Metaiodobenzylguanidine Therapy Research Articles

Repeated [131I]Metaiodobenzylguanidine Therapy in Two Patients with Malignant Pheochromocytoma

Approximately 10% of pheochromocytomas are malignant with a 5-yr survival rate of less than 40%. Promising results have been published on single high-dosage [131I]metaiodobenzylguanidine ([131I]MIBG) treatment for malignant pheochromocytoma. We present our experience with multiple intermediate-dosage [131I]MIBG therapy instead of single high-dosage therapy. The study took place at University Medical Centers and included two patients (one male, 36 yr of age, and one female, 43 yr of age) with widely spread metastatic pheochromocytoma and bad prognosis because of liver and lung metastases. Instead of a single high dosage, these two patients were treated with multiple intermediate dosages of [131I]MIBG. The first patient received 37 GBq (1 Ci) [131I]MIBG in five sessions [7400 MBq (200 mCi) each; interval range, 2-11 months]; the second patient received 66.6 GBq (1.8 Ci) [131I]MIBG in 12 sessions [5550 MBq (150 mCi) each; interval range, 2-14 months]. We measured efficacy, toxicity, and survival. Both patients had a complete symptomatic response and a partial tumor volume response. The first patient had a partial biochemical response, the second a complete biochemical response. In both cases, toxicity has been confined to nausea during treatment. Hematological toxicity was minimal, and both patients stayed euthyroid. The survival (so far) of these patients was 5 yr (clinical case 1) and 16 yr (clinical case 2) after initial diagnosis. Repeated intermediate-dosage [131I]MIBG treatment appears to be a reliable and well-tolerated radionuclide therapy and might be a useful adjunct in patients with malignant pheochromocytoma, providing longstanding palliation and prolonged survival.

Targeted radionuclide therapy for neuroendocrine tumours.

Evidence supporting the potential contribution of targeted radiotherapy to the management of neuroendocrine tumours is now strong. Acting systemically, this is an effective option for patients with inoperable or multi-site disease. Toxicity is generally low, being limited to reversible myelosuppression and theoretical nephrotoxicity. Prerequisites for treatment success include demonstration of high tumour uptake relative to non-target tissues on quantitative diagnostic radionuclide imaging and stable haematological and biochemical function. In addition to (131)I metaiodobenzylguanidine therapy, which is now well established, there is growing interest in radiolabelled peptide therapy using a range of somatostatin receptor analogues such as (90)Y DOTATOC and (90)Y lanreotide. The results of clinical experience are summarised and the direction for future research is discussed.

Monitoring the efficacy of iodine-131-MIBG therapy using fluorine-18-FDG-PET.

The purpose of this study was to assess the potential of fluorine-18 fluoro-2-deoxy-d-glucose positron emission tomography (18F-FDG-PET) for monitoring the efficacy of iodine-131 metaiodobenzylguanidine (131I-MIBG) therapy in neuroendocrine tumours. A total of seven 131I-MIBG therapies with 3.7 to 10.2 GBq were carried out in three patients suffering respectively from a phaeochromocytoma, a paraganglioma and a metastatic neuroendocrine tumour of an unknown primary. The post-therapeutic whole-body scintigrams were compared with the results of six 18F-FDG-PET studies performed at the time of the therapies. One patient received three PET scans prior to each one of the MIBG therapies, and one patient was studied twice. 18F-FDG uptake in tumour sites seemed to correlate well with tumour differentiation, showing no uptake in one patient with a highly differentiated neuroendocrine tumour, and moderate-to-intense uptake in the two other patients with metastatic disease. Those tumour sites that had a simultaneous positive uptake in both the MIBG scintigram and the PET scan showed response to therapy as a continuous reduction in MIBG uptake over time. They also showed a qualitative decrease in FDG accumulation during the follow-up. This was associated with a decrease in the mean and maximum standard uptake values of more than 50 % in some metastases, while the X-ray computed tomography showed no decrease in tumour volume. Two patients revealed additional metastases that were unknown on the basis of prior diagnostic or therapeutic PET scans and radiological follow-up. It may be concluded from these cases that 18F-FDG-PET is a valuable tool for an initial metabolic staging of neuroendocrine tumours prior to 131I-MIBG therapy, as it can reveal tumour sites beyond the reach of radioisotope therapy. It may also be of importance in assessing therapeutic potential in those tumour sites that do show positive MIBG uptake.

