TREATMENT OF CUSHING S DISEASE

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1 TREATMENT OF CUSHING S DISEASE Surgery, Radiation, Medication Peter J Snyder, MD Professor of Medicine

2 Disclosures Novartis Research grant Pfizer Consultant Ipsen Research grant Cortendo Research grant NovoNordisk Research grant 2

3 PRIMARY TREATMENT -TRANSSPHENOIDAL SURGERY Advantage The only treatment that offers the possibility of curing the disease by removing the cause Disadvantage Corticotroph microadenomas may be hard to find or may invade dura, so surgery may not be successful. Caveat Preoperatively it is imperative to be certain of excessive cortisol secretion, ACTH-dependency of the cortisol excess, and the pituitary as the source of the ACTH. 3

4 TSS REMISSION AND RECURRENCE Initial Remission Rates Microadenomas 87% (Clin Endo 2012; 76: 560) 73% (Eur J Endocrinol 2013; 168: 639) Macroadenomas 64% (Clin Endo 2012; 76: 560) 43% (Eur J Endocrinol 2013; 168: 639) Recurrence Rates Microadenomas 11.7% in 10 y (JCEM 2011; 96: 2057) 11.5% in 3 y (Clin Endocrinol 2002; 56: 25 Macroadenomas 4

5 SECONDARY TREATMENT Repeat Transsphenoidal Surgery Total Bilateral Adrenalectomy Radiation Medication 5

6 SECONDARY TREATMENT Repeat Transsphenoidal Surgery Consider when: Path confirms corticotroph adenoma and MRI shows residual Caveats: Less likely to be successful than first procedure Total Bilateral Adrenalectomy Consider when: Clinical consequences are dire Caveats: Macroadenomas are more likely to be aggressive; Nelson s syndrome a possible consequence Radiation Consider when: Unresectable adenoma, micro or macro Caveats: Normalization of cortisol takes months to years Medication Consider when: Temporizing measure needed Caveats: Long-term use necessary unless used as a temporizing measure 6

7 GAMMA RADIATION FOR CUSHING S DISEASE Average time to remission 13 (2-67) months Average time to relapse 18 months Control of tumor volume in 62/67; no change in 2/67; enlargement in 3 Adverse events: Oculomotor palsy 5; blindness -1; hormonal deficiencies - 20 J Neurosurg 2007; 106:980 7

8 MEDICATIONS TO TREAT CUSHING S DISEASE Adrenal Enzyme Inhibitors Somatostatin Receptor Agonist Glucocorticoid Receptor Blocker 8

9 ADRENAL ENZYME INHIBITORS Ketoconazole, racemic Ketoconazole, nonracemic (experimental) Metyrapone LCI699 (experimental) 9

10 ADRENAL STEROIDOGENESIS INHIBITORS European J Endocrinol 2015; 172: 6 10

11 KETOCONAZOLE FOR CUSHING S DISEASE Retrospective, French multicenter study of 200 patients with Cushing s disease Microadenomas (38%) and macroadenomas (62%) Prior surgery 68% J Clin Endocrinol Metab 2014; 99:

12 KETOCONAZOLE - EFFICACY FOR CUSHING S DISEASE J Clin Endocrinol Metab 2014; 99:

13 KETOCONAZOLE ADVERSE EVENTS Increase in liver enzymes 15.8% Gastrointestinal symptoms 13.1% J Clin Endocrinol Metab 2014; 99:

14 METYRAPONE FOR CUSHING S DISEASE Retrospective multicenter British study of 115 patients with Cushing s disease Microadenomas (70%) and macroadenomas (30%) Age (mean) 47.4 yr Median treatment dose 1375 mg Duration of treatment mean, 8 mo (3d 11.6 yr) J Clin Endocrinol Metab 2015;100:

15 METYRAPONE EFFICACY IN CUSHINGS DISEASE J Clin Endocrinol Metab 2015;100:

16 METYRAPONE ADVERSE EVENTS Gastrointestinal Upset 23% Hypoadrenalism 7% 16

17 PASIREOTIDE Somatostatin receptor agonist Binds to somatostatin receptor subtypes 2, 3 and 5 Administration: subcutaneously twice a day Advantages: Acts on the corticotroph adenoma Dose can be monitored by measurement of 24h urine cortisol Disadvantages Relatively weak most effective in mild hypercortisolism Diabetogenic 17

18 PASIREOTIDE EFFECT ON UFC NEJM 2012: 366, 10 18

19 MIFEPRISTONE Mechanism of Action: Glucocorticoid Receptor Inhibitor Advantages: Rapid onset (days) Reverses the manifestations of glucocorticoid excess (psychiatric symptoms, hyperglycemia, hypertension Disadvantages Does not reduce cortisol production, so measurement of cortisol cannot be used to judge efficacy Hypokalemia Functional cortisol deficiency Endometrial thickening Major Use: Rapid reversal of deleterious effects of cortisol excess while waiting for definitive treatment 19

20 MIFEPRISTONE EFFECT ON HGB A1C JCEM 2012;97:

21 MIFEPRISTONE EFFECT ON HOMA-IR JCEM 2012;97:

22 SECONDARY RX OF CUSHING S DISEASE - SUMMARY Repeat Transsphenoidal Surgery Total Bilateral Adrenalectomy Radiation Medication 22