Advancing the Treatment of Brain Tumours and the Role of Intraoperative Radiotherapy

SPECIAL REPORT

Advancing the Treatment of Brain Tumors and the Role of Intraoperative Radiotherapy Why Local Precision and Time Matters – The Importance of Reducing the Time Gap from Surgery to Systemic Therapy

IORT in Brain Metastases in 32 Patients at University Medical Center Mannheim – A Use Case Perspective

Pitfalls and Limitations Associated with Conventional Radiotherapy for the Brain

Kypho-IORT: Intraoperative Radiotherapy for Spinal Tumors and Metastases

How IORT Can Be Included into the Brain Metastases Treatment Workflow

Intraoperative Surgical Margin Radiotherapy – A New Strategy

Clinical Evidence of IORT for Brain Metastases and Glioblastoma Multiforme

IORT in the Treatment of Patients with Neuro Tumors Beyond Brain Metastases

IORT in the Neuro Guidelines – What is the Situation for Brain Metastases

Published by Global Business Media

SPECIAL REPORT

Advancing the Treatment of Brain Tumors and the Role of Intraoperative Radiotherapy Why Local Precision and Time Matters – The Importance of Reducing the Time Gap from Surgery to Systemic Therapy

IORT in Brain Metastases in 32 Patients at University Medical Center Mannheim – A Use Case Perspective

Pitfalls and Limitations Associated with Conventional Radiotherapy for the Brain

Kypho-IORT: Intraoperative Radiotherapy for Spinal Tumors and Metastases

How IORT Can Be Included into the Brain Metastases Treatment Workflow

Intraoperative Surgical Margin Radiotherapy – A New Strategy

Clinical Evidence of IORT for Brain Metastases and Glioblastoma Multiforme

IORT in the Treatment of Patients with Neuro Tumors Beyond Brain Metastases

IORT in the Neuro Guidelines – What is the Situation for Brain Metastases

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

Contents Foreword

3

Dr. Jonathan D. Agnew

Why Local Precision and Time Matters – 4 The Importance of Reducing the Time Gap from Surgery to Systemic Therapy for Palliative Tumor Treatments Jonathan D. Agnew, PhD, MBA, Adjunct Professor, Faculty of Medicine, University of British Columbia

Published by Global Business Media

Published by Global Business Media Global Business Media Limited 62 The Street Ashtead Surrey KT21 1AT United Kingdom Switchboard: +44 (0)1737 850 939 Fax: +44 (0)1737 851 952 Email: info@globalbusinessmedia.org Website: www.globalbusinessmedia.org Publisher Kevin Bell Business Development Director Marie-Anne Brooks Editor Dr. Jonathan D. Agnew, PhD, MBA Senior Project Manager Steve Banks Advertising Executives Michael McCarthy Abigail Coombes Production Manager Paul Davies

The Importance of Local Precision Timing and the Delivery of Adjuvant Radiotherapy IORT For Maximizing Precision and Time Precision and Time – the Major Advantages of IORT

Pitfalls and Limitations Associated with Conventional 6 Radiotherapy (SRS/WBRT/Fractionated EBRT) for the Brain Jonathan D. Agnew, PhD, MBA, Adjunct Professor, Faculty of Medicine, University of British Columbia

Understanding Conventional Radiotherapy for the Brain Neurological Failures Increased Morbidity Patient Discomfort Understanding the Concerns with Conventional Radiotherapy

How IORT Can Be Included into the Brain Metastases Treatment Workflow and What Must Be Considered to Avoid Compromising Patient Outcomes Henning Kahl MD, Senior Consultant & Associate Director of the Department of Radio-Oncology, University Hospital Augsburg, Germany

An interview with Dr. Henning Kahl, a leading Radiation Oncologist from Germany, showing his perspective on when and how to implement IORT as a novel treatment option into the treatment workflow for his brain metastases patients.

For further information visit: www.globalbusinessmedia.org

Clinical Evidence of IORT for Brain Metastases and Glioblastoma Multiforme – Looking at the Status Quo, Latest Publications, and Developments

The opinions and views expressed in the editorial content in this publication are those of the authors alone and do not necessarily represent the views of any organisation with which they may be associated.

Jonathan D. Agnew, PhD, MBA, Adjunct Professor, Faculty of Medicine, University of British Columbia

Material in advertisements and promotional features may be considered to represent the views of the advertisers and promoters. The views and opinions expressed in this publication do not necessarily express the views of the Publishers or the Editor. While every care has been taken in the preparation of this publication, neither the Publishers nor the Editor are responsible for such opinions and views or for any inaccuracies in the articles.

© 2021. The entire contents of this publication are protected by copyright. Full details are available from the Publishers. All rights reserved.

No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical photocopying, recording or otherwise, without the prior permission of the copyright owner.

9

12

Advantages of IORT for Brain Metastases and GBM INTRAGO and Related Reports Other Research on IORT IORT for Treating Brain Metastases: The Future is Bright

IORT in the Neuro Guidelines – What is the Situation 15 for Brain Metastases and What Can Be Treated and How? Professor Bernhard Meyer MD, Professor & Chair of the Department of Neurosurgery, Technical University of Munich, Germany Professor Stephanie E. Combs MD, Professor & Chair of the Department of Radiation Oncology, Technical University of Munich, Germany

An interview with Prof. Dr. Bernhard Meyer (Neurosurgeon) and Prof. Dr. Stephanie Combs (Radiation Oncologist) about the current role of IORT in the neuro tumor treatment environment and the status quo of IORT within the relevant treatment guidelines.

WWW.HOSPITALREPORTS.ORG | 1

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

Contents continued IORT in Brain Metastases in 32 Patients at University Medical Center Mannheim – A Use Case Perspective

17

Dr. med. Stefanie Brehmer, Senior Physician, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Department of Neurosurgery, Mannheim, Germany

Trial Synopsis Intraoperative Workflow Postoperative Workflow Experiences Conclusion

Kypho-IORT: Intraoperative Radiotherapy for Spinal Tumors and Metastases

20

PD Dr. med. Frederic Bludau, MD, Associate Professor Medical Faculty Mannheim, University of Heidelberg, Head of Spine-Surgery Department, Orthopaedic and Trauma Surgery Centre, University Medical Centre Mannheim

Case Presentation

Intraoperative Surgical Margin Radiotherapy – A New Strategy to Overcome the Spatial and Temporal Constraints of Glioblastoma Treatments

24

Kevin Petrecca, MD, PhD, Associate Professor in the Department of Neurology and Neurosurgery (McGill University), Associate Chair-Neurosurgery of the Department of Neurology and Neurosurgery (McGill University), Chief of the Department of Neurosurgery (McGill University Health Centre), Montreal Neurological Institute-Hospital, McGill University, Montreal, Canada

Limitations of Current Standard Treatments Understanding Pitfalls of Surgery and Radiotherapy Can We Do Better?

Development of Intraoperative Radiotherapy for Glioblastoma Testing Intraoperative Radiotherapy for Surgically Treatable Glioblastoma

IORT in the Treatment of Patients with Neuro Tumors Beyond Brain Metastases: The Evolving Role of New Targeted Treatment Approaches Jonathan D. Agnew, PhD, MBA, Adjunct Professor, Faculty of Medicine, University of British Columbia

IORT for GBM IORT for Spine Metastases Next Steps A Promising Future for IORT

2 | WWW.HOSPITALREPORTS.ORG

28

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

Foreword F

ew areas of medicine have challenged

more in-depth discussion of the pitfalls and limitations

clinicians and their patients more than

associated with conventional radiotherapy. In the third

tumors of the central nervous system (CNS). A

article, the report addresses the question of how IORT

diagnosis of brain metastases, spine metastases,

can be included into the brain metastases workflow

or glioblastoma multiforme (GBM) often means a

and the best ways to avoid compromising patient

sobering prognosis accompanied by major surgery

outcomes. Articles four and five consider the clinical

and systemic therapy.

evidence of IORT for brain metastases and the related

Conventional radiotherapy, including whole brain

issue of IORT in clinical guidelines, respectively. In

radiotherapy, fractionated external beam radiotherapy,

article six, a use case perspective of IORT for patients

and stereotactic radiosurgery, has been a mainstay

with brain metastases at a university medical center

of treatment for these diagnoses. Nonetheless,

is presented, followed by a review of the feasibility of

these approaches have their limitations. Delivering

IORT for the palliative treatment of spinal metastases

the highest possible dose to the affected area,

in article seven. Article eight examines intraoperative

ensuring that the surrounding healthy tissues and

surgical margin radiotherapy – a new strategy for the

nearby sensitive structures are not compromised, and

treatment of glioblastoma. The report concludes in

avoiding recurrence at the local site—these are the

a final outlook article on the evolving role of new

difficult challenges facing clinicians. Not surprisingly,

targeted treatment approaches for GBM and spine

major technical advances to tackle them are both

metastases.

necessary and welcome.

IORT offers an exciting opportunity for a major

This report examines one such advance:

advance in the treatment of CNS tumors. The growing

intraoperative radiotherapy (IORT) for the treatment

and robust scientific literature suggesting safety

of CNS tumors—including brain metastases,

and efficacy, as well as patient convenience, bode

spine metastases, and GBM—through a variety of

well for this technology. As the articles in this report

perspectives. The report opens in the first article with

demonstrate, the future of IORT is bright.

a discussion on the importance of reducing the time gap from surgery to systemic therapy for palliative tumor treatments, followed in the second article by a

Dr. Jonathan D. Agnew Editor

Dr. Jonathan D. Agnew PhD, MBA, is a medical writer and Adjunct Professor in the Faculty of Medicine at the University of British Columbia. He holds a PhD in health services research from the University of California, Berkeley, an MBA with distinction from the University of London, and an AB (hons.) in community health from Brown University.

WWW.HOSPITALREPORTS.ORG | 3

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

Why Local Precision and Time Matters – The Importance of Reducing the Time Gap from Surgery to Systemic Therapy for Palliative Tumor Treatments Jonathan D. Agnew, PhD, MBA, Adjunct Professor, Faculty of Medicine, University of British Columbia In the delivery of radiotherapy for palliative tumor treatments, local precision and time are critical factors. Reducing the gap between time of surgery and the administration of systemic therapy and ensuring targeted dose delivery through modalities such as intraoperative radiotherapy, for example, can lead to improved outcomes.

By reducing the surgery to radiotherapy interval, surgeons can avoid the repopulation time when tumor cells could proliferate

T

HE SUCCESS of the delivery of adjuvant radiation following surgical resection of brain metastases is dependent both on the timing and precision of that delivery. Both time to initiation of radiotherapy following surgery and the target delineation impact local control.1 This article draws on the scientific literature to discuss the importance of reducing the time gap from surgery to systemic therapy of palliative tumor treatments. The potential for intraoperative radiotherapy (IORT) to maximize both is also considered.

The Importance of Local Precision Local precision is important for three reasons.

First, local recurrence rather than distant metastasis is the main pattern of recurrence in patients with malignant gliomas. Preventing recurrence, therefore, requires dose delivery at the local area. Second, a higher dose can be delivered when local precision is possible than when less targeted modalities are used. Given that research shows a radiation dose-dependent effect on survival, the ability to provide the highest tolerable dose to the desired area is critical to clinical success. Finally, high precision administration of radiotherapy allows sparing of normal tissue and reducing the dose to organs at risk.

Local recurrence. It has been suggested that because all glioblastomas recur locally, there is an urgent need for more aggressive first line local treatment strategies like IORT. Weil et al provide a review of the literature showing that as treatment modalities become more precise, outcomes improve.2 For example, local and distant recurrence rates for patients treated with 4 | WWW.HOSPITALREPORTS.ORG

surgery followed by whole brain radiotherapy (WBRT) alone are 10%-30%. However, in patients with more targeted stereotactic radiosurgery (SRS) immediately followed by WBRT, local and distant recurrence rates range from 10% to 20%.

Higher dose delivery. For most tumors, local control is more likely when increasing doses can be administered. Research shows that glioblastoma multiforme (GBM) growth shows dose-dependency, with doses of at least 50 Gy required to improve overall survival.3,4 Higher doses are associated with improved survival: the RTOG 98–03 trial demonstrated that patients treated with lower doses showed the worst (11.6 months) and those with the highest doses showed the best survival rates (19.3 months) without increased rates of toxicities.5 As Calvo et al note, the reduction of the rate of cell survival can be achieved with smaller but targeted total dose in comparison to that achieved with conventional fractionated treatment.6 The administration of a high dose in a single fraction should result in the same local control as smaller conventional fractionated doses. In other words, clinicians can achieve the same intended clinical effect with an overall lower dose of radiation if that treatment is delivered in a targeted fashion.

