Chapters Transcript Video Updates in Breast Radiation Oncology Back to Symposium All right, good evening, everyone. Um, my name is Rebecca Shulman and I am a radiation oncologist at Fox Chase Cancer Center. Um, so I don't talk nearly as quickly as Doctor Williams, so I am going to focus on two clinical trials presented at, um, San Antonio this year. Uh, the first is the Europa study, uh, which was exclusive endocrine therapy. Or radiation therapy in women aged 70+ years with luminal like early breast cancer. Uh, this was a pre-planned, uh, interim analysis of a randomized phase 3 trial, um, and the second study I'm gonna talk about is supremo, which is, um, asking does post mastectomy radiotherapy in intermediate risk breast cancer impact overall survival? These were 10 year outcomes. Uh, so I'll start with the Europa. Just a little bit of background, uh, so we all know that there's a high prevalence of ER positive stage one breast cancer in women aged 70 years old, um, and reducing the treatment burden and, and balancing treatment efficacy is crucial in this patient population. The study rationale and objective, uh, so there have been challenges from previous studies. Uh, many of us are familiar with the older adult radiation omission, uh, studies, um, which required 5 years of endocrine therapy, CalGB, 2, they were very consistent in their results, uh, so both studies showed that omission of radiation increased, uh, local recurrence, but there was no impact on overall survival. And it's important to note, um, as we all know that the side effects and adherence, um, can be be an issue at times with endocrine therapy. Uh, we also needed, uh, direct comparison, so there's a lack of data comparing single modality radiation and endocrine therapy on outcomes and health related quality of life. Uh, and so the objective of Europa was to evaluate health related quality of life and ipsilateral breast tumor recurrence rates between radiation and endocrine therapy. Here's the trial design. So it was a phase 3 trial. Um, they are expected to accrue about 926 patients. Uh, all patients, uh, undergo breast conserving surgery with and without sentinel lymph node biopsies. Uh, all patients are pathologic T1, uh, and N0, either pathologic or clinical, invasive breast cancer, uh, ER PR positive, greater than 10%, KI 67. Uh, low or HER2 negative and age greater than or equal to 70 years. Uh, patients were randomized 1 to 1 exclusive postoperative radiation versus exclusive adjuvant endocrine therapy. Uh, they also had additional stratification factors, uh, based off of age, so 7079 versus 80, um, and also a performance status score. They had two, primary co- endpoints, so ipsilateral breast tumor recurrence rates of 5 years and health related quality of life, a global health score at 2 years. They had a number of secondary endpoints as well, which they did not cover in the interim analysis. Uh, in terms of treatments for radiation, um, all patients either went underwent whole breast radiation or partial breast radiation, um. I listed here the uh doses and fractionations. So if they were getting whole breasts, they either got 3 weeks of radiation, 15 total treatments, or 1 week of radiation to the whole breast. Uh, the majority of patients though got partial breast radiation in 5 total treatments. Uh, in terms of the endocrine therapy, uh, patients got aromatase inhibitors or tamoxifen, tamoxifen 5 to 10 years up to the treating physician. Uh, in terms of statistical assumptions, I just wanted to mention that they did have stopping rules, um, so if there were greater than 2% ipsilateral breast tumor recurrences, uh, per year or greater than 7%, uh, distant metastasis at any time, uh, they would stop the study. Um, here I just wanted to point out that in terms of the patients that received radiation, you can see that the majority, uh, received partial breast radiation, uh, compared to the whole breast irradiation. Uh, the majority three quarters were in the 70 to 79 age range, um, and the majority, uh, were of a good performance status, uh, 60%, but 40% were considered on the more frail side. Um, patient characteristics, the majority were, uh, pathologic T1B, T1C, um, and the majority were grade 2, but both groups were well balanced. Um, I'll focus your attention on the top left. This is their primary endpoint here, the global health score. Uh, you can see that the blue line is radiation, uh, the red is endocrine therapy, and we're looking at a mean difference in global health score. Uh, so endocrine therapy, you can see right even at 3 months, there's a decrease in the global health score compared to a radiation, um, and that decrease, um, in that score persists over 24 months, 2 years. Uh, they also did, uh, a number of symptom scale