Decreased cancer risk after iron reduction in patients with peripheral arterial disease: results from a randomized trial.
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.
Zacharski
Leo R
LR
Research Service (151), White River Junction VA Medical Center, Department of Veterans Affairs Medical Center, 215 North Hartland Road, White River Junction, VT 05009, USA. leo.r.zacharski@dartmouth.edu
Chow
Bruce K
BK
Howes
Paula S
PS
Shamayeva
Galina
G
Baron
John A
JA
Dalman
Ronald L
RL
Malenka
David J
DJ
Ozaki
C Keith
CK
Lavori
Philip W
PW
D000368:Aged; D015415:Biomarkers / Q000097:blood; D005260:Female; D005293:Ferritins / Q000097:blood*; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000150:complications / Q000453:epidemiology* / Q000517:prevention & control*; D016017:Odds Ratio; D016491:Peripheral Vascular Diseases / Q000150:complications*; D018962:Phlebotomy; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012107:Research Design; D018570:Risk Assessment; D012307:Risk Factors; D016037:Single-Blind Method; D014481:United States / Q000453:epidemiology
D015415:Biomarkers; D005293:Ferritins