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Dipartimento di Medicina Clinica e Chirurgia

Sezione di Endocrinologia

Università «Federico II», Napoli

Cushing’s Syndrome

• Prevalence: 40 cases/million1

• Incidence: 0.7-2.4 cases/million/year1

• F:M ratio: 3:11,2

• Age: 40-60 years (but can occur at any age)1

1. Pivonello R et al, Lancet Diabetes Endocrinol. 2016; 2. Lacroix A et al, Lancet 2015

Stratakis CA. Endocrinol Metab Clin North Am. 2016

• ACTH dependent (80%)

Cushing Disease (CD)Ectopic ACTH Secreting Tumors (EAS)

• ACTH independent/ Adrenal Cushing’s syndrome (20%)

Unilateral Cortisol Producing Adenomas (CPA)Primary Bilateral Adrenal Hyperplasia (PBAH)Primary Pigmented Nodular Adrenal Disease (PPNAD)Adrenocortical Carcinoma (ACC)

Cushing’s Syndrome

treatment goals

Nieman LK et al. J Clin Endocrinol Metab. 2015

Normalization of cortisol levels

Reversion of signs and symptoms of hypercortisolism

Treatment of hypercortisolism-related comorbidities

Treatment algorithm for current management of

Cushing’s Disease

Pivonello R et al Endocrine Reviews 2015

30.8-100%

(Mean=62.3, median=64.1)

Remission rates Recurrence rates

48.7-100%


0-36.4%(Mean=11.7,

median=10.9)

Microadenoma

Macroadenoma0-59%


OUTCOMES in patients with MICRO vs MACROadenoma

1st line pituitary surgery

Regular monitoring of cortisol levels and life-long follow up are crucial for all patients with Cushing’s disease


Mortality

• 0-70% (mean 0.6; median 0)

• Most frequent causes: myocardial infarction, pneumonia infection,meningitis

• Micro vs macro (?)

Complications

• Hypopituitarism: mean: 30%; median: 18%; range 0.9-93% (correlated with the extent of surgery)

• Diabetes insipidus: mean:12%, median: 8%; range 0.9-34%

• Deep vein thrombosis and pulmonary thromboembolis: mean: 3.8%, median: 3.2%; range 0.6-15%; prophylaxis with anticoagulant is suggested

• Meningitis: mean: 2,7%; median: 2,8%; range 0.4-13%; prophylaxis with antibiotics is generally performed

Pivonello R et al. Endocrine Reviews 2015; Nieman KL et al. J Clin Endocrinol Metab. 2015


Intraoperative identification: MRr: 87,7%

No intraoperative identification: MRr:36,3%4

Preoperative identification: MRr:79,5%

No preoperative identification: MRr: 68,2%4

Histological confirmation: MRr: 81,5%

No histological confirmation: MRr:48,5%4

1. Pecori Giraldi F et al. J Clin Endocrinol Metab. 2003; 2. Blevins LS et al. J Clin Endocrinol Metab. 1998; 3. BochicchioD et al. J Clin Endocrinol Metab. 1995; 4. Pivonello R et al Endocr ine Reviews 2015

Which factors negatively affect

the outcome of pituitary surgery?

Males: MRecR: 32%

Females: MRecR: 15%1

In Macroadenomas

odds ratio, 12.9 (95%CI, 1.4 –124; P <0.02)2

Intrasellar: MRr: 86%

Extrasellar: MRr: 40%3

Invasive tumors: MRr: 41,1%4

MRecR=mean recurrency rate;MRr=mean remission rate

Persistent or recurrent Cushing’s disease after surgery

Repeat pituitary surgery

Bilateral adrenalectomyRadiotherapy

Medicaltherapy

Nieman LK et al, J Clin Endocrinol Metab. 2015; Pivonello R et al. Endocrine Reviews 2015

Treatment for persistent/recurrent Cushing’s Disease:

different choices, different needs


1. Pivonello R et al. Endocr ine Reviews 2015; 2. Nieman KL et al. J Clin Endocrinol Metab. 2015


30-87.5%

(Mean=58%, median=61.1%)

0-60%(Mean=16.1%, median=9.1%)

