Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are highly vascular, catecholamine-secreting tumors that arise from sympathetic and parasympathetic lineage-derived cells from the adrenal medulla (pheochromocytomas) and from extra-adrenal cervical- thoracic and abdominal paraganglia (paragangliomas/PGLs/) (1-3). More than 35% of PHEOs/PGLs are hereditary and they are predominantly benign. However, approximately 10–15% can develop metastases to bone, liver, lungs and lymph nodes (4). More than 40% of metastatic PHEOs/PGLs are related to SDHB mutation carriers and SDHB-mutation carriers have a 19-fold higher risk of developing a metastatic disease (5) and a shorter survival than patients with a malignant PGL/PCC but without SDHB mutations with an only 36% 5-year probability of survival after diagnosis of metastatic disease (6).
Current therapeutic approaches to treat metastatic SDHB PHEOs/PGLs are very limited. Despite a vast interest and effort to develop new therapeutic approaches, data is either limited or still at an experimental level, although there are some promising results and observations. Then, malignant PHEOs/PGLs remain a huge diagnostic and therapeutic challenge owing to a lack of effective treatment options at present.
Current treatment options in metastatic PHEOs/PGLs are limited and consist of radiotherapy with [131I]-MIBG and chemotherapy with cyclophosphamide, vincristine, and dacarbazine (CVD) (8-9). However, at least 50% of patients with metastatic PHEOs/PGLs, especially those with SDHB mutations, do not benefit from [131I]-MIBG treatment due to a lack of the norepinephrine transporter system, resulting in suboptimal or no [131I]-MIBG-uptake (10). The use of CVD is a good alternative, but it is reserved for patients with rapidly growing tumors or extensive organ tumor burden (especially in the liver) and limited by treatment-related toxicity. Long-term survival is expected in some cases that may remain asymptomatic at the early stage of the metastatic disease. The absence of curative options for metastatic PHEOs/PGLs and the substantial toxicity associated with therapies are the rationale for the watch-and-wait in these situations. However, locorregional guided therapy, is the mainstream therapy for localized disease to prevent further serious complications; such us spinal cord compression as well as to palliate bone pain. Interventional radiology paired with external conformational radiation beam therapy and/or surgery are key therapeutic options.
There are some potential targets that could be used in treatment of these tumors. These targets are based on recent research data, new studies published about other neuroendocrine tumors, and current results mainly from the NIH research. Making therapeutic advances against PHEOs/PGLs, a very rare cancer may be the most formidable challenge facing patients and clinicians. Indeed, the rarity of PHEOs/PGLs makes the feasibility of phase III clinical trials uncertain, and the long survival duration of PHEOs/PGLs patients makes the demonstration of a proven survival benefit unlikely. Few prospective studies have investigated potential therapies for the disease.
The NIH is the largest center in the United States and worldwide to properly diagnose and treat patients with pheochromocytoma and paraganglioma. NIH research protocol focuses on the genetics, diagnosis, localization, and surgical and interventional radiological treatment of PHEOs/PGLs. The clinical goal of their program is to establish more effective diagnostic and localization techniques to ensure that no tumor goes undiagnosed as well as to establish new treatment options for this disease. Dr. Pacak together with his colleagues/collaborators introduced guidelines for screening of pediatric patients with SDHB gene mutations, recently he described the role of metastasis suppressor genes in the pathogenesis of malignant pheochromocytoma and identified a gene that plays a crucial role in the prediction of recurrence of future metastasis; proposed the role of IL-13PE and romidepsin in the treatment of these tumors and novel concept of therapy of these tumors by cell cycle synchronization and introducing a new animal model of metastatic pheochromocytoma. Dr. Pacak introduced novel experimental imaging approaches to detect tumor development in small animals. Described the role of a new HIF2A gain-of-function somatic mutation in the pathogenesis of paraganglioma and polycythemia. Recently, discovered a new syndrome of multiple paragangliomas, somatostatinomas, and polycythemia, called the Pacak-Zhuang Syndrome in which somatic and germline gain-of-function HIF2A mutations emphasize the role of the HIF-2α in the PHEO/PGL development and these findings designate HIF, especially HIF-2α, as a promising treatment target.
Their basic laboratory is working intensively in the development of an animal model of metastatic PHEO/PGL and the use of genomics and proteomics. Specifically, the development of an animal model of metastatic PHEO/PGL is crucial in testing various treatment modalities. Recently, they have introduced this metastatic model and used it successfully in experimental treatment approaches, including LB-1 compound. The studies of genomics and proteomics play an important role in the pathogenesis of metastatic disease and thus allow for earlier detection of malignancy or metastatic disease, which is an important part of their basic science studies. Those techniques help to identify some markers that can be very useful to predict metastasis or detect SDHB-related PHEO/PGL
More recently (paper currently under review) Dr. Pacak and collaborators have established the role of radiolabelled DOTA-peptides for SSTR-imaging in metastatic SDHB-related PHEOs/PGLs. In this study authors demonstrate the superiority of [68Ga]-DOTATATE PET/CT in the evaluation of this patients compared to all other and currently recommended functional imaging modalities and suggesting modifying imaging algorithm for PHEOs/PGLs, currently placing 18F-FDG PET/CT as the gold standard for these tumors. Furthermore, and more importantly this results show a very promising eligibility for using peptide radio receptor therapy (PRRT) or treatment with so called “cold” somatostatin receptor analogs for these patients as a new and long awaited treatment option. While (PRRT) has not been specifically evaluated in SDHB-related PHEOs/PGLs yet, it has already shown to lead to longer progression-free survival, mainly in gastroenteropancreatic NETs (11) but also in other metastatic neuroendocrine tumors, including PHEOs/PGLs (12). This is also extremely useful for patients in whom the location or extension of a PHEO/PGL lesion(s) (especially skull base) cannot be accessed by any surgical approach.
Thus, there is great interest and need to find new means of therapeutic options for low toxic-well tolerated long term treatment options for the low burden metastastic disease as well as effective treatment options in progressive metastatic PHEOs/PGLs.