Advancing the Treatment of Breast Cancer and the Role of Intra-Operative Single Dose Radiotherapy by Global Business Media

SPECIAL REPORT

Advancing the Treatment of Breast Cancer and the Role of Intra-Operative Single Dose Therapy

How Intra-Operative Single Dose Radiotherapy Can Offer an Effective and Cost-Efficient Alternative How Breast Cancer Specialists Are Looking for New Ways of Reducing the Duration of Radiation Therapy Pitfalls and Limitations Associated with Conventional EBRT How Immediate Irradiation During Surgery in the OR Can Prevent Tumor Reformation Choosing an Intraoperative Radiotherapy System The Importance of New Treatment Guidelines to Enable the Use of Targeted IORT in Clinical Practice The Evolving Role of New Targeted Approaches in the Treatment of Patients with Breast Cancer

Published by Global Business Media

ADVANCING THE TREATMENT OF BREAST CANCER AND THE ROLE OF INTRA-OPERATIVE SINGLE DOSE RADIOTHERAPY

SPECIAL REPORT

Advancing the Treatment of Breast Cancer and the Role of Intra-Operative Single Dose Therapy

Contents Introduction

Jonathan Agnew, Editor

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 Jonathan D. Agnew, PhD, MBA Senior Project Manager Steve Banks Advertising Executives Michael McCarthy Abigail Coombes Production Manager Paul Davies For further information visit: www.globalbusinessmedia.org 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. 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.

How Intra-Operative Single Dose Radiotherapy Can Offer an 3 Effective and Cost-Efficient Alternative to Conventional Whole Breast Radiotherapy for the Treatment of ESBC Jonathan D. Agnew, PhD, MBA, Adjunct Professor, Faculty of Medicine, University of British Columbia

Historical Background of IORT Efficient and Cost-Effective Treatment Clinically Effective Treatment Scientifically Proven Open-Up the Room for IORT

How Breast Cancer Specialists Are Looking for New Ways of Reducing the Duration of Radiation Therapy and Postoperative Treatment Times Without Compromising Patient Outcomes

An interview with two leading radiation oncologists from the EU and the USA – Dr. Valery Uhl & Dr. Agnès Tallet – showing their perspective of the daily challenges they are facing when trying to provide the best treatment options to their breast cancer patients

Pitfalls and Limitations Associated with Conventional EBRT – Increased Risk of Side Effects, Patient Discomfort and Longer Duration of Therapy

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

Medical Results Non-Medical Results Quality of Life

How Immediate Irradiation During Surgery in the OR Can Prevent Tumor Reformation Stimulated by Wound Healing After Resection

Pedro Lara MD, PhD, Head of the Department of Radiation Oncology in the San Roque University Hospital, Las Palmas, Spain; Professor and Chair of Radiology, Fernando Pessoa Canarias University; Director of the Canarian Institute for Cancer Research

Sterilization of the Tumor Bed Radiological Effects of IORT Immunological Effect on Cells Delayed Irradiation with EBRT

Key Considerations When Choosing an Intraoperative Radiotherapy System – Usability, Precision and Cost Effectiveness

An interview with Dr. Henning Kahl (DE) about the most important aspects when defining the right IORT option and selecting a treatment device for the own hospital

The Importance of New Treatment Guidelines to Enable the Use of Targeted IORT in Clinical Practice

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

Current Practice Guidelines for Radiotherapy Future Burden of Cancer Care Effectiveness and Efficiency of Targeted IORT Adapting Current Guidelines to Improve Quality, Cost and Access

The Evolving Role of New Targeted Approaches in the Treatment of Patients with Breast Cancer

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

Trends in Breast Cancer Incidence and Prevalence Trends in Treatment Options Successes in IORT Future Directions

WWW.HOSPITALREPORTS.ORG | 1

ADVANCING THE TREATMENT OF BREAST CANCER AND THE ROLE OF INTRA-OPERATIVE SINGLE DOSE RADIOTHERAPY

Foreword T

he number of women with breast cancer is

This report explores one such advance, the

increasing. The most common cancer among

development of targeted intraoperative radiotherapy

women, breast cancer rates are highest among

(IORT) for the treatment of patients with early-

women in developed countries. In the United

stage breast cancer. A growing body of scientific

States, for example, nearly one in eight women is

literature showing the clinical- and cost effectiveness

at risk of getting breast cancer during their lifetime.

of IORT demonstrates the unique potential of this

The link between breast cancer and risk factors

technology to improve patient outcomes, shorten

such as age and weight provides policymakers

treatment times, and reduce the burden on

and healthcare systems with the unfortunate

hospitals and health systems. The first article

scenario that, as populations get older and become

includes a review of the historical background and

increasingly obese, the number of breast cancer

development of IORT, as well as evidence showing

patients likely will continue to grow. Indeed, fully 3.2

its effectiveness. This is followed in the second article

million women are expected to have breast cancer

with a discussion on how breast cancer specialists

by the year 2050, and healthcare providers and

are seeking new ways of reducing the duration of

payers will be pressed to find effective and efficient

radiation therapy and postoperative treatment times

ways to treat them.

while maintaining quality outcomes. The third article

Breast cancer takes its toll at an individual level, too.

looks at the pitfalls and limitations associated with

Under standard treatment including external beam

conventional external beam radiotherapy. The fourth

radiotherapy, patients report skin changes, breast

article reviews how immediate irradiation during

hardness and firmness, breast shrinkage, affected

surgery in the OR can prevent tumor reformation

nipple position, arm and shoulder pain, breast pain,

stimulated by wound healing after resection,

breast swelling, and breast oversensitivity. Patient-

followed in the fifth article by an exploration of key

reported measures of well-being, such as poor body

considerations when choosing an IORT system.

image perception, worsened future perspectives, and

The importance of new treatment guidelines to

limited functional outcomes speak to the struggles

enable the use of targeted IORT in clinical practice

that breast cancer patients face.

is examined in the sixth article. The report concludes

Some comfort comes from the realization

with a discussion of the evolving role of targeted

that improvements in screening and treatment

approaches such as IORT in the treatment of

technologies have led to a reduction in breast cancer

breast cancer.

mortality. The ability to identify, diagnose, and treat breast cancer patients early and effectively is key to reducing the burden of the disease at both system and individual levels.

Dr. Jonathan D. Agnew Editor-in-Chief

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.

2 | WWW.HOSPITALREPORTS.ORG

ADVANCING THE TREATMENT OF BREAST CANCER AND THE ROLE OF INTRA-OPERATIVE SINGLE DOSE RADIOTHERAPY

How Intra-Operative Single Dose Radiotherapy Can Offer an Effective and Cost-Efficient Alternative to Conventional Whole Breast Radiotherapy for the Treatment of ESBC Jonathan D. Agnew, PhD, MBA, Adjunct Professor, Faculty of Medicine, University of British Columbia A robust and conclusive body of evidence shows that single dose intraoperative radiotherapy offers an effective and cost-efficient alternative to conventional whole breast external beam radiotherapy for the treatment of early-stage breast cancer.

NTRAOPERATIVE RADIOTHERAPY (IORT) is radiation administered during surgery. Typically used to treat cancer, IORT allows for the direct application of radiotherapy to a targeted area without harming surrounding tissue. Since its arrival in the mid-1960s, modern IORT has undergone significant developments that have led to its increasing use as a clinically effective, efficient, and scientifically proven treatment. Today, a conclusive body of evidence demonstrates that single dose radiotherapy can offer an effective and cost-efficient alternative to conventional whole breast radiotherapy for the treatment of early-stage breast cancer (ESBC).

Historical Background of IORT The modern era of IORT began with the introduction of intraoperative electron radiotherapy (IOERT). The early Japanese experience with IOERT suggested promising results on locally advanced abdominal neoplasms and unresectable radioresistant tumors. 1 The subsequent American experience employing the technology as a “boost,” in other words, in combination with standard external beam radiotherapy, demonstrated further success in patients with breast, gynecologic, and head and neck cancers.2 The advent of high-dose rate IORT (HDR-IORT) in the late 1980s marked a further advance, as it allowed for the treatment of larger and more complex anatomic surfaces than was previously possible.

These early approaches, however, had several drawbacks. Patients treated in an ordinary operating room would have to be transported to a radiation facility with proper equipment and shielding. The other option – creating specialized, dedicated operating rooms that incorporated radiotherapy machines – was costly. The advent of portable linear accelerators in the 1990s overcame these challenges, as they could be used safely in standard operating rooms. A further development came with the introduction of low-energy IORT in 1999. The use of low-energy x-ray radiation offers a higher relative biological effectiveness compared to other forms of IORT (i.e., less radiation required to produce the same change), as well as the practical advantage that it does not require extra measures for radiation protection beyond those provided by ordinary operating rooms.

From a societal perspective, IORT is both less expensive and more effective than EBRT

Efficient and Cost-Effective Treatment IORT represents an efficient approach to the treatment of ESBC when compared to conventional whole breast EBRT for both individual patients as well as hospitals and health care systems. From the patient perspective, IORT offers clear advantages over EBRT. Because it is applied as a single fraction at the time of surgery in an outpatient setting, the patient is spared the inconvenience of multiple returns for additional radiotherapy. Compared to EBRT, recovery time is faster and there are fewer side effects. Moreover, WWW.HOSPITALREPORTS.ORG | 3

ADVANCING THE TREATMENT OF BREAST CANCER AND THE ROLE OF INTRA-OPERATIVE SINGLE DOSE RADIOTHERAPY

IORT offers not only a clinically acceptable alternative, but provides additional convenience and cost-effectiveness

evidence suggests fewer non-breast cancer deaths associated with IORT compared to EBRT.3 At the hospital and health systems level, analyses suggest that IORT is a more costeffective option than EBRT. Because IORT allows for the delivery of a single fraction of radiotherapy at the time of surgery as opposed to multiple visits required with EBRT, hospitals can reduce wait times for ESBC treatment and radiology departments can focus on more complex cancers.4 Alvarado et al evaluated the cost-effectiveness of IORT compared to a standard six-week course of whole-breast EBRT.5 The results show that, from a societal perspective, IORT is both less expensive and more effective than EBRT. Indeed, the authors characterize IORT as a “disruptive innovation” that provides a less costly and more convenient option. Using a similar analytical technique, Vaidya et al conducted a cost-effectiveness analysis of IORT from the NHS perspective. In terms of quality adjusted life years, they found IORT a highly cost-effective strategy compared to EBRT.6

From the patient perspective, IORT offers clear advantages over EBRT. Because it is applied as a single fraction at the time of surgery in an outpatient setting, the patient is spared the inconvenience of multiple returns for additional radiotherapy

Clinically Effective Treatment

could replace EBRT for patients with ESBC.3 The study participants included 2,298 women with ESBC, age 45 years and above, and from 32 centers across 10 countries. Participants were randomly allocated and either given a standard course of whole breast radiotherapy for three to six weeks following surgery or given IORT during surgery immediately after lumpectomy and under the same anesthetic. For most of the patients in this second group (80%), this was the only radiotherapy that they received (the remaining 20%, who were at higher risk for recurrence of cancer also received supplemental EBRT). The results clearly showed that IORT is an effective alternative to EBRT. Across both groups, risk of recurrence was similar, and there was no statistically significant difference in overall survival or breast cancer mortality, among other measures of efficacy. Importantly, the results also showed far fewer deaths from causes other than breast cancer, likely because of the more targeted application of radiotherapy in IORT than is possible in whole breast EBRT. In a separate study based on the TARGIT-A study, the TARGIT-E trial was a prospective study investigating the efficiency of single-dose IORT for low-risk patients followed by whole breast radiotherapy only among elderly patients with certain risk factors.9 10 The study examined local relapse rates and observed relapsefree survival of 99.8% of patients after 2.5 years and 98.5% after 5 years. The authors conclude that the results support use of accelerated partial breast radiotherapy (including IORT) in this patient group.

