Metastatic Pheochromocytoma and Paraganglioma: Focus on Therapeutics

P.-F. Plouin; P. Fitzgerald; T. Rich; M. Ayala-Ramirez; N. D. Perrier; E. Baudin; C. Jimenez

doi:10.1055/s-0031-1299707

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2012; 44(05): 390-399
DOI: 10.1055/s-0031-1299707

Review

Metastatic Pheochromocytoma and Paraganglioma: Focus on Therapeutics

P.-F. Plouin

¹Paris-Descartes University, INSERM U-970, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit, Paris cedex 15, France

,

P. Fitzgerald

²Department of Endocrinology, University of California-San Francisco, San Francisco, CA, USA

,

T. Rich

³Department of Endocrine Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

,

M. Ayala-Ramirez

⁴Endocrine Neoplasia and Hormone Disorders, Unit 1461, The University of Texas MD Houston, Texas, USA

,

N. D. Perrier

³Department of Endocrine Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

,

E. Baudin

⁵Département de Médecine Nucléaire et de Cancérologie Endocrinienne,Institut Gustave Roussy 39 Bis, Villejuif, France

,

C. Jimenez

⁴Endocrine Neoplasia and Hormone Disorders, Unit 1461, The University of Texas MD Houston, Texas, USA

› Author Affiliations

Abstract

Metastatic pheochromocytomas and paragangliomas are rare and challenging tumors. The tumor burden, combined with excessive catecholamine production, predispose to a broad spectrum of complications that range from spinal cord compression to any organ damage, all of which may lead to decreased quality of life and overall survival. Current therapies include surgery, systemic chemotherapy and radiopharmaceutical agents. Surgery is often a preferred therapy because it may cure or allow a long-term remission in patients with locoregional or isolated resectable distant metastases. Additionally, surgery can palliate symptoms related to tumor burden or catecholamine excess. However, in patients for whom surgery is not an option, systemic chemotherapy and radiopharmaceutical agents are preferred options. Systemic chemotherapy and radiopharmaceutical agents such as ¹³¹I-Metaiodobenzylguanidine (¹³¹I-MIBG) may cause partial responses or stabilization of disease with better blood pressure control and symptomatic and performance status improvement. However, as these therapies are only palliative, patients’ quality of life and personal preferences should always be considered. The recognition of molecular pathways involved in the pheochromocytoma and paraganglioma tumorigenesis has driven the development of new therapeutic options. Agents such as tyrosine kinase, MAPK, PI3K, or hypoxia inducible factor inhibitors, alone or in combination, may represent novel therapeutic strategies that could be evaluated in prospective clinical trials. Transcriptional profiling and the development of personalized cancer medicine will help to pave the way for more specific therapeutic approaches and combinations.

