Pheochromocytoma and Paraganglioma:

Progress in Therapeutics

Camilo Jimenez, MDAssociate Professor

The University of Texas MD Anderson Cancer Center

Outline

• Introduction: anatomical definitions, clinical manifestations, biochemical diagnosis, genetics, imaging.

• Therapeutics:– Preoperative management

– Catecholamine crisis

– Constipation

– Clinical predictors of malignancy

– Systemic therapy

Anatomical definitions

Paraganglia

• Group of neuro-

endocrine cells that

migrate during

embryonic

development with

components of the

parasympathetic and

sympathetic ganglia.

Pheochromocytomas

• Chromaffin (+) tumors originated in the adrenal medulla. They may produce catecholamines such as epinephrine and/or norepinephrine predisposing to cardiovascular disease and other complications.

WHO 2004

Paragangliomas

• Paragangliomas are tumors that arise from extra-adrenal chromaffin cells and can originate either in the parasympathetic or sympathetic ganglia.

– Parasympathetic: chemodectomas, carotid body tumors, glomusjugular tumors, etc.

– Sympathetic: thoracic, abdominal, and pelvic tumors. They may produce norepinephrine and/or dopamine predisposing to cardiovascular disease and other endocrine complications

WHO 2004

Clinical Manifestations

• More than 100 symptoms and signs have been described in association with these tumors. Hypertension, headaches, palpitations, and diaphoresis are the most common ones.

Clinical manifestations

Symptom Frequency %

Headaches 60-90

Palpitations 50-70

Diaphoresis 55-75

Pallor 40-45

Nausea 20-40

Weight loss 10-20

Flushing 20-40

Fatigue 20-40

Anxiety – Panic attacks 25-40

Sustained hypertension 50-60

Paroxysmal hypertension 30

Orthostatic hypotension 10-50

Lenders, Lancet 2005

Clinical manifestations

• The clinical presentation of these tumors is highly variable and can overlap with the signs and symptoms associated with numerous other non-related clinical conditions.

• The critical first step in making the diagnosis is to suspect the presence of a tumor.

Biochemical Diagnosis

Sensitivity and specificity of screening

biochemical tests

Test Sensitivity % Specificity %

Plasma-free

metanephrines

99 89

Plasma catecholamines 84 81

Urinary catecholamines 86 88

Urinary fractionated

metanephrines

97 69

Urinary total

metanephrines

77 93

Vanillylmandelic acid 64 95

Lenders et al, JAMA, 2002

Drugs that may cause false positive elevations of plasma metanephrines

• Tricyclic antidepressants

• Alpha-blockers

• Beta-blockers

• Calcium channel

blockers

• Vasodilators

• Monoamine oxidase

inhibitors

• Sympathomimetics

• Stimulants

• Levodopa and

carbidopa

• Cocaine

Lenders, Lancet 2005

Imaging

• CT/MRI scans are sensitive tests for the localization of these tumors (>95%)

• Complimentary studies include MIBG, octreotide, FDG-PET, dopamine scans, etc

• 83-87% of these tumors are not malignant

Brito, Endocrine, 2015

Genetics

Strong hereditary background

0

5

10

15

20

25

30

35

40

45

50

1990 2005 2020

% hereditary cases

Neumann, NEJM, 2001; Amar L. JCO, 2005; Jimenez, JCEM, 2006; Dahia, 2011

MEN2, VHL, NF1, SDHx,TMEM127, MAX, FHEPAS-1

Therapeutics

Therapeutic challenges

• Patients with pheochromocytomas and paragangliomas are uncommon; thus, the clinicians experience on treating these patients is limited

• Treatment for acute and chronic complications is not well-recognized

• There are no expert guidelines on the follow-up and treatment of patients with malignant disease

• Therapeutic options for patients with malignancy are very limited

Preoperative Management

Back pain

Throbbing hedaches

Diaphoresis

Palpitations

Blood pressure 137/65

Normetanephrines = 2300 NG/ML (<400)

