Anne-Cécile Paepegaey1,2, Béatrix Cochand-Priollet2,3, Estelle Louiset4, Pierre-Olivier Sarfati5, Marco Alifano2,6, Nelly Burnichon2,7,8, Marie Bienvenu-Perrard9, Najiba Lahlou2,10, Léopoldine Bricaire1, Lionel Groussin1,2. 1. 1 Department of Endocrinology, Cochin Hospital , Assistance Publique Hôpitaux de Paris, Paris, France . 2. 2 Université Paris Descartes , PRES Sorbonne Paris Cité, Faculté de Médecine, Paris, France . 3. 3 Department of Pathology, Cochin Hospital , Assistance Publique Hôpitaux de Paris, Paris, France . 4. 4 INSERM, Unité 982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Mont-Saint-Aignan, France; Institute for Research and Innovation in Biomedicine, Normandie Rouen University , Mont-Saint-Aignan, France . 5. 5 Department of Digestive and Endocrine Surgery, Cochin Hospital , Assistance Publique Hôpitaux de Paris, Paris, France . 6. 6 Department of Thoracic Surgery, Cochin Hospital , Assistance Publique Hôpitaux de Paris, Paris, France . 7. 7 INSERM, UMR970, Paris-Cardiovascular Research Center , Paris, France . 8. 8 Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou , Service de Génétique, Paris, France . 9. 9 Department of Nuclear Medicine, Cochin Hospital , Assistance Publique Hôpitaux de Paris, Paris, France . 10. 10 Department of Hormonal Biology, Cochin Hospital , Assistance Publique Hôpitaux de Paris, Paris, France .
Abstract
BACKGROUND: Medullary thyroid carcinomas (MTCs) complicated by ectopic Cushing's syndrome (CS) have a poor prognosis, partially due to the difficulty in controlling hypercortisolism by adrenal blocking drugs. Recent reports (including the initial follow-up of this patient) have suggested that tyrosine kinase inhibitors (TKIs) may be a therapeutic option due to an anti-secretory action on ACTH. However, there is a lack of long-term follow-up studies. PATIENT FINDINGS: The case is reported of a 58-year-old man with MTC-related CS resistant to a combination of several anti-cortisolic drugs. Vandetanib, an oral multi-TKI that targets RET in particular, was initiated, and a rapid reversal of the hypercortisolism was observed without any change in tumor size. Vandetanib was briefly interrupted twice, once for 45 days because of side effects and a second time for 10 days to schedule surgical debulking. Each time, plasma cortisol and calcitonin levels increased after TKI withdrawal and were rapidly lowered by vandetanib reintroduction. As described in other cases of CS caused by MTC, a marked ACTH increase after desmopressin stimulation was observed before vandetanib therapy. In contrast, a blunted ACTH response to desmopressin was documented throughout the course of vandetanib treatment. This modulation of the tumoral ACTH production is a strong argument in favor of a TKI anti-secretory action. A left thyroid lobectomy and a modified neck dissection were performed one year after the initiation of vandetanib in order to reduce the tumor mass. An activating M918T RET (c.2753T>C) somatic mutation was identified in a lymph node metastasis. CONCLUSION: Three years and eight months after vandetanib initiation, there was no sign of recurrence of hypercortisolism. This case illustrates the long-term effectiveness of vandetanib in maintaining the control of hypercortisolism in MTC-related CS.
BACKGROUND: Medullary thyroid carcinomas (MTCs) complicated by ectopic Cushing's syndrome (CS) have a poor prognosis, partially due to the difficulty in controlling hypercortisolism by adrenal blocking drugs. Recent reports (including the initial follow-up of this patient) have suggested that tyrosine kinase inhibitors (TKIs) may be a therapeutic option due to an anti-secretory action on ACTH. However, there is a lack of long-term follow-up studies. PATIENT FINDINGS: The case is reported of a 58-year-old man with MTC-related CS resistant to a combination of several anti-cortisolic drugs. Vandetanib, an oral multi-TKI that targets RET in particular, was initiated, and a rapid reversal of the hypercortisolism was observed without any change in tumor size. Vandetanib was briefly interrupted twice, once for 45 days because of side effects and a second time for 10 days to schedule surgical debulking. Each time, plasma cortisol and calcitonin levels increased after TKI withdrawal and were rapidly lowered by vandetanib reintroduction. As described in other cases of CS caused by MTC, a marked ACTH increase after desmopressin stimulation was observed before vandetanib therapy. In contrast, a blunted ACTH response to desmopressin was documented throughout the course of vandetanib treatment. This modulation of the tumoral ACTH production is a strong argument in favor of a TKI anti-secretory action. A left thyroid lobectomy and a modified neck dissection were performed one year after the initiation of vandetanib in order to reduce the tumor mass. An activating M918T RET (c.2753T>C) somatic mutation was identified in a lymph node metastasis. CONCLUSION: Three years and eight months after vandetanib initiation, there was no sign of recurrence of hypercortisolism. This case illustrates the long-term effectiveness of vandetanib in maintaining the control of hypercortisolism in MTC-related CS.
Authors: Anna Angelousi; Aimee R Hayes; Eleftherios Chatzellis; Gregory A Kaltsas; Ashley B Grossman Journal: Endocr Relat Cancer Date: 2022-05-31 Impact factor: 5.900