SummaryBackgroundThe international standard radiotherapy schedule for breast cancer treatment delivers a high total dose in 25 small daily doses (fractions). However, a lower total dose delivered in fewer, larger fractions (hypofractionation) is hypothesised to be at least as safe and effective as the standard treatment. We tested two dose levels of a 13-fraction schedule against the standard regimen with the aim of measuring the sensitivity of normal and malignant tissues to fraction size.MethodsBetween 1998 and 2002, 2236 women with early breast cancer (pT1-3a pN0-1 M0) at 17 centres in the UK were randomly assigned after primary surgery to receive 50 Gy in 25 fractions of 2·0 Gy versus 41·6 Gy or 39 Gy in 13 fractions of 3·2 Gy or 3·0 Gy over 5 weeks. Women were eligible if they were aged over 18 years, did not have an immediate surgical reconstruction, and were available for follow-up. Randomisation method was computer generated and was not blinded. The protocol-specified principal endpoints were local-regional tumour relapse, defined as reappearance of cancer at irradiated sites, late normal tissue effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779.Findings749 women were assigned to the 50 Gy group, 750 to the 41·6 Gy group, and 737 to the 39 Gy group. After a median follow up of 5·1 years (IQR 4·4–6·0) the rate of local-regional tumour relapse at 5 years was 3·6% (95% CI 2·2–5·1) after 50 Gy, 3·5% (95% CI 2·1–4·3) after 41·6 Gy, and 5·2% (95% CI 3·5–6·9) after 39 Gy. The estimated absolute differences in 5-year local-regional relapse rates compared with 50 Gy 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. Photographic and patient self-assessments suggested lower rates of late adverse effects after 39 Gy than with 50 Gy, with an HR for late change in breast appearance (photographic) of 0·69 (95% CI 0·52–0·91, p=0·01). From a planned meta-analysis with the pilot trial, the adjusted estimates of α/β value for tumour control was 4·6 Gy (95% CI 1·1–8·1) and for late change in breast appearance (photographic) was 3·4 Gy (95% CI 2·3–4·5).InterpretationThe data are consistent with the hypothesis that breast cancer and the dose-limiting normal tissues respond similarly to change in radiotherapy fraction size. 41·6 Gy in 13 fractions was similar to the control regimen of 50 Gy in 25 fractions in terms of local-regional tumour control and late normal tissue effects, a result consistent with the result of START Trial B. A lower total dose in a smaller number of fractions could offer similar rates of tumour control and normal tissue damage as the international standard fractionation schedule of 50 Gy in 25 fractions.

SummaryBackgroundThe international standard radiotherapy schedule for early breast cancer delivers 50 Gy in 25 fractions of 2·0 Gy over 5 weeks, but there is a long history of non-standard regimens delivering a lower total dose using fewer, larger fractions (hypofractionation). We aimed to test the benefits of radiotherapy schedules using fraction sizes larger than 2·0 Gy in terms of local-regional tumour control, normal tissue responses, quality of life, and economic consequences in women prescribed post-operative radiotherapy.MethodsBetween 1999 and 2001, 2215 women with early breast cancer (pT1-3a pN0-1 M0) at 23 centres in the UK were randomly assigned after primary surgery to receive 50 Gy in 25 fractions of 2·0 Gy over 5 weeks or 40 Gy in 15 fractions of 2·67 Gy over 3 weeks. Women were eligible for the trial if they were aged over 18 years, did not have an immediate reconstruction, and were available for follow-up. Randomisation method was computer generated and was not blinded. The protocol-specified principal endpoints were local-regional tumour relapse, defined as reappearance of cancer at irradiated sites, late normal tissue effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779.Findings1105 women were assigned to the 50 Gy group and 1110 to the 40 Gy group. After a median follow up of 6·0 years (IQR 5·0–6·2) the rate of local-regional tumour relapse at 5 years was 2·2% (95% CI 1·3–3·1) in the 40 Gy group and 3·3% (95% CI 2·2 to 4·5) in the 50 Gy group, representing an absolute difference of −0·7% (95% CI −1·7% to 0·9%)—ie, the absolute difference in local-regional relapse could be up to 1·7% better and at most 1% worse after 40 Gy than after 50 Gy. Photographic and patient self-assessments indicated lower rates of late adverse effects after 40 Gy than after 50 Gy.InterpretationA radiation schedule delivering 40 Gy in 15 fractions seems to offer rates of local-regional tumour relapse and late adverse effects at least as favourable as the standard schedule of 50 Gy in 25 fractions.

