The time has come to revisit the practice of omitting adjuvant radiotherapy (RT) for older patients with early hormone receptor (HR)-positive breast cancer and instead consider a more individualized approach to RT and hormonal therapy, authors of a review article argued.
Modern technology and treatment protocols have reduced the toxicity and improved the tolerability of RT. Adjuvant protocols for RT have greatly reduced the treatment burden from the historical standard of 3-6 weeks to as little as 5 days in some instances. Aromatase inhibitors (AIs), the preferred hormonal therapy for older patients, carry risks of cardiovascular side effects, accelerated osteoporosis, and musculoskeletal weakness, all of which contribute to poor compliance, noted George E. Naoum, MD, of Northwestern University Memorial Hospital in Chicago, and Alphonse G. Taghian, MD, PhD, of Massachusetts General Hospital and Harvard Medical School in Boston, in the Journal of Clinical Oncology.
Clinical trials focus on overall survival (OS) and disease-free survival (DFS), which might be less meaningful to older patients for whom quality of life and treatment tolerance matter more. Key studies have shown that the addition of RT to hormonal therapy improves local control without a survival benefit versus hormonal therapy alone; however, the trials included a mix of older and younger patients, they added.
“We do think it is time to revisit the omission of adjuvant RT for older women 65 years and older with T1N0 luminal-A breast cancer and consider testing omitting hormonal treatment,” concluded Naoum and Taghian. Ongoing trials of short-course RT for this patient population “appears a reasonable approach as the primary treatment, and AI could be optional for patients who tolerate it.”
Toward a Precision-Medicine Approach
The authors addressed an issue that is attracting increased attention among breast cancer specialists and their patients, said Virginia Kaklamani, MD, of UT Health San Antonio MD Anderson Cancer Center in Texas.
“I’ve talked with colleagues about this for a while,” she told MedPage Today. “If you think about it, it’s 5 days of radiation versus 5 years of endocrine therapy. The benefits of radiation and endocrine therapy are a little bit different. When we talk about radiation, we mostly talk about local control. When we talk about hormonal therapy, we talk about recurrence, we talk about contralateral breast cancer.”
“In women over the age of 70, the risk of getting contralateral breast cancer is pretty low, and in general, these are lower-grade tumors. The risk of distant recurrence is typically 10-15, sometimes 20 years later. I think it’s reasonable to consider giving radiation instead of endocrine therapy,” she added.
The authors did a good job of describing the need for better tools to inform personalized treatment decisions, Kaklamani continued. Genomic assays, such as MammaPrint, have shown that patients with ultra-low risk scores do exceptionally well without endocrine therapy.
“If you start looking at all of the data, the approach I think we should have in the next 5 to 10 years is to look at the genomic characteristics of the tumor, and potentially giving lower-risk patients radiation without subjecting them to 5 years of endocrine therapy,” she said. “Ultimately, we need to be thinking of the patients and we need to be giving them the information about what is their benefit [with radiation therapy or endocrine therapy] and helping them make the decision that’s best for them. It all really has to do with an individual’s decision, how risk averse they are.”
A recent survey of oncologists showed that performance status held preeminence among factors influencing treatment decisions for older patients with breast cancer. The results suggest that age and performance status outrank clinical trial results in terms of clinical decision making, wrote Naoum and Taghian. The International Society of Geriatric Oncology (SIOG) suggests older patients with cancer are heterogeneous with regard to functional status, cognitive abilities, nutritional and psychological distress, social support, and engagement. The end result is a patient population vulnerable to overtreatment or undertreatment.
Two seminal trials of conventional (3-6 weeks) adjuvant RT in older patients with HR-positive breast cancer, CALGB 9343 and PRIME II, showed no survival benefit with the addition of RT to tamoxifen.
