Lessons learned: The upregulation of dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) are important mechanisms of resistance to 5-fluorouracil (5-FU) in metastatic colorectal cancer (mCRC) after long exposure to 5-FU.S-1 (containing a DPD inhibitor) combined with raltitrexed (a TS inhibitor) showed a moderate effect, which needs further study as a third- or later-line therapy in mCRC.
Background: 5-fluorouracil (5-FU) is a fundamental drug in the treatment of metastatic colorectal cancer (mCRC). Patients with mCRC are often exposed to 5-FU and/or its analogues for a long time because of its central role in treatment regimens. The upregulation of dihydropyrimidine dehydrogenase (DPD) and/or thymidylate synthase (TS) are important mechanisms of resistance of 5-FU. To evaluate the efficacy and safety of S-1 (containing a DPD inhibitor) and raltitrexed (a TS inhibitor) for refractory mCRC, a one-center, single-arm, prospective phase II trial was conducted.
Methods: Patients who had mCRC that had progressed after treatment with fluoropyrimidine, irinotecan, and oxaliplatin and who had at least one measurable lesion were eligible for this trial. Patients received oral S-1 (80-120 mg for 14 days every 3 weeks) plus an intravenous infusion of raltitrexed (3 mg/m2 on day 1 every 3 weeks). The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity.
Results: In total, 46 patients were enrolled. Three patients did not complete the first assessment because of adverse events and unwillingness, leaving tumor response evaluation available in 43 patients. Of 43 evaluable patients, the ORR was 13.9% and disease control rate was 58.1%. In the intention-to-treat population (n = 46), the ORR was 13.0% and disease control rate was 54.3%. Median PFS and median OS were 107 days (95% confidence interval [CI], 96.3-117.7) and 373 days (95% CI, 226.2-519.8), respectively. Most of the adverse effects were mild to moderate.
Conclusion: S-1 combined with raltitrexed for refractory mCRC showed moderate effect, and it is worthy of further study as third- or later-line therapy in mCRC.
经验获取
• 在长期使用 5‐氟尿嘧啶 (5‐FU) 之后，二氢嘧啶脱氢酶 (DPD) 和胸苷酸合成酶 (TS) 的上调是转移性结直肠癌 (mCRC) 中重要的 5‐FU 耐药机制。
• S‐1(含有一种 DPD 抑制剂)联合雷替曲塞(一种 TS 抑制剂)已显示出适度的效应，该治疗方案需要作为 mCRC 的三线或后线治疗进行进一步研究。
摘要
背景。 5‐氟尿嘧啶 (5‐FU) 是一种用于治疗转移性结直肠癌 (mCRC) 的基础药物。mCRC 患者通常会长期使用 5‐FU 和/或其类似物，因为它在治疗方案中具有核心作用。二氢嘧啶脱氢酶 (DPD) 和/或胸苷酸合成酶 (TS) 的上调是重要的 5‐FU 耐药机制。为了评估 S‐1(含有一种 DPD 抑制剂)和雷替曲塞(一种 TS 抑制剂)治疗难治型 mCRC 的疗效和安全性，我们进行了一项单中心、单组、前瞻性 II 期试验。
方法。经氟尿嘧啶、伊立替康和奥沙利铂治疗后出现疾病进展且具有至少一个可测量病灶的 mCRC 患者可入组本试验。患者接受口服 S‐1(用药剂量为 80–120 mg，每 3 周连续 14 天用药)和静脉输注雷替曲塞(用药剂量为 3 mg/m2，每 3 周的第 1 天用药)治疗。主要终点为客观缓解率 (ORR)。次要终点包括无进展生存期 (PFS)、总生存期 (OS) 和毒性。
结果。一共有 46 名患者入组。3 名患者由于出现不良反应且不愿意而未完成第一次评估，其余的 43 名患者可进行肿瘤缓解评估。在 43 名可评估的患者中，ORR 为 13.9%，疾病控制率为 58.1%。在意向性治疗人群 (n = 46) 中，ORR 为 13.0%，疾病控制率为 54.3%。中位 PFS 和中位 OS 分别为 107 天 [95% 置信区间 (CI)，96.3–117.7]和 373 天(95% CI，226.2–519.8)。大多数不良反应为轻度至中度。
结论。S‐1 和雷替曲塞联合治疗在难治型 mCRC 中显示出适度的效应，此项治疗值得作为 mCRC 的三线或后线治疗进行进一步研究。
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