Pheochromocytoma (PCC) and paraganglioma (PGL) are uncommon neoplasms with high morbidity in advanced stages. Effective systemic treatments are limited.
A multisite phase 2 trial evaluated sunitinib in patients with progressive PCC/PGL. Patients received 50 mg orally for 4–6 weeks.
Between May 2009 and May 2016, 25 patients were enroled. The median age was 50 years and 56% were male. Three patients (12%) received prior chemotherapy and 16 (64%) prior surgery. The DCR was 83% (95% CI: 61–95%) and median PFS 13.4 (95% CI: 5.3–24.6) months. Of 23 evaluable patients, 3 (13%) with germline mutations (SDHA, SDHB, RET) achieved a PR. The patient with mutated RET and MEN2A remains on treatment after 64 cycles. The median time on treatment was 12.4 (1–88.0) months. Grade 3 or 4 toxicities were as expected and manageable; fatigue (16%) and thrombocytopenia (16%) were most common. One patient with grade 3 hypertension and 2 with grade 3 cardiac events discontinued treatment.
Although the primary endpoint of disease control was met, the overall response rate of sunitinib was low in unselected patients with progressive PCC/PGL. Patients with germline variants in RET or in the subunits of SDH may derive greatest benefit.
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Ayala-Ramirez, M., Feng, L., Johnson, M. M., Ejaz, S., Habra, M. A., 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. 96, 717–725 (2011).
Ricketts, C. J., Forman, J. R., Rattenberry, E., Bradshaw, N., Lalloo, F., Izatt, L. et al. Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Hum. Mutat. 31, 41–51 (2010).
Turchini, J., Cheung, V. K. Y., Tischler, A. S., De Krijger, R. R., Gill, A. J. Pathology and genetics of phaeochromocytoma and paraganglioma. Histopathology 72, 97–105 (2018).
Amar, L., Bertherat, J., Baudin, E., Ajzenberg, C., Bressac-de Paillerets, B., Chabre, O. et al. Genetic testing in pheochromocytoma or functional paraganglioma. J. Clin. Oncol. 23, 8812–8818 (2005).
Fishbein, L., Leshchiner, I., Walter, V., Danilova, L., Robertson, A. G., Johnson, A. R. et al. Comprehensive molecular characterization of pheochromocytoma and paraganglioma. Cancer Cell. 31, 181–193 (2017).
Selak, M. A., Armour, S. M., MacKenzie, E. D., Boulahbel, H., Watson, D. G., Mansfield, K. D. et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell. 7, 77–85 (2005).
Kim, W. Y., Kaelin, W. G. Role of VHL gene mutation in human cancer. J. Clin. Oncol. 22, 4991–5004 (2004).
Favier, J., Igaz, P., Burnichon, N., Amar, L., Libe, R., Badoual, C. et al. Rationale for anti-angiogenic therapy in pheochromocytoma and paraganglioma. Endocr. Pathol. 23, 34–42 (2012).
Joshua, A. M., Ezzat, S., Asa, S. L., Evans, A., Broom, R., Freeman, M. et al. Rationale and evidence for sunitinib in the treatment of malignant paraganglioma/pheochromocytoma. J. Clin. Endocrinol. Metab. 94, 5–9 (2009).
Jimenez, C., Cabanillas, M. E., Santarpia, L., Jonasch, E., Kyle, K. L., Lano, E. A. et al. 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. 94, 386–391 (2009).
Ayala-Ramirez, M., Chougnet, C. N., Habra, M. A., Palmer, J. L., Leboulleux, S., Cabanillas, M. E. et al. Treatment with sunitinib for patients with progressive metastatic pheochromocytomas and sympathetic paragangliomas. J. Clin. Endocrinol. Metab. 97, 4040–4050 (2012).
Huang, H., Abraham, J., Hung, E., Averbuch, S., Merino, M., Steinberg, S. M. et al. Treatment of malignant pheochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: recommendation from a 22-year follow-up of 18 patients. Cancer 113, 2020–2028 (2008).
Patel, S. R., Winchester, D. J., Benjamin, R. S. A 15-year experience with chemotherapy of patients with paraganglioma. Cancer 76, 1476–1480 (1995).
Tanabe, A., Naruse, M., Nomura, K., Tsuiki, M., Tsumagari, A., Ichihara, A. Combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine in patients with malignant pheochromocytoma and paraganglioma. Horm. Cancer 4, 103–110 (2013).
