I-131 MIBG Therapy for Carcinoid Tumors

R. Edward Coleman, M.D. is Professor of Radiology and Director of the Division of Nuclear Medicine at Duke University Medical Center (DUMC). After receiving his medical degree from Washington University in St. Louis, he did postgraduate training at Barnes Hospital in St. Louis, the Royal Victoria Hospital in Montreal, and Mallinkrodt Institute of Radiology in St. Louis. After a short stint on the faculty at Washington University, he joined the faculty at the University of Utah for three (3) years before moving to DUMC as Professor of Radiology in 1979. Soon after the introduction of radiolabeled MIBG, Dr. Jerome Feldman, an endocrinologist with special interest and expertise in neuroendocrine tumors, and he began investigating and reporting on the use of MIBG in diagnosing and treating these tumors. He is the principal investigator on a clinical trials contract with Molecular Insight Pharmaceuticals, Inc.

Development of Metaiodobenzylguanidine (MIBG) Imaging

Radiolabeled MIBG was developed in 1980 at the University of Michigan by Wieland and colleagues because of their interest in imaging the adrenal gland and pheochromocytoma, a tumor of the adrenal gland. That group demonstrated prominent uptake of MIBG in the normal adrenal gland as well as in pheochromocytoma.

MIBG Imaging and Therapy at DUMC

MIBG was used in the early 1980’s at Duke for evaluating patients with suspected pheochromocytoma, one of the neuroendocrine tumors that accumulate this agent. Working with Dr. Feldman, we demonstrated that the mechanism of the accumulation of this agent in pheochromocytomas was the same as in platelets, i.e., a neuronal-pump mechanism. We were aware that the same mechanisms were present in carcinoid tumors and this early research resulted in our using it for imaging carcinoid tumors as well as pheochromocytomas. Our initial observation on the use of MIBG of carcinoid tumors in 23 patients was published in 1986 when we demonstrated that 61% of carcinoid tumors were detected by MIBG imaging. Even in this small population, we noted that greater accumulation of MIBG was demonstrated in tumors of midgut origin (ileum, cecum), than in tumors of foregut origin (pancreas, stomach), and it was not significantly concentrated by tumors of other foregut origin (bronchus). In a subsequent publication that reported the results in 82 patients, we confirmed the findings of the earlier study. In addition, we noted that accumulation of MIBG was more likely when the serum serotonin levels were elevated. Shortly after those studies were published, we began treating patients who had metastatic carcinoid tumors with larger doses of I-131 MIBG. In 2004, our results of treating 98 patients with metastatic carcinoid were published. Patients who experienced a symptomatic response to the therapy had improved survival over those who did not have a symptomatic response. Tumor markers such as 5-HIAA levels decreased significantly after the I-131 MIBG treatment. We observed that patients who received an initial high dose of the radioactive material had a better prognosis than those patients who initially received a lower dose. Decreases in blood counts were noted after therapy, but these decreases in counts improved to the baseline level with time.

In addition to studying the role of MIBG in carcinoid tumors, we evaluated its role in diagnosing and treating pheochromocytoma. In a study of 64 patients with suspected pheochromocytoma, the MIBG imaging had a sensitivity and specificity of 88%. In a study that evaluated the impact of MIBG therapy on 33 patients who had metastatic pheochromocytoma or paraganglioma, we noted that a symptomatic response led to an improved survival. Furthermore, patients with a measurable hormonal response demonstrated an increased survival in comparison to those with no response. Patients who received an initial high dose of the therapy had improved survival over those who had a low dose.

New Formulation of MIBG

The method of synthesizing MIBG developed at the University of Michigan and used at several other institutions had non-radioactive MIBG in the formulation. Recently, Molecular Insight Pharmaceuticals, Inc., has begun investigating a no-carrier-added formulation of MIBG (Azedra) for treating neuroendocrine tumors. Preliminary studies in animals and patients have demonstrated greater accumulation of MIBG in the tumors with better results in treating tumors in animal models. Patients with metastatic pheochromocytoma and paraganglioma are being treated with this new formulation. A Phase I study has been completed, and a Phase II study is to begin in early 2009. Although the Phase I trial was primarily designed for determining safety and maximum tolerated dose in patients with metastatic pheochromocytoma and paraganglioma, efficacy was demonstrated in some of the patients. The Phase II study is designed for treating patients with metastatic pheochromocytoma and paraganglioma, but it is anticipated that some patients with carcinoid tumors may be treated with this new formulation.

Future of Radiopharmaceutical Therapy

With the initial demonstration of response to the Azedra therapy in the Phase I trial, a Phase II study is anticipated. The potential for using Azedra therapy in patients with metastatic carcinoid tumor is also an exciting possibility.

In addition to the potential use of Azedra in treating metastatic carcinoid tumors, therapy with radiolabeled somatostatin analog is also promising. The same company that developed Azedra for therapy of neuroendocrine tumors is planning clinical trials of a somatostatin analog labeled with Yttrium-90 for therapy of carcinoid tumors. Previous studies in small numbers of patients have demonstrated therapeutically efficacy, but the agent is not generally available in the U.S. Clinical trials with this agent will be performed in anticipation of leading to approval by the FDA.


Literature cited:

1. Feldman JM, Frankel N, Coleman RE: Platelet uptake of the pheochromocytoma-scanning agent 131-I-meta-iodobenzylguanadine. Metabolism 33:397-399, 1984.

2. Feldman JM, Blinder RA, Lucas KJ, Coleman RE: Iodine-131 metaiodobenzylguanidine scintigraphy of carcinoid tumors. J Nucl Med 27:1691-1696, 1986.

3. Hanson MW, Feldman JM, Blinder RA, Moore JO, Coleman, RE: Carcinoid tumors: Iodine-131 MIBG scintigraphy. Radiology 172:699-703, 1989.

4. Safford SD, Coleman RE, Gockerman JP, Moore J, Feldman J, Leight GS, Tyler DS, Olson JA: Iodine-131 metaiodobenzylguanidine is an effective treatment for malignant pheochromocytoma and paraganglioma. Surgery 134: 956-962, 2003.

5. Safford SD, Coleman RE, Gockerman JP, Moore J, Feldman J, Onaitis MW, Tyler DS, Olson JA Jr: Iodine-131 metaiodobenzylguanidine treatment for metastatic carcinoid. Results in 98 patients. Cancer, 101:1987-93, 2004.

6. Hanson MW, Feldman JM, Beam CA, Leight GS, Coleman RE: Iodine 131-labeled metaiodobenzylguanidine scintigraphy and biochemical analyses of pheochromocytomas. Arch Int Med 151:1397-1402, 1991.

7. DeGrado TR, Zalutsky MR, Coleman RE, Vaidyanathan G: Effects of specific activity on meta-[131I] Iodobenzylguanidine kinetics in isolated rat heart. Nucl Med Biol 25:59-64, 1998.

8. Khan MU, Coleman RE: Diagnosis and therapy of carcinoid tumors – current state of the art and future directions. Nucl Med & Biol, 2008, in press.

9. James O, Coleman RE: Radioiodinated MIBG in paraganglioma and pheochromocytoma: previous results and early experiences using no-carrier-added MIBG. Nucl Med & Biol, 2008, in press.