Key words

paraganglioma - pheochromocytoma - adrenal tumor

Full Text

References

References
1 DeLellis RLR, Heitz P, Eng C. Pathology and Genetics: Tumours of Endocrine Organs (IARC WHO Classification of Tumours). Lyon, France: IARC Press; 2004
2 Amar L, Bertherat J, Baudin E, Ajzenberg C, Bressac-de PB, Chabre O, Chamontin B, Delemer B, Giraud S, Murat A, Niccoli-Sire P, Richard S, Rohmer V, Sadoul JL, Strompf L, Schlumberger M, Bertagna X, Plouin PF, Jeunemaitre X, Gimenez-Roqueplo AP. Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 2005; 23: 8812-8818
3 Feng F, Zhu Y, Wang X, Wu Y, Zhou W, Jin X, Zhang R, Sun F, Kasoma Z, Shen Z. Predictive factors for malignant pheochromocytoma: analysis of 136 patients. J Urol 2011; 185: 1583-1590
4 Goldstein RE, O’Neill Jr JA, Holcomb III GW, Morgan III WM, Neblett III WW, Oates JA, Brown N, Nadeau J, Smith B, Page DL, Abumrad NN, Scott Jr HW. Clinical experience over 48 years with pheochromocytoma. Ann Surg 1999; 229: 755-764
5 Chrisoulidou A, Kaltsas G, Ilias I, Grossman AB. The diagnosis and management of malignant phaeochromocytoma and paraganglioma. Endocr Relat Cancer 2007; 14: 569-585
6 Ayala-Ramirez M, Feng L, Johnson MM, Ejaz S, Habra MA, Rich T, Busaidy N, Cote GJ, Perrier N, Phan A, Patel S, Waguespack S, Jimenez C. Clinical Risk Factors for Malignancy and Overall Survival in Patients with Pheochromocytomas and Sympathetic Paragangliomas: Primary Tumor Size and Primary Tumor Location as Prognostic Indicators. J Clin Endocrinol Metab 2011; 96: 717-725
7 Amar L, Bertherat J, Baudin E, Ajzenberg C, Bressac-de Paillerets B, Chabre O, Chamontin B, Delemer B, Giraud S, Murat A, Niccoli-Sire P, Richard S, Rohmer V, Sadoul JL, Strompf L, Schlumberger M, Bertagna X, Plouin PF, Jeunemaitre X, Gimenez-Roqueplo AP. Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 2005; 23: 8812-8818
8 Dahia PL, Ross KN, Wright ME, Hayashida CY, Santagata S, Barontini M, Kung AL, Sanso G, Powers JF, Tischler AS, Hodin R, Heitritter S, Moore F, Dluhy R, Sosa JA, Ocal IT, Benn DE, Marsh DJ, Robinson BG, Schneider K, Garber J, Arum SM, Korbonits M, Grossman A, Pigny P, Toledo SP, Nose V, Li C, Stiles CD. A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet 2005; 1: 72-80
9 Waguespack SG, Rich T, Grubbs E, Ying AK, Perrier ND, Ayala-Ramirez M, Jimenez C. A Current Review of the Etiology, Diagnosis, and Treatment of Pediatric Pheochromocytoma and Paraganglioma. J Clin Endocrinol Metab 2010; 92: 779-786
10 Pacak K, Eisenhofer G, Ahlman H, Bornstein SR, Gimenez-Roqueplo AP, Grossman AB, Kimura N, Mannelli M, McNicol AM, Tischler AS. Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005. Nat Clin Pract Endocrinol Metab 2007; 3: 92-102
11 Maher ER. Von Hippel-Lindau disease. Curr Mol Med 2004; 4: 833-842
12 Gottlieb E, Tomlinson IP. Mitochondrial tumour suppressors: a genetic and biochemical update. Nat Rev Cancer 2005; 5: 857-866
13 Pollard PJ, Briere JJ, Alam NA, Barwell J, Barclay E, Wortham NC, Hunt T, Mitchell M, Olpin S, Moat SJ, Hargreaves IP, Heales SJ, Chung YL, Griffiths JR, Dalgleish A, McGrath JA, Gleeson MJ, Hodgson SV, Poulsom R, Rustin P, Tomlinson IP. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet 2005; 14: 2231-2239
14 Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, Pan Y, Simon MC, Thompson CB, Gottlieb E. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 2005; 7: 77-85
15 Brouwers FM, Eisenhofer G, Tao JJ, Kant JA, Adams KT, Linehan WM, Pacak K. High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing. J Clin Endocrinol Metab 2006; 91: 4505-4509
