Aim: To compare late toxicity after postoperative hypofractionated radiotherapy (RT) and standard fractionated RT in patients with early-stage breast carcinoma.
Methods: This retrospective study included 447 patients (Modulated Accelerated Radiotherapy [MARA-1]: 317 patients, and control group [CG]: 130 patients). In the CG, the whole breast received 50.4 Gy in 28 fractions (fx) using 3D-radiotherapy, plus a sequential electron boost (10 Gy in 4 fx) to tumor bed. In MARA-1 group, a forward-planned intensity-modulated radiotherapy technique with 40 Gy in 16 fx with a concomitant boost of 4 Gy to breast was used. The primary endpoint was to evaluate late toxicity, and secondary endpoints were acute toxicity, local control, and survival. NCT03461224.
Results: Median follow-up was 52 months (range: 3–115 months). Late skin and subcutaneous toxicity were acceptable: 5-year actuarial cumulative incidence of Grade (G) 3 late skin toxicity was 1.5% in CG and 0.0% in MARA-1. Five-year actuarial cumulative incidence of G3 late subcutaneous toxicity was 0.8% in CG and 0.3% in MARA-1. On multivariate analysis, tobacco smoking and planning target volume were associated with an increased risk of late G1 skin toxicity (HR: 2.15, 95% CI: 1.38–3.34 and HR: 1.12, 95% CI: 1.07–1.18, respectively), whereas patients with a larger planning target volume also showed an increased risk of G1 and G2 late subcutaneous toxicity (HR: 1.14, CI 95%: 1.08–1.20 and HR: 1.14, 95% CI: 1.01–1.28, respectively). MARA-1 patients also showed an increased risk of late G1 and G2 subcutaneous toxicity (HR: 2.35, 95% CI: 1.61–3.41 and HR: 3.07, 95% CI: 1.11–8.53, respectively) compared to CG.
Conclusion: In this retrospective analysis, postoperative accelerated-hypofractionated RT for early-stage-breast carcinoma was associated with higher incidence of subcutaneous side effects. However, this increase was limited to G1–G2 toxicity. In the future, development of predictive models could help in tailoring dose and fractionation based on the risk of toxicity.

Keywords: breast cancer, radiotherapy, hypofractionation, retrospective study 


Radiotherapy (RT) after surgery is a standard component of breast conserving therapy (BCT) for invasive breast cancer (BC). RT reduces the risk of local and regional recurrences and improves overall survival.1,2 Historically, the standard dose after breast conservative surgery was 50 Gy, delivered in 25 fractions (fx) of 2 Gy, with or without a boost to the tumor bed.3

With an improved understanding of α/β ratio of BC, accelerated-hypofractionated (AHF) regimens have been proposed. Available clinical data suggest an intermediate α/β ratio for BC, lower than that of other tumors and early-reacting tissues; thus, a clinical advantage from AHF regimens should be expected.4 Furthermore, AHF-RT may limit the engagement of patients and RT departments with discomfort and cost reduction.5 However, the use of AHF may theoretically result in increased late toxicity with worsened cosmetic results.6

Improvement of local control (LC) and OS in early-stage BC are the most common benefits of postoperative RT, and studies have demonstrated the noninferiority of AHF whole-breast irradiation as compared to conventionally fractionated whole-breast-irradiation.7–9 In 2011, the American Society for Radiation Oncology published consensus recommendations for the use of hypofractionated whole breast (HF-WB).10 Another study about acute toxic effects demonstrated significantly reduced higher maximum physician-assessed skin reaction, self-reported pain, and fatigue.11

Despite available evidence, the use of AHF schedules is still debated due to pending questions such as the optimal AHF treatment schedule, tolerability in high-risk patients requiring chemotherapy or regional nodes irradiation, cardiac toxicity in patients with left-sided tumor, and efficacy in patients with ductal carcinoma in situ.

The aim of this study was to evaluate the clinical results in terms of late skin and subcutaneous toxicity of AHF forward-planned intensity-modulated radiotherapy (IMRT) in patients with early-stage BC. Results were compared with a historical control group (CG) of patients treated with 3D-conformal postoperative RT delivered with conventional fractionation, before the introduction of AHF treatments in this setting in our department.