Evaluation of adverse reactions of systemic therapy for advanced renal cell carcinoma: clinical analysis of 200 cases
-
摘要: 目的 评估晚期肾癌系统性治疗不良反应发生情况及其与疗效的相关性。方法 回顾性分析2018年6月—2023年12月于上海交通大学医学院附属仁济医院一线接受靶向或靶向联合免疫治疗的200例晚期肾癌患者临床资料。分析不良事件的种类及发生率差异。分析≥3级治疗相关不良事件与客观缓解率(objective response rate，ORR)及无进展生存期(progression free survival，PFS)的相关性。结果 200例患者中，靶向治疗组一线治疗总体不良反应发生率为99.21%，靶免联合治疗组为100%。靶向治疗组≥3级不良反应发生率为61.64%，靶免联合治疗组为65.35%。靶向治疗组因不良反应停药发生率为17.32%，靶免联合治疗组为20.55%。一线治疗常见不良反应有蛋白尿、贫血、肌酐升高、高血压、腹泻、肝功能异常、血小板减少、甲状腺功能减退、高脂血症和手足综合征。≥3级不良反应主要为高血压、肝功能异常、蛋白尿和贫血。常见血液学不良反应有贫血、血小板减少、白细胞减少、中性粒细胞减少及淋巴细胞减少。2组治疗方案中出现≥3级不良反应都与更好的ORR及PFS获益相关(P < 0.05)。结论 靶向治疗和靶免联合治疗在中国晚期肾癌患者中安全性可控且相似，用药期间应加强不良事件的随访和管理，发生较严重不良反应与更好的治疗预后相关。Abstract: Objective To evaluate the occurrence of adverse reactions of systemic therapy for advanced renal cell carcinoma and their correlation with efficacy.Methods Clinical data of 200 patients with advanced renal cell carcinoma who received targeted or targeted immunotherapy in the first line in Renji Hospital, Shanghai Jiao Tong University School of Medicine from June 2018 to December 2023 were retrospectively analyzed. Treatment-related adverse events and grade ≥3 adverse events were analyzed. The correlation between grade≥3 treatment-related adverse events and objective response rate(ORR) and progression-free survival(PFS) was analyzed.Results The overall adverse reaction rate of first-line treatment in 200 patients was 99.21% in the targeted therapy group and 100% in the targeted immunotherapy group. The incidence of grade ≥3 adverse reactions was 61.64% in the targeted therapy group and 65.35% in the targeted immunotherapy group. The incidence of discontinuation due to adverse reactions was 17.32% in the targeted therapy group and 20.55% in the targeted immunotherapy group. The common adverse reactions of first-line treatment were proteinuria, anemia, blood creatinine elevation, hypertension, diarrhea, abnormal hepatic function, platelet count decline, hypothyroidism, hyperlipidemia, and hand-foot syndrome. Grade ≥3 adverse reactions were primarily hypertension, abnormal hepatic function, proteinuria, and anemia. Common hematologic adverse reactions were anemia, platelet count decline, leukopenia, neutropenia, and lymphopenia. The presence of grade ≥3 adverse reactions was associated with better ORR and PFS benefit in both treatment groups (P < 0.05).Conclusion Targeted therapy and targeted immunotherapy have controllable and similar safety profiles in Chinese patients with advanced renal cell carcinoma. The follow-up and management of adverse events should be strengthened during the medication, and the occurrence of serious adverse reactions is associated with a better therapeutic prognosis.