16 Neumann HP, Pawlu C, Peczkowska M, Bausch B, McWhinney SR, Muresan M, Buchta M, Franke G, Klisch J, Bley TA, Hoegerle S, Boedeker CC, Opocher G, Schipper J, Januszewicz A, Eng C. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA 2004; 292: 943-951
17 Klein RD, Jin L, Rumilla K, Young Jr WF, Lloyd RV. Germline SDHB mutations are common in patients with apparently sporadic sympathetic paragangliomas. Diagn Mol Pathol 2008; 17: 94-100
18 King KS, Prodanov T, Kantorovich V, Fojo T, Hewitt JK, Zacharin M, Wesley R, Lodish M, Raygada M, Gimenez-Roqueplo AP, McCormack S, Eisenhofer G, Milosevic D, Kebebew E, Stratakis CA, Pacak K. Metastatic Pheochromocytoma/Paraganglioma Related to Primary Tumor Development in Childhood or Adolescence: Significant Link to SDHB Mutations. J Clin Oncol 2011; 29: 4137-4142
19 Boedeker CC, Neumann HP, Maier W, Bausch B, Schipper J, Ridder GJ. Malignant head and neck paragangliomas in SDHB mutation carriers. Otolaryngol Head Neck Surg 2007; 137: 126-129
20 Benn DE, Gimenez-Roqueplo AP, Reilly JR, Bertherat J, Burgess J, Byth K, Croxson M, Dahia PL, Elston M, Gimm O, Henley D, Herman P, Murday V, Niccoli-Sire P, Pasieka JL, Rohmer V, Tucker K, Jeunemaitre X, Marsh DJ, Plouin PF, Robinson BG. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab 2006; 91: 827-836
21 Burnichon N, Rohmer V, Amar L, Herman P, Leboulleux S, Darrouzet V, Niccoli P, Gaillard D, Chabrier G, Chabolle F, Coupier I, Thieblot P, Lecomte P, Bertherat J, Wion-Barbot N, Murat A, Venisse A, Plouin PF, Jeunemaitre X, Gimenez-Roqueplo AP. The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. J Clin Endocrinol Metab 2009; 94: 2817-2827
22 Ricketts CJ, Forman JR, Rattenberry E, Bradshaw N, Lalloo F, Izatt L, Cole TR, Armstrong R, Kumar VK, Morrison PJ, Atkinson AB, Douglas F, Ball SG, Cook J, Srirangalingam U, Killick P, Kirby G, Aylwin S, Woodward ER, Evans DG, Hodgson SV, Murday V, Chew SL, Connell JM, Blundell TL, Macdonald F, Maher ER. Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Hum Mutat 2010; 31: 41-51
23 Schiavi F, Milne RL, Anda E, Blay P, Castellano M, Opocher G, Robledo M, Cascon A. Are we overestimating the penetrance of mutations in SDHB?. Hum Mutat 2010; 31: 761-762
24 Pasini B, McWhinney SR, Bei T, Matyakhina L, Stergiopoulos S, Muchow M, Boikos SA, Ferrando B, Pacak K, Assie G, Baudin E, Chompret A, Ellison JW, Briere JJ, Rustin P, Gimenez-Roqueplo AP, Eng C, Carney JA, Stratakis CA. Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet 2008; 16: 79-88
25 Gill AJ, Pachter NS, Chou A, Young B, Clarkson A, Tucker KM, Winship IM, Earls P, Benn DE, Robinson BG, Fleming S, Clifton-Bligh RJ. Renal tumors associated with germline SDHB mutation show distinctive morphology. Am J Surg Pathol 2011; 35: 1578-1585
26 Ricketts C, Woodward ER, Killick P, Morris MR, Astuti D, Latif F, Maher ER. Germline SDHB mutations and familial renal cell carcinoma. J Natl Cancer Inst 2008; 100: 1260-1262
27 Vanharanta S, Buchta M, McWhinney SR, Virta SK, Peczkowska M, Morrison CD, Lehtonen R, Januszewicz A, Jarvinen H, Juhola M, Mecklin JP, Pukkala E, Herva R, Kiuru M, Nupponen NN, Aaltonen LA, Neumann HP, Eng C. Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma. Am J Hum Genet 2004; 74: 153-159
28 Cascon A, Montero-Conde C, Ruiz-Llorente S, Mercadillo F, Leton R, Rodriguez-Antona C, Martinez-Delgado B, Delgado M, Diez A, Rovira A, Diaz JA, Robledo M. Gross SDHB deletions in patients with paraganglioma detected by multiplex PCR: a possible hot spot?. Genes Chromosomes Cancer 2006; 45: 213-219
