Treatment for Malignant Pheochromocytomas and Paragangliomas: 5 Years of Progress
- 651 Downloads
Purpose of Review
The purpose of this manuscript is to review the progress in the field of therapeutics for malignant pheochromocytomas and sympathetic paraganglioma (MPPG) over the past 5 years.
The manuscript will describe the clinical predictors of survivorship and their influence on the first TNM staging classification for pheochromocytomas and sympathetic paragangliomas, the treatment of hormonal complications, and the rationale that supports the resection of the primary tumor and metastases in patients with otherwise incurable disease. Therapeutic options for patients with bone metastasis to the spine will be presented. The manuscript will also review chemotherapy and propose a maintenance regimen with dacarbazine for patients initially treated with cyclophosphamide, vincristine, and dacarbazine. Finally, the manuscript will review preliminary results of several phase 2 clinical trials of novel radiopharmaceutical agents and tyrosine kinase inhibitors.
MPPGs are very rare neuroendocrine tumors. MPPGs are usually characterized by a large tumor burden, excessive secretion of catecholamines, and decreased overall survival. Recent discoveries have enhanced our knowledge of the pathogenesis and phenotypes of MPPG. This knowledge is leading to a better understanding of the indications and limitations of the currently available localized and systemic therapies as well as the development of phase 2 clinical trials for novel medications.
KeywordsMalignant pheochromocytoma Malignant paraganglioma Surgery Bone metastases Chemotherapy Clinical trials
Compliance with Ethical Standards
Conflict of Interest
Paola Jimenez, Claudio Tatsui, Aaron Jessop, Sonali Thosani, and Camilo Jimenez declare they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: •Of importance
- 4.Ayala-Ramirez M, Feng L, Johnson MM, Ejaz S, Habra MA, Rich T, et al. 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(3):717–25. https://doi.org/10.1210/jc.2010-1946.CrossRefPubMedGoogle Scholar
- 9.• Roman-Gonzalez A, Zhou S, Ayala-Ramirez M, Shen C, Waguespack SG, Habra MA, Karam JA, Perrier N, Wood CG, Jimenez C (2017) Impact of surgical resection of the primary tumor on overall survival in patients with metastatic pheochromocytoma or sympathetic paraganglioma. Ann Surg. https://doi.org/10.1097/SLA.0000000000002195. This study describes the benefits derived from the surgical resection of the primary tumor in patients with advanced disease. The study compared patients treated with surgery with those not treated surgically. Surgical resection of the primary was associated with overall survival improvement.
- 10.Roman-Gonzalez A, Jimenez C (2017) Malignant pheochromocytoma-paraganglioma: pathogenesis, TNM staging, and current clinical trials. Curr Opin Endocrinol Diabetes Obes. https://doi.org/10.1097/MED.0000000000000330.
- 11.Hescot S, Leboulleux S, Amar L, Vezzosi D, Borget I, Bournaud-Salinas C, et al. One-year progression-free survival of therapy-naive patients with malignant pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2013;98(10):4006–12. https://doi.org/10.1210/jc.2013-1907.CrossRefPubMedGoogle Scholar
- 15.• Jimenez C, Libutti SK, Landry CS, Lloyd RV, McKay RR, Rohren E, Seethala RR, Wang TS, Chen H, Perrier ND (2017) Adrenal-Neuroendocrine Tumors. In: Amin MB (ed) AJCC cancer staging manual. 8th edn. Springer, New York, pp 919–927. The first TNM staging system for patients with pheochromocytomas and paragangliomas. Google Scholar
- 17.Loriot C, Burnichon N, Gadessaud N, Vescovo L, Amar L, Libe R, et al. Epithelial to mesenchymal transition is activated in metastatic pheochromocytomas and paragangliomas caused by SDHB gene mutations. J Clin Endocrinol Metab. 2012;97(6):E954–62. https://doi.org/10.1210/jc.2011-3437.CrossRefPubMedGoogle Scholar
- 18.Amar L, Baudin E, Burnichon N, Peyrard S, Silvera S, Bertherat J, et al. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J Clin Endocrinol Metab. 2007;92(10):3822–8. https://doi.org/10.1210/jc.2007-0709.CrossRefPubMedGoogle Scholar
- 20.Fishbein L, Nathanson KL (2017) Pheochromocytoma and paraganglioma susceptibility genes: estimating the associated risk of disease. JAMA Oncol. https://doi.org/10.1001/jamaoncol.2017.0222.