The clinical effectiveness of IORT for ESBC is well-documented. In a retrospective study of data from the surveillance, epidemiology, and end results (SEER) database, Lei et al found that overall survival and cancer-specific survival rates were similar among patients who received IORT as for those who received external beam radiotherapy (EBRT), the usual standard of care. The authors conclude that IORT may be a reasonable alternative to EBRT for early breast cancer patients.7 In a comprehensive comparison of studies of IORT, Feng et el declared that “IORT plays an essential role in early-stage breast cancer treatment, and its application prospect is worth looking forward to.” The authors further note that IORT is accepted as an alternative or adjunct to EBRT following breast-conserving surgery.8

Scientifically Proven The most convincing evidence of the effectiveness of single-dose IORT come from a series of clinical trials, foremost among them the TARGIT-A study, a clinical trial data comparing IORT to EBRT. Like other research on IORT, this study confirms the clinical effectiveness of the technique. However, because of its robust study design (prospective randomized clinical trial), the number of subjects (over 2,200 patients), and the time following-up patients (up to 10 years), the TARGIT-A study data provide the strongest possible scientific evidence in favor of IORT. The TARGIT-A trial sought to determine whether IORT delivered as a single dose during surgery 4 | WWW.HOSPITALREPORTS.ORG

ADVANCING THE TREATMENT OF BREAST CANCER AND THE ROLE OF INTRA-OPERATIVE SINGLE DOSE RADIOTHERAPY

Open-Up the Room for IORT Patients with early-stage breast cancer have many treatment options, but evidence shows that IORT is a clinically- and cost-effective option. Compared with standard EBRT, IORT offers not only a clinically acceptable alternative, but provides additional convenience and cost-effectiveness. Indeed, IORT has been described as disruptive innovation that represents a paradigm shift in therapy.5 Unfortunately, current practice does not yet fully account for this important technological advance, and the standard of care remains EBRT following breast-conserving surgery. Although the American Society for Radiation Oncology (ASTRO)11 and the Groupe Europèen de Curietherapie of the European Society of Therapeutic Radiology

and Oncology (GEC-ESTRO)12 provide patient selection criteria for the use of partial-breast irradiation (including IORT), the National Comprehensive Cancer Network guidelines for breast cancer consider accelerated partial breast irradiation, such as single-dose IORT, as investigational.13 The exclusion of single-dose IORT for patients with ESBC represents a missed opportunity for patients, hospitals, and healthcare systems, which can benefit from reduced wait times, greater convenience from having radiation treatment in one setting at the time of surgery, lowered risk of non-breast cancers, as well as more efficient and cost-effective treatment. The research is clear: it is time to open up the operating room for IORT.

References: 1

Abe M, Takahashi M. Intraoperative radiotherapy: The japanese experience. International Journal of Radiation Oncology, Biology, Physics. 1981;7(7):863-868. doi:10.1016/0360-3016(81)90001-8

Gunderson LL, Calvo FA, Willett CG, Harrison LB, Santos M. General Rationale and Historical Perspective of Intraoperative Irradiation. In: Intraoperative Irradiation. Humana Press; 1999:1-24. doi:10.1007/978-159259-696-6_1

Vaidya JS, Bulsara M, Baum M, et al. Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (TARGIT-IORT) for early breast cancer: TARGIT-A randomised clinical trial. The BMJ. 2020;370. doi:10.1136/bmj.m2836

Esposito E, Anninga B, Honey I, et al. Is IORT ready for roll-out? ecancermedicalscience. 2015;9. doi:10.3332/ecancer.2015.516

Alvarado MD, Mohan AJ, Esserman LJ, et al. Cost-Effectiveness Analysis of Intraoperative Radiation Therapy for Early-Stage Breast Cancer. doi:10.1245/s10434-013-2997-3

Vaidya A, Vaidya P, Both B, Brew-Graves C, Bulsara M, Vaidya JS. Health economics of targeted intraoperative radiotherapy (TARGIT-IORT) for early breast cancer: A cost-effectiveness analysis in the United Kingdom. BMJ Open. 2017;7(8):e014944. doi:10.1136/bmjopen-2016-014944

The research is clear: it is time to open up the operating room for IORT

Lei J, Wang Y, Bi Z, Xue S, Ou B, Liu K. Intraoperative radiotherapy (IORT) versus whole-breast external beam radiotherapy (EBRT) in early stage breast cancer: results from SEER database. Japanese Journal of Radiology. 2020;38(1). doi:10.1007/s11604-019-00891-7

Feng K, Meng X, Liu J, et al. Update on intraoperative radiotherapy for early-stage breast cancer. American journal of cancer research. 2020;10(7):2032-2042. Accessed January 29, 2021. http://www.ncbi.nlm.nih.gov/pubmed/32774999

Neumaier C, Elena S, Grit W, et al. TARGIT-E(Lderly)-Prospective Phase II Study of Intraoperative Radiotherapy (IORT) in Elderly Patients with Small Breast Cancer.; 2012. Accessed January 30, 2021. http://www.biomedcentral.com/1471-2407/12/171

Wenz F. TARGIT E(lderly): Prospective phase II trial of intraoperative radiotherapy (IORT) in elderly patients with small breast cancer. Journal of Clinical Oncology. 2019;37(15_suppl):563-563. doi:10.1200/ jco.2019.37.15_suppl.563

Leonardi MC, Maisonneuve P, Mastropasqua MG, et al. How do the ASTRO consensus statement guidelines for the application of accelerated partial breast irradiation fit intraoperative radiotherapy? A retrospective analysis of patients treated at the European Institute of Oncology. International Journal of Radiation Oncology Biology Physics. 2012;83(3):806-813. doi:10.1016/j.ijrobp.2011.08.014

Polgár C, Limbergen E van, Pötter R, et al. Patient selection for accelerated partial-breast irradiation (APBI) after breast-conserving surgery: Recommendations of the Groupe Européen de CuriethérapieEuropean Society for Therapeutic Radiology and Oncology (GEC-ESTRO) breast cancer working group based on clinical evidence (2009). Radiotherapy and Oncology. 2010;94(3):264-273. doi:10.1016/j. radonc.2010.01.014

Abraham J, Aft R, Agnese D, et al. NCCN Guidelines Version 1.2021 Breast Cancer.; 2021.

WWW.HOSPITALREPORTS.ORG | 5

ADVANCING THE TREATMENT OF BREAST CANCER AND THE ROLE OF INTRA-OPERATIVE SINGLE DOSE RADIOTHERAPY

How Breast Cancer Specialists Are Looking for New Ways of Reducing the Duration of Radiation Therapy and Postoperative Treatment Times Without Compromising Patient Outcomes An interview with two leading radiation oncologists from the EU and the USA – Dr. Valery Uhl & Dr. Agnès Tallet – showing their perspective of the daily challenges they are facing when trying to provide the best treatment options to their breast cancer patients.

IORT offers numerous advantages. It is applied as a single fraction, at the time of surgery, in an outpatient setting, thus avoiding the several commutes of the patients that are mandatory for conventional external beam radiation therapy and thereby, lowers the whole treatment cost

6 | WWW.HOSPITALREPORTS.ORG

Valery Uhl MD, Radiation Oncologist in the San Francisco Bay Area of Northern California and President of the TARGIT Collaborative Group (TCG), USA Agnès Tallet MD, Head of Radiotherapy Department, l’Institut Paoli-Calmettes, Marseille, France

Case numbers for breast cancer are increasing worldwide. The treatment of affected women is becoming more and more a priority. What does such a diagnosis and treatment mean mentally and physically for your patients? [Dr. Uhl]: When a woman finds out she has breast cancer she is usually shocked and then starts to worry. [Dr. Tallet]: Yes, the announcement of cancer is in itself frightening. It is still in wits a sentence of programmed death, preceded by many bad changes in everyday life, such as limitation in children care, work stopping, troubles in sexual life, social dependence, among others. [Dr. Uhl]: And some women get depressed and this can affect their physical state and ability to cope with their everyday lives too. They just want to get rid of the cancer and go back to their “normal” lives as soon as possible. [Dr. Tallet]: However, breast cancer is one cancer with great hope of a cure, as it has been widely claimed, and patients initially are very combative and go through every treatment with as much energy as they can. Surgery is not an issue since it rapidly removes the primary disease. Conversely, adjuvant therapies are more reluctantly accepted. Some patients require

chemotherapy and are exhausted at the time of radiation therapy. They undergo irradiation but are commonly fed up with it, although they quite all complete the treatment. Endocrine therapy has an intermediate toxicity profile and is often early stopped.

And what are the key considerations from a medical perspective to support the patients here? [Dr. Uhl]: At first, it is very important that the patient receives the correct work up for her breast cancer so that she is properly staged. This guides the treatment plan and the options for treatment the patient may have. Currently, patients with early stage breast cancer have many treatment options. [Dr. Tallet]: In fact, several tracks may be investigated. First, an exhaustive announcement of the whole treatment schedule, as well as its timing, is needed. Each adjuvant or neoadjuvant treatment has to be explained and detailed, including all the expected side-effects. Second, when several options exist, the medical team has to present all the advantages and drawbacks of each and

ADVANCING THE TREATMENT OF BREAST CANCER AND THE ROLE OF INTRA-OPERATIVE SINGLE DOSE RADIOTHERAPY

choose the one that best fits the patient’s desire. It leads patients to feel involved in their treatment, and it increases patients’ confidence. Last, supportive care for adverse effects management is also of great value.