29 Gill AJ, Benn DE, Chou A, Clarkson A, Muljono A, Meyer-Rochow GY, Richardson AL, Sidhu SB, Robinson BG, Clifton-Bligh RJ. Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes. Hum Pathol 2010; 41: 805-814
30 van Nederveen FH, Gaal J, Favier J, Korpershoek E, Oldenburg RA, de Bruyn EM, Sleddens HF, Derkx P, Riviere J, Dannenberg H, Petri BJ, Komminoth P, Pacak K, Hop WC, Pollard PJ, Mannelli M, Bayley JP, Perren A, Niemann S, Verhofstad AA, de Bruine AP, Maher ER, Tissier F, Meatchi T, Badoual C, Bertherat J, Amar L, Alataki D, Van Marck E, Ferrau F, Francois J, de Herder WW, Peeters MP, van Linge A, Lenders JW, Gimenez-Roqueplo AP, de Krijger RR, Dinjens WN. An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. Lancet Oncol 2009; 10: 764-771
31 Timmers HJ, Kozupa A, Eisenhofer G, Raygada M, Adams KT, Solis D, Lenders JW, Pacak K. Clinical presentations, biochemical phenotypes, and genotype-phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas. J Clin Endocrinol Metab 2007; 92: 779-786
32 Zelinka T, Musil Z, Duskova J, Burton D, Merino MJ, Milosevic D, Widimsky Jr J, Pacak K. Metastatic pheochromocytoma: does the size and age matter?. Eur J Clin Invest 2011; 41: 1121-1128
33 Park J, Song C, Park M, Yoo S, Park SJ, Hong S, Hong B, Kim CS, Ahn H. Predictive characteristics of malignant pheochromocytoma. Korean J Urol 2011; 52: 241-246
34 van der Harst E, Bruining HA, Jaap Bonjer H, van der Ham F, Dinjens WN, Lamberts SW, de Herder WW, Koper JW, Stijnen T, Proye C, Lecomte-Houcke M, Bosman FT, de Krijger RR. Proliferative index in phaeochromocytomas: does it predict the occurrence of metastases?. J Pathol 2000; 191: 175-180
35 John H, Ziegler WH, Hauri D, Jaeger P. Pheochromocytomas: can malignant potential be predicted?. Urology 1999; 53: 679-683
36 Amar L, Baudin E, Burnichon N, Peyrard S, Silvera S, Bertherat J, Bertagna X, Schlumberger M, Jeunemaitre X, Gimenez-Roqueplo AP, Plouin PF. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J Clin Endocrinol Metab 2007; 92: 3822-3828
37 Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Kerlan V, Plouin PF, Rotig A, Jeunemaitre X. Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma. J Clin Endocrinol Metab 2002; 87: 4771-4774
38 Scholz T, Eisenhofer G, Pacak K, Dralle H, Lehnert H. Clinical review: Current treatment of malignant pheochromocytoma. J Clin Endocrinol Metab 2007; 92: 1217-1225
39 Eisenhofer G, Lenders JW, Siegert G, Bornstein SR, Friberg P, Milosevic D, Mannelli M, Linehan WM, Adams K, Timmers HJ, Pacak K. Plasma methoxytyramine: A novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status. Eur J Cancer 2011; Oct 28 [Epub ahead of print]
40 Adjalle R, Plouin PF, Pacak K, Lehnert H. Treatment of malignant pheochromocytoma. Horm Metab Res 2009; 41: 687-696
41 Eisenhofer G, Siegert G, Kotzerke J, Bornstein SR, Pacak K. Current progress and future challenges in the biochemical diagnosis and treatment of pheochromocytomas and paragangliomas. Horm Metab Res 2008; 40: 329-337
42 Rao F, Keiser HR, O’Connor DT. Malignant pheochromocytoma. Chromaffin granule transmitters and response to treatment. Hypertension 2000; 36: 1045-1052
43 Plouin PF. Use of plasma chromogranin A and urine fractionated metanephrines to diagnose pheochromocytoma?. Nat Clin Pract Endocrinol Metab 2008; 4: 314-315
44 Timmers HJ, Chen CC, Carrasquillo JA, Whatley M, Ling A, Havekes B, Eisenhofer G, Martiniova L, Adams KT, Pacak K. Comparison of 18F-fluoro-L-DOPA, 18F-fluoro-deoxyglucose, and 18F-fluorodopamine PET and 123I-MIBG scintigraphy in the localization of pheochromocytoma and paraganglioma. J Clin Endocrinol Metab 2009; 94: 4757-4767
