In my 1st blog, and free chapter release on why vitamin D should be looked at as a vitality sign for patients with cancer and addressed before starting conventional therapy, I highlighted the most obvious reason we should screen and treat a vitamin D deficiency, to help the ethnic minorities and obese patients who are the most likely to be vitamin D deficient and who stand the most to gain both in terms of baseline fatigue, insomnia and foggy brain (quality of life) and better cancer outcomes. This is absolutely a health equity issue, and perhaps the most fixable and impactful one America can focus on.
While vitamin D has been heavily studied for its potential impact on disease prevention and treatment, not as much so for quality of life in ‘healthy individuals’. Studies querying whether vitamin D is effective for fatigue in a healthy population is limited to one randomized placebo controlled trial and a single prospective cohort(Roy 2014), which isn’t a great look on the hierarchy of evidence, but as physicians promising to do no harm, it’s a far worse look to say we still need more randomized controlled trials (RCTs) to justify replacing an essential hormone deficiency that supports life of all sentient animals on this planet.
Let’s dive more into the EViDiF study(Roy 2014) where “healthy” individuals aged 18-75 years old who presented to a clinic with fatigue and no other acute medical issues. 77.2% were identified as having low D25 (<30ng/ml) even though 51.5% of the patients were on D supplementation (please dwell on what this says about our current ineffective practices). Among those who underwent vitamin D replacement therapy, 95.7% achieved normal D25 >30 ng/ml with a pretreatment mean of 19.71 ng/ml improved to 52.29 (p<0.001). Frankly, this is an amazing performance for rapid D3 replacement therapy and will be tough to replicate with individualized weight based dosing. At CTCA, we were only successful 60% of the time in the first year; this study did it 95% in 5 weeks. No toxicity and the mean fatigue score dropped from 31.5 to 11 p<0.001 (a 40 point fatigue score) or by 65% showing that the intervention was especially meaningful given placebo effects for fatigue in cancer patients is typically in the 20-30% range. These effect sizes are absolutely consistent with clinical experience when one starts to treat these deficiencies effectively.
Now let’s go into the dosing schema (not discussed in the chapter) which was D2 50,000 IU three times weekly for 5 weeks (three times the dose usually given for vitamin D deficiency in clinical practice, or the equivalent of D2 21,429 IU/day. That’s the comfort level physicians will need to have regarding D2 or D3 dosing, to be effective in the treatment of a severe vitamin D deficiency especially in obese individuals (D2 or D3 is fine in my opinion, I just don’t like binding my patients to a prescription which is required for D2 50,000 IU week). Please note, this was a loading dose schema limited to 5 weeks for individuals with a pre-selected vitamin D deficiency, not for long term use and certainly would be toxic if taken long term for normal BMI patients or patients with normal D25 levels already (which is why I didn’t put these details in the chapter). Know your D25 level and dose intelligently.
The only vitamin D randomized-placebo controlled study in healthy patients with a primary endpoint of fatigue was double-blinded and conducted by Nowak et al 2016. 120 healthy individuals (mean age 29) with severe deficiency (13-14 ng/ml for the D and placebo arm) and symptoms of fatigue were randomized to a one time dose of D3 100,000 IU (3571 IU/d) or placebo. The primary endpoint, change in the fatigue assessment scale (FAS) at 4 weeks, was significantly superior for vitamin D versus placebo (delta=2.5 points, p=0.01) but somewhat mild effect size. Of note, serum D25 did go up 14 ng/ml in the D group, but still left most patients under <30 ng/ml, and the increase in serum D25 significantly moderated the benefit on fatigue p=0.02, suggesting better replacement dosing would have been more effective.
How else do we know it’s not placebo? Clinical experience. The actual dose matters. For example, for me, I did not improve until I had a sufficient dose (started on 2000 IU/d and improved only when the dose went up to 5000 IU/d). When you treat patients, similarly, ineffective doses correlate with less likelihood of the patient having any symptom improvement. Second, if the patient forgets to take doses over time, recurrence of the fatigue eventually is assured (just like patients getting synthroid for hypothyroidism).
Any reasonable physician understands this as the clinical phenotype one would expect for an endogenous hormone that promotes wellness in a human being, not just a placebo effect. We would have stopped giving synthroid for subclinical hypothyroidism in the absence of any RCT to support it long ago, if we did not in fact see similar behavior in patients (clinical consequences for not treating it or staying on it). Since I would guess-timate at academic cancer centers at least in the U.S., <5% (this is generous as I suspect the number is 0%) probably routinely screen and replace correctly a vitamin D deficiency, it’s not surprising to me that a large community of brilliant academicians using the strictest quality of evidence to guide clinical care would have a natural blind spot to this correlation. No effective D3 dosing, no patients reporting fatigue improvement to raise the question. To be clear this is not a conspiracy, but a perfect example of what current FDA Director Marty Makary calls a blind spot in academic medicine.
Lastly, obviously not everyone with a low vitamin D25 has symptoms. I have talked to patients with <10ng/ml who claim to have no bothersome symptoms, and no improvement when replacing (more likely men than women in my experience). But we need to know this information more precisely to shape health care policy and quantify expected impact. So I am designing an investigator initiated study to look at rapid vitamin D replacement protocols for vitamin D deficient patients, with primary endpoints of looking at whether patients with fatigue at baseline have improvement before starting neoadjuvant chemotherapy with placebo crossover so that the group that does not get the rapid replacement before starting, still gets it during neoadjuvant treatment, and whether the target D25 achieved correlates to pCR rates. This avoids the ethical issues of placebo controlled D3 studies in the future. The secondary endpoint will be whether pCR rates correlate significantly to serum D25 level achieved and PFS if funded.
If you have any correlative or biological research questions on you wish to collaborate with me, please contact me at my @lumc.edu address.
The sweet smell of a moonstone peony flower in early spring
Leave a Reply