Treatment of malignant pheochromocytomas with 131-I metaiodobenzylguanidine and chemotherapy.

Malignant pheochromocytomas have exhibited partial responses to treatments with 131-I metaiodobenzylguanidine (MIBG) and with chemotherapy. The authors combined these two therapeutic methods to determine if beneficial effects from each would be additive. Patients with documented malignant pheochromocytomas were recruited with the intent of administering 131-I MIBG in three substantial amounts of radioactivity at 3-month intervals followed by a year of chemotherapy in which cyclophosphamide, dacarbazine, and vincristine were to be given in 21-day cycles. Six patients entered the protocol. After the 131-I MIBG treatments, three patients manifested declines in the presence of tumor (smaller tumor volume or abnormalities on bone and 131-I MIBG scans) and the function of tumor (decreased rate of normetanephrine excretion as the major index). Two patients completed at least 9 months of chemotherapy and showed further reductions in the presence and function of tumors and were classified as having partial responses. Progressive disease afflicted three of the other four subjects. Even though toxicity was minimal from 131-I MIBG, it was sufficient to force reduction in the dosages or duration of chemotherapy. A combination of 131-I MIBG treatments and chemotherapy produced additive effects in reducing malignant pheochromocytomas. Toxicity moderately curtailed the proposed chemotherapy protocol.

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.

131-I treatment of micronodular pulmonary metastases from papillary thyroid carcinoma.

BACKGROUND: Pulmonary metastases from papillary thyroid carcinoma shorten the survival of the hosts. Treatments with 131-I have been reported to induce disappearance of these tumors in a large proportion of afflicted patients. In this study, consecutive patients with diffuse micronodular lung metastases from papillary thyroid carcinoma were examined to determine if disappearance of tumor occurred, and how much disappeared, after substantial amounts of 131-I were administered. METHODS: Of 232 patients treated with 131-I for thyroid carcinoma between 1985 and 1994, 12 patients between the ages of 5 and 45 years exhibited evidence of micronodular metastases to the lungs that concentrated 131-I. Each patient had undergone total or nearly total thyroidectomy and cervical lymph node dissection. All neoplasms were well differentiated papillary carcinoma, but one also had focal, poorly differentiated insular components. Follicle formation by tumors varied from less than 10% to 100% of the histologic sections. Effects of treatment were measured by three indices: chest X-ray and/or CT images, scintigraphic images, and serum thyroglobulin levels. Individual activities of 131-I ranged from 2.2 gigabequerel (GBq) (initial activity in the 5-year-old patient) to 13 GBq, and were greater than 7.4 GBq in 6 patients. Only one treatment was given to three patients, two were given to seven, and more than two were given to two. The duration of follow-up was at least one year. RESULTS: In two patients, the only evidence of lung metastases was on scintigraphic images made a few days after treatment. Another patient had a normal X-ray but showed diffuse uptake of 131-I in the lungs on a diagnostic scintiscan. Of the nine patients with abnormal X-ray and CT images, seven showed improvement, but tumors disappeared in only two. In the ten patients with abnormalities on the diagnostic scintiscans, five eventually manifested no abnormality. At the outset, thyroglobulin levels exceeded 10 ng/mL in each patient; 3 individuals exhibited a decline in level by 25% or more, and a value of less than 6 ng/mL, uncomplicated by thyroglobulin antibodies, was seen in two patients. Only two patients attained normality in all three indices. Hematologic toxicity was modest and reversible. CONCLUSIONS: Despite a number of previous reports that pulmonary metastases from thyroid carcinoma disappear in approximately half of patients treated with 131-I, evidence of tumor reduction was found in most, but a complete remission occurred in only 2 of 12 patients. Nevertheless, 131-I therapy may be useful to decrease the tumor burden in many such patients.

Survival of patients with neuroblastoma treated with 125-I MIBG.

Recurrent or persistent neuroblastoma in stages III and IV is usually fatal despite modern therapies. Metaiodobenzylguanidine labeled with 131-I (131-I MIBG) concentrates in most neuroblastoma and when given in doses that impart therapeutic radiation, has produced remissions in patients with these tumors. However, success with 131-I MIBG has been limited. The physical characteristics of radiation imparted by 125-I MIBG theoretically could overcome some of the limitations that restrain the therapeutic effects of 131-I MIBG in patients with neuroblastoma. Thereby, 125-I MIBG may offer advantages over 131-I MIBG in the treatment of neuroblastoma. Ten children who manifested persistent/recurrent stage III or IV neuroblastoma were given 8.3 to 30.1 GBq or 224 to 814 mCi of 125-I MIBG in a phase I-II trial. Five of the patients had progression-free survivals > 1 year (continuing in three patients), and four of these subjects are surviving 17 to 52 months after treatment with 125-I MIBG. With appropriate doses of 125-I MIBG, life-threatening toxicity can be avoided. Thus, survivals after 125-I MIBG appear to be as long or longer than those historically observed following other treatments for patients similarly afflicted with refractory neuroblastoma.

