CONCURRENT WHOLE BRAIN RADIOTHERAPY AND SHORT-COURSE CHLOROQUINE IN PATIENTS WITH BRAIN METASTASES: A PILOT TRIAL.
CONCURRENT WHOLE BRAIN RADIOTHERAPY AND SHORT-COURSE CHLOROQUINE IN PATIENTS WITH BRAIN METASTASES: A PILOT TRIAL.
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DOI：
10.1007/s13566-013-0111-x
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发表时间：
2013-09-01
期刊：
影响因子：
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通讯作者：
Prendergast, George C
中科院分区：
文献类型：
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作者：
Eldredge, Harriet Belding;Denittis, Albert;Duhadaway, James B;Chernick, Michael;Metz, Richard;Prendergast, George C
在一项临床试验中，免疫调节药物氯喹（CQ）已被证明可提高高级别胶质瘤患者放疗后的生存率，但对脑转移患者的疗效尚不清楚。我们假设全脑放疗（WBRT）期间的短程CQ可以改善脑转移瘤患者对局部治疗的反应。进行了一项前瞻性、单队列研究，将WBRT与同期CQ相结合，以评估脑转移患者联合治疗的可行性和颅内反应。还检查了该组合的安全性、耐受性和总生存期，沿着IDO 2（吲哚胺2，3-双加氧酶2）的等位基因状态，IDO 2是一种受氯喹抑制的免疫调节酶，可能影响生存结局。CQ治疗（250 mg，每日口服）在WBRT（37.5戈伊，每日2.5戈伊）前1周开始，用于新诊断的原发性肺、乳腺或卵巢实体瘤脑转移患者（n=20）。主要终点是CQ和WBRT联合治疗后3个月的放射学缓解。次要终点包括毒性和总生存期。患者按IDO 2等位基因状态分层。在中位临床随访5个月（范围，0.5-31）后，16例患者可评价放射学缓解，其中2例患者完全缓解，13例患者部分缓解，1例患者病情稳定。没有出现治疗相关的≥3级毒性或因毒性而中断治疗。中位和平均总生存期分别为5.7和8.9个月（范围0.8-31）。与具有消除IDO 2酶活性的杂合或纯合构型的患者相比，在具有野生型IDO 2的患者中观察到总体存活率增加的趋势（10.4个月对4.1个月; p=0.07）。脑转移瘤患者接受WBRT联合短程CQ治疗耐受性良好。高颅内疾病控制率值得进一步研究。
The immune modulatory drug chloroquine (CQ) has been demonstrated to enhance survival following radiotherapy in patients with high-grade glioma in a clinical trial, but the efficacy in patients with brain metastases is unknown. We hypothesized that short-course CQ during whole brain radiotherapy (WBRT) would improve response to local therapy in patients with brain metastases. A prospective, single-cohort study was performed combining WBRT with concurrent CQ to assess both the feasibility of and intracranial response to combined therapy in patients with brain metastases. Safety, tolerability and overall survival of this combination was also examined, along with allelic status of IDO2 (indoleamine 2,3-dioxygenase 2), an immune modulatory enzyme inhibited by chloroquine that may affect survival outcomes. CQ therapy (250 mg by mouth daily) was initiated 1 week before WBRT (37.5 Gy in 2.5 Gy daily fractions) in patients with newly diagnosed brain metastases from biopsy-proven, primary lung, breast or ovarian solid tumors (n=20). The primary endpoint was radiologic response 3 months after combined CQ and WBRT therapy. Secondary endpoints included toxicity and overall survival. Patients were stratified by IDO2 allelic status. After a median clinical follow up of 5 months (range, 0.5–31), 16 patients were evaluable for radiologic response which was complete response in two patients, partial response in 13 patients and stable disease in one patient. There were no treatment-related grade≥3 toxicities or treatment interruption due to toxicity. Median and mean overall survival was 5.7 and 8.9 months, respectively (range, 0.8–31). A trend toward increased overall survival was observed in patients with wild-type IDO2 compared to patients with heterozygous or homozygous configurations that ablate IDO2 enzyme activity (10.4 mos vs. 4.1 mos.; p=0.07). WBRT with concurrent, short-course CQ is well tolerated in patients with brain metastases. The high intracranial disease control rate warrants additional study.