Sparing normal tissue. The dose that can be delivered safely to a tumor is limited by the risk of damaging normal tissues in close proximity.

With targeted therapy, healthy tissues are spared when they receive no or a lower dose than is the case with modalities that deliver a more diffuse dose. Moreover, sensitive structures such as the inner ears and visual pathways are also less or unaffected, thereby reducing treatmentassociated side effects.7

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

Timing and the Delivery of Adjuvant Radiotherapy Reducing the surgery to radiotherapy interval presents important advantages, both medical and non-medical.

Medical advantages. With brain metastases, the tissues under surgical intervention have a rich vascularization with aerobic metabolism, which makes them more sensitive to the action of the radiation.6 Moreover, research shows that the mean doubling time of a GBM stem cell may be as fast as 24 hours. Not surprisingly, the waiting time for radiotherapy, therefore, correlates with overall survival.8,9 By reducing the surgery to radiotherapy interval, surgeons can avoid the repopulation time when tumor cells could proliferate.

Non-medical advantages. Reducing the surgery to radiotherapy interval also offers patients greater convenience. Fewer visits are required for administration of multiple fractions when radiotherapy is delivered in a single, higher dose.

Costs may also be reduced to the extent that local control is achieved, and treatment of recurring metastases is avoided.

IORT For Maximizing Precision and Time Compared to conventional radiotherapies, IORT may offer greater potential for maximizing precision and reducing the surgery to radiotherapy interval.

Geometry adapted approach. Previous IORT studies showed inconsistent results, which have been attributed to the technical limits of

electron tubes. However, because target volume coverage appears to have the greatest influence on survival, geometry adapted IORT with spherically irradiating sources may significantly improve the efficiency of IORT.10 Greater precision. IORT offers a higher level of local precision than either WBRT or SRS. With WBRT, by definition, there is no local precision, as radiotherapy is applied to the entire brain. With SRS, there is a greater level of local precision than with WBRT; however, as the technology relies on forward directed beams, dose delivery may extend beyond the resection cavity and remaining tumor cells to healthy tissue and sensitive structures.

Reduced time. Conventional radiotherapy may be delivered sometime after surgery, often with multiple fractions administered over a period of weeks. However, with IORT, surgery and radiotherapy are delivered at the same time.

This dramatically reduces the surgery to radiotherapy time gap, with implications for greater local control, potentially improved survival rates, and patient convenience.

Precision and Time – the Major Advantages of IORT IORT delivered at the time of brain metastases resection is feasible, safe, and effective.

Combining surgery with IORT leads not only to ease of use for physicians, but also to convenience for patients as both therapies are combined into a single session. When increased precision and reduced time are in question, IORT for the palliative tumor treatments provides an increasingly attractive answer.

When increased precision and reduced time are in question, IORT for palliative tumor treatments provides an increasingly attractive answer

References:

Cifarelli CP, Vargo JA, Hack J, et al. Intraoperative radiotherapy (IORT) for surgically resected brain metastases: Local control and dosimetric analysis. https://doi.org/101200/JGO20195.suppl114. 2019;5(suppl):114-114. doi:10.1200/JGO.2019.5.SUPPL.114

1

2

Weil RJ, Mavinkurve GG, Chao ST, et al. Intraoperative radiotherapy to treat newly diagnosed solitary brain metastasis: initial experience and long-term outcomes. Journal of Neurosurgery. 2015;122(4):825-832. doi:10.3171/2014.11.JNS1449

3

Bleehen NM, Stenning SP. A Medical Research Council trial of two radiotherapy doses in the treatment of grades 3 and 4 astrocytoma.

The Medical Research Council Brain Tumour Working Party. British Journal of Cancer. 1991;64(4):769. doi:10.1038/BJC.1991.396

4

Walker MD, Strike TA$, Sheline GE. An analysis of does-effect relationship in the radiotherapy of malignant gliomasp. Inr J Rodiarion Oncology Biol Phys. 5:25-1731.

5

Tsien C, Moughan J, Michalski JM, et al. Phase I 3D Conformal Radiation Dose Escalation Study in Newly Diagnosed Glioblastoma: RTOG 9803.

International journal of radiation oncology, biology, physics. 2009;73(3):699. doi:10.1016/J.IJROBP.2008.05.034

6

Calvo FA, Meirino RM, Orecchia R. Intraoperative radiation therapy: First part: Rationale and techniques. Critical Reviews in Oncology/Hematology.

2006;59(2):106-115. doi:10.1016/J.CRITREVONC.2005.11.004

7

Combs SE, Steck I, Schulz-Ertner D, et al. Long-term outcome of high-precision radiotherapy in patients with brain stem gliomas: Results from a difficult-totreat patient population using fractionated stereotactic radiotherapy. Radiotherapy and Oncology. 2009;91(1):60-66. doi:10.1016/J.RADONC.2009.02.012

8

Do V, Gebski V, Barton MB. The effect of waiting for radiotherapy for grade III/IV gliomas. Radiotherapy and Oncology. 2000;57(2):131-136. doi:10.1016/S01678140(00)00257-7

9

Burnet NG, Jena R, Jefferies SJ, Stenning SP, Kirkby NF. Mathematical Modelling of Survival of Glioblastoma Patients Suggests a Role for Radiotherapy Dose Escalation and Predicts Poorer Outcome After Delay to Start Treatment. Clinical Oncology. 2006;18(2):93-103. doi:10.1016/J.CLON.2005.08.017

10

Giordano FA, Abo-Madyan Y, Brehmer S, et al. Intraoperative radiotherapy (IORT) – a resurrected option for treating glioblastoma?

Translational Cancer Research. 2014;3(1). doi:10.21037/2099 WWW.HOSPITALREPORTS.ORG | 5

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

Pitfalls and Limitations Associated with Conventional Radiotherapy (SRS/ WBRT/Fractionated EBRT) for the Brain Jonathan D. Agnew, PhD, MBA, Adjunct Professor, Faculty of Medicine, University of British Columbia Conventional radiotherapies such as whole brain radiotherapy, stereotactic radiosurgery, and fractionated external beam radiotherapy have been mainstays in the care of patients with metastases. Nonetheless, the risk of side effects from these treatments, including neurologic failures, increased morbidity, and patient discomfort, gives pause for concern and should be fully understood by both patients and clinicians.

Conventional radiotherapy is associated with increased morbidity in a variety of areas, such as: cerebrovascular effects, optic neuropathy, strokelike migrane attacks, endocrinopathy or ototoxicity

T

HE PAST decade has witnessed a shift in therapy for patients with brain metastases.

Concerns about safety and efficacy of the most widely used approach, whole brain radiotherapy (WBRT), have led to increased use of alternative approaches, including fractionated external beam radiotherapy (EBRT) and stereotactic radiosurgery (SRS). However, despite evidence that these approaches offer some advantages, including mitigating the risk of radiation necrosis and neurocognitive decline following treatment, challenges remain. Studies show that fractionated EBRT and SRS are linked to significant neurologic complications.

Moreover, an emerging literature suggests that conventional radiotherapy approaches for the brain are associated with reduced local control, higher radiation doses to sensitive structures, and radiographic or symptomatic radiation necrosis.

This article reviews the pitfalls and limitations associated with conventional radiotherapy, including neurological failures, increased morbidity, and patient discomfort.

Understanding Conventional Radiotherapy for the Brain Conventional radiotherapy for the brain includes WBRT, fractionated EBRT, and SRS. All are methods for delivering radiation therapy to cancer tumors, but they vary in the mechanisms used to deliver that radiation to the affected site.

With WBRT, the entire brain is irradiated.

This approach is used to treat patients with brain cancer for whom surgery or SRS is not recommended, for example, those with multiple tumors or tumors that cannot be removed by surgery.1,2 WBRT may be administered over a period of weeks.

6 | WWW.HOSPITALREPORTS.ORG

Fractionated EBRT involves the delivery of tightly targeted radiation through several daily treatments over a few days to a few weeks.

Whereas single-fraction radiosurgery is an appealing option for patients with a limited number of brain metastases, fractionated EBRT is preferred for those with lesions that are larger or close to sensitive structures.3 With SRS, radiation is delivered in a single dose and is usually an outpatient treatment. SRS is typically delivered via a linear accelerator (LINAC) machine that uses X-rays to treat tumors or by gamma knife machines that use small beams of gamma rays, and tumors are targeted using 3D imaging.4 Proton beam therapy, a newer type of SRS that delivers radiotherapy through charged particles, is not commonly used except in research centers.

Neurological Failures Conventional radiotherapy approaches, although a mainstay of treatment for patients with brain metastases, have been associated with neurological complications. For example, several clinical trials provide evidence of cognitive decline after treatment that includes WBRT. Brown et al report that patients receiving WBRT in addition to SRS, as opposed to those receiving SRS alone, showed greater cognitive deterioration at 3 months post-intervention.5 One randomized controlled trial of 58 patients with one to three newly diagnosed brain metastases was stopped early given a high probability that those randomly assigned to received SRS plus WBRT were significantly more likely to show a decline in learning and memory function than their SRS-only counterparts.6 Likewise, Aoyama et al report similar findings from a study of patients with one to four brain

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

metastases less than 3 cm in diameter randomly assigned to receive WBRT plus SRS or SRS alone.7 The authors found that the 12-month brain tumor recurrence rate was significantly higher in the SRS alone group. Importantly, however, in both groups there were significant numbers of deaths attributed to neurologic causes: 22.8% of patients in the WBRT + SRS group and 19.3% of patients in the SRS-alone group. The authors conclude that there were no significant differences between the two groups in systemic and neurologic functional preservation or in the toxic effects of radiation.

Similarly, in a study of 206 patients with 310 cerebral metastases less than 3.5 cm treated with SRS, researchers found that a significant percentage (13%) experienced neurological complications, with nearly 6% of patients experiencing several neurological complications (Radiation Therapy Oncology Group Grade 3 and 4). Likewise, brain radionecrosis occurred in 24% of treated lesions.8 Although the authors argue that SRS represents a feasible option as initial treatment for patients with brain metastases, they note that a significant subset of patients may develop neurological complications. Of concern is that while neurocognitive challenges can emerge within the first 3-12 months following conventional radiotherapy, changes can still occur years later.

Increased Morbidity A growing literature suggests that conventional radiotherapy is associated with increased morbidity in a variety of areas: l Cerebrovascular effects. The pathophysiology of late vascular events related to cranial radiotherapy involve arterial and capillary damage and can include cerebrovascular accidents, lacunar infarcts, occlusive disease, and hemorrhage.9 l Optic neuropathy. Although a rare complication, radiotherapy can cause cranial nerve palsies that impair vision months or years after treatment.10 l Stroke-like migraine attacks. This is a rare syndrome that presents with headaches and can occur years after radiotherapy.11 l Endocrinopathy. Endocrinopathies are relatively common among patients receiving cranial radiotherapy. Patients receiving fractionated doses greater than 50 Gy to the pituitary are at an increased risk of endocrine dysfunction.12 l Ototoxicity. Bhandare et al report observing radiotherapy toxicity in all parts of the auditory system, noting that total dose to organ is a significant risk factor.13

Patient Discomfort Patients undergoing fractionated EBRT or SRS experience various acute and subacute complications post treatment, including fatigue; exacerbation of existing neurologic symptoms such as headache, nausea, vomiting; and other generalized symptoms.

Fatigue is one of the most common side effects of conventional therapies, usually attributed to transient demyelination of white matter and associated with worsening of pre-existing neurologic symptoms.14 The vast majority of patients – up to 90% – experience fatigue following radiotherapy, and increased fatigue with treatment for primary brain tumors is linked to poorer survival rates.15,16 Moreover, symptoms may persist well after treatment ends. In their study of somnolence syndrome among patients undergoing radiation to the brain, Harjani et al report that symptoms can emerge as late as 10 weeks post therapy.17 Other general symptoms can also emerge following conventional therapy. Immediate side effects from fractionated EBRT and SRS, including nausea, dizziness/vertigo, seizures, and new persistent headaches occur in at least one-third of patients, and in some cases require hospitalization.18 Fractionated radiotherapy, for example, has long been known to lead to increased edema within 12 to 48 hours of SRS. Among patients with meningiomas treated with SRS, 28–50% of patients developed edema, of which 5-43% are symptomatic. This is significant because peritumoral edema can result in headache, nausea, vomiting, gait instability, and other sources of discomfort for patients.19

As patients with brain metastases and their clinicians make treatment decisions around conventional radiotherapy, a clear understanding of the risks involved is critical

Understanding the Concerns with Conventional Radiotherapy The list of complications and serious side effects associated with conventional radiotherapy includes items that are rare (e.g., optic neuropathy, stroke-like migraine attacks) as well as those that are more common (e.g., neurological failures). While some emerge soon after therapy is administered, others may not become evident for some months or years later. As patients with brain metastases and their clinicians make treatment decisions around conventional radiotherapy, a clear understanding of the risks involved is critical.

