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.     

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.     

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.     

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.     

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.     

Specific binding and uptake of 131I-MIBG and 111In-octreotide in metastatic paraganglioma--tools for choice of radionuclide therapy

Tumor-specific uptake of the radiolabeled nor-epinephrine analogue meta-iodobenzylguanidine via norepinephrine transporter or radiolabeled somatostatin analogues octreotide/octreotate via somatostatin receptors offers possibilities to diagnose and treat metastatic pheochromocytoma/paraganglioma. High uptake of 123I-meta-iodobenzylguanidine is dependent on high expression of vesicular monoamine transporters responsible for mediating uptake of biogenic amines into dense core granules. A patient with metastatic paraganglioma (liver and bone metastases) underwent surgical removal of the primary after injection of 131I-meta-iodobenzylguanidine and 111In-octreotide. Radioactivity was determined in biopsies from tumor and normal tissue biopsies. The tumor/blood concentration value was high: 180 for 131I-meta-iodobenzylguanidine 3 h after injection and 590 for 111In-octreotide 27 h after injection. Studies of primary tumor cell cultures demonstrated increased cell membrane binding and internalization over time for 131I-meta-iodobenzylguanidine. The vesicular monoamine transporter antagonist reserpine and the norepinephrine transporter inhibitor clomipramine reduced internalization by 90% and 70%, respectively, after 46 h of incubation. The results demonstrated increased cell membrane binding and internalization over time also for 111In-octreotide. Internalization was highest for a low concentration of 111In-octreotide. Excess of octreotide reduced internalization of 111In-octreotide with 75% after 46 h of incubation. In conclusion, uptake and tumor/blood concentration values of radiolabeled meta-iodobenzylguanidine and somatostatin analogues can be determined for metastatic pheochromocytoma/paraganglioma to evaluate the possibility to use one or both agents for therapy. For this patient, the high tumor/blood values clearly demonstrated that therapy using both radiopharmaceuticals would be most beneficial. In vitro studies verified specific cell-membrane binding and internalization in tumor cells of both radiopharmaceuticals.     

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.     

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.     

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.     

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.     

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.     

Iodine-131-lipiodol therapy in hepatic tumours

The incidence of hepatocellular carcinoma (HCC) is worldwide sharply on the rise and patients with advanced disease carry a poor prognosis. HCC is the sixth most common cancer and the third leading cause of cancer associated deaths in the world. Intra-arterially administered ¹³¹I-Lipiodol is selectively retained by hepatocellular carcinomas, and has been used as a vehicle for delivery of therapeutic agents to these tumours. In this review we focus on the therapeutic indications, usefulness and methods of treatment with 131-Iodine Lipiodol.The effectiveness of ¹³¹I-Lipiodol treatment is proven both in the treatment of HCC with portal thrombosis and also as an adjuvant to surgery after the resection of HCCs. It is at least as effective as chemoembolization and is tolerated much better. Severe liver dysfunction represents theoretic contraindication for radioembolization as well as for TACE. In such cases ¹³¹I-Lipiodol is an alternative therapy option especially in tumours smaller than 6 cm.     

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.     

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.     

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.