Fluorouracil, Epirubicin, and Cyclophosphamide Alone or With Paclitaxel
Fluorouracil, Epirubicin, and Cyclophosphamide Alone or With Paclitaxel
Background: Taxanes are among the most active drugs for the treatment of metastatic breast cancer, and, as a consequence, they have also been studied in the adjuvant setting.
Methods: After breast cancer surgery, women with lymph node–positive disease were randomly assigned to treatment with fluorouracil, epirubicin, and cyclophosphamide (FEC) or with FEC followed by weekly paclitaxel (FEC-P). The primary endpoint of study—5-year disease-free survival (DFS)—was assessed by Kaplan–Meier analysis. Secondary endpoints included overall survival and analysis of the prognostic and predictive value of clinical and molecular (hormone receptors by immunohistochemistry and HER2 by fluorescence in situ hybridization) markers. Associations and interactions were assessed with a multivariable Cox proportional hazards model for DFS for the following covariates: age, menopausal status, tumor size, lymph node status, type of chemotherapy, tumor size, positive lymph nodes, HER2 status, and hormone receptor status. All statistical tests were two-sided.
Results: Among the 1246 eligible patients, estimated rates of DFS at 5 years were 78.5% in the FEC-P arm and 72.1% in the FEC arm (difference = 6.4%, 95% confidence interval [CI] = 1.6% to 11.2%; P = .006). FEC-P treatment was associated with a 23% reduction in the risk of relapse compared with FEC treatment (146 relapses in the 614 patients in the FEC-P arm vs 193 relapses in the 632 patients in the FEC arm, hazard ratio [HR] = 0.77, 95% CI = 0.62 to 0.95; P = .022) and a 22% reduction in the risk of death (73 and 95 deaths, respectively, HR = 0.78, 95% CI = 0.57 to 1.06; P = .110). Among the 928 patients for whom tumor samples were centrally analyzed, type of chemotherapy (FEC vs FEC-P) (P = .017), number of involved axillary lymph nodes (P <.001), tumor size (P = .020), hormone receptor status (P = .004), and HER2 status (P = .006) were all associated with DFS. We found no statistically significant interaction between HER2 status and paclitaxel treatment or between hormone receptor status and paclitaxel treatment.
Conclusions: Among patients with operable breast cancer, FEC-P treatment statistically significantly reduced the risk of relapse compared with FEC as adjuvant therapy.
A comprehensive meta-analysis by the Early Breast Cancer Trialists' Collaborative Group has demonstrated that chemotherapy (mainly cyclophosphamide, methotrexate, and 5-fluorouracil [CMF]–like regimens) administered after surgery is able to reduce the annual odds of recurrence and death among operable breast cancer patients by 24% and 14%, respectively. In the late 1970s and the 1980s, anthracycline-containing combination treatments were tested as adjuvant therapy in prospective randomized trials and appeared to be statistically significantly more effective in preventing breast cancer relapse and death than CMF chemotherapy. The absolute benefit in terms of disease-free survival (DFS) obtained with anthracyclines (doxorubicin or epirubicin) compared with CMF is, however, small (3% at 5 years and 4% at 10 years), and the long-term toxic effects of these drugs, particularly their cardiac toxic effects, are important concerns and indicate that anthracycline-containing regimens should be used only for women who are most likely to benefit from them. It has been proposed that the subset of patients who actually benefit from treatment with anthracyclines (as opposed to CMF) are those whose tumors have amplification of the topoisomerase IIα gene or HER2 gene.
Taxanes are among the most active drugs for the treatment of metastatic breast cancer. Several adjuvant therapy trials comparing anthracycline-containing chemotherapy with taxane (paclitaxel and docetaxel)-containing regimens (ie, the first-generation taxane trials) showed an absolute improvement in 5-year DFS of 4%–7%. Because taxane-containing regimens are usually even more toxic than the conventional anthracycline-containing regimens and because the benefit is limited to a small percentage of patients, the identification of the subgroup of patients who actually benefit from taxane-containing regimens is crucial. Several attempts have been made, largely on the basis of retrospective subset analyses, to identify the molecular characteristics of the breast tumors from the patients who obtain the greatest benefit from taxane treatment. To date, hormone receptor (ie, estrogen and progesterone receptor) and HER2 status are two of the most important molecular factors that are prognostic and could be predictive of response to chemotherapy in early breast cancer. A recent study by the Cancer and Leukemia Group B (CALGB) has indicated that patients who obtain the maximum benefit from paclitaxel are those whose tumors overexpress the HER2 gene.
We previously reported the preliminary interim analysis of a first-generation taxane trial, the Grupo Español para la Investigación del Cáncer de Mama (GEICAM [Spanish Group for the Investigation of Breast Cancer]) trial 9906, which evaluated fluorouracil, epirubicin, and cyclophosphamide (FEC) alone vs the taxane-containing combination of FEC followed by weekly paclitaxel (FEC-P). We now present the final results of this study. We also investigate associations between various molecular characteristics and response to taxane treatment.
