CHICAGO (EGMN) – Simple oral therapy with capecitabine and cyclophosphamide was a popular regimen among women with metastatic breast cancer, but its 36% response rate fell short of the prespecified target of 42% in a single-arm, phase II trial conducted by the Southwest Oncology Group.

Median progression-free survival was 5.9 months among 96 evaluable patients of the 112-woman cohort. Response rates were similar regardless of how many lines of therapy the patient had received, but the progression-free survival midpoint dropped from 7.1 months for patients with no prior chemotherapy to 4.1 months for those with two prior chemotherapies, reflecting the natural course of the disease.

Only 15% of women aged 65 years and older responded, and their median progression-free survival was poorer, at only 2.9 months.

The disappointing results left the Southwest Oncology Group questioning whether they set the bar too high, said Dr. Anne F. Schott, a medical oncologist at the University of Michigan in Ann Arbor, who presented the results at the annual meeting of the American Society of Clinical Oncology. The response rate was only 25% in historical data leading to the approval of capecitabine.

In the phase III RIBBON 1 trial, reported at ASCO in 2009, the response rate of 35% for women with HER2-positive metastatic breast cancer that was treated with capecitabine plus bevacizumab would also have fallen below the 42% target, she said. Median progression-free survival was 8.6 months.

In the SOLTI 0301 trial, as reported in 2009 at the San Antonio Breast Cancer Symposium, the response rate among women who were given capecitabine and sorafenib for previously anthracycline-treated metastatic breast cancer was 38%, and median progression-free survival was 6.4 months.

“Response rate and progression-free survival of cyclophosphamide and capecitabine appear roughly comparable to combinations of capecitabine with bevacizumab and sorafenib, though such comparisons must be viewed with caution,” Dr. Schott said.

Although the bar was set high, she said it was appropriate, and thus allows the investigators to call this a negative trial and move on. “However, if either of these other capecitabine combinations becomes standard therapy, comparative effectiveness studies of these vs. our regimen would be warranted, and should include end points of toxicity, cost, and patient preferences for IV vs. oral treatment,” Dr. Schott said.

Session co-chair Prof. Hervé R. Bonnefoi of the Bergonié Cancer Institute and University of Bordeaux (France) asked whether there is room for a phase III study, given that the regimen is effective, convenient, and well tolerated. Dr. Schott said it’s a matter of where resources should be invested, and that the combination was unlikely to produce a survival benefit.

Median overall survival was 19.6 months overall, 17.8 months in older women, 24.7 months in women with no prior metastatic chemotherapy, and 8.6 months for those with two prior regimens.

Invited discussant Dr. Hope Rugo said the all-oral regimen had a reasonable response rate and median progression-free survival, but she noted that significant bone marrow toxicity occurred in about one-fifth of patients. Further validation with a comparative study would be required to fully understand the benefit of adding cyclophosphamide to capecitabine, she said.

Dr. Rugo, a breast cancer specialist at the University of California, San Francisco, told the audience that price will have to be taken into consideration with future therapies in the United States. Assuming a constant price for capecitabine, she calculated the U.S. cost of bevacizumab for a 70-kg patient at $7,650 per dose every 21 days, compared with $54 for cyclophosphamide (which is 140 times less expensive).

Patients in the S0430 trial received a median of six cycles of cyclophosphamide 100 mg daily on days 1-14 and then repeated after 1 week off, and capecitabine 1,500 mg twice daily on days 8-21 and then repeated after 1 week off.

At baseline, 81% of patients were postmenopausal, 58% were estrogen receptor positive, 54% had no prior metastatic chemotherapy, and 14% had received three prior chemotherapies. Their median age was 59 years (range, 34-88 years).

The Cancer Therapy Evaluation Program of the U.S. National Cancer Institute supported the study. The authors disclosed relationships with Genentech Inc. and Roche. Prof. Bonnefoi has acted as an advisor/consultant for GlaxoSmithKline, Pfizer Inc., and Sanofi-Aventis, and received honoraria from GSK, Novartis, and Sanofi-Aventis. Dr. Rugo has received research funding from Genentech, GSK, Pfizer, and Roche.

