At the 2023 ACRO Radiation Oncology Summit, Mylin Torres, MD, Winship Cancer Institute at Emory University, Atlanta, GA, gave a presentation on the optimal fractionation for patients with breast cancer.

Dr Torres focused on data which supports the use of 5-fraction radiation regimens as a new standard option for patients with early-stage breast cancer, reviewing the APB-IMRT-Florence, FAST, and FAST-Forward phase 3, randomized clinical trials. She also discusses the difference between partial- or whole-breast radiation.

Transcript:

Hello, my name is Mylin Torres. I'm a Professor of Radiation Oncology at Emory University. I'm also co-leader of the Cancer Prevention and Control Research Program at Winship Cancer Institute. It was my pleasure to present on optimal fractionation for early stage breast cancer at this year's 2023 ACRO Radiation Oncology Summit. In my presentation, I discussed the recent data supporting the use of 5 treatments as a potential new standard for patients with early stage breast cancer. I reviewed 3 different randomized studies looking at 5 treatments specifically.

The first one was the Florence trial, which compared 5 treatments to the partial breast every other day to conventionally-fractionated radiation of whole breast, to the whole breast. And what it found was that partial breast irradiation given over 5 days every other day was actually equivalent in terms of tumor control and overall survival and was actually superior to whole breast irradiation when it came to normal tissue toxicity either rated by physicians or patients.

In the latter 2 randomized trials that I reviewed, I talked about whole breast irradiation, specifically. Those 2 studies came out of the United Kingdom. The first was the UK FAST and the latter was the UK FAST-Forward study. In the UK FAST trial, this really pushed the envelope and went against what we thought was normally tolerated by the breast by allowing the experimental arm to have large fractions given once a week over a 5-week period compared to the 50 Gray at 2 Gray per fraction arm, which was then the standard. This study intentionally included patients at low risk for local recurrence, so patients had to be at least the age of 50 or older, had to have very small tumors, node negative, they could not have had received any chemotherapy, no regional nodal irradiation, and no radiation boost was allowed. In this study, with a follow-up of 10 years, the local recurrence rate was quite low no matter which treatment the patient received. And essentially what they found is that 28.5 Gray given in 5 fractions once per week was equivalent to the control arm of 50 Gray at 2 Gray per fraction with long-term follow-up with the primary endpoint being change in photographic appearance at 2 and 5 years.

By year 10, they did have a signal that perhaps more breast shrinkage and induration was starting to become realized in that larger fraction treatment that was given once a week. But essentially the conclusion was that once a week treatment looked to be pretty safe and efficacious for patients with early stage breast cancer.

And the last randomized trial that I reviewed, the UK FAST-Forward study, this was actually built upon the findings from the UK FAST trial. They looked at treatment given instead of once a week with large fractions, though they changed the regimen so that the fractions were given daily over a 5-day period in one week. So instead of five weeks, now we're given large fractions over a 1-week period daily. In this arm, the control arm for this study was actually different from the other 2. It was reflective of modern practice where essentially moderate hypofractionated treatment of 40 Gray in 15 fractions was the control arm versus the 2 experimental arms of 27 Gray in 5 fractions, and 26 Gray in 5 fractions all given over the period of 1 week.

In this study, the 27 Gray led to higher rates of toxicity to the breast compared to 40 Gray long term, whereas the 26 Gray was very comparable to the 40 Gray arm with the exception of breast induration outside of the lumpectomy cavity, where the 26 Gray arm was statistically significantly higher in terms of having more induration outside of the lumpectomy cavity. Although it was statistically significantly higher, the percentage difference was really about 1% between the 40 Gray and 26 Gray arm.

