentes tipos de aceleradores de partículas, encar-

ducción y miniaturización de aceleradores lineales (LINACs)

gados tanto por parte de privados, como del sector público.

para radioterapia intraoperatoria con electrones (IOeRT) y se encuentra en todos los continentes con instalaciones, sedes operativas, distribuidores y técnicos. Estamos hablando de la única empresa italiana, y entre las pocas en el mundo, capaz de proyectar, construir y comercializar LINACs para IORT.

LIAC® es el primer acelerador lineal compacto, móvil y autoblindado, desarrollado por SIT, para llevar a cabo procedimientos de IOeRT. El primer equipo se instaló en el Instituto Oncológico Europeo en el año 2003 y ha sido utilizado en más de 20 tipos de cáncer, incluyendo cáncer de mama,

La fabricación de LINACs requiere una combinación de expe-

estómago, cabeza y cuello, renal, pulmonar, tejidos blandos,

riencia de alto nivel en sectores muy variados, que van des-

colorectal, vejiga, pancreático y diferentes tipos de cáncer en

de la tecnología de ultra alto vacío hasta las microondas, las

pacientes pediátricos.

LIAC

EVITA TRASLADAR AL PACIENTE El equipo acompaña a la cirugía.

UNIDAD COMPACTA Y LIGERA El impacto durante la operación es mínimo y no requiere modificaciones en el quirófano

DISEÑO ESTRECHO El equipo se puede trasladar en ascensor y llegar donde se lo requiera.

DISPONIBLE Y OPERATIVO PARA VARIAS SALAS Desplazable a través de control remoto, permite optimizar su uso en cualquier sala de operaciones.

LIAC

Liac, el mejor acelerador compac to

Características de Liac

DeLeC ofrece la última versión del sistema que es el modelo LIAC HWL. En esta versión ya no son necesarias las mamparas protectoras utilizadas en modelos anteriores. El equipo ha sido equipado con blindaje adicional que permite esta ventaja importante en el flujo de trabajo diario sin haber modificado en gran medida el peso del equipo. El HWL incorpora además un sistema de planificación del tratamiento (TPS), acompañado de una solución atractiva propuesta por SIT que surge de la imposibilidad de utilizar las imágenes de diagnóstico preoperatorias para simular la entrega de la dosis. El TPS se basa en el seguimiento óptico y la navegación por ultrasonido, lo cual permite: la selección correcta de la región de interés, la adquisición de imágenes 3D en tiempo real (US o CT), realizar el contorneo, la planificación, el cálculo de dosis y la evaluación del histograma dosis volumen (DVH); como también, el acoplamiento guiado por imágenes, la reevaluación del DVH por el TPS y la ejecución del tratamiento.

LIAC

Características generales Cabezal/Unidad móvil: • Autoblindaje. No se requiere adicionar blindaje en las salas de operación. • Movilidad y fácil transporte, con 5 grados de libertad: 3 del cabezal (elevación, ángulo de inclinación y pitch) y 2 de la unidad móvil, manipulados a control remoto. • Dimensiones: 210 x 76 x 180 cm. Unidad de control y monitor para la visualización de los campos de tratamiento • Dimensiones de la unidad de control: 80 x 60 x 120 cm. • Sistema de Planificación basado en simulaciones Monte Carlo. Características del haz • Energías: 6, 8, 10, 12 [MeV] / 4, 6, 8, 10 [MeV]. • Tasa de dosis: 10÷30 Gy/min. • Tamaños de campo: 3, 4, 5, 6, 7, 8, 10 [cm] (9 y 12 cm a pedido). • Dosis superficial: ≥ 90%.

LIAC

Otras características • Apoyos extensibles para la mesa quirúrgica. • Aplicadores para los distintos tamaños de campo fabricados 100% de PMMA (polimetilmetacrilato), lo cual permite debido a su transparencia la visualización directa de la incisión quirúrgica y del tejido a irradiar, dándole precisión al

• Discos protectores de acero y PTFE (politetrafluoroetileno), materiales esterilizables y biocompatibles, disponibles en diferentes diámetros (entre 6 y 11 cm). Estos cuentan con pequeños orificios en el borde que permiten adherirlos al tejido subyacente.

método y evitando así la necesidad de cualquier bolus.

PUESTA EN MARCHA

LIAC

Procedimiento quirúrgico de cáncer de mama

LIAC

Aplicadores - Liac

Aplicadores de Liac para adaptar la entrega del tratamiento

LIAC

¿POR QUÉ IOERT?

Características del tratamiento

Esta modalidad de tratamiento puede ser utilizada en tumores que inicialmente no se pueden extirpar (irresecables), tumores resecados (extirpados) pero con restos residuales y en lechos de tumores ya extirpados pero con un diagnóstico de alto riesgo de recidiva local. En general, la IOeRT con LIAC es usada como única opción de tratamiento en tumores pequeños o en estadíos tempranos; en tumores grandes o en estadíos más avanzados puede complementarse con la EBRT, reduciendo el número de sesiones de esta última y alcanzando mejores resultados que con la EBRT como único tratamiento. Los tratamientos son cortos (2 min aprox.) con resultados eficaces e inmediatos. La elección de la combinación correcta de la energía del haz y del aplicador de PMMA permite incrementar la dosis superficial en más del 90%.

Isodose curve, applicator Ø 6 cm, 12 MeV, 0º bevel angle.

LIAC

Las intervenciones con LIAC permiten reducir o eliminar el stress del paciente ya que no debe ser trasladado a un servicio de radioterapia externa para recibir la dosis de radiación.

Se disminuye la tasa local de recurrencia, debido a que se irradia directamente el tejido residual o lecho tumoral evitando la proliferación y/o propagación de las células cancerígenas luego de la cirugía. Esto se logra gracias a que se trata de una radioterapia guiada anatómicamente por el oncólogo radioterapeuta, quien tiene visión directa del área de riesgo y puede realizar el desplazamiento temporal de los órganos y estructuras no afectados por el tumor, protegiéndolos del haz de electrones, lo que reduce o elimina el daño al tejido sano y conlleva a menores efectos secundarios. Para los tratamientos de cáncer de mama se utilizan los discos protectores insertados temporalmente entre el tejido blanco y la pared torácica resguardando así el tejido sano subyacente.

Isodose curve modified by RP disc Ø 8 cm, applicator Ø 6 cm, 12 MeV, 0º bevel angle.

LIAC

Pilares fundamentales

FLEXIBLE Y FÁCIL DE USAR

PODEROSO Y SEGURO

El peso de LIAC HWL es de solo 570 kg (1257 lb) y su arquitectura flexible permite un procedimiento de acoplamiento rápido que garantiza una cobertura adecuada de cualquier región anatómica donde se administrará el tratamiento IOeRT.

La alta movilidad de LIAC HWL cuando se combina con su alta tasa de dosis (el tiempo de irradiación IOeRT es inferior a 2 minutos), asegura la implementación de procedimientos operativos más rápidos y confiables. LIAC HWL permite al usuario administrar la dosis de IOeRT al objetivo muy rápido, evitando que los líquidos y el potencial de sangrado interfieran con la deposición de la dosis. La selección adecuada de energía y aplicador permite el tratamiento de cualquier volumen de interés clínico con un espesor de hasta 3,2 cm dentro de la isodosis al 90% (3,8 cm dentro de la isodosis al 80%). Se inserta temporalmente un disco de radioprotección entre la glándula mamaria y la pared torácica para proteger completamente el tejido sano que se encuentra debajo. NO NECESITA BLINDAJE O MODIFICACIONES ESTRUCTURALES DE LA SALA DE OPERACIÓN

FÁCIL TRASLADO Por sus dimensiones, LIAC HWL se puede mover fácilmente a través de su control remoto de un quirófano a otro y de un piso a otro utilizando cualquier elevador de camillas, asegurando su uso durante el mismo día en múltiples quirófanos.

LIAC HWL se ha diseñado específicamente para minimizar la dispersión de la radiación. No se necesita barrera adicional, fija o móvil dentro del quirófano. El nuevo diseño permite la mayor carga de trabajo posible: más de 300 pacientes por año sin ningún blindaje adicional en un quirófano estándar. EXTRAORDINARIA ESTABILIDAD Se aplicaron los últimos desarrollos tecnológicos a LIAC HWL para ofrecer al usuario una estabilidad superior. Los sistemas SIT marcan la diferencia por su estabilidad y LIAC HWL incluso eleva el umbral a un nivel nunca antes visto. RÁPIDO COMISIONAMIENTO LIAC HWL permite al hospital realizar el tratamiento IOeRT solo 5 días después de su entrega gracias a un software muy sofisticado desarrollado en simulación Monte Carlo. La puesta en servicio de LIAC HWL se realiza de acuerdo con los protocolos internacionales primarios mediante el uso de instrumentación dosimétrica estándar, así como el uso de software propietario basado en una simulación de Monte Carlo. El uso de dicho software permite reducir drásticamente la caracterización dosimétrica del acelerador a tres días después de la prueba de aceptación del sistema

LIAC

realizada en la fábrica principal. La dosimetría clínica de la totalidad de combinaciones (4 energías x 9 diámetros del aplicador x 4 ángulos de bisel) está disponible de inmediato, lo que permite evitar toda la caracterización experimental del sistema. Las publicaciones científicas respaldan este método y hoy en día la correspondencia entre los datos simulados y experimentales es increíblemente precisa. INSTALACIÓN PLUG AND PLAY Basta con conectar la unidad móvil y la unidad de control mediante un cable a la tensión del hospital. La instalación de LIAC HWL solo requiere la disponibilidad de: -enchufe (230/110 monofásico + tierra V 50/60 Hz); Solo 5 días después de la entrega en su lugar de destino, el sistema está listo para el primer tratamiento IOeRT. APLICACIÓN DE MAMA MULTICÁNCER Más de 30.000 pacientes diagnosticados con enfermedades neoplásicas han sido tratados en todo el mundo con LIAC HWL. Se adoptan internacionalmente dos protocolos desarrollados para el tratamiento del cáncer de mama: el protocolo ELIOT para dosis única de mama (realizado en su totalidad con sistemas SIT IOeRT) y el protocolo HIOB para la estimulación mamaria. Las dosis únicas IOeRT e IOeRT Boost están respaldadas actualmente por las pautas ESTRO y ASTRO. Muchos más estudios no mamarios demuestran la eficacia de la IOeRT y, en la actualidad, las pautas de la NCCN recomiendan 8 indicaciones de la IOeRT para el sarcoma de tejidos blandos, cáncer de recto, cáncer de colon, adenocarcinoma de páncreas, cáncer de cuello uterino, cáncer de endometrio, sarcoma uterino y cáncer de vejiga.

El disco de radioprotección suturable consta de dos discos, uno de acero AISI 316L y otro de PTFE, ambos biocompatibles de grado médico. El disco tiene 4 orificios a lo largo de la corona, lo que permite coserlo temporalmente al tejido ubicado inmediatamente debajo del lecho del tumor, lo que garantiza la protección del paciente y la capacidad de realizar un tratamiento IOeRT seguro. El disco de radioprotección no suturable consta de dos discos, uno fabricado en acero AISI 316L y otro fabricado en Tecapeeck, ambos de grado médico biocompatible. BRAZO MECÁNICO También está disponible un soporte de brazo mecánico: sujeta de forma segura y asegura el aplicador en cualquier posición deseada durante el procedimiento de acoplamiento realizado para IOeRT; es compacto y ligero, se puede acoplar fácilmente a cualquier mesa de operaciones y está listo para su uso inmediato.

APLICADORES EFICIENTES LIAC HWL colima la dosis con el objetivo a través de aplicadores hechos de PMMA de grado médico. Esta solución permite una dosis superficial muy alta especialmente diseñada para tratar objetivos expuestos quirúrgicamente. Los datos experimentales también mostraron que el PMMA es el mejor material disponible para limitar cualquier radiación parásita proveniente de la interacción haz-aplicador. DISCOS DE RADIOPROTECCIÓN El disco de radioprotección está diseñado para proteger el tejido sano durante el tratamiento con IOeRT del carcinoma de mama. Hay dos tipos de disco disponibles: disco de radioprotección suturable y no suturable. LIAC

Diferencias entre Liac y otros sistemas

LIAC se diferencia de otros sistemas por su versatilidad, ventaja operatoria y su uso para el tratamiento de variadas patologías. En la siguiente tabla se resumen algunas características importantes de la IOeRT realizada con LIAC que destacan sobre otras modalidades y sistemas de radioterapia, así como su uso en el tratamiento de patologías específicas.

Característica de la modalidad de RT

IOeRT con LIAC

Braquiterapia (Mammosite)

Sí

IORT con rayos X de baja intensidad

EBRT

Xoft

Intrabeam

Sí

2 min

5 días

30 min

+5 días

Tamaño Máximo del Tumor

Opción Oncoplástica

Móvil y Autoblindado

Dosis uniforme

Cáncer de mama (dosis única)

Cáncer de mama (boost)

Tumores dermatológicos

Tumores localmente avanzados

Procedimiento ejecutado durante la cirugía Tiempos de Tratamiento

Patología específica

LIAC

La siguiente es una tabla comparativa entre LIAC HWL y el sistema Intrabeam usado también para IOeRT:

Especificación

LIAC HWL (SIT)

Intrabeam (Zeiss)

Ventajas del LIAC

Permite el transporte mecánico asistido del equipo de un quirófano a otro en la misma institución de manera rápida y sencilla. Dadas sus dimensiones puede atravesar cualquier puerta de la institución.

Grados de libertad

6 (móvil)

6 (fijo en el suelo)

Sus colimadores permiten brindar la radiación con mayor alcance y a volúmenes mayores. La morfología de los colimadores del Intrabeam limita las aplicaciones a pequeños volúmenes.

Diámetro del colimador

100 mm máx.

50 mm máx.

Entregar IOeRT con el mejor rendimiento nunca fue tan fácil y seguro, para paciente y staff médico.

LIAC

Especificación

LIAC HWL (SIT)

Intrabeam (Zeiss)

Ventajas del LIAC

Tipo de radiación

Electrones

Fotones (rayos X)

Energías/Potenciales Nominales

6, 8, 10, 12 [MeV] (Modelo 12 MeV) 4, 6, 8, 10 [MeV] (Modelo 10 MeV)

40 y 50 kV

Mejor distribución de la dosis en el tejido blanco con la posibilidad de tratar volúmenes mayores.

Máximo volumen de tratamiento

Tiempo de tratamiento (20 Gy a 10 mm de profundidad)

Puede ser utilizado en mayor número de tratamientos basándose en su penetración y sus altas tasas de dosis. Con los electrones de alta energía se logra mayor penetración y por lo tanto mayor alcance de tratamiento a la región de interés, incrementando así el control local de la enfermedad. La penetración de los fotones de baja energía es menor perjudicando la cobertura de la zona a tratar.

196000 mm3

22000 mm3

< 2 minutos

35 - 50 minutos

Tiempos de tratamientos muy cortos.

RT Task Force/ACROP recommendations perative radiation therapy with electrons (IOERT) cancer SINGLE DOSE

as non-inferior to results and overall survival, e. IOeRT is now a valid ffered for selected tion criteria.

kup and biopsy on, histological ng multicentricity.

Additional investigations (optional) Magnetic Resonance Imaging (MRI)

ntraoperative histologic assessment by frozen section Sentinel node biopsy L I A C Tumour size Surgical margin width

BIBLIOGRAPHIC REFERENCE

Criterios de elegibilidad (para una sola dosis) ESTRO IORT Task Force/ACROP recommendations for intraoperative radiation therapy with electrons (IOERT) in breast cancer Gerd Fastner, Christoph Gaisberger, Julia Kaiser, Philipp Scherer, Antonella Ciabattoni, Anna Petoukhova, Elena Sperk, Philip Poortmans, Felipe A. Calvo, Felix Sedlmayer, Maria Cristina Leonardi PII: S0167-8140(20)30240-1 DOI: https://doi.org/10.1016/j.radonc.2020.04.059 Reference: RADION 8310

Criterios de elegibilidad según las pautas de APBI Scan the QR code to access the original article on the editor's web page. • Edad ≥50 años • Histologías ductales y otras favorables • Unicéntrico y unifocal INTRAOPERATIVE PHASE • Estado de receptor positivo The subsequent selection is made during surgery and is • pN0 (i-on/ the i +)pathology results of the specimens frozen based sections, including histologic type, resection margins and presence of metastases in the sentinel node. A negative sentinel node biopsy is now considered a pre-requisite for IOERT. Intraoperative histologic assessment by Sentinel node biopsy Tumour size Surgical margin width Intraoperative technical aspects Technical feasibility of IOERT (sufficient residual breast tissue) Postoperative histological assessment Surgical margin width Histology Tumour size Lymph node assessment

LIAC HWL es una solución de alta tecnología para realizar el tratamiento IOeRT inmediatamente después de la extirpación del tumor. El dispositivo se puede instalar en cualquier quirófano estándar sin necesidad de protección lateral o modificaciones estructurales en el quirófano y es capaz de administrar con éxito el tratamiento en solo 100 segundos.

LIAC

Otro sistema disponible en el mercado para su uso en IOeRT es el Mobetron 2000, cuyas características se muestran de forma comparativa con el LIAC en la siguiente tabla:

Característica

Peso

LIAC HWL

1257 lbs/570 Kg

Mobetron 2000

Ventajas del LIAC

3076 lbs/1395 Kg

Su peso es significativamente menor, por lo que las instalaciones no requieren de modificaciones estructurales, pudiendo ser trasportado incluso en los ascensores típicos de las instalaciones hospitalarias.

Es el acelerador de electrones móvil más pequeño y versátil del mercado.

Dimensiones

83” /210 cm 30”/76 cm 71”/180 cm

106”/269 cm 43”/108.5 cm 78”/198 cm

LIAC

Característica

LIAC HWL

Mobetron 2000

Ventajas del LIAC

Modo de transporte

La posición de transporte del equipo se coloca con el control pendant y luego puede ser desplazado.

El cabezal es maniobrado con el control y luego rotado manualmente hasta la posición de transporte.

Fácil manipulación del equipo con mínima dificultad para su transporte.

Cabezal: rango de rotación / inclinación / elevación

± 60° +30° / -15° 90 cm

± 45° +10° / -30° 30 cm

Rango superior de movimiento que permite ejecutar con mayor precisión y facilidad tratamientos en localizaciones como: colorectal, suelo pélvico, etc.

Área de cobertura (mostrada en rojo)

Tiene 50% más cobertura sin tener que usar los movimientos de la mesa quirúrgica.

Energías nominales

6, 8, 10, 12 [MeV] / 4, 6, 8, 10 [MeV]

6, 9, 12 MeV

Posee energías adicionales que permiten un rango más amplio de profundidades de tratamiento.

Tamaños de campo

3, 4, 5, 6, 7, 8, 10, 12 [cm]

3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10 [cm]

Tiene disponible (a pedido) un aplicador de mayor diámetro (12 cm).

0°, 15°, 30°

Proporciona 8 aplicadores adicionales que facilitan los tratamientos donde la anatomía requiere un aplicador con un ángulo de 45°.

Reconoce el diámetro de cada aplicador y no permite el tratamiento si el aplicador programado no corresponde con el colocado en el equipo, según lo establecido en la norma EN 60601-2-1.

El UPS permite finalizar el tratamiento o mantener el sistema en línea durante 15 minutos en caso de pérdida de energía o parpadeo. Mobetron requiere que la energía vuelva a encenderse y que se reinicie.

Ángulos de bisel

Verificación electrónica de aplicadores

UPS

0°, 15°, 30°, 45°

Sí

LIAC

LIAC HWL

Mobetron 2000

Planitud del campo

≤ 12% Ø 12 cm ≤ 7% Ø 10 cm ≤ 3% Ø 8, 7, 6 cm ≤ 9% Ø 4, 5 cm ≤ 12% Ø 3 cm

< 10%

Tasa de dosis con aplicador de referencia

10 ÷ 30 Gy/min

Característica

Ventajas del LIAC

Mejor planitud en la mayoría de los tamaños de campo disponibles.

10 Gy/min

La tasa de dosis puede ser modificada de acuerdo a cada caso, permitiendo tratamientos en tiempos muy cortos.

Fabricación de componentes clave

En la empresa

Subcontratada

La experiencia interna puede traducirse en un producto más competitivo, desarrollando la capacidad de controlar su producción y comprender la parte más crítica del equipo. Esto promueve los avances del producto en el rendimiento y la calidad de la máquina.

Control del equipo

PLC

PLC y Beckhoff basados en PC

El control PLC es menos probable que sufra bloqueos que son algo comunes en los sistemas basados en PC.

Transporte del equipo

Motorizado

Motorizado solo bajo pedido

Sus ruedas motrices están espaciadas a ambos lados de la máquina y se accionan de manera diferencial. Su peso se distribuye en un área más grande haciendo más fácil el transporte en los pisos de cerámica.

Recursos para el comisionamiento

Instrumentación dosimétrica estándar y software de simulación de Monte Carlo

Instrumentación dosimétrica estándar sin software de simulación

El uso del software de simulación de Monte Carlo permite reducir dramáticamente (3 días de trabajo) la caracterización dosimétrica del acelerador y por ende su puesta en marcha.

Discos de radioprotección

Ø 4, 5, 6, 7, 8, 9 [cm]

No ofrecido

Proporciona discos de radioprotección patentados especiales para los tratamientos de mama.

LIAC

L I S TA D E PAT O L O G Í A S T R ATA B L E S C O N L I A C TUMORES EN EL SISTEMA NERVIOSO CENTRAL

CÁNCER DE CABEZA Y CUELLO

CÁNCER DE MAMA

CÁNCER DE PULMON

CÁNCER GÁSTRICO

C Á N C E R PA N C R E ÁT I C O

CÁNCER DE VÍAS BILIARES Y VESÍCULA BILIAR

C Á N C E R C O LO R R E C TA L P R I M A R I O

C Á N C E R C O LO R R E C TA L RECURRENTE

SA R C O M A S R E T R O P E R I TO N E A L E S

SARCOMAS DE TEJIDO BLANDO Y EXTREMIDADES

SARCOMAS DE HUESO

Liac WHL Diseño italiano para alcanzar la máxima calidad de radioterapia intraoperatoria con electrones.

NEOPLASIAS GINECOLÓGICAS

CÁNCER GENITOURINARIO

N E O P L A C I A S P E D I ÁT R I C A S

LIAC

Bibliografía BAGHANI HR. ET AL., JOURNAL OF RADIOTHERAPY IN PRACTICE, 1 - 9 (2018). Breast intraoperative radiotherapy: a review of available modalities, dedicated machines and treatment procedure. SCHWARTZBERG B.S. ET AL., THE AMERICAN JOURNAL OF SURGERY, 1 - 5 (2018). Application of 21-gene recurrence score results and ASTRO suitability criteria in breast cancer patients treated with intraoperative radiation therapy (IORT). SORRENTINO L. ET AL., THE BREAST, VOL. 39: 123 - 130 (2018). One-step intraoperative radiotherapy optimizes conservative treatment of breast cancer with advantages in quality of life and work resumption. TAKENEN S. ET AL., BREAST CANCER RES TREAT, 165 (2): 261 - 271 (2017). Breast cancer electron intraoperative radiotherapy: assessment of preoperative selection factors from a retrospective analysis of 758 patients and review of literature. CORREA C., HARRIS E.E. ET AL., PRACTICAL RADIATION ONCOLOGY, 7 (2): 73 - 79 (2017). Accelerated Partial Breast Irradiation: Executive Summary for the Update of an ASTRO Evidence - Based Consensus Statement. FASTNER G. ET AL., STRAHLENTHER ONKOL., VOL. 192, NO. 1, PP: 1 - 7 (2016). Survival and local control rates of triple-negative breast cancer patients treated with boost-IOERT during breast-conserving surgery. FASTNER G., REITSAMER R., ET AL., RADIOTHER ONCOL. VOL.115 (SUPPLEMENT 1): S233-4, (2015). Hypofractionated WBI plus IORT-boost in early stage breast cancer (HIOB): Updated results of a prospective trial. FASTNER G. ET AL., INT. J. CANCER, VOL. 136, PP. 1193 - 1201 (2015). IOERT as anticipated tumor bed boost during breast-conserving surgery after neoadjuvant chemotherapy in locally advanced breast cancer - Results of a case series after 5-year follow-up. VERONESI U. ET AL., THE LANCET ONCOLOGY, VOL. 14: 1269 - 1277 (2013). Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial. FASTNER G., SEDLMAYER F., CIABATTONI A., ORECCHIA R., VALENTINI V. ET AL., RADIOTHERAPY AND ONCOLOGY, VOL. 108, ISSUE 2, PP. 279 - 286 (2013). IORT with electrons as boost strategy during breast conserving therapy in limited stage breast cancer: Long term results of an ISIORT pooled analysis. TAMAKI Y. ET AL., VOL. 53: 882 - 891 (2012). Efficacy of intraoperative radiotherapy targeted to the abdominal lymph node area in patients with esophageal carcinoma. - Accelerated partial breast irradiation using only intraoperative electron radiation therapy in the early stage breast cancer.

LIAC

LEONARDI M. C., MAISONNEUVE P., MASTROPASQUA G., MORRA A., LAZZARI R., ROTMENSZ N., SANGALLI C., LUINI A., VERONESI U., AND ORECCHIA R., INT. J. RADIATION ONCOL. BIOL. PHYS., VOL. 83, NO. 3, PP. 806 - 813 (2012). How do the ASTRO consensus statement guidelines for the application of accelerated partial breast irradiation fit intraoperative radiotherapy? A retrospective analysis of patients treated at the European Institute of Oncology. IVALDI G.B. ET AL., INT. J. RADIATION ONCOLOGY BIOL. PHYS., VOL. 72, NO. 2, PP. 485 - 493 (2008). Preliminary results of electron intraoperative therapy boost and hypofractionated external beam radiotherapy after breast-conserving surgery in premenopausal women. REITSAMER R. ET AL., INT. J. CANCER, VOL. 118, PP. 2882 - 2887 (2006). The Salzburg concept of intraoperative radiotherapy for breast cancer: Results and considerations. CALVO F., MEIRINO R. AND ORECCHIA R., CRITICAL REVIEWS IN ONCOLOGY/HEMATOLOGY, VOL. 59: 116 - 127, (2006). Intraoperative radiation therapy: Part 2. Clinical. RENI M. ET AL., INT. J. RADIATION ONCOLOGY BIOL. PHYS., VOL. 50, NO. 3, PP. 651 - 658 (2001). Effect on local control and survival of electron beam intraoperative irradiation for resectable pancreatic adenocarcinoma.

LIAC

Índice de publicaciones 1. Apples and oranges: comparing partial breast irradiation techniques

2. ESTR IORT Task Force/ACROP recommendations for intraoperative radiation therapy with electrons (IOERT) in breast cancer.

3. Degro practical guideline for partial-breast irradiation.

4. ESTRO IORT Task Force/ACROP recommendations for intraoperative radiation therapy in borderline-resected pancreatic cancer.

5. ESTRO/ACROP IORT recommendations for intraoperative radiation therapy in locally recurrent rectal cancer.

6. ESTRO IORT Task Force/ACROP recommendations for intraoperative radiation therapy in unresected pancreatic cancer

7. Intraoperative radiaction therapy (IORT) for soft tissue sarcoma - ESTRO IORT Task Force/ACROP recommendations.

101

8. Accelerated Partial Breast Irradiation: Executive summary for the update of an ASTRO Evidence-Based Consensus Statement

111

9. Commisioning, dosimetric characterization and machine performance assessment of the LIAC HWL mobile accelerator for Intraoperaitve Radiotherapy.

118

Reports of Practical Oncology and Radiotherapy 25 (2020) 780–782

Available online of at www.sciencedirect.com Breast intraoperative radiotherapy: a review available modalities, dedicated machines and treatment procedure

Reports of Practical Oncology and Radiotherapy journal homepage: http://www.elsevier.com/locate/rpor

Technical note

Apples and oranges: comparing partial breast irradiation techniques Orit Kaidar-Person a,&#x204e;,1 , Icro Meattini b,c,1 , Douglas Zippel d , Philip Poortmans e,f,1 a

Breast Radiation Unit, Radiation Therapy Department, Chaim Sheba Medical Center, Ramat Gan, Israel Radiation Oncology Department, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy Department of Experimental and Clinical Biomedical Sciences “M. Serio”, University of Florence, Florence, Italy d Meirav Breast Health Center, Department of Surgery C, Chaim Sheba Medical Center, Ramat Gan, Israel e Iridium Kankernetwerk, 2610 Wilrijk-Antwerp, Belgium f University of Antwerp, Faculty of Medicine and Health Sciences, 2610 Wilrijk-Antwerp, Belgium b c

a r t i c l e

i n f o

Article history: Received 7 June 2020 Accepted 27 July 2020

A few decades ago, breast conserving therapy (BCT), consisting of breast conserving surgery followed by radiation therapy (RT), was found to be equivalent to mastectomy in terms of overall survival.1 Since then, recurrence rates have one down sharply, opening the doors to further treatment de-escalation for low-risk breast cancer patients. As such, partial breast irradiation (PBI) is an RT approach able to decrease the treatment burden for patients by reducing both treated volumes and treatment duration. Several techniques for PBI (and tumour bed boost irradiation) are available. Hereby, we emphasize important key-points regarding the clinical and technical aspects of the most prevalent ones. These techniques can be divided into three main groups: brachytherapy, intra-operative RT (IORT), and external beam RT (EBRT). External beam and brachytherapy are widely available and accepted techniques.2,3 Conversely, controversy exists about the two different IORT techniques, one electron-based (IOeRT) and one using 50 kV X-rays. Recently, the ESTRO IORT Task Force has provided a comprehensive overview of IOeRT, and long-term results of a subgroup of the TARGIT-A trial, using a 50 kV X-ray device, have been published.4,5 However, the conclusion that several types of PBI are equivalent to whole breast RT requires a critical appraisal as physical RT properties are different for each PBI technique, influencing significantly dose distribution, irradiated volumes, dose homogeneity and skin doses, all of which may result in significant differences in clinical outcomes. Moreover, the timing of PBI in relation to primary surgery is different, which can be significant for patient selection,

∗ Corresponding author at: Head of breast radiation unit, Chaim Sheba Medical Center, Derch Sheba 2 street, 52662, Ramat Gan, Israel. E-mail address: orit.kaidarperson@sheba.health.gov.il (O. Kaidar-Person). 1 Three authors contributed equally to the writing of the manuscript. https://doi.org/10.1016/j.rpor.2020.07.008 1507-1367/© 2020 Published by Elsevier B.V. on behalf of Greater Poland Cancer Centre.

further management and outcomes. Hence, as radiation and surgical oncology professionals, we know that it is not possible to extrapolate the results from one PBI technique to another: this is like comparing “apples and oranges”. There are two basic principles behind PBI: i) to select low-risk breast cancer patients characterized by low postoperative ipsilateral breast tumour recurrence rates (IBTR); ii) to apply an accurate tumoricidal RT dose to the target volume. If these two concepts are both respected, then outcomes after PBI will not be inferior to whole breast RT, whatever PBI technique used. Therefore, our critical appraisal addresses these key principles. 1) The low-risk IBTR group is constituted of female patients aged more than 50 years, pT1, unifocal, grade 1-2, non-lobular/nonDCIS, negative surgical margins, luminal-like and uninvolved lymph nodes. Of these, patients aged more than 70 can be considered a very-low-risk IBTR group, who are also candidates for PBI and might even be treated with endocrine therapy alone, for example in the case of limited life-expectancy due to comorbidity. Importantly, for patients with dense breasts on mammography, a preoperative breast MRI should be considered if planned for PBI to assure unifocal disease.6,7 2) Concerning the target volume, we know from Holland et al. that the risk for residual cancer cells decreases with the distance from the edge of the primary tumour.8 Additionally, we also learned that the local recurrence risk depends on biological tumour factors. Taken together, for PBI which should be restricted for low-risk patients, a margin of 2 cm around the primary tumour site (i.e., the site of the highest likelihood of harbouring residual tumour foci) constitutes the clinical target volume (CTV).8,9 After tumour resection, which is rarely concentric, this margin can be reduced by the tumour-free margin excised around the primary tumour, ideally measured in the major 6 directions, leading to variable margins, varying between 0 and 2 cm. The resulting CTV is not only irregular

781

O. Kaidar-Person et al. / Reports of Practical Oncology and Radiotherapy 25 (2020) 780–782 Table 1 Main partial breast irradiation techniques. EBRT

Interstitial Brachytherapy PDR, HDR, LDR

Endocavitary balloona

IORT

IOeRT

Type of treatment Time of RT

Non-invasive Postoperative

Invasive Postoperative

yes

Invasive Intraoperative/ postoperative yes

Invasive Intraoperative

Specialized device/specialized centre Type of RT Coverage of clinical target volume RT volume prescription

Invasive Intraoperative/ postoperative yes

High-energy photons Best

Nuclide, mostly 192 Ir Good

Nuclide, mostly 192 Ir Fair to poor

50-kV photons Poor

High-energy electrons Good

∼ Tumour bed+20 mm to CTV; +5 mm to PTV

∼ Tumour bed+20 mm

Dose prescribed 10 mm from applicator surface

Dose prescribed 1 mm from applicator surface

one

Tumour bed+20 mm determined at time of surgery one

Poor Good

Good Good

Variable Poor

Lowest Good

Low dose at >10 mm from applicator surface; Specialized centres; dependent on tumour location within breast; invasive

Very low dose at >5 mm from applicator surface; Time added to surgery; No ﬁnal histology available; Specialized centres; dependent on tumour location within breast; invasive

Time added to surgery; No ﬁnal histology available; Specialized centres; dependent on tumour location within breast; invasive

Number of treatment days Different protocols: Different protocols: 5-15 1-10 Dose homogeneity Best Fair Sparing of normal tissue Least Good excluding skin Skin dose Low Low Technical feasibility for Best Good various size/shape/location Draw backs Dose to normal tissues; Specialized centres; Variability in determining dependent on tumour tumour bed especially after location within breast; oncoplastic surgery invasive

yes

IORT – intraoperative radiation using 50 kV X-ray device. EBRT – external beam radiation therapy; PDR- pulse dose rate; HDR-high dose rate; LDR-low dose rate; IOeRT- intraoperative electron radiation therapy. a Example: MammoSite (Hologic, Marlborough, MA).

but also not at all coincident with the surgical cavity, which is much too often used as the basis for a target volume shaped around it. This makes any “endo-cavitary” approach highly unlikely to be successful in covering the correct CTV.10 For postoperative approaches, tissue replacement and displacement during oncoplastic surgery highly complicates the identiﬁcation of the initial tumour site and, thereby, the CTV, even when using guidelines.9 Thus, these patients are often not suitable candidates for PBI, unless RT is given before the oncoplastic tissue rearrangement, as is feasible especially with IOeRT.4 Table 1 shows the variation in the ability to deliver the prescribed tumouricidal dose with an appropriate dose distribution to the entire anatomically deﬁned target volume. The decision which PBI-technique is most appropriate should be based on knowledge of the pros and cons of these modalities combined with appropriate

expertise, and knowledge of the various RT schedules for PBI (e.g., 5-fractions EBRT-regimen of the Florence trial).11 Importantly, the different PBI techniques require different skills. Mobile IORT technology led to growing use of IORT-PBI, mostly 50 kV low-energy X-rays (e.g., TARGIT-A trial) and IOeRT (e.g., ELIOT trial).5,12 However, these techniques are not identical, with large differences concerning dose distributions, dose homogeneity and skin doses. The 50 kV spherical applicator that is positioned within the lumpectomy cavity provides a surface dose around the applicator (one can only adjust the size of the applicator), with a steep dose gradient and leading to only 25% of the prescribed dose at 1 cm distance (Fig. 1A). Moreover, in case of bleeding in the lumpectomy cavity during the procedure it can lead to even more ineffective dose delivery while an applicator-skin distance less than 1 cm can lead to signiﬁcant skin doses and complications.

Fig. 1. Intraoperative radiation techniques. A: A 50 kV spherical applicator positioned within the lumpectomy cavity. The therapeutic prescribed dose is at the surface around the applicator, with a steep dose gradient and leading to only 25% of the prescribed dose at 1 cm distance. B: Intraoperative electron radiation applicator. During surgery the irradiated volume to be irradiated can be fully determined and adjusted.

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Conversely, for IOeRT the irradiated volume can be determined and fully adjusted at the time of surgery according to the size of the primary tumour and the local anatomy, while the skin is retracted (Fig. 1B). Therefore, an improved dose coverage and lower RTrelated skin complications rates can be obtained as compared to 50 kV X-rays. While mobile IORT techniques require some specific expertise, and interstitial brachytherapy-PBI is more demanding and mainly done at specialized centres, EBRT-PBI can be applied in every radiation oncology department. Contrary to IORT, brachytherapy- and EBRT-PBI can be done after recovery from the surgery and, most importantly, knowing final pathology results. This is important, as illustrated by Tallet et al. including IORT patients selected based on the GEC-ESTRO and ASTRO criteria for PBI, with one-third of the patients needing additional whole-breast-irradiation mainly due to the presence of lymph node involvement and/or an extensive intraductal component.6,7,13 This combination was associated with increased grade 3 toxicity (the IORT dose used for definitive treatment is 21 Gy, significantly higher than the 10 Gy that is mostly used if an IORT boost is planned with whole breast EBRT).4,13 For our patients, the main treatment outcomes of interest include both disease-related outcomes and RT-related toxicity. Efficacy of PBI is closely related to adequate patient selection and adequate dose delivery to the CTV. Adverse events and cosmetic results are strongly influenced by the adopted RT schedule, the irradiated volume (and ratio with the volume of the non-target ipsilateral breast), and the technique. As we indicated above and, in the table, the best results will be obtained when respecting the inseparability of all those parameters. Conflict of interest None Declared. Financial statement None Declared. Acknowledgments COI: PP is medical advisor of Sordina IORT Technologies spa.

References 1. Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med. 2002;347:1227–1232. 2. Coles CE, Griffin CL, Kirby AM, et al. Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled, phase 3, noninferiority trial. Lancet. 2017;390:1048–1060. 3. Polgar C, Ott OJ, Hildebrandt G, et al. Late side-effects and cosmetic results of accelerated partial breast irradiation with interstitial brachytherapy versus whole-breast irradiation after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: 5-year results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2017;18:259–268. 4. Fastner GGC, Kaiser J, Scherer P, et al. ESTRO IORT Task Force/ACROP recommendations for intraoperative radiation therapy with electrons (IOERT) in breast cancer. Radiother Oncol. 2020;149:150–157. 5. Vaidya JS, Bulsara M, Saunders C, et al. Effect of Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast Radiotherapy on Local Recurrence and Survival: Long-term Results From the TARGIT-A Randomized Clinical Trial in Early Breast Cancer. JAMA Oncol. 2020:e200249, http://dx.doi.org/10.1001/jamaoncol.2020. 0249, in press. 6. Polgar C, Van Limbergen E, Potter R, et al. Patient selection for accelerated partial-breast irradiation (APBI) after breast-conserving surgery: recommendations of the Groupe Europeen de Curietherapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) breast cancer working group based on clinical evidence (2009). Radiother Oncol. 2010;94:264–273. 7. Correa C, Harris EE, Leonardi MC, et al. Accelerated Partial Breast Irradiation: Executive summary for the update of an ASTRO Evidence-Based Consensus Statement. Pract Radiat Oncol. 2017;7:73–79. 8. Holland R, Veling SH, Mravunac M, Hendriks JH. Histologic multifocality of Tis, T1-2 breast carcinomas. Implications for clinical trials of breast-conserving surgery. Cancer. 1985;56:979–990. 9. Strnad V, Hannoun-Levi JM, Guinot JL, et al. Recommendations from GEC ESTRO Breast Cancer Working Group (I): Target definition and target delineation for accelerated or boost Partial Breast Irradiation using multicatheter interstitial brachytherapy after breast conserving closed cavity surgery. Radiother Oncol. 2015;115:342–348. 10. Bartelink H, Bourgier C, Elkhuizen P. Has partial breast irradiation by IORT or brachytherapy been prematurely introduced into the clinic? Radiother Oncol. 2012;104:139–142. 11. Meattini I, Marrazzo L, Saieva C, et al. Accelerated Partial-Breast Irradiation Compared With Whole-Breast Irradiation for Early Breast Cancer: Long-Term Results of the Randomized Phase III APBI-IMRT-Florence Trial. J Clin Oncol. 2020, http://dx.doi.org/10.1200/JCO.20.00650, in press. 12. Veronesi U, Orecchia R, Maisonneuve P, et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial. Lancet Oncol. 2013;14:1269–1277. 13. Tallet A, Racadot S, Boher JM, et al. The actual benefit of intraoperative radiation therapy using 50 kV x-rays in early breast cancer: A retrospective study of 676 patients. Breast J. 2020, http://dx.doi.org/10.1111/tbj.13827, in press.

Radiotherapy and Oncology 149 (2020) 150–157

Contents lists available at ScienceDirect

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Original Article

ESTRO IORT Task Force/ACROP recommendations for intraoperative radiation therapy with electrons (IOERT) in breast cancer Gerd Fastner a,⇑, Christoph Gaisberger a, Julia Kaiser a, Philipp Scherer a, Antonella Ciabattoni b, Anna Petoukhova c, Elena Sperk d, Philip Poortmans e,f, Felipe A. Calvo g,h, Felix Sedlmayer a, Maria Cristina Leonardi i a Department of Radiotherapy and Radio-Oncology, Paracelsus Medical University Hospital Salzburg, Landeskrankenhaus, Austria; b Department of Radiotherapy, San Filippo Neri Hospital, Rome, Italy; c Department of Medical Physics, Haaglanden Medical Centre, Leidschendam, The Netherlands; d Department of Radiation Oncology, Universitätsklinikum Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany; e Department of Radiation Oncology, Iridium Kankernetwerk; f Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk-Antwerp, Belgium; g Department of Oncology, Clínica Universidad de Navarra; h School of Medicine, Complutense University, Madrid, Spain; i Division of Radiation Oncology, European Institute of Oncology, IEO, IRCCS, Milan, Italy

a r t i c l e

i n f o

Article history: Received 30 April 2020 Accepted 30 April 2020 Available online 13 May 2020 Keywords: Breast cancer Accelerated partial breast irradiation Intraoperative radiation therapy Electron beam Single dose radiotherapy

a b s t r a c t The aim of this review is to provide a comprehensive overview of the role of intraoperative radiation therapy with electrons (IOERT) in breast conserving therapy (BCT), both as partial breast irradiation (PBI) as well as anticipated boost (‘‘IOERT-Boost”). For both applications, the criteria for patient selection, technical details/requirements, physical aspects and outcome data are presented. IOERT as PBI: The largest evidence comes from Italian studies, especially the ELIOT randomized trial. Investigators showed that the rate of in-breast relapses (IBR) in the IOERT group was significantly greater than with whole breast irradiation (WBI), even when within the pre-specified equivalence margin. Tumour sizes >2 cm, involved axillary nodes, Grade 3 and triple negative molecular subtypes emerged as statistically significant predictors of IBR. For patients at low risk for in-breast recurrence (ASTRO/ ESTRO recommendations), full dose IOERT was isoeffective with standard WBI. Hence, several national guidelines now include this treatment strategy as one of the standard techniques for PBI in carefully selected patients. IOERT Boost: The largest evidence for boost IOERT preceding WBI comes from pooled analyses performed by the European Group of the International Society of Intraoperative Radiation Therapy (ISIORT Europe), where single boost doses (mostly around 10 Gy) preceded whole-breast irradiation (WBI) with 50 Gy (conventional fractionation). At median follow-up periods up to ten years, local recurrence rates around 1% were observed for low risk tumours. Higher local relapse rates were described for grade 3 tumours, triple negative breast cancer as well as for patients treated after primary systemic therapy for locally advanced tumours. Even in this settings, long-term (>5y) local tumour control rates beyond 95% were achieved. These encouraging results are interpreted as being attributable to utmost precision in dose delivery (by avoiding a ‘‘geographic and/or temporal miss”), and the possible radiobiological superiority of a single high dose fraction, compared to the conventionally fractionated boost. IOERT also showed favourable results in terms of cosmetic outcome, assumedly thanks to the small treated volumes combined with complete skin sparing. 2020 Elsevier B.V. All rights reserved. Radiotherapy and Oncology 149 (2020) 150–157

Introduction In breast conserving treatment (BCT), radiation therapy following breast-conserving surgery (BCS) is performed as whole breast irradiation (WBI) or, increasingly, as accelerated partial breast irra⇑ Corresponding author at: Department of Radiotherapy and Radio-Oncology, Paracelsus Medical University Hospital Salzburg, Landeskrankenhaus, Salzburg, Austria. E-mail address: g.fastner@salk.at (G. Fastner).

diation (APBI), targeting the tissue surrounding the original tumour site (tumour bed) in selected patients with low local recurrence risks [1]. Increasing doses to the tumour bed have shown to reduce local recurrence rates, supporting the introduction of tumour bed boosts. Therefore, additional (boost) doses of 10–16 Gy are routinely applied with external electrons, photons, or interstitial brachytherapy. Early experiences with the use of intraoperative radiation therapy (IORT) were published in the late nineties [2]. The rational for

G. Fastner et al. / Radiotherapy and Oncology 149 (2020) 150–157

IORT, compared to other APBI techniques was to avoid geographic as well as temporal misses [3], reduced treated volumes with skin sparing potentially contributing to better cosmetic outcome, and shortening the overall treatment time. Moreover, during the last decade there has been growing evidence that IORT might exploit increased anti-tumour effects due to higher single dose during surgery [4–6]. Taking into account these findings, IORT has been investigated for both APBI and tumour bed boost. Following the introduction of mobile linear accelerators, IORT for breast cancer became increasingly popular in Europe during the last two decades. In 2014, Krengli et al. published a survey on the use of IORT across Europe among 31 radiation oncology centres. Data on more than 7.196 patients were available for various tumours, including 5.659 with breast cancer [7] in which single dose IORT for APBI was delivered in 33% of cases and boost followed by WBI in 66%. In 95.4% of cases, IORT was performed with electrons (IOERT) and in 4.6% with 50 kV X-rays. Single-doses APBI was administered in the range of 18 Gy (8%)–21 Gy (71.1%) and as a boost between 8 and 12 Gy. This paper aims to provide an overview on intraoperative radiation therapy with electrons (IOERT). Emphasis is placed on available trials, clinical outcome in terms of local control (LC) and overall survival (OS), as well as criteria for patient selection. Furthermore, technical and physical aspects are described, to help understand and consider IOERT a possible treatment option in daily practice. For possible applications of IORT with 50-kV orthovoltage X-rays, we refer to the recommended national UK guidelines [8]. IOERT as accelerated partial breast irradiation (APBI): ‘‘Full dose IOERT

151

Patient selection for full-dose IOERT Literature data points out that careful patient selection for IOERT as APBI is mandatory. The selection is a two-step process, consisting in a preoperative and intraoperative phase. The firststep includes physical examination, radiological work-up and biopsy of the tumour to assess breast size, tumour extent and location, histological and biological tumour features for clinical staging and excluding multicentricity. Thereafter, proper selection for APBI must be discussed in a multidisciplinary context, considering also patients’ age and comorbidities. The subsequent selection is made during surgery and is based on the pathology results of the specimens frozen sections, including histologic type, resection margins and presence of metastases in the sentinel node. A negative sentinel node biopsy is now considered a pre-requisite for IOERT. Pre-treatment investigations – – – –

Physical examination (breast size, tumour extent and location) Mammography Breast ultrasound Biopsy for histological examination

Additional investigations (optional) – Magnetic Resonance Imaging (MRI) Intraoperative histologic assessment by frozen section – Sentinel node biopsy – Tumour size – Surgical margin width

Evidence: systematic review (Table 1)

Intraoperative technical aspects

IOERT as sole radiation therapy for early breast cancer (BC) has been investigated since 1999 through phase I and II studies assessing the maximum tolerated dose and acute-intermediate toxicity [9]. The results of the phase I–II studies laid the foundation for the prospective, randomized phase III ELIOT trial [10] which investigated the efficacy of single fraction 21 Gy IOERT to the tumour bed compared with adjuvant whole breast irradiation (WBI) with conventional fractionation. The IOERT arm presented higher rates of 5-year in-breast recurrence (IBR) than the WBI arm (4.4% vs 0.4%), and higher regional node relapse rates, likely due to the smaller treated volume and the lack of non-intended axillary irradiation usually seen with the tangential fields. No significant difference in the 5-year rates of BC specific mortality and overall survival was observed between the two groups. The multivariate analysis showed that a tumour size larger than 2 cm axillary nodes involvements, grade 3 tumours and a triple negative molecular subtype were statistically significant predictors of IBR. In the following years, an international consensus panel of BC experts set and refined the eligibility criteria for APBI [11–13]. However, it remains challenging to fully apply these APBI guidelines in the case of IOERT as the complete pathologic report of the tumour is often not yet available when treatment is delivered. Therefore, great efforts must be made in gathering all relevant information concerning tumour biology by performing preoperative core needle biopsy and intraoperative frozen section assessment. Subgroup analyses conducted among patients treated in several institutions [14–17] confirmed the efficacy of IOERT in the suitable/good candidates category according to the American Society for Radiation Oncology (ASTRO) and the Groupe Européen de Curiethérapie – European Society for Radiotherapy & Oncology (GEC-ESTRO) criteria [11,13] (Table 1).

– Technical feasibility of IOERT (sufficient residual breast tissue) Postoperative histological assessment

– – – –

Surgical margin width Histology Tumour size Lymph node assessment

Eligibility criteria – Criteria according to APBI guidelines: Age 50 years; ductal and other favourable histologies; unicentric and unifocal; positive receptor status; pN0 (i /i+); to integrate with – Criteria according to ASTRO/GEC-ESTRO criteria: grade 1/2; tumour size 2 cm; Luminal A. Evidence from literature and comments Outside of clinical trials, patients should be selected according to the criteria set forward by the GEC-ESTRO and ASTRO/updated ASTRO guidelines for APBI [11–13]. Additional risk factors to be considered, emerged from mature results of the ELIOT randomised phase III trial [10]. Patients with

6/2006–12/2009

6/2007–10/2011

11/2000–12/2007

5/2004–7/2012

1/2005–12/2009

2/2010–2/2012

12/2007–3/2010

2/2006–1/2016

Maluta et al. [16,53] 2012– 2014

Osti et al. [44] 2013

Veronesi et al. [10] 2013

Hanna et al. [39]/Barros et al. [40] 2014

Cedolini et al. [50] 2014

Philippson et al. [52] 2014

Kawamura et al. [38] 2015

Takanen et al. [17] 2017

>48 years, size <2.5 cm, cN0, No no EIC

50 years, IDC, size 3 cm, no EIC,

Median age 58 years, median size 1.3 cm, 71.4% cN0

200

187

758

4 pts <48 years

Median age 64; T1-T2, any N, any grade, any margin status, any histology, uniand multi-focal tumours

>50 years, size <2.5 cm, No negative margins, cN0 since 2/2009

40 years, IDC and other No favourable, size 2 cm, pN0 (SN), free margin 1 mm, no EIC

48 years, IDC, size <3 cm, N0, N1mi, free margin >5 mm

>40 years (modified 50), IDC, size <3 cm (modified 2 cm), cN0

100%

94.4%; according to ASTRO-GECESTRO subgroups: 98.6% (low risk) 94.4% (high risk)

96.8%

98.7%

100%

99% (low risk)–90.8% (high risk)

100% (BCSS)

97.6% 98.9%

–

92.5% 97.8%

92.9% 97.3

–

1.2 % (low risk)-13.5% (high – risk)

0.5%

2% (0% in IOERT + EBRT group)

3.7% (4 true and 1 elsewhere)

4.4% vs. 0.4% in the WBI arm, (p < 0.0001)

2.7% (2 true, 1 elsewhere)

1.8%

94.4%

100%

Overall survival (%)

92.7% 100%

–

DFS (%)

3.3% – (2.3% true, 1% elsewhere); according to ASTRO-GECESTRO subgroups: 1.5% (low risk) 8.8% (high risk)

9.5% (3 true, 1 elsewhere)

15% (5 true, 3 elsewhere)

Local recurrences (%)

Patients’ categorization according to ASTRO and GECESTRO guidelines

Phase I/II dose escalation study Intraoperative IORT feasibility: 84,2%

Risk adapted treatment volume: field diameter at least 40 mm larger than the tumour size

Intraoperative IORT feasibility was 95.1%; 5 pts re-excised for positive margins

Preoperative MRI; Intraoperative IORT feasibility: 81.2%; Portal film to check collimatorshield alignment; Eligibility modified after ASTRO/ GEC-ESTRO guidelines

Randomized controlled equivalence trial

–

Out-trial patients 22 pts included in the dose escalation studies The same population was categorized according to ASTRO and GEC-ESTRO guidelines

Phase II trial

Phase II study of pre-excision IOERT

Phase I–II trial, lobular histology included (13%)

Comments

LR: local recurrence; BCSS: breast cancer specific survival; OS: overall survival; LRFS: local recurrence free survival; DFS: disease free survival; ASTRO: American Society for Radiation Oncology; GEC-ESTRO: The Groupe Européen de Curiethérapie and the European SocieTy for Radiotherapy & Oncology; MRI: Magnetic Resonance; WBI: whole breast irradiation: IOERT: intraoperative radiotherapy with electrons; EIC: extensive intraductal component; LVI: lymphovascular invasion; IDC: invasive ductal carcinoma.

