Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital, Tokyo, Japan.
Oncol Rep. 2013 Feb;29(2):437-44. doi: 10.3892/or.2012.2177. Epub 2012 Dec 10.
We evaluated the predictive relevance of several biomarkers on the survival of patients with stage III colorectal cancer treated with adjuvant chemotherapy of oral fluoropyrimidines. This was a multicenter phase II trial on adult patients with histologically confirmed resected stage III (Dukes' C) colorectal cancer. Patients received oral doxifluridine (800 mg/m2/day) in 3 divided doses, or oral uracil/tegafur (UFT) (400 mg/m2/day) in 2 divided doses for 5 days, every 7 days for 12 months with a 5-year follow-up. Outcome measures were disease-free survival and tissue markers [thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD) protein levels and TP, DPD, thymidylate synthase (TS) and orotate phosphoribosyltransferase (OPRT) mRNA levels in tumor samples and TS tandem-repeat type in blood samples]. There was a significant association between the intratumoral TP/DPD enzyme ratio and disease-free survival when the model included the drug, the parameter and the interactions between them [hazard ratio (HR)=2.76; P=0.00469]. The 5-year disease-free survival rate was statistically significantly higher in patients with high TP/DPD ratios [median ≥2.63: 71.9%; 95% confidence interval (CI) 61.4-80.0] compared to patients with low TP/DPD ratios (<2.63: 57.0%; 95% CI 46.3-66.3) (log-rank P=0.0277) following adjuvant therapy with oral fluoropyrimidines. No significant association was observed between the intratumoral TP/DPD enzyme ratio (cut-off value 2.0) and the disease-free survival rate in the doxifluridine group; primary endpoint (log-rank P=0.6850). The magnitude of the intratumoral TP/DPD enzyme ratio may be a potential indicator for the individualization of postoperative adjuvant chemotherapy with oral fluoropyrimidines for stage III colorectal cancer.
我们评估了几个生物标志物对接受氟嘧啶类辅助化疗的 III 期结直肠癌患者生存的预测相关性。这是一项多中心 II 期临床试验，纳入了经组织学证实的 III 期（Dukes' C）结直肠癌可切除的成年患者。患者接受多西氟尿嘧啶（800mg/m2/天），分 3 次服用，或替加氟/尿嘧啶（UFT）（400mg/m2/天），分 2 次服用，每天 5 天，每 7 天 1 次，持续 12 个月，随访 5 年。主要终点是无病生存率和组织标志物[胸苷磷酸化酶（TP）、二氢嘧啶脱氢酶（DPD）蛋白水平以及肿瘤样本中的 TP、DPD、胸苷酸合成酶（TS）和乳清酸磷酸核糖基转移酶（OPRT）mRNA 水平和血液样本中的 TS 串联重复类型]。当模型包括药物、参数及其相互作用时，肿瘤内 TP/DPD 酶比与无病生存率之间存在显著关联[风险比（HR）=2.76；P=0.00469]。接受氟嘧啶类辅助治疗的患者中，高 TP/DPD 比值[中位数≥2.63：71.9%；95%置信区间（CI）61.4-80.0]与低 TP/DPD 比值（<2.63：57.0%；95%CI 46.3-66.3）的患者相比，5 年无病生存率统计学上显著更高（对数秩检验 P=0.0277）。在多西氟尿嘧啶组中，肿瘤内 TP/DPD 酶比（截断值 2.0）与无病生存率之间无显著相关性；主要终点（对数秩检验 P=0.6850）。肿瘤内 TP/DPD 酶比的大小可能是 III 期结直肠癌患者接受氟嘧啶类辅助化疗个体化的潜在指标。