One treatment option for breast cancer is radiotherapy. Could you explain how this treatment option works and what the specific medical hurdle is here? [Dr. Uhl]: Radiotherapy is used for early stage breast cancer when a woman chooses to keep her breast instead of undergoing a mastectomy. Breast conservation has fewer side effects and the cure rate is the same whether a woman opts to keep her breast or have a mastectomy... [Dr. Tallet]...and especially adjuvant radiation therapy was proven to reduce the local recurrence risk by two-third and, thereby, to further improve overall survival. [Dr. Uhl]: The typical radiation portion of her treatment plan usually consists of daily (external beam) radiation treatments, Monday through Friday, for many weeks. This means she may have to take time off of work or away from her children at home for a portion of her day so that she can have her radiation treatments. [Dr. Tallet] But today, additional radiation schemes are validated and can be chosen according to the patient’s and tumor’s conditions. It can last for one day (IORT) to 6 weeks, five days a week. Long treatments, such as six weeks, are exhausting for elderly patients and are, therefore, quite not conceivable. Hypofractionated radiation therapy is, in these cases, a better option. Nonetheless, the elderly often harbor several comorbidities, and the radiation therapist will be more inclined to opt for the shortest treatments, as well as a scheme that best spares both the heart and lungs, provided it is not at the detriment of the local control rate. And where do you currently see the most promising future development opportunities in radiotherapy to overcome these hurdles? [Dr. Tallet]: Some progress has already occurred; hypofractionation schemes are currently in routine use; conformal radiation therapy and even intensity-modulated radiotherapy are more accurate; the use of deep inspiration breath-hold allows for both heart and lungs sparing and are of great help in patients with left-sided breast cancer. Several treatment plans can easily be compared. Some select

IORT is proven to be effective and easier accepted by the patients. It has been an appealing treatment each time we proposed it to the patient. Moreover, within the context of the current pandemic, we find new advantages of this technique

patients can be offered partial breast irradiation since several randomized trials showed its safety. Future improvements will include (but not limited to) the investigation of proton therapy and even FLASH radiation therapy for focused treatments. [Dr. Uhl]: Yes, the trend in radiation is definitely “less is more”. Hypofractionated courses of radiation for example have been shown to have the same cancer control rate and survival as extended courses of radiation. Faster courses of radiation also have fewer side effects and interfere less with the patients’ lives.

Which type of irradiation is most targeted and effective for breast cancer patients?

The most targeted and effective radiation for early stage breast cancer is definitely intraoperative radiation therapy (IORT). The patient receives all of her radiation over minutes in the Operating Room (OR) when she is getting her cancer removed

[Dr. Tallet]: Radiation therapy is by definition targeted since it utilizes objectives being to encompass a target (the volume to be irradiated), as well as constraints (on healthy tissue to be spared from the radiation dose). Nonetheless, the technique that best avoids the organs at risk is the one that delivers the full-dose to the target and the least-dose to the surrounding healthy tissue. Two methods meet this description, namely, brachytherapy and IORT. Both were shown in randomized controlled trials to be non-inferior to whole-breast irradiation in carefully selected patients...[Dr. Uhl]:...but the most targeted and effective radiation for early stage breast cancer is definitely intraoperative radiation therapy (IORT). The patient receives all of her radiation over minutes in the Operating Room (OR) when she is getting her

WWW.HOSPITALREPORTS.ORG | 7

ADVANCING THE TREATMENT OF BREAST CANCER AND THE ROLE OF INTRA-OPERATIVE SINGLE DOSE RADIOTHERAPY

cancer removed. There is no way to miss the lumpectomy cavity site since the Radiation Oncologist is in the OR with the breast cancer surgeon who just removed the cancer. The efficacy of IORT also has been proven in a large, international, prospective, randomized, risk adapted trial called TARGIT-A.

And what are the main advantages of IORT from your perspective of a radiation oncologist?

In my personal practice, IORT is offered as a treatment option on a regular basis and has become a very popular option during the Covid-19 pandemic since it reduces the patients’ risk of CV-19 exposure

[Dr. Uhl]: As said, definitive IORT allows the patient to have all her radiation in one setting: at the time of her lumpectomy. No extra visits to the radiation oncology department so no extra travel, no extra time off of work, no childcare issues, no transportation issues, etc. My patients who received IORT are very grateful they had this option. Also, as a Radiation Oncologist, I prefer IORT. This is especially true for LEFT sided breast cancers because IORT spares the heart and lungs from radiation, unlike External Beam Radiation Therapy (EBRT). The TARGIT-A trial found statistically significant fewer non breast cancer deaths in the IORT arm of the trial. This was attributed to less cardiovascular deaths. [Dr. Tallet]: Although restricted to highly selected patients, IORT offers numerous advantages. It is applied as a single fraction, at the time of surgery, in an outpatient setting, thus avoiding the several commutes of the patients that are mandatory for conventional external beam radiation therapy and thereby, lowers the whole treatment cost. It reduces treatment toxicity and provides better cosmetic outcomes by avoiding whole-breast fibrosis. When used as a boost, this radiation technique facilitates breast-oncoplastic surgery. It also allows for second conservative treatment at the time of local recurrence, if any (patients can be treated as if nothing had happened before).

What effect does this have on your patients on the other hand? [Dr. Uhl]: Patients who have IORT instead EBRT have a faster recovery since there are usually no more radiation treatments after the single treatment given in the OR at the same time as her breast surgery. Women can get back to their normal lives much faster than with EBRT. There are also fewer side effects, like breast pain, with

8 | WWW.HOSPITALREPORTS.ORG

IORT and the cosmetic outcome is superior. And as said before, there are fewer nonbreast cancer deaths with IORT, especially cardiovascular deaths. [Dr. Tallet]: And patients are thoroughly satisfied with this option. We observed a low rate of recurrence. As exposed in the first question, patients do not have any problem with surgery, and performing the adjuvant radiation therapy at the same time makes them feel as they had no cancer because the treatment resembles a treatment for benign pathologies.

This sounds as if IORT should be considered as standard of care in the future. What is the current status of IORT in the treatment priority for breast cancer patients? [Dr. Tallet]: IORT can be offered to highly selected patients. It was initially not widely accepted due to a limited follow-up of patients in the first TARGIT-A publication. However, this trial is now updated and confirms the previous results. Due to its easy use, patients eligible for partial breast irradiation benefit from this treatment in our institution. Nonetheless, there are still, in France, few radiation therapy facilities equipped with this system. The major problem is its lack of reimbursement, meaning that we work for free. Thus, any future implementation would call for a large investment without remuneration, which is inconceivable as you can imagine. [Dr. Uhl]: Unfortunately, in the USA, also not all Radiation Oncology Centers have an IORT unit such as INTRABEAM®, so many patients never hear about the option of IORT although they qualify for it. In the practices where the physicians have an IORT unit, IORT is offered to those patients who meet the eligibility criteria. Most women choose IORT over EBRT for the convenience as well as the proven advantages. In my personal practice, IORT is offered as a treatment option on a regular basis and has become a very popular option during the Covid-19 pandemic since it reduces the patients’ risk of CV-19 exposure.

Where do you see IORT in the future of breast cancer treatments and why? [Dr. Uhl]: In the USA, IORT is becoming more popular and the use of IORT has increased over 20-fold from 2009-2014. I see it being used more and more as partial breast and

ADVANCING THE TREATMENT OF BREAST CANCER AND THE ROLE OF INTRA-OPERATIVE SINGLE DOSE RADIOTHERAPY

hypofractionated radiation courses have become more popular. Also, as the reimbursement for radiation in the USA changes, faster courses of radiation will be used more frequently as they are more cost effective. [Dr. Tallet]: And IORT is proven to be effective and easier accepted by the patients. It has been an appealing treatment each time we proposed it to the patient. Moreover, within the context of the current pandemic, we find new advantages of this technique. Indeed, the elderly are particularly sensitive to getting infected, and we must limit as much as possible their commute to the hospital. Additionally, infection during the radiation therapy treatment course threatens to interrupt the treatment, and in this case, the whole treatment would be useless. Thus, favoring short treatments becomes crucial. Lastly, external beam radiation therapy in patients previously affected by the COVID-19 disease is not well documented and becomes of concern when the beams are susceptible to encompass some part of the lungs. For all these reasons, I think a wider use of IORT is desirable.

Are there any last considerations you would you like to give your peers on their way? [Dr. Tallet]: As usual, the IORT technique, as well as all other PBI techniques, requires a rigorous patient selection. Patients must be aware of the strict necessity of endocrine therapy uptake because most patients experiencing a local recurrence are those having stopped this adjuvant treatment. [Dr. Uhl]: So, if you are not performing IORT now, please look into this elegant form of very precise, targeted radiation. It is extremely accurate with very few side effects and many advantages to the patient and the health care system as well as globally (IORT has the lowest carbon footprint of all forms of breast cancer radiation). Read the TARGIT-A trial results from the British Medical Journal (Link) and join the TARGIT Collaborative Group (TCG) to learn more about IORT and also to receive support when you are ready to start and/or expand your IORT program. Your patients will thank you!

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 labeling varies by country.

WWW.HOSPITALREPORTS.ORG | 9

ADVANCING THE TREATMENT OF BREAST CANCER AND THE ROLE OF INTRA-OPERATIVE SINGLE DOSE RADIOTHERAPY

Pitfalls and Limitations Associated with Conventional EBRT – Increased Risk of Side Effects, Patient Discomfort and Longer Duration of Therapy Jonathan D. Agnew, PhD, MBA, Adjunct Professor, Faculty of Medicine, University of British Columbia Although associated with a reduced risk of local recurrence, conventional external beam radiotherapy (EBRT) following lumpectomy is not without cost. A body of research shows that conventional EBRT is associated with negative medical outcomes, practical difficulties, and poorer quality of life compared to more novel technologies.

Beyond these accessrelated issues, EBRT also imposes more complex workflows for hospitals and health systems than IORT

HOLE BRE AST ex ternal beam radiotherapy (EBRT) is the current standard of care following breast-conserving surgery (lumpectomy) for patients with early-stage breast cancer (ESBC). Citing evidence showing that whole breast radiation reduces the risk of local recurrence and has a beneficial effect on survival, the National Comprehensive Cancer Network guidelines for breast cancer recommend whole breast irradiation following lumpectomy.1 Nonetheless, EBRT is not without medical risk and cost, both in terms of dollars and quality of life. In terms of medical outcomes, EBRT is associated with radiation-induced secondary cancers, reduced lung function, and cardiac toxicity. Compared to other more novel technologies, notably intraoperative radiotherapy (IORT), EBRT is less cost-effective and efficient. Moreover, an extensive body of research shows that EBRT is associated with lower patientreported quality of life outcomes.

