硒二级预防非小细胞肺癌效果令人失望

《临床肿瘤学杂志》(Journal of Clinical Oncology)9月3日在线发表的一项随机双盲Ⅲ期研究显示，在完全切除1期非小细胞肺癌(NSCLC)的患者中，硒补充剂预防第二原发性肿瘤(SPT)的效果并不优于安慰剂(J. Clin. Oncol. 2013 Sept. 3 [doi: 10.1200/JCO.2013.49.2173])。

硒补充剂组的肺和总体SPT发生率(1.62和3.54/100人-年)与安慰剂组(1.30和3.39/100人-年)相似。硒补充剂组和安慰剂组的5年无病生存(DFS)率分别为74.4%和79.6%。


这项研究由休斯敦德克萨斯大学M.D.安德森癌症中心的Daniel D. Karp医生及其同事进行，纳入组织学检查证实1A或1B期NSCLC且完全切除这些癌症已有6~36个月的患者(年龄≥18岁)。1,040例患者接受200 mcg/d硒补充剂治疗48个月。521例患者接受安慰剂治疗。

在2009年10月的预定期中分析时，数据监测委员会确定“该研究非常不可能最终得出硒补充剂具有获益的明显证据”，并停止了随后1个月的入组，同时已入组患者停止治疗并进入随访期。

期中分析时，有83例肺SPT，相当于最初计划的终点的46%。硒补充剂组和安慰剂组的肺SPT发生率分别为1.91和1.36/100人-年。总体而言，硒补充剂组的SPT发生率较高，但与安慰剂组相比无显著差异。硒补充剂组和安慰剂组的5年DFS分别为72%和78%。

在2011年6月最近1次的分析时，有224例患者报告252起SPT。其中98起为肺癌，相当于最初计划的终点的56%。

虽然硒补充剂治疗较为安全，该组的1~2级毒性反应(31% vs. 26%)和≥3级毒性反应(2% vs. 3%)发生率与安慰剂组相似，并且硒补充剂组患者的糖尿病或皮肤癌风险未增加，但在SPT预防方面，两组无显著差异。

然而，当前研究和既往有关肺癌和头颈癌的SPT预防研究(包括评估维甲酸类化学预防的研究)反复发现，最低的SPT发生率往往见于从未吸烟者，其次为既往吸烟者。在当前研究中，硒补充剂组主动吸烟者的复发或SPT风险为30%，而既往吸烟者的风险为24%，从未吸烟者的风险为20%。此外，主动吸烟者或1年内停止吸烟者的3年和5年总生存率分别为85.5%和74.9%，而从未吸烟者的3年和5年总生存率分别为90%和83.6%。

研究者表示，虽然目前已明确知道对当前吸烟者给予补充剂如硒或维甲酸类并无益处，但来自当前研究的描述性数据表明，硒补充剂的任何获益仅限于基线硒水平低的患者，因此治疗血清硒水平低的从未吸烟者或许是较好的方法。

在目前这个肺癌分子靶向治疗的时代，对持续吸烟的未基于基因组学选择的患者人群坚持使用泛化的治疗方法，获得成功的可能性非常低。

该研究获国立癌症研究所等多家机构资助。一名研究者声明是Peloton Therapeutics的顾问。其余研究者声明无经济利益冲突。

随刊述评：展望下一代靶向化学预防

加州大学洛杉矶分校的Steven M. Dubinett医生和波士顿大学的Avrum Spira医生表示，鉴于包括上述研究在内的许多Ⅲ期化学预防研究均得出阴性结果，在这一水平对药物进行的研究应基于特定标准设定研究门槛(J. Clin. Oncol. 2013 Sept. 3 [doi: 10.1200/JCO.2013.51.2400])。


Avrum Spira医生

支持化学预防干预的证据应来自于多个客观研究来源，包括具有中间或替代终点的机械性、观察性、临床前和Ⅱ期研究。

最重要的是，肺癌高危患者的入组标准应基于有助于定义高危患者的异质性和预测患者对特定药物的反应的生物学特征。对高危患者的分子学异质性的进一步认识可使此类靶向化学预防成为可能。最有效的肺癌干预是有效预防。在致力于预防烟草使用和提供戒烟新机会的同时，需对既往吸烟者进行不断研究。

Dubinett医生声明无相关经济利益冲突。Spira医生声明是Allegro Diagnostics的顾问并持有该公司股份，而且还持有待批准用于识别肺疾病药物开发的新型通路的专利。

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By: SHARON WORCESTER, Internal Medicine News Digital Network

Selenium supplementation provided no benefit over placebo for the prevention of second primary tumors in patients with completely resected stage 1 non–small cell lung cancer in a randomized phase III trial.

In 1,040 patients who were randomized to receive selenium and 521 patients randomized to receive placebo, the incidence rates of lung and overall second primary tumors (SPTs) were similar (1.62 and 3.54 per 100 person-years vs. 1.30 and 3.39 per 100 person-years, respectively). Five-year disease-free survival (DFS) rates were 74.4% and 79.6% for the selenium and placebo groups, respectively, Dr. Daniel D. Karp of the University of Texas M.D. Anderson Cancer Center, Houston, and his colleagues reported.

