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.     

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)     

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 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.     

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.     

Outcome of [131I]metaiodobenzylguanidine therapy of neuroblastoma: seven years after.

Beginning in 1984 and based on a total of 40 treatments with [131I]metaiodobenzylguanidine (131I-MIBG) in most cases with a follow-up of 5 years or more, it seems to be worthwhile reevaluating our clinical data and draw some final conclusions: We treated 12 children with a neuroblastoma (NB) IV and 3 with a NB III. In no case 131I-MIBG was the primary therapy. The great majority suffered from recurrence. The mean treatment interval after chemotherapy was 6 months (range 0-54). We calculated a median cumulative tumor dose of 77 Gy (range 0-259) in patients with stage III and 30 Gy (range 4-267) in stage IV NB. The tumor half-life time of 131I-MIBG does not significantly differ between stage III (3 days) and IV (2-5 days). Although the median tumor dose of stage III NB exceeded that of stage IV, we found in NB IV a significant tumor remission in 7 out of 12 cases. On the other hand, a slight reduction of tumor size was seen in only 1 case of stage III NB. This indicates a lower radiation sensitivity of stage III NB. Despite this fact, the two patients with stage III NB who presented a sufficient 131I-MIBG-tumor uptake turned to become operable after 131I-MIBG. Stage IV patients improved, too, even if most of them suffered from recurrence with a very poor prognosis: 3 patients of stage IV lived longer than 48-60 month or are still alive. However, no one of this group remitted completely.(ABSTRACT TRUNCATED AT 250 WORDS)     

Preoperative [131I]metaiodobenzylguanidine therapy of neuroblastoma at diagnosis ("MIBG de novo").

The observed response of [131I]metaiodobenzylguanidine (131I-MIBG) therapy in advanced neuroblastoma after conventional therapy had failed, the noninvasiveness of the procedure, and the high metabolic activity of untreated tumors led to a new protocol to use 131I-MIBG therapy in newly diagnosed patients instead of combination chemotherapy prior to surgery. The objectives of this study are to improve the overall outcome of patients with neuroblastoma by introducing 131I-MIBG therapy as the first therapy in the treatment schedule, in order to reduce the tumor volume, enabling adequate surgical resection and avoiding toxicity and the induction of early drug resistance. The advantages of this approach are that the child's general condition is unaffected before surgical resection is performed and that chemotherapy is reserved to treat minimal residual disease. So far, 13 patients with inoperable neuroblastoma (stage III and IV) were treated with 131I-MIBG initially and then submitted to surgery. More than 50% decrease of the volume of the primary tumor was noted in 7 of 10 evaluable patients; 8 patients have so far been operated with complete resection in 2, greater than 95% resection in 5 and 80% resection in one patient. Three patients are still undergoing 131I-MIBG treatment. The toxicity of 131I-MIBG de novo is in contrast with the previous experience of 131I-MIBG therapy after conventional therapy: only 4 patients had thrombocytopenia and only 1 of 7 patients with bone marrow involvement developed bone marrow depression.(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.     

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.     

131I-MIBG therapy in the treatment of pheochromocytoma in children--own experiences

Three cases of pheochromocytoma in children/adolescents or young adults treated by 131I-MIBG are presented in this study. In one patient 131I-MIBG was administrated after ineffective surgical treatment and chemotherapy of a benign retroperitoneal tumor, whereas in two other patients 131I-MIBG therapy was carried out because of malignant pheochromocytoma dissemination. In a child with retroperitoneal paraganglioma decrease of tumor size and its fibrosis after 131I-MIBG therapy allowed radical surgery and complete recovery. In two other cases partial remission was achieved. All patients showed a good subjective response with improvement of the general condition and better blood pressure control. In two children adverse reactions such as leucopenia, hypothyroidism or hypogonadism were observed. The presented data confirm effectiveness and acceptable tolerance of 131I-MIBG treatment in pheochromocytoma, what is very important in pediatric patients.     

