Daponte Antonio, Ascierto Paolo Antonio, Gravina Adriano, Melucci Mariateresa, Scala Stefania, Ottaiano Alessandro, Simeone Ester, Palmieris Giuseppe, Comella Giuseppe
National Tumor Institute Via M Semmola, 80131 Naples, Italy.
Anticancer Res. 2005 Mar-Apr;25(2B):1441-7.
Temozolomide (TMZ) is an oral alkylating agent; it produces DNA methyl adducts, which are removed by the DNA repair enzyme AGAT. In vitro studies suggest that CDDP may enhance the antitumor activity of TMZ due to the ability of cisplatin (CDDP) to down-regulate AGAT activity. In a previous phase I study, the combination of TMZ and CDDP was tested, and the recommended dose for each drug was defined. On the basis of these results, we designed a phase II study to evaluate the activity and safety profile of the TMZ-CDDP association in patients with advanced melanoma.
From March 2001 to March 2002, 37 patients with metastatic melanoma, not amenable to surgery, were enrolled in this study. All eligible patients were treated with the combination of CDDP 75 mg/m2 i.v. d 1, TMZ 200 mg/m2 p.o. days 1-5 recycled every 4 weeks. Interferon alpha2b (IFN alpha2b) was administered at the end of chemotherapy to responsive patients at the dose of 5 M.I. U s.c. 3 times a week for 1 year.
A total of 174 courses were administered, with a median number of 4 courses/patient (range 1-10). After chemotherapy, 9 CRs and 9 PRs were observed for an overall response rate of 48.6% (95% C.I., 31.9%-65.6%). One of 5 patients with initial brain metastases showed a complete response to the therapy. Five out of 9 CR patients were still with no evidence of recurrence, ranging from 28+ to 82+ weeks. The median survival time was 48 weeks. The schedule was well tolerated, with the most frequent adverse events reported being nausea and vomiting (59%), alopecia (14%) and fatigue (11%), all well controlled by supportive therapy. Haemotological toxicities were mild to moderate. Side-effects attributable to IFN alpha2b were also mild and manageable.
The combination of TMZ and CDDP seems to be active in untreated patients with advanced melanoma. Absence of recurrence in the majority (5/9; 56%) of CR patients seems to indicate that IFN may act on the duration of the response to chemotherapy. The schedule was well tolerated, with nausea and vomiting as the most frequent adverse events.
替莫唑胺（TMZ）是一种口服烷化剂；它会产生DNA甲基加合物，这些加合物可被DNA修复酶AGAT清除。体外研究表明，顺铂（CDDP）可能会增强TMZ的抗肿瘤活性，因为顺铂有下调AGAT活性的能力。在之前的一项I期研究中，对TMZ与CDDP的联合用药进行了测试，并确定了每种药物的推荐剂量。基于这些结果，我们设计了一项II期研究，以评估TMZ-CDDP联合用药在晚期黑色素瘤患者中的活性和安全性。
2001年3月至2002年3月，37例无法进行手术的转移性黑色素瘤患者入组本研究。所有符合条件的患者接受CDDP 75 mg/m²静脉滴注，第1天；TMZ 200 mg/m²口服，第1 - 5天，每4周重复一次的联合治疗。化疗结束后，对有反应的患者给予α2b干扰素（IFNα2b），剂量为5百万国际单位皮下注射，每周3次，共1年。
共进行了174个疗程，每位患者的疗程中位数为4个（范围1 - 10个）。化疗后，观察到9例完全缓解（CR）和9例部分缓解（PR），总缓解率为48.6%（95%置信区间，31.9% - 65.6%）。5例初始有脑转移的患者中有1例对治疗表现出完全缓解。9例CR患者中有5例仍无复发迹象，时间范围为28 +至82 +周。中位生存时间为48周。该治疗方案耐受性良好，报告的最常见不良事件为恶心和呕吐（59%）、脱发（14%）和疲劳（11%），所有这些都通过支持治疗得到了很好的控制。血液学毒性为轻度至中度。IFNα2b引起的副作用也较轻且易于处理。
TMZ与CDDP的联合用药似乎对未经治疗的晚期黑色素瘤患者有活性。大多数（5/9；56%）CR患者无复发似乎表明IFN可能对化疗反应的持续时间有作用。该治疗方案耐受性良好，恶心和呕吐是最常见的不良事件。
