Experience with palliative [131I]metaiodobenzylguanidine therapy in advanced neuroblastoma.

Our experience with palliative [131I]metabenzylguanidine (131I-MIBG) therapy in 7 patients (6 children and 1 adult) affected by advanced neuroblastoma is reported. All patients (classified as IV stage) showed a progression following initial intensive therapy, including chemotherapy and, in some cases, hemi-body irradiation and surgery for their primary tumor. 131I-MIBG activity ranged for a single course between 2.77 GBq to 5.55 GBq on the basis of age, intensity of uptake, and the hematological assessment. Four patients received only one course of therapy due to progressive disease (2), early death (1) or persistent thrombocytopenia unrelated to 131I-MIBG therapy (1). Two patients received two courses and showed a partial response lasting 4 months and stable disease lasting 3 months respectively. Therapy was thereafter discontinued due to progression. One patient received 4 courses of therapy (cumulative activity = 19.61 GBq) in 5 months. A partial response for 9 months in the bone metastases was documented, but the therapy was discontinued due to persistent thrombocytopenia (58,000 plts/microL) lasting 4 months. Thrombocytopenia was the major side-effect, occurring in 5/7 patients over 8 courses of therapy for a mean period of 37 days (7-120 d). Thus, in our experience thrombocytopenia is the major factor limiting the therapeutic effect of 131I-MIBG therapy in palliative treatment.     

131I]metaiodobenzylguanidine treatment of malignant pheochromocytoma: experience of the Rome group.

Five cases of malignant pheochromocytoma (3 men and 2 women, aged 26-43 years) were treated with [131I]metaiodobenzylguanidine (131I-MIBG). One patient had a voluminous adrenal tumor and multiple distant metastases; two patients had a recurrent tumor; two others a post-surgical residual tumor. The therapeutic procedure essentially consisted of single doses (2.6-7.4 GBq) of 131I-MIBG administered by slow i.v. infusion, given in several therapeutic courses at 1-5 month intervals. The treatment resulted in a complete response in one case with residual tumor and in a partial response in the case with disseminated disease. Two cases showed stabilization of the disease, whereas therapy was ineffective in the fifth case. Nevertheless, pain relief was observed in this patient. The treatment had a very low toxicity and was well tolerated by all patients.     

131I]metaiodobenzylguanidine treatment of a malignant paraganglioma.

The bone metastases of a malignant, non-secreting paraganglioma were treated with [131I]metaiodobenzylguanidine (131I-MIBG) over a 10-year period. Initial treatment (131I-MIBG: 9.6 GBq) resulted in a decrease in the number of bone metastases from 16 to 2. At three years, a relapse with primary tumor regrowth and liver metastasis was again treated with 131I-MIBG (22.2 GBq). A decrease in the number of bone metastases and MIBG uptake was again observed.     

131I]metaiodobenzylguanidine therapy in 20 patients with malignant pheochromocytoma.

Twenty patients, 16 male and 4 female (aged 11-76 years), with metastatic pheochromocytoma were treated in our Institution between 1985 and 1990. Metastases occurred in all patients: at presentation in 11 patients, with a 10 to 30 month delay in 7 patients, and 9 and 28 years later respectively in 2 patients. Catecholamines hyperproduction was present in all patients. Metaiodobenzylguanidine (MIBG) uptake was found in 16 patients after a diagnostic dose and only after a therapeutic dose in 1 patient. Surgery was performed on primary tumor (18 patients) and on distant metastases (10 patients). 131I-MIBG therapy was performed in 11 patients, 9 of whom were evaluable. The cumulative activity ranged from 3.7 to 26.3 GBq (100 to 711 mCi) in 1 to 6 courses. We observed symptomatic improvement (5 patients) and partial tumor response in 2 patients, which lasted for 28 and 9 months respectively, terminating with a rapidly progressing disease involving the bone marrow. Stabilisation was observed in 3 patients. Moderate myelosuppression occurred in 4 patients. Fifteen patients died with a median survival of 16 months (range 3-60). Response to therapy was poor and further evaluation of the presently available therapeutic approaches is needed.     

Role of [131I]metaiodobenzylguanidine therapy in carcinoids.