Treatment of advanced neuroendocrine tumours using combination chemotherapy with lomustine and 5-fluorouracil.

Combination chemotherapy with the two agents streptozotocin (SZT), which is a nitrosurea, and 5-fluorouracil (5-FU), an alkylating agent, has a long-established role in the treatment of neuroendocrine tumours; however, it is often accompanied by considerable toxicity, and it has not been assessed in a comparative manner with other current chemotherapy regimens. In order to assess the therapeutic response and adverse effects using an alternative nitrosurea, lomustine (CCNU), which has a different side-effect profile, in combination with 5-FU, we have reviewed all patients with neuroendocrine tumours who received this form of treatment in our department. Retrospective analysis of the case notes of patients with metastatic neuroendocrine tumours who received treatment with the combination of CCNU and 5-FU, and who were followed up according to a defined protocol in a given time frame. Thirty-one patients with metastatic neuroendocrine tumours (18 with carcinoid tumours, five islet-cell tumours, five chromaffin-cell tumours and three medullary carcinoma of the thyroid) treated with the combination of CCNU and 5-FU, and when necessary additional therapy, over a 22-year period, were included in this analysis. The symptomatic, hormonal and tumoural responses before and after chemotherapy with the combination of CCNU and 5-FU over a median follow-up duration of 25 months (range 9-348 months) were recorded. Of the 31 patients (16 males; median age 52 years, range 20-86 years), eight (four males; median age 61 years, range 30-74 years) were treated with the combination of CCNU and 5-FU alone (Group 1), whereas the other 23 patients (12 males; median age 47 years, range 20-86 years) received additional therapy with other chemotherapeutic regimens, somatostatin analogues, alpha-interferon or radiolabelled meta-iodobenzylguanidine (131I-MIBG) therapy (Group 2). A total of 121 therapeutic cycles was administered (mean 3.9, range 1-14 cycles). None of the patients obtained a complete tumour response. A partial tumour response (not a complete but a 50% or greater reduction of all measurable tumour) was seen in six out of the 29 patients (21%) (four out of eight in Group 1 and two out of 21 in Group 2, respectively). There was no tumour progression in eight out of the 29 patients (27.5%) (one out of eight in Group 1 and seven out of 21 in Group 2, respectively). The median survival over the period of the study was 48 months (95% confidence interval, CI, 22-74 months). The overall 5-year survival rate was 42% (95% CI, 17-67%) for all patients and 50% (95% CI, 18-83%) for the carcinoid group alone, according to Kaplan-Meier analysis. A complete or partial symptomatic response was obtained in 12 out of 27 (44%) patients who presented with symptoms (four out of eight in Group 1 and eight out 19 in Group 2, respectively) and a complete or partial hormonal response in eight out of 19 patients (42.1%) who presented with hormonally active disease (two out of four in Group 1 and six out of 15 in Group 2, respectively). Nine out of the 15 (60%) patients with carcinoid tumours who presented with symptoms obtained a symptomatic response, five out of 10 patients (50%) a hormonal response, and four out of 16 (25%) patients a partial tumoural response, respectively. The combination of CCNU and 5-FU was safe and well tolerated. Serious side-effects necessitating the termination of CCNU and 5-FU were seen only in two patients, and mainly consisted of reversible bone marrow suppression. No chemotherapy-related death was recorded. Chemotherapy with CCNU and 5-FU, either alone or in combination with other therapeutic modalities, produces considerable symptomatic and hormonal improvement and moderate tumour regression/stabilization according to currently accepted WHO criteria, particularly in patients with metastatic gastroenteropancreatic neuroendocrine tumours with minimal adverse effects. However, long-term survival was still relatively poor. It may therefore be a valuable additional therapl was still relatively poor. It may therefore be a valuable additional therapeutic option, particularly for well-differentiated carcinoid and islet-cell tumours, but mainly reserved for when there is no response or progression of the disease after currently available first-line treatment with somatostatin analogues or radiopharmaceuticals.

