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

Disclosures

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

In This Article

Results

The CONSORT trial flow diagram for this study and a table showing comparability between treatment groups at entry to the study have been published.[23] Patients who were randomly assigned to iron reduction (n=636) and control (n=641) groups were demographically comparable at entry. The population was 98.8% male, with a mean age of 67 years. Mean ferritin levels were the same in control and iron reduction groups at baseline (mean=122.4 ng/mL, 95% CI=116.0 to 128.8 ng/mL, and 121.8 ng/mL, 95% CI=115.3 to 128.2 ng/mL, respectively; P=.86), resembling levels in the general population of comparable age[1] and in the pilot study.[21] The observed status of all 1277 patients entered was complete at the study conclusion based on clinical records at participating hospitals; the observed follow-up was approximately 4000 patient-years and the average observed follow-up 3.1 years. Because patient status could be tracked through the Austin database that captured outcome events that may have occurred elsewhere (usually at different VA hospitals), the average total follow-up was 1649 days or an average of 4.5 years per patient. Follow-up intervals for control and iron reduction patients were similar. A total of 3141 phlebotomy episodes were conducted among the 636 patients who were randomly assigned to iron reduction.

Details on overall compliance with phlebotomy in patients who were randomly assigned to iron reduction have been reported.[23] Eighty-eight percent of patients who were assigned to the iron reduction group had the required amount of blood removed within the first year after randomization. Sixty-five percent of patients had 50% or more of the calculated amount of blood actually removed (ie, >50% compliance with intervention). The average patient had 72% of the calculated amount of blood removed over the course of the study. Compliance with phlebotomy was unaffected by the severity of vascular disease and comorbid conditions at entry.[23]

A new diagnosis of histologically confirmed visceral malignancy was made in 98 patients (7.7% of the total study cohort) during follow-up. There is little basis for determining whether this incidence resembles that expected in the general population. Two patients had two new primary cancers diagnosed after entry: one patient in the control group had lung and colon cancer, and one patient in the iron reduction group had lung and upper aerodigestive cancer. These two patients were analyzed for the first occurrence of malignancy only (lung cancer in both cases). As reported previously,[23] participants in the control and iron reduction groups had comparable demographic variables (age; race; sex; tobacco and alcohol use; diagnosis of diabetes mellitus and hypertension; body mass index; levels of cholesterol, ferritin, fibrinogen, and homocysteine; and comorbidities) at baseline. Similarly, no differences were observed in these demographic variables at entry to the study among patients who subsequently developed cancer during follow-up vs those who did not.

Of the 98 new malignancies, 60 occurred in control patients and 38 in iron reduction patients ( Table 1 ) ( ; P=.023). Risk of lung, colorectal, upper aerodigestive, prostate, and other cancers ( Table 1 ) was lower with iron reduction. In a time-to-event analysis, the HR for a new cancer diagnosis was 0.65 (95% CI=0.43 to 0.97; P=.036; Figure 1). Displaying the data as cumulative incidence curves also showed reduced cancer risk with iron reduction (HR=0.61, 95% CI=0.49 to 0.92; P=018; Figure 2).

Figure 1.

Kaplan-Meier event curves for new cancer diagnoses for the entire study cohort by intervention group. Hazard ratio=0.65, 95% confidence interval=0.43 to 0.97; P=.036 (two-sided log-rank test); Cox proportional hazards χ2=4.4088. The vertical axis represents the Kaplan-Meier event estimates. Numbers below the horizontal axis represent the numbers of patients under observation at each follow-up time point. Error bars represent 95% confidence intervals.

Cumulative incidence curves of new cancer diagnoses for the entire study cohort by intervention group. Hazard ratio=0.61, 95% confidence interval=0.49 to 0.92; P=.019 (two-sided log-rank test); Cox proportional hazards χ2=5.4837. Numbers below the horizontal axis represent the numbers of patients under observation at each follow-up time point. Error bars represent 95% confidence intervals.

