Puglisi F, Cardellino G G, Crivellari D, Di Loreto C, Magri M D, Minisini A M, Mansutti M, Andreetta C, Russo S, Lombardi D, Perin T, Damante G, Veronesi A
Department of Clinical Oncology, University Hospital of Udine, Piazzale S.M. Misericordia, 33100 Udine, Italy.
Ann Oncol. 2008 Sep;19(9):1541-6. doi: 10.1093/annonc/mdn165. Epub 2008 Apr 25.
Preclinical data have indicated a synergistic interaction between docetaxel and capecitabine by means of taxane-induced up-regulation of thymidine phosphorylase (TP). On the basis of such premises, we conducted a phase II trial to determine the activity and tolerability of weekly docetaxel plus capecitabine in patients with metastatic breast cancer (MBC). Furthermore, we explored the relationship between TP tumor expression and benefit from this regimen.
Patients received docetaxel 36 mg/m(2) i.v. on days 1, 8, and 15 and capecitabine orally 625 mg/m(2) b.i.d. from days 8 to 21. Cycles were repeated every 4 weeks. In the correlative study, we evaluated the TP expression by immunohistochemistry and the TP messenger RNA expression by real-time RT-PCR in the primary tumor.
Forty-seven women were enrolled. In the intention-to-treat analysis, objective responses were achieved in 24 patients (51%). Fourteen additional patients (30%) had stable disease. The median time to progression (TTP) was 6 months (range 1-44 months). Median survival was 17 months (range 1-48 months). Overall, the treatment was well tolerated. The most common clinical adverse events (all grades) were alopecia (55%), nail changes (53%), fatigue/asthenia (51%), nausea/vomiting (51%), neutropenia (49%), and neuropathy (49%). A significantly higher TTP was observed in patients with TP-positive tumors (log-rank test, P = 0.009). Interestingly, a subgroup analysis confirmed this TTP benefit in patients with TP-positive tumors obtaining a tumor response (log-rank test, P = 0.03), whereas the statistical significance was lost in nonresponders (log-rank test, P = 0.3).
This study indicates that a regimen with low doses of capecitabine plus weekly docetaxel is active against MBC. The correlative analysis provides preliminary evidence that TP expression may be a predictive marker for therapeutic benefit.
临床前数据表明，多西他赛与卡培他滨之间存在协同相互作用，通过紫杉烷诱导胸苷磷酸化酶（TP）上调来实现。基于此前提，我们开展了一项II期试验，以确定每周使用多西他赛加卡培他滨治疗转移性乳腺癌（MBC）患者的活性和耐受性。此外，我们还探究了TP在肿瘤中的表达与该治疗方案疗效之间的关系。
患者在第1、8和15天静脉注射多西他赛36mg/m²，从第8天至21天口服卡培他滨625mg/m²，每日2次。每4周重复一个周期。在相关性研究中，我们通过免疫组织化学评估原发性肿瘤中TP的表达，并通过实时逆转录聚合酶链反应评估TP信使核糖核酸的表达。
47名女性入组。在意向性分析中，24例患者（51%）获得客观缓解。另有14例患者（30%）病情稳定。中位疾病进展时间（TTP）为6个月（范围1 - 44个月）。中位生存期为17个月（范围1 - 48个月）。总体而言，该治疗耐受性良好。最常见的临床不良事件（所有级别）为脱发（55%）、指甲改变（53%）、疲劳/乏力（51%）、恶心/呕吐（51%）、中性粒细胞减少（49%）和神经病变（49%）。TP阳性肿瘤患者的TTP显著更长（对数秩检验，P = 0.009）。有趣的是，亚组分析证实TP阳性且获得肿瘤缓解的患者有TTP获益（对数秩检验，P = 0.03），而在无缓解患者中则失去统计学意义（对数秩检验，P = 0.3）。
本研究表明，低剂量卡培他滨加每周多西他赛的方案对MBC有效。相关性分析提供了初步证据，表明TP表达可能是治疗获益的预测标志物。
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