大分割放疗联合替莫唑胺治疗大体积脑转移瘤的前瞻性临床研究

Efficacy of hypofractionated stereotactic radiotherapy combined with temozolomide for large brain metastases：a prospective clinical study

目的：前瞻性Ⅱ期临床研究分析大分割放疗联合替莫唑胺（ TMZ）治疗大体积脑转移瘤的疗效及安全性。方法2010—2015年共33例患者纳入研究，疗前、后中位KPS分别为70、80分，原发灶主要为NSCLC （58％）。脑转移瘤直径≥3 cm或体积≥6 cm3，放疗剂量52 Gy分13次或52．5 Gy分15次，同步TMZ 75 mg／m2／d，辅助TMZ 6周期（150 mg／m2，第1—5天，28天为1周期）。治疗中复查MRI，如瘤体积缩小≥20％则缩野。疗后2～3个月复查MRI评估疗效。结果总治疗病灶及大体积病灶数分别为95个及38个，＞10 cm324例（63％），中位GTV 15．3 cm3（5．7～142．8 cm3）。22例（67％）实现疗中缩野，中位GTV缩小率为44％（21％～88％）。中位总剂量为59．5 Gy，同步和辅助TMZ完成率分别为100％和21％。全组客观反应率为97％，1年LC、颅内PFS、OS分别为97％、70％、62％，中位生存期15．3个月。主要不良反应为1—2级恶心、呕吐，1例出现3级肝功能损伤。结论大分割放疗联合TMZ治疗大体积脑转移瘤安全有效，50％以上患者可实现疗中缩野，缩短治疗时间，减少损伤。临床试验注册 ClinicalTrials．gov，注册号：NCT02654106。

Objective To analyze the efficacy and safety of hypofractionated stereotactic radiotherapy （ FSRT ） combined with temozolomide （ TMZ ） for large brain metastases （ BMs ） in a prospective phaseⅡclinical trial.Methods From 2010 to 2015, a total of 33 patients were enrolled as subjects.The median Karnofsky Performance Status scores before and after treatment were 70 and 80, respectively.The major primary tumor was non-small cell lung cancer （57.6%）.The brain metastasis had a diameter of≥3 cm or a volume of ≥6 cm3 .The radiation dose was 52 Gy in 13 fractions or 52.2 Gy in 15 fractions.Patients received TMZ at a dose of 75 mg/m2 per day concurrently.The radiotherapy was followed by 6 cycles of adjuvant treatment with TMZ （150 mg/m2, days 1-5, 28 days per cycle）.Patients were reexamined by magnetic resonance imaging （ MRI） during the treatment.The radiation field would be shrunk if the gross target volume （ GTV） was reduced by≥20%.The treatment outcomes were evaluated by MRI at 2-3 months after treatment.Results The total numbers of tumors and GTVs were 95 and 38, respectively. Twenty-four （63%） out of the 38 GTVs had a volume larger than 10 cm3 and the median GTV was 15.3 cm3 （5.7-142.8 cm3）.Twenty-two （67%） out of the 33 patients achieved field shrinking during the treatment, and the median reduction rate of GTV was 44%（ 21%-88%） .The median total dose was 59.5 Gy, and 100%and 21.2%of patients completed the concurrent and adjuvant treatment with TMZ, respectively.In all patients, the overall response rate was 97.0%;the 1-year local control, intracranial progression-free survival, and overall survival rates were 97%, 70%, and 62%, respectively;the median survival time was 15.3 months.The main adverse reactions were grade 1-2 nausea and vomiting.One patient got grade 3 liver function impairment.Conclusions FSRT combined with TMZ is a safe and effective approach for treating large BMs.More than 50%of patients can achieve field shrinking to shorten treatment duration and reduce toxicity.Clinical Trial Registry ClinicalTrials.gov,registration number：NCT02654106.