| Abstract: |
Metaiodobenzylguanidine (MIBG) is an analog of guanethidine which has been used for imaging a variety of neuroendocrine tumors (NETs). While 131I-MIBG is approved by the FDA for imaging, it is not yet approved for therapy, whereas it is approved for therapy by the EMA. Thus, in the United States 131IMIBG used for therapy trials is either made in accordance with USP regulations or used under an investigational new drug application (IND). Procedure guidelines for the use of 131I-MIBG in therapy have been published. 131I-MIBG is used mostly to treat pheochromocytoma/paraganglioma (PHEO/PARA), carcinoid tumors, and neuroblastoma. Preparation of patients prior to treatment with 131I-MIBG includes discontinuing therapy with drugs known to interfere with uptake of MIBG by tumor cells and blocking thyroid uptake of radioiodine. Because patients may have nausea and vomiting after administration of MIBG, antiemetics are often administered prior to therapy and in the first 3 days postadministration. To minimize the bladder dose, hydration is encouraged. Candidates for 131IMIBG therapy should have a reasonable performance status and a life expectancy of at least 3 months. Acceptable hematopoietic parameters are required prior to MIBG therapy. There are no uniform guidelines for selecting or excluding patients from consideration for 131I-MIBG therapy. Most investigators require tumor localization on a diagnostic MIBG scan. Other selection criteria often include evidence of disease progression or symptoms. 131I-MIBG is administered i.v. by pump through a plastic indwelling catheter or central line. Slow administration is a precaution to minimize pharmacologic effects from the unlabeled MIBG. There is no standard activity for therapy. Most studies use fixed activities based on empirical evidence of limited toxicity. Others have used fixed activities adjusted to body weight based on dose escalation studies. Some studies use estimates of dose to radiosensitive organs to define a safe upper limit. Response assessment may be performed as early as 2 months, but more frequently at 3-6- month intervals unless the patient is known to have fast-growing disease. Follow-up typically involves anatomic and functional imaging with 123I-MIBG or [18F]FDG. The frequency of retreatment is variable, ranging from every 4 weeks to every 6 months. PHEO/PARA are tumors that originate in the chromaffin tissue of the adrenal medulla and sympathetic nervous system and often secrete catecholamines. Some PHEO/PARA are related to genetic defects and are associated with an increased incidence of malignant and/or extra-adrenal disease. The lymph nodes, bone, liver, and lung are the most common sites of metastases. The optimal therapy for PHEO/PARA consists of surgical resection when feasible. In patients in whom a surgical cure is not possible, chemotherapy regimens have been developed. However, given the often suboptimal response to chemotherapy, other therapeutic modalities such as 131I-MIBG are now being applied. Although many patients benefit from 131I-MIBG treatment, complete response rates are low. It appears that the response of soft tissue disease to MIBG therapy is superior to that of bone and that patients with smaller volume disease are more likely to respond than those with high-volume disease. Biochemical catecholamine response has often been reported after treatment. Responses vary in duration, with reported 5-year survivals between 45% and 85%. Low-, medium-, or high-dose activities of 131I-MIBG have been used in PHEO/PARA, but there have been no systematic comparisons between these groups. However, there is some evidence that higher activities >500 mCi or myeloablative regimens are associated with higher response rates. The use of high specific activity 131IMIBG for therapy seems to reduce acute side effects. Few data have been published regarding combined chemotherapy with 131I-MIBG therapy in this patient group. Carcinoids are slow-growing NETs that often secrete substances leading to hormonal syndromes. The most frequent sites for carcino ds are the gastrointestinal tract (73.7%) and the bronchopulmonary system (25.1%). Initial staging and follow-up relies on CTand MRI to evaluate for nodal and metastatic liver disease. Imaging with 111In-pentetreotide or, more recently, with 68Ga-somatostatin analogs is performed. Scintigraphy with 123I-/131I-MIBG is also often performed and a published review reported a sensitivity of 70%. At presentation, the best management is surgical resection, or in cases with metastatic disease, debulking for palliation. Unfortunately, metastatic disease at presentation is frequent, and no consistently effective therapeutic strategies are available. Symptomatic tumor response is often seen following therapy with cold octreotide analogs, whereas objective tumor regression is rare. Interferon may also result in symptomatic improvement. Multiple chemotherapy regimens have been utilized with none showing objective tumor responses greater than 15%. The uptake of 131I-MIBG in carcinoid led to the use of this radiopharmaceutical therapeutically. Recently, radiolabeled octreotide analogs have recently been utilized and shown a higher overall accumulation in carcinoids than MIBG. Although carcinoid patients rarely have a complete response to 131I-MIBG therapy, objective response rates of 11-27.5% and symptomatic response rates ranging from 38% to 92% have been reported. Biochemical responses are less common. Median 5-year survivals of 42-78% have been reported after 131I-MIBG therapy in carcinoid. Initial single activities of >14.8GBq (400mCi) have been recommended to improve survival and symptomatic improvement. Studies combining 131I-MIBG with chemotherapy or biologic therapy are rare. Neuroblastoma is a tumor that arises from primordial neural crest cells and is almost exclusively foundininfants andyoungchildren. It is the most common tumor of childhood. Therapy relies on induction chemotherapy, surgery, and radiotherapy (given that this is a radiosensitive tumor), followed by consolidation of remission with autologous stem cell transplant (ASCT) or cisretinoic acid with or without antibody immunotherapy. High-risk patients often relapse and are resistant to conventional therapy. 131I-MIBGtherapy has been utilized as first-line therapy, combined with chemotherapy or biologic therapy for consolidation, and as palliative therapy for patients with multiple relapses. Several 131IMIBG dosing strategies have been pursued. Most 131I-MIBG trials have selected patients with advanced disease that have failed firstline therapy, while others have incorporated 131I-MIBG into multiprong treatment strategies. Several trials demonstrated that repeated doses of 131I-MIBG could be administered safely. Partial objective responses have been reported in up to 40% of patients, but complete response rates are usuallymuch lower (seldom over 10%). Because many trials were not prospective, reporting criteria in terms of outcome were variable, and the parameters measured in terms of duration of response have been inconsistent and include survival, overall response, and event-free survival (EFS). The most significant toxicity associated with 131I-MIBG therapy in both children and adults is hematologic. Nadirs in children have been reported to occur approximately 28 days after a single 131I-MIBG administration (range 9-42). When chemotherapy is combined with 131I-MIBG therapy, this nadir may occur earlier and is felt to be predominantly driven by the chemotherapy. Patients treated with high activities of 131I-MIBG (≥444-666 MBq/kg (12-18 mCi/kg)) may require bone marrow transplant because of significant and prolonged marrow toxicity, particularly in heavily pretreated subjects. Because higher doses induce considerable neutropenia, significant infections are occasionally encountered. Myelodysplasia (MDS)/acute myelocytic leukemia have been reported in patients who have received both chemotherapy and large amounts of 131I-MIBG. Secondary malignancies have been also reported. The occurrence of secondary malignancies and bone marrow disorders indicates that these atients require close follow-up, especially those with prolonged survival. Hypothyroidism can also occur. Common systemic/constitutional toxicity associated with large doses of 131I-MIBG includes asthenia, nausea, and vomiting. Although 131I-MIBG localizes in normal organs such as the heart, lung, kidney, liver, and adrenals, complications related to cardiac, renal, liver, or adrenal insufficiency have been very limited. Pulmonary complications are most frequently related to infectious disorders. © Springer International Publishing Switzerland 2017. All rights reserved. |