From cumulative reported data the sensitivity of [131I]metaiodobenzylguanidine (131I-MIBG) scintigraphy of carcinoids appears to be greater than 60%; at our Institute 131I-MIBG scintigrams were positive in 51 of 70 patients with metastatic carcinoid. Twenty patients with symptomatic, metastatic disease have received 7.4 GBq doses of 131I-MIBG for palliation. Most of these patients had multiple large metastases showing no response to other therapies. No objective response (greater than 50% tumor volume reduction) was ever observed; however, 13 patients were relieved of symptoms, such as flushes, diarrhea, anorexia and pain. Palliation in some of these patients was meaningful and long lasting. Possible explanations for a palliative effect in the absence of objective remission are discussed. Treatment with escalating doses of stable MIBG (up to 80 mg) in 9 patients does not support the hypothesis that the palliation is due to a purely pharmacological effect. Palliation might be explained by the observation that carcinoid liver metastases may present both as hot and cold lesions; 131I-MIBG therapy will thus target exclusively at metabolically active metastases, which are responsible for the patient's symptoms.     

Role of [131I]metaiodobenzylguanidine therapy in medullary thyroid carcinoma.

In recent years several radiopharmaceuticals have become available, offering new possibilities for the diagnosis and therapy of medullary thyroid carcinoma (MTC). For the diagnosis and follow-up 201TI-chloride and 99mTc(V)-DMSA are the tracers of choice. Imaging with [131I]metaiodobenzylguanidine (131I-MIBG) and 131I-anti-CEA or anti-calcitonin antibodies or fragments is less sensitive but very specific. These tracers can be used to evaluate their potential therapeutic use. Cumulative reported data on the diagnostic use of 131I-MIBG in 178 MTC patients indicate that overall 34.5% of medullary cancers concentrate MIBG. At The Netherlands Cancer Institute 131I-MIBG scintigraphy was positive in 8 of 23 patients with MTC. Four of these patients have received therapeutic amounts of 131I-MIBG, resulting in 1 partial remission and meaningful palliation in 3 patients with metastatic MTC. It is concluded that, although the preliminary experience suggests that the objective response of MTC to 131I-MIBG therapy is limited, the palliation provided to these patients, for whom there is little other treatment, may be very meaningful.     

131I]metaiodobenzylguanidine therapy in medullary thyroid cancer: Guy's Hospital experience.

[131I]Metaiodobenzylguanidine (131I-MIBG) was utilized in the therapy of seven patients with medullary thyroid cancer. Treatment doses ranged from 3.7 to 11 GBq, for upto four total treatments. Six of the seven patients treated showed some response to treatment (from transient partial response to symptom palliation). Treatment was tolerated well in all patients, with minimal side-effects and no signs of hematologic radiotoxicity. These encouraging results emphasize the potential of 131I-MIBG as a form of targetted radiometabolic therapy in patients with medullary thyroid cancer.     

Long-term results of [131I]metaiodobenzylguanidine treatment of refractory advanced neuroblastoma.

Fourteen patients with advanced neuroblastoma, which was unresponsive to or had relapsed despite conventional therapy, were entered into a phase I/II trial of [131I]metaiodobenzylguanidine (131I-MIBG). Doses ranged from 1.85-8.14 GBq each (50-220 mCi), with cumulative doses of 1.85-24.20 GBq (50-654 mCi) in one to three doses. Side effects included mild nausea and vomiting and moderate myelosuppression which occurred in nine patients. Subjective responses occurred in five patients. Four patients had objective responses (one partial, two minor and one mixed). Two of these patients remain alive 80 and 60 months after beginning 131I-MIBG therapy. Comparison of the 131I-MIBG treated patients with 11 carefully matched control patients treated with an advanced current chemotherapy protocol (CCG 8605) was performed by means of Kaplan-Meier life table analysis. The 14% four-year survival with 131I-MIBG compared favorably with the 6% achieved by salvage chemotherapy. We thus believe 131I-MIBG may have a role in the management of neuroblastoma.     

131I]metaiodobenzylguanidine in neuroblastoma patients at diagnosis.

