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Journal of the Academy of Hospital Administration

Radiolabeled Metaiodobenzylguanidine (MIBG) in the Diagnosis and Treatment of Neural Crest Tumors

Author(s): Rakesh Kumar*, Shamim Ahmed Shamim**

Vol. 16, No. 2 (2004-07 - 2004-12)

Key Words:

Radioiodinated metaiodobenzylguanidine (MIBG), Neuroendocrine Tumors, Neuroblastoma, Pheochromocytoma.

Key Messages:

  1. I-131-MIBG is used for diagnosis and treatment of neuroendocrine tumors & staging.
  2. I-131 is also useful in evaluating treatment response of neuroendocrine tumor.

The development of radio-iodinated metaiodobenzylguanidine (MIBG) took place in 1980 at the University of Michigan. It is an aralkylguanidine, which is structurally similar to norepinephrine. It concentrates within secretory granules of catecholamine-producing cells.1 Radioiodinated MIBG can be used for localization of neural crest tumors of the amine precursor uptake and decarboxylation series (APUDomas) such as neuroblastoma and pheochromocytoma.2,3 In addition to imaging of various neural crest tumors, MIBG is used in therapy of neuroblastoma and pheochromocytoma.

Mechanism of Localization

Metaiodobenzylguanidine is the combination of the benzyl group of bretylium and the guanidine group of guanithidine. It is used for scintigraphic study of adrenergic nervous system. MIBG structurally resembles noradrenaline; localization appears to be through active uptake mechanism, with entry of the agent into catecholamine storage vesicles of adrenergic nerve ending and the cell of adrenal medulla. Once inside the cell, the majority of MIBG remains within the cytoplasm in neuroblastoma cells, whereas in pheochromocytoma cells, MIBG is actively transported into the granules. MIBG can be labeled with either I-123 or I-131. The I-131 MIBG is widely used for most routine applications mainly in adult patients because of ready availability and longer half-life, lower casts, and the possibility of obtaining delayed scans. In comparison, I-231 is a pure gamma-emitter with a short half-life of 13 h and principal photon energy of 159 keV, which is highly suitable for camera imaging. The whole-body radiation dose for I-231-MIBG is approximately 5% that of I-131-MIBG. However, it is cyclotron produced and has higher cost. The majority of I-131-MIBG is excreted unchanged through the urinary tract (40% - 55% in 24 h; 70% - 90% in 96 h). Small fractions are excreted in the gut.

Precautions

Numerous drugs including many antihypertensives, sympathomimetics, tricyclic antidepressants, and antipsychotics have been reported to inhibit MIBG tumor uptake and should therefore, be withdraw prior to imaging.4 Cardiac drugs, including calcium channel blockers (nifedipine) and angiotensin-converting enzyme inhibitors (captopril, enalapril) may interfere with visualization, and special attention should be paid to these agents when imaging patients with pheochromocytoma. Breast feeding should be discontinued for 48 hours when I-123 MIBG is used, and breast feeding should be terminated when I-131 MIBG is used. In pregnancy a clinical decision to weigh the benefits against the possible harm of the procedure is necessary.

Patient Preparation

When I-131-MIBG in used, patients are given a blocking dose of stable iodine preparation, potassium iodide or Lugol’s solution beginning 1 day before and continuing for 1 week after the administration of MIBG. This preparation of iodine is used to block the thyroid uptake. Recommended doses are 32 mg of potassium iodide daily for children ages 1 month to 3 years, 65 mg for those 3 to 13 years, and 130 mg for those older than 13 years. For newborns, the recommended dose is 16 mg only on the day before tracer injection.

The dose of MIBG is administered by slow intravenous injection over at least 5 min. Potential adverse effects of MIBG injection (vomiting, tachycardia, pallor, abdominal pain) are rare when rapid injection is used. Patients should be advised to take lots of fluids to facilitate the excretion of unbound radiopharmaceutical.

