This review offers evidence to explain cancer survival differences between AAs and WAs. AAs’ lower serum 25(OH)D concentrations (mainly from reduced vitamin D photoproduction owing to darker pigmentation) may account for much of the unexplained survival disparity after consideration of such factors as SES, stage at diagnosis, and treatment. All cancers for which a disparity in cancer-specific survival was reported also have evidence for a beneficial role of vitamin D, as do most of those for which we found disparities for all-cause survival.
One reason ecological studies are strong include that vitamin D plays an important role in reducing risk of cancer initiation and angiogenesis around tumors and metastases.84,85 Since cancer can take years to decades to reach the stage of detection or death, continued high serum 25(OH)D concentrations over much of the lifetime is required for greatest risk reduction. Most recent ecological studies include various cancer risk-modifying factors in the analysis.20-24 Also, ecological studies include many cases, thereby reducing the uncertainty of the values. Among 45-y-old British citizens, casual solar UVB irradiance in summer increased serum 25(OH)D concentrations by about 15 ng/ml,86 enough to have an important impact on cancer risk.25,29 For example, breast cancer incidence rates are highest in spring and fall.87 The reasons for the seasonal variations given were increased production of vitamin D in summer and melatonin in winter. Breast cancer has several subtypes, and rate of progression can vary widely, with some being very rapid. For slower growing cancers, serum 25(OH)D concentrations in summer may be sufficient to retard or reverse the growth.
Once cancer reaches the point where it can be diagnosed, vitamin D improves cancer-specific survival by several mechanisms, including antiangiogenesis and antimetastases.84,85 The disparities for hematopoietic cancers may be weak or nonexistent because angiogenesis and metastases are less important for blood cell-related tumors than for solid tumors. Higher serum 25(OH)D concentrations also affect all-cause mortality rates88 since vitamin D protects against several major life-threatening conditions for the elderly,89-91 including diabetes and cardiovascular disease, influenza and pneumonia, and falls and fractures.
Secondary hyperparathyroidism due to osteoblastic metastases and hungry bone syndrome has been described with advanced prostate and breast cancer, it is likely that a vitamin D replete state may minimize such occurrences.92 Bisphosphonates are commonly used in oncology. Pamidronate administration improved the secondary hyperparathyroidism due to “bone hunger syndrome” in a patient with osteoblastic metastases from prostate cancer. Coleman and McCloskey93 suggest that bisphosphonates may prevent metastases and reduce the risk of disease recurrence. Based on animal data,94 a vitamin D replete state may be helpful in reducing bisphosphonate induced osteonecrosis of the jaw.
Factors other than SES, stage at diagnosis, treatment, and vitamin D status might also explain the cancer survival disparities. For example, the lack of survival disparities for lung cancer may be due to a stronger effect from smoking than from vitamin D. Smoking cessation improves lung cancer survival rates associated with early-stage lung cancer.95
Obesity is significantly correlated with cancer risk for nearly all types of cancer listed in Tables 1 and 2.96,97 AAs tend to have higher body mass index than WAs. One reason is that obesity is linked to poverty in the United States because of energy-dense but nutrient-poor foods are cheaper due to subsidies.98 A second reason is that AAs have about twice the prevalence of apolipoprotein E ε4 (ApoE4) than WAs.99 ApoE4 increases production of cholesterol in the liver and of insulin in the pancreas to store excess food as fat for those with sporadic food supplies, such as hunter-gatherers. Interestingly, overweight and obesity rates for white and black men differ little, whereas AA women are much heavier than WA women (http://www.cdc.gov/NCHS/data/hestat/obesity_adult_07_08/obesity_adult_07_08.pdf). Thus, obesity does not seem to be a likely explanation for cancer disparities among men but could be for women. On the other hand, serum 25(OH)D concentrations are inversely correlated with body mass index, which has implications for cancer risk.100 Interestingly, for pancreatic cancer incidence, higher body mass index was significantly associated with risk for AA and WA men and WA women but with only insignificantly reduced risk for AA women.11
Cancer survival studies with respect to serum 25(OH)D concentrations at time of diagnosis offer strong evidence for a beneficial effect of vitamin D. All cancers with a beneficial effect of vitamin D on survival have been found inversely correlated with solar UVB doses, with the possible exception of chronic lymphocytic leukemia.41 There are also studies from Norway indicating improved survival for those diagnosed with breast, colon, prostate cancer and Hodgkin lymphoma in summer compared with winter.35
