Update on Cushing s disease (CD)

Transcription

1 Update on Cushing s disease (CD) Beverly MK Biller, MD Professor of Medicine Harvard Medical School Neuroendocrine Clinical Center Massachusetts General Hospital Boston, MA

2 Disclosure of potential relevant conflicts of interest and non-approved medications PI of research grants from Cortendo & Novartis to Massachusetts General Hospital Neuroendocrine Unit Occasional consulting for Cortendo, Novartis Slides will indicate investigational medications (includes those available for other indications but not approved for CD)

3 Cushing s disease (CD) Case 1 Patient photo - 36 year old pregnant woman with facial rounding hypertension fungal infections - Cushing s syndrome later diagnosed with high urine free cortisols (UFCs) - ACTH not suppressed - Head MRI? small right lesion - Inferior petrosal sinus sampling centralized Clear clinical and biochemical features of CS; testing points to pituitary

4 Cushing s disease (CD) Case 1 36 year old with CD pituitary surgery by expert surgeon very low cortisol levels post-op In remission good clinical improvement, euthyroid, eugonadal, normal growth hormone axis HPA axis recovered in ~1 year off glucocorticoids Before surgery Patient photo ~8 years after surgery; Moved to AZ Patient photo

5 Case 2-27 yo F with CD diagnosed after pregnancy - MRI showed 1cm macroadenoma - Pituitary surgery 2011 levels normal (not low) - Good clinical improvement over the next year Patient photos

6 Cushing s disease (CD) Cases What are their chances of recurrence? We used to say 5 10% of CD cases recur, but Patient photos Swearingen Ann Int Med 1999

7 Recurrent Cushing s after transsphenoidal surgery (28 studies with varied definitions of biochemical control, follow up, number of subjects) 0 Valassi 2010 (n=620) Alwani 2010 (n=79) Jagannathan 2009 (n=261) Fomekong 2009 (n=40) Atkinson 2008 (n=42) Jehle 2008 (n=193) Prevedello 2008 (n=167) Xing 2008 (n=266) Carrasco 2008 (n=68) Romanholi 2008 (n=57) Patil 2008 (n=215) Rollin 2007 (n=108) Pouratian 2007 (n=111) Acebes 2007 (n=44) Shah 2006 (n=65) Hoffmann 2006 (n=100) Esposito 2006 (n=40) Atkinson 2005 (n=63) Hammer 2004 (n=289) Rollin 2004 (n=41) Pereira 2003 (n=78) Chen 2003 (n=174) Flitsch 2003 (n=147) Shimon 2002 (n=82) Rees 2002 (n=54) Barbetta 2001 (n=68) Chee 2001 (n=61) Imaki 2001 (n=49) Patients (%) Recurrence rates were as high as 27%! (70 90% with expert surgeon) Studies in the last 5 years Remission Recurrence have shown even higher rates Most are from expert centers

8 Case new diabetes (DM), weight gain, blood pressure, asked re CD Told no, because - metformin controlled the DM - she was able to lose wt - serum cortisol was normal Came to Boston for evaluation 8/8 UFCs were normal; looked well but 66% of late night salivary cortisols (LNSCs) were high Patient photos 1990s ~2013

9 Case 1 Head MRI (first in many years) Mass on right side of pituitary gland ~1.5 x 1.3 x 0.7 cm Normal gland pushed left? right cavernous sinus invasion

10 Case 2 Fall 2013 recurrent symptoms emotional lability/moodiness weight gain but did not look Cushingoid Patient photo Serum cortisols done locally were normal LNSCs & UFCs 1-2 fold upper limit of normal Head MRIs unchanged over 2 years

11 Cases These patients had typical recurrences mild clinical features mild biochemical abnormalities one had unchanged MRI, abnormal UFCs one had normal UFCs, abnormal MRI Case 2 had a high probability of recurrence tumor >1cm no adrenal insufficiency post-op but Patients without positive predictors may also recur (Case 1) Patient photo (Tritos Nature Rev Endocrinol 2011)