Many drugs interfere with the uptake and storage of I-123 MIBG and I-131 MIBG. So these drugs should be withdrawal prior to the imaging. Interfering drugs include guanethidine, tricyclic antidepressant, antihypertensive (labetalol, metoprolol, amiodarone, resprine, nifidipine, nicardipine, captopril, and enapril), certain antipsychotics (chlorpromazine, promethazine, fluphenazine, droperidol, and haloperidol), cocaine etc.

Imaging Technique

Adult dose of I-131 MIBG is (1.2-2.2mCi), and I-123-MIBG is 10mCi. The children dose PELVIS should be calculated on the basis of a reference dose for an adult. The tracer is administered by slow intravenous injection. Images with I-131 MIBG are usually obtained at 24 hours, delayed imaging at 48 and 72 hours after injection. The preferred imaging device is a large field of view gamma camera with Figure 1: I-131 high energy, parallel-hole Scan of abdomen collimator. For studies with I-obtained after 48 123 MIBG scanning is hours of injection, performed 24 hours and 48 shows focal area hours. In suspected of abnormal MIBG pheochromocytoma the concentration in posterior view of the mid-left adrenal region. abdomen with the region of the This finding is adrenal glands is most suggestive of important. Additional planer pheochromocytoma. Images from base of skull to pelvis should be obtained. Single photon emission computed tomography (SPECT) studies are acquired at 24 h after I-123 MIBG administration, using rotating gamma camera equipped with parallel-hole, low or medium-energy collimator.

Image 1:I-131, PELVIS

Image 1

Adverse Effect of MIBG

Adverse effects of MIBG are very rare like tachycardia, pallor, vomiting, and abdomen pain after rapid injection of MIBG. Radiodinated MIBG clear from blood rapidly, about two third of dose excreted into urine in the first 24 hours after administration.

Normal Distribution of MIBG I-131/1-123 MIBG

Radioactivity normally seen in the liver, smaller uptake is seen in spleen, lungs, salivary glands, thyroid and myocardium. Normal adrenal medulla is only faintly visualized in less than 20% of cases at 48 hours.5 The normal adrenal medulla in seen more frequently with I-123 MIBG studies.

Clinical Applications

The scope of MIBG scintigraphy has expanded considerably in recent years. It is used not only to diagnose and stage various neural crest tumors but also at follow-up to assess response to therapy, exclude a subclinical relapse, and plan MIBG therapy.

Pheochromocytoma

These are usually derived from the adrenal medulla but may developed from chromoffin cell in or about sympathetic ganglia (extra adrenal pheochromocytoma or paragangiolomas). The pheochromocytomas are most important paraganglioma. These tumors produce catecholamine and produce clinical syndrome. The prevalence of pheochromocytoma is approximately 0.1%-0.4% of hypertensive patient. About 60% of pheochromocytoma patient present with sustained hypertension and other show increased blood pressure during attack. Most of pheochromocytomas are unilateral and solitary. About 10% are multiple, 10% are bilateral, and 10% are extra adrenal.

MIBG imaging has been used to locate pheochromocytomas of all types including sporadic intra adrenal lesions and those arising in association with MEN II A, MEN IIB neurofibromatosis and von Hippel Lindau disease7-9. Sensitivity for detection of pheochromocytoma is 88%, with a specificity of 92% and the characteristic appearance is unilateral focal uptake in the tumor (Figure-1)10. When these tumors are larger than 1.5cm in diameter, CT readily visualizes them. MIBG scintigraphy detects both large and small lesions and has the additional advantage that in up to 10% cases there can be multifocal or metastatic disease present at any site of body. These lesions can be detected by entire body examination5,7. MIBG scintigraphy is useful in extra-adrenal pheochromocytoma. Extra adrenal pheochromocytoma can occur from the base of skull to pelvis and often difficult to diagnose with CT because of their close relationship to other structure and their size. When compared with other imaging modalities, the radiolabeled MIBG appears to be superior to ultrasound and radiographs, and equivalent to CT and MRI.11 Venous sampling of catecholamine may indicate the level of a given lesion, but it in not a possible method of surveying the entire body. MIBG scintigraphy has the additional advantage of screening whole body therefore; it can easily detect any extra adrenal tumors, mutifocal disease.12 The screening ability is also of particular value when recurrent pheochromocytomas are suspected. MIBG is also useful in metastatic disease.

