NEJM：间歇性雄激素剥夺治疗可小幅改善前列腺癌患者生存质量

生存期亚组分析

大多数接受雄激素剥夺疗法的转移性荷尔蒙敏感型前列腺癌患者会出现去势抵抗性。假设疾病进展前予以雄激素替代治疗或可延长雄激素依赖。美国密歇根大学Hussain博士等人日前的研究显示，与持续性治疗相比，间歇性治疗导致生存质量有小幅改善，但生存期方面未得出统计学结论。论文发表于国际权威杂志NEJM 2013年4月最新一期在线版上。
体力状为0至2，前列腺特异性抗原(PSA)水平为5 ng每毫升或更高的新诊转移性、荷尔蒙敏感性前列腺癌患者，接受黄体生成激素释放激素以及抗雄激素药物治疗7个月。研究人员随后对PSA水平降到4 ng以下的患者随机分组，分别接受持续性或间歇性雄激素剥夺治疗，根据患者先前是否接受荷尔蒙治疗、体力状态、病变范围（最低限度或广泛扩散）对患者分层。主要复合目标为间歇治疗改善生存方面与持续性治疗相比是否具有非劣效性，方法为一侧检验，风险比上限为1.20，以及随机化3个月后组间患者有无生活质量差异。
结果显示，共有3040例患者入组，其中1535例纳入分析：765例患者随机分组接受持续性雄激素剥夺治疗，770例患者接受间歇性雄激素剥夺治疗。中位随访期9.8年。持续性治疗组患者中位生存期5.8年，间歇性治疗组则为5.1年（间歇性疗法死亡危害比，1.10; 90% 置信区间, 0.99 至1.23）。3个月时，间歇性疗法可产生更优的性功能和心理健康结局(分别为P<0.001和P=0.003)，但此后无优越性。治疗相关性高级不良反应的数量无显著的组间差异。
研究者写道，我们的试验未得出统计学结论，对于转移性荷尔蒙敏感性前列腺癌患者，生存期置信区间超出非劣效性上边界意味着我们不能排除与持续性治疗相比，间歇性治疗死亡风险增加20%，但几乎没有事件能够排除间歇性治疗有显著性劣效性。间歇性治疗导致生存质量有小幅改善。
与前列腺癌相关的拓展阅读：

• 地加瑞克治疗前列腺癌疗效佳
• Lancet Oncol：经皮雌激素治疗前列腺癌可减少并发症的发生
• 短期雄激素阻断治疗高危前列腺癌安全有效
• NEJM：前列腺癌手术后15年功能结局与放疗相似
• Lancet Oncol:激素敏感性前列腺癌是否需要多西他赛？
• Cancer Cell：前列腺癌中基因组大片区域受到表观遗传调控激活
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Intermittent versus Continuous Androgen Deprivation in Prostate Cancer
Background
Castration resistance occurs in most patients with metastatic hormone-sensitive prostate cancer who are receiving androgen-deprivation therapy. Replacing androgens before progression of the disease is hypothesized to prolong androgen dependence.
Methods
Men with newly diagnosed, metastatic, hormone-sensitive prostate cancer, a performance status of 0 to 2, and a prostate-specific antigen (PSA) level of 5 ng per milliliter or higher received a luteinizing hormone–releasing hormone analogue and an antiandrogen agent for 7 months. We then randomly assigned patients in whom the PSA level fell to 4 ng per milliliter or lower to continuous or intermittent androgen deprivation, with patients stratified according to prior or no prior hormonal therapy, performance status, and extent of disease (minimal or extensive). The coprimary objectives were to assess whether intermittent therapy was noninferior to continuous therapy with respect to survival, with a one-sided test with an upper boundary of the hazard ratio of 1.20, and whether quality of life differed between the groups 3 months after randomization.
Results
A total of 3040 patients were enrolled, of whom 1535 were included in the analysis: 765 randomly assigned to continuous androgen deprivation and 770 assigned to intermittent androgen deprivation. The median follow-up period was 9.8 years. Median survival was 5.8 years in the continuous-therapy groufp and 5.1 years in the intermittent-therapy group (hazard ratio for death with intermittent therapy, 1.10; 90% confidence interval, 0.99 to 1.23). Intermittent therapy was associated with better erectile function and mental health (P<0.001 and P=0.003, respectively) at month 3 but not thereafter. There were no significant differences between the groups in the number of treatment-related high-grade adverse events.
Conclusions
Our findings were statistically inconclusive. In patients with metastatic hormone-sensitive prostate cancer, the confidence interval for survival exceeded the upper boundary for noninferiority, suggesting that we cannot rule out a 20% greater risk of death with intermittent therapy than with continuous therapy, but too few events occurred to rule out significant inferiority of intermittent therapy. Intermittent therapy resulted in small improvements in quality of life. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00002651.)