Impact of red cell distribution width on future risk of cancer and all-cause mortality among cancer patients - the Tromsø Study.

Red cell distribution width (RDW) has recently been associated with the risk of cardiovascular disease and allcause mortality. The underlying mechanisms remain unresolved, but high levels of RDW may be caused by inflammation or poor nutritional status. Inflammation and malnutrition are known risk factors of cancer, and chronic inflammation may lead to cancer in several organs. Recent case control studies have shown associations between RDW and colon cancer and malign biliary obstruction. In addition, RDW has been shown to predict cancer in patients with unintentional weight loss, and to be associated with poor prognosis in patients with lung cancer and multiple myeloma. Since active malignancy is accompanied by a prolonged inflammatory response, and inflammatory processes influence RDW, the retrospective design of these previous studies makes it impossible to determine whether high RDW is causally related to cancer development. As limited knowledge exists regarding the association between high RDW and future cancer development or disease activity, we thus performed a large prospective population-based study to assess the impact of RDW on future risk of incident cancer, cancer stage and mortality among cancer patients. Participants were recruited from the fourth survey of the Tromsø Study conducted in 1994-95. A detailed description of the study design and population has been published elsewhere. The regional committee of medical and health research ethics approved the study, and all 25 383 included subjects gave their written consent to participate. Baseline information was collected by self-administered questionnaires, blood samples and a physical examination. Incident cancer diagnosis, grade and site, as well as mortality among the cancer patients, were recorded from the date of enrolment through to the end of follow-up on December 31, 2010. All cancer diagnoses in the Norwegian population are registered in the Cancer Registry of Norway, and information about cancer in the cohort was obtained by linkage to the cancer registry using a unique 11-digit personal identification number. In a recent evaluation of data quality, the Cancer Registry of Norway had a completeness of 98.8%, with 94% of the cases being histologically verified. Information on mortality was obtained by linkage to the national Cause of Death Registry at Statistics Norway. Statistical analyses were carried out with STATA, version 13 (Stata corporation, College Station, TX, USA). For analyses of the association between RDW and cancer, person-time of follow-up was calculated from the date of enrolment to the date when cancer was first diagnosed, to the date when the participant died or moved from the municipality of Tromsø, or to the end of the study period, whichever came first. Cox proportional hazard regression models were used to obtain crude, sex-adjusted, and multivariable adjusted hazard ratios (HR) with 95% confidence intervals (CI) for incident cancer according to RDW levels. The lowest RDW quartile was used as the reference category in the Cox models, and age was used as the timescale. The multivariable model included BMI, smoking, white blood cell count and haemoglobin. For analysis of the association between RDW and allcause mortality among cancer patients, person-time was calculated from the date of cancer diagnosis to the date of death, date of migration or the end of the study period. The three lower RDW quartiles were merged and used as the reference category in the mortality analysis. In total, 1 191 men and 1 114 women were diagnosed with cancer during 332 575 person-years of follow-up (median 15.7 years). The mean RDW levels were 12.8% for men and 12.9% for women. In our hospital laboratory, the reference range for RDW is 11.7-14.5%. Previously, we have published data on baseline characteristics across categories of RDW. Age, white blood cell counts, proportion of smokers and subjects with anaemia increased with higher categories of RDW, whereas the haemoglobin concentration decreased. The proportion of subjects with anaemia, defined as haemoglobin levels <12.0 g/dL in females and <13.0 g/dL in men, was higher in women than in men in all RDW categories, while the proportion of smokers showed a more pronounced increase across RDW quartiles in men than in women. The multivariable-adjusted risk of cancer was 30% higher in men in the highest compared with the lowest RDW quartile (HR 1.30, 95% CI 1.07-1.59) (Table 1), and men with RDW above the 95 percentile (RDW ≥14.3%) had an 83% higher cancer risk (HR 1.83, 95% CI 1.43-2.22). Apparently, there was no significant association between RDW and the risk of cancer in women (HR upper versus