Medical Results Radiation-induced secondary cancers, while rare, can occur after breast conserving surgery. Most often, secondary tumors occur in organs nearest to the radiation fields targeted during therapy, and evidence suggests that even small doses of radiation can cause cancer in organs distant from the irradiated tumor. In an analysis of secondary cancer risks of EBRT versus accelerated partial breast irradiation (APBI) and intraoperative radiotherapy, Aziz 10 | WWW.HOSPITALREPORTS.ORG

et al found that EBRT delivered higher doses of radiation to the lung, heart, spine, and contralateral breast than IORT or APBI and, therefore, more likely to result in a second malignancy after breast irradiation.2 EBRT is also associated with poorer lung function. In a follow-up study of women 11 years after treated for breast cancer with adjuvant radiotherapy, Goldman et al found a chronic and clinically significant reduction in pulmonary function.3 Similarly, Ooi et al found that pulmonary function, as indicated by lung function indices and radiological evidence of persistent lung injury, worsened among patients who received adjuvant radiotherapy following breast resection, with decline progressing during the first, third, and sixth months post-surgery, and becoming irreversible at 12 months.4 Despite the development of techniques to decrease cardiac dose among breast cancer patients, EBRT remains associated with cardiac toxicity. In their study of 34 patients recruited as part of the TARGIT-IORT trial, Woolf et al used blood samples to measure γ-H2AX formation in peripheral blood lymphocytes – a proxy for radiation exposure in the heart and cardiac vessels. They found that patients who received EBRT (treatment that requires at least 15 fractions) had a statistically higher increase in γ-H2AX formation than patients receiving IORT (treatment that is completed in a single fraction). As Jacobson and Siochi note, symptoms of cardiac injury from radiotherapy

ADVANCING THE TREATMENT OF BREAST CANCER AND THE ROLE OF INTRA-OPERATIVE SINGLE DOSE RADIOTHERAPY

EBRT is associated with radiation-induced secondary cancers, reduced lung function, and cardiac toxicity

times, inconveniencing patients and requiring additional administration for hospitals and health systems that must do more to coordinate care. Recognizing the additional number of visits by patients represents increased health risk during COVID-19, some have recommended IORT, not EBRT, as the preferred treatment modality for eligible patients.8

Quality of Life may not be immediately evident, but rather appear decades after exposure – a significant concern for breast cancer patients who will live decades after treatment.5

Non-Medical Results Compared to IORT, EBRT requires additional time and inconvenience for patients, resulting in a diminished quality of care. Because EBRT following breast cancer surgery typically involves daily treatments for a period of weeks, patients will have to travel to and from a radiation treatment facility. Recognizing that the distance patients travel for care is a barrier to access, Longacre et al examined the relationship between travel distance for radiation therapy and clinical factors. Their conclusion, based on data for 52,317 women from the Surveillance Epidemiology and End Results (SEER)-Medicare database, was that travel distance to radiation facilities may pose a significant burden for breast cancer patients.6 Similarly, Rudat et al compared compliance with treatment regimens for breast cancer surgery patients receiving adjuvant breast cancer radiotherapy, either as conventional fractionation (28 daily fractions) or hypofractionation (15 daily fractions).7 Their analysis found not only that patients with the less frequent regimen were more compliant, but that frequency of the regimen was the only independent predictor of compliance. In other words, social, demographic, and medical factors such as country of origin, marital status, and tumor grading and classification did not affect how likely a woman was to miss a radiotherapy treatment, only the number of treatment sessions mattered – an important finding when considering the disadvantages of EBRT to single-dose IORT. Beyond these access-related issues, EBRT also imposes more complex workflows for hospitals and health systems than IORT. Because EBRT is performed post-operatively, patients must return to a treatment facility multiple

EBRT is associated with lower quality of life measures when compared to other radiotherapy interventions. In a study of patient-reported outcomes for 1,265 patients receiving whole- or partial-breast EBRT, 42% of patients reported adverse events at five years post-treatment. Adverse events included skin changes, breast hardness/firmness, breast shrinkage, nipple position affected, arm/shoulder pain, breast pain, breast swelling, and breast oversensitivity.9 Additional findings come from the phase III TARGIT-A trial. Welzel et al examined quality of life measures among breast cancer patients who received IORT alone or EBRT. Compared to patients receiving IORT alone, patients who received EBRT reported greater general pain, more breast and arm symptoms, and worse role function (i.e., restrictions in daily activities).10 Similarly, Sorrentino et al found that breast cancer patients receiving EBRT took substantially longer to return to daily activities (70.6 days) than those receiving IORT (41 days).11 Finally, in a study using data from the APBIIMRT-Florence phase 3 randomized trial, researchers found that patients undergoing standard whole breast irradiation were more likely to report worse functional outcomes, body image perception, future perspectives, and breast and arm symptoms than their counterparts who received APBI.12 Guidelines recommending whole breast irradiation and EBRT are sound given the evidence demonstrating an associated reduced risk of local recurrence. However, despite these benefits, novel technological advances – including the introduction of IORT – have highlighted the pitfalls and limitations of EBRT. Data showing poorer medical results, the practical challenges for patients and health systems associated with multiple return visits for radiotherapy, and an extensive literature on poorer quality of life measures support the assertion that conventional EBRT is not without costs.

Compared to other more novel technologies, notably intraoperative radiotherapy (IORT), EBRT is less costeffective and efficient. Moreover, an extensive body of research shows that EBRT is associated with lower patient-reported quality of life outcomes

WWW.HOSPITALREPORTS.ORG | 11

ADVANCING THE TREATMENT OF BREAST CANCER AND THE ROLE OF INTRA-OPERATIVE SINGLE DOSE RADIOTHERAPY

References: 1

Abraham J, Aft R, Agnese D, et al. NCCN Guidelines Version 1.2021 Breast Cancer.; 2021.

Aziz MH, Schneider F, Clausen S, et al. Can the risk of secondary cancer induction after breast conserving therapy be reduced using intraoperative radiotherapy (IORT) with low-energy x-rays? Radiation Oncology. 2011;6(1):1-9. doi:10.1186/1748-717X-6-174

Blom Goldman U, Svane G, Anderson M, Wennberg B, Lind P. Long-term functional and radiological pulmonary changes after radiation therapy for breast cancer. Acta Oncologica. 2014;53(10):1373-1379. doi:10.3109/0284186X.2014.934967

Ooi GC, Kwong DL, Ho JC, et al. Pulmonary sequelae of treatment for breast cancer: A prospective study. International Journal of Radiation Oncology Biology Physics. 2001;50(2):411-419. doi:10.1016/ S0360-3016(01)01438-9

Jacobson GM, Siochi RA. Low-Energy Intraoperative Radiation Therapy and Competing Risks of Local Control and Normal Tissue Toxicity. Frontiers in Oncology. 2017;7(SEP):212. doi:10.3389/ fonc.2017.00212

Longacre CF, Neprash HT, Shippee ND, Tuttle TM, Virnig BA. Evaluating Travel Distance to Radiation Facilities Among Rural and Urban Breast Cancer Patients in the Medicare Population. The Journal of Rural Health. 2020;36(3):334-346. doi:10.1111/jrh.12413

Rudat V, Nour A, Hammoud M, Abou Ghaida S, Volker Rudat med, Abou Ghaida SAbouGhaida S. Better compliance with hypofractionation vs. conventional fractionation in adjuvant breast cancer radiotherapy Results of a single, institutional, retrospective study. Strahlentherapie und Onkologie. doi:10.1007/s00066-017-1115-z Vavassori A, Tagliaferri L, Vicenzi L, et al. Practical indications for management of patients candidate to Interventional and Intraoperative Radiotherapy (Brachytherapy, IORT) during COVID-19 pandemic – A document endorsed by AIRO (Italian Association of Radiotherapy and Clinical Oncology) Interventional Radiotherapy Working Group. Radiotherapy and Oncology. 2020;149:73-77. doi:10.1016/j. radonc.2020.04.040

Bhattacharya IS, Haviland JS, Kirby AM, et al. Patient-reported outcomes over 5 years after wholeOr partial-breast radiotherapy: Longitudinal analysis of the import low (CRUK/ 06/003) phase III randomized controlled trial. Journal of Clinical Oncology. 2019;37(4):305-317. doi:10.1200/JCO.18.00982 Welzel G, Boch A, Sperk E, et al. Radiation-related quality of life parameters after targeted intraoperative radiotherapy versus whole breast radiotherapy in patients with breast cancer: Results from the randomized phase III trial TARGIT-A. Radiation Oncology. 2013;8(1):9. doi:10.1186/1748-717X-8-9

12 | WWW.HOSPITALREPORTS.ORG

Sorrentino L, Fissi S, Meaglia I, et al. One-step intraoperative radiotherapy optimizes conservative treatment of breast cancer with advantages in quality of life and work resumption. Breast. 2018;39: 123-130. doi:10.1016/j.breast.2018.04.004

Meattini I, Saieva C, Miccinesi G, et al. Accelerated partial breast irradiation using intensity modulated radiotherapy versus whole breast irradiation: Health-related quality of life final analysis from the Florence phase 3 trial. European Journal of Cancer. 2017;76:17-26. doi:10.1016/j.ejca.2017.01.023

ADVANCING THE TREATMENT OF BREAST CANCER AND THE ROLE OF INTRA-OPERATIVE SINGLE DOSE RADIOTHERAPY

How Immediate Irradiation During Surgery in the OR Can Prevent Tumor Reformation Stimulated by Wound Healing After Resection Pedro Lara MD, PhD, Head of the Department of Radiation Oncology in the San Roque University Hospital, Las Palmas, Spain; Professor and Chair of Radiology, Fernando Pessoa Canarias University; Director of the Canarian Institute for Cancer Research The benefits of irradiation during surgery extend beyond simply killing cancer cells. By altering the microenvironment of the areas surrounding the tumor where recurrence is most likely, the radiological and immunological effects of immediate irradiation can prevent tumor reformation stimulated by wound healing.

HE PRESENCE of residual tumor cells is the common explanation for local recurrence of tumors following resection. Accordingly, current standards of care for breast-conserving surgery call for radiotherapy following resection.1 However, this explanation cannot fully account for the localization of breast cancer recurrences surrounding the original tumor and at the surgical scar site.2 Seeking to better understand this phenomenon, researchers have examined the role that wound fluid plays in tumor reformation. Tagliabue et al, for example, found that wound drainage fluid from re-excision specimens of breast cancer patients stimulated in-vitro growth of HER2overexpressing breast carcinoma cells. 3 Altering the molecular composition and biological activity of wound fluid may, therefore, represent an opportunity to reduce recurrence rates following breast conserving surgery. This article reviews how immediate irradiation during surgery can prevent tumor reformation stimulated by wound healing after resection. It considers the sterilization of the tumor bed, the radiological effects of IORT, and the immunological effects on cells. The implications of delayed irradiation with external beam radiotherapy (EBRT), in contrast to IORT, are also considered.