Metanephrines are normal

Von Hippel Lindau

Rich, Cancer Investigation, 2008

Surgery may provoke a release of

catecholaminesDrugs/Procedure Details

Procedure Mechanic intubation, peritoneal insufflation, tumor

palpation

Opiates Thiopental, nalbufine, meperidine, morphine

Neuromuscular

Blockers

Tubocurare, succinilcoline, mevacurio, atracurio

Tranquilizers and

antiemetics

Metoclopramide, droperidol

Simpaticomimetics Efedrine

Vagolitics Atropine

Impact of alpha-blockage on surgical

outcome

0

10

20

30

40

50

60

70

80

No alpha-blocker Alpha-blocker

Perioperative complications

Perioperative

complications

Goldstein, Annals of Surgery, 1999

Alpha-blocker

Type Dosage Half-life Side effects Availability/ Monthly

Price

Phenoxybenzamine

Non-selective,

non-competitive

10 – 140 mg/daily

10 days POP persistentHypotension,

reflex tachycardia,

nasal congestion

Edema

Difficult to get in many countriesUS 61.00-

1500

Prazosin Alpha-1 competitive

1-16 mg/daily

3- hours Orthostatism,tachycardia

Easy to find/ US

13.00

Terazosin Alpha-1Competitive

1-48 mg daily 24 hours Orthostatism,tachycardia

Easy to find/US

4.00

Doxazosin Alpha-1Competitive

1-48 mg daily 24 hours Orthostatism,tachycardia

Easy to find/US 20.00

Alpha-blockers

Organ Receptor Physiological Effect Symptom

Arterioles

Coronary Alpha-1 Contraction Angina

Skin and mucosa Alpha-1 Contraction Pallor

Skeletal muscle Alpha-1, Beta-2 Contraction,dilation

Cerebral Alpha-1 Contraction Stroke

Pulmonary Alpha-1 Contraction Pulmonary edema

Abdominal Viscera Alpha-1 Contraction Intestinal ischemia

Renal Alpha-1 Contraction Renal failure

Veins Alpha-1, Beta-2 Contractiondilation

Orthostatism

Heart

SA node Beta-1 ⌂ Inotropism Angina, arrhythmias

Atrium Beta-1 ⌂ Inotropism Angina, arrhythmias

AV node Beta-1 ⌂ Inotropism Angina, arrhythmias

His-Purkinje Beta-1 ⌂ Inotropism Angina, arrhythmias

Ventricle Beta-1 ⌂ Inotropism Angina, arrhythmias

Beta-blockers

• They should be initiated once the patient develops orthostatism and/or reflex tachycardia which indicate that alpha blockage has been obtained.

• Selective: Metoprolol, Atenolol

• Non-selective: Propranolol

• Labetalol and Carvedilol

Calcium Channel Blockers and ACE

inhibitors

• Indications:– Mild cases (e.g. small tumors identified by

radiographic screening in patient with hereditary predisposition) or unable to tolerate alpha-blockers

– As a supplement to alpha- and beta-blockers when BP is still difficult to control

– As a supplement to alpha- and beta-blockers in order to prevent toxicity associated with higher doses

Metyrosine

• Tyrosine hydroxilase inhibitor

• It decreases catecholamine secretion

• It has side effects that frequently prevent the use of effective doses: fatigue, depression, anxiety, diarrhea

• Price > US 1000

How long it takes to prepare someone

for surgery?

• 7-14 days

• At MDACC the average time is 8 days thanks to communication with the patient daily and frequent drug adjustments

• There is no need to admit the patient to the hospital or to use metyrosine.

• The patient should have a normal salt diet and free water intake. IV fluids may be necessary before surgery.

Catecholamine Crisis

Case Presentation

• 40 year old man with a history of a malignant paraganglioma presents to the ER with chest pain, shortness of breath, nausea, vomiting, headaches (“his head is about to explode”), and palpitations.

• Blood pressure is 230/140 mmHg, Pulse 124 pmn

• EKG shows sinus tachycardia. Troponin is normal. BNP is elevated at 2118.

