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Journal of Clinical Oncology, Vol 26, No 18 (June 20), 2008: pp. 2937-2939 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.16.1380
Shedding Light on Colorectal Cancer Prognosis: Vitamin D and BeyondCancer Prevention Program, Fred Hutchinson Cancer Research Center, and Department of Epidemiology, University of Washington, Seattle, WA
Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA With more than 153,000 new colorectal cancer cases per year and more than 52,000 patients dying annually from their disease, colorectal cancer is a major cause of cancer death in the United States.1 Yet, perhaps more importantly, the number of survivors of colorectal cancer in the population increases steadily, attributable in part to the implementation of new screening and treatment regimens. In 2002, the number of cancer survivors in the United States was estimated at 10.1 million,2 among them more than 1 million colorectal cancer survivors, and this number continues to rise. Yet, surprisingly, very little research has addressed how lifestyle factors, both during and after active treatment, can affect the prognosis of colorectal cancer patients. In this issue of the Journal of Clinical Oncology, Ng et al3 present data from the Nurses’ Health Study and the Health Professionals Follow-Up Study, showing a strong association between increasing plasma vitamin D levels (25(OH)D) and reduced mortality. These findings are impressive for their impact on overall mortality, suggesting a 48% reduction between the highest and lowest quartile of plasma 25(OH)D, with a linear and statistically significant trend. However, for colorectal cancer mortality, the multivariate hazard ratio was attenuated to a statistically nonsignificant reduction of 39% between the extreme quartiles, with no evident trend. Clearly, the sample size of about 300 patients and only 96 colorectal cancer–specific deaths was a limiting factor. Additional limitations result from the study design, because the study cohorts were not originally established to investigate cancer prognosis. For example, the blood draws used for the 25(OH)D measurement occurred before diagnosis—about 3 years on average—with variable time frames between the exposure measurement and subsequent cancer diagnosis. As the authors note, associations with prediagnostic 25(OH)D level may also reflect the influence of other factors known to be related to vitamin D status. Most important in this context could be physical activity, which is somewhat difficult to measure and quite difficult to adjust for,4,5 yet correlates with 25(OH)D levels,6 presumably due to increased sun exposure associated with outdoor exercise. In this study population, postdiagnosis physical activity was strongly associated with 25(OH)D (ptrend = 0.003); physical activity has been associated with improved survival after several types of cancer, including the colorectal cancer in this cohort.7 A further limitation is the lack of treatment information, a key component of prognostic studies. Nevertheless, despite these drawbacks, the findings by Ng et al3 are intriguing and important. They highlight the need for well-designed prognostic studies among cohorts of cancer patients, in which exposure assessments are uniformly obtained after diagnosis, treatment regimens are assessed, and information on prognostic tumor characteristics (such as microsatellite instability) is also available.8 We are just beginning to identify important lifestyle determinants of survival and prognosis, and vitamin D status may emerge as a promising predictor that could be modified. Vitamin D has also received much attention recently as a possible cancer-preventive agent. There is substantial evidence that it suppresses proliferation and promotes differentiation and apoptosis in colorectal cells, through effects on growth factors and cytokines, cell-cycle regulation, and apoptosis.9 Nevertheless, despite intensive study, the role of Vitamin D in the primary prevention of colorectal cancer remains uncertain. Ecologic analyses nearly 30 years ago associated sunlight exposure and resulting vitamin D synthesis with reduced risk of colorectal cancer.10 Subsequent epidemiologic studies of dietary vitamin D alone have been inconclusive,11-16 but more consistent risk reductions have been shown for analyses of both diet and supplements as sources of vitamin D.12,13,15-19 Plasma 25(OH)D, which reflects body stores of vitamin D from all sources, including diet, supplements, and