analyses, um, exploratory analyses, um, which I'm sure they'll flesh out more in their, um, final analysis, um, but for the most part here you can see that there is in terms of all symptoms, um, whether they be pain, nausea, vomiting, um, favored radiation. The only exception was that there was a minor, uh, increase in arm pain with, with radiation. Compared to endocrine therapy. Here are their outcomes. So a very impressive ipsilateral breast tumor recurrence and local regional recurrence for radiation and endocrine therapy was 0 for both arms at 2 years. Uh, in terms of adverse events, treatment related adverse events, there was a significant increase, uh, in adverse events with endocrine therapy compared to radiation. Here's just a list of all the adverse events, um, that patients experienced. Um, there was greater than 20% adverse events in the endocrine therapy, uh, arm. Um, again, here, the only thing that was increased with radiation was breast pain compared to endocrine therapy, but all was grade 1, grade 2. Uh, very important to note that 22% or so of patients required a switch in their endocrine therapy due to symptoms, and at 2 years, 12.4% of patients discontinued their endocrine therapy. Uh, so the summary of the study, radiation offers better health related, uh, quality of life global health core preservation than endocrine therapy at 24 months. Uh, there's a lower incidence of treatment related adverse events in the radiation arm. There were no warning signals regarding stopping rules, uh, and of course future directions, the final analysis will include ipsilate or breast tumor recurrence rates and long term outcomes, um. I just want to briefly discuss on a few discussion points. So you know, we have a number of omission of radiation studies, newer trials using molecular markers to identify who are the best candidates for for de-escalation. Um, unfortunately, all these trials, um, require 5 years of endocrine therapy, so it's not going to add, uh, to the Europa data, um, but still, of course, very, very meaningful. Uh, and lastly, I just wanted to point out, um, you know, the, the historic context of why, you know, studies were designed looking at omission of radiation is because it used to be so cumbersome for patients to come every single day, Monday through Friday for 5 to 6 weeks. Um, patients had a lot of acute and late toxicities. Um, there have been a lot of advances in radiation oncology and the treatment, um, and the doses and fractionations that we use, um. And partial breast, uh, radiation has been proved to be very safe, effective, well tolerated in a patient cohort like this, um, so, um, in the future, perhaps, um, you know, radiation or endocrine therapy may be a viable single modality treat treatment option for this low risk patient population, but of course the longer term data will be helpful. Um, next, I'm gonna switch gears here, um, and talk about the next study, supremo. So does post mastectomy radiotherapy and intermediate risk breast cancer impact overall survival? This was the, the 10-year result. Uh, the background here, so post mastectomy radiation, many, many years ago, meta-analysis of trials performed from 1964 to 1986 showed that post mastectomy radiation in patients with 1 to 3 nodes reduced 10 year local regional failures significantly, uh, 20% versus 4%, and reduced 20-year breast cancer modality, mortality, um, by about 8%, 50% versus 42%. Um, over the years, the applicability of these findings with modern systemic therapy is very controversial, um, and the magnitude of the local regional recurrence and overall survival benefit is smaller in more recent studies compared to historical ones, which has brought into question, uh, the benefit of post mastectomy radiation. So this study, the main eligibility were pathologic T1N1, pathologic T2N1, pathologic T3N0, histologically confirmed invasive breast cancer. They also included pathologic T2N0 if grade 3 and or lymphovascular invasion. All patients underwent a simple mastectomy and axillary staging. If the axillary node was positive, if and they had 123 nodes, then they required an axillary dissection. And all patients were fit for adjuvant or neoadjuvant chemotherapy if indicated, adjuvant endocrine therapy if indicated and postoperative radiation. Their primary endpoint was overall survival at 10 years. They also had a number of secondary endpoints, local and regional recurrence, disease-free and metastasis-free survival, cause of death, acute and late morbidity, quality of life, and cost-effectiveness. Statistical considerations, uh, the important thing was that they were looking for an overall survival benefit of 7 years, 7%, 7% difference. Um, here's the consular diagram. They enrolled patients from 2006 to 2013 to