What are the treatment options for Cushing's syndrome?

From the Guidelines

Treatment options for Cushing's syndrome depend on the underlying cause, but generally include surgery, medication, radiation therapy, and bilateral adrenalectomy, with the goal of normalizing cortisol levels while minimizing complications, as recommended by the most recent guideline update 1.

Overview of Treatment Options

• Surgery: transsphenoidal surgery to remove the tumor is the first-line treatment for ACTH-dependent Cushing's syndrome caused by pituitary tumors (Cushing's disease) with success rates of 65-90% 1
• Medication: steroidogenesis inhibitors like ketoconazole (400-1200 mg/day), metyrapone (500-6000 mg/day), or mitotane (2-6 g/day); glucocorticoid receptor antagonists like mifepristone (300-1200 mg/day); and pituitary-directed drugs like pasireotide (600-900 μg twice daily) can be used to control cortisol production 1
• Radiation therapy: may be used when surgery fails or is contraindicated, with options including fractionated proton beam radiotherapy and gamma knife stereotactic radiosurgery 1
• Bilateral adrenalectomy: a last resort that provides immediate control of hypercortisolism but requires lifelong glucocorticoid and mineralocorticoid replacement 1

Selection of Medical Therapy

• Factors to consider when selecting a medical therapy include the need for rapid normalization of cortisol, presence of residual tumor, history of bipolar or impulse control disorder, availability of expert pituitary endocrinologist, pregnancy or desire for pregnancy, drug intolerance or side effects, concomitant comorbidities, and cost and estimated therapy duration 1
• Adrenal steroidogenesis inhibitors like osilodrostat and metyrapone have the fastest action and are orally available, while etomidate can be used intravenously in very severe cases 1
• Pasireotide or cabergoline may be considered in mild disease with residual tumor and potential for tumor shrinkage, but cabergoline should be avoided in patients with a history of bipolar or impulse control disorder 1

Disease-Specific Treatment

• ACTH-dependent Cushing's syndrome caused by pituitary tumors (Cushing's disease): transsphenoidal surgery is the first-line treatment, with medication and radiation therapy as second-line options 1
• Adrenal causes: laparoscopic adrenalectomy is typically performed to remove the tumor or hyperplastic glands 1
• Ectopic ACTH syndrome: treatment focuses on the source tumor, with options including surgery, medication, and radiation therapy 1

From the FDA Drug Label

9 mg by subcutaneous injection twice a day. The recommended initial dose is either 0.6 mg or 0. 9 mg twice a day. Treatment of patients with poorly controlled diabetes mellitus should be intensively optimized with anti-diabetic therapy prior to starting SIGNIFOR Patients should be evaluated for a treatment response [clinically meaningful reduction in 24-hour urinary free cortisol (UFC) levels and/or improvement in signs or symptoms of the disease] and should continue receiving therapy with SIGNIFOR as long as benefit is derived

The treatment options for Cushing's syndrome include pasireotide (PO), which is administered subcutaneously twice a day, with an initial dose of either 0.6 mg or 0.9 mg.

• Key considerations for treatment include:
  • Optimizing anti-diabetic therapy in patients with poorly controlled diabetes mellitus prior to starting pasireotide
  • Evaluating patients for a treatment response, including a reduction in 24-hour urinary free cortisol (UFC) levels and/or improvement in signs or symptoms of the disease
  • Continuing therapy with pasireotide as long as benefit is derived 2

From the Research

Treatment Options for Cushing's Syndrome

• The primary treatment for Cushing's disease is transsphenoidal surgery to remove the ACTH-secreting adenoma 3, 4
• Pituitary radiotherapy and bilateral adrenalectomy are considered second-line therapies for persistent hypercortisolism 5, 6
• Medical therapy plays a key role in controlling cortisol excess, with options including adrenal steroidogenesis inhibitors, pituitary-targeted drugs, and glucocorticoid receptor blockers 5, 6
• Novel medical therapies, such as osilodrostat and levoketoconazole, are being developed and have shown increased efficacy and better tolerability in clinical trials 5
• Combination treatment strategies may also be effective in treating Cushing's disease 5
• Radiation therapy and bilateral adrenalectomy may be considered for patients who do not respond to surgery and medication 6, 7

Surgical Treatment

• Transsphenoidal surgery is considered the treatment of choice for most patients with Cushing's disease 3, 4
• Selective adenomectomy is attempted to preserve pituitary functions, with a remission rate of around 75% expected 5 years after surgery 3
• Recurrences may occur, even in patients who initially remit, and low postoperative serum cortisol levels and long-lasting adrenocortical insufficiency seem to be factors associated with a favorable long-term outcome 3
• Reoperation may be indicated for patients with persistent or recurrent disease, and is most successful in the hands of experienced surgeons and in cases where tumor is visible on MRI 4

Medical Management

• Medical therapy is used to control cortisol excess and achieve long-term remission 5
• Adrenal steroidogenesis inhibitors, such as osilodrostat and levoketoconazole, are used to reduce cortisol production 5
• Pituitary-targeted drugs and glucocorticoid receptor blockers may also be used to control cortisol excess 5, 6
• Combination treatment strategies may be effective in treating Cushing's disease, and emerging data suggests increased efficacy and better tolerability with these novel therapies 5