Ectopic cushing in a patient with medullary thyroid carcinoma: hypercortisolism control and tumor reduction with Sunitinib
Pedro Marques . Margarida da Silva Vieira . Maria João Bugalho
Received: 7 April 2014/ Accepted: 28 June 2014 @ Springer Science+Business Media New York 2014
Medullary thyroid carcinoma (MTC) is rarely associated with ectopic Cushing’s syndrome (CS). Management of this condition is challenging. Kinase inhibitors (KI) may play a role in this setting [1-3]. We report the case of an advanced MTC and ectopic CS successfully treated with Sunitinib.
In 2005, the patient had a total thyroidectomy and bilateral modified radical neck dissection followed by radiotherapy. RET germline mutation screening was neg- ative. In 2011, imaging studies documented mediastinal and pulmonary metastases. The patient remained asymp- tomatic, and no treatment was undertaken. In July 2013, at the age of 64, he developed proximal muscle weakness and weight gain in less than 1 month. Physical examination revealed plethora, moon facies, abdominal obesity, hyper- tension, and ankle edema.
Tests were consistent with ACTH-dependent CS: plasma ACTH = 83.4 pg/mL (normal <46); morning serum corti- sol = 33 µg/dL (reference range 5-25); midnight serum cortisol = 29.8 µg/dL; 24-h urine free cortisol (UFC) = 2,647 µg/24 h (reference range 21-85). There was no sup- pression under dexamethasone. No adenoma was seen on pituitary magnetic resonance. The known mediastinal and lung metastases had increased in number and dimensions (Fig. 1), and calcitonin was 10,065 ng/L. 68Ga-DOTANOC- PET/CT showed low expression of somatostatin receptors in the metastatic lesions.
P. Marques ☒ · M. da Silva Vieira · M. J. Bugalho
Endocrinology Department, Instituto Português de Oncologia de Lisboa, Francisco Gentil, 1099-023 Lisbon, Portugal e-mail: pedro.miguel.sousa.marques@gmail.com
M. J. Bugalho
Clínica Universitária de Endocrinologia, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal
After starting metyrapone, there were clinical and lab- oratorial improvements (Fig. 1). However, fatigue, nausea, and diarrhea made us to consider alternative approaches. Somatostatin analogs were excluded, considering the low expression of somatostatin receptors. Bilateral adrenalec- tomy was considered a treatment of last resort.
Based on previous reports on the use of KI to control ectopic secretion of ACTH [1-3] and taking into account our own experience with Sunitinib, in the setting of MTC, we decided to use this KI. After starting treatment, ACTH normalized, UFC remained controlled, and calcitonin decreased (Fig. 1). The initial dose of 50 mg/day was adjusted to 25 mg/day due to complaints of fatigue, diar- rhea, and myalgia. Using the lower dose, on a continuous schedule, it was possible to maintain the treatment. After 3 months, RECIST evaluation documented partial response (Fig. 1). After 20 weeks under Sunitinib, the patient remains asymptomatic with normal ACTH and UFC.
In this case, ACTH secretion was likely due to MTC, considering the parallel worsening of CS and MTC. The priority was correction of the life-threatening hypercorti- solism. Therefore, metyrapone was introduced, and a remarkable reduction in UFC was observed.
Treatment with Sunitinib leads to a dramatic reduction in ACTH and calcitonin levels almost immediately as such not correlating with tumor response. If an additional and direct effect, on cortisol synthesis, contributed to the final results, remains unknown.
The control of hypercortisolism with different KIs [1-3] is likely to suggest an antisecretory class effect yet un- derexplored. The antisecretory effect observed with Vandetanib [1, 2] or Sorafenib [3] was not associated with tumor reduction. On the contrary, treatment with Sunitinib resulted in control of hypercortisolism and tumor shrink- age; the low dose of 25 mg allowed a continuous regimen
a
3000
Metyrapone
Sunitinib
130,0
b
24000-
Metyrapone
I
Sunitinib
150
2800-
120,0
22000-
140
140
2600
2.647
106
110,0
20000-
20.332
130
2400
100,0
18000-
116
120
2200
113
110
2000
85,9
87,9
90,0
83,45
16000-
UFC (µg/24h)
80,0
ACTH (pg/mL)
Calcitonin (ng/L)
100
1800
14000
90
CEA (ng/mL)
1600
70,0
12000
80
1400
1.473
60,0
70
1200
52,6
10000-
10.065
50,0
8.956
60
1000
43,5
41,5
45,5
8000
52
40,0
7.234
48
50
800
32,9
6000-
40
30,0
600
5.065
30
400
395
20,0
4000-
20
200
10,0
2000-
10
45
69
94
14
32
44
36
0
0
0
1
2
3
5
0
4
6
7
8
9
10
1
12
13
14
I 5161
18
19 20
22
2
24
25
2
27 28
31
29 30
0
0
I
2
3
4
5
6
7
8
9
101 I
12 13
14
15 61
81 9 20 21
22
23
24
25
26
7
28
29
30 31
Weeks
Weeks
c
S
1
43,6 mm
51,6 mm
24,6 mm
15.5 mm
23,0 mm
32.0 mm
d
32,3 mm
26,2 mm
30,8 mm
29,9 mm
28.1 mm
46,8 mm
possibly more adequate than the standard protocol to control hypercortisolism.
In sum, KIs appear as a promising alternative to manage ectopic CS due to MTC.
Conflict of interest The authors have nothing to disclose.
intolerable toxicity). c, d Computed tomography scans showing disease progression and objective response to Sunitinib according to the Response Evaluation Criteria in Solid Tumors: 6 months before the onset of Cushings syndrome (left-sided images), the diagnostic moment of Cushing’s syndrome prior the initiation of Sunitinib (middle images) and 3 months after treatment with Sunitinib (right- sided images)
References
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S.A. Wells, F.M. Balis, Vandetanib in children and adolescents with multiple endocrine neoplasia type 2B associated medullary thyroid carcinoma. Clin. Cancer Res. 19, 4239-4248 (2013)
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Complete resolution of hypercortisolism with sorafenib in a patient with advanced medullary thyroid carcinoma and ectopic ACTH syndrome. Thyroid (2014). doi:10.1089/thy.2013.0571