The current status of meta-iodobenzylguanidine and related agents for the diagnosis of neuro-endocrine tumors.

Metaiodobenzylguanidine (MIBG) has been in clinical use for 15 years and has been shown to have high sensitivity (about 85%) and specificity (> 95%) for the location of all types of pheochromocytomas. Similar results have been achieved with neuroblastomas. A wide range of other neuroendocrine lesions including carcinoids, medullary thyroid cancer and nonsecretory paragangliomas may also be imaged, but the lower sensitivity. The newly developed radiolabeled somatostatin analogs may have greater utility for these lesions. MIBG scintigraphy may also provide a unique in vivo probe for study of the sympathetic autonomic nervous system, particularly in the heart. Various radiolabels for MIBG and its analogs permit planar scintigraphy, SPECT, PET, intraoperative probe localization and radiopharmaceutical therapy.

The current status of radioiodinated metaiodobenzylguanidine therapy of neuro-endocrine tumors.

The avidity of many metastatic pheochromocytomas and neuroblastomas for metaiodobenzylguanidine (MIBG) observed at diagnostic scintigraphy has led to attempts to treat these lesions with large doses of MIBG. We and others have achieved therapeutic responses with 131I-MIBG (usually partial) in about a third of malignant pheochromocytomas. A small but important subgroup of advanced, poor prognosis neuroblastomas which have been resistant to all other therapies have also shown responses including occasional long-term survival (> 5 years) and apparent complete responses to 131I-MIBG. Because the physical properties of 131I are suboptimal for the delivery of therapeutic radiation to bone marrow micrometastases, a frequent problem in neuroblastoma, we have performed preliminary studies in poor prognosis Stage III and VI neuroblastoma using 125I-MIBG which has more satisfactory emissions. This has led to prolonged tumor stabilization and survival (> 19 to > 52 months) in 5 of 10 patients. MIBG radiopharmaceutical treatment of neuroendocrine tumor patients must still be considered an experimental but nevertheless promising treatment modality.

Predictors of toxicity in treating patients with neuroblastoma by radiolabeled metaiodobenzylguanidine.

We searched for methods that would enable prescriptions of the maximum tolerable doses of iodine-131 metaiodobenzylguanidine (MIBG) and iodine-125 MIBG in the treatment of patients with neuroblastoma. We correlated doses, defined in different ways, with subsequent platelet levels in treated patients to determine accurate predictors of the most frequent toxicity, thrombocytopenia. Nine patients with neuroblastoma were given 131I-MIBG (4.9-8.1 GBq or 132-220 mCi) and ten were given 125I-MIBG (8.3-30.0 GBq or 224-809 mCi) as initial treatments. These therapies were sufficiently varied that correlations could be made between indices of the doses and the subsequent toxicity as reflected in circulating platelet levels. Predictors of toxicity were: whole-body absorbed dose of radiation (cGy) calculated from pretherapy tracer doses of 131I-MIBG; GBq/kg of body weight; and GBq/m2 of body surface area. Toxicity was recorded as the nadir of the platelet level and platelet/pretherapeutic level (platelet ratio). For treatments with 131I-MIBG, the highest correlation was obtained between cGy and the log10-transformed platelet ratio (r = -0.86), but comparison of GBq/m2 and the platelet nadir (r = -0.76) or the platelet ratio (r = -0.74) or the log10 transformed platelet ratio (r = -0.73) gave comparable and statistically significant results. For treatments with 125I-MIBG, significant correlations were obtained between GBq/m2 and the platelet ratio (r = -0.81) or GBq/kg and the log10-transformed platelet ratio; the correlation between cGy and any toxicity index was low. Per administered GBq, 131I-MIBG was 2.6 times more potent than 125I-MIBG in causing a platelet ratio of 0.1.(ABSTRACT TRUNCATED AT 250 WORDS)

Radiopharmaceutical therapy of malignant pheochromocytoma with [131I]metaiodobenzylguanidine: results from ten years of experience.

Twenty-eight patients with histologically proven metastatic or invasive, unresectable pheochromocytomas, which were shown to concentrate and retain tracer doses of [131I]metaiodobenzylguanidine (131I-MIBG), were treated with therapeutic quantities of this radiopharmaceutical. Between one and six doses ranging from 97 to 301 mCi (cumulative dose 111-916 mCi) were administered. Partial response in tumor size was achieved in 8/28 patients and partial biochemical responses in 12/28 patients. No pharmacological toxicity was observed. Mild radiation sickness (nausea, vomiting, anorexia) occurred in 21/28. Minor degrees of leukopenia and thrombocytopenia were observed in 3/28. There were three cases of hypothyroidism but no significant hepatic, renal, adrenocortical or autonomic nervous dysfunction. We conclude that therapeutic 131I-MIBG can achieve significant therapeutic responses in some cases of malignant pheochromocytoma without pharmacological toxicity and only mild radiotoxicity.