The evidence supporting this protocol is provided by three large phase III multi-centre international randomised trials with 10 year follow-up results, and the Cancer Australia guidelines systematic review update.
A Canadian studyr by Whelan et al randomized 1234 women with completely excised invasive breast cancer (pT1-2, N0, M0) to 50Gy/25# or 42.4Gy/16# treating 5 fractions per week. The 10-year cumulative incidence of local recurrence was 6.7% among women in the conventional group versus 6.2% among women assigned to the hypofractionated group (absolute difference 0.5 percentage points, 95% CI -2.5 to 3.5). The 10 year probability of survival was similar between the two groups (84.4% conventional vs. 84.6% hypofractionated group). There was also no significant difference in the rate of good or excellent cosmetic outcome between the conventional and hypofractionated groups.
UK START-A and START-B trials
The 10-year updater on UK START-Ar and START-Br trials also confirmed the efficacy and safety of hypofractionated radiotherapy in women with completely excised invasive breast cancer (pT1-3a, N0-1, M0). START-A randomized 2236 women to receive 50Gy/25# compared with 41.6Gy/13# or 39Gy/13# all over 5 weeks. START-B randomized 2215 women to 50Gy/25# or 40Gy/15# with both regimens involving 5 fractions per week.
In both trials, there was no significant difference in 10 year locoregional control between the conventional and hypofractionated regimens. Both trials also showed a significant reduction in late normal tissue effects in the hypofractionated groups, with the START-A trial showing less breast induration, telangiectasia and oedema in the 39Gy group, and START-B showing less breast shrinkage, telangiectasia and oedema in the 40Gy group than the 50Gy group.
For 10 year all-cause mortality, in the START-A trial there was no significant difference between 41.6Gy and 50Gy (18.4% vs. 19.8%, p=0.74) or the 39GY and 50Gy groups (20.3% vs. 19.8%, p=0.69) In the START-B trial, the hypofractionated group had a significant reduction in the rate of distant metastases, which contributed to a small reduction in the rate of all-cause mortality in this group compared with conventional fractionation (15.9% vs. 19.2%, p=0.042). However, this reduction cannot be readily explained in terms of radiotherapy-related factors. There were significantly fewer 10 year distant relapses in the 40Gy group compared with the 50Gy group (12.3% vs 16%, p=0.014), which contributed to the significantly higher rate of OS in the 40Gy compared with the 50Gy group.
Planned sub-group analysis in the Canadian trial showed that treatment effect was similar regardless of age, tumour size, oestrogen-receptor status, or use of cytotoxic chemotherapy. The Canadian trial did not utilise a tumour boost because study was initiated at a time prior to publication of studies supporting boost irradiation.r The Canadian trial excluded patients with node positive disease and large breast (separation >25cm).
Post-hoc subgroup analyses of the combined hypofractionated regimens versus conventional fractionation in the START-A and START-B trials showed that the treatment effect was not significantly different irrespective of age, breast size, tumour grade, axillary node status, cytotoxic chemotherapy or tumour bed boost radiotherapy. However, only a small proportion of patients in the START-A and START-B trials received regional nodal irradiation, or contemporary adjuvant chemotherapy.
A number of studies showed no difference in rates of local relapse for grade 3 breast cancers receiving hypofractionation compared with conventional fractionation.rrr Bane et alr found that molecular subtype predicted for local recurrence in women enrolled in the hypofractionated whole breast irradiation trial after a median follow up of 12 years. However, tumour grade, molecular subtype and hypoxia did not predict response to hypofractionation suggesting that patients with node-negative breast tumours of all grades and molecular subtypes may be safely treated with hypofractionated regimens. This is supported by the recent Cancer Australia guidelines.r