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 3 rd 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
OH H H OH C C H NH 2 OH NORADRENALINE OH H H OH C C H OH N H 135 patients from 3 German referral centres (2003-2012) ADRENALINE CH 3 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 Riester et al. Eur J Endocrinol 2015
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) * Grimson et al J Am Med Assoc 1949
Berends et al. JCEM 2020
Goals of pre-surgical management • Prevent anesthesia and surgery induced catecholamine storm and its consequences on the cardiovascular system BUT ALSO • Prevent PRE-operative complications • Relieve of symptoms • Control blood pressure, heart rate, volume status, glucose metabolism, bowel motility
Pre-surgical management Berends et al. JCEM 2020
α -adrenergic receptor blockers
PRESCRIPT trial First prospective study on pre- treatment in PPGL To compare the efficacy of phenoxybenzamine and doxazosin Buitenwerf et al. JCEM 2020
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
Debate on the necessity of blockade 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 (?) • No data on vasoactive drugs and fluids required (determinants of outcome) • Results from high volume center is not generally applicable Groeben, Walz et al. Br J Anaesthesia 2017
Debate on the necessity of blockade Do we need a randomized trial? • Ethics • Sample size: n>1000 to detect 50% decrease in complications Risk stratification: who (not) to treat?? • 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
Partial, cortical-sparing adrenalectomy • 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?) Neumann et al., JAMA 2019
Partial, cortical-sparing adrenalectomy • 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 • ‘Cortical-sparing adrenalectomy 13% developed local recurrence • should be considered in all patients 2% developed metastases (unrelated to • with hereditary PHEO <5 cm’ partial ADX?) Neumann et al., JAMA 2019
Partial, cortical-sparing adrenalectomy • 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 • ‘Cortical-sparing adrenalectomy 13% developed local recurrence • should be considered in all patients 2% developed metastases (unrelated to • with hereditary PHEO <5 cm’ partial ADX?) SHARED DECISION Neumann et al., JAMA 2019
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 Management of catecholamine induced symptoms / complications • adrenergic blockade • laxatives • (metyrosine) Targeted treatment Nölting, Grossman, Pacak. Exp Clin Endocrinol Diabetes 2019
Molecular classification of PPGL Fishbein et al. Cancer Cell 2017
Molecular classification of PPGL Fishbein et al. Cancer Cell 2017
Molecular targeting in VHL Cabozantinib Axitinib PT2385/PT2399 Gläsker et al. Oncotargets and Therapy 2020
Molecular targeting in VHL Experience in PPGL Cabozantinib Axitinib PT2385/PT2399 Gläsker et al. Oncotargets and Therapy 2020, Jimenez et al. JCEM 2009 / Curr Oncol Rep 2017
Sunitinib in m+ PPGL 32 yo female with VHL with m+ PPGL, RCC and pNET Jimenez et al. JCEM 2009
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
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