WWW.HOSPITALREPORTS.ORG | 7

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

References:

Suh JH, Kotecha R, Chao ST, Ahluwalia MS, Sahgal A, Chang EL. Current approaches to the management of brain metastases. Nature Reviews Clinical Oncology 2020 17:5. 2020;17(5):279-299. doi:10.1038/s41571-019-0320-3

1

2

Definition of WBRT - NCI Dictionary of Cancer Terms - National Cancer Institute. Accessed July 31, 2021. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/wbrt

3

Baliga S, Garg MK, Fox J, et al. Fractionated stereotactic radiation therapy for brain metastases: a systematic review with tumour control probability modelling.

The British Journal of Radiology. 2017;90(1070). doi:10.1259/BJR.20160666

4

Stereotactic body radiotherapy - Type - Mayo Clinic. Accessed July 31, 2021. https://www.mayoclinic.org/tests-procedures/sbrt/pyc-20446794

5

Brown PD, Jaeckle K, Ballman K v., et al. Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases: A Randomized Clinical Trial. JAMA. 2016;316(4):401. doi:10.1001/JAMA.2016.9839

6

Chang EL, Webel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. The Lancet Oncology. 2009;10(11):1037-1044. doi:10.1016/S1470-2045(09)70263-3

7

Aoyama H, Shirato H, Tago M, et al. Stereotactic Radiosurgery Plus Whole-Brain Radiation Therapy vs Stereotactic Radiosurgery Alone for Treatment of Brain Metastases: A Randomized Controlled Trial. JAMA. 2006;295(21):2483-2491. doi:10.1001/JAMA.295.21.2483

8

Minniti G, Clarke E, Lanzetta G, et al. Stereotactic radiosurgery for brain metastases: analysis of outcome and risk of brain radionecrosis.

Radiation Oncology 2011 6:1. 2011;6(1):1-9. doi:10.1186/1748-717X-6-48

9

Murphy ES, Xie H, Merchant TE, Yu JS, Chao ST, Suh JH. Review of cranial radiotherapy-induced vasculopathy. Journal of Neuro-Oncology 2015 122:3.

2015;122(3):421-429. doi:10.1007/S11060-015-1732-2

10

Lessell S. Friendly fire: neurogenic visual loss from radiation therapy. Journal of neuro-ophthalmology : the official journal of the North American NeuroOphthalmology Society. 2004;24(3):243-250. doi:10.1097/00041327-200409000-00014

11

Kerklaan JP, Nijeholt GJL á, Wiggenraad RGJ, Berghuis B, Postma TJ, Taphoorn MJB. SMART syndrome: a late reversible complication after radiation therapy for brain tumours. Journal of Neurology. 2011;258(6):1098. doi:10.1007/S00415-010-5892-X

12

Pai HH, Thornton A, Katznelson L, et al. Hypothalamic/pituitary function following high-dose conformal radiotherapy to the base of skull: demonstration of a dose–effect relationship using dose–volume histogram analysis. International Journal of Radiation Oncology*Biology*Physics. 2001;49(4):1079-1092. doi:10.1016/S0360-3016(00)01387-0

13

Bhandare N, Antonelli PJ, Morris CG, Malayapa RS, Mendenhall WM. Ototoxicity after radiotherapy for head and neck tumors. International Journal of Radiation Oncology*Biology*Physics. 2007;67(2):469-479. doi:10.1016/J.IJROBP.2006.09.017

14

Rahman R, Alexander BM, Wen PY. Neurologic Complications of Cranial Radiation Therapy and Strategies to Prevent or Reduce Radiation Toxicity.

Current Neurology and Neuroscience Reports 2020 20:8. 2020;20(8):1-12. doi:10.1007/S11910-020-01051-5

15

Brown PD, Ballman K v., Rummans TA, et al. Prospective Study of Quality of Life in Adults with Newly Diagnosed High-grade Gliomas.

Journal of Neuro-Oncology 2005 76:3. 2005;76(3):283-291. doi:10.1007/S11060-005-7020-9

16

Powell C, Guerrero D, Sardell S, et al. Somnolence syndrome in patients receiving radical radiotherapy for primary brain tumours: A prospective study.

Radiotherapy and Oncology. 2011;100(1):131-136. doi:10.1016/J.RADONC.2011.06.028

17

Harjani RR, Gururajachar JM, Krishnaswamy U. Comprehensive assessment of Somnolence Syndrome in patients undergoing radiation to the brain.

Reports of Practical Oncology & Radiotherapy. 2016;21(6):560-566. doi:10.1016/J.RPOR.2016.08.003

18

Werner-Wasik M, Rudoler S, Preston PE, et al. Immediate side effects of stereotactic radiotherapy and radiosurgery. International Journal of Radiation Oncology*Biology*Physics. 1999;43(2):299-304. doi:10.1016/S0360-3016(98)00410-6

19

Rahman R, Alexander BM, Wen PY. Neurologic Complications of Cranial Radiation Therapy and Strategies to Prevent or Reduce Radiation Toxicity.

Current Neurology and Neuroscience Reports 2020 20:8. 2020;20(8):1-12. doi:10.1007/S11910-020-01051-5

Patients undergoing fractionated EBRT or SRS experience various acute and subacute complications post treatment, including fatigue; exacerbation of existing neurologic symptoms such as headache, nausea, vomiting; and other generalized symptoms

8 | WWW.HOSPITALREPORTS.ORG

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

How IORT Can Be Included into the Brain Metastases Treatment Workflow and What Must Be Considered to Avoid Compromising Patient Outcomes Henning Kahl MD, Senior Consultant & Associate Director of the Department of Radio-Oncology, University Hospital Augsburg, Germany An interview with Dr. Henning Kahl, a leading Radiation Oncologist from Germany, showing his perspective on when and how to implement IORT as a novel treatment option into the treatment workflow for his brain metastases patients.

1. Metastases are a very severe disease for patients, more so when they appear in the brain, and the treatment of affected patients is difficult. Which are the most common case types of brain metastases you treat in your daily work?

Until today, systemic treatment failed to show a benefit for the vast majority of patients suffering from brain metastases. Local therapy (i.e. surgery and radiotherapy) is still the backbone of brain metastases treatments. Unfortunately, the most common type are multiple brain metastases, causing neurological symptoms. About one third of the patients have only a single or few brain metastases, and about 10% of all new patients with brain metastases are candidates for surgery because of large symptomatic metastases.

3. What are the conventional treatment options you have as a physician, and when do you choose which treatment option?

Conventional treatment options are either radiotherapy alone or surgery followed by radiotherapy. In some rare cases, for example patients with multiple small asymptomatic brain metastases from BRAF (B-Raf protooncogene) mutated malignant melanoma, there is an option for treatment with targeted therapy.

As mentioned before, most patients present with multiple brain metastases and in this setting whole brain radiotherapy is used. For patients with few and not too big brain metastases, focal radiotherapy (i.e. radiosurgery) is applied.

Surgery is a treatment option for patients in good performance status suffering from a singular large metastasis causing symptoms.

2. Could you explain what are the main challenges when treating brain metastases for physicians, and what is the biggest problem of this disease for the patient?

Although the situation improved over the last decade, brain metastases are still connected with a poor survival prognosis. However, it is still a main threat to the life expectancy and quality of life of affected patients. As of today, we get more and more very effective systemic treatments for stage IV cancer patients, prolonging their life, which brings treatment related longterm neurotoxicity into focus. From the perspective of a physician, it is very important to include the clinical status, general prognosis and systemic treatment options in the decision on how to best treat brain metastases for each patient.

4. One treatment option you mentioned was radiotherapy. Could you explain how this treatment option exactly works and what the specific medical hurdles are?

Radiotherapy uses ionizing radiation to destroy cancer cells. In general, there are two ways of treating brain metastases: The “classical” way is fractionated whole brain radiotherapy, which allows you to treat large volumes. Radiation therapy is a local therapy, effective only within the treated volume. But ionizing radiation cannot distinguish between normal tissue cells and cancer cells. So, within the treatment volume, you affect normal cells as well as cancer cells.

Using fractioned radiotherapy, we take advantage of the ability of normal tissue to repair damage caused by radiation. The reason why we split up such treatments into several sessions is just to protect the normal tissue as good as possible.

For IORT, the advantage is that you can treat the patient directly after the surgery is completed, and you can treat from inside the cavity with low energy x-rays (keV), which gives you the chance to spare big areas in the brain

WWW.HOSPITALREPORTS.ORG | 9

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

On the other hand, we have got a different treatment option called focal therapy. Focal therapy can only be used for small volumes.

Within these very precisely defined volumes we are able to apply very effective high doses of radiation in a single session. This treatment is an option for single or few brain metastases.

The main benefits of IORT are when the patient gets awake after surgery, the whole treatment is done, and no additional appointments are needed. Then, after wound healing, systemic treatment can start earlier and we have got a very high local control rate of about 88% at one year with a very, very low rate of radiation necrosis in our IORT patients

10 | WWW.HOSPITALREPORTS.ORG

5. And how do you conduct your patient selection in order to define who is eligible for radiotherapy treatments?

In general, there are several clinical features helping us to decide which is the best treatment for each patient. These clinical features are the clinical status, Karnofsky index, the status of the systemic disease, whether the patient has a controlled disease or a metastatic disease in the rest of the body, the size and absolute number of brain metastases. Patients with many brain metastases and a poor prognostic and clinical status are candidates for fractionated whole brain radiotherapy while patients in a good performance status, with one or few small lesions, are candidates for focal radiotherapy, i.e. radiosurgery or fractionated stereotactic radiotherapy. Patients with a good prognosis but a few big or huge symptomatic metastases are candidates for a surgery. If you perform surgery in a patient, you also have to use radiotherapy to the cavity to provide sufficient local control. This is why all patients who have undergone surgery are seen by the radiation oncologist as well to apply adjuvant radiotherapy.

6. Okay, so you have different radiotherapy techniques for different treatment settings and depending on the case you choose the best fit, what are the main RT techniques available for brain metastases, and what are the main differences between them?

The “classical” treatment of brain metastases is the fractionated whole brain radiotherapy. In this setting, you are able to treat a big volume and lots of metastases. On the other hand, we have got radiosurgery or hypofractionated stereotactic radiotherapy techniques, with these techniques you can treat a small volume only. Here, there is no distinction between tumor cells or normal tissue within the treatment volume like during a surgery. The radiation beam is able to destroy the tissue and turns it into a scar. In this setting, it is important that the volume you treat is not too large to avoid toxicity in normal brain tissue. In the post-surgical setting, the standard of care now is to treat the cavity left by the surgeon locally, avoiding whole brain radiotherapy. This is usually done with either a hypofractionated, stereotactic or intraoperative radiotherapy (IORT).

7. One of the radiotherapy treatment options for the brain you mentioned was IORT. Could you explain why IORT is especially feasible for brain metastases, and what are the advantages of IORT for the physician and the patient?

After surgery, a radiotherapy treatment is needed to obtain the best local control in this area. In this setting nowadays a focal therapy, i.e. a cavity boost, is used. Mostly, this technique is applied as an external beam radiotherapy (EBRT), which is performed about two or three weeks after surgery is completed. For this external beam radiotherapy, you need high megavolt (MeV) photons to reach the area you want to treat. For IORT, the advantage is that you can treat the patient directly after the surgery is completed, and you can treat from inside the cavity with low energy x-rays (keV), which gives you the chance to spare big areas in the brain which would otherwise be irradiated when using EBRT. The biggest advantage for the patient is that the treatment of brain metastases is a one-stop shop. This means that the treatment is already completed when the patient gets awake after surgery because IORT is performed directly after the resection of the metastases while the patient is still under anaesthesia. The biggest advantage for the physician is that you reduce the overall treatment time, because most of these patients need systemic treatment due to the fact that they have additional metastatic burden in the body. When using IORT, the patients are ready for systemic treatment directly after the completion of the surgery. Additionally, you get extremely good local control rates with very, very favorable complication rates by using IORT, i.e. scarcely any radiation necrosis, compared with postoperative external beam radiosurgery or hypofractionated radiotherapy.

