Journal of the National Cancer Institute Advance Access published online on July 8, 2008
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djn209
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Published by Oxford University Press 2008.
ARTICLES |
Decreased Cancer Risk After Iron Reduction in Patients With Peripheral Arterial Disease: Results From a Randomized Trial
Affiliations of authors: White River Junction VA Medical Center, Research Service, Department of Veterans Affairs Medical Center, White River Junction, VT (LRZ, PSH); VA Palo Alto Health Care System, Research Service, Department of Veterans Affairs Medical Center, Palo Alto, CA (BKC, GS, PWL); North Florida/South Georgia Veterans Health, Research Service, Department of Veterans Affairs Medical Center, Gainesville, FL (CKO); Department of Medicine, Dartmouth Medical School, Lebanon, NH (LRZ, JAB, DJM); Department of Surgery, Stanford University Medical School, Palo Alto, CA (RLD); College of Medicine, University of Florida, Gainesville, FL (CKO); Department of Health Research and Policy, Stanford University Medical School, Palo Alto, CA (PWL)
Correspondence to: Leo R. Zacharski, MD, Research Service (151), White River Junction VA Medical Center, Department of Veterans Affairs Medical Center, 215 North Hartland Road, White River Junction, VT 05009 (e-mail: leo.r.zacharski{at}dartmouth.edu).
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.
| CONTEXT AND CAVEATS Prior knowledge Having excess iron in the blood is associated with an increased risk for some cancers. Study design Analysis of cancer risk among patients with peripheral arterial disease who participated in a multicenter randomized controlled single-blinded trial of iron reduction through blood collection for prevention of atherosclerotic complications of arterial disease. Contribution Patients in the iron reduction group had a lower risk of subsequent cancer, and those who developed cancer had lower cancer-specific deaths and deaths from any cause than patients in the control group who developed cancer. At baseline, iron levels were similar in the two study arms. However, during follow-up, patients in the iron reduction group had lower iron levels than patients in the control group. In both groups, iron levels of all patients who developed cancer were higher during follow-up than those of patients who did not develop cancer. Implications Iron reduction is associated with reduced risk of cancer and death in this population. Limitations The trial was not originally designed to compare risks of cancer in the two groups. The lower ranges of iron levels reported here among patients who did not develop cancer cannot be used as a guide to reduce cancer incidence in the general population. From the Editors
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Author Contributions: Leo R. Zacharski, Bruce K. Chow, Paula S. Howes, Galina Shamayeva, John A. Baron, Ronald L. Dalman, David J. Malenka, C. Keith Ozaki, and Philip W. Lavori participated in the design of the study and in the writing of the study protocol; approved the final protocol; participated in the collection, analysis, and interpretation of the data; participated in ongoing supervision of the study and in the writing of the manuscript; and approved the final manuscript for submission. Leo R. Zacharski, Bruce K. Chow, Paula S. Howes, and Philip W. Lavori obtained funding for the study. Leo R. Zacharski, Bruce K. Chow, Philip W. Lavori, and Galina Shamayeva had access to the full study data and take responsibility for the integrity and analyses of the data. Bruce K. Chow, Galina Shamayeva, and Philip W. Lavori performed the statistical analyses. Leo R. Zacharski, Bruce K. Chow, Paula S. Howes, Galina Shamayeva, and Philip W. Lavori provided administrative, technical, and material support.
Study Administration—Study Chairman's Office: Leo R. Zacharski, MD (Study Chairman); Paula S. Howes, MS, APRN, National Study Coordinator; and M. Heath. Executive Committee: Leo R. Zacharski, MD (Chairman); Bruce K. Chow; Paula S. Howes; C. Keith Ozaki, MD; Ronald L. Dalman, MD; John A. Baron, MD; and David J. Makenka, MD. Data Safety and Monitoring Board: B. Massie, MD (Chairman); P. Carson, MD; T. Colton, PhD; K. Detre, PhD; M. Gaziano, MD; and S. Gottlieb, MD. Endpoints Adjudication Committee: J. F. Plehn, MD (Chairman); M. D. Tischler, MD; P. S. Rahko, MD; D. C. Hess, MD; T. J. DeGraba, MD; and L. C. Pettigrew, MD.
National Human Rights Committee: C. Giese (Chairperson) and 11 members. The Palo Alto Cooperative Studies Program Coordinating Center: P. Lavori, B. Chow, G. Shamayeva, L. Planting, L. Sheridan, and B. Ventura. Participating VA Medical Centers (listed in descending order of the number of patients enrolled): Little Rock, AR (M. Moursi, C. McDonald, J. Englehart, and D. Doggett); Madison, WI (J. Hoch, J. Burks, and B. Dunlap); Houston, TX (A. Blaustein, C. Pellegrino, C. Rowe, L. Lacy, and R. Scott); Gainesville, FL (C. K. Ozaki, A. Irwin, and P. Irwin); Reno, NV (R. DePalma, H. T. Cafferata, P. May, V. Hayes, K. Solomon, and F. McKeon); Pittsburgh, PA (M. Amidi, A. Sonel, M. Bell, J. Moorhead, and M. DiTommas); Leavenworth, KS (D. Courtney, M. Cook, and J. Moppin); Long Beach, CA (I. Gordon, L. Willis, W. Wong, K. Zalecki, D. Guizado, E. Berry, and J. Ng); Hines, IL (J. Third, A. White, J. Azolin, M. Ryan, A. Zuluaga, and A. Vondruska); Palo Alto, CA (R. L. Dalman, A. Hoffman, S. Thunen, S. Marinos, and D. Yu); White River Junction, VT (R. J. Powell, D. Balestra, D. O’Rourke, E. Belles, and P. Howes); Louisville, KY (S. Wagner, K. Doeshuk, M. Olligus, M. Alshaher, and T. Abdul-Baki); Salt Lake City, UT (S. Galt, M. Elstad, G. Treiman, L. Bhiranghi, C. Korowski, M. Jalilvand, D. Jost, S. Hatton-Ward, and S. Granger); Lexington, KY (T. Schwarcz, E. Endean, N. Lewis, J. Warner-Carpenter, P. Rowan, and B. Broughton,); San Juan, PR (L. R. Ospina, J. Santos, A. Deleon, and C. Pedrosa); Milwaukee, WI (R. Cambria, G. Seabrook, A. Scott, S. Framberg, and C. Kallio); Boston, MA (W. Johnson, M. Watkins, J. Hamilton, A. Wrobel, and B. Dionian), Durham, NC (J. Gray, C. Peterson, N. Lee, and K. Swails); Cleveland, OH (S. Busuttil, J. Jean-Claude, D. Fox, K. Kallen, J. Miklacic, R. Jones, and L. Tucker); Providence, RI (J. Slaiby, N. Crandell, L. Marquis, and M. J. Roy); Birmingham, AL (D. Whitley, L. Adams, J. Bailey-Griffin, J. Poirier, M. Egan, K. Mitchell, and C. Inman); New York, NY (S. Sedlis, R. Burris, M. May, E. Anteola, and M. Keary); West Haven, CT (B. Sumpio, B. Borromeo, and A. Dardick); Indianapolis, IN (D. Cikrit, B. Solooki, and C. Adams).
The authors thank the members of the Study Group, Data Monitoring Board, Endpoints Adjudication Committee, and National Human Rights Committee for their commitment to the study.
Manuscript received December 21, 2007; revised May 21, 2008; accepted May 27, 2008.
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