Current and Future Treatments for Malignant Pheochromocytoma and Sympathetic Paraganglioma

Abstract

Pheochromocytomas (PHs) and sympathetic paragangliomas (SPGs) are rare neuroendocrine tumors. Approximately 17 % of these tumors are malignant, but because no molecular or histologic markers for malignancy exist, patients are often diagnosed with malignant PHs or SPGs after unresectable disease has formed. Patients with progressive metastatic tumors and overwhelming symptoms are currently treated with systemic chemotherapy and radiopharmaceutical agents such as metaiodobenzylguanidine. These therapies lead to partial radiographic response, disease stabilization, and symptomatic improvement in approximately 40 % of patients, and systemic chemotherapy is associated with a modest improvement in overall survival duration. However, over the past decade, substantial progress has been made in clinical, biochemical, and radiographic diagnosis of PHs and SPGs. Approximately 50 % of patients with malignant PHs and SPGs have been found to carry hereditary germline mutations in the succinate dehydrogenase subunit B gene (SDHB), and anti-angiogenic agents such as sunitinib have been found to potentially play a role in the treatment of malignant disease, especially in patients with SDHB mutations. In some patients, treatment with sunitinib has been associated with partial radiographic response, disease stabilization, decreased fluorodeoxyglucose uptake on positron emission tomography, and improved blood pressure control. These findings have led to the development of prospective clinical trials of new targeted therapies for metastatic disease. Here, we provide an updated review of the clinical and genetic predictors of malignant disease, radiographic diagnosis of malignant disease, and information from the most relevant studies of systemic therapies, as well as proposed treatment guidelines for patients with metastatic or potentially malignant PHs and SPGs.

THERAPY OF ENDOCRINE DISEASE: Treatment of malignant pheochromocytoma and paraganglioma

“…Hormone-and tumor-related symptoms, including hypertension, constipation, and pain Serum chromogranin A levels and urinary and/or plasma metanephrine, normetanephrine, and methoxytyramine levels indexed to urinary creatinine levels Genetic syndrome Best scintigraphic imaging among lungs (50%) (8,14,15). Liver and bone magnetic resonance imaging, which may be more informative than computed tomography, is thus used for staging and follow-up (16,17).…”

“…Dedicated skeletal imaging to detect bone metastases ( Fig. 1) and the clinical characterization of any bone metastases found are mandatory (15). In the absence of validated prognostic parameters, in asymptomatic patients with MPPs with no threatening masses, radiographic studies to assess disease progression should be conducted every 3 months for the first year.…”

“…Finally, death from other cancers, although rare, should be considered, especially in the context of genetic syndromes (19,20). The reported 5-year overall survival rates of MPP patients range from 40 to 77% (2,8,15,18). One study found the presence of a SDHB mutation, after adjustment for tumor burden, to be the single most powerful prognostic factor, though this observation is yet to be confirmed (8).…”

Pheochromocytomas

“…Chemotherapy is largely reserved for those patients not amenable to surgical therapy and who do not respond to radionuclide treatment. The most common regimen of cyclophosphamide, vincristine, and dacarbazine (CVD) has been shown to be of some value in palliating symptoms of advanced disease, reducing the rate of tumor growth, and occasionally decreasing tumor size [62,63]. Experience with alternative chemotherapeutic agents for pheochromocytomas is limited and mostly based on isolated case reports and small series.…”

Patient with Inoperable Pheochromocytoma

“…In most cases, they are found in the adrenal gland medulla. The malignant forms constitute about 17% of all cases; malignancy is more frequent in sporadic occurrences 2 .…”