45 Timmers HJ, Brouwers FM, Hermus AR, Sweep FC, Verhofstad AA, Verbeek AL, Pacak K, Lenders JW. Metastases but not cardiovascular mortality reduces life expectancy following surgical resection of apparently benign pheochromocytoma. Endocr Relat Cancer 2008; 15: 1127-1133
46 White BD, Stirling AJ, Paterson E, Asquith-Coe K, Melder A. Diagnosis and management of patients at risk of or with metastatic spinal cord compression: summary of NICE guidance. BMJ 2008; 337: a2538
47 Wilkinson AN, Viola R, Brundage MD. Managing skeletal related events resulting from bone metastases. BMJ 2008; 337: a2041
48 Eisenhofer G, Rivers G, Rosas AL, Quezado Z, Manger WM, Pacak K. Adverse drug reactions in patients with phaeochromocytoma: incidence, prevention and management. Drug Saf 2007; 30: 1031-1062
49 McBride JF, Atwell TD, Charboneau WJ, Young Jr WF, Wass TC, Callstrom MR. Minimally invasive treatment of metastatic pheochromocytoma and paraganglioma: efficacy and safety of radiofrequency ablation and cryoablation therapy. J Vasc Interv Radiol 2011; 22: 1263-1270
50 Prejbisz A, Lenders JW, Eisenhofer G, Januszewicz A. Cardiovascular manifestations of phaeochromocytoma. J Hypertens 2011; 29: 2049-2060
51 Brouwers FM, Eisenhofer G, Lenders JW, Pacak K. Emergencies caused by pheochromocytoma, neuroblastoma, or ganglioneuroma. Endocrinol Metab Clin North Am 2006; 35: 699-724 viii
52 Adjalle R, Plouin PF, Pacak K, Lehnert H. Treatment of malignant pheochromocytoma. Horm Metab Res 2009; 41: 687-696
53 Mundschenk J, Lehnert H. Malignant pheochromocytoma. Exp Clin Endocrinol Diabetes 1998; 106: 373-376
54 Kopf D, Goretzki PE, Lehnert H. Clinical management of malignant adrenal tumors. J Cancer Res Clin Oncol 2001; 127: 143-155
55 Nonaka K, Makuuchi H, Naruse Y, Kobayashi T, Goto M. Surgical excision of malignant pheochromocytoma in the left atrium. Jpn J Thorac Cardiovasc Surg 2000; 48: 126-128
56 Kaltsas GA, Besser GM, Grossman AB. The diagnosis and medical management of advanced neuroendocrine tumors. Endocr Rev 2004; 25: 458-511
57 Mannelli M. Management and treatment of pheochromocytomas and paragangliomas. Ann NY Acad Sci 2006; 1073: 405-416
58 Whalen RK, Althausen AF, Daniels GH. Extra-adrenal pheochromocytoma. J Urol 1992; 147: 1-10
59 Sisson JC, Shapiro B, Beierwaltes WH, Glowniak JV, Nakajo M, Mangner TJ, Carey JE, Swanson DP, Copp JE, Satterlee WG, Wieland DM. Radiopharmaceutical treatment of malignant pheochromocytoma. J Nucl Med 1984; 25: 197-206
60 Castellani MR, Seghezzi S, Chiesa C, Aliberti GL, Maccauro M, Seregni E, Orunesu E, Luksch R, Bombardieri E. (131)I-MIBG treatment of pheochromocytoma: low versus intermediate activity regimens of therapy. Q J Nucl Med Mol Imaging 2010; 54: 100-113
61 Fitzgerald PA, Goldsby RE, Huberty JP, Price DC, Hawkins RA, Veatch JJ, Dela Cruz F, Jahan TM, Linker CA, Damon L, Matthay KK. Malignant pheochromocytomas and paragangliomas: a phase II study of therapy with high-dose 131I-metaiodobenzylguanidine (131I-MIBG). Ann NY Acad Sci 2006; 1073: 465-490
62 Sudbrock F, Schmidt M, Simon T, Eschner W, Berthold F, Schicha H. Dosimetry for 131I-MIBG therapies in metastatic neuroblastoma, phaeochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging 2010; 37: 1279-1290
63 Buckley SE, Chittenden SJ, Saran FH, Meller ST, Flux GD. Whole-body dosimetry for individualized treatment planning of 131I-MIBG radionuclide therapy for neuroblastoma. J Nucl Med 2009; 50: 1518-1524
