Decreased Cancer Risk After Iron Reduction in Patients With Peripheral Arterial Disease: Results From a Randomized Trial

Leo R. Zacharski; Bruce K. Chow; Paula S. Howes; Galina Shamayeva; John A. Baron; Ronald L. Dalman; David J. Malenka; C. Keith Ozaki; Philip W. Lavori


J Natl Cancer Inst. 2008;100(14):996-1002. 

In This Article

Abstract and Introduction

Background: Excess iron has been implicated in cancer risk through increased iron-catalyzed free radical-mediated oxidative stress.
Methods: A multicenter randomized, controlled, single-blinded clinical trial (VA Cooperative Study #410) tested the hypothesis that reducing iron stores by phlebotomy would influence vascular outcomes in patients with peripheral arterial disease. Patients without a visceral malignancy in the last 5 years (n=1277) were randomly assigned to control (n=641) or iron reduction (n = 636). Occurrence of new visceral malignancy and cause-specific mortality data were collected prospectively. Cancer and mortality outcomes in the two arms were compared using intent-to-treat analysis with a Cox proportional hazards regression model. Statistical tests were two-sided.
Results: Patients were followed up for an average of 4.5 years. Ferritin levels were similar in both groups at baseline but were lower in iron reduction patients than control patients across all 6-month visits (mean=79.7 ng/mL, 95% confidence interval [CI]=73.8 to 85.5 ng/mL vs 122.5 ng/mL, 95% CI=115.5 to 129.5 ng/mL; P<.001). Risk of new visceral malignancy was lower in the iron reduction group than in the control group (38 vs 60, hazard ratio [HR] = 0.65, 95% CI=0.43 to 0.97; P=036), and, among patients with new cancers, those in the iron reduction group had lower cancer-specific and all-cause mortality (HR=0.39, 95% CI=0.21 to 0.72; P=.003; and HR = 0.49, 95% CI=0.29 to 0.83; P=.009, respectively) than those in the control group. Mean ferritin levels across all 6-monthly visits were similar in patients in the iron reduction and control groups who developed cancer but were lower among all patients who did not develop cancer than among those who did (76.4 ng/mL, 95% CI=71.4 to 81.4 ng/mL, vs 127.1 ng/mL, 95% CI=71.2 to 183.0 ng/mL; P=.017).
Conclusions: Iron reduction was associated with lower cancer risk and mortality. Further studies are needed to define the role of body iron in cancer risk.

Body iron stores accumulate imperceptibly with aging because intake exceeds loss and no biologic mechanism exists for excretion of iron in excess of physiological requirements.[1] Iron accumulation has been implicated in the risk of several chronic diseases, including cardiovascular disease and cancer, through increased iron-catalyzed free radical-mediated oxidative stress.[1,2,3,4,5,6,7,8,9] Clinical cohort studies have found that measures of body iron stores or dietary iron intake may be associated with increased risk of cancer and cancer mortality.[9,10,11,12,13,14] Colorectal cancer has received particular attention in this regard.[6,11] Cancer risk rises after menopause in women[5,12] in association with rising iron stores.[1] A cause-and-effect relationship between levels of iron stores and cancer risk is suggested by studies showing that blood donation (which reduces body iron) is associated with lower cancer risk[13,14] and that blood transfusion (delivery of an iron load) adversely affects cancer outcome.[15,16] Kato et al. [17] reported a cohort of patients with hepatitis C who were treated with iron reduction and followed for 12 years. These patients had a statistically significantly lower risk of developing hepatocellular carcinoma compared with a demographically similar cohort not treated with iron reduction. Although studies in animal models suggest that limitation or removal of iron may prevent cancer occurrence and growth,[18,19,20] no such data exist for malignancy in humans.

A randomized trial of calibrated phlebotomy was conducted in patients with advanced peripheral arterial disease.[21,22,23,24] Although this clinical trial was designed as a cardiovascular disease study, it provided a setting for controlled, prospective collection of data on risk of new malignancy. The occurrence of new visceral malignancy according to histological type and organ of origin and death according to cause was determined in this cohort of patients, who had no clinical evidence of visceral malignancy within the preceding 5 years.


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