Donald Trump Vitamin D and Cancer

Thanks for watching! My name's Donald Trump. I'm a medical oncologist from Roswell Park Cancer Institute in Buffalo, New York. And I'm going to talk for a few minutes about the approach that I and my colleagues at Roswell Park have taken to understanding and exploring vitamin D as it relates to cancer. As some word of background, my colleague, Dr. Candice Johnson, and I got interested in vitamin D primarily from the standpoint of its use as a cancer therapy and have focused particularly on very high doses of 125D3 calcitriol as a way to kill cancer cells, inhibit angiogenesis, and potentiate chemotherapy. All of those effects have been clearly demonstrated in the lab, and we are exploring mechanisms in the lab and approaches in clinical trials in the clinic. In the course of that work, I also caught up with 40 or 50 years of other science to recognize that vitamin D deficiency was a frequent problem, have followed the work and learned from Doctors Garland and Haney and Hollick and many others, And we've begun to look at the frequency of vitamin D deficiency in cancer patients at a comprehensive cancer center. And that's what I will talk with you for the next 20 or 25 minutes. Just as a word of orientation, since I'm 3,000 miles away from most of you all, Roswell Park is a comprehensive cancer center. We have about 3,000 employees and 300 faculty members, and we see about 7,500 new cancer patients per year. We're the only National Cancer Institute-designated center in upstate New York. The sun does shine on Roswell Park. This is our clinical and ambulatory building, but you also have to remember where Roswell Park is. Buffalo, it's latitude 42.89, just on the eastern shore of Lake Erie. So Buffalo is clearly in the zone where ambient light exposure, UV index, would not be expected to account for a huge intake of vitamin D among our patients. You will hear today, and you've already heard considerable evidence regarding the role of vitamin D deficiency in cancer, allusion to multiple sclerosis. We'll hear a very nice talk on cardiovascular disease, infections, autoimmune disease, many associations with vitamin D deficiency about which we need to learn considerably more. In terms of sick patients, Dr. Haney already referred to this paper by Dr. Thomas and his colleagues at the Massachusetts General Hospital showing over 40% of hospitalized patients had vitamin 25 hydroxy D levels less than 15 nanograms per ml. And in the spirit of Dr. Haney's discussion about what's normal and deficient and insufficient, Dr. Thomas considered 15 nanograms per mL to be the lower limit of normal, a level that most of us would now consider substantially deficient. We began to study cancer, as I mentioned, and particularly from the standpoint of using the most active form of vitamin D, 125D3, as a cancer therapy, but then also began to realize from studies such as this one from Ed Giovannucci and his group at Harvard, looking at the health profession study and estimating the impact of a decrement or an increment in the 25-hydroxy D level, that there seemed to be considerable evidence to support the hypothesis that those individuals with low vitamin D levels were at greater risk of getting cancer. We then wondered whether cancer patients would be even more likely to be vitamin D deficient than individuals in the normal population, recognizing that there had really been very few, if any, studies of patients with diagnosed cancer and looking at 25-hydroxy D levels in those individuals. So our initial studies about three years ago were simply to do surveys in our comprehensive cancer center to evaluate the frequency of vitamin D deficiency we have looked at prostate cancer patients colorectal cancer patients bone marrow transplant recipients and are currently doing studies about which I'll tell you a little on the prospective evaluation of vitamin D3 supplementation in prostate cancer and separate studies in colorectal cancer patients. This was the first study that I did. I'm a medical oncologist. My practice is in prostate cancer and have spent several years evaluating the potential role of vitamin D in the therapy of prostate cancer. And as it turns out, we shouldn't have been surprised that in our population, among 120 patients, all ambulatory patients with prostate cancer, most of whom had undergone androgen deprivation, that low vitamin D levels, below 32 nanograms per mL, were quite common. 