Synchronous versus sequential chemo-radiotherapy in patients with early stage breast cancer (SECRAB): A randomised, phase III, trial

Abstract

Background: The optimal sequence of adjuvant chemotherapy and radiotherapy for breast cancer is unknown. SECRAB assesses whether local control can be improved without increased toxicity. Methods: SECRAB was a prospective, open-label, multi-centre, phase III trial comparing synchronous to sequential chemo-radiotherapy, conducted in 48 UK centres. Patients with invasive, early stage breast cancer were eligible. Randomisation (performed using random permuted block assignment) was stratified by centre, axillary surgery, chemotherapy, and radiotherapy boost. Permitted chemotherapy regimens included CMF and anthracycline-CMF. Synchronous radiotherapy was administered between cycles two and three for CMF or five and six for anthracycline-CMF. Sequential radiotherapy was delivered on chemotherapy completion. Radiotherapy schedules included 40 Gy/15F over three weeks, and 50 Gy/25F over five weeks. The primary outcome was local recurrence at five and ten years, defined as time to local recurrence, and analysed by intention to treat.ClinicalTrials.gov NCT00003893. Findings: Between 02-July-1998 and 25-March-2004, 2297 patients were recruited (1150 synchronous and 1146 sequential). Baseline characteristics were balanced. With 10.2 years median follow-up, the ten-year local recurrence rates were 4.6% and 7.1% in the synchronous and sequential arms respectively (hazard ratio (HR) 0.62; 95% confidence interval (CI): 0.43-0.90; p = 0.012). In a planned sub-group analysis of anthracycline-CMF, the ten-year local recurrence rates difference were 3.5% versus 6.7% respectively (HR 0.48 95% CI: 0.26-0.88; p = 0.018). There was no significant difference in overall or disease-free survival. 24% of patients on the synchronous arm suffered moderate/severe acute skin reactions compared to 15% on the sequential arm (p < 0.0001). There were no significant differences in late adverse effects apart from telangiectasia (p = 0.03). Interpretation: Synchronous chemo-radiotherapy significantly improved local recurrence rates. This was delivered with an acceptable increase in acute toxicity. The greatest benefit of synchronous chemoradiation was in patients treated with anthracycline-CMF.

Neoadjuvant Treatment Options in Soft Tissue Sarcomas

“…Concomitant use of anthracyclines and RT brings the risk of extensive skin, mucosal, and cardiac toxicity. However, data from breast cancer studies do not confirm this hypothesis [69,70]. Studies on CHT+RT in adjuvant treatment for STS do not suggest a significant increase in toxicity, even in a subgroup of elderly patients [71,72].…”

Post-neoadjuvant treatment with capecitabine and trastuzumab emtansine in breast cancer patients—sequentially, or better simultaneously?

“…In this context it is interesting to mention that in the SECRAB trial, which studied simultaneous vs. sequential use of 5‑FU-based chemotherapy in breast cancer patients, hypofractionation (radiotherapy with 15 fractions versus >15 fractions) was associated with lower acute side effects [ 10 ]. Therefore, Fernando et al.…”

“…Therefore, Fernando et al. advised that patients treated with synchronous chemoradiotherapy should be treated with a three-weekly radiotherapy regimen to avoid additional acute skin toxicity [ 10 ].…”

“…In the neoadjuvant setting, this mostly comprised patients with locally advanced or inflammatory breast cancer who were refractory to standard chemotherapy (recent overview by Corradini et al [5]). In the adjuvant setting, randomized controlled trials of 5-FU-containing regimens (along with cyclophosphamide and methotrexate or mitoxantrone) given concurrently vs. sequentially with adjuvant radiotherapy were conducted in the 1990s [6][7][8][9][10]. In these studies, an improvement in oncologic outcome, at least in subgroups, could be seen with concurrent administration of chemotherapy, with the exception of one trial [8].…”

“…[ 5 ]). In the adjuvant setting, randomized controlled trials of 5‑FU-containing regimens (along with cyclophosphamide and methotrexate or mitoxantrone) given concurrently vs. sequentially with adjuvant radiotherapy were conducted in the 1990s [ 6 – 10 ]. In these studies, an improvement in oncologic outcome, at least in subgroups, could be seen with concurrent administration of chemotherapy, with the exception of one trial [ 8 ].…”