Treatment of Cushing's Disease

Introduction to Treatment Options

• The Endocrine Society recommends stereotactic radiosurgery (SRS) as a treatment option for persistent or recurrent Cushing's disease, achieving biochemical control in 80% of patients, with conventional radiation therapy typically delivering 45-50 Gy in fractions of less than 2 Gy 1
• Bilateral adrenalectomy may be considered as a last resort for patients with Cushing's disease, particularly those with bilateral adrenal hyperplasia 1
• The American College of Endocrinology suggests that transsphenoidal surgery (TSS) is the first-line treatment for Cushing's disease, with remission rates of 65-90% for microadenomas and 50-65% for macroadenomas 1, 2

Medical Therapy

• Medical therapy is indicated for patients with Cushing's disease when surgery is contraindicated or delayed, or in cases of persistent or recurrent disease after surgery, and may improve metabolic, cardiovascular, and coagulation parameters 1
• The Endocrine Society recommends medical therapy with steroidogenesis inhibitors such as ketoconazole (400-1200mg/day), metyrapone (1-4.5g/day), and osilodrostat for patients who are not candidates for surgery or have persistent/recurrent disease, with pituitary-directed therapy with pasireotide and cabergoline used in combination with steroidogenesis inhibitors 1
• The American College of Endocrinology suggests that medical therapy may be considered for patients with severe disease and life-threatening complications, and requires lifelong monitoring for potential side effects 1

Radiation Therapy

• SRS achieves biochemical control in 80% of patients, and conventional RT typically delivers 45-50 Gy in fractions of less than 2 Gy, with a recommended spacing of at least 3-5 mm between tumor and optic chiasm, and chiasm dose less than 8 Gy 1
• Adjuvant medical therapy is required during the latency period until radiation therapy takes effect, and results in immediate control of cortisol excess 1

Surgical Therapy

• Laparoscopic unilateral adrenalectomy is the recommended treatment for adrenal adenoma, with postoperative glucocorticoid replacement until HPA axis recovery, and open adrenalectomy is recommended for suspected malignancy, as recommended by the National Comprehensive Cancer Network and the American College of Endocrinology 2, 3
• Surgical resection of the tumor is the recommended treatment for localized ectopic ACTH-secreting tumors, with adrenostatic agents, such as ketoconazole and mitotane, used to control cortisol production in cases where surgery is not possible, as noted by the Endocrine Society and the National Comprehensive Cancer Network 4, 2, 1

Diagnostic Evaluation

• The following tests are recommended for evaluating adrenal function:

• The Endocrine Society recommends using liquid chromatography-tandem mass spectrometry (LC-MS/MS) instead of immunoassays for cortisol measurement, especially when patients are taking medications like metyrapone, osilodrostat, or mitotane that increase 11-deoxycortisol levels 1
• Urine volume and glomerular filtration rate strongly predict 24-hour urinary free cortisol (UFC) levels, and patients should avoid strenuous physical activity for at least 24 hours, ideally 48 hours, before and during a 24-hour urinary free cortisol test to ensure accurate results 1, 5
• Multiple late-night salivary cortisol (LNSC) collections (≥2) on consecutive days improve diagnostic accuracy 1

Post-Treatment Monitoring

• Lifelong monitoring is required for pituitary hormone deficiencies, which occur in 25-50% of patients, and for tumor recurrence after radiation therapy 1
• After bilateral adrenalectomy, monitoring of plasma ACTH and pituitary imaging is recommended starting 6 months post-surgery, due to the risk of Nelson's syndrome (25-40% after 5-10 years) 1
• The Endocrine Society guidelines recommend using any of three tests to rule out exogenous glucocorticoid use before biochemical testing, and refer to endocrinology for further evaluation and management in patients with symptoms such as unexplained weight gain, hypertension, and glucose intolerance 6, 1
• Annual clinical screening is essential for patients with MACS not managed surgically to monitor for new or worsening comorbidities, such as type 2 diabetes mellitus, hypertension, osteoporosis, fractures, dyslipidemia, and proximal myopathy, as recommended by the American College of Endocrinology and the Endocrine Society 3, 1

Special Considerations

• In children with Cushing's syndrome, surgical resection is the first-line treatment, and thromboprophylaxis should be reserved for selected cases due to bleeding risk, with Cushing's disease accounting for 75-80% of pediatric cases in children over age 6, and adrenal causes more common in younger children, as noted by the National Institute of Child Health and Human Development and the Endocrine Society 7, 1
• Preoperative medical therapy may be considered in severe cases with life-threatening complications or when surgery is delayed, and estrogen therapy or pregnancy can increase CBG levels and potentially lead to false positives in DST results, as recommended by the Endocrine Society 1

Complications and Follow-up

• Adrenal insufficiency is the most common complication after successful treatment, requiring careful glucocorticoid replacement and patient education, with hydrocortisone (15-25 mg daily in divided doses) being a common replacement therapy, as recommended by the Endocrine Society and the National Comprehensive Cancer Network 8, 2
• Recurrence can occur years after initial remission, requiring lifelong monitoring, and the National Comprehensive Cancer Network and the Endocrine Society recommend follow-up imaging and biomarkers every 3-6 months for functioning tumors, and annual clinical screening for patients not managed surgically, with at least 2-3 24-hour urine samples collected for UFC measurement to confirm the diagnosis of Cushing's syndrome, as recommended by the Endocrine Society 1, 2
• Nelson's syndrome is a potential complication after bilateral adrenalectomy, with progressive pituitary tumor growth and increased ACTH levels, and drug interactions and thromboembolic risk should be monitored in patients with Cushing's syndrome, as noted by the Endocrine Society 1