Therapeutic Objectives Update on the Management of Lewis S. Blevins, Jr., M.D. Correct the syndrome by lowering daily cortisol secretion to normal Eradicate any tumor that might threaten the health of the patient Avoid permanent endocrine deficiency Avoid permanent dependency on medications Treatment of co-morbidities D.N. Orth NEJM 285:243-247,1971. Surgical Results Surgical Results: Macroadenomas FirstAuthor n Cure (%) Recurrence (%)Mean f/u (m) Invitti 288 69 17 Bochicchio 668 76 13 46 Blevins 96 85 16 49 Sonino 103 77 26 72 Mampalam 216 79 5 46 Swearingen 161 85 7 24 Nakane 100 92 9 39 Hammer 289 82 9 131 Author n Cure (%) Recurrence (%) f/u (m) Blevins 21 67 36 62 Swearingen De Tomassi 17 37 65 68 18 12 104 42 1
Suggested Postoperative Approach Assume patients are rendered disease free May check serum cortisol postoperative day 2 Treat most patients with replacement doses of steroids Assess serum cortisol and ACTH levels in 4-6 weeks 36h post last dose of steroids Reasses at 3 month intervals When off steroids asses 24h UFC and diurnal variation Follow accordingly Causes of Surgical Failures Incomplete or failed tumor resection Invasive disease 8% of microadenomas 62% macroadenomas Negative MRI 26% failure vs. 13% Negative histopathology 47% failure vs. 17% Scheithauer et al. J Neurosurg 65:733-744, 1986. Bochicchio et al. JCEM 80:3114-3120,1995. Causes of Surgical Failures Incorrect preoperative diagnosis Syndrome of ectopic ACTH hypersecretion Underreported, 2-5% Ectopic pituitary adenoma Cavernous sinus, suprasellar, stalk adenoma Corticotroph hyperplasia ~4% of pituitary-dependent cases of Cushing s Pseudo-Cushings Factitious Recurrent 2
for residual and recurrent Repeat surgery Radiotherapy Medical therapy Bilateral total adrenalectomy Combination therapy Repeat surgery Author n Cure (%) Recurrence (%) Blevins 9 4 44 (micro) 0 (macro) Friedman 33 73 13 Ram 17 71 25? Swearingen 28 46? Locatelli 12 67? Observations on Repeat Surgery Patients may derive benefit even though not rendered disease free Restoration of normal cortisol levels Resolution of mass effects Alteration of tumor biology Morbidity and mortality are higher Advise repeat surgery when there is a reasonable chance that a subsequent procedure will accomplish clinically important benefits without significant risk. Radiotherapy Stereotactic Radiosurgery Identifiable lesion on MRI Documented intrasellar microadenoma if postoperative MRI is normal Opportunity to treat with low risk of injury to visual pathways Conventional Radiotherapy Widespread inoperable or invasive disease Lesions adjacent to visual pathways Latent risks 3
Conventional Radiotherapy Estrada et al: 83% in remission 6-60 m post-xrt Stereotactic Radiotherapy Sheehan et al: Gamma knife 63% of patients entered remission Mean time to remission 12 m (3-48m) 7% developed recurrent disease (19-38m) 16% developed additional pituitary deficits Devin et al: CPK 49% long-term control Mean time to normalization of UFC was 7.5 m 19% with recurrent hypercortisolism (17-64m) 40% developed pituitary insufficiency J Neurosurg 93:738-742,2000. Stereotact Funct Neurosurg 82:254-262,2004. Stereotactic Radiotherapy Indications for Medical Therapy Delay in surgical intervention of greater than 4-8 weeks During treatment planning and while awaiting the beneficial effects of XRT Vanderbilt Nashville, TN 4