Median 62.4

11 (46 Gy/ 2 Gy/fx)

WBI

65 years, IDC, size 2 cm, No N0, free margin >2 mm, positive estrogen receptors. No LVI or EIC in the primary biopsy

>48 years, IDC, size 3 cm, cN0

>45 years, size 2 cm, N0, G1–G2, positive estrogen receptors, no EIC on biopsy

Patient selection

1305 (654 >48–75 years, 2.5 cm, cN0 WBI in the WBI and control arm 651 IOERT) (50 Gy/2 Gy/ fx)

Median 72 38

Median 23.3

Mean 69.46

Median 50.7

Median 69.6

Median 110 27 months

Median 62 226

1822

1/2000–12/2008

Veronesi et al. [49] 2010/ Leonardi et al. [14,15] 2012–2013

Median 36.1

Median 72 42

11/2004–11/2007

Lemanski et al. [48,51] 2010–2013

Median 48 47

Patients

Median 69 71

10/2000–11/2002

Mussari et al. [47] 2006

Follow-up (months)

VanderWalde et al. [42]/Ol- 3/2003–7/2007 lilla et al. [36]/Kimple et al. [41] 2013/2007/ 2011

Study period

Author

Table 1 Overview of clinical studies after full-dose IOERT. 152 ESTRO IORT Task Force/ACROP recommendations for IOERT in breast cancer

153

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tumour size >2 cm, grade 3, triple negative status and 4 positive nodes should not be offered IOERT full dose. It should be noted that the presence of lymphovascular invasion (LVI) and extensive intraductal component (EIC) could not be ruled out on microbiopsy, leaving a margin of uncertainty for the fulfilment of these criteria of the consensus guidelines [14,15]. The challenge of patient selection was described by Guenzi and colleagues, who showed that by the end of the selection process, only 43% of patients candidate for IOERT were eligible to receive this treatment. In addition, if definitive pathology proves to be worse than anticipated, additional WBI might be necessary even after full-dose IORT. Peripheral breast tumour sites, namely the axillary tail and the inframammary fold, can be critical for IOERT delivery due to insufficient residual breast parenchyma affecting the correct exposure of the target volume to radiation. The same restrictions apply to IOERT in the boost setting. To date, there is no consensus on the use of MRI to properly select patients for APBI. MRI is proven to detect disease characteristics (e.g. extension, multifocality, etc) that could change eligibility in a certain percentage of patients (11% in a pooled analysis from a systematic review) [18] who would otherwise be considered candidates based on standard workup. IOERT as boost (IOERT-Boost) Evidence: systematic review (Table 2) Information on outcome after IORT-boost with electrons (IOERT-Boost) is available from various cohort analyses, with the largest deriving from a pooled analysis of the International Society of Intraoperative Radiation Therapy (ISIORT) Europe (Table 2). In these unselected retrospective studies, boost-IOERT plus WBI consistently resulted in high in-breast control rates, with observered 6- and 10-year local recurrence rates (LRR) of 0.8% and 2.7% respectively [19,20].In a matched-pair design study, 188 patients who

received a boost with external beam electrons (6x2Gy) were compared to 190 patients after IOERT-boost. At 5-year follow up, IOERT-patients had no in-breast relapses, compared to 4.3 % for those who had electron-boost (p = 0.0018) [21]. In subgroups at ‘‘higher risk” for in breast recurrences (IBR), e.g. patients with locally advanced breast cancer (LABC) after primary systemic therapy (PST) or triple negative subtypes (TN), IOERTBoost data compare favourably to those after other boost methods [22,23]. Following PST and a median follow-up (FUP) of 6 years, an observed 6-year local control rate (LCR) of 98.5 % was recorded [22], whereas specific TN-breast cancer subtypes turned out to be locally less controllable (8-year LCR of 89%) [23]. This observation that tumour biology represents an important negative predictor for IBR has been recently corroborated by the 10-years results of 770 patients of any risk profile [20]. In this analysis, TN and HER2+ subtypes (estrogen and progesteron receptor negative/ Her2neu positive) turned out to be the only significant negative predictors for in breast relapses in uni- and multivariate analyses, with an HR of 15.02 and 12.87, respectively (p < 0.05)[20]. Surprisingly, no higher risk for IBR was seen for those with high-graded tumours (G3) and nodal involvement, although a trend toward higher risk was seen in the presence of in-situ components (HR of 2.11, p = 0.11), which confirms long-term data from the EORTC-Boost trial [24]. Although a boost has in principle been proven to be an effective means for local recurrence (LR) reduction in any age group [25,26], RT in general is currently questioned for elderly patients due to missing efficacy in survival endpoints [27]. However, in the light of ongoing de-escalation strategies, some of the IOERTBoost patients classified as lower risk for recurrence are now rather considered to be eligible for PBI, either with full-dose IOERT or alternative techniques [28] depending on specific selection criteria [12,13]. A complete omission of RT in elderly women is still a matter of debate with somehow conflicting recommendations in various national guidelines or consensus statements [1,27].

Table 2 Evidence on IOERT-Boost. Author

FUP

Patients

Patient selection

Technology IORT dose (range)

Merrick HW et al. (1997) [55]

71 mo (up to 144) Min. 24 mo 109 mo (60–180) nc

Stage I–II

IOERT

101 51/50 50

Stage I–II (III) Stage I–II Stage I–II Stage I–II Stage (0) I–III Stage I–III Stage II–III

IOERT/no

Stage I–II

IOERT

Dmax: 7–12 Gy

770

Stage I–III Stage I–II

IOERT

Dmax: 5–12 Gy Dmax: 11 Gy

Dubois JB et al. [(1997) [54] Lemanski C et al. (2006) [57] Ciabattoni A et al. (2004) [56] Reitsamer R et al. (2006) [21] Ivaldi GB et al (2008) [31] Fastner G et al. (2013) [19]

51/81 mo

8.9 mo (0.8–32.4) 72.4 mo (0.8–239) Fastner G et al. (2015) [22] 59/67.5 mo (3–120) Fastner G et al. (2016) [23] 97 mo (20–170) Kaiser J et al 121 mo (2018) [20] (4–200) Fastner G et al. (2020) [30] 45 mo (0–74)

234 (122/ 112) 378 (190/ 188) 204 1109 107 (81/26)

583

IOERT IOERT/ext. e IOERT/ext. e IOERT IOERT IOERT/ext. e

IOERT

EBRT

OS/DFS

Comments

Dmax: 10–15 Gy

45–50 Gy Fx: 1.7–2 Gy

crude 100%

D90%: 10 Gy D90%: 9–20 Gy Dmax: 10 Gy Dmax: 10 Gy Dmax: 13.3 Gy Dmax: 6–15 Gy Dmax: 10 Gy

45 Gy Fx:2 Gy 50 Gy Fx:2 Gy 50 Gy Fx: nc 51–56 Gy Fx: 1.7 Gy 37.05 Gy Fx: 2.85 50–54 Gy Fx: 1.7–2 Gy 51–57 Gy Fx: 1.7– 1.8 Gy 54 Gy Fx:1.6– 1.85 Gy 54 Gy Fx:1.6–2 Gy 40.5 Gy Fx: 2.7 Gy

crude 100% vs nc crude 96%

OS: crude 90.5% nc nc

crude 100% vs 98.2% (nc) ***** 100% vs 95.7% (ss) ****100%

*** 99.2% vs 88.1% (ns) OS: ***91.4% *** 98.5% OS: ***86.4%

** 89 %

OS: **75%

* 97.2%

OS: nc *85.7% DFS: nc ******97.8%

crude 100%

= median, mo = months, * = actuarial 10-year rate; ** = actuarial 8-year rate; *** = actuarial 6-year rate, **** = actuarial 9-months rate,***** = actuarial 5-year rate, ****** = actuarial 3-year rate ext. e = external electrons, LC = local control, OS = overall survival, nc = no comments, ss = statistical significant, ns = not significant, D90% = 90%reference-isodose, Fx: Dose per fraction, OS = overall survival, LC = local control, FUP: Follow-up.

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ESTRO IORT Task Force/ACROP recommendations for IOERT in breast cancer

Patient selection for IOERT-Boost Eligible patients are those with histologically confirmed invasive breast cancer clinical stages I–III, who are candidates for BCS and WBI, with no limits to the kind of systemic treatment (substances and time sequence), age, molecular sub-type (Luminal A, Luminal B, HER2+ and TN [29]) tumour size and nodal status. External beam radiation therapy After surgery and IOERT-Boost, WBI can start as routinely when the wound is healed. There are no restriction in terms of WBI technique (e.g. tangential field techniques, IMRT or VMAT) after a 3D CT-based planning procedure in supine or prone position. WBI can be performed either with conventional fractionation (1.8– 2.0 Gy up to 50 Gy), or with hypofractionation [1] (2.66–2.85 Gy per fraction up to 40.5 and 37.05 Gy, respectively) [30–32]. Using the linear-quadratic model, we calculated that a 10 Gy IOERT-Boost should be equivalent to 23 Gy in 2 Gy daily fractions (EQD2). Biological iso-effectiveness of higher single-doses, calculated with the LQ alpha/beta model, was shown for dose ranges between 10 and 18 Gy [33], with the upper threshold still being a matter of debate [34].The combination of boost IOERT and HFWBI was first published by Ivaldi et al. in a phase II trial, showing acceptable treatment tolerance after short-term follow-up [31]. More evidence to support this regimen is expected from the multicentre ‘‘HIOB-trial” (ClinicalTrials.gov Identifier: NCT01343459), which started in January 2011 as an ISIORT investigator initiated study. In this trial, Boost IOERT of 10 Gy is combined with hypofractionated WBI (15 2.7 Gy) for stage I/II breast cancer. Annual in-breast recurrence rates are defined as benchmarks for successful treatment, in three different age groups (>50, 41–50, 35–49). Superiority of the intervention is defined by rates of inbreast control below the best-published results of ‘‘state-of-theart” radiation therapy. Beside tumour related endpoints, major emphasis has been placed on cosmetic outcome. While this study is still recruiting patients, an interim analysis on 3yrs-results has recently been published, showing very low early and late toxicity, satisfactory cosmetic results, and no locoregional recurrence [30]. Technical aspects of IOERT (full-dose and boost-concept) IOERT procedures IOERT is delivered either with conventional or mobile linear accelerators (Linacs) and does not interfere with surgical procedures according to standard oncologic criteria of BCS. After the excision of the tumour, the surgeon mobilizes the part of the remaining breast around the tumour bed by separating the deep side from the fascia of the major pectoral muscle and the superficial side from the subcutaneous tissue at the level of the anterior adipose lamina, to expose the target volume to the radiation beam. The surgical margins are then temporarily approximated to restore the anatomy of the gland and to allow IOERT to be delivered [9,35]. When IOERT is given before tumour excision, the surgeon makes an incision on the skin over the tumour and inserts the applicator over the intact tumour [36]. However, IOERT after tumour removal represents the preferable sequence with highest clinical evidence. To spare underlying tissues from radiation, a shielding disc available in various diameters, can be inserted between the surface of the pectoralis muscle and the posterior side of the reconstructed mammary gland. The shielding disc is generally made of two layers of different materials: one of high and the other of low atomic number. For example, lead and aluminium can be used in combination, with lead facing the breast parenchyma to stop electrons, while the aluminium blocks the electrons back-scattered by the lead [37]. Alternative materials can be used [38–40], allowing for

transmission of up to 15% of the maximum prescribed dose. Although the use of a shielding disc is recommended in case of full-dose IOERT, it is not mandatory, as the treated tissues can stop most of the electrons depending on their energy and the thickness of the tissue itself. A shielding disc is not used when IOERT is administered before tumour excision [36,41,42] and is optional when IOERT is performed as boost. In order to avoid an unwanted dose delivery by electrons escaping through the applicator wall, a skin retractor (with hooks to a plastic ring in order to stretch skin margins away from the radiation field) is advantageous. IOERT is delivered through applicators (tubes) with different diameters, ranging from 3 to 12 cm, either flat ended or bevelled. For BC, applicator sizes usually range from 4 to 6 cm. The sterile applicator (poly methyl methacrylate (Perspex) or metal) is placed directly in contact with the target volume. Depending on the system, docking is either performed by rigid tube attachment to the linear accelerator (hard docking) or the applicator firmly clamped to the operation table while moving the gantry until it reaches the proper position through laser alignments (soft docking). The applicator size is chosen in order to ensure the proper coverage of a given target volume around the surgical sutured breech, depending on the tumour size and location. Electron energies range between 4 and 12 MeV and are chosen according to the needs of the clinical target volume (CTV) definition (Supplementary table A.1). For exact treatment positioning, a mobile operating table with six degrees of freedom could help to reach particularly difficult target position. Furthermore, for soft-docking systems, a camera and light-source should be installed at the head of the Linac, in order to visually check the correct alignment between the head itself and the electron applicator, (via monitor) as well as to document the treated area (Fig. 1a). Irradiated volume, post treatment patient care and technical requirements for IOERT delivery are reported as supplementary material (Supplementary item A.1–A.4, Supplementary table A.2). Dose prescription The dose can be prescribed at Dmax (100%) or at D90. Dmax, D90, D45 and their corresponding tissue depths (d) should be specified along the central beam and clinical axis (in mm) respectively (Figs. 1b and c). As illustrated in Fig. 1b, this axes discrimination is only relevant if the electron tube ending has a beveled angle (15 , 30 or 45 ), at 0 the two axes coincide. V90 is defined as the volume of tissue included in the 90% isodose and should be reported in ml (cc). As for geometric reasons, depending on available planning systems, V90 can be calculated by the formula of a rotating ellipsoid (4 3.14/3 a2 b) (Fig. 1d). Full dose IOERT The most commonly used dose is 21 Gy prescribed at the depth of the 90% isodose (which corresponds to 23.3 Gy at 100%). To make a comparison for standard fractionated treatment, the biological equivalent dose (BED) using a/b ratio of 4 Gy/50 Gy is 75 Gy while for single fraction 21 Gy is 131 Gy [43]. Other investigators reported a dose of 21 Gy prescribed at the 100% isodose [16,44]: in this case the whole target was included in the 80% isodose and covered by the dose of 16.8 Gy. The aim for this dose reduction was to be as close as possible to the BED of 50 Gy with conventional fractionation; in fact, the BED for single dose of 16.8 Gy is 87 Gy, which is comparable to 75 Gy BED of standard fractionation scheme of 2 Gy in 25 sessions. When IORT is delivered to the intact tumour (prior to excision), the dose is decreased to 15 Gy at 90% isodose, since no chest wall shielding is applicable in this setting. In this case, the energy of electrons is chosen to cover the intact tumour plus a 1.0 cm margin beyond the 90% isodose line [36,42,45]. The authors state that chest wall

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Fig. 1a. Treatment position: Tube adjustment by laser-light and monitor support (dedicated linac).

beveled electron tube

Fig. 1b. Dmax (100%), D90, D45 and their corresponding tissue depths (d) of the tumour bed (brown) should be specified along the central beam and clinical axis (in mm) respectively.

Fig. 1c. Tissue depth measurement by ultrasound (along the clinical axis), corresponding electron energy and dose prescription of Dmax 11 Gy.

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ESTRO IORT Task Force/ACROP recommendations for IOERT in breast cancer

Disclaimer

Fig. 1d. V90 is defined as that tissue volume which is encompassed by the 90% isodose and should be indicated in ml. As for geometric reasons, depending on available planning systems, V90 can be calculated by the formula of a rotating ellipsoid (4 3.14/3 a2 b). b = half of distance between the two 90% depths, a = radius of the 90% isodose.

dose was initially limited to 10 Gy and subsequently raised up to 15 Gy [41]. Evidence from literature and comments The dose of 21 Gy at the 90% isodose was established as the maximum tolerated dose after a phase I and subsequently tested in a phase II study to assess acute and intermediate toxicity. Both were conducted at the European Institute of Oncology in Milan [46]. IOERT Boost The dose prescribed as boost usually ranges from 9 Gy to 12 Gy at the 90% isodose (10 Gy and 13 Gy at Dmax) [19,30,31]. Exit doses at the anterior rib surface should not exceed a limit of 7 Gy (Fig. 1c). More technical aspects concerning treatment delivery, care during the course of IOERT, recording and reporting as well as applicator removal are described in detail in the supplementary material (supplementary item A.5–A.8). Acknowledgements Intraoperative radiotherapy (IORT) is a multidisciplinary oncological activity requiring a close collaboration of team members, using optimal tools and techniques. The authors of this guideline acknowledge the remarkable contribution of all the health professionals involved in the care of patients who are candidates for IORT procedures. Authors are grateful to the ESTRO/ACROP reviewers Giovanni Battista Ivaldi, Roland Reitsamer, Mario Ciocca and Birgitte Vrou Offersen for their useful and constructive comments and for the logistic support from Eralda Azizaj. Conflicts of interest statement Felipe Calvo, Maria Cristina Leonardi and Philip Poortmans are member of the IOeRT Consortium, established on 21 December 2019, supported by Sordina IORT Technologies spa; Philip Poortmans is medical advisor of Sordina IORT Technologies spa, starting from 1 April 2020 on; Felix Sedlmayer received HIOB study grants from IntraOP Medical; Elena Sperk received travel grants and speaker honorarium from Zeiss Meditec AG, Oberkochen, Germany. The other authors have declared no conflicts of interest.

ESTRO cannot endorse all statements or opinions made on the guidelines. Regardless of the vast professional knowledge and scientific expertise in the field of radiation oncology that ESTRO possesses, the Society cannot inspect all information to determine the truthfulness, accuracy, reliability, completeness or relevancy thereof. Under no circumstances will ESTRO be held liable for any decision taken or acted upon as a result of reliance on the content of the guidelines. The component information of the guidelines is not intended or implied to be a substitute for professional medical advice or medical care. The advice of a medical professional should always be sought prior to commencing any form of medical treatment. To this end, all component information contained within the guidelines is done so for solely educational and scientific purposes. ESTRO and all of its staff, agents and members disclaim any and all warranties and representations with regards to the information contained on the guidelines. This includes any implied warranties and conditions that may be derived from the aforementioned guidelines. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.radonc.2020.04.059. References [1] Sedlmayer F, Sautter-Bihl ML, Budach W, Dunst J, Fastner G, Feyer P, et al. DEGRO practical guidelines: radiotherapy of breast cancer I: radiotherapy following breast conserving therapy for invasive breast cancer. Strahlenther Onkol 2013;189:825–33. [2] Sedlmayer F, Reitsamer R, Wenz F, Sperk E, Fussl C, Kaiser J, et al. Intraoperative radiotherapy (IORT) as boost in breast cancer. Radiat Oncol (London, England) 2017;12:23. [3] Wenz F, Blank E, Welzel G, Hofmann F, Astor D, Neumaier C, et al. Intraoperative radiotherapy during breast-conserving surgery using a miniature x-ray generator (Intrabeam(R)): theoretical and experimental background and clinical experience. Womens Health (Lond) 2012;8:39–47. [4] Belletti B, Vaidya JS, D’Andrea S, Entschladen F, Roncadin M, Lovat F, et al. Targeted intraoperative radiotherapy impairs the stimulation of breast cancer cell proliferation and invasion caused by surgical wounding. Clin Cancer Res 2008;14:1325–32. [5] Veldwijk MR, Neumaier C, Gerhardt A, Giordano FA, Sütterlin M, Herskind C, et al. Comparison of the proliferative and clonogenic growth capacity of wound fluid from breast cancer patients treated with and without intraoperative radiotherapy. Transl Cancer Res 2015;4:173–7. [6] Herskind C, Wenz F. Radiobiological aspects of intraoperative tumour-bed irradiation with low-energy X-rays (LEX-IORT). Transl Cancer Res 2014;3:3–17. [7] Krengli M, Calvo FA, Sedlmayer F, Sole CV, Fastner G, Alessandro M, et al. Clinical and technical characteristics of intraoperative radiotherapy. Analysis of the ISIORT-Europe database. Strahlenther Onkol 2013;189:729–37. [8] National Institute for Health and Clinical Excellence. (2018). Early and locally advanced breast cancer: diagnosis and treatment. Nice guideline (NG 101). [9] Veronesi U, Orecchia R, Luini A, Gatti G, Intra M, Zurrida S, et al. A preliminary report of intraoperative radiotherapy (IORT) in limited-stage breast cancers that are conservatively treated. Eur J Cancer (Oxford, England: 1990) 2001;37:2178–83. [10] Veronesi U, Orecchia R, Maisonneuve P, Viale G, Rotmensz N, Sangalli C, et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial. Lancet Oncol 2013;14:1269–77. [11] Smith BD, Arthur DW, Buchholz TA, Haffty BG, Hahn CA, Hardenbergh PH, et al. Accelerated partial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO). Int J Radiat Oncol Biol Phys 2009;74:987–1001. [12] Correa C, Harris EE, Leonardi MC, Smith BD, Taghian AG, Thompson AM, et al. Accelerated Partial Breast Irradiation: executive summary for the update of an ASTRO Evidence-Based Consensus Statement. Pract Radiat Oncol 2017;7:73–9. [13] Polgar C, Van Limbergen E, Potter R, Kovacs G, Polo A, Lyczek J, et al. Patient selection for accelerated partial-breast irradiation (APBI) after breastconserving surgery: recommendations of the Groupe Europeen de Curietherapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) breast cancer working group based on clinical evidence (2009). Radiother Oncol 2010;94:264–73.

G. Fastner et al. / Radiotherapy and Oncology 149 (2020) 150–157 [14] Leonardi MC, Maisonneuve P, Mastropasqua MG, Morra A, Lazzari R, Rotmensz N, et al. How do the ASTRO consensus statement guidelines for the application of accelerated partial breast irradiation fit intraoperative radiotherapy? A retrospective analysis of patients treated at the European Institute of Oncology. Int J Radiat Oncol Biol Phys 2012;83:806–13. [15] Leonardi MC, Maisonneuve P, Mastropasqua MG, Morra A, Lazzari R, Dell’Acqua V, et al. Accelerated partial breast irradiation with intraoperative electrons: using GEC-ESTRO recommendations as guidance for patient selection. Radiother Oncol 2013;106:21–7. [16] Maluta S, Dall’Oglio S, Marciai N, Gabbani M, Franchini Z, Pietrarota P, et al. Accelerated partial breast irradiation using only intraoperative electron radiation therapy in early stage breast cancer. Int J Radiat Oncol Biol Phys 2012;84:e145–52. [17] Takanen S, Gambirasio A, Gritti G, Kalli M, Andreoli S, Fortunato M, et al. Breast cancer electron intraoperative radiotherapy: assessment of preoperative selection factors from a retrospective analysis of 758 patients and review of literature. Breast Cancer Res Treat 2017;165:261–71. [18] Di Leo G, Trimboli RM, Benedek A, Jereczek-Fossa BA, Fossati P, Leonardi MC, et al. MR imaging for selection of patients for partial breast irradiation: a systematic review and meta-analysis. Radiology 2015;277:716–26. [19] Fastner G, Sedlmayer F, Merz F, Deutschmann H, Reitsamer R, Menzel C, et al. IORT with electrons as boost strategy during breast conserving therapy in limited stage breast cancer: long term results of an ISIORT pooled analysis. Radiother Oncol 2013;108:279–86. [20] Kaiser J, Kronberger C, Moder A, Kopp P, Wallner M, Reitsamer R, et al. Intraoperative tumor bed boost with electrons in breast cancer of clinical stages I through III: updated 10-year results. Int J Radiat Oncol Biol Phys 2018;102:92–101. [21] Reitsamer R, Sedlmayer F, Kopp M, Kametriser G, Menzel C, Deutschmann H, et al. The Salzburg concept of intraoperative radiotherapy for breast cancer: results and considerations. Int J Cancer 2006;118:2882–7. [22] Fastner G, Reitsamer R, Ziegler I, Zehentmayr F, Fussl C, Kopp P, et al. IOERT as anticipated tumor bed boost during breast-conserving surgery after neoadjuvant chemotherapy in locally advanced breast cancer–results of a case series after 5-year follow-up. Int J Cancer 2015;136:1193–201. [23] Fastner G, Hauser-Kronberger C, Moder A, Reitsamer R, Zehentmayr F, Kopp P, et al. Survival and local control rates of triple-negative breast cancer patients treated with boost-IOERT during breast-conserving surgery. Strahlenther Onkol 2016;192:1–7. [24] Vrieling C, van Werkhoven E, Maingon P, Poortmans P, Weltens C, Fourquet A, et al. Prognostic factors for local control in breast cancer after long-term follow-up in the EORTC boost vs no boost trial: a randomized clinical trial. JAMA Oncol 2017;3:42–8. [25] Antonini N, Jones H, Horiot JC, Poortmans P, Struikmans H, Van den Bogaert W, et al. Effect of age and radiation dose on local control after breast conserving treatment: EORTC trial 22881-10882. Radiother Oncol 2007;82:265–71. [26] Bartelink H, Maingon P, Poortmans P, Weltens C, Fourquet A, Jager J, et al. Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial. Lancet Oncol 2015;16:47–56. [27] Burstein HJ, Curigliano G, Loibl S, Dubsky P, Gnant M, Poortmans P, et al. Estimating the benefits of therapy for early-stage breast cancer: the St. Gallen International Consensus Guidelines for the primary therapy of early breast cancer 2019. Ann Oncol 2019;30:1541–57. [28] Kirby AM. Updated ASTRO guidelines on accelerated partial breast irradiation (APBI): to whom can we offer APBI outside a clinical trial?. Br J Radiol 2018;91:20170565. [29] Curigliano G, Burstein HJ, Winer EP, Gnant M, Dubsky P, Loibl S, et al. Deescalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017. Ann Oncol 2017;28:1700–12. [30] Fastner G, Reitsamer R, Urbanski B, Kopp P, Murawa D, Adamczyk B, et al. Toxicity and cosmetic outcome after hypofractionated whole breast irradiation and boost-IOERT in early stage breast cancer (HIOB): first results of a prospective multicenter trial (NCT01343459). Radiother Oncol 2020;146:136–42. [31] Ivaldi GB, Leonardi MC, Orecchia R, Zerini D, Morra A, Galimberti V, et al. Preliminary results of electron intraoperative therapy boost and hypofractionated external beam radiotherapy after breast-conserving surgery in premenopausal women. Int J Radiat Oncol Biol Phys 2008;72:485–93. [32] Haviland JS, Owen JR, Dewar JA, Agrawal RK, Barrett J, Barrett-Lee PJ, 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] Brenner DJ. The linear-quadratic model is an appropriate methodology for determining isoeffective doses at large doses per fraction. Semin Radiat Oncol 2008;18:234–9. [34] Veldwijk MR, Zhang B, Wenz F, Herskind C. The biological effect of large single doses: a possible role for non-targeted effects in cell inactivation. PLoS One 2014;9:e84991.

157

[35] Intra M, Luini A, Gatti G, Ciocca M, Gentilini OD, Viana AA, et al. Surgical technique of intraoperative radiation therapy with electrons (ELIOT) in breast cancer: a lesson learned by over 1000 procedures. Surgery 2006;140:467–71. [36] Ollila DW, Klauber-DeMore N, Tesche LJ, Kuzmiak CM, Pavic D, Goyal LK, et al. Feasibility of breast preserving therapy with single fraction in situ radiotherapy delivered intraoperatively. Ann Surg Oncol 2007;14:660–9. [37] Martignano A, Menegotti L, Valentini A. Monte Carlo investigation of breast intraoperative radiation therapy with metal attenuator plates. Med Phys 2007;34:4578–84. [38] Kawamura M, Itoh Y, Sawaki M, Kikumori T, Tsunoda N, Kamomae T, et al. A phase I/II trial of intraoperative breast radiotherapy in an Asian population: 5year results of local control and cosmetic outcome. Radiat Oncol (London, England) 2015;10:150. [39] Hanna SA, de Barros AC, de Andrade FE, Bevilacqua JL, Piato JR, Pelosi EL, et al. Intraoperative radiation therapy in early breast cancer using a linear accelerator outside of the operative suite: an ‘‘image-guided” approach. Int J Radiat Oncol Biol Phys 2014;89:1015–23. [40] Barros AC, Hanna SA, Carvalho HA, Martella E, Andrade FE, Piato JR, et al. Intraoperative full-dose of partial breast irradiation with electrons delivered by standard linear accelerators for early breast cancer. Int J Breast Cancer 2014;2014:568136. [41] Kimple RJ, Klauber-DeMore N, Kuzmiak CM, Pavic D, Lian J, Livasy CA, et al. Cosmetic outcomes for accelerated partial breast irradiation before surgical excision of early-stage breast cancer using single-dose intraoperative radiotherapy. Int J Radiat Oncol Biol Phys 2011;79:400–7. [42] Vanderwalde NA, Jones EL, Kimple RJ, Moore DT, Klauber-Demore N, Sartor CI, et al. Phase 2 study of pre-excision single-dose intraoperative radiation therapy for early-stage breast cancers: six-year update with application of the ASTRO accelerated partial breast irradiation consensus statement criteria. Cancer 2013;119:1736–43. [43] Rosenstein BS, Lymberis SC, Formenti SC. Biologic comparison of partial breast irradiation protocols. Int J Radiat Oncol Biol Phys 2004;60:1393–404. [44] Osti MF, Carnevale A, Bracci S, Amanti C, Lombardi A, Maggi S, et al. Exclusive electron intraoperative radiotherapy in early-stage breast cancer: a monoinstitutional experience. Anticancer Res 2013;33:1229–35. [45] Kimple RJ, Klauber-DeMore N, Kuzmiak CM, Pavic D, Lian J, Livasy CA, et al. Local control following single-dose intraoperative radiotherapy prior to surgical excision of early-stage breast cancer. Ann Surg Oncol 2011;18:939–45. [46] Orecchia R, Ciocca M, Lazzari R, Garibaldi C, Leonardi MC, Luini A, et al. Intraoperative radiation therapy with electrons (ELIOT) in early-stage breast cancer. Breast (Edinburgh, Scotland) 2003;12:483–90. [47] Mussari S, Sabino Della Sala W, Busana L, Vanoni V, Eccher C, Zani B, et al. Fulldose intraoperative radiotherapy with electrons in breast cancer. First report on late toxicity and cosmetic results from a single-institution experience. Strahlenther Onkol 2006;182:589–95. [48] Lemanski C, Azria D, Gourgou-Bourgade S, Ailleres N, Pastant A, Rouanet P, et al. Electrons for intraoperative radiotherapy in selected breast-cancer patients: late results of the Montpellier phase II trial. Radiat Oncol 2013;8:191. https://doi.org/10.1186/1748-717X-8-191. [49] Veronesi U, Orecchia R, Luini A, Galimberti V, Zurrida S, Intra M, et al. Intraoperative radiotherapy during breast conserving surgery: a study on 1,822 cases treated with electrons. Breast Cancer Res Treat 2010;124:141–51. [50] Cedolini C, Bertozzi S, Seriau L, Londero AP, Concina S, Moretti E, et al. Feasibility of concervative breast surgery and intraoperative radiation therapy for early breast cancer: a single-center, open, non-randomized, prospective pilot study. Oncol Rep 2014;31:1539–46. [51] Lemanski C, Azria D, Gourgon-Bourgade S, Gutowski M, Rouanet P, SaintAubert B, et al. Intraoperative radiotherapy in early-stage breast cancer: results of the Montpellier phase II trial. Int J Radiat Oncol Biol Phys 2010;76:698–703. [52] Philippson C, Simon S, Vandekerkhove C, Hertens D, Veys I, Noterman D, et al. Early invasive cancer and partial intraoperative electron radiation therapy of the breast: experience of the Jules Bordet Institute. Int J Breast Cancer 2014;2014:. https://doi.org/10.1155/2014/627352627352. [53] Maluta S, Dall’Oglio S, Goer DA, Marciai N. Intraoperative electron radiotherapy (IOERT) as an alternative to standard whole breast irradiation: only for low-risk subgroups?. Breast Care (Basel) 2014;9:102–6. [54] Dubois JB, Hay M, Gely S, Saint-Aubert B, Rouanet P, Pujol H. IORT in breast carcinomas. Front Radiat Ther Oncol 1997;31:131–7. [55] Merrick 3rd HW, Battle JA, Padgett BJ, Dobelbower Jr RR. IORT for early breast cancer: a report on long-term results. Front Radiat Ther Oncol 1997;31:126–30. [56] Ciabattoni A, Fortuna G, Ciccone V, Drago S, Grassi G, Consorti R, et al. IORT in breast cancer as boost: preliminary results of a pilot randomized study on use of IORT for Stage I and II breast cancer. Radiother and Oncol 2004;73:35–6. [57] Lemanski C, Azria D, Thezenas S, Gutowski M, Saint-Aubert B, Rouanet P, et al. Intraoperative radiotherapy given as a boost for early breast cancer: long-term clinical and cosmetic results. Int J Radiat Oncol Biol Phys 2006;64:1410–5.

Strahlenther Onkol https://doi.org/10.1007/s00066-020-01613-z

REVIEW ARTICLE

DEGRO practical guideline for partial-breast irradiation V. Strnad1 · D. Krug2 · F. Sedlmayer3 · M. D. Piroth4 · W. Budach5 · R. Baumann6 · P. Feyer7 · M. N. Duma8 · W. Haase9 · W. Harms10 · T. Hehr11 · R. Fietkau1 · J. Dunst2 · R. Sauer1 · Breast Cancer Expert Panel of the German Society of Radiation Oncology (DEGRO) Received: 20 February 2020 / Accepted: 19 March 2020 © The Author(s) 2020

Abstract Purpose This consensus statement from the Breast Cancer Working Group of the German Society for Radiation Oncology (DEGRO) aims to define practical guidelines for accelerated partial-breast irradiation (APBI). Methods Recent recommendations for relevant aspects of APBI were summarized and a panel of experts reviewed all the relevant literature. Panel members of the DEGRO experts participated in a series of conferences, supplemented their clinical experience, performed a literature review, and formulated recommendations for implementing APBI in clinical routine, focusing on patient selection, target definition, and treatment technique. Results Appropriate patient selection, target definition for different APBI techniques, and basic rules for appropriate APBI techniques for clinical routine outside of clinical trials are described. Detailed recommendations for APBI in daily practice, including dose constraints, are given. Conclusion Guidelines are mandatory to assure optimal results of APBI using different techniques.

Keywords Breast cancer · Partial breast irradiation · Guideline · APBI · Early breast cancer

Introduction To date, the gold standard for local treatment of patients aged 50 years or more with early breast cancer (pT1–2, pN0) and low-risk factors is breast-conserving surgery followed by postoperative whole-breast irradiation (WBI), typ V. Strnad

vratislav.strnad@uk-erlangen.de 1

University Hospital Erlangen, Erlangen, Germany

University Hospital Schleswig-Holstein, Kiel, Germany

Paracelsus Medical University Hospital Salzburg, Salzburg, Austria

Helios University Hospital Wuppertal, Witten/Herdecke University, Wuppertal, Germany

Heinrich-Heine-University Hospital Düsseldorf, Düsseldorf, Germany

St. Marien-Krankenhaus Siegen, Siegen, Germany

Vivantes Hospital Neukoelln, Berlin, Germany

University Hospital, Jena, Germany

St.-Vincentius-Hospital Karlsruhe, Karlsruhe, Germany

St. Claraspital Basel, Basel, Switzerland

Marienhospital Stuttgart, Stuttgart, Germany

ically without tumor-bed boost irradiation, which requires a treatment time of 3–6 weeks. Nowadays partial-breast irradiation (PBI) is also proposed for these patients; however, this strongly depends on the technique used [1–8]. PBI is a treatment approach able not only to shorten the course of radiation therapy (RT), but also to reduce the radiation exposure to the lung, the heart, the breasts, and the skin significantly, depending on the treatment technique [9–11]. Over the past 20 years, different modalities of PBI have been tested, mostly successfully, in a number of phase 2 and 3 clinical trials. The studied techniques are external beam radiation (photons, protons), single- and multicatheter brachytherapy, electronic brachytherapy, seed brachytherapy, non-invasive brachytherapy, and intraoperative radiation techniques (IORT) either with electrons or with 50-kV photons. Today, results from over 15,000 patients recruited within phase 3 trials testing partial-breast irradiation are available [1, 2, 5, 6, 12–19] and as a consequence, selected PBI techniques have been introduced into daily clinical routine. However, only small trials deal with PBI techniques using protons, brachytherapy (BT) using seeds, non-invasive BT, or numerous single-catheter devices. Thus, for the purpose of this guideline, we only analyzed techniques tested in randomized phase 3 trials.

50 Gy/25 fr. + boost

50 Gy/25 fr. + boost 50 Gy/25 fr. ± boost

GEC-ESTRO [1, 3, 4]

ELIOT [15] 3451

1305

1184

258

4216

2135

10 × 3.85 Gy 3D-RT in 5 days

10 × 3.85 Gy 3D-RT or HDR siBT or BT in 5–10 days BT: HDR 7 × 5.2 Gy in 4 days; or EB 50 Gy in 5 weeks HDR-BT 8 × 4 Gy or 7 × 4.3 Gy in 5 days; or PDR-BT 50 Gy in 5 days IORT 1 × 21 Gy IORT 1 × 20 Gy

2018

520

102

40 Gy/15 fr. IMRT

5 × 6 Gy IMRT in 2 weeks

10 × 3.75 Gy 3D-RT in 5 days

PBI

Patients (n)

0.4 vs. 4.4 p < 0.0001 1.3 vs. 3.3 p = 0.042

3.9 vs. 4.6 n.a. 5.1 vs. 5.9 p = 0.77 0.9 vs. 1.4 p = 0.42

1.5 vs. 1.5 p = 0.86 1.1 vs. 0.5 p = 0.016* 2.8 vs. 3.0 n. s.

n.a.

Local recurrence (%) WBI PBI

n.a.

79.7 vs. 78.1 p = 0.10 85 vs. 84 n. s. 94.4 vs. 95.0 p = 0.79

n.a.

Disease-free survival (%) WBI PBI

96.9 vs. 98.8 p = 0.59 94.7 vs. 96.1 p = 0.099

91.3 vs. 90.6 p = 0.35 80 vs. 82 n. s. 95.5 vs. 97.3 p = 0.11

96.6 vs. 99.4 p = 0.057 94 vs. 94 p = 0.69 n.a.

n.a.

Overall survival (%) WBI PBI

29 months

5.8 years

6.6 years

10.2 years

8.6 years

6.02 years

5.0 years

Follow-up (median)

n.a. not available/not reported, n. s. not significant, fr. fractions, IMRT intensity-modulated radiation therapy, EB electron beam, WBI whole breast irradiation, PBI partial-breast irradiation, 3D-RT conformal external beam, BT multicatheter brachytherapy, HDR high-dose-rate, PDR pulse-dose-rate, siBT single device brachytherapy (MammoSite, Cytyc Corporation, Palo Alto, CA) *p-value for non-inferiority

TARGIT [14]

NSBAP B-39 [12, 17] Budapest [23]

50 Gy/25 fr. or 42.5 Gy/16 fr. + boost 50 Gy/25 fr. + boost 50 Gy

48 Gy/24 fr. ± boost 50 Gy/25 fr. + boost 40 Gy/15 fr.

RAPID [13, 18, 21]

IMPORT-LOW [2]

Florence [16]

Barcelona [5]

WBI

Table 1 Summary of currently available Phase 3 PBI trials Trial Treatment

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Methods The authors evaluated the relevant literature, identified established and controversial topics via working conferences, circular emails, and meetings, and supplemented this information with their clinical experience to formulate the current guidelines. This report document was reviewed and approved by the full panel, and by the DEGRO Executive Committee. Currently available phase 3 trials are listed in Table 1.

Results External beam radiation therapy The use of external beam radiation therapy (EBRT) for PBI appears to be very attractive, because this technique is broadly available worldwide. In two small randomized trials from Barcelona and Florence [5, 16] with 105 and 520 patients, respectively, patients were either treated with using intensity-modulated EBRT for PBI or using WBI. In general, similar efficacy (local recurrence rate, diseasefree survival, and overall survival), toxicity, and cosmetic outcome were reported. However, the statistical power of both trials to prove non-inferiority of recurrence rates was inadequate. Other trials—IMPORT LOW, RAPID, and NSBAP-B39/RTOG 0413—studied sufficient numbers of patients. IMPORT LOW [2] is a multicenter, randomized, controlled, phase 3, non-inferiority trial done in the UK. Patients were randomly assigned to receive 40 Gy in 15 fractions of whole-breast radiotherapy (control), 36 Gy in 15 fractions of whole-breast radiotherapy with a simultaneous integrated boost to 40 Gy to the tumor bed (reduceddose group), or 40 Gy to the partial breast only (partialbreast group) also in 15 daily treatment fractions. For localization of the tumor bed, surgical clips were preferably used, but if this was not possible, ultrasound, MRI, or CT was used [20]. Field-in-field intensity-modulated radiotherapy was delivered using standard tangential beams that were simply reduced in length for the partial-breast group. The protocol specified forward-planned field-in-field IMRT delivered by standard medial and lateral tangential beams reduced in length but not in width. Non-target breast tissue medial or lateral to the planning target volume was thereby included in the high dose zone. Altogether, 2018 women were recruited. 674 patients were analyzed in the wholebreast radiotherapy (control) group, 673 in the reduceddose group, and 669 in the partial-breast group. After a median follow-up 72.2 months, the cumulative 5-year local relapse incidence was 1.1% in the control group, 0.2% in the reduced-dose group, and 0.5% in the partial-

breast group; hence, a non-inferiority of PBI using 2.66 Gy in 15 fractions in 3 weeks was confirmed. Patient and clinical assessments recorded similar adverse effects after reduced-dose or partial-breast radiotherapy, including two patient domains achieving statistically significantly lower adverse effects (change in breast appearance [p = 0.007 for partial-breast] and breast harder or firmer [p = 0.002 for reduced-dose and p < 0.0001 for partial-breast]) compared with whole-breast radiotherapy. Thus, for PBI in 3 weeks, equivalent or fewer late normal tissue adverse effects were seen. The IMPORT LOW trial is the only phase 3 trial of partial-breast radiotherapy to use the same overall treatment time and radiation technique in the whole-breast and partial-breast radiotherapy groups. Because the same regimen is used, differences in treatment outcome can be attributed to differences in treatment volume [2]. In the RAPID trial [13, 18, 21] with altogether 2135 patients and a median follow-up of 8.6 years, patients aged >40 years with invasive or in situ breast cancer 3 cm were randomly assigned after breast-conserving surgery to 3DCRT APBI or WBI. WBI was delivered daily to 42.5 Gy in 16 fractions or 50 Gy in 25 fractions using tangential fields. Additional boost irradiation of 10 Gy in four to five fractions after WBI was based on criteria such as young age or close margins. Patients allocated to APBI were treated with three to five noncoplanar conformal fields. The clinical target volume was the tumor bed on computed tomography, including the surgical clips plus a 1-cm margin inside breast tissue. The planning target volume was the clinical target volume plus a 1-cm margin. The dose-evaluation volume was the subvolume of the planning target volume inside breast tissue. The prescribed dose was 38.5 Gy in 10 fractions treated twice daily over 5 to 8 days [13, 21]. After a median followup of 36 months, adverse cosmesis at 3 years was increased among those treated with APBI compared with WBI, as assessed by trained nurses (29% vs. 17%; p < 0.001), by patients (26% vs. 18%; p < 0.0022), and by physicians reviewing digital photographs (35% vs. 17%; p < 0.001; [21]). The most recent analysis after a median follow-up of 8.6 years confirmed these findings: accelerated partial-breast irradiation (APBI) using three-dimensional conformal radiotherapy (3D-CRT) significantly increased grade 2 (28% APBI vs. 12% WBI) and grade 3 late radiation toxicity (4.5% APBI vs. 1% WBI, p < 0.001) and adverse cosmesis (31% vs. 15%; p = 0.001). Nonetheless, APBI vs. WBI showed similar oncological efficacy: local recurrence rate 2.3% vs. 1.7% after 5 years and 3.0% vs. 2.8% after 8 years. These data were presented at the San Antonio Breast Cancer Symposium 2018 [13] and published recently [18]. Thus, this trial confirmed non-inferiority of APBI using EBRT to WBI in preventing local recurrence, but because of increased late side effects and adverse cosmesis, the authors were unable

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to recommend the twice-a-day regime over 5 days for APBI using EBRT. In the NSBAP-B-39/RTOG 0413 [12, 17] phase 3 trial, a total of 4216 patients with early breast cancer were randomized to whole-breast irradiation with 50 Gy (1.8–2.0 Gy/fraction) followed by an optional boost to ≥60 Gy or to partial-breast irradiation in 10 treatments given over 5 to 10 days (34 Gy in 3.4-Gy fractions using interstitial brachytherapy or Mammosite balloon catheter or 38.5 Gy in 3.85-Gy fractions using 3D conformal external beam). There were 24% of patients with pure DCIS and 10% of patients with positive lymph nodes among the recruited patients. Furthermore, in the WBI arm, 80% of patients received boost irradiation and in the PBI arm, the most frequently used technique was 3D conformal EBRT (71%) and the MammoSite (Cytyc Corporation, Palo Alto, CA) single-entry device (23.3%). Only 5.7% of patients received multicatheter brachytherapy as the PBI technique. After a median follow-up of 10.2 years, similar cumulative incidences of in-breast recurrences (4.6% APBI vs. 3.9% WBI), distant disease-free survival (96.7% APBI vs. 97.1% WBI, p = 0.1), and overall survival (90.6% APBI vs. 91.3% WBI, p = 0.35) were observed [12, 17]. In this trial, the intent-to-treat and as-treated analyses could not refute the hypothesis that PBI is inferior and cannot declare that WBI and PBI are equivalent in controlling local in-breast tumor recurrence. However, the absolute difference in the 10-year cumulative incidence of IBTR was only 0.7%. An important and notable finding was that upon analyzing only true early breast cancer patients using ASTRO criteria [22], the 10-year cumulative in-breast recurrence rate was significantly lower in both arms (2.7% APBI vs. 2.3% WBI). In addition, slightly different non-significant rates of grade 3 (9.6% APBI vs. 7.1% WBI) and grade 4–5 toxicity (0.5 APBI vs. 0.3% WBI) late side effects were reported. Of note, the target volumes of external APBI seem to differ remarkably between IMPORT LOW and the American trials. In the IMPORT trial, target volumes were generously designed, also due to the fact that surgical clip demarcation of the tumor bed was not mandatory. Treatment was performed mostly by tangential field techniques, ending up rather in “half-breast” irradiations. In the RAPID as well as in the NSBAP-B-39/RTOG 0413 trial, despite similar PTV definitions, treatment delivery was more conformal by the use of several non-coplanar fields, thus encompassing less tissue. Unfortunately, none of the authors have so far provided absolute dimensions of treated volumes for the study patients.

Brachytherapy The use of multicatheter interstitial brachytherapy for APBI has been tested in two phase 3 trials so far.

Polgar et al. [23] randomized 258 patients with earlystage invasive breast cancer to receive either WBI or APBI with multicatheter HDR brachytherapy or with electron beam irradiation. After a median follow-up of 10.2 years, the 10-year rate of local recurrence was 5.9% and 5.1% in the APBI and WBI arms, respectively. The rate of excellent to good cosmetic results was 81% in the APBI, and 63% in the control group (p < 0.01). However, the statistical power of the trial regarding non-inferiority is limited due to the number of randomized patients. In the Group Européen de Curiethérapie/European Society for Radiotherapy and Oncology (GEC-ESTRO) multicentric phase 3 trial [1, 3, 4], a total of 1184 patients were randomized to WBI or APBI using multicatheter brachytherapy. Patients were considered eligible for the trial if they were aged 40 years or older; had pTis or pT1–2a (lesions of 3 cm diameter), pN0/pN1mic, and M0 breast cancer (stage 0, I, and IIA); had undergone local excision of the breast tumor with microscopically clear resection margins of at least 2 mm in any direction (in cases of invasive lobular carcinoma or DCIS, at least 5 mm); and had no lymph or blood vessel invasion (L0, V0). For patients allocated to irradiation of the whole breast, two tangential opposing megavoltage (4–10 MV) photon beams were typically used. A total dose of 50.0–50.4 Gy was delivered with daily fractions of 1.8–2.0 Gy in 25–28 fractions. The tumor bed boost dose was 10 Gy in five fractions, delivered with electrons. For patients allocated to APBI, the clinical target volume consisted of the tumor bed with an adequate safety margin in all directions. The size of the safety margin (calculated as the sum of the width of the clear pathological surgical margin plus the radiation safety margin) had to be at least 20 mm, and this margin was defined individually for every patient. APBI was delivered with high-dose-rate (HDR) or pulsed-doserate (PDR) multicatheter brachytherapy. A total dose of 32 Gy in eight fractions (8 × 4.0 Gy) or 30.3 Gy in seven fractions (7 × 4.3 Gy), with fractionation twice a day, was used for HDR brachytherapy. A total dose of 50 Gy with pulses of 0.60–0.80 Gy/h (one pulse per h, 24 h/day) was given by PDR brachytherapy. Addressing non-inferiority, the analysis of this trial’s findings was not primarily based on the intention-to-treat principle, because this approach sometimes introduces bias towards no difference, which is anticonservative in this setting, i.e., would exaggerate estimates of equivalence. Instead, the primary analysis was performed “as treated”: after a median follow-up of 6.6 years, non-inferiority was reported for the 5-year local control rate (1.4% APBI vs. 0.9% WBI, p = 0.42). Secondary (sensitivity) analyses, both a “per-protocol” analysis and an “intention-to-treat” analysis, were done to examine the consistency of results: 5-year local recurrence was 0.97% or 1.07% (WBI) vs. 1.38% or 1.33% (APBI), respectively

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(p = 0.53 and p = 0.42). Disease-free survival (~94–95%) and overall survival (95–97%) were also similar in both arms. Moreover, a similar incidence of the majority of late side effects was shown. The cumulative incidence of any late side effect of grade 2 or worse at 5 years was similar in both groups, with 27.0% in the whole-breast irradiation group versus 23.3% in the APBI group (p = 0.12). However, the cumulative incidence of grade 2–3 late skin toxicity at 5 years was significantly different, with 10.7% in the whole-breast irradiation group versus 6.9% (4.8–9.0) in the APBI group (p = 0.020; [1, 3]). Finally, detailed analysis of quality of life questionnaires in this trial during follow-up showed that global health status was stable in both groups, but a moderate, statistically significant difference between the groups in the breast symptoms scale was found. Breast symptom scores were significantly higher, i.e., worse, after whole-breast irradiation than after APBI [4]. For single-catheter devices, the evidence is currently limited. In the NSBAP-B-39/RTOG 0413 trial, a subgroup of patients (23.3%) was treated with the MammoSite singleentry device. As described above, the first results of this trial were presented at the San Antonio Breast Cancer Symposium 2018; however, at the time of writing the presented guideline, corresponding subgroup analyses were not available. Thus, a valid assessment was not possible. For other brachytherapy APBI techniques, no phase 3 data are available.