Rhetoric vs Evidence
“The rhetorical practical question becomes who would want 6 weeks of daily RT for zero OS gain, while a simple daily pill for 5 years can provide all the benefits of systemic tumor control?” the authors continued. “Moreover, 90% LC [local control] rates at 10 years with omission of RT — for a 70-year-old — outweigh the burden of daily RT and its potential cardiopulmonary side effects.”
“Consequently, recommending only AIs — which have been shown to be superior to TAM [tamoxifen] for this population — and omitting 5-6 weeks of daily RT seemed a convenient option for many caregivers and patients in 1994 (when CALGB started),” they added. “In fact, the current National Comprehensive Cancer Network (NCCN) guidelines endorse hormonal therapy alone for 70-year-old patients with early hormonal-sensitive tumors on the basis of CALGB and PRIME-II results.”
However, early trials of adjuvant RT did not stratify patients by performance status and employed more toxic, time-consuming, and inconvenient conventional RT protocols. Modern image guidance, accelerated partial breast irradiation (APBI), breath-hold technique, and ultra-hypofractionation had yet to be developed.
Although phase III trials consistently showed better local control with the addition of RT to hormonal therapy, clinicians interpreted the findings as suggesting RT could be omitted, said Naoum and Taghian. More than two decades later, results of CALGB 9343 and PRIME II are still applied, and patients are offered omission of RT. Even current clinical trials involve use of advanced biomarkers to identify patients for RT omission.
“One can argue that we are overselecting patients to solely omit RT without clear reasons,” the authors wrote. “Is it the side effects of radiation? Since RT was found beneficial, we should rather work on improving its tolerance and convenience as treatment, not studying its omission.”
The initial geriatric assessment, as well as discussions regarding therapies and associated toxicities, will allow patients to establish expectations for quality of life, they continued. Despite support from the NCCN and SIOG, geriatric assessment remains underused in older patients with cancer.
Recently the FAST-Forward trial showed comparable 5-year local control rates and no difference in patient-reported outcomes between 5-day and 3-week RT protocols. Updated 10-year results from another randomized trial confirmed the safety of a five-fraction RT protocol, which received favorable patient- and physician-reported cosmesis ratings.
Given the accumulating positive evidence for adjuvant RT in older patients with breast cancer, a logical question is whether hormonal therapy can be safely omitted. Naoum and Taghian cited several recent studies that have provided evidence suggesting similar outcomes, including survival, with RT alone or hormonal therapy alone.
Investigators in the ongoing phase III EUROPA trial “did it right,” by randomizing 926 patients older than 70 with early HR-positive breast cancer to APBI or AI alone. A phase II trial has a goal of recruiting 90 patients for the same randomization. The authors said a similar trial, possibly including patients younger than 70, is warranted for the U.S.
The article is a reflection of the progress made in treating breast cancer and a current interest in treatment de-escalation, said Erica L. Mayer, MD, MPH, of Dana-Farber Cancer Institute in Boston.
“After decades of progress in our ability to treat early breast cancer, much research focus has turned to the topic of de-escalation: selecting best candidates for modern therapies and omitting treatments in others, where benefits are marginal and potentially outweighed by risks,” said Mayer, an American Society of Clinical Oncology expert, via email. “As noted by the authors, thoughtfully designed trials and careful analyses of existing data are necessary to bring us to a place when we can confidently omit traditional therapies for early breast cancer patients while maintaining excellent outcomes.”
Naoum reported no disclosures. Taghian disclosed a relationship with UpToDate and reported a patent interest and expert testimony.
Kaklamani disclosed relationships with AstraZeneca, Daiichi Sankyo, Genentech, Genomic Health, Gilead Sciences, Pfizer, and Puma Biotechnology.
Mayer disclosed relationships with Novartis, AstraZeneca, Gilead Sciences, Pfizer, and Eli Lilly.
Journal of Clinical Oncology
Source Reference: Naoum GE, Taghian AG “Endocrine treatment for 5 years or radiation for 5 days for patients with early breast cancer older than 65 years: Can we do it right?” J Clin Oncol 2022; DOI: 10.1200/JCO.22.02171.