辅助治疗失败的高度复发风险胃肠间质瘤患者再次应用伊马替尼的疗效观察

Efficacy observation on imatinib reintroduction in gastrointestinal stromal tumor with high recurrence risk after imatinib adjuvant therapy failure

目的评估高度复发风险胃肠间质瘤（GIST）辅助治疗失败后再次应用伊马替尼治疗的可行性。方法回顾性分析2005年8月至2016年1月间在北京大学肿瘤医院消化肿瘤内科接受再次伊马替尼标准剂量治疗（400mg／d或600mg／d）的24例辅助治疗失败（停药3个月后出现复发）的高度复发风险GIST患者的临床和随访资料。分析再次伊马替尼治疗的客观疗效和无复发生存率，并比较不同辅助治疗时限患者的疗效差异。结果24例复发患者中，男性21例，女性3例，中位年龄53（39-72）岁。伊马替尼治疗前肿瘤组织基因突变检测显示，20例为c-Kit外显子11突变，3例为外显子9突变，1例为c-Kit／PDGFRA野生型。全组患者中位复发时间为14（95％CI：7．9—20．0）月；其中接受伊马替尼辅助治疗1年（9例）和2年（9例）者复发时间均为14（95％CI分别11．1—16．9和8．2—19．8）月，接受辅助治疗3年的3例患者则分别为24、41和54月。接受辅助治疗5年的2例患者复发时间分别为4和18月，接受辅助治疗6年的1例患者复发时间为6月。GIST复发后，20例外显子11突变和1例野生型患者接受伊马替尼400mg／d治疗。3例外显子9突变患者接受伊马替尼600mg／d治疗。再次接受伊马替尼治疗后，11例（45．8％）患者获得部分缓解，12例（50．0％）肿瘤稳定，1例肿瘤进展。既往伊马替尼辅助治疗1年的患者获得的肿瘤缓解率（6／9）显著高于既往辅助治疗超过2年者（3／15，20％），差异有统计学意义（P=0．036）。全组接受伊马替尼再次治疗后的中位无进展生存期（PFS）为31（95％CI：23．6～38．4）月，其中9例既往伊马替尼辅助治疗1年者中位PFS为50．0（95％CI：27．3—72．7）月；9例辅助治疗2年者中位PFS为26．0（95％CI：10．7—41.3）月；6例辅助治疗超过3年者未达到中位PFS；3组比较差异无统计学意义（P=0．295）。结论伊马替尼辅助治疗停止后出现复发的GIST患者，再次使用伊马替尼标准剂量治疗可获得肯定的疗效。伊马替尼辅助治疗时限对伊马替尼再次治疗的疗效可能有影响。

Objective To evaluate the feasibility of imatinib reintroduction in gastrointestinal stromal tumor （GIST） with high recurrence risk after imatinib adjuvant therapy failure. Methods Clinical and fallow-up data of 24 recurrent GIST patients with high recurrence risk receiving imatinib standard dose reintroduction （400 mg/d or 600 mg/d） after stopping imatinib adjuvant treatment more than 3 months in Department of GI Oncology of Peking University Cancer Hospital from August 2005 to January 2016 were retrospectively analyzed. The objective response rate （ORR）, relapse-free survival （RFS） of imatinib reintroduction were evaluated and the difference of efficacy in patients receiving different imatinib adjuvant therapy duration were compared. Results Of 24 patients, 21 were male and 3 were female. The median age was 53 years （39-72 years）. Mutation detection of tumor tissues before imatinib therapy showed 20 patients had c-Kit exon 11 mutation, 3 patients exon 9 mutation and 1 patient c-Kit/PDGFRA wild type mutation. The median recurrence time was 14 months in all the patients （95%CI： 7.9-20.0） and in those patients receiving imatinib adjuvant therapy for 1 or 2 years （9 patients in each group, 95%CI： 11.1-16.9 and 8.2-19.8 respectively）. The median recurrence time of 3 patients receiving imatinib adjuvant therapy for 3 years was 24, 41 and 54 months respectively. Of 2 patients receiving imatinib adjuvant therapy for 5 years, the median recurrence time was 4 and 18 months. Only one patient received imatinib adjuvant therapy for 6 years, and the recurrence time was 6 months. Twenty patients with exon 11 mutation and 1 patient with wide type received imatinib treatment at a dose of 400 mg daily, and 3 patients with exon 9 mutation received the dosage of 600 mg per day. Among the patients receiving imatinib reintroduction, 11 patients （45.8%） got partial response（PR）, 12 patients（50.0%） had stable disease and 1 patient had progression disease. The response rate in patients receiving imatinib adjuvant therapy for 1 year （6/9, 67% ） was significantly higher than that in patients receiving adjuvant therapy for ≥ 2 years （3/15, 20%）（P= 0.036）. The median progression-free survival （PFS） of imatinib reintroduction was 31 months in all the patients（95%CI： 23.6-38.4）. The median PFS in patients receiving imatinib adjuvant therapy for 1 year（9 cases）, 2 years （9 cases） and ≥3 years （6 cases） was 50 months（95%CI：27.3-72.7）, 26 months （95%CI：10.7-41.3） and fall short of median PFS. No significant difference was observed among three groups （P = 0.295）. Conclusions Imatinib reintroduction is still effective to GIST after imatinib adjuvant therapy failure. The different imatinib adjuvant therapy duration can influence the benefit of imatinib reintroduction.