Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling: a patient-level meta-analysis of 37 298 women with early breast cancer in 26 randomised trials

Abstract

Summary Background Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment schedules, might enhance efficacy. Methods To clarify the relative benefits and risks of dose-intense and standard-schedule chemotherapy in early breast cancer, we did an individual patient-level meta-analysis of trials comparing 2-weekly versus standard 3-weekly schedules, and of trials comparing sequential versus concurrent administration of anthracycline and taxane chemotherapy. The primary outcomes were recurrence and breast cancer mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded dose-intense versus standard-schedule first-event rate ratios (RRs). Findings Individual patient data were provided for 26 of 33 relevant trials identified, comprising 37 298 (93%) of 40 070 women randomised. Most women were aged younger than 70 years and had node-positive disease. Total cytotoxic drug usage was broadly comparable in the two treatment arms; colony-stimulating factor was generally used in the more dose-intense arm. Combining data from all 26 trials, fewer breast cancer recurrences were seen with dose-intense than with standard-schedule chemotherapy (10-year recurrence risk 28·0% vs 31·4%; RR 0·86, 95% CI 0·82–0·89; p<0·0001). 10-year breast cancer mortality was similarly reduced (18·9% vs 21·3%; RR 0·87, 95% CI 0·83–0·92; p<0·0001), as was all-cause mortality (22·1% vs 24·8%; RR 0·87, 95% CI 0·83–0·91; p<0·0001). Death without recurrence was, if anything, lower with dose-intense than with standard-schedule chemotherapy (10-year risk 4·1% vs 4·6%; RR 0·88, 95% CI 0·78–0·99; p=0·034). Recurrence reductions were similar in the seven trials (n=10 004) that compared 2-weekly chemotherapy with the same chemotherapy given 3-weekly (10-year risk 24·0% vs 28·3%; RR 0·83, 95% CI 0·76–0·91; p<0·0001), in the six trials (n=11 028) of sequential versus concurrent anthracycline plus taxane chemotherapy (28·1% vs 31·3%; RR 0·87, 95% CI 0·80–0·94; p=0·0006), and in the six trials (n=6532) testing both shorter intervals and sequential administration (30·4% vs 35·0%; RR 0·82, 95% CI 0·74–0·90; p<0·0001). The proportional reductions in recurrence with dose-intense chemotherapy were similar and highly significant (p<0·0001) in oestrogen receptor (ER)-positive and ER-negative disease and did not differ significantly by other patient or tumour characteristics. Interpretation Increasing the dose intensity of adjuvant chemotherapy by shortening the interval between treatment cycles, or by giving individual drugs sequentially rather than giving the same drugs concurrentl...

Early Triple Negative Breast Cancer: Conventional Treatment and Emerging Therapeutic Landscapes

“…A more recent large meta-analysis of 26 trials of adjuvant therapy clearly showed that dose-dense chemotherapy improves the outcome in terms of BC recurrence (28% vs. 31.4%), BC specific mortality (18.9% vs. 21.3%), and overall mortality (22.1% vs. 24.8%) with similar safety profiles. However, the benefit was not affected by hormone receptor status [73].…”

Efficacy and safety of tailored and dose‐dense adjuvant chemotherapy and trastuzumab for resected HER2‐positive breast cancer: Results from the phase 3 PANTHER trial

“…In addition, the relative contribution of increasing dose density versus dose tailoring to the efficacy of the regimen cannot be discerned. Thus, although the number of cycles and cumulative doses of chemotherapy differed between the 2 treatment groups, it is likely that the observed difference was driven not by the larger number of cycles but rather by the increased dose density in the experimental treatment; however, data directly comparing 6 to 8 cycles of sequential anthracyclines and taxanes are lacking …”

“…Thus, although the number of cycles and cumulative doses of chemotherapy differed between the 2 treatment groups, it is likely that the observed difference was driven not by the larger number of cycles but rather by the increased dose density in the experimental treatment; however, data directly comparing 6 to 8 cycles of sequential anthracyclines and taxanes are lacking. 2,13 Available data demonstrate the feasibility of combining DD chemotherapy and trastuzumab in both neoadjuvant and adjuvant settings. [14][15][16][17][18][19] However, to our knowledge this is the first report of phase 3 data from randomized allocation to DD adjuvant chemotherapy and trastuzumab versus standard interval chemotherapy and trastuzumab, for HER2-positive BC.…”

“…Patient outcomes after the resection of early breast cancer (BC) have been conclusively demonstrated to improve after the administration of adjuvant polychemotherapy . Further improvements in patient survival are achieved with its dose‐dense (DD) administration (ie, every 2 weeks) . Among the cornerstones of adjuvant chemotherapy regimens are anthracyclines, which can cause dose‐dependent and often irreversible cardiotoxicity, although without compromising the survival benefit derived from anthracycline‐containing chemotherapy …”

“…1 Further improvements in patient survival are achieved with its dose-dense (DD) administration (ie, every 2 weeks). 2 Among the cornerstones of adjuvant chemotherapy regimens are anthracyclines, which can cause dose-dependent and often irreversible cardiotoxicity, although without compromising the survival benefit derived from anthracycline-containing chemotherapy. 1,3 On the other hand, the introduction of trastuzumab into the treatment of human epidermal growth factor receptor 2 (HER2)-positive BC has marked a watershed in targeted cancer therapy.…”