8. And in which specific brain metastases settings would you consider IORT as a good treatment alternative to conventional radiotherapy or use it to complement it based on your experiences?

Nearly all the surgically treated patients with brain metastases are good candidates for IORT. In my hospital, we demand a minimal distance to the brain stem of five millimeters and sometimes if there is a metastasis, in an eloquent area, the neurosurgeon hesitates to put additional stress by putting the applicator in the cavity. But in general, there is no real position of a surgically treated metastases which is not a good candidate for IORT as well.

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

9. How would a complete treatment workflow then look like step-by-step from diagnosis to follow-up from a surgical and from a radiotherapy point of view when IORT is included for brain metastases?

All patients are seen in the multidisciplinary tumor board and within this setting it is decided whether the patient is a candidate for surgery. Patients suitable for surgery usually get an appointment in my department, where we offer them IORT as an alternative treatment method to postoperative EBRT. If the patient consents to IORT, the resection of the metastases is performed, and we demand a frozen section confirmed malignancy. If this is reported, we measure the size of the cavity with a dummy applicator, then the device is set up for IORT, is draped and the device with the applicator is placed in the resection cavity by the neurosurgeon. After that, the treatment is started and the mean treatment time in my hospital is about 12 minutes. After completion of the IORT treatment, the applicator is removed, and the surgery is completed. Then, I see the patient six weeks after the IORT for a first consultation where I get a clinical status of the patient. As the IORT is a focal treatment of the cavity only and there is an additional risk of developing distant brain metastases, we perform a three-monthly MRI follow-up for all patients treated with IORT. But this is the same policy as for patients treated focally with EBRT after resection of brain metastases as well.

11. From a patient perspective: What are the associated benefits of IORT during, directly and after surgery and in a later state?

The main benefits of IORT is the situation of the one-stop shop. When the patient gets awake after surgery, the whole treatment of the brain metastases is done, and no additional appointments are needed. Then after wound healing, the possible additional systemic treatment can start earlier and in the long run we have got a very high local control rate of about 88% at one year with a very, very low rate of radiation necrosis in our IORT patients. This becomes important if you compare these values with the data of EBRT using radiosurgery as a cavity boost.

12. Are there any last considerations you would like to give your peers on their way when considering IORT for brain metastases?

From my perspective as a radiation oncologist, IORT is a very valuable tool in my toolbox and especially in the brain it offers very good treatment options with very high local control and low toxicity. The patients I talked to were very positive about being treated in a one-stop shop, and the follow-up results show that the oncological outcome is very favorable.

Nearly all the surgically treated patients with brain metastases are good candidates for IORT

10. Is IORT lengthening the workflow in the OR and if yes does it matter?

IORT is slightly lengthening the procedure in the OR, in my cases it was in median about 25 minutes. This was not a big issue for the setting in my hospital. Time to discharge of the patient from the hospital is not prolonged for patients who were treated with IORT. And there was also no increase of the surgical complication rate for IORT cases.

The statements of the doctor in this interview reflect only his personal opinions and experiences and do not necessarily reflect the opinions of any institution with whom he is affiliated. The doctor in this interview is consultant of Carl Zeiss Meditec AG and has received financial compensation. Carl Zeiss Meditec AG, 2021. All rights reserved. Products, services or offers referenced in this interview may not be available in all countries and product labelling varies by country.

WWW.HOSPITALREPORTS.ORG | 11

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

Clinical Evidence of IORT for Brain Metastases and Glioblastoma Multiforme – Looking at the Status Quo, Latest Publications, and Developments Jonathan D. Agnew, PhD, MBA, Adjunct Professor, Faculty of Medicine, University of British Columbia Intraoperative radiotherapy (IORT) for brain metastases and glioblastoma multiforme (GBM) offers a promising approach to a disease with an extremely poor prognosis.

Clinical trial data and other research from the peer-reviewed literature suggest that IORT is associated with more positive outcomes, including progression-free survival, and is a safe and effective treatment modality.

Authors reporting on the results of the INTRAGO trial have provided evidence of the safety and efficacy of IORT for treating GBM

D

ESPITE MULTIMODAL therapy, brain metastases and glioblastoma multiforme (GBM) are associated with a very low survival rate. Recognizing the generally extremely poor prognosis, researchers have argued that intraoperative radiotherapy (IORT) could be a promising approach to avoid tumor cell proliferation between surgery and radiochemotherapy while sparing healthy tissue.1 Previous research on the success of IORT for the treatment of other types of cancer, namely breast cancer, suggest some of the possibilities in treating other types of tumors.

This article considers the potential advantages of IORT for brain metastases and GBM and reviews some of the most recent studies, including those stemming from the INTRAGO trial, as well as other published research.

Advantages of IORT for Brain Metastases and GBM IORT offers potentially three major advantages over conventional radiotherapy for the treatment of brain metastases and GBM: no delay in time to initiation of radiation following surgery, decreased uncertainty in target delineation, and the possibility of dose escalation beyond that seen in stereotactic radiosurgery (SRS). IORT allows the delivery of a single dose to the tumor tissue. With conventional radiotherapy modalities, increasing the total radiation dose may improve local control, but at the cost of causing damage to normal tissue and sensitive surrounding structures.

For example, a retrospective study comparing

12 | WWW.HOSPITALREPORTS.ORG

stereotactic radiosurgery (SRS) to IORT found that patients treated with SRS plans to standard 15-20 Gy and 30 Gy marginal dose experienced significantly higher doses to the optic apparatus and brainstem compared to patients treated with IORT at 30 Gy.2 IORT, in contrast, does not rely on forward-directed beams. Instead, spherically irradiating devices are used to enable geometry optimized IORT. This may enable sufficient dose delivery to the resection cavity and to remaining tumor cells.

INTRAGO and Related Reports The intraoperative radiotherapy in glioblastoma multiforme study (INTRAGO) phase I/II was a dose escalation study that included patients aged 50 years or older with histologically confirmed glioblastoma multiforme (GBM).3 Those with previous cranial radiation therapy in any location, astrocytoma ≤ WHO grade III, gliomatosis cerebri, or selected other conditions were excluded from the study. The study’s primary goal was the definition of the maximal tolerated dose, with progression-free survival (PFS) and overall survival (OS) included as secondary endpoints.

Authors reporting on the results of the INTRAGO trial have provided evidence of the safety and efficacy of IORT for treating GBM. Reporting on the initial results, Giordano et al find that among patients in the INTRAGO trial, most grade III adverse events were attributed to either CT or tumor progression. Moreover, local PFS was consistently higher than distant PFS, suggesting the efficacy of IORT.4 In another report based on

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

the INTRAGO trial, no dose-limiting toxicities, i.e., wound healing deficits, cerebral bleeding/ ischemia, brain necrosis and early termination of radiochemotherapy, were found among 14 patients with histologically confirmed glioblastoma multiforme within 3 months after IORT.5 In a subsequent publication, the authors reported the results of 15 patients treated at three dose levels, of whom 13 underwent incomplete resection, six had unresected satellites, and three did not receive per-protocol treatment.6 Median follow-up was 13.8 months. No IORT-related deaths occurred. The median PFS was 11.2 months, and the median OS was 16.2 months.

The authors state that the data suggest IORT is associated with manageable toxicity.

Förster et al analyzed MRIs of patients enrolled in the INTRAGO study.7 Eleven of 15 INTRAGO patients with a median age of 60 years were included. Distant failure was observed in 63% of patients, and all but one patient demonstrated enhancement of varying patters around the resection cavity. In other words, as the authors summarize, nearly all patients developed contrastenhancing lesions of varying extent around the resection cavity – results that differed significantly between IORT patients and control group patients receiving standard therapy alone.

INTRAGO II, a phase 3 randomized clinical trial with an estimated enrolment of 314 participants has a projected study completion date of March 2024.8 The study is testing if the median PFS of patients with newly diagnosed glioblastoma multiforme (GBM) can be improved by the addition of intraoperative radiotherapy (IORT) to standard radiochemotherapy.

Other Research on IORT Han et al evaluated preliminary results of IORT in 26 patients with primary brain tumors.9 Among the 20 patients alive without tumor recurrence 14 months later, none showed significant necrosis after IORT, and 18 recovered from surgery without any complications. They conclude that IORT to a dose of 8-12 Gy is safe without any increase in post-operative complications. In a similarly sized, nonrandomized prospective study, Weil et al followed 23 patients with histologically confirmed brain metastases who were treated with IORT. They found that local control, distant control, and long-term survival were comparable to those of other commonly used modalities.

They conclude that surgery combined with

IORT seems a potential adjunct to patient treatment for central nervous system involvement by systemic cancer.10 Cifarelli et al report the results of a retrospective analysis of patients treated with IORT following surgical resection of brain metastases.11 Among the 54 patients in the study, the most common primary diagnosis was non-small cell lung cancer, and all were treated with IORT. The authors calculated local failure (88%), distant brain control (58%), and OS (73%) one-year post IORT. Based on these results, they conclude that IORT is both safe and effective for delivering adjuvant radiation to the brain metastases resection cavities.

Sarria et al present the results of the first international pooled analysis of patients with GBM treated with IORT in addition to standard of care therapy.12 Their analysis of data from 51 patients treated in five centers in Germany, China, and Peru included results from INTRAGO alongside other studies. The authors report that, compared to historical data, their analysis suggests improved efficacy and safety of IORT with lowenergy X-rays for newly diagnosed glioblastoma.

Dose homogeneity is important to ensure that diseased tissue receives the intended dose, while normal tissue receives a reasonably low dose and critical organs receive less than the respective tolerance dose. In an innovative examination of IORT, SRS, and intensity modulated radiotherapy (IMRT), Dahshan et al calculated the homogeneity index for each platform and compared the results using data from 14 patients treated after surgical resection of brain metastases.13 Their findings confirm that IORT offers improved dose homogeneity compared with SRS in single-fraction treatment.

IORT for Treating Brain Metastases: The Future is Bright A growing scientific literature supports the notion of the safety and efficacy of IORT for the treatment of brain metastases. The INTRAGO trial suggests that IORT is both safe and effective results that are confirmed by a variety of studies from centers around the world. Given its potential to reduce the delay in time to initiation of radiation following surgery, increase certainty in target delineation, and allow for dose escalation beyond that seen in conventional radiotherapy modalities, it is safe to say that the future for IORT – and the patients who may benefit from this therapy – is indeed bright.

Dose homogeneity is important to ensure that diseased tissue receives the intended dose, while normal tissue receives a reasonably low dose and critical organs receive less than the respective tolerance dose. Findings confirm that IORT offers improved dose homogeneity compared with SRS in singlefraction treatment

WWW.HOSPITALREPORTS.ORG | 13

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

References:

Giordano FA, Abo-Madyan Y, Brehmer S, et al. Intraoperative radiotherapy (IORT)—a resurrected option for treating glioblastoma? Translational Cancer Research. 2014;3(1). doi:10.21037/2099

1

2

Vargo JA, Sparks KM, Singh R, Jacobson GM, Hack JD, Cifarelli CP. Feasibility of dose escalation using intraoperative radiotherapy following resection of large brain metastases compared to post-operative stereotactic radiosurgery. Journal of Neuro-Oncology 2018 140:2. 2018;140(2):413-420. doi:10.1007/S11060018-2968-4

3

Giordano FA, Brehmer S, Abo-Madyan Y, et al. INTRAGO: intraoperative radiotherapy in glioblastoma multiforme – a Phase I/II dose escalation study. BMC Cancer. 2014;14(1). doi:10.1186/1471-2407-14-992

4

Giordano FA, Brehmer S, Muerle B, et al. Initial Results of a Phase 1/2 Trial on Intraoperative Radiation Therapy (IORT) in Newly Diagnosed Glioblastoma Multiforme (INTRAGO). International Journal of Radiation Oncology, Biology, Physics. 2016;96(2):E67-E68. doi:10.1016/J.IJROBP.2016.06.761

5

Giordano FA, Brehmer S, Mürle B, et al. RTHP-05. Intraoperative radiotherapy (IORT) using low-energy e-rays in a cohort of predominantly incompletely resected newly diagnosed glioblastoma multiforme (INTRAGO trial). Neuro-Oncology. 2016;18(suppl_6):vi174-vi175. doi:10.1093/NEUONC/NOW212.731

6

Giordano FA, Brehmer S, Mürle B, et al. Intraoperative Radiotherapy in Newly Diagnosed Glioblastoma (INTRAGO): An Open-Label, Dose-Escalation Phase I/II Trial. Neurosurgery. 2019;84(1):41-49. doi:10.1093/NEUROS/NYY018

7

Förster A, Böhme J, Maros ME, et al. Longitudinal MRI findings in patients with newly diagnosed glioblastoma after intraoperative radiotherapy. Journal of Neuroradiology. 2020;47(2):166-173. doi:10.1016/J.NEURAD.2019.01.090

8

Intraoperative Radiotherapy in Newly Diagnosed Glioblastoma Multiforme - Full Text View - ClinicalTrials.gov. Accessed August 3, 2021. https://clinicaltrials.gov/ct2/show/NCT02685605?term=INTRAGO&draw=2&rank=1

9

Han X, Fu B, Wu M, et al. P13.13 Intraoperative radiotherapy with INRABEAM in primary brain tumors after resection: preliminary reports of 26 cases.

