Mitotane (op’DDD) restores growth and puberty in nine children with Cushing’s disease

Abstract

To investigate whether low-dose mitotane (up to 2 g/day) could be a temporary therapeutic alternative to transsphenoidal surgery (TSS) in pediatric Cushing’s disease (CD). Twenty-eight patients with CD aged 12.2 years (± 2.2) were referred to our center. We compared nine patients treated with mitotane alone for at least 6 months to 13 patients cured after surgery. Primary outcomes were changes in growth velocity, BMI and pubertal development. The following results were obtained: (1) Mitotane improved growth velocity z-scores (−3.8 (±0.3) vs −0.2 (±0.6)), BMI z-scores (2.1 (±0.5) vs 1.2 (±0.5) s.d.) and pubertal development. After 1 year on mitotane, the mean BMI z-score was not significantly different in both groups of patients. (2) Control of cortisol secretion was delayed and inconsistent with mitotane used as monotherapy. (3) Side effects were similar to those previously reported, reversible and dose dependent: unspecific digestive symptoms, concentration or memory problems, physical exhaustion, adrenal insufficiency and hepatitis. (4) In one patient, progressive growth of a pituitary adenoma was observed over 40 months of mitotane treatment, allowing selective adenomectomy by TSS. In conclusions, low-dose mitotane can restore growth velocity and pubertal development and decrease BMI in children with CD, even without optimal control of cortisol secretion. It may promote pituitary tumor growth thus facilitating second-line TSS. However, given its possibly life-threatening side effects (transient adrenal insufficiency and hepatitis), and in the absence of any reliable follow-up procedures, this therapy may be difficult to manage and should always be initiated and monitored by specialized teams.

Paediatric Cushing’s disease: Epidemiology, pathogenesis, clinical management and outcome

“…The main indications for ketoconazole are when awaiting TSS, after unsuccessful TSS, and during the period after RT and before normalisation of cortisol. A recent French report described treatment of 9 paediatric CD patients with ‘low-dose’ mitotane (titrated from 1 g/day to normalise UFC levels) [ 90 ]. After 12 months of therapy, height velocity and BMI SD scores improved significantly with changes comparable to those seen in 13 matched subjects in remission following TSS.…”

“…Mitotane improved some features of CD but without perfect control of hypercortisolism. The adverse effects included digestive symptoms, weakness and AI, which were dose-dependent, making this therapy largely inappropriate for long-term therapy in children [ 90 ]. Monitoring of cortisol levels is also problematic.…”

EDP-mitotane in children: reassuring evidence of reversible side-effects and neurotoxicity

“…We identified an additional 14 case reports and case series describing side-effects and neurotoxicity in 94 children with ACC or Cushing treated with EDP and/or mitotane (Table 1 ). Gastro-intestinal side-effects including nausea, vomiting, anorexia, requirement of a nasopharyngeal tube, diarrhea and abdominal pain were reported in nine studies [ 20 , 22 – 28 ]. These side-effects were completely reversible after dose reduction or cessation of mitotane.…”

“…The effect of endocrine activity of ACC itself also has an important effect on growth and development, especially the negative effects of cortisol production and the effects of sex hormones on pubertal development. However, it is generally observed that hormone levels return to normal after initial resection and adjuvant treatment [ 28 , 29 ].…”

Efficacy and safety of pasireotide for Cushing's disease

“…Ketoconazole, metyrapone and mitotane are the most commonly used medical therapies, and target the adrenal glands. [ 13 – 15 ] These drugs do not treat the underlying cause of the disease and restore normal function of the hypothalamo-pituitary-adrenal axis. [ 16 , 17 ]…”