Cancer as a Ferrotoxic Disease: Are We Getting Hard Stainless Evidence?
Authors: G. Edgren, O. Nyren, M. Melbye
Journal: JNCI Journal of the National Cancer Institute (2008)

Iron is an essential mineral to all human tissues. Incorporated in the heme complex, it is necessary for the hemoglobin-borne transport of oxygen and generation of ATP in the electron transport chain. But iron may also have direct toxic effects, and iron uptake is con- sequentially tightly regulated in the human body ( 1 ). Recognizing the pro-oxidative properties of iron and its tendency to accumulate with age in properly nourished individuals, investigators have hypothesized that iron might be involved in the causation of many of the chronic diseases that are linked to a Western lifestyle ( 2 - 4 ), and believers have coined the term ferrotoxic disease ( 5 ). For example, sex differences in iron levels have been hypothesized to contribute to the differences between men and women in the risk of cardiovascular disease ( 6 ).  cancer occurrence (hazard ratio (HR) = 0.65, 95% confi dence interval (CI) = 0.43 to 0.97; P = .036) than the 641 patients in the control arm. Patients who developed cancer in the iron reduction group had higher mean ferritin levels across all follow-up visits than those in the same intervention arm who did not develop cancer, suggesting that the treatment advantage could have been even bigger if compliance had been better. Furthermore, the 38 iron-reduced patients who developed cancer during follow-up had lower risks of death from cancer (HR = 0.39, 95% CI = 0.21 to 0.72; P = .003) and all-cause mortality (HR = 0.49, 95% CI = 0.29 to 0.83; P = .009) in the fairly short period that passed between cancer diagnosis and end of follow-up than the 60 control patients who were also diagnosed with cancer. Zacharski et al. ( 14) should be congratulated on their efforts. Their trial is both innovative and well executed; its only major limitation is that it was not designed to study cancer as the outcome and that the present report is based on an ad hoc analysis. This could have been a serious threat to the validity of the conclusions if the investigators had dredged data for many specifi c outcomes or combinations of outcomes. In this case, however, it seems as if the cancer analyses were second on the list after cardiovascular out- comes, and the authors commendably restricted themselves to only one aspect, namely incidence of total  cancer. It is not clear, however, what is meant by visceral cancer and why the authors chose this as the outcome and not total cancer. Are the fi ndings biologically plausible? Strikingly, cumulative risk curves for the intervention and control groups began to sepa- rate at 6 months, ie, after only one phlebotomy. In fact, almost all the effects observed in the present study between the phlebotomy arm and control arm regarding cumulative incidence were seen within the fi rst 2 years of entry to the study. The authors speculate that late-stage effects of iron depletion on already established tumors might be prominent, but we remain skeptical. The observed risk difference is unexpected in terms of both timing and magnitude. Moreover, although a higher proportion of lung can- cers in the control group may partly explain the observed marked advantage for iron-depleted vs nondepleted cancer patients as far as cancer-specifi c and all-cause mortality is concerned, there are