Treatment of resistant neuroblastoma with high dosage [131I]metaiodobenzylguanidine (131I-MIBG) appears effective since encouraging results have been obtained so far even in patients with very advanced, intensively pre-treated disease. We have already reported a stage III NB patient treated at diagnosis, who is at present in complete remission with a 4-year follow-up. To further explore the potential role of this new drug in untreated patients, we administered radionuclide to two children with stage III neuroblastoma. Both cases received 131I-MIBG at relatively low doses, and showed a significant reduction of the tumor mass and, interestingly enough, no evidence of 131I-MIBG uptake of a tracer dose in the remaining tumor. Particularly in case 1, the permanence and subsequent progression of the part of the tumor mass without 131I-MIBG uptake, after therapeutic doses of 131I-MIBG which apparently destroyed the 131I-MIBG-positive cell population, clearly suggest heterogeneity at diagnosis, with a dual neuroblastoma cell population, one with 131I-MIBG uptake and the other without. Aside from the biological implications of the heterogeneous MIBG uptake in neuroblastoma at diagnosis, our findings suggest that in stage III neuroblastoma patients even a relatively small dose of 131I-MIBG administered at diagnosis is sufficient to either completely destroy the primary tumor, as reported by our group, or to destroy that part of the tumor which shows 131I-MIBG uptake (as in the present cases), without any significant hematologic toxicity. Furthermore, a single course of 131I-MIBG at the dosage employed here does not appear to jeopardize the subsequent use of chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

The use of [131I]metaiodobenzylguanidine in the treatment of neuroblastoma after conventional therapy.

Eleven cases of neuroblastoma (10 males and 1 female; 9 aged 1-13 years, and two aged 17 and 38 years, respectively) ten of which were refractory to chemotherapy, were submitted to treatment with [131I]metaiodobenzylguanidine (131I-MIBG). The therapeutic procedure consisted essentially of single doses (2.6-9.5 GBq) of 131I-MIBG mostly split into two parts, administered by slow i.v. infusion and given in several therapeutic courses, usually at 1-2 month intervals. The treatment resulted in: 1 complete response, 1 partial response, 1 minor response, 4 stabilized diseases and 2 progressive diseases (two patients were not evaluable due to rapid progression of the disease). Pain relief was observed in all cases and particularly in four patients who suffered severe tumor pain. The major side-effects recorded were: hypertensive crises over a 6-day period in one case, fever lasting a few days in another and bone marrow depression in two intensively pretreated patients. A slight hematologic toxicity was observed, however, in almost all cases.     

131I]metaiodobenzylguanidine and high-dose chemotherapy with bone marrow rescue in advanced neuroblastoma.

High-dose chemotherapy (HDT) and autologous bone marrow rescue (ABMR) is routinely used as consolidation treatment in advanced neuroblastoma. This study is presently examining the efficacy and toxicity of combined [131I]metaiodobenzylguanidine (131I-MIBG) therapy with HDT and ABMR. Five children (4 male, 1 female), median age of 8 years (range 4-11 years) were treated, 3 at relapse and 2 after initial chemotherapy. A single infusion of 131I-MIBG (median activity 11.1 GBq, range 7.4-11.2 GBq) was followed by HDT and ABMR 14-32 days later. High-dose chemotherapy consisted of carboplatin and melphalan in 4 patients, and vincristine, etoposide, carboplatin and melphalan in 1. One patient developed a septicaemia and died, and another failed to engraft; both had extensive bone marrow infiltration at the time of 131I-MIBG therapy. The combined therapy was well tolerated by the three other patients. Two children have relapsed and died (including one who failed to engraft), and 2 are alive 17 and 41 months after ABMR. In the absence of extensive bone marrow metastases, combined therapy offers potential as a means of consolidating treatment in advanced neuroblastoma.     

Efficacy and safety of [131I]metaiodobenzylguanidine therapy for patients with refractory neuroblastoma.

Metaiodobenzylguanidine (MIBG) is a guanethidine derivative that is selectively concentrated in sympathetic nervous tissue. MIBG labeled with 123I or 131I has proven to be a specific and sensitive tool for detection of primary and metastatic pheochromocytoma and neuroblastoma. Eleven patients, with refractory stage IV neuroblastoma were treated with a total of 23 courses of 131I-MIBG, 100-400 mCi/m2/course. Total activity administered per course ranged from 90-550 mCi; maximum cumulative radioactivity per patient was 1356 mCi. The 131I-MIBG was given as a 2 hour infusion. Total body dose was calculated from whole body activity measurements, ranging from 73-250 cGy. The main toxicity was thrombocytopenia, with platelet nadirs to less than 25,000/microL in 5/23 courses (5 patients), all occurring in patients with greater than 25% replacement by tumor in the bone marrow. Neutropenia to a nadir of less than 500/microL was seen in only 2 patients, both with greater than 50% bone marrow replacement after 2 and 4 courses of 131I-MIBG, respectively. Tumor doses were calculated in patients with an evaluable measurable lesion, and ranged from 312-6329 cGy per course. Two of the eleven patients had partial responses, with one long-term survivor with stage IV neuroblastoma with no evidence of active disease now 4 years off treatment. Two other patients survive with stable disease after 3 treatments, at 3+ and 5+ months. Seven patients died with progressive disease. This study shows that treatment with 131I-MIBG is safe and can be effective in refractory neuroblastoma, particularly in patients who do not have extensive bone and bone marrow involvement.     