12 Recurrence may be many years after surgery 31 series with N>40: relapse between 6m-12y Case 1 recurred at 21 years! Longest we ve seen: 27y Sequence of hormone changes in recurrent CD midnight cortisol (serum or saliva) usually precedes UFC mean time to elevation: 38 months for midnight cortisol 45 months for 1mg overnight DST 51 months for UFC Cases All post-op patients must be followed Can t rely on UFC alone for diagnosis Use LNSC, ONDST LNSC appears to be most sensitive test Patient photos (Khalil EJE 2011, Tritos Nature Rev Endocrinol 2011, Carroll ENDO 2014, Danet-Lamasou Clin Endo 2014)

13 Late night salivary cortisol How many of you use this test? please raise your hand if you do High sensitivity and specificity (93-100%) Especially helpful in early Cushing s, recurrences Normal levels exclude dx in most cases Easily performed at home Before dental care; avoid hand creams Pt chews on cotton, places into tube, mails Several samples recommended Normal ranges differ widely by lab May be high in day/night switch, late pregnancy, other circumstances It took effort to get this available at our hospital Insurance coverage is variable and differs according to lab

14 Late night salivary cortisol to screen for early stage recurrence of CD after pituitary surgery 30 Remission LNSC (nm) Sequences normal range Sequences: successive measurements of LNSC for each individual patient Danet Lamasou Clin Endo 2014

15 Late night salivary cortisol to screen for early stage recurrence of CD after pituitary surgery 30 Remission 30 Recurrence LNSC (nm) Some LNSCs not high in recurrent CD Sequences normal range LNSC (nm) Sequences Sequences: successive measurements of LNSC for each individual patient Sandouk JCEM 2018 Danet Lamasou Clin Endo 2014

16 Mortality among CD patients in remission Lindholm 0.31 ( ) Hammer 1.18 ( ) Dekkers 1.80 ( ) Clayton Overall (I squared = 82.2%; p = 0.001) 3.30 ( ) 1.20 ( ) Clayton R N et al. JCEM 2011;96:

17 Mortality among CD patients with recurrence Lindholm 5.06 ( ) Hammer 2.80 ( ) Dekkers 4.38 ( ) Clayton Overall (I squared = 67.2%, p = 0.027) 16.0 ( ) 5.50 ( ) Clayton R N et al. JCEM 2011;96:

18 What are the treatment options for recurrent Cushing s disease? MEDICATIONS Pituitary gland PITUITARY SURGERY Cabergoline* Pasireotide CRH ACTH RADIATION Adrenal glands Ketoconazole* Metyrapone* Mitotane* Etomidate* ADRENALECTOMY Cortisol GRs on target tissues Mifepristone GR (* not FDA approved for Cushing s) Tissues

19 Repeat transsphenoidal surgery PROS Well-tolerated Immediate effect (if successful) Chance for permanent tumor removal CONS Glucocorticoids needed until axis recovers Higher chance of pituitary hormone deficiencies Risk of recurrence Lower chance of success than 1 st (50-75%)

20 Remission rates after repeat transsphenoidal surgery for persistent or recurrent CD Varied definitions of biochemical control, follow up, Ns Wagenmakers 2009 (N=8) Patil 2008 (N=36) Aghi 2008 (N=13) Hofmann 2008 (N=35) Hofmann 2006 (N=16) Benveniste 2005 (N=30) Locatelli 2005 (N=12) Shimon 2002 (N=13) Knappe 1996 (N=24) Ram 1994 (N=17) Friedman 1989 (N=31) Nakane 1987 (N=8) (McLaughlin Can J Neurol Sci 2011) 1 st surgery remission rates 70-90% 2 nd surgery remission rates lower, but it works for some patients Remission Rate (%)

21 Bilateral adrenalectomy PROS Immediate remission from cortisol excess Permanent (usually) Well tolerated, especially if laparoscopic CONS Risks of abdominal surgery Lifelong need for glucoand mineralocorticoids (risk of adrenal crisis) Long term risks - Nelson s syndrome (corticotroph tumor progression) - Recurrence (rare)

22 Radiation CONVENTIONAL Conventional Six weeks of daily tx Fractionated Radiosurgery (RS) Single high dose to target Lower dose to other tissue 3 types Linear accelerator (LINAC) Gamma knife Proton beam LINAC No direct comparisons available RS may be faster For CD, similar cortisol control gamma knife proton beam 22

