间歇激素治疗会缩短前列腺癌生存期

芝加哥(EGMN)——根据迄今规模最大、时间最长的比较间歇与持续雄激素剥夺治疗的临床试验结果，转移性前列腺癌患者如果定期暂停激素治疗，其寿命将缩短数年。一些进展期前列腺癌患者希望改善生活质量而又不愿降低疗效，因而采取间歇雄激素治疗(IAD)，而在美国临床肿瘤学会(ASCO)年会上公布的上述研究结果显然不支持这种做法。

这项试验始于1995年，当时患者的中位生存期为2.5~3年，医生们希望间歇疗法可以减轻副作用对生活质量的冲击。在实验数据的基础上，研究者推测，使用较小累计剂量药物可能延迟激素治疗耐药性的出现。根据非劣性试验的设计要求，在95%置信区间内，调查人员应能排除死亡风险相对增加≥20%。

据第一作者、密歇根大学综合癌症中心泌尿科的Maha Hussain博士介绍，受影响最大的是病情最轻的患者，这些患者接受间歇治疗或持续治疗的中位生存期分别为5.2年和7.1年。在这项由西南肿瘤组(SWOG)主导的Ⅲ期研究中，7年时持续治疗组有半数患者仍健在，而间歇治疗组仅有42%的患者仍存活。

IAD对广泛病变患者则似乎无不良影响，间歇治疗组与持续治疗组的中位总生存期分别为5年和4.4年。研究者表示这一结果“非常令人惊讶”，因为它与基于既往所有试验的传统观点迥然不同。Hussain博士称，7年时两组患者均有约1/3仍健在。总的来说，IAD不符合非劣效性标准。经过中位时间9.2年的随访，随机分组接受持续治疗者的中位生存期为5.8年，而IAD组患者仅为5.1年。

Hussain博士表示：“基于上述研究结果，持续治疗仍然是标准疗法。对于广泛病变患者，间歇治疗不逊于持续治疗，但对于轻症患者，间歇治疗的劣势很明显。这提示重症与轻症之间存在生物学固有差异，值得进一步研究。”在被问及是否推荐广泛病变患者采用间歇疗法时，Hussain博士回应称，上述数据来自于二次分析，应谨慎解读其意义，而且许多新疗法正陆续出现，为转移性前列腺癌患者带来了更多选择。

至于为何这项非劣性试验显示出了既往研究从未出现的负面效果，Hussain博士和新闻发布会主持人、华盛顿大学医学院的Bruce J. Roth博士列出了若干原因。值得注意的是，SWOG 9346（组间-0162）试验规模较大，涉及美国、加拿大和欧洲的5个癌症研究组，截至2008年共招募了3,040例前列腺特异性抗原(PSA)≥5的新诊断转移性前列腺癌患者。

此外，本试验仅将接受持续治疗(戈舍瑞林和比卡鲁胺)7个月后PSA≤4的新发转移性疾病患者随机分组，初始时间歇治疗组和持续治疗组分别有770例和759例患者。患者的中位年龄为70岁，约半数（48%）为广泛病变，14%为非裔美国人。间歇治疗组患者每月接受监测，根据预先确定的参数恢复治疗。而既往研究招募的患者处于疾病更早期阶段，医生难以确定其对激素治疗是否有应答。本试验招募的是“最可能从激素治疗中获益”的患者。

Roth博士说：“这项研究首次表明，采取间歇疗法是需要付出代价的，对于最常采用间歇疗法的轻症患者，这一代价大约是2年的中位生存期。这是一个重要的事实。我估计，患者如果得知了这项研究结果，就不会再要求医生采取间歇治疗了。与2年寿命比起来，潮热等不良反应就不算什么了。”

研究者披露与多家制药公司存在利益关系。

 

CHICAGO (EGMN)—Enjoying periodic breaks from hormonal therapy can take years off the life of a man with metastatic prostate cancer, according to results of the largest and longest clinical trial comparing intermittent androgen deprivation with continuous therapy.

