Category: Other - Side effects of immunotherapy
Immune related endocrine adverse effects (IReAs) caused by checkpoint inhibitors (CI) used in the treatment of advanced cancers are rare and often under recognized, but they can be potentially life-threatening.
69 y/o male with stage 4 metastatic colon cancer was evaluated 10 days following the receipt of a single dose of Pembrolizumab (P). He reported extreme fatigue, syncope, nausea, cold intolerance and constipation. Exam: Orthostasis and HR = 104/min. Biochemical evaluation before P: Am cortisol 12 (5-23 mcg/dl), TSH 3.4 (0.4 -4 UIU/ml). Post P: Am cortisol < 1.8, ACTH 4 (6-50 pg/ml), FT4 0.7 (0.76 -1.46 ng/dl),TT3 57.5 (60-180 ng/dl), TSH 7.31,Total T 200 (240-827 ng/dl), Free T 17.4 (46-224 pg/ml), FSH 12.7 (1.4 -18.1 mIU/ml ), LH 5.6 (1.5 -9.3 mIU/ml), PRL102 (2.1-17 ng/ml).IGF-1 and renin/aldosterone were WNL. Na 139, K 3.6, BG 103. TPO, TSI, TRAB, GAD65 and 21 alpha hydroxylase antibodies were negative. ACTH stimulation test: baseline, 30, 60 mins cortisol of < 1.8, 12, and 19 respectively.Pituitary MRI revealed enlarged pituitary gland 12 mm (baseline 4 mm), 4 weeks after receiving P.
Results : Physiologic hydrocortisone (15/10 mg) PO and Levothyroxine 50 mcg daily were initiated. 3 weeks later, he required ventilator support for P induced pneumonitis resulting in respiratory failure. This warranted IV methyl prednisone, followed by rapid prednisone taper to a maintenance dose of 20 mg daily lifelong and P was discontinued indefinitely. At the 6 week follow-up, hypotension and fatigue improved, FT4 was WNL, and pituitary enlargement had resolved. He transitioned to inpatient hospice care on account of progression of the underlying cancer off P
1. The incidence of P induced hypophysitis is 0.5 -1.1 %, whereas primary hypothyroidism occurs in 3.9 % of patients.
2. Our patient developed primary hypothyroidism and secondary AI, simultaneously. The reported time for onset of hypophysitis and primary hypothyroidism, after exposure to P is 4-10 weeks and 6 weeks respectively, and is attributed to cumulative dose toxicity. In this case, it was observed within 10 days of receipt of a single dose.
3. Active surveillance of patients receiving CI presenting with evidence of hormone deficiency and/or focal neurological findings facilities prompt recognition and timely management of IReAs. Endocrine evaluation prior to starting CI should be considered.
4. In contrast to other causes of hypophysitis, the adrenal, thyroid and gonadal axes are affected in descending order of frequency, in P treated patients. Diabetes insipidus is infrequently noted.
5. Check point inhibitors can be continued in most cases if underlying endocrinopathies are adequately treated.
Georgetown University Hospital
Silver Spring, Maryland
Clinical endocrinology fellow