Update on of interest and non-approved medications Cushings disease - PDF document

Disclosure of potential relevant conflicts Update on of interest and non-approved medications Cushing’s disease PI of research grants from Cortendo & Novartis to MGH Occasional consulting for Cortendo, HRA Pharma, Ipsen, Novartis Beverly MK Biller, MD Slides will indicate investigational medications Professor of Medicine Harvard Medical School (includes those available for other indications but not approved for Cushing’s) Neuroendocrine Clinical Center Massachusetts General Hospital Boston, MA Cushing’s disease (CD) Case The Endocrine Society Clinical Guidelines First- line treatment for Cushing’s Syndrome � 36 year old pregnant woman with: • Facial rounding • Hypertension • Fungal infections Operation by an experienced surgeon PATIENT � Cushing’s syndrome later is recommended as the initial treatment PHOTO diagnosed with high UFC levels; ACTH not low � Pituitary MRI: ? small right lesion So, other therapies should be used mainly for � IPSS: Centralized persistent or recurrent Cushing’s disease Clear clinical and biochemical features of CS; testing pointed to pituitary Nieman JCEM 2015

Cushing’s disease (CD) Case 2 - 27 yo F with CD diagnosed after pregnancy • 36 year old with CD � pituitary surgery by expert surgeon � very low cortisol levels post-op - MRI showed 1cm macroadenoma • In remission � good clinical improvement, euthyroid, eugonadal, - Pituitary surgery 2011 � levels normal (not low) normal growth hormone axis - Good clinical improvement over the next year • HPA axis recovered in ~1 year � off glucocorticoids Before surgery PATIENT ~8 years PATIENT PATIENT PHOTOS after surgery PHOTO PHOTO Moved away Cushing’s disease (CD) Cases Recurrent Cushing’s after transsphenoidal surgery (28 studies with varied definitions of biochemical control, follow up, number of subjects) Patients (%) What are their chances of recurrence? 0 10 20 30 40 50 60 70 80 90 100 Valassi 2010 (n=620) Alwani 2010 (n=79) Jagannathan 2009 (n=261) Fomekong 2009 (n=40) Remission Atkinson 2008 (n=42) We used to say 5-10% of CD cases recur, but y , Recurrence Jehle 2008 (n=193) Prevedello 2008 (n=167) Xing 2008 (n=266) Carrasco 2008 (n=68) We We were wrong – it is higher! Recurrence rates were as Romanholi 2008 (n=57) Patil 2008 (n=215) Rollin 2007 (n=108) high as 27%! Pouratian 2007 (n=111) Acebes 2007 (n=44) Shah 2006 (n=65) Hoffmann 2006 (n=100) Studies in the last 5 years have Esposito 2006 (n=40) PATIENT Atkinson 2005 (n=63) Hammer 2004 (n=289) shown even higher rates Rollin 2004 (n=41) Pereira 2003 (n=78) PHOTOS Chen 2003 (n=174) Most are from expert centers Flitsch 2003 (n=147) Shimon 2002 (n=82) Rees 2002 (n=54) Barbetta 2001 (n=68) Chee 2001 (n=61) Imaki 2001 (n=49) Swearingen Ann Int Med 1999

Case Case PATIENT PATIENT • 2012 new diabetes (DM), weight PHOTO • Fall 2013 recurrent symptoms PHOTOS gain, ↑ blood pressure − emotional lability/moodiness • Asked local endo if CD back; told − weight gain no: metformin helped DM, lost − but did not look Cushingoid weight, serum cortisol “normal” 1990s • Serum cortisols done locally were “normal” • Came to Boston for evaluation • LNSCs & UFCs 1-2 fold upper limit of normal • 8/8 UFCs were normal; looked well • but 66% of late night salivary • Head MRIs unchanged over 2 years cortisols (LNSCs) were high ~2013 Cases Case PATIENT • These patients had typical recurrences PHOTOS − mild clinical & biochemical abnormalities Head MRI − one had unchanged MRI, abnormal UFCs − one had normal UFCs, abnormal MRI (first in many years) • Recurrence may be many years after surgery Mass on right side of − 31 series with N>40: relapse between 6m-12y − This patient recurred at 21 years! Longest we’ve seen: 27y pituitary gland ~1.5 x 1.3 x 0.7 cm • Sequence of hormone changes in recurrent CD − ↑ midnight cortisol (serum or saliva) usually precedes ↑ UFC Normal gland pushed left − mean time to elevation: - 38 months (m) for midnight cortisol - 45 m for 1mg overnight DST - 51 m for UFC ? right cavernous sinus • Thus, all post-surgery patients must be followed invasion – can’t rely on UFC alone for diagnosis (use LNSC, ONDST) – LNSC appears to be most sensitive test (Khalil EJE 2011, Tritos Nature Rev Endocrinol 2011, Carroll ENDO 2014 , Danet-Lamasou Clin Endo 2014 )

