Low-dose Use of Chemotherapy, Lysodren, May Treat Children Ineligible for Surgery, Study Reports

Low-dose Lysodren (mitotane) can help restore growth rates and pubertal development, and lower body mass index (BMI) in children with Cushing’s disease who are not eligible for pituitary surgery. But side effects can be serious and need to be monitored closely, a study reports.

The study, “Mitotane (op’DDD) restores growth and puberty in nine children with Cushing’s disease,” was published in the journal Endocrine Connections.

Cushing’s disease is generally caused by a tumor in the pituitary gland known as a pituitary adenoma. Patients show high levels of cortisol, which can significant a child’s growth and puberty.

While a diagnosis of Cushing’s disease is easy to make once suspected, treating the disease remains a challenge.

The gold standard for treating pediatric and adult patients is transnasal transsphenoidal surgery (TSS) — a minimally invasive procedure in which a surgeon goes through the nose to remove the pituitary adenoma — with selective microadenomectomy, or removal of the adrenal gland. But between 25% and 50% of all patients can either not undergo this surgery or are not helped by it.

Lysodren, an oral chemotherapy, has a direct toxic effect on the zona reticularis — the innermost layer of the adrenal cortex, which is responsible for producing cortisol.

It is used in adults with inoperable adrenocortical cancer. And studies have shown that Lysodren, at lower concentrations, reduces cortisol levels.

Still, Lysodren is rarely used to treat Cushing’s, and then almost exclusively in adults. Although mentioned in scientific/medical publications as an adjuvant (add-on) therapy for this disease in children, its efficacy and safety in these patients have not been reported to date.

Researchers in France set out to investigate whether low-dose Lysodren (up to 2 g per day) can serve as a temporary therapeutic alternative to TSS in cases of pediatric Cushing’s disease.

They compared outcomes in nine patients treated with Lysodren alone for at least six months to 13 others who underwent TSS at a clinic between 1978 and 2014. All were of similar age, BMI, growth expectations, and had similar nighttime cortisol blood levels. The primary measures used were changes in growth rate, body mass index (BMI), and pubertal development.

Results indicated that Lysodren use improved all three outcomes: growth rate, BMI, and pubertal development. After one year of treatment, the average BMI of patients was not significantly different those treated with surgery.

But they found that control of cortisol levels via secretion was slow and inconsistent when Lysodren was used as monotherapy.

Side effects were also notable — if similar to those reported in other uses of this chemotherapy — and included digestive symptoms, concentration or memory problems, physical exhaustion, adrenal insufficiency (very low levels of cortisol). The most serious was acute severe hepatitis leading to temporary liver failure in a girl, who eventually needed to be treated with TSS.

Progressive growth of a pituitary adenoma after 40 months of Lysodren treatment was also reported in a boy, again requiring TSS.

Still, low-dose Lysodren was found to restore growth rate, pubertal development, and improve BMI in children with Cushing’s disease, even without full control over cortisol secretion.

“Our observations support the view that side effects are likely to be reversible and dose dependent, we propose that the use of mitotane should be considered in pediatric CD, always in the context of close clinical and biochemical follow-up as well as thorough training of patients and their families,” the researchers concluded.

They also noted that treatment “may promote pituitary tumor growth [and] thus facilitate second-line TSS.”

While Lysodren may be an alternative when TSS is not feasible, “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,” the researchers concluded.