no, no chest wall or radiation versus chest wall or radiation and ultimately in the intention to treat population, they had about 800 patients in each arm. Uh, here are the patient characteristics, um. Um, it showed that there were 20%, uh, were HER2, uh, 10% were, were triple negative, uh, 25% were actually lymph node, uh, negative, um, and the majority of patients were N0 or N1. Uh, here's their primary endpoint overall survival. Uh, you can see that there's no difference in overall survival between chest wall or radiation and no chest wall or radiation. Um, when they broke up overall survival by, uh, N0 versus N positive, um, there was also no benefit. Uh, when they looked at chest wall recurrence though. You see that they had to really zoom into those curves to see the difference. This was statistically significant, but the absolute benefit was minimal. It was 1% versus 2.5% for chest wall recurrence. Again, when they broke up by N0 versus N positive, the benefit was really seen in the node positive patients. Uh, the same holds true for regional recurrence. So when you looked at the population entirely, uh, there was no difference in regional recurrence. Uh, but when you broke it up by N0 and N positive patients, there was a benefit, um, in the end node positive patients. Uh, in terms of metastasis free and disease free survival, there were no statistical differences between chest wall radiation and no chest wall radiation. So the conclusions by the authors, uh, in patients with 1 to 3 positive nodes or pathologic node zero, with other risk factors, um, adjuvant chest wall radiation with optimal systemic therapy does not improve overall survival at 10 years and results in a small absolute reduction of chest wall recurrences at 10 years, less than 10%, which is not clinically meaningful. Uh, there are incremental improvements in multidisciplinary care which explain these results, and adjuvant chest wall radiation should be admitted in most patients meeting inclusion criteria for supremo. Um, I think it's very important, um, to note a few things about this study. So, uh, practice of axillary management has changed. Uh, all patients in the study had axillary dissection if they were node positive, um. They also did not look at any sort of high-risk subgroups, at least in their presentation, a triple negative, medial central tumors, young age, LVI, um, and we didn't have any, uh, presented data on the systemic therapies used. Um, this is just, uh, to point out that, uh, for the radiation oncologists, the study, uh, only included chest wall radiation, which is not something that we routinely do here, uh, in the United States, um, and the question becomes, is nodal radiation important? And I would argue that it is. There was a meta-analysis that showed, um. That there is a trend of improvement in breast cancer mortality even in the pathologic, uh, node, um, patients with 1 to 3 positive nodes. Um, that same, um, meta-analysis showed that actually the patients that had the greatest benefit in breast cancer mortality were those that had medial tumors and perhaps that's because we were covering the internal mammary lymph nodes, and those patients may have the greatest benefit. So the take home messages and, and my opinions personally, um, in patients that meet inclusion criteria for supremo and undergo mastectomy and axillary lymph node dissection, I do agree that likely there's no need for chest wall radiation in most pathologic T2N0 grade 3. Um, and or LVI patients, and the benefit of chest wall or radiation is likely small, um, in 1 to 3 positive nodes. Um, of note in the study, most of the patients again were, were more favorable. There were only 12 patients with 3 positive lymph nodes. No conclusion can be made about T3N0 patients, even though that was part of the inclusion criteria. They only encompassed 0.4% of the study. And I still think there's a role for post mastectomy radiation to include regional nodal radiation in patients with 1 to 3 positive lymph nodes and high risk features, including young age, grade 3, LVI, medial central triple negative breast cancer. Um, also important to note, um, that in the 2014, um, meta-analysis, the overall survival benefit of post mastectomy radiation was seen after 10 years at 1520 years, so longer follow-up is still needed. Uh, and importantly, I think it's, it's important for us to be cautious, um, when we're planning our radiation, um, in that we, we don't want to be de-escalating, uh, surgery and radiation simultaneously. That's it. Thank you. OK. Created by Related Presenters Rebecca M. Shulman, MD Assistant Professor, Department of Radiation Oncology, Fox Chase Cancer Center Assistant Professor, Department of Radiation Oncology, Fox Chase Cancer Center View full profile
