We observed strong positive associations between serum levels of 25-OHD and prognosis for this young group of patients diagnosed with cancers of the breast, colon, lung, and lymphoma. For all cancers combined, the risk of dying during follow-up among patients in the highest quartile of 25-OHD was 36% (95% CI, 26%, 49%) of the risk observed among patients in the lowest quartile.
The relationship between serum 25-OHD levels and cancer survival has been examined in several studies, including our own [17
]. The present analyses extend our previous findings on patients with prostate cancer. Our findings for the four cancer types are consistent with those of several recent reports. For example, Ng and colleagues [8
] studied the relationship between 25-OHD levels and survival in 304 patients with colorectal cancer. They observed a significantly decreased hazard ratio (HR 0.52, 95% CI, 0.29, 0.94) for overall survival when patients in the highest quartile of 25-OHD were compared with patients in the lowest quartile. A non-significant trend toward improved colorectal cancer-specific mortality also was seen. The average interval between blood draw and cancer diagnosis in that study was 6 years.
Two studies have investigated the association between circulating 25-OHD levels, measured at the time of diagnosis, and prognosis in patients with non-small cell lung cancer, one in early-stage patients and the other in patients with advanced disease [18
]. A positive association between 25-OHD levels and survival was suggested for patients with early-stage disease, whereas no clear association was demonstrated for advanced stages. In a study of 512 early-stage breast cancer cases by Goodwin et al. [10
], women with vitamin D levels <50 nmol/L had a significantly increased risk of distant recurrence and death compared to women with 25-OHD levels ≥50 nmol/L.
Our result for all types of lymphoma combined is comparable with the results for the solid tumors studied and is consistent with the results for two studies by Drake et al. [12
] and Shanafelt et al. [13
], respectively. These authors defined insufficient vitamin D status as 25-OHD levels <62.5 nmol/L and found a poorer prognosis for this group among patients with non-Hodgkin’s lymphoma and chronic lymphocytic leukemia.
It is important to distinguish studies of serum vitamin D and cancer survival from studies of serum vitamin D and cancer incidence and/or cancer mortality in populations. With the exception of studies of colorectal cancer, where prospective incidence/mortality studies have generally shown protective effect of serum 25-OHD, most studies of serum 25-OHD and the risk of cancer have not shown convincing evidence of risk reduction and some have shown apparent increases in cancer risk [20
]. One explanation for the discrepancy in the results of these studies concerns the effects of vitamin D on different stages in the carcinogenic process. Laboratory studies have convincingly shown effects of the hormonal form of vitamin D on cancer promotion and progression [21
]. However, few data are available on the possible effects of vitamin D on cancer initiation (i.e., the initial events in causing cell transformation from normal to malignant phenotype). Thus, it is conceivable that vitamin D does not affect cancer initiation and therefore does not influence epidemiologic studies of cancer incidence. Conversely, the established effects of vitamin D on tumor promotion may underlie the positive associations observed in epidemiologic studies of cancer survival.
There are several possible explanations for the observed associations between higher serum levels of 25-OHD and improved cancer survival. These include chance, selection bias, confounding, effect of the cancer on 25-OHD levels (“reverse causality”), and effect of serum 25-OHD levels on survival. The sample size, and the similar association pattern observed for the four cancer types examined, makes chance an unlikely explanation. Because our sample is population-based with no loss to follow-up, selection bias can largely be excluded. We do not have information about lifestyle factors that are correlated to 25-OHD and that might influence survival (see Jacobs et al. [22
]). Obvious factors, in particular for breast and colon cancer, would be physical activity and body mass index (BMI). In the breast cancer study by Goodwin et al. [10
], information about BMI was included in the analyses. The results did not show any essential influence on the strength of the association between 25-OHD and prognosis. Even when adjusting for strong prognostic factors for breast cancer and some treatment information, only a limited attenuation was seen. Ng et al. [8
] included information on BMI and post-diagnostic physical activity in their colorectal study, but no strong influence on the association between 25-OHD and survival was observed.
