低剂量阿帕替尼逆转肉瘤化疗耐药及其安全性的临床研究

Retrospective study on the efficacy and safety of low dose apatinib in reversing chemotherapy resistance in sarcoma

目的探索抗血管生成小分子靶向药物阿帕替尼是否能逆转晚期肉瘤的化疗耐药及安全性。方法回顾性收集2018年5月至2021年11月就诊于华中科技大学同济医学院附属协和医院肿瘤中心,化疗后进展随后接受原化疗方案联合低剂量阿帕替尼治疗的晚期肉瘤患者的资料,评估该方案的疗效及安全性。主要观察终点为疾病无进展生存期(PFS),次要观察终点为客观缓解率(ORR)、疾病控制率(DCR)、总生存时间(OS)和不良反应(AE)。共分为骨肉瘤、软组织肉瘤和未分化小圆细胞肉瘤3组,并按联合治疗的最佳疗效、原化疗线数、原化疗最佳疗效和原化疗PFS等因素进行分层分析,以初步探索联合治疗的获益情况。结果共计30例患者被纳入本研究,其中男20例,女10例,年龄(25.6±14.7)岁。包括骨肉瘤9例,软组织肉瘤11例,未分化小圆细胞肉瘤10例。无患者达到完全缓解,8例(26.7%)患者达到部分缓解,19例(63.3%)达到疾病稳定,总体ORR为26.7%(8/30),DCR为90.0%(27/30)。总体中位PFS为4.1个月,中位OS为13.1个月。三种不同亚型的肉瘤中,骨肉瘤的ORR达到44.4%(4/9),中位PFS为4.1个月,中位OS尚未达到;未分化小圆细胞肉瘤的ORR达到40.0%(4/10),中位PFS为6.4个月,中位OS为10.9个月;软组织肉瘤无客观缓解患者,中位PFS为3.5个月,中位OS为7.3个月。获得客观缓解的患者相对于疾病稳定的患者有更好的PFS(12.8比3.8个月,P=0.015),原化疗PFS≥6个月的患者有更好的PFS获益(12.7比2.7个月,P<0.001)。但原化疗线数、原化疗最佳疗效对本联合方案的PFS均无影响。安全性方面,阿帕替尼的相关毒性均不超过2级,4级化疗相关不良反应主要为血液学毒性,其中有2例患者因粒细胞缺乏伴发热中断治疗。结论低剂量阿帕替尼逆转骨肉瘤和未分化小圆细胞肉瘤的化疗耐药有一定疗效,总体安全性可接受。

Objective To explore whether apatinib can reverse the chemotherapy resistance of patients with advanced sarcoma.Methods The clinical data of advanced sarcoma patients after chemotherapy who received the original chemotherapy regimen combined with low-dose apatinib in Cancer Center of Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology from May 2018 to November 2021 were collected retrospectively to evaluate the efficacy and safety of this regimen.The primary end point was progression-free survival(PFS),and the secondary end points were objective response rate(ORR),disease control rate(DCR),overall survival(OS)and adverse events(AE).The patients were grouped according to the diagnosis:osteosarcoma,soft tissue sarcoma and undifferentiated small round cell sarcoma.And the benefits of combination treatment was investigated with the stratified analysis of best outcome of combined therapy,lines of chemotherapy received,best response and PFS of original chemotherapy.Results A total of 30 patients were included in this study,including 20 males and 10 females.The mean age was(25.6±14.7)years.There were 9 cases of osteosarcoma,11 cases of soft tissue sarcoma and 10 cases of undifferentiated small round cell sarcoma.No patient achieved complete response,8 patients(26.7%)achieved partial response,19 patients(63.3%)achieved disease stability,the ORR was 26.7%(8/30),and the DCR was 90.0%(27/30).The median PFS and OS were 4.1 and 13.1 months respectively.Among the three different subtypes of sarcoma,the ORR of osteosarcoma was 44.4%(4/9),the median PFS was 4.1 months,and the median OS was not yet achieved;the ORR of undifferentiated small round cell sarcoma was 40%(4/10),the median PFS was 6.4 months,and the median OS was 10.9 months;No response was observed in soft tissue sarcoma,and the median PFS and median OS was 3.5 and 7.3 months respectively.Patients who achieved objective response had better PFS than patients with stable disease(12.8 vs 3.8 months,P=0.015),and patients with PFS≥6 months of original chemotherapy had better PFS benefits(12.7 vs 2.7 months,P<0.001).However,the number of original chemotherapy lines and the best response of original chemotherapy had no significant effect on the PFS of this combination regimen.In terms of safety,the related toxicity of apatinib was no more than grade 2,and the grade 4 chemotherapy-related adverse reactions was mainly hematological toxicity,of which 2 patients interrupted treatment because of febrile neutropenia.Conclusion Low dose apatinib is effective in reversing chemotherapy resistance of osteosarcoma and undifferentiated small round cell sarcoma with acceptable adverse reactions.