Standard Versus Continuous Administration of Capecitabine in Metastatic Breast Cancer (GEICAM/2009‐05): A Randomized, Noninferiority Phase II Trial With a Pharmacogenetic Analysis

• Published in: The oncologist (Dayton, Ohio) Vol. 20; no. 2; pp. 111 - 112
• Main Authors: Martín, Miguel, Martínez, Noelia, Ramos, Manuel, Calvo, Lourdes, Lluch, Ana, Zamora, Pilar, Muñoz, Montserrat, Carrasco, Eva, Caballero, Rosalía, García‐Sáenz, José Ángel, Guerra, Eva, Caronia, Daniela, Casado, Antonio, Ruíz‐Borrego, Manuel, Hernando, Blanca, Chacón, José Ignacio, De la Torre‐Montero, Julio César, Jimeno, María Ángeles, Heras, Lucía, Alonso, Rosario, De la Haba, Juan, Pita, Guillermo, Constenla, Manuel, González‐Neira, Anna
• Format: Journal Article
• Language: English
• Published: Durham, NC, USA AlphaMed Press 01.02.2015
• Subjects: Adult; Aged; Aged, 80 and over; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Capecitabine - administration & dosage; Capecitabine - adverse effects; Clinical Trial Results; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil - administration & dosage; Hand-Foot Syndrome - etiology; Hand-Foot Syndrome - pathology; Humans; Middle Aged; Pharmacogenetics; Treatment Outcome
• ISSN: 1083-7159; 1549-490X; 1549-490X
• DOI: 10.1634/theoncologist.2014-0379

Background. The approved capecitabine regimen as monotherapy in metastatic breast cancer (MBC) is 1,250 mg/m2 twice daily for 2 weeks on and 1 week off (Cint). Dose modifications are often required because of severe hand‐foot syndrome (HFS). We tested a continuous regimen with a lower daily dose but a similar cumulative dose in an attempt to reduce the severity of adverse events (AEs) while maintaining efficacy. Methods. We randomized 195 patients with HER‐2/neu‐negative MBC to capecitabine 800 mg/m2 twice daily throughout the 21‐day cycle (Ccont) or to Cint to assess noninferiority in the percentage of patients free of progression at 1 year. Secondary endpoints included efficacy and safety. Associations between polymorphisms in capecitabine metabolism‐related genes and drug response were assessed. Results. The percentage of patients free of progression at 1 year was 27.3% with Cint versus 25.3% with Ccont (difference of −2.0%; 95% confidence interval: −15.5% to 11.5%, exceeding the 15% deemed noninferior). Differences regarding other efficacy variables were also not found. Grade 3–4 HFS was the most frequent AE (41.1% in Cint vs. 42.3% in Ccont). Grade 3–4 neutropenia, thrombocytopenia, diarrhea, and stomatitis were more frequent with Cint. A 5′ untranslated region polymorphism in the carboxylesterase 2 gene was associated with HFS. One polymorphism in cytidine deaminase and two in thymidine phosphorylase were associated with survival. Conclusion. Our study was unable to show noninferiority with the continuous capecitabine regimen (Ccont) compared with the approved intermittent regimen (Cint). Further investigation is required to improve HFS. Polymorphisms in several genes might contribute to interindividual differences in response to capecitabine. 摘要 研究背景. 卡培他滨获批的用于转移性乳腺癌（MBC）的单药治疗方案已被证明有效，其单药治疗方案为 1250 mg/m2，每日 2 次，使用 2 周后休息一周（Cint方案）。由于可能发生严重的手‐足综合征（HFS），因而常常需要调整剂量。研究者设计了一个新的连续给药方案，日剂量较低而累积剂量相当，试图在维持疗效的同时减轻不良反应事件（AE）。 研究方法. 将 195 例 HER‐2/neu 阴性的 MBC 患者随机分为 Ccont 组（卡培他滨 800 mg/m2，每日 2 次，连用 21 天）或 Cint 组。评价两组患者在 1 年无进展率方面是否具有非劣效性。次要终点包括有效性和安全性。并评估卡培他滨代谢相关的基因多态性与药物反应之间的相关性。 研究结果. Cint 组与 Ccont 组的 1 年无进展率分别为 27.3% 和 25.3%[率差为‐2.0%，95% 可信区间（CI）：‐15.5% ∼ 11.5%，超出 15% 的预设非劣效范围]。其他有效性指标也未发现显著差异。最常见的 AE 是 3 ∼ 4 级 HFS（Cint组 41.1% vs. Ccont 组 42.3%）。3∼4 级中性细胞减少、血小板减少、腹泻以及口腔炎在 Cint 组较多见。羧酸酯酶 2 基因 5’ 非翻译区的多态性与 HFS 相关。 1 个胞苷脱氨酶多态性和 2 个胸苷磷酸化酶多态性与生存相关。 研究结论. 卡培他滨连续方案（Ccont）与标准间歇给药方案（Cint）相比的非劣效性在该研究中未能得到证实。需要开展进一步研究以改善 HFS。某些基因的多态性可能是导致卡培他滨药物反应个体差异的原因。The Oncologist 2015;20:111–112