Human megakaryocytes cultured in vitro accumulate serotonin but not meta-iodobenzylguanidine whereas platelets concentrate both.

Thrombocytopenia is the major toxicity of radio-iodinated meta-iodobenzylguanidine (MIBG) therapy in patients with recurrent neuroblastoma. MIBG is taken up in platelets via the serotonin transporter. Given the delayed appearance and long duration of the thrombocytopenia, it seems likely that the precursor megakaryocytes are the primary targets of [131I]MIBG radiotoxicity. We investigated MIBG and serotonin uptake in cultured human megakaryocytes grown in vitro from CD34(+) cells obtained from bone marrow. With radio-iodinated MIBG, cell-associated radioactivity was negligible, even after prolonged incubations for up to 16 hours. In contrast, after 4 or 16 hours with 10(-8) M [3H]serotonin, 6% or 14% of the added substrate was accumulated in the megakaryocytes. This uptake approached saturation above 10(-7) M and was reduced greater than 90% by coincubation by imipramine. This indicates specific uptake, which was confirmed by fluvoxamine and citalopram. The serotonin reuptake inhibitors fluvoxamine (0.3 nM) and citalopram (1 nM) effectively reduced serotonin uptake to 44% +/- 3% and 30% +/- 9% of the controls, respectively. Megakaryocytes efficiently retain serotonin in storage granules, as concluded from the consistent reductive effect of tetrabenazine on uptake, retention, and localization (micro-autoradiographic) of serotonin. Thus, serotonin, but not MIBG, is taken up by cultured megakaryocytes.

Management of Malignant Phaeochromocytoma: A Retrospective Review of the use of MIBG and Chemotherapy in the West Midlands

Metastatic malignant phaeochromocytoma is a rare disorder, with no randomized and few prospective data to facilitate choice between the two main treatment modalities, chemotherapy and radiolabelled metaiodobenzylguanidine (MIBG). In the last decade the latter modality has been preferred and radiological response rates of 30% have been reported. There are fewer patients described in the literature who have received chemotherapy but one prospective trial of chemotherapy reported radiological response rates of 57%. A recent prospective trial combining the two modalities has been disappointing with only one patient completing the treatment schedule. We present six patients with malignant phaeochromocytoma or paraganglioma who received MIBG therapy. Four patients also received chemotherapy.A retrospective review of the case notes was performed. Radiological and hormonal responses were determined and the time to progression after each modality was calculated. One partial hormonal response was seen with MIBG treatment. One complete and one partial hormonal response and one partial radiological response were seen with chemotherapy. The median time to disease progression from commencement of MIBG was 12 months (range 3–44) and from commencement of chemotherapy used as first or second line treatment was 22.5 months (range 7–25).Chemotherapy may be a more active modality in this disease than previously considered. MIBG uptake may increase after a partial radiological response to chemotherapy, enabling subsequent MIBG therapy. Researchers carrying out future trials on combined therapy should consider administering chemotherapy prior to MIBG for the reasons that we outline in this article.

