Vandetanib Successfully Controls Medullary Thyroid Cancer-Related Cushing Syndrome in an Adolescent Patient

Abstract

Context:

Ectopic Cushing syndrome due to ACTH secretion from metastatic medullary thyroid cancer (MTC) is associated with significant morbidity and mortality.

Objective:

The aim of the study was to describe the first case of Cushing syndrome associated with MTC in a pediatric patient and the successful reversal of Cushing syndrome with tyrosine kinase inhibitor (vandetanib) therapy.

Patient and Methods:

A 17-year-old Brazilian adolescent presented with metastatic MTC and associated ACTH-dependent ectopic Cushing syndrome in the context of multiple endocrine neoplasia type 2B. When the patient was treated with the tyrosine kinase inhibitor vandetanib, rapid decrease in serum cortisol and improvement of clinical symptoms were observed.

Conclusion:

We describe the first pediatric case of clinical and biochemical improvement of paraneoplastic MTC-related Cushing syndrome after treatment with vandetanib. Vandetanib and possibly other tyrosine kinase inhibitors may be a novel beneficial option in patients with neuroendocrine tumor-related ectopic Cushing syndrome.

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor that arises from the parafollicular C cells of the thyroid gland. MTC accounts for 4% of the thyroid cancer cases in adults and between 5 and 8% of all thyroid cancer cases in children (1, 2). Seventy-five percent of MTC cases are sporadic, and the remaining cases occur in the context of the autosomal dominant familial multiple endocrine neoplasia (MEN) type 2 syndrome, which includes MEN 2A, MEN 2B, and familial MTC.

MTC tumors secrete tumor-specific biomarkers such as calcitonin and carcinoembryonic antigen. As neuroendocrine neoplasms, they may also secrete a variety of hormones including calcitonin-related peptide, serotonin, substance P, vasoactive intestinal peptide, ACTH, catecholamines, and histamine metabolites (3). Ectopic Cushing syndrome due to ACTH-producing MTC is an uncommon but well-described entity with over 50 cases reported in the literature. Ectopic Cushing syndrome from MTC is associated with significant morbidity and mortality, with approximately 50% of the patients dying secondary to complications of hypercortisolism (4). Control of hypercortisolism with inhibitors of steroidogenesis or ACTH secretion is often unsuccessful, and bilateral adrenalectomy is frequently required.

Reversal of Cushing syndrome by the tyrosine kinase inhibitor vandetanib was recently reported in a 58-year-old man with a metastatic, ACTH-producing MTC (5). In this report, the patient had failed treatment with metyrapone, mitotane, somatostatin analogs, and ketoconazole, but he responded to therapy with 300 mg per day of vandetanib, as evidenced by a simultaneous decrease in serum cortisol, calcitonin, and desmopressin-stimulated plasma ACTH concentrations. Imaging did not reveal reduction in the size of the tumor, and the authors suggested a direct antisecretory effect of vandetanib on the MTC cells. Here, we report the first pediatric patient with MTC-induced Cushing syndrome reversed by vandetanib, who was followed for a 5-year period. To our knowledge, this is also the first pediatric case of MTC-induced Cushing syndrome reported in the literature (6).

Case Report

A 17-year-old Brazilian man with a history of MEN 2B and metastatic MTC due to a germline M918T RET mutation was referred to the National Institutes of Health (NIH) for participation in the pediatric phase I/II trial of vandetanib (NCT00514046) as the first medical treatment targeting RET in children and adolescents (7) (the patient was included in the publication describing the results of this clinical trial, but he was not described in detail). He presented with a thyroid nodule at the age of 14 years 6 months, but he was lost to follow-up, and further investigation was not undertaken until he presented 1 year later with a thyroid nodule, cough, and watery diarrhea. Imaging revealed bilateral thyroid lesions, pathological cervical and mediastinal lymph nodes, and bilateral pulmonary and left iliac bone metastases. He underwent total thyroidectomy with central and lateral neck dissection, followed by right pulmonary segmentectomy, mediastinal lymph node resection, and neck and mediastinal radiation. Pathology was consistent with MTC that had metastasized to the cervical and mediastinal lymph nodes and lung parenchyma.

