双极雄激素序贯免疫检查点抑制剂治疗转移性去势抵抗性前列腺癌4例  

Bipolar androgen therapy followed by immune checkpoint inhibitors in metastatic castration resistant prostate cancer:A report of 4 cases

作　　者：刘圣杰[1] 侯惠民[1] 吕政通 丁鑫 王璐[1] 张磊[1] 刘明[1] LIU Sheng-jie;HOU Hui-min;LV Zheng-tong;DING Xin;WANG Lu;ZHANG Lei;LIU Ming(Department of Urology,Beijing Hospital,National Center of Gerontology,Institute of Geriatric Medicine,Chinses Academy of Medical Sciences,Beijing 100070,China)

机构地区：[1]北京医院泌尿外科,国家老年医学中心,中国医学科学院老年医学研究院,北京100730

出　　处：《北京大学学报（医学版）》2022年第4期766-769,共4页Journal of Peking University:Health Sciences

基　　金：国家自然科学基金(81900700);北京医院临床研究启航专项(BJ-2022-157)。

摘　　要：雄激素与前列腺癌治疗的关系一直困扰着泌尿外科肿瘤领域,Huggins等[1]发现雄激素剥夺治疗(androgen deprivation therapy,ADT)可抑制前列腺癌细胞生长,补充雄激素可促进细胞增殖,这种理论成为前列腺癌内分泌治疗的理论基础,然而,美国约翰·霍普金斯大学的Sidney Kimmel癌症中心Denmeade等[2]发现低剂量雄激素可促进前列腺癌细胞增殖,而高剂量雄激素可抑制前列腺癌细胞增殖,据此,2010年提出了雄激素水平骤升骤降快速交替的双极雄激素治疗(bipolar androgen therapy,BAT)。BAT指在前列腺癌患者持续ADT的基础上,予单次高剂量的外源性雄激素,每28天1个循环,实现睾酮超生理水平和去势水平的快速交替,高剂量雄激素诱导的DNA断裂和凋亡是短暂的,睾酮的快速循环可能导致DNA的反复损伤,增强其抗肿瘤作用[3]。2020年4月Sidney Kimmel癌症中心Mark等[4]报告了3例转移性去势抵抗性前列腺癌(metastatic castration resistant prostate cancer,mCRPC)患者使用BAT和恩杂鲁胺治疗后行免疫检查点治疗的前列腺特异性抗原(prostate specific antigen,PSA)和客观反应,发现免疫检查点抑制剂可能对使用过BAT和恩杂鲁胺免疫激活治疗后的前列腺癌患者具有治疗潜力。北京医院泌尿外科对于中国mCRPC患者BAT治疗后行免疫检查点抑制剂治疗的疗效和安全性开展了前瞻性单臂临床研究,本文分享4例完成BAT序贯免疫检查点抑制剂治疗的患者疗效及其安全性结果。本研究开始前已经北京医院伦理委员会审查批准(2020BJYYEC-180-03),所有入组患者均签署知情同意书。The relationship between androgen and prostate cancer treatment has plagued the field of urologic oncology. To investigate the efficacy and safety of bipolar androgen therapy(BAT) followed by immune checkpoint inhibitor therapy in patients with metastatic castration resistant prostate cancer(mCRPC). In August 2020, Beijing Hospital conducted an investigator-initiated study: Bipolar androgen therapy followed by immune checkpoint inhibitor therapy in metastatic castration resistant prostate cancer. Up to now, the study has included 4 patients who completed the entire cycle of treatment. The mean age of the patients was 74.5(68 to 82) years old, the mean prostate-specific antigen(PSA) was 20.8(9.9 to 8.36) μg/L, the mean testosterone was 0.50(0.00 to 1.81) μg/L, and the Gleason score were 10 and 9, 7, 7 respectively. The pain scale score before treatment was 1.5(1 to 2). In this study, 4 patients completed the entire cycle of treatment, and the treatment effect of the patients showed great heterogeneity. PSA in case 1 decreased from 24.0 μg/L to 0.47 μg/L, testosterone increased from 0.175 6 μg/L to 2.62 μg/L. PSA in case 2 increased from 9.939 μg/L to 168.536 μg/L, and testosterone increased from 0.0 μg/L increased to 2.85 μg/L. PSA increased from 13.31 μg/L to 39.278 μg/L in case 3, testosterone increased from 0.0 μg/L to 2.54 μg/L. and PSA increased from 36.0 μg/L to 350.2 μg/L in the case 4, testosterone increased from 1.81 μg/L to 3.85 μg/L. Except for one patient who showed significant PSA remission, the PSA levels of the remaining three patients remained high overall. There were no adverse reactions reported in 4 patients. In the follow-up, case 1 continued to use PD-1 monoclonal antibody(median progression free survival time was 10 months). Two patients who had previously been resistant to enzalutamide received enzalutamide again after the whole cycle of treatment, and their PSA decreased again, which indicated that the patient was sensitive to enzalutamide again. BAT had a certain therapeu

关 键 词：前列腺癌 双极雄激素 免疫检查点抑制剂 疗效 安全性 

分 类 号：R737[医药卫生—肿瘤]