Intraoperative radiotherapy with electrons In the ELIOT study [15], 1305 patients between 48 and 75 years of age and with tumors smaller than 2.5 cm were randomized to receive either single-dose intraoperative radiotherapy with electrons (IOERT) with 21 Gy (90% isodose) as PBI (experimental arm) or adjuvant WBI with 50 Gy in 25 fractions followed by an external electron boost of 10 Gy in 5 fractions (standard arm). Patients with four or more positive axillary nodes additionally received regional node irradiation up to 50 Gy (2 Gy/fraction). After a median follow-up of 5.8 years, significantly more inbreast recurrences were noted following full-dose IOERT (n = 35; 4.4%) than after WBI (n = 4; 0.4%; p < 0.0001). No significant difference in overall survival was observed and acute toxicity was lower in the experimental ELIOT arm. In a multivariate analysis for negative predictors, the highest risk for in-breast recurrence in the ELIOT arm was seen in patients with tumor sizes >2 cm, four or more positive lymph nodes, G3, and hormonal or triplenegative subtypes. Patients with at least one of these factors (n = 199) had a significantly higher risk of recurrence (11.5%, p < 0.0001) compared to those who had none (n = 452, 1.5%). These findings are corroborated by analyses of subgroups conducted among patients treated in

several institutions [24–26]. In particular, the Milanese group investigated the outcome in 1822 out-trial patients treated solely by IOERT for low-risk breast cancer patients who were classified as “suitable” or “good” candidates according to the ESTRO/ASTRO guideline. Reported 5-year recurrence risks amounted to 1.5% for 294 “ASTRO suitable” women and 1.9% for 573 “ESTRO good” candidates [24, 25]. Almost identical results were published by Maluta et al. from a phase II study in 226 low-risk breast cancer patients who received solely IOERT with 21 Gy: after a median follow-up of 62 months, 4 in-breast recurrences were noted, corresponding to a local relapse rate of 1.77% [26].

Accelerated partial breast irradiation with 50-kV photons For APBI with low-energy 50-kV photons, the Intrabeam device (Carl Zeiss Meditec, Oberkochen, Germany) delivers 50-kV photons to the tumor bed by using spherical applicators with a diameter of 15 to 50 mm that are inserted into the lumpectomy cavity. The prescribed dose is usually 20 Gy applied to the applicator surface. This dose attenuates to 5–7 Gy (depending on the applicator diameter) at a 1 cm distance from the applicator surface. The use of APBI with 50-kV photons with the Intrabeam system has been studied in the phase 3 TARGIT A-trial [14]. In this prospective randomized controlled phase III trial, patients were randomized to APBI with the Intrabeam system or whole-breast radiotherapy with or without a boost. Patients were eligible if they were ≥45 years old, had a tumor size 3.5 cm, and were candidates for breast-conserving surgery. Using a riskadapted approach, patients in the experimental arm could receive additional whole-breast radiotherapy in case of further risk factors (lobular invasive cancer, extensive intraductal component). Results of 3451 patients were published with a median follow-up of 29 months [14]. The calculated 5-year local recurrence rate was 1.3% in the standard arm and 3.3% in the experimental arm (p = 0.042, which was not considered statistically significant at the predefined significance level of 0.01). Using the absolute difference in the binomial proportions of local recurrence, non-inferiority was demonstrated. There was no statistically significant difference in terms of regional recurrences, breast cancer mortality, or overall survival; however, non-breast cancerrelated mortality at 5 years was significantly lower in the experimental arm (1.4% vs. 3.5%; p = 0.0086). The authors separately assessed the risk of local recurrence in the prepathology (IORT given simultaneously during surgery) and post-pathology (IORT given after surgery as a second procedure by reopening the wound after the initial excision) strata. Non-inferiority could only be shown for the prepathology stratum (5-year local recurrence rate 2.1% vs. 1.1%), but not for the post-pathology stratum (5-year local

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recurrence rate 5.4% vs. 1.7%). To account for the relatively short median follow-up, the authors presented subgroup analyses for pre-pathology cohorts with a median follow-up 44 months (1450 patients) and 60 months (817 patients), yielding similar absolute differences in 5-year local recurrence rates compared to the whole pre-pathology cohort. The significant difference regarding non-breast cancer-related mortality was restricted to the pre-pathology cohort. The incidence of grade III/IV radiotherapy-related skin complications was significantly lower in the experimental arm, although absolute numbers were small. A prespecified subgroup analysis according to the progesterone receptor (PR) status was published [27]. In the whole trial cohort, the 5-year local recurrence rate for patients in the experimental arm compared to patients in the standard arm was similar in PR-positive patients (2.3% vs. 1.5%; p = 0.51), but higher for patients with PR-negative tumors (7.0% vs. 0.5%; p = 0.017). Corica et al. [28, 29] published results from a substudy of the TARGIT A-trial on quality of life and cosmesis. 126 patients treated in Australia were analyzed. The cosmetic outcome from different assessment methods favored the experimental arm, with significantly better cosmesis in the experimental arm at 5 years. Several quality of life subdomains also showed significant differences in favor of the experimental arm, among them the breast symptoms subdomain. Similar Abo-Madyan et al. [30] recently analyzed the long-term outcome of 184 patients enrolled onto the TARGIT A-trial at a single institution. Median follow-up was 8.5 years. There were only two local recurrences, resulting in a 5-year local recurrence rate of 0% (one recurrence after 70.3 months) for the experimental arm and 1.1% for the control arm (one recurrence after 4.5 months in a patient refusing all forms of adjuvant treatment). However, 42% and 14% of patients in the experimental arm received additional whole-breast radiotherapy or exclusive whole-breast radiotherapy, respectively. Thus, only 41% of patients in the experimental arm received IORT as the sole adjuvant radiotherapy treatment. In total, the results of APBI with 50 kV IORT as presented in the TARGIT A-trial contain significant uncertainties and considerable limitations, as already heatedly discussed by many authors [31–38]. Criticism has centered on several aspects of the trial, which will be discussed in the following: 1. Duration of follow-up: The median follow-up of 29 months is immature and only 35% of the patients had 5-year follow-up at the time of the analysis. This is especially important due to the high number of patients with hormone receptor-positive tumors, who have a risk of recurrence well beyond 5 years. 2. Non-inferiority design: The estimate used for the local recurrence rate of 6% at 5 years in the standard arm is

considerably higher than what would be considered acceptable today. The TARGIT-A authors used binomial proportions of local recurrence (i.e., number of recurrences divided by the number of patients) rather than Kaplan–Meier estimates of local recurrence rates. The use of binomial proportions has been criticized, since it does not take into account that only 1222 patients had a median follow-up of 5 years, which might lead to a dilution of the treatment effect. The authors presented results from cohorts with different follow-up times. Nevertheless, since these cohorts are nested within each other, the value of this analysis is questionable. Furthermore, as described in the NICE report 2018 [37], the TARGIT-A investigators quantified the difference in the Kaplan–Meier estimates of local recurrence, and its 95% CI, using two different methods. The integrated difference method presented by the investigators is not commonly used, provided more favorable results for Intrabeam, and was not pre-specified in the TARGIT-A protocol. Moreover, because the non-inferiority margin was based on the absolute difference in local recurrence, the same margin could not be used for assessing non-inferiority if the integrated difference method were to be accepted. 3. Use of whole-breast radiotherapy in the experimental arm: The trial used a risk-adapted approach for APBI. Thus, whole-breast radiotherapy could be added to APBI, which was the case for 15% of patients in the experimental arm. There were some pre-specified criteria for additional whole-breast radiotherapy, but each center could also add further criteria. There is no subgroup analysis of local recurrence rates in patients who received IORT alone. The use of additional whole-breast radiotherapy was considerably higher in the pre-pathology stratum (21.6%) than in the post-pathology stratum (3.6%), which might also have contributed to the better outcomes in the pre-pathology subgroup. This creates uncertainty as to whether IORT alone is a safe treatment option in certain patient subgroups. In conclusion, in the face of these shortcomings, several international guidelines have discouraged the use of 50kV IORT outside of clinical trials [39, 40]. This DEGRO expert panel concluded that because of the uncertainty of interpretation in the evidence available, the 50-kV system (Intrabeam) cannot be recommended for routine adjuvant treatment of early invasive breast cancer after breast-conserving surgery and should preferentially be used in the context of a clinical trial. Clinicians wishing to undertake APBI with 50-kV photons should ensure that patients understand the uncertainties about the procedure—particularly, patients should be counseled that follow-up is too short for general recommendations; that in corresponding clinical trial, still after very short not adequate follow-up, the risk of local

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recurrence was higher with APBI; and be informed about alternative treatment options [22, 37]. When used, it should be restricted to women with all of the following criteria: invasive cancer, aged >70 years, tumor <2 cm, resection margins >2 mm, grade 1— 2, pN0, ER positive, HER2 negative, L0, V0, and EIC negative.

Recommendation General issues We recommend that PBI with multicatheter brachytherapy or external beam radiation therapy after breast-conserving surgery (BCS) should be completed preferably in less than 12 weeks (typically within 6–10 weeks) and no later than 20 weeks, as better local tumor control and survival can probably be expected by keeping a shorter interval between BCS and radiotherapy [41–48]. Of note, a recent analysis illustrated that starting radiation therapy shortly after BCS seems not to be associated with a better long-term outcome [49]. If patients receive chemotherapy, PBI can be started after systemic treatment—in this scenario, we recommend starting PBI within 4 weeks after chemotherapy. It is also possible to start PBI before systemic treatment within 12 weeks. Radiation therapy can also be given in the interval between the chemotherapy courses. In general, the physicians who indicate PBI have to reflect on the fact that level 1 evidence for non-inferiority of PBI in comparison to whole-breast irradiation is given for external beam techniques and for multicatheter brachytherapy [8, 50]. If the patient is interested in PBI with IORT techniques, the patient should be counseled in detail that there are uncertainties in the two available PBI phase 3 trials [14, 15]. One of the crucial problems of both PBI methods is that due to the lack of a final pathology report at the time of IORT, no definitive selection criteria could be applied at the time of PBI. As a consequence, the long-term results of PBI with electrons are only adequate if appropriately selected subgroups are analyzed [25, 26]. To warrant such appropriate selection at the time of breast-conserving surgery and IORT is very difficult. Some postulate that this patient selection is indeed prospectively possible, but no published data on this topic are currently available. Lowenergy x-ray IORT for PBI should be used within the context of a prospective registry or clinical trial; when used, it should be restricted to certain conditions, as discussed above.

Selection criteria

pean and US guidelines many times [22, 39, 51–55], and the credibility of different selection criteria has been proven in corresponding contemporary phase 3 trials [1, 2, 5, 6, 12–15]. Considering the fact only those APBI trials using strict selection are positive trials [1, 2, 12, 13] as well as corresponding deliberations in study protocols and current recommendations [22, 56], we recommend for daily routine, outside of any clinical trials, to only consider patients for PBI if all of following selection criteria are fulfilled: 1. Age ≥50 years. 2. Histology: any invasive carcinoma (any grade) or DCIS low to intermediate nuclear grade. 3. Tumor size: 3 cm (Tis, T1–T2). 4. Unifocal and unicentric DCIS or breast cancer. 5. Resection margins: a. invasive cancer—negative by at least 2 mm, b. invasive lobular histology or DCIS—negative by at least 5 mm. 6. No lymph vessel invasion (L0) and no hemangiosis (V0). 7. pN0/pNmi. The following should be considered as contraindications for APBI: 1. Stage IIB–IV breast cancer. 2. Resection margins that cannot be microscopically assessed. 3. Extensive intraductal component (EIC). 4. Paget’s disease or pathological skin involvement. 5. Age 40 years. 6. Triple-negative or HER2-positive phenotype. 7. Neoadjuvant chemotherapy in treatment history. Special attention should be paid to the practice of patient selection if APBI with intraoperative electrons or kV photons has been indicated. Here, the selection is a twostep process, consisting of a preoperative and an intraoperative phase. During the first-step selection, topographical, histological, and biological tumor features including radiological work-up are assessed. The second step takes place during surgery, based on histological examination of frozen sections, freedom of margins, and negative status of sentinel nodes. Nonetheless, it remains challenging to fully consider all APBI guidelines during delivery of IOERT when the final pathologic assessment is not yet available. In particular, the presence of lymphovascular invasion (LVI) and an extensive intraductal component (EIC) cannot be fully ruled out on preoperative core needle biopsy and intraoperative frozen section, leaving a margin of uncertainty for final eligibility. If definitive pathology is worse than anticipated, subsequent WBI might be necessary despite full-dose IORT.

Patient selection for PBI alone after BCS in patients with early breast cancer has been described in detail in Euro-

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Target definition for APBI with multicatheter brachytherapy or EBRT For target definition and delineation, irrespective of whether EBRT or brachytherapy techniques for PBI are intended, the ESTRO recommendations depending on the used BCS technique should be used [57, 58]. The following basic rules should be respected: 1. Detailed knowledge of the primary surgical procedure, of all details of the pathology report including size of resection margins in six directions, and of preoperative imaging (mammography and/or MRI and/or ultrasound) is obligatory. 2. Use of 4–6 surgical clips marking the borders of the lumpectomy is highly recommended for APBI. 3. Different resection margins in different directions should be respected. Total safety margins are defined as the sum of “size of existing surgical resection margin” plus “size of the added safety margin.” The recommended value of the total safety margin is 2 cm around the surgical bed considering the size of surgical resection margins in all six directions. 4. Target definition and delineation after closed-cavity surgery, oncoplastic cavity surgery, and after open-cavity surgery differ. Target definition and delineation after closed-cavity surgery

The target is related to the scar inside the breast and to the surgical clips. Use of CT imaging is standard. The following steps are proposed to delineate the target (see Fig. 1): 1. 2. 3. 4. 5. 6.

Delineation of the skin scar and of the clips. Delineation of whole surgical scar (WS) inside the breast. Delineation of ImTV (imaging-correlated target volume). Delineation of ETB (estimated tumor bed). Delineation of CTV (clinical target volume). Delineation of PTV (planning target volume).

While delineation of the skin scar and the clips does not need further explanation, the delineation of next structures requires more attention. In summary, the “whole surgical scar” (WS) means delineating the whole visible surgical bed including the visible scar tissue inside the breast and all the clips—the whole “path” of surgeons inside the breast tissue, starting on skin scar and ending at the deepest point on the thoracic wall. Definition and delineation of ImTV (imaging-correlated target volume) can be done using only preoperative imaging and is based on the tumor size and tumor localization inside the breast. The next structure—estimated tumor bed (ETB)—is a reflection of three factors—“surgical clips,” “WS,” and “ImTV.” ETB is defined as the part of the whole scar which represented the

Fig. 1 Target delineation after closed-cavity surgery. WS whole scar (green), ImTV imaging-correlated target volume (dark blue), ETB estimated tumor bed (yellow), CTV clinical target volume (orange), PTV(Brachy) planning target volume for brachytherapy (dark-red), PTV(EBRT) planning target volume for external beam radiation therapy (light red), PTVEVAL planning target volume for evaluation (light-blue)

tumor localization in the breast—strictly related to the localization and size of ImTV. The CTV is defined as ETB plus corresponding total safety margins—20 mm minus individual surgical margin in the corresponding direction, but at least 10 mm (for example: a surgical margin of 7 mm requires a safety margin of 13 mm). The thoracic wall and the skin are at no times a part of CTV. Definition of PTV is important if EBRT-based APBI is intended. In this case we recommend as standard to add an additional margin of ≥10 mm for the PTV, and the thoracic wall and skin can be parts of the PTV. Additionally, in such cases, a special feature—a “help structure” for meaningful analysis of DVH, termed PTVEVAL—should be also generated. PTVEVAL corresponds to the PTV without thoracic wall, lung, skin, and air (Fig. 1). If multicatheter-based APBI is planned, then typically CTV = PTV, and only in the case of an absence of clips or impaired visibility of surgical scar or cavity do we recommend adding an adapted PTV margin (5–10 mm) in the region of doubt (excluding thoracic wall and skin). For more details, please see the corresponding guidelines [57].

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Target definition and delineation after oncoplastic surgery

An important precondition here is that the position of surgical clips be intra-parenchymal and that placement occurs before the rotation of glandular tissue. Accordingly, the clipped area should be delineated in all corresponding CT slices as a surgical bed. As a consequence the “preliminary CTV” is defined, similar to the situation described above, as a “clipped area” plus corresponding total safety margins—meaning 20 mm minus the smallest individual surgical margin, but at least 10 mm (for example: a surgical margin of 2 mm requires a safety margin of 18 mm in all directions). If multicatheter brachytherapy is intended, the “final CTV” after oncoplastic surgery is defined as the “preliminary CTV” + 10 mm. If EBRT is intended, PTV is defined as the “preliminary CTV” + ≥20 mm. Concerning thoracic wall and skin, the same rules as those described above should be applied.

to cover the depth with at least 90% of the prescribed dose (usually energies between 4 and 10–12 MeV). In case of tumors adjacent to the chest wall, the full depth distance to the shield is considered. Of note: in comparison to external techniques, no safety margins for set-up have to be considered.

Target definition for APBI with IORT with low-energy photons (Intrabeam) In principle, using IORT with the Intrabeam device, the target volume is predetermined by the surgical approach. Complete macroscopic excision of the tumor is required. Furthermore, based on histological examination of frozen sections, freedom of margins and negative status of sentinel nodes is required. Then, after insertion of the adequate spherical applicator (see above), the targeted volume corresponds to the volume adapted to the sphere and is determined by the size of the sphere.

Target definition and delineation after open-cavity surgery

The target is related to the lumpectomy (seroma) cavity inside the breast and to the surgical clips, and use of CT imaging is standard. Lumpectomy cavity boundaries have to be defined by a combination of breast tissue changes apparent on CT images, in terms of tumor pathology and preoperative imaging, fluid collection within the lumpectomy cavity, and surgical clips when available. The CTV is defined as lumpectomy cavity plus corresponding total safety margins—20 mm minus individual surgical margin in the corresponding direction, but at least 5 mm (for example: a surgical margin of 6 mm requires a safety margin of 14 mm). The thoracic wall and the skin are at no times a part of CTV. For more details see please the corresponding guidelines [58].

Target definition for APBI with IORT with electrons IORT with electrons is performed after tumor excision and confirmation of negative margins, before oncoplastic reconstruction. In order to encompass sufficient breast tissue adjacent to the excised tumor, the walls of the excision hole are temporarily sutured to the center. The target volume has to encompass at least 20 mm in any direction with the exception of the skin, which is completely out of the irradiated volume, and the chest wall, which is usually protected by a shield disc. Tube diameters have to be chosen accordingly; diameters less than 5–6 cm are discouraged. The target volume thickness is assessed by intraoperative ultrasound or by inserting a needle probe at one or more representative points of the parenchyma, depending on the shape of the tumor bed and chest wall curvature. According to measurements, electron beam energies are selected

Techniques External beam radiation therapy For external beam radiation-based APBI in supine and prone patient positions, different 3D external beam techniques with non-coplanar or with mini-tangent beams in combination with an en face electron field, step and shoot (SS) and sliding window (SW) intensity-modulated radiotherapy (IMRT) techniques, and VMAT/intensity-modulated arc therapy techniques have been used in several prospective trials [2, 12, 13, 59–69]. In principle, independent of the EBRT technique, the same principles of EBRT as for other indications are applied. Typically, the 3D-CRT plans are created with four or five wedged conformal noncoplanar fields from tangential directions, the IMRT plans with five or six coplanar fields, and the intensity-modulated arc therapy plans consist of two or more coplanar arcs. Adequate target volume coverage and acceptable doses to the organs at risk are achievable with all techniques. Some analyses recommend the SW-IMRT technique as the best EBRT technique for APBI [70]. The reproducibility and precision of the position of the patient and of the tumor should be verified with available imaging tools. When, as strictly recommend, surgical clips are in situ, 2D imaging is often sufficient to achieve appropriate positioning and the kV-kV planar imaging method is recommended. Without surgical clips in situ, 3D images should be acquired, and the recommended method of verification is the kV cone beam CT [71]. Image-based verification of reproducibility and precision should be performed before each fraction of APBI.

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The prescribed dose should be specified respecting ICRU 50 and ICRU 62 at reference point (typically corresponding with isocenter), and dose–volume histogram analysis of target coverage should confirm that 100% of the prescribed dose covers >90% of the PTV/PTV-EVAL. Restrictions for surrounding tissues should be respected. Using EBRT for APBI, the dose constraints for the target and for organs at risk are identical to those described below for brachytherapy and are summarized below.

Brachytherapy Brachytherapy techniques represent the most investigated irradiation techniques for APBI. Regarding the performance, features, and reproducibility as well as regarding the possibilities to shape adequate dose distribution, there exist large differences among diverse brachytherapy techniques. Today there are several brachytherapy techniques available—multicatheter brachytherapy; single-entry intracavitary devices like the MammoSite balloon; singleentry multilumen catheter devices like SAVI (strut-adjusted volume implant, Cianna Medical, Aliso Viejo, CA), CONTURA Multi-Lumen Balloon (Bard Biopsy Systems, Tempe, AZ), or ClearPath (NorthAmerican Scientific Inc., Chatsworth, CA); electronic brachytherapy, seeds brachytherapy, and non-invasive brachytherapy [72–81]. Among all these techniques, level 1 evidence is only available for multicatheter brachytherapy [1]. For image-guided multicatheter brachytherapy-based APBI, we recommend in general to respect basic rules of image-guided interstitial brachytherapy for breast cancer [82, 83]. Treatment planning and catheter insertion depend in detail on the availability of appropriate imaging facilities (x-ray, CT, MRI, ultrasound) and on the kind of breastconserving surgery (open cavity, closed cavity, plastic reconstruction). Treatment planning and catheter insertion should be performed according current ESTRO-ACROP guidelines [84]. Furthermore, the catheter reconstruction, normalization of dose distribution, dose specification, dose prescription, optimization methods, and quality management issues should be implemented in line with this guideline [84].

IORT with electrons Technical details of IOERT have been published repeatedly [85, 86]. IOERT is nowadays mostly performed on mobile linear accelerators with tube sizes of 5–8 cm in diameter and electron energies usually ranging from 4–12 MeV according to a given target volume (see above).

IORT with 50-kV photons The Intrabeam device provides a point source of 50-kV x-rays at the center of a spherical applicator. Applicator diameters ranging from 1.5–5.0 cm are available. After tumor removal, the size of the sphere is determined by the radio-oncologist in close collaboration with the breast surgeon. The spherical applicator is then inserted into the surgical cavity. The appropriately sized applicator should fit comfortably without tension in the surrounding tissue. Subsequently, the subcutaneous tissues will be gathered with a purse-string suture over the sphere to adapt the target breast tissue well to the surface of the applicator sphere. Also, at the bottom of the resection cavity, the breast tissue should be adapted to the applicator surface, i.e., contracting the tissue using a purse-string suture, if necessary. The skin, but not the breast tissue, should be kept away from the applicator using, e.g., a piece of wet gauze to prevent direct contact. It is suggested to keep the skin at a distance of at least 1 cm from the sphere. For tumors near to the skin ( 1 cm), an elliptical piece of overlying skin should be excised. The calculation of the radiation dose to the heart, left ventricle, and especially to the left anterior descending branch of the coronary artery the thickness of the chest wall (muscle and rib cage) should be always perfomed. Possibly, if there is no adequate distance, the surface of the applicator sphere should be kept away or covered with a protective cap at the chest wall. However, in most patients, the normal thickness of the chest wall (muscle and rib cage) may provide adequate shielding.

Dose–volume parameters and dose constraints For an objective assessment of any treatment plan, quantitative parameters have to be analyzed and reflected. It’s in the nature of things that such appropriate objective analysis is not possible for PBI using IORT techniques. Table 2 lists the most common dose–volume parameters used in PBI with interstitial multicatheter breast brachytherapy and EBRT. Based on the ESTRO-ACROP guideline [84] and NSABP Protocol B-39/RTOG 0413 [87], we recommend the following target-related dose–volume limits: 1. Coverage index (CI): V100 ≥ 90–95% (i.e., at least 90% of the PTV had to receive the PD) 2. V150 <65 cm3 3. V200 <15 cm3

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Table 2 The most common dose–volume parameters used for reporting partial-breast irradiation. (Adapted according [84])

Table 3 Recommended dose–volume limits for organ at risk. (Modified according [84])

Parameter

Organ

Constraints

Ipsilateral non-target breast Skin

V90 <10% V50 <40(50)% D1cm3 <90% D0.2cm3 <100% D0.1cm3 <90% D1cm3 <80% Mean heart dose, MHD <8% (<2.5 Gy) D0.1cm3 <50% Mean lung dose, MLD <8% (<3–4 Gy) D0.1cm3 <60% stochastic effects: MLD <1–1.5 Gy

Reference dose related VPD V1.5xPD DNR—dose non-uniformity ratio (only for brachytherapy) DHI—dose homogeneity index (only for brachytherapy) Target related VPTV Vxx CI—coverage index (V100) COIN—conformal index Dxx OAR related Dmean VxGy Vxx Dxcm3

Definition/calculation Absolute volume irradiated by the prescribed dose Absolute volume irradiated by 1.5 x the prescribed dose V1.5xPD/VPD

Rib Heart

(VPD – V1.5xPD)/VPD Lung Volume of the PTV Percentage of PTV receiving xx% of the PD V100/100 PTVPD/VPTV PTVPD/VPD Percentage dose that covers xx% of the PTV Mean dose in organ Relative volume x receiving Gy Percentage of organ receiving xx% of the PD Relative dose given to most exposed x cm3 of organ

PD prescribed dose, PTVPD volume in planning target volume receiving at least the PD

4. Absolute volume irradiated by prescription dose—DPD 300 cm3 5. Dose non-uniformity ratio—DNR 35 (only for brachytherapy) 6. Conformal index—COIN ≥65 (only for brachytherapy) 7. Dose homogeneity—maximal dose should not exceed 110% of prescribed dose (only for EBRT) The recommended dose–volume limits for OARs [10, 84, 87], according the current available data, are presented in Table 3. For IOERT, the following dose reports and constraints are recommended: the dose is prescribed at Dmax (100%) or at D90. Dmax, D90, D45 and their corresponding tissue depths (d) should be specified along the central beam and clinical axis (in mm), respectively. V90 is defined as the tissue volume which is encompassed by the 90% isodose and should be indicated in ml (cc). V90 can be calculated by the formula of a rotating ellipsoid (4 × 3.14/3 × a2 × b). During IOERT, the skin is outside the treated area and thus not affected by radiation. In rare cases when IOERT takes place without a chest wall protection shield, the dose to the anterior rib surface should not exceed 10 Gy. In case of shield use, the rib dose falls by nature far under this

MHD mean heart dose, MLD mean lung dose, V volume, D dose

value. Likewise, exit doses to lung and—in case of leftsided BC—heart structures amount to less than 1 Gy, which is not considered as clinically relevant.

Dose schedule External beam radiation therapy The recommended schedules with EBRT are: 1. Total dose 40 Gy, 2.66 Gy in 1 fraction/day ~15 fraction over 3 weeks 2. Total dose 38.5 Gy, 3.85 Gy in 1 fraction/day ~10 fraction over 10 days

Brachytherapy The recommended schedule with PDR brachytherapy is total dose 50 Gy, pulsed-dose 0.5–0.8 Gy/pulse, scheduled every hour, 24 h per day, total treatment time 4–5 days. The recommended schedules for HDR brachytherapy are 8 × 4 Gy, 10 × 3.4 Gy, and 7 × 4.3 Gy, twice per day, with an interval between fractions of at least 6 h, and with a total treatment time of 4–5 days. Other fractionations can be used. However, the chosen fractionation should correspond to a biologically equivalent total dose EQD2 (a/b = 4–5 Gy) in the range of 42–45 Gy.

IORT with electrons Full-dose IOERT is to date most frequently performed with 21 Gy, prescribed at the depth of the 90% isodose line (Dmax 23.3 Gy).

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IORT with 50-kV photons

References

The prescribed dose is usually 20 Gy applied to the applicator surface. This dose attenuates to 5–7 Gy (depending on the applicator diameter) at a distance of 1 cm from the applicator surface. Thus, the tumor bed typically receives 20 Gy, at the surface this attenuates to 5–7 Gy at a depth of 1 cm. The dose to the skin should be <7 Gy. This can be realized by keeping the skin ≥1 cm away from the sphere.

1. Strnad V, Ott OJ, Hildebrandt G et al (2016) 5-year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: a randomised, phase 3, non-inferiority trial. Lancet 387(10015):229–238 2. Coles CE, Griffin CL, Kirby AM et al (2017) Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial. Lancet 390(10099):1048–1060 3. Polgar C, Ott OJ, Hildebrandt G et al (2017) Late side-effects and cosmetic results of accelerated partial breast irradiation with interstitial brachytherapy versus whole-breast irradiation after breastconserving surgery for low-risk invasive and in-situ carcinoma of the female breast: 5-year results of a randomised, controlled, phase 3 trial. Lancet Oncol 18(2):259–268 4. Schafer R, Strnad V, Polgar C et al (2018) Quality-of-life results for accelerated partial breast irradiation with interstitial brachytherapy versus whole-breast irradiation in early breast cancer after breastconserving surgery (GEC-ESTRO): 5-year results of a randomised, phase 3 trial. Lancet Oncol 19(6):834–844 5. Livi L, Meattini I, Marrazzo L et al (2015) Accelerated partial breast irradiation using intensity-modulated radiotherapy versus whole breast irradiation: 5-year survival analysis of a phase 3 randomised controlled trial. Eur J Cancer 51(4):451–463 6. Polgar C, Fodor J, Major T, Sulyok Z, Kasler M (2013) Breastconserving therapy with partial or whole breast irradiation: tenyear results of the Budapest randomized trial. Radiother Oncol 108(2):197–202 7. Clarke M, Collins R, Darby S et al (2005) 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 randomised trials. Lancet 366(9503):2087–2106 8. Coles CE, Yarnold JR (2016) Accelerated partial breast irradiation: the new standard? Lancet 387(10015):201–202 9. Lettmaier S, Kreppner S, Lotter M et al (2011) Radiation exposure of the heart, lung and skin by radiation therapy for breast cancer: a dosimetric comparison between partial breast irradiation using multicatheter brachytherapy and whole breast teletherapy. Radiother Oncol 100(2):189–194 10. Hoekstra N, Fleury E, Merino LTR et al (2018) Long-term risks of secondary cancer for various whole and partial breast irradiation techniques. Radiother Oncol 128(3):428–433 11. Piroth MD, Baumann R, Budach W et al (2019) Heart toxicity from breast cancer radiotherapy: current findings, assessment, and prevention. Strahlenther Onkol 195(1):1–12 12. Vicini FACR, White JR, Julian TB, Arthur DW, Rabinovitch RA, Kuske RR, Parda DS, Ganz PA, Scheier MF, Winter KA, Paik S, Kuerer HM, Vallow LA, Pierce LJ, Mamounas EP, Costantino JP, Bear HD, Germaine I, Gustafson G, Grossheim L, Petersen IA, Hudes RS, Curran WJ Jr., Wolmark N (2018) Primary results of NSABP B-39/RTOG 0413 (NRG Oncology): a randomized phase III study of conventional whole breast irradiation (WBI) versus partial breast irradiation (PBI) for women with stage 0, I, or II breast cancer. In: 41st Annual San Antonion Breast Cancer Symposium 41st Annual San Antonion Breast Cancer Symposium, December 4-10 (Abstract GS4-04), San Antonio 2019 13. Whelan TJJ, Levine M, Berrang T, Kim D-H, Gu CS, Germain I, Nichol A, Akra M, Lavertu S, Germain F, Fyles A, Trotter T, Perera F, Balkwill S, Chafe S, McGowan T, Muanza T, Beckham W, Chua B, Olivotto IRAPID (2018) A randomized trial of accelerated partial breast irradiation using 3-dimensional conformal radiother-

Conclusion APBI has been tested in a total of nine phase 3 trials with more than 15,000 patients over the past 10 years [1, 2, 5, 6, 12–16]. These trials show that for strictly selected patients with early breast cancer, PBI by EBRT, multicatheter brachytherapy, or IORT with electrons is non-inferior to the results of whole-breast irradiation in terms of local control, disease-free survival, and overall survival, and is in some aspects superior regarding late side effects and quality of life. Furthermore, we conclude that PBI requires expertise encompassing: 1. appropriate patient selection. 2. appropriate target delineation considering the applied technique of breast-conserving surgery. 3. a high-level quality assurance program regarding the respective technique of PBI. In light of current data, PBI using multicatheter brachytherapy, EBRT, or IORT with electrons is a valid alternative treatment option after breast-conserving surgery and can be offered for carefully selected low-risk breast cancer patients in clinical routine using the proposed selection criteria. Funding Open Access funding provided by Projekt DEAL. Conflict of interest V. Strnad, D. Krug, F. Sedlmayer, M.D. Piroth, W. Budach, R. Baumann, P. Feyer, M.N. Duma, W. Haase, W. Harms, T. Hehr, R. Fietkau, J. Dunst, R. Sauer, and DEGRO declare that they have no competing interests. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4. 0/.

Strahlenther Onkol apy (3D-CRT). In: 41th San Antonio Breast Cancer Symposium 41th San Antonio Breast Cancer Symposium, December 4-8 (Abstract GS4-03), San Antonio 2019 14. Vaidya JS, Wenz F, Bulsara M et al (2014) Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet 383(9917):603–613 15. Veronesi U, Orecchia R, Maisonneuve P et al (2013) Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial. Lancet Oncol 14(13):1269–1277 16. Rodriguez N, Sanz X, Dengra J et al (2013) Five-year outcomes, cosmesis, and toxicity with 3-dimensional conformal external beam radiation therapy to deliver accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys 87(5):1051–1057 17. Vicini FA, Cecchini RS, White JR et al (2019) Long-term primary results of accelerated partial breast irradiation after breast-conserving surgery for early-stage breast cancer: a randomised, phase 3, equivalence trial. Lancet 394(10215):2155–2164 18. Whelan TJ, Julian JA, Berrang TS et al (2019) External beam accelerated partial breast irradiation versus whole breast irradiation after breast conserving surgery in women with ductal carcinoma in situ and node-negative breast cancer (RAPID): a randomised controlled trial. Lancet 394(10215):2165–2172 19. Krug D, Dunst J (2019) Whole- or partial-breast radiotherapy after 5 years from a patient perspective: longitudinal analysis of the IMPORT LOW (CRUK/06/003) phase III trial. Strahlenther Onkol 195(8):767–768 20. Coles CE, Wilson CB, Cumming J et al (2009) Titanium clip placement to allow accurate tumour bed localisation following breast conserving surgery: audit on behalf of the IMPORT Trial Management Group. Eur J Surg Oncol 35(6):578–582 21. Olivotto IA, Whelan TJ, Parpia S et al (2013) Interim cosmetic and toxicity results from RAPID: a randomized trial of accelerated partial breast irradiation using three-dimensional conformal external beam radiation therapy. J Clin Oncol 31(32):4038–4045 22. Correa C, Harris EE, Leonardi MC et al (2017) Accelerated partial breast irradiation: executive summary for the update of an ASTRO evidence-based consensus statement. Pract Radiat Oncol 7(2):73–79 23. Polgar C, Major T, Fodor J et al (2010) Accelerated partialbreast irradiation using high-dose-rate interstitial brachytherapy: 12-year update of a prospective clinical study. Radiother Oncol 94(3):274–279 24. Leonardi MC, Maisonneuve P, Mastropasqua MG et al (2012) How do the ASTRO consensus statement guidelines for the application of accelerated partial breast irradiation fit intraoperative radiotherapy? A retrospective analysis of patients treated at the European Institute of Oncology. Int J Radiat Oncol Biol Phys 83(3):806–813 25. Leonardi MC, Maisonneuve P, Mastropasqua MG et al (2013) Accelerated partial breast irradiation with intraoperative electrons: using GEC-ESTRO recommendations as guidance for patient selection. Radiother Oncol 106(1):21–27 26. Maluta S, Dall’Oglio S, Marciai N et al (2012) Accelerated partial breast irradiation using only intraoperative electron radiation therapy in early stage breast cancer. Int J Radiat Oncol Biol Phys 84(2):e145–152 27. Vaidya JS, Wenz F, Bulsara M et al (2016) An international randomised controlled trial to compare TARGeted Intraoperative radioTherapy (TARGIT) with conventional postoperative radiotherapy after breast-conserving surgery for women with earlystage breast cancer (the TARGIT-A trial). Health Technol Assess 20(73):1–188 28. Corica T, Nowak AK, Saunders CM et al (2016) Cosmesis and breast-related quality of life outcomes after Intraoperative radiation

therapy for early breast cancer: a substudy of the TARGIT-A trial. Int J Radiat Oncol Biol Phys 96(1):55–64 29. Corica T, Nowak AK, Saunders CM et al (2018) Cosmetic outcome as rated by patients, doctors, nurses and BCCT.core software assessed over 5 years in a subset of patients in the TARGIT-A Trial. Radiat Oncol 13(1):68 30. Abo-Madyan Y, Welzel G, Sperk E et al (2019) Single-center longterm results from the randomized phase-3 TARGIT-A trial comparing intraoperative and whole-breast radiation therapy for early breast cancer. Strahlenther Onkol 195(7):640–647 31. Hepel J, Wazer DE (2015) A flawed study should not define a new standard of care. Int J Radiat Oncol Biol Phys 91(2):255–257 32. Silverstein MJ, Fastner G, Maluta S et al (2014) Intraoperative radiation therapy: a critical analysis of the ELIOT and TARGIT trials. Part 2—TARGIT. Ann Surg Oncol 21(12):3793–3799 33. Zietman A. Letters Regarding the TARGIT-A Trial (2015) The editor’s introduction. Int J Radiat Oncol Biol Phys 92(5):951–952 34. Vaidya JS, Bulsara M, Wenz F et al (2015) Pride, prejudice, or science: attitudes towards the results of the TARGIT-A trial of targeted Intraoperative radiation therapy for breast cancer. Int J Radiat Oncol Biol Phys 92(3):491–497 35. Shah C, Wobb J, Khan A (2016) Intraoperative radiation therapy in breast cancer: still not ready for prime time. Ann Surg Oncol 23(6):1796–1798 36. Cuzick J (2014) Radiotherapy for breast cancer, the TARGIT-A trial. Lancet 383(9930):1716 37. National Institute for Health and Care Excellence Intrabeam radiotherapy system for adjuvant treatment of early breast cancer. Technology appraisal guidance. https://www.nice.org.uk/guidance/ ta501. Last access: 31 Jan 2018 38. Thompson MK, Poortmans P, Chalmers AJ et al (2018) Practicechanging radiation therapy trials for the treatment of cancer: where are we 150 years after the birth of Marie Curie? Br J Cancer 119(4):389–407 39. Shah C, Vicini F, Wazer DE, Arthur D, Patel RR (2013) The American Brachytherapy Society consensus statement for accelerated partial breast irradiation. Brachytherapy 12(4):267–277 40. Correa C, Harris EE, Leonardi MC et al (2017) Accelerated partial breast irradiation: executive summary for the update of an ASTRO evidence-based consensus statement. Pract Radiat Oncol 7(2):73–79 41. Huang J, Barbera L, Brouwers M, Browman G, Mackillop WJ (2003) Does delay in starting treatment affect the outcomes of radiotherapy? A systematic review. J Clin Oncol 21(3):555–563 42. Recht A, Come SE, Gelman RS et al (1991) Integration of conservative surgery, radiotherapy, and chemotherapy for the treatment of early-stage, node-positive breast cancer: sequencing, timing, and outcome. J Clin Oncol 9(9):1662–1667 43. Hebert-Croteau N, Freeman CR, Latreille J, Brisson J (2002) Delay in adjuvant radiation treatment and outcomes of breast cancer—a review. Breast Cancer Res Treat 74(1):77–94 44. Froud PJ, Mates D, Jackson JS et al (2000) Effect of time interval between breast-conserving surgery and radiation therapy on ipsilateral breast recurrence. Int J Radiat Oncol Biol Phys 46(2): 363–372 45. Nixon AJ, Recht A, Neuberg D et al (1994) The relation between the surgery-radiotherapy interval and treatment outcome in patients treated with breast-conserving surgery and radiation therapy without systemic therapy. Int J Radiat Oncol Biol Phys 30(1):17–21 46. Olivotto IA, Lesperance ML, Truong PT et al (2009) Intervals longer than 20 weeks from breast-conserving surgery to radiation therapy are associated with inferior outcome for women with earlystage breast cancer who are not receiving chemotherapy. J Clin Oncol 27(1):16–23

Strahlenther Onkol 47. Mikeljevic JS, Haward R, Johnston C et al (2004) Trends in postoperative radiotherapy delay and the effect on survival in breast cancer patients treated with conservation surgery. Br J Cancer 90(7):1343–1348 48. Cefaro GA, Genovesi D, Marchese R et al (2007) The effect of delaying adjuvant radiation treatment after conservative surgery for early breast cancer. Breast J 13(6):575–580 49. van Maaren MC, Bretveld RW, Jobsen JJ et al (2017) The influence of timing of radiation therapy following breast-conserving surgery on 10-year disease-free survival. Br J Cancer 117(2):179–188 50. Vicini F, Shah C, Arthur D, Khan A, Wazer D, Keisch M (2016) Partial breast irradiation and the GEC-ESTRO trial. Lancet 387(10029):1717–1718 51. Chen PY, Vicini FA (2007) Partial breast irradiation. Patient selection, guidelines for treatment, and current results. Front Radiat Ther Oncol 40:253–271 52. Shaitelman SF, Lin HY, Smith BD et al (2016) Practical implications of the publication of consensus guidelines by the American society for radiation oncology: accelerated partial breast irradiation and the national cancer data base. Int J Radiat Oncol Biol Phys 94(2):338–348 53. Polgar C, Van Limbergen E, Potter R et al (2010) Patient selection for accelerated partial-breast irradiation (APBI) after breast-conserving surgery: recommendations of the Groupe Europeen de Curietherapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) breast cancer working group based on clinical evidence (2009). Radiother Oncol 94(3):264–273 54. Smith BD, Arthur DW, Buchholz TA et al (2009) Accelerated partial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO). Int J Radiat Oncol Biol Phys 74(4):987–1001 55. Smith BD, Arthur DW, Buchholz TA et al (2009) Accelerated partial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO). J Am Coll Surg 209(2):269–277 56. Miranda FA, Teixeira LAB, Heinzen RN et al (2019) Accelerated partial breast irradiation: current status with a focus on clinical practice. Breast J 25(1):124–128 57. Strnad V, Hannoun-Levi JM, Guinot JL et al (2015) Recommendations from GEC ESTRO breast cancer working group (I): target definition and target delineation for accelerated or boost partial breast irradiation using multicatheter interstitial brachytherapy after breast conserving closed cavity surgery. Radiother Oncol 115(3): 342–348 58. Major T, Gutierrez C, Guix B et al (2016) Recommendations from GEC ESTRO breast cancer working group (II): target definition and target delineation for accelerated or boost partial breast irradiation using multicatheter interstitial brachytherapy after breast conserving open cavity surgery. Radiother Oncol 118(1):199–204 59. Swanson TA, Vicini FA (2008) Overview of accelerated partial breast irradiation. Curr Oncol Rep 10(1):54–60 60. Offersen BV, Overgaard M, Kroman N, Overgaard J (2009) Accelerated partial breast irradiation as part of breast conserving therapy of early breast carcinoma: a systematic review. Radiother Oncol 90(1):1–13 61. Strom EA, Ovalle V (2014) Initial clinical experience using protons for accelerated partial-breast irradiation: longer-term results. Int J Radiat Oncol Biol Phys 90(3):506–508 62. Formenti SC, Hsu H, Fenton-Kerimian M et al (2012) Prone accelerated partial breast irradiation after breast-conserving surgery: five-year results of 100 patients. Int J Radiat Oncol Biol Phys 84(3):606–611 63. Jozsef G, DeWyngaert JK, Becker SJ, Lymberis S, Formenti SC (2011) Prospective study of cone-beam computed tomography im-

age-guided radiotherapy for prone accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys 81(2):568–574 64. Wen B, Hsu H, Formenti-Ujlaki GF et al (2012) Prone accelerated partial breast irradiation after breast-conserving surgery: compliance to the dosimetry requirements of RTOG-0413. Int J Radiat Oncol Biol Phys 84(4):910–916 65. Kainz K, White J, Herman J, Li XA (2009) Investigation of helical tomotherapy for partial-breast irradiation of prone-positioned patients. Int J Radiat Oncol Biol Phys 74(1):275–282 66. White JR, Meyer JL (2011) Intensity-modulated radiotherapy for breast cancer: advances in whole and partial breast treatment. Front Radiat Ther Oncol 43:292–314 67. Marrazzo L, Meattini I, Arilli C et al (2019) Auto-planning for VMAT accelerated partial breast irradiation. Radiother Oncol 132:85–92 68. Lozza L, Fariselli L, Sandri M et al (2018) Partial breast irradiation with CyberKnife after breast conserving surgery: a pilot study in early breast cancer. Radiat Oncol 13(1):49 69. Obayomi-Davies O, Kole TP, Oppong B et al (2016) Stereotactic accelerated partial breast irradiation for early-stage breast cancer: rationale, feasibility, and early experience using the CyberKnife radiosurgery delivery platform. Front Oncol 6:129 70. Stelczer G, Major T, Meszaros N, Polgar C, Pesznyak C (2019) External beam accelerated partial breast irradiation: dosimetric assessment of conformal and three different intensity modulated techniques. Radiol Oncol 53(1):123–130 71. Stelczer G, Tatai-Szabo D, Major T et al (2019) Measurement of dose exposure of image guidance in external beam accelerated partial breast irradiation: evaluation of different techniques and linear accelerators. Phys Med 63:70–78 72. Shah C, Badiyan S, Wilkinson BJ et al (2013) Treatment efficacy with accelerated partial breast irradiation (APBI): final analysis of the American Society of Breast Surgeons MammoSite((R)) breast brachytherapy registry trial. Ann Surg Oncol 20(10):3279–3285 73. Yashar C, Attai D, Butler E et al (2016) Strut-based accelerated partial breast irradiation: report of treatment results for 250 consecutive patients at 5 years from a multicenter retrospective study. Brachytherapy 15(6):780–787 74. Altman MB, Mooney KE, Edward S et al (2018) Efficiency of using the day-of-implant CT for planning of SAVI APBI. Brachytherapy 17(1):40–49 75. Ivanov O, Dickler A, Lum BY, Pellicane JV, Francescatti DS (2011) Twelve-month follow-up results of a trial utilizing Axxent electronic brachytherapy to deliver intraoperative radiation therapy for early-stage breast cancer. Ann Surg Oncol 18(2):453–458 76. Huang YJ, Su FF, Gaffney DK et al (2018) Skin dose estimation using virtual structures for Contura Multi-Lumen Balloon breast brachytherapy. Brachytherapy 17(6):956–965 77. Pignol JP, Caudrelier JM, Crook J, McCann C, Truong P, Verkooijen HA (2015) Report on the clinical outcomes of permanent breast seed implant for early-stage breast cancers. Int J Radiat Oncol Biol Phys 93(3):614–621 78. Arthur DW, Vicini FA, Todor DA, Julian TB, Cuttino LW, Mukhopadhyay ND (2013) Contura Multi-Lumen Balloon breast brachytherapy catheter: comparative dosimetric findings of a phase 4 trial. Int J Radiat Oncol Biol Phys 86(2):264–269 79. Kirisits C, Rivard MJ, Baltas D et al (2014) Review of clinical brachytherapy uncertainties: analysis guidelines of GEC-ESTRO and the AAPM. Radiother Oncol 110(1):199–212 80. King TA, Bolton JS, Kuske RR, Fuhrman GM, Scroggins TG, Jiang XZ (2000) Long-term results of wide-field brachytherapy as the sole method of radiation therapy after segmental mastectomy for T(is,1,2) breast cancer. Am J Surg 180(4):299–304 81. Strnad V, Hildebrandt G, Potter R et al (2011) Accelerated partial breast irradiation: 5-year results of the German-Austrian multicenter phase II trial using interstitial multicatheter brachytherapy

Strahlenther Onkol alone after breast-conserving surgery. Int J Radiat Oncol Biol Phys 80(1):17–24 82. Strnad V (2014) Breast cancer. In: Strnad V, Pötter R, Kovács G (eds) Practical handbook of brachytherapy. UNIMED, Hamburg, pp 184–199 83. Das RK, Thomandsen B (2009) Physics of accelerated partial breast irradiation. In: Wazer (ed) Accelerated partial breast irradiation. DG Arthur, FA ViciniSpringer Berlin-Heidelberg, DE, pp 73–99 84. Strnad V, Major T, Polgar C et al (2018) ESTRO-ACROP guideline: interstitial multi-catheter breast brachytherapy as accelerated partial breast irradiation alone or as boost—GEC-ESTRO breast cancer working group practical recommendations. Radiother Oncol 128(3):411–420

85. Kaiser J, Reitsamer R, Kopp P et al (2018) Intraoperative electron radiotherapy (IOERT) in the treatment of primary breast cancer. Breast Care 13(3):162–167 86. Veronesi U, Orecchia R, Luini A et al (2001) A preliminary report of intraoperative radiotherapy (IORT) in limited-stage breast cancers that are conservatively treated. Eur J Cancer 37(17):2178– 2183 87. (2007) (RTOG) RTOG. NSABP PROTOCOL B-39 / RTOG PROTOCOL 0413: A Randomized Phase III Study of Conventional Whole Breast Irradiation (WBI) Versus Partial Breast Irradiation (PBI) for Women with Stage 0, I, or II Breast Cancer. https://www. atcwustledu/protocols/nsabp/b-39/0413.pdf. Last access: 31 Jan 2018

Clinical and Translational Radiation Oncology 23 (2020) 91–99

Contents lists available at ScienceDirect

Clinical and Translational Radiation Oncology journal homepage: www.elsevier.com/locate/ctro

ESTRO IORT Task Force/ACROP recommendations for intraoperative radiation therapy in borderline-resected pancreatic cancer Felipe A. Calvo a,b,⇑, Jose M. Asencio c, Falk Roeder d,e, Robert Krempien f, Philip Poortmans g, Frank W. Hensley h, Marco Krengli i a

Department of Oncology, Clínica Universidad de Navarra, Madrid, Spain School of Medicine, Complutense University, Madrid, Spain Department of General Surgery, Hospital General Universitario Gregorio Marañón, Institute for Sanitary Research Gregorio Marañón (IiSGM), Madrid, Spain, Complutense University of Madrid, Madrid, Spain d Department of Radiotherapy and Radio-Oncology, Paracelsus Medical University Hospital Salzburg, Landeskrankenhaus, Salzburg, Austria e CCU Molecular Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany f Department of Radiotherapy, Helios Hospital Berlin-Buch, Berlin, Germany g Paris Sciences & Lettres PSL University, Paris, France h Department of Radiation Oncology, University Hospital of Heidelberg, Heidelberg, Germany i Radiotherapy Unit, Department of Translation Medicine, University of Piemonte Orientale, Novara, Italy b c

a r t i c l e

i n f o

Article history: Received 30 April 2020 Accepted 10 May 2020 Available online 15 May 2020 Keywords: Pancreatic cancer Borderline Intraoperative radiotherapy IORT IOERT Electron beam Pancreatic resection

a b s t r a c t Radiation therapy (RT) is a valuable component of multimodal treatment for localized pancreatic cancer. Intraoperative radiation therapy (IORT) is a very precise RT modality to intensify the irradiation effect for cancer involving upper abdominal structures and organs, generally delivered with electrons (IOERT). Unresectable, borderline and resectable disease categories benefit from dose-escalated chemoradiation strategies in the context of active systemic therapy and potential radical surgery. Prolonged preoperative treatment may act as a filter for selecting patients with occult resistant metastatic disease. Encouraging survival rates have been documented in patients treated with preoperative chemoradiation followed by radical surgery and IOERT (>20 months median survival, >35% survival at 3 years). Intensive preoperative treatment, including induction chemotherapy followed by chemoradiation and an IOERT boost, appears to prolong long-term survival within the subset of patients who remain relapse-free for>2 years (>30 months median survival; >40% survival at 3 years). Improvement of local control through higher RT doses has an impact on the survival of patients with a lower tendency towards disease spread. IOERT is a well-accepted approach in the clinical scenario (maturity and reproducibility of results), and extremely accurate in terms of dose-deposition characteristics and normal tissue sparing. The technique can be adapted to systemic therapy and surgical progress. International guidelines (National Comprehensive Cancer Network or NCCN guidelines) currently recommend use of IOERT in cases of close surgical margins and residual disease. We hereby report the ESTRO/ACROP recommendations for performing IOERT in borderline-resectable pancreatic cancer. 2020 The Author(s). Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

1. Introduction Pancreatic cancer is the seventh leading cause of cancer death worldwide [1]. Although significant improvements in overall survival rates have been observed in the last three decades, overall outcome remains poor [2]. Multimodality therapy including preoperative and adjuvant systemic treatment with RT components are

⇑ Corresponding author.

needed for disease that is locally advanced or borderline resectable on presentation. Surgery is a curative element of therapy, although few patients present with resectable disease [3,4]. For locally advanced disease including borderline imaging resectability, preoperative treatment with systemic agents and/or external beam radiotherapy (EBRT) (18 studies published from 1966 to 2015, 959 patients analysed) reported an objective response in 31.5%; 65.3% underwent resection (57.4% R0) with a median survival of 17.9 months (25.9 months for resected patients) [5]. The potential of preoperative therapy in borderline

E-mail address: fcalvom@unav.es (F.A. Calvo).

https://doi.org/10.1016/j.ctro.2020.05.005 2405-6308/ 2020 The Author(s). Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

F.A. Calvo et al. / Clinical and Translational Radiation Oncology 23 (2020) 91–99

resectable patients has been recently updated [6]. In the era of preoperative FOLFIRINOX (5-Fluorouracil, irinotecan and oxaliplatin), the meta-analysis data for patients with borderline pancreatic cancer (13 studies, 253 patients) shows a tendency towards favourable resection rates of 39.4% and R0 specimens of 63.5% [7]. International pooled analysis (518 patients) has indicated that postoperative RT significantly improves survival: 23.0 months with doses of>45 Gy with conventional fractionation vs 13.0 months with doses of less than 45 Gy with conventional fractionation [8]. Clinical results of intraoperative radiation therapy (IORT) using high-energy electron beams (IOERT) have been consistently reported in the last four decades [9,10]. IOERT used as a boost strategy (integrated for a dose-escalation multimodality approach) or as the only RT component was tested for localized non-resected, borderline or post-resection pancreatic cancer [11,12]. Favourable improvement in local control has been described in cohorts treated with extended resection through the addition of intraoperative irradiation [13,14]. In this decade, IOERT is considered a risk-adapted methodology for maximizing loco-regional control as a safe, accurate and efficient radiation dose-escalation technique [15–17]. In this study, the ESTRO IORT Task Force working group reports recommendations for performing in resected and in borderline resectable pancreatic cancer underwent resection after preoperative treatment (borderline-resected). These recommendations aim to define clinical indications, patient selection and technical aspects in a multidisciplinary setting in order to standardize treatment modalities across centres already using IOERT, and to help institutions that intend to start IOERT programmes for pancreatic cancer.