Sterilization of the Tumor Bed Local recurrences of tumors arise primarily in the tumor bed, and because increased local control is associated with improved overall

survival, events close to the tumor bed are critical for final prognosis.4 Guidelines recommend, therefore, that a radiation boost to the tumor bed be given to patients at risk for recurrence.1 These guidelines are based on randomized trials that have shown decreased in-breast recurrences following an additional boost of radiation. For example, Antonini et al found that a boost reduced reappearance of cancer at the primary tumor site by a factor of two.5 Similarly, in a clinical trial of breast cancer patients, Bartelink et al concluded statistically significant reduced rates of recurrence among patients who received supplementary dose of radiation to the tumor bed compared to those who received no such boost. 6 These findings are supported by other research. In a review of randomized controlled trials comparing patient groups with and without breast cancer tumor bed boost radiotherapy, the authors concluded that local control rates are increased with the boost to the tumor bed.7

Radiological and immunological effects of immediate irradiation can prevent tumor reformation stimulated by wound healing

Radiological Effects of IORT Evidence suggests that the radiological effects of IORT play a role in reducing the likelihood of local recurrence by altering the microenvironment of the tumor bed. To understand the biological basis of this phenomenon, researchers incubated breast cancer cells with wound fluid obtained from breast cancer patients who underwent IORT and found that the irradiated wound fluid induced a radiological response, supporting the notion WWW.HOSPITALREPORTS.ORG | 13

ADVANCING THE TREATMENT OF BREAST CANCER AND THE ROLE OF INTRA-OPERATIVE SINGLE DOSE RADIOTHERAPY

Evidence suggests that the radiological effects of IORT play a role in reducing the likelihood of local recurrence by altering the microenvironment of the tumor bed

14 | WWW.HOSPITALREPORTS.ORG

that IORT can alter the microenvironment by affecting nearby unirradiated cells.8 One element of the microenvironment is the presence of mesenchymal stromal cells (MSC), which, because of their regenerative potential, are associated with the promotion of tumor growth. Eliminating MSCs, therefore, may prevent tumor recurrence. Uhlig et al examined the effect of IORT on one type of MSC, breast adiposed tissue-derived MSC (bASC).9 They studied 41 patients undergoing breast-conserving surgery, 20 of whom received IORT and 21 who did not. The results showed that none of the breast tissue samples exposed to IORT yielded persistent outgrowth of bASC. Other elements of the tumor bed microenvironment are also likely affected by the radiological effects of IORT to inhibit local recurrence. For example, IORT may counteract the potential proliferation and division of residual malignant cells during wound healing by inducing the expression of specific microRNA.10 Piotrowski et al, for example, compared wound fluid exposed to IORT with unexposed wound fluid from cancer patients undergoing breast conserving surgery. 11 They found that IORT-treated wound fluid has anti-cancer properties and induces radiation-like damage in breast cancer cells.

Immunological Effect on Cells Radiotherapy impacts growing cancers by inducing cell death. However, radiotherapy also activates the immune system, for example, by causing the release of antigens from irradiated cells, increased inflammation in tumors, and sensitization of tumors to T cell responses.12 Indeed, the impact of the specific immune microenvironment is recognized as a major determinant of clinical progress for many tumors.13 These interactions between radiotherapy and the immune system can be leveraged to improve the efficacy of radiotherapy. Shiao and Coussens posit that cells’ radiobiological response activates different T-cell lines, thereby switching on the adaptive immune system.14 This is supported by case reports highlighting the potential for radiotherapy to spark a systemic antitumor immune response.15

Because it is applied to patients during surgery and under the same anesthesia, the use of IORT means that there is virtually no delay between tumor removal and radiotherapy

One of the more intriguing aspects of the immunological effect of radiotherapy on cells is how it counters the immune evasion of tumors. Tumors evade the immune system through an altered antigen presentation – in the case of breast and other cancers, this happens in part by diminishing the expression of MHC-I molecules, which are critical for immune system recognition of the tumor.16 Radiotherapy, in contrast, augments expression of MHC-I molecules and, therefore, reduces the ability to evade the immune system.

Delayed Irradiation with EBRT The primary difference between IORT and standard EBRT following breast-conserving surgery is the timing of the radiotherapy. Because it is applied to patients during surgery and under the same anesthesia, the use of IORT means that there is virtually no delay between tumor removal and radiotherapy. In contrast, standard EBRT is applied after surgery, usually over a period of several weeks. The gap in time between tumor removal and radiotherapy treatment necessarily implies a delay in realizing the positive effects of IORT for preventing tumor reformation stimulated by wound healing. This notion is supported by studies comparing the effect of IORT with EBRT on wound fluid and finding that the former has anti-cancer properties.2,8-10 Delays in the delivery of radiotherapy increase the opportunity and time for wound fluid to assist in regeneration of cancerous cells.

ADVANCING THE TREATMENT OF BREAST CANCER AND THE ROLE OF INTRA-OPERATIVE SINGLE DOSE RADIOTHERAPY

References: 1

Abraham J, Aft R, Agnese D, et al. NCCN Guidelines Version 1.2021 Breast Cancer.; 2021.

Belletti B, Vaidya JS, D’Andrea S, et al. Targeted intraoperative radiotherapy impairs the stimulation of breast cancer cell proliferation and invasion caused by surgical wounding. Clinical Cancer Research. 2008;14(5):1325-1332. doi:10.1158/1078-0432.CCR-07-4453

Tagliabue E, Agresti R, Carcangiu ML, et al. Role of HER2 in wound-induced breast carcinoma proliferation. Lancet. 2003;362(9383):527-533. doi:10.1016/S0140-6736(03)14112-8

Linares-Galiana I, Berenguer-Frances MA, Cañas-Cortés R, et al. Changes in peripheral immune cells after intraoperative radiation therapy in low-risk breast cancer. Journal of radiation research. 2021;62(1):110-118. doi:10.1093/jrr/rraa083

Antonini N, Jones H, Horiot JC, et al. Effect of age and radiation dose on local control after breast conserving treatment: EORTC trial 22881-10882. Radiotherapy and Oncology. 2007;82(3):265-271. doi:10.1016/j.radonc.2006.09.014

Bartelink H, Horiot J-C, Poortmans P, et al. Recurrence Rates after Treatment of Breast Cancer with Standard Radiotherapy with or without Additional Radiation. New England Journal of Medicine. 2001;345(19):1378-1387. doi:10.1056/nejmoa010874

Kindts I, Laenen A, Depuydt T, Weltens C. Tumour bed boost radiotherapy for women after breastconserving surgery. Cochrane Database of Systematic Reviews. 2017;2017(11). doi:10.1002/14651858. CD011987.pub2

Kulcenty K, Piotrowski I, Rucinski M, et al. Surgical wound fluids from patients with breast cancer reveal similarities in the biological response induced by intraoperative radiation therapy and the radiationinduced bystander effect— transcriptomic approach. International Journal of Molecular Sciences. 2020;21(3). doi:10.3390/ijms21031159

Uhlig S, Wuhrer A, Berlit S, Tuschy B, Sütterlin M, Bieback K. Intraoperative radiotherapy for breast cancer treatment efficiently targets the tumor bed preventing breast adipose stromal cell outgrowth. Strahlentherapie und Onkologie. 2020;196(4):398-404. doi:10.1007/s00066-020-01586-z

Fabris L, Berton S, Citron F, et al. Radiotherapy-induced miR-223 prevents relapse of breast cancer by targeting the EGF pathway. Oncogene. 2016;35(37):4914-4926. doi:10.1038/onc.2016.23

Piotrowski I, Kulcenty K, Murawa D, Suchorska W. Surgical wound fluids from patients treated with intraoperative radiotherapy induce radiobiological response in breast cancer cells. Medical Oncology. 2019;36(2):14. doi:10.1007/s12032-018-1243-z

Spiotto M, Fu YX, Weichselbaum RR. The intersection of radiotherapy and immunotherapy: Mechanisms and clinical implications. Science Immunology. 2016;1(3). doi:10.1126/sciimmunol.aag1266

de la Cruz-Merino L, Illescas-Vacas A, Grueso-López A, Barco-Sánchez A, Míguez-Sánchez C. Radiation for awakening the dormant immune system, a promising challenge to be explored. Frontiers in Immunology. 2014;5(MAR). doi:10.3389/fimmu.2014.00102

Shiao SL, Coussens LM. The Tumor-Immune Microenvironment and Response to Radiation Therapy. Springer. doi:10.1007/s10911-010-9194-9

Kalbasi A, June CH, Haas N, Vapiwala N. Radiation and immunotherapy: A synergistic combination. Journal of Clinical Investigation. 2013;123(7):2756-2763. doi:10.1172/JCI69219

Marincola F, Jaffee E, Hicklin D, immunology SF-A in, 1999 undefined. Escape of human solid tumors from T–cell recognition: Molecular mechanisms and functional significance. Elsevier. Accessed February 6, 2021. https://www.sciencedirect.com/science/article/pii/S0065277608609116

WWW.HOSPITALREPORTS.ORG | 15

ADVANCING THE TREATMENT OF BREAST CANCER AND THE ROLE OF INTRA-OPERATIVE SINGLE DOSE RADIOTHERAPY

Key Considerations When Choosing an Intraoperative Radiotherapy System – Usability, Precision and Cost Effectiveness An interview with Dr. Henning Kahl (DE) about the most important aspects when defining the right IORT option and selecting a treatment device for the own hospital. Henning Kahl MD, Senior Consultant & Associate Director of the Department of Radio-Oncology at the University Hospital Augsburg, Germany

But just by being part of the surgical process, the understanding of the situs is dramatically better and gives me as a radiation oncologist the opportunity to contour the target volume more precisely

Why did your hospital chose IORT as an option and what has finally driven the purchase decision? When we made the decision to get involved with IORT, it was 2007, we were pretty much centered on breast cancer. The TARGIT-A trial was running, and it was an exciting and new indication for IORT, and we had a problem which we thought would be solved by it. So, we were interested in making boosts with the IORT system, because as a radiation oncologist, you always face the challenge to delineate the boost area after breast conserving therapy. And this is a hard thing to do because there are major anatomical changes due to the surgery. And with IORT, you can solve that because IORT happens just after the surgeon has removed the tumor and you are sure that you are in the right place, which is a major advantage of this method. Further on, we foresaw that the demand from the patient side would increase due to the increasing evidence that this method might be equivalent to external beam radiotherapy and certain breast cancer cases.

How do you start the process of evaluating which device fits to your needs and which factors play the most important role? When we came to debate this, it was a decision made between the radiation oncology department and the gynecological department. Because, as I told you, we focused on breast cancer first

16 | WWW.HOSPITALREPORTS.ORG

and both heads of the departments were sure that this would be a game changer. And as the TARGIT-A trial was running with the INTRABEAM® which offered so much extra possibilities to use it in other places as well, they chose to buy this machine.

And how do you come to a decision for an IORT device at the end, is it a single decision or who has the lead and who the last word? The definite decision was made on the financial management level, and for that several calculations were made based on the German DRG system, seeing if we could reimburse the costs of buying such a device. And on the basis of the case numbers at that time, breast cancer cases were calculated and that was how the decision was made to buy this machine.

