Concurrent vs sequential adjuvant chemotherapy and hormone therapy in breast cancer: a multicenter randomized phase III trial

Abstract

Background: The most appropriate timing of chemotherapy and hormone therapy administration is a critical issue in early breast cancer patients. The purpose of our study was to compare the efficacy of concurrent vs sequential administration of adjuvant chemotherapy and tamoxifen.

Methods: Women with node-positive primary breast cancer were randomly assigned to receive tamoxifen (20 mg/d for 5 years) during (concurrent arm) or after (sequential arm) adjuvant chemotherapy. Chemotherapy consisted of alternating regimens of cyclophosphamide, epidoxorubicin, and 5-fluorouracil and cyclophosphamide, methotrexate, and 5-fluorouracil every 21 days for a total of 12 cycles. The primary endpoint was overall survival (OS), and secondary endpoints were toxic effects and disease-free survival (DFS). No provision for interim analyses was made in the original study protocol. Survival curves were estimated by the Kaplan-Meier method. Multivariable Cox regression models, adjusted for age, menopausal status, tumor stage, and lymph node and hormone receptor status, were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided.

Results: From 1985 to 1992, 431 patients were randomly assigned and studied according to the intention-to-treat principle. After a maximum of 15.4 years of follow-up (median 12.3 years), the estimated actuarial 10-year OS was equivalent for the two study arms (concurrent arm: 111 patients, 66%, 95% CI = 59% to 72%; sequential arm: 114 patients, 65%, 95% CI = 59% to 72%, P = .86). No differences in DFS and toxic effects were evident. Four interim analyses were performed, but no alpha error adjustment was necessary because of the largely negative results of this final analysis (sequential vs concurrent arm: HR of death = 1.06, 95% CI = 0.78 to 1.44, P = .76; HR of relapse = 1.16, 95% CI = 0.88 to 1.52, P = .36).

Conclusions: No statistically significant differences in OS, DFS, and toxic effects between concurrent and sequential adjuvant chemo- and hormone therapies were observed. Our study does not support the superiority of one schedule of chemo- and hormone-therapy administration over the other. However, because of the limited statistical power of the study, these results must be considered with caution.

Figure 1

CONSORT diagram. Patient disposition during the study. Concurrent arm = tamoxifen concurrent with chemotherapy; sequential arm = tamoxifen after completion of chemotherapy. DFS = disease-free survival; OS = overall survival.

Figure 2

Kaplan–Meier survival curves for all randomly assigned patients. A) Overall survival and B) Disease-free survival. P values from two-sided log-rank test. Concurrent arm = tamoxifen concurrent with chemotherapy; sequential arm = tamoxifen after completion of chemotherapy; CI = confidence interval; DFS = disease-free survival; N = number of patients at risk; OS = overall survival; Y = year.

Figure 3

Forest plot for overall survival of subgroups. Comparison of the concurrent vs the sequential arm within strata formed by each prognostic factor. The solid line shows the no effect point, and the dotted line shows overall treatment effect for the whole dataset. HR and CI were obtained from a Cox model in which all variables were included as covariates. All variables were categorical and implied established factors associated with prognosis and/or response to chemotherapy and hormone therapy. Interaction terms assessing the homogeneity of the effect of experimental treatment across strata of each covariate were introduced in the model one at a time. P values are from two-sided likelihood ratio tests. All P values shown are from tests for interaction, except for the last at the bottom, which is the overall comparison of sequential arm vs concurrent arm adjusted for all prognostic factors. The solid line corresponds to no effect and the dotted line shows overall treatment effect for the whole dataset. Concurrent = tamoxifen concurrent with chemotherapy; sequential = tamoxifen after completion of chemotherapy. CI = confidence interval; ER = estrogen receptor; HR = hazard ratio; Neg = negative; PgR = progesterone receptor; Pos = positive; pT1,2 = primary tumor stage 1,2, according to the American Joint Committee on Cancer staging system staging system.

Figure 4

Forest plot for disease-free survival of subgroups. Comparison of the concurrent vs the sequential arm within strata formed by each prognostic factor. The solid line shows the no effect point, and the dotted line shows overall treatment effect for the whole dataset. HR and CI were obtained from a Cox model in which all variables were included as covariates. All variables were categorical and implied established factors associated with prognosis and/or response to chemotherapy and hormone therapy. Interaction terms assessing the homogeneity of the effect of experimental treatment across strata of each covariate were introduced in the model one at a time. P values are from two-sided likelihood ratio tests. All P values shown are from tests for interaction, except for the last at the bottom, which is the overall comparison of sequential arm vs concurrent arm adjusted for all prognostic factors. Concurrent = tamoxifen concurrent with chemotherapy; sequential = tamoxifen after completion of chemotherapy. CI = confidence interval; ER = estrogen-receptor; HR = hazard ratio; Neg = negative; PgR = progesterone receptor; Pos = positive; pT1,2 = primary tumor stage 1,2, according to the American Joint Committee on Cancer Staging System.