【作者】 陈峰；

【导师】 丁森泰；

【作者基本信息】 山东大学 ， 外科学（泌尿外科）（专业学位）， 2022， 硕士

【摘要】 研究背景:肾细胞癌(RCC)的发病率在成人恶性肿瘤中约占2%～3%。在泌尿系统中仅次于前列腺癌和膀胱癌,却是泌尿系统死亡率最高的恶性肿瘤。由于肾癌的早期症状较隐匿,30%的患者在确诊时已有肾外转移。即使进行根治性肾切除术,30%的患者仍有复发或远处转移。一旦肾细胞癌发生转移,患者5年生存率极低,仅有12%。传统放疗、化疗和干扰素α等对转移性肾细胞癌(mRCC)的均疗效欠佳,中位生存期仅为18个月。随着2005年美国食品和药物管理局(FDA)批准索拉非尼治疗晚期肾细胞癌,晚期肾细胞癌的治疗进入以靶向治疗为主的时代。然而,几乎所有患者在靶向治疗过程中都会产生耐药。因此,迫切需要寻找新的治疗策略来持续改善晚期肾细胞癌患者的预后。近年来,随着对免疫系统调节机制研究的深入和免疫检查点抑制剂(ICI)的出现,以肿瘤免疫治疗为核心的生物治疗得到了迅速发展。2015年,FDA批准纳武利尤单抗(一种程序性细胞死亡受体1(PD-1)抑制剂)用于晚期肾癌的二线治疗,这标志着晚期肾癌免疫治疗的开始。美国国家综合癌症网络(NCCN)指南建议对国际转移性肾细胞癌联合数据库评分(IMDC)低、中、高风险人群进行首次治疗时即采用联合治疗,但2020年,美国临床肿瘤学会(ASCO)会议公布,KEYNOTE 426研究长期的亚组分析结果表明,低风险患者不能从联合治疗中获益。基于此,在2020年出版的中国临床肿瘤学会(CSCO)肾癌诊断和治疗指南中,针对低风险患者的Ⅰ级建议仍然是靶向治疗,而针对中高危患者的Ⅰ级建议则是免疫联合治疗。目前,替雷利珠单抗等ICI在我国已被批准用于治疗尿路上皮癌,但尚无批准用于治疗肾癌的免疫治疗药物,且尚缺乏相关真实世界研究。因此,本文针对该热点研究进行文献检索,并对山东省立医院近2年行靶向联合ICI治疗患者信息进行收集总结,初步评价其疗效与安全性,丰富临床工作者对该治疗方案在真实世界中的认知。目的:对目前国内外靶向ICI治疗晚期肾癌研究进展进行检索总结并结合本院单中心真实世界临床病例初步评价其有效性和安全性。材料和方法:选取山东省立医院2019年10月至2021年12月收治的17例行靶向联合ICI治疗的晚期肾细胞癌患者为研究对象。在联合用药期间,至少每2个周期进行1次分析评价,评价其治疗效果及相关不良反应发生情况。结果:中位随访时间为7.0(1.2～12.4)个月。17例均可评价疗效,其中部分缓解13例,疾病稳定3例,疾病进展1例。总体客观缓解率为76.5%(13/17)、疾病控制率为94.1%(16/17)。因随访时间较短,本研究未达到中位总生存期(mOS)及中位无进展生存期(mPFS)。所有患者不良反应发生率为94.1%(16/17),3/4级不良反应发生率为17.6%(3/17),无5级死亡患者。常见不良反应包括胃肠道反应(9/17)、皮肤反应(8/17)、高血压(6/17),本组出现2例血液毒性、2例牙龈炎、1例亚临床心肌损伤、1例免疫性肝炎、1例胰腺炎患者。未见肾脏毒性、免疫性肺炎、骨关节及肌毒性及其他少见毒性。结论:抗血管靶向药物联合免疫检查点PD-1/PD-L1抑制剂治疗晚期肾癌疗效显著,重度不良反应发生率低且不良反应可控,可作为一线治疗优选或初始多靶点酪氨酸激素抑制剂靶向治疗失败患者的后线选择。更多还原