Neuro-Oncology. 2014;16(Suppl 2):ii68. doi:10.1093/NEUONC/NOU174.259

10

Weil RJ, Mavinkurve GG, Chao ST, et al. Intraoperative radiotherapy to treat newly diagnosed solitary brain metastasis: initial experience and long-term outcomes. Journal of Neurosurgery. 2015;122(4):825-832. doi:10.3171/2014.11.JNS1449

11

Cifarelli CP, Brehmer S, Vargo JA, et al. Intraoperative radiotherapy (IORT) for surgically resected brain metastases: outcome analysis of an international cooperative study. Journal of Neuro-Oncology 2019 145:2. 2019;145(2):391-397. doi:10.1007/S11060-019-03309-6

12

Sarria GR, Sperk E, Han X, et al. Intraoperative radiotherapy for glioblastoma: an international pooled analysis. Radiotherapy and Oncology. 2020;142:162-167. doi:10.1016/J.RADONC.2019.09.023

13

Dahshan BA, Weir JS, Bice RP, et al. Dose homogeneity analysis of adjuvant radiation treatment in surgically resected brain metastases: Comparison of IORT, SRS, and IMRT indices. Brachytherapy. 2021;20(2):426-432. doi:10.1016/J.BRACHY.2020.11.004

IORT offers potentially three major advantages over conventional radiotherapy for the treatment of brain metastases and GBM: no delay in time to initiation of radiation following surgery, decreased uncertainty in target delineation, and the possibility of dose escalation

14 | WWW.HOSPITALREPORTS.ORG

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

IORT in the Neuro Guidelines – What is the Situation for Brain Metastases and What Can Be Treated and How? Professor Bernhard Meyer MD, Professor & Chair of the Department of Neurosurgery, Technical University of Munich, Germany Professor Stephanie E. Combs MD, Professor & Chair of the Department of Radiation Oncology, Technical University of Munich, Germany An interview with Prof. Dr. Bernhard Meyer (Neurosurgeon) and Prof. Dr. Stephanie Combs (Radiation Oncologist) about the current role of IORT in the neuro tumor treatment environment and the status quo of IORT within the relevant treatment guidelines.

1. Which patients or cases do you personally treat with IORT in your institution in the neurosurgical/oncological setting?

[Prof. Dr. Meyer]: As for now we treat mainly patients with solitary brain metastases with a high pressure for urgent systemic therapy with IORT. 2. How do you choose these patients from a radiotherapy technique point of view, on which clinical evidence for IORT do you rely, are there already clinical publications or valid clinical studies available that justify this technique for the brain?

[Prof. Dr. Combs]: The indication for IORT is always based on an interdisciplinary discussion.

For brain tumors, a large randomized trial is currently recruiting to consolidate the data for IORT. For brain metastases, smaller series are available however no prospective comparison with postoperative radiotherapy to the resection cavity or whole brain radiotherapy. IORT has the benefit that it can be applied during surgery and, depending on the situation, postoperative radiotherapy may not be necessary.

Therefore, systemic treatment can be initiated quickly, if required.

3. Does your experience support perception of clinical data for IORT for brain metastases?

[Prof. Dr. Combs]: At our center, we have excellent experience with IORT in primary or secondary brain tumors. However, you have to keep in mind that imaging may be different after IORT compared to external radiotherapy (EBRT) and further studies are required to fully understand the response patterns after IORT. 4. Overall, is the discussed clinical data already enough to use this technique on

patients or are there any other regulations and guidelines you need to follow and what do they say about IORT? [Prof. Dr. Combs]: The decision for radiotherapy always depends on the recommendation of a board-certified radiation oncologist with all radiation protection credentials. If, from the disease standpoint, radiotherapy is necessary, which technique is applied depends on the experience and the center’ equipment. For IORT, data is available that supports its use, also for brain metastases, and therefore the decision can be well taken. However, interdisciplinary discussion is always essential and depending on the size of a lesion, on histology or on any additional disease burden, percutaneous radiotherapy may be the better option.

5. What is the main goal when you treat (palliative) patients with brain metastases from a surgical point of view?

[Prof. Dr. Meyer]: I would not consider the treatment of brain metastases “palliative” in all patients nowadays. Survival times have increased dramatically for some forms of cancer due to targeted therapies. That is why a patient suffering from a solitaire metastasis would benefit from a combined one-stop intraoperative therapy to receive systemic therapy as early as possible.

If [...] radiotherapy is necessary, which technique is applied depends on the experience and the center’ equipment.

For IORT, data is available that supports its use, also for brain metastases, and therefore the decision can be well taken

6. From a radiation oncology point of view, does it make a difference for your patients if you treat them with conventional brain RT modalities or use IORT and what do they prefer?

[Prof. Dr. Combs]: There is no specific preference, it depends on the individual clinical case. IORT may be a quick solution for some patients, while others profit from larger safety margins or multiple WWW.HOSPITALREPORTS.ORG | 15

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

target treatments that IORT cannot address.

Also, if multiple options are available at a center, patient preference plays an important role in decision making.

Survival times have increased dramatically for some forms of cancer due to targeted therapies. That is why a patient suffering from a solitary metastasis would benefit from a combined one-stop intraoperative therapy to receive systemic therapy as early as possible

7. Can IORT be easily implemented into the treatment workflow besides guideline questions, based on your personal experiences?

[Prof. Dr. Meyer]: That is very easy in a relatively high-tech environment, which most neurosurgical ORs are. And obviously you need a very good cooperation with your partner, the Radiation Oncologist [Prof. Dr. Combs]: The radiation oncologist comes into the operating room as soon as the neurosurgeon has removed the lesion, this can be well organized. The decision for IORT must be made beforehand and the patient needs to be informed before the surgical intervention.

8. How does the multidisciplinary team work together now? Does it pay off to have an IORT device in your hospital in terms of better outcomes?

[Prof. Dr. Meyer]: It is too early to talk about better outcomes, to answer this we first need more data.

[Prof. Dr. Combs]: From my perspective, it always pays off to offer interdisciplinary treatments. If a radiation oncologist comes into the operating room, the understanding and communication between disciplines is strengthened and improved – and all players benefit from improved communication, the largest margin of benefit of course is for the patient.

9. What role do you think IORT will play in the next 10 years for the treatment of different brain tumors and metastases for your medical disciplines?

[Prof. Dr. Meyer]: It needs to be defined, yet. I am sure that there will be a benefit for one or the other cohort of patients. [Prof. Dr. Combs]: To fully answer this question further randomized trials for different indications are still necessary. Clearly, IORT will have a central place in the radiation oncologist’s armamentarium.

10. What needs to change on a regulatory and healthcare provider level to make this technique widely available to all patients in need for such a targeted radiotherapy treatment?

[Prof. Dr. Combs]: Certainly, more data is necessary, as well as optimal communication about the data published and individual experience. This evidence then must be discussed and distributed within the societies, and also reimbursement must be secured.

[Prof. Dr. Meyer]: I agree.

11. Are there any last considerations you would like to give your peers on their way?

[Prof. Dr. Meyer]: Well, only in a general manner, to be open for new ideas and being willing to test them properly. [Prof. Dr. Combs]: Always think ahead and question what you do, whatever is the standard today may prove to be insufficient tomorrow. Always be meticulous, eager to learn and push for innovations. And walk through your environment with open eyes and ears and learn from your neighboring disciplines.

The statements of the doctors in this interview reflect only their personal opinions and experiences and do not necessarily reflect the opinions of any institution with whom they are affiliated. The doctors in this interview are consultants of Carl Zeiss Meditec AG and have received financial compensation. Carl Zeiss Meditec AG, 2021. All rights reserved. Products, services or offers referenced in this interview may not be available in all countries and product labelling varies by country.

16 | WWW.HOSPITALREPORTS.ORG

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

IORT in Brain Metastases in 32 Patients at University Medical Center Mannheim – A Use Case Perspective Dr. med. Stefanie Brehmer, Senior Physician, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Department of Neurosurgery, Mannheim, Germany The role of a sufficient treatment of brain metastases gains more and more importance as prognosis in cancer patients improves due to new and innovative therapies. Some years ago, the occurrence of brain metastasis defined a highly palliative setting but now even in this situation there is an improvement of prognosis in a subset of patients with brain metastases.1,2 But these efforts leave a gap for the treatment of space-occupying lesions still mandatory for neurosurgical resection and the need for a fast start of systemic cancer treatment.

I

ORT SEEMS to be an optimal option to meet this need. For further investigation of reliability and feasibility in 2017 we started our INTRAMET trial (NCT03226483) to evaluate IORT after the resection of brain metastases.

Trial Synopsis The primary objective is local recurrence at the resection cavity. Secondary objectives are overall survival, occurrence of new brain metastases, progression free survival, time to further cancer treatment, cognitive state, and quality of life as well as occurrence of surgical revisions due to wound healing disorders, infections, bleeding, ischemia and radionecrosis within 6 months after IORT. Inclusion and exclusion criteria are shown in table 1.

Intraoperative Workflow Resection is performed to our clinical standard.

If the tumor shows no dural contact and frozen section proves a metastasis, distance to risk structures is checked with neuro-navigation (should be more than 2 cm to optic nerve and brainstem for prescription of 30Gy radiation dose). The biggest possible applicator to fit in the resection cavity is chosen (often smaller as the preoperatively measured size of the metastasis in the MRI due to subsidence of the resection cavity after tumor removal). Of special importance is a tight fit of the applicator to the brain without any air or fluid between cavity wall and applicator to receive a homogenous radiation field in the brain. Based on our experience, a thin layer of Surgicel® for haemostasis is unproblematic.

Sufficient treatment of brain metastases gains more and more importance but efforts leave a gap for the treatment of spaceoccupying lesions and the need for a fast start of systemic cancer treatment. IORT seems to be an optimal option

Inclusion criteria

Exclusion criteria

Preliminary (preoperative):

n

n

Age ≥ 18 years, KPS ≥ 50%

n

Given informed consent

n

Adequate birth control In MRI (T1 +contrast) resectable non-dural lesion

n

Adequate distance to optic nerve, chiasm, and brainstem

n

n

to meet this need

leptomeningeal spread and dural attachment (assessed pre- and intraoperatively) rozen section reveals primary CNS tumor, F lymphoma, SCLC or germinoma Psychiatric or social condition potentially interfering with compliance

n

Contraindication against anesthesia, surgery, MRI and/or contrast agents

n

Pregnant or breast-feeding women

n

Final (intraoperative): n

IORT is technically feasible

n

Frozen section confirming a metastasis

Table 1: Inclusion and exclusion criteria

WWW.HOSPITALREPORTS.ORG | 17

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

Figure 1: Intraoperative treatment workflow of INTRAMET

As radiation is performed all staff leaves the operation theater – an access whilst radiation is possible in case of emergency with usual X-ray protection gear similar whilst intraoperative fluoroscopy.3

Postoperative Workflow

In principle, follow-up does not differ from patients receiving resection from brain metastases and classical postoperative radiotherapy

In principle, follow-up does not differ from patients receiving resection from brain metastases and classical postoperative radiotherapy. As we expected, decelerated wound healing as a potential problem from IORT a careful observation of the wound has special emphasis in follow up.

From our experiences with IORT in glioblastoma,4 we expected more postoperative MRI-changes in follow-up. To interpret them, it is of great importance to distinguish between local recurrence and radionecrosis. For this reason, an MR measurement protocol with thin layer T1 (with and without Gadolinium contrast), thin layer Flair, DTI and perfusion imaging was established for our patients. In case of new contrast enhancement during follow up, perfusion imaging should help to clarify this issue.

