Nivolumab/prednisolone/sunitinib

Abstract

Various toxicity: case report A 62-year-old man developed thyrotoxicosis and hyperglycaemia during treatment with sunitinib and prednisolone, respectively. Additionally, he developed type 1 diabetes mellitus, hypophysitis and hyponatraemia during treatment with nivolumab for metastatic renal cell carcinoma [routes not stated; not all dosages stated]. The man presented to a hospital with hyponatremia. In 2003, he was diagnosed with right renal cell carcinoma, and underwent right nephrectomy. Seven years later, a cancerous lesion was found in his right clavicle. Subsequent bone biopsy showed metastasis of the renal cell carcinoma. He then underwent multiple rounds of chemotherapy, which included sunitinib, pazopanib and axitinib, and developed thyrotoxicosis during treatment with sunitinib. Treatment with sunitinib was discontinued. In 2018, he was initiated on nivolumab 3 mg/kg in every 2 weeks. After administration of the seventh cycle of nivolumab, he reported fatigue and dizziness, and was admitted to the urology department. On physical examination, his blood pressure was 93/59 mm Hg, pulse was 73 beats/minute, and body temperature was 36.5°C. Laboratory tests showed the followings: elevated levels of WBC count, AST, glucose, HbA1c, serum C-peptide immunoreactivity (CPR), creatinine and prolactin; normal levels of red blood cells, platelet count, blood urea nitrogen, ALT, GGTP, K, plasma osmolality, GH, LH, FSH, testosterone, AVP, TSH, FT3 and FT4, and decreased level of haemoglobin, haematocrit, total protein, albumin, Na, Cl, ACTH, cortisol, IGF-1, U-Osmolality with U-Na 28 mmol/l, U-K 17 mmol/ l, U-Cl 29 mmol/l and U-Creatinine 29 mg/dl. He had hyponatraemia with low levels of cortisol and adrenocorticotropic hormone (ACTH), suggesting adrenal insufficiency. His symptoms and laboratory data suggested that the clinically suspected adrenal insufficiency was possibly due to pituitary adrenocortical hypofunction induced by nivolumab immunotherapy, despite the absence of changes in the size and density of the pituitary gland revealed on brain MRI. He was initiated on steroid replacement therapy with prednisolone 40 mg/day. After starting steroid therapy, his physical condition improved rapidly. The dose of steroid was tapered, but he became hyperglycaemic because of the steroid treatment, which was managed with insulin. Further, he was maintained on hydrocortisone. Because the ability to secrete insulin was unimpaired with CPR 2.37 ng/ml, he was started on liraglutide therapy, and nivolumab treatment was continued. After his symptoms subsided, the corticotropin-releasing hormone (CRH) load test was performed, which revealed that the serum ACTH level and cortisol response to CRH were very low. Following the 10th cycle of nivolumab treatment, he was referred again because of high blood sugar levels. He was admitted to the hospital for suspected fulminant type 1 diabetes mellitus (FT1DM) associated with nivolumab treatment and was started on drip infusion therapy. On physical examination, his blood pressure was 148/72 mm Hg, pulse was 75 beats/minute, and body temperature was 36.3°C. His mouth was dry and his skin turgor was poor, but he did not complain of any other symptoms. Although his plasma blood glucose levels were high, his haemoglobin A1c (HbA1c) levels suggesting a rapid progression of hyperglycaemia. Abdominal CT showed no pancreatic abnormality. A glucagon stimulation test revealed insulin depletion, but he showed serum anti-glutamic acid decarboxylase (GAD) antibody and urinary ketone negativity. Other laboratory tests showed the followings: elevated level of WBC count, platelet count, blood urea nitrogen, creatinine, amylase, GGTP, and glucose; normal level of red blood cells, haemoglobin, lipase, elastase-1, AST, ALT, K, Cl, pH, pCO2, pO2, bicarbonate, and a decreased level of haematocrit, total protein, albumin, Na, anion gap, serum CPR, Urinary CPR. Laboratory investigations showed hyperglycaemia, but no acidosis or ketonuria was found. On the basis of these findings, FT1DM excluded, and a diagnosis of insulin-dependent diabetes (type 1 diabetes mellitus) was made. The man was treated with fluid infusion and continuous insulin infusion. His potassium and other electrolyte levels were found within the normal range, and serum potassium fluctuations were within the normal range even after the introduction of insulin therapy. On the second day, he was switched to multiple daily injections of insulin therapy. With these treatments, his blood glucose level remained stable, and he received an additional 10 immune checkpoint inhibitors treatments for renal cell carcinoma for over a year.