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局部晚期宫颈癌患者中替拉扎胺联合放疗和每周顺铂的 1 期研究。

Phase 1 study of tirapazamine in combination with radiation and weekly cisplatin in patients with locally advanced cervical cancer.

机构信息

Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

出版信息

Int J Gynecol Cancer. 2010 Jul;20(5):827-33. doi: 10.1111/IGC.0b013e3181dc827e.

Abstract

INTRODUCTION

Hypoxia is an adverse prognostic factor in locoregionally advanced cervical cancer treated with radiation. The aim of this phase I study was to develop a well-tolerated regimen that added tirapazamine to the standard regimen of radiation and weekly low-dose cisplatin.

METHODS

Eligible patients had previously untreated carcinoma of the cervix, stages IB2 to IVA. The starting schedule was radiotherapy (45-50.4 Gy external beam radiation followed by brachytherapy), with concomitant weekly intravenous cisplatin, 40 mg/m on weeks 1 to 6 and weekly intravenous tirapazamine, 290 mg/m in weeks 1 to 5.

RESULTS

Eleven patients were enrolled. The median age was 52 years (range, 31-65 years). Ten patients had squamous cell carcinoma and 1 patient had adenocarcinoma; 5 patients had stage 1B2 disease, 1 had stage IIA, 3 had stage IIB-3, 1 had stage IIIB, and 1 had stage IVA. The first 2 patients on dose level 1 experienced a dose-limiting toxicity (DLT): 1 experienced grade 3 alanine amino transferase elevation and grade 4 pulmonary embolism, and 1 experienced grade 3 ototoxicity. Doses were decreased to dose level -1 with a 30-mg/m dose of cisplatin and a 260-mg/m dose of tirapazamine. Three patients were treated without any DLTs. Six patients were then treated on dose level -1a: a 35-mg/m dose of cisplatin and a 260-mg/m doses of tirapazamine with 2 DLTs--grade 3 neutropenia with dose omission and grade 4 pulmonary embolism with major hemodynamic compromise. Three of 10 evaluable patients have experienced locoregional failure.

CONCLUSIONS

The combination of weekly tirapazamine and cisplatin with radiation for locally advanced cervical cancer was associated with more toxicity than anticipated with the recommended dose level being tirapazamine 260 mg/m and cisplatin 30 mg/m. Further study of this weekly schedule is not warranted.

摘要

简介

在接受放疗的局部晚期宫颈癌中,缺氧是一个不利的预后因素。本Ⅰ期研究的目的是开发一种耐受良好的方案,即在标准放疗和每周低剂量顺铂的基础上加入替拉扎胺。

方法

入组患者均为未接受治疗的宫颈癌,分期为 IB2 至 IVA。起始方案为放疗(45-50.4 Gy 外照射后行近距离放疗),同时给予每周静脉注射顺铂 40mg/m2,第 1-6 周;每周静脉注射替拉扎胺 290mg/m2,第 1-5 周。

结果

共入组 11 例患者。中位年龄为 52 岁(范围 31-65 岁)。10 例为鳞癌,1 例为腺癌;5 例为 1B2 期,1 例为 2A 期,3 例为 2B-3 期,1 例为 3B 期,1 例为 4A 期。剂量水平 1 的前 2 例患者出现剂量限制毒性(DLT):1 例出现 3 级丙氨酸氨基转移酶升高和 4 级肺栓塞,1 例出现 3 级耳毒性。顺铂剂量降至 30mg/m2,替拉扎胺剂量降至 260mg/m2。3 例患者无 DLT 发生。然后,6 例患者接受剂量水平-1a 治疗:顺铂剂量为 35mg/m2,替拉扎胺剂量为 260mg/m2,发生 2 例 DLT——3 级中性粒细胞减少症伴剂量遗漏和 4 级肺栓塞伴主要血流动力学受损。10 例可评估患者中有 3 例出现局部区域复发。

结论

每周替拉扎胺联合顺铂联合放疗治疗局部晚期宫颈癌的毒性高于预期,推荐剂量水平为替拉扎胺 260mg/m2 和顺铂 30mg/m2。因此,不推荐进一步研究该每周方案。

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