Efficiency and tolerance of mitotane in Cushing's disease in 76 patients from a single center.

CONTEXT Alternatives to transsphenoidal pituitary surgery may be required in Cushing's disease (CD) as a first- or second-line treatment. Mitotane is a potent anti-cortisolic drug but has been rarely investigated in the treatment of CD. OBJECTIVE Evaluation of the efficacy and tolerance of mitotane in CD patients. DESIGN AND SETTING Retrospective analysis of 76 patients treated with mitotane from 219 patients diagnosed with CD between 1993 and 2009 in a single center. MAIN OUTCOME MEASURE Remission was defined as normalization of 24-h urinary free cortisol (24-h-UFC). RESULTS Remission was achieved in 48 (72%) of the 67 long-term treated patients, after a median time of 6.7 (5.2-8.2) months. Mean plasma mitotane concentration at the time of remission was 10.5 ± 8.9 mg/l, with a mean daily dose of 2.6 ± 1.1 g. A negative linear relationship was observed between plasma mitotane concentration and 24-h-UFC (P<0.0001). Seventeen of 24 (71%) patients with durable remission subsequently experienced recurrence, after a median time of 13.2 (5.0-67.9) months. At the time of treatment discontinuation, ACTH concentration was statistically associated with a lower recurrence probability (hazard ratios 0.57 (0.32-1.00), P=0.05). Intolerance leading to treatment discontinuation occurred in 19 patients (29%). A pituitary adenoma became identifiable during mitotane treatment in 12 (25%) of the 48 patients with initial negative pituitary imaging allowing subsequent transsphenoidal surgery. CONCLUSION Mitotane is useful at different stages of CD. Mitotane dose adjustment based on plasma concentration monitoring and side effects could control hypercortisolism in the majority of CD patients.

[1]  X. Bertagna,et al.  Midnight salivary cortisol for the initial diagnosis of Cushing's syndrome of various causes. , 2004, The Journal of clinical endocrinology and metabolism.

[2]  D. Warren,et al.  Determination of mitotane (o,p-DDD) and its metabolites o,p-DDA and o,p-DDE in plasma by high-performance liquid chromatography. , 1999, Therapeutic drug monitoring.

[3]  P. Cappabianca,et al.  The medical treatment of Cushing's disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. , 2009, The Journal of clinical endocrinology and metabolism.

[4]  R. N. Dexter,et al.  Treatment of Cushing's disease. Correction of hypercortisolism by o,p'DDD without induction of aldosterone deficiency. , 1969, The New England journal of medicine.

[5]  Y. Wang,et al.  Treatment of pituitary-dependent Cushing's disease with the multireceptor ligand somatostatin analog pasireotide (SOM230): a multicenter, phase II trial. , 2009, The Journal of clinical endocrinology and metabolism.

[6]  H. Slooten,et al.  O,p′-DDD (Mitotane) levels in plasma and tissues during chemotherapy and at autopsy , 2004, Cancer Chemotherapy and Pharmacology.

[7]  H. Slooten,et al.  Blood levels of o,p′-DDD following administration in various vehicles after a single dose and during long-term treatment , 2004, Cancer Chemotherapy and Pharmacology.

[8]  J. Ware,et al.  Random-effects models for longitudinal data. , 1982, Biometrics.

[9]  E. Baudin,et al.  Impact of monitoring plasma 1,1‐dichlorodiphenildichloroethane (o,p′DDD) levels on the treatment of patients with adrenocortical carcinoma , 2001, Cancer.

[10]  D. Schteingart,et al.  Sustained remission of Cushing's disease with mitotane and pituitary irradiation. , 1980, Annals of internal medicine.

[11]  W. Rohde,et al.  [The long-term therapy of hypothalamic-hypophyseal Cushing's syndrome with mitotane (o,p'-DDD)]. , 2008, Deutsche medizinische Wochenschrift.

[12]  L. Dogliotti,et al.  Low-dose monitored mitotane treatment achieves the therapeutic range with manageable side effects in patients with adrenocortical cancer. , 2000, The Journal of clinical endocrinology and metabolism.

[13]  A. Grossman,et al.  Short and long‐term responses to metyrapone in the medical management of 91 patients with Cushing's syndrome , 1991, Clinical endocrinology.

[14]  I. Morange,et al.  Ketoconazole revisited: a preoperative or postoperative treatment in Cushing's disease. , 2008, European journal of endocrinology.

[15]  J. Romijn,et al.  Pasireotide alone or with cabergoline and ketoconazole in Cushing's disease. , 2010, The New England journal of medicine.

[16]  L. Vilar,et al.  Effectiveness of cabergoline in monotherapy and combined with ketoconazole in the management of Cushing’s disease , 2010, Pituitary.

[17]  E. Baudin,et al.  Rapidly progressing high o,p'DDD doses shorten the time required to reach the therapeutic threshold with an acceptable tolerance: preliminary results , 2006, Clinical endocrinology.

