vitamin D, coffee decreases advanced cancers

 There were two recent articles suggesting that vitamin D supplementation or coffee are associated with decreased development of advanced cancer (see vit d dec advanced cancer jamaopen2020 in dropbox, or doi:10.1001/jamanetworkopen.2020.25850)

 

Details: 

-- 25,871 participants in the VITAL study were randomized to vitamin D3 2000 IU/d and/or marine omega-3 fatty acids 1 g/d supplements in a multicenter US study, all free from cancer and cardiovascular disease at baseline

-- 51% female, mean age 67, 71% white/20% Black, BMI <25 in 31%, 25-30 in 40%, >30 in 29%, current smoking 7%, diabetes 14%, alcohol use 69%, baseline use of vitamin D supplements (<=800IU/d) 43%, baseline 25(OH) D level 31ng/mL 

-- baseline mammography or breast biopsy was done within 10 years in 94% of women, colonoscopy or other colon cancer screening within 10 years in 90%, PSA screening in men in past 10 years in 77% [ie, a pretty strong routine cancer screening history]

-- primary outcome: composite incidence of metastatic and fatal invasive cancer; secondary outcome: the effect of BMI on this outcome 

--1617 were diagnosed with invasive cancer over a median intervention period of 5.3 years 

-- though not mentioned in this secondary analysis, the initial VITAL study did a random assessment of 1644 participants at one year finding that those on vitamin D supplement increased their 25(OH)D levels to 42 ng per mL, with minimal change in the placebo group (see vit d and cancer cardiovasc dz VITAL study nejm 2019 in dropbox or DOI: 10.1056/NEJMoa1809944) 

 

Results: 

-- the overall study found no significant differences for cancer incidence by treatment arm: HR 0.96 (0.88-1.06)

-- advanced cancers (metastatic or fatal): 

    -- vitamin D vs placebo: 226 of 12,927 participants (1.7%) vs 274 of 12,944 on placebo (2.1%), 17% reduction HR 0.83 (0.69-0.99), p=0.04 

        -- the curves start to diverge after about two years 

-- total metastatic cancer and cancer mortality (n=25,254), by BMI 

    -- BMI <25: 58 events on vitamin D and 96 on placebo, 38% reduction HR 0.62 (0.45-0.86), p=0.004 

        -- total metastatic cancer: 24 events on vitamin D and 39 on placebo, nearly significant 37% reduction HR 0.63 (0.38-1.05) 

        -- total cancer mortality: 38 events on vitamin D and 68 on placebo, HR 0.58 (0.39-0.86), p=0.007 

    -- BMI 25-30: nonsignificant 11% reduction HR 0.89 (0.67-1.17) 

    -- BMI >30: nonsignificant, HR 1.05 (0.74-1.49) 

    -- overall, significant interaction for vitamin D supplementation with BMI, p=0.03 

-- total cancer mortality: nearly significant 17% decrease, HR 0.83 (0.67-1.02), p=0.08 

-- no difference in analysis stratified by race/ethnicity 

-- no difference in analysis stratified by baseline serum 25(OH)D levels <20 vs >20 ng/ mL 

-- no difference between the groups in terms of hypercalcemia, kidney stones, or GI symptoms 

 

Commentary: 

-- A recent meta-analysis of 10 trials found a decrease in total cancer mortality but not total cancer incidence with vitamin D supplementation (see vit d dec cancer deaths annonc 2019 in dropbox or doi:10.1093/annonc/mdz059) 

-- this current trial looked specifically at those with more advanced or fatal cancers, also suggesting a beneficial role for vitamin D supplementation.  

-- mechanistically, vitamin D may have many roles in the body, including promoting cell differentiation, inhibiting cancer cell proliferation, as well as being anti-inflammatory, immunomodulatory, pro-apoptotic, and antiangiogenic. Vitamin D receptors are present on the vast majority of cells in the human body, including those in the immune system. 

-- it is notable that this group at baseline had what seemed to be adequate vitamin D levels per current guidelines, with mean 25(OH)D levels of 31 ng/mL, though some of the observational epidemiologic studies in the past have suggested that higher vitamin D levels are associated with decreased cancer risk (e.g. the Nurses’ Health Study found decreases in breast cancer risk associated with a level of 48 ng/mL (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026605/ ) 

-- several other trials have found results similar to those found in the VITAL study, including a stronger effect for advanced disease and cancer deaths than found with cancer incidence, or finding those with normal BMIs to be more protected. 

    -- Though, even the original VITAL study found that the incidence of cancer was statistically lower in the subgroup who had normal BMI, with 206 cancers in the vitamin D group, 278 cancers in the placebo group, with a hazard ratio of 0.76 (0.63-0.90).  

