Sorafenib induces rapid control of ectopic ACTH syndrome in a patient with metastatic medullary thyroid cancer

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 471-496-Thyroid Neoplasia & Case Reports
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-471
Ana Oliveira Hoff*, Joao Evangelista Bezerra-Neto, Gilberto Castro Jr. and Antonio Marcondes Lerario
ICESP/University of Sao Paulo, Sao Paulo, Brazil
Background: Metastatic medullary thyroid cancer (MTC) is usually an indolent disease, but when rapidly progressive, it is associated with severe symptoms and responds poorly to systemic chemotherapy. This paradigm is rapidly changing with the advent of molecular targeted therapy. Prospective phase II and III trials with different agents have demonstrated tumor response rates of up to 45% with significant improvement of progression-free survival (1-3). As a result, vandetanib was the first drug approved by the FDA for the treatment of progressive metastatic MTC (4). Here, we report an additional potential effect of tyrosine kinase inhibitors.

Clinical case: A 45 year-old male patient with metastatic MTC was referred to our institution after being treated unsuccessfully with two chemotherapy regimens. In addition to widespread and bulky metastatic disease (cervical, lung, liver and bones) the patient presented with severe diarrhea, muscle weakness and weight gain. Physical examination revealed plethoric facies, central obesity and profound proximal muscle weakness, which led to the suspicion of Cushing’s syndrome. Biochemical analysis revealed ACTH-dependent hypercortisolism suggestive of ectopic ACTH syndrome - basal serum ACTH 76 pg/mL (normal range 12-55) and 24 hr urinary cortisol 946 mcg/24hr (normal range 50-310). The calcinonin and CEA levels were 12456 pg/mL (normal range <8,4) and 210,4 ng/mL (normal range <10), respectively. As vandetanib or active clinical trials were not available at our institution, we opted to initiate the patient on off-label sorafenib 400 mg twice a day.  After two weeks, laboratory evaluation revealed complete resolution of hypercortisolism associated with significant clinical improvement. The 24 hr urinary cortisol levels were 70,4 and 49 mcg/24 hr 15 and 21 days after initiating sorafenib therapy. Serum cortisol, ACTH and calcitonin levels also decreased significantly after 15 days of sorafenib therapy (7.2 mcg/dL, 23 pg/mL and 8057 pg/mL, respectively). 

Conclusion: Despite a reduction of calcitonin and CEA levels, we question whether the rapid control of hypercortisolism was not only related to tumor mass reduction  but possibly secondary to a direct effect of sorafenib on hormonal secretion. To date, the only well-defined hormonal abnormality observed in patients treated with TKI is hypothyroidism, which occurs in a substantial proportion of patients (5).  The rapid correction of hypercortisolism was beneficial to this patient, however, it raises the question whether common side effects of TKI treatment such as fatigue, anorexia, nausea and vomiting are, at some extent, secondary to hypoadrenalism. Studies will be necessary to investigate the role of sorafenib and other TKIs in the pituitary-adrenal axis.

1. Wells SA, Jr., Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol 2012;30:134-41. 2. Lam ET, Ringel MD, Kloos RT, et al. Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer. J Clin Oncol;28:2323-30. 3. Kurzrock R, Sherman SI, Ball DW, et al. Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol 2011;29:2660-6. 4. Thornton K, Kim G, Maher VE, et al. Vandetanib for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease: u.s. Food and drug administration drug approval summary. Clinical cancer research : an official journal of the American Association for Cancer Research 2012;18:3722-30. 5. Hamnvik OP, Larsen PR, Marqusee E. Thyroid dysfunction from antineoplastic agents. Journal of the National Cancer Institute 2011;103:1572-87.

Nothing to Disclose: AOH, JEB, GC Jr., AML

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