【Abstract】 Background:incidence rate of RCC is about 2%to 3%of adult malignant tumors.It is the third only to prostate cancer and bladder cance in urinary system.But RCC has the highest mortality rate in urinary system.Because the early symptoms of RCC are hidden,30%of patients have extrarenal metastasis when making a definite diagnosis.Even after radical nephrectomy,30%of patients still have recurrence or distant metastasis.Once metastasis occurs,the 5-year survival rate of patients is only 12%.Effects of traditional radiotherapy,chemotherapy and interferon-α,etc on mRCC are not obvious.The current median survival is only 18 months.Since Sorafenib was approved by the U.S.FDA for the treatment of mRCC in 2005,the treatment of mRCC has entered an era dominated by targeted therapy.However,almost all patients will be resistant to targeted therapy.Therefore,it is necessary and urgent to find new treatment protocols in order to continuously improve the prognosis of patients with mRCC.In recent years,with the deepening of the research on the regulatory mechanism of the immune system and the emergence of ICI,the biotherapy with tumor immunotherapy as the core has developed rapidly.In 2015,FDA approves Nivolumab,an anti PD-1 was used for the second-line treatment of mRCC,which marked the beginning of immunotherapy for mRCC.NCCN guidelines recommend that combination therapy be used for the first treatment of low,medium and high-risk people by IMDC,but in 2020,The ASCO conference announced that the long-term subgroup analysis results of KEYNOTE 426 study showed that low-risk patients could not benefit from combination therapy.Based on this,in the CSCO guidelines for RCC published in 2020,the class I recommendations for low-risk patients are still targeted therapy,while the class I recommendations for medium and high-risk patients with mRCC are combined immunotherapy.At present,,ICI drugs such as Tirelizumab have been approved for the treatment of urothelial cancer in our country,but have not been approved for the treatment of RCC.And there is still a lack of real-world research on targeted drug combined with ICI in the treatment of mRCC.Therefore,this paper retrieves related literature about this hot research,collects and summarizes the information of patients treated with targeted duug combined ICI in Shandong Provincial Hospital in recent 2 years,preliminarily evaluates its efficacy and safety,for enriching the clinical workers’cognition of the treatment scheme in the real world.Objective:to retrieve and summarize the research progress of targeted drug combined ICI in the treatment of mRCC at home and abroad,and preliminarily evaluate its effectiveness and safety bansed on our hospital single-center real world clinical cases.Materials and methods:17 patients with mRCC treated by targeted drugs combined with ICI in Shandong provincial hospital from October 2019 to December 2021 were selected for this research objects.The efficacy of combined medication shall be evaluated at least once every two cycles,and the treatment effect and related adverse reactions shall be analyzed.Results:the median follow-up time was 7.0(1.2～12.4)months,17 cases could all evaluate the curative effect,including 13 cases of PR,3 cases of SD and 1 case of PD.The ORR was 76.5%(13/17),the DCR was 94.1%(16/17).Due to the short follow-up time,this study did not reach the mOS and mPFS.The incidence of adverse reactions in all patients was 94.1%(16/17),and the incidence of grade 3/4 adverse reactions was 17.6%(3/17),and there was no grade 5 death.The common adverse reactions included gastrointestinal reactions(9/17),skin reactions(8/17)and hypertension(6/17).There were 2 patients with hematotoxicity in this group,2 patients with gingivitis,1 patient with subclinical myocardial injury,1 patient with immune hepatitis,and 1 patient with pancreatitis.There were no patients with renal toxicity,immune pneumonia,osteoarthritis and muscle toxicity and other rare toxicity in this group.Conclusion:The combination of anti vascular targeted drugs and immune checkpoint PD-1/PD-L1 inhibitors has significant clinical efficacy in the treatment of mRCC.The incidence of severe adverse reactions is low and controllable.It can be used as the first-line treatment or the back-line choice for patients with initial multitarget tyrosine hormone inhibitor targeted treatment failure.更多还原