COMPARISON WITH 1ST LINE PITUITARY SURGERY:• Lower immediate remission rate than 1st line surgery;• Similar recurrence rate than 1st line surgery; • Higher prevalence of hypopituitarism (up to 79%) than 1st surgery, but lower than radiotherapy

CANDIDATES• Residual tumors well-defined, small, non invasive• Surgical and pathological tumor identification at time of •first attempt of selective adenomectomy• Evidence of incomplete resection at pituitary imaging

Pituitary radiotherapy

CANDIDATES• Patients with unsuccessful surgery, unresponsive, intolerant or escaped to medical therapy• Patients without indication or with contraindications to surgery or patients who refuse surgery, especially for aggressive and/or invasive pituitary tumors


10-100%Mean=60.8%,

median=57.2%

0-100%Mean=12.3%, median=0%

STEREOTACTIC (SRT)CONVENTIONAL (CRT)


19.6-100%Mean=63.8%, median=60%

0-62.5%Mean=15.9%, median=0%

FACTORS NEGATIVELY AFFECT THE OUTCOME OF RADIOTHERAPY:• Tumor remnants > 10 mm• Distance from optic chiasm < 5 mm• Hormone-suppressive drugs at start of radiotherapy


• SRT does not appear to be more efficacious than CRT• Hypopituitarism is a risk with all forms of radiation, but seem to be slightly lower for SRT


78.9-100%Mean=96.8%, median=100%

0-12%Mean=1.7%, median=0%

CANDIDATES

• Resistant or intolerant to medical therapies

• Decline or unresponsive to radiotherapy• Low chance of successful surgery• Patients with prolonged severe disease, but without contraindications for surgery• Patients who wish to avoid the risk of hypopituitarism

Bilateral adrenalectomy

FACTORS ASSOCIATED WITH HIGH RISK OF CORTICOTROPH TUMOR PROGRESSION :• Duration of Cushing’s disease• ACTH levels in the years after BADX• Rate of increase of ACTH levels after BADX

BADX=bilateral adrenalectomyPivonello R et al Endocrine Reviews 2015

• BADX is a safe and effective procedure (adrenal insufficiency)• Almost all CD comorbidities significantly improve after BADX

Medical therapy

CANDIDATES• Patients with unsuccessful surgery• While awaiting effect of radiotherapy• Patients who refused pituitary surgery• Non-visible adenomas in the absence of dedicated pituitary surgeon• Adenomas with unfavourable location for further surgery• Macroadenomas extending beyond the sella• Severe co-morbidities/high surgical risk

TSS=Transsphenoidal selective adenomectomy; ADX=Bilateral adrenalectomy; PASI=Pasireotide;RX=Radiotherapy; CAB=Cabergoline; MIFE=Mifepristone; LC=LCI699; LYSO=Mitotane;KTZ=Ketoconazole; MET=MetopyronePivonello R et al Endocrine Reviews 2015 ; Bertagna X et al. J Clin Endocrinol Metab. 2013

THE CHOICE OF THE MOST “RIGHT” MEDICAL THERAPY MUST BE PERSONALIZED CONSIDERING:

• age • sex • tumor features• co-morbidities• hypercortisolism severity • drug side effects• drug controindications• drug rapidity of action

Role of medical therapy:

past vs present

Medical Treatment Indication

Long term medical therapy alone is rarely indicated. Drug control of hypercortisolism is suitable for:

• patients awaiting a response to radiotherapy

• preoperative preparation to correct severe disease complications quickly

• whenever a palliative treatment is needed

Adrenal-directed medical therapy is effective in the majority of patients whereas currently medical therapiestargeted to the corticotroph tumor have not been uniformly successful but represent a major non surgicaladvance in the treatment of CD.

PAST1

Medical Treatment Indication

Long term medical therapy may be indicated as second-line treatment in CD in the following cases:

• after TSS in patients with CD, either with or without RT/radiosurgery

• patients with CD who are not surgical candidates

• patients awaiting a response to radiotherapy

• severe co-morbidities and acute complications

Steroidogenesis inhibitors are indicated in the first and third condition; pituitary-directed drugs are indicatedin all conditions; glucocorticoid antagonist is indicated in the first and second condition in presence ofdiabetes or glucose intolerance. In patients who are not surgical candidates, pituitary-directed drugs arepreferentially used.