endogenous synthesis from UV-B exposure, has been associated with reductions in the risk of colorectal cancer of approximately 50% between the highest and lowest quintile,20,21 although not all studies have reported decreased risks.22 Vitamin D synthesis in the skin varies with latitude, skin color, and sun exposure, but almost always has a greater effect on plasma 25(OH)D than dietary intake.23-25 Accordingly, observational studies of the relationship between vitamin D and colorectal cancer are susceptible to confounding factors related to sun exposure, which are difficult to assess. As discussed previously, this can include the notoriously difficult to measure amount of physical activity, with exercise known to be a very strong protective factor for colorectal cancer.7 In addition, race can be a major determinant of vitamin D status, because melanin in skin reduces the rate of synthesis; vitamin D deficiency is particularly widespread among African Americans,26,27 including many African American cancer survivors.27a Randomization can eliminate these sources of confounding, and some randomized trials have been conducted on vitamin D and colorectal and other cancers.28-30 The multicenter Women's Health Initiative included a trial of calcium (1,000 mg calcium/d) plus vitamin D supplementation (400 IU/d) in 36,282 postmenopausal women with a mean follow-up of 7 years; this intervention was designed to test efficacy against fractures, and colorectal cancer was a secondary outcome.30 The study reported no association between supplementation and colorectal cancer (hazard ratio, 1.08; P = .51), calling into question the reduced risks seen in observational studies. However, the study's design may have limited its ability to detect a protective effect, in that the dose of vitamin D was at the current recommended level (which some advocate as possibly too low for colorectal cancer prevention20) and supplement use in the control group was neither restricted nor uncommon; on average at enrollment, intakes were 1,151 mg/d of calcium and 367 IU/d of vitamin D, twice the national average.30 A reduced incidence of all cancers was reported from a much smaller randomized trial (n = 1,179) of calcium (1,400-1,500 mg/d) plus vitamin D (1,000 IU/d; relative risk, 0.40; P = .01), though numbers were inadequate to distinguish specific cancers and follow-up was just 4 years.28 Both of these randomized trials were limited by relatively short follow-up; if vitamin D acts early in colorectal carcinogenesis, the duration of these trials may have been insufficient to note an effect on risk. In addition, the trials to date have combined supplementation with vitamin D and calcium, and calcium itself probably has cancer chemopreventive properties through the binding of secondary bile acids or via calcium-sensing receptor signaling.9 A multicenter prevention trial, the Vitamin D/Calcium Polyp Prevention Study, is currently in the recruitment phase (goal n = 2,000) and will address both colorectal adenoma and cancer occurrence among patients with a history of colorectal adenomas. The study will investigate calcium (1,200 mg/d) and vitamin D (1,000 IU/d), both independently and jointly. This separate investigation and the higher dose of vitamin D should shed more light on the potential chemopreventive effects of vitamin D.31 However, by virtue of its design, this trial will test the efficacy of vitamin D in secondary, rather than primary, chemoprevention of colorectal adenomas. Findings from the Aspirin/Folate Prevention trial suggest that some agents, such as folic acid, may have a dual role in carcinogenesis32: although folic acid is chemopreventive before the establishment of preneoplastic lesions, it may foster the growth of existing cancer precursors.33-35 Thus, it is critical that recommendations on risk or preventive factors that have been established when studying the etiology of cancer are not extended inappropriately to cancer survivors. The results presented here by Ng et al3 suggest that opposed roles of vitamin D status in prevention and progression are unlikely, although the question cannot be answered with certainty until more targeted research studies have been completed. Based on the results presented in JCO, should colorectal cancer patients be advised to take vitamin D supplements? For primary cancer prevention, Gorham et al20 propose intakes of 1,000 to 2,000 IU/d. Should cancer patients consider similar intakes? In light of the risk of hypercalcemia, the Institute of Medicine defines