64 Gonias S, Goldsby R, Matthay KK, Hawkins R, Price D, Huberty J, Damon L, Linker C, Sznewajs A, Shiboski S, Fitzgerald P. Phase II study of high-dose [131I]metaiodobenzylguanidine therapy for patients with metastatic pheochromocytoma and paraganglioma. J Clin Oncol 2009; 27: 4162-4168
65 Weiss B, Vora A, Huberty J, Hawkins RA, Matthay KK. Secondary myelodysplastic syndrome and leukemia following 131I-metaiodobenzylguanidine therapy for relapsed neuroblastoma. J Pediatr Hematol Oncol 2003; 25: 543-547
66 Martiniova L, Perera SM, Brouwers FM, Alesci S, Abu-Asab M, Marvelle AF, Kiesewetter DO, Thomasson D, Morris JC, Kvetnansky R, Tischler AS, Reynolds JC, Fojo AT, Pacak K. Increased uptake of [(1)(2)(3)I]meta-iodobenzylguanidine, [(1)F]fluorodopamine, and [(3)H]norepinephrine in mouse pheochromocytoma cells and tumors after treatment with the histone deacetylase inhibitors. Endocr Relat Cancer 2011; 18: 143-157
67 Keiser HR, Goldstein DS, Wade JL, Douglas FL, Averbuch SD. Treatment of malignant pheochromocytoma with combination chemotherapy. Hypertension 1985; 7 (3 Pt 2) I18-I24
68 Averbuch SD, Steakley CS, Young RC, Gelmann EP, Goldstein DS, Stull R, Keiser HR. Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. Ann Intern Med 1988; 109: 267-273
69 Huang H, Abraham J, Hung E, Averbuch S, Merino M, Steinberg SM, Pacak K, Fojo T. Treatment of malignant pheochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: recommendation from a 22-year follow-up of 18 patients. Cancer 2008; 113: 2020-2028
70 Patel SR, Winchester DJ, Benjamin RS. A 15-year experience with chemotherapy of patients with paraganglioma. Cancer 1995; 76: 1476-1480
71 Ayala-Ramirez M, Feng L, Habra MA, Rich T, Dickson PV, Perrier N, Phan A, Waguespack S, Patel S, Jimenez C. Clinical benefits of systemic chemotherapy for patients with metastatic pheochromocytomas or sympathetic extra-adrenal paragangliomas: Insights from the largest single-institutional experience. Cancer 2011; Oct 17 [Epub ahead of print]
72 Grogan RH, Mitmaker EJ, Duh QY. Changing paradigms in the treatment of malignant pheochromocytoma. Cancer Control 2011; 18: 104-112
73 Bravo EL, Kalmadi SR, Gill I. Clinical utility of temozolomide in the treatment of malignant paraganglioma: a preliminary report. Horm Metab Res 2009; 41: 703-706
74 Gimenez-Roqueplo AP, Favier J, Rustin P, Mourad JJ, Plouin PF, Corvol P, Rotig A, Jeunemaitre X. The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. Am J Hum Genet 2001; 69: 1186-1197
75 Favier J, Briere JJ, Burnichon N, Riviere J, Vescovo L, Benit P, Giscos-Douriez I, De Reynies A, Bertherat J, Badoual C, Tissier F, Amar L, Libe R, Plouin PF, Jeunemaitre X, Rustin P, Gimenez-Roqueplo AP. The Warburg effect is genetically determined in inherited pheochromocytomas. PLoS One 2009; 4: e7094
76 Guzy RD, Sharma B, Bell E, Chandel NS, Schumacker PT. Loss of the SdhB, but Not the SdhA, subunit of complex II triggers reactive oxygen species-dependent hypoxia-inducible factor activation and tumorigenesis. Mol Cell Biol 2008; 28: 718-731
77 Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356: 115-124
78 Favier J, Plouin PF, Corvol P, Gasc JM. Angiogenesis and vascular architecture in pheochromocytomas: distinctive traits in malignant tumors. Am J Pathol 2002; 161: 1235-1246
79 Salmenkivi K, Heikkila P, Liu J, Haglund C, Arola J. VEGF in 105 pheochromocytomas: enhanced expression correlates with malignant outcome. APMIS. 2003. 111. 458-464
80 Brieger J, Bedavanija A, Gosepath J, Maurer J, Mann WJ. Vascular endothelial growth factor expression, vascularization and proliferation in paragangliomas. ORL J Otorhinolaryngol Relat Spec 2005; 67: 119-124
