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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
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.
INTRAOPERATIVE 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.
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,
From a societal perspective, IORT is both less expensive and more effective than EBRT
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
Clinically Effective Treatment
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 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.
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
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 2 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 3 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 4 Esposito E, Anninga B, Honey I, et al. Is IORT ready for roll-out? ecancermedicalscience. 2015;9. doi:10.3332/ecancer.2015.516 5 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 6 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 7 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 8 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 9 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 10 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 11 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 12 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 Curiethérapie-
European 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 13 Abraham J, Aft R, Agnese D, et al. NCCN Guidelines Version 1.2021 Breast Cancer.; 2021.
The research is clear: it is time to open up the operating room for IORT
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
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.
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
