Center for Gastric Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea.
Cancer Chemother Pharmacol. 2013 Nov;72(5):953-64. doi: 10.1007/s00280-013-2272-0. Epub 2013 Aug 28.
We conducted a phase I study of S-1 combined with irinotecan and oxaliplatin (TIROX) to determine the maximum-tolerated dose (MTD) and recommended dose (RD) and to assess its safety, pharmacokinetics, pharmacogenetics, and preliminary efficacy in patients with metastatic colorectal cancer (MCRC) or metastatic gastric cancer (MGC).
Patients received escalating doses of S-1 (30-40 mg/m² b.i.d.) orally on days 1-14, an escalating dose of intravenous irinotecan (120-150 mg/m²) on day 1, and a fixed dose of intravenous oxaliplatin (85 mg/m²) on day 1 every 3 weeks.
Twenty-three patients (10 MCRC, 13 MGC; 13 chemonaive, 10 previously treated for metastatic disease) were treated across six dose levels. Because only one patient experienced a dose-limiting toxicity of grade 3 anorexia at the highest dose level (S-1 40 mg/m² b.i.d., irinotecan 150 mg/m², and oxaliplatin 85 mg/m²) (n = 8), the MTD was not obtained, and this level was established as the RD. With a median of 10 cycles per patient, the most common grade 3 or 4 adverse events included neutropenia (43 %), diarrhea (13 %), and nausea (13 %). In 22 efficacy-evaluable patients, the objective tumor response rate was 59.1 % (75 % for both MCRC and MGC in the first-line setting) and the disease control rate was 100 %. The exploratory pharmacokinetic/pharmacogenetic study showed that CYP2A6 variants (*4, *7, *9) are associated with a lower metabolic ratio of S-1 (exposure ratio of 5-fluorouracil to tegafur).
The new triplet TIROX regimen has shown promising antitumor activity and a favorable toxicity profile in patients with MCRC and MGC.
我们进行了一项 I 期研究，评估 S-1 联合伊立替康和奥沙利铂（TIROX）治疗转移性结直肠癌（mCRC）或转移性胃癌（mGC）患者的最大耐受剂量（MTD）和推荐剂量（RD），以及安全性、药代动力学、药物遗传学和初步疗效。
患者接受 S-1（30-40 mg/m²，每日 2 次）口服治疗，第 1-14 天，伊立替康（120-150 mg/m²）静脉滴注，第 1 天，奥沙利铂（85 mg/m²）静脉滴注，第 1 天，每 3 周一次。
23 例患者（10 例 mCRC，13 例 mGC；13 例初治，10 例既往转移性疾病治疗）接受了 6 个剂量水平的治疗。由于仅 1 例患者在最高剂量水平（S-1 40 mg/m²，每日 2 次，伊立替康 150 mg/m²，奥沙利铂 85 mg/m²）时出现 3 级厌食毒性（n = 8），未确定 MTD，该水平被确定为 RD。中位治疗 10 个周期后，最常见的 3 级或 4 级不良事件包括中性粒细胞减少症（43%）、腹泻（13%）和恶心（13%）。在 22 例可评估疗效的患者中，客观肿瘤缓解率为 59.1%（一线治疗中 mCRC 和 mGC 分别为 75%），疾病控制率为 100%。探索性药代动力学/药物遗传学研究表明，CYP2A6 变异体（*4、*7、*9）与 S-1 代谢比（5-氟尿嘧啶与替加氟的暴露比）降低相关。
新的三联 TIROX 方案在 mCRC 和 mGC 患者中显示出有希望的抗肿瘤活性和良好的毒性特征。