72% of our patients had levels that I would consider vitamin D deficiency. We also looked at a separate group of men who were recently diagnosed and had clinically localized prostate cancer. So these are men generally before they've had any treatment for prostate cancer. Most of these men eventually went on to get either prostate removal or prostate irradiation. But we found, and again, perhaps not surprisingly, that 70% of these individuals had 25-hydroxy-D levels below the 32-nanogram-per per mil range. And then we also looked at 100 normal individuals. These were normal individuals largely drawn from those individuals who accompanied the cancer patients at Roswell Park to their clinic visits. Our normal populations are drawn from the significant others of the patients that we care for and 70% of these individuals also had vitamin D levels less than 32 nanograms per ml so these data to me indicate that at least prostate cancer patients are no more likely to be vitamin D deficient than normal individuals that based on these data, there's no strong indication that the extent of prostate cancer or the presence or absence of androgen deprivation has a major effect on the frequency of vitamin D levels less than 32 nanograms per mL. But at least in the latitude in which we live in Buffalo, New York, deficient vitamin D levels occur in almost three-quarters of our individuals. A colleague of mine, Dr. Marwan Fakih, did a similar study in colorectal cancer patients, 315 patients monitored or evaluated retrospectively. More than 80% of these individuals also were vitamin D deficient and more than a quarter had vitamin D levels less than 15 nanograms per mL. Again, supporting the hypothesis that vitamin D deficiency is very common among our cancer patients. Dr. Feky looked at associations between severe vitamin D deficiency as defined as less than or greater than 15 nanograms per mL and found two intriguing observations. First, that there was more than a two-and-a-half fold greater risk of being severely vitamin D deficient if you had rectal cancer than if you had colon cancer. And he also found that among individuals receiving chemotherapy for colorectal cancer, this is either chemotherapy for advanced disease or adjuvant chemotherapy following surgery or surgery and radiation therapy, there was more than a three-and-a-half fold greater likelihood that those individuals would be by severely vitamin D deficient suggesting a difference in both the tumor type influencing tumor location influencing severe vitamin D deficiency and perhaps more importantly because because it is manipulatable, suggesting the fact that the concomitant administration of cytotoxic chemotherapy, at least that chemotherapy used in colorectal cancer, is associated with a much higher risk of severe vitamin D deficiency. Dr. Philip McCarthy, a colleague who oversees our hematopoietic stem cell transplantation program, was primarily interested in osteoporosis and the development of osteoporosis after bone marrow transplantation. And so he began a prospective study in which he looked at patients who had DEXA scans before transplant and 106 patients who had DEXA scans I'll see you next time. study in which he looked at patients who had DEXA scans before transplant and 106 patients who had DEXA scans after bone marrow transplant and found that reduced bone density between pre- and post-transplant findings was very common both when looking at the spine and looking at the femur, and that also, interestingly, almost a quarter of these individuals who tended to be young individuals, these are mostly patients receiving bone marrow transplant for autologous transplant for lymphoma, allergen transplant for acute leukemia generally a young popular youngish population of individuals median age I think was about 40 or 42 high frequency of osteoporosis among those individuals before they began their transplant presumably this is influenced by prior chemotherapy, prior use of high-dose glucocorticoids, and interesting evidence that in a relatively short period of time following bone marrow transplant, there was a substantially greater frequency of reduced bone mineral density in these patients. The rate of observed versus expected rate of bone mineral density loss was 45 times greater than expected in the spine, 30 times greater in the femur. Within four months of bone marrow transplant, Dr. McCarthy's calculations suggested that you account for what, under normal circumstances, might amount to 10 to 12 years of bone mineral density loss in normal individuals, data strongly supporting the observation of severe impact on bone integrity of a bone marrow transplant. If one looked at parameters associated with osteoporosis, we found, again, a very high frequency of vitamin D deficiency and not much difference pre- and post-transplant. Fully half of these individuals had 25 hydroxy D levels, less than 20 nanograms per mL. These were the PTH and calcium levels in those patients as well. So again, supporting the observation found in colorectal and prostate cancer patients that among patients predominantly with hematopoietic malignancies in Buffalo, New York, vitamin D deficiency and, in fact, severe vitamin D deficiency is very common. Now, we are currently in the midst of two prospective trials exploring parameters associated with administration of supplemental vitamin D3. I'm conducting a trial in prostate cancer patients wherein we are randomizing patients to receive either 4, 6, 8, or 10,000 international units over a 9-month period of time and examining the response to those levels of supplementation and seeking to explore those factors which account for differences in responses, a point that was emphasized by Dr. Haney in his talk, that people differ in their response to supplementation with vitamin D3. Dr. Fakih is doing a similar study, but he has chosen to use a