Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial

Abstract

Background: Tamoxifen is standard adjuvant treatment for postmenopausal women with hormone-receptor-positive breast cancer. We assessed the benefit of adding chemotherapy to adjuvant tamoxifen and whether tamoxifen should be given concurrently or after chemotherapy.

Methods: We undertook a phase 3, parallel, randomised trial (SWOG-8814, INT-0100) in postmenopausal women with hormone-receptor-positive, node-positive breast cancer to test two major objectives: whether the primary outcome, disease-free survival, was longer with cyclophosphamide, doxorubicin, and fluorouracil (CAF) given every 4 weeks for six cycles plus 5 years of daily tamoxifen than with tamoxifen alone; and whether disease-free survival was longer with CAF followed by tamoxifen (CAF-T) than with CAF plus concurrent tamoxifen (CAFT). Overall survival and toxicity were predefined, important secondary outcomes for each objective. Patients in this open-label trial were randomly assigned by a computer algorithm in a 2:3:3 ratio (tamoxifen:CAF-T:CAFT) and analysis was by intention to treat of eligible patients. Groups were compared by stratified log-rank tests, followed by Cox regression analyses adjusted for significant prognostic factors. This trial is registered with ClinicalTrials.gov, number NCT00929591.

Findings: Of 1558 randomised women, 1477 (95%) were eligible for inclusion in the analysis. After a maximum of 13 years of follow-up (median 8.94 years), 637 women had a disease-free survival event (tamoxifen, 179 events in 361 patients; CAF-T, 216 events in 566 patients; CAFT, 242 events in 550 patients). For the first objective, therapy with the CAF plus tamoxifen groups combined (CAFT or CAF-T) was superior to tamoxifen alone for the primary endpoint of disease-free survival (adjusted Cox regression hazard ratio [HR] 0.76, 95% CI 0.64-0.91; p=0.002) but only marginally for the secondary endpoint of overall survival (HR 0.83, 0.68-1.01; p=0.057). For the second objective, the adjusted HRs favoured CAF-T over CAFT but did not reach significance for disease-free survival (HR 0.84, 0.70-1.01; p=0.061) or overall survival (HR 0.90, 0.73-1.10; p=0.30). Neutropenia, stomatitis, thromboembolism, congestive heart failure, and leukaemia were more frequent in the combined CAF plus tamoxifen groups than in the tamoxifen-alone group.

Interpretation: Chemotherapy with CAF plus tamoxifen given sequentially is more effective adjuvant therapy for postmenopausal patients with endocrine-responsive, node-positive breast cancer than is tamoxifen alone. However, it might be possible to identify some subgroups that do not benefit from anthracycline-based chemotherapy despite positive nodes.

Funding: National Cancer Institute (US National Institutes of Health).

Figure 1

Consort diagram of study design, accrual and eligibility for Southwest Oncology Group trial SWOG-8814 (The Breast Cancer Intergroup of North America 0100). The figure shows the number randomized, the number who were fully eligible (and analyzed), and the number who actually received their assigned treatment.

Figure 2

Southwest Oncology Group trial SWOG-8814 (The Breast Cancer Intergroup of North America 0100) Kaplan-Meier disease-free survival and overall survival distributions for 1116 eligible patients at risk on the combined CAF plus tamoxifen groups (566, CAF-T; 550, CAFT) and 361 on tamoxifen alone. Panel A shows the disease-free survival for the combined CAF plus tamoxifen groups versus tamoxifen alone, log-rank P=0.002, stratified by number of positive nodes, hormone receptor status, and time from definitive surgery.. Panel B depicts the overall survival for the CAF plus tamoxifen versus tamoxifen comparison, stratified log-rank P=0.043. Panel C represents the disease-free survival for the CAFT versus CAF-T comparison, stratified log-rank P=0.055. Panel D shows the overall survival with 10-year estimates for the CAFT versus CAF-T comparison, stratified log-rank P=0.27. Ten-year survival estimates with 95% confidence intervals are also given.

Figure 3

Southwest Oncology Group trial SWOG-8814 (North American Breast Intergroup 0100) Kaplan-Meier disease-free survival and overall survival distributions for 566 patients on CAF-T, 550 on CAFT, and 361 on tamoxifen alone. Panel A describes the disease-free survival advantage for the sequential approach, log-rank P=0.002 stratified by number of positive nodes, hormone receptor status, and time of surgery, and Panel B shows superior overall survival the CAF-T group, stratified log-rank P=0.074. Ten-year survival estimates and hazard ratios adjusted for prognostic covariates with 95% confidence intervals are also given.

Figure 4

Southwest Oncology Group trial SWOG-8814 (North American Breast Intergroup 0100) forest plots of hazard ratios and 95% confidence intervals for major subsets for disease-free survival. Panel A describes the disease-free survival advantage for chemotherapy by possible subsets unadjusted for other covariates. Panel B shows the benefit of CAF-T over CAFT in each subset. The dashed vertical line represents the overall unadjusted hazard ratio in each plot.