The optimal duration of tamoxifen use has been addressed by the EBCTCG meta-analysis and by several large randomized trials.[85,87,88,89] Results from the EBCTCG meta-analysis show a highly significant advantage of 5 years versus 1 to 2 years of tamoxifen with respect to the risk of recurrence (proportionate reduction 15.2%; P <.001) and a less significant advantage with respect to mortality (proportionate reduction 7.9%; P = .01). Results from the NSABP-B-14 study, which compared 5 years of adjuvant tamoxifen to 10 years of adjuvant tamoxifen for women with early-stage breast cancer, indicate no advantage for continuation of tamoxifen beyond 5 years in women with node-negative, ER-positive breast cancer.[Level of evidence: 1iA]
Another trial that included both node-positive and node-negative women also demonstrated the equivalence of 5 years and 10 years of therapy.[Level of evidence: 1iiDii] In both trials, there was a trend toward a worse outcome associated with a longer duration of treatment. In one trial EST-5181, node-positive women who had already received 5 years of tamoxifen following chemotherapy were randomly assigned to continue therapy or observation. In the ER-positive subgroup, a longer time to relapse was associated with continued tamoxifen use, but no improvement in OS was observed. The current recommendation is that adjuvant tamoxifen be discontinued after 5 years in all patients as current standard therapy. Clinical trials such as the Adjuvant Tamoxifen Longer Against Shorter (ATLAS) trial and the Adjuvant Tamoxifen Treatment--Offer More? (CRC-TU-ATTOM) trial have addressed different durations of adjuvant tamoxifen, and results are pending.
(Refer to the Letrozole section in the Aromatase inhibitors section of this summary for more information.)
Tamoxifen and chemotherapy
That chemotherapy should add to the effect of tamoxifen in postmenopausal women has been postulated.[91,92] In a trial (NSABP-B-16) of node-positive women older than 50 years with hormone receptor-positive tumors, 3-year DFS and OS rates were better in those who received doxorubicin, cyclophosphamide, and tamoxifen versus tamoxifen alone (DFS was 84% vs. 67%; P = .004; OS was 93% vs. 85%; P = .04).[Level of evidence: 1iiA] The NSABP-B-20 study compared tamoxifen alone with tamoxifen plus chemotherapy (cyclophosphamide, methotrexate, and fluorouracil [5-FU] [CMF] or sequential methotrexate and 5-FU) in women with node-negative, ER-positive breast cancer. After 12 years of follow-up, the chemotherapy plus tamoxifen regimen resulted in 89% DFS and 87% OS compared with a 79% DFS and 83% OS with tamoxifen alone.[Level of evidence: 1iiA]
In another study of postmenopausal women with node-positive disease, tamoxifen alone was compared with tamoxifen plus three different schedules of CMF. A small, DFS advantage was conferred by the addition of early CMF to tamoxifen in women with ER-positive disease.[Level of evidence: 1iiDii] However, another study in a similar patient population, in which women were randomly assigned to receive adjuvant tamoxifen with or without CMF, showed no benefit in the chemotherapy arm; in this study, intravenous (day 1 every 3 weeks) rather than oral cyclophosphamide was used.[Level of evidence: 1iiA] The overall results of the available evidence suggest that the addition of chemotherapy to tamoxifen in postmenopausal women with ER-positive disease results in a significant, but small, survival advantage.