Impact on Outcomes of Ultra Hypofractionation or Hypofractionation Regimens and Proton or Xrays Therapy in a Phase III Randomized Controlled Trial MC1635

Carlos Vargas^1*Kimberley Corbin²Lisa McGee¹Robert Mutter²Heather Gunn¹Michael Golafshar¹Christopher Dodoo¹Laura Vallow³Dean Shumway²Sameer Keole¹Sean Park²Michele Halyard¹patricia cronin¹Barbara Pockaj¹

• ¹Mayo Clinic Arizona, Scottsdale, United States
• ²Mayo Clinic, Rochester, Minnesota, United States
• ³Mayo Clinic Florida, Jacksonville, Florida, United States

Background and AimsTo report the results of different treatment fractionation schedules and modalities in our Phase III randomized controlled trial, MC1635, with a focus on proton therapy outcomes.MethodsBetween February 2018 and February 2020, patients with localized breast cancer (pT0-3 pN0-1 M0) were offered participation in a Phase 3 randomized clinical trial comparing adjuvant hypofractionation (HF) to 40 Gy in 15 fractions versus ultra-hypofractionation (UHF) to 25 Gy in 5 fractions to the breast or chest wall without nodal radiation, with an optional simultaneously integrated boost. Patients were offered treatment with proton therapy or x-ray radiation and based on their decision dynamically allocated in permuted blocks allowing for meaningful comparisons within the same modality.ResultsOne hundred seven patients were randomized to receive UHF (n=53; x-rays n=26, protons n=27) and HF (n=54; x-rays n=28, protons n=26) adjuvant radiation. The median follow-up was 51 months. Proton therapy or x-rays showed no grade ≥3 adverse events, and one cosmetic deterioration from good to poor (p=0.99). Overall cumulative grade 2 toxicity was 4.2%, (x-rays UHF 0%, HF 0%; protons UHF 3.7%, HF 15.4%). Analyses of grade 2 toxicity by modality showed a minimally significant difference favoring x-rays over protons (-0.09; 95% CI -0.02 – -0.17). However, interactions between modality and fractionation showed grade 2 toxicity for UHF was no different between protons and x-rays (0.04; 95% CI -0.03-0.11), while for HF, there was a minimal benefit for x-rays (0.15; 95% CI 0.02-0.29). In the analysis of QoL, we observed uniform benefits for UHF over HF regardless of modality for skin burning at the end of treatment EOT (p<0.01), itching at EOT (p<0.01), and skin color at EOT (p<0.01). Five-year freedom from invasive local failure, as well as cause-specific and overall survival, was 100% for all cases. Disease-free survival at 5 years for all groups was 96% (95% CI 91-100%) and not different among them p=0.49.ConclusionsUltra-hypofractionated radiation with protons or x-rays, delivering 25 Gy over five treatments, was associated with low adverse events and improved QoL of mild severity or higher. Within modalities, UHF vs HF showed a larger benefit for proton therapy.