Management of pheochromocytoma & paraganglioma Henri Timmers, - - PowerPoint PPT Presentation

Management of pheochromocytoma & paraganglioma

Henri Timmers, MD, PhD Radboud University Medical Center

• Dept. of Internal medicine, section of Endocrinology

Disclosures

None

Overview

Management of pheochromocytoma/paraganglioma (PPGL)

• Peri-surgical
• Metastatic disease

pheochromocytoma paraganglioma

PPGL in VHL

Genotype dependent

• Penetrance 25-30%
• Dx mainly in 3rd decade (from 4 yo)
• 95% adrenal, 5% extra-adrenal (mainly retroperitoneum)
• 15% bilateral / multifocal (in children 38%)
• 5% metastatic
• Noradrenergic

Maher et al. Q J Medicatie 1990, Aufforth et al. JCEM 2015, Barontini et al. BP&RCE&M 2010, Eisenhofer et al. Clinical Chemistry 2011, Bausch et al. ERC 2013

Riester et al. Eur J Endocrinol 2015

135 patients from 3 German referral centres (2003-2012) 15 (11%) with life threatening complications, 2 died

Tako-Tsubo cardiomyopathy, myocardial infarction, acute pulmonary edema, stroke, ischemic ileus, acute renal failure, hypertensive crisis, multi organ failure

OH OH N OH OH C H H C H OH H CH3 C H H NH2 C H OH

NORADRENALINE ADRENALINE

* Grimson et al J Am Med Assoc 1949

Complications of PPGL surgery

• Dramatic fall in mortality (from 40% to 1-3%) and morbidity (current

cardiovascular complication rate 9%)

• Due to advances in

 medical management: α-adrenergic blockade introduced in 1949 *  anaesthesiology  surgery (minimally invasive)  early diagnosis (adrenal incidentaloma and carrier screening)

Berends et al. JCEM 2020

• Prevent anesthesia and surgery induced catecholamine storm and its consequences
• n the cardiovascular system

BUT ALSO

• Prevent PRE-operative complications
• Relieve of symptoms
• Control blood pressure, heart rate, volume status, glucose metabolism, bowel

motility

Goals of pre-surgical management

Berends et al. JCEM 2020

Pre-surgical management

α-adrenergic receptor blockers

PRESCRIPT trial

Buitenwerf et al. JCEM 2020

First prospective study on pre- treatment in PPGL To compare the efficacy of phenoxybenzamine and doxazosin

PRESCRIPT trial

144 patients, 30 day post-operative follow-up

• No mortality
• Cardiovascular complication rate of 8%, related to hemodynamic instability

Phenoxy vs doxa

• Cummulative time outside BP range (SBP>160, MAP <60 mmHg) 11.1% vs 12.2%, NS
• No differences in post op hypotension & complications
• More intraoperative hemodynamic instablility with doxa: higher need of vasodilator drugs
• Post-operative hypotension in 40%, vasopressors needed in 33%
• Side effects in 85%: grade I-II, transient (no difference between phenoxy/doxa)

Buitenwerf et al. JCEM 2020

Groeben, Walz et al. Br J Anaesthesia 2017

Groeben, Walz et al.

• Retrospective analysis of 110 patients WITH α-blockade

versus 166 with ‘no’ blockade

• No difference in max SBP and episodes SBP >250 mmHg
• No complications observed (?)

Debate on the necessity of blockade

• No data on vasoactive drugs and fluids required (determinants of outcome)
• Results from high volume center is not generally applicable

Do we need a randomized trial?

• Ethics
• Sample size: n>1000 to detect 50% decrease in complications
• Risk stratification: who (not) to treat??

Debate on the necessity of blockade

with blockade without blockade

Drugs to be avoided in patients with PPGL

Pacak et al., JCEM 2007 Neary et al. N Engl J Med 2011

Surgical management

• Scopic adrenalectomy
• posterior retroperitoneoscopic
• transperitoneal laparoscopic (BMI >45 and tumor >7cm)
• Open adrenalectomy (‘large and invasive’)

Langenhuijsen et al. J Endourol 2013 Walz et al. World J Surg. 2010

• 625 patients with bilateral ADX for PHEO
• 64% synchronous, 36% metachronous
• 35% VHL
• 324 (52%) planned as partial ADX (28% at

initial surgery); technical success in 77%

• After ‘successful’ partial ADX
• 24% still developed adrenal insufficiency
• 13% developed local recurrence
• 2% developed metastases (unrelated to

partial ADX?)

Partial, cortical-sparing adrenalectomy

Neumann et al., JAMA 2019

• 625 patients with bilateral ADX for PHEO
• 64% synchronous, 36% metachronous
• 35% VHL
• 324 (52%) planned as partial ADX (28% at

initial surgery); technical success in 77%

• After ‘successful’ partial ADX
• 24% still developed adrenal insufficiency
• 13% developed local recurrence
• 2% developed metastases (unrelated to

partial ADX?)

Partial, cortical-sparing adrenalectomy

Neumann et al., JAMA 2019

‘Cortical-sparing adrenalectomy should be considered in all patients with hereditary PHEO <5 cm’

• 625 patients with bilateral ADX for PHEO
• 64% synchronous, 36% metachronous
• 35% VHL
• 324 (52%) planned as partial ADX (28% at

initial surgery); technical success in 77%

• After ‘successful’ partial ADX
• 24% still developed adrenal insufficiency
• 13% developed local recurrence
• 2% developed metastases (unrelated to

partial ADX?)

Partial, cortical-sparing adrenalectomy

Neumann et al., JAMA 2019

‘Cortical-sparing adrenalectomy should be considered in all patients with hereditary PHEO <5 cm’

SHARED DECISION

Metastatic PPGL

• All PPGLs are potentially malignant; no reliable histological / molecular markers
• Metastatic defined by lesions in tissues where chromaffin cells are normally absent:

lymph nodes, bone, liver, lung

• 5 year survival 40-74%
• SDHB mutation strongest predictor of metastases / prognosis

Lam et al. Endocrine pathology 2017; Chrisoulidou et al. Endocr Relat Cancer 2007

Management of metastatic PPGL

Nölting, Grossman, Pacak. Exp Clin Endocrinol Diabetes 2019

Targeted treatment

Management of catecholamine induced symptoms / complications

• adrenergic blockade
• laxatives
• (metyrosine)

Molecular classification of PPGL

Fishbein et al. Cancer Cell 2017

Fishbein et al. Cancer Cell 2017

Molecular classification of PPGL

Molecular targeting in VHL

Gläsker et al. Oncotargets and Therapy 2020

Cabozantinib Axitinib PT2385/PT2399

Molecular targeting in VHL

Gläsker et al. Oncotargets and Therapy 2020, Jimenez et al. JCEM 2009 / Curr Oncol Rep 2017

Cabozantinib Axitinib

Experience in PPGL

PT2385/PT2399

Sunitinib in m+ PPGL

Jimenez et al. JCEM 2009

32 yo female with VHL with m+ PPGL, RCC and pNET

Sunitinib in m+ PPGL

Ayala-Ramirez et al. JCEM 2010

FIrst Randomized STudy in Malignant Progressive Pheochromocytoma and Paraganglioma

Management of metastatic PPGL

Nölting, Grossman, Pacak. Exp Clin Endocrinol Diabetes 2019

Conclusion

Endocrine Society clinical practice guideline on PPGL, JCEM 2014

Conclusion

Endocrine Society clinical practice guideline on PPGL, JCEM 2014

Thank you