23 Radiation Varied RT methods, definitions of tumor & biochemical control, follow up, Ns 15 studies with at least 20 pts Wilson 2014 Petit 2008 Minniti 2007 Jagannathan 2007 Colin 2005 Devin 2004 Kobayashi 2002 Sheehan 2000 Laws 1999 Witt 1998 Estrada 1997 Tsang 1996 Levy 1991 Murayama 1992 Littley 1990 Biochemical control (28-86%) Tumor control (83-100%) Patients (%) (Starke Curr Opin Endocrinol Diab Obes 2010, Tritos Nature Rev Endocrinol 2011, Wilson J Clin Neurosci 2014) 23

24 Radiation PROS Well-tolerated Single treatment (if stereotactic radiosurgery) Tumor control (most pts) Cortisol control (some pts) CONS Delayed effectiveness Medical treatment needed until effective Long term risks - Pituitary deficiencies - Damage to nearby tissue - Secondary tumors - Recurrence (rare) Starke Curr Opin Endocrinol Diab Obes 2010, Tritos Nature Rev Endocrinol 2011, Wilson J Clin Neurosci 2014

25 Case 2 29 yo F with history of Cushing s surgery 2011 Fall 2013 recurrent Cushing s, options were discussed Patient photo Patient asked, Isn t there a medication I can take instead of having surgery again?

26 Potential targets for medical Tx of Cushing s disease Pituitary gland CRH Cabergoline* Pasireotide ACTH Adrenal glands GRs on Rationale: Ketoconazole* affinity for receptors on corticotroph target adenomas tissues Metyrapone* cabergoline for dopamine Mifepristone Mitotane* Cortisol(D2) receptor pasireotide for somatostatin (sst5) receptor Etomidate* GR LCI699* ACTH secretion (* not FDA approved for Cushing s) Tissues

27 Cabergoline in Cushing s disease Responder means normal UFC Nonresponders normal range months Early response, Later escape Long-term responders 20 Cushing s disease pts, mean UFC > 2-fold above nl 2-year study: 1-7mg/wk cabergoline (median 3.5mg/wk) 2 dropouts for asthenia, hypotension ; adrenal insufficiency? Cardiac echos: tricuspid regurg progressed in 1, no change in others Similar findings in two other studies; suggests this is an option for CD (not FDA approved for Cushing s disease) (Pivonello JCEM 2009, Godbout EJE 2010, Vilar Pituitary 2010)

28 Pasireotide - baseline & month 6 UFCs UFC (μg/24h) Individual patients sorted by baseline UFC Color denotes starting dose µg s.c. bid 900 µg s.c. bid 720 * N=103 Baseline UFC Month 6 UFC Month 6 UFC ULN normal <52.5 μg/24h Normal UFC, n (%) 12 (14.6) 21 (26.3) 33 (20.4) 600 µg sc bid 900 µg sc bid All patients Colao NEJM 2012 Colao NEJM 2012

29 Clinical changes on pasireotide up to 12m Colao NEJM 2012 FDA approved for CD pts not controlled with/able to have surgery

30 Subcutaneous pasireotide side effects Adrenal insufficiency symptoms in 13 (8%) Responded to dose reduction and/or temporary corticosteroids Most frequent side effects were gastrointestinal Similar to other SMS analogues, except for hyperglycemia 73% of patients had at least one hyperglycemia event No diabetic ketoacidosis or hyperosmolar coma Attainment of UFC control did not prevent hyperglycemia Colao NEJM 2012

31 Changes in glycemia on pasireotide Mean fasting plasma glucose (mg/dl) Colao NEJM µg bid (n=82) 900 µg bid (n=80) Baseline Day 15 Month 3 Month 6 Month µg bid (n=82) 900 µg bid (n=80) Mean HbA 1c (%) Baseline Month 2 Month 6 Month 12 Of the 67 patients who were normoglycemic at baseline, 14 (21%) remained normal, 29 (43%) became pre-diabetic and 23 (34%) became diabetic during treatment Mechanism based on study in healthy volunteers: Henry JCEM 2013 Pasireotide reduces incretin & insulin secretion, without affecting insulin sensitivity