Again, these were relatively low-risk, early stage breast cancer patients in high proportion, about 80% of these patients were above the age of 50, most were node negative, most had very small tumors and most were ERPR positive, HER2/neu negative. In spite of the fact that the trialists had intentionally tried to include patients with more high-risk disease with the inclusion criteria being the exact same criteria that they used for the STARK trials, which was inclusion of patients who were at least the age of 18 with tumors T1 to T3, N0 to N1. In spite of this, patients who were enrolled tended to be very favorable low-risk, as I stated previously. And it looked like among these patients in particular, which were highly represented on this trial, that essentially that the FAST-Forward regimen of 26 Gray in 5 fractions did just as well as those patients with who received 40 Gray in 15 fractions in terms of efficacy:  tumor control with the low rates of local recurrence with a median follow-up of about 71 months and local recurrence, no matter which treatment a patient received, was around 1% to 2%, quite low and reflective of what we see in the modern era.

It looks that like 5 treatments are probably here to stay. Whether you choose to give partial-breast or whole-breast irradiation may be reflective of the clinical context. If you choose to give a whole-breast irradiation, it may be in the context of where you are unable to clearly delineate the lumpectomy cavity due to missing surgical clips, lack of seroma, or if a patient had oncoplastic reduction. It could be that it's difficult to reliably set up the breast and a lack of reproducibility, particularly in our large breasted patients, where essentially the breast is not sitting in the same area and in the event that it's not able to be visualized well with image-guided radiation therapy (IGRT).

If you are to use one of the FAST regimens, the recommended FAST trial dose-volume histogram (DVH) standards on further analysis was really to try to keep that dose-maximum ≤107%, the breast planning target volume (PTV) of 105%, ≤5%. However, if you look at the experimental arms on both the FAST regimen and FAST-Forward regimen, the arms that had poor and worse cosmetic outcome were just slightly above those that did not. So in the FAST regimen, it was really 30 Gray versus 28.5 Gray given once a week. And in the FAST-Forward regimen, it was 27 Gray versus 26 Gray. And if you look at those numbers, the 30 and 27 Gray are really about 105% that of the 28.5 and 26 Gray, respectively. So with that in mind, and that because those higher doses led to worse cosmetic outcome, when I do these plans, I try to keep the dose-maximum ≤105%.

Other things to consider when you are thinking about using these accelerated fractionation regimens is that genomic assays were not available back when these studies were designed in patients who have high genomic assays, high grade tumors, young age, treated with chemotherapy, even large breast size, and large surgical defect in scar. These higher risk clinical scenarios for both cancer recurrence and poor cosmesis were really underrepresented in the Florence, UK FAST, and FAST-Forward trials. And in those patients, I would consider doing moderate hypofractionation with 40 Gray in 15 fractions, or 42.6 Gray in 16 fractions with or without a boost.

In conclusion, in all of breast radiation oncology, there's a clear trend to decrease total radiation dose, the number of treatment days, and target volumes in breast cancer patients. For patients with early-stage, low-risk breast cancer, certainly there's a trend to decreasing the number of treatments and even a trend to perhaps observing these patients, particularly if they're going to go on to hormone therapy. But 5 fraction radiation regimens are emerging as a new standard option for sure.

I do caution providers that with survival expected to be longer than 10 years in many patients, it's important to consider potential toxicities associated with larger doses per day, given over a shorter period of time.

Thank you.

Source:

Torres M. “Optimal Fractionation for Breast Cancer: Are Five Treatments the New Standard?” Presented at: Radiation Oncology Summit: ACRO 2023; March 15-18, 2023; Lake Buena Vista, FL

Meattini I, Marrazzo L, Saieva C, et al. Accelerated partial-breast irradiation compared with whole-breast irradiation for early breast cancer: Long-term results of the randomized phase III APBI-IMRT-Florence trial. J Clin Oncol. 2020;38(35):4175-4183. doi:10.1200/JCO.20.00650

Brunt AM, Haviland JS, Sydenham M, et al. Ten-year results of FAST: A randomized controlled trial of 5-fraction whole-breast radiotherapy for early breast cancer. J Clin Oncol. 2020;38(28):3261-3272. doi:10.1200/JACO.19.02750

Brunt AM, Haviland JS, Wheatley DA, et al. Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward):5-year efficacy and late normal tissue effects results from a multicentre, non-interiority, randomised, phase 3 trial. Lancet. 2020;395(10237):1613-1626. doi:10.1016/S0140-6736(20)30932-6