Abstract GS1-01: Increasing the dose density of adjuvant chemotherapy by shortening intervals between courses or by sequential drug administration significantly reduces both disease recurrence and breast cancer mortality: An EBCTCG meta-analysis of 21,000 women in 16 randomised trials
Authors: R Gray, R Bradley, J Braybrooke, C Davies, H Pan, R Peto, J Bliss, D Cameron, J Mackey, L Del Mastro, S Swain, M Untch, J Bergh, K Pritchard, L Norton
Journal: Cancer Research (2018)

Abstract Background: Much contemporary adjuvant chemotherapy uses conventional 3-weekly scheduling. Yet, cytokinetic modelling suggests that increasing the dose density of cytotoxic therapy by shortening the intervals between courses, or by using sequential rather than concurrent treatment schedules may enhance efficacy.1 At least 15 randomised trials have directly tested this hypothesis and this meta-analysis by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) brings together the worldwide evidence to clarify the balance of risks and benefits of dose-dense chemotherapy. Methods: Individual patient data were provided for 98% (21,537/21,944) of women randomised in relevant trials: 7 randomised trials (10,004 women, 2240 breast cancer recurrences, 1481 breast cancer deaths) that compared 2-weekly dose-dense chemotherapy versus the same chemotherapy given 3-weekly, and 9 trials (11,533 women, 2773 breast cancer recurrences, 1711 breast cancer deaths) that compared sequential with concurrent anthracycline and taxane-based chemotherapy. Primary outcomes were time to recurrence and breast cancer mortality. Results: Highly significant reductions in disease recurrence [rate ratio (RR)=0.83 (95%CI 0.76-0.91), p=0.00004] were seen with 2-weekly compared with 3-weekly chemotherapy, and 10 year breast cancer mortality was 3.0% lower [16.7% vs 19.7%: RR=0.85 (95% CI 0.76-0.95), p=0.003]. Overall survival was also improved [RR=0·86 (95% CI 0·78−0·95), p=0.003]. Similarly, for sequential versus concurrent taxane plus anthracycline chemotherapy the rate ratio for disease recurrence was 0.86 (95% CI 0.79-0.93, p=0.0001), 10-year breast-cancer mortality was 2.3% lower [19.2% vs 21.5%: RR=0.87 (95% CI 0.79-0.96), p=0.005], and overall survival was improved [RR=0·85 (0·78−0·94), p=0.0008]. The proportional reductions in recurrence with dose-dense chemotherapy were similar and highly significant (both p&amp;lt;0.002) in ER-positive and in ER-negative disease, and did not differ significantly by any other patient or tumour characteristics, including age, HER2 status, nodal status, tumour size, or grade. Increasing dose density did not have any material adverse effect on non-breast-cancer mortality, which was similar with 2-weekly and with 3-weekly chemotherapy [RR=0·93 (95% CI 0·74−1·17), p=0.6] and was if anything lower with sequential than with concurrent chemotherapy [RR=0·73 (95% CI 0·55−0·97), p=0.03]. Trial publications also indicate that, with haematopoietic growth factor support, dose-dense chemotherapy does not substantially increase toxicity. Conclusion: Increasing the dose density of adjuvant chemotherapy is safe and results in fewer disease recurrences and fewer deaths from breast cancer. Reference: 1 Norton, L. Evolving concepts in the systemic therapy of breast cancer. Seminars in Oncology, 1997: S10-3 – S10-10. Citation Format: Gray R, Bradley R, Braybrooke J, Davies C, Pan H, Peto R, Bliss J, Cameron D, Mackey J, Del Mastro L, Swain S, Untch M, Bergh J, Pritchard K, Norton L, for the EBCTCG. Increasing the dose density of adjuvant chemotherapy by shortening intervals between courses or by sequential drug administration significantly reduces both disease recurrence and breast cancer mortality: An EBCTCG meta-analysis of 21,000 women in 16 randomised trials [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS1-01.