32 Pasireotide LAR* (once monthly) Screening mufc 150 patients randomized to 10mg/month or 30mg/month Proportion of Responders (normal UFC) at month 7 by pasireotide LAR dose according to baseline UFC group 2.0 to 5.0 x ULN 36.7% 35.3% n=18/49 n=18/51 Pasireotide LAR 10 mg Pasireotide LAR 30 mg 1.5 to <2.0 x ULN 52.0% 52.0% n=13/25 n=13/25 Side effects were similar to bid subcutaneous *(not FDA approved for Cushing s) Percentage of responders (mufc ULN at month 7) Lacroix Lancet Diabetes Endocrinol 2017

33 Potential targets for medical Tx of Cushing s disease CRH Pituitary Several gland used for over 50 years Reduce cortisol by inhibiting adrenal steroidogenesis Cabergoline* Pasireotide ACTH in pituitary Cushing s (? of escape) ACTH Adrenal glands Ketoconazole* Metyrapone* Mitotane* Etomidate* LCI699* Cortisol GRs on target tissues Mifepristone GR (* not FDA approved for Cushing s) Tissues

34 Ketoconazole Approved for treatment of fungal infections Inhibits several enzyme steps in cortisol production 4 past studies w/ >15 CD pts: cortisol control 49-99% What s new? Large multicenter, retrospective French study 200 patients on monotherapy at 14 centers over 17y Mean final dose 780mg/d (range mg) Control (2 consecutive normal UFCs) in 49% Clinical improvements in DM, HTN, hypokalemia ~20% discontinued for intolerance most common: gastrointestinal, adrenal insuff, pruritis Liver enzyme elevations in 18% (>5XULN, 2.5%) Conclusion: effective with acceptable side effects (not FDA approved for Cushing s) (Castinetti EJE 2008 & JCEM 2014, Sonino Clin Endo 1991, Valassi Clin Endo 2012, clinicaltrials.gov)

35 Metyrapone 11deoxycortisol Inhibits last enzyme step in cortisol synthesis Cortisol control reportedly ~75% 3 studies from 1970s to early 1990s (15-53 patients) 11 OHlase X Cortisol What s new? Large multicenter, retrospective UK study (ENDO 2014 oral) 160 patients on metyr monotherapy at 13 centers over 16y Control based on cortisol day curve or UFC or am cortisol 74% controlled overall in Cushing s syndrome (about 2/3rds who took metyrapone over 5m had CD) (not FDA approved for Cushing s) (Jeffcoate BMJ 1977, Thorén Acta Endocrinol (Copenhagen)1985, Verhelst Clin Endo 1991, Daniel ENDO 2014)

36 Change in 9am cortisol during treatment for each individual patient Slide kindly provided by John Newell-Price Reduction Increase Dose in CD patients with eucortisolemia was ~1.4 g/d 25% had side effects (most common: GI, hypoadrenalism) Conclusion: effective with satisfactory safety profile 900 Normal: 600nmol/L=21.7 mcg/dl (not FDA approved for Cushing s) (Jeffcoate BMJ 1977, Thorén Acta Endocrinol (Copenhagen)1985, Verhelst Clin Endo 1991, Daniel ENDO (Daniel 2014) JCEM 2015) 151 patients

37 Investigational medication LCI699 (osilodrostat)* Mechanism of action Potent inhibitor of 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) Blocks last steps in cortisol and aldosterone production ACTH Hormones distal to the block fall and proximal hormones rise Cholesterol Abnormal feedback loop in Cushing s disease Pregnenolone Progesterone 11-deoxycorticosterone Dehydroepiandrosterone Androstenedione Estrone LCI699 X Corticosterone 18-OH corticosterone CYP11B2 11-deoxycortisol X Cortisol CYP11B1 (* not FDA approved) Testosterone Estradiol Aldosterone - Oral, longer half-life than metyrapone (allows twice-daily dosing) - Higher potency (in vitro IC 50 for CYP11B1 of 2.5 nm vs. 7.5 nm) 37 IC 50, half maximal inhibitory concentration

38 Open-label, proof-of-concept study with LCI699* was positive in 12 adults with Cushing s disease Oral medication, given twice daily Dose escalated every 2 weeks until UFC normalized Maintained until day 70, followed by 2-week washout 7 LCI699 dose escalation Washout Mean UFC ± SE (fold ULN) Bertagna JCEM 2014 At day 70: 11/12 had normal UFC Most common side effects: fatigue, nausea Day (* not FDA approved) 38

