Loyola University Stritch School of Medicine, Maywood, IL, USA.
Southwest Oncology Group Statistical Center, Seattle, WA, USA.
Lancet. 2009 Dec 19;374(9707):2055-2063. doi: 10.1016/S0140-6736(09)61523-3. Epub 2009 Dec 10.
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.
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.
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.
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.
National Cancer Institute (US National Institutes of Health).
他莫昔芬是激素受体阳性乳腺癌绝经后妇女的标准辅助治疗药物。我们评估了辅助他莫昔芬联合化疗的获益，以及他莫昔芬是应该与化疗同时使用还是在化疗后使用。
我们进行了一项 3 期、平行、随机试验（SWOG-8814，INT-0100），纳入了激素受体阳性、淋巴结阳性的绝经后乳腺癌患者，以检验两个主要目标：接受环磷酰胺、多柔比星和氟尿嘧啶（CAF）每 4 周 6 个周期联合 5 年每日他莫昔芬治疗的患者与单独使用他莫昔芬的患者相比，无病生存是否更长；以及 CAF 后序贯他莫昔芬（CAF-T）与 CAF 同期联合他莫昔芬（CAFT）相比，无病生存是否更长。总体生存和毒性是每个目标的预先设定的重要次要结局。该开放标签试验的患者通过计算机算法以 2:3:3 的比例（他莫昔芬：CAF-T：CAFT）随机分组，对符合条件的患者进行意向治疗分析。通过分层对数秩检验比较各组，然后使用调整了显著预后因素的 Cox 回归分析进行分析。这项试验在 ClinicalTrials.gov 注册，编号为 NCT00929591。
在 1558 名随机分配的女性中，1477 名（95%）符合纳入分析的条件。在最长 13 年的随访（中位随访 8.94 年）后，637 名女性出现无病生存事件（他莫昔芬组 361 名患者中有 179 例，CAF-T 组 566 名患者中有 216 例，CAFT 组 550 名患者中有 242 例）。对于第一个目标，CAF 联合他莫昔芬组（CAFT 或 CAF-T）的治疗在无病生存的主要终点上优于他莫昔芬单独治疗（调整后的 Cox 回归风险比[HR]0.76，95%CI0.64-0.91；p=0.002），但在总体生存的次要终点上仅略有优势（HR 0.83，0.68-1.01；p=0.057）。对于第二个目标，调整后的 HR 倾向于 CAF-T 优于 CAFT，但无病生存（HR 0.84，0.70-1.01；p=0.061）或总体生存（HR 0.90，0.73-1.10；p=0.30）未达到统计学意义。中性粒细胞减少症、口腔炎、血栓栓塞、充血性心力衰竭和白血病在联合 CAF 加他莫昔芬组比他莫昔芬组更常见。
与单独使用他莫昔芬相比，CAF 联合他莫昔芬序贯治疗对激素反应性、淋巴结阳性的绝经后乳腺癌患者更有效。然而，尽管淋巴结阳性，可能有一些亚组无法从蒽环类药物为基础的化疗中获益。
美国国立卫生研究院（美国国立癌症研究所）。