Background: Taxanes are among the most active drugs for the treatment of metastatic breast cancer, and, as a consequence, they have also been studied in the adjuvant setting.
Methods: After breast cancer surgery, women with lymph node–positive disease were randomly assigned to treatment with fluorouracil, epirubicin, and cyclophosphamide (FEC) or with FEC followed by weekly paclitaxel (FEC-P). The primary endpoint of study—5-year disease-free survival (DFS)—was assessed by Kaplan–Meier analysis. Secondary endpoints included overall survival and analysis of the prognostic and predictive value of clinical and molecular (hormone receptors by immunohistochemistry and HER2 by fluorescence in situ hybridization) markers. Associations and interactions were assessed with a multivariable Cox proportional hazards model for DFS for the following covariates: age, menopausal status, tumor size, lymph node status, type of chemotherapy, tumor size, positive lymph nodes, HER2 status, and hormone receptor status. All statistical tests were two-sided.
Results: Among the 1246 eligible patients, estimated rates of DFS at 5 years were 78.5% in the FEC-P arm and 72.1% in the FEC arm (difference = 6.4%, 95% confidence interval [CI] = 1.6% to 11.2%; P = .006). FEC-P treatment was associated with a 23% reduction in the risk of relapse compared with FEC treatment (146 relapses in the 614 patients in the FEC-P arm vs 193 relapses in the 632 patients in the FEC arm, hazard ratio [HR] = 0.77, 95% CI = 0.62 to 0.95; P = .022) and a 22% reduction in the risk of death (73 and 95 deaths, respectively, HR = 0.78, 95% CI = 0.57 to 1.06; P = .110). Among the 928 patients for whom tumor samples were centrally analyzed, type of chemotherapy (FEC vs FEC-P) (P = .017), number of involved axillary lymph nodes (P <.001), tumor size (P = .020), hormone receptor status (P = .004), and HER2 status (P = .006) were all associated with DFS. We found no statistically significant interaction between HER2 status and paclitaxel treatment or between hormone receptor status and paclitaxel treatment.
Conclusions: Among patients with operable breast cancer, FEC-P treatment statistically significantly reduced the risk of relapse compared with FEC as adjuvant therapy.
A comprehensive meta-analysis by the Early Breast Cancer Trialists' Collaborative Group has demonstrated that chemotherapy (mainly cyclophosphamide, methotrexate, and 5-fluorouracil [CMF]–like regimens) administered after surgery is able to reduce the annual odds of recurrence and death among operable breast cancer patients by 24% and 14%, respectively. In the late 1970s and the 1980s, anthracycline-containing combination treatments were tested as adjuvant therapy in prospective randomized trials and appeared to be statistically significantly more effective in preventing breast cancer relapse and death than CMF chemotherapy. The absolute benefit in terms of disease-free survival (DFS) obtained with anthracyclines (doxorubicin or epirubicin) compared with CMF is, however, small (3% at 5 years and 4% at 10 years), and the long-term toxic effects of these drugs, particularly their cardiac toxic effects, are important concerns and indicate that anthracycline-containing regimens should be used only for women who are most likely to benefit from them. It has been proposed that the subset of patients who actually benefit from treatment with anthracyclines (as opposed to CMF) are those whose tumors have amplification of the topoisomerase IIα gene or HER2 gene.
Taxanes are among the most active drugs for the treatment of metastatic breast cancer. Several adjuvant therapy trials comparing anthracycline-containing chemotherapy with taxane (paclitaxel and docetaxel)-containing regimens (ie, the first-generation taxane trials) showed an absolute improvement in 5-year DFS of 4%–7%. Because taxane-containing regimens are usually even more toxic than the conventional anthracycline-containing regimens and because the benefit is limited to a small percentage of patients, the identification of the subgroup of patients who actually benefit from taxane-containing regimens is crucial. Several attempts have been made, largely on the basis of retrospective subset analyses, to identify the molecular characteristics of the breast tumors from the patients who obtain the greatest benefit from taxane treatment. To date, hormone receptor (ie, estrogen and progesterone receptor) and HER2 status are two of the most important molecular factors that are prognostic and could be predictive of response to chemotherapy in early breast cancer. A recent study by the Cancer and Leukemia Group B (CALGB) has indicated that patients who obtain the maximum benefit from paclitaxel are those whose tumors overexpress the HER2 gene.
We previously reported the preliminary interim analysis of a first-generation taxane trial, the Grupo Español para la Investigación del Cáncer de Mama (GEICAM [Spanish Group for the Investigation of Breast Cancer]) trial 9906, which evaluated fluorouracil, epirubicin, and cyclophosphamide (FEC) alone vs the taxane-containing combination of FEC followed by weekly paclitaxel (FEC-P). We now present the final results of this study. We also investigate associations between various molecular characteristics and response to taxane treatment.
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