Does patient satisfaction play a role in your clinical practice? Patient satisfaction is of paramount importance in the clinical setting. The highest priority is a cure of the medical issues but even a higher goal is to achieve it in a way that a patient is comfortable with. So, a lot of tumor patients we deal with suffer severely and need life changing treatments. So, it is a good thing if you can offer a patient an effective antitumor treatment that does affect their way of living only in a very small measure. And this

ADVANCING THE TREATMENT OF BREAST CANCER AND THE ROLE OF INTRA-OPERATIVE SINGLE DOSE RADIOTHERAPY

also reflects in the feedback you get from the patients afterwards. In the follow-up decisions, as a radiation oncologist you often face patients that have a lot of fear because of the treatment with radiation, because of the word “radiation”. And afterwards, when they say: “Okay, this was a treatment that was easy to achieve and that was effective” and did not hamper their way of living in any way it is very positive to experience the feedback you get from your patients. And in days when patient advocacy societies have bigger and bigger impact, especially in the breast cancer setting, it is very important. So, positive patient feedback is a good way to get noticed by these patient advocacy societies and you are able to get new patients.

Does it make a difference for your patients if you treat with device A or device B and what do they prefer? I think it is not so much the device you use for a treatment, it is more important what the use of the device means for the patient. So, if you use IORT, you often shorten the treatment. And I think for the patient it does not matter that much if you have a device A or a device B that are both able to shorten the treatment in the same way. I think it would be all the same to the patient. But the big difference can be, if you have a device A which is external beam radiotherapy leading to weeks of treatment and you have a device B that offers you a single dose where a patient goes into surgery and anesthesia and after waking up everything is done. In my opinion that is a very appealing thing for the patient. I see this situation often because I use IORT also in the treatment of brain metastases and in this area, I always offer patients both ways: a post-operative stereotactic fractionated treatment or an intraoperative treatment of the tumor bed. And within the talks I had with patients, I always experienced that the patients favor to go into surgery and be done instead of facing another fractionated radiotherapy as this really matters to them.

Could you explain the case mix in your hospital a little bit? My department offers the full spectrum of radiation oncology. We have four linear accelerators; we have a big brachytherapy suite and we use IORT for simultaneous radio immune- and

-chemotherapy. And within a year we have about 2,500 patients and the full spectrum of radiation oncology with focus on high precision therapy.

So once you chose IORT at the end what is your experience, are you more efficient than before? According to my view, IORT is a valuable tool in my toolbox because there are often situations where the dose limits treatments due to close proximity of organs at risk. Sometimes these organs at risk can be separated easily during surgery by just distancing them with a gauze or something similar. And this offers the patient the opportunity to receive a higher dose in high risk situations. And this is a big advantage and makes my life as a radiation oncologist easier. And another point is that during the time we used the IORT device, we learned more and more indications. And, as I mentioned before, we started with breast and then got into neuro. So, we use it for a tumor bed irradiation after resection of brain metastases as well. We are participating in the INTRAGOtrial to use it as a boost in glioblastomas. But we also use it in other applications. You know, nowadays more and more oligometastatic patients get treatment and sometimes it is hard to achieve high doses big enough to deliver security within treatment area. From a surgical perspective, sometimes you see close margin situations, which you cannot avoid. So, this is a good opportunity to go in with IORT to increase the dose as an addition to a percutaneous radiotherapy.

(With IORT) the patients are no longer just surgical patients or just radiation oncology patients, but they are always patients being treated by a multidisciplinary team

Is IORT lengthening the workflow in the OR? As a matter of fact, yes, it adds some time in the OR depending on the dose you apply and on the size of the applicator, we mostly use spherical applicators, but we experienced truly that there is a steep learning curve. The more you use the machine and the more familiar the OR staff gets with setting up the machine, the less time you spend in the OR. Christopher Cifarelli did a study on the additional time in brain metastases, which would be about 16 minutes* and this is very acceptable, I think. If you look at the breast setting in my experience there sometimes is an additional time of about half an hour. But I think the more you streamline that, the less important that factor becomes.

WWW.HOSPITALREPORTS.ORG | 17

ADVANCING THE TREATMENT OF BREAST CANCER AND THE ROLE OF INTRA-OPERATIVE SINGLE DOSE RADIOTHERAPY

What happened amongst the colleagues when you started with your IORT program?

IORT is something which is pointing to the future and I expect to have an increasing amount of IORT indications in the future medical development

This is a very interesting question, because when we started IORT and used it more and more often in the OR the surgeons realized this by saying: ”Oh, what are you doing here?”. And as you got closer and closer together in the OR with the surgeon and started to really join and do more work during surgery, the more the surgeons realized that you are a real doctor. And it makes a huge difference regarding the understanding of ways certain diseases are handled and also the surgical strategy becomes more and more clear to me now, because I just join them during the surgery and can see their problems. And on the other hand, the more I join in, they understand what is important for me as a radiation oncologist. So, a wonderful side effect of the implementation of IORT is that you get a closer connection to your surgeons in every field. This is valid in all the fields which I work in from neurosurgery, over breast surgery and also the field of abdominal surgery.

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? Yes, as I mentioned already, this is a big difference because of the connection to the surgeons from the surgical perspective, they now realize me as a clinical doctor, a colleague that treats patients. And in my perspective the understanding of surgical techniques has increased dramatically. The next thing is by learning what the problem of the radiation oncology is sometimes their reaction or the perception of treating certain tumors changes. Because if the surgeon knows

there is a chance that I might get an additional dose to it, he perhaps sometimes thinks earlier on discussing cases preoperatively. There are certain cases where I was called to the OR and during the surgery we decided not to perform an IORT. But just by being part of the surgical process, the understanding of the situs is dramatically better and gives me as a radiation oncologist the opportunity to contour the target volume more precisely. And I am definitely sure that the better the understanding between the different disciplines is, the better are the outcomes. Because the patients are no longer just surgical patients or just radiation oncology patients, but they are always patients being treated by a multidisciplinary team. So definitely it pays off for the patient and it pays off for the hospital.

Are there any last considerations you would you like to give your peers on their way? Yes, I think the chance to use IORT really is a valuable tool in the toolbox for radiation oncologists to improve outcomes of surgical patients. And in my field, there is a big change from fractionated radiotherapy to more hypofractionated doses and higher single doses. And there is a lot of change in the understanding of immunological effects of high doses. So, this is a very interesting and evolving field, because with the IORT you apply high doses and you reduce the distance between surgery and adjuvant treatment to zero. So, these are both effects that are very important and are also a very interesting field for scientific research. So IORT is something which is pointing to the future and I expect to have an increasing amount of IORT indications in the future medical development.

* Cifarelli, C.P., et al. (2019). Intraoperative radiotherapy (IORT) for surgically resected brain metastases: outcome analysis of an international cooperative study. J Neurooncol 145, 391–397. https://doi.org/10.1007/s11060-019-03309-6 The statements of the doctor in this interview reflect only his personal opinion and experiences and do not necessarily reflect the opinion of any institution with whom he is affiliated. The doctor in this interview is a 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 labeling varies by country.

18 | WWW.HOSPITALREPORTS.ORG

ADVANCING THE TREATMENT OF BREAST CANCER AND THE ROLE OF INTRA-OPERATIVE SINGLE DOSE RADIOTHERAPY

The Importance of New Treatment Guidelines to Enable the Use of Targeted IORT in Clinical Practice Jonathan D. Agnew, PhD, MBA, Adjunct Professor, Faculty of Medicine, University of British Columbia As medical technology advances, practice guidelines must evolve to ensure that patients receive the highest quality care. In the case of breast cancer patients, a growing and robust literature showing the benefits of targeted intraoperative radiotherapy highlights the need for revised standards to enable its use in clinical practice.

HE INTRODUCTION of new medical technologies often presents health care systems – providers, patients, and payers – with an important choice, namely how and under what conditions the technology should be disseminated. Treatment guidelines play a critical role in this process, as they guide clinicians making the day-to-day decisions on which patients should have access to novel care. Sometimes, absent clear evidence of effectiveness or efficiency, the prudent decision is to keep guidelines as-is and continue with the current therapy until more convincing data suggest that a change should be made. However, in the case of targeted intraoperative radiotherapy (targeted IORT), a growing body of evidence showing its clinical effectiveness and economic efficiency amid a growing burden of cancer care suggests that the time has now come for such a change. This article reviews current national and international practice guidelines for radiotherapy for patients undergoing breast conserving surgery, considers the growing burden of cancer care facing health care systems, examines data on the clinical effectiveness and efficiency of targeted IORT, and proposes an approach for adapting current guidelines to incorporate this technological advance. Current Practice Guidelines for Radiotherapy A variety of national and international bodies provide guidelines for the treatment of cancer, including the National Comprehensive Cancer Network (NCCN), the American Society for Radiation Oncology (ASTRO), and the European Society for Medical Oncology (ESMO). This section reviews these bodies’ recommended

guidelines for the use of radiotherapy among patients undergoing breast conserving surgery. In its “Principles of Radiation Therapy,” the NCCN guidelines for breast cancer recommend whole breast irradiation following lumpectomy.1 Although silent on IORT specifically, the guidelines do state that for accelerated partial breast irradiation (APBI) more generally, “studies are ongoing and patients are encouraged to participate in clinical trials.” EBRT is, instead, the recommended modality for radiotherapy. The ASTRO evidence-based consensus statement on APBI specifically refers to IORT, stating that when compared to whole breast irradiation, all APBI – including IORT – offer several benefits, including reduced treatment time.2 Nonetheless, the statement recommends that low-energy x-ray IORT for partial breast irradiation “should be used within the context of a prospective registry or clinical trial…[and] should be restricted to women with invasive cancer considered ‘suitable’ for partial breast irradiation.” The ESMO Clinical Practice Guidelines for the treatment of early breast cancer state that APBI, including IORT, might be an acceptable treatment option for patients with a low risk for local recurrence, who are age 50 years or older, and with tumors that fall within certain parameters.3 Moreover, the guideline notes that “more and long-term results of several past and ongoing prospective randomised APBI trials are awaited.”

