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

• utcomes) 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

• f 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

• f 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?

References

 Brahmer Julie R et al. Management of immune-related adverse events in

patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. Journal of Clinical Oncology 2018 June 10; 36(17):1714-1768.

 Barroso-Sousa R et al. Incidence of endocrine dysfunction following the use of

different immune checkpoint inhibitor regimens, a systemic review and meta-

• analysis. JAMA Oncol 2018 Feb; 4(2):173-182.

 De Fillette J et al. A systematic review and meta-analysis of endocrine-related

adverse events associated with immune checkpoint inhibitors. Horm Metab Res 2019 Mar; 51(3):145-156.

 Lupi I et al. Clinical heterogeneity of hypophysitis secondary to PD-1/PD-L1

blockade: insights from four cases. Endocrinol Diabetes Metab Case Rep 2019 Oct 12 epub ahead of print