Mortality among CD patients in remission Mortality among CD patients with recurrence Lindholm 0.31 (0.14-0.69) 5.06 (2.27-11.26) Lindholm • Hammer 1.18 (0.56-2.48) • Hammer • 2.80 (1.33-5.87) Dekkers 1.80 (0.75-4.32) Dekkers • 4.38 (1.82-10.52) Clayton 3.30 (1.37-7.93) Clayton • 16.0 (6.66-38.44) Overall Overall 1.20 (0.45-3.18) 5.50 (2.69-11.26) (I-squared = 82.2%; p = 0.001) (I-squared = 67.2%, p = 0.027) 1 7.93 0.126 0.026 1 38.4 Clayton R N et al. JCEM 2011;96:632-642. Clayton R N et al. JCEM 2011;96:632-642. Endocrine Society Clinical Guidelines – Treatment of Cushing’s synrome What are the treatment options for recurrent Cushing‘s disease? Cushing’s syndrome and etiology established biochemically CRH Treat co-morbidities R RADIATION Pituitary gland Pituitary gland PITUITARY SURGERY ACTH- dependent Cushing’s syndrome dent Cushing’s synd e ACTH- independent Cushing’s syndrome ACTH- independent Cushing’s s Cabergoline * Presumed EAS Presu Presumed CD Presumed EAS Pasireotide Imaging: Based on IPSS or >6 ed o Imaging: Tumour Adrenal imaging aging No tumor mm mass m ACTH MEDICATIONS Resection not Remission Tumor resection umor r Unilateral or bilateral adrenalectomy rena possible Adrenal glands Ad l l d ADRENALECTOMY Monitor for Failed surgery, no surgery, Failed surgery, no surgery, Treat metastatic disease if R Remission recurrence or recurrence or recurrence applicable GRs on G GR Rs on n Ketoconazole * target tissues Control hypercortisolism ol hypercortisolism If Cushing’s disease, consider: er: Metyrapone * Mifepristone � Repeat transsphenoidal surgery urgery Cortisol � Pituitary-directed medical treatment Mitotane * Repeat localization � Radiotherapy and steroidogenesis inhibitors studies if applicable Etomidate * For all etiologies, consider: GR � Steroidogenesis inhibitors � GC receptor antagonist � Bilateral adrenalectomy (* not FDA approved for Cushing’s) Nieman JCEM 2015 Tissues

Remission rates after repeat transsphenoidal Repeat transsphenoidal surgery surgery for persistent or recurrent CD Varied definitions of biochemical control, follow up, Ns Wagenmakers 2009 (N=8) • Pros Patil 2008 (N=36) − Well tolerated Aghi 2008 (N=13) − Immediate effect (if successful) 1 st surgery Hofmann 2008 (N=35) − Chance for tumor removal and remission remission Hofmann 2006 (N=16) rates 70-90% Benveniste 2005 (N=30) • Cons Locatelli 2005 (N=12) 2 nd surgery − Glucocorticoids needed until axis recovers remission Shimon 2002 (N=13) − Higher risk of pituitary hormone deficiencies rates lower, but Knappe 1996 (N=24) it works for − Risk of recurrent Cushing’s Ram 1994 (N=17) some patients − Lower chance of success than 1 st surgery (<75%) Friedman 1989 (N=31) Nakane 1987 (N=8) 0 20 40 60 80 100 Remission Rate (%) (McLaughlin Can J Neurol Sci 2011) Radiation Radiation CONVENTIONAL CONVENTIONAL • Pros • Conventional Six weeks of daily tx − Well tolerated Six weeks of daily tx Fractionated − Single treatment (if radiosurgery) − Provides tumor control in most patients • Radiosurgery (RS) LINAC − Biochemical control in some patients − Single high dose to target • Cons − Lower dose to other tissue − Delayed effectiveness (6 months to many years) gamma knife − 3 types proton beam − Medical treatment needed in the interim › Linear accelerator (LINAC) − Long term risks: › Gamma knife › Pituitary hormone deficiencies/need for replacement › Proton beam › Risk to surrounding neurovascular structures › Risk of secondary neoplasia No direct comparisons available › Recurrence (rare) • RS may be faster • For CD, similar cortisol control (Starke Curr Opin Endocrinol Diab Obes 2010, Tritos Nature Rev Endocrinol 2011, Wilson J Clin Neurosci 2014) 19 20