During oncological evaluation at the NIH, the patient was also diagnosed with ACTH-dependent ectopic Cushing syndrome. He had a yearlong history of progressively worsening centripetal obesity, violaceous striae, easy bruising, fungal infections, hypertension, severe acne, and proximal muscle weakness. Biochemical evaluation showed elevated urinary free cortisol (UFC) (745 μg/24 h; normal range, 4–56), elevated plasma ACTH (87 pg/mL; normal range, < 46), and low potassium (2.6 mmol/L; normal range, 3.3–5.1). Plasma fractionated metanephrine (102 pg/mL; normal range, 12–61) and serum calcitonin (1683 pg/mL; normal range, < 16) were elevated. There was a loss of diurnal cortisol and ACTH variation, failure to suppress to 8 mg dexamethasone, and lack of response to CRH. Magnetic resonance imaging was negative for pituitary adenomas, but adrenal computed tomography revealed bilateral nodular hyperplasia.

After a 1-month treatment with 200 mg (100 mg/m²/d) of vandetanib for his metastatic MTC, UFC concentration returned to normal (6.6 μg/24 h) simultaneously with a 50% drop in calcitonin concentrations, whereas by 6 months of treatment there was complete resolution of Cushing syndrome symptoms, normalization of plasma ACTH, and a further decrease in the calcitonin concentration (175 pg/mL) (Figure 1). During cycle 3, which was 3 months after vandetanib initiation, the vandetanib dose was decreased to 125 mg once daily (62.5 mg/m²/d) secondary to intolerable diarrhea. The clinical and biochemical responses of Cushing syndrome were maintained, despite the dose reduction. The previously noted hypokalemia was corrected before initiation of vandetanib, and sequential follow-up of QTc intervals did not show significant prolongation. Overall, vandetanib did not result in significant reduction of MTC tumor burden, but the patient met criteria for stable disease as radiographically quantified by response evaluation criteria in solid tumors (RECIST) (version 1.0) (8). The patient remained in clinical and biochemical remission from Cushing syndrome for the duration of treatment with vandetanib (26 mo), and he did not develop any clinical or biochemical evidence of adrenal insufficiency. On computed tomography scan evaluation of the adrenal glands, no significant morphological adrenal changes were noted during vandetanib therapy. Vandetanib was discontinued at the age of 19 years 5 months due to MTC tumor progression, as required by the experimental treatment protocol. Cushing syndrome relapsed biochemically within 5 months (plasma ACTH, 71.3 pg/mL; calcitonin, 1258 pg/mL; morning cortisol, 23.1 μg/dL; UFC, 49.6 μg/d) and clinically within 8 months of stopping vandetanib treatment.

Figure 1.

Serum morning cortisol (AM cortisol), ACTH, calcitonin, and UFC concentrations during treatment. Gray zone represents the normal ACTH reference range (0–46 pg/mL). Other normal reference ranges are: UFC, 4–56 μg/24 h; serum AM cortisol, 5–25 μg/dL; and calcitonin, 0–15.9 pg/mL. *, Vandetanib dose was reduced from 200 to 125 mg a day, due to intolerable diarrhea.

