Between January, 1999, and December, 2002, 2236 patients were enrolled in START Trial A at 17 centres in the UK (). A total of 1129 patients enrolled in the quality of life study and 1306 in the photographic assessment study (with 878 patients enrolled in both substudies).
Demographic and clinical characteristics at randomisation were well balanced between treatment groups (). Of the women prescribed chemotherapy, many (555/793, 70·0%) received an anthracycline-containing regimen, which was balanced between randomised radiotherapy schedules (178/259 [68·7%] for 50 Gy; 185/264 [70·1%] for 41·6 Gy; and 192/270 [71·1%] for 39 Gy). Cyclophosphamide, methotrexate, and fluorouracil combination therapy alone was prescribed in 227 women (28·6% of those receiving chemotherapy), which was similarly balanced between randomised groups (77 [29·7%] for 50 Gy; 78 [29·5%] for 41·6 Gy; and 72 [26·7%] for 39 Gy). 19 women (six for 50 Gy, nine for 41·6 Gy, and four for 39 Gy) received an adjuvant taxane. Of the 1805 women prescribed tamoxifen or another endocrine therapy, most (1790, 99·2%) were continuing treatment at randomisation (603/606 [99·5%] for 50 Gy; 611/618 [98·9%] for 41·6 Gy; and 576/581 [99·1%] for 39 Gy).
Data for oestrogen receptor status was not collected as part of START Trial A, but routine policy in most of the centres during the accrual period was to prescribe tamoxifen only to patients who were oestrogen-receptor positive or whose oestrogen receptor status was unknown. Hence tamoxifen use was a reasonable surrogate for oestrogen receptor status in the trial, which was balanced between the treatment groups. In the quality of life subgroup 21·6% patients underwent mastectomy. There were only 29 major treatment deviations (including early stopping of treatment, patient refusal of allocated treatment, and patients found to be ineligible for reasons including presence of relapses), resulting in 98·7% compliance with allocated treatment (). Compliance with completion of quality of life questionnaires over 5 years was more than 90%.
Median follow-up of surviving patients was 5·1 years (IQR 4·4–6·0), with a maximum follow-up of 8·0 years. At the time of analysis, 1881 patients (84·1%) were alive and without relapse, 36 (1·6%) were alive with local-regional relapse (without distant relapse), 54 (2·4%) were alive with distant relapse (including 14 with local-regional relapse), 256 (11·4%) had died (including 43 with local-regional relapse), and nine (0·4%) had no follow-up.
At the time of analysis, 93 (4·2%) patients had had local-regional tumour relapse, and the hazard ratios relative to the 50 Gy group were 1·05 (95% CI 0·63–1·75) after 41·6 Gy and 1·26 (95% CI 0·77–2·08) after 39 Gy (). The estimated absolute differences in local-regional relapse rates compared with 50 Gy at 5 years were 0·2% (95% CI −1·3% to 2·6%) after 41·6 Gy and 0·9% (95% CI −0·8% to 3·7%) after 39 Gy. Since the main concern over hypofractionation is an excess risk rather than a possible benefit, a more precise estimate of the potential excess risk of local-regional relapse was obtained from the upper limit of the one-sided 95% CI for the absolute difference in 5-year local-regional relapse rates for each 13-fraction schedule compared with 50 Gy. These indicated an estimated maximum 2·1% and 3·2% excess risk associated with 41·6 Gy and 39 Gy compared with 50 Gy, respectively. The Kaplan-Meier and cumulative hazard rate plots for local-regional relapse according to fractionation schedule () illustrate the low event rate in all randomised groups.
Survival analyses of relapse and mortality according to fractionation schedule in START Trial A
Kaplan-Meier plot (A) and Nelson-Aalen cumulative hazard plot (B) of local-regional tumour relapse in 2236 patients
The unadjusted α/β value for local-regional relapse estimated from a Cox proportional hazards regression model was 4·8 Gy (95% CI 0–16·3). Adjusting for prognostic factors resulted in extremely wide confidence limits, since the main effects for total dose and total dose × dose per fraction were not independently predictive of local-regional relapse in the regression model. Hence, the α/β value for local-regional relapse was left as a crude estimate.
Rates of distant relapse, disease-free survival, and overall survival were similar between the fractionation schedules, with no evidence of a clinically significant detriment for either of the hypofractionated schedules compared with 50 Gy ().