PRESENT2

TSS= trans-sphenoidal surgery; RT=radiotherapy; CD=Cushing’s disease1.Biller et al. J Clin Endocrinol Metab. 2008 2.Nieman et al. J Clin Endocrinol Metab. 2015

Pituitary-targeted agents

Indication

Pasireotide Cushing’s disease*

Cabergoline Off label

Adrenal-directed agents

Indication

Ketoconazole Cushing’s Syndrome

Metyrapone Cushing’s Syndrome

Mitotane Off-label

Glucocorticoid receptor antagonists

Indication

MifepristoneHyperglycemia in patients with

Cushing’s syndrome and DM/IGT*

Remission Rate: M= 31.2, m=30, (R=25–40%)

Remission Rate: 15.9-28.8% ( 6 mo); 13.4-25% (12 mo)

Remission Rate: M=64.3, m=50, (R=44.7–92.9%)

Remission Rate: M= 71, m=75.5, (R= 45.4–100%)

Remission Rate: M= 86.9, m=82.6, (R=71.6–100%)

Remission Rate: M=57.7, m=60, (R=38.1–75%)


Currently available medical therapies

DM=diabetes mellitus; IGT=impaired glucose tolerance

Pituitary-directed agents

AE, adverse event*Treatment of adult patients with Cushing’s disease for whom surgery is not an option or for whom surgery has failed

Approved in EU and USA*

Largest prospective study and evidence-based effectiveness

May induce tumorshrinkage

AEs:Similar to first-generation somatostatin analogues, except for the degree and frequency of hyperglycaemia

Patients should be monitored for changes in glucose homeostasis

Pasireotide

Pivonello R et al Endocrine Reviews 2015; Colao A et al. N Engl J Med 2012; Schopohl J et al. Pituitary 2015

European advisory board recommendations for managing pasireotide-related hyperglycemia in patients with Cushing’s disease

Patients with Cushing’s disease receiving pasireotide treatment

Patients withNGT

Patients withIGT/IFG

Patients with diabetes mellitus receiving OADs

Patients with diabetes mellitus receiving insulin therapy

SMBG twice/week (1st week),once weekly thereafter

SMBG 6 times/day(1st week)

SMBG 6 times/day (1st week),4 times/day thereafter

No hyperglycemiaHyperglycemia:

Initiate treatment

Start/continue with metformin

Metformin + DPP-4 inhibitor

Metformin + GLP-1 receptor agonist

Metformin + insulinConsider adding a DPP-4 inhibitor or

a GLP-1 receptor agonist

If HbA1c >7.0–7.5%

Colao A et al. Pituitary 2014

Continue SMBG once weekly for the first 3 months

If HbA1c >7.0–7.5%

If HbA1c >7.0–7.5%

If HbA1c >7.0–7.5%

NGT: normal glucose tolerance; IGT: impaired glucose tolerance; IFG: impaired fasting glycemia; OAD: oral antidiabetic drugs; SMBG: self-monitoring of blood glucose;GLP-1: glucagone like peptide -1; DPP-4: dipeptidyl peptidase-4

Pituitary-directed agents

Pros Cons

Efficacious

Well tolerated

May induce tumotshrinkage

AEs: Transient moderate asthenia; mild dizziness and nausea

Only limited numbers of patients evaluated

One quarter of patients fail to achieve long-term control because of ‘escape’

Echocardiography recommended to monitor for development of valvulopathy

AE, adverse event*Treatment of adult patients with Cushing’s disease for whom surgery is not an option or for whom surgery has failed

Cabergoline

Pivonello R et al Endocrine Reviews 2015; Colao A et al. N Engl J Med 2012; Schopohl J et al. Pituitary 2015; Pivonello R et al. JCEM 2009; Godbout A et al. Eur J Endocrinol 2012

Approved in EU and USA*

Largest prospective study and evidence-based effectiveness

May induce tumorshrinkage

AEs:Similar to first-generation somatostatin analogues, except for the degree and frequency of hyperglycaemia

Patients should be monitored for changes in glucose homeostasis

Pasireotide

Rapid action

Effective in the short term

Preferred in Men or Pregnancy

AEs: GI, hirsutism, HTN, hypokalaemiaNo prospective studiesFour-times-daily dosingPotential ‘escape’ from treatment response

