应用阿帕替尼治疗进展期软组织肉瘤的临床效果与安全性评估

Efficacy and safety of apatinib in the treatment of advanced soft tissue sarcoma

目的 评估阿帕替尼对进展期软组织肉瘤患者的临床疗效与安全性。方法 对2017年1月至2019年8月华中科技大学同济医学院附属协和医院肿瘤中心应用阿帕替尼单药治疗的进展期软组织肉瘤患者54例的临床资料进行回顾性分析。其中男28例,女26例;年龄(38.5±17.9)(6~74)岁;病理亚型包括腺泡状软组织肉瘤(ASPS)10例、滑膜肉瘤7例、平滑肌肉瘤7例、横纹肌肉瘤6例、未分化小圆细胞肉瘤5例、未分化多形性肉瘤4例、脂肪肉瘤4例、血管肉瘤3例和其他8例。以疾病无进展生存期(PFS)、客观缓解率(ORR)、疾病控制率(DCR)和总生存时间(OS)等指标对疗效进行评价;通过观察治疗相关不良反应对药物的安全性进行评价;利用COX比例风险模型对发生率较高的非血液学不良反应与疗效相关性进行分析。结果 患者总体中位PFS为5.8个月;ASPS、未分化多形性肉瘤和平滑肌肉瘤为治疗优势亚型,中位PFS分别为24.3个月、8.3个月和7.4个月;1例(1.8%)患者达到完全缓解,10例(18.5%)达到部分缓解,34例(63.0%)达到疾病稳定;ORR为20.4%(11例/54例),DCR为83.3%(45例/54例)。中位OS为9个月。最常见的血液学不良反应是白细胞减少(22例/54例,40.7%)和贫血(21例/54例,38.9%),最常见的非血液学不良反应是手足综合征(30例/54例,55.6%)、甘油三脂升高超过1 mmol/L(33例/44例,75%)、胆红素升高(26例/54例,48.1%)、高血压(25例/54例,46.3%)和胆固醇升高(25例/44例,56.8%),其中多为Ⅰ~Ⅱ级。发生手足综合征与未发生手足综合征患者的中位PFS分别为12.5个月和3.4个月,差异有统计学意义(P<0.001);发生腹泻与未发生腹泻患者的中位PFS分别为35.0个月和4.5个月,差异有统计学意义(P<0.001);发生高脂血症且胆固醇升高超过1.5 mmol/L与未达上述标准患者的中位PFS分别为24.3个月和4.0个月,差异有统计学意义(P=0.004);发生高血压和蛋白尿的患者有PFS延长的趋势;口腔溃疡、甘油三脂升高超过1 mmol/L和胆红素升高与PFS无显著相关性。结论 应用阿帕替尼治疗进展期软组织肉瘤患者可获得令人满意的临床效果,不良反应基本可控,且部分不良反应可能作为疗效预测指标。

Objective To evaluate the efficacy and safety of apatinib in the treatment of advanced soft tissue sarcoma. Methods Clinical data of 54 patients with advanced soft tissue sarcoma received apatinib as monotherapy in Cancer Center of Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology from January 2017 to August 2019 were analyzed retrospectively. There were 28 males and 26 femals with an age of(38.5±17.9)(6-74)years. The pathological subtypes included alveolar soft part sarcoma(ASPS)(n=10), synovial sarcoma(n=7), leiomyosarcoma(n=7), rhabdomyosarcoma(n=6), undifferentiated small round cell sarcoma(n=5), undifferentiated pleomorphic sarcoma(n=4), liposarcoma(n=4), angiosarcoma(n=3) and the others(n=8). 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 effects. Results The median PFS of was 5.8 months. ASPS, undifferentiated pleomorphic sarcoma and leiomyosarcoma were the dominant subtypes with the median PFS was 24.3 months, 8.3 months and 7.4 months, respectively. Of the all patients, one(1.8%) achieved complete response, 10(18.5%) achieved partial response and 34(63.0%) achieved disease stability. The ORR and the DCR were 20.4%(11/54) and 83.3%(45/54), respectively. The median OS was 9 months. The most common hematological adverse reactions were leukopenia(22/54,40.7%) and anemia(21/54,38.9%). The most common non-hematological adverse reactions were hand-foot syndrome(30/54,55.6%), elevated triglycerides exceeding 1 mmol/L(33/44,75%), elevated bilirubin(26/54,48.1%), hypertension(25/54,46.3%) and elevated cholesterol(25/44,56.8%). The median PFS of patients with hand-foot syndrome and without hand-foot syndrome was 12.5 and 3.4 months, respectively(P<0.001). The median PFS of patients with diarrhea and without diarrhea was 35.0 and 4.5 months(P<0.001), respectively. The median PFS of patients with elevated cholesterol exceeding 1.5 mmol/L and those who did not meet the above criteria were 24.3 and 4 months(P=0.004), respectively. Patients with hypertension and albuminuria tended to have prolonged PFS. Oral ulcers, elevated triglycerides exceeding 1 mmol/L and elevated bilirubin were not significantly correlated with PFS. Conclusion The efficacy of apatinib in the treatment of advanced soft tissue sarcoma is satisfactory and the adverse reactions were tolerated, moreover the occurrence of some adverse reactions may be used as predictors of efficacy.