Clinical Trials and Therapeutics

Members

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


Background

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:

  1. Excessive secretion of catecholamines (adrenaline and/or noradrenaline)
  2. Tumor burden

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.


Our goals

  1. To provide patients and health care providers with information on recent advances on the diagnosis and treatment of malignant pheochromocytoma and paraganglioma
  2. To provide patients and health care providers with information on available clinical trials
  3. To educate patients and health care providers on drug interactions that could predispose to complications such as hypertension, constipation, and others
  4. To provide patients and health care providers with information regarding therapeutic interventions that may help to alleviate symptoms due to excessive hormonal secretion and tumor burden.


Recommendations for initial assessment

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:

  1. A pheochromocytoma larger than 5 cm in size
  2. A sympathetic paraganglioma
  3. The presence of a germline SDHB mutation

The initial evaluation of patients with any of these predictors of malignancy or with metastases requires:

  1. Identification of symptoms related to tumor burden and catecholamine excess
  2. Identification of co-morbidities (i.e. diabetes mellitus)
  3. Evaluation of performance status
  4. Measurements of plasma metanephrines and/or 24-hour urinary fractionated metanephrines and chromogranin A and/or serum methoxytyramine if available
  5. CT/MRI of the neck, chest, abdomen, and pelvis
  6. FDG-PET scan
  7. MIBG scan (useful when considering therapy with MIBG)
  8. Genetic counseling and gene testing


Therapy

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

  1. It is very important to try to control or normalize symptoms such as hypertension, pain, and constipation before any antitumor intervention
  2. Medications that could worsen hypertension or constipation should be avoided (i.e. opiate analgesics can worsen constipation)
  3. Avoid medications that could precipitate a catecholamine crisis (i.e. metoclopramide)

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:

  1. Bland or chemo-embolization
  2. Criotherapy
  3. Radiofrequency ablation
  4. External Beam Radiation therapy

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

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.

  1. Radiopharmaceutical agents - I131Metaiodobenzylguanidine (I131MIBG) can lead to a tumor shrinkage (partial radiographic response), disease stabilization, and symptomatic improvement in approximately 30-60% of patients with malignant pheochromocytomas and paragangliomas. Occasional patients treated I131MIBG have exhibited tumor disappearance (complete radiographic response). I131MIBG is effective in patients with MIBG-avid tumors; it is not indicated, however, for patients with tumors that do not concentrate MIBG. Radiolabeled somatostatin analogues have been seldom studied. They could be a therapeutic option for patients with tumors with substantial expression of somatostatin receptors, especially when the MIBG uptake is limited.
  2. Chemotherapy - Systemic Chemotherapy with cyclophosphamide, vincristine and dacarbazine (CVD) is the best recognized chemotherapy protocol in clinical practice to treat patients with malignant pheochromocytomas and paragangliomas. CVD could lead to tumor shrinkage, disease stabilization, and symptomatic improvement in approximately 40% of patients. Chemotherapy is also associated with a modest improvement in overall survival duration and it has been effective in making some patients with initially unresectable disease, candidates for surgical resection (neo-adjuvant chemotherapy). Chemotherapy might be considered the first-line treatment for patients with tumors that progress rapidly, independent of the amount of tumor MIBG uptake.
  3. Molecular Targeted Therapies - Malignant pheochromocytomas and sympathetic paragangliomas, in particular those associated with SDHB and VHL mutations, are characterized by an increased formation of abnormal vessels (angiogenesis) around the tumor that facilitates tumor survival and spread. Sunitinib is an antiangiogenic agent that in some patients has been associated with tumor shrinkage, disease stabilization, decreased fluorodeoxyglucose uptake on positron emission tomography, and improved blood pressure control. Information on the potential benefits derived from molecular targeted therapies is still limited. Nevertheless there are some prospective clinical trials that will help us to clarify the role of these drugs in patients with malignant pheochromocytomas and paragangliomas. Currently sunitinib and another antiangiogenic agent pazopanib are being evaluated in prospective clinical trials.


Clinical Trials

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:

    Canada
  1. Study Of Sunitinib In Patients With Recurrent Paraganglioma/Pheochromocytoma
  2. USA
  3. Pazopanib Hydrochloride in Treating Patients With Advanced or Progressive Malignant Pheochromocytoma or Paraganglioma
  4. Compassionate Use of 131I-MIBG for Patients With Malignant Pheochromocytoma
  5. Iodine I 131 Metaiodobenzylguanidine in Treating Patients With Recurrent, Progressive, or Refractory Neuroblastoma or Malignant Pheochromocytoma or Paraganglioma
  6. Europe
  7. First International Randomized Study in Malignant Progressive Pheochromocytoma and Paraganglioma (FIRSTMAPPP)

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