131I-MIBG radionuclide therapy is safe and cost-effective in the control of symptoms of the carcinoid syndrome

Background The standard treatment used to control the symptoms of carcinoid syndrome (CS) involves subcutaneous injections of the somatostatin analogue octreotide. This is expensive (US$8000–16 000 per year), and treatment may be for many years. The aim of this study was to evaluate the efficacy and cost-effectiveness of our experience over the last 5 years with 1-131-labelled metaiodobenzylguanidine (MIBG) radionuclide therapy in the palliation of patients with CS.Methods A consecutive series of 20 symptomatic patients (referred between 1994 and 1999) with CS were evaluated. Fifteen of them underwent123I-MIBG scanning. Of the 13 patients with significant tracer uptake in metastatic deposits compared to background, 12 underwent a course of therapeutic131I-MIBG (one patient refused). Symptoms, biochemical markers, CT scans, follow-up123I-MIBG scans, and the requirement for octreotide were used to assess outcome of treatment. Costs of131I-MIBG and octreotide treatments were compared. Results MIBG treatment was well tolerated in all with only transient side-effects. Ten patients showed a measurable clinical improvement. Seven had a complete clinical response. The mean duration of response was 15.4 months. Octreotide was not required or was reduced in eight patients. Treatment with131I-MIBG resulted in a saving of US$1000 per patient, with effective symptom control, when compared to octreotide.Conclusion 1-131 MIBG therapy is a safe and cost-effective therapeutic option to successfully control symptoms in patients with carcinoid syndrome.

131I]‐ and [125I]metaiodobenzylguanidine therapy in macroscopic and microscopic tumors: A comparative study in SKNSH human neuroblastoma and PC12 rat pheochromocytoma xenografts

131I]‐ and [125I]metaiodobenzylguanidine therapy in macroscopic and microscopic tumors: A comparative study in SKNSH human neuroblastoma and PC12 rat pheochromocytoma xenografts

131I]- and [125I]metaiodobenzylguanidine therapy in macroscopic and microscopic tumors:A comparative study in SK-N-SH human neuroblastoma and PC12 rat pheochromocytoma xenografts

[(131)I]Metaiodobenzylguanidine ([(131)I]MIBG) targeted radiotherapy is effective in debulking childhood neuroblastoma. The high-energy beta-emitter [(131)I]MIBG is, however, not very well suited to treat submillimeter tumors. The [(125)I]MIBG emission is more fully absorbed in small target volumes and therefore advocated for treatment of microscopic neuroblastoma. We investigated whether i.v. [(125)I]MIBG can have a therapeutic advantage over i.v. [(131)I]MIBG in realistic animal models. We used BALB/c nu/nu mice, bearing neuroadrenergic xenografts which differ in MIBG handling, i.e., extragranular vs. granular MIBG storage in the SK-N-SH human neuroblastoma and PC12 rat pheochromocytoma, respectively. Groups of 4-9 animals were treated with 10-100 MBq radioiodinated MIBG. Responses were calibrated against the effect of 4-5 Gy of external beam X-rays. SUBCUTANEOUS XENOGRAFTS: Due to the more extensive MIBG accumulation, the estimated MIBG exposure of the PC12 tumor was nearly 20-fold higher compared with the SK-N-SH xenograft which corresponded with a marked, i.e., nine-fold increased tumor growth delay after radioiodinated MIBG therapy. Both xenografts were equally sensitive to high-dose rate local irradiation. In neuroblastoma as well as pheochromocytoma, the therapeutic efficacy of [(131)I]MIBG was 6 times higher compared to the [(125)I]MIBG which is in reasonable agreement with the reported "131-I over 125-I" ratio of approximately 9 for the calculated absorbed radiation doses per unit of radioactivity. Apparently, the neuroblastoma was not relatively more sensitive to the (ultra)short range emitter [(125)I]MIBG than the pheochromocytoma, indicating that its therapeutic efficacy is independent of the intracellular MIBG storage mode. MICROSCOPIC TUMORS: The pheochromocytoma model consisted of widespread disease after i.v. cell injection with survival as endpoint. For the neuroblastoma, we induced focal intrahepatic microscopic tumors by intrasplenic injection and evaluated total liver weights 26 days after therapy. Theoretically, the therapeutic potential of [(125)I]MIBG at the cellular level should be at least as high as [(131)I]MIBG, but we failed to show any effect of [(125)I]MIBG therapy in both models. In contrast, measurable responses were obtained with [(131)I]MIBG, but these were lower than in the s.c. tumors when related to the responses induced by external X-rays. In conclusion, [(131)I]MIBG is decreasingly effective in microscopic disease and can therefore not be curative as a single agent. Our results strongly argue against the clinical use of [(125)I]MIBG and indicate that conventional total body irradiation was superior to [(131)I]MIBG for microscopic neuroblastoma. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 312-325 (2000).

