From the Dana-Farber Cancer Institute, Boston (R.J.M, J.M.C.); University Hospitals, Leuven and KU Leuven, Leuven (E.V.C., H.P.), and Universitaire Ziekenhuizen Antwerp, Edegem (M.P.) - all in Belgium; University of Pisa, Pisa (A.F.), IRCCS Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca Sul Cancro, Genoa (A.S.), and the Fondazione Poliambulanza Istituto Ospedaliero, Brescia (A.Z.) - all in Italy; National Cancer Center Hospital East, Chiba (T.Y., A.O.), Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo (N.M.), Shizuoka Cancer Center, Shizuoka (K.Y.), National Cancer Center Hospital, Tokyo (Y.S.), Hokkaido University Hospital, Hokkaido (Y.K.), and Taiho Pharmaceutical, Tokyo (M.I.) - all in Japan; Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla, Seville (R.G.-C.), and Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona (J.T.) - all in Spain; Centre Eugène Marquis, Rennes, France (E.B.); Royal Melbourne Hospital, Melbourne, VIC, Australia (B.T.); University of Southern California Norris Comprehensive Cancer Center, Los Angeles (H.-J.L.); Yale Cancer Center, New Haven, CT (H.H.); Taiho Oncology, Princeton, NJ (F.B., H.M.); and Stathmi, New Hope, PA (L.M.).
N Engl J Med. 2015 May 14;372(20):1909-19. doi: 10.1056/NEJMoa1414325.
Early clinical trials conducted primarily in Japan have shown that TAS-102, an oral agent that combines trifluridine and tipiracil hydrochloride, was effective in the treatment of refractory colorectal cancer. We conducted a phase 3 trial to further assess the efficacy and safety of TAS-102 in a global population of such patients.
In this double-blind study, we randomly assigned 800 patients, in a 2:1 ratio, to receive TAS-102 or placebo. The primary end point was overall survival.
The median overall survival improved from 5.3 months with placebo to 7.1 months with TAS-102, and the hazard ratio for death in the TAS-102 group versus the placebo group was 0.68 (95% confidence interval [CI], 0.58 to 0.81; P<0.001). The most frequently observed clinically significant adverse events associated with TAS-102 were neutropenia, which occurred in 38% of those treated, and leukopenia, which occurred in 21%; 4% of the patients who received TAS-102 had febrile neutropenia, and one death related to TAS-102 was reported. The median time to worsening performance status (a change in Eastern Cooperative Oncology Group performance status [on a scale of 0 to 5, with 0 indicating no symptoms and higher numbers indicating increasing degrees of disability] from 0 or 1 to 2 or more) was 5.7 months with TAS-102 versus 4.0 months with placebo (hazard ratio, 0.66; 95% CI, 0.56 to 0.78; P<0.001).
In patients with refractory colorectal cancer, TAS-102, as compared with placebo, was associated with a significant improvement in overall survival. (Funded by Taiho Oncology-Taiho Pharmaceutical; RECOURSE ClinicalTrials.gov number, NCT01607957.).
早期临床试验主要在日本进行，结果表明，口服替氟尿苷和盐酸拓扑替康复方制剂 TAS-102 对难治性结直肠癌有效。我们进行了一项 3 期临床试验，进一步评估了 TAS-102 在全球难治性结直肠癌患者中的疗效和安全性。
在这项双盲研究中，我们按 2:1 的比例将 800 例患者随机分配接受 TAS-102 或安慰剂治疗。主要终点为总生存期。
与安慰剂组相比，TAS-102 组的中位总生存期从 5.3 个月延长至 7.1 个月，TAS-102 组与安慰剂组的死亡风险比为 0.68（95%置信区间[CI]，0.58 至 0.81；P<0.001）。与 TAS-102 相关的最常见的临床显著不良事件是中性粒细胞减少症，发生率为 38%，白细胞减少症发生率为 21%；4%的 TAS-102 治疗患者发生发热性中性粒细胞减少症，有 1 例与 TAS-102 相关的死亡报告。TAS-102 组恶化的表现状态（Eastern Cooperative Oncology Group 表现状态的变化[范围为 0 至 5，0 表示无症状，数字越高表示残疾程度越高]从 0 或 1 变为 2 或更高）的中位时间为 5.7 个月，安慰剂组为 4.0 个月（风险比，0.66；95%CI，0.56 至 0.78；P<0.001）。
与安慰剂相比，在难治性结直肠癌患者中，TAS-102 可显著改善总生存期。（由 Taiho Oncology-Taiho 制药公司资助；RECOURSE ClinicalTrials.gov 编号，NCT01607957。）