Pros Cons

Rapid action

Effective in the short term

Preferred in Women

AEs: GI, abnormal LFTs, male hypogonadism

No prospective studies

Many drug interactions; strong CYP3A4 inhibitor

Potential ‘escape’ from treatment response

AE, adverse events; GI, gastrointestinal; LFT, liver function test; HTN, hypertension

Ketoconazole

Metyrapone

MitotaneEffective in the short term and long-term

AEs: GI, neurological, teratogenic, adrenolytic

Delayed efficacy

Adrenal-directed agents

Pivonello R et al. Endocr Rev. 2015; Castinetti F. et al. J Clin Endocrinol Metab. 2014; Daniel E. et al. J Clin Endocrinol Metab. 2015 ; Baudry C et al. Eur J Endocrinol. 2012

Cortisol-receptor-targeted agents

Pivonello R et al. Endocr Rev. 2015; Johanssen S & Allolio B. Eur J Endocrinol 2007; Fleseriu M et al. J Clin Endocrinol Metab 2012

*In adults with endogenous Cushing’s syndrome who have type 2 diabetes/glucose intolerance and have not responded to, or who are not candidates for, surgery

Mifepristone

Pros Cons

FDA approved*

Improves clinical signsand symptoms

AEs: Adrenal insufficiency; moderate-to-severe hypokalaemiaNausea, fatigue, headache; endometrial thickening was reported in half of women

Efficacy can only be determined by changes in clinical parameters

Tumour volume not decreased

Contraindicated during pregnancy

What treatment options are on the horizon in Cushing’s disease?

Adrenalglands

Cortisol

Glucocorticoidreceptors

(peripheral tissues)

ACTH

Pasireotide LAR

LevoketoconazoleRoscovitine

Gefitinib

Phase III

Phase II

CORT125134451

Osilodrostat (LCI699)

Pasireotide & cabergoline(CAPACITY)


Adrenalglands

Cortisol



ACTH

• A long-acting release (LAR) pasireotide formulation, for monthly intramuscularadministration, is currently under approval process for Cushing’s disease (CD)

• Approximately 40% of CD patients achieved mUFC ≤ ULN at month 7 (10-30 mg)

• Pasireotide LAR treatment improved clinical signs and symptoms, and Cushing QOLscore over 12 months

• Its safety profile is consistent with that of twice-daily pasireotide s.c.

• Most commonly reported AEs were hyperglycaemia-related: LAR 76.7% vs s.c. 73%

• A new antidiabetic medication was initiated in 45.7% and 54% of patients treatedwith s.c. and LAR formulations, respectively

• Pasireotide LAR can be an effective treatment option with a convenient monthlyadministration schedule for patients with Cushing’s disease

PASIREOTIDE LAR

Lacroix A et al. Lancet Diabetes Endocrinol.CD=Cushing’s disease, mUFC: mean urinary free cortisol; ULN: upper limit of normal


Adrenalglands

Cortisol



ACTH

• Oral inhibitor of 11β-hydroxylase (the enzyme responsible for catalyzing the finalstep of cortisol synthesis)

• Rapidly absorbed (Tmax ≈1 hour), longer elimination half-life of 3-5 hours (vs < 2of metyrapone), allowing a twice daily multiple dosing

• Higher potency [IC50 against 11β-hydroxylase 2.5 nM vs 7.5 nM of metyrapone],allowing higher efficacy at lower doses

• LCI699 normalized UFC in 78.9% of patients at week 22

• It was generally well tolerated: most AEs were expected based on the mechanismof action (increased adrenal precursors, increased ACTH, increased testosterone,nausea, diarrhea, asthenia, adrenal insufficiency, nasopharyngitis)

• Confirmatory phase III studies (LINC 3 & 4) will evaluate the effects of LCI699 in alarger population to confirm long-term efficacy and safety of LCI699 for thetreatment of patients with Cushing's disease

Osilodrostat (LCI699)

Bertagna X. et al. JCEM 2014; Fleseriu M et al. Pituitary. 2016 IC50, half-maximal inhibitory concentration, UFC: urinary free cortisol, AE: adverse event