Two alternative tyrosine kinase inhibitors (sunitinib and sorafenib) were administered sequentially at the recommended pediatric doses, but they were discontinued due to disease progression after 7 and 8 months, respectively. Neither of the two drugs was successful in limiting MTC or Cushing syndrome progression, but sunitinib appeared to have had a modest effect on delaying ACTH, UFC, and serum cortisol concentration rise (Figure 1; 26–35 mo of treatment). There was no decrease in the calcitonin levels, but instead sorafenib treatment required a dose reduction for intolerable palmar-plantar erythrodysesthesia syndrome. Neither of these two tyrosine kinase inhibitors was able to control Cushing syndrome, prompting the addition of ketoconazole to control hypercortisolism. The patient remained on ketoconazole for 19 months, but neither UFCs nor ACTH concentrations normalized despite escalation of the dose to 200 mg three times daily. MTC continued to progress, but the patient's morbidity was predominantly attributed to Cushing syndrome, including hypertension, hypokalemia, excessive weight gain, poor wound healing, and inability to walk secondary to muscle weakness. His clinical status precluded the safe initiation of other tyrosine kinase inhibitors to control his MTC and possibly the Cushing syndrome, such as cabozantinib (XL184), a recently approved RET inhibitor for treatment of advanced MTC (9). The patient underwent bilateral adrenalectomy at the age of 22 years. Pathology showed bilateral adrenal cortical hyperplasia with metastatic medullary thyroid carcinoma to the left adrenal parenchyma, periadrenal soft tissue, and vascular spaces that stained strongly positive for calcitonin and weakly positive for ACTH (Figure 2). The patient's clinical status improved after adrenalectomy and permitted the initiation of cabozantinib (XL184) therapy. However, and despite an initial promising response to XL184, the patient recently succumbed to his disease.

Figure 2.

Adrenal parenchyma with clusters of neuroendocrine neoplasm (A, hematoxylin and eosin; ×100) stains positive for calcitonin (B, immunohistochemistry stain; ×100) in agreement with the diagnosis of metastatic MTC. Immunohistochemistry stain for ACTH shows weak positivity in neoplastic cells (C, ×400).

Discussion

Ectopic ACTH-dependent Cushing syndrome is responsible for approximately 10–15% of the adult Cushing syndrome cases, but it is estimated to occur much less frequently in the pediatric population (6). Cushing syndrome due to MTC-induced paraneoplastic production of ACTH is rare, and there are approximately 50 adult patient cases described in the literature. In a retrospective study of 1640 adult patients with MTC, ectopic MTC-related Cushing syndrome was observed in only 0.6% of patients, whereas previous studies reported a higher prevalence, possibly due to selection bias (4, 10, 11). The diagnosis of MTC-related Cushing syndrome is based on the presence of hypercortisolism (with high or inappropriately normal ACTH concentrations) that is not suppressed by high-dose dexamethasone, the absence of a pituitary adenoma, and the parallel progression of Cushing syndrome and MTC (4). Tumor immunostaining is occasionally positive for ACTH, CRH, or proopiomelanocortin. Sporadic or symptomatic MTCs have the poorest prognosis, and the outcome is further worsened in the presence of a paraneoplastic syndrome. In the Barbosa et al (4) study, 80% of the patients with MTC did not survive longer than 12.8 months after the additional diagnosis of Cushing syndrome; half of them died secondary to complications related to hypercortisolism, such as peritonitis or hypokalemia-induced fatal cardiac arrhythmia.

Patients with ectopic Cushing syndrome are typically treated with adrenolytics, suppressors of steroidogenesis, or somatostatin analogs. However, Cushing control is usually suboptimal. Bilateral adrenalectomy can be curative, although its efficacy is often limited when surgery occurs late in the disease course or when surgical resection of MTC metastases is incomplete. In the Barbosa et al (4) study, only one of 10 patients with MTC-induced Cushing syndrome was cured with surgical resection of MTC, and one other patient was successfully controlled with anticortisolic drugs (4). In two cases of severe Cushing syndrome, nonresponsive to MTC treatment or anticortisolic drugs, bilateral adrenalectomy was performed, but it did not improve survival, likely because the intervention occurred too late in the disease course.

