Endocrine Abstracts

Case history: A 64-year-old man was diagnosed with sporadic medullary thyroid cancer in 2018 after presenting with diarrhoea and a neck mass. He underwent a total thyroidectomy, neck dissection and post-operative radiotherapy, for extensive T4N1bM0 disease involving the tracheal wall and oesophagus. He was left with hypoparathyroidism, taking 1-alfacalcidol 1 mg OD. He also had T2DM on Gliclazide. In 2023 his calcitonin had risen to 12,220 pmol/l, with recurrent severe diarrhoea, and a change in voice with stridor. CT showed residual tumour invading the trachea, nodal disease in the mediastinum and multiple lung nodules. He was referred to our centre for further management. He had a somatic Met918Thr RET mutation. MDT discussion confirmed need to start systemic therapy and given the risk of fistulation with potent VEGF inhibitors such as Cabozantinib, Selpercatinib was started at an initial dose of 120 mg twice daily.

Investigations: Immediately prior to starting Selpercatinib the corrected calcium was 2.02 mmol/l (NR 2.1 to 2.5) with a phosphate of 1.34 mmol/l on a stable dose of 1-alfacalcidol only. 2 weeks after starting treatment, he was tolerating treatment well with significant improvement in his diarrhoea. However corrected calcium had fallen to 1.4 mmol/l and phosphate increased to 2.22 mmol/l. PTH was 2.1 pmol/l (0.8 to 5.7) and Vitamin D was 65 nmol/l. ECG showed a QTc of 489 mS. He retrospectively reported tingling in his hand for 24 hours.

Results and Treatment: He was admitted to a monitored bed and commenced on an intravenous Calcium Gluconate infusion, alfacalcidol was increased to 1 mg BD and he was started on Calcium Carbonate 4.5 g TDS. Corrected calcium improved over 48 hours to 1.9 mmol/l and phosphate fell to 1.58 mmol/l.

Conclusions and points for discussion: Despite a considerable rapid improvement in systemic symptoms and diarrhoea, severe hypocalcaemia developed within 2 weeks of treatment with Selpercatinib, on a background of previously well controlled post-operative hypoparathyroidism. Acute admission and prolonged intravenous Calcium were required. Selpercatinib, a selective RET inhibitor, had shown significant efficacy in RET mutated metastatic medullary thyroid cancer. In the phase 3 trial [1], hypocalcaemia was reported in 10.4% of patients (Grade 3 or higher in 1%). This was lower than in the control group (treated with either Cabozantinib or Vandetanib) where 25.8% had hypocalcaemia (Grade 3 or higher in 7.2%). Despite this, clinicians need to be aware of the risk of severe hypocalcaemia with Selpercatinib, the mechanism of which is currently unclear.[1] Hadoux et al. NEJM 2023 389:1851-61