131I]metaiodobenzylguanidine therapy of malignant pheochromocytoma: interference of medication

Malignant pheochromocytoma may present as a widespread metastatic disease, which is little or non-responsive to external beam radiotherapy and chemotherapy. The prognosis of these patients is bad due to both the progressive metastasis and the secretion of excess catecholamines which may cause hypertensive episodes. For these conditions [131I]metaiodobenzylguanidine (131I-MIBG) therapy may be an alternative treatment modality to induce both tumor remission and reduction of hormonal activity of the disease. The experience with 131I-MIBG therapy in four patients with metastatic malignant pheochromocytoma at The Netherlands Cancer Institute is reviewed. One patient with abdominal tumor recurrence and metastases to the lymph nodes and lungs had a partial remission of disease for 3 years; a second had a mixed response together with palliation and two other patients had stable disease, but were relieved of bone pain and severe hypertension, respectively. It is essential to be aware of the medication the patient is using, as many drugs are known or may be expected to interfere with the uptake and/or retention of 131I-MIBG by the tumor cells. The case of a significant reduction of 131I-MIBG uptake and retention by Labetalol in one of the patients is discussed. It is concluded that 131I-MIBG therapy may induce objective remission in patients with malignant pheochromocytoma and is certainly meaningful in the reduction of hormonal activity, the control of hypertension and the relief of pain from metastases.     

Treatment of neuroblastoma with [131I]metaiodobenzylguanidine: long-term results in 25 patients.

From 1984 to 1990 we have treated altogether 25 children with [131I]metaiodobenzylguanidine (131I-MIBG) for a refractory, relapsed or metastasized neuroblastoma. Three children had stage III and 22 children had stage IV of the disease; at diagnosis their ages were between 4 months and 10 years. Children with stage III disease had at diagnosis a median age of 3.0 years and at treatment 3.8 years. After first-line chemotherapy 2 children had achieved a complete remission (CR), while in 1 child the tumor did not respond (NR) to the initial treatment. At the time of 131I-MIBG treatment 2 children had relapsed and in the other one no further response was achievable. The children were treated by a 13.5 +/- 12.9 mCi/kg BW per course with a mean total dose of 280.7 +/- 243.9 mCi. One child achieved CR by 131I-MIBG alone, while in 2 cases no measurable success was observed. All 3 children were treated additionally by surgery, chemotherapy and bone marrow transplantation (BMT). Two children have died but one is alive and in CR. The 22 children with stage IV disease were treated in two different study groups. In group A, 14 children were studied for side-effects and response to 131I-MIBG. All children were pretreated with standard chemotherapy. Five were treated in relapse, 5 in progression and 3 at a refractory state of the disease; only 1 child was in complete remission when being treated with 131I-MIBG. Group A patients were treated with a mean of 2.4 courses, with 10.3 mCi/kg BW for each course.(ABSTRACT TRUNCATED AT 250 WORDS)     

Preliminary results of [131]metaiodobenzylguanidine treatment in metastatic malignant pheochromocytoma.

The poor results of traditional therapy (for purposes of recovery or palliation) in malignant pheochromocytoma and the well proven uptake of [131I]metaiodobenzylguanidine (131I-MIBG) shown by these tumors, induced us to evaluate the clinical usefulness of radiometabolic therapy with 131I-MIBG. Four patients with malignant pheochromocytoma were subjected to 131I-MIBG therapy, between 1987 and 1991, in our department. They all were in an advanced stage of the disease and showed severe symptoms and poor reaction to traditional therapy. The cumulative activity given was 7.4-22.2 GBq. All patients demonstrated transient subjective improvement; in addition, both biochemical and haemodynamic parameters ameliorated. Two patients showed a reduction in the size and number of metastases seen on scintigraphy. One patient died due to progression of the disease. Three patients are still alive and in good condition. No remarkable early or late side-effects were reported. We suggest that 131I-MIBG radiometabolic therapy in advanced-stage malignant pheochromocytoma could be useful in reducing symptoms. Further investigation might show whether a greater reduction in the size of the tumor could be achieved using different therapeutic schedules or by treating the disease in its earlier stages.     