Brain uptake of iodine-131 metaiodobenzylguanidine following therapy of malignant pheochromocytoma.

Intracranial metaiodobenzylguanidine (MIBG) uptake is occasionally and only faintly visualized on diagnostic studies. Recently, intense normal cerebellar uptake was described on posttherapy MIBG images. Experience at the University of Michigan with posttherapy MIBG scintigraphy of pheochromocytoma was reviewed. The patterns and correlates of intracranial uptake after therapeutic 1-131 MIBG in 25 patients (61 patient treatment encounters) were evaluated by review of records and blinded consensus interpretation of diagnostic and posttherapeutic MIBG scans. Thirty-nine (64%) patient treatment encounters demonstrated at least faint (grade 1) MIBG uptake in one or more brain sites; the most common site was the cerebellum. There was a statistically significant relation between intracranial uptake and 1) size of therapeutic dose and 2) patient age, but no relation between intracranial uptake and gender, body mass index, plasma epinephrine level, plasma norepinephrine level, urine metanephrine level, or the therapy-to-imaging interval. Although the influence of age on the pattern and intensity of intracranial uptake is unexplained, the relation to therapy dose may be explained by the possible generation of MIBG metabolites that can cross the blood-brain barrier (high activity administered and the delay until imaging). Further studies are needed to define mechanisms of intracranial uptake and relation to responses and toxicity after MIBG therapy of neuroendocrine tumors.

Effect of adrenergic receptor ligands on metaiodobenzylguanidine uptake and storage in neuroblastoma cells.

The effects of adrenergic receptor ligands on uptake and storage of the radiopharmaceutical [125I]metaiodobenzylguanidine (MIBG) were studied in the human neuroblastoma cell line SK-N-SH. For uptake studies, cells were incubated for 15 min with varying concentrations of alpha-agonist (clonidine, methoxamine, and xylazine), alpha-antagonist (phentolamine, tolazoline, phenoxybenzamine, yohimbine, and prazosin), beta-antagonist (propranolol, atenolol), beta-agonist (isoprenaline and salbutamol), mixed alpha/beta antagonist (labetalol), or the neuronal blocking agent guanethidine, prior to the addition of [125I]MIBG (0.1 microM). The incubation was continued for 2 h and specific cell-associated radioactivity was measured. For the storage studies, cells were incubated with [125I]MIBG for 2 h, followed by replacement with fresh medium with or without drug (MIBG, clonidine, or yohimbine). Cell-associated radioactivity was measured at various times over the next 20 h. Propanolol reduced [125I]MIBG uptake by approximately 30% (P<0.01) at all concentrations tested, most likely due to nonspecific membrane changes. However, incubation with the other beta-agonists or antagonists failed to elicit significant reductions in uptake. In contrast, all of the alpha-agonists significantly inhibited uptake (P<0.05); guanethidine >xylazine >clonidine=methoxamine. The alpha-antagonists demonstrated a broad range of inhibition (phenoxybenzamine >>phentolamine >prazosin >>yohimbine=tolazoline)(P< 0.05). The mixed ligand, labetolol, inhibited MIBG uptake in a dose-dependent manner with an apparent IC50 of 0.65 microM. The retention studies demonstrated that unlabeled MIBG caused profound self-inhibition (P<0.01). Clonidine produced a modest inhibition of retention and yohimbine had no effect. Labetalol, phenoxybenzamine, guanethidine, and propranolol reduced uptake of [125I]MIBG by neuroblastoma cells in culture. Although only labetalol has been reported to cause false-negative MIBG scans, our results suggest that these other drugs have the potential to interfere with MIBG imaging and therapy, particularly at high doses. Adrenergic drugs did not alter cytoplasmic retention of [125I]MIBG in neuroblastoma cells but may have potential in tumors such as phenochromocytoma, where granular storage of MIBG has been observed. Inhibition of [125I]MIBG retention by unlabeled MIBG supports the use of high specific activity radioiodinated MIBG for both diagnosis and therapy.