Multimodality palliative treatment of (111)In-pentetreotide negative/(123)I-MIBG positive metastatic carcinoid - a case report

Patients with carcinoid tumours frequently present with metastatic disease. There are only a few therapeutic options for these patients, and the main goal of palliative treatment is to reduce symptoms and thus to improve quality of life. Current therapy includes surgical resection, hepatic artery embolisation, chemotherapy and somatostatin analogue treatment; however, all these options have limitations. It seems probable that therapeutic modalities based on radiopharmaceuticals may provide better therapy, not only in relation to symptom reduction but may also improve patient survival. In this case report we present a 46-year-old woman with a symptomatic carcinoid, who at the time of diagnosis had liver and abdominal lymph node metastases, the primary tumour being located in the terminal ileum. (111)In-pentetreotide scanning was negative, whereas (123)I-MIBG scanning showed high avidity in the tumour tissue. After right hemicolectomy, two courses of (131)I-MIBG treatment were given (12.95 GBq and 12 GBq, respectively). After the second dose of (131)I-MIBG temporary pancytopenia was present. Octreotide therapy was given empirically only for a short time and was stopped because of drug intolerance. The patient underwent tricuspid and pulmonary valve replacement because of her carcinoid heart disease, followed by two courses of embolisation of liver metastases. While (131)I-MIBG therapy reduced the patient's symptoms of flushing and diarrhoea, there has not yet been any effect on tumour response or 5-HIAA production. This case illustrates the multimodality and multidisciplinary approach to such patients.     

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.     

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.     

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.     

Preliminary results of [131I]metaiodobenzylguanidine treatment in metastatic carcinoid tumors.

The successful use of [131I]metaiodobenzylguanidine (131I-MIBG) in the scintigraphic localisation and treatment of several tumors deriving from neuroectoderm has led us to its application in metastatic carcinoid tumors. We selected five patients (two men and three women; age range 53-79 years) who showed progression of the disease with severe related symptoms, poor response to traditional therapy and a good uptake of 131I-MIBG in neoplastic tissue. A cumulative radioactivity of 3.7-22.2 GBq was given. All patients had a clear subjective improvement with a better quality of life for a period of 2-36 months, sometimes accompanied by decreased 5-hydroxyindoleacetic acid urinary excretion. Results concerning objective remission of the disease were unsatisfactory. No remarkable early or late side-effect was noted. We believe 131I-MIBG is useful for symptomatic treatment of metastatic carcinoid in seriously ill patients too. Different treatment schedule and recruitment of patients with less advanced disease could make pathological remission a possible goal.     

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.     

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.     

Proteinuria in metastatic pheochromocytoma is associated with an increased risk of Acute Respiratory Distress Syndrome, spontaneously or after therapy with 131i-meta-iodobenzylguanidine (131I-MIBG)

Acute Respiratory Distress Syndrome (ARDS) has been reported rarely in pheochromocytoma, occurring spontaneously or after therapy with 131I-meta-iodobenzylguanidine (131I-MIBG). Our objective was to determine whether proteinuria is associated with an increased risk of ARDS. This was a retrospective analysis of a prospective cohort study of 64 patients with metastatic pheochromocytoma or paraganglioma treated with 131I-MIBG on institutional protocols. Proteinuria was defined as at least one urinalysis positive for at least trace protein within 1 month prior to 131I-MIBG or within 1 month prior to spontaneous ARDS. Proportions were compared using Fisher's exact test. Urinalyses within the defined time period were available for 48 patients, 8 of whom had proteinuria. Of the 8 patients with proteinuria, 5 developed ARDS: 3 within 10 days following 131I-MIBG, two 6 months following 131I-MIBG. Both patients who developed ARDS 6 months after 131I-MIBG had proteinuria within 1 month before apparently spontaneous ARDS. None of the 40 patients whose urinalyses were all negative for protein developed ARDS. None of the 16 patients with missing urinalyses developed ARDS. Patients with antecedent proteinuria were more likely to develop ARDS than those without proteinuria (63% vs. 0%; p<0.0001). The following variables were not significantly associated with ARDS: 131I-MIBG activities administered, number of 131I-MIBG administrations, age, hypertension, or secretion of catecholamines or metanephrines. In patients with metastatic pheochromocytoma or paraganglioma, proteinuria is associated with ARDS and urine protein should be examined prior to administering 131I-MIBG.     

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.     

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.