The findings were published online Sept. 3 ahead of print in the Journal of Clinical Oncology.

Patients included in the double-blind study were adults aged 18 years or older who were 6-36 months out from complete resection of histologically proven stage 1A or 1B non–small cell lung cancer (NSCLC). Selenium was given at a dose of 200 mcg daily for up to 48 months (J. Clin. Oncol. 2013 Sept. 3 [doi: 10.1200/JCO.2013.49.2173]).

At a planned interim analysis in October 2009, a data monitoring committee determined that "it was highly unlikely that this study could eventually show significant evidence of benefit from selenium," and the following month accrual was discontinued and participating patients discontinued treatment and entered the follow-up phase.

At the interim analysis, there were 83 cases of lung SPT, corresponding to 46% of the originally planned end points. The incidence rates of lung SPT were 1.91 and 1.36 per 100 person-years in the selenium and placebo groups, respectively.

"Overall, the SPT incidence rate was higher in the selenium arm but not significantly. Five-year DFS was 72% for selenium and 78% for placebo," the authors noted.

At the more recent analysis in June, 2011, there were 252 reported SPTs in 224 patients. Of these, 98 were lung cancers, corresponding to 56% of the originally planned end points.

Although prior studies suggested a possible benefit of selenium for tertiary chemoprevention in completely resected NSCLC patients, the findings of the current study suggest otherwise. Although selenium treatment was safe, with similar rates of grade 1 to 2 toxicity (31% and 26%, respectively), and grade 3 or greater toxicity (2% and 3%, respectively) occurring in the treatment and placebo groups, and no increased risk of diabetes or skin cancer among those treated with selenium, no significant differences were seen with respect to SPT prevention, the investigators said.

However, a recurring theme in this and prior SPT prevention trials in lung cancer and head and neck cancer – including studies evaluating retinoids for chemoprevention – is that the lowest rates of SPTs tend to be seen in never-smokers, followed by former smokers, they noted.

In the current study, active smokers in the selenium group had a 30% risk of recurrence or SPT, compared with a 24% risk for former smokers and a 20% risk for never-smokers. Also, the 3- and 5-year overall survival rates were 85.5% and 74.9%, respectively, in those who were active smokers or who had stopped smoking within 1 year, compared with 90% and 83.6%, respectively, for never-smokers.

"It is now clear that there is no demonstrable benefit in giving supplements such as selenium or retinoids to current smokers. However, the data suggest that a better approach might be to treat never-smokers with low serum selenium levels," they said, explaining that descriptive data from the current study suggest that any beneficial effect of selenium is limited to patients with a low baseline selenium level.

"In the current era of molecularly targeted therapies for lung cancer, it seems that persisting with broad approaches in genomically unselected patient populations who continue to smoke is highly unlikely to be successful," they said.

This study was supported by Public Health Service Grants and grants from the National Cancer Institute, the National Institutes of Health, and the Department of Health and Human Services. One coauthor of this study, Dr. David H. Johnson, reported serving as a consultant or adviser for Peloton Therapeutics. The remaining authors reported having no disclosures.

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Looking toward next-generation targeted chemoprevention

Given the numerous negative phase III chemoprevention studies, including the study by Dr. Karp and his colleagues, the portal of entry for an agent to this level of investigation should now be based on specific criteria.

Evidence supporting efficacy of a chemopreventive intervention should be derived from multiple objective research sources, including mechanistic, observational, preclinical, and phase II studies with intermediate or surrogate endpoints.

Most importantly, study entry for those at risk for lung cancer should be based on biologic features that help define the heterogeneity of those at elevated risk, and predict response to a given agent, they added.

Advances in the understanding of molecular heterogeneity in high-risk patients is allowing for the possibility of such targeted chemoprevention.

The most effective intervention for lung cancer will be effective prevention. In parallel with efforts to prevent the use of tobacco and provide new opportunities for smoking cessation, continued research in chemoprevention is warranted for the former smokers. Our increasing knowledge of the complexity as well as heterogeneity of the field of injury is informed by investigations utilizing molecular profiling approaches and assessment of the inflammatory microenvironment of premalignancy, noting that progress in understanding the molecular pathogenesis of lung cancer, along with advances in the understanding of molecular definitions of risk, is bringing us closer to the next generation of targeted chemoprevention for lung cancer.

Dr. Steven M. Dubinett and Dr. Avrum Spira made their remarks in an editorial (J. Clin. Oncol. 2013 Sept. 3 [doi: 10.1200/JCO.2013.51.2400]) that accompanied the published study. Dr. Dubinett is with the University of California, Los Angeles, and Dr. Spira is with Boston University. Dr. Dubinett had no relevant disclosures. Dr. Spira disclosed serving as a consultant or advisor for, and owning stock in, Allegro Diagnostics. He also has a patent pending for the identification of novel pathways for drug development for lung disease.