Pretreatment with [131I] metaiodobenzylguanidine and surgical resection of advanced neuroblastoma.

Pretreatment with [131I] metaiodobenzylguanidine (MIBG) followed by surgical resection in advanced neuroblastoma (stage 3 and 4) has been studied in relation to resectability, morbidity and mortality, survival rate after two years, control of distant metastasis and serum levels of LDH as prognostic factors. Twenty-one patients with advanced neuroblastoma were primarily treated with MIBG radiotherapy, followed by surgical resection. Sixteen patients had stage 4 disease. Between 2 and 6 courses of MIBG treatment were given per patient. In 17 patients gross complete resection was achieved. Two patients developed complications directly related to the operation, one died as a result of this. The overall mortality was 38%. MIBG therapy resulted in partial response in 13 patients and in stable disease in 8 patients. Two years survival in the group with partial response was 86% and in the group with stable disease 28%. Because of the resulting excellent general condition of the patients the interval between pretreatment with MIBG and surgery could be very short. Follow-up till December 1994 showed that 13 children were alive for 3 to 47 months. Seven had no evidence of disease. Preoperative MIBG de novo treatment in advanced neuroblastoma is equal to induction chemotherapy, but less toxic.

Metastatic phaeochromocytoma with a long-term response after iodine-131 metaiodobenzylguanidine therapy

Iodine-131 metaiodobenzylguanidine ([131I]MIBG), a radiopharmaceutical agent, is used for treating malignant phaeochromocytoma. [131I]MIBG therapy results in a hormone response rate of approximately 50%, but generally it yields only a partial or no tumour response. We present a case of a 46-year-old woman with a familial history of von Hippel-Lindau disease, who was treated with [131I]MIBG for a metastatic phaeochromocytoma involving the lungs, liver and bones. The patient received a cumulative dose of 33.3 GBq (900 mCi) and a complete hormone response was observed, as evaluated on the basis of catecholamine and metanephrine levels. Conventional radiography, computerized tomography and [131I]MIBG scintigraphy indicated that a near-complete tumour regression was achieved, with no evidence of relapse during a 4-year follow-up period. This case thus demonstrates that treatment with [131I]MIBG may lead to a dramatic tumour response in malignant phaeochromocytoma presenting both soft tissue and bone metastases.

First line targeted radiotherapy, a new concept in the treatment of advanced stage neuroblastoma

33 previously untreated advanced stage neuroblastoma patients were treated with [131I]meta-iodobenzylguanidine (MIBG). The number of treatments varied between 2 and 7 per patient (mean 3). Toxicity was seldom severe. Only thrombocytopenia WHO-grade 4 was noticed. Response was documented before surgery for the primary tumour was performed. There was one complete response (CR), 18 partial responses (PR), 11 had stable disease (SD) and 3 had progressive disease (PD). After MIBG therapy and surgery, 12 of 33 patients achieved a CR. This approach is feasible, comparable to multidrug chemotherapy in efficacy and less toxic. Long term results are not known yet.

Multi-modality megatherapy with [131I]meta-iodobenzylguanidine, high dose melphalan and total body irradiation with bone marrow rescue: feasibility study of a new strategy for advanced neuroblastoma.

New therapeutic approaches are needed for advanced neuroblastoma as few patients are currently curable. We describe an innovative strategy combining [131I]meta-iodobenzylguanidine ([131I]mIBG) therapy with high dose chemotherapy and total body irradiation. The aim of combining these treatments is to overcome the specific limitations of each when used alone to maximise killing of neuroblastoma cells. Five children received combined therapy with [131I]mIBG followed by high dose melphalan and fractionated total body irradiation. Autologous bone marrow transplantation was undertaken in 3 patients and allogeneic in 2 patients. One patient received additional localised radiotherapy to residual bulk disease. One patient is alive without relapse 32 months after treatment. 4 patients relapsed after remissions of 9, 10, 14 and 21 months. These results indicate that this combined modality approach is feasible and safe, but further evaluation is necessary to establish whether it has advantages over conventional megatherapy using melphalan alone.

