Colleoni Marco, Gray Kathryn P, Gelber Shari, Láng István, Thürlimann Beat, Gianni Lorenzo, Abdi Ehtesham A, Gomez Henry L, Linderholm Barbro K, Puglisi Fabio, Tondini Carlo, Kralidis Elena, Eniu Alexandru, Cagossi Katia, Rauch Daniel, Chirgwin Jacquie, Gelber Richard D, Regan Meredith M, Coates Alan S, Price Karen N, Viale Giuseppe, Goldhirsch Aron
Marco Colleoni, Giuseppe Viale, and Aron Goldhirsch, European Institute of Oncology; Giuseppe Viale, University of Milan, Milan; Lorenzo Gianni, Ospedale degli Infermi, Rimini; Fabio Puglisi, University Hospital of Udine, University of Udine, Udine; Carlo Tondini, Osp. Papa Giovanni XXIII, Bergamo; Katia Cagossi, Ospedale di Carpi, Carpi, Italy; Kathryn P. Gray, Shari Gelber, Richard D. Gelber, Meredith M. Regan, and Karen N. Price, International Breast Cancer Study Group Statistical Center; Kathryn P. Gray, Shari Gelber, Richard D. Gelber, and Meredith M. Regan, Dana-Farber Cancer Institute; Kathryn P. Gray and Richard D. Gelber, Harvard T.H. Chan School of Public Health; Richard D. Gelber and Meredith M. Regan, Harvard Medical School; Richard D. Gelber and Karen N. Price, Frontier Science and Technology Foundation, Boston, MA; István Láng, National Institute of Oncology, Budapest, Hungary; Beat Thürlimann, Kantonsspital, St Gallen; Beat Thürlimann, Elena Kralidis, and Daniel Rauch, Swiss Group for Clinical Cancer Research, Bern; Elena Kralidis, Kantonsspital Aarau, Aarau; Daniel Rauch, Spital Thun, Thun, Switzerland; Ehtesham A. Abdi, The Tweed Head Hospital, Tweed Heads, New South Wales and Griffith University, Southport, Queensland; Ehtesham A. Abdi and Jacquie Chirgwin, Australia and New Zealand Breast Cancer Trials Group; Jacquie Chirgwin, Box Hill and Maroondah Hospitals and Monash University, Melbourne, Victoria; Alan S. Coates, International Breast Cancer Study Group and University of Sydney School of Public Health, Sydney, New South Wales, Australia; Henry L. Gomez, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru; Barbro K. Linderholm, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden; and Alexandru Eniu, Cancer Institute Ion Chiricuta, Cluj, Romania.
J Clin Oncol. 2016 Oct 1;34(28):3400-8. doi: 10.1200/JCO.2015.65.6595. Epub 2016 Jun 20.
To evaluate the benefit of low-dose cyclophosphamide and methotrexate (CM) maintenance, which previously demonstrated antitumor activity and few adverse effects in advanced breast cancer, in early breast cancer.
International Breast Cancer Study Group (IBCSG) Trial 22-00, a randomized phase III clinical trial, enrolled 1,086 women (1,081 intent-to-treat) from November 2000 to December 2012. Women with estrogen receptor- and progesterone receptor-negative (< 10% positive cells by immunohistochemistry) early breast cancer any nodal and human epidermal growth factor receptor 2 status, were randomly assigned anytime between primary surgery and 56 days after the first day of last course of adjuvant chemotherapy to CM maintenance (cyclophosphamide 50 mg/day orally continuously and methotrexate 2.5 mg twice/day orally on days 1 and 2 of every week for 1 year) or to no CM. The primary end point was disease-free survival (DFS), which included invasive recurrences, second (breast and nonbreast) malignancies, and deaths.
After a median of 6.9 years of follow-up, DFS was not significantly better for patients assigned to CM maintenance compared with patients assigned to no CM, both overall (hazard ratio [HR], 0.84; 95% CI, 0.66 to 1.06;P = .14) and in triple-negative (TN) disease (n = 814; HR, 0.80; 95% CI, 0.60 to 1.06). Patients with TN, node-positive disease had a nonstatistically significant reduced HR (n = 340; HR, 0.72; 95% CI, 0.49 to 1.05). Seventy-one (13%) of 542 patients assigned to CM maintenance did not start CM. Of 473 patients who received at least one CM maintenance dose (including two patients assigned to no CM), 64 (14%) experienced a grade 3 or 4 treatment-related adverse event; elevated serum transaminases was the most frequently reported (7%), followed by leukopenia (2%).
CM maintenance did not produce a significant reduction in DFS events in hormone receptor-negative early breast cancer. The trend toward benefit observed in the TN, node-positive subgroup supports additional exploration of this strategy in the TN, higher-risk population.
评估低剂量环磷酰胺和甲氨蝶呤（CM）维持治疗在早期乳腺癌中的益处，此前该治疗在晚期乳腺癌中已显示出抗肿瘤活性且不良反应较少。
国际乳腺癌研究组（IBCSG）22 - 00试验是一项随机III期临床试验，从2000年11月至2012年12月共纳入1086名女性（1081名意向性治疗患者）。雌激素受体和孕激素受体均为阴性（免疫组化阳性细胞<10%）的早期乳腺癌患者，无论腋窝淋巴结状态及人表皮生长因子受体2状态如何，在初次手术至辅助化疗最后一个疗程首日起56天内的任何时间，被随机分配接受CM维持治疗（环磷酰胺50mg/天口服，持续1年；甲氨蝶呤2.5mg，每周第1天和第2天口服，每日2次，共1年）或不接受CM维持治疗。主要终点为无病生存期（DFS），包括侵袭性复发、第二原发性（乳腺和非乳腺）恶性肿瘤及死亡。
经过中位6.9年的随访，接受CM维持治疗的患者与未接受CM维持治疗的患者相比，DFS并无显著改善，总体情况（风险比[HR]，0.84；95%置信区间[CI]，0.66至1.06；P = 0.14）以及三阴性（TN）疾病患者（n = 814；HR，0.80；95% CI，0.60至1.06）均如此。TN、腋窝淋巴结阳性疾病患者的HR有非统计学意义的降低（n = 340；HR，0.72；95% CI，0.49至1.05）。分配至CM维持治疗组的542名患者中，71名（13%）未开始CM治疗。在473名接受至少一剂CM维持治疗的患者（包括2名分配至不接受CM维持治疗组的患者）中，64名（14%）发生了3级或4级治疗相关不良事件；血清转氨酶升高是最常报告的不良事件（7%），其次是白细胞减少（2%）。
CM维持治疗在激素受体阴性早期乳腺癌中并未显著降低DFS事件。在TN、腋窝淋巴结阳性亚组中观察到的获益趋势支持在TN、高风险人群中进一步探索该策略。