Adrenalglands

Cortisol



ACTH

• Levoketoconazole is the single 2S,4R enantiomer of ketoconazole

•Hypothesized to provide better efficacy (lower IC50, allowing the same efficacy atlower doses)and to provide better safety (lower hepatic toxicity)

Initial results from the phase III Multicenter, Open Label SONICS study

Levoketoconazole

Rotstein DM et al. J Med Chem. 1992; Princen HM et al. J Clin Invest. 1986; O’Callaghan YC et al. Eur J Nutr. 1999; Fleseriu M. et al. ENEA 2018

IC50, half-maximal inhibitory concentration, mUFC: mean urinary free cortisol; ULN: upper limit of normal , AE: adverse event

Efficacy: UFC responder analysis at the end of the maintenence phase

All patients (N=94)

Primary endpoint of mUFC normalization withoutdose increase

30%

95% CI, 21%-40%; p=0.0154

mUFC normalization regardless of dose increase38%

95% CI, 28%-49%

≥ 50% mUFC decrease or normalization, regardless of dose increase

48%

95% CI, 37%-58%

Maintenance phase completers with mUFC data and ≥ 50% UFC reduction from baseline

76%

Fasting glucose, HbA1c, total and low-density lipoprotein cholesterol, weight, andBMI had significant mean decrease (p<0.0001) from baseline

AEs All patients (N=94)

Nausea 30 (32%)

Headache 26 (28%)

Peripheral edema 18 (19%)

Hypertension 16 (17%)

Fatigue 15 (16%)

Diarrehea 14 (15%)

ALT > 1xULN to 3xULN 29 (30.9%)

ALT > 3xULN to 5xULN 7 (7.4%)

ALT > 5xULN 3 (3.2%)

GGT increased 12 (13%)

Liver monitoring detected mild to moderate liver signals ina minority of subjects that were fully reversible


• CORT125134, also known as relacorilant, is a selective glucocorticoid receptorantagonist under investigation (100-350 mg/day)

• In a first-in-human study, the agent was well tolerated following repeated dosesup to 250 mg once a day for 14 days, and anti-glucocorticoid effects weresubstantiated

CORT125134

Hunt H et al. Clin Pharmacol Drug Dev. 2018; https://clinicaltrials.gov; NCT02804750

Adrenalglands

Cortisol



ACTH

NCT02804750: Phase 2 Study of the Safety and Efficacy ofCORT125134 in the Treatment of Endogenous Cushing's Syndrome

Neurosurgery Nowadays pituitary surgery still remains the first-line approach for Cushing’s disease.

Radiotherapy

Radiotherapy has lost its importance over the time but it still remains a valid alternative approach in patients who are not candidates or are not cured by pituitary surgery and/or with unresponsiveness, intolerance or escape to medical therapies.

Medical Therapy

Medical therapy was considered rarely for the treatment of Cushing’s disease until few years ago.This approach gained more and more importance recently, indeed, the number of drugs availableis increased quickly. This approach is suggested for patients who are not cured or are notcandidates for pituitary surgery, in patients awaiting a response to radiotherapy or in patientswith severe co-morbidities and acute complications. There is a recent trend to personalize themedical treatment on the basis of patient, disease and tumor characteristics

Bilateral Adrenalectomy

Bilateral adrenalectomy is generally the last option to consider for the treatment of Cushing’sdisease. This approach might be useful for patients with severe hypercortisolism and who are notcured or are not candidates for the othertreatment alternatives. Hypocortisolism andcorticotroph tumor progression are troubling consequences.