fixed dose of 2,000 international units and is studying patients with colorectal cancer, seeking to explore the same questions. That is, what are those factors associated with extent of repletion or failure to be repleted with fairly aggressive dosing of vitamin D3? The endpoints in these evaluations I've already noted. We are examining polymorphisms in vitamin D metabolizing enzymes as well as clinical factors and looking at the response in 25-hydroxy-D level. These are the preliminary data among the men with prostate cancer at the upper three levels that I have studied, confirming again that before vitamin D supplementation, that's each of these three groups, the majority of patients had low vitamin D levels. Uniformly at each of these three doses, the average 25-hydroxy-D level increased, interestingly, to about the same level in all three of those groups. Occasional patients went higher than the upper limit of normal of 100 nanograms per mL. No patient in this study had any evidence of hypercalcemia or any other toxicity. By the way, our protocol was written for those patients whose level went over 120. We reduced the dose in their further follow-up. But I think it's important to emphasize that no patient had any clinical signs or manifestations of vitamin D intoxication. And that's also consistent with the data Dr. Haney reviewed suggesting the vitamin D intoxication doesn't occur with levels less than 200 nanograms per mL. It's also important to emphasize the substantial variation in response to, in each of the cohorts, there was a multifold difference in response to the same dose of replacement D3, and we are currently in the midst of completing this study and beginning to develop an analysis of factors associated with this interpatient variation. Dr. Fakih, as you recall, studied patients, all of whom got 2,000 international units per day. This was the baseline levels in those individuals, emphasizing, again, the high frequency of vitamin D deficiency. And interestingly, as I noted before, those individuals on chemotherapy, it doesn't show up dramatically in this portrayal, but those patients who were on chemotherapy were more likely to have severe vitamin D deficiency than those patients not on chemotherapy. And intriguingly, the response to 2,000 international units per day was also substantially blunted among those patients who were on chemotherapy than those patients who were not receiving chemotherapy or had not received it within three months of entering this trial and also again a substantial variation in 25-hydroxy D-level achieved after administration of 2,000 international units per day, a four- to five-fold range of D-levels achieved on day 90. This is another portrayal of those same data showing that response as measured by achieving a 25-hydroxy-D level of 32 nanograms per mL was substantially more common among patients who were not on chemotherapy than among those on chemotherapy, indicating that at least the chemotherapy drugs we use for colorectal cancer, substantially blunt the response to vitamin D replacement therapy. I think a substantial need in this arena is continued careful evaluation of the impact that vitamin D supplementation has on important clinical outcomes. From a public health standpoint, I think one can easily argue that we should measure vitamin D and make sure we replete patients, normal individuals, sufficiently. But I think scientifically, which does influence public policy as well as cost and benefit analysis, we still, I think, need information about exactly what will be accomplished by vitamin D replacement. The observational and association studies are important, but I think this area continues to require prospective investigation. We are just beginning a randomized evaluation of 6,000 international unit replacement among men who have chosen a watchful waiting strategy for localized prostate cancer. These are men who have low-grade, projected to be relatively unaggressive prostate cancers and have elected not to have any treatment at all for these patients. There are data from Reinhold Veith in Toronto that suggests that vitamin D replacement therapy, D3 replacement, will slow the rate of rise of PSA, which is a projected surrogate for activity of the cancer. That was a relatively small single arm study and in this uh... prospective study we will use a higher dose of uh... d three replacement and conduct an evaluation in a randomized fashion examining rate of rise of p s a with nine months of uh... uh... vitamin d replacement therapy uh... as a as a process product of our studying and bringing more to the attention of our clinicians at our cancer center uh... studying and more aggressively replacing patients with uh... d three since we have shown that almost everybody is vitamin d deficient uh... we are but i will look uh... retrospectively at least least, at other potentially important and associated outcomes with vitamin D deficiency, such as infection rate, thrombosis, and toxicity of chemotherapy or other cancer treatments, because I continue to be interested in nailing down more clearly the relationship between vitamin D deficiency, treatment outcome, and