The data are expected to squelch the use of intermittent androgen therapy (IAD) in men seeking quality-of-life improvements without reducing the efficacy of treatment for advanced disease. Previous studies suggested no harm would be done, but up to now physicians did not have a definitive comparison with continuous androgen deprivation (CAD).

“This study for the first time demonstrates that there is a price to pay, and in the patients most likely to receive intermittent therapy in this country and around the world, the minimal disease patients, it is almost 2 years’ median survival. So I think that is an important fact,” said Dr. Bruce J. Roth, moderator of a press briefing at the American Society of Clinical Oncology annual meeting, where the outcomes are being presented in a plenary session on Sunday, June 3.

The greatest impact was seen in men with minimal disease, who lived a median of 5.2 years if randomized to intermittent therapy vs. 7.1 years with continuous treatment, according to Dr. Maha Hussain, the lead author. Half of the men in the continuous arm, but only 42% on intermittent therapy, were alive at 7 years in the phase III intergroup study led by the Southwest Oncology Group (SWOG).

Men with extensive disease fared no worse on IAD – their median overall survival reached 5 years vs. 4.4 years among those on CAD. The investigators found this “striking and surprising because it goes against conventional belief based on all the trials that have been done thus far with this disease,” said Dr. Hussain, a professor of medicine and urology at the University of Michigan Comprehensive Cancer Center in Ann Arbor. A third of these men were alive at 7 years, regardless of which regimen they received.

Overall, IAD did not meet the standard of non-inferiority to CAD, Dr. Hussain emphasized. At a median 9.2 years of follow-up, men randomized to CAD lived a median of 5.8 years vs. 5.1 years with IAD.

“Because of these findings continuous therapy continues to be the standard of care,” said Dr. Hussain; IAD was not inferior to CAD in patients with extensive disease, but it was “significantly inferior” in men with minimal disease. “These observations suggest inherent biological differences and warrant further evaluations”

Asked whether she might recommend IAD in men with extensive disease, she cautioned that the data in this group came from a secondary analysis and are not understood. Moreover, many new therapies are emerging, giving more options to men with metastatic prostate cancer.

The trial was started in 1995; at that time median survival was 2.5 – 3 years, and physicians hoped that intermittent therapy could relieve side effects impinging on quality of life. Based on experimental data, investigators hypothesized that delivering less drug over time might delay resistance to hormonal therapy. The non-inferiority trial design required that the investigators could rule out a 20% or greater relative increase in risk of death with a 95% confidence interval.

Dr. Hussain and Dr. Roth offered a number of reasons why the non-inferiority trial revealed a negative impact that was not seen in the previous studies.

Notably, the SWOG 9346 (Intergroup -0162) trial was larger, involving 5 cancer research groups in the United States, Canada, and Europe. They accrued 3,040 patients with newly diagnosed metastatic prostate cancer and a PSA of at least 5 by 2008.

In addition, the trial randomized only men with newly metastatic disease who had achieved a PSA of 4.0 or less after 7 months of CAD with goserelin and bicalutamide – starting 770 patients on IAD and continuing 759 patients to CAD. The median age was 70, about half (48%) had extensive disease, and 14% were African Americans. Men on IAD were monitored monthly and went back on therapy based on predetermined parameters.

Previous studies enrolled populations with earlier stage disease before physicians could determine whether they were responsive to hormone therapy or not, noted Dr. Roth, professor of medicine in the division of oncology at Washington University School of Medicine. The men in this trial “were the most likely to benefit from hormone therapy.”

While the number of men trying IAD is not known, it is used in the United States, Dr. Roth said. He does not offer it to his patients – and will not offer it going forward – but often sees it in the charts of patients referred to him.

“A 2-year difference in median survival is huge,” he said, predicting patients would not press for IAD once they discussed the research with their physicians.

“Are you going to trade off hot flashes for a 2-year decrease in median overall survival with IAD?” he proposed asking a patient. “I think the average patient will say, ‘Those hot flashes are not so bad.’”

The investigators disclosed numerous relationships with pharmaceutical companies.