how to manage Tania Gallant MD, FRCPC Endocrinologist, The Moncton - PowerPoint PPT Presentation

Immune-related Endocrinopathy- how to manage Tania Gallant MD, FRCPC Endocrinologist, The Moncton Hospital

Disclosures  Ad board honoraria: Abbott, Astra-Zeneca

Objectives  By the end of this presentation, the participant will be able to:  Recognize thyrotoxicosis and become familiar with initial investigations and early management  Initiate investigations for possible adrenal insufficiency, including distinguishing central from primary adrenal insufficiency  Initiate therapy for adrenal insufficiency

Jama Oncology Feb 2018 Meta-analysis  Included 38 studies involving 7551 patients (not all studies reported all outcomes) incidence of endocrine adverse effects  Hypothyroidism – overall 6.6% (range 3.8-13.2%)  Hyperthyroidism-- overall 2.9% (range 0.6-8%)  Hypophysitis – overall 6.4% (range 0.1 to 6.4%)  Of note, PD-1 or PD-L1 inhibitors have incidence at low end of that range  Primary adrenal insufficiency – overall 0.7% (4.2% in combo treatment)  Insulin deficient diabetes – overall 0.2% (13 cases and all but one was on PD-1 inhibitor)  Of note, the high end of all of these were in patients on combination of ipilimumab and nivolumab

Case# 1 JP

Presentation  70 M with Stage IV non-small cell lung CA  On nivolumab since April 2018  In later January 2019, complaining of increased fatigue and somnolence  No headaches, vision changes, weight loss, presyncope/syncope, salt-craving  Investigations were ordered

Jan 22 2019 investigations  A.M. cortisol < 28 nmol/L  Lytes, creatinine, random glucose normal  TSH 3.697 mIU/L

Where is the problem?  Pituitary vs adrenal--- NEED TO DO AN ACTH  Of note, primary adrenal insufficiency is reported but not as common as secondary adrenal insufficiency in patients on immune checkpoint inhibitors  Need to know as will impact treatment  Do before you start glucocorticoids  Cannot diagnosed adrenal insufficiency in a patient already on at least replacement doses of glucocorticoids  Dexamethasone 0.5 to 0.75mg daily or  Prednisone 5mg daily or  Hydrocortisone 20-25mg daily  Also assess for any other significant sources of glucocorticoid exposuresure  Especially intra-articular steroid injections or high potency inhaled corticosteroids

JP’s ACTH was 0.3  However, it was done 3 days after he was initiated on Prednisone 20mg daily  TSH normal, free T4 not done, lytes/creatinine/glucose normal, total testosterone levels low end of normal range Sellar MRI done a few weeks later – pituitary completely normal   Of note, studies show that this does not rule out hypophysitis Patient’s a.m. cortisol repeated a few times but patient couldn’t recall his prednisone  dose at those times  On a dose of prednisone 6-7mg daily, a.m. cortisol remained <28 nmol/L with ACTH 0.2 (almost 5 months after initial treatment)  free T4 normal and total testosterone levels remained low normal but stable  Switched to hydrocortisone to see if could prompt some recovery with a shorter acting steroid, but no change in a.m. cortisol or ACTH levels a month later

Key Points re Adrenal insufficiency  CANNOT diagnose adrenal insufficiency in a patient already on supraphysiologic doses of glucocorticoids  Baseline a.m. cortisol, ACTH, lytes/creatinine and glucose prior to initiating steroids  Do not need to have the results prior to initiating steroids if high index of suspicion, especially in an ill patient  Initial doses depend on severity (stress p.o. dosing for moderate illness vs IV therapy in adrenal crisis) If asymptomatic or mild symptoms and tests indeterminant – may need other confirmatory testing   If acute hypophysitis with mass symptoms  Can consider high dose steroids with prednisone 1mg/kg/day initially  As hypophysitis is most likely cause, check further pituitary profile:  TSH with free T4 (even if TSH normal), LH, total testosterone (before 10 AM)  Consult Endocrinologist or General Internal Medicine

Case#2 CP

Presentation  61 F, stage IVa non-small cell lung CA  Started on Pembrolizumab June 30 2018 for disease progression  Since about mid-August until seen by her oncologist in mid-September, noted the following symptoms:  Increased sweating, heat intolerance, palpitations, hand tremours, weight loss (approx. 8 lbs), muscle weakness, exertional dyspnea, muscle weakness, dry/itchy skin, L eye discomfort, fatigue, irritability  Tests are performed

