Eric Baudin, MD, PhD
Oncologie Endocrinienne et Médecine Nucléaire
39 rue Camille Desmoulins
Institut Gustave Roussy, 94805 cedex
Villejuif, France
T : (0) 1 42 11 42 42
F : (0) 1 42 11 52 24
Eric.BAUDIN@igr.fr
Felix Beuschlein, MD
Medizinische Klinik und Poliklinik IV
Klinikum der Universität München
Raum D2.37
Ziemssenstr. 1
D-80336 München, Germany
T: (089) 5160 2110 (2116)
F: (089) 5160 4467
felix.beuschlein@med.uni-muenchen.de
Martin Fassnacht, MD
Dept. of Internal Medicine IV
Hospital of the University of Munich
Ziemssenstr. 1
80336 Munich
Germany
T: +49-89-5160 2940
F: +49-89-5160 2942
Martin.Fassnacht@med.uni-muenchen.de
Department of Internal Medicine I, Endocrine and Diabetes Unit,
University Hospital Würzburg, University of Würzburg,
Oberdürrbacher Strasse 6, D-97080
Würzburg, Germany
Paul A. Fitzgerald, MD
University of California San Francisco
350 Parnassus Avenue, Suite 710
San Francisco, CA 94117
T: (415) 665 1136
F: (415) 665 8500
Paul.Fitzgerald@ucsf.edu
Camilo Jimenez, MD
Department of Endocrine Neoplasia and Hormonal Disorders
The University of Texas MD Anderson Cancer Center
1400 Pressler Street Unit 1461
Houston, Texas 77030
T: (713) 792 2841
F: (713) 794 4065
cjimenez@mdanderson.org
Mitsuhide Naruse, MD, PhD
Department of Endocrinology, Metabolism, and Hypertension
Clinical Research Institute
National Hospital Organization Kyoto Medical Center
1-1 Mukaihata Cho, Fukakusa, Fushimi-Ku, Kyoto,
612-8555, Japan
T: 81(75) 641 9161 ext. 6134
F: 81(75) 641-9254
mnaruse@kyotolan.hosp.go.jp
Akiyo Tanabe, MD, PhD
Department of Medicine II
Tokyo Women's Medical University,
8-1, Kawada-cho, Shinjuku-ku,
Tokyo, 162-8666, Japan
T/F: 81-3-3359-5559
akiyotana@endm.twmu.ac.jp
Steven Waguespack, MD
Department of Endocrine Neoplasia and Hormonal Disorders
The University of Texas MD Anderson Cancer Center
1400 Pressler Street Unit 1461
Houston, Texas 77030
T: (713) 792 2841
F: (713) 794 4065
swagues@mdanderson.org
Pheochromocytomas and paragangliomas are neuroendocrine tumors that could be localized in the head and neck, chest, abdomen or pelvis. Although most of these tumors are benign, 15-17%of these tumors are malignant and they can spread to lymph nodes, the skeleton, lungs, and liver. Malignant pheochromocytomas and paragangliomas are aggressive and predispose patients to increased morbidity and mortality due to two different aspects:
The excessive hormonal secretion may cause hypertension, heart attacks, strokes, arrhythmias, and/or constipation. The tumor burden may cause pain, fractures, spinal cord compression, and many other complications depending on the tumor location. Only 60% of patients with malignant pheochromocytomas or paragangliomas are alive after 5 years of initial diagnosis.
It is currently very difficult to differentiate benign from malignant pheochromocytoma and paraganglioma. Different from other tumors, the histological characteristics of benign and malignant pheochromocytomas and paragangliomas overlap, and malignancy can only be defined with certainty by the presence of metastases. There are, however, some recognized clinical predictors of metastases that could indicate the need for a more extensive initial assessment, more aggressive surgical intervention, and closer long-term follow-up.
These predictors are:
The initial evaluation of patients with any of these predictors of malignancy or with metastases requires:
Therapy against malignant pheochromocytomas and paragangliomas is very complex and requires a sophisticated multidisciplinary approach. Patients with these tumors require evaluations by experts in endocrinology, oncology, nuclear medicine, endocrine/oncological surgery, pathology, and genetics. As patients with malignant pheochromocytomas and paragangliomas are rare, therapeutic approaches are based on a limited number of research publications and the clinicians’ experience. Consequently, patients with malignant pheochromocytomas and paragangliomas are better served by academic tertiary centers with experience in the management of this disease.
Patients with malignant pheochromocytomas and paragangliomas represent a very heterogeneous group of patients. The aggressiveness and prognosis of metastases and recurrences vary widely and treatment should be individualized. In some patients, metastases remain relatively indolent and these patients may do better with active surveillance rather than treatment.
The following briefly describes general therapeutic approaches against this disease:
Hormone-related symptoms
Surgery
Surgical resection is the only curative treatment for patients with localized pheochromocytomas and paragangliomas. However, for most patients with metastatic disease, surgery is not curative. The goals of surgery for patients with apparently curable disease are to abolish catecholamine hypersecretion for subsequent normalization of blood pressure and symptomatic relief of other hormonal manifestations of disease, to prevent further tumor growth or progression to metastatic disease, and to allow long-term remission. In patients with non-curable disease, the goals of surgery are to reduce hormone secretion and tumor macroscopic burden, prevent complications related to a critical anatomical location, and, perhaps, increase the efficacy of other therapies. At the metastatic stage, surgery is proposed mainly to patients with slowly progressive disease.
In addition to surgery, interventional radiology and radiation therapy could offer several therapeutic modalities that could help to control disease in the liver, the skeleton, and other organs.
Examples of these modalities are:
Antiresorptive Therapy
Approximately 70% of patients with malignant pheochromocytomas and paragangliomas have bone metastases. Bone metastases frequently cause severe pain, cord compression, pathologic fractures, and occasionally hypercalcemia. In addition, bone metastases are associated with a decreased overall survival. Patients with bone metastases may benefit from periodic antiresorptive therapy with bisphosphonates or denosumab as these medications could prevent the above mentioned skeletal events.
Systemic therapies are indicated for patients with progressive unresectable disease and/or patients with overwhelming symptoms that are difficult to control with alpha- and beta-blockade and other medications (i.e. patients with severe hypertension). Different modalities of systemic therapies could be offered to patients with malignant pheochromocytomas and paragangliomas including radiopharmaceutical agents, systemic chemotherapy, and molecular targeted therapies. These therapies may cause positive responses in 40-60% of patients. However, they are palliative rather than curative.
Current clinical trials are focused on the evaluation of molecular targeted therapies or radiopharmaceutical agents against malignant pheochromocytomas and paragangliomas. All available clinical trials against malignant pheochromocytomas and paragangliomas are listed in the www.clinicaltrials.gov webpage. This webpage contains the lists of centers and principal investigators and their contact information.
The following are the current clinical trials recruiting patients:
Progenics Pharmaceuticals has re-initiated a clinical trial to evaluate the safety and efficacy of AzedraTM (Ultratrace® lobenguane | 131) in patients with malignant relapsed or refractory pheochromocytoma and paraganglioma. AzedraTM is a very high specific activity form of iobenguane | 131, produced using a proprietary Ultratrace® platform. This technology is designed to prevent unlabeled or “cold” iobenguane from being carried through the manufacturing process to the final formulation which allows Azedra to deliver more effective tumor destruction while avoiding the typical side effects caused by the low specific activity product.
For complete information on this clinical trial including a list of participating Institutions, please visit the study registry entry, or contact:
Jessica D Jensen, MPH
Director, Clinical Operations
Tel: 914.789.2843
jjensen@progenics.com