-
Key words:
- advanced renal cell carcinoma /
- targeted therapy /
- immunotherapy /
- adverse reactions
-
-
表 1 研究队列治疗方案
治疗方案 例数 百分比/% 一线 200 单靶向治疗 127 63.5 培唑帕尼 49 24.5 阿昔替尼 32 16.0 舒尼替尼 29 14.5 索拉非尼 17 8.5 靶免联合治疗 73 36.5 阿昔替尼+特瑞普利单抗 29 14.5 阿昔替尼+替雷利珠单抗 20 10.0 阿昔替尼+帕博利珠单抗 6 3.0 舒尼替尼+信迪利单抗 5 2.5 培唑帕尼+替雷利珠单抗 4 2.0 卡博替尼+替雷利珠单抗 4 2.0 阿昔替尼+卡瑞利珠单抗 3 1.5 安罗替尼+替雷利珠单抗 2 1.0 二线 85 单靶向治疗 30 35.3 阿昔替尼 16 18.8 培唑帕尼 8 9.4 安罗替尼 5 5.9 索拉非尼 1 1.2 靶免联合治疗 55 64.7 阿昔替尼+特瑞普利单抗 15 17.6 阿昔替尼+替雷利珠单抗 13 15.3 阿昔替尼+帕博利珠单抗 11 12.9 安罗替尼+替雷利珠单抗 5 5.9 舒尼替尼+特瑞普利单抗 4 4.7 阿昔替尼+信迪利单抗 3 3.5 索拉非尼+特瑞普利单抗 2 2.4 舒尼替尼+信迪利单抗 2 2.4 用药周期 < 6个月 47 23.5 6~12个月 41 20.5 >12月 112 56.0 
下载: 导出CSV
表 2 一线靶向及靶免联合治疗常见不良反应及发生率
% 不良反应类型 靶向治疗组(127例) 靶免联合治疗组(73例) 总体 ≥3级 总体 ≥3级 蛋白尿 40.16 7.09 47.95 10.96 贫血 42.52 7.09 35.61 5.48 肌酐升高 37.00 1.57 39.73 4.11 高血压 37.80 11.81 36.99 15.07 腹泻 31.50 2.36 41.10 6.85 肝功能异常 28.35 7.87 38.36 15.07 血小板减少 32.28 5.51 27.40 4.11 甲状腺功能减退 22.05 0 42.47 2.74 高脂血症 21.26 5.51 34.25 5.48 手足综合征 17.32 1.57 27.40 6.85
下载: 导出CSV
表 3 二线靶向及靶免联合治疗常见不良反应及发生率
% 不良反应类型 靶向治疗组(30例) 靶免联合治疗组(55例) 总体 ≥3级 总体 ≥3级 蛋白尿 36.67 6.67 40.00 9.10 贫血 30.00 10.00 29.09 5.46 肌酐升高 40.00 0 45.45 0 高血压 23.33 16.67 32.72 7.28 腹泻 20.00 3.33 27.27 7.28 肝功能异常 26.67 13.33 30.91 12.73 血小板减少 30.00 10.00 18.18 3.64 甲状腺功能减退 16.67 0 14.55 1.82 高脂血症 26.67 6.67 21.82 5.46 手足综合征 13.33 3.33 12.73 1.82
下载: 导出CSV
表 4 一线治疗血液学常见不良反应及发生率
% 不良反应类型 靶向治疗组(127例) 靶免联合治疗组(73例) 总体 ≥3级 总体 ≥3级 贫血 42.52 7.09 35.61 5.48 白细胞减少 22.83 3.94 16.44 0 血小板减少 32.28 5.51 27.40 4.11 中性粒细胞减少 11.81 2.36 8.22 2.74 淋巴细胞减少 15.74 4.72 10.96 5.48
下载: 导出CSV
表 5 严重TRAEs组和无严重TRAEs组临床基线特征
例 临床因素 严重TRAEs组(126例) 无严重TRAEs组(74例) 性别 男 95 54 女 31 20 年龄/岁 ≥60 44 31 < 60 82 43 BMI/(kg/m2) < 18.5 12 5 18.5~25.0 74 62 >25.0 40 7 手术方式 肾部分切除术 17 13 肾根治性切除术 75 51 未做 34 10 肿瘤位置 左侧 62 39 右侧 56 33 双侧 8 2 原发肿瘤最大直径/cm >7 69 37 ≤7 57 37 IMDC分层 低危 33 12 中危 67 39 高危 26 23 KPS评分 80~100 102 60 50~70 20 10 < 50 4 4 ECOG评分 0~1 81 51 2~4 45 23 初诊AJCC分期 Ⅰ 20 12 Ⅱ 12 6 Ⅲ 33 16 Ⅳ 61 40
下载: 导出CSV
-
[1] Motzer RJ, Jonasch E, Agarwal N, et al. Kidney cancer, version 3.2022, NCCN clinical practice guidelines in oncology[J]. J Natl Compr Canc Netw, 2022, 20(1): 71-90. doi: 10.6004/jnccn.2022.0001
[2] Hsieh JJ, Purdue MP, Signoretti S, et al. Renal cell carcinoma[J]. Nat Rev Dis Primers, 2017, 3: 17009. doi: 10.1038/nrdp.2017.9
[3] National Comprehensive Cancer Network. Kidney cancer(v. 1.2024)[EB/OL]. [2024-07-07].