a tolerable upper intake level for vitamin D of 2,000 IU/d for adults, a level that can be achieved among users of multiple supplements.36 Toxicity due to hypercalcemia, which may also have a genetic component, has also been a limiting factor in clinical trials using calcitriol, the most potent form of vitamin D; these trials also suggest limited treatment success for prostate cancer.37,38 Supplement use among cancer patients is known to be high, with 64% to 81% of survivors reporting use of any vitamin or mineral supplements, and 26% to 77% reporting use of any multivitamins.39 Cancer patients commonly initiate use after diagnosis, yet often do not discuss this choice with their physicians.39 This is of concern because of possible interference between supplement use and chemotherapy and radiation therapy, which has been insufficiently studied.39 Many cancer patients want to know what they themselves can do, how they can protect themselves against recurrence of their disease, and how they can return to an active, healthy life. However, to date, we have little research to support science-based recommendations on supplement use and other lifestyle changes for cancer survivors.40 The study by Ng et al3 is one of the first steps toward learning more about health behaviors that can affect colorectal cancer prognosis. We need to follow up with large cohorts of colorectal cancer patients designed specifically to investigate the effects of vitamin D supplementation and other lifestyle choices on survival. If these results can be replicated, and the Vitamin D/Calcium Polyp Prevention Study trial shows promising results, then a randomized trial among colorectal cancer patients would be essential to obtain an unequivocal answer on whether colorectal cancer patients should be advised to take vitamin D supplements. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Cornelia M. Ulrich Financial support: Cornelia M. Ulrich Administrative support: Cornelia M. Ulrich Collection and assembly of data: Cornelia M. Ulrich, Rebecca S. Holmes Manuscript writing: Cornelia M. Ulrich, Rebecca S. Holmes Final approval of manuscript: Cornelia M. Ulrich, Rebecca S. Holmes REFERENCES 1. American Cancer Society: Cancer Facts & Figures 2007. Atlanta, GA, American Cancer Society, 2007 2. Institute of Medicine, National Research Council: From Cancer Patient to Cancer Survivor: Lost in Transition. Washington, DC, National Academies Press, 2006 3. Ng K, Meyerhardt J, Wu K, et al: Circulating 25-hydroxyvitamin D levels and survival in patients with colorectal cancer. J Clin Oncol 26:2984-2991, 2008 4. Ainsworth BE, Sternfeld B, Slattery ML, et al: Physical activity and breast cancer: Evaluation of physical activity assessment methods. Cancer 83:611-620, 1998[CrossRef][Medline] 5. 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Sieg J, Sieg A, Dreyhaupt J, et al: Insufficient vitamin D supply as a possible co-factor in colorectal carcinogenesis. Anticancer Res 26:2729-2733, 2006[Medline] 22. Otani T, Iwasaki M, Sasazuki S, et al: Plasma vitamin D and risk of colorectal cancer: The Japan Public Health Center-Based Prospective Study. Br J Cancer 97:446-451, 2007[CrossRef][Medline] 23. Adams JS, Clemens TL, Parrish JA, et al: Vitamin-D synthesis and metabolism after ultraviolet irradiation of normal and vitamin-D-deficient subjects. N Engl J Med 306:722-725, 1982[Medline] 24. Heaney RP, Davies KM, Chen TC, et al: Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 77:204-210, 2003 25. Holick MF: McCollum Award Lecture, 1994: Vitamin D—New horizons for the 21st century. Am J Clin Nutr 60:619-630, 1994 26. 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Trump DL, Potter DM, Muindi J, et al: Phase II trial of high-dose, intermittent calcitriol (1,25 dihydroxyvitamin D3) and dexamethasone in androgen-independent prostate cancer. Cancer 106:2136-2142, 2006[CrossRef][Medline] 38. Schwartz GG, Hall MC, Stindt D, et al: Phase I/II study of 19-nor-1alpha-25-dihydroxyvitamin D2 (paricalcitol) in advanced, androgen-insensitive prostate cancer. Clin Cancer Res 11:8680-8685, 2005 39. Velicer CM, Ulrich CM: Vitamin and mineral supplement use among US adults after cancer diagnosis: A systematic review. J Clin Oncol 26:665-673, 2008 40. American Institute for Cancer Research: Nutrition Guidelines for Cancer Survivors After Treatment. Washington, DC, American Institute for Cancer Research, 2006 Related Article
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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