THYROID Volume 24, Number 6, 2014 ª Mary Ann Liebert, Inc. DOI: 10.1089/thy.2013.0571
CASE STUDIES, and PATIENTS WITH REMARKABLE FEATURES OR RARE DISORDERS
Complete Resolution of Hypercortisolism with Sorafenib in a Patient with Advanced Medullary Thyroid Carcinoma and Ectopic ACTH (Adrenocorticotropic Hormone) Syndrome Romualdo Barroso-Sousa,1 Antonio Marcondes Lerario,2,3 Joao Evangelista,1,3 Carla Papadia,2 Delmar M. Lourenc¸o Jr.,2 Chin Shien Lin,4 Marco Antonio Kulcsar,4 Maria Candida Fragoso,3 and Ana O. Hoff 2
Background: The treatment of advanced medullary thyroid carcinoma (MTC) has evolved significantly over the past decade. The discovery of genetic abnormalities in MTC has led to the development of targeted therapies such as vandetanib and cabozantinib. Other kinase inhibitors (KI), such as sorafenib, have been investigated in this setting and are an alternative therapeutic option. The lack of specificity of these KIs to a single target may result in additional, unexpected effects. In this report, we describe a patient with metastatic MTC and Ectopic ACTH (adrenocorticotropic hormone) Syndrome in whom treatment with sorafenib resulted in complete resolution of hypercortisolism. Summary: A 45-year-old male with progressive metastatic MTC presented with clinical manifestations suspicious for Cushing’s syndrome. Investigation revealed ACTH-dependent hypercortisolism suggestive of Ectopic ACTH Syndrome. Treatment with sorafenib 400 mg twice a day was initiated resulting in a rapid and significant reduction of cortisol and ACTH levels associated with dramatic clinical improvement. The rapid and effective control of hypercortisolism in the absence of a significant tumor reduction raises the question of whether sorafenib may have a direct effect on ACTH or cortisol hypersecretion. Conclusions: This report suggests a previously unknown potential effect of sorafenib on the pituitary–adrenal axis. Further studies will be necessary to investigate the role of sorafenib in other cases of ACTH excess and to understand the mechanisms by which it alters steroid synthesis, action, or secretion.
Introduction
M
edullary thyroid carcinoma (MTC) is a malignant tumor that arises from the neuroendocrine calcitoninproducing parafollicular C cells of the thyroid gland, and it accounts for approximately 5% of all thyroid cancers (1). Germline activating mutations in the RET (rearranged during transfection) proto-oncogene occur in virtually all patients with hereditary MTC (2). In sporadic MTC, somatic mutations of the RET gene are observed in 40–60% of the tumors, while mutations of H-RAS and K-RAS have been observed in about 43–56% of RET-negative tumors (3,4). These, in addition to overexpression of EGFR, c-MET, and VEGFR, are important genetic abnormalities responsible for the development of MTC (1). The discovery of these molecular abnormalities provided the basis for the development of targeted molecular therapies
for advanced metastatic MTC. In the past two years, two kinase inhibitors (KI)—vandetanib and cabozantinib— have been approved by the Food and Drug Administration (FDA) for the treatment of progressive metastatic MTC (5,6). Other KIs, such as sorafenib, have been investigated in Phase II studies, and represent a therapeutic off-label option (7). As other neuroendocrine cells, parafollicular C cells have the potential to produce peptides such as adrenocorticotropic hormone (ACTH) and/or corticotropin releasing factor (CRF) that can ultimately result in Cushing’s syndrome (CS). Ectopic ACTH Syndrome (EAS) is an uncommon cause of CS. Small-cell lung carcinoma (SCLC) is the most frequent malignancy associated with EAS; other associated tumors include neuroendocrine tumors arising from the lung, bronchus, thymus, pancreas, and from the thyroid gland (8). Despite being uncommon, EAS in MTC is usually
Departments of 1Medical Oncology, 2Endocrinology, and 4Head and Neck Surgery, Instituto do Caˆncer do Estado de Sa˜o Paulo (ICESP), Sa˜o Paulo, Brazil. 3 Department of Endocrinology, University of Sa˜o Paulo, Sa˜o Paulo, Brazil.
