靶向治疗时代转移性肾癌多学科综合治疗的单中心经验总结

目的总结在靶向药物治疗基础上单中心转移性肾癌的多学科诊疗经验。方法回顾性分析2007年12月至2019年2月中山大学肿瘤防治中心经多学科诊疗团队(multi-disciplinary team,MDT)诊治的168例转移性肾癌(metastatic renal cell,mRCC)患者的临床数据。根据治疗方式将患者分为3组。单纯靶向药物治疗(A组)76例,男55例,女21例;年龄52(17~73)岁;透明细胞癌60例,非透明细胞癌16例;国际转移性肾细胞癌联合数据库(International Metastatic Renal Cell Carcinoma Database consortium,IMDC)预后评分低危11例,中危48例,高危17例;初诊时即有转移44例;行原发灶切除术63例。靶向药物治疗+局部治疗(B组)66例,男55例,女11例;年龄54(21~86)岁;透明细胞癌49例,非透明细胞癌17例;IMDC预后评分低危13例,中危39例,高危14例;初诊时即有转移32例;行原发灶切除术56例。靶向药物治疗+局部治疗+免疫治疗(C组)26例,男19例,女7例;年龄52(23~83)岁;透明细胞癌15例,非透明细胞癌11例;IMDC预后评分低危9例,中危13例,高危4例;初诊时即有转移9例;行原发灶切除术26例。3组患者一般资料比较差异均无统计学意义(P>0.05)。一线靶向治疗药物为舒尼替尼、索拉非尼、阿昔替尼。舒尼替尼50 mg,每日1次,用药4周停2周;索拉非尼400 mg,每日2次;阿昔替尼5 mg,每日2次。接受舒尼替尼、索拉非尼、阿昔替尼一线治疗者分别为103、18、39例。靶向药物治疗时间均>6个月。免疫治疗采用派姆单抗(Pembrolizumab)2 mg/kg静脉应用,每3周1次,或低剂量(20 mg)派姆单抗孵育经体外扩增后的自体外周血树突状细胞细胞因子诱导杀伤细胞(dendritic cells cytokine induced killer,DC.CIK),每周1次,4次后改为每2周1次。18例采用DC.CIK,8例采用派姆单抗。局部治疗方式包括立体定向放疗(stereotactic body radiation therapy,SBRT)和外科治疗(手术切除或能量消融治疗)。根据靶向药物治疗效果,转移灶部位、数量、与周围器官关系,以及患者的意愿,经MDT专家讨论后决定局部治疗方式。92例接受局部治疗,其中单纯外科治疗34例,单纯SBRT 37例,外科治疗+SBRT 21例。比较3组的疗效和不良反应情况,分析不同治疗方法与患者总生存时间(overall survival,OS)的关系。结果168例中位随访23个月(6~117个月)。中位无进展生存时间(progression free-survival,PFS)为18.3个月,中位OS为33.5个月;2年生存率为66%,5年生存率为35%。A、B、C组的中位OS分别为29.8个月、44.6个月和未达,2年生存率分别为58%、67%和89%,5年生存率分别为12%、46%和57%。在靶向药物治疗的基础上接受联合治疗者的预后均优于单纯靶向药物治疗者,5年总OS分别为51%和11%。C组的中高危mRCC患者预后明显优于A、B组。在接受免疫治疗的患者中,靶向药物治疗联合DC.CIK与联合派姆单抗的中位OS分别为49.1个月和53.1个月,差异无统计学意义(P=0.541)。单因素分析结果显示,OS与IMDC评分、原发灶切除、治疗模式相关(P<0.05)。多因素分析结果显示,OS与治疗模式、原发灶切除显著相关(P<0.05),靶向药物治疗+免疫治疗+局部治疗可使mRCC患者死亡风险下降约60%(HR=0.39,95%CI 0.17~0.89,P=0.026)。78例使用靶向药物治疗发生3~4级不良反应,12例因无法耐受一线靶向药物治疗不良反应而停药或换药。16例采用靶向药物联合免疫治疗发生3~4级药物不良反应,主要为疲乏8例次、白细胞降低4例次、血小板降低3例次、转氨酶和胆红素升高3例次。靶向药物治疗联合DC.CIK治疗的严重不良反应发生例数少于联合派姆单抗治疗(6例与12例),特别是显著降低了血液学毒性(2例与5例)和肝毒性(0例与3例),差异均有统计学意义(P<0.05)。外科治疗后出现ClavienⅢ~Ⅳ级并发症16例次,主要为感染和切口延期愈合6例次、不全肠梗阻4例次,围手术期输血15例次。SBRT治疗后6例出现美国放射肿瘤协作组评分(Radiotherapy Oncology Group,RTOG)3级不良反应,其中骨髓抑制4例,皮肤反应和放射性神经炎2例,未观察到≥4级不良反应。结论在靶向药物治疗基础上联合免疫治疗和局部治疗的mRCC患者预后明显优于采用单纯靶向药物治疗的患者。经MDT诊疗的综合治疗可使mRCC患者生存获益。

Multi-disciplinary management for metastatic renal cell carcinoma in the ear of targeted therapy: a single center experience

Objective To report the experience on the multi-disciplinary management of metastatic renal cell(mRCC)patients in a single center.Methods Data of 168 mRCC patients treated by multi-disciplinary team(MDT)at Sun Yat-sen University Cancer Center from December 2007 to February 2019 was retrospectively analyzed.Three treatment groups were identified,including 76 patients with 55 males and 21 females,received anti-angiogenic agents alone(Group A),66 patients with 55 males and 11 males,received anti-angiogenic agents plus local therapy(Group B)and 26 patients,with 19 males and 7 females,received anti-angiogenic agents plus immunotherapy and local therapy(Group C).The Sunitinib,Sorafenib,Axitinib were chosen for the TKI.The Pembrolizumab was used for immunotherapy.The stereotactic body radiation therapy and surgical excision were considered as the local therapy.The study aims to compare the age,gender,IMDC score,pathology,nbephrectomy,adverse events,progression-free survival and overall survival(OS).Results Of all patients,the median follow-up duration was 23 months(ranging 6-117 cmonths).The PFS was 18.3 months and median OS was 33.5 months.The 2 years and 5 years survival rate was 66%and 35%,respectively.The median OS of Group A,B and C were 29.8 months,44.6 months and not reached.2y-OS was 58%,67%and 89%,while 5y-OS 12%,46%and 57%.There was no difference in age,gender,IMDC score,pathology,synchronous metastases or nephterectomy between the three groups.The prognostic result in TKI based combination therapy was superior to TKI therapy alone,which the 5y-OS was 51%and 11%,respectively.The prognostic result in group C's moderate-high risk mRCC patients was superior to group A and B.The median OS in TKI+DC and CIK+Pembrolizumab was 49.1 months and 53.1 months.On univariate analyses,IMDC score,nephrectomy and treatment group was associated with OS(P<0.05).On multivariate analyses,treatment group,nephrectomy was associated with OS(P<0.05).The risk of death of Group C decreased about 60%HR 0.39(0.17,0.89),P=0.026].78(46.4%)patients on TKI alone and 16(61.5%)patients treated with TKI plus immunotherapy had Grade 3 or 4 adverse events.16(20.3%)patients had ClavienⅢ-Ⅳtoxicity after surgical procedures.6(5.7%)patients had Grade 3 toxiciy after SBRT.Conclusions Patients treated with combined therapy had better survival than those treated with anti-angiogenic agents alone.MDT approach could bring survival benefit to mRCC patients.