Ayala-Ramirez, M., Feng, L., Habra, M. A., Rich, T., Dickson, P. V., 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 118, 2804–2812 (2012).
Niemeijer, N. D., Alblas, G., van Hulsteijn, L. T., Dekkers, O. M., Corssmit, E. P. Chemotherapy with cyclophosphamide, vincristine and dacarbazine for malignant paraganglioma and pheochromocytoma: systematic review and meta-analysis. Clin. Endocrinol. 81, 642–651 (2014).
Hadoux, J., Favier, J., Scoazec, J. Y., 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 135, 2711–2720 (2014).
Cassol, C. A., Winer, D., Liu, W., Guo, M., Ezzat, S., Asa, S. L. Tyrosine kinase receptors as molecular targets in pheochromocytomas and paragangliomas. Mod. Pathol. 27, 1050–1062 (2014).
Fleming, T. R. One-sample multiple testing procedure for phase II clinical trials. Biometrics 38, 143–151 (1982).
Jasim, S., Suman, V. J., Jimenez, C., Harris, P., Sideras, K., Burton, J. K. et al. Phase II trial of pazopanib in advanced/progressive malignant pheochromocytoma and paraganglioma. Endocrine 57, 220–225 (2017).
Mejean, A., Ravaud, A., Thezenas, S., Colas, S., Beauval, J. B., Bensalah, K. et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N. Engl. J. Med. 379, 417–427 (2018).
Eisenhofer, G., Huynh, T. T., Pacak, K., Brouwers, F. M., Walther, M. M., Linehan, W. M. et al. 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 11, 897–911 (2004).
Lopez-Jimenez, E., Gomez-Lopez, G., Leandro-Garcia, L. J., Munoz, I., Schiavi, F., Montero-Conde, C. et al. Research resource: transcriptional profiling reveals different pseudohypoxic signatures in SDHB and VHL-related pheochromocytomas. Mol. Endocrinol. 24, 2382–2391 (2010).
Dahia, P. L., Ross, K. N., Wright, M. E., Hayashida, C. Y., Santagata, S., Barontini, M. et al. A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet. 1, 72–80 (2005).
Forsythe, J. A., Jiang, B. H., Iyer, N. V., Agani, F., Leung, S. W., Koos, R. D. et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol. Cell Biol. 16, 4604–4613 (1996).
Gossage, L., Eisen, T. Alterations in VHL as potential biomarkers in renal-cell carcinoma. Nat. Rev. Clin. Oncol. 7, 277–288 (2010).
Roskoski, R. Jr., Sadeghi-Nejad, A. Role of RET protein-tyrosine kinase inhibitors in the treatment RET-driven thyroid and lung cancers. Pharm. Res. 128, 1–17 (2018).
Gonias, S., Goldsby, R., Matthay, K. K., 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. 27, 4162–4168 (2009).
Hamidi, O., Young, W. F. Jr., Gruber, L., Smestad, J., Yan, Q., Ponce, O. J. et al. Outcomes of patients with metastatic phaeochromocytoma and paraganglioma: a systematic review and meta-analysis. Clin. Endocrinol. 87, 440–450 (2017).
Baudin, E., Habra, M. A., Deschamps, F., Cote, G., Dumont, F., Cabanillas, M. et al. Therapy of endocrine disease: treatment of malignant pheochromocytoma and paraganglioma. Eur. J. Endocrinol. 171, R111–R122 (2014).
Lenders, J. W., Duh, Q. Y., Eisenhofer, G., Gimenez-Roqueplo, A. P., Grebe, S. K., Murad, M. H. et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 99, 1915–1942 (2014).
Nolting, S., Grossman, A. B. Signaling pathways in pheochromocytomas and paragangliomas: prospects for future therapies. Endocr. Pathol. 23, 21–33 (2012).
The authors declare no competing interests.
Ethics approval and consent
This study was approved by the University Health Network (UHN) Research Ethics Board (REB) and submitted at each participating site. REB protocol number 08-0108. All patients provided informed consent as per study protocol. This consent included patient consent to collect clinical, demographic, genetic and outcome data for study publication. This study was conducted in accordance with the Declaration of Helsinki.
This study is available withinthis publication and in the supplementary material. Further patient data can be requested from the corresponding author.
This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).
This study was funded as part of an Investigator Initiated Trial from Pfizer Canada. Dr Jennifer Knox, the Principal Investigator was the study sponsor.
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