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Cancer Epidemiology Biomarkers & Prevention Vol. 15, 1562-1564, August 2006
© 2006 American Association for Cancer Research

Null Results in Brief

Lung Cancer Chemoprevention: A Randomized, Double-Blind Trial in Linxian, China

Farin Kamangar1, You-Lin Qiao2, Binbing Yu3, Xiu-Di Sun2, Christian C. Abnet1, Jin-Hu Fan2, Steven D. Mark4, Ping Zhao2, Sanford M. Dawsey1 and Philip R. Taylor1

1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland; 2 Cancer Institute of the Chinese Academy of Medical Sciences, Beijing, China; 3 Information Management Services, Silver Spring, Maryland; and 4 Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, Colorado

Requests for reprints: Farin Kamangar, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, Room 3034, Bethesda, MD 10892-7232. Phone: 301-594-2936; Fax: 301-496-6829. E-mail: kamangaf{at}mail.nih.gov and You-Lin Qiao, Department of Cancer Epidemiology, Cancer Institute, Chinese Academy of Medical Sciences, P.O. Box 2258, Beijing 100021, P.R. China. Phone: 86-10-6771-3648; Fax: 86-10-6771-3648. E-mail: qiaoy{at}public.bta.net.cn


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We examined the effect of supplementation with four different combinations of vitamins and minerals in the prevention of lung cancer mortality among 29,584 healthy adults from Linxian, China. In accord with a partial factorial design, the participants were randomly assigned to take either a vitamin/mineral combination or a placebo for 5.25 years. The combinations tested in this trial were as follows: factor A, retinol and zinc; factor B, riboflavin and niacin; factor C, ascorbic acid and molybdenum; factor D, ß-carotene, {alpha}-tocopherol, and selenium. Lung cancer deaths (n = 147) identified during the trial period (1986-1991) and 10 years after the trial ended (1991-2001) were the study outcome. No significant differences in lung cancer death rates were found for any of the four combinations of supplements tested in this study, using log-rank tests (all P values are >0.20) or Cox proportional hazards models adjusted for age, sex, commune, and other treatments. No significant interactions were seen for age, sex, or smoking status. Supplementation with combinations of vitamins and minerals at nutrient-repletion levels for 5.25 years did not reduce lung cancer mortality in this nutrient-inadequate population in Linxian, China. (Cancer Epidemiol Biomarkers Prev 2006;15(8):1562–4)


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
The people of Linxian, China, suffer from extremely high rates of esophageal and gastric cancers, but have much lower rates of other cancers (1). The Linxian General Population Trial was a randomized intervention launched to examine the effects of four combinations of vitamins and minerals in reducing esophageal and gastric cancer incidence in this area (1). The results of this trial, which extended from 1986 to 1991, presented data on esophageal and gastric cancers, but small numbers limited the power for similar assessments for other cancers (1, 2). An extended follow-up through 2001 now permits evaluation of effects on lung cancer prevention, the fourth most common cause of cancer death in Linxian. In addition to main effects, we also present results on interactions with sex, age, and smoking status.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Design of the Trial and Posttrial Follow-up
Elsewhere, we have given a detailed description of the design and conduct of the Linxian General Population Trial and its extended follow-up (1, 3). In brief, participants included 29,584 healthy adults ages 40 to 69 years from four Linxian communes. In accord with a 24 partial factorial design, participants were randomly assigned to one of eight treatment groups, allowing testing for the effects of four different vitamin/mineral combinations: factor A, retinol and zinc; factor B, riboflavin and niacin; factor C, ascorbic acid and molybdenum; factor D, ß-carotene, {alpha}-tocopherol, and selenium. Doses ranged from one to two times the U.S. Recommended Daily Allowances. Supplements were distributed from March 1986 to May 1991, and the overall pill disappearance rate was 93%. Throughout the trial period, local health care providers recorded cancer incidence and mortality data at monthly intervals. Diagnostic material for 85% of the cancer cases in this study were reviewed by a panel of American and Chinese experts. In the subsequent 10 years posttrial, study subjects were contacted monthly by village health workers or interviewers, diagnostic materials were collected, and cancer diagnoses were verified by senior Chinese diagnosticians from Beijing. Case ascertainment is considered complete and loss to follow-up minimal (n = 176 or < 1%). Outcomes for the present study were based on follow-up data through May 2001.

The conduct of the Linxian General Population Trial was approved by the institutional review boards of the Cancer Institute of Chinese Academy of Medical Sciences and the U.S. National Cancer Institute.

Statistical Methods
We plotted Kaplan-Meier curves and used log-rank tests to compare time to lung cancer deaths between those who received versus those who did not receive each factor. We used Cox proportional hazards models to compare lung cancer death by each treatment combination adjusting for other treatments. Further addition of sex, age (<55 versus ≥55 years), and residence area (commune) did not materially affect results. Interactions with age, sex, and smoking status were also examined. The assumption of proportionality was verified for each of the analyses. Throughout the paper, all P values are two-sided and P ≤ 0.05 was considered as significant.

