ORLANDO (EGMN) — Crossing patients with metastatic breast cancer over from induction therapy with gemcitabine/docetaxel to capecitabine alone or from induction therapy with capecitabine/docetaxel to gemcitabine alone made no difference in overall response rate, progression-free survival, or overall survival in a phase III study of 475 women.

Similar proportions of patients responded to induction therapy with gemcitabine/docetaxel and to induction therapy with capecitabine/docetaxel: 35% and 41%, respectively (P = .216).

The response rates after crossover to a single agent also were similar: 15% of patients who went from gemcitabine/docetaxel to capecitabine and 7% of those who went from capecitabine/docetaxel to gemcitabine (P = .184), Dr. Andrew D. Seidman reported at the annual meeting of the American Society of Clinical Oncology.

“The intent-to-treat survival curves for patients in this trial are virtually superimposable, with a median of just under 2 years (23 months),” said Dr. Seidman, an oncologist at Memorial Sloan-Kettering Cancer Center in New York.

Investigators saw no significant difference in the primary end point of time to progression, he noted. The medians were 9.3 months with gemcitabine/docetaxel induction and 8.9 months with capecitabine/docetaxel (P = .385).

That said, Dr. Seidman added, “In an exploratory post hoc analysis of patients who crossed over to the prespecified second-line therapy – capecitabine crossover from gemcitabine/docetaxel – trended toward greater clinical benefit compared with the reverse sequence, suggesting that this sequence may be preferable.”

Despite the additional analysis, the study’s implications were clear, according to the invited discussant, Dr. Daniel F. Hayes. “It didn’t seem to matter how these patients were treated. Their overall survival was identical,” said Dr. Hayes, an oncologist at the University of Michigan Comprehensive Cancer Center in Ann Arbor.

Eli Lilly and Co., which makes gemcitabine, sponsored the study. Dr. Seidman reported that he has been a paid consultant and speaker for Eli Lilly and Sanofi-Aventis. In addition, three coinvestigators are employed by Eli Lilly.

Dr. Hayes reported that he receives research funding from several pharmaceutical companies and that his brother is the vice-president for neuroscience at Eli Lilly.

For the gemcitabine/docetaxel induction period, patients received 1,000 mg/m² intravenous gemcitabine on days 1 and 8 and 75 mg/m² intravenous docetaxel on day 1 of a 21-day cycle. Cycles repeated until disease progression, when patients were crossed over to 1,000 mg/m² oral capecitabine twice-daily on days 1-14 of a 21-day cycle that was repeated until disease progression.

For the capecitabine/docetaxel induction period, patients received 1,000 mg/m² of oral capecitabine twice daily on days 1-14 and 75 mg/m² intravenous docetaxel on day 1 of a 21-day cycle. Cycles repeated until disease progression, when patients were crossed over to 1,000 mg/m² intravenous gemcitabine on days 1 and 8 of a 21-day cycle that was repeated until disease progression.

Dr. Seidman noted that the docetaxel/capecitabine arm employed a 20% lower dose of capecitabine than in other trials, which had high incidences of hand-foot syndrome.

Eligible patients had locally advanced or metastatic breast cancer, but no more than one prior course of chemotherapy for metastatic breast cancer. Patients were excluded if they had prior taxane therapy for metastatic breast cancer, prior gemcitabine or capecitabine therapy, concurrent trastuzumab therapy, or central nervous system metastases.

A total of 475 patients were included in the intent-to-treat population, of which 463 were evaluable for safety. In all, 236 patients started therapy with gemcitabine/docetaxel, but 43 patients in this arm left the trial because of adverse events. A total of 227 patients started therapy with capecitabine/docetaxel, with 67 dropping out because of adverse events.

All told, 158 patients – a third of the intent-to-treat population – crossed over to monotherapy. Most (50 patients on capecitabine and 53 on gemcitabine) discontinued monotherapy because of disease progression.

A total of 207 patients with measurable disease were evaluable for response to gemcitabine/docetaxel induction therapy and 191 patients were evaluable in the capecitabine/docetaxel induction therapy arm. Totals of 72 and 70 patients were evaluable for response to capecitabine or gemcitabine monotherapy, respectively.

For the 77 patients who crossed over to capecitabine from capecitabine/docetaxel, median time to progression was 4.5 months; median time to progression for the 81 patients who crossed over to gemcitabine from capecitabine/docetaxel was 2.3 months (P = .145).

Patients in both arms received a median of six cycles of combination therapy and three cycles of subsequent monotherapy. Dose adjustments were made to docetaxel in about half of patients in each arm. Dose adjustments were made for roughly 90% of patients receiving gemcitabine or capecitabine during the combination treatment and for about half of patients during monotherapy.

“Grade 3/4 neutropenia, leucopenia, and thrombocytopenia were statistically more common with gemcitabine/docetaxel than with capecitabine/docetaxel,” Dr. Seidman said. (See table.)

In terms of nonhematologic adverse events, grade 3/4 fatigue and increases in alanine aminotransferase/aspartate aminotransferase were more common for patients on gemcitabine/docetaxel, while grade 3/4 nausea/vomiting, hand-foot syndrome, and mucositis were more common for patients on capecitabine/docetaxel.