Table 2 Institutional contemporary experiences regarding IOERT component in borderline resectable disease treated with preoperative chemoradiation with or without FOLFIRINOX induction. Parameter

Mayo Clinic 2013 [16]

MGH 2018 [15]

Period of analysis

2002–2010

2010–2015

Initial local status: & Resected/Borderline & Median T size

11 (35%) –

8 (12%) 3.6 cm

Preoperative therapy & Chemo-radiation & Induction FOLFIRINOX

31* –

68* 68*

Resected & # patients & R0 & R1 & R2

17 (55%) 11 (65%) 5 (29%) 1 (6%)

41 (60%) 19 (46%) 16 (39%) 6 (15%)

IOERT & # patients & Dose range

14 of 17 (79%) 10–15 Gy

22 of 41 (54%) 8–13 Gy

Outcomes for resection + IOERT & Local control & Median OS & 3 years OS

94% 23 months + 40%

73% 35 months –

MGH: Massachusetts General Hospital, IOERT: IntraOperative Electron Radiation Therapy, R0: complete resection of the tumour or complete remission, R1: microscopic residual tumour, R2: macroscopic residual tumour, LC: Local control, OS: Overall Survival, * Entire group

3. Pre-treatment investigations 2. Evidence review and update

Studies required for candidate selection include the following:

We performed a retrospective bibliographic review of timeperiod, treatment strategies, disease characteristics and clinical results reported, including an intraoperative irradiation component, typically with electrons (IOERT) between 1981 and 2016. Table 1 contains data evaluated in 31 reports on post-resection disease status (1,435 patients analysed) [12,14–17,18–44]. Table 2 summarizes contemporary clinical results [15,16], including preoperative induction chemotherapy, chemo-radiation and surgical exploration (with or without resection, with or without IOERT) in unresectable or borderline resectable disease. In 2017, Krempien et al. published an IOERT review on pancreatic cancer with a selective update of post-resected status results [11].

1. 2. 3. 4. 5. 6. 7.

Pathology of adenocarcinoma History and physical examination American Society of Anaesthesiologists (ASA) score Conventional blood tests CA 19.9 Abdominal Multidetector computed tomography angiography Esophago-gastric duodenoscopy and Endoscopic ultrasonography 8. Chest computed tomography (CT) Potential supportive actions to be considered preoperatively include the following:

Table 1 Chronologic data analysis from a 35 years literature review period on IORT for Pancreatic cancer after surgical resection (31 articles, 1.435 patients). Treatment Characteristics

1981–1989

1990–1999

2000–2009

2010–2018

Resected & #Studies & #Patients References

5 46 [18–21,28]

12 257 [14,22–24,29–36]

8 611 [25–26,37–39,41–43]

6 521 [12,15–17,27,44]

IORT & Dose range (Gy) & Mean dose (Gy) & Electron beam & 250 kV

10–40 25 100% –

10–30 15 100% –

7.5–25 15 100% –

10–30 15 75% 25%

EBRT delivered > 50% patients

75%

39%

75%

50%

Adjuvant CT > 50% pts

70%

100%

60%

Median Survival & Range (months) & Mean (months)

5–12.6 9.5

10–19 15

9–28 15

19–35 23

IORT: IntraOperative Radiation Therapy; EBRT: external beam radiotherapy; CT: chemotherapy; Gy: Gray; kV: kilovoltage

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1. Self-expanding stent 2. Gastro-jejunostomy 3. Neurolysis Additional studies in high-risk patients, as clinically indicated, include the following: 1. Magnetic Resonance Imaging (MRI) / magnetic resonance cholangiopancreatography 2. Positron Emission Tomography (PET)-CT 3. Laparoscopy

4. Pre-treatment imaging for clinical staging Accurate diagnosis, clinical staging and treatment of pancreatic cancer require extensive interdisciplinary interaction and cooperation between specialties (diagnostic radiology, interventional upper endoscopy, nuclear medicine, surgery, medical oncology, radiation oncology). Accurate clinical staging is based on angiographic high-quality (helical) multidetector computed tomography (CT) with advanced volumetric techniques to accurately define the relationship of the tumour to the celiac axis and superior mesenteric vessels in three dimensions. In the absence of extrapancreatic disease, the relationship of the low-density tumour mass to the superior mesenteric artery (SMA) and celiac axis is the main focus of preoperative imaging studies. Endoscopic ultrasound-guided needle biopsy is a preferred method of diagnosis. Endoscopic retrograde cholangiopancreatography may be of use in decompression of the biliary tract in patients with jaundice and pruritus. Local tumour resectability is most accurately assessed by preoperative imaging studies: intraoperative exploration is an inadequate method to assess critical tumour–vessel relationships [45,46]. Objective, reproducible radiographic criteria define potentially resectable disease as the absence of extrapancreatic disease, absence of superior mesenteric vein (SMV) or portal vein encasement, abutment or distortion, or associated thrombi, and presence of a patent SMV–portal vein confluence and distinct fat planes around the SMA, celiac axis and hepatic artery [47]. Pretreatment staging to exclude patients with locally advanced disease is crucial to allow for accurate interpretation of results from studies examining the value of multimodality therapy in patients with pancreatic cancer. Borderline resectable tumours, which may benefit from preoperative therapy, include tumours with abutment or encasement of the SMV/portal vein without arterial involvement, in which sufficient vessel is present proximally and distally to permit resection and venous reconstruction, gastroduodenal artery encasement without extension to the celiac axis and with or without abutment or minor encasement of the hepatic artery, abutment of less than 180 of the SMA [48]. The margin most frequently reported as positive in patients who undergo pancreaticoduodenectomy is along the SMV or proximal SMA. IOERT following pancreatic resection should accurately document the pathologic status of the retroperitoneal margin of resection. PETCT at initial staging contributes complementary information on potential distant metastasis and the metabolic profile of the primary lesion [49].

5. Patient selection for IOERT All patients diagnosed with localized pancreatic cancer have to be extensively evaluated and discussed at a multidisciplinary tumour board (MTB) for defining the optimal multimodal treatment strategy, including exploratory laparotomy, with or without resection, and IOERT.

A significant proportion of unresectable or borderline resectable patients will be advised to undergo preoperative strategies (including a preoperative chemoradiation component) and should be restaged before laparotomy in terms of performance status, imaging and CA19.9 evolution. Patients amenable to the multidisciplinary approach including IOERT should have a good performance status (ECOG less than 2) and without distant metastases. The strongest recommendation exists for patients with clinical stage > IA (UICC TNM, 2016). Table 3 reports patient selection for IOERT: disease status, treatment sequence and radiation dose recommendations.

6. External beam radiation therapy For patients with borderline-resectable cancers, pre-operative EBRT plus concurrent chemotherapy is preferably given prior to exploratory laparotomy and possible surgical resection/IOERT. External-beam radiation therapy (EBRT) is delivered using 3dimensional conformal irradiation (3D-CRT) or intensitymodulated irradiation (IMRT), daily, over a period of 5–6 weeks at a dose of 45.0–50.4 Gy in 1.8 daily fractions, together with 5FU, capecitabine or institutional chemo-radiation regimes. IMRT shows dosimetric advantages, sparing renal and liver parenchyma, stomach and small bowel. The planning target volume (PTV) takes into account organ motion and encompassing the clinical target volume (CTV) that includes areas consisting of the tumour itself and areas at risk of tumour involvement and occult (at-risk) nodal metastases. Nodal target volumes for tumours in the head of the pancreas include the pancreaticoduodenal, peripancreatic, porta hepatis, celiac and suprapancreatic nodes. The portion of the duodenal loop at risk of involvement with extrapancreatic tumour extension is also included. For lesions involving the body and tail of the pancreas, the suprapancreatic, celiac and splenic hilar nodes should be included in the CTV; inclusion of more medially placed lymph nodes (pancreaticoduodenal and porta hepatis) may be optional, depending on the ability to spare normal organs and structures. Normal tissue tolerances should be carefully respected. Details regarding dose-volume histogram parameters for treatment of pancreatic malignancies with RT have been recently updated (50). The dose limits of the kidneys, liver, stomach, small bowel and spinal cord will influence the selection of beam arrangement. In situations where IOERT has been administered or is intended to be administered to tumour or tumour bed located in proximity of vertebral column, the spinal-cord dose should be limited to 35.0–40.0 Gy. In the postoperative setting, similar planning principles can be used, with the operative bed and areas of potential residual tumour or microscopic extension taking the place of the initial gross tumour volume in treatment planning. Table 3 Patient selection for IOERT: disease, treatment sequence and radiation dose recommendations. Disease Status Clinical setting

Borderline resected pancreatic cancer

Indications Borderline/resected Stage > IA (UICC TNM, 2016) Treatment Preoperative chemoradiation followed by resection + IOERT boost Radiotherapy Dose IOERT boost 10 to 12.5 Gy for negative resection margins (R0) 12.5 to 15 Gy for microscopic positive resection margins (R1) 15 to 20 Gy for macroscopic or gross residual tumor (R2) 3D-CRT or 45–50.4 Gy (in 1.8–2 Gy per fraction) IMRT

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7. Surgical procedure 7.1. Surgical factors and tumour resection (pancreaticoduodenectomy; distal pancreatectomy) Pancreaticoduodenectomy involves the excision of the pancreatic head, duodenum, gallbladder and bile duct, with or without removal of the gastric antrum. Access to the peritoneal cavity is through a longitudinal midline incision or a bilateral subcostal incision. Once in the abdominal cavity, all intra-abdominal organs and peritoneal surfaces are carefully inspected and palpated to exclude distant metastatic disease. Any suspicious lesions should be biopsied and sent for frozen-section examination, as presence of distant metastasis is a contraindication to proceeding with resection. A wide Kocher manoeuvre is performed lifting all lymphatic tissue over the medial aspect of the right kidney, inferior vena cava and left renal vein. The gastrocolic ligament is divided, with special attention to preserving the gastroepiploic arcade if pyloric preservation is being entertained. The neck of the pancreas is then carefully dissected off the SMV. Dissection of the porta hepatis is usually initiated by excising the common hepatic artery lymph node to facilitate exposure. The gastroduodenal and right gastric artery are identified, legated and divided. The superior portion of the pancreatic neck is dissected off the portal vein. Cholecystectomy is then performed and the common hepatic duct is divided. The gastric antrum or duodenum is divided using a liner gastrointestinal stapler. The jejunum is then transected approximately 10 cm from the ligament of Treitz with subsequent mobilization of its mesentery, as well as mobilization of the third and fourth portions of the duodenum. The pancreatic neck is transected. The pancreatic head and uncinate process are now dissected from the portal vein and SMV by legating and dividing the often-multiple venous tributaries that are encountered. Vascular resection of the SMV–portal vein confluence using either lateral venectomy or segmental venous resection and reconstruction should be performed when there is no tissue plane between the tumour and SMV and portal vein. Medial retraction of the SMV– portal vein confluence and the SMA is identified. All of the soft tissue along the right lateral aspect of the SMA should be excised. Special attention should be paid to this step, given the high incidence of local recurrence. In spite of all efforts, a microscopically positive margin will occur in between 10% and 20% of cases due to perineural invasion along the mesenteric plexus at the SMA origin and microscopic lymphatic spread beyond the extent of the palpable tumour. Prior to obtaining frozen-section histologic examination of the surgical margins, the specimen is appropriately oriented and the areas in question are identified. Reconstruction after pancreaticoduodenectomy have to be start after IOERT procedure to avoid irradiation of anastomotic structures (see below). Reconstruction will be start with the pancreaticojejunostomy. A retrocolic end-to-side duct-to-mucosa technique using interrupted sutures is recommended. Then, distal to the pancreaticojejunostomy, the hepaticojejunostomy is completed in a single layer using either interrupted or running sutures, depending on the calibre of the common hepatic duct. An antecolic, end-to-side duodenojejunostomy (or gastrojejunostomy if pyloric preservation has not been used) in two layers is then completed approximately 40– 50 cm from the hepaticojejunostomy. The abdomen is then irrigated copiously prior to placing surgical drains and performing abdominal closure. Perhaps one of the most debated technical aspects of the pancreaticoduodenectomy is the extent of the associated lymphadenectomy (standard vs extended). A standard lymphadenectomy (standard pancreaticoduodenectomy) commonly refers to the resection of gastric and pyloric nodes, nodes to the right of the hepatoduodenal ligament, anterior and posterior pancreaticoduodenal nodes, nodes to the right of the SMA and nodes

anterior to the common hepatic artery. An extended lymphadenectomy (extended pancreaticoduodenectomy) includes the skeletonization of the common and proper hepatic arteries, celiac axis nodes, all nodes to the left and right of the hepatoduodenal ligament, circumferential skeletonization of the SMA between the aorta and the inferior pancreaticoduodenal artery, all nodes in the anterolateral aspect of the aorta and the inferior vena cava, in continuity with Gerota’s fascia, between the celiac axis and the inferior mesenteric artery. 8. IOERT procedure: Post-resection 8.1. IOERT: Methods and techniques of treatment IOERT for pancreatic cancer has predominantly been delivered with megavoltage electrons (IOERT) produced by a medical linear accelerator (Fig. 1) [50]. Although brachytherapy and orthovoltage treatment have been described, the data on efficacy is uncertain. Therefore, these recommendations will focus IOERT. The electron beam energy and dose of IOERT are determined by the resection status and geometry of the treated field. Bolus is not recommended due to the fact that intraoperative fluid is present after tissue manipulation and resection. Protections inside the tumour bed are not recommended too, due to the dosimetric uncertainties introduced by such action. The best protection is mechanical retraction for temporary displacement of dose-sensitive structures at risk. Surgical retractors for large upper abdominal interventions are most helpful for properly exposing the radiation target and for expediting IOERT applicator positioning, displacement of normal tissue and iconographic documentation of the final pre- and post-intraoperative irradiation assemblage. 9. Radiation target definition After marginal resection of borderline resectable or resectable lesions, the tumour bed contains retroperitoneal soft tissue, vascular structures (portal vein, superior mesenteric artery and vein, aorta), the prevertebral ligament and the anterior part of the vertebral bone (Fig. 1). The sectioned bile duct, the pancreatic remnant, colon and stomach are excluded from the IOERT field and should be under visual control and mechanically retracted. The upper pole of the right kidney can also be controlled and displaced by palpation. Under appropriate haemostasis, intraoperative fluid is not a limiting factor for selection of electron beam energy as long as the fluid level covering the target volume is stable. The target at risk should

Fig. 1. A post-pancreatectomy tumour bed area including the description of remaining anatomical structures. SMA: superior mesenteric artery.

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include the whole circumferences of the mentioned vascular structures and the post-resected retroperitoneal surface with a safety margin, which can be adequately treated with lower-energy electrons in the 9–12 MeV range. Intraoperatively, the radiation oncologist and surgeon consult regarding the retroperitoneal area at risk of residual tumour after maximal resection, and the volume at risk is encompassed within a field defined by an IOERT applicator with a margin of at least 1–2 cm laterally, covering the PTV including anatomic, dosimetric and geometric uncertainties; in depth, a margin of 0,1–0,5cm margin should allow for penetration uncertainties. The post-pancreatectomy tumour bed is appropriately encompassed by applicators in the range of 7 to 10 cm. For larger field sizes, consider the use of bevelled applicators; field abutments should be discouraged. Fig. 2 illustrates an IOERT applicator in position for treatment of a tumour bed post-pancreatectomy. The whole process can be summarized as follows: 1. Tumour bed definition/assessment: surgical margin status (inspection of the surgical field and the posterior aspect of the surgical specimen; optional frozen section pathology). Perivascular tissue characteristics in borderline lesions. 2. Normal uninvolved tissue to be excluded (mobilized out) from the IOERT radiation volume: bile duct (sections); pancreatic remnant (sectioned if it exists); stomach; colon; small bowel; liver; upper pole of right kidney. 3. Normal tissue at risk to be included in the radiation target volume: circumferential vasculature structures (inferior cava vein; portal vein; superior mesenteric artery and vein, aorta; legated left gastric artery); lymphatic and retroperitoneal soft tissue; prevertebral ligament. Such decisions should be agreed at the time of IOERT. 10. Applicator selection The applicator selection and adaptation to the post-surgical bed at risk should consider the following technical elements of decisions:

1. Size (diameter): in the range of 1 to 2 cm larger than the original maximal dimension of the tumour (T) in the staging imaging studies, including the area at risk or positive margins. Availability of applicators with a diameter of 5 to 10 cm provides a safe range. 2. Bevel angle: to appropriately encompass the surgical bed the anatomical configuration of the right sided head of the pancreas surgical bed, 15 to 30 bevel angles are recommended. The same criteria apply to primaries in the tail of the pancreas (opposite direction). Dominant lesions in the body of the pancreas are properly encompassed with 0 to 15 angles.

11. IOERT irradiation IOERT irradiation consists of the following: 1. Electron energy selection: 90% isodose should encompass in depth the full circumference of vessels involved, in contact or at risk, together with retroperitoneal tissue and prevertebral ligament. The estimations of this distance can be made using real-time intraoperative measurements, together with data obtained from the presurgical CT scan. Meticulous haemostasis and intra-abdominal surgical fluid are relevant for electron energy selection. In the event of fluid instability at the radiation target, a superior electron energy level selection is an alternative. 2. Dose selection (single fraction boost component): resection specimens at low risk after favourable dissection procedure doses of 10 to 12.5 Gy are recommended. Specimen with close or suspected/confirmed cancer involved margins doses in the range from 12.5 to 15 Gy are recommended. After laborious vascular and/or soft tissue dissection with suspected residual cancer, 15 to 20 Gy should be considered, even in the event of vascular anastomosis.

12. Dose prescription For tumours resected without identifiable residual gross tumour volume, doses in the range of 10.0–12.5 Gy are applied. Depending on the extent of suspected residual microscopic malignant disease, this range may be 12.5–15 Gy. For gross residual disease, doses of 15–20 Gy have been employed. During surgery, care must be taken to accurately identify the depth of the spinal cord beneath the IOERT field using anatomic landmarks and a review of preoperative CT imaging. A library of predefined isodose curve distribution for a range of IOERT applicator diameters, bevel shapes and electron beam energies has to be available for intraoperative consultation (Fig. 3). The electron energy should be chosen to adequately encompass the target tissues within the 90% isodose curves, with attention to the spinal cord dose contribution.

13. Treatment delivery

Fig. 2. IOERT applicator positioned encompassing the tumour bed (vascular structures and retroperitoneal tissue margin) excluding from the radiation beam: pancreatic stump, bile duct, liver and transverse colon. SMA: superior mesenteric artery.

Before dose delivery, the appropriate physical and dosimetrical parameters (electron energy, applicator size, length and bevel angle, monitor units, bolus choice, should be checked by a medical physicist as well as by the physician (radiation oncologist) in a four-eyes principle. Usually, a medical physicist or a radiation therapist (RTT) aligns the gantry to the applicator for soft-docking system and enters the data in the control console. During irradiation (approximately 1–2 min, depending on dose and dose rate), nobody is allowed to stay in the operation room except the patient for radiation protection purposes.

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Fig. 3. A virtual 2D simulation (7 cm diameter applicator, 15 bevel angle) and dosimetric representation (10 MeV electron beam) of an IOERT post-pancreatectomy procedure: A. CT contoured including tumour, adjacent organs at risk and upper abdominal vasculature, B. Post resected tumour bed estimation (3D): retroperitoneal tissue and vasculature, C. Applicator positioning: 7 cm diameter, 15 bevel angle and D. Isodose distribution: 10 MeV electron beam.

14. Applicator removal After IOERT irradiation, the surgeon or radiation oncologist performs applicator removal with the assistance of a surgical assistant/nurse. Special attention should be paid during this step to avoid traumatization of surrounding tissues and possible bleeding. In the event of bleeding during irradiation, blood should first be aspirated in order to clearly visualize the end of the collimator in contact with the patient’s tissues and allow for a safe manoeuvre. 15. Recording and reporting Clinical and dosimetry forms should be filled out with all relevant patient, tumour and treatment parameters. Clinical data should include demographic data, performance status, symptoms and serum tests, including CA19-9, comorbidities and Charlson comorbidity index. Tumour-related data should include imaging studies, a biopsy report, clinical and pathological stage, grading and possible biomolecular studies. Treatment data should include bile-duct permeability manoeuvres, preoperative treatments, the surgical report and main characteristics of the IOERT procedure, including applicator diameter, bevel angle, bolus, beam energy, dose prescription and duration of the procedure. In vivo dosimetry is strongly recommended as a quality-assurance procedure. Radiation target contents should be described: organs and structures included in the radiation beam. Radiation protection of normal uninvolved tissues: description of temporary mobilization or intra-field customized protection. The documentation of the radiation target, adjacent - if necessary mobilized - normal tissue and used shielding should ideally include drawings or photos. Preoperative MRI and CT-scans can be obtained to identify the primary tumour, regional lymph nodes and critical organs in order to design a provisional treatment plan. No fully reliable treatment planning systems currently exist for intraoperative irradiation; however, the availability of preoperative images may help with

identifying anatomical structures to guide the positioning of the collimator. Whenever obtained, all these imaging data should be included in the patient’s final documentation. Additionally, clinical photographs of the applicator positioning and surface anatomy in the IOERT target volume are recommended. Intraoperative ultrasound can also be helpful in some cases to verify tumour size in depth and the location of critical structures such as kidneys and major vessels. The final documentation of the IOERT procedure should also include the surgical notes and the anaesthesiology report. Table 4 contains a summary of the relevant IOERT parameters for local treatment. 16. Recommendation on patient care: 16.1. Care during the course of IOERT The sterile field should be guaranteed throughout the IOERT procedure. Before irradiation, sterile drapes should cover the surgical bed and the part of the applicator inside and near the surgical bed. In some cases, an aspiration drain may be useful to avoid bleeding outside the surgical bed. The patient should be carefully observed by means of a camera during irradiation and vital parameters should be monitored and be visible from outside the operating room. In the event of an emergency, irradiation should be stopped immediately and nurses, anaesthesiologists and surgeons should be prepared to enter the operating room at any time immediately after cessation of irradiation. 17. Post-treatment patient care and follow-up Patients treated with IOERT for pancreatic tumours require thorough care, as after any other surgical procedure for pancreatic tumours. All vital and clinical parameters should be monitored in the days following the procedure, and special attention should be

F.A. Calvo et al. / Clinical and Translational Radiation Oncology 23 (2020) 91–99 Table 4 Reporting parameters for IORT electrons beam procedures in resected pancreatic cancer. Iort Parameters Target volume description

IORT factors

Integrated pre-IORT treatment factors

Tumour residue (R0, R1, R2) Normal tissues exposed Normal tissues protected/mobilized Special conditions: & Vascular manipulation & Others Applicator size/diameter & Bevelled end (degrees) Electron energy & Isodose prescription Total dose Number of fields & Report every parameter for every field & Overlapping & Field –within-a-field Protections Fluid stability Time of beam on Gantry angulation In vivo dosimetry (system/site measured) Surgery: type of resection and margin status (R0, R1, R2) & Technique and reconstruction Preoperative & Chemoradiation (CRT) & Induction chemotherapy + CRT Postoperative & CRT & CRT + adjuvant chemotherapy

paid to blood tests, including renal and liver functions, bowel movements and onset of new symptoms and signs. After IOERT for pancreatic-head tumours, the risk of duodenal radiation damage, even with bleeding, should be taken into account. In the event of persistent pain and anaemia with faecal occult blood, medical therapy and endoscopy/surgical procedures should be considered. In the case of unresected or partially resected lesions, the risk of bleeding related to haemorrhage from arteries and veins encased by the tumour tissue that undergoes necrosis should be carefully considered. In the event of significant bleeding, re-operation aiming at haemostasis should be considered where possible. After the IOERT procedure, alone or combined with surgical resection, the patient may receive further treatments, including postoperative RT and adjuvant systemic treatment. Therefore, the follow-up schedule starts after treatment completion and usually does not substantially differ from that of pancreatic cancer treated without IOERT. During imaging studies, special attention should be paid to any tissue potentially involved in the IOERT volume such as the duodenum and major vessels.

plus 50-Gy external beam RT (conventional fractionation), including post-resection vascular anastomosis [52,53]. 19. Conclusions and future directions Long-term survival and disease control are achievable in selected patients with borderline-resectable pancreas cancer, with a tendency towards improved survival reported for patients who underwent resection after intensive-induction systemic and locoregional full-dose chemoradiation. IOERT as part of a multimodality treatment option for borderline or resected pancreatic cancer has been shown to promote high local control at the site of the primary tumour without a significant increase in treatment toxicity. With advances in the ability of systemic therapy to treat occult systemic metastases, the importance of sustained longterm local and regional control is increasing interest in the expansion of IOERT. Strategies for selecting appropriate patients for aggressive local therapy in resected and borderline-resectable settings will advance through improvements in imaging, biomarkers and genetics, as well as through the timing of when to administer IOERT and/or resection. In-vivo-dosimetry and intra-operative imaging should be encouraged to improve the accuracy, reproducibility and documentation and provide data for evaluation and tailoring of IOERT. IOERT is a risk-adaptable technique in the era of personalized oncology [54]. New opportunities for systemic or regional therapy (intrahepatic and intraperitoneal), targeted therapies, vaccines and immunotherapy should be evaluated in an attempt to improve systemic disease control. As improvements are being made in distant disease control, the benefit of improved local control with regimens including IOERT may become even more decisive [55,56]. 20. Disclosures Jose M. Asencio Is member of the IOeRT Consortium, established on 21 December 2019, supported by Sordina IORT Technologies spa Felipe A. Calvo: Is member of the IOeRT Consortium, established on 21 December 2019, supported by Sordina IORT Technologies spa Philip Poortmans Is member of the IOeRT Consortium, established on 21 December 2019, supported by Sordina IORT Technologies spa Is medical advisor of Sordina IORT Technologies spa, starting from 1 April 2020 on Marco Krengli

18. Adverse effects IOERT in the setting of post-resection pancreatic cancer is typically well tolerated. In the European pooled analysis, acute treatment toxicity was minimal and limited to grade 2. Surgical adverse events consisted of pancreatic fistula in 27%, delayed gastric emptying in 22%, haemorrhage in 18%, repeat laparotomy in 15%, abdominal abscess in 14%, sepsis in 3%, and perioperative mortality in 2% [42]. Large animal experimental studies have analysed the pathologic response of the pancreas and duodenum [51]. Clinical and experimental data of upper abdominal tissues and organs support good tolerance to a 10-Gy to 20-Gy IOERT boost

Received travel grants from IntraOp Medical Corporation, CA, USA

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The authors are grateful to Dr. Javier Serrano of Hospital Gregorio Marañon for his assistance on the manuscript development. Authors are grateful to the ESTRO/ACROP reviewers Wim Dries, Philipp Scherer, Dirk Verellen, Alexandra Stewart and Antonino De Paoli for their useful and constructive comments. References [1] Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87–108. [2] Cloyd JM, Katz MH, Prakash L, Varadhachary GR, Wolff RA, Shroff RT, et al. Preoperative therapy and pancreatoduodenectomy for pancreatic ductal adenocarcinoma: a 25-year single-institution experience. J Gastrointest Surg 2017;21:164–74. [3] Bouvier AM, Bossard N, Colonna M, Garcia-Velasco A, Carulla M, Manfredi S, et al. EUROCARE-5 working group. Trends in net survival from pancreatic cancer in six European Latin countries: results from the SUDCAN populationbased study. Eur J Cancer Prev 2017;26:S63–9. [4] Ahola R, Siiki A, Vasama K, Vornanen M, Sand J, Laukkarinen J. Patients with resected, histologically re-confirmed pancreatic ductal adenocarcinoma (PDAC) can achieve long-term survival despite T3 tumour or nodal involvement. The Finnish Register Study 2000–2013. Pancreatology 2017;17:822–6. https://doi.org/10.1016/j.pan.2017.07.192. [5] Tang K, Lu W, Qin W, Wu Y. Neoadjuvant therapy for patients with borderline resectable pancreatic cancer: A systematic review and meta-analysis of response and resection percentages. Pancreatology 2016;16:28–37. [6] Zhan HX, Xu JW, Wu D, Wu ZY, Wang L, Hu SY, et al. Neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of prospective studies. Cancer Med 2017;6:1201–19. [7] Petrelli F, Coinu A, Borgonovo K, Cabiddu M, Ghilardi M, Lonati V, et al. FOLFIRINOX-based neoadjuvant therapy in borderline resectable or unresectable pancreatic cancer: a meta-analytical review of published studies. Pancreas 2015;44:515–21. [8] De Filippo L, Mattiucci GC, Morganti AG, Falconi M, Van Stiphout RGPM, Alfieri S, et al. The impact of dose on survival in adjuvant chemoradiation pancreatic cancer. Radiother Oncol 2017;suppl1:S330. [9] Czito BG, Calvo FA, Haddock MG, Palta M, Willett CG. Intraoperative irradiation. In: Gunderson LL, Tepper JE, editors. Clinical Radiation Oncology. Philadelphia: Elsevier Saunders; 2016. p. 325–40. [10] Sole CV, Calvo FA, Ferrer C, Pascau J, Marsiglia H. Bibliometrics of intraoperative radiotherapy: analysis of technology, practice and publication tendencies. Strahlenther Onkol 2014;190:1111–6. [11] Krempien R, Roeder F. Intraoperative radiation therapy (IORT) in pancreatic cancer. Radiat Oncol 2017;12:8–14. [12] Ogawa K1, Karasawa K, Ito Y, Ogawa Y, Jingu K, Onishi H, Aoki S, Wada H, Kokubo M, Etoh H, Kazumoto T, Takayama M, Negoro Y, Nemoto K, Nishimura Y. Intraoperative radiotherapy for resected pancreatic cancer: a multiinstitutional retrospective analysis of 210 patients, Int J Radiat Oncol Biol Phys 2010;77:734-42 [13] Hiraoka T. Extended radical resection of cancer of the pancreas with intraoperative radiotherapy. Baillieres Clin Gastroenterol 1990;4:985–93. [14] Hiraoka T, Uchino R, Kanemitsu K, et al. Combination of intraoperative radiation with resection of cancer of the pancreas. Int J Pancreatol 1990;7:201–7. [15] Keane Florence K, Wo Jennifer Y, Ferrone Cristina R, Clark Jeffrey W, Blaszkowsky Lawrence S, Allen Jill N, Kwak Eunice L, Ryan David P, Lillemoe Keith D, Fernandez-del Castillo Carlos, Hong Theodore S. Intraoperative Radiotherapy in the Era of Intensive Neoadjuvant Chemotherapy and Chemoradiotherapy for Pancreatic Adenocarcinoma. Am J Clin Oncol 2018;41(6):607–12. https://doi.org/10.1097/COC.0000000000000336. [16] Ashman JB, Moss AA, Rule WG, Callister MG, Reddy KS, Mulligan DC, et al. Preoperative chemoradiation and IOERT for unresectable or borderline resectable pancreas cancer. J Gastrointest Oncol 2013;4:352–60. [17] Calvo FA, Sole CV, Atahualpa F, Lozano MA, Gomez-Espi M, Calin A, et al. Chemoradiation for resected pancreatic adenocarcinoma with or without intraoperative radiation therapy boost: Long-term outcomes. Pancreatology 2013;13:576–82. [18] Manabe T, Baba N, Nonaka A, et al. Combined treatment using radiotherapy for carcinoma of the pancreas involving the adjacent vessels. Int Surg 1988;73:153–6. [19] Nishimura A, Sakata S, Iida K, et al. Evaluation of intraoperative radiotherapy for carcinoma of the pancreas: prognostic factors and survival analyses. Radiat Med 1988;6:85–91. [20] Cromack DT, Maher MM, Hoekstra H, et al. Are complications in intraoperative radiation therapy more frequent than in conventional treatment? Arch Surg 1989;124:229–34. [21] Gilly F, Romestaing P, Gerard J, et al. Experience of three years with intraoperative radiation therapy using the Lyon intra-operative device. Int Surg 1990;75:84–8. [22] Calvo F, Santos M, Abuchaibe O, et al. Intraoperative radiotherapy in gastric and pancreatic carcinoma: a European experience. Front Radiat Ther Oncol 1991;25:270–3.

[23] Dobelbower R, Konski A, Merrick H, et al. Intraoperative electron beam radiation therapy (IOEBRT) for carcinoma of the exocrine pancreas. Int J Radiat Oncol Biol Phys 1991;20:113–9. [24] Fossati V, Cattaneo G, Zerbi A, et al. The role of intraoperative therapy by electron beam and combination of adjuvant chemotherapy and external radiotherapy in carcinoma of the pancreas. Tumouri 1995;81:23–31. [25] Ihse I, Andersson R, Ask A, et al. Intraoperative radiotherapy for patients with carcinoma of the pancreas. Pancreatology 2005;5:438–42. [26] O’Connor J, Sause W, Hazard L, et al. Survival after attempted surgical resection and intraoperative radiation therapy for pancreatic and periampullary adenocarcinoma. Int J Radiat Oncol Biol Phys 2005;63:1060–6. [27] Jingu K, Tanabe T, Nemoto K, et al. Intraoperative radiotherapy for pancreatic cancer: 30-year experience in a single institution in Japan. Int J Radiat Oncol Biol Phys 2012;83:e507–11. [28] Hoekstra HJ, Restrepo C, Kinsella TJ, Sindelar WF. Histopathological effects of intraoperative radiotherapy on pancreas and adjacent tissues: a postmortem analysis. J Surg Oncol 1988;37:104–8. [29] Ozaki H, Kinoshita T, Kosuge T, Egawa S, Kishi K. Effectiveness of multimodality treatment for resectable pancreatic cancer. Int J Pancreatol 1990;7:195–200. [30] Gotoh M, Monden M, Sakon M, et al. Intraoperative irradiation in resected carcinoma of the pancreas and portal vein. Arch Surg 1992;127:1213–5. [31] Johnstone P, Sindelar W. Patterns of disease recurrence following definitive therapy of adenocarcinoma of the pancreas using surgery and adjuvant radiotherapy: correlations of a clinical trial. Int J Radiat Oncol Biol Phys 1993;27:831–4. [32] Zerbi A, Fossati V, Parolini D, et al. Intraoperative radiation therapy adjuvant to resection in the treatment of pancreatic cancer. Cancer 1994;73:2930–5. [33] Staley CA, Lee JE, Cleary KR, et al. Preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for adenocarcinoma of the pancreatic head. Am J Surg 1996;171:118–25. [34] Farrell T, Barbot D, Rosato F. Pancreatic resection combined with intraoperative radiation therapy for pancreatic cancer. Cancer 1997;226:66–9. [35] Coquard R, Ayzac L, Gilly F-N, et al. Intraoperative radiotherapy in resected pancreatic cancer: feasibility and results. Radiother Oncol 1997;44:271–5. [36] Sindelar WF, Kinsella TJ. Studies of intraoperative radiotherapy in carcinoma of the pancreas. Ann Oncol 1999;10(suppl4):226–30. [37] Reni M, Panucci M, Ferreri A, et al. Effect on local control and survival of electron beam intraoperative Irradiation for resectable pancreatic adenocarcinoma. Int J Radiat Oncol Biol Phys 2001;50:651–8. [38] Alfieri S, Morganti AG, Di Giorgio A, Valentini V, Bossola M, Trodella L, et al. Improved survival and local control after intraoperative radiation therapy and postoperative radiotherapy: a multivariate analysis of 46 patients undergoing surgery for pancreatic head cancer. Arch Surg 2001;136:343–7. [39] Okamoto A, Matsumoto G, Tsuruta K, et al. Intraoperative radiation therapy for pancreatic adenocarcinoma: the Komagome hospital experience. Pancreas 2004;28:296–300. [40] Takamori H, Hiraoka T, Kanemitsu K, Tsuji T, Hamada C, Baba H. Identification of prognostic factors associated with early mortality after surgical resection for pancreatic cancer–under-analysis of cumulative survival curve. World J Surg 2006;30:213–8. [41] Nakagohri T, Kinoshita T, Konishi M, Takahashi S, Tanizawa Y. Clinical results of extended lymphadenectomy and intraoperative radiotherapy for pancreatic adenocarcinoma. Hepatogastroenterology 2007;54:564–9. [42] Valentini V, Calvo F, Reni M, et al. Intra-operative radiotherapy (IORT) in pancreatic cancer: joint analysis of the ISIORT-Europe experience. Radiother Oncol 2009;9:54–9. [43] Showalter TN, Rao AS, Rani Anne P, Rosato FE, Rosato EL, Andrel J, et al. Does intraoperative radiation therapy improve local tumour control in patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma? A propensity score analysis. Ann Surg Oncol 2009;16:2116–22. [44] Bachireddy P, Tseng D, Horoschak M, et al. Orthovoltage intraoperative radiation therapy for pancreatic adenocarcinoma. Radiat Oncol 2010;5:105–7. [45] Fuhrman GM, Charnsangavej C, Abbruzzese JL, et al. Thin-section contrastenhanced computed tomography accurately predicts the resectability of malignant pancreatic neoplasms. Am J Surg 1994;167:104–13. [46] Robinson EK, Lee JE, Lowy AM, Fenoglio CJ, Pisters PWT, Evans DB. Reoperative pancreaticoduodenectomy for periampullary carcinoma. Am J Surg 1996;172:432–8. [47] Spitz FR, Abbruzzese JL, Lee JE, et al. Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas. J Clin Oncol 1997;15:928–37. [48] Callery M, Chang K, Fishman E, Talamonti M, William Traverso L, Linehan D. Pretreatment assessment of resectable and borderline resectable pancreatic cancer: expert consensus statement. Ann Surg Oncol 2009;16:1727–33. [49] Chang JS, Choi SH, Lee Y, Kim KH, Park JY, Song SY, et al. Clinical usefulness of 18 F-fluorodeoxyglucose-positron emission tomography in patients with locally advanced pancreatic cancer planned to undergo concurrent chemoradiation therapy. Int J Radiat Oncol Biol Phys 2014;90:126–33. [50] Miller RC, Valentini V, Moss A, D’Agostino GR, Callister MD, Hong TS, et al. Pancreas cancer. In: Gunderson LL, Willett CG, Calvo FA, Harrison LB, editors. Intraoperative irradiation: techniques and results. New York: Humana Press, Springer; 2011. p. 249–72.

F.A. Calvo et al. / Clinical and Translational Radiation Oncology 23 (2020) 91–99 [51] Ahmadu-Suka F, Gillette EL, Withrow SJ, Husted PW, Nelson AW, Whiteman CE. Pathologic response of the pancreas and duodenum to experimental intraoperative irradiation. Int J Radiat Oncol Biol Phys 1988;14:1197–204. [52] Evans DB, Lee JE, Leach SD, Fuhrman GM, Cusack Jr JC, Rich TA. Vascular resection and intraoperative radiation therapy during pancreaticoduodenectomy: rationale and technique. Adv Surg 1996;29:235–62. [53] Vujaskovic Z, Willett CG, Tepper LE, Kinsella TJ, Gunderson LL. Normal tissue tolerance to IOERT, EBRT or both: animal and clinical studies. In: Gunderson

LL, Willett CG, Calvo FA, Harrison LB, editors. Intraoperative irradiation: techniques and results. New York: Humana Press, Springer; 2011. p. 119–40. [54] Calvo FA. Intraoperative irradiation: precision medicine for quality cancer control promotion. Radiat Oncol 2017;12:36–7. [55] Calvo FA, Valentini V. Radiotherapy for pancreatic cancer: systematic nihilism or intraoperative realism. Radiother Oncol 2008;87:314–7. [56] Li Y, Feng Q, Jin J, Shi S, Zhang Z, Che X, et al. Experts’ consensus on intraoperative radiotherapy for pancreatic cancer. Cancer Lett. 2019;1 (449):1–7.

Clinical and Translational Radiation Oncology 24 (2020) 41–48

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ESTRO/ACROP IORT recommendations for intraoperative radiation therapy in locally recurrent rectal cancer Felipe A. Calvo a,b,d,⇑, Claudio V. Sole c,d, Harm J. Rutten e,f, Wim J. Dries k, Miguel A. Lozano g, Mauricio Cambeiro a, Philip Poortmans h,i, Luis González-Bayón d,j a

Department of Oncology, Clínica Universidad de Navarra, Universidad de Navarra, Madrid, Spain School of Medicine, Complutense University, Madrid, Spain c Department of Radiation Oncology, Instituto de Radiomedicina, Santiago, Chile d Institute for Sanitary Research, Hospital General Universitario Gregorio Marañón, Madrid, Spain e Department of Surgery, Catharina Hospital, Eindhoven, the Netherlands f GROW: School of Oncology and Developmental Biology, University of Maastricht, Maastricht, the Netherlands g Department of Radiation Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain h Department of Radiation Oncology, Institut Curie, Paris, France i Paris Sciences & Lettres - PSL University, Paris, France j Department of General Surgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain k Departments of Medical Physics and Radiotherapy, Catharina Hospital, Eindhoven, the Netherlands b

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Article history: Received 10 June 2020 Accepted 14 June 2020 Available online 17 June 2020 Keywords: Rectal cancer Recurrent disease Oligo-recurrence Intraoperative radiotherapy Rescue surgery Electron beam

a b s t r a c t Multimodal strategies have been implemented for locally recurrent rectal cancer scheduled for complete surgical resection. Irradiation and systemic therapy have been added to improve the oncological outcome, as surgery alone was associated with a poor prognosis. Intraoperative irradiation (IORT) is a component of irradiation intensification. Long-term cancer control and a higher survival rate were consistently reported in patients who had IORT as a component of their multidisciplinary treatment. The experience reported by expert IORT groups is reviewed and recommendations to guide clinical practice are explained in detail. 2020 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Evidence review and update . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pre-treatment investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Patient selection for IORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Pre-treatment imaging clinical staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. External beam radiation therapy (EBRT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Surgical procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Surgical factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. IORT factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IORT Procedure: Post resection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. IORT: treatment methods and techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Radiation target definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Applicator selection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. IOERT irradiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5. Treatment delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

42 42 43 43 43 43 43 43 44 44 44 44 45 45 45

⇑ Corresponding author at: Department of Oncology, Clínica Universidad de Navarra, Madrid, Spain. E-mail address: fcalvom@unav.es (F.A. Calvo).

https://doi.org/10.1016/j.ctro.2020.06.007 2405-6308/ 2020 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

F.A. Calvo et al. / Clinical and Translational Radiation Oncology 24 (2020) 41–48

5.6. Applicator removal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7. Recording and reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Recommendations on patient care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Care during the course of IORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Post-treatment patient care and follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. QA recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. Treatment tolerance and adverse effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions and future directions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The topography of loco-regional recurrences of rectal cancer is heterogeneous after surgical resection (with or without radiotherapy), with a dominant pattern of relapse within the postero-lateral hemipelvis [1,2]. After TME surgery alone, subsites of relapse in the pelvic area are presacral (32%), lateral (18%), anterior (18%), anastomosis (24%) and perineum (5%) [3]. After adjuvant or neoadjuvant chemoradiation, local recurrences can be classified as 65% in-field, 16% marginal and 19% out-field radiation therapy recurrences. The total rate of presacral in-field recurrences reported is 41%, and the low pelvic region was dominant for both preoperative (60%) and postoperative (43%) irradiation [4,5]. Haddock has recently reviewed and summarized the results of IOERT investigations for treatment of locally recurrent colorectal cancer in the megavoltage era [6]. Although improvements in surgical technique (total mesorectal excision) and neoadjuvant therapy have significantly reduced the incidence of pelvic recurrence of rectal cancer, management of local recurrence remains problematic. Failure to control pelvic recurrence leads to pain, bleeding, and urinary and rectal obstruction, and can be the cause of death even in the absence of distant metastatic disease. In general, control of locally recurrent cancer requires multimodality therapy, with the only possible exception of early central anastomotic recurrences, which are limited to the bowel wall and can be cured with resection alone [7]. A particularly challenging group of patients with locally recurrent rectal cancer includes those who have received a course of pelvic irradiation for their primary tumour or other pelvic malignancy, such as prostate or cervical cancer [8]. Reirradiation is possible with some limitations regarding dose and volume. In general,

45 45 46 46 46 46 46 47 47 47

reirradiation targets are limited to the gross tumour volume with exclusion of the entire small bowel. Previously irradiated patients are at a higher risk of local relapse (37% vs 22% at 3 years) due to proven biological adversity (radioresistance) and surgical limitations after previous resection [9]. Nevertheless, studies have shown an overall improved oncological outcome in reirradiated patients [10,11]. These results indicate the feasibility of reirradiation containing an IORT component with electron beam energy technology (IOERT).

2. Evidence review and update A retrospective review of the literature from 1991 to 2017 [9– 42] has identified 29 publications (27 journal articles and 2 book chapters) including a total of 2,358 patients with recurrent colorectal cancer treated with intraoperative radiation therapy. The reporting institutions are considered expert centres with regard to multimodality treatment for locally recurrent rectal cancer. Table 1 [9,11–24] contains data from selected publications of studies that included more than 30 patients and provided long-term follow-up information. The final number of analysed patients treated between 1978 and 2010 was 1,947. The IORT techniques used were electron beam intraoperative irradiation (1,700, 87%), singledose high-dose rate brachytherapy (129, 7%), and orthovoltage 250 kV (41, 2%) or 50 kV (32, 2%). A selective analysis focused on the relevance of post-resection disease status at the time of IORT and its impact on cancer outcome is shown in Table 2 [9,11,14– 18,21,22,24], which includes a selection of publications containing specific data regarding R0, R1 and R2 status (data modified from reference 6).

Table 1 Clinical results in locally recurrent rectal cancer: 3 decades review. AUTHOR YEAR (ref.)

# PATIENTS

PERIOD

Suzuki et al. [12] 1995 Bussieres et al. [13] 1996 Eble et al. [14] 1998 Aletkiar et al. [15] 2000 Lyndel et al. [16] 2001 Wiig et al. [17] 2002 Dresen et al. [18] 2008 Haddock et al. [9] 2011 Daly et al. [19] 2012 Guo et al. [20] 2012 Roeder et al. [21] 2012 Calvo et al. [22] 2013 Alberda et al. [23] 2014 Hyngtorm et al. [24] 2014 Holman et al. [11] 2017

42 73 31 74 49 59 147 607 41 32 97 60 59 70 565

1981–1988 less than 1995 1991–1995 1992–1998 1978–1997 1990–1999 1994–2006 1981–2008 1990–2009 2000–2009 1991–2006 1995–2011 1996–2012 2001–2010 1981–2010

RADIOTHERAPY IORT Gy

EBRT Gy(delivered)

10–30 10–25 12–20 10–18 15–20 15–20 10–17.5 7.5–30 7.5–20 5 (@1cm) 10–20 10–20 10 10–15 10–20

45 (94%) 39 (49%) 41.4 (45%) 50.4 (39%) 19.8–50 (100%) 40–56 (100%) 30–50.4 (84%) 36–50 (96%) 30–54 (52%) 50.4 (82%) 41.4 (52%) 45–50 (47%) 27–52 (100%) 39–50.4 (82%) 36–50 (90%)

R1/2

IORT type

80% 57% 58% 28% 31% 65% 43% 63% 85% 45% 47% 37% 68% 46% 56%

electrons electrons electrons IOHDRB electrons electrons electrons electrons 250 Kv Kv electrons electrons IOHDRB IOHDRB electrons

62% 31% 71% 39% 35% 55% 54% 72% 51% 68% 54% 44% 37% 56% 55%

40% 20% 58% 23% 27% 28% 31% 30% 32% 20% 30% 43% 33% 56% 33%

IORT: IntraOperative Radiation Therapy, EBRT: External Beam Radiation Therapy, Gray: Gy, LC: Local Control, OS: Overall Survival, R1: microscopic positive resection margins, R2: gross residual tumor.

F.A. Calvo et al. / Clinical and Translational Radiation Oncology 24 (2020) 41–48 Table 2 Outcome results by resection status. RESECTION STATUS (ref.)

PERIOD

#PTS

EBRT (Gy)

IORT (Gy)

3-5y LC (mean value)

3-5y OS (mean value)

R0 [8,11,14–18,21,22] R1 [8,11,14–18,21,22] R2 [8,11,14,16,18,21]

1978–2010 1981–2010 1978–2010

793 599 362

41,4 – 50,4 41,4 – 50,4 41,4 – 50,4

10–20 10–20 10–20

43%–82% (72%) 19%–67% (41%) 18%–75% (37%)

37%–80% (56%) (11%–44%) (37%) 13%–33% (22%)

#PTS: number of patients, IORT: IntraOperative Radiation Therapy, EBRT: External Beam Radiation Therapy, Gray: Gy, LC: Local Control, OS: Overall Survival, R0: free margins, R1: microscopic positive resection margins, R2: gross residual tumor.