Ketoconazole 38 patients, 5 stopped 1 st week. 200-1200 mg (daily) for 23 months (mean). 45% responders. All controlled patients responded within 3 months. Fleseriu M. Neurosurg Clinics. 2012, in press. Castinetti F. Eur J Endocrinol 2008;158(1):91-99. Mifepristone Mifepristone and DM Glucocorticoid (GC) receptor antagonist at higher doses. binding affinity 3-4X> dex; 10+X > cortisol Anti-glucocorticoid effects at 4 mg/kg 1 mg of dexamethasone effectively competes 400 mg mifepristone in normal subjects Potent anti-progestin activity. FDA approved February 2012: Korlym TM for hyperglycemia associated with Cushing s Syndrome. Doses 300-1200 mg daily. 54 case reports SEISMIC study: 50 pts, 43 CD HbA1c (%) 10 9 8 7 6 5 4 p<0.001 vs baseline p<0.001 vs baseline N=25 N=20 N=22 Baseline Week 16 Week 24/ET Nieman LK. Pituitary. 2002;5(2):77-82, Castinetti,, Eur J Endo 2009, 160 (1003-1010) Fleseriu M et al. J Clin Endocrinol Metab. 2012; Jun;97(6):2039-2049. mean ± SD 5
% Change from baseline 2% 1% 0% -1% -2% -3% -4% -5% -6% Mifepristone and weight D7 D14 D28 W6 W8 W10 W12 W16 W20 W24 /ET Baseline 99.5 ± 4.4 kg n=46 Pasireoride Pasireotide is a 2 nd - generation somatostatin analog Binds to sst receptors inhibits ACTH secretion cortisol High binding affinity for sst 1, 2, 3, 5 Pituitary adenomas causing CD frequently over-express sst 5-7% -8% -9% mean ± SE Fleseriu M et al. J Clin Endocrinol Metab. 2012; Jun;97(6):2039-2049. * P<0.001 vs baseline 5.7 %± 1.5 vs Baseline Figure 1: Pharmacologic action of pasireotide. Source: Novartis Endocrinologic and Metabolic Drugs Advisory Committee Meeting, Nov. 7, 2012 Colao A, et al. NEJM. 2012 Pasireotide Study Design: 12-month, phase 3, MC, DB, 2-arm, randomized trial in adults with persistent/recurrent CD or newly diagnosed CD who were not surgical candidates Treatment Regimens: pasireotide 600 µg BID (n = 82), 900 µg BID (n = 80) Results: Proportion with normalization of UFC levels at Month 6 w/out prior dose increase: 600 µg: 15% (95% CI 7, 22), 900 µg: 26% (95% CI 17, 36) Proportion with mean UFC ULN or 50% decrease from baseline at Month 6: 600 µg: 34%, 900 µg: 41% Pasireotide Mean changes in clinical signs/sx from baseline to Month 12: Systolic BP: 6.1 mmhg (95% CI: 9.8, 2.4; p = 0.03) Diastolic BP: 3.7 mmhg (95% CI: 6.2, 1.2; p = 0.03) Triglycerides: 2 mg/dl (95% CI: 27, 0; p-value NS) LDL cholesterol: 15 mg/dl (95% CI: 23, 8; p < 0.001) Weight: 6.7 kg (95% CI: 8.0, 5.4; p < 0.001) HR-QOL score, improved 11.1 points (95% CI: 6.8, 15.5; p-value NS) At Months 6 and 12, facial rubor, supraclavicular fat, and dorsal fat pads were diminished in patients with available photos Improvements in signs/sx not limited to those who achieved normal UFC Table 1: Mean change in UFC levels from baseline to Month 12 24 Figure 2: Improvement in physical features from baseline to Month 12. Source: Novartis Endocrinologic and Metabolic Drugs Advisory Committee Meeting, Nov. 7, 2012 6
Bilateral Total Adrenalectomy Adrenalectomy should only be employed as a last resort when all else has failed and the patient is in grave danger due to the consequences of hypercortisolism. The success and relatively low risk of complications of laparoscopic bilateral adrenalectomy, as demonstrated by centers such as The Mayo Clinic and Oregon Health Sciences University, require that we reconsider our attitudes towards adrenalectomy in patients with hypercortisolism. Treatment of A close doctor-patient relationship is essential. Decisions regarding treatment must depend on clinical, biochemical, and radiological findings and the level of expertise of the treating physicians. Patients should be permitted to make informed decisions regarding available treatment options. Life-long follow-up is essential. Serious consideration should be given to referral to a tertiary medical center for advice and management. 7