Change in breast appearance (photographic) was assessed in 1055 patients with both a baseline and at least one follow-up image (354 for 50 Gy, 357 for 41·6 Gy, and 344 for 39 Gy). Not all patients had photographs available at both 2 and 5 years, for reasons including the 5-year assessment not yet being due at the time of scoring and analysis, patient refusal, and withdrawal from the photographic study due to relapse. There were no associations between score for change in breast appearance (photographic) at 2 years or patient demographic or treatment characteristics and whether or not the patient had a 5-year assessment (data not shown). Mild changes were graded for 302 (28·6%) patients and marked changes for 32 (3·0%) patients, by 5 years. The hazard ratios for any (mild or marked) change in breast appearance compared with the 50 Gy group were 1·09 (95% CI 0·85–1·40, p=0·62) after 41·6 Gy and 0·69 (95% CI 0·52–0·91, p=0·01) after 39 Gy (). shows that the treatment differences were evident at 2 years, and persisted to 5 years. The α/β estimate for any change in breast appearance (photographic) was 3·1 Gy (95% CI 1·6–4·6) adjusted for age, adjuvant therapy, lymphatic radiotherapy, breast size, and surgical deficit.
Kaplan-Meier plot of mild/marked change in breast appearance (photographic) in 1055 patients with breast conserving surgery
Forest plot of late normal tissue effects assessed as moderate/marked by patients and mild/marked from photographs
Patient quality of life self-assessments of late normal tissue effects were available for 1080 patients (95·7% of all patients in the quality of life study) with a baseline and at least one completed follow-up questionnaire (359 for 50 Gy, 364 for 41·6 Gy, and 357 for 39 Gy). Changes in breast appearance and breast hardness (breast conserving surgery patients) were the most common changes (). According to patient quality of life self-assessments of five key normal tissue effects on the breast or breast area, rates of moderate or marked effects by 5 years were similar after 41·6 Gy and 50 Gy. Rates of moderate or marked normal tissue effects tended to be lower after 39 Gy than after 50 Gy, with a significantly lower rate of change in skin appearance after 39 Gy than after 50 Gy (p=0·004). summarises the survival analyses of the photographic and patient quality of life self-assessments of late normal tissue effects for START Trial A, showing results generally in favour of the 39 Gy group compared with 50 Gy, and similar rates of effects after 41·6 Gy compared with 50 Gy.
The incidence of ischaemic heart disease, symptomatic rib fracture and symptomatic lung fibrosis was low at this stage during follow-up, and balanced between the schedules (). In the 41·6 Gy group, there was one case of pneumonitis 9 months after treatment and one patient who developed mild symptoms and signs of brachial plexopathy 2 years after treatment. Two patients (both 50 Gy in 25 fractions) experienced an unusually marked acute skin reaction during their radiotherapy treatment, culminating in extensive moist desquamation. Neither of these patients had received adjuvant chemotherapy.
Incidence of ischaemic heart disease, symptomatic rib fracture, and symptomatic lung fibrosis according to fractionation schedule
There were 26 patients (1·2%) with contralateral breast cancer (13 after 50 Gy [1·7%], five after 41·6 Gy [0·7%], eight after 39 Gy [1·1%]), and 44 patients (2·0%) had other second primary cancers (15 after 50 Gy [0·7%], ten after 41·6 Gy [0·4%], 19 after 39 Gy [0·8%]), the most frequent being lung (six), ovarian (six), renal (four), and colorectal (four). The remaining 24 incidences of second primary cancers consisted of one or two cases of several different types.
When all patients in the RMH/GOC trial (1410 patients) and START Trial A (2236) were included in a meta-analysis, the unadjusted estimate of the α/β value for local-regional relapse was 4·1 Gy (95% CI 0·9–7·4). Adjusting for known prognostic factors (age, chemotherapy, tamoxifen, lymphatic radiotherapy, type of primary surgery, boost, and pathological tumour size) gave an adjusted α/β value for local-regional relapse of 4·6 Gy (95% CI 1·1–8·1). Including all the 1202 RMH/GOC trial and 1055 START Trial A patients with available photographic assessment data in a meta-analysis, the unadjusted estimate of the α/β value for any change in breast appearance was 3·6 Gy (95% CI 2·4–4·9). Adjusting for age, chemotherapy, tamoxifen, breast size, and surgical deficit gave an adjusted α/β value of 3·4 Gy (95% CI 2·3–4·5).