Experiences 32 patients were treated in our trial since March 2017 and IORT fits well in our clinical and surgical workflow. All patients could be

Figure 2: Postoperative treatment workflow of INTRAMET

18 | WWW.HOSPITALREPORTS.ORG

treated with an irradiation dose of 30Gy on the applicator surface. Usually, small size applicators could be used (1.5 cm - 14 patients; 2 cm - 14 patients; 2.5 cm - 3 patients and 3 cm - 2 patients). Irradiation time varied between roughly 9-30 minutes, so that including a preparation time with sterile draping and mounting of the INTRABEAM of 15-30 minutes surgery was prolonged about 60 minutes.

A subgroup analysis of the early motor function in our patients with metastases in the motor cortex (5 patients – all with preoperative deficits) showed no drop in intraoperatively assessed MEP monitoring whilst applicator insertion, irradiation, or applicator removal.

Intraoperative SSEP monitoring even showed an improvement, if SSEPs dropped whilst resection, as the insertion of the applicator compensated a previous brain shift.

Of these 5 patients, 4 recovered to normal motor function within 6 weeks. 1 patient, who experienced a postoperative drop in motor function, got back to preoperative status also within 6 weeks. Overall, we know these courses from surgery of metastases in eloquent regions of the brain without IORT, so that we can assume that there is no direct negative effect using IORT in the motor cortex.

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

Figure 3: Example of a scar reaction in a long-term course of a female patient with pulmonary adenocarcinoma receiving total resection of a left temporal metastasis and IORT with 30Gy, MRI pictures taken between post-op and 36 months

By now, the mean follow-up of our patient is 18.06 months. In our 32 patients we had 2 cases of local recurrence, which is comparable with the rates of classic postoperative radiotherapy treatment after the resection of brain metastases.5 5 cases of radionecrosis occurred, but intracerebral or dural contrast-enhancing scar tissue (not typical for recurrence or radionecrosis) was seen in 14 patients. A typical example of a scar reaction is shown in Figure 3. Here we have the long-term course of a lady with pulmonary adenocarcinoma receiving total resection of a left temporal metastasis and IORT with 30Gy. After 6 months of follow-up-MRI, she developed a new contrast enhancing around the resection cavity. Perfusion was low, so that scar tissue was suspected. The long-term follow-up confirmed that, as there was no further change over the next 2.5 years.

Recent studies showed that the biological effectiveness of IORT with low energy X-rays is not comparable to classic linear accelerator settings.6 Our pattern of MR-findings underlines that and the importance of profound knowledge in how to interpret the postoperative MRI scans, especially as rescue therapies for local or distant failure in the brain are limited.

Conclusion Our data support that IORT after the resection of brain metastases is a reliable method to sufficiently minimize local recurrence according to the current guidelines in the neurosurgical treatment of brain metastases. The method is feasible and fits well into neurosurgical workflows.

Interpretation of follow-up MRIs is challenging but manageable with appropriate MRI-sequences and experience.

IORT after the resection of brain metastases is a reliable method to sufficiently minimize local recurrence according to the current guidelines in the neurosurgical treatment of brain metastases

References:

Peters S, Camidge DR, Shaw AT, et al. Alectinib versus Crizotinib in Untreated ALK -Positive Non–Small-Cell Lung Cancer. New England Journal of Medicine.

2017;377(9):829-838. doi:10.1056/nejmoa1704795

1

2

Rishi A, Yu HHM. Current Treatment of Melanoma Brain Metastasis. Current Treatment Options in Oncology. 2020;21(6). doi:10.1007/s11864-020-00733-z

3

Schneider F, Clausen S, Jahnke A, et al. Radiation protection for an intraoperative X-ray source compared to C-arm fluoroscopy. Z Med Phys. 2014;24(3): 243-251. doi:10.1016/j.zemedi.2013.10.006

4

Forster A, Bohme J, Maros ME, et al. Longitudinal MRI findings in patients with newly diagnosed glioblastoma after intraoperative radiotherapy.

J Neuroradiol. Published online 2019. doi:10.1016/j.neurad.2019.01.090

5

Brown PD, Ballman K v, Cerhan JH, et al. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC.3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. Published online 2017. doi:10.1016/s1470-2045(17)30441-2

6

Shamsabadi R, Baghani HR, Azadegan B, Mowlavi AA. Impact of spherical applicator diameter on relative biologic effectiveness of low energy IORT X-rays: A hybrid Monte Carlo study. Physica Medica. 2020;80(June):297-307. doi:10.1016/j.ejmp.2020.11.018

The statements of the doctor writing this article reflect only her personal opinions and experiences and do not necessarily reflect the opinions of any institution with whom she is affiliated. The doctor in this article is consultant of Carl Zeiss Meditec AG and has received financial compensation. Carl Zeiss Meditec AG, 2021. All rights reserved. Products, services or offers referenced in this article may not be available in all countries and product labeling varies by country.

WWW.HOSPITALREPORTS.ORG | 19

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

Kypho-IORT: Intraoperative Radiotherapy for Spinal Tumors and Metastases PD Dr. med. Frederic Bludau, MD, Associate Professor Medical Faculty Mannheim, University of Heidelberg, Head of Spine-Surgery Department, Orthopaedic and Trauma Surgery Centre, University Medical Centre Mannheim An effective single-stage treatment alternative for patients suffering from spinal metastases

S

The treatment goal of spinal metastases therefore has to be local control of the metastases before SREs occur and re-establishing stability of the vertebral bodies to treat pain and prevent further deformation

20 | WWW.HOSPITALREPORTS.ORG

PINAL METASTASES are a growing problem in the modern oncological treatment. Better systemic treatment options led to a longer overall survival of the patients, which increases the lifetime risk of symptomatic bone metastases. The spine is the most often affected region of the skeleton.

Even with antiresorptive treatment, many of these patients suffer from skeletal related events (SREs).

SRE in the spine can manifest with pain, especially axial pain when weight-bearing and in spinal deformation due to fractures of the vertebral bodies. Both causing immobility of the patients, which leads to a reduced lifespan and a poor quality of life. SREs in the spine can also compromise the spinal canal or the existing nerveroots due to uncontrolled tumor mass expansion, causing radiculopathy or spinal cord compression with paraplegia. The treatment goal of spinal metastases therefore has to be local control of the metastases before SREs occur and reestablishing stability of the vertebral bodies to treat pain and prevent further deformation. Therefore, a sorrow evaluation of spinal metastases has to be performed to take reasonable measures.

The Spine Instability Neoplastic Score (SINS) is widely used and has displaced the former score published by Taneichi.1,2 The outdated rule of thumb to treat only symptomatically metastasis and wait with the treatment in those patients who are not yet symptomatic has been completely abandoned.

Actual scientific research supports the hypothesis of a better overall survival if the tumor mass is reduced as quickly as possible.3-5 With new minimally invasive treatment options with minimal morbidity, the treatment indication is no longer limited to patients in excellent conditions but can also be applied to patients who have a limited remaining life expectancy.

The Kypho-IORT, first applied in 2009, fits perfectly for the majority of the patients into this

framework.6 In Kypho-IORT, access is created transpedicular into the vertebral body via a minimal skin incision. Ideally, the center of the metastasis should be reached. After a specimen has been taken, intraoperative radiotherapy (IORT) is performed with 8 Gy in 13 mm from the isocenter over a period of about 5.5 min., for which a special designed needle applicator is used. After the irradiation took place, a cement augmentation of the affected vertebral body is performed (vertebroplasty or kyphoplasty), preventing further collapse of the vertebral body.

Using kyphoplasty, first a balloon is inflated in the vertebral body to reestablish the vertebral body height and to create a void which can be filled with bone cement (pmma = polymethylmethacrylate) and unwanted cement leakage is avoided.

The method Kypho-IORT was invented in 2007

by Prof. Obertacke (head of our trauma surgery department at Mannheim university hospital) and Prof. Wenz (former head of our radiation-oncology clinic at Mannheim university hospital).

In a phase-0 study we performed a specimen evaluation, if the delivered dose to the vertebral body will affect other organs at risk (e.g., myelon, aorta) in any way. Therefore, dose chambers were placed in the spinal canal and next to the vertebral body, collecting data of the adjunct vertebrae during live treatment. We did this, to prove the theoretical dose-distribution calculations; at this time only Montecarlo calculations in a watermodel existed.7 After having proven the safety for the organs at risk, we conducted a first clinical trial, aiming at the safety and technical feasibility of the method8 and could not observe any radiation related problems. In rare cases, the drift-tube of the XRS4 (INTRABEAM®) was bent, due to a narrow-designed working cannula. Therefore, modified cannulas were selected and used to ease the surgical procedure successfully and technical related issues could not be found anymore.9 Another remarkable finding of this first clinical trial was the excellent pain control,

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

Figure 1. Kaplan-Meier-Diagram of the local tumor-control and local progression free survival of Kypho-IORT-treated spinal metastases with excellent tumor control of approx. 96% at 12-months and 94% at 24-months. Numbers at risk as shown (dead patients are censored).

After most careful investigation of this

regardless of the underlying primaries. The median pre-operative pain-level of 5 points (VAS 10) dropped to 2 (of 10) on the first postoperative day.10 Since radiation is only released in the vertebral body, additional shielding is no longer necessary, the radiation protection measures have been researched.11 To further enhance the potential of the method for best local-control, we launched a dose-escalation study in a classic 3-plus-3 design.12 The study could exaggerate the dose-level to a safe final dose of 8 Gy in 13 mm from the isocenter. The dose could be increased by a factor of 4 without any noticeable adverse reactions or dose toxicities. The pain-relief, achieved by the Kypho-IORT, was identical to the early observations. Starting from the second post-operative day, the median pain level was 0 (of 10 VAS). More than that, it was shown that the achieved analgesia persisted throughout the lifelong post-operative period and also the local control was excellent. The 12-months local control rate in the non-dose-escalation-study population was 96%.

The latest published work aimed at the longterm local control of the treated patients. 100 of 104 patients or their relatives could be reached and interviewed. In these 100 patients, 143 treated vertebral bodies could be investigated. A total of 10 local failures could be observed, resulting in a local control rate of 95.9% after 12 months, 94.2% after 24 and 85.5% after 36 months.13 The mean overall survival was 2.2 years, the median survival 1 year (Figure 1).

So far, all vertebral bodies could be reached via a transpedicular approach from thoracic level 2 to lumbar level 5. Also, a cervical vertebral body was treated, using a minimal invasive ventral SmithRobinson-approach, as well as the body of the sacrum, using the transiliac long-axis. Besides treatment of metastases, two treatment-cases of aggressive hemangiomas already have been reported. Having nowadays the opportunity to accurately predict the dose distribution using online treatment planning including tissue heterogeneity correction, a maximal tailored treatment is possible.14 After most careful investigation of this new method, we can conclude that it is a safe and reliable treatment option for patients suffering from spinal metastases. We think it is feasible to treat up to 4 metastases, or better 4 vertebral bodies, during one session. The metastasis must not spread into the spinal canal or the posterior structures. By complying with these limitations, the treatment results are excellent compared to EBRT, but also to SBRT. In contrast to the mentioned alternatives the affected vertebral body is immediately stabilized, the risk for a post-radiation fracture or a fracture-progress, often seen in SBRT, is eliminated. Also, the phenomena of a post-irradiation pain flare could not be observed in Kypho-IORT. The treatment is substantially shorter compared to fractionated EBRT. Kypho-IORT being a minimal-invasive procedure does not require a pause of systemic therapy. The integrated sample taking of every metastasis is beneficial, especially in terms of targeted or hormone therapy.

new method, we can conclude that it is a safe and reliable treatment option for patients suffering from spinal metastases

WWW.HOSPITALREPORTS.ORG | 21

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

Kypho-IORT is a valuable alternative for several groups of patients. On one hand, those who are in an advanced stage of the disease, having probably only 6-12 more months to live. These patients benefit from a one-stop shop procedure, a very short hospitalization time, immediate pain relief and stabilization of the mechanically

weakened spine as well as the certainty that a recurrence during the remaining lifetime is very unlikely. On the other hand, especially young cancer-patients with the diagnosis of a clinically silent metastasis benefit from the safe irradiation and the excellent long-term control, probably improving their overall survival.

Case Presentation

Kypho-IORT is a valuable alternative

The presented case shows an approx. 50 years old female patient, suffering from metastasized breast cancer. The cancer was primarily metastasized in the first lumbar vertebrae, it was the only metastasis to be found. The vertebra showed a large osteolytic mass and loss of structural stability, the SINS-Score was 11 of 19 points, showing a manifested instability. The patient suffered from severe axial pain in walking and upright position. We opted for Kypho-IORT not only to sterilize the only metastasis but also to support the affected vertebra and regain stability.

