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.     

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.     

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)     

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.     

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.     

131I]metaiodobenzylguanidine therapy in carcinoid tumors.

Our experience with [131I]metaiodobenzylguanidine (131I-MIBG) therapy in two patients with carcinoid tumor is described. These patients were selected because of multiple areas of uptake on 131I-MIBG scan, consistent with the extent of the disease. Both patients presented diarrhea and liver metastases. Para-aortical lymphonodes and skeletal metastases were present in the first and the second patient, respectively. Previous treatment involved r-alpha-interferon, surgery or radiotherapy. In both cases 131I-MIGB therapy was started in December 1990 and is still continuing. No haematologic or hepatic side-effects have been observed. Mild hypotension (90/60 mmHg) occurred in one patient during the first course of therapy and was resolved by corticoid treatment. A stabilization of disease and a progressive reduction of diarrhea have been observed in both patients. In the second patient an initial decrease in liver metastases was confirmed by ultrasonography 7 months after the beginning of therapy.     

Therapy of pheochromocytoma with [131I]metaiodobenzylguanidine.

Fourteen patients with chromaffin tumors were treated with [131]metaiodobenzylguanidine (131I-MIBG); 13 of them suffered from malignant and one from benign pheochromocytoma. In all patients clinical symptoms were improved. In some of these patients tumor shrinkage was observed. In one patient surgery of all tumor tissue was made possible by 131I-MIBG treatment. As shown in one patient, close follow-up is necessary in any case because remnant tumor tissue may start growing again after a long period of rest.     

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.     

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)     

Prognosis of children with malignant pheochromocytoma. Report of 2 cases and review of the literature

Malignant pheochromocytomas are rare in childhood and the prognosis of children with this tumor is not well known. We present 2 pediatric observations of malignant pelvic pheochromocytoma. Symptoms in both cases were headache and hypertension. The tumor invaded the sacral bone. Angiogram helped to localize the tumor and metastases, and allowed preoperative embolization of the tumor in 1 case. The first child underwent incomplete surgical resection, (131)I-MIBG therapy and radiotherapy, and is still alive 2 years after diagnosis. The second child died from metastatic invasion a few weeks after discovery of the tumor. We reviewed previous reports of children with malignant pheochromocytomas (30 cases). Primary tumor was extraadrenal in 50% of cases. The 3-year survival rate was 73 +/- 9% (mean +/- SD). Apart from surgical resection, no particular treatment appeared to be more effective than others in reducing mortality.     

131I]metaiodobenzylguanidine therapy after conventional therapy for neuroblastoma.

[131I]Metaiodobenzylguanidine (131I-MIBG) is used for diagnostic scintigraphy and targeted therapy in a range of neural crest tumors, which exhibit an active uptake-1 mechanism at the cell membrane and cytoplasmatic storage in neurosecretory granules. A good and selective concentration and a long retention in the tumor, as is generally the case in neuroblastoma, are the basis for successful 131I-MIBG treatment. At The Netherlands Cancer Institute a phase II study was carried out in 53 patients with progressive recurrent disease after conventional therapy had failed. Despite the unfavorable basis for treatment, 131I-MIBG therapy induced 7 complete remissions, 23 partial remissions and arrest of disease (no change) in 10. Nine patients had progressive disease and one patient was lost to follow-up. The palliative effect of the treatment under these conditions was impressive. The duration of remissions varied from 2 to 38 months. The best results were obtained in patients with voluminous soft tissue disease. In general the treatment was well tolerated by children and the toxicity was mild, provided the bone marrow was not invaded by the disease. It is concluded that 131I-MIBG therapy has a definitive place in the treatment of neuroblastoma after conventional treatment has failed. As the invasiveness and toxicity of this therapy compare favorably with that of chemotherapy, immunotherapy and external beam radiotherapy, 131I-MIBG therapy is the best palliative treatment for patients with advanced recurrent neuroblastoma.     

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.     

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)     

Summary, conclusions, and future directions of [131I]metaiodobenzylguanidine therapy in the treatment of neural crest tumors.