The UVB-vitamin D-cancer hypothesis receives its strongest support from ecological studies.19-24,27,28 Observational studies also provide good support if the various studies are examined carefully and a good reason is found for why many observational studies have not found a beneficial effect of vitamin D in reducing the risk of cancer. Nested case-control studies have a reduced strength since only a single serum 25(OH)D concentration measurement or oral intake assessment is made at time of enrollment, with follow-up periods lasting between 3 and 28 y.101 As the follow-up time increases beyond about 3–7 y, the single measurement is less meaningful.101,102 Case-control studies, on the other hand, use serum 25(OH)D concentration or vitamin D oral intake values at the time of diagnosis. A review of observational studies of breast and colorectal cancer incidence with respect to serum 25(OH)D concentration found statistically significant inverse correlations for breast cancer out to 3 y and for colorectal cancer out to 12 y of follow-up.101 Thus, the recently reported results from the Vitamin D Pooling Project study of rarer cancer types (endometrial, esophageal, gastric, ovarian, pancreatic, and renal cancer and non-Hodgkin lymphoma)103 probably failed to find an inverse correlation between incidence of these cancers and prediagnostic serum 25(OH)D concentrations because the mean follow-up period was 6.63 y and because there were so few cases that the 95% confidence intervals were about 50%. The correlation between serum 25(OH)D concentrations measured at different times decreases with time, dropping to a regression coefficient of 0.40 after 14 y.104
Several ways exist to test the UVB-vitamin D-cancer hypothesis as an additional contributing factor for cancer survival disparities. One would be to measure serum 25(OH)D concentrations of newly diagnosed cancer patients and at several intervals during the course of the cancer. Another would be to supplement newly diagnosed cancer patients with sufficient vitamin D to bring serum 25(OH)D concentrations up to 40–80 ng/ml and compare results for those not supplemented, perhaps from previous patients in the same practice. A recent publication described the rationale for vitamin D supplementation,105 which is being done in some cancer treatment centers.106,107 Increasing serum 25(OH)D concentrations would also reduce the risk of severe sepsis associated with cancer surgery108 as well as many other comorbid diseases.89-91
We acknowledge that while it appears very likely that vitamin D is an important and often ignored factor in the biology of cancer, the issue of cancer etiology is complex and is clearly multifactorial. Moreover, outcomes studies may have skewed results since AA men are less likely to participate in cancer screening trials.109 Black women may be less physically active.110 An inverse relationship between physical activity and breast cancer in AA women has been reported.111 Some of the adverse cancer outcomes may relate to less than optimal care. Esnaola et al.112 reported that AA patients are less likely to receive resection in non-metastatic rectal cancer. Rolnick et al.113 demonstrated that AA colorectal cancer survivors are less likely to receive post-treatment colorectal surveillance. Similar findings have been found in prostate cancer.114 These may not necessarily reflect racism in that physicians may make recommendations based on a patient’s access to health care, presence of insurance, etc.115 In addition, poor health literacy in AA women may also impact access to available health care strategies.116
Cultural differences may also play a role with cultural insensitivity among providers compounding the issue. Margolis et al.117 demonstrated significant racial differences in belief prior to lung cancer surgery. Some of these differences result in refusal of surgery on the part of AA patients. AAs have less trust in their health providers and may not accept physicians’ assertions regarding treatment.117 Spiritually based health interventions may be more effective in AAs.118 Van Ness et al.119 indicates that lack of religiousness maybe associated with poor cancer survival in AA women. Church attendance may be associated with greater emotional and social support, which is linked to better outcomes in breast cancer.
We must also consider the possibility that apart from direct cellular benefits of vitamin D on cancer that vitamin D deficiency has indirect effects which are hard to quantify but may have a significant impact on cancer outcomes. Vitamin D deficiency is also associated with a higher prevalence of depression and neurocognitive symptoms, which makes patients intrinsically less likely to seek medical attention. Treating vitamin D deficiency may ameliorate symptoms of depression.120
Some risk factors such as diet can be modified and increased consumption of vegetables may decrease the risk of breast cancer in AAs, possibly by altering estrogen/progesterone receptor status.121 Fortunately, it does appear that tumors are not intrinsically more aggressive in AAs.122 In Veterans with equal access to health care, lung and colon cancer are not necessarily more aggressive diseases in AAs.123 Dignam reported that black women, diagnosed at comparable disease stage as white women and treated appropriately, tend to experience similar breast cancer prognoses and survival.124
Some of the residual disparity for prostate cancer may be due to the higher prevalence of the ApoE4 allele among AAs than WAs,99 which is related to increased cholesterol production. Cholesterol is an important risk factor for high-grade prostate cancer.125 Increased low-density lipoprotein concentrations increased the risk of prostate cancer for AAs but not WAs.126
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