Pre-operative CT-Scan of the thoraco-lumbar junction

for several groups of patients. Those who are in an advanced stage of the disease benefit from a one-stop shop procedure, a very short hospitalization time, immediate pain relief and stabilization.

Young, cancer-patients,

Left: sagittal reconstruction; Right: axial reconstruction; Notice the destruction of the upper endplate and the beginning kyphotic deformation of the vertebrae. No involvement of spinal canal or posterior elements Post-operative CT-scan of the TL-junction

especially, benefit from the safe irradiation and the excellent long-term control, probably improving their overall survival

The irradiated vertebrae is stabilized with PMMA. Intraoperative cement-extrusion in the disc-space TH12-L1 due to the metastatic defect in the endplate L1. This extrusion is clinical asymptomatic but can cause mechanical stress to the lower endplate of TH12, the risk of a non-metastatic fracture of TH12 is increased.

Three months after breast ablation, the Kypho-IORT of the first lumbar vertebrae was performed successfully. Surprisingly, a differing Herceptin receptor status (Primary: Her-2 negative, Metastasis: Her-2 positive) was found in the histological sample of the metastasis. Therefore, the systemic treatment was adopted. The patient was in stable disease without new metastases for five years, showing now progress in a mid-thoracic vertebra, which was treated with EBRT. 22 | WWW.HOSPITALREPORTS.ORG

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

References: Fisher, C.G., et al., A novel classification system for spinal instability in neoplastic disease: an evidence-based approach and expert consensus from the Spine Oncology Study Group. Spine (Phila Pa 1976), 2010. 35(22): p. E1221-9.

1

Taneichi, H., et al., Risk factors and probability of vertebral body collapse in metastases of the thoracic and lumbar spine. Spine (Phila Pa 1976), 1997.

22(3): p. 239-45.

2

Palma, D.A., et al., Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial. Lancet, 2019. 393(10185): p. 2051-2058.

3

Gomez, D.R., et al., Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol, 2016. 17(12): p. 1672-1682.

4

Radwan, N., et al., A phase II randomized trial of Observation versus stereotactic ablative RadiatIon for OLigometastatic prostate CancEr (ORIOLE).

BMC Cancer, 2017. 17(1): p. 453.

5

Wenz, F., et al., Kypho-IORT--a novel approach of intraoperative radiotherapy during kyphoplasty for vertebral metastases. Radiat Oncol, 2010. 5: p. 11.

6

Schneider, F., et al., Development of a novel method for intraoperative radiotherapy during kyphoplasty for spinal metastases (Kypho-IORT).

Int J Radiat Oncol Biol Phys, 2011. 81(4): p. 1114-9.

7

Schmidt, R., et al., Kyphoplasty and intra-operative radiotherapy, combination of kyphoplasty and intra-operative radiation for spinal metastases: technical feasibility of a novel approach. Int Orthop, 2012. 36(6): p. 1255-60.

8

Bludau, F., et al., [Learning and teaching abilities of a newly inaugurated operation technique. Analysis of learning curves and transferability exemplified

by Kypho-IORT]. Orthopade, 2013. 42(9): p. 772-9.

9

Reis, T., et al., Intraoperative radiotherapy during kyphoplasty for vertebral metastases (Kypho-IORT): first clinical results. Tumori, 2012. 98(4): p. 434-40.

10

Schneider, F., et al., Radiation protection for an intraoperative X-ray source compared to C-arm fluoroscopy. Z Med Phys, 2014. 24(3): p. 243-51.

11

Bludau, F., et al., Phase I/II trial of combined kyphoplasty and intraoperative radiotherapy in spinal metastases. Spine J, 2018. 18(5): p. 776-781.

12

Bludau, F., et al., Long-term outcome after combined kyphoplasty and intraoperative radiotherapy (Kypho-IORT) for vertebral tumors.

Radiat Oncol, 2020. 15(1): p. 263.

13

Schneider, F., et al., Precision IORT - Image guided intraoperative radiation therapy (igIORT) using online treatment planning including tissue heterogeneity correction. Phys Med, 2017. 37: p. 82-87.

14

The statements of the doctor writing this article reflect only his personal opinions and experiences and do not necessarily reflect the opinions of any institution with whom he is affiliated. The doctor in this article is consultant of Carl Zeiss Meditec AG and has received financial compensation.

Carl Zeiss Meditec AG, 2021. All rights reserved. Products, services or offers referenced in this article may not be available in all countries and product labeling varies by country.

WWW.HOSPITALREPORTS.ORG | 23

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

Intraoperative Surgical Margin Radiotherapy – A New Strategy to Overcome the Spatial and Temporal Constraints of Glioblastoma Treatments Kevin Petrecca, MD, PhD, Associate Professor in the Department of Neurology and Neurosurgery (McGill University), Associate Chair-Neurosurgery of the Department of Neurology and Neurosurgery (McGill University), Chief of the Department of Neurosurgery (McGill University Health Centre), Montreal Neurological InstituteHospital, McGill University, Montreal, Canada Isocitrate dehydrogenase wild-type glioblastoma (glioblastoma) is a treatment resistant cancer. Surgical resection, radiotherapy, and chemotherapy are standards of care. Challenges to total surgical resection and curative radiotherapy are inherent and unique to the host organ. The effectiveness of cytotoxic and targeted therapeutic approaches is limited by glioblastoma’s cellular heterogeneity, which

The volume of residual

includes gradients of stem and differentiated cancer cells, non-cancer brain cells, and immune cells.1-4

tumor following surgery is a critical determinant of progression free and overall survival - the fewer imaging detectable glioblastoma cells following surgery, the longer patients live

I

N THE absence of curative treatments, imaging detectable disease progression following surger y, radiotherapy, and temozolomide chemotherapy remains anchored at less than 1 year on average, and sufferers succumb to the disease within the following year.

Limitations of Current Standard Treatments The volume of residual tumor following surgery is a critical determinant of progression free and overall survival – the fewer imaging detectable glioblastoma cells following surgery, the longer patients live. 5 But in almost all patients, resection of all glioblastoma cells cannot be achieved because of the presence of cancer cells in brain regions that cannot be removed, and adjuvant treatments are thus required.

While the non-sacrificable nature of many brain regions prevents surgical removal of all glioblastoma cells, it similarly limits curative radiotherapy dosing. Treatment beyond 60Gy risks injuring adjacent and nearby brain and nerves. Standard dosing that minimizes radiotherapy induced ischemia and inflammatory responses is not sufficient to prevent cancer cell survival or their proliferation.

The effectiveness of temozolomide is limited mainly to methylguanine methyltransferase promoter hypermethylated glioblastomas.

The median overall survival advantage for all patients treated with temozolomide and radiotherapy is 2.5 months.6

Understanding Pitfalls of Surgery and Radiotherapy To explore the practical limitations of surgery and radiotherapy, it is useful to determine where

Figure 1. Glioblastomas Progress at the Resection Cavity Margin. Pre- and Post-treatment MRIs showing total resection of contrast-enhancing tumor. MRI showing recurrence at the resection margin.

24 | WWW.HOSPITALREPORTS.ORG

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

Figure 2. Glioblastoma Progression During the Time Gap Between Surgery and Radiotherapy. Sequential MRIs showing development of contrast-enhancing tumor following total resection of contrast-enhancing tumor and prior to starting radiotherapy.

glioblastomas recur. Progression within the surgical and radiation field suggests that these treatments are insufficient. Distant recurrences suggest that these cancer cells were not detected by imaging and were thus outside of treatment fields, or were originally within treatment fields and then invaded to the distant site and proliferated.

Studies examining the location of progression in patients with post-surgical residual contrastenhancing tumor reported progression at the residual tumor site in almost all cases.7 Examination of recurrence location in patients with no post-surgical contrast-enhancing tumor revealed that 90% occur at the surgical resection margin.8 This failure pattern suggests that: highdensity invasive cancer cells at the surgical margin are more resistant to adjuvant treatments than the low-density invasive cancer cells that are >5 mm beyond the surgical margin; or the probability of cancer cell proliferation is highest at the site where the cell density is highest. Even in patients in which the resection was extended beyond the contrast-enhancing portion of the tumor, this local recurrence pattern holds (Figure 1).

Another important limitation inherent in the current treatment approach is the time interval between surgery and the completion of adjuvant treatments. Radiotherapy usually begins 3-5 weeks after surgery and requires another 6 weeks to complete. These time gaps provide a window of opportunity for residual cancer cells to proliferate, increasing the cancer burden from its lowest point immediately following surgery (Figure 2). The potential advantage of surgical resection is thus mitigated by the prolonged time required to deliver an effective radiation dose.

Can We Do Better?

Considering the spatial surgical challenge – recurrences at the resection margin, and the temporal radiotherapy challenge – too long a gap between surgery and radiotherapy, we can endeavor to develop augmented and early

treatment strategies based on principles that aim to solve these deficiencies.

Intra-operative radiotherapy (IORT) has the potential to address these deficiencies.

“Robotic” miniature accelerators generating a spherical dose distribution of low-energy x-rays have been engineered into a device that can deliver radiation to the surgical margin, with the majority of the dose absorbed by tissues within a few millimeter depth along the surgical margin (Figure 3).

Since the highest density of post-resection cancer cells is at the surgical margin, and the site of recurrences is at the surgical margin, it is reasonable to consider that a radiotherapy boost to this site can be an effective treatment approach. Increased radiation dosing to the resection cavity margin has been shown to improve outcomes.9 The second potential advantage of this approach is timing. The immediacy of this treatment reduces the window of opportunity for proliferation that currently exists, providing a bridge to standard of care radiotherapy. Since the dose fall-off of INTRABEAM IORT is steep, it would seemingly be less suitable in cases where greater than 5-10 millimeters of residual tumor remains following resection or in cases with distant tumors.

Development of Intraoperative Radiotherapy for Glioblastoma The effectiveness of this treatment approach was tested in INTRAGO-I, a phase I/II trial that assessed the safety and tolerability of IORT in patients with newly diagnosed glioblastoma.10 Twenty to 40 Gy of low-energy photons were delivered immediately following tumor resection to the resection margin, and adjuvant radiotherapy and temozolomide was given to most patients.

Fifteen patients were treated: 13 of these had incomplete resections; 6 had unresected satellite tumors; and 3 did not receive standard adjuvant treatments. The MGMT promoter was

Intra-operative radiotherapy (IORT) has the potential to address these deficiencies. Increased radiation dosing to the resection cavity margin has been shown to improve outcomes.

The immediacy of this treatment reduces the window of opportunity for proliferation that currently exists, providing a bridge to standard of care radiotherapy

WWW.HOSPITALREPORTS.ORG | 25

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

While not designed to

Figure 3. Treatment of the resection cavity with low-energy IORT. A. Following resection, macroscopic and microscopic

test effectiveness, the

delivered by a spherical applicator sterilizes 4- to 5-mm of the cavity margin (depending on the radiation dose) while

results from INTRAGO-I are compelling.

A majority of the IORT dose penetrates less than 5 millimeters beyond the surgical margin [...] Taking this into consideration, a 17.8-month local progression free survival outcome, 2-3 times longer than reported in contemporary studies is encouraging

26 | WWW.HOSPITALREPORTS.ORG

residual tumor gives rise to local recurrence, the dominant failure pattern in glioblastoma. IORT using low-energy x-rays preserving underlying brain tissue due to the low penetration depth of the photons. B. The IORT system used in this trial (Intrabeam, Carl Zeiss Meditec AG, Jena, Germany) consists of a carrier system with 6 degrees of freedom, a mounted x-ray source and a set of 8 applicators, ranging from 1.5 to 5 cm in diameter that can be placed on the source. C. the measured dose distribution (calibrated gafchromic film) in a solid water phantom (4 cm applicator). D. Dose distributions of all applicators. Note that low-energy X-rays are absorbed within the first few millimeters of tissue (50% of the total dose is absorbed within 3-7 mm).10 Adapted with permission from Oxford University Press.

unmethylated in 10 patients. The results showed that the treatment was well tolerated and IORTrelated toxicity was low. For those receiving adjuvant treatments, the median progression free survival was 11.3 month (95% CI: 10.9-11.6), the median local progression free survival was 17.8 months (95% CI: 9.7-25.9), and the median overall survival was 17.8 months (95% CI: 13.9-21.7).

Testing Intraoperative Radiotherapy for Surgically Treatable Glioblastoma While not designed to test effectiveness, the results from INTRAGO-I are compelling.

