HYPofractionated Adjuvant RadioTherapy in 1 Versus 2 Weeks in High-risk Patients With Breast Cancer (HYPART): A Non-inferiority, Open-label, Phase III Randomized Trial.

Aim: To test a 1-week schedule of hypofractionated adjuvant whole breast/chest wall and/or regional nodal radiotherapy against 2 weeks for loco-regional control, acute and late toxicities, quality of life (QoL), survival and second cancers after primary surgery in patients with breast cancer.

Review of literature Four randomised trials involving a total of >8000 women have compared a lower total dose in fewer larger fractions against 50Gy in 25 fractions, and all have reported favourable results in terms of local tumour control and late adverse effects.1-4 Appropriate adjustments to total dose allow 15- or 16-fraction schedules to be delivered over 3 weeks that are at least as safe and effective as standard 5-week regimens.

A 2008 Cochrane review of altered radiotherapy fractionation in early breast cancer1 including The Royal Marsden Hospital/Gloucestershire Oncology Centre and Ontario trials totalling 2644 women with mainly axillary node negative tumours <5cm diameter concluded that radiotherapy fractions larger than 2Gy were at least as effective as 2Gy fractionation for a) local-recurrence free survival (absolute difference 0.4%, 95% CI 1.5% to 2.4%), b) breast appearance (risk ratio (RR)1.01, 95% CI 0.88 to 1.17; p=0.86), c) survival at five years (RR 0.97, 95% CI 0.78 to 1.19; p=0.75), d) late skin toxicity at five years (RR 0.99, 95% CI 0.44 to 2.22; p=0.98, or e) late radiation toxicity in subcutaneous tissue (RR1.0, 95% CI 0.78 to 1.28; p=0.99).1 The UK START A trial(N=2236) showed that the estimated absolute differences in 5-year local-regional relapse rates compared with the control schedule of 50Gy in 2Gy fractions were 0.2% (95% CI 1.3% to 2.6%) after41.6Gy and 0.9% (95% CI 0.8% to 3.7%) after 39Gy. In STARTA, photographic and patient self- assessments suggested lower rates of late adverse effects after 39 Gy than with 50 Gy, with a hazard ratio(HR) for late change in photographic breast appearance of 0.69(95% CI 0.52 to 0.91,p=0.01).3 In the UK START B trial(N=2215) the estimated absolute difference in 5-year local-regional relapse rates for 40.05 Gy compared with 50Gy was -0.7% (95% CI 1.7% to 0.9%),and the HR for late change in photographic breast appearance was 0.83 (95% CI 0.66 to1.04). These START trials reported similar local tumour control with some evidence of lower rates of late adverse effects after schedules with fraction sizes larger than 2 Gy compared with the international standard 25-fraction regimen.4 The international standard regimen for whole breast radiotherapy prior to publication of these studies was a total dose of 50Gy in 25 fractions (daily doses) over 5weeks following surgical resection of the primary tumour in women with early breast cancer. With the establishment of safety and efficacy of moderate hypofractionation another 'new standard of care' using 40-41Gy in 15 to 16 fractions over 3 weeks has been established, as evidenced by recommendations by the National Institute for Health and Clinical Excellence(NICE). 5 Although interesting and practically helpful, such moderate hypofractionation is unlikely to represent the useful limits of hypofractionation for whole breast or even regional nodal radiotherapy.

Further hypofractionated radiotherapy has been tested using once weekly schedule to the whole breast in the UK FAST study.5 Assuming an α/β value between 3 and 4 two different schedules were hypothesised to be equally effective (28.5 Gy and 30Gy in 5 fractions over 5 weeks) to the 50Gy in 25 fraction over 5 weeks schedule. Initial analysis has shown a higher rate of moist desquamation using the 50Gy regimen; however photographic assessment after a median follow-up of 28.4 months has shown more mild or marked change in the photographic appearance with the hypofractionated schedule.4 Clinical assessments of breast appearance changes were similar to the 50Gy group when using the 28.5Gy schedule but worse with the 30Gy schedule. Final results from the study are awaited. The UK FAST Forward study randomly allocated 4096 patients to 40Gy/15#/3 weeks, 27Gy/5#/1 week, or 26Gy/5#/1 week to the whole breast or chest wall.6 They concluded that 26Gy/5#/1 week was non-inferior to the standard of 40Gy/15#/3 weeks for local tumour control, and was as safe in terms of normal tissue effects up to 5 years in patients with early-stage breast cancer.

Hypofractionated radiotherapy has been used at PGIMER and comparable clinical outcomes have been published with moderate hypofractionation.7-9 Although Indian breast cancer patients present at a younger age, with more advanced stage, and a higher percentage of grade 3 and triple negative tumours compared to the western population. These adverse factors may not be important when comparing hypofractionated radiotherapy with standard fractionation.9 Reservations exist for extreme hypofractionation to the regional nodes citing increasing risk of brachial plexopathy when hypofractionating to the supraclavicular fossa although moderate hypofractionation has been used at our institute for the last 5 decades without reports of any brachial plexopathy.10,11 Similarly, moderately hypofractionated 2-week regimes have been used in clinical trials and have been found to be safe.10 Given the above evidence, 40Gy in 15 fractions has been recommended as the standard of care in the UK even for cases that will include irradiation of the supraclavicular fossa.