Combined brachytherapy with intermittent hormonal therapy in treating clinical moderate and high risk non-metastatic prostate cancer

目的 探讨125I放射性粒子植入术联合间歇性内分泌治疗用于临床中高危非转移性前列腺癌的有效性和安全性.方法 2011年7月至2013年8月采用前瞻性非随机法入组患者.入组标准:经前列腺穿刺活检诊断为前列腺腺癌;临床评估为非转移性前列腺癌,且存在任一临床中危及高危因素(cT≥T2b期,Gleason评分≥7分,穿刺前PSA≥10 ng/ml);同意接受前列腺125I放射性粒子植入术及内分泌治疗.排除标准:既往使用过新辅助或辅助内分泌治疗;已有肿瘤远处转移;不能耐受内分泌治疗等.按治疗方法不同将入组患者分为研究组和对照组.两组各入组50例.研究组患者行前列腺125I放射性粒子植入术,术后即刻口服比卡鲁胺胶囊(50 mg,每日1次)治疗,术后1周左右开始注射亮丙瑞林(3.75 mg,每28天1次);对照组患者行单纯间歇性内分泌治疗,口服比卡鲁胺胶囊(50 mg,每日1次)治疗,注射亮丙瑞林(3.75 mg,每28天1次).随访期间患者每个月检测血清PSA水平,当PSA＜0.2 ng/ml并稳定3个月则停止内分泌治疗;当PSA≥1.0 ng/ml,并连续3次升高,则重新开始内分泌治疗.每6个月行胸部X线片及全身骨扫描检查.记录患者治疗前及治疗后每3个月的IPSS评分.研究组患者术后每3个月评估患者的尿道及直肠不良反应情况.观察两组患者PSA降至停药水平的比例、初次内分泌治疗时间及初次内分泌治疗后稳定时间等,并计算总体生存率、肿瘤特异性生存率、无再次接受内分泌治疗生存率、无骨转移生存率、无去势抵抗性前列腺癌进展生存率等.结果 研究组患者年龄65～88岁,平均76.4岁;穿刺前PSA 4.0～ 117.0 ng/ml,平均28.4 ng/ml;穿刺Gleason评分6分5例,7分29例,≥8分16例;临床分期T2期40例,T3期10例;临床危险分层中危组26例,高危组24例.对照组年龄61～85岁,平均75.6岁;穿刺前PSA 5.3～213.0 ng/ml,平均37.3 ng/ml;穿刺Gleason评分6分1例,7分28例,≥8分21例;临床分期T2期35例,T3期15例;临床危险分层中危组22例,高危组28例.两组上述指标的比较差异均无统计学意义(均P＞0.05).两组患者随访24 ～ 40个月,平均31.6个月.研究组50例(100％) PSA均降至停药水平,应用内分泌治疗时间4 ～12个月,平均6.3个月;21例(42％) PSA水平再次升高并满足重新用药标准,再次应用内分泌治疗.对照组47例(94％) PSA降至停药水平,应用内分泌治疗时间5～ 15个月,平均7.2个月;34例(68％)PSA水平再次升高并满足重新用药标准,再次应用内分泌治疗.两组PSA降至停药水平患者比例及初次内分泌治疗时间的比较差异均无统计学意义(均P＞0.05).研究组和对照组初次内分泌治疗后稳定时间分别为27.2个月和17.7个月,差异有统计学意义(P＜0.001).Kaplan-Meier生存曲线分析结果显示,两组间肿瘤特异性生存率及总体生存率差异均无统计学意义(均P＞0.05),无再次接受内分泌治疗生存率(P =0.002)、无骨转移生存率(P =0.040)、无去势抵抗性前列腺癌进展生存率(P =0.005),差异均有统计学意义.结论 与单纯间歇性内分泌治疗相比,联合应用125I放射性粒子植入术和间歇性内分泌治疗能够延长临床中高危非转移性前列腺癌患者的内分泌治疗间歇期,并可有效控制疾病进展,此方法安全、有效.Objective To investigate the clinical value of 125I particle implantation brachytherapy combined with intermittent hormonal therapy for treating clinical moderate and high risk non-metastatic prostate cancer.Methods A prospective study was proceeded and 100 cases with moderate and high risk (cT≥T2b,Gleason score ≥ 7,pre-biopsy PSA ≥ 10 ng/ml)non-metastatic prostate cancer were included.The selected patients were divided into two group.In the study group,patients were treated with 125I particle implantation combined with intermittent hormonal therapy.In the control group,patients were treated with only intermittent hormonal therapy.Hormonal therapy was maximal androgen blockage for two groups,including bicalutamide 50 mg oral every day and Leuprorelin 3.75 mg subcutaneous injection every 28 days.There were 50 cases in each group and clinical trial agreements were signed.During follow-up,PSA were tested every month.Chest X-ray and whole-body hone scanning were checked every 6 months.Hormonal therapy was stopped when patient's PSA level fell to 0.2 ng/ml,and keep stabilized for 3 months.When PSA level elevated for 3 times continuously and over 1 ng/ml,hormonal therapy was initiated again.The IPSS scores were documented before treatment and every 3 months after treatment.Adverse reactions of urinary tract and rectum were assessed every 3 months after 125I particle implantation in study group.The ratio of the first time to stop hormonal therapy,the time duration of first hormonal therapy and stable phase,re-hormonal therapy free survival rate,bone metastasis free survival rate,castration resistance prostate cancer(CRPC) free survival rate,cancer-specific free survival rate and overall survival rate were compared.Results The 100 cases in this study were followed up for 24-40 months,with an average time of 31.6 months.In study group,the PSA level in all cases descended to the level of stopping hormonal therapy.The time duration of hormone therapy ranged from 4 to 12 months,with an average time of 6.3 months.21 (42％) cases had a PSA elevation again to restart hormonal therapy.In control group,the PSA level in 47 cases descended to the level of stopping hormonal therapy.The time duration of hormone therapy ranged from 5 to 15 months,with an average time of 7.2 months.34 (68％) cases had a PSA elevation again to restart hormonal therapy.There was no significant difference in percentage of cases of stopping hormone therapy and in time duration of hormonal therapy for the first cycle.Instead,there were significant differences in stable phase after first cycle hormonal therapy between two groups (27.2 months vs.17.7 months;P ＜ 0.001).When analyzed by Kaplan-Meier survival curve,there was no significant difference in cancer-specific survival rate and overall survival rate.There were significant differences in Re-hormonal therapy free survival (P =0.002),bone metastasis free survival (P =0.04) and CRPC free survival(P =0.005).Conclusions Compared with intermittent hormonal therapy alone,125I particle implantation brachytherapy combined with intermittent hormonal therapy could prolong the hormonal sensitive time in moderate and high risk nonmetastatic prostate cancer patients and control the progress of the prostate cancer.中国科学引文数据库(CSCD)6448-4523