81 Takekoshi K, Isobe K, Yashiro T, Hara H, Ishii K, Kawakami Y, Nakai T, Okuda Y. Expression of vascular endothelial growth factor (VEGF) and its cognate receptors in human pheochromocytomas. Life Sci 2004; 74: 863-871
82 Burnichon N, Vescovo L, Amar L, Libe R, de Reynies A, Venisse A, Jouanno E, Laurendeau I, Parfait B, Bertherat J, Plouin PF, Jeunemaitre X, Favier J, Gimenez-Roqueplo AP. Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma. Hum Mol Genet 2011; 20: 3974-3985
83 Lopez-Jimenez E, Gomez-Lopez G, Leandro-Garcia LJ, Munoz I, Schiavi F, Montero-Conde C, de Cubas AA, Ramires R, Landa I, Leskela S, Maliszewska A, Inglada-Perez L, de la Vega L, Rodriguez-Antona C, Leton R, Bernal C, de Campos JM, Diez-Tascon C, Fraga MF, Boullosa C, Pisano DG, Opocher G, Robledo M, Cascon A. Research resource: Transcriptional profiling reveals different pseudohypoxic signatures in SDHB and VHL-related pheochromocytomas. Mol Endocrinol 2010; 24: 2382-2391
84 Eisenhofer G, Huynh TT, Pacak K, Brouwers FM, Walther MM, Linehan WM, Munson PJ, Mannelli M, Goldstein DS, Elkahloun AG. Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel-Lindau syndrome. Endocr Relat Cancer 2004; 11: 897-911
85 Middeke M, Hoffmann S, Has san I, Wunderlich A, Hofbauer LC, Zielke A. In vitro and in vivo angiogenesis in PC12 pheochromocytoma cells is mediated by vascular endothelial growth factor. Exp Clin Endocrinol Diabetes 2002; 110: 386-392
86 Zielke A, Middeke M, Hoffmann S, Colombo-Benkmann M, Barth P, Hassan I, Wunderlich A, Hofbauer LC, Duh QY. VEGF-mediated angiogenesis of human pheochromocytomas is associated to malignancy and inhibited by anti-VEGF antibodies in experimental tumors. Surgery 2002; 132: 1056-1063 discussion 1063
87 Druce MR, Kaltsas GA, Fraenkel M, Gross DJ, Grossman AB. Novel and evolving therapies in the treatment of malignant phaeochromocytoma: experience with the mTOR inhibitor everolimus (RAD001). Horm Metab Res 2009; 41: 697-702
88 Gross DJ, Munter G, Bitan M, Siegal T, Gabizon A, Weitzen R, Merimsky O, Ackerstein A, Salmon A, Sella A, Slavin S. The role of imatinib mesylate (Glivec) for treatment of patients with malignant endocrine tumors positive for c-kit or PDGF-R. Endocr Relat Cancer 2006; 13: 535-540
89 Kulke MH, Stuart K, Enzinger PC, Ryan DP, Clark JW, Muzikansky A, Vincitore M, Michelini A, Fuchs CS. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol 2006; 24: 401-406
90 Joshua AM, Ezzat S, Asa SL, Evans A, Broom R, Freeman M, Knox JJ. Rationale and evidence for sunitinib in the treatment of malignant paraganglioma/pheochromocytoma. J Clin Endocrinol Metab 2009; 94: 5-9
91 Jimenez C, Cabanillas ME, Santarpia L, Jonasch E, Kyle KL, Lano EA, Matin SF, Nunez RF, Perrier ND, Phan A, Rich TA, Shah B, Williams MD, Waguespack SG. Use of the tyrosine kinase inhibitor sunitinib in a patient with von Hippel-Lindau disease: targeting angiogenic factors in pheochromocytoma and other von Hippel-Lindau disease-related tumors. J Clin Endocrinol Metab 2009; 94: 386-391
92 Kaelin Jr WG. The von Hippel-Lindau tumour suppressor protein: O₂ sensing and cancer. Nat Rev Cancer 2008; 8: 865-873
93 Sang N, Stiehl DP, Bohensky J, Leshchinsky I, Srinivas V, Caro J. MAPK signaling up-regulates the activity of hypoxia-inducible factors by its effects on p300. J Biol Chem 2003; 278: 14013-14019
94 Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ, Abraham RT. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 2002; 22: 7004-7014
95 Santarpia L, Habra MA, Jimenez C. Malignant pheochromocytomas and paragangliomas: molecular signaling pathways and emerging therapies. Horm Metab Res 2009; 41: 680-686