安罗替尼联合替莫唑胺治疗复发性高级别脑胶质瘤疗效观察

Efficacy of anlotinib plus temozolomide on recurrent high-grade glioma

目的 探讨复发性高级别脑胶质瘤患者应用安罗替尼联合替莫唑胺方案化疗的效果及安全性。方法 复发性高级别脑胶质瘤患者63例,23例应用安罗替尼联合替莫唑胺方案化疗者为安罗替尼组,40例应用替莫唑胺/伊立替康/依托泊苷/依托泊苷联合卡铂等方案化疗者为对照组。比较2组ECOG评分、WHO分级、Ki-67表达、IDH1基因突变率、MGMT基因甲基化率、TP53基因突变类型等临床资料;每化疗2个周期评估客观有效率、疾病控制率,至肿瘤进展或发生严重不良反应停药;随访至2022年2月,比较2组中位无进展生存期和总生存期、治疗期间不良反应发生率;绘制森林图,分析复发性高级别脑胶质瘤患者疾病进展、死亡的风险及影响因素。结果 2组年龄、性别、ECOG评分、WHO分级、Ki-67表达、IDH1基因突变率、MGMT基因甲基化率、TP53基因突变类型比较差异均无统计学意义(P>0.05)。化疗2个周期后,安罗替尼组客观有效率(52.2%)、疾病控制率(91.3%)均高于对照组(20.0%、67.5%)(χ^(2)=6.977,P=0.008;χ^(2)=4.489,P=0.034)。随访至2022年2月,安罗替尼组死亡17例,对照组死亡32例;安罗替尼组中位无进展生存期[5.3个月(95%CI:4.9~5.7)]、中位总生存期[11.0个月(95%CI:9.7~12.3)]均长于对照组[2.0个月(95%CI:1.2~2.8)、6.7个月(95%CI:5.9~7.5)](χ^(2)=11.356,P=0.001;χ^(2)=10.341,P=0.001)。森林图分析结果显示,复发性高级别胶质瘤患者应用安罗替尼联合替莫唑胺方案化疗疾病进展风险的HR为0.37(95%CI:0.20~0.69),男性(P=0.017)、Ki-67<40%(P=0.014)者无进展生存期获益更多;死亡风险的HR为0.37(95%CI:0.20~0.70),男性(P=0.020)、TP53野生型(P=0.010)、Ki-67<40%(P=0.021)者总生存期获益更多。安罗替尼组治疗及随访期间3~4级不良反应发生率(39.1%)与对照组(55.0%)比较差异无统计学意义(χ^(2)=1.471,P=0.225)。结论 复发性高级别脑胶质瘤患者应用安罗替尼联合替莫唑胺方案化疗可延缓疾病进展,延长生存期,不良反应轻,男性、Ki-67<40%及TP53野生型患者获益更多。

Objective To investigate the efficacy and safety of anlotinib combined with temozolomide in the treatment of recurrent high-grade glioma. Methods In 63 patients with recurrent high-grade glioma, 23 patients received anlotinib plus temozolomide(anlotinib group), and 40 patients received chemotherapy of temozolomide, irinotecan, etoposide or etoposide combined with carboplatin(control group). The clinical data as ECOG performance status, WHO grade, Ki-67 expression, IDH1 gene mutation rate, MGMT methylation rate and TP53 gene mutation type were compared between two groups. The objective response rate and disease control rate were assessed every two cycles. The treatment was terminated till disease progress or severe adverse effects. Following up to February 2022, the median progress free survival median overall survival, and adverse effects were compared between two groups. Forest plots were drawn to analyze the risk and influencing factors of disease progress or death. Results There were no significant differences in the age, gender, ECOG performance status, WHO grade, Ki-67 expression, IDH1 gene mutation rate, MGMT methylation rate and TP53 gene mutation type between two groups(P>0.05).After two cycles, the objective response rate and disease control rate were higher in anlotinib group(52.5%, 91.3%) than those in control group(20.0%, 67.5%)(χ^(2)=6.977, P=0.008;χ^(2)=4.489, P=0.034). Till February 2022, 17 patients died in anlotinib group, and 32 patients died in control group. The median progress free survival and median overal survival were longer in anlotinib group [5.3 months(95%CI: 4.9-5.7), 11.0 months(95%CI:9.7-12.3)] than those in control group [2.0 months(95%CI: 1.2-2.8), 6.7 months(95%CI: 5.9-7.5)](χ^(2)=11.356, P=0.001;χ^(2)=10.341, P=0.001). Forest plots analysis showed the hazard ratio of disease progress in anlotinib group was 0.37(95%CI:0.20-0.69).The male patients(P=0.017)and patients with Ki-67<40%(P=0.014)had better progress free survival.The hazard ratio of death was0.37(95%CI:0.20-0.70).The male patients(P=0.020)and patients with TP53 wild type(P=0.010)and Ki-67 <40%(P=0.021)had better overal survival.The adverse effect rate in grade 3-4during the treatment and follow-up period showed no significant difference between anlotinib and control groups(39.1% vs.55.0%)(χ^(2)=1.471,P=0.225).Conclusions Anlotinib plus temozolomide could delay the disease progression and prolong the survival,and the adverse effect is mild in the treatment of recurrent high-grade glioma.The male patients,and patients with Ki-67<40% and wild type TP53benefit more.