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ZD1694:一种新型胸苷酸合成酶抑制剂,对晚期结直肠癌患者的治疗具有显著活性。托姆德克斯结直肠癌研究组

ZD1694: A novel thymidylate synthase inhibitor with substantial activity in the treatment of patients with advanced colorectal cancer. Tomudex Colorectal Study Group.

作者信息

Zalcberg J R, Cunningham D, Van Cutsem E, Francois E, Schornagel J, Adenis A, Green M, Iveson A, Azab M, Seymour I

机构信息

Austin and Repatriation Medical Centre, Victoria, Australia.

出版信息

J Clin Oncol. 1996 Mar;14(3):716-21. doi: 10.1200/JCO.1996.14.3.716.

Abstract

PURPOSE

Tomudex (ZD1694; Zeneca Ltd, Macclesfield, United Kingdom) appears to have a favorable toxicity profile (defined in phase I studies) and antitumor activity in a broad range of epithelial tumors. We report here the results of a large phase II study of Tomudex in advanced colorectal cancer (CRC).

PATIENTS AND METHODS

One hundred seventy-seven patients were entered onto the study between October 1992 and September 1993. Patients were required to have advanced CRC without prior chemotherapy (adjuvant chemotherapy was permissible) and at least one measurable lesion. Tomudex (ZD1694) was administered at a dose of 3 mg/m2 intravenously once every 3 weeks in the absence of toxicity or disease progression. Patients were assessed for objective response, progression, and survival.

RESULTS

Of 177 patients entered onto the study, 5% had received prior adjuvant chemotherapy and 83% had liver metastases. Objective responses were seen in 26% of patients (95% confidence interval, 19% to 33%; four complete responses [CRs] and 41 partial responses [PRs]) while median time to progression was 4.2 months and median survival 9.6 months. All sites were audited, and responses were reviewed by an independent panel. Common toxicities included mild reversible transaminitis, nausea and vomiting, and asthenia or flu-like symptoms, and World Health Organization (WHO) grade 3 and 4 leukopenia and diarrhea were seen in 6% and 9.8% of patients, respectively. Stomatitis and alopecia were common.

CONCLUSION

In this large multicenter phase II study of patients with advanced CRC, interesting activity was seen (objective response rate, 26%). In addition, Tomudex has an acceptable toxicity profile and a convenient dosing schedule (single intravenous injection every 3 weeks) and thus appears to offer real potential as a novel agent for the treatment of patients with advanced CRC.

摘要

目的

拓扑替康(ZD1694;英国麦克尔斯菲尔德的阿斯利康有限公司)在I期研究中显示出良好的毒性特征,并且在多种上皮性肿瘤中具有抗肿瘤活性。我们在此报告拓扑替康用于晚期结直肠癌(CRC)的大型II期研究结果。

患者与方法

1992年10月至1993年9月期间,177例患者入组该研究。患者需患有晚期CRC,未接受过先前的化疗(允许辅助化疗)且至少有一个可测量病灶。在无毒性或疾病进展的情况下,拓扑替康(ZD1694)以3mg/m²的剂量静脉注射,每3周一次。评估患者的客观缓解、疾病进展和生存情况。

结果

177例入组研究的患者中,5%接受过先前的辅助化疗,83%有肝转移。26%的患者出现客观缓解(95%置信区间,19%至33%;4例完全缓解[CR]和41例部分缓解[PR]),而中位疾病进展时间为4.2个月,中位生存期为9.6个月。对所有研究点进行了审核,缓解情况由独立小组进行复查。常见毒性包括轻度可逆性转氨酶升高、恶心和呕吐、乏力或流感样症状,分别有6%和9.8%的患者出现世界卫生组织(WHO)3级和4级白细胞减少及腹泻。口腔炎和脱发很常见。

结论

在这项针对晚期CRC患者的大型多中心II期研究中,观察到了有意义的活性(客观缓解率为26%)。此外,拓扑替康具有可接受的毒性特征和方便的给药方案(每3周一次静脉注射),因此似乎作为一种治疗晚期CRC患者的新型药物具有真正的潜力。

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