It has been suggested that genetic factors may account for a substantial proportion of the variability in serum 25-OHD [23
], and thus genetics could confound an association between serum 25-OHD and survival. However, the same genetic factors then need to be causally linked to the case fatality of the cancer. Because the positive associations between 25-OHD and cancer survival seen in the present study are strong, the association between a potential confounder and 25-OHD and the association between the potential confounder and the cancer survival rate must also be strong [25
]. Thus far, studies on the heritability of vitamin D have not provided sufficient information to permit conclusions about the role of genetic factors in cancer survival [24
An effect of cancer lowering the serum level of 25-OHD (“reverse causality”) is possible. In line with studies suggesting lower vitamin D levels among hospitalized or elderly persons, we may hypothesize that cancer also may influence the serum level of 25-OHD (see Bandeira et al. [26
]). We consider that reverse causality is unlikely to be a major explanation for our findings for several reasons. First, patients with less than 1 month of survival after blood draw, for whom low levels of 25-OHD could reflect poor health, were excluded. In addition, we conducted additional analyses in which patients with less than 2 and less than 3 months of survival time were excluded. The association between 25-OHD quartiles and prognosis was almost unchanged (data not shown). Second, for diseases like breast cancer, the functional status at the time of diagnosis is often unimpaired, and the mean survival is relatively long. Moreover, as shown in Table , positive associations between serum levels of 25-OHD and prognosis of solid tumors are seen within each stage of disease at the time of diagnosis (although, as expected, the number of fatal cases is limited for patients with localized cancer). This observation weakens the argument for reverse causality. It is noteworthy in this regard that Fang et al. recently reported that 25-OHD levels were significantly associated with survival from prostate cancer when serum levels were determined prior to the diagnosis of cancer [11
Alternately, it is conceivable that higher serum levels of serum 25-OHD are causally related to improved cancer survival. A significant protective effect for serum 25-OHD on mortality from all causes has recently been reported in the National Health and Nutrition Examination Survey, a population-based study in the United States [27
]. This interpretation is plausible mechanistically because laboratory studies demonstrate pleiotropic anti-cancer effects of vitamin D (1,25(OH)2
D) on many tumor types [8
]. An improvement in survival from cancer in patients given 25-OHD has yet to be demonstrated in a randomized trial, however.
Table shows that, for all types of cancer studied, patients with vitamin D levels in the lowest quartile experienced the shortest survival. The strength of the associations for the four cancer types was similar. The “cut point” for vitamin D sufficiency optimum for non-skeletal health is the subject of intense debate [29
]. Whether 25-OHD levels below 50 nmol/L would be the best definition of deficiency is unclear. However, our results are comparable with those reported by Goodwin et al. [10
], who also used a cut point of 50 nmol/L.
Our study has limitations, e.g., only one measurement of vitamin D status was obtained. Although the use of a single measurement potentially makes the study vulnerable to dilution effects, results of a recent population-based study demonstrate that the intra-individual variation in a single serum measurement of 25-OHD is low and that a single measurement is an accurate measurement of an individual’s long-term vitamin D status [30
]. Thus, any random variation introduced by imprecision associated with single measurement would reduce the magnitude of the hazard ratios observed. The long storage time of the serum before 25-OHD measurement could also be a weakness. However, the strength of the association persisted when storage time before the analyses was included in the analyses (Table , Model III).
Treatment information was not available. Secular changes in the treatment conceivably could influence survival rates if, over the time course of this study, newer treatments were significantly better than older treatments and if serum levels of 25-OHD increased over time. However, this type of confounding would require improvement in treatment to have occurred for all four types of cancer under study. Survival rates, especially from lung cancer, have not changed appreciably in Norway (http://www.kreftregisteret.no\cin2009english
). Moreover, our analysis indicates that 25-OHD levels actually decreased slightly by calendar year of diagnosis (i.e., changed in a conservative direction).
Conversely, this study is population-based and has several other strengths. For example, the use of date of diagnosis as the start of follow-up minimizes the possibility that the associations observed between vitamin D status and survival are due to reverse causality. The ability to control for disease stage is an important advantage as it minimizes the possibility that the apparent low survival hazard is a result of advanced disease lowering the serum levels of 25-OHD. Additionally, no potential selection has been introduced as all donors in JANUS who subsequently developed cancer and were admitted to the Norwegian Radium hospital donated a serum sample to the JANUS serum bank.
In conclusion, the present study demonstrates positive associations between circulating serum levels of 25-OHD, measured at the time of diagnosis, and length of survival for patients with cancer of breast, colon, lung, and lymphoma. These findings confirm previous ecologic data on vitamin D and cancer survival in Norway and add to a growing body of literature, indicating that serum levels of 25-OHD are positively associated with cancer survival. Intervention studies of vitamin D administration among cancer patients will be required to determine whether these observations are causal.