Calcium Crisis: Cabozantinib-Induced Hypocalcemia

Introduction: Cabozantinib is a multi-targeted tyrosine kinase inhibitor (TKI) used to treat various malignancies, including metastatic medullary thyroid carcinoma and advanced neuroendocrine tumors. Hypocalcemia is a rare and poorly understood adverse effect of cabozantinib. We report a case of severe but asymptomatic hypocalcemia in a patient on cabozantinib therapy. Case Description: 36M with stage IIIb chronic kidney disease, type I diabetes mellitus, and stage IV pancreatic neuroendocrine tumor presented with generalized weakness, nausea, and vomiting. The patient had previously undergone unsuccessful surgical treatment and was recently started on cabozantinib due to disease progression. Examination was negative for Chvostek and Trousseau signs. Initial labs revealed calcium 5.4 mg/dL, magnesium 0.4 mg/dL, and creatinine 5.8 mg/dL (baseline: 1.9–2.0 mg/dL). Urinalysis was unremarkable. Imaging showed chronic left kidney obstruction with ureteropelvic junction ectasia and right renal atrophy. AKI was due to prerenal azotemia, as it resolved rapidly with intravenous fluids. Parathyroid hormone (PTH) was markedly elevated at 634 pg/mL. Fractional excretion of calcium was 0.03%. A spot urine Mg:Cr ratio revealed 6.4mg/24h of urinary magnesium excretion. The patient remained asymptomatic despite the severity of hypocalcemia. He was treated with intravenous calcium gluconate and magnesium sulfate, and cabozantinib therapy was discontinued. His electrolytes normalized. Discussion: Cabozantinib-associated hypocalcemia is a rare but potentially serious complication that can affect about 2% patients. Labs in our patient ruled out renal magnesium and calcium wasting. PTH was elevated, presumably in response to hypocalcemia, excluding hypoparathyroidism as the mechanism of hypocalcemia. There are several proposed mechanisms reported in the literature. Inhibition of VEGFR may impair osteoclast activity, leading to reduced calcium mobilization. Inhibition of c-Met and RET pathways may affect PTH secretion, which was ruled out with a high PTH in our patient. Finally, impairment of vitamin D activation may contribute to hypocalcemia. Management may require dose adjustment or drug discontinuation in severe cases, along with close monitoring of calcium and magnesium levels.