What is the recommended treatment for Cushing's disease?

Management of Cushing's Disease

Selective transsphenoidal adenomectomy performed by an experienced pituitary surgeon is the first-line treatment for Cushing's disease. 1

First-Line Treatment

• Surgical removal of the ACTH-secreting pituitary adenoma while preserving normal pituitary tissue is the optimal initial therapy for Cushing's disease 1, 2
• Surgery should be performed by a surgeon specializing in pituitary procedures, as surgeon experience significantly impacts success rates 1
• Early post-operative remission correlates with successful adenoma identification during surgery, while long-term remission is associated with younger age, smaller adenoma size, and absence of cavernous sinus or dural invasion 1

Management of Persistent or Recurrent Disease

Second-Line Options:

1. Repeat Transsphenoidal Surgery

   • Indicated for patients with persistent or recurrent disease, especially when tumor is visible on MRI 1
   • Can achieve early biochemical remission rates of up to 93% in pediatric patients 1, 3

2. Radiotherapy

   • Recommended for recurrent disease not amenable to curative surgery 1, 4
   • Options include:
     • Stereotactic radiotherapy
     • Fractionated proton beam therapy
     • Gamma knife radiosurgery 1, 5
   • Highly conformal radiotherapeutic techniques should be used according to availability 5
   • For children and adolescents, the total radiation dose recommendation is usually 45-50.4 Gy, 1.8 Gy per fraction 5
   • Note: Radiation effects are not immediate; medical therapy is typically needed while awaiting radiotherapy effects 4, 6

3. Medical Therapy

   • Used to reduce cortisol burden while awaiting definitive treatment or as adjunctive therapy 1, 7
   • Steroidogenesis inhibitors are the agents of choice:
     • Ketoconazole: Best tolerated and effective as monotherapy in about 70% of patients 7, 8
     • Metyrapone: Effective but may cause hirsutism and hypenandrogenism 3, 7
     • Mitotane: Effective as single agent but has more side effects 7
     • Pasireotide (Signifor LAR): FDA-approved for Cushing's disease at an initial dose of 10 mg intramuscularly every 4 weeks, with possible increase to maximum 40 mg 9

4. Bilateral Adrenalectomy

   • Considered for patients with severe refractory Cushing's disease or life-threatening emergencies 3
   • Provides permanent cure of hypercortisolism but results in unavoidable chronic adrenal insufficiency 6
   • Risk of developing Nelson syndrome (pituitary tumor growth, increased ACTH, hyperpigmentation) if not accompanied by pituitary radiation 4

Monitoring and Follow-up

• Lifelong follow-up is essential as recurrence can occur up to 15 years after apparent surgical cure 1, 3
• Monitor for development of hypopituitarism following surgery or radiotherapy 1, 4
• Evaluate for growth hormone deficiency 3-6 months postoperatively in patients who have not completed linear growth 1
• When using medical therapy, assess efficacy through urinary free cortisol, salivary cortisol, and clinical symptoms 3
• Consider changing treatment if cortisol levels remain elevated after 2-3 months with maximum tolerated doses 3

Important Clinical Considerations

• Before initiating medical therapy with pasireotide, baseline evaluations should include fasting plasma glucose, HbA1c, liver tests, ECG, serum potassium, and serum magnesium levels 9
• Patients with moderately impaired hepatic function (Child-Pugh B) should receive reduced doses of pasireotide, and it should be avoided in severe hepatic impairment 9
• Bilateral inferior petrosal sinus sampling may help lateralize pituitary ACTH secretion when no lesion is visible on MRI 1
• The choice between second-line treatments should consider patient-specific factors including comorbidities, medication side effect profiles, and patient preferences 6, 2