Double the Battle: Two Cases of Irreversible Endocrinopathies in Patients Already Fighting Metastatic Cancer

Abstract

Abstract Immune Checkpoint Inhibitors (ICI) have been approved since 2011 to treat patients with advanced solid and hematological malignancies and have had remarkable results. However, case reports of endocrine adverse events are becoming increasingly reported and can be fatal if not recognized early. Here we present two unique cases of rare endocrinopathies after the use of ICIs. A 47 year old male with metastatic melanoma presented with nausea, vomiting, polyuria, polydipsia of 5 days. Three weeks prior, he was started on nivolumab and ipilimumab. On presentation, he was tachycardic and tachypneic. Lab work was remarkable for a glucose of 676, Na 129, K 6.2, CO2 6, Cr 2.43 (baseline of 1.1) and beta-hydroxybutyrate of 11.7 with elevated HgA1c of 7.1%. DKA was diagnosed and fluids and insulin drip were started. Further work up revealed a normal cortisol level, TFTs and C-peptide <1 consistent with new-onset type I diabetes mellitus in the setting of two ICI agents. Patient was started on insulin regimen. An 81 year old female with metastatic bladder cancer on Pembrolizumab was admitted with 2 weeks of fatigue, positional dizziness and dyspnea. She recently presented with hyperkalemia attributed to dehydration. On admission, she was hypotensive with a blood pressure of 81/59 with normal heart rate and no fever. She had dry mucous membranes on exam but no abnormal skin. Further work up revealed an AM cortisol of <1, ACTH of 458 and positive Cosyntropin stim test, consistent with primary adrenal insufficiency. CT-Abdomen Pelvis did not reveal any acute adrenal masses. She was started on hydrocortisone at discharge with fludrocortisone due to hypotension. ICIs are categorized as target programmed death-1 receptor inhibitors (PD-1) nivolumab, pembrolizumab, cemiplimab, programmed death-ligand 1 inhibitors (PDL1) atezolizumab, avelumab, durvalumab and cytotoxic T-lymphocyte associated protein-4 (CTLA-4) iplimumab. Immune checkpoint proteins are T-cell surface receptors that cause inhibition when they bind to their ligands to limit the immune response. Tumors manipulate these inhibitory pathways to evade rejection. ICIs no longer halt the immune response and result in effective cancer treatment. However, a robust immune response can go on to attack healthy tissue resulting in endocrinopathies such as hypophysitis, hypo-or hyperthyroidism, diabetes mellitus or adrenal insufficiency. Acute hypocortisolemia or thyroid storm can be fatal if not identified acutely. Current guidelines recommend baseline screening with TFTs, morning cortisol and ACTH and screening monthly thereafter in patients on ICIs. In this report, we present two unique cases of irreversible endocrinopathies in patients treated with ICI who developed type I diabetes and primary adrenal insufficiency. These cases warn physicians to be vigilant with patients on ICI and consider the possibility of life-threatening endocrinopathies.