    -- or, see http://gmodestmedblogs.blogspot.com/2018/04/vitamin-d-and-cancer-risk-cohort-study.html and http://gmodestmedblogs.blogspot.com/2018/04/vitamin-d-and-cancer-rct.html

 

-- It is unclear why the effects of vitamin D were largely evident in normal weight people. Obesity, especially of the central type, is associated with increased inflammatory biomarkers. And there may be some impaired immune function in those who are obese 

    -- also, studies have found that obese patients need a higher dose of vitamin D to achieve the same 25(OH)D levels (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201256/ , which also has an extensive review of the vitamin D and cancer data and purported physiologic mechanisms). Of note, those with higher BMIs have more adiposity and vitamin D is stored in fat, perhaps an important mechanism that leads to lower serum levels in overweight or obese patients. (And, for example, parathyroid hormone levels, a marker for vitamin D deficiency, are higher in obese versus lean patients). 

 

-- it is still not clear what the optimal dose or serum level of vitamin D is. Some of the other studies looking at cancer risk or its clinical course by vitamin D supplementation used varying amounts, some at least twice as high as in this study. And it may well be that different levels of vitamin D are clinically important for different parts of the body (i.e. bone may do well with a level of 30 ng/mL, but optimizing immunologic benefit or decreasing cancer incidence may require a very different level) 

-- as with many of these studies looking at single interventions (vitamin D, in this case), this is conceptually a reductionist approach, since the vast quantity of prevalent diseases are associated with an array of psychosocial/behavioral/lifestyle factors. It is hardly surprising that correcting an abnormally low vitamin D level (even if it does have an important effect on disease incidence or progression) may not show significant effect by itself, if there are concurrently many other disease-increasing issues, such as diet, housing, food, exercise, stress, depression, etc., etc., etc. 

 

Limitations: 

-- we still do not know what the optimal dose of vitamin D is for immune function or cancer prevention. In a sample of the VITAL patients, they achieved a level of 42 ng per mL with the 2000 IU vitamin D supplement, but it is not clear that this level was maintained throughout the study, or if a higher level might have been more beneficial. And this may be different in patients who are overweight or obese 

-- there were no data provided around lifestyle and social issues, such as diet/exercise/stress/depression, and these pretty clearly affected cancer incidences and perhaps severity. These would be particularly important to know in evaluating the effect of a single factor, such as vitamin D 

 

So, a few points: 

-- vitamin D is likely (to me) to be an important vitamin, given it has receptors throughout the body and on almost all cells, likely an evolutionary consequence (our species did, after all, start in the sun-bathed, vitamin D-plentiful Fertile Crescent)

-- it is extraordinarily unlikely that adequate vitamin D levels by themselves would dramatically affect the multiple diseases modern people have, though still might be one of the very important components

    -- but its magnitude of apparently healthy effects (anti-inflammatory, immunomodulatory, antineoplastic, etc.) are an important component of maintaining a healthy body 

-- so, for example, it is not surprising that many different cancers have been found to be affected by vitamin D deficiency as in the VITAL study. and, this finding itself is interesting since the different cancers are often associated with different risk factors

    -- and perhaps this is reflected in the finding that vitamin D is more associated with cancer progression than cancer incidence

-- and, the good news is for those of us who have migrated out of the Fertile Crescent, vitamin D is easily accessible, very cheap, and almost without significant adverse effects (unless someone takes huge amounts of it, not an easy task) 

 

So, I think it is a reasonable objective for us clinicians to treat vitamin D deficiency as a component of healthcare maintenance... as can be done by just supplementing everyone in areas of the country with insufficient sun, or by targeting those with documented low levels of 25(OH)D levels

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Another similar study found increasing survival in patients with advanced or metastatic colorectal cancer, this time tracking with increasing coffee intake (see coffee and dec advanced cancer jamaonc2020 or doi:10.1001/jamaoncol.2020.3938)

    -- 1171 patients previously untreated with locally advanced or metastatic colorectal cancer and involved in various chemotherapy regimens, who answered food frequency questionnaires from 2005 to 2018, found that after 5.4 years 93% had died or had disease progression 

    -- each additional cup of coffee a day decreased cancer progression by 5%, HR 0.95 (0.91-1.00); and decreased death by 7%, HR 0.93 (0.89-0.98) 

        -- this all increased to a 36% benefit in overall survival and a 22% benefit in progression-free survival for those drinking at least 4 cups of coffee a day 

    -- they attributed the benefit from coffee to its antioxidant, anti-inflammatory, and insulin sensitizing effect 

maybe take vitamin d with a large cup of coffee each morning????

geoff

 

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