Comparing 5 and 15 Fractions for Whole Breast Irradiation After Breast Conserving Surgery

Adjuvant radiotherapy after breast conserving surgery for breast cancer reduces the locoregional recurrence rate and improves overall survival. In recent years, it has become clear that breast cancer cells are more sensitive to fraction dose than originally presumed. Large randomized trials confirm this hypothesis: moderate hypofractionation schemes in 15 or 16 fractions are at least equivalent in tumor control and toxicity although the total dose is lower than the traditional 50 Gy in 25 fractions. Further acceleration to 5 fractions is expected to have an even larger radiobiological advantage regarding tumor control. Additional advantages are patient comfort and a better use of radiotherapy resources. Due to capacity problems some radiotherapy departments are faced with waiting lists which not only delay the time between surgery and radiotherapy, but also interfere with the introduction of more sophisticated treatment techniques like prone whole-breast irradiation (WBI). Prone WBI has several advantages over supine WBI: less acute skin toxicity and improved breast cosmesis and reduced doses to heart and lung leading to less radiation-induced heart diseases and secondary lung cancer induction.

Hypofractionation and acceleration (shorter radiotherapy schemes with less fractions and a higher dose per fraction) are attractive both for the patient (less treatment sessions) and for the hospital (more treatment capacity and shorter waiting lists). Moderate hypofractionation in 15 or 16 fractions has been generally accepted as a valid alternative for the historical schedules of 25-30 fractions for whole-breast irradiation (WBI) after breast conserving surgery (BCS). With a median follow-up of 9.9 years, the UK START-B trial showed no significant difference in locoregional control between a hypofractionated schedule of 40.05 Gy in 15 fractions and a normofractionation scheme of 50 Gy in 25 fractions1. The Canadian schedule of 42.5 Gy in 16 fractions was also not inferior to the 50 Gy/25 fractions after 10 years of follow-up2. Aside from the obvious advantage of shortening the overall treatment time from 5 weeks to 3 weeks, both for the patient and the radiotherapy department, there might be some radiobiological advantages too. In the START-B trial, breast shrinkage, telangiectasia and breast oedema were significantly less frequent in the hypofractionation group. Better disease free survival and overall survival were also reported in the 15 fractions group, due to less distant relapses. The superiority of hypofractionation on survival and cosmesis was not observed in the Canadian trial.

While Belgium is a country with extensive health care facilities, some countries have a limited number of radiotherapy departments and patients have to travel a long distance for radiation. In those countries the pressure to evolve to even more retracted radiotherapy schemes is high. WBI in 5 fractions of 5.7 Gy over 5 weeks was tested in the FAST trial. A first analysis after 3 years demonstrated equivalence in toxicity and tumor control in comparison with the standard prescription of 25 x 2 Gy3. This accelerated schedule is in particular attractive for older patients since they often face logistic problems (frailty, impaired mobility, transportation difficulties). This sometimes leads to omission of radiotherapy leading to a reduced breast cancer specific survival4,5. For this reason, at UZ Gent a feasibility trial was started testing a highly accelerated schedule in 5 fractions over 10-12 days in patients of 65 years or older. The investigators used the FAST-scheme for WBI (5 x 5.7 Gy), however, fractions were delivered on alternate weekdays resulting in an overall treatment time of 10 to 12 days instead of five weeks. The trial also included patients requiring a boost (5 x 6.5 Gy). With patient inclusion nearly finished, an interim analysis shows <10% grade 2-3 erythema, with only one case of moist desquamation, located at a skin fold6. In this study the investigators propose a multi-center randomized trial comparing our accelerated schedule in 5 fractions with a moderate hypofractionation scheme of 15 fractions in patients treated with WBI, and allowing a simultaneously integrated boost and regional nodal irradiation in both treatment arms. The primary endpoint is breast retraction 2 years after radiotherapy.