Equivalent Toxicity, PROs Noted With Higher Radiation Dose Over Fewer Fractions After Breast Conserving Surgery


Patients who were treated with extreme hypofractionation after breast conserving surgery saw no increase in ill-treatment effects compared with those receiving moderate hypofractionation.

Whole breast radiotherapy with extreme hypofractionation (EH) at 25 Gy in 5 fractions in patients with localized breast cancer who previously underwent breast conserving surgery was deemed to be as safe and well tolerated as moderate hypofractionation (MH; 40 Gy in 15 fractions), according to data from the phase 3 MC1635 trial (NCT03324802) that were presented during the 2021 American Society for Radiation Oncology (ASTRO) Annual Meeting.1

“We showed similar quality-of-life and cosmesis between arms,” said Cameron Thorpe, MD, who is resident in Radiation Oncology at the Mayo Clinic in Phoenix, Arizona.

The investigators of this trial set out to determine if standard of care for early breast cancer of lumpectomy plus radiation could be administered over a shorter period, with noninferiority of the new schedule being the main trial hypothesis. Recent data from the UK FAST-Forward trial (NCT04148586) indicated that treatment with 26 Gy in 5 fractions (n = 1368) was noninferior to 40 Gy in 15 fractions (n = 1361) in terms of ipsilateral breast tumor relapse (2.1% vs 1.4%, respectively) and did not lead to significantly higher rate of moderate or marked tissue effects (9.9% vs 11.9%; P = .17).2

The primary end point of the trial was the rate of grade 3 or higher late adverse effects (AEs) and/or deterioration of cosmesis. Secondary end points include cause-specific survival, disease-free survival, distant recurrence, incidence of late AEs, locoregional control, overall survival, and patient-reported outcomes (PROs).

One-hundred and seven women with pT1-T3, pN0-N1, M0 breast cancer who underwent breast conserving surgery were randomized 1:1 to MH (n = 54) or EH (n = 53) with optional integrated boosts of 48 Gy and 30 Gy, respectively. Interim analysis end points were toxicity per CTCAE, PROs, quality of life (QOL), and cosmesis at 3 months or more.

Baseline patient characteristics were well balanced between the 2 arms. The median age was 64 years (range, 41.1-81.7), with most patients having tumors smaller than 2 cm (80%), node-negative disease (95%), and invasive ductal carcinoma (55%). Other histologies included invasive lobular carcinoma (20%), mixed histology (7%), ductal carcinoma in situ (16%), or other (3%). Tumor grades were most commonly grade 2 (41%), followed by grade 1 (31%) and grade 3 (28%).

Characteristics showed that few patients received neoadjuvant therapy (8%) and the majority of patients in the total cohort received sentinel lymph node biopsy (68%). Treatment modality was split evenly (50% each) between proton and photon radiation and only about 1 in 5 patients (21%) were treated with the optional boost.

At a median follow-up of 20 months, there were no grade 3 toxicities observed in this cohort. Grade 2 toxicities that were noted included radiation dermatitis in 7.4% of the MH group and 3.8% of the EH group; fibrosis in 0% and 1.9%, respectively; and lymphedema in 0% and 1.9%. Overall, the rate of grade 2 events in the 2 corresponding groups were 7.4% and 7.5%.

“Dermatitis happened as expected, at treatment or at the first follow-up at 3 months. Lymphedema and fibrosis happened at the 3-month and 12-month [follow-up], respectively,” said Thorpe.

Reporting of mild or worse skin burns by PRO was more common in the MH arm than the EH arm (odds ratio [OR], 3.7; CI, 1.5-8.9; P = .004). QOL measures at different timepoints from baseline throughout 2 years of the study indicated no difference between the treatment arms. Subdomains of PROs by Breast Cancer Treatment Outcomes Scales of breast aesthetic, breast function, and breast sensitivity also showed no difference on either treatment.

Deterioration of cosmesis, defined as progression of excellent/good to fair/poor or fair to poor at 3 months or more, was noted in 1.6% of patients treated with MH and 1.7% of those receiving EH (P = .4). The average Harvard cosmesis score was similar between the 2 arms at all time points recorded.

“MC1635 suggests that extreme hypofractionation with 25 Gy in 5 fractions for early breast cancer is well tolerated compared with moderate hypofractionation. Of course, further follow-up is warranted,” said Thorpe. He concluded by proposing additional research questions, such as can EH be used when reginal nodal irradiation is indicated and is it equally effective for HER2-positive, triple-negative, luminal A, and luminal B breast cancer subtypes.


  1. Thorpe CS, DeWees TA, Corbin KS, et al. MC1635: Randomized Phase III Trial of Hypofractionated Radiotherapy to the Whole Breast After Breast Conserving Surgery. Int J Rad Onc Biol Phys. 2021;111(suppl 3):S6-S7. doi:10.1016/j.ijrobp.2021.07.048
  2. Murray Brunt A, 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-inferiority, randomised, phase 3 trial. Lancet. 2020;395(10237):1613-1626. doi:10.1016/S0140-6736(20)30932-6
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