What are the treatment options for Cushing's disease?

Treatment for Cushing's Disease

The first-line treatment for Cushing's disease is selective transsphenoidal adenomectomy performed by an experienced pituitary surgeon, with the goal of removing the ACTH-secreting adenoma while preserving normal pituitary tissue. 1, 2

Treatment Algorithm

First-Line Treatment

• Selective transsphenoidal surgery is the primary treatment option for Cushing's disease, with remission rates ranging from 50-90% when performed by experienced surgeons 1, 2
• Surgeon experience is a significant predictor of success, making referral to a center with expertise in pituitary surgery essential 1
• Early post-operative remission is associated with successful identification of the adenoma during surgery, while factors favoring long-term remission include younger age, smaller adenoma size, and absence of cavernous sinus invasion 1

Second-Line Options for Persistent or Recurrent Disease

• Repeat transsphenoidal surgery may be considered for patients with persistent or recurrent disease, especially when tumor is visible on MRI, with remission rates up to 93% reported in some patient populations 1, 2
• Radiotherapy options include:
  • Stereotactic radiotherapy
  • Fractionated proton beam therapy
  • Gamma knife radiosurgery
  • These are indicated for recurrent disease not amenable to curative surgery 1, 2
• Medical therapy options include:
  • Adrenal steroidogenesis inhibitors (metyrapone, ketoconazole) to reduce cortisol burden while awaiting definitive treatment 1, 2
  • Pasireotide (SIGNIFOR LAR) at an initial dose of 10 mg intramuscularly every 28 days, which can be increased up to 40 mg if needed after 4 months of treatment 3
• Bilateral adrenalectomy may be considered for patients with severe refractory disease or life-threatening emergencies 2

Special Considerations

Bone Health Management

• Skeletal fragility is a frequent and early complication of hypercortisolism, with vertebral fractures occurring in 30-50% of patients 4
• Bisphosphonates should be initiated for patients with decreased bone mineral density, even if BMD is in the normal range, due to the increased fracture risk 4
• Calcium and vitamin D supplementation should be provided as supportive treatment 4

Monitoring During Treatment

• Evaluate treatment efficacy through measurement of:
  • Urinary free cortisol
  • Salivary cortisol levels
  • Clinical symptom improvement 2
• Consider changing treatment if cortisol levels remain elevated after 2-3 months with maximum tolerated doses 2

Long-term Follow-up

• Lifelong follow-up is essential as recurrence can occur up to 15 years after apparent surgical cure 1, 2, 4
• Monitor for development of hypopituitarism following surgery or radiotherapy 1
• In pediatric patients who have not completed linear growth, evaluate for growth hormone deficiency 3-6 months postoperatively 1, 4

Medication Considerations

Pasireotide (SIGNIFOR LAR)

• FDA-approved for Cushing's disease when pituitary surgery is not an option or has not been curative 3
• Requires baseline evaluations before initiation:
  • Fasting plasma glucose and HbA1c
  • Liver tests
  • ECG, serum potassium and magnesium levels 3
• Patients with poorly controlled diabetes should have anti-diabetic therapy optimized prior to starting pasireotide 3

Common Side Effects of Medical Therapies

• Metyrapone: hirsutism, dizziness, arthralgia, fatigue, hypokalemia, nausea, and possible hyperandrogenism 2
• Ketoconazole: hepatotoxicity, gastrointestinal disorders, and adrenal insufficiency 2

Pitfalls and Caveats

• Surgery success rates vary significantly based on surgeon experience, making referral to specialized centers crucial 1
• Fractures may occur even in patients with BMD in the normal or osteopenic range, necessitating comprehensive bone health assessment 4
• Medical therapy should be considered temporary while awaiting definitive treatment with surgery or radiotherapy in most cases 1, 2
• Bilateral inferior petrosal sinus sampling (BIPSS) may help lateralize pituitary ACTH secretion when no lesion is visible on MRI, with predictive value for lateralization of 75-80% 1