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

奥兰多(EGMN)——在一项包含475例女性的III期研究中，转移性乳腺癌患者采用吉西他滨/多西紫杉醇诱导然后转为卡培他滨单药治疗，或采用卡培他滨/多西紫杉醇诱导然后转为吉西他滨单药治疗，两组的整体反应率、无进展生存率或整体生存率无差异。

吉西他滨/多西紫杉醇诱导治疗与卡培他滨/多西紫杉醇诱导治疗的患者反应比例相似，分别为35%和41%(P=0.216)。

转为单药治疗后的反应率也相似，吉西他滨/多西紫杉醇转为卡培他滨及卡培他滨/多西紫杉醇转为吉西他滨治疗的患者反应率分别为15%和7%(P=0.184)，纽约Sloan-Kettering纪念肿瘤中心的肿瘤学家Andrew D. Seidman医生在美国临床肿瘤学会年会上报告。

“试验中意向治疗的患者生存曲线基本重叠，中位生存期刚好不到2年(23个月)，” Seidman医生说。

他指出，研究者未发现两组患者的主要终点——至疾病进展时间存在差异。吉西他滨/多西紫杉醇诱导及卡培他滨/多西紫杉醇诱导治疗患者的中位至疾病进展时间分别为9.3和8.9个月(P=0.385)。

Seidman医生补充道，“但在一项对转为预先设定的二线治疗的患者的探索性事后分析中发现，由吉西他滨/多西紫杉醇转为卡培他滨治疗较相反次序的治疗具有更多临床获益的趋势，提示这种治疗次序可能更优。”

根据特约评论者安娜堡市密西根综合肿瘤中心的肿瘤学家Daniel F. Hayes医生的观点，尽管与补充分析的结果存在一定分歧，该研究的意义却非常明确。Hayes医生说， “这些患者采用的治疗次序似乎并不重要，因为总的生存率是相同的。”

该研究由吉西他滨的制造商礼来公司发起。Seidman医生报告他一直是作为礼来和赛诺菲－安万特公司的有偿咨询专家和发言人。另外还有三位协同研究者是礼来公司的雇员。

Hayes医生报告他接受了一些医药公司的研究基金，其兄弟是礼来公司神经科学部门的副总裁。

在吉西他滨/多西紫杉醇诱导阶段，每个治疗周期为21天，患者于周期第1天和第8天接受静脉内吉西他滨1,000 mg/m²，并于周期第1天接受静脉内多西紫杉醇75 mg/m²。重复周期直至疾病进展，而后患者转为21天的周期，第1~14天每日2次口服卡培他滨1,000 mg/m²治疗，重复治疗周期直至疾病进展。

在卡培他滨/多西紫杉醇诱导阶段，每个治疗周期为21天，患者于周期第1~14天接受每日2次口服卡培他滨1,000 mg/m²，并于周期第1天接受静脉内多西紫杉醇75 mg/m²。重复周期直至疾病进展，而后患者转为21天的周期，第1天和第8天接受静脉内吉西他滨1,000 mg/m²治疗，重复治疗周期直至疾病进展。

Seidman医生指出多西紫杉醇/卡培他滨组中卡培他滨采用较其他试验中低20%的剂量，因较高的剂量会增高手足综合征的发病率。

入选标准为局部进展或转移性乳腺癌患者，转移性乳腺癌患者之前接受化疗的疗程不超过一次。排除标准为患者之前曾接受转移性乳腺癌的紫杉醇治疗、吉西他滨或卡培他滨治疗，同时接受单抗类药物治疗，或发生中心静脉系统的转移。

意向治疗人群共包括475例患者，其中463例患者可进行安全性评估。共有236例患者最初接受吉西他滨/多西紫杉醇治疗，其中43例患者因不良事件中途退出试验。共227例患者最初接受卡培他滨/多西紫杉醇治疗，其中67例因不良事件退出。

总共158例患者(意向治疗人群的1/3)转为单药治疗。其中大多数患者(50例接受卡培他滨治疗者及53例接受吉西他滨治疗者)因疾病进展停用单药治疗。

在总共207例病变可测量的患者中可评估对吉西他滨/多西紫杉醇诱导治疗的反应，卡培他滨/多西紫杉醇诱导治疗组中可评估治疗反应的患者共191例。可评估对卡培他滨或吉西他滨单药治疗反应的患者分别有72例和70例。

自吉西他滨/多西紫杉醇转为卡培他滨治疗的77例患者的中位至疾病进展时间为4.5个月；自卡培他滨/多西紫杉醇转为吉西他滨治疗的81例患者的中位至疾病进展时间为2.3个月(P=0.145)。

两组患者均接受了中位数为6个周期的联合治疗和随后中位数为3个周期的单药治疗。对每组中约一半的患者进行了多西紫杉醇的剂量调整。吉西他滨或卡培他滨治疗的患者在联合治疗阶段大概有90%的患者进行了剂量调整，在单药治疗阶段则约有一半患者进行剂量调整。

“吉西他滨/多西紫杉醇治疗者中3/4级中性粒细胞减少、白细胞减少和血小板减少显著多于卡培他滨/多西紫杉醇治疗者，”Seidman医生说。

关于非血液学不良事件，吉西他滨/多西紫杉醇治疗中3/4级疲倦和丙氨酸氨基转移酶/天冬氨酸氨基转移酶增高更多见，卡培他滨/多西紫杉醇治疗中3/4级恶心/呕吐、手足综合征和黏膜炎更多见。