the effect of vitamin D supplementation on cancer risk as well as the course of cancer, as well as cancer toxicity associated with cancer therapy. We are now routinely assessing vitamin D levels in most of our breast and lung cancer patients, and as I said, have clinical trials underway in stem cell transplantation, prostate cancer, and colorectal cancer. So in conclusion, not surprising probably to anybody in this audience, vitamin D deficiency is common in our cancer center. We've already seen evidence, and there will be more discussion today, about its association with many illnesses. And in my view, the appropriate management in cancer patients is to measure vitamin D, supplement, and remeasure to adjust supplementation to assure that vitamin D levels are in the normal range. My own approach in my patients is to shoot for high normal range. Being a medical oncologist, I continue to think that more might be better and more is safe, but we are in the process of trying to study that as well. this is a listing of substantial number of individuals at our Center whom dr. Johnson and I have cajoled coerced or stimulated into getting involved in vitamin D studies both at the basic level as well as in clinical investigation and I'd like to thank Carol and the organizers of this conference for the opportunity to share what we're doing. Thank you very much. Have you noticed a drop in the PSA level with the use of the vitamin D? The question was a drop in PSA with vitamin D use there there are several small studies including some that we've done uh that indicate that very high dose calcitriol is associated with a decrease in vitamin d and psa level or a decrease in the rate of rise of psa i think vith study is the only one that I'm aware of in which D3 supplementation was associated with a slowing in PSA rise. But there's a lot of data preclinically that you can kill prostate cancer cells with very high exposures of vitamin D, 125, and a small study that says D3 repletion slows the rise.'ve seen some anecdotally i have some feeling that we may see a decrease in the psa in some patients with aggressive repletion but it's all purely anecdotal at the moment just a question of clarification uh were your dose ranging studies placebo that you described. I mean, is there a zero dose? Not in the active supplementation that we've done yet. In the 6,000-international-unit dose we will do in prostate cancer, that is placebo-controlled. Any information on vitamin D with radiation therapy? There's evidence that vitamin D exposure sensitizes tumor cells to radiation, but we've done no studies in patients specifically getting radiation. Some of the patients with prostate cancer and colorectal cancer have gotten radiation. there doesn't seem to be a separable association between lower vitamin D levels and recent radiation treatment, but the numbers are small enough that a small effect might be missed. Dr. Trump? Yes, sir. If you could reiterate, with the chemo for your prostate and colon, did you say the chemo interfered with the absorption of vitamin D? I don't have any data on chemo for prostate cancer. The population that we've surveyed, relatively few of those patients were on chemotherapy. Hormone therapy, androgen deprivation, does not seem to be associated with a greater risk of vitamin D deficiency in my patients. The patients with colorectal cancer getting chemotherapy were more likely to have severe vitamin D deficiency and more likely to respond poorly to vitamin D supplementation. We don't know why. There may be an element of, you know, the weight differences in those populations may be different. I think it's quite plausible that the drugs that we use affect the vitamin D-anabolizing and catabolizing enzymes differently, and that we'll find that the pharmacology of D3 is different in the presence of other drugs. But those are the things we're trying to sort out. We have no data on absorption. Dr. Trump, I was hoping you would share your clinical opinion as to what the target for high normal range is. My clinical opinion is 60 to 75. My patients with prostate cancer, I, based on nothing but impulse and bias, I try to get their levels into the high normal 60 to 70 range. Thank you, Dr. Muchnick from Torrance. Was there any effort made to look at those individual patients whose vitamin D levels actually went down with separate large supplementation to explain that well vitamin D levels were measured in every patient and in no patient did they go down in several patients they didn't go up for the individual court seems I'm sorry the graph you showed seem to show as many were going down actually a little lower after vitamin D supplementation well I I... I can understand how they wouldn't go up very high, but I can't understand how they go down. Okay, you're right. And I think the other thing, we did not do what Dr. Haney was careful in doing, and that is to sit the patients in front of us and make sure they take the vitamin D. So I think at least part of this explanation may be non-adherence. Thank you so much, Dr. Trump, for your very enlightening talk. I appreciate it. Thank you. Transcription by ESO. Translation by —