- 22.Thosani S, Ayala-Ramirez M, Palmer L, MI H, Rich T, Gagel RF, et al. The characterization of pheochromocytoma and its impact on overall survival in multiple endocrine neoplasia type 2. J Clin Endocrinol Metab. 2013;98(11):E1813–9. https://doi.org/10.1210/jc.2013-1653.CrossRefPubMedPubMedCentralGoogle Scholar
- 25.Ayala-Ramirez M, Palmer JL, Hofmann MC, de la Cruz M, Moon BS, Waguespack SG, et al. Bone metastases and skeletal-related events in patients with malignant pheochromocytoma and sympathetic paraganglioma. J Clin Endocrinol Metab. 2013;98(4):1492–7. https://doi.org/10.1210/jc.2012-4231.CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Niemeijer ND, Alblas G, van Hulsteijn LT, Dekkers OM, Corssmit EP. Chemotherapy with cyclophosphamide, vincristine and dacarbazine for malignant paraganglioma and pheochromocytoma: systematic review and meta-analysis. Clin Endocrinol. 2014;81(5):642–51. https://doi.org/10.1111/cen.12542.CrossRefGoogle Scholar
- 31.Ayala-Ramirez M, Feng L, Habra MA, Rich T, Dickson PV, Perrier N, et al. Clinical benefits of systemic chemotherapy for patients with metastatic pheochromocytomas or sympathetic extra-adrenal paragangliomas: insights from the largest single-institutional experience. Cancer. 2012;118(11):2804–12. https://doi.org/10.1002/cncr.26577.CrossRefPubMedGoogle Scholar
- 33.Tay CG, Lee VW, Ong LC, Goh KJ, Ariffin H, Fong CY (2017) Vincristine-induced peripheral neuropathy in survivors of childhood acute lymphoblastic leukaemia. Pediatr Blood Cancer. https://doi.org/10.1002/pbc.26471.
- 34.Kavcic M, Koritnik B, Krzan M, Velikonja O, Prelog T, Stefanovic M, Debeljak M, Jazbec J (2017) Electrophysiological studies to detect peripheral neuropathy in children treated with vincristine. J Pediatr Hematol Oncol. https://doi.org/10.1097/MPH.0000000000000825.
- 35.Hadoux J, Favier J, Scoazec JY, Leboulleux S, Al Ghuzlan A, Caramella C, et al. SDHB mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma. Int J Cancer. 2014;135(11):2711–20. https://doi.org/10.1002/ijc.28913.CrossRefPubMedGoogle Scholar
- 36.Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer—a GERCOR study. J Clin Oncol Off J Am Soc Clin Oncol. 2006;24(3):394–400. https://doi.org/10.1200/JCO.2005.03.0106.CrossRefGoogle Scholar
- 37.Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, et al. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(24):3004–11. https://doi.org/10.1200/JCO.2012.42.3749.CrossRefGoogle Scholar
- 38.Oza AM, Cook AD, Pfisterer J, Embleton A, Ledermann JA, Pujade-Lauraine E, et al. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. Lancet Oncol. 2015;16(8):928–36. https://doi.org/10.1016/S1470-2045(15)00086-8.CrossRefPubMedPubMedCentralGoogle Scholar
- 41.Basu S, Abhyankar A, Jatale P. The current place and indications of 131I-metaiodobenzylguanidine therapy in the era of peptide receptor radionuclide therapy: determinants to consider for evolving the best practice and envisioning a personalized approach. Nucl Med Commun. 2015;36(1):1–7. https://doi.org/10.1097/MNM.0000000000000209.CrossRefPubMedGoogle Scholar
