Breast invasive cancer adjuvant EBRT hypofractionation whole breast

Efficacy

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.

Canadian trial

A Canadian study^r 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 update^r on UK START-A^r and START-B^r 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.

Sub-groups

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 al^r 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

Toxicity

A summary of the most clinically significant toxicities associated with this protocol are included in the table below.

*Concerns have been raised about doses to the heart with hypofractionated schedules. The heart is sensitive to radiation whatever fractionation is used, with no dose threshold for adverse effects. START-A and B showed no increased cardiac events with hypofractionated regimens, however, follow-up in these studies is considered too short to assess late cardiac events. The START-A and B trials excluded patients with pre-existing heart disease from the analysis – other studies have demonstrated that the absolute effect of radiotherapy on heart is greater in patients with established cardiovascular system risk factors.^r The risk of cardiovascular disease in breast radiotherapy patients increases with longer follow-up beyond 10 years.^rr In one of these 2 retrospective reviews patients were treated with 4.3Gy per fraction.^r

Appelt et al^r examined the predictions of the linear quadratic model on the estimated fraction size-corrected dose to heart for four hypofractionated regimens used in START-A, START-B and Canadian trials and conventional fractionation for a range of a/ß ratios. The 40Gy/15#, 39Gy/13# and 42.5Gy/16# regimens were estimated to have lower dose to heart, adjusted for fraction size using the linear quadratic model, compared to conventional fractionation. However, 41.6Gy/13# was estimated to result in higher dose to heart if heart a/ß=1.