Meta-iodobenzylguanidine uptake in platelets, megakaryoblastic leukaemia cell lines MKPL-1 and CHRF-28-11 and erythroleukaemic cell line HEL.

The major toxicity encountered with [131I]-Meta-iodobenzylguanidine (MIBG) therapy in neuroblastoma patients is an often isolated thrombocytopenia. We believe that this results from MIBG-induced radiotoxicity of the megakaryocytes. Since it is difficult to obtain enough human megakaryocytes for uptake studies, we investigated whether the megakaryocytic cell lines, MKPL-1, CHRF-288-11 and HEL, are good models to study serotonin and MIBG accumulation in human megakaryocytes. Compared with platelets, low levels of specific MIBG accumulation (imipramine-sensitive) were shown in all cell lines, but that of serotonin was negligible in MKPL-1 and CHRF-288-11. Furthermore, the proportion of specific uptake of both MIBG and serotonin appeared greatest in the HEL cells. Although these cells seem to be good candidates to study serotonin and MIBG uptake, they are not a good model to investigate MIBG and serotonin accumulation in human megakaryocytes since they have no functional storage granules.

Radioiodinated metaiodobenzylguanidine: a review of its biodistribution and pharmacokinetics, drug interactions, cytotoxicity and dosimetry

Since the introduction of radioiodinated metaiodobenzylguanidine in 1980, considerable research has been performed, both in the chemical field and in medical sciences. However, despite the wide use of radioiodinated metaiodobenzylguanidine, knowledge about its pharmacology is still limited. This paper reviews the biodistribution and pharmacokinetics, drug interactions, cytotoxicity and dosimetry of radioiodinated metaiodobenzylguanidine. Iodine-131 metaiodobenzylguanidine therapy is in general well tolerated, but its effectiveness needs improvement. Also whole-body dosimetry as part of treatment planning needs to be improved. Future prospects on these items are included in this review.

Meta-iodobenzylguanidine in children

Meta-iodobenzylguanidine (MIBG) is an effective imaging agent for neuroblastoma and pheochromocytoma in children, MIBG is concentrated by the neurosecretory granules of normal and neoplastic tissues of neural crest origin. The typical normal scintigraphic uptake pattern of MIBG includes the salivary glands, lung, myocardium, liver, gastrointestinal tract, and contents of the urinary bladder. When MIBG is labeled with iodine-123 (123I), the adrenal glands often are seen. The sensitivity and specificity of MIBG imaging is extremely high in both neuroblastoma and pheochromocytoma. MIBG may detect extensive bone and bone marrow involvement in neuroblastoma, in the absence of findings on bone marrow aspiration and biopsy, plain radiographs, and bone scintigraphy. MIBG labeled with 131I has been used with moderate success in the palliation of advanced neuroblastoma and pheochromocytoma. Early therapeutic intervention in advanced neuroblastoma is promising. Current controversies in the application of MIBG include (1)131I versus 123I as a label for imaging studies: Although improved image quality and reduced absorbed radiation dose are achieved with [123I]MIBG imaging, is it actually more efficacious in the detection of neuroblastoma? (2) Use of bone scintigraphy in neuroblastoma: Given the small number of false-negative MIBG scans for bone involvement, can the bone scan be dropped as a routine study in the follow-up of neuroblastoma? (3) Other new imaging agents: Is there a role for labeled monoclonal antibodies, somatostatin analogs, and magnetic resonance imaging of marrow in the routine follow-up of neuroblastoma? (4) Iodine-125 MIBG therapy in neuroblastoma: Is the improved energy deposition of 125I at extremely short range useful in the ablation of micrometastases? (5) Early therapy with MIBG in neuroblastoma: Is there a role for MIBG therapy in the initial therapeutic regimens of children with advanced neuroblastoma? Twelve years after the initial report of its use in humans, MIBG has become an important imaging agent in pediatric neural tumors, one that is used routinely and efficaciously in many centers. In the next few years we will continue to learn more about its use, particularly in the therapy of advanced neural crest tumors.