Background: SECRAB is a large multicentre randomised controlled trial designed to determine the optimal sequence of CT and RT for women with EBC. The second objective of this trial was to determine if CT and RT treatment modalities could be given together without increased toxicity or compromising either modality. See abstract no 851519 for details of CT and RT scheduling. Methods: Data on acute skin reaction was collected on completion of RT and graded as mild, moderate or severe. Late toxicity data was collected annually and included lymphoedema, telangiectasia, severe subcutaneous fibrosis, brachial plexopathy, rib fracture, ischaemic heart disease, symptomatic lung fibrosis, and clinical radiation pneumonitis. Results: Between Jul 98 and Mar 04, 2296 women were randomised. Acute toxicity data was collected on 2267 patients who received RT. The distribution of RT schedules was balanced across treatment arms, with the majority of patients (67%) receiving 40Gy/15F (15F). Significantly more patients in the Syn arm experienced a delay of >10 days in CT delivery (11% vs 5%, p < 0.0001). Very few patients experienced a >7 days delay in RT in either arm (Syn n=12 vs Seq n=3). In a sub-set of 880 patients dose intensity of CT was not significantly different between the two arms. Percentage skin toxicities for the Syn and Seq arms respectively were: None 22.9 vs 36.3; Mild 52.4 vs 48.1; Moderate 20.2 vs 13.6; Severe 3.8 vs 1.1. A significantly (p < 0.001) higher proportion of patients on the Syn arm suffered a moderate or severe skin reaction compared to those on the Seq arm. An unplanned exploratory analysis by duration of RT showed that patients receiving >15F (45Gy/20F or 50Gy/25F) had a significantly worse acute skin reaction than those receiving 15F (25% vs 16%, p=<0.001). 5 patients on the Syn arm were admitted to hospital as a result of a severe RT reaction, 3 received >15F. Acute radiation pneumonitis was 0.3% in both arms (n=5 in total). Percentage late toxicities for the Syn and Seq arms respectively were not significantly different for: moderate/severe lymphoedema 6.1 (n=70) vs 5.5 (n=64); severe subcutaneous fibrosis 1.3 (n= 15) vs 0.6 (n=7); brachial plexopathy 0.2 (n=2) vs 0.1 (n=1); rib fracture 0.6 (n=7) vs 0.4 (n=5); ischaemic heart disease 0.4 (n=5) vs 0.4 (n=2); symptomatic lung fibrosis 0.3 (n=15) vs 0.3 (n=7); and late clinical radiation pneumonitis 0.1 (n=1) vs 0.1 (n=1). Howevermoderate/severe telangiectasia was 2.5% vs 1.3% in the Syn and Seq arms respectively (p =0.05). This difference was not seen in patients receiving 15F. Conclusions: The delivery of Syn CT-RT in the adjuvant treatment of EBC is associated with an increase in acute skin toxicity however the percentage of severe reactions is less than 5%. These skin reactions were seen predominantly in patients treated with concurrent RT (>15F). An increase in late skin telangiectasia was also seen in patients receiving >15F. There was no difference in other late toxicities recorded. Syn CT-RT is feasible in the adjuvant treatment of EBC and does not result in a reduction in dose intensity of delivered CT. The optimal schedule is 40Gy/15F which is now the standard regime used in the UK. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-11-05.