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

 芝加哥(EGMN)——卡培他滨与环磷酰胺的单纯二联口服治疗是转移性乳腺癌的常规治疗方案，但由西南肿瘤学组开展的一项单组、II期试验结果显示，该方案的有效率为36%，未达到预先设定的42%的目标。

 

该研究队列由112名女性构成，96例可评估的患者中位无进展生存期为5.9个月。无论患者接受了多少线治疗药，其有效率均相近，但在无进展生存的终点方面，无化疗史患者最长，为7.1个月，而既往接受两种化疗者最短，为4.1个月，这反映了该病的自然病程。

 

年龄为65岁或更年长的患者中仅有15%治疗有效，其中位无进展生存状况较差，仅为2.9个月。

 

密歇根大学安娜堡分校肿瘤内科专家Anne F. Schott博士在美国临床肿瘤学会年会上公布了上述研究结果并指出，这些结果令人大失所望，使西南肿瘤学组质疑他们是否将基准设定得过高。批准卡培他滨的历史数据中有效率仅为25%。

 

在2009年ASCO会上报告的III期RIBBON 1试验中，HER2阳性的转移性乳腺癌女性接受卡培他滨与贝伐单抗二联治疗的有效率为35%，亦低于42%的目标，中位无进展生存期为8.6个月，她说。

 

在SOLTI 0301试验中，正如2009年圣安东尼乳腺癌研讨会上报告的结果，先前接受过蒽环类药物治疗的转移性乳腺癌患者在接受卡培他滨与索拉非尼联合治疗后有效率为38%，中位无进展生存期为6.4个月。

 

“环磷酰胺与卡培他滨联合治疗的有效率和无进展生存状况大致与卡培他滨联合贝伐单抗相当，尽管这类比较必须予以审慎看待，”Schott博士说。

 

她指出，尽管基准设定得较高，但仍很合理，因此允许研究者称此试验为阴性试验并继续进行。“然而，若其他卡培他滨联合治疗中的任何一种联合方案成为标准治疗，则应对这些试验与我们的治疗方案进行有效性比较研究，而且应该包括毒性终点、费用及患者对静脉用药与口服用药的偏爱比较，”Schott博士说。

 

会议副主席、法国Bergonié癌症研究所及波尔多大学的 Hervé R. Bonnefoi教授询问，若治疗方案有效、方便且耐受性良好，是否有进行III期研究的空间。Schott博士说这是一个投资方向的问题，联合治疗产生生存收益的可能性不大。

 

中位总生存期总共为19.6个月，较年长者为17.8个月，而无转移性化疗治疗史的女性为24.7个月，之前接受过2种治疗方案的患者为8.6个月。

 

特邀讨论者Hope Rugo博士称，全口服药治疗方案均有一个合理的有效率和中位无进展生存期，但她指出，有大约1/4的患者会发生严重的骨髓不良反应。为充分了解卡培他滨辅以环磷酰胺治疗的收益，还需要通过一项比较研究做进一步的验证。

 

旧金山加州大学的乳腺癌专家Rugo博士告诉听众，美国在今后的治疗中将不得不考虑价格因素。假如卡培他滨的价格平稳，她计算得出美国1例体重为70 kg的患者每21天每剂贝伐单抗治疗的费用为7,650美元，而环磷酰胺为54 美元(价格低140倍)。

 

S0430试验中的患者接受了环磷酰胺治疗，中位周期数为6，方案为第1~14天，100 mg/天，停药1周后重复进行治疗，而卡培他滨为在第8~21天，日剂量为1500 mg，分2次口服，停药1周后重复进行治疗。

 

基线时，81%的患者为绝经后妇女，58%为雌激素受体阳性，54%无既往转移性化疗治疗史，14%既往曾接受过3种化疗。其中位年龄为59岁(范围，34~88岁)。

 

本研究得到了美国国家癌症研究所的癌症治疗评估计划的支持。作者们披露与基因泰克公司和罗氏有关联。Bonnefoi教授担任葛兰素史克、辉瑞及赛诺菲-安万特公司的顾问，并收到葛兰素史克、诺华和赛诺菲-安万特公司的酬金。Rugo博士收到了基因泰克、葛兰素史克、辉瑞和罗氏公司的研究基金。

 

爱思唯尔 版权所有