Kathy D. Miller, MD; Jeffrey E. Lee, MD


July 29, 2016

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Kathy D. Miller, MD: Hi. I am Kathy Miller, professor of medicine at the Indiana University School of Medicine in Indianapolis, Indiana. Welcome to Medscape Oncology Insights, coming to you from the 2016 Annual Meeting of the American Society of Clinical Oncology.

Joining me today is Dr Jeffrey Lee, professor and chair of the Department of Surgical Oncology at the University of Texas MD Anderson Cancer Center in Houston, Texas. Welcome, Jeff.

Jeffrey E. Lee, MD: Thank you, Kathy.

Dr Miller: When we talk about melanoma therapies, we immediately think about immunotherapy, but you recently published a study[1] looking at a potentially active agent that has been a household word for generations: vitamin D. Why are you looking at vitamin D in melanoma?

Dr Lee: We have been interested in the role of inflammation in controlling the response to cancer for some time. Vitamin D has important anti-inflammatory properties, and there was preliminary information that suggested that vitamin D might be important in controlling an individual's response to cancer,[2,3] including melanoma. For these reasons, we wanted to look at vitamin D.

Dr Miller: Tell me about your study. Did you look only at vitamin D levels in patients?

Patients with low vitamin D levels might be at higher risk of developing cancer, having cancer progress, or dying of cancer, including in melanoma.

Dr Lee: Correct. Information from a number of preliminary studies suggested that low vitamin D levels in patients with a variety of cancers might be bad.[4,5] In other words, patients with low vitamin D levels might be at higher risk of developing cancer, having cancer progress, or dying of cancer, including in melanoma. We wanted to take the opportunity to look at this issue in a large number of melanoma patients who had had blood drawn for vitamin D levels close to presentation, who had been consistently followed, and for whom we had excellent data on outcomes.

Dr Miller: What did you find?

Lower Levels of Vitamin D Linked to More Severe Melanoma

Dr Lee: As one would expect, we found that vitamin D levels were higher in the summer months than in the winter months, even in melanoma patients. We controlled for the month of blood draw in our analysis. We also found that lower levels of vitamin D were linked to more severe forms of melanoma at presentation. Patients with low vitamin D levels were more likely to have thicker tumors and higher-stage disease than patients with higher levels of vitamin D.

Dr Miller: That sounds a little counterintuitive to me, because I think of melanoma as a disease driven by sun exposure. It does not take more than 15 or 20 minutes of sun exposure each day to get sufficient vitamin D. How many patients with melanoma actually had low levels?

Individuals with even low levels of chronic inflammation will have low levels of vitamin D...even if they are taking vitamin D supplements.

Dr Lee: The average level of vitamin D in our patient population was 25 ng/mL, which is about midway between what we would consider deficient and what we would consider sufficient. However, one quarter of the patients in our study had vitamin D levels less than 20 ng/mL, so 25% of melanoma patients in our investigations had deficient levels of vitamin D.

That does sound counterintuitive, but we know that in addition to sun exposure, there are other factors that control vitamin D, such as systemic inflammation. Individuals with even low levels of chronic inflammation will have low levels of vitamin D, even if they are getting what we would consider to be sufficient or even excessive sun exposure—and sometimes even if they are taking vitamin D supplements.

Dr Miller: Those rates of vitamin D insufficiency are very similar to what has been seen in some of the breast cancer population studies.[6,7] I suppose that another possible explanation is that the melanoma that you are seeing is the result of sun exposure from much earlier in life, and as these folks reached adulthood, they stayed indoors more and did not have the same ongoing sun exposure.

Dr Lee: That is absolutely correct. Lower levels of vitamin D are endemic in the US population. This is one of the reasons that we wanted to look at vitamin D levels particularly in our patient population. The data from other investigations, including in breast cancer patients, are remarkably similar to what we identified in our melanoma patients.

Vitamin D Levels Need to Be Tested in Melanoma Patients

Dr Miller: You mentioned the association between vitamin D and inflammation. Does that suggest that low levels of vitamin D might also influence response to immunotherapies?

Vitamin D and other inflammatory biomarkers are important to test for in ongoing and future clinical trials of patients who are receiving immunotherapy.

Dr Lee: It is very possible. One of the limitations of our study is that the blood samples of our melanoma patients were collected before the introduction of modern immunotherapies, including checkpoint inhibitors. For this reason, and others, we did not attempt to control for any systemic therapies in our study, including immunotherapies.

But we absolutely believe that vitamin D and other inflammatory biomarkers are important to test for in ongoing and future clinical trials of patients who are receiving immunotherapy. We think that measuring and, perhaps in the future, moderating inflammatory responses through vitamin D supplementation and other methods may be an important way that we can improve response rates to immunotherapies and other treatments for melanoma and other cancers.

Dr Miller: I think the supplement question is going to come up pretty quickly, because you have already nicely shown that patients who have very low levels have higher risk for disease and a worse outcome. What do we know about supplementing vitamin D in those patients?

Dr Lee: There is at least one prospective trial that is going on now in Europe in patients with intermediate- to high-risk melanoma to see whether supplementation with vitamin D will reduce the chances of their melanomas returning or progressing.[8]

Dr Miller: As an adjuvant study?

Dr Lee: As an adjuvant study. It is a little premature for us to consider widespread supplementation of vitamin D for melanoma patients in an attempt to reduce their risk for recurrence. However, it may be reasonable to test vitamin D levels in patients who have had treatment for melanoma. If they are deficient, we can consider supplementing them up to a normal level, because supplementation with vitamin D is a very safe thing to do.

Chronic Inflammation May Negate Vitamin D Supplementation

Dr Miller: You mentioned that with chronic inflammation, whether it is because of active melanoma or other active health problems, supplementation might not be effective. How do you monitor that? What do you do if the patient is taking vitamin D but the level is not going up?

Dr Lee: In that situation, I would look for other reasons that the patient might have low vitamin D. We know that patients with evidence of chronic inflammation—for example, patients who have an elevated C-reactive protein (CRP) level, a general measure of chronic inflammation—will also have low levels of vitamin D. In our study, even though we found strong evidence for a correlation between an elevated level of CRP and a low level of vitamin D, we were also able to show statistically that the association of vitamin D with poor outcome measures was independent of the CRP level.

However, if I had a patient in whom I was replacing vitamin D and I was confident that they were taking the vitamin D supplement regularly, I would look for other reasons, such as chronic inflammation, that might be treatable in other ways that would allow us to make more progress with the vitamin D level.

Dr Miller: Thank you, Jeff, for coming and talking to us about this important and potentially simple intervention for our patients.

Dr Lee: You are very welcome.

Dr Miller: Thank you for joining us for this edition of Medscape Oncology Insights. This is Kathy Miller, reporting from ASCO 2016.


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