In the case of targeted intraoperative radiotherapy (targeted IORT), a growing body of evidence showing its clinical effectiveness and economic efficiency amid a growing burden of cancer care suggests that the time has now come for such a change

Future Burden of Cancer Care Breast cancer is the most common cancer among women.4 However, breast cancer mortality is, happily, decreasing. Using data from 36 European countries, Carioli et al report that breast WWW.HOSPITALREPORTS.ORG | 19

ADVANCING THE TREATMENT OF BREAST CANCER AND THE ROLE OF INTRA-OPERATIVE SINGLE DOSE RADIOTHERAPY

However, current clinical guidelines either do not refer explicitly to targeted IORT or, if they do, understand it through the lens of an experimental modality. Not only does this approach fail to account for the most recent data, notably the TARGIT-A trial, but it also represents missed opportunities

20 | WWW.HOSPITALREPORTS.ORG

cancer mortality rates in the European Union declined 15% between 2002 and 2012, and the authors predict a further decline of 10% to 2020.5 For North America and Oceania similarly welcome trends, which are attributed to improved treatment and diagnosis, are also reported.6 In contrast, evidence shows that breast cancer incidence is increasing and expected to reach 3.2 million women by 2050.4 Rates vary considerably across the world, but are highest in developed regions, including North America, North and Western Europe, and Australia/New Zealand. Moreover, increasing rates of obesity, which is associated with breast cancer diagnosis, may further push these rates higher.7 As incidence of breast cancer increases, the way it is treated has also changed. Data on trends in breast cancer surgical techniques show that breast conserving surgeries, including partial mastectomy, with or without oncoplastic reconstruction, have dramatically increased. Jonczyk et al report a 46% increase in partial mastectomy from 2005-2016, coinciding with a decrease in mastectomy rates – a trend that they posit will continue to impact the future of breast cancer surgery.8

Effectiveness and Efficiency of Targeted IORT IORT is a clinically effective treatment. The TARGIT-A study, which compared IORT to EBRT, concluded that IORT is an effective alternative to EBRT, noting that risk of recurrence, overall survival, and breast cancer mortality were similar across both groups of patients.9 The findings of this research, which followed nearly 2,300 women from over 30 countries, is complemented by earlier studies demonstrating the clinical effectiveness of IORT among various patient populations.10-14 Likewise regarding efficiency: in comparison to EBRT, targeted IORT offers clear advantages for patients, providers, and health care

systems. IORT is provided as a single fraction of radiotherapy during surgery to patients under the same anesthetic, requiring fewer patient visits needed for the multiple visits associated with EBRT. Moreover, IORT can reduce wait times for treatment and reduce demand for radiology department resources.15 In comparison to the standard six-week course of EBRT, IORT is more cost effective.16,17

Adapting Current Guidelines to Improve Quality, Cost and Access In the context of increasing incidence of breast cancer, particularly in developed countries, alongside a growing preference for breast conserving surgery over mastectomy, demand for IORT is likely to grow. Moreover, the demonstrated clinical effectiveness of targeted IORT, as well as the potential efficiency gains it offers, suggest a much greater role for this technology. However, current clinical guidelines either do not refer explicitly to targeted IORT or, if they do, understand it through the lens of an experimental modality. Not only does this approach fail to account for the most recent data, notably the TARGIT-A trial, but it also represents missed opportunities. Without guidelines that direct physicians to treat appropriate patients with targeted IORT, health systems and hospitals will continue with more costly and organizationally complex EBRT; patients will be left with the inconvenience of returning to treatment facilities multiple times rather than completing radiotherapy at the same time as surgery; and physicians will miss the opportunity to treat patients via a care modality of proven efficacy. Updating treatment guidelines, such as those from the NCCN, ASTRO, and ESMO, with the most recent scientific data to enable the use of targeted IORT in clinical practice will allow patients, physicians, hospitals, and health systems to realize the benefits of this new technology.

ADVANCING THE TREATMENT OF BREAST CANCER AND THE ROLE OF INTRA-OPERATIVE SINGLE DOSE RADIOTHERAPY

References: 1

Abraham J, Aft R, Agnese D, et al. NCCN Guidelines Version 1.2021 Breast Cancer.; 2021.

Correa C, Harris EE, Leonardi MC, et al. Accelerated Partial Breast Irradiation: Executive summary for the update of an ASTRO Evidence-Based Consensus Statement. Practical Radiation Oncology. 2017;7(2):73-79. doi:10.1016/j.prro.2016.09.007

Cardoso F, Kyriakides S, Ohno S, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2019;30(8):1194-1220. doi:10.1093/annonc/mdz173

Momenimovahed Z, Salehiniya H. Epidemiological characteristics of and risk factors for breast cancer in the world. Breast Cancer: Targets and Therapy. 2019;11:151-164. doi:10.2147/BCTT.S176070

Carioli G, Malvezzi M, Rodriguez T, Bertuccio P, Negri E, la Vecchia C. Trends and predictions to 2020 in breast cancer mortality in Europe. Breast. 2017;36:89-95. doi:10.1016/j.breast.2017.06.003

Carioli G, Malvezzi M, Rodriguez T, Bertuccio P, Negri E, la Vecchia C. Trends and predictions to 2020 in breast cancer mortality: Americas and Australasia. Breast. 2018;37:163-169. doi:10.1016/j. breast.2017.12.004

Steele CB, Thomas CC, Henley SJ, et al. Vital Signs : Trends in Incidence of Cancers Associated with Overweight and Obesity — United States, 2005–2014 . MMWR Morbidity and Mortality Weekly Report. 2017;66(39):1052-1058. doi:10.15585/mmwr.mm6639e1

Jonczyk MM, Jean J, Graham R, Chatterjee A. Surgical trends in breast cancer: a rise in novel operative treatment options over a 12 year analysis. Breast Cancer Research and Treatment. 2019;173(2):267-274. doi:10.1007/s10549-018-5018-1

Kraus-Tiefenbacher U, Bauer L, Scheda A, et al. Intraoperative radiotherapy (IORT) is an option for patients with localized breast recurrences after previous external-beam radiotherapy. BMC Cancer. 2007;7. doi:10.1186/1471-2407-7-178

Esposito E, Anninga B, Honey I, et al. Is IORT ready for roll-out? ecancermedicalscience. 2015;9. doi:10.3332/ecancer.2015.516

Alvarado MD, Mohan AJ, Esserman LJ, et al. Cost-Effectiveness Analysis of Intraoperative Radiation Therapy for Early-Stage Breast Cancer. doi:10.1245/s10434-013-2997-3

WWW.HOSPITALREPORTS.ORG | 21

ADVANCING THE TREATMENT OF BREAST CANCER AND THE ROLE OF INTRA-OPERATIVE SINGLE DOSE RADIOTHERAPY

The Evolving Role of New Targeted Approaches in the Treatment of Patients with Breast Cancer Jonathan D. Agnew, PhD, MBA, Adjunct Professor, Faculty of Medicine, University of British Columbia The increasing prevalence of breast cancer, as well as trends away from full mastectomy toward breast-conserving surgical interventions, speak to an evolving role for new targeted approaches in the treatment of breast cancer. The ongoing diffusion and development of these technologies means that the next decades will likely witness improvements in efficiency and effectiveness as these approaches are combined with other therapies and expanded to different patient populations.

Building on the successes of targeted IORT, researchers have suggested several avenues for development, positing that the future of targeted IORT may include the use of IORT combined with immunotherapy, IORT combined with nanoparticles, IORT devices that produce heavy ions, and a better understanding of how IORT can be used among additional patient populations

22 | WWW.HOSPITALREPORTS.ORG

HE INCIDENCE of breast cancer is growing, driven by factors such as an aging population, lifestyle factors, exposure to exogenous hormones, and others. Additionally, evidence suggests a growing preference for breast conserving surgery. These trends, along with advances in technology and evidence showing the efficacy and costeffectiveness of intraoperative radiotherapy (IORT), have created an opportunity for expanded use of targeted IORT. This article considers the evolving role of new targeted approaches in the treatment of patients with breast cancer, starting with a look at trends in breast cancer incidence and prevalence, developments in treatment preferences, recent successes in IORT, and potential future applications of this technology.

Trends in Breast Cancer Incidence and Prevalence Breast cancer is the most common cancer among women and one of the leading causes of death. Fortunately, advances in screening and therapeutic approaches have meant that women are less likely to die from the disease, as evidenced by declines in breast cancer mortality in Europe, North America, and Australasia,1,2 although rises in other parts of the world have been observed, most likely linked to increased risk factors such as reduced fertility, exposure to

exogenous hormones, and unhealthy changes in diet and lifestyle.3 Although declines in breast cancer mortality where they have been observed are welcome news, the increasing incidence of the disease presents a sobering reality. Breast cancer occurs everywhere in the world, and incident rates vary considerably by race, ethnicity, and age. Those in developed countries are significantly more likely to have breast cancer – compare an incident rate of 27 per 100,000 in Middle Africa and East Asia to 92 per 100,000 in North America.4 The Asia-Pacific region accounts for fully one quarter of all breast cancer cases, and incidence continues to rise.3 Lifetime risk of developing breast cancer is 12.4% for women in the United States. Moreover, as breast cancer risk is positively correlated with age and weight, the incidence of breast cancer is expected to increase along with an aging and increasingly obese population.4,5

Trends in Treatment Options Surgical options for patients with breast cancer vary, and over time preferences have changed. Jonczyk et al examined trends in surgical options for patients undergoing breast cancer surgery, including partial mastectomy, mastectomy without reconstruction, mastectomy with reconstruction, and partial mastectomy with oncoplastic reconstruction. Using data from nearly 200,000

ADVANCING THE TREATMENT OF BREAST CANCER AND THE ROLE OF INTRA-OPERATIVE SINGLE DOSE RADIOTHERAPY

Combining IORT with nanoparticles presents another possibility for innovative use of this technology. The use of nanoparticles in radiotherapy has been shown to increase the radiosensitization of tumors, thereby potentially improving therapeutic outcomes

patients over the 11-year period from 2005 to 2016, they found that partial mastectomy increased more than any other type of surgery.6 These findings correspond with data from a decade earlier showing steady growth in breastconserving surgery in California across age and race/ethnic groups.7

Successes in IORT A growing body of research has demonstrated the clinical and cost-effectiveness of targeted IORT. In contrast to earlier IORT technologies, targeted IORT uses low-energy x-ray radiation that offers a higher relative biological effectiveness and does not require extra measures for radiation protection beyond those provided by ordinary operating rooms. Targeted IORT avoids risks associated with external beam radiotherapy (EBRT), including radiation-induced secondary cancers, reduced lung function, and cardiac toxicity.8-11 Data suggest IORT is associated with better quality of life measures.12-15 Along with single centre reports, recent and robust clinical trial data show that targeted IORT is a clinically effective alternative to EBRT.16-18 These findings are complemented by studies showing the costeffectiveness of targeted IORT.19,20

Future Directions Building on the successes of targeted IORT, researchers have suggested several avenues

for development, positing that the future of targeted IORT may include the use of IORT combined with immunotherapy, IORT combined with nanoparticles, IORT devices that produce heavy ions, and a better understanding of how IORT can be used among additional patient populations. Evidence suggests that IORT is effective not only in killing cancerous cells through irradiation, but also has immunological effects that prevent the recurrences of tumors by altering the local microenvironment.21-25 A review of research on radiotherapy for the treatment for brain metastases suggest that radiation-induced enhancement of immune activity provides an opportunity for a synergetic application of combined IORT and immunotherapy.26 Future research further investigating the clinical effectiveness of combined IORT and immunotherapy, the sequence of IORT and immunotherapy, and the safety of concurrent immunotherapy and surgery may shed light on the potential of this approach. Combining IORT with nanoparticles presents another possibility for innovative use of this technology. The use of nanoparticles in radiotherapy has been shown to increase the radiosensitization of tumors, thereby potentially improving therapeutic outcomes. Although in-vitro and in-vivo studies have yet to be conducted, early modeling suggests this is a promising technique for boosting the therapeutic efficiency of IORT.27 More advanced applications, such as using nanoparticles with the capacity to intensify radiation effects, have been suggested as further possibilities.28 Paunesku and Woloschak speculate that IORT devices that emit heavy ions or protons might become possible in the future.28 Current targeted IORT extends to an area 10 mm from the surface – the ability to extend radiation deeper and further than 10 mm from the resection margin may expand the clinical applications of targeted IORT. The opportunity exists for IORT use to be expanded beyond those populations in which it has most recently been studied. The strongest evidence to date showing the effectiveness of targeted IORT relative to EBRT, the TARGIT-A trial, involved patients aged 45 years and older.18 Researchers from that study note that women who fell out of the eligibility criteria for TARGIT-A have been invited to participate in the TARGIT-B (“boost”) trial, which examines targeted IORT as a tumor bed boost with EBRT boost in younger women or women with a higher risk of disease. The result of this study, if positive, may open targeted IORT to these additional patient populations.

