Hypofractionated Comprehensive Regional Nodal Irradiation: A New Standard of Care?

By Rafael Ferreira de Carvalho, MD, University of Kentucky

Presenting Author: Karen E. Hoffman, MD, FASTRO

Hypofractionated and accelerated regimens have become the standard of care for whole breast radiation (WBI) without Regional Nodal Irradiation (RNI) for the past decade, based on the results of the Ontario¹ and UK-Start A/B trials.² However, none of those trials were designed to look at the subgroup of patients requiring RNI. This subgroup was excluded from the Ontario trial and only represented 14% and 7% of the Start A and B trials, respectively.³ In addition, patients requiring treatment to the internal mammary node chain were excluded from the START trials.

Karen Hoffman, MD, FASTRO, (MDACC) presented the results of the Phase III SAPHIRE Trial, which randomized 324 locally advanced breast cancer patients for hypo (HF)- vs. conventionally fractionated (CF) RNI. This is a superiority trial, having perometry-assessed lymphedema (≥10% relative difference from the pre-operative measurement) as the primary endpoint.

After a median follow-up of 4.75 years, the study did not reach a statistically significant difference to the primary endpoint but showed a trend toward a superiority benefit to the HF arm (29% vs. 36%, p=0.24). In contrast, the study showed a statistically significant difference in the secondary endpoint, physician-assessed lymphedema (15% vs. 27%, p < 0.001). Any grade ≥ 2 toxicity was significantly lower in the HF arm (52% vs. 78%, p<0.001). The locoregional recurrence (LR) rate was very low overall, with no significant difference between groups.

Before those results, the evidence of hypofractionation was mainly based on a subgroup or pooled analysis from the previous trials. A pooled analysis of 864 patients from START-pilot, START-A, and START-B who received RNI showed no difference in terms of lymphedema as compared to standard fractionation.³ However, this data is biased by the high heterogeneity and the difference in dose/fractionation among those three trials.

Based on the lack of evidence, ASTRO 2018 guidelines didn’t include this group in the recommendations for HF regimens.⁴ The main concerns in adopting the HF-RNI strategy are associated with the toxicity profile (mainly with the risk of increased toxicity in low alpha/beta ratio normal tissue) and the outcomes in this group with a higher risk of LR.

The current NCCN Guidelines include an alternative recommendation for HF to the RNI in patients not undergoing breast reconstruction.⁵

Even not reaching the significance of the primary endpoint yet, this study represents high-quality evidence in favor of hypofractionation for RNI. Comparable LRR, lower overall toxicity, and a trend toward improved lymphedema rate, in association with reduced financial toxicity, are topics to be discussed with the patients when proposing treatment to the RNI. Congratulations to Dr. Hoffman for this contribution to our patients.

References:

1. Whelan TJ, Pignol J-P, Levine MN, et al. Long-Term Results of Hypofractionated Radiation Therapy for Breast Cancer. New England Journal of Medicine. 2010;362(6):513-20.
2. Haviland JS, Owen JR, Dewar JA, et al. The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. The Lancet Oncology. 2013;14(11):1086-94.
3. Haviland JS, Mannino M, Griffin C, et al. Late normal tissue effects in the arm and shoulder following lymphatic radiotherapy: Results from the UK START (Standardisation of Breast Radiotherapy) trials. Radiotherapy and Oncology. 2018/01/01;126(1).
4. Smith BD, Bellon JR, Blitzblau R, et al. Radiation therapy for the whole breast: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based guideline. Practical Radiation Oncology. 2018;8(3):145-52.
5. Version 4.2024 NCCNN. Version 4.2024, 07/03/24^© 2024 National Comprehensive Cancer Network^® (NCCN^®) 2024.

Abstract 100, Primary Outcome Analysis for Shortening Adjuvant Photon Irradiation to Reduce Edema (SAPHIRE): A Randomized, Phase III Trial of Hypo- vs. Conventionally Fractionated Regional Nodal Irradiation (RNI) was presented during the SS 01 - Breast Cancer 1: Clinical Trials session of the 66th ASTRO Annual Meeting.