替莫唑胺联合干扰素-β治疗复发恶性脑胶质瘤的Ⅱ期临床研究

Phase Ⅱ trial of temozolomide plus interferon-β in recurrent malignant glioma patients

背景与目的：替莫唑胺（temozolomide，TMZ）期放疗及辅助化疗是新诊断的恶性脑胶质瘤患者的术后标准辅助治疗方案。但对于复发患者目前仍无标准挽救治疗方案。干扰素．B是一种临床常用的细胞因子类药物．不但具有直接的肿瘤抑制作用，也具有免疫调节和抗血管生成效应。体内外研究显示，干扰素-β可增强TMZ和亚硝脲类药物的化疗敏感性，从而增强其抗胶质瘤作用。本项Ⅱ期临床研究评价TMZ联合干扰素-β治疗复发恶性脑胶质瘤的疗效和不良反应。方法：年龄大于18岁、经病理确诊为WHO分级Ⅲ～Ⅳ级的胶质瘤、既往经标准一线TMZ化／放疗联合治疗后复发进展患者入组。患者接受干扰素-β3MIU／次，d1、3、5，皮下注射；TMZ200mg／（mz·d），d2-6，13服；28天为一周期，直至疾病进展或毒性不可耐受。每8周行脑MRI检查评价肿瘤反应率。主要研究终点是客观有效率（CR＋PR）、无进展生存时间（PFS）和6个月的PFS率，次要终点是总生存时间（os）和毒性。结果：2010年7月至2012年10月期间共30例（17例Ⅳ级和13例Ⅲ级胶质瘤）患者入组。男23例，女7例，年龄22～73岁，中位年龄44．5岁。卡氏体力状况评分（KamofskyPerformanceStatusScore，KPS）70—100分，中位KPS评分80分。病理类型：间变星形细胞瘤10例，间变少突胶质瘤2例，间变少突一星形细胞瘤1例，胶质母细胞瘤17例。Ⅲ级和Ⅳ级胶质瘤治疗的客观有效率分别是38．5％和29．4％（P〉0．05），中位PFS分别是10．0个月f95％CI：0．5～19．5）和5．0个月（95％CI：3．0～7．0），中位0S分别是未达到和9．5个月（95％CI：7．7—11．3），P〈0．05。主要不良反应包括I～Ⅱ级中性粒细胞下降（4例），血小板减少（3例），恶心／呕吐（3例），疲乏（8例），肝功能异常（3例），无Ⅲ／Ⅳ级不良反应。结论：替莫唑胺联合干扰素-β治疗复发恶性脑胶质瘤具有一定疗效，不良反应可耐受，值得扩大病例数进一步研究。

BACKGROUND ＆ OBJECTIVE： Temozolomide （TMZ） concomitant with radiotherapy and adjuvant TMZ chemotherapy is standard adjuvant treatment for newly diagnosed malignant glioma patients. However,there is still no effective standard second-line treatment for recurrent patients. Interferon-β is a widely used cytokine in clinic as immunoloregulation agent. Studies in vivo and vitro showed that interferon-β may enhance the chemosensitivity of temozolomide and nitrosoureas The present study was to evaluate the efficiency and side effects oftemozolomide plus interferon-β in recurrent malignant glioma patients. METHODS： Patients （age 〉 18 years） with histologically proven grade Ⅲ- 1V glioma that was progressive or recurrent after prior standard radiotherapy with temozolomide chemotherapy were eligible for the study. Patients were scheduled to receive interferon-β 3MU subcutaneous injections on days 1,3 and 5,while temozolomide 200mg/m2 orally on days 2 to 5, of a 4-week cycle until tumor progression or unacceptable toxicity. Tumor response was assessed by magnetic resonance imaging every 8 weeks. The primary end point were objective response （complete response [CR] plus partial response [PR]） by Response Assessment in Neuro-Oncology Working Group（RANO） and progression free survival （PFS）. Secondary end points included overall survival and toxicity. RESULTS： From July of 2010 to October of 2012, thirty patients were assessed （17 with grade IV glioma and 13 with grade III glioma）. There were 23 males and 7 females, and the median age was 44.5 years （ranged from 22 to 73）. The median Kamofsky Performance Status Score （KPS）was 80 （70-100）. Radiographic responses were noted in 38.5% of grades Ill patients and 29.4% of grade IV patients （P 〉0.05）. The median PFS were 10.0 months （95%CI, 0.5-19.5） vs 5.0 months （95%CI：3.0-7.0） for grades Ⅲ and IV patients respectively,the median OS were not availability for grade Ⅲpatients and 9.5 months （95%CI,7.7-11.3） for grade IV patients （P〈0.05）.The most common toxicities include grade I -II neutropenia（4 cases）,thrombocytopenia（3 cases）, nausea and vomitting （3 case）,fatigue （8 cases）and liver dysfunction （3 cases）. Grade IU or IV toxicities were uncommon. CONCLUSION： Temozolomide plus interferon-β has moderate activity for recurrent grades Ⅲ and IV gliomas with acceptable toxicity, and thus worth further investigation.