The role of diagnostic [131I/123I]metaiodobenzylguanidine (*I-MIBG) scintigraphy in the management of pheochromocytoma and neuroblastoma is established, but for other neural crest tumors is less defined. Radiopharmaceutical therapy of all these tumors with large activities of suitably radiolabeled MIBG is a compelling concept. In the five years since the first workshop on 131I-MIBG therapy held in Rome, the initial therapeutic promise appears to have been maintained for neuroblastoma and pheochromocytoma. A significant fraction of patients enter partial remission but complete remission is rare and relapse frequent. To date, experience with other neuroendocrine tumors and the use of 125I in place of 131I remains limited. Many promising areas remain incompletely explored. These include development of appropriate in vitro cultures and animal models, basic pharmacological mechanisms, drug interactions, macro- and microdosimetry and human clinical trials. The latter includes determining dose-limiting toxicity of 131I- and 125I-MIBG, treatment of patients at earlier times or stages of disease, optimal integration with other therapy including granulocyte-stimulating factor and marrow transplant rescue from otherwise limiting myelotoxicity. Progress to date has been slow and painstaking, but nevertheless significant, while the future holds both challenges and promise.     

Imaging and uptake mechanism of 131I-meta-iodobenzylguanidine in medullary thyroid carcinoma

131I-meta-iodobenzylguanidine (131I-MIBG) was also taken up by medullary thyroid carcinoma (MTC) as well as by pheochromocytoma in two patients with Sipple's syndrome. However, the mechanism of 131I-MIBG uptake by MTC has not been clarified yet. We measured tissue catecholamine levels in three MTC, since MTC can produce several active substances. Catecholamines were detected in various amounts in all MTC, but not in normal thyroid tissues. These findings suggest that MTC can produce catecholamines and therefore, 131I-MIBG is taken up and stored in catecholamine vesicles of MTC, like pheochromocytoma and neuroblastoma. We conclude that 131I-MIBG may be applied not only to diagnosis but also for the treatment of patients with MTC.     

131I]metaiodobenzylguanidine therapy in advanced neuroblastoma.

Forty-two children with advanced neuroblastoma who either failed with first-line therapy or relapsed after achieving a complete remission, were considered for treatment with [131I]metaiodobenzylguanidine (131I-MIBG). We subdivided 42 cases into 5 groups, in accordance with the stage of disease at diagnosis, response to first-line therapy and relapse. A total of 99 courses of 131I-MIBG were administered with doses ranging from 2.8 to 6.0 GBq. One child received six courses, 3 four courses, 18 three courses, 6 two courses and 15 one course of 131I-MIBG. The total delivered dose in single measurable lesions ranged from 286 to 1691 cGy with an uptake factor ranging from 3% to 10%. We obtained a major response in primary tumors, and a long-term response was observed in 5 cases, lasting more than 2 years without further chemotherapy.     

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)     

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.     

External beam radiation therapy (EBRT) for patients with malignant pheochromocytoma and non-head and -neck paraganglioma: combination with 131I-MIBG

In patients with malignant pheochromocytoma and paraganglioma, 131I-MIBG radiotherapy can achieve an objective response rate of 30-50% with the dose limiting toxicity being hematologic. Patients with disseminated disease, who also have a few index bulky or symptomatic lesions, may benefit from the addition of targeted external beam radiotherapy alone or in combination with systemic 131I-MIBG. The records of patients with malignant paraganglioma who were treated with external beam radiotherapy at the University of Pennsylvania from February 1973 to February 2011 were reviewed in an institutional review board approved retrospective study. Of the 17 patients with tumors in the thorax, abdomen, or pelvis, 76% had local control or clinically significant symptomatic relief for at least 1 year or until death. As expected, the predominant toxicity was due to irradiation of tumor-adjacent normal tissues without clinically significant hematologic toxicity. Due to widespread systemic metastases with areas of bulky, symptomatic tumor, 5 of the 17 patients were treated with sequential 131I-MIBG (2 mCi/kg per treatment) and external beam radiotherapy to 9 sites. In these patients, all areas that were irradiated with external beam radiotherapy showed durable objective response despite all patients eventually experiencing out-of-field systemic progression requiring other treatment. Four of these patients remain alive with excellent performance status 16, 18, 23, and 24 months after external beam radiotherapy. External beam radiotherapy can be highly effective in local management of malignant paraganglioma and can be used in conjunction with 131I-MIBG due to nonoverlapping toxicities with excellent control of locally bulky tumors.