Uptake of the neuron-blocking agent meta-iodobenzylguanidine and serotonin by human platelets and neuro-adrenergic tumour cells.

The adrenomedulla-imaging agent meta-iodobenzylguanidine (MIBG) is concentrated by various tumours of neuroectodermal origin. Radio-iodinated [131I]MIBG is therefore increasingly used for diagnosis and therapy of these disorders. To study the cause of thrombocytopenia associated with [131I]MIBG therapy, we investigated the uptake of MIBG in human platelets in comparison with that of serotonin. Specific imipramine-sensitive uptake of [131I]MIBG was much slower than of [3H]serotonin, but after prolonged incubation high and serotonin-equivalent uptake levels were observed. Accumulation of MIBG saturated at 10- to 100-fold higher concentration than serotonin, and the affinity for uptake and intracellular storage in platelets was much higher for serotonin than for MIBG. Conversely, serotonin was not detectably concentrated by neuroadrenergic Uptake-I in SK-N-SH neuroblastoma and PC12 pheochromocytoma cells. Fluvoxamine inhibited the uptake of norepinephrine and MIBG in PC12 cells, similarly to that of serotonin in platelets. However, the drug was 100-fold more effective in inhibiting platelet transport of MIBG than of serotonin. The results indicate that MIBG uptake in platelets is not mediated by a neuro-adrenergic Uptake-I, but probably proceeds via the serotonin transport system. MIBG concentration by platelets was at least as efficient as in neuro-adrenergic tumour cells and has therefore (radio)biological potential for injuring these cells or precursor megakaryocytes. Platelet uptake of MIBG could be selectively blocked by fluvoxamine in concentrations which minimally affected its accumulation in neuro-adrenergic target cells.

Calculating radiation absorbed dose for pheochromocytoma tumors in 131-I MIBG therapy

A protocol for calculating radiation absorbed dose to pheochromocytoma tumors during treatment with 131I-labeled metaiodobenzylguanidine (MIBG) is described. The technique calls for (a) obtaining tumor volumes from Computed Tomography and/or Magnetic Resonance Imaging, (b) computing energy absorbed by assuming complete beta-particle absorption and a standard shape for gamma-ray absorption and (c) scaling from tracer to therapy dose rate by the ratio of administered activities. Also a 131I time-activity curve is obtained from planar, Anger-camera, conjugate-view images of the tumor and a known-strength source, both over a series of days. In addition, to correct for any systematic errors in the calculated uptakes, a larger activity of 123I MIBG is administered separately and quantitative Single Photon Emission Computed Tomography (SPELT) is undertaken. A known-strength source also undergoes SPECT to calibrate the tomograms. Correction for Compton scattering is accomplished by the dual-energy-window technique. The subtraction fraction was found to be 0.7 for the 1 2 ″ crystal camera and the mean reduction in tumor counts for seven tumors from Compton correction was 0.76. The normalization factor needed to bring the conjugate-view activities into agreement with the SPELT values ranged from 0.74 to 1.06. A test study on an anthro~morphic phantom indicated that the error in resultant activities might be estimated as ± 13%. Application o the protocol led to the calculation of real, or potential (when decision was finally made to not administer therapy radiation absorbed dose to seven tumors in three patients from an administration of about 8 GBq of MIB . For two metastatic tumors in a 19-year old patient who did not have her primary cancer resected, the calculated) radiation absorbed dose was 170 and 180 Gy. For the four metastatic deposits evaluated in two older patients, both of whom had their primary tumor surgically removed, the values ranged from 18 to 31 Gy.