Lack of response to octreotide in Cushing’s syndrome due to metastatic adrenocortical carcinoma a
NN Chan , A J Isaacs
Postgraduate Medical Journal, Volume 75, Issue 880, February 1999, Pages 96-98,
https://doi.org/10.1136/pgmj.75.880.96
Published: 01 February 1999 Article history
Summary
Functional metastatic adrenocortical carcinoma is an uncommon cause of Cushing’s syndrome, which rarely responds to conventional treatment. A patient presenting with Cushing’s syndrome secondary to adrenocortical carcinoma underwent surgical resection. Post-operatively, she developed metastatic disease resistant to conventional chemotherapy. Octreotide, a somatostatin analogue which is effective in the treatment of several types of neuroendocrine tumour, was tried to ameliorate her secretory symptoms, but without any therapeutic effect.
Keywords: adrenocortical carcinoma, Cushing’s syndrome, octreotide
Issue Section: Short report
Gift article access
As a benefit of your subscription, you can share temporary access to restricted articles.
Adrenocortical carcinoma is a highly malignant tumour which is usually diagnosed late in its course. In some cases, the tumours are functional leading to Cushing’s syndrome and other endocrine manifestations. There is no effective cure in this condition and the prognosis is very poor. Octreotide has recently been reported as effective in controlling the secretory symptoms in a single case with only short-term follow-up.1 We describe a patient with Cushing’s syndrome due to metastatic adrenocortical carcinoma whose secretory symptoms were not improved with somatostatin analogue therapy.
Case report
A 42-year-old woman presented in July 1996 with rapid onset of weight gain, facial fullness, easy bruising and proximal myopathy. Examination revealed floridly Cushingoid features, with no signs of virilization. Her blood pressure was 160/98 mmHg; 09.00 h cortisol was 848 (normal range 200-700) nmol/l with loss of diurnal variation and urinary free cortisol (UFC) was 2930 (normal range 0-340) nmol/1/24 h. High- dose dexamethasone failed to suppress both plasma and UFC. Adrenocorticotropin (ACTH) was undetectable. Serum testosterone was 0.7 (normal range 0-3) nmol/l. Magnetic resonance imaging (MRI) scan confirmed a 6 x 4 cm right-sided adrenal mass (figure 1). Metyrapone 250 mg tid was commenced and the patient subsequently underwent a right adrenalectomy. Histology confirmed adrenocortical carcinoma. Postoperatively, her UFC fell to 106 nmol/l/24 h. However, her Cushingoid symptoms worsened 2 weeks later with raised UFC. Computed tomography (CT) showed intrapulmonary metastases without evidence of intra-abdominal local recurrence. Despite being given six cycles of chemotherapy with cisplatin, 5-fluorouracil, epirubicin and increasing doses of metyrapone, the patient’s symptoms failed to improve, her UFC level remained markedly elevated and there was CT evidence of progression of pulmonary metastases.
SC8 TSE/M SL10
H
10 cm
AP 18 post
Octreotide therapy was subsequently commenced at a dose of 50 µg subcutaneously bid and gradually increased to 300 µg tid but without symptomatic relief and UFC excretion continued to rise (figure 2). Octreotide therapy was discontinued one month after initiation as the patient felt unwell with symptoms of bloating and abdominal pain. Metyrapone was increased to 750 mg qid and aminoglutethimide 250 mg tid was subsequently added, followed by a course of mitotane. These treatments failed to achieve any
clinical or biochemical benefit. The patient developed skeletal metastases and UFC increased further eventually reaching 16450 nmol/l prior to her death 16 months after diagnosis.
17 000
10 000
Mitotane
9000
OCTREOTIDE
Urinary free cortisol (mmol/1/24 h)
8000
CHEMOTHERAPY
7000
6000
5000
Surgery
4000
3000
2000
1000
0
Jul
Aug
Sep
Oct
ct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct No
1996
1997
Months
Discussion
Adrenocortical carcinoma is a rare cause of Cushing’s syndrome. Metastasis occurs in more than half of these patients at diagnosis- and the rate of surgical cure is low3 with a median survival of 6 months in patients with metastatic disease.4 Regular monitoring of UFC is important to detect early recurrence, enabling prompt initiation of chemotherapy to improve survival. Mitotane therapy has been reported to improve survival in patients with metastatic disease following surgical resection,4 but only when high
serum levels are achieved.” Efficacy has been claimed for other agents, but usually on the basis of single case studies and negative results tend to go unreported.