• The patient is not compliant with his antihypertensive treatment

Medication Preparation Dose Details

Nitroprusside: dilator (arterial > vein); rapid action 30 seconds, peak at two

minutes

50 mg in 250 cc of D5W. Should be protected from the light

0.5-5 ug/kg/minNo used for more than 24 hours.

Cyanide toxicity/lactic acidosis; tachycardia, hypotension

Nicardapine calcium channel blocker; vasodilator

25 mg in 250 cc of D5W

Loading 1-2.5 mg/1-2 min; Infusion 5-15 mg/h

Reflex mild tachycardia, prevents coronary spasm

Magnesium Sulfate, vasodilator, antiarrhytmic,decreases

catecholamine secretion

40 g in 500 cc of Ringer solution

Loading 1-2 g; infusion 1-3 g/h

Muscular weakness, high magnesium

Fenoldopam 10 mg in 250 cc of NS

0.1-1.6 ug/kg/min Renoprotective, causes tachycardia

Phentolamine alpha-blocker

100 mg in 500 cc of D5W

Bolus 5-15 mg; infusion 0.2-2mg/min

Half-life 19 minutesTachycardia

Urapidil 12.5 g in 250 cc of NS CNS effects

Esmolol

• B1-blocker

• Short half-life of 9 minutes

• Very fast action

• Excellent to control tachycardia once a vasodilator has been started

• Loading 500 ug/kg over one minute

• Infusion 50-300 ug/kg/min

Gastrointestinal disease

Case presentation

• 46 year-old man with history of malignant paraganglioma presents with hypertension, palpitations, headaches, sweats, and constipation for longer than 1 year (last bowel movement was hard and happened 8 days ago). The patient noticed fever, nausea, and lack of appetite. On physical examination bowel sounds are decreased.

• Creatinine and WBC are elevated

• Plasma normetanephrines 49.5 nmol/L (<0.90)

Case presentation

Constipation

• It happens in 6% of patients

• It is usually mild but occasional cases are severe

• It may predispose to hemorrhoids, stercoral ulcers, toxic megacolon, bleeding, perforation, and obstruction.

• Alpha- and beta-blockers do not treat constipation. Laxatives are required and their chose depends on the severity.

• It is preventable with diet rich in fiber and liquids

Thosani, EJE, 2015

Treatment of Metastatic Disease.

Overall Survival Metastatic vs. Non-

metastatic PH/SPG

60%

Jimenez C, Curr Oncol Rep, 2013

50% have synchronic metastases50% have metachronic metastases

PASS

Thomson, Am J Surg Pathol, 2002

Wu, Am J Surg Pathol, 2009

MIBG

Meta-Iodobenzylguanidine (MIBG)

• Described by Wieland et al in 1979 at the University of Michigan

• Iodination in the meta position

– Stable and highly resistant to in vivo metabolism

• ~90% excreted intact in the urine

– 40-50% within 24 hours

• MIBG is not a norepinephrine analog

– Substrate for norepinephrine transporter (NET)

Norepinephrine Transporter

Summary of the largest clinical

studies with MIBG and

chemotherapyStudy ORR Median OS

MIBG

Krempff 33 58 months

Safford 38 UK

Gredick 47 UK

Gonias 27 42 months

Wakabashi UK 56 months

Chemotherapy

Ayala-Ramirez 25 5 year OS 51%

Huang 55 3 year OS 50%

Tanabe 47 UK

Hadoux 33 3 year OS 55%

Baudin Eric, EJE, 2014

Azedra®

Similarity:

▪ Both MIBG labeled at the meta position with I-131

▪ Both target the Noradrenaline transporter

Differences: Ultratrace I-131 MIBG Conventional I-131 MIBG

Manufacturing process

From solid phase precursor (resin)

By simple isotope exchange

Specific activity of drug product

~92.5 MBq/μg

(very high)

~ 1.59 MBq/μg1

(low)

