Yoshida Kazuhiro, Wada Yoshiyuki, Tanabe Kazuaki, Ukon Kei, Hihara Jyun
Dept. of Surgical Oncology Research Institute for Radiation Biology and Medicine, Hiroshima University, Japan.
Gan To Kagaku Ryoho. 2006 Jun;33 Suppl 1:83-6.
In the present article, we have summarized the phase I/II clinical trials on combination therapy of S-1 and docetaxel. With result of the phase I study, patients were treated with intravenous infusion of 40 mg/m2 docetaxel on day 1 and oral S-1 80 mg/m2/day on days 1 to 14 every 3 weeks. Forty eight patients received a total of 272 treatment cycles. No complete responses (CRs) and 27 partial responses (PRs) were observed for an overall response rate (CR+PR) of 56.2% (95% CI, 38-66%). Eighteen patients (37.5%) had stable disease (SD), and 3 patients (6.2%) had progressive disease (PD) as best response. The tumor control rate (CR+PR+SD) was 93.8% (95% CI, 83-98%). The median overall survival was 14.3 months (95% CI: 10.7-20.3 months) and the median time to tumor progression was 7.3 months (95% CI: 4.2-10.7 months). The most common grade 3-4 hematologic toxicities were neutropenia 58.3%, leukopenia 41.7%, febrile neutropenia 8.3%, and anemia 8.3%. The most common grade 3 nonhematologic toxicities were anorexia 14.6%, stomatitis 8.3%, nausea 6.3%, diarrhea 4.2%, constipation 4.2%, and vomiting 2.1%. No grade 4 nonhematologic toxicities were reported, and all treatment-related toxicities were resolved. The mechanisms underlying these synergistic effects of S-1 and docetaxel were examined by expression and activity analyses of 5-FU metabolic enzymes. The expressions of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) were decreased and that of orotate phosphorybosyl transferase (OPRT) was increased in mRNA, protein level and activity assay after the treatment with docetaxel and 5-FU in the TMK-1 gastric cancer cell. These findings strongly indicate that the combination chemotherapy of docetaxel and S-1 is effective against gastric carcinomas and therefore is a good candidate as a standard chemotherapeutic strategy in treating these tumors.
在本文中，我们总结了S-1与多西他赛联合治疗的I/II期临床试验。根据I期研究结果，患者在第1天接受40mg/m²多西他赛静脉输注，在第1至14天口服S-1 80mg/m²/天，每3周重复一次。48例患者共接受了272个治疗周期。未观察到完全缓解（CR），观察到27例部分缓解（PR），总缓解率（CR+PR）为56.2%（95%CI，38-66%）。18例患者（37.5%）病情稳定（SD），3例患者（6.2%）病情进展（PD）为最佳反应。肿瘤控制率（CR+PR+SD）为93.8%（95%CI，83-98%）。中位总生存期为14.3个月（95%CI：10.7-20.3个月），中位肿瘤进展时间为7.3个月（95%CI：4.2-10.7个月）。最常见的3-4级血液学毒性为中性粒细胞减少58.3%、白细胞减少41.7%、发热性中性粒细胞减少8.3%和贫血8.3%。最常见的3级非血液学毒性为厌食14.6%、口腔炎8.3%、恶心6.3%、腹泻4.2%、便秘4.2%和呕吐2.1%。未报告4级非血液学毒性，所有与治疗相关的毒性均得到缓解。通过对5-氟尿嘧啶代谢酶的表达和活性分析，研究了S-1与多西他赛这些协同作用的潜在机制。在TMK-1胃癌细胞中，用多西他赛和5-氟尿嘧啶治疗后，胸苷酸合成酶（TS）和二氢嘧啶脱氢酶（DPD）的表达在mRNA、蛋白质水平和活性测定中均降低，而乳清酸磷酸核糖转移酶（OPRT）的表达增加。这些发现有力地表明，多西他赛与S-1联合化疗对胃癌有效，因此是治疗这些肿瘤的标准化疗策略的良好候选方案。