Figure 2: I-131

image 2

Whole body scans obtained after 48 hours of injection, shows multiple focal areas of abnormal MIBG concentration in skull, abdomen and pelvis. The abdominal MIBG is primary tumor (neuroblastoma), while skull and pelvic MIBG uptake is due to bone metastases.

Adrenal Medullary Hyperplasia

Adrenal medullary hyperplasia is associated with multiple endocrine neoplasia (MEN 2A and MEN 2B syndrome). MIBG scintigraphy shows increased bilateral adrenal uptake during 2-3 days of examination period. The computed tomography (CT) and magnetic resonance imaging are not able to detect adrenal medullary hyperplasia until it is in advanced stage. MIBG scintigraphy plays an important role in detection adrenal medullary hyperplasia.

Neuroblostoma

Neuroblostoma is the second most common solid tumors of childhood, highly malignant, that often presents at an advanced stage. Scintigraphy plays important role in detection, staging, and monitoring responses to therapy and in distinction of residual tumor from scar. Imaging quality is better with I-123 than I-131 MIBG. The prognosis in neuroblastoma is highly dependent on staging. It is important, then, to accurately localize the full extent of disease before initiating therapy. Traditional staging investigations include CT and MR imaging, bone scan, and bone marrow aspiration biopsy. The specificity of MIBG scintigraphy approaches 100%, whereas sensitivity for staging has been reported to be 90% - 95% in various studies (Figure-2).1 The highest sensitivity is shown in detection of bone deposits where it reveals more lesion than bone scintigraphy with 99m-Tc MDP.13 It appears that to detect skeletal neuroblastoma both MIBG and Tc99m-MDP bone scans may be useful. MIBG provides a better idea of extent of disease, whereas 99mTc-MDP bone scans are needed because of the problem of false-negative MIBG scans.

MIBG in the Diagnosis of other Neuroendocrine Tumors Imaging

Medullary thyroid carcinoma (MTC):

It derives from c-cells, which are derivative of neural crest. Specificity of MIBG in detection of MTC is high 95% but sensitivity is low 34%.13

Carcinoid tumors:

Carcinoid tumors are neuroendocrine tumors of the gut and pancreas. About 50-60% of carcinoids are able to concentrate radiolabeled MIBG.14

Other neural crest tumors:

Detection of tumors other than pheochromocytomas, neuroblastomas, medullary carcinoma of thyroid and carcinoids is very limited. Only few of these tumors show some MIBG uptake, and show wide disparity in MIBG uptake between the different tumor sites. More than half of gangioloneuromas, few cases of schwannoma, retinoblastoma, Merkel cell tumors, and APUDomas of unknown origin are visualized I-131 MIBG scintigraphy.

Therapy of Neuroendrocrine Tumors with Radioiodinated Metaiodobenzylguanidine

In metastatic pheochromocytoma deposits, it is observed that I-131 MIBG show intense uptake and prolonged retention because of this property I-131 MIBG raised the possibility of therapy with and other related radiopharmaceuticals.15 Other neuroendocrine tumors of the amine precursor uptake and decarboxylation (APUDomas) type such as neuroblastomas, MTC and carcinoid accumulate MIBG have been candidates for experimental radionuclide therapy.8

