Sequential ACT, currently the standard chemotherapy for operable node-positive breast cancer, yielded significantly better overall survival and disease-free survival than did two short-course regimens, according to a report in the June 3 issue of the New England Journal of Medicine.

This finding, from a large, phase III clinical trial by the National Surgical Adjuvant Breast and Bowel Project (NSABP), suggests that the cumulative dose may be more important than the dose intensity per cycle, said Dr. Sandra M. Swain of the NSABP and the Washington (D.C.) Hospital Center and her associates.

The investigators compared three chemotherapy regiments: sequential ACT (a 24-week regimen of doxorubicin and cyclophosphamide followed by docetaxel), concurrent ACT (a 12-week regimen of combined doxorubicin, cyclophosphamide, and docetaxel), and a similarly short regimen of combined doxorubicin and docetaxel without cyclophosphamide.

The study involved 5,264 patients at 185 medical centers across North America who had undergone primary surgery for invasive breast adenocarcinoma and had shown evidence of tumor in at least one axillary lymph node. These study subjects were randomly assigned to sequential ACT (1,753 patients) concurrent ACT (1,758 patients), or doxorubicin plus docetaxel (1,753 patients).

After a median follow-up of 73 months, there were 803 deaths.

Sequential ACT yielded an overall survival rate of 83%, representing a significant reduction in mortality compared with concurrent ACT (79% overall survival) and doxorubicin-docetaxel (also 79% overall survival).

Similarly, sequential ACT yielded a 74% disease-free survival rate, significantly better than the 69% disease-free survival with concurrent ACT and the 69% disease-free survival with doxorubicin-docetaxel, Dr. Swain and her colleagues said (New Engl. J. Med. 2010;362:2053-65).

The incidence of grade 3 or 4 adverse events was higher with sequential ACT (65%) than with concurrent ACT (48%) or doxorubicin-docetaxel (45%). However, treatment-related deaths were comparable at fewer than 1% in all three groups.

An “intriguing” ancillary finding in this trial was that among 2,343 women who were premenopausal at diagnosis, both overall survival and disease-free survival were significantly better in those who developed amenorrhea after chemotherapy than in those who continued to menstruate.

This finding supports the idea that chemotherapy may benefit patients indirectly by means of ovarian suppression. “However, one cannot rule out that the association of improved outcome with increased frequency of ovarian suppression might be correlative rather than cause and effect.

“Another possibility includes altered drug metabolism in individual patients which could lead to differences in efficacy or rates of ovarian suppression,” the investigators noted.

In an accompanying editorial, however, Dr. Matthew Ellis of Washington University in St. Louis noted that another trial (Cancer and Leukemia Group B 9741) supported dose density. Thus, one of the main conclusions of the trial by Dr. Swain and colleagues – that a longer duration of treatment was better – “should not be considered a general principle, but rather a product of the unbalanced design of the study,” he wrote.

Dr. Ellis also described the overall survival advantage as “a modest gain” when the longer duration of therapy, the increased dose, and higher toxicity are considered. It is “hard to escape the conclusion that this trial marks the end of the road for generic studies of combinations of anthracycline, taxane, and cyclophosphamide,” he said, citing investigations of targeted therapies and calling for “smarter trials” that capture not only patient outcomes but also biological samples.

This study was supported by the Washington Hospital Center Foundation, the National Cancer Institute, the National Institutes of Health, and the U.S. Department of Health and Human Services. Docetaxel was donated by Sanofi-Aventis. Dr. Swain reported support from Rhone-Poulenc Rorer, Genentech Inc., Sanofi-Aventis, Bristol-Myers Squibb Co., Susan G. Komen for the Cure, Living in Pink, Safeway Inc., Eisai Inc., GlaxoSmithKline, Pfizer Inc., Onyx Pharmaceuticals Inc., Novartis, Roche, Abraxis BioScience Inc., BiPar Sciences Inc., and Wyeth.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