1062
EFFECTIVE CONTROL OF ECTOPIC ACTH SYNDROME WITH SORAFENIB
associated with extensive metastatic disease and is therefore associated with a poor prognosis. Control of hypercortisolism by drugs that inhibit cortisol synthesis such as ketoconazole and metyrapone is usually initiated prior to antitumor treatment to improve the clinical status and enable treatments that aim at tumor mass reduction to achieve control of ACTH production. Here, we report a case of progressive metastatic MTC with EAS in whom treatment with sorafenib, despite being initiated prior to introduction of cortisol synthesis inhibitors, resulted in an unexpectedly rapid control of hypercortisolism without significant reduction of the tumor mass. Methods
The patient provided written consent, and the Institutional Research Ethics Committee approved publication of the case report. Serum and urinary cortisol, ACTH, and calcitonin levels were measured by chemiluminescent assays (Immulite 2000 system, Siemens Healthcare, Surrey, United Kingdom). CEA levels were measured by an eletrochemiluminescent assay. The reference ranges for serum cortisol, urinary cortisol, ACTH, calcitonin, and CEA are 5–25 lg/dL, 50–310 lg/24 h, 12–55 pg/mL,
CASE STUDIES, and PATIENTS WITH REMARKABLE FEATURES OR RARE DISORDERS
Complete Resolution of Hypercortisolism with Sorafenib in a Patient with Advanced Medullary Thyroid Carcinoma and Ectopic ACTH (Adrenocorticotropic Hormone) Syndrome Romualdo Barroso-Sousa,1 Antonio Marcondes Lerario,2,3 Joao Evangelista,1,3 Carla Papadia,2 Delmar M. Lourenc¸o Jr.,2 Chin Shien Lin,4 Marco Antonio Kulcsar,4 Maria Candida Fragoso,3 and Ana O. Hoff 2
Background: The treatment of advanced medullary thyroid carcinoma (MTC) has evolved significantly over the past decade. The discovery of genetic abnormalities in MTC has led to the development of targeted therapies such as vandetanib and cabozantinib. Other kinase inhibitors (KI), such as sorafenib, have been investigated in this setting and are an alternative therapeutic option. The lack of specificity of these KIs to a single target may result in additional, unexpected effects. In this report, we describe a patient with metastatic MTC and Ectopic ACTH (adrenocorticotropic hormone) Syndrome in whom treatment with sorafenib resulted in complete resolution of hypercortisolism. Summary: A 45-year-old male with progressive metastatic MTC presented with clinical manifestations suspicious for Cushing’s syndrome. Investigation revealed ACTH-dependent hypercortisolism suggestive of Ectopic ACTH Syndrome. Treatment with sorafenib 400 mg twice a day was initiated resulting in a rapid and significant reduction of cortisol and ACTH levels associated with dramatic clinical improvement. The rapid and effective control of hypercortisolism in the absence of a significant tumor reduction raises the question of whether sorafenib may have a direct effect on ACTH or cortisol hypersecretion. Conclusions: This report suggests a previously unknown potential effect of sorafenib on the pituitary–adrenal axis. Further studies will be necessary to investigate the role of sorafenib in other cases of ACTH excess and to understand the mechanisms by which it alters steroid synthesis, action, or secretion.
Introduction
M
edullary thyroid carcinoma (MTC) is a malignant tumor that arises from the neuroendocrine calcitoninproducing parafollicular C cells of the thyroid gland, and it accounts for approximately 5% of all thyroid cancers (1). Germline activating mutations in the RET (rearranged during transfection) proto-oncogene occur in virtually all patients with hereditary MTC (2). In sporadic MTC, somatic mutations of the RET gene are observed in 40–60% of the tumors, while mutations of H-RAS and K-RAS have been observed in about 43–56% of RET-negative tumors (3,4). These, in addition to overexpression of EGFR, c-MET, and VEGFR, are important genetic abnormalities responsible for the development of MTC (1). The discovery of these molecular abnormalities provided the basis for the development of targeted molecular therapies
for advanced metastatic MTC. In the past two years, two kinase inhibitors (KI)—vandetanib and cabozantinib— have been approved by the Food and Drug Administration (FDA) for the treatment of progressive metastatic MTC (5,6). Other KIs, such as sorafenib, have been investigated in Phase II studies, and represent a therapeutic off-label option (7). As other neuroendocrine cells, parafollicular C cells have the potential to produce peptides such as adrenocorticotropic hormone (ACTH) and/or corticotropin releasing factor (CRF) that can ultimately result in Cushing’s syndrome (CS). Ectopic ACTH Syndrome (EAS) is an uncommon cause of CS. Small-cell lung carcinoma (SCLC) is the most frequent malignancy associated with EAS; other associated tumors include neuroendocrine tumors arising from the lung, bronchus, thymus, pancreas, and from the thyroid gland (8). Despite being uncommon, EAS in MTC is usually
Departments of 1Medical Oncology, 2Endocrinology, and 4Head and Neck Surgery, Instituto do Caˆncer do Estado de Sa˜o Paulo (ICESP), Sa˜o Paulo, Brazil. 3 Department of Endocrinology, University of Sa˜o Paulo, Sa˜o Paulo, Brazil.
1062
EFFECTIVE CONTROL OF ECTOPIC ACTH SYNDROME WITH SORAFENIB
associated with extensive metastatic disease and is therefore associated with a poor prognosis. Control of hypercortisolism by drugs that inhibit cortisol synthesis such as ketoconazole and metyrapone is usually initiated prior to antitumor treatment to improve the clinical status and enable treatments that aim at tumor mass reduction to achieve control of ACTH production. Here, we report a case of progressive metastatic MTC with EAS in whom treatment with sorafenib, despite being initiated prior to introduction of cortisol synthesis inhibitors, resulted in an unexpectedly rapid control of hypercortisolism without significant reduction of the tumor mass. Methods
The patient provided written consent, and the Institutional Research Ethics Committee approved publication of the case report. Serum and urinary cortisol, ACTH, and calcitonin levels were measured by chemiluminescent assays (Immulite 2000 system, Siemens Healthcare, Surrey, United Kingdom). CEA levels were measured by an eletrochemiluminescent assay. The reference ranges for serum cortisol, urinary cortisol, ACTH, calcitonin, and CEA are 5–25 lg/dL, 50–310 lg/24 h, 12–55 pg/mL,