We considered the possibility that ferritin levels before cancer diagnosis might be associated with subsequent cancer occurrence. However, mean ferritin levels at baseline (when populations were otherwise apparently similar) were similar among all patients who subsequently developed cancer (n=98) and among those who did not (n=1179; 115.1 ng/mL, 95% CI=98.4 to 131.8 ng/mL, vs 122.5 ng/mL, 95% CI=117.7 to 127.2 ng/mL, respectively; P=.31). Mean baseline ferritin levels were also similar for subjects who were randomly assigned to control vs iron reduction who subsequently acquired cancer (114.5 ng/mL, 95% CI=93.5 to 135.5 ng/mL vs 116.1 ng/mL, 95% CI=87.4 to 144.8 ng/mL, respectively; P=.93). A non-statistically significant trend toward increasing ferritin levels over time of follow-up was observed in patients who subsequently developed cancer (see below). Cancer was the primary cause of death for 36 (5.6%) patients in the control group vs 14 (2.2%) in the iron reduction group (P=.003). Time-to-event analysis showed a lower rate of death due to cancer in patients who were randomly assigned to iron reduction vs control (HR=0.39, 95% CI=0.21 to 0.72; P=.003; Figure 3). Displaying the data as cumulative incidence curves also showed reduced death due to cancer (HR=0.39, 95% CI=0.21 to 0.72; P=.002; Figure 4). All-cause mortality in patients diagnosed with cancer was also reduced among patients who were randomly assigned to iron reduction (HR=0.49, 95% CI=0.29 to 0.83; P=.009).

Kaplan-Meier event curves for cancer as the primary cause of death for the entire study cohort by intervention group. Hazard ratio=0.39, 95% confidence interval=0.21 to 0.72; P=.003 (two-sided log-rank test); Cox proportional hazards χ2=8.9631. The vertical axis represents the Kaplan-Meier event estimates. Numbers below the horizontal axis represent the numbers of patients under observation at each follow-up time point. Error bars represent 95% confidence intervals.

Cumulative incidence curves of cancer as the primary cause of death for the entire study cohort by intervention group. Hazard ratio=0.39, 95% confidence interval=0.21 to 0.72; P=.002 (two-sided log-rank test); Cox proportional hazards χ2=9.6476. Numbers below the horizontal axis represent the numbers of patients under observation at each follow-up time point. Error bars represent 95% confidence intervals.

Mean ferritin levels across all 6-monthly follow-up visits remained unchanged from baseline levels among control patients (122.5 ng/mL, 95% CI=115.5 to 129.5 ng/mL) but declined statistically significantly among iron reduction patients (79.7 ng/mL, 95% CI=73.8 to 85.5 ng/mL) (P<.001). The mean ferritin level during follow-up in patients who were randomly assigned to iron reduction having 50% or greater compliance with phlebotomy was 58.3 ng/mL, 95% CI=55.2 to 61.4 ng/mL, which was consistent with levels that were targeted by the protocol.[19,20] Overall mean ferritin levels during follow-up were non-statistically significantly higher in patients who developed cancer (n=98, 115.3 ng/mL, 95% CI=91.8 to 138.8 ng/mL) than in patients who did not (n=1179, 100.3 ng/mL, 95% CI=95.6 to 105.0 ng/mL) (P=.098). Mean ferritin levels during follow-up remained unchanged from baseline levels in control patients who developed cancer (107.7 ng/mL, 95% CI=91.0 to 124.5 ng/mL) and were comparable to baseline levels in iron reduction patients who developed cancer (127.1 ng/mL, 95% CI=71.2 to 183.0 ng/mL) (P=.4).

Mean ferritin levels across all follow-up visits among patients who were randomly assigned to iron reduction were statistically significantly lower in patients who did not develop cancer (76.4 ng/mL, 95% CI=71.4 to 81.4 ng/mL) than in those who did (127.1 ng/mL, 95% CI=71.2 to 183.0 ng/mL) (P=.017). Thus, patients who were randomly assigned to iron reduction and did not develop cancer appeared to have better compliance with the intervention than patients who developed cancer. The effect of compliance with intervention was examined by plotting the log relative risk for new cancer diagnoses vs percent compliance with intervention. The results (Figure 5) appear to show reduced risk of new cancer in patients having greater than about 60% compliance with phlebotomy, corresponding to a ferritin level of less than 54.8 ng/mL, 95% CI=51.6 to 57.9 ng/mL. Seventy-five percent of new cancers occurred among patients having mean ferritin levels during follow-up of greater than about 57 ng/mL. An attempt was made to fit the Cox model with an effect for compliance more than vs less than 60%, but differences were not statistically significant because of insufficient statistical power.

Association between percent compliance with the intervention (horizontal axis) and the log relative hazard for new cancer diagnoses (vertical axis) for patients who were randomly assigned to the iron reduction intervention. The solid line indicates percent compliance; broken lines delimit the 95% confidence intervals.

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