Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 1650 Orleans Street, CRB1-1M52, Baltimore, MD 21231, USA.
Breast Cancer Res Treat. 2013 May;139(1):135-43. doi: 10.1007/s10549-013-2516-z. Epub 2013 Apr 16.
The pro-drug capecitabine is approved for treatment of anthracycline- and paclitaxel-resistant metastatic breast cancer. However, toxicity and large interpatient pharmacokinetic variability occur despite body surface area (BSA)-dosing. We hypothesized that a fixed-dose schedule would simplify dosing and provide an effective and safe alternative to BSA-based dosing. We conducted an open label, single-arm, two-stage study of oral capecitabine with fixed starting dose (3,000 mg total daily dose in two divided doses × 14 days q21 days) in patients with metastatic breast cancer. We correlated pharmacodynamic endpoints [e.g., efficacy (response) per RECIST and toxicity], adherence and pharmacokinetics/pharmacogenetics. Sample size of 45 patients was required to detect a 25 % response rate from null response rate of 10 % using a Simon two-stage design. Twenty-six patients were enrolled in the first-stage and 21 were evaluable after a median of four cycles of capecitabine. Two thirds of patients received either the same dose or a dose 500 mg lower than what would have been administered with a commonly used 2,000 mg/m(2) BSA-dosing schedule. Eight patients had stable disease but progressed after a median of seven cycles. Despite a clinical benefit rate of 19 %, no RECIST responses were observed following the first stage and the study was closed. Dose-reductions were required for grade 2 hand-foot syndrome (28 %) and vomiting (5 %). Adherence was similar when using both patient-reported and Medication Event Monitoring System methods. High interpatient variability was observed for capecitabine and metabolite pharmacokinetics, but was not attributed to observed pharmacogenetic or BSA differences. Single agent activity of capecitabine was modest in our patients with estrogen receptor-positive or -negative metastatic breast cancer and comparable to recent studies. BSA was not the main source of pharmacokinetic variability. Fixed-dose capecitabine is feasible, and simplifies dosing.
卡培他滨前药被批准用于治疗蒽环类和紫杉醇耐药的转移性乳腺癌。然而，尽管采用了体表面积（BSA）剂量，但仍会出现毒性和较大的个体间药代动力学变异性。我们假设固定剂量方案将简化剂量，并为基于 BSA 的剂量提供一种有效且安全的替代方案。我们进行了一项开放性、单臂、两阶段研究，评估转移性乳腺癌患者口服卡培他滨的固定起始剂量（总剂量 3000mg，每天两次，每次 1500mg，每 21 天给药 14 天）。我们将药效终点[例如，根据 RECIST 评估的疗效（反应）和毒性]、顺应性和药代动力学/药物遗传学进行了相关性分析。使用 Simon 两阶段设计，需要 45 例患者的样本量才能从 10%的零反应率中检测到 25%的反应率。在中位 4 个周期的卡培他滨治疗后，26 例患者入组第 1 阶段，21 例患者可评估。三分之二的患者接受的剂量与常用的 2000mg/m2 BSA 剂量方案相比，要么相同，要么低 500mg。8 例患者疾病稳定，但在中位 7 个周期后进展。尽管临床获益率为 19%，但在第 1 阶段后没有观察到 RECIST 反应，研究结束。28%的患者出现 2 级手足综合征，5%的患者出现呕吐，需要减少剂量。使用患者报告和药物事件监测系统方法时，依从性相似。卡培他滨及其代谢物的药代动力学个体间变异性很大，但与观察到的药物遗传学或 BSA 差异无关。在我们的雌激素受体阳性或阴性转移性乳腺癌患者中，卡培他滨单药治疗活性适中，与最近的研究相似。BSA 不是药代动力学变异性的主要来源。固定剂量卡培他滨是可行的，并且简化了剂量。
