不可切除Ⅲ期NSCLC持续静脉泵注恩度联合同期放化疗前瞻性多中心Ⅱ期临床试验初步结果

Continuous intravenous pumping （CIP） of recombinant human endostatin （Endostar） combined with concurrent radiochemotherapy in patients with unresectable stage Ⅲ non-small-cell lung cancer： preliminary data of a prospective multicenter phase Ⅱ clinical trial

目的评估隔周持续静脉泵注恩度联合同期放化疗对不可切除Ⅲ期NSCLC的有效性及安全性。方法2012--2015年共73例患者入组，年龄31—69岁，男52例、女11例，鳞癌41例、腺癌19例、大细胞癌1例、未分化癌2例。ⅢA期27例、ⅢB期36例。第1、3、5、7周每天接受恩度7．5mg／m2持续泵注5d，第2周开始接受6-7周的3DRT60～66Gy分30～33次，同期依托泊苷50ms／m。第1～5天加顺铂50ms／m。第1、8、28天重复化疗两程。CTCAE3．0评估不良反应。完成治疗后4周按RECIST1．1标准评价近期疗效。结果63例进行评价。1例患者因2级肾功能不全、1例因4级骨髓抑制未行第2程化疗，61例均完成治疗。完成治疗后4周评价疗效，CR8例，PR40例，SD11例，PD4例，客观缓解率76％。3＋4级中性粒细胞减少23例，3＋4级贫血9例．3＋4级血小板减少10例。3级恶心或呕吐3例，3级放射性食管炎8例，1＋2、3级RP分别为12、2例。未观察到2级以上心血管毒性发生。中随访时间13．6个月，随访期间21例死亡，15例死于肺癌进展。中位PFS14．8个月。1年PFS、OS分别为51％、78％。结论恩级泵注给药提高了患者依从性，联合同期放化疗不可切除Ⅲ期NSCLC近期疗效和耐受性良好，疗效评价尚需进一步累积病例和长期随访。临床试验注册Clinical Trials．gov，注册号：NCT01733589。

Objective Preclinical models have shown that recombinant human endostatin （Endostar） can transiently normalize the tumor vasculature to make it more efficient for oxygen delivery, which provides a treatment window of enhancing tumor radiosensitivity. This study is to evaluate the safety and efficacy of continuous intravenous pumping （CIP） of Endostar combined with standard concurrent radiochemotherapy for unresectable stage Ⅲ non-small-cell lung cancer （NSCLC）. Methods In this prospective study, patients with unresectable stage ⅢA or llIB NSCLC received CIP of Endostar （7.5 mg/m2 ） over 5 days at week 1,3,5 ,and 7.During week 2-8,patients received two 28-day cycles of etoposide 50 mg/m2 on day 1-5 and cisplatin 50 mg/m2 on day 1,8,with concurrent thoracic radiation of 60-66 Gy in 30-33 fractions over 6-7 weeks. Acute toxicities were evaluated using CTCAE 3. O. Tumor response was evaluated using RECIST 1.1 criteria. Results Between Nov.2012 and Jun.2015,63 patients were eligible for toxicity and efficacy evaluation, including 52 （83%） male and 11 （16%） female, gl （65%） with squamous cell carcinoma, 19 （30%） with adenocarcinoma, 1 （2%） with large cell carcinoma and 2 （3%） with undifferentiated carcinoma, and 27 （43%） with stage ⅢA disease and 36（57%） with ⅢB disease, respectively. The median age was 59（31-69） years. All patients completed the treatment as planned,except that 2 patient missed one cycle chemotherapy for unrecovered grade 2 renal function impairmentandgrade IV myelosuppression. There were 8 （ 13%）, 40 （ 64%）, 11 （18%） and 4 （6%） patients achieved complete response, partial response, stable disease and progressive disease, respectively. The objective remission rate （ORR） is 76%. There were 23 patients （37%） with grade 3 ＋ 4 neutropenia, 9 （14%） with grade 3 ＋ 4 anemia,and 10（16%） with grade 3＋4 thrombocytopenic. Two patients （5%） developed grade 3 nausea/ vomiting. Grade 3 acute esophagitis, grade 1 ＋2 and grade 3 pneumonitis were observed in 8（13%）, 12 （19%） and 2（3%） patients,respectively. No grade 2 cardiovascular toxicity was observed.Up to the last follow-up,the median follow-up time was 13.6 months.21 deaths were observed,including 15 died of cancer progression. The median PFS was 14. 8 months. The 1-year PFS, OS was 51%, 78%, respectively. Conclusions For patients with unresectable stageIII NSCLC, CIP of Endostar enhanced patient compliance, and combined with concurrent radiochemotherapy is tolerable and the short term outcomes are promising. Long term survival data await further follow up. Clinical Trial Registry ClinicalTrials. gov, registration number： NCT01733589.