Efficacy for hypofractionation
The evidence supporting hypofractionation in this protocol is provided by a Cochrane review, three large phase III multi-centre international randomised trials with 10-year follow-up results, and the Cancer Australia guidelines systematic review update.r
The Cochrane review by Hickey et al. of 9 randomised trials (n = 8228) showed no significant differences in survival (local recurrence-free survival, breast cancer-specific survival or overall survival) between hypofractionated and conventionally fractionated radiation therapy.r Three of the trials included in the review are discussed below.
A Canadian study by Whelan et al. randomised 1234 women with completely excised invasive breast cancer (pT1-2, N0, M0) to 50 Gy/25fx or 42.5 Gy/16fx treating 5 fractions per week.r The 10-year cumulative incidence of local recurrence was 6.7% among women in the conventional group versus 6.2% among women in the hypofractionated group (absolute difference 0.5 percentage points, 95% CI: -2.5 to 3.5). The 10-year probability of survival was similar (84.4% conventional vs. 84.6% hypofractionated group). There were no significant differences in the rate of good or excellent cosmetic outcomes.
UK START-A and START-B trials
The 10-year updater on UK START-Ar and START-Br trials confirmed the efficacy and safety of hypofractionated radiation therapy in women with completely excised invasive breast cancer (pT1-3a, N0-1, M0). START-A randomised 2236 women to receive 50 Gy/25fx compared with 41.6 Gy/13fx or 39 Gy/13fx all over 5 weeks. START-B randomised 2215 women to 50 Gy/25fx or 40 Gy/15fx 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 39 Gy group, and START-B showing less breast shrinkage, telangiectasia and oedema in the 40 Gy group than the 50 Gy group.
For 10-year all-cause mortality, in the START-A trial there was no significant difference between 41.6 Gy and 50 Gy (18.4% vs. 19.8%, p = 0.74) or the 39 Gy and 50 Gy 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 radiation therapy-related factors. There were significantly fewer 10-year distant relapses in the 40 Gy group compared with the 50 Gy group (12.3% vs 16%, p = 0.014), which contributed to the significantly higher rate of OS in the 40 Gy compared with the 50 Gy 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, as it 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 >25 cm).
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. 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 did not show any difference in rates of local relapse for grade 3 breast cancers treated with hypofractionated radiation therapy compared with conventionally fractionationated radiation therapy.rrr Bane et al. found molecular subtype predicted for local recurrence in women enrolled in the hypofractionated whole breast irradiation trial after a median follow up of 12 years.r However, tumour grade, molecular subtype and hypoxia did not predict response to hypofractionationated radiation therapy. This suggests 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
Efficacy for conventional fractionation
The evidence supporting conventional fractionation in this protocol is provided by a meta-analysis of individual patient data from 17 phase III randomised trials involving 10801 patients.r Between 1976 and 1999, trials randomised patients with stage I and II breast cancer to receive surgery alone (either lumpectomy or quadrantectomy) vs. surgery plus radiation therapy (dose/fractionation schedules ranged between 40-50 Gy in 2-2.5 Gy/fractions). The end points were locoregional recurrence and breast cancer death. After a median follow up of 9.5 years per woman, the addition of radiation therapy reduced the 10-year risk of locoregional or distant first recurrence from 35.0% to 19.3% (absolute reduction 15.7%, 95% CI 13.7–17.7, p<0.00001) and the 15-year risk of breast cancer death from 25.2% to 21.4% (absolute reduction 3.8%, 95% CI 1.6–6.0, p = 0.00005).
Breast conserving surgery (BCS) used in conjunction with radiation therapy produces equivalent survival results when compared to mastectomy alone.r Although the absolute recurrence reduction varies according to age, grade, oestrogen-receptor status, tamoxifen use, and extent of surgery,r there has not been a low risk group identified who does not benefit from radiation therapy. The absolute benefit may be small enough in some patients to justify omission of radiation therapy based on patient/tumour factors.rrr Results were significant for both node-positive and node-negative patients.r The delivery of radiation therapy post BCS should be considered standard care in all women for the purposes of decreasing local recurrence and improving survival.
Figure 1: 10-year risk of any first recurrence and 15 year risk of breast cancer death and death from any cause
© Lancet 2011r
Role of boost
The EORTC 22881-10882 trial found a tumour bed boost of 10-16 Gy significantly reduces the risk of local recurrence.r In this trial, 5318 patients were randomised to receive BCS + whole breast radiation therapy (50 Gy) + 16 Gy tumour bed boost (n = 2661) or BCS + whole breast radiation therapy only (n = 2657). The addition of a boost reduced local recurrence from 7.3% to 4.3% at 5 years and 10.2% to 6.2% at 10 years (p<0.0001). At 20 years, the cumulative incidence of ipsilateral breast tumour recurrence was 16.4% in the no boost group vs 12% in the boost group. All age groups had a statistically significant relative risk reduction with the addition of a boost; with the largest risk reduction seen in those ≤ 40 years of age (23.9% to 13.5% at 10 years). Absolute benefit decreases with age. Survival was equivalent. These results were confirmed in the 20-year publication.r
Timing of radiation therapy
Conclusions from individual studies are varied, however; some evidence suggests delays to the commencement of radiation therapy post BCS may be associated with increased risk of local recurrence.r