Tests for CP  Baseline thyroid indices 2 days before initiation of Pembrolizumab in June showed TSH 0.232 mIU/L with free T4 15.7 and free T3 4.4  Early August 2019: TSH 0.008 and free T4 20.3 (ULN 19)  September 19 2019: TSH <0.004 with free T4 39.4

Additional info  Patient had a previous history of congestive heart failure and atrial fibrillation  Was already on bisoprolol 10mg daily  Had been on amiodarone previously but it had been stopped in March 2018  Oncologist put her pembrolizumab on hold after Sept. labs  On examination:  no signs of Graves’ eye disease  Heart rate 110/minute  Notable bilateral hand tremor  Thyroid painful on palpation so limited exam possible, especially on the right side (of note, it did not bother her when it was not being palpated)

Further investigations/management  September 24 2019: Nuclear medicine scintigraphy: thyroid poorly visualized c/w likely thyroiditis  However, most thyrotoxicosis phase of thyroiditis resolves on average after 4-6 weeks and this was already 7 weeks of overt thyrotoxicosis biochemically  In addition, amiodarone can result in falsely poor uptake on thyroid scintigraphy even many months after cessation of therapy and noted asymptomatic subclinical hyperthyroidism biochemically even prior to starting pembrolizumab  So I opted to start her on methimazole while pursuing other investigations  Later results, TSH receptor antibodies and TPO antibodies negative

Further update on CP  Oct 2019 f/u: improved but still hyperthyroid so methimazole increased to 20mg daily  Early Dec 2019: TSH 0.572 with free T4 9.5 and free T3 3.9 and liver enzymes high  Decreased methimazole to 10mg daily  One week later, liver enzymes still high and CT liver/GB normal, so methimazole stopped  Jan 2019: TSH 0.981 with free T4 13.1  March 2019: TSH 1.135 mIU/L

Key points on Thyroid disease  More common with PD-1 and PD-L1 inhibitors Most appear to be related to a destructive thyroiditis but few cases of Graves’  disease  How to distinguish Nuclear medicine thyroid uptake and scan can help – will be increased in Graves’ disease  and low in thyroiditis TSH receptor antibodies are elevated in Graves’ disease   Thyroiditis is self-limited Supportive therapy – eg. Beta-blocker   If unclear or severe, treat with antithyroid drugs (eg. Methimazole) initially  At risk of post-thyroiditis transient or permanent hypothyroidism  So need to monitor TSH every 4-6 weeks until stable on two consecutive readings

Thyroid disease continued  Hyperthyroidism is reasonable to consult endocrinologist  No evidence that stopping immune checkpoint inhibitor is necessary/alters trajectory of disease  If hypothyroidism  If TSH is above 10 mIU/L but free T4 is still in normal range, may consider starting with partial replacement Levothyroxine dose as could be a transient problem vs monitoring  If TSH is above 10 mIU/L with free T4 below the lower limit of normal, consider full replacement (1.6 mcg/kg ideal body weight/day) Levothyroxine replacement – may start at 25mcg daily with weekly titration if elderly patient and concerned re tachyarrhythmia with too rapid replacement  If Myxedema coma, medical emergency, ICU, IV levothyroxine, etc  If start Levothyroxine, it takes several weeks to reach steady state so typically monitor TSH every 6-8 weeks initially and then make dose adjustments accordingly  Family physicians are typically first line physicians for the management of primary hypothyroidism (except myxedema)

Summary of Key Points  If suspect adrenal (primary or secondary) insufficiency  Always do a.m. cortisol and ACTH at baseline as well as lytes/creatinine/glucose Start steroids promptly – dose depending on initial presentation   If primary adrenal insufficiency, also needs fludricortisone replacement  Consult endocrinology/internal medicine  If hypophysitis  Also check TSH with free T4 and LH/total testosterone levels  Always replace steroids for at least 1-2 days prior to replacement with Levothyroxine  Thyrotoxicosis Most self-limited thyroiditis – symptom control with beta-blocker and investigate   Refer to endocrinology if unclear etiology or moderate/severe

Further key points  Primary hypothyroidism – Levothyroxine replacement if indicated  No evidence that interrupting immune checkpoint inhibitors impacts the course of these diseases once they are established  Therefore, leave to oncologist’s discretion as to the degree of severity of the patient’s illness at presentation as to whether interruption is reasonable  Good clinical practice guideline from the American Society of Clinical Oncology published in June 2018 (see reference list)

Thank you! Questions?