Unlabeled MIBG ineach dose

None Large amount

Safety No cold MIBG, low CV risks Excess MIBG, high CV risks

Efficacy High levels of radioactivitydelivered to tumor per dose

Low levels of radioactivitydelivered to tumor per dose

Ultratrace® vs. Conventional I-131 MIBG

AZEDRA® (iobenguane I 131) in patients with metastatic and/or recurrent and/or

unresectable pheochromocytoma or paraganglioma: Results of a multicenter,

open-label, pivotal phase 2b study

NCT00874614

Study Design

•Primary endpoint

• Proportion of patients with a reduction

(including discontinuation) of all

antihypertensive medication(s) by at least

50% for ≥ 6 months

•Secondary endpoints

• Objective tumor response by RECIST 1.0

• Biochemical tumor marker response

• Overall survival up to 5 years post- first

therapeutic dose

• Safety

Study Duration and Treatment

• 12-month efficacy phase followed by 4-years long-term follow-up

• Dosimetric dose: 111-222 MBq (3-6 mCi)

• Up to 2 therapeutic doses:– Each at ~18.5 GBq (500 mCi) (or 296 MBq/kg

[8 mCi/kg] for Patients ≤ 62.5 kg)

approximately 3 months apart

Disposition of Patients

Enrolled N=81

Did not meet

eligibility criteria

(n=7)

Received

Dosimetric Dose, N=74

Not MIBG-avid (n=5); Early

withdrawal (n=1)

Received 1st

Therapeutic DoseN=68

Received 2nd

Therapeutic DoseN=50

Discontinued from Efficacy Phase

(n=23)

Completed the

Efficacy Phase, N=45

1. Analysis cutoff : March

10, 2017

LTFU phase

Completed/

Continuing in LTFUN=231

Demographics and

Baseline Characteristics

Characteristic All Dosed (N=74)

Male sex, n (%) 41 (55.4)

Age at enrollment (years)

Mean (std dev) 51.1 (13.77)

Median (Min, Max) 54.5 (16, 76)

Age group, n (%)

< 18 1 (1.4)

18 – 30 7 (9.5)

30 – 64 54 (73.0)

≥ 65 12 (16.2)

Primary diagnosis at enrollment, n (%)

Pheochromocytoma 53 (71.6)

Paraganglioma 21 (28.4)

Characteristic All Dosed (N=74)

Prior Treatments, n (%)

Includes Surgery 66 (89.2)

Includes Conventional I-131

MIBG

22 (29.7)

Includes Chemotherapy

(CVD and/or others)

28 (37.8)

Number of Prior Treatment Modalities, n (%)

One only 21 (28.4)

Two only 31 (41.9)

Three or more 20 (27.0)

None documented 2 (2.7)

Location of Metastases, n (%)

Lymph nodes 40 (54.1)

Bone 39 (52.7)

Lung and/or Liver

metastases1

32 (50.0)1

Others 24 (32.4)

Clinical Benefit (primary

endpoint)

• As of primary analysis data cutoff, the primary endpoint was achieved in 25% (95% CI, 0.16 – 0.37) of all patients

who received at least one Tx dose, achieving the pre-specified success criteria. Specifically, it was achieved in

32% (16/50) of patients who received two Tx doses, and

5.6% (1/18) of patients who received only one Tx dose

• Median duration of clinical benefit in primary endpoint responders was 13.3 (range 8.0-60.2) months

• 31.4% (16/51) of patients who were not responders on the

primary endpoint also experienced ≥ 50% reduction of antihypertensive medication(s), albeit for < 6 months

Pati

en

ts w

ho

exp

eri

en

ced

a c

lin

ical

ben

efi

t (S

ub

ject

ID)

Time (months)

Duration of ≥ 50% Reduction in Antihypertensive Use

Anti-tumor Activity

Best confirmed overall tumor responsea

At least onetherapeutic dose

(N=68)

One Therapeutic dose

(N=18)

Twotherapeutic doses

(N=50)

Evaluated patients*,

n

64 14 50

CR 0 0 0

PRa 15 (23.4) 0 15 (30.0)

SDb 44 (68.8) 10 (71.4) 34 (68.0)

PD 3 (4.7) 2 (14.3) 1 (2.0)