Table 3 Patient selection for IORT: disease, treatment sequence and radiation dose recommendations. DISEASE STATUS Clinical setting Indications

locally recurrent rectal cancer Potentially Resectable, debulking surgery, oligometastatic Postero-lateral pelvic space

Dominant sites of involvement TREATMENT Preoperative chemo/RT followed by resection + IOERT boost RADIOTHERAPY DOSE IORT boost 12.5–15 Gy for negative resection margins (R0) 15–20 Gy for microscopic positive resection margins (R1) 15 to 20 Gy for macroscopic or gross residual tumor (R2) External Beam Radiation Therapy 45–50 Gy (in 25–28 fractions) (EBRT) full course External Beam Radiation Therapy 25–35 Gy (12–15 fractions) re-irradiation

3. Pre-treatment investigations 3.1. Patient selection for IORT Patients diagnosed with locally recurrent rectal cancer should be discussed and re-evaluated by a specialized tumour board. Before any multimodality treatment decision can be made, a workup regarding imaging should be available. Table 3 shows patient selection for IORT Studies required for candidate selection include the following:

Patient factors: Data primary tumour treatment Comorbidity/ASA Physical exam Conventional blood test Tumour factors: Biopsy if possible CEA MRI (PET)CT abdomen (liver) and thorax

Potential supportive actions to be considered preoperatively include the following: - Deviating colostomy - Self-expanding stent (anastomotic relapse) - Pain management Additional studies in patients at high risk for synchronic systemic disease or peritoneal carcinomatosis may include the following: - Diagnostic Laparoscopy

Neoadjuvant strategies will be recommended in a significant number of locally recurrent patients and these strategies will be followed by a waiting period before surgery. Due to this prolonged treatment time, patients should be restaged before the definitive surgical procedure. 3.2. Pre-treatment imaging clinical staging Clinical assessment of patients is performed by means of abdomino-pelvic computed tomography (CT) and magnetic resonance imaging (MRI), which demonstrate the extension of the recurrent mass and the topographical relationship to critical organs or structures. In addition, PET-CT may help to exclude distant metastatic disease. 3.3. External beam radiation therapy (EBRT) The use of EBRT combined with IORT as a part of the intensive treatment for locally recurrent rectal cancer has been reported over the past four decades [43]. Fluoropyrimidine -sensitized full-dose preoperative EBRT using multiple-field techniques, including 3D conformal or rotational intensity-modulated irradiation (3D CRT, IMRT, VMAT), have been used based on institutional protocols and available technology. Primary radiation volumes usually include the dorsal pelvis (i.e. at least mesorectum, presacral area, internal iliac lymphnodes, and depending on the location of the tumour recurrence the obturator region and/ or anal region. Reirradiation volumes usualy include the tumour or gross target volume (GTV)) with a margin of 1 cm to the clinical target volume (CTV) and another 1 cm margin to the planning target volume (PTV). The CTV should not be adjusted to anatomical structures since the normal anatomy is distorted by previous surgery and recurrent tumours often grow into the pelvic wall. Pelvic volumes should reach a total cumulative dose of 45 Gy to 50.4–54 Gy [44]. IMRT is useful in decreasing small-bowel volumes when reirradiation strategies are used. The total dose of reirradiation should be individualized after evaluation of possible dose-limiting factors. In most reports, 30 Gy in conventional fractionated schemes was considered acceptable [9–11]. Image-guided radiotherapy approaches may be used to reduce PTV margins if possible. 4. Surgical procedures 4.1. Surgical factors After a full course of preoperative chemoradiation or reirradiation, surgical exploration is undertaken following a waiting period of 6–12 weeks, which allows for tumour downsizing. The delay also permits the resolution of treatment-induced acute side effects. Accurate preoperative staging is important because IOERT primarily benefits those patients who can undergo a grossly complete tumour resection. Ideal patients are those with a high Karnofsky score who are willing to undergo major surgery that may include stoma creation and possible pelvic exenteration. Resectable oligometastatic disease is not a contraindication for treatment of local

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recurrence. Invasion of pelvic nerves or the sciatic notch (i.e. no sciatica or sacral/buttock pain) or invasion of the S1 and S2 bodies or foramina are considered a contraindication for resection by most pelvic surgeons. If a deviating colostomy is necessary, preoperative evaluation by a stoma therapist should be considered. Surgery usually requires a midline incision, which allows extension as necessary and permits the construction of a single-sided or even double stoma after bladder resection. Adhesiolysis and abdomen evaluation for liver and peritoneal metastases is mandatory. If metastases are found that are not resectable with curative intent (i.e. extended peritoneal carcinomatosis), resection can only be palliative and may need to be reconsidered, and intraoperative irradiation is not performed. If no metastases are evident or are limited and can be resected for cure, the patient undergoes abdominoperineal resection, low anterior resection or pelvic exenteration, depending upon the extent and location of the tumour. En bloc wide resection is the best option: grossly complete resection of the tumour is desirable. Haemostasis after resection is important because of fluid accumulation in the tumour bed, which may decrease the IOERT dose at a certain depth (bolus effect). If anastomosis can be performed, it will be done after the intraoperative radiation dose delivery. In order to minimize the potential for complications, tension-free anastomosis is pivotal and, in most cases, it is preferable to mobilize the entire left colon and use the unirradiated bowel (descending colon) for the proximal end of the anastomosis. 4.2. IORT factors As well as the pre-treatment evaluation, the final decision to treat with IORT is also based on perioperative findings such as the pathologic margin assessment. It is important that both the radiation oncologist and surgeon make a collaborative judgment in order to define the area at highest risk for subsequent local relapse and to determine the optimal position of the IORT target. Margins of resection are determined by means of frozen-section analysis of the surgical specimen and sometimes the tumour bed. 5. IORT Procedure: Post resection 5.1. IORT: treatment methods and techniques IORT for locally recurrent rectal cancer has predominantly been delivered with megavoltage electrons produced by a medical linear accelerator. There are not sufficient scientific data to support the use of brachytherapy or orthovoltage delivery systems for IORT

and for the remaining of this report the term IOERT will be used referring to megavolt electron-based IORT. The electron beam energy and dose of IORT are determined by the resection status and geometry of the treated target. For most applicators, dose distribution does not require the use of bolus. Accumulation of intra surgical fluid could influence radiation penetration in an unpredictable way and should be avoided. Shielding lead inside the tumour bed radiation target is not recommended due to the dosimetric uncertainties that this involves. The best possible protection is mechanical retraction to displace dose-sensitive structures outside the IORT field. Surgical retractors for the displacement of remaining uninvolved movable structures such as the rectal stump, bladder, prostate, uterus, vagina, small bowel, descending colon and ureters are most helpful for exposing the radiation target properly (presacral area or posterior and lateral pelvic space) and expediting positioning of the IORT applicator. Displacement of normal tissue should be documented with photos, drawings or written reports. 5.2. Radiation target definition Persisting tumour adherence after preoperative chemoradiotherapy, inadequate radial margins (close <1 mm) and high risk of relapse, including enlarged nodes or adherence to surrounding structures, are considered indications for an IOERT boost. Patients with potentially positive margins are candidates for IOERT. The tumour bed can be marked to facilitate positioning of the IOERT applicator and the IOERT beam collimation. An IOERT applicator is selected according to the location and size of the area to be irradiated. The internal diameters of circular applicators typically range from 4 to 10 cm in diameter. Applicator size is selected to allow full coverage of the residual disease in a high-risk area, which is generally located in the presacral area or pelvic sidewall. Usually, the largest applicator that will fit into the area is preferred. The applicator shape is chosen so that the geometry fits the specific situation. The applicator must abut the site being treated. Most applicators have bevelled ends up to 45 , enabling good position of the applicator to sloping surfaces in the pelvis and maximize dose homogeneity. Sensitive normal tissue should not be included in the beam and fluid buildup in the treatment area should also be avoided. The applicator accurately collimates the electron beam to the target area and also serves to retract sensitive normal tissue, especially small bowel or ureters (Fig. 1). Visceral retraction and packing are also usually necessary. A distal rectal stump, which will be used to create an anastomosis, should be excluded from the IOERT field either by retraction outside the applicator or with

Fig. 1. IORT electron procedure view of a recurrent rectal cancer with associated uretero-hidronefrosis: A. Pelvic cavity exposed and right ureteral dilatation. B. Simulated IOERT applicator positioning to treat recurrent tumor bed. The involved ureter is included in the treatment volume. C. Post-resection recurrent tumor bed area to be treated by IOERT. The right ureter has been sectioned and mobilized out of the electron beam collimator. After irradiation an uretero-ureteral anastomosis to the left ureter will be performed for urinary tract reconstruction.

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the use of lead to shield sensitive normal tissue. During treatment, suction catheters should be positioned to minimize fluid buildup within the applicator. Most IOERT treatments in rectal cancer are applied via a transabdominal approach, as the area of concern is usually the posterior presacrum or posterolateral pelvic sidewall. A perineal port is occasionally used after abdominoperineal resection to treat the coccyx or distal presacrum, distal pelvic sidewall or portions of the prostate, and base of the bladder when exenteration is not performed. The goal of IOERT delivery is to avoid re-recurrences in patients who have close or microscopically positive margins after surgical resections. However, clear margins should always be the primary goal of resection. In these cases, doses in the range of 10 to 12.5 Gy are applied. Unintended macroscopically involved margins may be treated with higher doses: 15.0 Gy or even 20 Gy as a single boost. There is little evidence that IOERT has value in unresected cases and should be performed only in the framework of a trial. A library of predefined isodose-curve distributions for a range of IORT applicator diameter, bevelled-end shapes and electron beam energies should be available for intraoperative consultation. An electron energy should be chosen to adequately encompass the target tissues at risk within the 90% isodose curves. The prescribed dose is specified at the 90% isodose. The whole process can be summarized as follows: 1. Definition of radiation target volume: tumour bed assessment; surgical margin status (inspection of the surgical field and the posterior aspect of the surgical specimen). 2. Normal uninvolved tissue to be excluded (mobilized out) from the IOERT radiation volume: rectal remnant (if present); uninvolved intrapelvic organs (bladder, prostate, uterus, vagina, ovaries); distal colon; small bowel; ureters. 3. Normal tissue at risk to be included in the radiation target volume: postero-lateral pelvic area; vascular and lymphatic structures (iliac regions). 5.3. Applicator selection IORT applicator adaptation to the postoperative bed at risk: 1. Size selection (diameter): able to encompass the presacral region and/or lateral pelvic walls at risk (the largest able to fit in the pelvic cavity). The availability of diameters of between 4 and 10 cm is a safe range for applicator sizes. 2. Bevelled end selection: bevelled ends of between 30 and 45 adapted to the anatomical configuration of the presacral region in the pelvic cavity are recommended for small pelvis sites to appropriately encompass the surgical bed with residual disease or at risk of recurrence. The same criteria apply in the case of dominant lateral pelvic wall involvement.

field should be avoided. When bone tissue is part of the target volume, a higher electron energy could be selected. If the surface dose of the chosen applicator is less than 90%, bolus with an appropriate thickness should be applied. Dose selection (single fraction boost component): doses of 10 to 12.5 Gy are recommended for resection specimens at low risk after a favourable dissection procedure. In specimens with close or suspected/confirmed cancer-involved margins, the recommended dose ranges from 12.5 to 15 Gy. After laborious vascular and/or soft-tissue dissection with suspected residual cancer, a dose of 12.5 to 15 Gy should be considered. A medical physicist should be involved pre- or intra-operatively in the choice of bolus, or corrections for special situations (e.g. residual air gap, additional screening, bone tissue density correction). In vivo dosimetry is strongly recommended as a quality-assurance procedure. 2. In the case of multiple IOERT target volumes, overlapping of the corresponding irradiation volumes should be avoided. Enlarging the irradiated volume by using abutting fields should be avoided, as significant hot & cold spots are likely. 5.5. Treatment delivery Before dose delivery, the appropriate physical and technical parameters (electron energy, tube size, length and bevel angle, monitor units, bolus choice, use of additional shielding inside the irradiated area) are checked by a medical physicist as well as by the physician (radiation oncologist) in a four-eyes principle. Usually, a medical physicist or a radiation therapist (RTT) aligns the gantry to the applicator for soft-docking system and enters the data in the control console. During irradiation (approximately 1– 2 min, depending on dose and dose rate), nobody is allowed to stay in the operation room except the patient for radiation protection purposes. Patients should be carefully monitored by camera during the irradiation process and vital parameters should be monitored and be visible from outside the operating room. In event of an emergency, irradiation should be stopped immediately and nurses, anaesthesiologists and surgeons should be prepared to enter the operating room at any time immediately after cessation of irradiation. 5.6. Applicator removal After treatment has been completed, special attention should be paid to applicator removal in order to avoid any trauma to surrounding tissues and possible bleeding. In the event of bleeding during the irradiation time, it is advisable to aspirate the blood first in order to clearly visualize the end of the collimator in contact with the patient’s tissue and allow for a safe manoeuvre. Removal of the applicator may be performed by the surgeon or by the radiation oncologist.

5.4. IOERT irradiation 5.7. Recording and reporting To guarantee the sterile field throughout the procedure, before irradiation, sterile drapes should cover the surgical bed and the part of the collimator inside and near the surgical bed. An aspiration drain may be useful to prevent fluid accumulation and avoid a bolus effect. IOERT irradiation consists of: 1. Electron energy selection: 90% isodose should encompass in depth the tissue content involved or at risk with a safety dosimetric margin (0.1–0.5 cm). Fluid stability is key for appropriate energy selection. This depth can be estimated by real-time intraoperative measurements, together with data obtained from the preoperative CT scan. Fluid accumulation in the IORT

Clinical and dosimetry forms should be completed with all relevant patient, tumour and treatment parameters. Information should include demographics, performance status, symptoms and serum tests, including CEA, comorbidities and Charlson comorbidity index. Tumour-related data should include imaging studies, biopsy report, clinical and pathological stage, grading and possible biomolecular characteristics. Treatment data should include neoadjuvant treatments (including reirradiation), the surgical report (size, location and frozen sections of margins) and main characteristics of the IORT procedure, such as collimator diameter, bevel angle, bolus, beam energy, dose prescription and duration of the procedure. In vivo dosimetry is strongly recommended as a

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quality-assurance procedure. Radiation target contents should be described: organs and structures included in the IOERT radiation beam. Radiation protection of normal uninvolved tissue should be described: the manoeuvres for temporary mobilization or intra-field customized protection (in particular rectal stump, small bowel, bladder and ureters) (Fig. 1). Documentation of the radiation target, adjacent - if necessary mobilized - normal tissue and used shielding should ideally include drawings or photos. No fully reliable treatment planning systems currently exist for intraoperative irradiation; however, the availability of preoperative images may help to identify at-risk anatomical structures involved and to guide the positioning of the collimator. All these imaging data should be included in the patient’s final documentation, if available. Photographs of final applicator positioning and surface anatomy in the IOERT target is recommended. Intraoperative ultrasound may also be helpful in some cases for verifying residual tumour thickness in depth and the location of critical structures such as ureters and major vessels. The final documentation of the IORT procedure should also include the surgical notes and the anaesthesiology report. Table 4 shows parameters for the IORT electron beam procedure in locally recurrent rectal cancer.

anaesthesiologists and surgeons should be prepared to enter the operating room at any time immediately after cessation of irradiation. 6.2. Post-treatment patient care and follow-up Patients treated with IORT for locally recurrent rectal cancer require thorough care. All vital and clinical parameters should be monitored in the days following the procedure, and special attention should be paid to blood tests, including renal and liver functions, bowel movements and onset of new symptoms and signs. After the IORT procedure combined with surgical resection, the patient may receive further treatment, including postoperative adjuvant systemic treatment. The follow-up schedule starts after treatment has been completed and the patient is discharged from hospital. During imaging studies, special attention should be paid to any tissue potentially included in the IOERT volume, such as the sacrum, rectal remnant and ureters. Systemic treatment has recently been reported as a part of neoadjuvant therapy to further improve oncological outcome [46]. 6.3. QA recommendations Specific IORT QA actions include:

6. Recommendations on patient care 6.1. Care during the course of IORT The sterile field should be guaranteed throughout the IORT procedure. Before irradiation, sterile drapes should cover the surgical bed and the part of the collimator inside and near the surgical bed. Patients should be carefully monitored by camera during the irradiation process and vital parameters should be monitored and be visible from outside the operating room. In event of an emergency, irradiation should be stopped immediately and nurses, Table 4 Reporting parameters for IORT electron beam procedures in recurrent rectal cancer. IORT PARAMETERS Target volumen description

IORT factors

Integrated pre-IORT treatment factors

Tumour residue (R0, R1, R2)Normal tissues exposedNormal tissues protected/mobilizedSpecial conditions:Vascular manipulationOthers (extended resections; pelvectomies) - Applicator size /diameter & Bevelled end (degrees) - Electron energy & Isodose prescription - Total dose - Number of fields & Report every parameter for every field & Overlapping (yes / no) & Field –within-a-field (description) - Protections - Fluid stability - Time of beam on - Gantry angulation - In vivo dosimetry (system/site measured) - Surgery: type of resection (R0, R1, R2) - Preoperative & Re-irradiation: limited course & Full course of chemoradiation (CRT) & Induction chemotherapy + CRT (full or limited course) - Postoperative & Re-irradiation: limited course & Full course of CRT & CRT + adjuvant chemotherapy & Induction chemotherapy + CRT + adjuvant chemotherapy

- MDT evaluation and scheduling - Pre-treatment beam calibration: dose per monitor unit for each radiation energy - Equipment and applicators performance - Safety interlocks check-up - QA report completion, inter-specialty signature and registration - Clinical report of technical parameters in the electronic chart 6.4. Treatment tolerance and adverse effects Patients with locally recurrent rectal cancer often experience significant tumour-related and treatment-related toxicity. Most treatment-induced effects are multifactorial and it is often difficult to attribute toxicity to a single modality. In a systematic review of 29 published studies including 3,003 patients with locally advanced primary or recurrent colorectal cancer, IOERT was associated with significant improvement in local control and survival without an increase in total, urologic or anastomotic complications [43]. Increased risk of wound complications following IOERT was also noticed. Wound infections and pelvic abscess are the most commonly reported complications, occurring in 25% or more of IOERT patients in several series [28,40,46]. Expert reports have registered a total incidence of severe, lifethreatening or fatal deep infection or abscesses in 13% of cases, with 7% potentially attributable to IOERT [21,45]. With the addition of IOERT to EBRT, the dose-limiting normal tissue is typically peripheral nerve and neuropathy is the most commonly reported toxicity attributed to IOERT in the pelvis. IOERT-related neuropathy most commonly manifests as pain without weakness or sensory loss. When it occurs, the pain is often chronic and may be severe, but is often manageable with gabapentin or pregabalin. Both the incidence and severity of IOERT-related neuropathy appear to be related to the IOERT dose. Even in previously irradiated patients, the incidence of neuropathy is related to the IOERT dose and not to the total cumulative dose including EBRT. In locally recurrent disease, IOERT doses of 12.5 Gy or less were associated with a 5% incidence of grade 2–3 neuropathy compared to 14% for IORT doses of 15 Gy or higher [24]. IOERT dose-sensitive structures in the pelvis anatomy are the peripheral nerves, ureters, bladder, small intestine, rectal stump, ovaries, urethra and vagina. The uterus and prostate are considered

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relatively resistant to escalated doses, including IOERT boost. Neuropathy is dose-dependent: 3% for 12 Gy boost and 23% for 15 Gy boost. Ureter dysfunction is reported in 56% of ureters included in the IOERT field (any dose) and in less than 15% of ureters excluded [16]. Late toxicities described included small-bowel obstruction in 14% of patients, wound infection/breakdown in 9%, fistula with abscess in 8%, bladder dysfunction in 7%, sexual dysfunction in 6%, enteritis/proctitis in 3%, and abdominopelvic abscess in 3% [21].

7. Conclusions and future directions Treatment of locally recurrent rectal cancer that includes reirradiation strategies has evolved over the past 30 years. The current international consensus recognizes the value of preoperative strategies with chemoradiation and the potential of IOERT boost in recurrent patients (NCCN guidelines). IOERT is a feasible, tolerable and efficient radiation-boosting technique that can be explored in tailored treatment for patients with locally recurrent rectal cancer [47]. Recommendations available to guide tailoring IORT in recurrent disease in terms of local tumour control promotion include implementing strategies with short-course preoperative pelvic irradiation, hypofractionated radiation or reirradiation [48], including an IORT component. Invivo-dosimetry and intra-operative imaging could improve the accuracy, reproducibility and documentation and provide data for evaluation and tailoring of IOERT. This requires further defining correlations between biological equivalent dose (BED) calculations, topographic patterns of recurrence, and prognostic features for local effects. This information is not available at present. It will open the clinical scope for using single-dose IORT alone, with field-within-a-field dosimetric modulations, and in combination with systemic therapy in the oligometastatic model. The pioneering work of expert institutions has been validated internationally and with long-term follow-up analysis [6,11,49]. Acknowledgements Intraoperative radiotherapy (IORT) is a multidisciplinary oncological activity requiring a demanding the integration of individual technical quality and team work coordination. The authors of this guideline acknowledge the remarkable contribution of all the health professionals involved in the care of patient candidates to IORT procedures. Authors are grateful to reviewers Robert Krempien, Philipp Scherer, Alexandra Stewart, Dirk Verellen for their useful and constructive comments and to Eralda Azizaj (ESTRO staff member responsible for the work of ACROP) for facilitating the review and journal submission process. References [1] Sole CV, Calvo FA, Serrano J. Post-chemoradiation intraoperative electronbeam radiation therapy boost in resected locally advanced rectal cancer: Long term results focused on topographic pattern of locoregional relapse. Radiother Oncol 2014;112:52–8. [2] Ogura A, Konishi T, Cunningham C, Garcia-Aguilar J, Iversen H, Toda S, et al. Lateral node study consortium. Neoadjuvant (Chemo)radiotherapy with total mesorectal excision only is not sufficient to prevent lateral local recurrence in enlarged nodes: results of the multicenter lateral node study of patients with low ct3/4 rectal cancer. J Clin Oncol 2019;37:33–43. https://doi.org/10.1200/ JCO.18.00032. [3] Kusters M, Marijnen CA, Van de Velde CJ, et al. Patterns of local recurrence in rectal cancer; a study of the Dutch TME trial. Eur J Surg Oncol 2010;36:470–6. [4] Kusters M, van de Velde CJ, Beets-Tan RG, et al. Patterns of local recurrence in rectal cancer: a single center experience. Ann Surg Oncol 2009;6:289–96.

[5] Yu TK, Bhosale PR, Crane CH, Yyier RB, et al. Patterns of locoregional recurrence after surgery and radiotherapy or chemoradiation for rectal cancer. Int J Radiat Oncol Biol Phys 2008;71:1175–80. [6] Haddock MJ. Intraoperative radiation therapy for colon and rectal cancers: a clinical review. Radiat Oncol 2017;12:11–9. [7] Salo JC, Paty PB, Guillem J. Surgical salvage of recurrent rectal carcinoma after curative resection: a 10-year experience. Ann Surg Oncol 1999;6:171–7. [8] Valentini V, Morganti AG, Gambacorta MA. preoperative hyperfractionated chemoradiation for locally recurrent rectal cancer in patients previously irradiated to the pelvis: a multicentric phase II study. Int J Radiat Oncol Biol Phys 2006;64:1129–39. [9] Haddock MG, Miller RC, Nelson H. Combined modality therapy including intraoperative electron irradiation for locally recurrent colorectal cancer. Int J Radiat Oncol Biol Phys 2011;79:143–50. [10] Bosman SJ, Holman FA, Nieuwenhuijzen GA, Martijn H, Creemers GJ, Rutten HJ. Feasibility of reirradiation in the treatment of locally recurrent rectal cancer. Br J Surg 2014;101:1280–9. https://doi.org/10.1002/bjs.9569. [11] Holman FA, Bosman SJ, Haddock MG, Gunderson LL, Kusters M, Nieuwenhuijzen GA, et al. Results of a pooled analysis of IOERT containing multimodality treatment for locally recurrent rectal cancer: results of 565 patients of two major treatment centres. Eur J Surg Oncol 2017;43:107–17. [12] Suzuki K, Gunderson LL, Devine RM, et al. Intraoperative irradiation after palliative surgery for locally recurrent rectal cancer. Cancer 1995;75:939–52. [13] Bussieres E, Gilly FN, Rouanet P, et al. Recurrences of rectal cancers: results of a multimodal approach with intraoperative radiation therapy. Int J Radiat Oncol Biol Phys 1996;34:49–56. [14] Eble MJ, Lehnert T, Treiber M, Latz D, Herfarth C, Mannenmacher M. Moderate dose intraoperative and external beam radiotherapy for locally recurrent rectal cancer. Radiother Oncol 1998;49:169–74. [15] Alektiar KM, Zelefsky MJ, Paty PB. High-dose-rate intraoperative brachytherapy for recurrent colorectal cancer. Int J Radiat Oncol Biol Phys 2000;48:219–26. [16] Lindel K, Willett CG, Shellito PC, Ott MJ, Clark J, Grossbard M, et al. Intraoperative radiation therapy for locally advanced recurrent rectal or rectosigmoid cancer. Radiother Oncol 2001;58:83–7. [17] Wiig JN, Tveit KM, Poulsen JP. Preoperative irradiation and surgery for recurrent rectal cancer. Will intraoperative radiotherapy (IORT) be of additional benefit? A prospective study. Radiother Oncol 2002;62:207–13. [18] Dresen RC, Gosens MJ, Martijn H, Nieuwenhuijzen GA, Creemers GJ, DanielsGooszen AW, et al. Radical resection after IORT-containing multimodality treatment is the most important determinant for outcome in patients treated for locally recurrent rectal cancer. Ann Surg Oncol 2008;15:1937–47. [19] Daly ME, Kapp DS, Maxim PG, Welton ML, Tran PT, Koong AC, et al. Orthovoltage intraoperative radiotherapy for locally advanced and recurrent colorectal cancer. Dis Colon Rectum 2012;55:695–702. [20] Guo S, Reddy CA, Kolar M, Woody N, Mahadevan A, Deibel FC, et al. Intraoperative radiation therapy with the photon radiosurgery system in locally advanced and recurrent rectal cancer: retrospective review of the Cleveland clinic experience. Radiat Oncol 2012;7:110. [21] Roeder F, Goetz JM, Habl G, Bischof M, Krempien R, Buechler MW, et al. Intraoperative Electron Radiation Therapy (IOERT) in the management of locally recurrent rectal cancer. BMC Cancer 2012;12:592. [22] Calvo FA, Sole CV, Alvarez de Sierra P, Gómez-Espí M, Blanco J, Lozano MA, et al. Prognostic impact of external beam radiation therapy in patients treated with and without extended surgery and intraoperative electrons for locally recurrent rectal cancer: 16-year experience in a single institution. Int J Radiat Oncol Biol Phys 2013;86:892–900. [23] Alberda WJ, Verhoef C, Nuyttens JJ, Rothbarth J, van Meerten E, de Wilt JH, et al. Outcome in patients with resectable locally recurrent rectal cancer after total mesorectal excision with and without previous neoadjuvant radiotherapy for the primary rectal tumor. Ann Surg Oncol 2014;21:520–6. [24] Hyngstrom JR, Tzeng CW, Beddar S, Das P, Krishnan S, Delclos ME, et al. Intraoperative radiation therapy for locally advanced primary and recurrent colorectal cancer: ten-year institutional experience. J Surg Oncol 2014;109:652–8. [25] Abuchaibe O, Calvo FA, Azinovic I, Aristu J, Pardo F, Alvarez-Cienfuegos J. Intraoperative radiotherapy in locally advanced recurrent colorectal cancer. Int J Radiat Oncol Biol Phys 1993;26:859–67. [26] Hashiguchi Y, Sekine T, Kato S. Indicators for surgical resection and intraoperative radiation therapy for pelvic recurrence of colorectal cancer. Dis Colon Rectum 2003;46:31–9. [27] Nuyttens JJ, Kolkman-Deurloo IK, Vermaas M, Ferenschild FT, Graveland WJ, De Wilt JH, et al. High-dose-rate intraoperative radiotherapy for close or positive margins in patients with locally advanced or recurrent rectal cancer. Int J Radiat Oncol Biol Phys 2004;58:106–12. [28] Guiney MJ, Smith JG, Worotniuk V, Ngan S, Blakey D. Radiotherapy treatment for isolated loco-regional recurrence of rectosigmoid cancer following definitive surgery: Peter MacCullum Cancer Institute Experience, 1981– 1990. Int J Radiat Oncol Biol Phys 1997;38:1019–25. [29] Martinez-Monge R, Nag S, Martin EW. Three different intraoperative radiation modalities (electron beam, high-dose-rate brachytherapy, and iodine-125 brachytherapy) in the adjuvant treatment of patients with recurrent colorectal adenocarcinoma. Cancer 1999;86:236–47. [30] Kramer T, Share R, Kiel K, Rosman D. Intraoperative radiation therapy of colorectal cancer. In: Abe M, editors. Intraoperative radiation therapy. New York: Pergamon Press; 308. p. 10–1991.

F.A. Calvo et al. / Clinical and Translational Radiation Oncology 24 (2020) 41–48

[31] Lanciano R, Calkins A, Wolkov H, et al. A phase I, II study of intraoperative radiotherapy in advanced unresectable or recurrent carcinoma of the rectum: a RTOG study. In: Abe M, editors. Intraoperative radiation therapy. New York: Pergamon Press; 311. p. 3–1991. [32] Lybeert MLM, Martijn H, DeNeve W, Crommelin MA, Ribot JG. Radiotherapy for locoregional relapses of rectal carcinoma after initial radical surgery: definite but limited influence of relapse free survival and survival. Int J Radiat Oncol Biol Phys 1992;24:241–6. [33] Kishan AU, Voog JC, Wiseman J, Cook RR, Ancukiewicz M, Lee P, et al. Standard fractionation external beam radiotherapy with and without intraoperative radiotherapy for locally recurrent rectal cancer: the role of local therapy in patients with a high competing risk of death from distant disease. Br J Radiol 2017;90(1076):20170134. [34] Susko M, Lee J, Salama J, Thomas S, Uronis H, Hsu D, et al. The use of reirradiation in locally recurrent. Non-metastatic rectal cancer. Ann Surg Oncol 2016;23:3609–15. [35] Brady JT, Crawshaw BP, Murrell B, Dosokey EM, Jabir MA, Steele SR, et al. Influence of intraoperative radiation therapy on locally advanced and recurrent colorectal tumors: a 16-year experience. Am J Surg 2017;213:586–9. [36] Klink CD, Binnebösel M, Holy R, Neumann UP, Junge K. Influence of intraoperative radiotherapy (IORT) on perioperative outcome after surgical resection of rectal cancer. World J Surg 2014;38:992–6. [37] Tan J, Heriot AG, Mackay J, Van Dyk S, Bressel MA, Fox CD, et al. Prospective single-arm study of intraoperative radiotherapy for locally advanced or recurrent rectal cancer. J Med Imaging Radiat Oncol 2013;57:617–25. [38] Klaver YL, Lemmens VE, Nienhuijs SW, Nieuwenhuijzen GA, Rutten HJ, de Hingh IH. Intraoperative radiotherapy and cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. Five consecutive case reports of locally advanced rectal cancer with synchronous peritoneal carcinomatosis. Strahlenther Onkol 2013;189:256–60. [39] Turley RS, Czito BG, Haney JC, Tyler DS, Mantyh CR, Migaly J. Intraoperative pelvic brachytherapy for treatment of locally advanced or recurrent colorectal cancer. Tech Coloproctol 2013;17:95–100.

[40] Abdelfatah E, Page A, Sacks J, Pierorazio P, Bivalacqua T, Efron J, et al. Postoperative complications following intraoperative radiotherapy in abdominopelvic malignancy: a single institution analysis of 113 consecutive patients. J Surg Oncol 2017;115:883–90. [41] Pezner RD, Chu DZ, Ellenhorn JD. Intraoperative radiation therapy for patients with recurrent rectal and sigmoid colon cancer in previously irradiated fields. Radiother Oncol 2002;64:47–52. [42] Kolkman-Deurloo IK, Nuyttens JJ, Hanssens PE, Levendag PC. Intraoperative HDR brachytherapy for rectal cancer using a flexible intraoperative template: standard plans versus individual planning. Radiother Oncol 2004;70:75–9. [43] Mirnezami R, Chang GJ, Das P, et al. Intraoperative radiotherapy in colorectal cancer: systematic review and meta-analysis of techniques, long-term outcomes, and complications. Surg Oncol 2013;22:22–35. [44] Minsky BD, Rödel CM, Valentini V. Rectal cancer. In: Gunderson LL, Tepper JE, editors. Clinical radiation onocology. Elsevier; 2016. p. 992–1018. [45] Vermeer TA, Orsini RG, Daams F, Nieuwenhuijzen GA, Rutten HJ. Anastomotic leakage and presacral abscess formation after locally advanced rectal cancer surgery: incidence, risk factors and treatment. Eur J Surg Oncol 2014;40:1502–9. [46] van Zoggel DMGI, Bosman SJ, Kusters M, Nieuwenhuijzen GAP, Cnossen JS, Creemers GJ, et al. Preliminary results of a cohort study of induction chemotherapy-based treatment for locally recurrent rectal cancer. Br J Surg. 2018;105:447–52. [47] Wiig JN, Giercksky KE, Tveit KM. Intraoperative radiotherapy for locally advanced or locally recurrent rectal cancer: Does it work at all?. Acta Oncol 2014;53:865–76. [48] Mohiuddin M, Marks GM, Lingareddy V, Marks J. Curative surgical resection following re-irradiation for recurrent rectal cancer. Int J Radiat Oncol Biol Phys 1997;39:643–9. [49] Rominger CJ, Gelber RD, Gunderson LL. Radiation therapy alone or in combinationwith chemotherapy in the treatment of residual or inoperable carcinoma of the rectum and rectosigmoid or pelvic recurrence following colorectal surgery. Am J Clin Oncol 1985;8:118–27.

Radiotherapy and Oncology 148 (2020) 57–64

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Original Article

ESTRO IORT Task Force/ACROP recommendations for intraoperative radiation therapy in unresected pancreatic cancer Felipe A. Calvo a,b,⇑, Marco Krengli c, Jose M. Asencio d,e, Javier Serrano d,e, Philip Poortmans f, Falk Roeder g, Robert Krempien h, Frank W. Hensley i a Department of Oncology, Clínica Universidad de Navarra; b School of Medicine, Complutense University, Madrid, Spain; c Radiotherapy Unit, Department of Translation Medicine, University of Piemonte Orientale, Novara, Italy; d Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid; e Facultad de Medicina, Univ. Complutense de Madrid, Spain; f Paris Sciences & Lettres – PSL University, Paris, France; g Department of Radiotherapy and Radiation Oncology, Paracelsus Medical University, Landeskrankenhaus, Salzburg, Austria; h Department of Radiotherapy, Helios Hospital Berlin-Buch; and i Department of Radiation Oncology, University Hospital of Heidelberg, Germany

a r t i c l e

i n f o

Article history: Received 30 March 2020 Accepted 30 March 2020 Available online 8 April 2020 Keywords: Pancreatic cancer Locally advanced Unresected disease Intraoperative radiotherapy IORT IOERT

a b s t r a c t Radiation therapy (RT) is a valuable component of multimodal treatment for localized pancreatic cancer. Intraoperative radiation therapy (IORT) is a very precise sub-component of RT that can intensify the irradiation effect for cancer involving an anatomically well-defined volume, generally delivered with electrons (IOERT). Unresectable disease categories benefit from dose-escalated chemoradiation strategies in the context of active systemic therapy and potential radical surgery. Prolonged preoperative treatment may act as a filter for selecting patients with occult resistant metastatic disease. Long-term survivors were observed among unresected patients treated with external beam RT and an IOERT boost (OS 6% at 3 years; 3% >5 years). Improvement of local control through higher RT doses has an impact on the survival of patients with a lower tendency towards disease spread. IOERT is a well-accepted asset in the clinical scenario (maturity and reproducibility of results, albeit of low official level of evidence) and extremely accurate in terms of dose-deposit characteristics and normal tissue sparing. It is a technique that can be integrated with systemic therapy and surgical progress. International guidelines (National Comprehensive Cancer Network or NCCN guidelines) currently recommend the use of IOERT in cases of close surgical margins and residual disease. We report the ESTRO/ACROP recommendations for performing IOERT in unresected pancreatic cancer. 2020 Elsevier B.V. All rights reserved. Radiotherapy and Oncology 148 (2020) 57–64

Pancreatic cancer is the seventh leading cause of cancer death worldwide [1]. Although significant improvements in overall survival rates have been observed in the last three decades, overall outcome remain poor [2]. Multimodality therapy including preoperative and adjuvant systemic treatment with RT components is needed for locally advanced disease that is not or borderline resectable on presentation. Surgery is a curative element of therapy, although few patients present with resectable disease [3,4]. In the last 2 years, systematic reviews and meta-analysis have reported results in locally advanced disease with a tendency towards improved survival (from randomized trial data) with chemoradiation [5], improved survival with consolidation chemoradiation after induction chemotherapy [6] and superiority of the combination of folinic acid, 5-fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX) over other previously reported systemic ⇑ Corresponding author at: Department of Oncology, Clínica Universidad de Navarra, Madrid, Spain. E-mail address: fcalvom@unav.es (F.A. Calvo).

therapy combinations in median overall survival with a median overall survival of 24.2 months across studies (57% of patients receiving RT) [7]. Dose escalation >61 Gy in radical chemoradiation candidates improves survival and loco-regional control [8]. Preoperative therapy with systemic agents and/or RT (18 studies published from 1966 to 2015, 959 patients analysed) showed an objective response in 31.5%; 65.3% underwent resection (57.4% R0) and a median survival of 17.9 months (25.9 months for resected patients) for patients with locally advanced or borderline resectable disease on imaging, [9]. Hypofractionated stereotactic body external-beam radiation therapy (EBRT) systematic review data (19 trials, 1009 patients) describe acceptable tolerability (<10% severe adverse effects) and overall survival ranging from 5.7 to 47 months (median 17), and a 1-year loco-regional control rate of 72.5% [10]. Recently, early promising results from investigations using emerging techniques such as particle therapy (protons and heavy ions), SBRT and online MRI-guided RT to improve the ballistics

IORT in unresected pancreatic cancer

and accuracy of radiation delivery were presented at meetings [11]. Clinical results of intraoperative radiation therapy (IORT) using high-energy electron beams (IOERT), the term that we will use from here on, have been consistently reported in the last four decades [12,13]. IOERT used as a boost strategy (integrated for a doseescalation multimodality approach) or as the only RT component was tested for localized unresected, borderline or post-resection pancreatic cancer [14,15]. In this guideline, the ESTRO Task Force working group reports recommendations for performing IOERT in unresected pancreatic cancer. These recommendations aim to define clinical indications, patient selection and technical aspects in a multidisciplinary setting in order to standardize treatment modalities across centres already using IOERT, and to help institutions that intend to start IOERT programmes for pancreatic cancer.

Table 2 Institutional contemporary experiences regarding IOERT component in unresectable disease treated with preoperative chemoradiation with or without FOLFIRINOX induction. Mayo Clinic 2013 [50]

MGH 2018 [51]

Period of analysis

2002–2010

2010–2015

Initial local status: Unresectable Median T size

20 (65%) –

60 (88%) 3.6 cm

Preoperative therapy Chemo-radiation Induction FORFIRINOX

31* –

68* 68*

14 of 14 (100%) 17.5–20 Gy

17 of 27 (63%) 15–17 Gy

71% 10 months +17 %

41% 25 months >50%

IOERT # patients Dose range

Outcomes for IOERT Local control Median OS 2 years OS

Evidence review and update

In 2017, Krempien et al. published an IOERT review that included selected studies in locally advanced/unresected pancreatic cancer [14]. We now performed an updated retrospective bibliographic review of the 1981–2018 period and examined treatment strategies, disease characteristics and clinical results that included an intraoperative irradiation component, predominantly with electrons. Table 1 contains data evaluated in 36 reports (1961 patients analysed) in unresected localized pancreatic cancer [16–49,50,51]. Data support a possible contribution to a prolonged local control in unresectable patients, even if we lack evidence obtained by prospective randomized trials (Table 2).

Potential supportive actions to be considered preoperatively include following: – Self-expanding stent – Gastro-jejunostomy – Neurolysis Additional studies in high-risk patients, as clinically indicated, include the following:

Pre-treatment investigations

– Magnetic Resonance Imaging (MRI)/magnetic cholangiopancreatography – Positron Emission Tomography (PET)–CT – Laparoscopy

Information and evaluations required for candidate selection include following: – – – – – – – –

Parameter

Pathology of adenocarcinoma History and physical examination American Society of Anaesthesiologists (ASA) score Conventional blood test CA 19.9 Multidetector computed tomography angiography Endoscopic ultrasonography Chest computed tomography (CT)

resonance

Accurate diagnosis, clinical staging, and treatment of pancreatic cancer requires extensive interdisciplinary interaction and cooperation between specialties (diagnostic radiology, interventional upper endoscopy, nuclear medicine, surgery, medical oncology and radiation oncology). Accurate clinical staging is based on angiographic high-quality (helical) multidetector computed

Table 1 Chronologic data analysis from a 35 years literature review period on IOERT for pancreatic cancer: unresectable disease (36 articles, 1.961 patients). Disease status

1981–1989

1990–1999

2000–2009

2010–2018

Resected # Studies # Patients References

11 448 [16–26]

11 409 [27–37]

8 379 [38–45]

4 725 [15,46–50]

10–40 20 100%

10–30 20 100%

EBRT delivered >50% pts

62%

76%

91%

58%

Adjuvant CT >50% pts

45%

37%

73%

72%

8–16 10

3–18 10

7–13 11

9–25 17

IOERT Dose range (Gy) Mean dose (Gy) Electron beam 250 kV

Median survival Range (months) Mean (months)

IOERT: IntraOperative Electron Radiation Therapy, EBRT: External Beam Radiation Therapy, CT: chemotherapy, Gy: Gray.

F.A. Calvo et al. / Radiotherapy and Oncology 148 (2020) 57–64

tomography (CT) with advanced volumetric techniques to accurately define the relationship of the tumour to the celiac axis and superior mesenteric vessels in three dimensions. In the absence of extrapancreatic disease, the relationship of the low-density tumour mass to the superior mesenteric artery (SMA) and celiac axis is the main focus of preoperative imaging. Endoscopic ultrasound-guided needle biopsy is a preferred method of diagnosis. Endoscopic retrograde cholangiopancreatography may be of use in decompression of the biliary tract in patients with jaundice and pruritus. Local tumour resectability is most accurately assessed using preoperative imaging, intraoperative exploration being an inaccurate method to assess critical tumour–vessel relationships [49,52]. Objective, reproducible radiographic criteria define potentially resectable disease as the absence of extrapancreatic disease, the absence of superior mesenteric vein (SMV) or portal vein encasement, abutment or distortion, or associated thrombi and presence of a patent SMV–portal vein confluence, and distinct fat planes around the SMA, celiac axis and hepatic artery. [53]. MRI staging as staging tool with superior soft tissue contrast is useful in the detection of small, non-contour-deforming tumours and for characterizing indeterminate pancreatic findings at computed tomography [54]. PET/CT imaging has the potential to provide accurate whole-body staging in a single examination and assess metabolic changes after neoadjuvant therapy. PET/MRI hybrid imaging can further define local and systemic extension [55].

Patient selection for IOERT All patients diagnosed with localized pancreatic cancer are to be extensively evaluated and discussed at a multidisciplinary tumour board (MTB) for defining the optimal multimodal treatment strategy, including exploratory laparotomy and IOERT [56]. A significant proportion of unresected or borderline resectable patients will be advised to undergo preoperative strategies, like induction chemotherapy followed by a response-adapted policy for local treatment intensification or preoperative chemoradiation. Afterwards, they should be re-evaluated before laparotomy in terms of performance status, imaging and CA19.9 evolution. Patients amenable to the multidisciplinary approach including IOERT should have a good performance status (ECOG <2), no distant metastases, and unresectability confirmed at laparatomy. The strongest recommendation exists for patients with clinical stage IA-III (UICC TNM, 2016). Table 3 reports patient selection for IOERT: disease, treatment sequence and radiation dose recommendations.

Table 3 Patient selection for IOERT: disease, treatment sequence and radiation dose recommendations. Disease status Clinical setting Indications Stage

Locally advanced pancreatic cancer Unresectable IA–III (UICC TNM, 2016)

Treatment Preoperative chemoradiation followed by exploratory laparotomy + IOERT boost or Induction chemotherapy with a response-adapted policy for local treatment intensification patient selection including IOERT and/or external beam radiation therapy Radiation therapy dose IOERT boost 15–20 Gy for macroscopic or gross residual tumour (R2) 3D-CRT or IMRT 45–50.4 Gy (in 1.8 Gy per fraction)

External beam radiation therapy For patients with unresectable cancers, preoperative EBRT plus concurrent chemotherapy is preferably given prior to exploratory laparotomy and possible surgical resection/IOERT. EBRT is delivered using 3-dimensional conformal irradiation (3D-CRT) or (volumetric) intensity modulated irradiation (IMRT, VMAT), daily, over a period of 5–6 weeks at a dose of 45.0–50.4 Gy in 1.8 daily fractions along with 5-FU, capecitabine or institutional chemoradiation regimes. Stereotactic body hypofractionated radiotherapy (SBRT) is an emerging alternative form preoperative irradiation approach. Target volumes include the tumour including its extension into surrounding tissues and/or organs, part of or the entire pancreatic gland and regional lymph nodes depending on the original location of the tumour within the pancreas. Details regarding dose volume histogram parameters for treatment of pancreatic malignancies with RT have been recently updated [57]. In situations where IOERT has been administered or is due to be administered to a medial lesion over the vertebral column, the spinal cord dose should be limited to 35.0–40.0 Gy. Surgical procedure Surgical factors and tumour exposure for IOERT Access to the peritoneal cavity is through a longitudinal midline incision or a bilateral subcostal incision. Once in the abdominal cavity, all intra-abdominal organs and peritoneal surfaces are carefully inspected and palpated to exclude distant metastatic disease. Any suspicious lesions should be biopsied and sent for frozensection examination, as presence of distant metastasis is a limitation for a radical-intent approach. In case of distant metastases, surgery can still be valuable for palliation (abdominal pain palliation), biliary-digestive bypass and stabilization of local disease. Surgical manoeuvres are directed to assure direct access of the radiation beam to the primary lesion, with temporarily positioning the stomach, transverse colon and duodenum out of the target volume. IOERT procedure IOERT: treatment methods and technique. IOERT for pancreas cancer has predominantly been delivered with megavoltage electrons (IOERT) produced by a medical linear accelerator [58]. Brachytherapy or orthovoltage data do not allow for scientific analysis or recommendations at present. The electron beam energy and dose of IOERT are determined by the resection status and geometry of the treated field. Bolus is not used due to the fact that intraoperative fluid is present after tissue manipulation and resection. Protections inside the tumour bed are not recommended due to the dosimetric uncertainties introduced by such action. The best protection is mechanical retraction for temporary displacement of dose-sensitive structures at risk. Surgical retractors for large upper abdominal interventions are most helpful for properly exposing the radiation target and for expediting IOERT applicator positioning, displacement of normal tissue and iconographic documentation of the final pre- and post-intraoperative irradiation assemblage. Radiation target definition Unresectable tumours undergoing exploratory laparotomy can be dimensionally assessed by means of a combination of CT measurements in the preoperative study and direct palpation intraoperatively. Dimensions estimated by laparotomy tend to be larger than radiologically estimated dimensions (effect of soft tissues

IORT in unresected pancreatic cancer

and inflammatory pancreatic changes induced by preoperative therapy). Generally, maximum tumour dimension is over 3 cm. To ensure direct exposure of the palpable lesion to the IOERT applicator, the stomach should be mobilized superiorly, the transverse colon inferiorly and a clear view of the second and third portion is required to minimize the portion of the structure included in the IOERT field. The need to include the whole circumference of the duodenum is a contraindication of IOERT at doses over 10 Gy. The duodenum can be partially included in the IOERT field (<50% of the circumference) if a biliary-digestive bypass is performed. The volumetric characteristics of the unresected lesion often require applicator sizes in the range of 5 to 9 cm, circumferential shapes, with bevel angles of between 0 and 30 to properly adapt to the tumour size/morphology, with a 1–2 cm safety margin and the ability to reach the anatomy under the subcostal arch, thereby helping to temporarily displace mobile upper abdominal dose-sensitive structures (stomach, transverse colon, small bowel). Electron energy beams in the range of at least 12 MeV are required to achieve adequate coverage of the depth of the target tumour volume. The whole process can be summarized as follows: 1. IOERT target definition: the unresected mass should be assessed by means of direct intraoperative inspection (visual and palpation data). Three-dimensional estimation of the lesion metrics should include a comparison between the real-time intraoperative information and the preoperative CT-scan measurements. The key distance to be defined is the thickness of the tumour to guide the electron energy selection. 2. Normal uninvolved tissue to be excluded (mobilized out) from the IOERT radiation volume: stomach, transverse colon, small bowel and duodenum (second and third portion can be partially included). 3. Normal tissue at risk to be included in the radiation target volume: biliary tree (generally permeated with a stent device); pancreatic cancer involved parenchyma; vascular structures predefined by angio-CT study; retroperitoneal tissues; duodenum: full circumference included is a contraindication (biliarydigestive surgical bypass may provide limited mobilization of the duodenum to favour IOERT with partial inclusion of the structure instead of full circumferential presence); coeliac plexus (most unresectable lesions present an associated level of abdominal pain derived from coeliac plexus dysfunction, which has been reported to benefit from IOERT in terms of palliation). Such decisions should be agreed at the time of IOERT.

Applicator selection Applicator selection adaptation to the unresected cancer mass (Fig. 1) should consider the following technical elements of decisions: 1. Size (diameter): most unresectable lesions are in the range of 3– 8 cm in diameter (maximal transversal distance, ellipsoid or spheroid). Applicators should encompass the cancer mass with a margin of 0.5–1 cm. When positioning, particular attention should be paid to the location of the duodenum (second and third portion) to avoid full-circumference inclusion of the structure in the IOERT radiation volume. A set of circular applicators ranging from 5 to 10 cm in diameter will cover conventional needs. 2. Bevel angle: 15–30 bevelled applicators may help with temporary mechanical displacement of the duodenal loop.

Clinical photographs of the applicator positioning and surface anatomy in the IOERT target volume are recommended. IOERT irradiation IOERT irradiation consists of the following: 1. Electron energy selection: the 90% isodose should encompass the full thickness of the unresected mass in the most unfavourable distance of the posterior extension evaluated using the preoperative CT scan. Energies of 12 MeV are generally required. 2. Dose selection: 15 to 20 Gy are recommended for macroscopic disease, combined with high-precision external irradiation techniques to promote local control and abdominal pain palliation. Dose prescription For gross residual or unresected tumours, doses of 15–20 Gy have been employed. During surgery, care must be taken to accurately identify the depth of the spinal cord beneath the IOERT field using anatomic landmarks and a review of preoperative CT imaging. A library of predefined isodose curve distribution for a range of IOERT applicator diameters, bevel shapes and electron beam energies have to be available for intraoperative consultation. The electron energy should be chosen to adequately encompass the target tissues within the 90% isodose curves, with attention to the spinal cord dose (Fig. 2). Applicator removal After treatment completion, special attention should be paid to applicator removal in order to avoid traumatization of surrounding tissues and possible bleeding. In the event of bleeding during irradiation, blood should first be aspirated in order to clearly visualize the end of the collimator in contact with the patient’s tissues and allow for a safe manoeuvre. Removal of the applicator may be performed by the surgeon or by the radiation oncologist, and with the assistance of a surgical assistant/nurse. Recording and reporting Clinical and dosimetry forms should be filled out with all relevant patient, tumour and treatment parameters. Clinical data should include demographic data, performance status, symptoms and serum tests, including CA19-9, comorbidities and Charlson comorbidities index. Tumour-related data should include imaging studies, a biopsy report, clinical and pathological stage, grading and possible biomolecular studies. Treatment data should include bile-duct permeability manoeuvres, preoperative treatments, the surgical report and main characteristics of the IOERT procedure, including collimator diameter, bevel angle, bolus, beam energy, dose prescription and duration of the procedure. In vivo dosimetry is strongly recommended as a quality-assurance procedure. Radiation target contents should be described: organs and structures included in the radiation beam. Radiation protection of normal uninvolved tissues: description of temporary mobilization or intra-field customized protection. Preoperative MRI and CT-scans can be obtained to identify the primary tumour, regional lymph nodes and critical organs in order to design a provisional treatment plan. No fully reliable treatment planning systems currently exist for intraoperative irradiation; however, the availability of preoperative images may help with identifying anatomical structures to guide the positioning of the collimator. Whenever obtained, all these imaging data should be included in the patient’s final documentation. Intraoperative ultra-

F.A. Calvo et al. / Radiotherapy and Oncology 148 (2020) 57–64

Fig. 1. IOERT applicator (8 cm diameter, 15 bevel angle) positioning encompassing an unresected pancreatic tumoural mass allowing protection by temporary displacement of stomach, transverse colon, small bowel and duodenum (partially).