- 45.Gonias S, Goldsby R, Matthay KK, Hawkins R, Price D, Huberty J, et al. Phase II study of high-dose [131I]metaiodobenzylguanidine therapy for patients with metastatic pheochromocytoma and paraganglioma. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27(25):4162–8. https://doi.org/10.1200/JCO.2008.21.3496.CrossRefGoogle Scholar
- 46.Barrett JA, Joyal JL, Hillier SM, Maresca KP, Femia FJ, Kronauge JF, et al. Comparison of high-specific-activity ultratrace 123/131I-MIBG and carrier-added 123/131I-MIBG on efficacy, pharmacokinetics, and tissue distribution. Cancer Biother Radiopharm. 2010;25(3):299–308. https://doi.org/10.1089/cbr.2009.0695.CrossRefPubMedGoogle Scholar
- 47.Coleman RE, Stubbs JB, Barrett JA, de la Guardia M, Lafrance N, Babich JW. Radiation dosimetry, pharmacokinetics, and safety of ultratrace iobenguane I-131 in patients with malignant pheochromocytoma/paraganglioma or metastatic carcinoid. Cancer Biother Radiopharm. 2009;24(4):469–75. https://doi.org/10.1089/cbr.2008.0584.CrossRefPubMedGoogle Scholar
- 48.• Jimenez C, Pryma DA, Sullivan DC, Schwarz JK, Noto RB, Stambler N, Armor T, Jensen JJ, Israel RJ ( 2015) Long term follow-up of a pivotal phase 2 study of Ultratrace® iobenguane I-131 (AZEDRATM) in patients with malignant relapsed/refractory pheochromocytoma (Pheo)/paraganglioma (Para). Endocrine Society’s 97th Annual Meeting and Expo, March 5–8, 2015 - San Diego. This abstract described the preliminary results of the phase 2 study of patients with MPPG treated with Ultratrace iobenguan I-131. The results showed that treatment caused sustained blood pressure control in 35% of patients. Ultratrace was associated with partial responses and stable disease in more than 90% of patients. Google Scholar
- 51.Ayala-Ramirez M, Chougnet CN, Habra MA, Palmer JL, Leboulleux S, Cabanillas ME, et al. Treatment with sunitinib for patients with progressive metastatic pheochromocytomas and sympathetic paragangliomas. J Clin Endocrinol Metab. 2012;97(11):4040–50. https://doi.org/10.1210/jc.2012-2356.CrossRefPubMedPubMedCentralGoogle Scholar
- 52.Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN Trial. J Clin Oncol Off J Am Soc Clin Oncol. 2017;35(6):591–7. https://doi.org/10.1200/JCO.2016.70.7398.CrossRefGoogle Scholar
- 53.Smith M, De Bono J, Sternberg C, Le Moulec S, Oudard S, De Giorgi U, et al. Phase III study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34(25):3005–13. https://doi.org/10.1200/JCO.2015.65.5597.CrossRefGoogle Scholar
- 55.• Jimenez C, Waguespack S, Habra MA, Busaidy N, Dadu R, Tamsen G, Jessop A (2017) A phase 2 clinical trial with cabozantinib for patients with malignant pheochromocytoma and paraganglioma: preliminary results. The University of Texas MD Anderson Cancer Center, Oral Presentation, Global Academic Programs Symposium, Houston. Preliminary results of this phase 2 study described an objective response rate of 45%, with clinical benefits observed in 91% of patients. No serious adverse events were reported. PFS was 11 months. Google Scholar
- 57.• Patchell RA, Tibbs PA, Regine WF, Payne R, Saris S, Kryscio RJ, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet. 2005;366(9486):643–8. https://doi.org/10.1016/S0140-6736(05)66954-1. This study demonstrated that patients with spine metastases treated with decompressive surgical resection followed by radiation therapy had better outcomes than patients treated with radiation therapy alone. CrossRefPubMedGoogle Scholar
