间歇性雄激素剥夺治疗结果不明确

《新英格兰医学杂志》4月3日在线发表的一项针对转移性激素敏感性前列腺癌患者的10年研究显示，间歇性雄激素剥夺治疗在生存结局方面未能证明非劣效于标准持续性雄激素剥夺治疗(N. Engl. J. Med. 2013 April 3 [doi: 10.1056/NEJMoa1212299])。

在这项国际随机临床研究中，密歇根大学安阿伯分校血液学/肿瘤学科Maha Hussain博士及其同事在1995~2008年间从美国、英国和加拿大的多个中心纳入1,749例新诊断转移性激素敏感性前列腺癌且前列腺特异性抗原(PSA)水平≥5 ng/ml的患者。所有患者经7个月戈舍瑞林、比卡鲁胺或类似药物诱导治疗有效。

根据患者的体能状态、既往激素治疗和转移性疾病程度对患者进行分层。局限于脊柱、骨盆骨或淋巴结的癌被认为极轻微，而累及肋骨、长骨或内脏的癌被认为广泛。患者随后随机接受间歇性或标准持续性激素剥夺治疗。

在间歇性治疗组中，在PSA恢复至基线水平或至20 ng/ml后才恢复治疗。根据研究者自己的判断，也可在PSA水平达10 ng/ml或出现症状时恢复雄激素剥夺治疗。如果患者经后续7个月治疗有效，则开始另一个停止治疗的间期。中位随访时间为9.8年。

结果显示，总中位生存时间为3.7年。持续性治疗组有445例死亡，间歇性治疗组有483例死亡。两组80%的死亡与癌症相关。

间歇性治疗组随机化的中位生存时间为5.1年，而持续性治疗组为5.8年。研究者告诫，组间缺乏显著性差异并不表明生存率相似。间歇性治疗甚至可能有损生存，因为该组死亡风险相对增加10%。并且在统计学上，不能排除死亡风险相对增加20%的可能性。

研究者无法证明间歇性雄激素剥夺治疗是非劣效于还是劣效于持续性雄激素剥夺治疗。

事后分析显示，所有亚组的疗效总体一致。以多西他赛获得批准的2004年为界，2004年以前与以后存活的患者在生存方面无显著差异。然而，研究者告诫，不应过分解读亚组分析的结果。

两个研究组在随机化后3个月的生活质量指标方面存在差异。与持续性治疗组相比，间歇性治疗组患者的阳痿发生率显著较低并且心理健康评分显著更佳。间歇性治疗组的性欲评分也高于持续性治疗组，但差异无统计学显著性。

间歇性治疗组生活质量指标方面的优势在随机化后9个月仍观察到，但此后逐渐降低。15个月时，间歇性治疗组唯一评分较佳的生活质量指标是总体躯体功能。

两个研究组的3级和4级不良事件例数非常相似。

该研究获美国国立癌症研究所、美国公共卫生服务部和阿斯利康公司资助。阿斯利康公司提供研究中所用的戈舍瑞林和比卡鲁胺，但未参与研究设计、数据收集和分析及论文撰写。Hussain博士声明与阿斯利康公司存在联系，其他研究者与多家药企存在联系。

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By: MARY ANN MOON, Internal Medicine News Digital Network

Intermittent androgen deprivation fell short of proving its noninferiority in a 10-year study comparing survival outcomes for intermittent and standard continuous androgen deprivation in men with metastatic hormone-sensitive prostate cancer.

In the international randomized clinical trial designed to test the noninferiority of intermittent androgen deprivation, the findings were "statistically inconclusive," according to a report published online April 3 in the New England Journal of Medicine.

In short, "the trial results are inconclusive," said Dr. Maha Hussain of the division of hematology/oncology, University of Michigan, Ann Arbor, and her associates. "The median survival after randomization was 5.1 years in the intermittent-therapy group, as compared with 5.8 years in the continuous-therapy group."

The researchers also cautioned that "the lack of a significant difference between the groups does not imply similar survival."

Intermittent therapy might even compromise survival, they said, as a 10% relative increase in the risk of death was associated with that treatment approach. And statistically, a possible 20% relative rise in mortality risk could not be ruled out.

It was hoped that intermittent androgen deprivation would improve patients’ quality of life by reducing adverse effects from the treatment and would improve survival by staving off the androgen resistance, which eventually develops in most patients.

Dr. Hussain and her colleagues compared intermittent with continuous androgen deprivation in 1,749 men enrolled during 1995-2008 at multiple sites across the United States, the United Kingdom, and Canada.

The study subjects all had newly diagnosed, metastatic, hormone-sensitive prostate cancer and a prostate-specific antigen (PSA) level of 5 ng/mL or higher. All had responded to a 7-month induction course of goserelin, bicalutamide, or a similar agent.

The study subjects were stratified by their performance status, prior hormone therapy, and the extent of their metastatic disease. Cancer confined to the spine, pelvic bones, or lymph nodes was considered minimal while that involving the ribs, long bones, or visceral organs was considered extensive.

The subjects were then randomly assigned to receive either intermittent or standard, continuous androgen-deprivation therapy.

In intermittent therapy, treatment was suspended until PSA values returned to baseline levels or to 20 ng/mL. At the discretion of the researchers, androgen deprivation also could be resumed when PSA levels reached 10 ng/mL or when symptoms developed. If patients responded to a subsequent 7-month course of the therapy, another off-treatment interval was begun.

The study subjects were followed for a median of 9.8 years.

Overall median survival was 3.7 years. There were 445 deaths in the continuous-therapy group and 483 deaths in the intermittent-therapy group. Deaths were cancer-related in approximately 80% of the members of both groups, the investigators reported (N. Engl. J. Med. 2013 April 3 [doi: 10.1056/NEJMoa1212299]).

The researchers were unable to show that intermittent androgen-deprivation therapy was either noninferior or inferior to continuous androgen-deprivation therapy.

Treatment effects were "generally consistent" across all subgroups of patients in a post hoc analysis of the data. For example, there was no significant difference in survival between patients who were alive before 2004, when treatment with docetaxel was approved, and those who were alive in 2004 or later. However, "caution should be taken not to overinterpret the results of the subgroup analyses," Dr. Hussain and her associates noted.

The two study groups differed in quality-of-life measures at 3 months after randomization. Men assigned to intermittent therapy were significantly less likely to report impotence and had significantly better mental health scores than did those assigned to continuous androgen deprivation. The intermittent-therapy group also tended to have higher scores for libido, but that difference did not reach statistical significance.

The advantage in quality-of-life measures persisted at 9 months after randomization but gradually declined. By 15 months, the only quality-of-life measure that scored better in the intermittent-therapy group was overall physical functioning.

There was a "remarkably similar" number of grade 3 and grade 4 adverse events in both study groups, the researchers said.

This study was funded by the U.S. National Cancer Institute, the U.S. Public Health Service, and AstraZeneca. AstraZeneca donated goserelin and bicalutamide used in this study but had no role in the study design, data collection or analysis, or writing the manuscript. Dr. Hussain reported ties to AstraZeneca, and her associates reported ties to numerous industry sources.