Considering that the majority of the IORT dose penetrates less than 5 millimeters beyond the surgical margin, it is likely that the benefit of this treatment was reduced in patients with post-resection volumes that extended beyond

this perimeter. Taking this into consideration, a 17.8-month local progression free survival outcome, 2-3 times longer than reported in contemporary studies,11 is encouraging.

Now, INTRAGO-II, an International Multicenter Randomized Phase III Trial on INTraoperative RAdiotherapy in Newly Diagnosed GliOblastoma Multiforme (INTRAGO II) is currently underway to determine if the addition of IORT to standard of care therapies will improve outcomes for suffers of glioblastoma in whom no or less than 5 millimeters of residual contrast-enhancing tumor remains following resection. Three-hundred and fourteen patients will be blindly randomized to receive standard of care surgery plus radiotherapy and temozolomide versus those receiving surgery plus IORT followed by standard of care radiotherapy and temozolomide. This trial is now recruiting at sites internationally.

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

References: Couturier, C. P. et al. Single-cell RNA-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy. Nat. Commun. 11, 1–19 (2020).

1

Klemm, F. et al. Interrogation of the Microenvironmental Landscape in Brain Tumors Reveals Disease-Specific Alterations of Immune Cells.

Cell 181, 1643-1660.e17 (2020).

2

Patel, A. P. et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344, 1396–1401 (2014).

3

Singh, S. K. et al. Identification of human brain tumour initiating cells. Nature 432, 396–401 (2004).

4

Stummer, W. et al. Prospective cohort study of radiotherapy with concomitant and adjuvant temozolomide chemotherapy for glioblastoma patients with no or minimal residual enhancing tumor load after surgery. J Neurooncol. 108, 89–97 (2012).

5

Stupp, R. et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 10, 459-66 (2009).

6

Minniti, G. et al. Patterns of failure and comparison of different target volume delineations in patients with glioblastoma treated with conformal radiotherapy plus concomitant and adjuvant temozolomide. Radiother. Oncol. 97,377–381 (2010).

7

Petrecca, K. et al. Failure pattern following complete resection plus radiotherapy and temozolomide is at the resection margin in patients with glioblastoma.

J. Neurooncol. 111, 19–23 (2013).

8

Shenouda, G et al. A Phase 2 Trial of Neoadjuvant Temozolomide Followed by Hypofractionated Accelerated Radiation Therapy With Concurrent and Adjuvant Temozolomide for Patients With Glioblastoma. Int. J. Radiat. Oncol. Biol. Phys. 97, 487-494 (2017).

9

Giordano, FA et al. Intraoperative Radiotherapy in Newly Diagnosed Glioblastoma (INTRAGO): An Open-Label, Dose-Escalation Phase I/II Trial.

Neurosurgery 84, 41-49 (2019).

10

Stupp, R. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352, 987–996 (2005).

11

The statements of the doctor writing this article reflect only his personal opinions and experiences and do not necessarily reflect the opinions of any institution with whom he is affiliated. The doctor in this article is consultant of Carl Zeiss Meditec AG and has received financial compensation Carl Zeiss Meditec AG, 2021. All rights reserved. Products, services or offers referenced in this article may not be available in all countries and product labeling varies by country.

Another important limitation inherent in the current treatment approach is the time interval between surgery and the completion of adjuvant treatments. Radiotherapy usually begins 3-5 weeks after surgery and requires another 6 weeks to complete. These time gaps provide a window of opportunity for residual cancer cells to proliferate

WWW.HOSPITALREPORTS.ORG | 27

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

IORT in the Treatment of Patients with Neuro Tumors Beyond Brain Metastases: The Evolving Role of New Targeted Treatment Approaches Jonathan D. Agnew, PhD, MBA, Adjunct Professor, Faculty of Medicine, University of British Columbia Data suggest a promising role for intraoperative radiotherapy (IORT) in the treatment of neuro tumors beyond brain metastases, such as glioblastoma multiforme (GBM) and spine metastases. Ensuring that patients benefit from these potential developments will require focused research, guidelines development, and training for clinicians.

As evidence suggesting its potential for treating patients with glioblastoma multiforme (GBM) and spine metastases grows, researchers, clinicians, and healthcare decision makers will have to consider how best to ensure the appropriate dissemination of this technology

28 | WWW.HOSPITALREPORTS.ORG

I

ORT REPRESENTS a promising advance in the treatment of neuro tumors beyond the brain. As evidence suggesting its potential for treating patients with glioblastoma multiforme (GBM) and spine metastases grows, researchers, clinicians, and healthcare decision makers will have to consider how best to ensure the appropriate dissemination of this technology. This article considers the potential role for IORT in GBM and spine metastases, with a focus on the available scientific evidence, as well as the necessary steps – such as additional research, guidelines development, and training – to enable patients to realize the fullest possible benefits of IORT.

IORT for GBM A variety of studies point to the potential for IORT in treating GBM. As early as 1991, Matsutani and Nakamura reported on the results of 129 adult patients with newly diagnosed cerebral glioblastoma treated with IORT.1 They noted that IORT was the best available treatment modality available to irradiate the areas adjacent to the margin with a sufficient dose for sterilization.

A decade later, Nemoto et al reported on 32 patients with malignant gliomas treated with IORT over the period 1987 to 1997.2 These patients were matched with a control group treated with postoperative external radiation therapy. Although the authors found no significant difference between survival rates in the IORT patients and control patients, they acknowledge that their study may have suffered from a critical design flaw, namely that because IORT cannot be used for patients with deepseated tumors, multifocal tumors, diffuse infiltrating tumors, very large tumors, or infra-

tentorial tumors, it is possible that the selection criteria of patients for IORT greatly influenced the treatment outcomes.

The arrival of INTRAGO, a phase I/II clinical trial and dose escalation study including patients aged 50 years or older with histologically confirmed GBM, marked the beginning of a more scientifically rigorous approach to understanding the potential benefits of IORT for patients with GBM. Early results are promising, and researchers have provided evidence of the safety and efficacy of IORT for treating GBM. Giordano et al, for example, found that among INTRAGO trial subjects, local progression-free survival was consistently higher than distant progression-free survival, suggesting the efficacy of IORT.3 Similarly, another study based on the INTRAGO trial found no dose-limiting toxicities among 14 patients with histologically confirmed GBM within three months after IORT.4 In a subsequent publication, the authors reported the results of 15 patients treated with IORT at three dose levels.5 No IORT-related deaths occurred, and the authors state that the data suggest IORT is associated with manageable toxicity.

Further findings are expected from a phase 3 randomized clinical trial, INTRAGO II, which is testing if the median progression-free survival of patients with newly diagnosed GBM can be improved by the addition of IORT with standard radiochemotherapy.6

IORT for Spine Metastases The most robust data on the benefits of IORT for spinal metastases come from the Kypho-IORT trial. Kypho-IORT was an interventional, open label, single group

ADVANCING THE TREATMENT OF BRAIN TUMORS AND THE ROLE OF INTRAOPERATIVE RADIOTHERAPY

assignment phase I/II clinical trial of 18 participants completed in July 2013.7 Patients over 50 years old with a Karnofsky Performance Status of at l east 60% and one to three painful vertebral metastases confined to the vertebral body were eligible to participate.8 As none of the nine patients enrolled in phase I showed dose-limiting toxicities, 52 patients were subsequently enrolled into a phase II. Following significant improvements in pain scores, a persistent pain reduction beyond the first postoperative day, and promising progression-free survival statistics, the authors concluded that IORT is safe and immediately provides sustained pain relief with local control for patients with spine metastases.

Next Steps Ensuring that patients realize the greatest possible benefit from IORT will require that researchers, clinicians, and health care decision makers take important steps in several areas, including future research, guidelines development, and training for clinicians.

A robust research agenda. A robust research agenda building on forthcoming clinical trial data (e.g., Kypho-IORT), as well as additional studies evaluating IORT results in terms of local control and complication rates, is necessary to guide clinicians as to the best applications of this technology.

Guidelines development. Treatment guidelines play a critical role in the safe and appropriate dissemination of new technologies, as they guide clinicians making the day-to-day decisions on which patients should have access to a given therapeutic modality. Researchers and clinicians must ensure that key guidelines reflect the developing understanding of the benefits of IORT for GBM and spine metastases.

Training programs. Training programs for clinicians are prerequisites to the safe and appropriate use of IORT and, therefore, to the eventual realization of the maximum benefits of this technology. Training should cover matters such as patient selection, dosing, and other technical specifications.

A Promising Future for IORT As Gzell notes, radiotherapy-based treatments cannot rely solely on advances in chemotherapy or immunotherapy to improve the overall survival of patients with glioblastoma.9 Indeed, advances in radiotherapy technologies themselves are necessary. IORT represents one of – if not the most significant – such advance in the area of radiotherapy for neuro tumors. The ongoing release of clinical trial data, supported by clinical guideline development and training for clinicians, will ensure a promising future for IORT where patients are able to realize the maximum benefits of this innovative technology.

Advances in radiotherapy technologies themselves are necessary. IORT represents one – if not the most significant – advance in the area of radiotherapy for neuro tumors. The ongoing release of clinical trial data will ensure a promising future for IORT

References: M atsutani M, Nakamura O. Intraoperative Radiation Therapy (IORT) for Cerebral Glioblastoma. Neuro-Oncology. Published online 1991:181-183. doi:10.1007/978-94-011-3152-0_32

1

2

Nemoto K, Ogawa Y, Matsushita H, et al. Intraoperative radiation therapy (IORT) for previously untreated malignant gliomas. BMC Cancer 2002 2:1.

2002;2(1):1-5. doi:10.1186/1471-2407-2-1

3

Giordano FA, Brehmer S, Muerle B, et al. Initial Results of a Phase 1/2 Trial on Intraoperative Radiation Therapy (IORT) in Newly Diagnosed Glioblastoma Multiforme (INTRAGO). International Journal of Radiation Oncology, Biology, Physics. 2016;96(2):E67-E68. doi:10.1016/J.IJROBP.2016.06.761

4

Giordano FA, Brehmer S, Mürle B, et al. RTHP-05. Intraoperative radiotherapy (IORT) using low-energy e-rays in a cohort of predominantly incompletely resected newly diagnosed glioblastoma multiforme (INTRAGO trial). Neuro-Oncology. 2016;18(suppl_6):vi174-vi175. doi:10.1093/NEUONC/NOW212.731

Giordano FA, Brehmer S, Mürle B, et al. Intraoperative Radiotherapy in Newly Diagnosed Glioblastoma (INTRAGO): An Open-Label, Dose-Escalation Phase I/II Trial. Neurosurgery. 2019;84(1):41-49. doi:10.1093/NEUROS/NYY018

5

6

Intraoperative Radiotherapy in Newly Diagnosed Glioblastoma Multiforme - Full Text View - ClinicalTrials.gov. Accessed August 3, 2021. https://clinicaltrials.gov/ ct2/show/NCT02685605?term=INTRAGO&draw=2&rank=1

7

Kypho-IORT: Intraoperative Radiotherapy During Kyphoplasty for Spinal Metastases - Full Text View - ClinicalTrials.gov. Accessed August 4, 2021. https:// clinicaltrials.gov/ct2/show/NCT01280032?term=NCT01280032&draw=2&rank=1

8

Bludau F, Welzel G, Reis T, et al. Phase I/II trial of combined kyphoplasty and intraoperative radiotherapy in spinal metastases. The Spine Journal.

2018;18(5):776-781. doi:10.1016/J.SPINEE.2017.09.011

9

Gzell C, Back M, Wheeler H, Bailey D, Foote M. Radiotherapy in Glioblastoma: the Past, the Present and the Future. Clinical Oncology. 2017;29(1):15-25. doi:10.1016/J.CLON.2016.09.015

WWW.HOSPITALREPORTS.ORG | 29

Healthcare Professionals Make More Effective Evidence Based Clinical Decisions With Hospital Reports

For the past decade, Hospital Reports has been helping healthcare professionals, within both public and private hospitals, to improve patient outcomes Our Special Reports provide readers with an unparalleled depth of information on specialist subjects, which receive limited coverage in the mainstream medical media.

Each report is designed to help healthcare professionals to make more effective treatment decisions, by providing a unique mix of: • Subject specific clinical information • Insight and knowledge from internationally recognised key opinion leaders • Clinical guidelines • Independent data and analysis • Unbiased editorial content

www.hospitalreports.org subscriptions@globalbusinessmedia.org www.globalbusinessmedia.org