No assessment 2 (3.1) 2 (14.3) 0CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease*Patients evaluable for response were done by central review. No assessment signifies patients who discontinued therapy before the first scana Per RECIST, PR required confirmation at a subsequent visitb Including MR=moderate response

• Best confirmed overall response during the 12-month efficacy phase was PR,

achieved in 23.4% (15/64) of patients who received at least one therapeutic dose, and 30% (15/50) of patients who received two therapeutic doses

• Overall, 92.2% of patients achieved tumor response of confirmed PR or SD

Persistence of Tumor Response• The proportion of patients who experienced PR increased over

time, suggesting persistent anti-tumor effects of treatment

• The majority of patients remaining at Month 12 continued to

have PR/SDOverall Tumor Response over Time by RECIST in Patients Who

Received at Least One Therapeutic Dose (N=68)

Response by

RECIST 1.0

Month 3

n (%)

Month 6

n (%)

Month 9

n (%)

Month 12

n (%)

Complete

Response0 0 0 0

Partial Response 4 (5.9) 6 (8.8) 10 (14.7) 16 (23.5)

Stable Disease 57 (83.8) 39 (57.4) 36 (52.9) 24 (35.3)

Progressive

Disease

3 (4.4) 1 (1.5) 4 (5.9) 5 (7.4)

No Evaluation 4 (5.9) 22 (32.4) 18 (26.5) 23 (33.8)

Tumor Response and

Primary Endpoint• Confirmed PR occurred in 41.2% (7/17) of patients who were considered

responders for the primary endpoint, and 17.0% (8/47) of patients who were not responders for the primary endpoint

• 100% (17/17) of primary endpoint responders achieved PR/SD during the efficacy phase

• 89.3% (41/47) of primary endpoint non-responders achieved PR/SD; 6.4% (3/47) had PD Maximum Percent Change from Baseline in Measurable Target

Lesion

RECIST 1.0, Central

Review

One primary endpoint

responder is not included in the graph because the patient did not have measurable target lesions

Safety

• The most common (≥50%) treatment-emergent adverse events (TEAEs) in all patients who received any dose of the drug were nausea, myelosuppression, and fatigue

• No severe acute hypertension or hypertensive crises were observed in patients during or immediately following drug administration

Incidence of All-grade TEAEs

Occurring in at Least 20% of

Patients

TEAE,

preferred term

All dosed (N=74)

n (%)

Nausea 53 (71.6)

Thrombocytopenia 49 (66.2)

Anemia 43 (58.1)

Leukopenia 41 (55.4)

Fatigue 41 (55.4)

Neutropenia 39 (52.7)

Vomiting 36 (48.6)

Dizziness 28 (37.8)

Dry mouth 28 (37.8)

Headache 21 (28.4)

Hypotension 18 (24.3)

Decreased appetite 17 (23.0)

Constipation 16 (21.6)

Diarrhea 16 (21.6)

Study Conclusions

• Study IB12B, the largest prospective clinical trial to date, has demonstrated multiple clinical benefits of AZEDRA® (iobenguane I 131) treatment– Control of catecholamine-associated hypertension and sustained

reduction of antihypertensive medications – Majority of patients experienced anti-tumor benefit, both primary

endpoint responders and non-responders– Greater clinical benefits in patients who received two therapeutic

doses

• The most common treatment-emergent adverse events were consistent with expected radiation-related risks of hematologic toxicities, nausea/vomiting, fatigue, and dizziness– Hematological toxicities resolved within 4-8 weeks and without the

need for stem cell transplantation– No severe hypertension, hypertensive crises or acute CV side effects

were observed

Other Therapies

• Clinical trials:

– Cabozantinib

– Hypoxia Inducible Factor Inhibitor

– Luthatera

– Immunotherapy

• Chemotherapy

Conclusions

• Patients with PPG may be prone to metabolic or tumor burden complications that may impact survival.

• Genomic, molecular studies, and clinical observations are very important to identify potential therapies and impulse trial development for this disease

• A brighter future for patients with MPP is at front!

cjimenez@mdanderson.org