A phase III, intergroup, randomized, double-blind, chemoprevention trial of selenium (Se) supplementation in resected stage I non-small cell lung cancer (NSCLC).

Abstract

CRA7004 Background: Selenium was reported to have possible lung cancer chemopreventive benefits based on a large skin cancer trial secondary observation. (JAMA 1996; 276: 1957-1963). Since that time, research continued to suggest that Se could decrease risk of second primary tumor (SPT) in persons with resected NSCLC. In 2007, a publication from another group suggested an increased association of Se with type 2 diabetes (Annals Int Med 147:217-223). Methods: From Oct 2000-Nov 2009, 6 groups, led by ECOG, carried out a double blind, placebo controlled trial using selenized yeast 200 micrograms daily in a 2:1 randomization vs. placebo for 48 mo in completely resected stage I NSCLC. Participation was 6–36 mo post-op and required a negative mediastinal node biopsy, no excessive vitamin intake, normal liver function, a negative chest x-ray, and no other evidence of recurrence. Planned size of 1,960 participants had been designed to detect a 40% decrease in SPTs with 80% power. Methylation studies of sputum and blood (S. Belinsky) add important biologic correlates to this project. Results: Interim analysis occurred in Oct 2009 after 1,561/1,772 pts reached step 2 (completion of the 4 week (step 1) run-in period requiring at least 75% of the study drug to be taken). Endpoints included SPTs, recurrence, and toxicity. A total of 216 SPTs developed of which 84 (38.9%) were lung cancer. SPT (lung/overall) incidence was 1.36/3.66 per 100 person yrs for placebo vs. 1.91/4.11 for Se (p=.150). 5 yr progression free survival was 78% for placebo vs. 72% for Se. Study was stopped according to futility analysis. Grade 1 or 2 toxicity occurred in 38% of placebo and 39% Se. Grade 3 toxicity was 3% placebo vs. <1% Se. Compliance was excellent (>95% at 2 yrs). Conclusions: No increase in diabetes mellitus or skin cancer was detected. Se was safe but conferred no benefit over placebo. Methylation studies are continuing. [Table: see text]

Selenium and Lung Cancer: A Systematic Review and Meta Analysis

“…The Linxian, China chemoprevention trial also found no effect from a low dose regimen combining beta carotene, alpha-tocopherol, and selenium at doses one to two times the US recommended daily allowance (RDA) for 5.25 years [39]. In findings presented at the American Society of Clinical Oncology in 2010, Karp reported no significant effects from use of selenium on lung cancer recurrence in resected patients, with a second primary tumor rate of 1.91/4.11 per 100-person years in the selenium group and 1.36/3.66 for placebo [40]. Five year progression free survival was 72% for selenium compared to 78% for placebo [40].…”

“…In findings presented at the American Society of Clinical Oncology in 2010, Karp reported no significant effects from use of selenium on lung cancer recurrence in resected patients, with a second primary tumor rate of 1.91/4.11 per 100-person years in the selenium group and 1.36/3.66 for placebo [40]. Five year progression free survival was 72% for selenium compared to 78% for placebo [40].…”

“…In the NPC trial, an exposure-response gradient was found across tertiles of baseline plasma selenium level, with risk highest in the top tertile of baseline plasma selenium level (≥121.6 ng/mL, HR 2.70, 95%CI 1.30–5.61) but non-significant findings in those below this level [42]. Karp et al failed to show an association between selenium and diabetes [40].…”

Methyl Selenocysteine: Single-Dose Pharmacokinetics in Men

“…10 The association of selenium supplementation with decreased risk was especially marked for prostate cancer. 8 In a large trial largely motivated by NPC, Karp and colleagues randomized over 1500 patients with resected non-small cell lung cancer to selenized yeast or to placebo; the trial, designed for a 4-year treatment period, was halted after futility analysis showed that the endpoints of second primary tumors and progression free survival were not likely to be different in selenium and placebo groups 11 . In the much larger SELECT study, closed after subjects were followed for an average of 5.5 years, a 200 mcg/day supplement of Se in the form of selenomethionine (SeMet) had no impact on the incidence of prostate or any other cancer.…”

“…First, different forms of Se were used in the two trials: 7,12,13 SeMet in SELECT, selenized yeast in NPC. On the other hand, the agent of the randomized trial led by Karp et al was selenized yeast (largely selenomethionine) 11 , and that showed no evidence of effectiveness. Another possible source of differences among these trials is that substantial numbers of the subjects in the NPC trial were close to being selenium deficient, while few of those in the lung cancer trial or SELECT were; the mean baseline plasma selenium level of NPC participants was approximately 115 ng/ml, that of SELECT participants approximately 136 ng/ml.…”