The treatment approach of Cushing’s disease is changed during the time…

Conclusions

Thank you

Cushing team

Chiara SimeoliRosario Ferrigno

Fortuna PapaNicola Di PaolaFederica Caputo

Maria Cristina De MartinoAnnamaria Colao

Dipartimento di Medicina Clinica e Chirurgia

Sezione di Endocrinologia

Università «Federico II», Napoli

No Residual Tumor

Severe Impairment of clinical picture Mild Impairment of clinical picture

Severe hypercortisolism Mild hypercortisolism

•Pasireotide•Cabergoline•Ketoconazole, Metyrapone•Mifepristone

•Ketoconazole, Metyrapone• *Mifepristone

•Cabergoline•Pasireotide

•Ketoconazole, Metyrapone•*Mifepristone

•Pasireotide• Ketoconazole, Metyrapone•*Mifepristone




Male Female Male FemaleMale Female Male Female

•Metyrapone•*Mifepristone

•Ketoconazole•*Mifepristone

•Pasireotide•Metyrapone•*Mifepristone

•Pasireotide•*Mifepristone

:•Cabergoline•Pasireotide


•Metyrapone•*MIfepristone

•Ketoconazole•Mifepristone

*Mifepristone in case of severe diabetes

Choosing right drug after pituitary surgery failure

Choosing right drug after pituitary surgery failure

Residual Tumor

Severe Impairment of clinical picture Mild Impairment of clinical picture


•Pasireotide•Cabergoline

•Ketoconazole, Metyrapone• *Mifepristone



•Pasireotide• Ketoconazole, Metyrapone•*Mifepristone

•Pasireotide•Ketoconazole, Metyrapone•*Mifepristone



Male Female Male FemaleMale Female Male Female

•Metyrapone•*Mifepristone

•Ketoconazole•*Mifepristone

•Pasireotide•Metyrapone•*Mifepristone

•Pasireotide•*Mifepristone


•Metyrapone•Pasireotide•*MIfepristone

•Ketoconazole•Pasireotide•Mifepristone

*Mifepristone in case of severe diabetes


Feelders et al. N Engl J Med. 2010

• Prospective, open-label, multicentre study• 17 patients with uncontrolled CD• PAS (300–750 mg/day) + CAB (0.5-1.5 mg/day) + ketoconazole (600 mg/day)• Follow-up: 80-days

Combination therapy: pasireotide alone or with cabergoline and ketoconazole

Final complete response in 88% of patients

• Prospective study• 11 patients with ACTH-dependent CS and severe hypercortisolism; 4 CD; 7 EAS• Mitotane (3-5 g/24h), metyrapone (3-4.5 g/24h), ketokonazole (400-1200 mg/24h)• Mean duration of combination treatment : 1-9 months (median: 3.5 months)

• Marked clinical improvement in 100% of patients

• Rapid onset of action

• Adverse effects, including hypokalemia (100%), nausea

and vomiting (63.7%), acute adrenal insufficiency (36.4%),

dizziness and confusion (9.1%), and increases in liver

enzymes (18.2–81.8%), were reported in a significant

percentage of patients.

UFC levels in each of 11 patients before and 1-3 days

after the initiation of triple therapy

Combination therapy with mitotane, metyrapone and ketokonazole is an effective and well

tolerated alternative to bilateral adrenalectomy when immediate etiological treatment of

severe CS is not feasible, but caution should be paid to adverse effects

Combination therapy: mitotane, metyrapone and ketokonazole

Kamenicky P et al. J Clin Endocrinol Metab. 2011

Savage M.O. et al, Pituitary, 2007; Storr HL et al, Trends Endocrinol Metab. 2007

Choosing Right Therapy:

Pediatric Cases

First-line approach

Transsphenoidal surgery

Cure Rates: 45-78%

Complications: low rates hypopituitarism; a particular attention is necessary for GH-

deficiency

Second-line approach

Radiotherapy

Cure Rates: 92%

Complications: low rates hypopituitarism

Third-line approach

Bilateral adrenalectomy

Initially bilateral adrenaletcomy waswidely practised but nowadays is

preferred when patients are extremely unwell or not fit to

undergo pituitary surgery

Medical therapy to lower cortisol using metyrapone or ketoconazole is a useful short-term option prior to surgery or radiotherapy but cannot be recommended as a long-term definitive therapy for CD.

First-line Approach

Pituitary surgery is usually thefirst treatment option in pregnant CD

patients performed between the end of the first trimester and the early second

trimester a period associated with a lower rate of maternal and fetal complications

Second-line Approach

Medical therapy is a second-line option and was generally started during the

second or third trimesters.

Choosing Right Therapy:

Pregnancy

Bronstein M.D. et al, European Journal of Endocrinology, 2015

Pregnancy

In patients with CD during pregnancy, 42.5% were not submitted to specific

treatment of hypercortisolism, trying only to control comorbidities.

Radiotherapy and mitotane, are contraindicated in this period because of their potential harmful or teratogenic effects and their delayed outcomes

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