Learning points
· functional adrenal cortical carcinoma is a rare cause of Cushing’s syndrome which produces disabling secretory symptoms
· most cases present late with evidence of metastasis and hence prognosis is poor
· early detection with surgical resection is the most effective treatment
· mitotane therapy has limited success in metastatic disease following surgical resection
· the role of octreotide therapy in symptom relief has not been established
Somatostatin therapy has been shown to be effective in several neuroendocrine tumours including acromegaly, thyrotropin-secreting adenomas, pancreatic and gastrointestinal endocrine tumours,” and functional carcinoid tumours. It has also been shown to inhibit pathological ACTH secretion in Nelson’s syndrome and ectopic ACTH-producing tumours but to be ineffective in ACTH-dependent Cushing’s disease.1 Furthermore, there is no clear rationale for its use in ACTH-independent Cushing’s syndrome and despite one favourable report, its efficacy in metastatic adrenocortical carcinoma has not been established. Somatostatin analogue therapy is expensive and is not without side-effects including gastrointestinal disturbances, hyperglycaemia and gall stone formation (on long-term use).
We conclude that a trial of octreotide, if justified at all, should be reserved for patients with functional metastatic adrenocortical carcinoma who have failed to respond to, or are intolerant of, conventional
adrenal blocking agents and cytotoxic chemotherapy. Close monitoring is mandatory with prompt discontinuation of therapy in the absence of clinical and biochemical improvement.
Acknowledgements
We thank Dr C A Foster for referring the patient and Drs R H Phillips and D H Cove for help in her management.
References
1 Pandha HS, Harrington K, Saini S, Lynn J, Peters M, Waxman J (1995) Secretory symptoms from metastatic adrenal cortical carcinoma responding to octreotide. Postgrad Med J 71:229-230. Google Scholar ☐ ☐ PubMed ☐ WorldCat Crossref
2 Didolkar MS, Bescher RA, Elias EG, Moore RH (1981) Natural history of adrenal cortical carcinoma: a clinicopathological study of 42 patients. Cancer 47:2153-2161. Google Scholar ☐ Crossref ☐ PubMed ☐ WorldCat
3 Lipsett MB, Hertz R, Ross GT (1963) Clinical and pathophysiologic aspects of adrenocortical carcinoma. Am J Med 35:374-383.
Google Scholar ☐ Crossref ☐ PubMed ☐ WorldCat
4 Icard P, Chapuis Y, Andresian B, Bernard A, Proy C (1992) Adrenocortical carcinoma in surgically treated patients: a retrospective study on 156 cases by the French Association of Endocrine Surgery. Surgery 112:972-979.
Google Scholar PubMed
☐ WorldCat
5 Haak HR, Hermans J, van de Velde CJ, et al. (1994) Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients. Br J Cancer 69:947-951. Google Scholar ☐ Crossref ☐ PubMed ☐ WorldCat
6 Lamberts SWJ, Uitterlinden P, del Pozo E (1985) Long-term treatment of acromegaly with the somatostatin analog SMS201-995. N Engl J Med 313:1576-1580. Google Scholar ☐ Crossref ☐ PubMed ☐ WorldCat
7 Chanson P, Weintraub BD, Harris AG (1993) Octreotide therapy for thyroid-stimulating hormone-secreting pituitary adenomas: a follow-up of 52 patients. Ann Intern Med 119:236-240. Google Scholar ☐ Crossref ☐ PubMed ☐ WorldCat
8 Wood SM, Kraenzlin ME, Adrian TE, Bloom SR (1985) Treatment of patients with pancreatic endocrine tumours using a new long-acting somatostatin analogue symptomatic and peptide responses. Gut 26:438-444. Google Scholar ☐ Crossref ☐ PubMed ☐ WorldCat
9 Harris AG, Redfern JS (1995) Octreotide treatment of carcinoid syndrome: analysis of published dose-titration data. Aliment Pharmacol Ther 9:387-394. Google Scholar ☐ Crossref ☐ PubMed ☐ WorldCat
10 De Herder WW, Lamberts SW (1996) Is there a role for somatostatin and its analogs in Cushing’s syndrome? Metab Clin Exp 45 (suppl 1) 83-85. Google Scholar ☐ PubMed ☐ WorldCat
@ The Fellowship of Postgraduate Medicine, 1999
This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/pages/standard-publication-reuse-rights)