An interview with Dr. Jennifer Mammen from Johns Hopkins University, author on "Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update." She discusses the identification, evaluation, and management of endocrine toxicities in patients receiving ICPis, including thyroid-related irAEs, primary AI, hypophysitis, and diabetes in Part 6 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines Podcast Series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today, we're continuing our series on the management of immune-related adverse events. I am joined by Dr. Jennifer Mammen from Johns Hopkins University in Baltimore, Maryland, author on Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update and Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline. And today, we're focusing on endocrine toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here, Dr. Mammen. JENNIFER MAMMEN: My pleasure, Brittany. BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Mammen, do you have any relevant disclosures that are related to these guidelines? JENNIFER MAMMEN: I do not. BRITTANY HARVEY: OK. Thank you. Then, to start us off, what are the immune-related endocrine toxicities addressed in this guideline? JENNIFER MAMMEN: Yeah. So irAEs affect the thyroid and the pituitary most commonly. But we also addressed the possibility of primary adrenal toxicity and also the emerging toxicity of insulin-dependent type 1 diabetes, which, while rare, can present with grade 4 toxicity in the form of diabetic ketoacidosis. BRITTANY HARVEY: Understood. Then, starting with adverse events affecting the thyroid, what are the key recommendations for identification, evaluation, and management of thyrotoxicosis? JENNIFER MAMMEN: So thyrotoxicosis after ICI exposure is almost entirely due to subacute thyroiditis. That's a transient inflammation of the thyroid gland that causes a few weeks of high levels of thyroid hormone, followed by at least several weeks of hypothyroidism as the stores of thyroid hormone are replenished. In the irAE context, many patients do not ever actually recover adequate thyroid function and will remain hypothyroid, requiring thyroid hormone long term. Because the thyrotoxicosis is transient and results from the release of preformed thyroid hormone, anti-thyroid drugs do not help and actually can even make the hypothyroidism phase worse. Therefore, the treatment is really supportive care with beta blockers in particular to control symptoms of the hypothyroidism, such as tachycardia, tremor, or anxiety. BRITTANY HARVEY: In addition to those points for thyrotoxicosis, what are the key recommendations for primary hypothyroidism? JENNIFER MAMMEN: Yeah. So primary hypothyroidism is very common both in the general population and now in this population as a result of thyroiditis. Many patients might actually already be on thyroid hormone when starting immunotherapy. When the pituitary is working, the pituitary hormone thyrotropin or TSH is a reliable indicator of the adequacy of thyroid hormone replacement. And the goal is to use a dose of thyroid hormone that maintains the TSH in the mid reference range, generally between 1 and 3 million international units per liter. When a patient is first presenting or diagnosed with hypothyroidism, for example, in that second phase of thyroiditis, a weight-based dose can be used to estimate the needed replacement dose. For those with higher BMI, generally, an ideal body weight rather than an actual body weight gives a better estimate. And those specific recommendations are in the guidelines. Proton pump inhibitors, calcium/iron supplementation, or GI inflammation can all decrease the absorption of thyroid hormone. And so even the thyroid hormone is really common, and many oncologists are used to managing it, it can be tricky in these patients if there's issues with malabsorption. And so, therefore, an endocrinology consultation can be helpful to titrate and ensure that the dosing is adequate. Once that adequate dose, that stable dose is found, if other factors don't change, dose requirements are generally quite stable and can be monitored annually either by a primary care physician or an oncologist. BRITTANY HARVEY: Great. Those are important points. Then, addressing the immune-related adverse event that impacts the pituitary, what are the key recommendations for identification, evaluation, and management of hypophysitis? JENNIFER MAMMEN: So hypophysitis is inflammation of the pituitary, as you said. And although there are five hormone systems at risk, it's actually most common that the thyroid and the adrenal gland axes are what are affected. The diagnosis is made by a combination of assessing the pituitary hormone and the primary hormone, in this case, the thyroid hormone and cortisol along with the TSH and ACTH, which is the pituitary hormone that regulates the adrenal gland. With primary gland failure, as we said, the pituitary hormones will be elevated. But in hypophysitis, the problem actually comes from the pituitary. And so TSH and ACTH will be low or inappropriately normal for the low primary thyroid hormone level. There are several key points for oncologists who might need to initiate therapy before the patient can see endocrinology. First, thyroid hormone increases the metabolism of cortisol. And so if you've diagnosed central hypothyroidism due to hypophysitis, it's really important to replace cortisol, if needed, before replacing thyroid hormone, because in someone with both deficits, thyroid hormone alone can precipitate an adrenal crisis. Thus, the ASCO Guidelines really emphasize the need to assess both before starting thyroid hormone and also give the option to use steroids empirically, if needed, since the diagnosis can be sorted out later by an endocrinologist. A second important point is that headaches, visual changes, and diabetes insipidus, which is loss of fluid and generally marked by hypernatremia, those are much more common with metastatic disease in the pituitary rather than hypophysitis. And so such symptoms should really prompt a pituitary MRI when they're found in the setting of hormonal losses. The management of central hypothyroidism is similar to that of primary hypothyroidism. But as I said, the TSH is no longer a reliable marker for adequate replacement. So the goal, then, shifts from a TSH in the reference range to a free T4 at the upper half of the reference range. Adrenal insufficiency, as with thyroid hormone insufficiency, is managed by physiologic hormone replacement, and that's best done using hydrocortisone. This is a short-acting steroid that can be given in a way to imitate the natural diurnal rhythm. We use 2/3 of the dose in the morning and 1/3 in the early afternoon, allowing levels to fall as they naturally would overnight. Dose-titration is based on symptoms. And usually, 15 to 25 milligrams of a total daily dose is adequate to control symptoms from adrenal insufficiency. I do think all patients should see endocrinology at some point if they have been diagnosed with hypophysitis because they do need education on sick day rules, otherwise known as stress dosing, and also to be instructed on wearing an emergency alert bracelet or necklace or something. Long-acting steroids can be used for patients who have adherence problems. And of course, those long-acting steroids are more appropriate for the treatment of any other irAE that a patient may develop. While on higher doses of prednisone, patients can discontinue hydrocortisone and then restart it when the prednisone dose is weaned down below 5 milligrams daily. If there's a question about whether the central adrenal insufficiency is from hypophysitis or due to suppression after weaning off high-dose exposure, use of hydrocortisone because of the diurnal rhythm actually allows the adrenal axis to recover normally. And so after weeks, you can test for adrenal recovery using a morning endogenous level 24 hours after the last dose is given, which is another advantage to using the hydrocortisone mode of hormone replacement. BRITTANY HARVEY: Understood. And I appreciate you highlighting those key points for oncologists. Then, following that, what are the key recommendations for primary adrenal insufficiency? JENNIFER MAMMEN: Yeah. So primary adrenal insufficiency, you'll see the ACTH elevated just like in primary thyroid disease, and the cortisol will be low. Again, this situation is actually much more common with metastatic disease, and therefore, imaging is called for if you find that pattern of hormonal changes. It's been case-reported to happen with ir