39 Potential targets for medical Tx of Cushing s disease Pituitary gland CRH Cabergoline* Blocks action Pasireotide of cortisol at glucocorticoid receptor (GR) Doesn t lower cortisol; ACTH and cortisol ACTH in pituitary Cushing s Adrenal glands Ketoconazole* Metyrapone* Mitotane* Etomidate* LCI699* Cortisol GRs on target tissues Mifepristone (* not FDA approved for Cushing s) Tissues GR

40 Mifepristone in Cushing s Syndrome Oral glucocorticoid (GR) antagonist - greater affinity than cortisol or dexamethasone for the receptor Also has antiprogestin activity Phase 3 clinical trial in 50 patients reported in 2012 FDA approval for Cushing s syndrome with hyperglycemia Blocks receptor (does not cortisol) so response was assessed clinically Patients had diabetes/impaired glucose tolerance or HTN Primary endpoints related to improvements in these disorders (25% reduction in AUCgluc on OGTT, 5mmHb reduction in DBP) (Fleseriu JCEM 2012)

41 Decrease in HbA1c in diabetes cohort mean ± SD HbA1c (%) p<0.001 vs baseline p<0.001 vs baseline Glucoses on OGTT and insulin levels also decreased significantly Diabetes drugs were reduced in 7/15 patients 5 4 N=25 N=20 N=22 Baseline Week 16 Week 24/ET (Fleseriu JCEM 2012)

42 Decrease in weight % Change from baseline (mean ± SE) 2% 1% 0% -1% -2% -3% -4% -5% -6% -7% -8% -9% D7 D14 D28 W6 W8 W10 W12 W16 W20 W24 /ET Global Clinical Assessment of many features, including appearance in photographs, rated by 3 independent reviewers improved in 88% of patients (p<0.001) Baseline 99.5 ± 4.4 kg n= ± 1.5% p<0.001 vs Baseline (Fleseriu JCEM 2012, Katznelson Clin Endo 2013)

43 Mifepristone side effects Adrenal insufficency (AI) Classified as AI or typical symptoms & treatment with glucocorticoid (dex) in 7 High measured cortisols despite AI may be misleading Most common: nausea, fatigue, headache Hypokalemia Common, associated with alkalosis, edema; treated with K & spironolactone Likely due to mineralocorticoid receptor activation from rising cortisol Endometrial Effects (progesterone receptor blockade) Increased endometrial thickness in half of women 5 cases of vaginal bleeding 3 women had D&C for unresolved endometrial thickening after discontinuation Thyroid elevated TSH Lipids decreased HDL (Fleseriu JCEM 12, Endocrine Practice 13)

44 Possible future treatment options Examples of new agents in development* Phase III Phase II Preclinical/other Long-acting pasireotide Roscovitine Retinoic acid Levo-ketoconazole Gefitinib Silibinin Osilodrostat (LCI699) CORT ALD1613 (* not FDA approved for Cushing s)

45 How do we decide which medication to use? Consider many factors Tailor choice to each patient s individual situation Cost and availability Severity/urgency, treatment goals (cortisol/tumor) Medical history and patient factors Side-effect profile Method of delivery (oral versus injection) Other medications (beware drug drug interactions)* * Especially with mifepristone and ketoconazole

46 Case 2 Outcome 29 yo F Cushing s disease recurrence Options discussed, patient considering choices Patient photo Phone call to fellow patient was excited to report. Pregnant! What are the treatment options now? Choices are limited Metyrapone* started - targeted UFCs in normal pregnant range, fold above ULN - due to concern about precursors proximal to 11ßOHlase blockade, careful monitoring of potassium & blood pressure (weekly OB visits) She delivered a healthy boy! (* not FDA approved for this use) (Lindsay JCEM 2005)

47 Before 2 nd surgery 2013 Case 1 Outcome She decided to undergo second transsphenoidal surgery by an expert pituitary surgeon; I d be happy with another 20-year remission by spending just 1 day in the hospital in remission Diabetes and hypertension resolved (medications stopped) Pituitary hormone replacements adjusted, feeling well After 2 nd surgery June 2014 Make sure they can see I have clavicles again! Most recent Patient photos

48 Conclusions All patients in remission from CD should have lifelong monitoring for recurrence Late night salivary cortisol levels are more sensitive than other tests Treatment is important to lower mortality risk Management should be individualized; novel treatments are in development

49 Thank you Questions?