University of Colorado Cancer Center, 12801 E 17th Avenue, RC-1 South, Rm 8123, MS 8117, Aurora, CO 80045, USA.
Invest New Drugs. 2011 Oct;29(5):1057-65. doi: 10.1007/s10637-010-9413-7. Epub 2010 Mar 23.
The primary aim of this study was to characterize the 6-month overall survival and toxicity associated with second-line capecitabine treatment of advanced pancreatic cancer patients harboring the TYMS *2/*2 allele. The secondary aim was to analyze the response rate and pharmacokinetics of capecitabine-based therapy in this patient population. Lastly, TYMS, ATM and RecQ1 single nucleotide polymorphism were analyzed relative to overall survival in patients screened for study participation.
Eighty patients with stage IV pancreatic cancer were screened for the *2/*2 TYMS allele. Patients with the *2/*2 TYMS polymorphism were treated with capecitabine, 1,000 mg/m2 twice daily for 14 consecutive days of a 21 day cycle. Screened patients not possessing TYMS *2/*2 were monitored for survival. Pharmacokinetic analysis was done during Cycle 1 of the therapy.
Sixteen of the 80 screened patients tested positive for *2/*2 TYMS variant. Four out of the 16 eligible patients were treated on study. The study was terminated early due to poor accrual and increased toxicity. Three patients experienced grade 3 non-hematologic toxicities of palmer-plantar erythrodysesthesia, diarrhea, nausea and vomiting. Grade 2 toxicities were similar and occurred in all patients. Only one patient was evaluable for response after completion of three cycles of therapy. The presence of the *2/*2 TYMS genotype in all of the screened patients trended toward a decreased overall survival.
To our knowledge, this study represents the first genotype-directed clinical trial for patients with pancreatic adenocarcinoma. Although the study was closed early, it appears capecitabine therapy in pancreatic cancer patients harboring the TYMS *2/*2 variant may be associated with increased non-hematologic toxicity. This study also demonstrates the challenges performing a genotype-directed study in the second-line setting for patients with advanced pancreatic cancer.
本研究的主要目的是描述携带 TYMS*2/*2 等位基因的晚期胰腺癌患者二线卡培他滨治疗的 6 个月总生存率和毒性。次要目的是分析该患者人群中基于卡培他滨的治疗的反应率和药代动力学。最后，分析 TYMS、ATM 和 RecQ1 单核苷酸多态性与接受研究筛选的患者的总生存率的关系。
对 80 例 IV 期胰腺癌患者进行 TYMS*2/2 等位基因筛查。携带 TYMS 多态性的患者接受卡培他滨治疗，每天两次，每次 1000mg/m2，连续 14 天，每 21 天为一个周期。未携带 TYMS2/*2 的筛选患者进行生存监测。在治疗的第 1 周期进行药代动力学分析。
80 名筛查患者中有 16 名检测出 TYMS*2/2 变体阳性。16 名合格患者中有 4 名接受了治疗。由于入组人数少和毒性增加，该研究提前终止。3 名患者出现 3 级非血液学毒性（手掌-足底红斑感觉迟钝、腹泻、恶心和呕吐）。2 级毒性相似，所有患者均出现。完成 3 个周期治疗后，只有 1 名患者可评估反应。所有筛选患者携带2/*2 TYMS 基因型与总生存率降低有关。
据我们所知，这是第一项针对胰腺腺癌患者的基于基因型的临床试验。尽管该研究提前结束，但携带 TYMS*2/*2 变体的胰腺癌患者接受卡培他滨治疗可能与非血液学毒性增加有关。本研究还表明，在晚期胰腺癌二线治疗中开展基于基因型的研究具有挑战性。