Power Calculation
Approximately half the trial subjects (range 14,771-14,790) received each of the vitamin/mineral combinations, and the other half received other combinations and/or placebo. Approximately 75 lung cancer deaths (range 68-81) were reported among participants who were in the reference group for each treatment combination. These numbers provided 94% power to detect a risk ratio of 0.5 with a two-sided {alpha} = 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Through May 2001, a total of 147 lung cancer deaths were reported in this cohort. Table 1 shows the demographic characteristics, smoking, and alcohol consumption in lung cancer patients versus the rest of the cohort. Lung cancer patients were more likely to be older, to be male, to smoke, and to consume alcohol.


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  		Table 1. Demographic characteristics, smoking, and alcohol consumption in lung cancer patients versus non–lung cancer participants in the Nutrition Intervention Trial

 
Figure 1 shows the Kaplan-Meier curves for each of the four vitamin/mineral combinations. The vertical lines demarcate the trial period, and each of the two 5-year posttrial follow-up periods. No significant associations were observed; all log-rank P values were >0.20. The hazard ratios and 95% confidence intervals for death from lung cancer from Cox models were 0.82 (0.59-1.14) for factor A, 1.16 (0.84-1.60) for factor B, 1.01 (0.73-1.39) for factor C, and 0.98 (0.71-1.35) for factor D. There were no significant interactions by age at randomization (<55 versus ≥55 years), sex, or smoking status (ever versus never smoker).


Figure 1
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  		Figure 1. Kaplan-Meier curves for death from lung cancer by vitamin/mineral components in the Nutrition Intervention Trial.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Chemoprevention of primary lung cancer has been the subject of three large-scale randomized trials (4-6). The Alpha-Tocopherol, Beta-Carotene Cancer Prevention study (4) randomized 29,133 middle-aged male smokers in southern Finland to receive {alpha}-tocopherol, ß-carotene, both, or neither. No association between lung cancer incidence and {alpha}-tocopherol intervention (risk ratio, 0.98; 95% confidence interval, 0.86-1.12) was seen, but ß-carotene treatment increased risk (1.18, 1.03, 1.36). The ß-Carotene and Retinol Efficacy trial study (5) randomized 18,314 middle-aged U.S. smokers and former smokers to a combination of ß-carotene and retinol or placebo, and found an increase in lung cancer incidence (1.28, 1.04-1.57) in the active treatment arm. The Physicians' Health Study (6) enrolled 22,071 male U.S. physicians, ages 40 to 84 years, into a randomized trial; 12 years of supplementation with ß-carotene did not change the incidence of lung cancer (0.97, 0.83-1.13).

With only 31 lung cancer deaths diagnosed during the intervention phase of the General Population Intervention Trial (1991), we previously reported that factor D ({alpha}-tocopherol, ß-carotene, and selenium) was associated with a nonsignificant reduced risk of lung cancer death (risk ratio, 0.55; 95% confidence interval, 0.26-1.14; ref. 2). However, with longer follow-up and more cases, none of the four combinations tested in the Linxian General Population Trial affected lung cancer mortality.

The strengths of this study are that it used a randomized, double-blind design, it had long-term follow-up with complete ascertainment of cases, and it examined previously untested factors for lung cancer prevention. Previous studies have shown data on {alpha}-tocopherol, ß-carotene, and retinol, but this is the first study to evaluate several other vitamins and mineral in lung cancer chemoprevention. The people of Linxian are deficient in many micronutrients (1), which may limit the generalizability of these results. Nevertheless, the results of this study are similar to other chemoprevention studies (4-6), which did not find benefit from vitamins in reducing lung cancer incidence or mortality.

In summary, supplementation with combinations of vitamins and minerals at nutrient-repletion levels for 5.25 years did not reduce lung cancer mortality in this nutrient-inadequate population in Linxian, China.


   Footnotes
 
Grant support: National Cancer Institute contracts number N01-SC-91030 and N01-RC-47701, and Intramural Research Program of the NIH, National Cancer Institute.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 4/17/06; accepted 5/31/06.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Blot WJ, Li JY, Taylor PR, et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 1993;85:1483–92.[Abstract/Free Full Text]
  2. Blot WJ, Li JY, Taylor PR, Li B. Lung cancer and vitamin supplementation. N Engl J Med 1994;331:614.[Free Full Text]
  3. Tran GD, Sun XD, Abnet CC, et al. Prospective study of risk factors for esophageal and gastric cancers in the Linxian general population trial cohort in China. Int J Cancer 2005;113:456–63.[CrossRef][Medline]
  4. The ATBC Cancer Prevention Study Group. The effect of vitamin E and ß carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group. N Engl J Med 1994;330:1029–35.[Abstract/Free Full Text]
  5. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of ß carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334:1150–5.[Abstract/Free Full Text]
  6. Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of long-term supplementation with ß carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 1996;334:1145–9.[Abstract/Free Full Text]



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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
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