Recently, vandetanib was shown to reverse ACTH-dependent ectopic Cushing syndrome in an adult patient with MTC (treated for 10 wk), which is in agreement with the observations in our 17-year-old patient (treated for 26 mo) (5). Vandetanib inhibits tyrosine kinase activity of the RET receptor, vascular endothelial growth factor receptor-2, and epidermal growth factor receptor. All three receptors are implicated in MTC tumorigenesis (12), but RET is the primary driver of tumor cell growth (13). Vandetanib is FDA-approved for the treatment of symptomatic or progressive MTC in adult patients with unresectable, locally advanced, or metastatic disease. In the National Cancer Institute phase I/II trial of vandetanib in children and adolescents with MEN 2B-associated MTC, the confirmed objective partial response rate was 47% in 15 subjects with M918T mutations (7). Activity of other tyrosine kinase inhibitors with RET inhibition has been described in MTC, and cabozantinib (XL184) was recently approved as the second agent after vandetanib for the treatment of advanced MTC (9). Tyrosine kinase inhibitors (gefitinib, sunitinib, and sorafenib) have also been used previously in the treatment of neuroendocrine tumors of the pancreas, VIPomas, carcinoids, pheochromocytomas, and paragangliomas (15–18). Gefitinib showed a potential benefit in the treatment of hypercortisolism secondary to pituitary ACTH-secreting adenomas. A substantial decrease in proopiomelanocortin mRNA expression and ACTH secretion was observed in human pituitary corticotroph adenoma cell lines treated with gefitinib, whereas tumor growth and serum ACTH levels were decreased in mice allografted with an epidermal growth factor receptor-overexpressing corticotroph tumor cell line (19).

Vandetanib was efficacious in the treatment of our patient's hypercortisolism, as evidenced by prolonged remission of Cushing syndrome and rapid hypercortisolism rebound (within 5 mo) after vandetanib discontinuation. Vandetanib was discontinued because of MTC tumor progression (as required by the research treatment protocol), despite good control of Cushing syndrome. A mild increase in ACTH concentration (59.3 pg/mL; normal, <46 pg/mL) was noted before vandetanib discontinuation. This finding may have signified early development of Cushing syndrome resistance to the drug, but it was not associated with respective increases in UFC or serum cortisol concentrations.

The development of MTC resistance to vandetanib and other tyrosine kinase inhibitors is well described and is believed to be due to specific RET mutation genotypes (20). Our patient showed both biochemical and clinical control of Cushing syndrome, despite the lack of a significant decrease in tumor burden. Control of hypercortisolism was continuous for the entire duration of treatment with vandetanib (26 mo), despite the interval progression of MTC. This observation supports the theory of a direct antisecretory effect of vandetanib on MTC cells, which may be independent of its antineoplasmatic effect, as also suggested by Baudry et al (5).

It is unclear why sunitinib or sorafenib did not have similar efficacy in the management of MTC-related Cushing syndrome. Differences in the ability of the tyrosine kinase inhibitors used to inhibit RET may have contributed to differences in clinical activity observed. Although the IC₅₀ for RET inhibition in vitro is in the low nanomolar range for all tyrosine kinase inhibitors used (21, 22), the plasma steady-state concentration of vandetanib is substantially greater compared to sorafenib and sunitinib (21), which could have impacted on clinical activity. In addition, although sunitinib and sorafenib inhibit the tyrosine kinase activity of RET, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor, preliminary MTC studies have shown predominantly partial response results, which could explain the above observation (23, 24). Another theoretical possibility is that treatment with vandetanib had a role in the development of tumor resistance to subsequent tyrosine kinase inhibitors (14, 25).

In conclusion, vandetanib was effective in the treatment of this adolescent patient's MTC-related Cushing syndrome and was associated with prolonged control of hypercortisolism independent of MTC tumor progression. Further studies are needed to confirm this observation and investigate the effectiveness of tyrosine kinase inhibitors in the treatment of other neuroendocrine tumor-related ectopic Cushing syndrome.