Fig. 2. A virtual 2D simulation (7 cm diameter applicator, 15 bevel angle) and dosimetric representation (12 MeV electron beam) of an IOERT procedure in an unresected tumour with a minor remission after primary chemo-radiation: CT including tumour and adjacent organs at risk prechemo-radiation (extensive vascular involvement). Postchemo-radiation tumour restaging (minor remission, still evident vascular involvement). Contouring of tumour and adjacent normal organs and structures. Applicator (7 cm diameter, 15 bevel angle) positioning encompassing the target (unresected tumour). Isodose distribution representation of a 12 MeV electron beam.

sound can be helpful to verify tumour size in depth and the location of critical structures such as kidneys and major vessels. The final documentation of the IOERT procedure should also include the surgical notes and the anaesthesiology report. Table 4 contains a summary of the IOERT parameters.

Recommendation on patient care

bed. In some cases, an aspiration drain may be useful to avoid bleeding outside the surgical bed. The patient should be carefully observed by means of a camera during irradiation and vital parameters should be monitored and be visible from outside the operating room. In the event of an emergency, irradiation should be stopped immediately and nurses, anaesthesiologists and surgeons should be prepared to enter the operating room at any time immediately after cessation of irradiation.

Care during the course of IOERT The sterile field should be guaranteed throughout the IOERT procedure. Before irradiation, sterile drapes should cover the surgical bed and the part of the collimator inside and near the surgical

Post-treatment patient care and follow-up Patients treated with IOERT for pancreatic tumours require thorough care, as after any other surgical procedure for pancreatic

IORT in unresected pancreatic cancer

Table 4 Reporting parameters for IOERT electrons beam procedures in unresected pancreatic cancer.

QA recommendations Specific IOERT QA actions include:

IOERT parameters Target volume description

– – – –

IOERT factors

– Applicator size/diameter Bevelled end (degrees) – Electron energy Isodose prescription – Total dose – Number of fields Report every parameter for every field Overlapping (yes/no) Field –within-a-field – Protections – Fluid stability – Time of beam on – Gantry angulation – In vivo dosimetry (system/site measured)

Integrated pre-IOERT treatment factors

Tumour exposure Normal tissues exposed Normal tissues protected/mobilized Special conditions: % of duodenum included

– Surgery: tumour exposure + bypass/derivations/reconstructions – Preoperative Chemoradiation (CRT) Induction chemotherapy + CRT – Postoperative CRT CRT + adjuvant chemotherapy

tumours. All vital and clinical parameters should be monitored in the days following the procedure, and special attention should be paid to blood tests, including renal and liver functions, bowel movements and onset of new symptoms and signs. After IOERT for pancreatic head tumours, the risk of duodenal radiation damage, even with bleeding, should be considered. In the event of persistent pain and anaemia with faecal occult blood, medical therapy and endoscopy/surgical procedures should be considered. In the case of unresected or partially resected lesions, the risk of bleeding related to haemorrhage from arteries and veins encased by the tumour tissue that undergoes necrosis should be carefully taken into account. In the event of significant bleeding, reoperation aiming at haemostasis should be considered where possible. After the IOERT procedure, alone or combined with surgical resection, the patient may receive further treatments, including postoperative RT and adjuvant systemic treatment. Therefore, the follow-up schedule starts after treatment completion and usually does not substantially differ from that of pancreatic cancer treated without IOERT. During imaging studies, special attention should be paid to any tissue potentially involved in the IOERT volume such as the duodenum and major vessels. Adverse effects during follow-up IOERT in the setting of unresected pancreatic cancer is typically well tolerated. Large-animal experimental studies have analysed the tissue changes of pancreas and duodenum after radiation [59]. Clinical and experimental data of upper abdominal tissues and organs support good tolerance to a 10-Gy to 20-Gy IOERT single-dose boost plus 50-Gy external beam RT (conventional fractionation), including post-resection vascular anastomosis [60,61].

– MDT evaluation and scheduling – Pre-treatment beam calibration: dose per monitor unit for each radiation energy – Equipment and applicators performance – Safety interlocks check-up – QA report completion, inter-specialty signature and registration – Clinical report of technical parameters in the electronic chart Conclusions and future directions Long-term survival and disease control are achievable in a proportion of well-selected patients with locally unresected pancreas cancer. IOERT, as part of a multimodality treatment plan for pancreas cancer, either locally advanced or unresected, has proven to promote high local control at the site of the primary tumour without a significant increase in treatment toxicity. With advances in the ability of systemic therapy to treat occult systemic metastases, the importance of sustained long-term local and regional control bears increasing interest, including in the expansion of the indications for IOERT. Strategies for selecting appropriate patients for aggressive local therapy in the unresected setting will advance through improvements in imaging, biomarkers and genetics, as well as through the timing of when to administer IOERT. IOERT is a risk-adaptable technique in the era of personalized oncology [50,51,62]. New opportunities for systemic or regional therapy (intrahepatic and intraperitoneal), targeted therapies, vaccines and immunotherapy (in particular in the unresected model) should be evaluated in an attempt to improve disease control. As improvements are being made in distant disease control, the benefit of improved local control with regimens that include IOERT may become even more decisive [63]. Disclaimer ESTRO cannot endorse all statements or opinions made on the guidelines. Regardless of the vast professional knowledge and scientific expertise in the field of radiation oncology that ESTRO possesses, the Society cannot inspect all information to determine the truthfulness, accuracy, reliability, completeness or relevancy thereof. Under no circumstances will ESTRO be held liable for any decision taken or acted upon as a result of reliance on the content of the guidelines. The component information of the guidelines is not intended or implied to be a substitute for professional medical advice or medical care. The advice of a medical professional should always be sought prior to commencing any form of medical treatment. To this end, all component information contained within the guidelines is done so for solely educational and scientific purposes. ESTRO and all of its staff, agents and members disclaim any and all warranties and representations with regards to the information contained on the guidelines. This includes any implied warranties and conditions that may be derived from the aforementioned guidelines. Conflict of interest statement The authors declare that they have no competing interests. None of the authors has any financial and personal relationships with other people or organisations that could inappropriately influence (bias) of this work.

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Acknowledgements Intraoperative radiotherapy (IORT) is a multidisciplinary oncological activity requiring a close collaboration of team members, using optimal tools and techniques. The authors of this guideline acknowledge the remarkable contribution of all the health professionals involved in the care of patients who are candidates for IORT procedures. Authors are grateful to the ESTRO/ACROP reviewers Philipp Scherer, Vincenzo Valentini and Dirk Verellen for their useful and constructive comments and to Eralda Azizaj (ESTRO staff member responsible for the work of ACROP) for facilitating the review and journal submission process.

References [1] Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87–108. [2] Cloyd JM, Katz MH, Prakash L, Varadhachary GR, Wolff RA, Shroff RT, et al. Preoperative therapy and pancreatoduodenectomy for pancreatic ductal adenocarcinoma: a 25-year single-institution experience. J Gastrointest Surg 2017;21:164–74. [3] Bouvier AM, Bossard N, Colonna M, Garcia-Velasco A, Carulla M, Manfredi S, et al. Trends in net survival from pancreatic cancer in six European Latin countries: results from the SUDCAN population-based study. Eur J Cancer Prev 2017;26:S63–9. [4] Ahola R, Siiki A, Vasama K, Vornanen M, Sand J, Laukkarinen J. Patients with resected, histologically re-confirmed pancreatic ductal adenocarcinoma (PDAC) can achieve long-term survival despite T3 tumour or nodal involvement. The Finnish Register Study 2000–2013. Pancreatology 2017;17:822–6. https://doi.org/10.1016/j.pan.2017.07.192. [5] Ambe C, Fulp W, Springett G, Hoffe S, Mahipal A. A meta-analysis of randomized clinical trials of chemoradiation therapy in locally advanced pancreatic cancer. J Gastrointest Cancer 2015;46:284–90. [6] Chang JS, Chiu YF, Yu JC, Chen LT, Chang HJ. The role of consolidation chemoradiotherapy in locally advanced pancreatic cancer receiving chemotherapy: an updated systematic review and meta-analysis. Cancer Res Treat 2018;50:562–74. https://doi.org/10.4143/crt.2017.105. [7] Suker M, Beumer BR, Sadot E, Marthey L, Faris JE, Mellon EA, et al. FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis. Lancet Oncol 2016;17:801–10. [8] Chung SY, Chang JS, Lee BM, Kim KH, Lee KJ, Seong J. Dose escalation in locally advanced pancreatic cancer patients receiving chemoradiotherapy. Radiother Oncol 2017;123:438–45. [9] Tang K, Lu W, Qin W, Wu Y. Neoadjuvant therapy for patients with borderline resectable pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. Pancreatology 2016;16:28–37. [10] Petrelli F, Comito T, Ghidini A, Torri V, Scorsetti M, Barni S. Stereotactic body radiation therapy for locally advanced pancreatic cancer: a systematic review and pooled analysis of 19 trials. Int J Radiat Oncol Biol Phys 2017;97:313–22. [11] Mizumoto T, Terashima K, Matsuo Y, Nagano F, Demizu Y, Mima M, et al. Proton radiotherapy for isolated local recurrence of primary resected pancreatic ductal adenocarcinoma. Ann Surg Oncol 2019;26:2587–94. [12] Sole CV, Calvo FA, Ferrer C, Pascau J, Marsiglia H. Bibliometrics of intraoperative radiotherapy: analysis of technology, practice and publication tendencies. Strahlenther Onkol 2014;190:1111–6. [13] Czito BG, Calvo FA, Haddock MG, Palta M, Willett CG. Intraoperative irradiation. In: Gunderson LL, Tepper JE, editors. Clinical radiation oncology. Philadelphia: Elsevier Saunders; 2016. p. 325–40. [14] Krempien R, Roeder F. Intraoperative radiation therapy (IORT) in pancreatic cancer. Radiat Oncol 2017;12:8–14. [15] Ogawa K, Karasawa K, Ito Y, Ogawa Y, Jingu K, Onishi H, et al. Intraoperative radiotherapy for resected pancreatic cancer: a multi-institutional retrospective analysis of 210 patients. Int J Radiat Oncol Biol Phys 2010;77:734–42. [16] Cai S, Hong TS, Goldberg SI, Fernandez-del Castillo C, Thayer SP, Ferrone CR, et al. Updated long-term outcomes and prognostic factors for patients with unresectable locally advanced pancreatic cancer treated with intraoperative radiotherapy at the Massachusetts General Hospital, 1978 to 2010. Cancer 2013;119:4196–204. [17] Abe M, Takahashi M. Intraoperative radiotherapy: the Japanese experience. Int J Radiat Oncol Biol Phys 1981;7:863–8. [18] Wood WC, Shipley WU, Gunderson, et al. Intraoperative irradiation for unresectable pancreatic carcinoma. Cancer 1982;49:1272–5. [19] Shipley W, Wood W, Tepper J, et al. Intraoperative electron beam irradiation for patients with unresectable pancreatic carcinoma. Ann Surg 1984;200:25–32. [20] Tepper JE, Shipley WU, Warshaw AL, et al. The role of misonidazole combined with intraoperative radiation therapy in the treatment of pancreatic carcinoma. J Clin Oncol 1987;5:579–84.

[21] Gunderson L, Martin J, Kvols L, et al. Intraoperative and external beam irradiation +/ 5-FU for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 1987;13:319–29. [22] Tuckson W, Goldson A, Ashayeri E, et al. Intraoperative radiotherapy for patients with carcinoma of the pancreas. The Howard University Hospital experience, 1978–1986. Ann Surg 1988;207:648–54. [23] Roldan G, Gunderson LL, Nagorney DM, et al. External beam versus intraoperative and external beam irradiation for locally advanced pancreatic cancer. Cancer 1988;61:1110–6. [24] Manabe T, Baba N, Nonaka A, et al. Combined treatment using radiotherapy for carcinoma of the pancreas involving the adjacent vessels. Int Surg 1988;73:153–6. [25] Nishimura A, Sakata S, Iida K, et al. Evaluation of intraoperative radiotherapy for carcinoma of the pancreas: prognostic factors and survival analyses. Radiat Med 1988;6:85–91. [26] Willich N, Denecke H, Krimmel K, et al. The Munich experience in intraoperative irradiation therapy of pancreatic cancer. Ann Radiol 1989;32:484–6. [27] Cromack DT, Maher MM, Hoekstra H, et al. Are complications in intraoperative radiation therapy more frequent than in conventional treatment? Arch Surg 1989;124:229–34. [28] Gilly F, Romestaing P, Gerard J, et al. Experience of three years with intraoperative radiation therapy using the Lyon intra-operative device. Int Surg 1990;75:84–8. [29] Abe M, Shibamoto Y, Ono K, Takahashi M. Intraoperative radiation therapy for carcinoma of the stomach and pancreas. Front Radiat Ther Oncol 1991;25:258–69. [30] Calvo F, Santos M, Abuchaibe O, et al. Intraoperative radiotherapy in gastric and pancreatic carcinoma: a European experience. Front Radiat Ther Oncol 1991;25:270–3. [31] Dobelbower R, Konski A, Merrick H, et al. Intraoperative electron beam radiation therapy (IOEBRT) for carcinoma of the exocrine pancreas. Int J Radiat Oncol Biol Phys 1991;20:113–9. [32] Kojima Y, Kimura T, Yasukawa H, et al. Radiotherapy-centered multimodal treatment of unresectable pancreatic carcinoma. Int Surg 1991;76: 87–90. [33] Garton GR, Gunderson LL, Nagorney DM, et al. High-dose preoperative external beam and intraoperative irradiation for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 1993;27:1153–7. [34] Kasperk R, Klever P, Andreopoulos D, et al. Intraoperative radiotherapy for pancreatic carcinoma. Br J Surg 1995;82:1259–61. [35] Fossati V, Cattaneo G, Zerbi A, et al. The role of intraoperative therapy by electron beam and combination of adjuvant chemotherapy and external radiotherapy in carcinoma of the pancreas. Tumouri 1995;81:23–31. [36] Mohiuddin M, Regine WF, Stevens J, et al. Combined intraoperative radiation and perioperative chemotherapy for unresectable cancers of the pancreas. J Clin Oncol 1995;13:2764–8. [37] Shibamoto Y, Manabe T, Baba N, et al. High dose, external beam and intraoperative radiotherapy in the treatment of resectable and unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys 1990;19:605–11. [38] Schuricht AL, Spitz F, Barbot D, et al. Intraoperative radiotherapy in the combined-modality management of pancreatic cancer. Am Surg 1998;64:1043–9. [39] Furuse J, Kinoshita T, Kawashima M, et al. Intraoperative and conformal external-beam radiation therapy with protracted 5-fluorouracil infusion in patients with locally advanced pancreatic carcinoma. Cancer 2003;97:1346–52. [40] Okamoto A, Matsumoto G, Tsuruta K, et al. Intraoperative radiation therapy for pancreatic adenocarcinoma: the Komagome hospital experience. Pancreas 2004;28:296–300. [41] Ihse I, Andersson R, Ask A, et al. Intraoperative radiotherapy for patients with carcinoma of the pancreas. Pancreatology 2005;5:438–42. [42] Ma H, Di Z, Wang X, et al. Effect of intraoperative radiotherapy combined with external beam radiotherapy following internal drainage for advanced pancreatic carcinoma. World J Gastroenterol 2004;10:1669–771. [43] Sunamura M, Karasawa K, Okamoto A, Ogata Y, Nemoto K, Hosotani R, et al. Phase III trial of radiosensitizer PR-350 combined with intraoperative radiotherapy for the treatment of locally advanced pancreatic cancer. Pancreas 2004;28:330–4. [44] Yamaguchi K, Kobayashi K, Ogura Y, Nakamura K, Nakano K, Mizumoto K. Tanaka M Radiation therapy, bypass operation and celiac plexus block in patients with unresectable locally advanced pancreatic cancer. Hepatogastroenterology 2005;52:1605–12. [45] O’Connor J, Sause W, Hazard L, et al. Survival after attempted surgical resection and intraoperative radiation therapy for pancreatic and periampullary adenocarcinoma. Int J Radiat Oncol Biol Phys 2005;63:1060–6. [46] Willett CG, Del Castillo CF, Shih HA, et al. Long-term results of intraoperative electron beam irradiation (IOERT) for patients with unresectable pancreatic cancer. Ann Surg 2005;241:295–9. [47] Jingu K, Tanabe T, Nemoto K, et al. Intraoperative radiotherapy for pancreatic cancer: 30-year experience in a single institution in Japan. Int J Radiat Oncol Biol Phys 2012;83:e507–11. [48] Chen Y, Che X, Zhang J, et al. Long-term results of intraoperative electron beam radiation therapy for nonmetastatic locally advanced pancreatic cancer: Retrospective cohort study, 7-year experience with 247 patients at the National Cancer Center in China. Medicine (Baltimore) 2016;95:e4861.

IORT in unresected pancreatic cancer

[49] Ogawa K, Karasawa K, et al. Intraoperative radiotherapy for unresectable pancreatic cancer: a multi-institutional retrospective analysis of 144 patients. Int J Radiat Oncol Biol Phys 2011;80:111–8. [50] Ashman JB, Moss AA, Rule WG, Callister MG, Reddy KS, Mulligan DC, et al. Borad M Preoperative chemoradiation and IOERT for unresectable or borderline resectable pancreas cancer. J Gastrointest Oncol 2013;4:352–60. [51] Keane FK, Wo JY, Ferrone CR, Clark JW, Blaszkowsky LS, Allen JN, et al. Intraoperative radiotherapy in the era of intensive neoadjuvant chemotherapy and chemoradiotherapy for pancreatic adenocarcinoma. Am J Clin Oncol 2018;41:607–12. [52] Fuhrman GM, Charnsangavej C, Abbruzzese JL, et al. Thin-section contrastenhanced computed tomography accurately predicts the resectability of malignant pancreatic neoplasms. Am J Surg 1994;167:104–13. [53] Robinson EK, Lee JE, Lowy AM, Fenoglio CJ, Pisters PWT, Evans DB. Reoperative pancreaticoduodenectomy for periampullary carcinoma. Am J Surg 1996;172:432–8. [54] Jha P, Yeh BM, Zagoria R, Collisson E, Wang ZJ. The role of MR imaging in pancreatic cancer. Magn Reson Imaging Clin N Am 2018;26:363–73. [55] Fraum TJ, Ludwig DR, Hope TA, Fowler KJ. PET/MRI for gastrointestinal imaging: current clinical status and future prospects. Gastroenterol Clin North Am 2018 Sep;47(3):691–714. [56] Spitz FR, Abbruzzese JL, Lee JE, et al. Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas. J Clin Oncol 1997;15:928–37.

100

[57] Herman JM, Crane CH, Iacobuzio-Donahue C, Abrams RA. Pancreatic cancer. In: Gunderson LL, Tepper JE, editors. Clinical radiation oncology. Philadelphia: Elsevier; 2016. p. 934–59. [58] Miller RC, Valentini V, Moss A, D’Agostino GR, Callister MD, Hong TS, et al. Pancreas cancer. In: Gunderson LL, Willett CG, Calvo FA, Harrison LB, editors. Intraoperative irradiation: techniques and results. New York: Humana Press, Springer; 2011. p. 249–72. [59] Ahmadu-Suka F, Gillette EL, Withrow SJ, Husted PW, Nelson AW, Whiteman CE. Pathologic response of the pancreas and duodenum to experimental intraoperative irradiation. Int J Radiat Oncol Biol Phys 1988;14:1197–204. [60] Evans DB, Lee JE, Leach SD, Fuhrman GM, Cusack Jr JC, Rich TA. Vascular resection and intraoperative radiation therapy during pancreaticoduodenectomy: rationale and technique. Adv Surg 1996;29: 235–62. [61] Vujaskovic Z, Willett CG, Tepper LE, Kinsella TJ, Gunderson LL. Normal-tissue tolerance to IOERT, EBRT, or both: animal and clinical studies. In: Gunderson LL, Willett CG, Calvo FA, Harrison LB, editors. Intraoperative irradiation. New York: Humana Press, Springer; 2011. p. 119–40. [62] Calvo FA. Intraoperative irradiation: precision medicine for quality cancer control promotion. Radiat Oncol 2017;12:36–7. [63] Calvo FA, Valentini V. Radiotherapy for pancreatic cancer: systematic nihilism or intraoperative realism. Radiother Oncol 2008;87:314–7.

Radiotherapy and Oncology 150 (2020) 293–302

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Guidelines

Intraoperative radiation therapy (IORT) for soft tissue sarcoma – ESTRO IORT Task Force/ACROP recommendations Falk Roeder a,⇑, Virginia Morillo b, Ladan Saleh-Ebrahimi c, Felipe A. Calvo d, Philip Poortmans e, Carlos Ferrer Albiach b a Department of Radiotherapy and Radio-Oncology, Paracelsus Medical University Hospital Salzburg, Landeskrankenhaus, Salzburg, Austria; b Department of Radiation Oncology, Instituto de Oncologia, Hospital Provincial de Castellon, Spain; c Praxis für Strahlentherapie Dachau und Freising, Dachau, Germany; d Department of Oncology, Clínica Universidad de Navarra, Madrid, Spain; e Department of Radiation Oncology, Institut Curie, Paris, France

a r t i c l e

i n f o

Article history: Received 23 June 2020 Accepted 7 July 2020 Available online 15 July 2020 Keywords: Soft tissue sarcoma Intraoperative radiotherapy Electron beam Anticipated boost IORT

a b s t r a c t Purpose: To describe guidelines for the use of intraoperative radiation therapy (IORT) in the treatment of soft-tissue sarcomas (STS). Methods: A panel of experts in the field performed a systematic literature review, supplemented their clinical experience and developed recommendations for the use of IORT in the treatment of STS. Results: Based on the evidence from the systematic literature review and the clinical experience of the panel members, recommendations regarding patient selection, incorporation into multimodal treatment concepts and the IORT procedure itself are made. The rationale for IORT in extremity and retroperitoneal STS is summarized and results of the major series in terms of patient and treatment characteristics, oncological outcome and toxicity are presented. We define surgical factors, volumes for irradiation, technical requirements, dose prescription, recording and reporting, treatment delivery and care during the course of IORT covering the main IORT techniques used for the treatment of STS. In extremity STS, evidence originates from a few small prospective and mainly from retrospective single centre studies. Based on those reports, IORT containing-approaches result in very high local control rates with low rates of acute and late toxicity. In retroperitoneal sarcomas, evidence is derived from one prospective randomized trial, a few prospective and a large number of retrospective studies. The randomized trial compared IORT combined with moderate doses of postoperative external-beam radiation therapy (EBRT) to high-dose postoperative EBRT alone after gross total resection, clearly favouring the IORT-containing approach. These results have been confirmed by the prospective and retrospective studies, which similarly showed high local control rates with acceptable toxicity, mainly favouring combinations of preoperative EBRT and IORT. Conclusions: IORT-containing approaches result in high rates of local control with low to acceptable toxicity rates. Based on the available evidence, we made recommendations for the use of IORT in STS. Clinicians and researchers are encouraged to use these guidelines in clinical routine as well as in the design of future trials. 2020 Elsevier B.V. All rights reserved. Radiotherapy and Oncology 150 (2020) 293–302

Soft tissue sarcomas (STS) represent a rare and heterogeneous group of malignant diseases [1]. They arise most often in the extremities and trunk ( 55%), followed by the retroperitoneal/int raabdominal space ( 35%) and the head and neck region ( 10%) [1]. The most important prognostic factors include tumour grade, tumour size, location (deep vs. superficial) and resection margin [2,3]. Complete surgical removal is the cornerstone of curative intent treatment, although its extent has been subject to change ⇑ Corresponding author at: Department of Radiotherapy and Radio-Oncology, Paracelsus Medical University Hospital Salzburg, Landeskrankenhaus, Salzburg, Austria. E-mail address: f.roeder@salk.at (F. Roeder).

in the last decades [4]. Modern oncological concepts do not focus solely on the achievement of tumour control and survival but also on preservation of functionality and quality of life [4,5]. Therefore, extensive surgical procedures (for example amputations) have been increasingly replaced by multimodal organ- and/or function-preserving concepts [4]. Within such approaches less extensive surgery with smaller margins, combined with additional local treatment modalities like radiation therapy (RT) is used to maintain adequate local control (LC) while achieving better functional outcomes and quality of life. External beam RT (EBRT) is most frequently used either pre- or postoperatively. High doses are needed in high-risk situations like microscopically incomplete

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resections or recurrent disease [4]. The ability to deliver such doses can be limited via EBRT alone because of considerable risks of severe side effects to surrounding normal tissues, jeopardising the benefits of the function preserving approach. The main rationale for the application of at least parts of the total dose via intraoperative RT (IORT) in those cases is the possibility to move radiosensitive structures out of the radiation field resulting in reduced toxicity while maintaining the enhanced biological effect of the high single RT dose for local control [6–10]. However, the high single dose also includes a potential risk for increased late toxicity if not properly used. Therefore, the aim of this guideline is to summarize recommendations on adequate patient selection, incorporation into multimodal concepts, technical procedures, irradiation volumes, dose prescription, recording and reporting, treatment delivery and patient care for IORT procedures in adult patients with STS. These are based on the available evidence supplemented by expert opinion added by members of the task group and briefly summarized in the following sections. The full guideline is available via an electronic supplement file (see supplementary material). Because of the distinct differences between extremity and retroperitoneal STS [11], they will be discussed separately. Methodology For the purpose of this guideline, STS is defined according to the WHO classification [12]. IORT is defined as the use of a high dose of radiation in a single fraction delivered to the tumour bed or to residual disease during a surgical procedure intracorporally by

Fig. 1.

102

linear accelerators via electrons (IOERT) or photons or by brachytherapy using high-dose rate techniques (IOHDR). A systematic literature search in Pubmed was performed on August 9th 2017 resulting in 335 articles. The systematic search was accompanied by a meticulous manual search, which retrieved 2 further relevant articles. After exclusion of non-suitable publications, 13 articles dealing with extremity STS and 28 articles focusing on retroperitoneal STS were finally selected (Fig. 1).

Rationale for IORT Extremity STS Since Rosenberg et al. [13] showed similar overall survival comparing amputation with limb sparing surgery followed by RT, the combination approach has emerged as the standard of care. Randomized trials [5] and large-scale population based analyses [3] clearly confirmed that postoperative EBRT leads to improved local control. Subsequently, preoperative EBRT has been proven to be equally effective in terms of LC and OS compared to postoperative EBRT [14]. However, EBRT may come along with increased toxicity. Especially the size of the (high-dose) volume has been shown to negatively correlate with late toxicity including fibrosis, oedema and impaired joint function, resulting in unfavourable functional outcomes [15]. Compared to an external beam RT boost, an intraoperative boost usually results in a much smaller irradiated volume because it can be precisely guided to the high-risk region under visual control without additional margins to compensate for daily positioning errors [4]. Organs at risk including major

F. Roeder et al. / Radiotherapy and Oncology 150 (2020) 293–302

nerves or skin can be excluded from the target volume, which further reduces late toxicities and improve functional outcome [4]. Retroperitoneal STS Surgery is the cornerstone of curative intent treatment in retroperitoneal sarcoma [4]. In contrast to extremity sarcoma, wide margins are often not achievable [16–19] and local progression remains the dominant pattern of failure [19–24]. This constitutes an even stronger rationale for the addition of RT per se, however no mature randomized data is available to support this assumption. Because postoperative RT is often limited by the tolerance of surrounding organs at risk and high doses are usually needed because of the often close or positive margins, early interest existed for IORT as a boost technique. A small randomized trial by the NCI compared IORT in combination with moderate doses of postoperative EBRT with conventional doses of postoperative EBRT alone. The combined IORT-EBRT approach resulted in a significantly improved local control with reduced late gastrointestinal toxicity [20]. However, some series reported distinct differences between central (in-field IORT) control and local/abdominal control [16]. While the combination of IORT and EBRT seemed effective in sterilizing the high risk region in most of the patients, the limited dose of postoperative EBRT alone insufficiently controlled residual disease in the adjacent low-risk regions probably due to the known limitations for dose and target volume coverage [4]. Compared to the postoperative approach, preoperative RT offers several benefits, including a more precise target volume definition, reduced doses to adjacent organs at risk because of their displacement through the tumour itself, a possible devitalisation of tumour cells prior to surgery, a higher biological effect in the absence of postoperatively altered tissue oxygenation, fibrosis and thickening of the pseudocapsule, at least moderate tumour shrinkage and the avoidance of treatment delays due to postoperative complications [17,20,25]. This results in less toxicity combined with increased local control and is further enhanced by an intraoperative boost if close or positive margins are present. Therefore, a combination of preoperative EBRT with IORT is strongly preferred compared to IORT followed by postoperative EBRT [4]. Main results Care must be taken in the interpretation of the results given the mainly retrospective nature of IORT data on extremity sarcoma and the absence of randomized trials comparing IORT-containing and non-IORT approaches. Extremity STS Based on the available literature (see Table 1), the combination of limb-sparing surgery, IORT and EBRT results consistently in excellent 5-year local control rates of 82–97% [4,26–38]. The series reported by Tinkle et al. found 58% in recurrent cases [28]. Those results seem at least equal to major non-IORT series, reporting 5-year LC rates of 83–93% [11,39–47], especially considering the higher proportions of patients with unfavourable prognostic factors in the IORT series [4]. Aside from direct oncological outcomes, IORT-containing approaches result consistently in very high limb preservation rates (81–100%) [4,26,27–31,33,35–37] with good functional outcome (59–100%) [4,27–29,33,35,36]. This might be attributed to the smaller high-dose volume compared to an EBRT boost, as field size was clearly associated with increased late toxicity in a randomized trial using EBRT alone [15]. Randomized trials confirming the benefit using IORT-containing compared to nonIORT approaches should be conducted to confirm this benefit.

295

Retroperitoneal STS Based on the available literature including data from prospective phase II studies (see Table 2), the combination of preoperative EBRT and IORT consistently results in high 5-year local control rates of 51–89% [4,18,25,51–53,57,59,61,66]. At least according to direct inter-study comparisons, those results seem to be superior to surgery alone or surgery combined with EBRT with regard to local control and in some series to overall survival [20,25,72]. Preoperative EBRT should be preferred to the postoperative approach as it is associated with superior local control and lower toxicity rates [25,59,72]. Although some groups reported excellent central (in IORT field) local control rates with acceptable toxicities using IORT and postoperative EBRT [16,20], locoregional (abdominal) control was rather poor [16]. This might reflect the general limitations of the postoperative approach in target coverage/dose and normal tissue (especially small bowel) tolerance levels. No major differences in wound healing disturbances or postoperative complication rates are observed after IORT compared to non-IORT-containing approaches [4]. If care is taken to at least limit the IORT dose to major nerves, gastrointestinal structures and ureters, IORT-containing approaches result in acceptable rates of late toxicity [4,16,18,25]. Randomized trials confirming these benefits of IORT-containing approaches are to be conducted. Tolerance of organs at risk (OAR) Extremity STS IORT of extremity STS is usually well tolerated [4]. Wound complications rates do not seem to be increased compared to surgery and EBRT alone [27,29,30,73]. Neuropathy remains a dose limiting toxicity mainly dependent on the single dose applied during IORT rather than the total biologically equivalent dose of the combined treatment. Based on the data from retroperitoneal and GI-cancers, the risk of (severe neuropathy) seems to increase extensively if doses of >12.5 Gy are applied [20,74,75]. Bone necrosis and fractures have been reported in 3–7% in major IORT series [27,29,35,73]. These results are in the range of reported rates (1–9%) with EBRT alone [47,76,77]. Surgical exposure of nerve or bone may enhance the risk of radiation-induced damage. Muscle fibrosis, which may be triggered by IORT and/or the EBRT component, is associated with the irradiated volume [15,38], although clear distinction from fibrosis and scar formation caused by surgery is difficult.

Retroperitoneal STS IORT of retroperitoneal sarcomas is usually well tolerated [4]. As IOERT treatments in the retroperitoneal space are mainly targeted to the deep tumour bed, wound healing is usually not compromised by the IORT procedure [20]. Similarly, gastrointestinal toxicities are not increased with the use of IORT as gastrointestinal structures like stomach, small or large bowel are usually moved out of the IORT area. Major IORT series reported severe chronic gastrointestinal side effects (mainly chronic enteritis) in 11–13% using IORT followed by moderate doses of EBRT [16,20] compared to a significantly increased rate of 50% with high-dose postoperative EBRT as shown by the NCI trial [20]. In contrast to gastrointestinal side effects, ureteral stenosis has been frequently described in association with IORT in the retroperitoneal space. Miller et al. [78] observed a statistically increased 5-year incidence of 41% in irradiated compared to 19% in non-irradiated ones. The risk was further clearly dose-dependent. Thus, ureters should be excluded from the IORT area whenever possible or at least the dose should be limited to the reasonable minimum. Neuropathy has been identified as a probably dose limiting toxicity also in the retroperitoneal space [20]. Similarly to extremity STS, the risk for severe neuropathy seems to increase extensively

103

104

2017 2015 2015 2014 2014 2014 2005 2006 2003 2003 2003 2001 2001

Carbo-Laso et al. [26] Roeder et al. [27] Tinkle et al. [28] Roeder et al. [29] Calvo et al. [30] Call et al. [31] Tran et al. [32] Oertel et al. [33] Kretzler et al. [34] Azinovic et al. [35] Rachbauer et al. [36] Edmonson et al. [37] van Kampen et al. [38]

1995–2003 1991–2011 2000–2011 2005–2010 1986–2012 1990–2009 1995–2001 1991–2004 1989–1999 1986–1994 1996–2002 1994–1997 1991–1997

Period

r, sc r, sc r, sc p, sc r, mc r, sc r, sc r, sc r, sc r, sc r, sc p, sc r, sc

Type

39 183 26 34 159 61 17 153 28 45 39 39 68

n 158 64 35 43 53 71 23 33 520 93 24 70 n.r.

f/u 85 78 0 100 100 87 94 62 39 58 95 100 71

PD n.r. 68 54 88 84 82 65 49*1 61 87 n.r.*2 n.r.*3 n.r.

EBRT

85 100 42 100 100 100 76 100 89 80 100 97 78

EBRT 45 45 52*4 46 45 50.4 50.3 45 50.6*5 30–60 50 45 40

Dose

IORT

100 100 100 91 100 100 100 100 100 100 100 97 100

IORT

5y-LC 82 86 58 97 82 91 86*7 83*8 84 80*9 100*10 90*9 88

Dose 10 15 15 15 12.5 7.5–20 12.5 15 14.5*5*6 15 12–15*6 10–20 15

e e� e� e� e� e� e� e� e�/HDR e� HDR e�/HDR e� �

Tech. 64 71 50 79 72 72 78*7 83*8 66 64*9 82*10 80 70

5y-OS 82 95 81*11 94 94*11 97 n.r. 90 n.r. 88 100 95 n.r.

LP n.r. 83 77 81 n.r. n.r. n.r. 86 59 77 100 n.r. n.r.

AT3+:13%, LT3+:12% (N:8%, F:5%) LT:20% (NP3+:8%, F:6%) AT3+:23%, LT3+:31% LT3:18% (N:12%, N3:3%, BN:3%) AT3+:14%, LT3+:10% (N3+:4%) NP3:2%, BN:2% n.r. AT2+:23%, LT2+:17% (NP2+:5%) LT3+: 24% (N3:5%, F:10%) N:16% (25%*12), BN:2%, F:4% N:0%, F:0% F:3% N3:2%, F:4%, Fi:23%, Fi3+:6%

Toxicity

10% non-extremity tumours phase II, all received CHT fi rel. to IOERT volume*13

8% GRD, 16% MD

upper extremity only

rec. only, 58% prior EBRT phase II, all received CHT

Comments

year: year of publication, period: study period, type: study type, r: retrospective, p: prospective, sc: single centre, mc: multi centre, n:number of patients, f/u: median follow-up in months, n.r.: not reported, PD: primary disease (%), R0: microscopic clear resection margin (%), EBRT: patients receiving external-beam RT (%), EBRT dose: median EBRT dose in Gy, IORT: patients receiving intraoperative RT (%), tech.: IORT technique, e-: electrons, HDR: high doserate brachytherapy, IORT dose: median IORT dose in Gy, 5y-LC: actuarial 5-year local control rate (%), 5y-OS: actuarial 5-year overall survival (%), LP: limb preservation rate (%), FO: good functional outcome (%), ATx: acute toxicity grade x, LTx: late toxicity grade x, N: neuropathy all grades, Nx: neuropathy grade x, F: fracture, BN: bone necrosis (without fracture), Fi: fibrosis, Fix: fibrosis grade x, CHT: chemotherapy, GRD: gross residual disease, MD: metastatic disease, rec.: recurrences, rel.: related, *1: modified R0 definition (1 cm free margin), *2: all marginal, *3: 38% marginal, *4: in patients without prior EBRT (no RE-EBRT performed), *5: mean, *6: prescribed to applicator surface in HDR patients, *7: 3-year rate, *8: in initially non-metastatic patients, *9: crude rate, *10: 2-year rate, *11: actuarial 5-year amputation free survival, *12: if nerve included into IORT area, *13: toxicity analysis based on 53patents receiving IORT + EBRT.

Year

Author

Table 1 Published IORT series in extremity STS.

296 ESTRO IORT Task Force/ACROP recommendations for soft-tissue-sarcoma

2017 2015

2014

2014 2014 2013 2010 2010

2011 2008 2007 2007

2006 2006 2006

2006 2004 2003 2002 2002 2001

2000 1996 1993

1993 1991 1988

Wang et al. [48]

Hull et al. [49] Kelly et al. [50]

Stucky et al. [51]

Roeder et al. [25] Gronchi et al. [52] Sweeting et al. [53] Yoon et al. [54] Dziewirski et al. [55]

Pezner et al. [56] Zagar et al. [57] Caudle et al. [58] Ballo et al. [59]

Dziewirski et al. [60] Pawlik et al. [61] Pierie et al. [62]

Krempien et al. [16] Bobin et al. [63] De Paoli et al. [64] Gilbeau et al. [65] Petersen et al. [18] Gieschen et al. [66]

Alektiar et al. [67] Bussières et al. [68] Sindelar et al. [20]

Gunderson et al. [69] Willett et al. [70] Kinsella et al. [71]

Period

n.r. 1981–1989 1980–1985

1992–1996 1991–1994 1980–1985

1991–2004 1988–2001 1999–2003 1990–2000 1981–1995 1980–1996

1998–2004 1996–2002 1973–1998

1990–2008 2000–2008 1994–2004 1960–2003

2007–2013 2003–2010 2001–2009 2003–2008 1998–2006

1996–2011

2003–2013 2003–2011

1988–2013

Type

sc sc sc sc

sc sc sc sc sc sc

r, sc r, sc p, sc, ran

r, r, r, r, r, r,

r, sc p, mc r, sc

r, r, r, r,

p, sc p, mc r, sc r, sc r, sc

r, sc

r, sc r, mc

SEER

33 31 14 18 63 46 72 14*2 27*2 67 24 30 45 87 16 13 32 19 15 20 20 20 15 20

352*1 15*1 13*1 46 32 172 37 26 27 83 18 28 84

min. 15 38 min. 15

33 17 96

30 53 27 53 42 38

20 40 27

49 19 19 47

33 58 43 33 40

53 37 39 45

f/u n.r.

50 70 n.r.*3

37 74 n.r.*3

9 75 100 100 39 21 50 100 49 78

67 77 64 73

85 76 72 71 23

85 100 100 64

n.r.

GTR

94 84 93 100 100 100 95 100 100 82 92 63 96 83 100 100 94 79 100 100 55 85 100 100

96 95 100 89 88

98 97 100 89

n.r.

0 100 100 100 0 29 100 0 75*4 100 100 0 5 0 0 30 95 0 0

0 61 100 60

14*4 0 100 100*4 94 0 95 0 100 100 94 79*4 0

pre.

EBRT post.

52 0 0 0 67 63 0 93 28*4 0 0 78 63 100 100 70 5 100 100

100 39 0 40

15*4 6 0 0 0 0 0 0 29*4 40

87*4 0

Dose

50 45 40–50 40–50 45 45–50 50.4 49 47.6 45–50.4 45 45–50 50 35–40 50–55 45–60.4 40–50 35–40 50–55

26–60 59.4 45 45–66

45–55*5 50.4 45–50.4 50 50

100 50.4 50

n.r.

61 52 36 100 0 52 39 100 0 100 100 77 38 100 100 0 75 100 100 0 100 60 100 0

0 100 e 35 47 0 100 0 85 18 100 43 68

IORT

e e e

HDR e e

e e e e e e

HDR e e

e e e e

e e e e HDR

e e

Tech.

Dose

15 10–20 20

12–15 17 20

15 15 15 15 15 10–20

20 15 10–20

10–20 11 12.5 15

12 12 12.5 10–12 20

10–20

10 10

n.r.

5y-LC

67 77*10 50*7*10 51 46 51 60*7 n.r. n.r. 40 46*6 73*6 40 59 83 61 62 76*10 60*6 20*6 85*6 81*9 55 30

87*12 86*6 91 65 89 46 72 63*6*7 64 90*11 65*7*8

n.r.

5y-OS

55 70*10 74*10 n.r. n.r. 55 61*7 77 45 64 56 n.r. 60 48 74 30 45 60*10 45*12 52*12 49 71*6 38 50

81 93*13 85 60 60 74 59 72 87*11 50*7*8

55*12 34*12

Toxicity

RS: 22% n.r. LT3+:29% (N3+:21%) LR3+:4% AT2+:20%, LT3+:21% LT3+: 8% (N3: 8%) LT3+: 10% (N3+:6%) AT3+:7%, LT3+:4% (N2:18%) GI3 + 18%, F3: 9%, N3:10%, UO:5% LT3+:25% (N3+:12%) n.r. BO3+:18%, F3+:6%, N2:6% PC3+:21%, LT3+:11% AE:7%, CE:13%, F:0%, N3+:47% AE:60%, CE:50%, F:25%, N3+:0% AT3+:10%, LTR3+:20% (N3+:5%) LT3+:15% (N3+:10%, UO3+:10%) AE:7%, CE:13%, F:0%, N:27% AE:60%, CE:35%, F:30%, N:5%

AT3+:9%, LT3+:21% AT3+:10%, LT3+:55% (GI3+:19%) AT3+:7%, PC3+:36% RT3+:2%

PC3+:22% PC3 + 12% PC3+:5% AT3: 3%, AT2:31% (N2:16%) n.r. AT3+:15%, PC3+:33%, LT3+:6% PC3+:21%, HT:27%, NV:11%*14 PC3+:17%, PC3+:29%, LT3+:14% RS:18%, LT3+:18%*15 (N3+:6%)

n.r.

Comments

LC +/ IORT sig AE, CE, F +/ IORT sig

LC +/ IORT sig. AE, CE, N IORT +/ sig

OS +/ IORT sig.

LC/OS IORT +/ EBRT sig.

LC +/ RT sig.

LC S+/ RT sig.

OS EBRT +/ IORT sig. OS IORT +/ EBRT sig.

year: year of publication, period: study period, n.r.: not reported, type: study type, r: retrospective, p: prospective, sc: single centre, mc: multi centre, ran: randomized, n: number of patients, f/u: median follow-up in months, min.: minimum, PD: primary disease (%), GTR: gross total resection (%), EBRT: external-beam RT, pre.: patients receiving preoperative EBRT (%), post.: patients receiving postoperative EBRT (%), dose: median EBRT dose in Gy, IORT: intraoperative RT, IORT(lower line):patients receiving IORT (%), tech.: technique of IORT, e-: electrons, HDR: high-dose rate brachytherapy, dose: median IORT dose in Gy, 5y-LC: actuarial 5-year local control rate, 5y-OS: actuarial 5-year overall survival rate, AT: acute toxicity all grades, ATx: acute toxicity grade x, LT: late toxicity all grades, LTx: late toxicity grade x, RS: re-surgery, PC: postoperative complications all grades, PCx: postoperative complications grade x, UO: ureteral obstruction all grades, UOx: ureteral obstruction grade x, N: neuropathy all grades, Nx: neuropathy grade x, AE: acute enteritis all grades, CE: chronic enteritis all grades, F: fistula all grades, Fx: fistula grade x, BO: bowel obstruction all grades, Box: bowel obstruction grade x, GI: gastrointestinal all grades, GIx: gastrointestinal grade x, RT: radiation therapy associated all grades, RTx: RT associated grade x, HT: hematological all grades, HTx: hematological grade x, NV: nausea/vomiting all grades, NVx: nausea/vomiting grade x, *1: liposarcoma subgroup only, *2: only irradiated patients, *3: stratified according to primary vs recurrent disease, *4: some patients received pre- and postoperative EBRT, *5: simultaneous-integrated boost, *6: crude rate, *7: in patients with GTR, *8: in patients with IORT, *9: 4-year rate, *10: 2-year rate, *11: 3-year rate, *12: median OS in months, *13: disease specific survival, *14: preoperative chemoradiation, *15: IORT + EBRT.

Year

2017

Author

Table 2 published IORT series in retroperitoneal STS.

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Table 3 Technical details in major studies using preoperative EBRT in retroperitoneal STS (modified from Baldini et al. [77]). Author

Institution

Year

CTV

CTV adaption

PTV

Dose

Technique

4D ME

Pisters et al. [82] Tzeng et al. [83] Yoon et al. [54] Swanson et al. [84] Roeder et al. [17] EORTC [85] McBride et al. [86] Dickie et al. [87] DeLaney et al. [88]

MDACC U. Alabama MGH U. Florida U. Heidelberg multicentre BWH/DFCI PMH MGH

2003 2006 2010 2012 2012 2012 2013 2013 2017

n.r. n.r. GTV + 1.5 cm GTV + 2 cm GTV + 1.5 cm GTV + 6 mm GTV + 1–1.5 cm GTV + 0.5–2 cm*1 GTV + 1–1.5 cm

n.r. n.r. F, B F, B, Bo n.r. F, B, S, A F, B, A, S, RP L B, K, L, Bo, A, S

GTV + 1–5 cm GTV + 1–1.5 cm CTV + 0.5 cm CTV + 0.5 cm CTV + 0.5 cm CTV + 9–12 mm*2 CTV + 0.5 cm CTV + 0.5 cm CTV + 0.5 cm

18–50.4*3 45 (SIB 57.5) 45–50.4 50.4 45–50 (SIB 50–55) 50.4 50 50–50.4 50.4 (SIB 60.2–63)

3D, IMRT 3D, IMRT IMRT, P 3D, IMRT, P IMRT 3D, IMRT 3D, IMRT 3D, IMRT P

No No Yes No No No No No Yes

EORTC: European Organisation for Research and Treatment of Cancer Protocol 62092–22092, MDACC: MD Anderson Cancer Center, U.: University of, MGH: Massachusetts General Hospital, BWH:Brigham and Womeńs Hospital, DFCI: Dana Faber Cancer Institute, PMH: Princess Margaret Hospital, year: year of publication, CTV: clinical target volume, n.r.: not reported, GTV: gross tumour volume, mm: millimeter, cm: centimeter, F: fascia, B: bone, Bo: bowel, S: skin, A: air gap, RP: retroperitoneal compartment, L: liver, K: kidney, PTV: planning target volume, dose: prescribed total dose in Gy, SIB: simultaneous integrated boost, 3D: three-dimensional conformal RT, IMRT: intensitymodulated RT, P: protons, 4D-ME: four-dimensional motion evaluation, *1: 0.5–2 cm medial/lateral/anterior/posterior, 2 cm superior/inferior, *2: 9 mm anterior/medial, 12 mm superior/inferior/posterior/lateral, *3: dose escalation trial.

with IORT doses >12.5 Gy [16,18,20,25]. Therefore, major nerves should be excluded from the IORT area whenever possible or dose should be limited.

smaller boost volume. Postoperative EBRT dose may be adapted based on the given intraoperative dose and the final margin status. Retroperitoneal STS

Patient selection All patients diagnosed with soft-tissue sarcoma should be discussed within a multidisciplinary tumour board prior to treatment initiation to define the optimal treatment. Pre-treatment investigation should at least include history and physical examination, MRI (or multidetector CT if MRI is contraindicated) of the primary tumour region, chest CT and histological confirmation via biopsy. In extremity STS, RT is usually indicated in patients with highrisk features including high tumour grade, (anticipated) close or positive resection margin, tumour size >5 cm, deep tumour location (in relation to the fascia) and locally recurrent disease [73]. If preoperative EBRT is planned, an additional IORT might be added if close or positive margins are found or assumed intraoperatively (based on the surgeons assessment or on frozen sections). If postoperative EBRT is planned, an intraoperative boost can usually replace the external boost phase. In retroperitoneal STS, the indication for EBRT is more controversial but usually accepted for lesions with (anticipated) close or positive resections margins especially in the presence of other risk factors including tumour size >5 cm, high tumour grade or locally recurrent disease. EBRT should be done preoperatively and can be combined with an additional IORT boost if close or positive margins are found or anticipated intraoperatively (based on the surgeońs assessment or on frozen sections).

The indication for EBRT is usually present in lesions with (anticipated) close or positive resections margins especially in the presence of other risk factors like tumour size >5 cm, high tumour grade or locally recurrent disease. Preoperative EBRT is clearly preferable compared to postoperative EBRT because of major advantages regarding dose to organs at risk and target volume coverage [21,25]. The use of contemporary RT techniques including IMRT with IRGT and motion management is strongly recommended. ConsensusTable 4 Relevant parameters for reporting of IORT procedures. IORT PARAMETERS Demographics

Surgical factors

IORT procedure

IOERT

EbRT

– – – – – – – – – – – – – – – – –

Extremity-STS EBRT is usually applied in conventional fractionation using 3D-CRT or (preferably) IMRT techniques with adequate imageguidance following the general principles of sarcoma radiation therapy. Detailed consensus-based target volume delineation and dose prescription guidelines have been proposed [79,80]. Preoperative EBRT is usually given in one phase up to a dose of 50 Gy to the PTV followed by surgery 4–6 weeks after. A postoperative boost in case of R1 or R2 resections [14], can be replaced by a (much smaller) IORT boost. Postoperative EBRT is usually performed in 2 phases. A dose of 50 Gy is typically prescribed to an extended PTV, followed by a RT dose of 10–20 Gy based on surgical margin status to a limited PTV. The latter ‘‘boost” phase can be replaced by a preceded IORT boost, again typically resulting in a

106

– –

HDR-IORT

– –

–

age, gender histology, grade clinical stage prior EBRT (area, dose, fractionation) actual surgical approach intraop. margin (frozen sections if available) size/location of high risk area size/location of gross residual disease uninvolved organs/structures included uninvolved organs/structures removed or shielded relevant intraoperative complications date duration prescribed dose prescription method electron energy applicator size shape bevel angle fluid drainage bolus material thickness source activity applicator size shape catheters number distance to each other distance to surface gauze packing/sutures

IORT: intraoperative radiation therapy, EBRT: external-beam RT, IOERT: intraoperative electron RT, HDR-IORT: high-dose rate brachytherapy intraoperative RT.

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based target volume delineation and dose prescription guidelines have been proposed [81], although considerable differences in published studies exist [54,82–88] (Table 3). Dose is usually limited to 50 Gy in 25 fractions or 50.4 Gy in 28 fractions but dose can be easily escalated by adding an IORT boost.

