Immunotherapy in Melanoma: Recognizing an Endocrinopathy

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Michael A. Postow, MD: Endocrinopathy, or immunologic activation against hormone glands, is one of the other common side effects that people can have with immune therapy, and this happens in patients getting PD-1 alone or combinations of ipilimumab and PD-1 together. How do we deal with the endocrinopathy? The 2 most commonly affected organs are the thyroid gland in the neck and the pituitary gland, which hangs outside of the brain in the skull base. What do we do about this? Any patient that’s having any kind of symptoms—fatigue is a common symptom, headache is a common symptom, sometimes people will just feel depressed, and it’s important not to blow that off and say, “Well, this patient is just depressed because they have cancer and they’re going through treatment,”—it’s important to think, “Maybe this patient has an endocrinopathy.” How do we evaluate that? We check the thyroid function testing, which is evaluating the free T4 and the TSH, and we also can check the pituitary function with markers such as ACTH and cortisone levels. I don’t think that you necessarily have to check all these lab tests at every single infusion. However, if a patient is symptomatic, I do think it’s worth checking these lab tests—ACTH, cortisol, TSH, and free T4—and thinking about endocrinopathy.

Importantly, if a patient is having a headache, it may be worthwhile for them to get a brain MRI, specifically looking for pituitary inflammation, which you could see on a brain MRI. And many times, radiologists are not looking for the pituitary specifically. They may hear, “Patient with metastatic melanoma and headache” and think, “I’m going to look for brain metastases,” and the report may just say, “No brain metastases.” But as oncologists and nurses, we have to go back to the radiologist many times and say, “That’s important that this patient doesn’t have brain metastases, but what does the pituitary look like?” And sometimes the radiologist will go back and say, “Well, this pituitary is actually inflamed” and that may make one think about hypophysitis, which is inflammation of the pituitary.

So, the treatment of either thyroid problems or pituitary problems is really recognizing which hormones may be deficient. If a patient doesn’t have a thyroid hormone, replace the thyroid hormone with a drug called levothyroxine. If the patient doesn’t have a pituitary that’s functioning well, replace the pituitary function with corticosteroids—maybe something like prednisone initially if a patient is symptomatic with a headache—but then moving on to something like hydrocortisone to replace the steroids in a longer-term fashion; something like 20 mg of hydrocortisone every morning and 10 mg in the afternoon.

Sometimes the thyroid needs to additionally be replaced when the pituitary is inflamed because the pituitary also controls the thyroid. So, the bottom line with endocrinopathy is, think very deeply about it. Always keep it in your mind. I do recommend checking TSH in all patients getting ipilimumab or the combination of ipilimumab and nivolumab at every single dose. I think it’s very easily forgotten, and it’s important to recognize because people can feel much better once you get them on hormones they need.

As we’ve been talking about endocrinopathies or hormone effects of some of these immune therapies, they are really some of the trickiest issues to diagnose and some of the ones that are easily forgotten if we don’t have them on the top of our minds. So, when you have a patient that we’re treating who may be having suspicion for an endocrinopathy, what kind of bells are going off in your head when you’re talking with these patients that tell you that maybe this patient is having an endocrinopathy? What kinds of things will people be having that makes you think, “We need to check hormone levels”? What comes to mind?

Claire Crowley, RN: Well, immediately what comes to mind is if they’ve gained a significant amount of weight or lost a significant amount of weight, that’s something we’d look into. Also, things like their fatigue levels, which they’ll be reporting, any mood changes, intolerances to heat or cold, things like that. And a lot of times, people think fatigue is just from the immunotherapy and it’s not something to report. So, we try to emphasize to our patients that they may have never heard of hypophysitis or hyperthyroidism or hypothyroidism, but they are side effects and they can happen and they should be aware of them.

Michael A. Postow, MD: Absolutely. I agree. And I think the thyroid problems and the pituitary problems can be some of the most tricky things because people may not want to admit that they’re just tired or that they’re gaining weight, and we have to be really astute to picking up on those kinds of things. Let’s say we think that there’s a patient that may have hypophysitis, so inflammation of the pituitary or some change in their thyroid function. What kinds of tests do you think are good for us to send in terms of laboratory tests or other kinds of imaging? What tests would you recommend people send in for these things?

Claire Crowley, RN: Well, in terms of lab values, we would get a TSH, free T4, ACTH, cortisol level, and we’d also, in terms of imaging, try to get a brain MRI to see if there was any inflammation in the pituitary gland.

Michael A. Postow, MD: Right, and I completely agree. It’s one of these things that, in addition to the free T4, T3, TSH for the thyroid function, and the ACTH and cortisol for pituitary axis function, we may also want to make sure that we pay attention to the glucose value because sometimes there can be rare cases of diabetes that can happen when the pancreas gets inflamed. And so, the glucose being really elevated may be something that we also want to keep in mind that could be signals for an endocrinopathy. So, I think those are all the important lab tests and the imaging. And, again, as we were talking about earlier, to push the radiologist that’s reading these brain MRIs to know that this is not a brain MRI just to rule out brain metastases, we really want to make sure that the pituitary is not inflamed. Let’s say that we have a diagnosis now of low thyroid, for example, which is very common. What would you say you do to treat those kinds of patients?

Claire Crowley, RN: Well, we’d probably start them on Synthroid (levothyroxine). We’d calculate what dose is appropriate for them and, depending on their response to it, we would continue to manage it or refer them to endocrinology.

Michael A. Postow, MD: Absolutely. Levothyroxine is a very easy supplemental thyroid hormone that you can start a patient on. And there are different guidelines that affect the initial dosing for levothyroxine, so I would refer to the prescribing information on that. But patients can feel remarkably better when they get started with levothyroxine. So, I think that’s a great supplemental medication. And then, let’s say that the steroid axis is down—so cortisol is low, ACTH is low—we suspect this patient has hypophysitis. We may have this patient on prednisone for a little while, but then they would need to be on longer-term hydrocortisone supplementation. I think one key to just emphasize on top of that is that when you have a patient on hydrocortisone supplementation long term and they have a stressful event, like infection or surgery, they may need stress-dose steroids to get over that acute event. And it may be something that we might not think about otherwise, but we’ve had patients that have had orthopedic surgical procedures or come in for various infections and have hypophysitis. They’ve been maintained on hydrocortisone-replacement steroid hormone and all of a sudden, their blood pressure is low and they’re really sick and no one really knows why. It’s because they need stress-dose steroids to get over that stressful event.

Transcript Edited for Clarity



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