[18]  R. N. Dexter,et al.  [Treatment of Cushing's disease]. , 1969 .

[19]  E. Laws,et al.  OUTCOMES AFTER REPEAT TRANSSPHENOIDAL SURGERY FOR RECURRENT CUSHING'S DISEASE , 2008, Neurosurgery.

[20]  L. Dogliotti,et al.  Prospective evaluation of mitotane toxicity in adrenocortical cancer patients treated adjuvantly. , 2008, Endocrine-related cancer.

[21]  T. Fahey.  Adjuvant Mitotane Treatment for Adrenocortical Carcinoma , 2008 .

[22]  D. McCance,et al.  Long‐term remission rates after pituitary surgery for Cushing's disease: the need for long‐term surveillance , 2005, Clinical endocrinology.

[23]  W. Ludlam.  Repeated transsphenoidal pituitary surgery (TS) via the endoscopic technique: a good therapeutic option for recurrent or persistent Cushing's disease (CD) , 2009 .

[24]  E. Wallace,et al.  Cushing's syndrome due to adrenocortical hyperplasia. Treatment with an inhibitor of adrenocortical secretions. , 1961, The New England journal of medicine.

[25]  H. V. van Slooten,et al.  The treatment of adrenocortical carcinoma with o,p'-DDD: prognostic implications of serum level monitoring. , 1984, European journal of cancer & clinical oncology.

[26]  J. Bertherat,et al.  Corticotroph tumor progression after adrenalectomy in Cushing's Disease: A reappraisal of Nelson's Syndrome. , 2007, The Journal of clinical endocrinology and metabolism.

[27]  M. Laudat,et al.  Treatment of Cushing's disease by O,p'DDD. Survey of 62 cases. , 1979, The New England journal of medicine.

[28]  R. A. Zeeuw,et al.  Plasma level monitoring of mitotane (o,p'-DDD) and its metabolite (o,p'-DDE) during long-term treatment of cushing's disease with low doses , 2004, European Journal of Clinical Pharmacology.

[29]  W. Ludlam.  Late Recurrences of Cushing's Disease after Initial Successful Transsphenoidal Surgery , 2008 .

[30]  D. Schteingart.  Midnight Salivary Cortisol Determination for Assessing the Outcome of Transsphenoidal Surgery in Cushing's Disease , 2009 .

[31]  R. Pivonello.  Medical therapy of Cushing's disease , 2008 .

[32]  G. Fleuren,et al.  Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients. , 1994, British Journal of Cancer.

[33]  V. Montori,et al.  The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. , 2008, The Journal of clinical endocrinology and metabolism.

[34]  G. Gordon,et al.  Remission in Cushing's syndrome with o,p'-DDD. , 1966, The Journal of clinical endocrinology and metabolism.

[35]  I. Gich,et al.  A reappraisal of the medical therapy with steroidogenesis inhibitors in Cushing's syndrome , 2012, Clinical endocrinology.

[36]  N. Patronas,et al.  Pituitary Magnetic Resonance Imaging in Normal Human Volunteers: Occult Adenomas in the General Population , 1994, Annals of Internal Medicine.

[37]  J. Stockman.  A 12-Month Phase 3 Study of Pasireotide in Cushing's Disease , 2013 .

[38]  T. Fojo,et al.  Management of endocrine manifestations and the use of mitotane as a chemotherapeutic agent for adrenocortical carcinoma. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[39]  P Blondeau,et al.  Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. , 1990, The New England journal of medicine.

[40]  G. Thompson,et al.  Possible mechanism and treatment of o,p'DDD-induced hypercholesterolaemia. , 1992, The Quarterly journal of medicine.

[41]  D. Schteingart.  Patients with Cushing's syndrome are care-intensive even in the era of laparoscopic adrenalectomy , 2010 .

[42]  P. Chanson,et al.  Long-term results of stereotactic radiosurgery in secretory pituitary adenomas. , 2009, The Journal of clinical endocrinology and metabolism.

[43]  P. Chanson,et al.  Mitotane, metyrapone, and ketoconazole combination therapy as an alternative to rescue adrenalectomy for severe ACTH-dependent Cushing's syndrome. , 2011, The Journal of clinical endocrinology and metabolism.

[44]  R. Pariente,et al.  Cushing's Syndrome , 1944, Definitions.

[45]  J. Bertherat,et al.  Management of Cushing's syndrome due to ectopic adrenocorticotropin secretion with 1,ortho-1, para'-dichloro-diphenyl-dichloro-ethane: findings in 23 patients from a single center. , 2010, The Journal of clinical endocrinology and metabolism.

[46]  W. Ludlam.  Treatment of Adrenocorticotropin-Dependent Cushing's Syndrome: A Consensus Statement , 2008 .