IORT procedure IORT procedural – summary Surgical factors: Surgery follows the general principles of sarcoma surgery. Whenever possible, a wide (microscopically complete) resection should be attempted. Care prior to/during the course of IORT: Assessment of the intraoperative situation with regard to aim of treatment, resection margin, target volume definition, removal/shielding of structures at risk and consecutive technical details of the treatment should be jointly discussed and performed by the surgeon and the radiation oncologist. The technical procedure itself may be done by the radiation therapist or the radiation physicist together with the radiation oncologist in accordance to national laws and regulations. It should always account for possible physical, medical or technical issues as anticipated by any of the team members including a four-eye principle for all steps. Monitoring of the patient should be performed by the anaesthesiologist during the complete course of irradiation. Recording and reporting: Clinical and dosimetric forms should be filled out with all relevant data regarding patient, tumour and treatment related parameters (Table 4). Treatment delivery: Electron treatments should preferably be delivered via dedicated or mobile linacs, brachytherapy treatments preferably by HDR remote afterloaders inside the operation theatre. The sterile field should be guaranteed for the complete IORT procedure. Applicator removal: Special attention should be paid to applicator removal in order to avoid any harm of surrounding tissues and possible bleeding. Post-treatment care and follow-up: Post-treatment care generally follows the recommendations and principles of postsurgical care. Regular follow-up should be performed according to the usual soft-tissue sarcoma principles

IOERT - technical summary Radiation target volume definition: Deep tumour bed with a safety margin of 1–2 cm in all directions after gross total resection, otherwise cover gross residual disease with a margin of 0.5–1 cm in all directions. Normal uninvolved tissue to be excluded (moved out or covered with lead shielding): skin (mandatory), major nerves and bladder if technical and oncologically feasible, stomach and bowel structures, kidney and ureters. Normal tissues at risk to be included: adjacent muscles/connective tissue structures, adjacent bone, adjacent vessels (or grafts) in full thickness. Applicator adaption: positioning and fixation by surgeon and radiation oncologist, fixation as required by the used system (airor soft docking: fixation at the table, hard docking: fixation by direct connection with the linac). Size selection: 1 cm larger than the axial diameter of the target area. If coverage of the complete surgical bed is not possible with one applicator, consider abutting (but not overlapping) fields or restriction to the region with highest risk for positive margin. Bevelled end selection: as required for appropriate target coverage based on the individual anatomical situation.

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Electron energy selection: 90% isodose should encompass the target volume in depth. Estimations of this distance should be made by intraoperative assessment in combination with presurgical imaging studies. In certain situations intraoperative ultrasound may be helpful. Meticulous haemostasis and drainage of fluid is relevant for ensuring that energy selection is adequate during the entire procedure. In case of an unstable fluid level continuous drainage is preferred over selection of higher electron energies. Dose selection: suspected close margins 10–12.5 Gy, suspected involved margins 12–15 Gy, gross residual disease 15–20 Gy. Limitation of the dose to 12.5 Gy is recommended if major nerves have to be included to reduce the risk of severe neuropathy, if oncologically appropriate. Limitation of dose is strongly recommended if gastrointestinal structures, contralateral kidney, ureters or bony structures have to be included. IOHDR – technical summary Radiation target definition: Deep tumour bed with a safety margin of 0.5–1 cm after gross tumour resection. Patients with gross residual disease are usually not good candidates for IOHDR. Normal uninvolved tissue to be excluded (moved out or covered with lead shielding): skin (mandatory), major nerves and bladder if technical and oncologically feasible, stomach and bowel structures, kidney and ureters. Normal tissues at risk to be included: adjacent muscles/connective tissue structures, adjacent bone, adjacent vessels or grafts. Applicator adaption: size, shape and number of catheters should be individually adapted to cover the target area with a 1 cm margin axially. Applicator has to be placed and fixed with proper packing and/or sutures to ensure direct contact between the applicator and tissue surface throughout the entire target area and the entire treatment time. In case of organs at risk directly adjacent to the applicator surface, shielding may be considered due to the high doses at the applicator surface. Plan selection: Dose is usually prescribed to the surface centre of the target volume at 0.5 cm tissue depth (equivalent to 0.5 cm from the applicator surface or 1 cm from the plane of catheters). A suitable plan should be selected from a plan atlas. Incorporation of the applicator curvature should be weighed against the risk to use an inappropriate curvature based on the intraoperative assessment. Dwell positions and times may be adjusted according to the individual anatomical situation according to the center’s experience. Dose selection: see above (IOERT section), Conclusion This review and guidelines of the ESTRO Task Force on IORT provides a comprehensive summary of indications, requirements and set-up for intraoperative treatment for soft tissue sarcoma. Disclaimer ESTRO cannot endorse all statements or opinions made on the guidelines. Regardless of the vast professional knowledge and scientific expertise in the field of radiation oncology that ESTRO possesses, the Society cannot inspect all information to determine the truthfulness, accuracy, reliability, completeness or relevancy thereof. Under no circumstances will ESTRO be held liable for any decision taken or acted upon as a result of reliance on the content of the guidelines. The component information of the guidelines is not intended or implied to be a substitute for professional medical advice or medical care. The advice of a medical professional should always be

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sought prior to commencing any form of medical treatment. To this end, all component information contained within the guidelines is done so for solely educational and scientific purposes. ESTRO and all of its staff, agents and members disclaim any and all warranties and representations with regards to the information contained on the guidelines. This includes any implied warranties and conditions that may be derived from the aforementioned guidelines. Conflict of interest Felipe Calvo: Is member of the IOeRT Consortium, established on 21 December 2019, supported by Sordina IORT Technologies spa. Carlos Ferrer Albiach: Is member of the IOeRT Consortium, established on 21 December 2019, supported by Sordina IORT Technologies spa. Virginia Morillo: No COI. Philip Poortmans: Is member of the IOeRT Consortium, established on 21 December 2019, supported by Sordina IORT Technologies spa. Is medical advisor of Sordina IORT Technologies spa, starting from 1 April 2020 on. Falk Roeder: Received travel grants and speaker honoraria from IntraOp Medical and Lilly Germany. Ladan Saleh-Ebrahimi: No COI. Acknowledgements Intraoperative radiotherapy (IORT) is a multidisciplinary oncological activity requiring a close collaboration of team members, using optimal tools and techniques. The authors of this guideline acknowledge the remarkable contribution of all the health professionals involved in the care of patients who are candidates for IORT procedures. Authors are grateful to the ESTRO/ACROP reviewers Philipp Scherer, Robert Krempien and Frank W. Hensley. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.radonc.2020.07.019. References [1] National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines) Soft Tissue Sarcoma Version 2.2014, www. Nccn.org. [2] Soft tissue and visceral sarcomas: ESMO clinical practice guidelines for diagnostics, treatment and follow-up. ESMO/European Sarcoma Network Working Group. Ann Oncol 2015;25 (suppl 3):102-112. [3] Jebsen NL, Trovik CS, Bauer HC, Rydholm A, Monge OR, Sundby Hall K, et al. Radiotherapy to improve local control regardless of surgical margin and malignancy grade in extremity and trunk wall soft tissue sarcoma: a Scandinavian sarcoma group study. Int J Radiat Oncol Biol Phys 2008;71:1196–203. [4] Roeder F, Krempien R. IORT in sarcoma. Radiat Oncol 2017;12:20. [5] Yang JC, Chang AE, Baker AR, Sindelar WF, Danforth DN, Topalian SL, et al. Randomized prospective study of the benefit of adjuvat radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1998;16:197–203. [6] Roeder FF, Goetz JM, Habl G, Bischof M, Krempien R, Buechler MW, et al. Intraoperative Electron Radiation Therapy (IOERT) in the management of locally recurrent rectal cancer. BMC Cancer 2012;12:592. [7] Roeder F, Treiber M, Oertel S, Dinkel J, Timke C, Funk A, et al. Patterns of failure and local control after intraoperative electron boost radiotherapy to the presacral space in combination with total mesorectal excision in patients with locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2007;67:1381–8. [8] Roeder FF, Timke C, Uhl M, Habl G, Hensley FW, Buechler MW, et al. Aggressive local treatment containing intraoperative radiation therapy (IORT) for patients with isolated local recurrences of pancreatic cancer: a retrospective analysis. BMC Cancer 2012;12:295. [9] Roeder F, Timke C, Oertel S, Hensley FW, Bischof M, Muenter MW, et al. Intraoperative electron radiotherapy in the management of aggressive fibromatosis. Int J Radiat Oncol Biol Phys 2010;76:1154–60.

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[10] Roeder FF, Timke C, Saleh-Ebrahimi L, Schneider L, Hackert T, Hartwig W, et al. Clinical phase I/II trial to investigate neoadjuvant intensity-modulated short term radiation therapy (5x5 Gy) and intraoperative radiation therapy (15 gy) in patients with primarily resectable pancreatic cancer – NEOPANC. BMC Cancer 2012;12:112. [11] Zagars GK, Ballo MT, Pisters PW, Pollock RE, Patel SR, Benjamin RS, et al. Prognostic factors for patients with localized soft-tissue sarcoma treated with conservation surgery and radiation therapy: an analysis of 1225 patients. Cancer 2003;97:2530–43. [12] WHO classification of tumours of soft tissue and bone. Fourth edition 2013. Edited by Fletcher CD, Bridge JA, Hogendoorn PC and Mertens F. ISBN-13 9789283224341. [13] Rosenberg SA, Tepper J, Glatstein E, et al. The treatment of soft-tissue sarcomas of the extremities. Ann Surg 1982;196:305–14. [14] ÓSullivan B, Davis AM, Turcotte R, Bell R, Catton C, Chabot P, Wunder J, Kandel R, Goddard K, Sadura A, Pater J, Zee B. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomized trial. Lancet 2002;359:2235-2241. [15] Davis AM, ÓSullivan B, Turcotte R et al. Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol 2005;75:48-53. [16] Krempien R, Roeder F, Oertel S, Weitz J, Hensley FW, Timke C, et al. Intraoperative electron-beam therapy for primary and recurrent retroperitoneal soft-tissue sarcoma. Int J Radiat Oncol Biol Phys 2006;65:773–9. [17] Roeder FF, Schulz-Ertner D, Nikoghosyan AV, Huber PE, Edler L, Habl G, et al. Clinical phase I/II trial to investigate preoperative dose-escalated intensitymodulated radiation therapy (IMRT) and intraoperative radiation therapy (IORT) in patients with retroperitoneal soft tissue sarcoma. BMC Cancer 2012;12:287. [18] Petersen IA, Haddock MG, Donohue JH, Nagorney DM, Grill J, Sargent DJ, et al. Use of intraoperative electron beam radiotherapy in the management of retroperitoneal soft tissue sarcomas. Int J Radiat Oncol Biol Phys 2002;52:469–75. [19] Heslin MJ, Lewis JJ, Nadler E, Newman E, Woodruff JM, Casper ES, et al. Prognostic factors associated with long-term survival for retroperitoneal sarcoma: implications for management. J Clin Oncol 1997;15:2832–9. [20] Sindelar WF, Kinsella TJ, Chen PW, DeLaney TF, Tepper JE, Rosenberg SA, et al. Intraoperative radiotherapy in retroperitoneal sarcomas. Final results of a prospective, randomized clinical trial. Arch Surg 1993;128:402–10. [21] Pawlik TM, Ahuja N, Herman JM. The role of radiation in retroperitoneal sarcomas: a surgical perspective. Curr Opin Oncol 2007;19:359–66. [22] Catton CN, O’sullivan B, Kotwall C, Cummings B, Hao Y, Fornasier V. Outcome and prognosis in retroperitoneal soft tissue sarcoma. Int J Radiat Oncol Biol Phys 1994;29:1005–10. [23] Lewis JJ, Leung D, Woodruff JM, Brennan MF. Retroperitoneal soft-tissue sarcoma: analysis of 500 patients treated and followed at a single institution. Ann Surg 1998;228:355–65. [24] Stoeckle E, Coindre JM, Bonvalot S, Kantor G, Terrier P, Bonichon F, et al. Prognostic factors in retroperitoneal sarcoma: a multivariate analysis of a series of 165 patients of the French Cancer Center Federation Sarcoma Group. Cancer 2001;92:359–68. [25] Roeder F, Ulrich A, Habl G, Uhl M, Saleh-Ebrahimi L, Huber PE, et al. Clinical phase I/II trial to investigate preoperative dose-escalated intensity-modulated radiation therapy (IMRT) and intraoperative radiation therapy (IORT) in patients with retroperitoneal soft tissue sarcoma: interim analysis. BMC Cancer 2014;14:617. [26] Carbo-Laso E, Sanz-Ruiz P, Calvo-Haro JA, et al. Intraoperative radiotherapy for extremity soft-tissue sarcomas: can long-term local control be achieved ? Int J Clin Oncol 2017;22:1094–102. [27] Roeder F, Lehner B, Saleh-Ebrahimi L, Hensley FW, Ulrich A, Alldinger I, Mechtersheimer G, Huber PE, Krempien R, Bischof M, Debus J, Uhl M. Intraoperative electron radiation therapy combined with external beam radiation therapy and limb sparing surgery in extremity soft tissue sarcoma: a retrospective single center analysis of 183 cases. Radiother Oncol. 2015 Dec 1. pii: S0167-8140(15)00619-2. doi: 10.1016/j.radonc.2015.11.014. [Epub ahead of print]. [28] Tinkle CL, Weinberg V, Braunstein SE, et al. Intraoperative radiotherapy in the management of locally recurrent extremity soft-tissue sarcoma. Sarcoma 2015;2015:913565. [29] Roeder F, Lehner B, Schmitt T, Kasper B, Egerer G, Sedlaczek O, et al. Excellent local control with IOERT and postoperative EBRT in high grade extremity sarcoma: results from a subgroup analysis of a prospective trial. BMC Cancer 2014;14:350. [30] Calvo FA, Sole CV, Polo A, Cambeiro M, Montero A, Alvarez A, et al. Limbsparing management with surgical resection, external-beam and intraoperative electron-beam radiation therapy for boost for patients with primary soft tissue sarcoma of the extremity: a multicentric pooled analysis of long-term outcomes. Strahlenther Onkol 2014;190:891–8. [31] Call JA, Stafford SL, Petersen IA, et al. Use of intraopertaive radiotherapy for upper-extremity soft-tissue sarcomas – analysis of disease outcome and toxicity. Am J Clin Oncol 2014;37:81–5. [32] Tran QN, Kim AC, Gottschalk AR, et al. Clinical outcomes of intraoperative radiation therapy for extremity sarcomas. Sarcoma 2006;2006:91671. [33] Oertel S, Treiber M, Zahlten-Hinguranage A, Eichin S, Roeder F, Funk A, et al. Intraoperative electron boost radiation followed by moderate doses of external

F. Roeder et al. / Radiotherapy and Oncology 150 (2020) 293–302

[34]

[35]

[36]

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

[46]

[47]

[48] [49]

[50]

[51]

[52]

[53]

[54]

[55]

[56] [57]

[58]

beam radiotherapy in limb-sparing treatment of patients with extremity softtissue sarcoma. Int J Radiat Oncol Biol Phys 2006;64:1416–23. Kretzler A, Molls M, Gradinger R, Lukas P, Steinau HU, Würschmidt F. Intraoperative radiotherapy of soft tissue sarcomas of the extremity. Strahlenther Onkol 2004;180:365–70. Azinovic I, Martinez Monge R, Aristu JJ, et al. Intraoperative radiotherapy electron boost followed by moderate doses of external beam radiotherapy in resected soft-tissue sarcoma of the extremities. Radiother Oncol 2003;67:331–7. Rachbauer F, Sztankay A, Krecy A, et al. High-dose-rate intraoperative brachytherapy (IOHDR) using flab technique in the treatment of soft tissue sarcomas. Strahlenther Onkol 2003;179:480–5. Edmonson JH, Petersen IA, Shives TC, et al. Chemotherapy, irradiation, and surgery for function-preserving therapy of primary extremity soft tissue sarcomas. Cancer 2002;94:786–92. van Kampen M, Eble MJ, Lehnert T, et al. Correlation of intraoperatively irradiated volume and fibrosis in patients with soft-tissue sarcoma of the extremities. Int J Radiat Oncol Biol Phys 2001;51:94–9. Hui AC, Ngan SY, Wong K, Powell G, Choong PF. Preoperative radiotherapy for soft tissue sarcoma: the peter MacCallum cancer centre experience. Eur J Surg Oncol 2006;32:1159–64. Dagan R, Indelicato DJ, McGee L, Morris CG, Kirwan JM, Knapik J, et al. The significance of a marginal excision after preoperative radiation therapy of soft tissue sarcoma of the extremity. Cancer 2012;118:3199–207. MacDermed DM, Miller LL, Peabody TD, Simon MA, Luu HH, Haydon RC, Montag AG, Undevia SD, Connell PP. Primary tumor necrosis predicts distant control in locally advanced soft tissue sarcomas after preoperative concurrent chemoradiotherapy. Int J Radiat Oncol Biol Phys 2010;76:1147-53. Kraybill WG, Harris J, Spiro IJ, Ettinger DS, DeLaney TF, Blum RH, et al. Phase II Study of neoadjuvant chemotherapy and radiation therapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: radiation therapy oncology group trial 9514. J Clin Oncol 2006;24:619–25. Felderhof JM, Creutzberg CL, Putter H, Nout RA, Bovee JV, Dijkstra PD, et al. Long term clinical outcome of patients with soft-tissue sarcomas treated with limb-sparing surgery and postoperative radiotherapy. Acta Oncol 2012;52:745–52. Alektiar KM, Brennan MF, Singer S. Local Control comparison of adjuvant brachytherapy to intensity-modulated radiotherapy in primary high-grade sarcoma of the extremity. Cancer 2011;117:3229–34. Lee J, Park YJ, Yang DS, yoon WS, Lee JA, Rim CH, Kim CY. Treatment outcome of conservative surgery plus postoperative radiotherapy for extremity soft tissue sarcoma. Radiat Oncol J 2012;30:62-69. Sampath S, Schultheiss TE, Hitchcock YJ, Randall RL, Shrieve DC, Wong JY. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma: multiinstitutional analysis of 821 patients. Int J Radiat Oncol Biol Phys 2011;81:498–505. Folkert M, Singer S, Brennan MF, Kuk D, Qin LX, Kobayashi WK, et al. Comparison of local recurrence with conventional and intensity-modulated radiation therapy for primary soft-tissue sarcomas of the extremity. J Clin Oncol 2014;32:3236–41. Wang LB, McAneny D, Doherty G, et al. Effect of intraoperative radiotherapy in the treatment of retroperitoneal sarcoma. Int J Clin Oncol 2017;22:563–8. Hull MA, Molina G, Niemierko A, Haynes AB, Jacobson A, De Amorim Bernstein K, et al. Improved local control with an aggressive strategy of preoperative (with or without intraoperative) radiation therapy combined with combined with radical surgical resection for retroperitoneal sarcoma. J Surg Oncol 2017;9999:1–6. Kelly KJ, Yoon SS, Kuk D, et al. Comparison of perioperative radiation therapy and surgery versus surgery alone in 204 patients with primary retroperitoneal sarcoma: a retrospective 2-institution study. Ann Surg 2015;262:156–62. Stucky CC, Wasif N, Ashman JB, et al. Excellent local control with preoperative radiation therapy, surgical resection, and intra-operative electron radiation therapy for retroperitoneal sarcoma. J Surg Oncol 2014;109:798–803. Gronchi A, De Paoli A, Dani C, Merlo DF, Quangliulo V, Grignani G, et al. Preoperative chemo-radiation therapy for localized retroperitoneal sarcoma: a phase I-II study from the Italian Sarcoma Group. Eur J Cancer 2014;50:784–92. Sweeting RS, Deal AM, Laguna OH, Bednarski BK, Meyers MO, Yeh JJ, et al. Intraoperative electron radiation therapy as an important treatment modality in retroperitoneal sarcoma. J Surg 2013;185:245–9. Yoon SS, Chen YL, Kirsch DG, et al. Proton-beam, intensity-modulated, and/or intraoperative electron radiation therapy combined with agressive anterior surgical resection for retroperitoneal sarcomas. Ann Surg Oncol 2010;17:1515–29. Dziewirski W, Rutkowski P, Zbigniew I, et al. Surgery combined with brachytherapy in patients with retroperitoneal sarcomas. J Contemp Brachy 2010;2:14–23. Pezner RD, Liu A, Chen YJ, et al. Full-dose adjuvant postoperative radiation therapy for retroperitoneal sarcomas. Am J Clin Oncol 2011;34:511–6. Zagar TM,Shenk RR,Kim JA,Harpp D,Kunos CA,Abdul-karim FW et al. Radiation therapy in addition to gross total resection of retroperitoneal sarcoma results in prolonged survival: results from a single institution study. J Oncol 2008;824036. Caudle AS, Tepper JE, Calvo BF, Meyers MO, Goyal LK, Cance WG, et al. Complications associated with neoadjuvant radiotherapy in the multidisciplinary treatment of retroperitoneal sarcomas. Ann Surg Oncol 2007;14:577–82.

301

[59] Ballo MT, Zagars GK, Pollock RE, Benjamin RS, Feig BJ, Cormier JN, et al. Retroperitoneal soft tissue sarcoma: an analysis of radiation and surgical treatment. Int J Radiat Oncol Biol Phys 2007;67:158–63. [60] Dziewirski W, Rutkowski P, Nowecki ZI, Salamacha M, Morysinki T, Tulik A, et al. Surgery combined with intraoperative brachytherapy in the treatment of retroperitoneal sarcomas. Ann Surg Oncol 2006;13:245–52. [61] Pawlik TM, Pisters PW, Mikula L, Feig B, Hunt KK, Cormient JN, et al. Long-term results of two prospective trials of preoperative external beam radiotherapy for localized intermediate.or high-grade retroperitoneal soft tissue sarcoma. Ann Surg Oncol 2006;13:508–17. [62] Pierie JP, Betensky RA, Choudry U, Willett CG, Souba WW, Ott MJ. Outcomes in a series of 103 retroperitoneal sarcomas. EJSO 2006;32:1235–41. [63] Bobin JY, Al-Lawati T, Granero LE, Adham M, Romestaing P, Chapet O, et al. Surgical management of retroperitoneal sarcomas associated with external and intraoperative electron beam radiotherapy. Eur J Surg Oncol 2003;29:676–81. [64] De Paoli A, Bertola G, Boz G, et al. Intraoperative radiation therapy for retroperitoneal soft tissue sarcomas. J Exp Clin Cancer Res 2003;22:157–61. [65] Gilbeau L, Kantor G, Stoeckle E, Lagarde P, Thomas L, Kind M, et al. Surgical resection and radiotherapy for primary retroperitoneal soft tissue sarcoma. Radiother Oncol 2002;65:137–43. [66] Gieschen HL, Spiro IJ, Suit HD, Ott MJ, Rattner DW, Ancukiewicz M, et al. Longterm results of intraoperative electron beam radiotherapy for primary and recurrent retroperitoneal sarcoma. Int J Radiat Oncol Biol Phys 2001;50:127–31. [67] Alektiar KM, Hu K, Anderson L, Brennan MF, Harrison L. High-dose rate intraoperative radiation therapy (HDR-IORT) for retroperitoneal sarcomas. Int J Radiat Oncol Biol Phys 2000;47:157–63. [68] Bussières E, Stöckle EP, Richaud PM, Avril AR, Kind MM, Kantor G, et al. Retroperitoneal soft tissue sarcomas: a pilot study of intraoperative radiation therapy. J Surg Oncol 1996;62:49–56. [69] Gunderson LL, Nagorney DM, McIllrath DC, et al. External beam and intraoperative electron irradiation for locally advanced soft tissue sarcomas. Int J Radiat Oncol Biol Phys 1993;25:647–56. [70] Willett CG, Suit HD, Tepper JE, et al. Intraoperative electron beam radiation therapy for retroperitoneal soft tissue sarcomas. Cancer 1991;68:278–83. [71] Kinsella TJ, Sindelar WF, Lack E, Glatstein E, Rosenberg SA. Preliminary results of a randomized study of adjuvant radiation therapy in resectable adult retroperitoneal soft tissue sarcomas. J Clin Oncol 1988;6:18–25. [72] Van de Voorde L, Delrue L, van Eijkeren M, de Meerleer G. Radiotherapy and surgery – an indispensable duo in the treatment of retroperitoneal sarcoma. Cancer 2011;117:4355–64. [73] Kunos C, Colussi V, Getty P, Kinsella T. Intraoperative electron radiotherapy for extremity sarcomas does not increase acute or late morbidity. Clin Orthop Rel Res 2005;446:247–52. [74] Gunderson LL, Nelson H, Martenson JA, Cha S, Haddock M, Devine R, et al. Locally advanced primary colorectal cancer: intraoperative electron and external beam irradiation +/- 5-FU. Int J Radiat Oncol Biol Phys 1997;37:601–14. [75] Haddock, MG, Miller RC, Nelson H. Pemberton JH, Dozois EJ, Alberts SR, Gunderson LL. Combined modality therapy including intraoperative electron irradiation for locally recurrent colorectal cancer. Int J Radiat Oncol Biol Phys 2011;79:143-50. [76] Gortzak Y, Lockwood GA, Mahendra A (2010) et al. Prediction of pathologic fracture risk of the femur after combined modality treatment of soft tissue sarcoma of the thigh. Cancer. 116:1553-9. [77] Andrä C, Klein A, Dürr HR, Rauch J, Lindner LH, Knoesel T, et al. External-beam radiation therapy combined with limb-sparing surgery in elderly patients (>70years) with primary soft-tissue sarcomas of the extremities: a retrospective analysis. Strahlenther Onkol 2017;193:604–11. [78] Miller RC, Haddock MG, Petersen IA, Gundersson LL, Furth AF. Intraoperative electron-beam radiotherapy and ureteral obstruction. Int J Radiat Oncol Biol Phys 2006;64:792–8. [79] Haas RL, Delaney TF, ÓSullivan B, Keus RB, Le pechoux C, Olmi P, Poulsen JP, Seddon B, Wang D. Radiotherapy for management of extremity soft tissue sarcomas: why, when, and where ?. Int J Radiat Oncol Biol Phys 2012;84:57280. [80] Wang D, Bosch W, Roberge D, Finkelstein SE, Petersen I, Haddock M, et al. Int J Radiat Oncol Biol Phys 2011;81:525–8. [81] Baldini EH, Wanf D, Haas RL, et al. Treatment guidelines for preoperative radiation therapy for retroperitoneal sarcoma: preliminary consensus of an international expert panel. Int J Rdiat Oncol Biol Phys 2015;92:602–12. [82] Pisters PW, Ballo MT, Fenstermacher MJ, Feig BW, Hunt KK, Raymond KA, et al. Phase I trial of preoperative concurrent doxorubicin and radiation therapy, surgical resection and intraoperative electron-beam radiation therapy for patients with localized retroperitoneal sarcoma. J Clin Oncol 2003;21:3092–7. [83] Tzeng CW, Fiveash JB, Popple RA, et al. Preoperative radiation therapy with selective dose escalation to the margin at risk for retroperitoneal sarcoma. Cancer 2006;107:371–437. [84] Swanson EL, Indelicato DJ, Louis D, et al. Comparison of three dimensional (3D) conformal proton radiotherapy (RT),3D conformal photon RT, and intensity – modulated RT for retroperitoneal and intra-abdominal sarcomas. Int J Radiat Oncol Biol Phys 2012;83:1549–57. [85] European Organisation for Research and Treatment of Cancer. EORTC Protocol 62092-22092: a phase randomized study of preoperative radiotherapy plus surgery versus surgery alone for patients with retroperitoneal sarcomas

109

302

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(RPS)-STRASS 2012.https://www.eortc.be/clinicaltrials/Details.asp?protocol= 62092&. [86] McBride SM, Raut CP, Lapidus M, et al. Locoregional recurrence after preoperative radiation therapy for retroperitoneal sarcoma: Adverse impact of multifocal disease and potential implications of dose escalation. Ann Surg Oncol 2013;20:2140–7. [87] Dickie C, ÓSullivan B. Target volume delineation and treatment planning for conformal radiation therapy (IMRT). In: Lu JJ, Lee NY, editors. Target volume

110

delineation and field setup: a practical guide for conformal and intensitymodulated radiation therapy. Berlin: Springer; 2013. [88] Delaney TF, Chen YL, Baldini et al. Phase 1 trial of preoperative image guided intensity modulated proton radiation therapy with simultaneously integrated boost to the high risk margin for retroperitoneal sarcomas. Adv Radiat Oncol 2017;2:85-93.

Practical Radiation Oncology (2017) 7, 73-79

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Special Article

Accelerated Partial Breast Irradiation: Executive summary for the update of an ASTRO EvidenceBased Consensus Statement Candace Correa MD a , Eleanor E. Harris MD b , Maria Cristina Leonardi MD c , Benjamin D. Smith MD d , Alphonse G. Taghian MD, PhD e , Alastair M. Thompson MD f , Julia White MD g , Jay R. Harris MD h,⁎ a

Department of Radiation Oncology, Faxton St. Luke's Healthcare, Utica, New York Department of Radiation Oncology, East Carolina University, Greenville, North Carolina c Department of Radiation Oncology, European Institute of Oncology, Milan, Italy d Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas e Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts f Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas g Department of Radiation Oncology, Ohio State University Cancer Center, Columbus, Ohio h Department of Radiation Oncology, Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts b

Received 18 August 2016; accepted 12 September 2016

Abstract Purpose: To update the accelerated partial breast irradiation Consensus Statement published in 2009 and provide guidance on use of intraoperative radiation therapy (IORT) for partial breast irradiation in earlystage breast cancer, based on published evidence complemented by expert opinion. Methods and materials: A systematic PubMed search using the same terms as the original Consensus Statement yielded 419 articles; 44 articles were selected. The authors synthesized the published evidence and, through a series of conference calls and e-mails, reached consensus regarding the recommendations. Supplementary material for this article (doi:10.1016/j.prro.2016.09.007) can be found at www.practicalradonc.org. Conflicts of interest: Before initiation of this update, all members of the Update Task Force were required to complete disclosure statements. These statements are maintained at the American Society for Radiation Oncology (ASTRO) Headquarters in Arlington, Virginia, and pertinent disclosures are published with this report. The ASTRO Conflict of Interest Disclosure Statement seeks to provide a broad disclosure of outside interests. Where a potential conflict is detected, the disclosure and any remedial measures to address potential conflicts are taken and noted in the consensus statement.BDS receives research funding from Varian Medical Systems. MCL holds position of the National Coordinator of IORT Working Group on behalf of the Italian Society of Radiation Oncology and is the co-investigator in an ongoing boost IORT followed by extreme hypofractionation to whole breast with IMRT in postmenopausal women. AT is a site principal investigator for the Targeted Intraoperative Radiotherapy (TARGIT-A) trial and coauthor for the resulting publication. EEH is the writing committee member for the TARGIT-A trial and a coauthor for the resulting publication; she is also a principal investigator for the NRG institutional and committee member for the NRG Breast Cancer Working Group. JW receives research funding from the Komen Foundation and IntraOp Medical and paid travel expenses and research funding from Qfix; she is also a member of the National Cancer Institute (NCI) Breast Cancer Steering Group and a member-liaison of the NCI Breast Cancer Local Disease Task Force. CC is a steering committee member of the Early Breast Cancer Trialists Collaborative Group (EBCTCG). None of the relationships disclosed was viewed as having any substantive impact upon the consensus statement. Each author contributed equally on the consensus statement. ⁎ Corresponding author. Jay R. Harris, MD, Distinguished Professor, Department of Radiation Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave., Rm YC1472, Boston, MA 02215. E-mail address: jay_harris@dfci.harvard.edu (J.R. Harris). http://dx.doi.org/10.1016/j.prro.2016.09.007 1879-8500/© 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

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Results: The new recommendations include lowering the age in the “suitability group” from 60 to 50 years and in the “cautionary group” to 40 years for patients who meet all other elements of suitability (Table 1). Patients with low-risk ductal carcinoma in situ, as per Radiation Therapy Oncology Group 9804 criteria, were categorized in the “suitable” group. The task force agreed to maintain the current criteria based on margin status. Recommendations for the use of IORT for breast cancer patients include: counseling patients regarding the higher risk of ipsilateral breast tumor recurrence with IORT compared with whole breast irradiation; the need for prospective monitoring of long-term local control and toxicity with low-energy radiograph IORT given limited follow-up; and restriction of IORT to women with invasive cancer considered “suitable.” Conclusion: These recommendations will provide updated clinical guidance regarding use of accelerated partial breast irradiation for radiation oncologists and other specialists participating in the care of breast cancer patients. © 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

Introduction Accelerated partial breast irradiation (APBI) is a localized form of radiation delivered after lumpectomy to only the part of the breast where the tumor was removed. This procedure requires close collaboration between the surgeon and the radiation oncologist. When compared with whole breast irradiation (WBI), APBI offers several benefits, including reducing treatment time and sparing healthy tissue. Initial research indicates APBI can be as effective as WBI in terms of survival and controlling local recurrences in select patients. Recently, interest has also grown in intraoperative radiation therapy (IORT), which treats the partial breast with a single dose of radiation using either low-energy radiographs or electrons, most commonly delivered at the time of surgery. The American Society for Radiation Oncology (ASTRO) consensus statement on APBI was originally published in 2009. The Board of Directors approved the proposal to partially update consensus statement in January 2015. This update addresses key question (KQ) 1 from the original guideline: Which patients may be considered for APBI outside of a clinical trial? It also considers a new KQ: Which patients may be considered for intraoperative partial breast irradiation (PBI)? This update is endorsed by the Society of Surgical Oncology.

Methods For information on the literature review, the grading of the recommendations and evidence, and the consensus methodology, please see the full version (supplementary materials at www.practicalradonc.org).

Results KQ1: Which patients may be considered for APBI outside of a clinical trial? Age Recommendation Statements: A. Include age greater than or equal to 50 years in the “suitable” group (moderate quality of evidence [MQE], recommendation rated as “Weak,” 100% Agreement).

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B. Patients who are aged 40 to 49 years and who meet all other elements of suitability are considered “cautionary” (lower quality of evidence, recommendation rated as “Weak,” 100% Agreement). C. Retain patients with age younger than 40 years or those who are 40 to 49 years without meeting other elements of suitable in the “unsuitable” group (no evidence rating, recommendation rated as “Weak,” 100% Agreement). Three randomized trials evaluating APBI versus WBI have been published or updated since the original ASTRO consensus statement. In the Groupe Européen de Curiethérapie of the European Society for Radiotherapy and Oncology (GEC-ESTRO) trial, 1184 patients were enrolled in a phase 3, noninferiority trial and were randomized to WBI plus a tumor bed boost or APBI delivered with multicatheter interstitial brachytherapy. 1 The 5-year risk of ipsilateral breast tumor recurrence (IBTR) was less than 2% in both treatment arms, and the study concluded that APBI was not inferior to WBI. In addition, there were no differences in toxicity through 5 years. The lower limit of age on the GEC-ESTRO trial was 40 years, and there was no evidence of increased risk of IBTR with APBI for women in their 40s. However, only 14% of women enrolled were b50 years of age. 1 In the National Institute of Oncology Budapest trial in which 128 received primarily multicatheter brachytherapy APBI, 23% of patients were younger than age 50. In this trial, patients younger than age 40 were excluded after 2001 because of an early analysis that reported unacceptably high IBTR risk in these patients. 2 At a median follow-up of 10.2 years, 5.5% had an in-breast recurrence, but no further analysis by age was done. 3 In the University of Florence trial, 15.8% of the 260 randomized to intensity modulated radiation therapy (IMRT) APBI were b50 years old. With a median follow-up of 5 years, 1.5% had an in-breast recurrence and age was not a significant factor associated with recurrence. 4 In each trial, roughly 90% or more of enrolled patients had T1, N0 and hormone-sensitive disease. Data from other large randomized phase 3 trials evaluating APBI, including the National Surgical Adjuvant Breast and Bowel Project B39/Radiation Therapy Oncology Group (RTOG) 0413 trial 5 and Randomized Trial of Accelerated Partial Breast Irradiation trials, 6 are pending.

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Updates to institutional prospective studies of APBI cited in the original Consensus Statement have also been reviewed. The Austrian Multi Institutional study has reported its findings specifically for age. 7 In this phase 2 study of 274 stage I, hormone-sensitive breast cancer patients who received multicatheter APBI, 5-year local recurrence for patients b50 years of age was 7.5%, and for patients ≥50 years was 1.1% (P = .030). Younger women were more likely to have received chemotherapy, and those with chemotherapy less likely to have had anti-hormone therapy (AHT). Five-year local recurrence for hormone-sensitive patients (n = 264) with AHT was 1.1%, and without AHT was 12% (0.0087). In an analysis from 3 prospective trials studying mostly brachytherapy delivery of APBI at William Beaumont Hospital, the lack of adjuvant tamoxifen therapy use, age b50, and estrogen receptor(-) status were significantly associated with the development of in-breast recurrence. 8 In the Massachusetts General Hospital phase 2 trial of 3-dimensional (3D) conformal radiation therapy (3D-CRT) APBI, an IBTR occurred in 2 of 15 women aged 40 to 49 (14% actuarial risk) compared with 3 of 83 in those age ≥50 years (3% actuarial risk), with median follow-up 71 months, although this difference was not statistically significant. 9 The 2 patients less than 50 years of age who had an IBTR both had triple negative disease. Among APBI registry studies that have updated results, Shah reported no difference by age in invasive ductal patients treated with APBI in the American Society of Breast Surgeons MammoSite registry trial final analysis, although in ductal carcinoma in situ (DCIS) patients, the 5-year IBTR rate was 19% in those aged b50 compared with 5.8% for aged N50 years. 10

Margins Recommendation statement A. Maintain the current selection criteria for “suitable,” “cautionary,” and “unsuitable” patients based on margin status (no evidence rating, recommendation rated as “Weak,” 75% Agreement).

Pure DCIS Recommendation statement: A. Include patients with low-risk DCIS as per RTOG 9804 criteria (ie, screen-detected, low to intermediate nuclear grade, less than or equal to 2.5 cm size, resected with margins negative at ≥3 mm), in the “suitable” group (MQE, recommendation rated as “Weak,” 100% Agreement). The RTOG 9804 randomized clinical trial included women with screen-detected DCIS, low to intermediate nuclear grade, ≤2.5 cm size, resected with margins negative at ≥3 mm. 11 With a median follow-up of 7.2 years, risk of IBTR was 6.7% risk in the observation arm

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compared with 0.9% in the WBI arm. Similar results were noted in the initial publication of the Eastern Cooperative Oncology Group (ECOG) 5194 trial among patients meeting similar criteria, with observation yielding a 6.1% risk of IBTR at 6.7 years’ median follow-up and 14.4% risk at 12 years. 12,13 These inclusion criteria therefore define a group of patients with low-risk DCIS for whom observation confers a low absolute risk of IBTR and for whom the addition of WBI confers a small but measurable absolute benefit in prevention of IBTR. When applied to APBI, 41 patients in the MammoSite registry met the low-risk enrollment criteria for the ECOG 5194 study and experienced a 5-year risk of an IBTR of 0%. 14 The 5-year rate of IBTR among all 194 DCIS patients in the MammoSite registry was 3.4%. 15 A pooled analysis of 300 women with DCIS from the MammoSite registry and a single institution similarly showed a 2.6% 5-year risk of IBTR. 16 In addition, a single-institution study evaluating 99 DCIS patients treated with either balloon brachytherapy, interstitial brachytherapy, or 3D-CRT external beam radiation therapy (EBRT) APBI demonstrated a 1.4% 5-year risk of IBTR. 17 When analyzed by the ECOG 5194 risk criteria, the risk was 2% for patients meeting these low-risk criteria. Other series similarly showed a 0% 5-year IBTR risk among 32 women with DCIS treated with multicatheter brachytherapy. 18 In contrast, one single-institution investigation reported a trend toward higher risk of time to IBTR among pure DCIS tumors compared with invasive ductal carcinomas at 4 years after MammoSite (hazard ratio, 3.57; P = .06). 19 One prospective multicenter trial using MammoSite in 41 DCIS patients showed a 9.8% 5-year risk of IBTR, all outside the treatment field. 20 Data from randomized trials of APBI versus WBI with selection criteria including patients with DCIS are pending. However, given the low risk of IBTR in low-risk DCIS with wide local excision alone, coupled with favorable results following APBI for low-risk DCIS in several series, the task force recommends inclusion of low-risk DCIS patients in the “suitable” group. The work group notes that hormonal therapy alone or observation may also be appropriate therapy for certain patients in this favorable subset.

New key question: Which patients may be considered for intraoperative PBI? Recommendation statements: A. Patients interested in cancer control equivalent to that achieved with WBI postlumpectomy for breast conservation should be counseled that in 2 clinical trials the risk of IBTR was higher with IORT (high quality of evidence, recommendation rated as “Strong,” 87.5% Agreement).

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Table 1

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Comparison of patient groups in original and updated consensus statements

Patient group

Risk factor

Original

Update

Suitability

Age Margins T stage DCIS

≥60 y Negative by at least 2 mm T1 Not allowed

≥50 y No change Tis or T1 If all of the below: • Screen-detected • Low to intermediate nuclear grade • Size ≤2.5 cm • Resected with margins negative at ≥3 mm

Cautionary

Age

50-59 y

Margins DCIS

Close (b2 mm) ≤3 cm

• 40-49 y if all other criteria for "suitable" are met • ≥50 y if patient has at least 1 of the pathologic factors below and does not have any "unsuitable" factors Pathologic factors: • Size 2.1-3.0 cm a • T2 • Close margins (b2 mm) • Limited/focal LVSI • ER(-) • Clinically unifocal with total size 2.1-3.0 cm b • Invasive lobular histology • Pure DCIS ≤3 cm if criteria for "suitable" not fully met • EIC ≤3 cm No change ≤3 cm and does not meet criteria for “suitable”

Age

b50 years

Margins DCIS

Positive N3 cm

Unsuitable

• b40 y • 40-49 y and do not meet the criteria for cautionary No change No change

The size of the invasive tumor component. Microscopic multifocality allowed, provided the lesion is clinically unifocal (a single discrete lesion by physical examination and ultrasonography/ mammography) and the total lesion size (including foci of multifocality and intervening normal breast parenchyma) falls between 2.1 and 3.0 cm. b

B. Electron beam IORT should be restricted to women with invasive cancer considered “suitable” for PBI (Table 1) based on the results of a multivariate analysis with median follow-up of 5.8 years (MQE recommendation rated as “Strong,” 100% Agreement). C. Low-energy x-ray IORT for PBI should be used within the context of a prospective registry or clinical trial, per ASTRO Coverage with Evidence Development (CED) statement. When used, it should be restricted to women with invasive cancer considered “suitable” for partial breast irradiation (Table 1) based on the data at the time of this review (MQE, recommendation rated as “Weak”).

Clinical trials Two large phase 3 trials, the Intraoperative radiotherapy with electrons (ELIOT) trial and the TARGIT trial, compared WBI with IORT PBI using either electron beam (ELIOT) 21 or low-energy x-rays (Intrabeam device, TARGIT). 22 Both trials reported increased risk of IBTR after IORT. In ELIOT, the 5-year IBTR risk was 4.4% (35/651) after IORT versus 0.4% (4/654) after WBI.

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ELIOT has a median of 5.8 years follow up (n =1305). However, ELIOT patients with invasive cancer fitting the “suitability” criteria had a very low rate of IBTR. 23 Among these patients, the 5-year occurrence of IBTR was approximately 1.5%, pointing out the importance of patient selection. 23 In TARGIT, the 5-year IBTR risk was 3.3% (23/3375) in the low-energy x-ray IORT arm compared to 1.3% (11/3375), (P = .042) in the WBI arm. 22 The overall median follow up for TARGIT is 2.4 years (n = 3451). The task force acknowledges that the initial 1222 patients have a median follow up of five years, however notes the five-year IBTR risk is based on the overall short follow up of the TARGIT trial, which limits precision of the five-year risk estimates. Although there was no statistically significant difference in IBTR risk for patients treated with IORT versus WBI in the TARGIT prepathology subgroup (2.1% (10 of 2234) with IORT vs 1.1% (6 of 2234) with WBI), 22 the task force thought greater weight should be placed on evaluation of the efficacy of IORT in the prespecified primary analysis population that included all patients. The task force also noted concerns from the chair of the TARGIT Data Monitoring Committee

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regarding misuse of the noninferiority criterion and the responses from the authors. 24,25 For these reasons, the task force felt low-energy x-ray IORT should continue to be used within the context of a prospective registry or clinical trial to ensure long-term local control and toxicity outcomes are prospectively monitored. Further, given the increased risk of IBTR, the task force advised that low-energy x-ray IORT, when used, be confined to patients with the lowest risk of IBTR, specifically those in the “suitable” group (Table 1). Since there are no data on the use of IORT with DCIS, the task force recommended its use be limited to patients with invasive breast cancer. These statements will be reconsidered and revised as appropriate when important new evidence warrants modification of the recommendation.

Adverse effects Adverse effects are different after IORT compared with WBI. In the available trials, fat necrosis 26,27 was increased with IORT, whereas skin side effects were lower. 24,26 Mild breast fibrosis 26,28,29 occurred with electron beam radiation on ELIOT, with no significant difference compared with WBI in the ELIOT trial. 26 IORT techniques may allow improved critical organ sparing compared with WBI. Lung fibrosis in the ELIOT trial 30 and deaths from cardiovascular causes in the TARGIT trial were lower in the IORT groups. 8 In some studies, low-energy radiographs followed by WBI was associated with double the risk of breast fibrosis (to 37.5%), increased patient-reported pain, and decreased patient-reported quality of life compared with WBI alone. 30-33 In contrast, other studies have reported outcomes with IORT followed by WBI that appear acceptable and comparable to either WBI alone or WBI with a conventional EBRT boost. 33-35 As such, the task force felt the combination of IORT and WBI should be used only with caution and limited to women with higher risk features on final pathology.

Additional considerations Patients meeting criteria for treatment with IORT generally have a low absolute risk of IBTR, yet this risk persists over a long period, likely at least 10 years. These biologic considerations, coupled with the current follow-up reported from the ELIOT and TARGIT trials, it is recommended that patients treated with IORT undergo routine long-term follow-up for at least a 10 years to screen for IBTR.

Comment on external beam APBI Since 2009, several key studies have provided important new data on the complication profile of APBI delivered with EBRT 3D-CRT or IMRT. Most important,

APBI consensus statement update

the Randomized Trial of Accelerated Partial Breast Irradiation trial randomized 2135 patients to WBI or 3D-CRT APBI. 6 Although the IBTR risk has not yet been reported, cosmetic outcome, as assessed separately by patients, nurses, and physician panels, was consistently worse at 3 and 5 years in patients randomized to 3D-CRT APBI. 15 In contrast, the University Florence phase 3 trial reported that IMRT APBI resulted in improved physician-rated cosmetic outcome compared with WBI. 4 Single-arm studies have also reported higher rates of fair to poor cosmetic outcomes in approximately 20% of patients treated with EBRT-based APBI. 29,36,37 However, other clinical series of APBI delivered with 3D-CRT or IMRT reported acceptable cosmetic outcomes. 9,38-45 These conflicting studies raise the hypothesis that subtle variations in planning techniques and/or dose constraints may substantially modify the therapeutic ratio of EBRT-based APBI. 46-48 In light of ongoing research, particularly the National Surgical Adjuvant Breast and Bowel Project B-39/RTOG 0413 trial, 5 which has yet to report cosmetic outcomes for patients treated with 3D-CRT APBI, the task force opted not to make a specific recommendation either for or against the use of EBRT-based APBI at this time.

Conclusion APBI has been tested in a limited number of trials with more than 1000 patients over the past 10 years. These trials show that, in properly selected breast cancer patients, APBI has provided outcomes similar to WBI. In light of new literature, the suitability criteria for APBI have now been updated, as summarized in Table 1. It is hoped that this update will provide ongoing direction for radiation oncologists and other specialists participating in the care of breast cancer patients.

Acknowledgments The authors thank expert reviewers Bruce Haffty, MD, FACR, FASTRO; Thomas Buchholz, MD, FACR, FASTRO; Catherine Park, MD; Lori Pierce, MD, FASCO, FASTRO; and ASTRO staff members Margaret Amankwa-Sakyi, Sokny Lim, and Caroline Patton for literature review assistance and administrative support. This document was prepared by the Accelerated Partial Breast Irradiation Update task force. ASTRO guidelines present scientific, health, and safety information and may to some extent reflect scientific or medical opinion. They are made available to ASTRO members and to the public for educational and informational purposes only. Any commercial use of any content in this guideline without the prior written consent of ASTRO is strictly prohibited. Adherence to this guideline will not ensure successful

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treatment in every situation. Furthermore, this guideline should not be deemed inclusive of all proper methods of care or exclusive of other methods of care reasonably directed to obtaining the same results. The ultimate judgment regarding the propriety of any specific therapy must be made by the physician and the patient in light of all circumstances presented by the individual patient. ASTRO assumes no liability for the information, conclusions, and findings contained in its guidelines. In addition, this guideline cannot be assumed to apply to the use of these interventions performed in the context of clinical trials, given that clinical studies are designed to evaluate or validate innovative approaches in a disease for which improved staging and treatment are needed or are being explored. This guideline was prepared on the basis of information available at the time the task force was conducting its research and discussions on this topic. There may be new developments that are not reflected in this guideline update, and that may, over time, be a basis for ASTRO to consider revisiting and updating the guideline.

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11.

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13.

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References 17. 1. Strnad V, Ott OJ, Hildebrandt G, et al. 5-year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: a randomised, phase 3, non-inferiority trial. Lancet. 2016;387(10015):229-238. 2. Polgar C, Major T. Current status and perspectives of brachytherapy for breast cancer. Int J Clin Oncol. 2009;14(1):7-24. 3. Polgar C, Fodor J, Major T, Sulyok Z, Kasler M. Breast-conserving therapy with partial or whole breast irradiation: ten-year results of the Budapest randomized trial. Radiother Oncol. 2013;108(2):197-202. 4. Livi L, Meattini I, Marrazzo L, et al. Accelerated partial breast irradiation using intensity-modulated radiotherapy versus whole breast irradiation: 5-year survival analysis of a phase 3 randomised controlled trial. Eur J Cancer. 2015;51(4):451-463. 5. Radiation Therapy (WBI Versus PBI) in Treating Women Who Have Undergone Surgery For Ductal Carcinoma In Situ or Stage I or Stage II Breast Cancer. https://clinicaltrials.gov/ct2/show/NCT00103181? term=NSABP+B-39%2FRTOG+0413&rank=2. Accessed 10/21/2016. 6. Olivotto IA, Whelan TJ, Parpia S, et al. Interim cosmetic and toxicity results from RAPID: a randomized trial of accelerated partial breast irradiation using three-dimensional conformal external beam radiation therapy. J Clin Oncol. 2013;31(32):4038-4045. 7. Ott OJ, Hildebrandt G, Potter R, et al. Accelerated partial breast irradiation with multi-catheter brachytherapy: Local control, side effects and cosmetic outcome for 274 patients. Results of the German-Austrian multi-centre trial. Radiotherapy and oncology journal of the European Society for Therapeutic Radiology and Oncology. 2007;82(3):281-286. 8. Shah C, Wilkinson JB, Lyden M, Beitsch P, Vicini FA. Predictors of local recurrence following accelerated partial breast irradiation: a pooled analysis. International journal of radiation oncology, biology, physics. 2012;82(5):e825-e830. 9. Pashtan IM, Recht A, Ancukiewicz M, et al. External beam accelerated partial-breast irradiation using 32 gy in 8 twice-daily

116

18.

19.

20.

21.

22.

23.

24.