据6月3日出版的《新英格兰医学杂志》(NEJM)中的一篇报道，序贯化疗是目前淋巴结阳性的可手术乳腺癌的标准化疗方案，其总生存率和无病生存率均优于两种短程化疗方案。

 

此研究结果源于由美国国家乳腺与肠道外科辅助治疗项目组(NSABP)进行的一项大型III期临床试验，表明每个疗程的累积剂量可能比剂量强度更重要，NSABP与华盛顿(哥伦比亚特区)医院中心的Sandra M. Swain 博士及其同事们说。

 

研究者们对以下3组化疗方案进行了比较：序贯ACT化疗(阿霉素+环磷酰胺序贯多烯紫杉醇，疗程24周)，同步ACT化疗(阿霉素+环磷酰胺+多烯紫杉醇联，疗程 12周)，以及相近的短程化疗 (阿霉素+多烯紫杉醇，不联用环磷酰胺)。

 

该研究共涉及北美地区185家医学中心的5,264例患者，这些患者均因为浸润性乳腺癌而行初次手术治疗，并且都至少有一个腋窝淋巴结转移。这些研究对象被随机分配至序贯ACT化疗组(1,753例患者)、同步ACT化疗组(1,758例患者)和阿霉素+多烯紫杉醇治疗组(1,753例患者)。

 

在73个月的中位随访期之后，有803例患者死亡。

 

序贯ACT化疗组的总生存率为83%，与同步ACT化疗组(总生存率为 79%)和阿霉素+多烯紫杉醇化疗组(总生存率也为79%)相比，其死亡率明显下降。

 

同样，序贯ACT化疗组的无病生存率为74%，显著优于同步ACT化疗组(69%)和阿霉素+多烯紫杉醇治疗组(69%)，Swain博士及其同事们说(New Engl. J. Med. 2010;362:2053-65)。

 

序贯ACT化疗组的3或4级不良事件的发生率(65%)高于同步ACT化疗组(48%)和阿霉素+多烯紫杉醇治疗组(45%)。但3组之间治疗相关的死亡率相当，均低于1%。

 

该试验的一个“有趣”辅助发现是，在2,343例诊断为乳腺癌时处于绝经前期的患者中，化疗后绝经的女性总生存率和无病生存率明显高于化疗后仍未绝经者。

 

该结果证明，化疗可通过抑制卵巢功能给患者带来间接收益。“但也不能排除结局的改善与抑制卵巢功能频率的增加可能有关而非因果关系的可能性。”

 

“另一个可能性为药物代谢的个体化差异可能会导致疗效或卵巢功能抑制率的不同，”研究者们指出。

 

然而，圣路易斯华盛顿大学的Matthew Ellis博士在随刊的编者按中指出，另一项试验(癌症和白血病研究组B9741)支持剂量强度。因此，Swain博士和同事们的一个主要研究结论(疗程越长，疗效会越好)“不应该作为基本原则，而应视为这项研究设计不均衡的产物，”他写道。

 

Ellis博士也将总生存率优势描述为“适度获益”，应该考虑到疗程越长，剂量就会增加，而毒性也会越大。“难以否认以下结论，即该试验标志着对蒽环类抗生素+紫杉烷类药物+环磷酰胺联合治疗方案的体裁研究的终止，”他说，同时引用了靶向治疗研究，并呼吁进行“较新型的试验”，而这类较新型的试验不仅追踪患者的转归，还采集生物学样本。

 

本研究由美国华盛顿医院中心基金会、美国国家癌症研究所、美国国立卫生研究院和美国卫生与公众服务部资助。多烯紫杉醇由赛诺菲-安万特制药集团提供。Swain博士报告得到以下公司的资助：罗纳普朗克药厂、基因泰克公司、赛诺菲-安万特制药集团、百时美-施贵宝公司、苏珊科曼乳癌基金会、Living in Pink公司、美国西夫韦公司、卫材药业(美国)有限公司、葛兰素史克制药公司、辉瑞制药有限公司、美国奥尼克斯制药公司、诺华、罗氏、美国阿博利斯生物科学有限公司、BiPar科学有限公司以及惠氏。

 

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