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Hypofractionated radiation therapy (RT) for localized breast cancer improves patient convenience and reduces treatment cost. Here, we report the results of MC1635 randomized trial.

Between 04/04/2018 and 02/11/2020, localized breast cancer patients (T1-T3, N0-N1, M0) after breast conserving surgery (BCS) were enrolled. Patients were randomized to receive whole breast RT with moderate hypofractionation to 40 Gy in 15 fractions (Arm A) or extreme hypofractionation to 25 Gy in 5 fractions (Arm B). An optional concurrent integrated boost to 48 Gy on Arm A or 30 Gy on Arm B was allowed.  All patients were treated daily (Monday-Friday). Analysis of early toxicity (CTCAE V5.0) (<3 months), late toxicity (>3months) quality of life (QOL), cosmesis, PRO-CTCAE, and our final end point (1) grade 3 or higher late adverse event, 2) deterioration of cosmesis from excellent/good to fair/poor or from fair to poor. QOL was assessed via PROMIS, overall Linear Analogue Self-Assessment (LASA), and The Breast Cancer Treatment Outcome Scale (BCTOS). Deterioration of cosmesis was defined as change from excellent/good to fair/poor or from fair to poor according to the Harvard Cosmesis Scale. 

One hundred seven patients were randomized to either Arm A (n=54) or Arm B (n=53). Median follow-up was 36 months. Patient characteristics included: IDC 55%, ILC 20%, mixed 7%, DCIS 16%, other 3%; grade 1 or 2 72%, grade 3 28%; triple negative 9%, ER/PR+ 84%, and Her2+ 7%. Treatment characteristics included: SLNB 68%, ALND 32%; spot scanned protons 50%, 3D x-rays 50%; and an integrated boost 21%.  No significant differences in any characteristics were noted between the two arms. For our final end point no patient present with a grade 3 or higher toxicity and no deterioration in cosmesis were seen (p=0.89). Grade 2 toxicities were seen in 7.4% of Arm A and 7.5% of Arm B. This primarily consisted of radiation dermatitis (6 patients) with 1 patient with fibrosis and 1 patient with lymphedema.  The average Harvard Cosmesis score was similar between arms at all timepoints. QOL was similar between arms, as well. Patient-reported radiation skin burns of ‘moderate to severe’ as assessed by PRO-CTCAE were more commonly reported in Arm A (58.7%) vs Arm B (27.9%) (odds ratio 3.7, CI 1.5-8.9; p=0.004).  Patient satisfaction was very high with more than 98% of patients in both arms saying that they would do RT again. No cancer recurrences or deaths have been seen in either arm.

Extreme hypofractionation using 25 Gy in 5 fractions is non inferior to moderate hypofractionation in terms of toxicity and cosmesis.  Our final results in addition to the results from Fast Forward stablish extreme hypofractionation over 5 days as the most appropriate treatment schedule after BCS. Our schedule of 25 Gy may have some additional advantages over other extreme hypofractionations doses given its superiority in patient reported toxicity over moderate hypofractionation.