25.

fractions: 5-year results of a prospective study. Int J Radiat Oncol Biol Phys. 2012;84(3):e271-e277. Shah C, Wilkinson JB, Keisch M, et al. Impact of margin status on outcomes following accelerated partial breast irradiation using single-lumen balloon-based brachytherapy. Brachytherapy. 2013;12(2):91-98. McCormick B, Winter K, Hudis C, et al. RTOG 9804: a prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation. J Clin Oncol. 2015;33(7):709-715. Hughes LL, Wang M, Page DL, et al. Local excision alone without irradiation for ductal carcinoma in situ of the breast: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009;27(32): 5319-5324. Solin LJ, Gray R, Hughes LL, et al. Surgical Excision Without Radiation for Ductal Carcinoma in Situ of the Breast: 12-Year Results From the ECOG-ACRIN E5194 Study. J Clin Oncol. 2015;33(33):3938-3944. Goyal S, Vicini F, Beitsch PD, et al. Ductal carcinoma in situ treated with breast-conserving surgery and accelerated partial breast irradiation: comparison of the Mammosite registry trial with intergroup study E5194. Cancer. 2011;117(6):1149-1155. Jeruss JS, Kuerer HM, Beitsch PD, Vicini FA, Keisch M. Update on DCIS outcomes from the American Society of Breast Surgeons accelerated partial breast irradiation registry trial. Ann Surg Oncol. 2011;18(1):65-71. Vicini F, Shah C, Ben Wilkinson J, Keisch M, Beitsch P, Lyden M. Should ductal carcinoma-in-situ (DCIS) be removed from the ASTRO consensus panel cautionary group for off-protocol use of accelerated partial breast irradiation (APBI)? A pooled analysis of outcomes for 300 patients with DCIS treated with APBI. Ann Surg Oncol. 2013;20(4):1275-1281. Shah C, McGee M, Wilkinson JB, et al. Clinical outcomes using accelerated partial breast irradiation in patients with ductal carcinoma in situ. Clin Breast Cancer. 2012;12(4):259-263. McHaffie DR, Patel RR, Adkison JB, Das RK, Geye HM, Cannon GM. Outcomes after accelerated partial breast irradiation in patients with ASTRO consensus statement cautionary features. Int J Radiat Oncol Biol Phys. 2011;81(1):46-51. Zauls AJ, Watkins JM, Wahlquist AE, et al. Outcomes in women treated with MammoSite brachytherapy or whole breast irradiation stratified by ASTRO Accelerated Partial Breast Irradiation Consensus Statement Groups. Int J Radiat Oncol Biol Phys. 2012;82(1): 21-29. Abbott AM, Portschy PR, Lee C, et al. Prospective multicenter trial evaluating balloon-catheter partial-breast irradiation for ductal carcinoma in situ. Int J Radiat Oncol Biol Phys. 2013;87(3): 494-498. Veronesi U, Orecchia R, Maisonneuve P, et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial. Lancet Oncol. 2013;14(13):1269-1277. Vaidya JS, Wenz F, Bulsara M, et al. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet. 2014;383(9917): 603-613. Leonardi MC, Maisonneuve P, Mastropasqua MG, et al. How do the ASTRO consensus statement guidelines for the application of accelerated partial breast irradiation fit intraoperative radiotherapy? A retrospective analysis of patients treated at the European Institute of Oncology. Int J Radiat Oncol Biol Phys. 2012;83(3):806-813. Vaidya JS, Bulsara M, Wenz F, et al. Pride, Prejudice, or Science: Attitudes Towards the Results of the TARGIT-A Trial of Targeted Intraoperative Radiation Therapy for Breast Cancer. Int J Radiat Oncol Biol Phys. 2015;92(3):491-497. Cuzick J. Radiotherapy for breast cancer, the TARGIT-A trial. Lancet. 2014;383(9930):1716.

Practical Radiation Oncology: March-April 2017 26. Livi L, Buonamici FB, Simontacchi G, et al. Accelerated partial breast irradiation with IMRT: new technical approach and interim analysis of acute toxicity in a phase III randomized clinical trial. Int J Radiat Oncol Biol Phys. 2010;77(2):509-515. 27. Rampinelli C, Bellomi M, Ivaldi GB, et al. Assessment of pulmonary fibrosis after radiotherapy (RT) in breast conserving surgery: comparison between conventional external beam RT (EBRT) and intraoperative RT with electrons (ELIOT). Technol Cancer Res Treat. 2011;10(4):323-329. 28. Maluta S, Dall'Oglio S, Goer DA, Marciai N. Intraoperative Electron Radiotherapy (IOERT) as an Alternative to Standard Whole Breast Irradiation: Only for Low-Risk Subgroups? Breast care (Basel, Switzerland). 2014;9(2):102-106. 29. Leonardi MC, Maisonneuve P, Mastropasqua MG, et al. Accelerated partial breast irradiation with intraoperative electrons: using GEC-ESTRO recommendations as guidance for patient selection. Radiother Oncol. 2013;106(1):21-27. 30. Sperk E, Welzel G, Keller A, et al. Late radiation toxicity after intraoperative radiotherapy (IORT) for breast cancer: results from the randomized phase III trial TARGIT A. Breast Cancer Res Treat. 2012;135(1):253-260. 31. Chang DW, te Marvelde L, Chua BH. Prospective study of local control and late radiation toxicity after intraoperative radiation therapy boost for early breast cancer. Int J Radiat Oncol Biol Phys. 2014;88(1):73-79. 32. Welzel G, Hofmann F, Blank E, et al. Health-related quality of life after breast-conserving surgery and intraoperative radiotherapy for breast cancer using low-kilovoltage X-rays. Ann Surg Oncol. 2010;17(suppl 3):359-367. 33. Kraus-Tiefenbacher U, Bauer L, Scheda A, et al. Long-term toxicity of an intraoperative radiotherapy boost using low energy X-rays during breast-conserving surgery. Int J Radiat Oncol Biol Phys. 2006;66(2):377-381. 34. Blank E, Kraus-Tiefenbacher U, Welzel G, et al. Single-center long-term follow-up after intraoperative radiotherapy as a boost during breast-conserving surgery using low-kilovoltage x-rays. Ann Surg Oncol. 2010;17(suppl 3):352-358. 35. Welzel G, Boch A, Sperk E, et al. Radiation-related quality of life parameters after targeted intraoperative radiotherapy versus whole breast radiotherapy in patients with breast cancer: results from the randomized phase III trial TARGIT-A. Radiat Oncol. 2013;8:9. 36. Hepel JT, Tokita M, MacAusland SG, et al. Toxicity of three-dimensional conformal radiotherapy for accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys. 2009;75(5):1290-1296. 37. Jagsi R, Ben-David MA, Moran JM, et al. Unacceptable cosmesis in a protocol investigating intensity-modulated radiotherapy with active

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38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

breathing control for accelerated partial-breast irradiation. Int J Radiat Oncol Biol Phys. 2010;76(1):71-78. Chafe S, Moughan J, McCormick B, et al. Late toxicity and patient self-assessment of breast appearance/satisfaction on RTOG 0319: a phase 2 trial of 3-dimensional conformal radiation therapy-accelerated partial breast irradiation following lumpectomy for stages I and II breast cancer. Int J Radiat Oncol Biol Phys. 2013;86(5):854-859. Lei RY, Leonard CE, Howell KT, et al. Four-year clinical update from a prospective trial of accelerated partial breast intensitymodulated radiotherapy (APBIMRT). Breast Cancer Res Treat. 2013;140(1):119-133. Lewin AA, Derhagopian R, Saigal K, et al. Accelerated partial breast irradiation is safe and effective using intensity-modulated radiation therapy in selected early-stage breast cancer. Int J Radiat Oncol Biol Phys. 2012;82(5):2104-2110. Formenti SC, Hsu H, Fenton-Kerimian M, et al. Prone accelerated partial breast irradiation after breast-conserving surgery: five-year results of 100 patients. Int J Radiat Oncol Biol Phys. 2012;84(3):606-611. Rodriguez N, Sanz X, Dengra J, et al. Five-year outcomes, cosmesis, and toxicity with 3-dimensional conformal external beam radiation therapy to deliver accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys. 2013;87(5):1051-1057. Chen PY, Wallace M, Mitchell C, et al. Four-year efficacy, cosmesis, and toxicity using three-dimensional conformal external beam radiation therapy to deliver accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys. 2010;76(4):991-997. Reeder R, Carter DL, Howell K, et al. Predictors for clinical outcomes after accelerated partial breast intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys. 2009;74(1):92-97. Vera R, Trombetta M, Mukhopadhyay ND, Packard M, Arthur D. Long-term cosmesis and toxicity following 3-dimensional conformal radiation therapy in the delivery of accelerated partial breast irradiation. Pract Radiat Oncol. 2014;4(3):147-152. Shaitelman SF, Kim LH, Grills IS, et al. Predictors of long-term toxicity using three-dimensional conformal external beam radiotherapy to deliver accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys. 2011;81(3):788-794. Leonard KL, Hepel JT, Hiatt JR, Dipetrillo TA, Price LL, Wazer DE. The effect of dose-volume parameters and interfraction interval on cosmetic outcome and toxicity after 3-dimensional conformal accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys. 2013;85(3):623-629. Mellon EA, Sreeraman R, Gebhardt BJ, Mierzejewski A, Correa CR. Impact of radiation treatment parameters and adjuvant systemic therapy on cosmetic outcomes after accelerated partial breast irradiation using 3-dimensional conformal radiation therapy technique. Pract Radiat Oncol. 2014;4(3):e159-e166.

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ZEMEDI-10836; No. of Pages 10

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Commissioning, dosimetric characterization and machine performance assessment of the LIAC HWL mobile accelerator for Intraoperative Radiotherapy Peter Winkler ∗ , Stefan Odreitz-Stark, Eva Haas, Martin Thalhammer, Richard Partl Department of Therapeutic Radiology and Oncology, Medical University of Graz, Auenbrugger Platz 32, A-8036 Graz, Austria Received 2 March 2020; accepted 3 June 2020

Abstract Background: The LIAC HWL (Sordina IORT Technologies, Vicenza, Italy) is a recently designed mobile linear accelerator for intraoperative electron radiotherapy (IOeRT), producing high dose rate electron beams at four different energy levels. It features a software tool for the visualization of 2D dose distributions, which is based on Monte Carlo simulations. The aims of this work were to (i) assess the dosimetric characteristics of the accelerator, (ii) experimentally verify calculated data exported from the software and (iii) report on commissioning as well as performance of the system during the first year of operation. Methods: The electron energies of the LIAC HWL used in this study are 6, 8, 10 and 12 MeV. Diameters of the cylindrically shaped applicators range from 3 to 10 cm. We studied two applicator sets with different length ratios of proximal and terminal applicator sections. Reference dosimetry, linearity as well as short- and long-term stability were measured with a PTW Advanced Markus chamber, relative depth dose and profiles were measured using an unshielded diode. Percentage-depthdose (PDD) and transversal dose profile (TDP) data were exported from the simulation software LIACSim and compared with our measurements. Results: The device reaches dose rates up to 40 Gy/min (for 12 MeV). Surface doses for the 10 cm applicators are higher than 90%, X-ray background is below 0.6% for all energies. Simulations and measurements of PDD agreed well, with a maximum difference in the depth of the 50% isodose of 0.7 mm for the flat-ended applicators and 1 mm for the beveled applicators. The simulations slightly underestimate the dose in the lateral parts of the field (difference < 1.8% for flat-ended applicators). The two different applicator sets were dosimetrically equivalent. Long-term stability measurements for the first year of operation ranged from -2.1% to 1.6% (mean: -0.1%). Conclusions: The system is dosimetrically well suited for IOeRT and performed stably and reliably. The software tool for visualization of dose distributions can be used to support treatment planning, following thorough validation. Keywords: Intra operative electron radiotherapy, Dosimetry, Commissioning

∗ Corresponding

author. E-mail: peter.winkler@medunigraz.at (P. Winkler).

Z Med Phys xxx (2020) xxx–xxx https://doi.org/10.1016/j.zemedi.2020.06.004 www.elsevier.com/locate/zemedi

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1 Introduction In intraoperative radiotherapy (IORT), a high dose of radiation is delivered in a single fraction during a surgical procedure with direct access to the tumor or tumor bed. Various IORT techniques, using electrons, low-energy X-rays or HDR brachytherapy, are currently available and have been in clinical use for many years 1–3 for the treatment of several sites like breast,4,5 head-and-neck cancer,6 sarcomas,7,8 pancreatic cancer,9 rectal cancer10 and others. Ideally, the application of IORT is carried out in the operating theater (OR) to avoid the need for transferring the patient during the procedure. There are only a few systems for intraoperative electron radiotherapy that are approved by the regulatory bodies and are – or have in the past been – commercially available. To our best knowledge, the following systems are available: Novac 7, LIAC and LIAC HWL (Sordina IORT Technologies, Vicenza, Italy), with HWL standing for high workload, and Mobetron (IntraOp Medical Corporation, Sunnyvale, CA, USA). These machines are mobile, can be situated in the OR, and are maneuvered into the treatment position just before radiation. After completion of the docking procedure, i.e. the connection of the treatment head with the applicator part that is placed in the surgical area, the radiation treatment is accomplished. These IOeRT devices offer high dose rates of several Gy per minute.11,12 Available electron beam energies are typically in the range of 4 to 12 MeV. IOeRT machines are designed for light weight and are optimized to produce only low stray radiation. Beam stopping devices, either to be placed independently or integrated in the assembly of the machine, are utilized to shield stray radiation in the beam direction exiting the patient. These technical provisions, especially the low leakage or stray dose contamination, make it possible to operate IOeRT machines in ORs without the need for extensive constructional measures regarding structural design or radiation shielding.12–15 Although the design of IOeRT machines is rather elementary and the amount of beam-shaping and supplementary devices is limited, several physical assessments and quality assurance measures have to be carried out before a new system can be clinically used.13,16 Because of the fact that these devices produce a very high dose per pulse, special attention needs to be paid to the ion recombination correction factor (ks) of the ionization chamber used for reference dosimetry.17,18 Using the method proposed by Boag et al.19 and Laitano et al.,20 a reliable determination of ks for the Advanced Markus chamber (PTW Freiburg, Germany) is possible for dose-per-pulse rates up to 70 mGy. This has been cross-validated with film 17 and ferrous sulphate-dosimetry.18 An experimental study on ion recombination effect in the Advanced Markus chamber confirmed the assumption that ion recombination was dependent on the dose-per-pulse rather than the dose rate.21 It is not

recommended to use the two-voltage analysis (TV) approach described in the IAEA TRS-398 protocol.22 The LIAC (Sordina IORT Technologies, Vicenca, Italy) mobile IOeRT accelerator – the predecessor model of the LIAC HWL that is subject of our study - is available in two different energy configurations: (4, 6, 8 and 10 MeV or 6, 8, 10 and 12 MeV). The dose rates on this accelerator range up to 12 Gy/min for 12 MeV.23 Monte Carlo simulations for the dosimetric characteristics of this machine have been calculated and were compared with measurements.24–26 The dosimetric characteristics of the LIAC have also been compared to electron beams of similar nominal energy from a conventional Varian 2100C/D linear accelerator.11 This study showed that on the LIAC surface doses are higher and flatness in transversal dose profiles is better compared to the conventional accelerator. Iaccarino et al.24 attempted to characterize the beams of the LIAC dosimetrically with a minimal set of dosimetric data. For that purpose, simulated percentage depth dose (PDD) distributions were calculated by linear combinations of previously simulated mono-energetic electron beams. The optimal weights for the linear combinations were obtained by means of optimization, minimizing the difference between measurements and simulations. This approach serves as a basis for a dose planning tool, which is made available to customers together with LIAC machines (“LIAC MU Calculation” and “LIAC simulation”). This planning tool provides output factors as well as relative dose distributions in three dimensions calculated in water for all applicators and energy modes. It can provide a valuable benefit for the set-up of the treatment, provided that the simulations are thoroughly validated by measurements beforehand. To our best knowledge, no reports have been published yet on dosimetry, commissioning or machine performance of the LIAC HWL. This system is available since 2017 and has been re-designed by the manufacturer based on the predecessor model LIAC. The re-design involved electron scattering foils as well as changes in applicator design and length and hence influences dose rate, beam homogenization and, presumably, energy spectrum and depth dose. The aim of this study is to assess and report the dosimetric characteristics of the newly designed IOeRT machine LIAC HWL (S.I.T – Sordina IORT Technologies, Vicenza, Italy). To our best knowledge, no data concerning this device have been published yet. The second main aim of this study is the validation of machine-specific Monte Carlo simulated data that are provided by the manufacturer in the “LIAC MU Calculation” and “LIACsim” software modules. This validation is an essential requirement for the clinical use of the software. Furthermore, we examined two different applicator sets for dosimetric equivalence. Finally, we report on machine parameters we assessed during commissioning and on long-term beam stability of the system in the first year of operation.

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2 Materials and Methods 2.1 LIAC HWL mobile accelerator The LIAC HWL is a dedicated mobile accelerator designed for intraoperative electron radiations in the operating room. The machine is available in two different energy configurations: the “10 MeV model” with nominal energies of 4, 6, 8 and 10 MeV and the “12 MeV model” (6, 8, 10 and 12 MeV). Beam collimation is realized by means of PMMA (polymethylmethacrylate) applicators. These applicators have a cylindrical shape. Each applicator consists of an upper and a lower (terminal) part, connected with a hard docking junction. The overall length of an applicator is 40 cm, with diameters ranging from 3 cm to 10 cm. Applicators with 12 cm diameter are available but were not used in this study. There are four different bevel angles available (0◦ , 15◦ , 30◦ , 45◦ ). This study focuses on the flat-ended (0◦ ) applicators, results for the beveled applicators are presented in brief only. We have compared two different applicator sets: In set 1, the length of the upper and lower applicator parts are 16.5 cm and 23.5 cm, respectively; in set 2, these lengths are 10.5 cm and 29.5 cm, respectively. The source-to-surface distance of the LIAC HWL is 64.5 cm. This is 6.8 cm less compared to the predecessor model LIAC.11 While the configuration of the scattering foil system of the LIAC has been described in detail, only basic information has been disclosed by the manufacturer for the new LIAC HWL design. According to this information, a thin aluminum scattering foil and a 55 m titanium foil are the only metallic scattering components in the beam. The pulse rates in the standard clinical configuration are 10 Hz for 10/12 MeV, 15 Hz for 8 MeV and 20 Hz for 6 MeV, respectively. The nominal dose rates for the 10 cm diameter applicator as stated by the manufacturer range from 10 Gy/min (for 6 MeV) to 30 Gy/min (12 MeV), resulting in a very high dose per pulse. 2.2 Dosimetric equipment Output factor (OF), percentage depth dose and transverse dose profile measurements were performed in a small water phantom (MP3-XS, PTW, Freiburg, Germany) using an unshielded diode (Diode E, type 60017, PTW) 27 and a Unidos Electrometer (Unidos Webline, T10021, PTW). This detector has a disk-shaped silicon diode detector with a sensitive volume of 0.03 mm3 and a water-equivalent entrance window thickness of 1.33 mm. For reference dosimetry (absolute dose measurement in the reference conditions), we used a planeparallel ionization chamber (Advanced Markus chamber, type 34045, PTW) in combination with the Unidos electrometer with a bias voltage of 400 V. This ionization chamber has a vented sensitive volume of 0.02 cm3 , an electrode distance of 1 mm and a water-equivalent entrance window thickness of

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1.06 mm (including the protective cap for use in water). We used the method proposed by Laitano et al.20 to determine ks for each energy individually, and assessed the agreement with previously published values for beams with a similar dose per pulse. Changes in ks due to changing dose rate for different applicators were not For beam stability measurements, we used the Advanced Markus Chamber in a water-equivalent white polystyrene (RW3) slab phantom (PTW). We evaluated long-term stability and short-term stability of the machine for all energies. 2.3 Vendor-supplied Monte Carlo simulations and output factors The vendor provides Monte Carlo simulations, and a software package for visualization thereof (LIACSim), together with the machine. These machine-specific simulations are generated by adjusting combinations of monoenergetic simulated beams to measured beams for a subset of energy/applicator combinations.24 The simulations comprise the 3D dose distribution, modelled to fit the particular beam energies with respect to the PDD curves. Furthermore, OF for all applicators and energies are determined using Monte Carlo simulations by the vendor, based on a method proposed by Iaccarino et al..24 OF are defined as the ratio between the measured dose for a certain applicator and the dose of the 10 cm diameter applicator in the depth of dose maximum for each energy. Measuring and verifying these vendor-provided OF is not an obligatory part of the customer acceptance test procedure, but it has to be part of machine commissioning. We exported central-axis PDD and TDP at the depth of dose maximum from the vendor’s software in order to compare them quantitatively with our measurements. 2.4 Measurements 2.4.1 Dosimetric characteristics and evaluation parameters We measured OF, PDD and TDP, the latter at the depth of dose maximum, of all energy/applicator combinations for applicator set 1. Evaluation values (metrics) were used according to the vendor’s recommendations as described in the acceptance procedures. All evaluation parameters are listed in Table 1. We performed reference dosimetry according to IAEA TRS 398 22 with slight adaptions. Protocol-compliant reference conditions for the measurement of absorbed dose to water are not applicable for the LIAC HWL (SSD = 64.5 cm, no 10x10 cm2 field available). The reference depth as recommended by dosimetry protocols 13,22,28,29 (i.e. zref = 0.6 * R50 -0.1) is problematic for the beams of this machine, because it is significantly beyond the plateau region. Burns et al.30 recommended choosing a depth for reference dosimetry with a low dose gradient, to reduce the uncertainty associated with corrections related to the gradient. Considering these

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Table 1 Evaluation parameters for percentage depth dose (PDD) and transverse dose profile (TDP) curves. The flattened region f was defined as 80% of field width (the field width being defined by the 50% isodose). Parameter definitions are given where necessary. PDD Parameter Depth of dose max Depth of 90% dose value Depth of 50% dose value Practical range

Abbreviation R100 [mm] R90 [mm] R50 [mm] Rp [mm]

Dose value at 1 mm depth X-ray background# Most probable energy at phantom surface# Mean energy at phantom surface# TDP Field size Penumbra

D 1 mm [%] X-Ray Bck. [%] Ep0 [MeV] E0(mean) [MeV] FS [cm] Pen [mm]

Maximum dose value inside the flattened region Minimum dose value inside the flattened region Flatness Symmetry

Dmax [%] Dmin [%] Flat [%] Sym [%]

Field size at SID#

FS(SID) [cm]

Definition

The depth at which the tangent plotted through the steepest section of the PDD curve intersects with the extrapolation line of the bremsstrahlung background Value of the intersection from Rp calculation = 0.22 + 1.98*Rp + 0.0025 * Rp2 =0.656 + 2.059 * R50 + 0.022 * R502

Distance between 80% and 20% dose points, expressed as percentage of CAX dose (averaged for left & right field boundary)

Max. variation (Dmax – Dmin) / 2 within the flattened region Maximum dose ratio (D(x) / D(-x))max * 100% within the flattened region# FS * (SID / (SDD) with SDD = SID + measurement depth

Parameter calculated for flat-ended applicators (0◦ ) only.

circumstances, we followed the conclusion of Scalchi et al.18 and chose the depth of maximum dose (dmax ) for reference dosimetry. The measurement depth was adjusted to changing dmax for different applicators. For measurements with beveled applicators the accelerator was rotated in the xz-plane (“roll”) to compensate for the beveling. Hence, crossplane-TDP are scanned in the rotation plane of the accelerator (parallel to the bevel), inplane TDP parallel to the rotation axis.

2.4.2 Dosimetric equivalence of different applicator sets All aforementioned measurements were performed for applicator set 1 (length of terminal applicator: 23.5 cm). To assess the supposed dosimetric equivalence of the two applicators sets, we repeated the following measurements with applicator set 2 (length of terminal applicator: 29.5 cm): reference dosimetry (for the 10 cm diameter applicator), output factors (6 cm applicator), PDD and TDP (7 cm and 10 cm applicators), and finally the check used for the evaluation of long-term stability in a slab phantom. PDD and TDP measurements were compared using Low’s Gamma criterion31 with 1 mm distance-to-agreement and 1% dose difference tolerance levels. For all other measurements, a direct numerical comparison was done and relative deviations were calculated. The assessment of dosimetric equivalence of the two applicator sets was done for the flat-ended (0◦ bevel angle) applicators only.

2.4.3 Commissioning and machine performance parameters Checks of short-term stability and linearity were part of the acceptance procedure. For short-term stability, five measurements were performed consecutively and the range was calculated. This was repeated on three consecutive days. Linearity was analyzed by measuring the dose values for 300, 1000, 2000 and 3000 monitor units (MU), corresponding to 3 Gy, 10 Gy, 20 Gy and 30 Gy, respectively, and comparing the normalized dose values (dose/MU). This dose range contains the typical dose range in clinical irradiations. For both the short-term stability and linearity, the relative range (percentage ratio of the range to the average value) was calculated for the reference applicator for all available beam energies. Long-term stability of the machine was assessed by measurements of the output (300 MU) in a water-equivalent slab phantom for all energies. These measurements were repeated approximately every two weeks for a 12-month period. No re-calibration of the LIAC was done during this period. Deviations from the reference values in terms of mean value and standard deviation (SD) were calculated. 2.5 Uncertainty analysis For reference dosimetry (and all dependent parameters) we used the approach described in the IAEA TRS 398 protocol 22 to estimate measurement uncertainties, considering higher uncertainties for ks (3%) related to the high dose per pulse

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Table 2 Dose rates measured in reference dosimetry settings, pulse rates as preset by the system, calculated dose per pulse (DPP) and ion recombination correction factors (ks). Energy

6 MeV

8 MeV

10 MeV

12 MeV

Dose rate [Gy/min] Pulse rate [Hz] Dose per pulse [mGy] ks

10.7 ± 0.4 20 8.9 ± 0.3 1.0009 ± 0.03

15.7 ± 0.5 15 17.4 ± 0.6 1.0017 ± 0.03

19.2 ± 0.6 10 32.0 ± 1.0 1.0032 ± 0.03

26.9 ± 0.9 10 44.8 ± 1.5 1.0044 ± 0.03

Table 3 Output factors relative to the 10 cm applicator for all applicators and energies. Output factors Appl. \Energy

6 MeV

8 MeV

10 MeV

12 MeV

3 cm 4 cm 5 cm 6 cm 7 cm 8 cm 10 cm

1.186 ± 0.007 1.339 ± 0.008 1.358 ± 0.008 1.313 ± 0.008 1.255 ± 0.007 1.165 ± 0.006 1

1.317 ± 0.004 1.415 ± 0.004 1.408 ± 0.004 1.340 ± 0.004 1.266 ± 0.004 1.172 ± 0.004 1

1.421 ± 0.004 1.465 ± 0.004 1.424 ± 0.004 1.335 ± 0.004 1.250 ± 0.004 1.157 ± 0.003 1

1.500 ± 0.008 1.503 ± 0.008 1.441 ± 0.007 1.344 ± 0.007 1.246 ± 0.006 1.155 ± 0.005 1

17,20

and uncertainties for beam quality corrections published by Zink et al.32 The overall uncertainty in the measured OF values is given by the quadratic sum of the uncertainties originating from detector positioning, applicator positioning, and short-term stability of the machine, respectively (Type-A uncertainties according to ISO definitions 33 ). For the estimation of uncertainty in PDD and TDP parameters, we calculated 1 SD for six repeated measurements on different days (with a new machine- and phantom-setup) for the 10 cm applicator. All uncertainties were calculated for all energies separately. Simulations: The statistical error in the Monte Carlo simulations is less than 1.0% according to the manufacturer.24

and 0.2% for all other energies, for symmetry it is 0.8% for 6 MeV and 0.5% for all other energies. The measurement of the penumbra width exhibits uncertainties of 0.3 mm (6 MeV), 0.5 mm (8 MeV), 0.6 mm (10 MeV) and 0.5 mm (12 MeV), respectively. 3.2 Dose rates, dose per pulse and ion recombination correction factors The measured dose rates as well as calculated dose per pulse and ks for the Advanced Markus chamber are shown in Table 2. Dose rates were measured in the reference dosimetry settings (i.e.: 10 cm applicator; at depth of dose maximum). 3.3 Output factors

3 Results 3.1 Uncertainty analysis Reference dosimetry: We assumed a value of 0.6% for the combined uncertainty regarding the standards laboratory for plane-parallel chambers as recommended by IAEA TRS 398.22 The combined uncertainty related to the “user electron beam” is dominated by the uncertainty of ks, which is assumed to be 3%. With 0.4% uncertainty in the beam quality correction factor and under consideration of the machine’s long-term stability the combined standard uncertainty is 3.3%. Output factors: The overall measurement uncertainty is 0.6% (6 MeV), 0.3% (8 MeV), 0.2% and 0.4% (12 MeV), respectively. PDD and TDP: Measurement uncertainties in TDP parameters are 0.4 mm for R100 and 0.2 mm in Rp, R50 and R90, respectively. Uncertainty for flatness is 0.4% for 6 MeV

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Flat-ended applicators: Relative OF are shown in Table 3. The highest OF per energy can be found for the 4 cm and 5 cm applicators (energy dependent), ranging from 1.358 to 1.503 for 6 MeV and 12 MeV, respectively. This corresponds to a dose rate of up to 40 Gy/min for 12 MeV (4 cm diameter applicator). Our OF measurements revealed moderate deviations from the Monte Carlo simulated values provided by the vendor. Two OF showed deviations above 2% between simulations and measurements (12 MeV/4 cm: 2.9%; 8 MeV/5 cm: 2.1%), all other deviations were below 1.8%. Figure 1 shows a comparison of measured and Monte Carlo simulated OF values. Beveled applicators: Relative OF are slightly higher compared to 0◦ applicators, up to 6% on average for the 45◦ applicators. The difference between measurement and simulation was consistently less than 2%, except for one applicator (4 cm diameter).

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Fig. 1. Comparison of Monte Carlo simulated (vendor provided) and measured relative output factors for all applicator/energy combinations, respectively.

3.4 Percentage depth dose and transverse dose proﬁle Flat-ended applicators: The tables showing the complete evaluation of PDD and TDP data (according to Table 1) for all beam energies and applicators are included in the appendix (table App.1 / supplementary material). By way of example, Table 4 shows the full evaluation dataset for the 6 cm applicator. R90 values for the different applicators ranged from 15.8 mm to 17.0 mm (6 MeV), 20.7 mm to 21.9 mm (8 MeV), 24.4 mm to 26.5 mm (10 MeV) and 27.3 mm to 30.7 mm (12 MeV), respectively. R50 values (see Fig. A1, supplementary material) ranged from 23.5 mm to 24.3 mm (6 MeV), 30.3 mm to 31.4 mm (8 MeV), 35.9 mm to 38.9 mm (10 MeV) and 40.5 mm to 45.6 mm (12 MeV), respectively. X-ray background was less than 0.6% for all energies. Figure 2 shows PDD plots for the 3 cm, 6 cm and 10 cm applicators. Surface dose and R50 values are shown in figure A1 (supplementary material). Flatness was better than 3.5% in all of the measured TDP plots except for the 3 cm applicators, where the flatness for all energies was between 6.1% and 7.3%, and the 10 cm applicator/10 MeV combination (here it was 5.4%). The distances from the 90% dose level to the geometrical beam edge for the 10 cm applicator were 4 mm and 10 mm for 10 MeV and 12 MeV, respectively. The width of the penumbra ranged from 4.1 to 5.4 mm for all applicators except for the 10 cm applicator, where we measured penumbra widths of 5.2 mm (6 MeV) up to 6.8 mm (12 MeV). For the three higher energies, symmetry in both inplane and crossplane directions was better than 103.5%. For 6 MeV it was better than 103.8%, except for the 10 cm applicator, where it was 107% in inplane direction. Generally symmetry was better in crossplane than in inplane direction. Figure 3 shows crossplane TDP plots for the 3 cm, 6 cm, 8 cm and 10 cm applicators for all energies.

Flatness and symmetry values for inplane TDP are shown in the appendix (Table App.1 / supplementary material). Beveled applicators: Due to the measurement geometry for PDD (perpendicular to the water surface and thus tilted to the applicator axis) R100, R90, Rp and R50 values are significantly lower than for the 0◦ applicators. R90 values for the different applicators ranged from 8.2 mm to 16.5 mm (6 MeV), 10.3 mm to 20.9 mm (8 MeV), 11.7 mm to 25.1 mm (10 MeV) and 12.7 mm to 28.4 mm (12 MeV), respectively. Symmetry in inplane direction was on average 102.3%, with a maximum value of 106.6% for the 10 cm diameter, 30◦ bevel angle applicator at 6 MeV. Flatness was better than 6% except for the smallest applicator (up to 9%). Flatness and symmetry in crossplane direction are higher, according to the bevel angle. By way of example, table App.2 (supplementary material) shows the full evaluation dataset for the 6 cm diameter, 45◦ bevel angle applicator. 3.5 Comparison of measurements and vendor-supplied simulations Flat-ended applicators: In terms of PDD characteristics our measurements agreed well with the data extracted from simulated PDD curves (Fig. 2). For R90 the highest deviations observed were 1.1 mm (range: -1.1 to 0.8; mean: 0.08 mm), for R50 they were 0.7 mm (range: -0.6 to 0.7, mean 0.0 mm). Larger differences in the depth of dose maximum are caused by the flat dose plateau around the maximum. Relative dose values in the measured PDD profiles at the depth of simulated dose maximum were at least 99.8% (average for all energies/applicators: 99.89%). The measured X-ray background values matched well with the simulations. For the 3 cm applicator/12 MeV, the absolute difference was 0.3%; for all other energy/applicator combinations, it was below 0.1%.

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Table 4 Evaluation parameters for PDD and TDP data (measurements and simulations) for all beam energies and one applicator (6 cm diameter). Relative differences between measurements (“meas.”) and vendor-provided simulations (“sim”) are shown (“diff [%]”), except for flatness, were absolute difference is shown. 6 MeV

R100 [mm] R90 [mm] R50 [mm] Rp [mm] D 1 mm [%] X-Ray Bck. [%] Ep0 [MeV] E0(mean) [MeV] Field size [cm] Pen. [mm] Dmax [%] Dmin [%] Flat [%] Sym [%] FS (SID) [cm]

8 MeV

10 MeV

12 MeV

meas.

sim.

diff. [%]

meas.

sim.

diff. [%]

meas.

sim.

diff. [%]

meas.

sim.

diff. [%]

10.5 16.41 24.01 32.03 87.7 0.15 6.59 5.59 6.19 4.5 105.5 100.0 2.565 101.6 6.10

10.8 16.62 24.27 32.27 86.22 0.2 6.64 5.82 6.19 5.4 101.5 97.4 1.945 100.8 6.09

2.9 1.3 1.1 0.7 -1.7 0.1 0.8 4.1 -0.1 20.1 -3.8 -2.6 -0.6 -0.8 -0.1

13.99 21.55 31.26 41.15 89.51 0.36 8.41 7.28 6.22 4.7 103.4 99.7 2.08 101.0 6.10

13.1 21.52 31.04 40.79 87.77 0.29 8.34 7.26 6.21 5.5 101.6 97.8 1.81 101.1 6.09

-6.4 -0.1 -0.7 -0.9 -1.9 -0.1 -0.8 -0.3 -0.2 17.2 -1.7 -1.9 -0.3 0.2 -0.2

15 26.45 38.18 49.98 90.92 0.43 10.18 8.9 6.23 4.5 103.4 99.7 1.905 100.4 6.10

15.7 26.53 38.03 49.71 89.53 0.4 10.12 9.01 6.21 4.9 101.9 99.9 1.055 100.6 6.09

4.7 0.3 -0.4 -0.5 -1.5 0.0 -0.6 1.2 -0.2 7.6 -1.5 0.2 -0.9 0.1 -0.2

17 30.58 44.49 58.18 91.76 0.42 11.82 10.37 6.24 4.9 102.8 100.0 1.36 100.9 6.10

18.8 30.73 44.38 57.85 90.79 0.48 11.76 10.34 6.22 5.1 100.9 98.6 1.25 100.6 6.08

10.6 0.5 -0.2 -0.6 -1.1 0.1 -0.5 -0.3 -0.3 5.9 -1.8 -1.4 -0.1 -0.3 -0.3

Fig. 2. PDD plots for all 4 beam energies (from left to right: 6 MeV, 8 MeV, 10 MeV and 12 MeV) for two different applicator diameters: (a) 3 cm, (b) 6 cm; solid lines: measurements, cross marks: simulations.

In the transversal dose profiles, the simulations slightly underestimate the dose in the lateral parts of the field (Fig. 3). For the 6 cm applicator at 10 MeV, the simulated value is 1.8% lower than the measured one at 24 mm off-axis distance. Depending on applicator size and energy, this underestimation leads to different effects on the TDP evaluation parameters. Hence, the absolute differences in the observed flatness values range between +/-2% comparing measurements and simulations. The penumbra widths are generally overestimated in the simulations. On average for all applicators, penumbra widths in the measurements were lower by 0.8 mm (6 MeV), 0.6 mm (8 MeV), 0.1 mm (10 MeV) and 0.3 mm (12 MeV) than they were in the simulations. Out-of-field doses 15 mm outside of the nominal field edge are on average 0.5% lower in the measurements than in the simulations. Beveled applicators: PDD values agreed well with simulated data. For R50 the difference was 0.35 mm on average (maximum < 1 mm). Differences in flatness were below 3%. Symmetry values in inplane direction were generally higher in our measurements compared to simulated data, with differences up to 6.5% for the combination

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10 cm applicator / 6 MeV and up to 3.5% for all other applicator/energy combinations. A comparison of measured and simulated values is shown in the appendix for 6 cm diameter, 45◦ bevel angle applicator (Table App.2 / supplementary material).

3.6 Dosimetric equivalence of different applicator sets The reference dosimetry measurement for the 8 MeV beam using applicator set 2 was 0.6% higher than in applicator set 1. For all other energies, the difference was less than 0.3%. The differences in the measured output factors between the two applicator sets were consistently less than 0.5%. PDD and TDP curves for the two applicator sets were compared using the gamma evaluation method, resulting in 100% gamma passing rate and mean gamma values of 0.16 for PDD and 0.22 for TDP. Exemplary plots for the 12 MeV beam (7 cm applicators) including local gamma values are shown in Figure 4.

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Fig. 3. TDP plots, scanned in crossplane direction, for all 4 beam energies ((a) 6 MeV, (b) 8 MeV, (c) 10 MeV, (d) 12 MeV) for four different applicator diameters (from innermost to outermost: 3 cm, 6 cm, 8 cm, 10 cm); solid lines: measurements, dotted lines: simulations.

the reference values. Mean deviations ± 1 SD were -0.43 ± 0.79%, -0.12 ± 0.82%, -0.11 ± 0.84% and 0.20 ± 0.88% for the four beam energies. We found no significant time-trends during the assessed period.

4 Discussion

Fig. 4. PDD and TDP plots for the 12 MeV beam, 7 cm applicator; applicator set 1: solid red lines; applicator set 2: dotted lines; gammavalues (plotted against the secondary axis).

3.7 Short-term stability and linearity Relative ranges of the short-term stability, averaged over three days with five measurements each, were 0.30%, 0.23%, 0.12% and 0.18% for beam energies of 6 MeV, 8 MeV, 10 MeV and 12 MeV, respectively. Relative ranges of the dose linearity (measured for dose values of 3 to 30 Gy as described above) were 0.13%, 0.49%, 0.65% and 1.3%, respectively, for the four beam energies. 3.8 Long-term stability The result of our long-term stability survey is shown in figure A2 (supplementary material). We acquired 27 measurements in total for each energy during a 12-month period. All measurements, except for one, were within 2% of

The LIAC HWL is a newly designed mobile accelerator for intraoperative radiotherapy. The device is capable of delivering very high dose rates up to 40 Gy/min for the highest beam energy of 12 MeV and small applicators. Thus, the dose per pulse is also high, ranging up to approximately 45 mGy/pulse for the applicator used for reference dosimetry. According to recent publications,17,18,21 it is nonetheless feasible to perform reference dosimetry with an ionization chamber, provided that an appropriate method for the determination of the ion recombination correction factor is used.20 The ks factors we calculated ranged from 1.0009 (6 MeV) to 1.0044 (12 MeV) and agreed well with published values for similar electron beams.17 The dosimetric characteristics of different mobile IOeRT accelerators have been described previously, namely the Novac 7,34 Mobetron 12,14 and LIAC.11,23–26 The LIAC HWL shows considerably higher dose rates than these machines. While dose rates up to 10 Gy/min are reported for the Mobetron system and dose rates up to 30 Gy/min for the LIAC, the LIAC HWL delivers up to 40 Gy/min (Table 3). Similar to the LIAC,11 the OF of the LIAC HWL increases with decreasing applicator size for all energies. The commissioning procedure and dosimetric characteristics of the Mobetron system (IntraOp Medical Corporation, Sunnyvale, CA, USA) have been reported by Wootton et al.12 for the latest version of the machine, and by Mills et al.14

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for an earlier version. This mobile IOeRT machine produces electron beams with nominal energies of 6, 9 and 12 MeV and dose rates up to 10 Gy per minute.12 According to the manufacturer’s information, the LIAC HWL device is a new design based on the concept of the LIAC. Unsurprisingly, the dose distributions in the beams of this machine are similar to those devices in many aspects. We found high surface dose values ranging from 85% (for 6 MeV) to 94% (for 12 MeV). For the 8, 10 and 12 MeV beams, we found R50 values very close to those published for the LIAC.11,24 However, for the 6 MeV beam, the R50 value in our study was 24 mm and hence approximately 3 mm deeper than that found in those publications. X-ray background was noticeably low, ranging from 0.15% (6 MeV) to 0.42% (12 MeV). Presumably, this is a result of the new scattering foil design. Flatness was well within clinically acceptable tolerance values except for the largest applicator (10 cm) at higher energies (10 and 12 MeV). Even for those beams, the IEC specification for beam flatness is met, as the distance from the 90% dose level and the geometrical beam edge does not exceed 10 mm. However, when using the largest applicator with high energies for treatment, the limited field uniformity should be kept in mind. Symmetry values in inplane direction are significantly higher for the lower energies (generally around 3.5%), especially for 6 MeV and the largest applicator (up to 7%). For the calculation of OF and the visualization of 2D dose distributions a software package is provided by the manufacturer (LIACSim). It follows the approach of characterizing the machine’s dosimetry with a minimal set of dosimetric data.24 Although not yet a complete treatment planning system, it is nevertheless a valuable tool for the selection of a suitable energy and applicator combination for the treatment. LIACSim displays PDDs and TDPs in arbitrary depths and off-axis distances as well as isodose distributions in two dimensions. The data forming the basis of LIACSim is derived from Monte Carlo simulations, individually adapted for the respective machine. A main focus of our work was to compare OF, PDD and TDP data exported from LIACSim with our measurements, since the use of LIACSim software as support for clinical decision making requires a comprehensive assessment of the software. It is beyond the scope of this paper to discuss the Monte Carlo simulations in detail, which form the basis of LIACSim. We observed a very good agreement between simulations of relative dosimetry and measurements for the flat-ended applicators, with no differences reaching a level of clinical relevance. For two OFs, the difference exceeded 2%. LIACSim tends to underestimate the dose in the lateral parts of the field. Furthermore the penumbra widths are generally overestimated in the simulations, but only for 6 MeV and (slightly) for 8 MeV these differences exceed the measurement uncertainty. Based on these findings we decided to use LIACSim to support clinical decisions on energy selection. The OF-table in the software “LIAC MU Calculation”, as provided by the manufacturer based

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on Monte Carlo simulations, had to be corrected only for a few applicator/energy combinations, where the difference between simulation and measurement exceeded 2%. Following our request, the manufacturer designed an additional set of applicators. In this applicator set, the terminal parts of the applicators are 6 cm longer than in the standard applicator set and are therefore better suited for treatments in the abdominal or pelvic regions. The machine-mounted upper parts of the applicators are accordingly 6 cm shorter to maintain the same overall length. The measurements we performed to compare the dosimetric characteristics of the two applicator sets showed negligible differences. We consider the two applicator sets to be replaceable without the need for repeated full commissioning. The LIAC HWL appeared to be very stable in terms of short-term variability. Linearity for the clinically used dose range (3 to 30 Gy) also met the acceptance criteria. During the first year of operation, the machine proved to operate stably and reliably. 107 out of 108 long-term stability measurements showed deviations below 2%. We had no machine failures during this first year of operation, and uptime of the system was 100% for treatments as well as for acceptance, quality assurance and dosimetric utilization.

5 Conclusion The LIAC HWL is dosimetrically well suited for IOeRT, considering surface dose, X-ray background, beam flatness, dose rate and output reproducibility. The software tool for visualization of dose distributions can be used to support treatment planning. However, in our opinion, the contained data should be thoroughly validated beforehand. We encountered no substantial problems with the system or machine failures during commissioning and the first year of clinical operation.

Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Conﬂict of interest The authors have no conflict of interest to disclose.

Appendix A Supplementary data Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j. zemedi.2020.06.004.

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References 1 Calvo FA, Meirino RM, Orecchia R. Intraoperative radiation therapy: First part: Rationale and techniques. Crit Rev Oncol Hematol 2006;59:106–15. 2 Calvo FA, Meirino RM, Orecchia R. Intraoperative radiation therapy: Part 2 Clinical results. Crit Rev Oncol Hematol 2006;59:116–27. 3 Pilar A, Gupta M, Ghosh Laskar S, Laskar S. Intraoperative radiotherapy: review of techniques and results. Ecancermedicalscience 2017;11:750. 4 Fastner G, Reitsamer R, Ziegler I, Zehentmayr F, Fussl C, Kopp P, et al. IOERT as anticipated tumor bed boost during breast-conserving surgery after neoadjuvant chemotherapy in locally advanced breast cancer–results of a case series after 5-year follow-up. Int J Cancer 2015;136:1193–201. 5 Veronesi U, Orecchia R, Maisonneuve P, Viale G, Rotmensz N, Sangalli C, et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial. Lancet Oncol 2013;14:1269–77. 6 Wald P, Grecula J, Walston S, Wei L, Bhatt A, Martin D, et al. Intraoperative electron beam radiotherapy for locoregionally persistent or recurrent head and neck cancer. Head Neck 2019;41:2148–53. 7 Calvo FA, Sole CV, Polo A, Cambeiro M, Montero A, Alvarez A, et al. Limb-sparing management with surgical resection, external-beam and intraoperative electron-beam radiation therapy boost for patients with primary soft tissue sarcoma of the extremity: a multicentric pooled analysis of long-term outcomes. Strahlenther Onkol 2014;190:891–8. 8 Roeder F, Lehner B, Saleh-Ebrahimi L, Hensley FW, Ulrich A, Alldinger I, et al. Intraoperative electron radiation therapy combined with external beam radiation therapy and limb sparing surgery in extremity soft tissue sarcoma: a retrospective single center analysis of 183 cases. Radiother Oncol 2016;119:22–9. 9 Chen Y, Che X, Zhang J, Huang H, Zhao D, Tian Y, et al. Longterm results of intraoperative electron beam radiation therapy for nonmetastatic locally advanced pancreatic cancer: Retrospective cohort study, 7-year experience with 247 patients at the National Cancer Center in China. Medicine (Baltimore) 2016;95:e4861. 10 Roeder F, Treiber M, Oertel S, Dinkel J, Timke C, Funk A, et al. Patterns of failure and local control after intraoperative electron boost radiotherapy to the presacral space in combination with total mesorectal excision in patients with locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2007;67:1381–8. 11 Baghani HR, Aghamiri SM, Mahdavi SR, Akbari ME, Mirzaei HR. Comparing the dosimetric characteristics of the electron beam from dedicated intraoperative and conventional radiotherapy accelerators. J Appl Clin Med Phys 2015;16:5017. 12 Wootton LS, Meyer J, Kim E, Phillips M. Commissioning, clinical implementation, and performance of the Mobetron 2000 for intraoperative radiation therapy. J Appl Clin Med Phys 2017;18:230–42. 13 Beddar AS, Biggs PJ, Chang S, Ezzell GA, Faddegon BA, Hensley FW, et al. Intraoperative radiation therapy using mobile electron linear accelerators: report of AAPM Radiation Therapy Committee Task Group No 72. Med Phys 2006;33:1476–89. 14 Mills MD, Fajardo LC, Wilson DL, Daves JL, Spanos WJ. Commissioning of a mobile electron accelerator for intraoperative radiotherapy. J Appl Clin Med Phys 2001;2:121–30. 15 Krechetov AS, Goer D, Dikeman K, Daves JL, Mills MD. Shielding assessment of a mobile electron accelerator for intra-operative radiotherapy. J Appl Clin Med Phys 2010;11:3151.

16 Hensley FW. Present state and issues in IORT Physics. Radiat Oncol 2017;12:37. 17 Ghorbanpour Besheli M, Simiantonakis I, Zink K, Budach W. Determination of the ion recombination correction factor for intraoperative electron beams. Zeitschrift fur medizinische Physik 2016;26:35–44. 18 Scalchi P, Ciccotelli A, Felici G, Petrucci A, Massafra R, Piazzi V, et al. Use of parallel-plate ionization chambers in reference dosimetry of NOVAC and LIAC((R)) mobile electron linear accelerators for intraoperative radiotherapy: a multi-center survey. Med Phys 2017;44:321–32. 19 Boag JW, Hochhauser E, Balk OA. The effect of free-electron collection on the recombination correction to ionization measurements of pulsed radiation. Phys Med Biol 1996;41:885–97. 20 Laitano RF, Guerra AS, Pimpinella M, Caporali C, Petrucci A. Charge collection efficiency in ionization chambers exposed to electron beams with high dose per pulse. Phys Med Biol 2006;51:6419–36. 21 Petersson K, Jaccard M, Germond JF, Buchillier T, Bochud F, Bourhis J, et al. High dose-per-pulse electron beam dosimetry - A model to correct for the ion recombination in the Advanced Markus ionization chamber. Med Phys 2017;44:1157–67. 22 IAEA. Absorbed Dose Determination in External Beam Radiotherapy, Technical Reports Series No. 398. Vienna: IAEA; 2006. 23 Gungor G, Aydin G, Mustafayev TZ, Ozyar E. Output factors of ionization chambers and solid state detectors for mobile intraoperative radiotherapy (IORT) accelerator electron beams. J Appl Clin Med Phys 2019;20:13–23. 24 Iaccarino G, Strigari L, D’Andrea M, Bellesi L, Felici G, Ciccotelli A, et al. Monte Carlo simulation of electron beams generated by a 12 MeV dedicated mobile IORT accelerator. Phys Med Biol 2011;56: 4579–96. 25 Righi S, Karaj E, Felici G, Di Martino F. Dosimetric characteristics of electron beams produced by two mobile accelerators Novac7 and Liac, for intraoperative radiation therapy through Monte Carlo simulation. J Appl Clin Med Phys 2013;14:3678. 26 Robatjazi M, Tanha K, Mahdavi SR, Baghani HR, Mirzaei HR, Mousavi M, et al. Monte Carlo Simulation of Electron Beams produced by LIAC Intraoperative Radiation Therapy Accelerator. Journal of biomedical physics & engineering 2018;8:43–52. 27 Pimpinella M, Andreoli S, De Angelis C, Della Monaca S, D’Arienzo M, Menegotti L. Output factor measurement in high dose-per-pulse IORT electron beams. Phys Med 2019;61:94–102. 28 Almond PR, Biggs PJ, Coursey BM, Hanson WF, Huq MS, Nath R, et al. AAPM’s TG-51 protocol for clinical reference dosimetry of high-energy photon and electron beams. Med Phys 1999;26:1847–70. 29 Gerbi BJ, Antolak JA, Deibel FC, Followill DS, Herman MG, Higgins PD, et al. Recommendations for clinical electron beam dosimetry: supplement to the recommendations of Task Group 25. Med Phys 2009;36:3239–79. 30 Burns DT, Ding GX, Rogers DW. R50 as a beam quality specifier for selecting stopping-power ratios and reference depths for electron dosimetry. Med Phys 1996;23:383–8. 31 Low DA, Harms WB, Mutic S, Purdy JA. A technique for the quantitative evaluation of dose distributions. Med Phys 1998;25:656–61. 32 Zink K, Wulff J. Beam quality corrections for parallel-plate ion chambers in electron reference dosimetry. Phys Med Biol 2012;57:1831–54. 33 ISO/IEC. Guide to the expression of uncertainty in measurement (GUM: 1995). Geneve: 2008. 34 Pimpinella M, Mihailescu D, Guerra AS, Laitano RF. Dosimetric characteristics of electron beams produced by a mobile accelerator for IORT. Phys Med Biol 2007;52:214–6197.

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