Randomized Placebo-Controlled Study of Tamoxifen After Adjuvant Chemo
Randomized Placebo-Controlled Study of Tamoxifen After Adjuvant Chemo
Background: In the early 1990s, the role of adjuvant tamoxifen in premenopausal women with early breast cancer (EBC) was not established. Similarly, optimum timing relative to adjuvant chemotherapy and efficacy of tamoxifen in hormone receptor-negative tumors were unclear.
Patients and methods: Premenopausal women with EBC, any hormone receptor status, after surgery received standard adjuvant chemotherapy [doxorubicin (adriamycin)/cyclophosphamide, cyclophosphamide/methotrexate/5-fluorouracil, or cyclophosphamide/epirubicin/5-fluorouracil] followed by randomization to tamoxifen or placebo for 5 years. Outcomes were overall survival (OS), disease-free survival (DFS), toxicity, and compliance with therapy.
Results: Median follow-up for 672 women was 9.7 years. Multivariate analysis showed improved DFS [78.2% versus 71.3% at 5 years; hazard ratio (HR) 0.77; P = 0.056] and a trend for improved OS (86.6% versus 82.1% at 5 years; HR 0.78; P = 0.12). There was no evidence of greater benefit for the receptor-positive subgroup. Compliance with treatment was suboptimal in both arms, with 103 (31%) women on tamoxifen and 70 (21%) on placebo-stopping therapy early because of toxicity, refusal, or other choices.
Conclusions: Adjuvant tamoxifen, given after chemotherapy to premenopausal women with EBC, improved 5-year DFS. Poor compliance may have reduced treatment efficacy.
In 1992, the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) published the 1990 meta-analysis of 75 000 women in randomized trials evaluating systemic adjuvant therapies for early breast cancer (EBC). This established the benefits of polychemotherapy alone, and tamoxifen alone, in reducing recurrence and improving survival. However, the meta-analysis indicated little advantage for tamoxifen added to polychemotherapy [6362 women—risk reduction (RR) recurrence 7%, RR mortality 3%] in women <50 years. This meta-analysis also established 5 years of tamoxifen as an optimum duration, but its role in women with estrogen receptor (ER)-negative tumors remained unresolved.
Superiority of sequential rather than concurrent use of tamoxifen with chemotherapy was not confirmed until publication of Intergroup 0100 study results in 2002. However, a theoretical concern, together with experimental data, indicating that tamoxifen given concurrently with chemotherapy could decrease rates of cell division reducing susceptibility to cell cycle active chemotherapy agents, provided the basis for sequential use of tamoxifen in several adjuvant chemohormonal trials started in the 1990s. The interaction of chemotherapy and tamoxifen may be quite complex in premenopausal women. Chemotherapy-induced amenorrhea is often associated with better outcomes, although controversy remains. In 1992, there was substantial uncertainty as to whether tamoxifen administered with or after chemotherapy in premenopausal women was redundant or conferred benefit similar to that seen in postmenopausal women.
Thus, in 1992, the National Cancer Institute of Canada—Clinical Trials Group (NCIC CTG) Breast Committee initiated Mammary (MA).12 in premenopausal women with node-positive breast cancer, evaluating the benefit of 5 years of adjuvant tamoxifen versus placebo following completion of adjuvant chemotherapy. Participants could opt for one of three well-established chemotherapy regimens, cyclophosphamide/methotrexate/5-fluorouracil (CMF), cyclophosphamide/epirubicin/5-fluorouracil (CEF) as used in an NCIC CTG trial that had just been completed, or doxorubicin (adriamycin)/cyclophosphamide (AC).
Abstract and Introduction
Abstract
Background: In the early 1990s, the role of adjuvant tamoxifen in premenopausal women with early breast cancer (EBC) was not established. Similarly, optimum timing relative to adjuvant chemotherapy and efficacy of tamoxifen in hormone receptor-negative tumors were unclear.
Patients and methods: Premenopausal women with EBC, any hormone receptor status, after surgery received standard adjuvant chemotherapy [doxorubicin (adriamycin)/cyclophosphamide, cyclophosphamide/methotrexate/5-fluorouracil, or cyclophosphamide/epirubicin/5-fluorouracil] followed by randomization to tamoxifen or placebo for 5 years. Outcomes were overall survival (OS), disease-free survival (DFS), toxicity, and compliance with therapy.
Results: Median follow-up for 672 women was 9.7 years. Multivariate analysis showed improved DFS [78.2% versus 71.3% at 5 years; hazard ratio (HR) 0.77; P = 0.056] and a trend for improved OS (86.6% versus 82.1% at 5 years; HR 0.78; P = 0.12). There was no evidence of greater benefit for the receptor-positive subgroup. Compliance with treatment was suboptimal in both arms, with 103 (31%) women on tamoxifen and 70 (21%) on placebo-stopping therapy early because of toxicity, refusal, or other choices.
Conclusions: Adjuvant tamoxifen, given after chemotherapy to premenopausal women with EBC, improved 5-year DFS. Poor compliance may have reduced treatment efficacy.
Introduction
In 1992, the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) published the 1990 meta-analysis of 75 000 women in randomized trials evaluating systemic adjuvant therapies for early breast cancer (EBC). This established the benefits of polychemotherapy alone, and tamoxifen alone, in reducing recurrence and improving survival. However, the meta-analysis indicated little advantage for tamoxifen added to polychemotherapy [6362 women—risk reduction (RR) recurrence 7%, RR mortality 3%] in women <50 years. This meta-analysis also established 5 years of tamoxifen as an optimum duration, but its role in women with estrogen receptor (ER)-negative tumors remained unresolved.
Superiority of sequential rather than concurrent use of tamoxifen with chemotherapy was not confirmed until publication of Intergroup 0100 study results in 2002. However, a theoretical concern, together with experimental data, indicating that tamoxifen given concurrently with chemotherapy could decrease rates of cell division reducing susceptibility to cell cycle active chemotherapy agents, provided the basis for sequential use of tamoxifen in several adjuvant chemohormonal trials started in the 1990s. The interaction of chemotherapy and tamoxifen may be quite complex in premenopausal women. Chemotherapy-induced amenorrhea is often associated with better outcomes, although controversy remains. In 1992, there was substantial uncertainty as to whether tamoxifen administered with or after chemotherapy in premenopausal women was redundant or conferred benefit similar to that seen in postmenopausal women.
Thus, in 1992, the National Cancer Institute of Canada—Clinical Trials Group (NCIC CTG) Breast Committee initiated Mammary (MA).12 in premenopausal women with node-positive breast cancer, evaluating the benefit of 5 years of adjuvant tamoxifen versus placebo following completion of adjuvant chemotherapy. Participants could opt for one of three well-established chemotherapy regimens, cyclophosphamide/methotrexate/5-fluorouracil (CMF), cyclophosphamide/epirubicin/5-fluorouracil (CEF) as used in an NCIC CTG trial that had just been completed, or doxorubicin (adriamycin)/cyclophosphamide (AC).