https://www.nccnchina.org.cn/guide/detail/406 .[4] Ljungberg B, Albiges L, Abu-Ghanem Y, et al. European association of urology guidelines on renal cell carcinoma: the 2022 update[J]. Eur Urol, 2022, 82(4): 399-410. doi: 10.1016/j.eururo.2022.03.006
[5] Gupta K, Miller JD, Li JZ, et al. Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma(mRCC): a literature review[J]. Cancer Treat Rev, 2008, 34(3): 193-205. doi: 10.1016/j.ctrv.2007.12.001
[6] Motzer RJ, Bacik J, Schwartz LH, et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma[J]. J Clin Oncol, 2004, 22(3): 454-463. doi: 10.1200/JCO.2004.06.132
[7] 王荀, 郑军华, 翟炜. EAU 2024热点速递: 肾细胞癌的临床研究进展[J]. 临床泌尿外科杂志, 2024, 39(6): 544-546, 550. https://lcmw.whuhzzs.com/article/doi/10.13201/j.issn.1001-1420.2024.06.016
[8] Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma(METEOR): final results from a randomised, open-label, phase 3 trial[J]. Lancet Oncol, 2016, 17(7): 917-927. doi: 10.1016/S1470-2045(16)30107-3
[9] Larkin JMG, Eisen T. Kinase inhibitors in the treatment of renal cell carcinoma[J]. Crit Rev Oncol Hematol, 2006, 60(3): 216-226. doi: 10.1016/j.critrevonc.2006.06.008
[10] Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase Ⅲ trial[J]. Lancet, 2008, 372(9637): 449-456. doi: 10.1016/S0140-6736(08)61039-9
[11] Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon Alfa in patients with metastatic renal cell carcinoma[J]. J Clin Oncol, 2023, 41(11): 1965-1971. doi: 10.1200/JCO.22.02623
[12] Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma(AXIS): a randomised phase 3 trial[J]. Lancet, 2011, 378(9807): 1931-1939. doi: 10.1016/S0140-6736(11)61613-9
[13] Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase Ⅲtrial[J]. J Clin Oncol, 2023, 41(11): 1957-1964. doi: 10.1200/JCO.22.02622
[14] Motzer RJ, Tykodi SS, Escudier B, et al. Final analysis of the CheckMate 025 trial comparing nivolumab(NIVO)versus everolimus(EVE)with>5 years of follow-up in patients with advanced renal cell carcinoma(aRCC)[J]. J Clin Oncol, 2020, 38(6_suppl): 617. doi: 10.1200/JCO.2020.38.6_suppl.617
[15] Eigentler TK, Hassel JC, Berking C, et al. Diagnosis, monitoring and management of immune-related adverse drug reactions of anti-PD-1 antibody therapy[J]. Cancer Treat Rev, 2016, 45: 7-18. doi: 10.1016/j.ctrv.2016.02.003
[16] Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma[J]. N Engl J Med, 2021, 384(14): 1289-1300. doi: 10.1056/NEJMoa2035716
[17] Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma[J]. N Engl J Med, 2019, 380(12): 1116-1127. doi: 10.1056/NEJMoa1816714
[18] Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma[J]. N Engl J Med, 2019, 380(12): 1103-1115. doi: 10.1056/NEJMoa1816047
[19] Atkinson TM, Ryan SJ, Bennett AV, et al. The association between clinician-based common terminology criteria for adverse events(CTCAE)and patient-reported outcomes(PRO): a systematic review[J]. Support Care Cancer, 2016, 24(8): 3669-3676. doi: 10.1007/s00520-016-3297-9
[20] Yan XQ, Ye MJ, Zou Q, et al. Toripalimab plus axitinib versus sunitinib as first-line treatment for advanced renal cell carcinoma: RENOTORCH, a randomized, open-label, phase Ⅲ study[J]. Ann Oncol, 2024, 35(2): 190-199. doi: 10.1016/j.annonc.2023.09.3108
[21] Wang DY, Mooradian MJ, Kim D, et al. Clinical characterization of colitis arising from anti-PD-1 based therapy[J]. Oncoimmunology, 2019, 8(1): e1524695. doi: 10.1080/2162402X.2018.1524695
[22] Zhu AX, Duda DG, Ancukiewicz M, et al. Exploratory analysis of early toxicity of sunitinib in advanced hepatocellular carcinoma patients: kinetics and potential biomarker value[J]. Clin Cancer Res, 2011, 17(4): 918-927. doi: 10.1158/1078-0432.CCR-10-0515
[23] Filep JG. Endogenous endothelin modulates blood pressure, plasma volume, and albumin escape after systemic nitric oxide blockade[J]. Hypertension, 1997, 30(1 Pt 1): 22-28.
[24] Michaelson MD, Cohen DP, Li S, et al. Hand-foot syndrome(HFS)as a potential biomarker of efficacy in patients(pts)with metastatic renal cell carcinoma(mRCC)treated with sunitinib(SU)[J]. J Clin Oncol, 2011, 29(7_suppl): 320. doi: 10.1200/jco.2011.29.7_suppl.320
[25] Schmidinger M, Vogl UM, Bojic M, et al. Hypothyroidism in patients with renal cell carcinoma: blessing or curse?[J]. Cancer, 2011, 117(3): 534-544. doi: 10.1002/cncr.25422
[26] Rixe O, Billemont B, Izzedine H. Hypertension as a predictive factor of Sunitinib activity[J]. Ann Oncol, 2007, 18(6): 1117. doi: 10.1093/annonc/mdm184
[27] Verzoni E, Cartenì G, Cortesi E, et al. Real-world efficacy and safety of nivolumab in previously-treated metastatic renal cell carcinoma, and association between immune-related adverse events and survival: the Italian expanded access program[J]. J Immunother Cancer, 2019, 7(1): 99. doi: 10.1186/s40425-019-0579-z
[28] Tannir NM, Motzer RJ, Plimack ER, et al. Outcomes in patients(pts)with advanced renal cell carcinoma(aRCC)who discontinued(DC)first-line nivolumab + ipilimumab(N+I)or sunitinib(S)due to treatment-related adverse events(TRAEs)in CheckMate 214[J]. J Clin Oncol, 2019, 37(7_suppl): 581. doi: 10.1200/JCO.2019.37.7_suppl.581
-
图(2)
表(5)
计量
- 文章访问数: 657
- PDF下载数: 166
- 施引文献: 0