Large doses of I-131 MIBG have been administered for experimental therapy of malignant pheochromocytoma and other neuroendocrine tumors that shows avid accumulation of radiopharmaceutical.16 In a resent review of 116 patients treated with varying doses of I-131 MIBG reported partial response (>50% decline in catecholamine and metabolite levels and greater decrease in tumors volume) in 18 to 88% of patients.16 Improvement in bone pain, retroperitoneal metastasis, and decrease in blood pressure is seen.16 Most of the neuroblastomas show prolonged and intense uptake of diagnostic dose I-123 and I-131 MIBG, large doses radio- iodinated has been used to treat metastatic neuroblastomas.17 Other tumors of neuroendocrine origin, which show increased uptake I-123/ I-131 MIBG, might be treated with large doses of I-131.18

References

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  2. Kimmig B, Brandeis WE, Eisenhut M, et al. Scintigraphy of neuroblastoma with I-131-metaiodobenzylguanidine. J Nucl Med 1984; 25:773-775.
  3. Von Moll L, McEwan AJ, Shapiro B, et al. Iodine I-131 MIBG scintigraphy of neuroendocrine tumors other than pheochromocytoma and neuroblastoma. J Nucl Med 1987; 28:979-988.
  4. Khagaghi FA, Shapiro BM, et al. Labetalol reduces I131 MIBG uptake by phaeochromocytoma and normal tissues. J Nucl Med 1989; 30:481-9.
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  6. Swanson DP, Carey JE, Brown LE, et al. Human absorbed dose calculations for I-131 and I-123 labeled metaiodobenzylguanidine (MIBG): a potential myocardial and adrenal medualla imaging agent. In: proceedings of the 3rd International Radiopharmaceutical Dosimetry Symposium. Health and Human Services Publication FDA 81-81-66, Rockville, Maryland 1981; pp. 213-214.
  7. Sisson JC, Frager MS, Valk TW et al. Scintigraphy localization of pheochromocytoma. N Engl J Med 1981;305(1):12-17.
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  11. Welchick M G, Alavi A, Kressel H Y, Engelman K. Localisation of pheochromocytoma: MIBG, CT and MRI correlation. J nucl med 1989;30: 328-336.
  12. Mozley P D, Kim C K, Mohsin J, Jat E , Alavi A. The efficacy of iodine-123-MIBG as a screening test for pheochromocytoma. J Nucl Med 1994;35: 1138-1144
  13. Lumbrose J D, GUermazi F, Hartmann O et al. MIBG scans in neuroblastomas: sensitivity and specificity. A review of 115 scans. In: Evan A E, D’Angio G J, Knudson AG, Seeger R C (eds) Advances in neuroblastomas research, vol 2. Alan R Liss, New York, 1988, pp 689-705
  14. Fischer M, Kamanabroo D, Sonderkamp H, Proske T. Scintigraphic imaging of carcinoid tumours with 131Imetaiodobenzylguanidine. Lancet. 1984 21;:165.
  15. Sisson JC, Shapirg B, Beierwaltes WH et al. Radiopharmaceutical treatment of malignant pheochromocytoma. J Nucl Med 1984;25: 197-206
  16. Shaprio B, Sisson JC, Wieland DM et al. Radiopharmaceutical therapy of malignant pheochromocytoma with I-131 MIBG: results from 10 years of experience. J Nucl Biol Med 1991; 35:269-276.
  17. Shulkin BL, Shaprio B. Radioiodinated meta-iodinated benzylguanidine in the management of neuroblastomas. In: Pochedly C, ed. Neuroblastoma. Boca Raton, FL: CRC Press, 1990:171-198.
  18. Shaprio B. Summary, conclusion, and future directions of I-131 meta-iodobenzylguanidine therapy in the treatment of neural crest tumors. J Nucl Biol Med 1991;35:357-363.

* Associate Professor, Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India

** Junior Resident, Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India

Address for correspondence:

Dr. Rakesh Kumar,
F-74, Ansari Nagar (West),
AIIMS Campus, New Delhi- 110029
Phone: +091-11-26588663,
Fax: +091-11-26100949,
Email: [email protected]

Journal of the Academy of Hospital Administration, Volume 16 No. 2 July-December 2004

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