The opportunity exists for IORT use to be expanded beyond those populations in which it has most recently been studied

WWW.HOSPITALREPORTS.ORG | 23

ADVANCING THE TREATMENT OF BREAST CANCER AND THE ROLE OF INTRA-OPERATIVE SINGLE DOSE RADIOTHERAPY

References: Carioli G, Malvezzi M, Rodriguez T, Bertuccio P, Negri E, la Vecchia C. Trends and predictions to 2020 in breast cancer mortality in Europe. Breast. 2017;36:89-95. doi:10.1016/j.breast.2017.06.003 2 Carioli G, Malvezzi M, Rodriguez T, Bertuccio P, Negri E, la Vecchia C. Trends and predictions to 2020 in breast cancer mortality: Americas and Australasia. Breast. 2018;37:163-169. doi:10.1016/j. breast.2017.12.004 3 Ghoncheh M, Mahdavifar N, Darvishi E, Salehiniya H. Epidemiology, incidence and mortality of breast cancer in Asia. Asian Pacific Journal of Cancer Prevention. 2016;17(sup3):47-52. doi:10.7314/ APJCP.2016.17.S3.47 4 Momenimovahed Z, Salehiniya H. Epidemiological characteristics of and risk factors for breast cancer in the world. Breast Cancer: Targets and Therapy. 2019;11:151-164. doi:10.2147/BCTT.S176070 5 Steele CB, Thomas CC, Henley SJ, et al. Vital Signs : Trends in Incidence of Cancers Associated with Overweight and Obesity — United States, 2005–2014 . MMWR Morbidity and Mortality Weekly Report. 2017;66(39):1052-1058. doi:10.15585/mmwr.mm6639e1 6 Jonczyk MM, Jean J, Graham R, Chatterjee A. Surgical trends in breast cancer: a rise in novel operative treatment options over a 12 year analysis. Breast Cancer Research and Treatment. 2019;173(2):267-274. doi:10.1007/s10549-018-5018-1 7 Morris CR, Cohen R, Schlag R, Wright WE. Increasing trends in the use of breast-conserving surgery in California. American Journal of Public Health. 2000;90(2):281-284. doi:10.2105/AJPH.90.2.281 8 Aziz MH, Schneider F, Clausen S, et al. Can the risk of secondary cancer induction after breast conserving therapy be reduced using intraoperative radiotherapy (IORT) with low-energy x-rays? Radiation Oncology. 2011;6(1):1-9. doi:10.1186/1748-717X-6-174 9 Blom Goldman U, Svane G, Anderson M, Wennberg B, Lind P. Long-term functional and radiological pulmonary changes after radiation therapy for breast cancer. Acta Oncologica. 2014;53(10):1373-1379. doi:10.3109/0284186X.2014.934967 10 Ooi GC, Kwong DL, Ho JC, et al. Pulmonary sequelae of treatment for breast cancer: A prospective study. International Journal of Radiation Oncology Biology Physics. 2001;50(2):411-419. doi:10.1016/ S0360-3016(01)01438-9 11 Jacobson GM, Siochi RA. Low-Energy Intraoperative Radiation Therapy and Competing Risks of Local Control and Normal Tissue Toxicity. Frontiers in Oncology. 2017;7(SEP):212. doi:10.3389/ fonc.2017.00212 12 Bhattacharya IS, Haviland JS, Kirby AM, et al. Patient-reported outcomes over 5 years after wholeOr partial-breast radiotherapy: Longitudinal analysis of the import low (CRUK/ 06/003) phase III randomized controlled trial. Journal of Clinical Oncology. 2019;37(4):305-317. doi:10.1200/JCO.18.00982 13 Welzel G, Boch A, Sperk E, et al. Radiation-related quality of life parameters after targeted intraoperative radiotherapy versus whole breast radiotherapy in patients with breast cancer: Results from the randomized phase III trial TARGIT-A. Radiation Oncology. 2013;8(1):9. doi:10.1186/1748-717X-8-9 14 Sorrentino L, Fissi S, Meaglia I, et al. One-step intraoperative radiotherapy optimizes conservative treatment of breast cancer with advantages in quality of life and work resumption. Breast. 2018;39: 123-130. doi:10.1016/j.breast.2018.04.004 15 Meattini I, Saieva C, Miccinesi G, et al. Accelerated partial breast irradiation using intensity modulated radiotherapy versus whole breast irradiation: Health-related quality of life final analysis from the Florence phase 3 trial. European Journal of Cancer. 2017;76:17-26. doi:10.1016/j.ejca.2017.01.023 16 Lei J, Wang Y, Bi Z, Xue S, Ou B, Liu K. Intraoperative radiotherapy (IORT) versus whole-breast external beam radiotherapy (EBRT) in early stage breast cancer: results from SEER database. Japanese Journal of Radiology. 2020;38(1). doi:10.1007/s11604-019-00891-7 17 Feng K, Meng X, Liu J, et al. Update on intraoperative radiotherapy for early-stage breast cancer. American journal of cancer research. 2020;10(7):2032-2042. Accessed January 29, 2021. http://www.ncbi.nlm.nih.gov/pubmed/32774999 18 Vaidya JS, Bulsara M, Baum M, et al. Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (TARGIT-IORT) for early breast cancer: TARGIT-A randomised clinical trial. The BMJ. 2020;370. doi:10.1136/bmj.m2836 19 Alvarado MD, Mohan AJ, Esserman LJ, et al. Cost-Effectiveness Analysis of Intraoperative Radiation Therapy for Early-Stage Breast Cancer. doi:10.1245/s10434-013-2997-3 20 Vaidya A, Vaidya P, Both B, Brew-Graves C, Bulsara M, Vaidya JS. Health economics of targeted intraoperative radiotherapy (TARGIT-IORT) for early breast cancer: A cost-effectiveness analysis in the United Kingdom. BMJ Open. 2017;7(8):e014944. doi:10.1136/bmjopen-2016-014944 21 Spiotto M, Fu YX, Weichselbaum RR. The intersection of radiotherapy and immunotherapy: Mechanisms and clinical implications. Science Immunology. 2016;1(3). doi:10.1126/sciimmunol.aag1266 22 de la Cruz-Merino L, Illescas-Vacas A, Grueso-López A, Barco-Sánchez A, Míguez-Sánchez C. Radiation for awakening the dormant immune system, a promising challenge to be explored. Frontiers in Immunology. 2014;5(MAR). doi:10.3389/fimmu.2014.00102 23 Shiao SL, Coussens LM. The Tumor-Immune Microenvironment and Response to Radiation Therapy. Springer. doi:10.1007/s10911-010-9194-9 24 Kalbasi A, June CH, Haas N, Vapiwala N. Radiation and immunotherapy: A synergistic combination. Journal of Clinical Investigation. 2013;123(7):2756-2763. doi:10.1172/JCI69219 25 Marincola F, Jaffee E, Hicklin D, immunology SF-A in, 1999 undefined. Escape of human solid tumors from T–cell recognition: Molecular mechanisms and functional significance. Elsevier. Accessed February 6, 2021. https://www.sciencedirect.com/science/article/pii/S0065277608609116 26 Herskind C, Wenz F, Giordano FA. Immunotherapy combined with large fractions of radiotherapy: Stereotactic radiosurgery for brain metastases-implications for intraoperative radiotherapy after resection. Frontiers in Oncology. 2017;7(JUL):147. doi:10.3389/fonc.2017.00147 27 Omyan G, Gholami S, Zad AG, Severgnini M, Longo F, Kalantari F. Monte Carlo simulation and analytical calculation methods to investigate the potential of nanoparticles for INTRABEAM® IORT machine. Nanomedicine: Nanotechnology, Biology, and Medicine. 2020;30:102288. doi:10.1016/j. nano.2020.102288 28 Paunesku T, Woloschak GE. Future Directions of intraoperative Radiation Therapy: A Brief Review. Future Directions of Intraoperative Radiation Therapy: A Brief Review Front Oncol. 2017;7:300. doi:10.3389/fonc.2017.00300 1

24 | WWW.HOSPITALREPORTS.ORG

ADVANCING THE TREATMENT OF BREAST CANCER AND THE ROLE OF INTRA-OPERATIVE SINGLE DOSE RADIOTHERAPY

Notes:

WWW.HOSPITALREPORTS.ORG | 25

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

subscriptions@globalbusinessmedia.org www.globalbusinessmedia.org

Advancing the Treatment of Breast Cancer and the Role of Intra-Operative Single Dose Radiotherapy

Articles inside

An interview with Dr. Henning Kahl (DE) about the most important aspects when defining the right IORT option and selecting a treatment device for the own hospital

Current Practice Guidelines for Radiotherapy Future Burden of Cancer Care Effectiveness and Efficiency of Targeted IORT Adapting Current Guidelines to Improve Quality, Cost and Access

Historical Background of IORT Efficient and Cost-Effective Treatment Clinically Effective Treatment Scientifically Proven Open-Up the Room for IORT

How Intra-Operative Single Dose Radiotherapy Can Offer an Effective and Cost-Efficient Alternative to Conventional Whole Breast Radiotherapy for the Treatment of ESBC

Medical Results Non-Medical Results Quality of Life

An interview with two leading radiation oncologists from the EU and the USA – Dr. Valery Uhl & Dr. Agnès Tallet – showing their perspective of the daily challenges they are facing when trying to provide the best treatment options to their breast cancer patients

Sterilization of the Tumor Bed Radiological Effects of IORT Immunological Effect on Cells Delayed Irradiation with EBRT