Results of [131I]metaiodobenzylguanidine treatment in metastatic carcinoid.

The results obtained with [131I]metaiodobenzylguanidine (131I-MIBG) treatment in 6 patients affected by metastatic carcinoid are reported. 131I-MIBG was given in single doses of 3.7-8.0 GBq, reaching a maximum cumulative dose of 29.5 GBq in 4 courses. Objective responses were not observed, but in 4 cases an apparent stabilisation of the disease for more than 1 year was obtained. A subjective response regarding the carcinoid syndrome was observed in 4 cases. No response was seen in 2 cases. No adverse side-effects of any importance were observed, usually being prevented by a mild medication.     

Therapeutic use of [131I]metaiodobenzylguanidine in neuroblastoma: a phase II study in 26 patients. "Société Fran?aise d'Oncologie Pédiatrique" and Nuclear Medicine Co-investigators.

Seven French Medical Centers were involved in a cooperative study evaluating [131I]Metaidobenzylguanidine (131I-MIBG) therapy in advanced neuroblastoma. Children (median age 4 years) had initially a stage III (4 patients) or stage IV (22 patients) neuroblastoma. Before MIBG treatment, 14 patients had a primarily refractory disease, 10 patients were relapsing; in 8 cases, autologous bone marrow transplantation had been performed. Tumour sites were in 24 patients: 13/24 local disease, 8/24 bone metastases, and 7 bone marrow involvement. Catecholamines were elevated in 7/24 patients. The median activity of 131I-MIBG per injection ranged from 30 to 108 mCi; the number of injections varied from 1 to 5. We observed 5/10 pain palliations and 10/24 stabilizations of the disease course for 1 to 7 months with no objective volume tumour response. Haematologic toxicity caused a platelet count less than 150,000/microL in 4 patients, less than 100,000 in 1 patient and less than 50,000 in 7 patients.     

The role of [131I]metaiodobenzylguanidine in the treatment of medullary thyroid carcinoma: results in five cases.

Therapeutic doses of [131I]metaiodobenzylguanidine (131I-MIBG) were administered to 5 patients, 3 men and 2 women aged from 33 to 66 years, with proven medullary thyroid carcinoma (one "intermediate" papillary/medullary tumor). The treatment procedure consisted of single doses (3.7-8.5 GBq) of 131I-MIBG given by slow i.v. infusion at 2-8 month intervals. In two advanced-stage patients the treatment played an important palliative role, ranging from an objective response (substantial, but not complete, regression of the tumor) to pain relief which was significant for these patients. In three other cases with residual/recurrent tumor, 131I-MIBG complemented conventional treatment in the attempt to effect a cure which actually was achieved in one case. The only side-effect observed was a transient, mild hematologic toxicity in some cases.     

Results of [131I]metaiodobenzylguanidine therapy administered to three patients with malignant pheochromocytoma.

Three patients with malignant pheochromocytoma were treated with [131I]metaiodobenzylguanidine (131I-MIBG). In two patients with widespread metastatic disease, the effect of treatment was palliative and of short duration. In the third case, with only residual tumor and no metastases, the treatment was effective after 22 GBq of 131I-MIBG.     

131I]metaiodobenzylguanidine therapy in paraganglioma.

Our experience with [131I]metaiodobenzylguanidine (131I-MIBG) therapy in a 10 year old boy is reported. At disease onset, in May 1988, this boy presented a large mass in the upper left abdominal quadrant, which was resected with a histopathological diagnosis of extra-adrenal malignant pheochromocytoma (paraganglioma). He subsequently underwent two further surgical resections and chemotherapy. When 131I-MIBG therapy was started, in June 1990, skeletal and abdominal metastases were present. These localizations were revealed by 131I-MIBG scans and confirmed by x-ray examination. At present 6 courses of therapy have been performed with a cumulative activity of 29.6 GBq. Side-effects have been limited to vomiting and mild thrombocytopenia, lasting 2 weeks during the second course of therapy. After 15 months of therapy, a progressive reduction of MIBG uptake, coupled with a stabilization of the lythic lesions, has been observed.