Introduction: TACT2, a multicentre phase III trial with E-CMF as control (NEAT Poole NEJM 2006), tests 2 hypotheses in a 2x2 factorial design: A) accelerating chemotherapy (CT) offers superior benefits (CALGB9741 Citron JCO 2003); B) the oral 5FU prodrug X gives similar efficacy but preferential side-effect profile to CMF. Here, focus is on hypothesis B with results for compliance, QL & acute toxicities (physician & patient (pt) reported) during CMF vs. X Materials & Methods: 4391 pts (4371 women, 20 men) with node+ve/high risk node-ve invasive EBC were recruited between Dec 2005-08. Treatment was E(100mg/m2 x 4) q3wk vs q2wk aE(100mg/m2 x 4 + pegfilgrastim 6mg d2) followed by classical CMF q4wk x 4 vs X(2500mg/m2/day x 14) q3wk x 4. Detailed CTCAE toxicity was assessed in a subset (38 centres, 2086 pts receiving ≥1 cycle CMF or X). 1279/2086 also participated in substudy of pt-reported outcomes (EORTC QLQ-C30 and TACT2-specific toxicities). 826 had complete dataset (baseline, cycles 4&8). P-values are trend tests across all grades & %grade 3+ are reported. QL assessed via linear regression models adjusted for baseline, end cycle 4 score, & aE vs E. P<0.01 classed as significant QL in cycles 5-8 was better with X than CMF for global QL& fatigue (P<0.001). Pts reporting clinically meaningful deterioration (>10 points): global QL CMF 106/398 (27%), X 79/428 (18%); fatigue CMF 164/398 (41%), X 122/428 (29%)). Conclusion: TACT2, the largest adjuvant EBC trial with X, confirms that X has preferential side-effect profile and global QL compared to CMF, with no evidence that prior aE compromised treatment delivery. Dose delivery data are consistent with advanced disease observations that for some pts, 2000mg/m2/day may be correct dose. Results: 4264 (97%) pts continued on CT beyond cycle 4. 3726 completed all 8 cycles (E-CMF 951 (85%), aE-CMF 938 (86%), E-X 932 (84%), aE-X 905 (83%). For cycles 5-8, %RDI > 85% was 69% after E and 68% after aE. Cycles delivered on time CMF 59%, X 63%; cycles without dose reduction CMF 75%, X 62%. 15 deaths in total within 30 days of CT: 9 on CMF, 6 on X. Worst grade toxicities which differed between CMF & X during cycles 5-8: Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-10-07.

Background: The optimal sequence of CT and RT for women with EBC has yet to be defined. SECRAB aimed to determine i) if synchronous (Syn) CT-RT improves loco-regional relapse rates (LRR) and ii) whether the treatments could be given together without increased toxicity or compromising the dose intensity of either CT or RT. The first endpoint of this study is presented in this abstract. Methods: SECRAB was a prospective, randomised trial comparing sequential (Seq) to Syn CT-RT. Permitted RT schedules included 40Gy/15F over 3 weeks, 45Gy/20F over 4 weeks and 50Gy/25F over 5 weeks. Syn RT was administered between cycles 2 and 3 for CMF or 5 and 6 for anthracycline-CMF. Syn patients treated using 15F were treated predominantly using a sandwich schedule while those receiving >15F were treated concurrently with CT. Seq RT was delivered on CT completion. Key eligibility criteria were completely excised EBC, fit for and requiring adjuvant CT and RT. The trial was powered to produce a definitive event driven analysis: 150 loco-regional relapses having 85% power to detect 4% 2-sided differences in the primary endpoint of overall LRR. Results: Between Jul 98 and Mar 04, 2296 women were randomised. Baseline characteristics were well balanced. 63% of patients were node positive indicating a high risk population. 2 patients did not receive CT and 23 did not receive RT. 5 patients in the latter group had a loco-regional relapse prior to planned RT (Seq n=3). With a median follow-up of 8.8 years there were 93 and 76 loco-regional relapses in the Seq and Syn arms and 5-year LRR were 7.4% (95% CI 5.9-9.1) and 5.4% (95% CI 4.2-7.0) respectively. There was no significant difference in overall LRR (HRSyn 0.82; 95% CI 0.6-1.1; p=0.19). There was a trend for benefit for Syn treatment which was consistent across different subgroups (grade, lymph node status, tumour size, vascular invasion and excision margin). In an unplanned subgroup analysis, a trend for benefit for Syn treatment was seen predominantly in patients with the presence of lymphovascular invasion (LRR 11.9% Seq vs 8.2% Syn) and also in patients with 0 and 1-3 positive nodes (LRR 7.8% Seq vs 5.2% Syn) but not in those with 4 or more positive nodes. Similar rates were observed for distant recurrences (22.2% vs 22.2%), contralateral recurrences (2.9% vs 2.7%), and new primary cancers (2.9% vs 2.6%) in the Seq and Syn arms respectively. There was also no significant difference in overall survival which was 83% and 82% in the Syn and Seq arms respectively at 5-years (HRSyn 0.99; 95% CI 0.8-1.2; p=0.87). Modest differences in acute skin toxicity and telangiectasia were observed between the two study arms. There was no difference in other late toxicities. The second primary endpoint of safety, toxicity and dose intensity is described in detail elsewhere (abstract no 850168). Conclusions: SECRAB is the largest sequencing trial in EBC to date. Delivering Syn CT-RT using CMF or anthracycline-CMF and a 3 weekly RT fractionation shortens the overall treatment time. Although not statistically significant there was a trend to improved locoregional control with Syn treatment. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S4-4.