- 59.Wang XS, Rhines LD, Shiu AS, Yang JN, Selek U, Gning I, et al. Stereotactic body radiation therapy for management of spinal metastases in patients without spinal cord compression: a phase 1-2 trial. Lancet Oncol. 2012;13(4):395–402. https://doi.org/10.1016/S1470-2045(11)70384-9.CrossRefPubMedPubMedCentralGoogle Scholar
- 60.Yamada Y, Bilsky MH, Lovelock DM, Venkatraman ES, Toner S, Johnson J, et al. High-dose, single-fraction image-guided intensity-modulated radiotherapy for metastatic spinal lesions. Int J Radiat Oncol Biol Phys. 2008;71(2):484–90. https://doi.org/10.1016/j.ijrobp.2007.11.046.CrossRefPubMedGoogle Scholar
- 62.Sahgal A, Bilsky M, Chang EL, Ma L, Yamada Y, Rhines LD, et al. Stereotactic body radiotherapy for spinal metastases: current status, with a focus on its application in the postoperative patient. J Neurosurg Spine. 2011;14(2):151–66. https://doi.org/10.3171/2010.9.SPINE091005.CrossRefPubMedGoogle Scholar
- 63.Fisher CG, DiPaola CP, Ryken TC, Bilsky MH, Shaffrey CI, Berven SH, et al. A novel classification system for spinal instability in neoplastic disease: an evidence-based approach and expert consensus from the Spine Oncology Study Group. Spine (Phila Pa 1976). 2010;35(22):E1221–9. https://doi.org/10.1097/BRS.0b013e3181e16ae2.CrossRefGoogle Scholar
- 64.Fisher CG, Versteeg AL, Schouten R, Boriani S, Varga PP, Rhines LD, et al. Reliability of the spinal instability neoplastic scale among radiologists: an assessment of instability secondary to spinal metastases. AJR Am J Roentgenol. 2014;203(4):869–74. https://doi.org/10.2214/AJR.13.12269.CrossRefPubMedGoogle Scholar
- 65.Fisher CG, Schouten R, Versteeg AL, Boriani S, Varga PP, Rhines LD, et al. Reliability of the Spinal Instability Neoplastic Score (SINS) among radiation oncologists: an assessment of instability secondary to spinal metastases. Radiat Oncol. 2014;9:69. https://doi.org/10.1186/1748-717X-9-69.CrossRefPubMedPubMedCentralGoogle Scholar
- 69.Sciubba DM, Gallia GL, McGirt MJ, Woodworth GF, Garonzik IM, Witham T, et al. Thoracic kyphotic deformity reduction with a distractible titanium cage via an entirely posterior approach. Neurosurgery. 2007;60(4 Suppl 2):223–230; discussion 230-221. https://doi.org/10.1227/01.NEU.0000255385.18335.A8.PubMedGoogle Scholar
- 70.Xu R, Garces-Ambrossi GL, McGirt MJ, Witham TF, Wolinsky JP, Bydon A, et al. Thoracic vertebrectomy and spinal reconstruction via anterior, posterior, or combined approaches: clinical outcomes in 91 consecutive patients with metastatic spinal tumors. J Neurosurg Spine. 2009;11(3):272–84. https://doi.org/10.3171/2009.3.SPINE08621.CrossRefPubMedGoogle Scholar
- 73.Laufer I, Iorgulescu JB, Chapman T, Lis E, Shi W, Zhang Z, et al. Local disease control for spinal metastases following “separation surgery” and adjuvant hypofractionated or high-dose single-fraction stereotactic radiosurgery: outcome analysis in 186 patients. J Neurosurg Spine. 2013;18(3):207–14. https://doi.org/10.3171/2012.11.SPINE12111.CrossRefPubMedGoogle Scholar