| Abstract: |
Metaiodobenzylguanidine (MIBG) is an analog of guanethidine which has been used for imaging a variety of neuroendocrine tumors (NETs). While131I-MIBG is approved by the FDA for imaging, no reagents are yet approved for therapy. Thus,131I-MIBG 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 of131I-MIBG in therapy have been published.131I-MIBG is used mostly to treat neuroblastoma, pheochromocytoma/paraganglioma (PHEO/PGL), and carcinoid tumors. Preparation of patients prior to treatment with131I-MIBG includes discontinuing therapy with drugs known to interfere with uptake of MIBG by tumor cells. Blocking the thyroid is necessary. Because patients may have nausea and vomiting after administration of MIBG, antiemetics are often administered prior to therapy and in the first 3 days post-administration. To minimize the bladder dose, hydration is encouraged. Candidates for131I-MIBG 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 for131I-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 with123I-MIBG or [18F]FDG. The frequency of retreatment is variable, ranging from every 4 weeks to every 6 months. PHEO/PGL are tumors that originate in chromaffin tissue of the adrenal medulla or sympathetic nervous system and often secrete catecholamines. Some PHEO/PGL are related to genetic defects which are associated with an increased incidence of malignant and/or extra-adrenal disease. Lymph nodes, bone, liver, and lung are the most common sites of metastases. The optimal therapy for PHEO/PGL consists of surgical resection when feasible. Given the often suboptimal response to chemotherapy, newer therapeutic modalities such as131I-MIBG are now being applied. Although many patients can benefit from131I-MIBG treatment, complete response rates are low. There is a suggestion that the response of soft tissue disease to MIBG therapy is superior to that of bone. It also appears that patients with smaller volume disease following surgical resection are more likely to respond. Biochemical catecholamine response has been often reported after treatment. The duration of responses is variable, with 5-year survivals between 45% and 85%. There has not been a systematic comparison of regimens using low, mid, or high activities of131I-MIBG in PHEO/PGL. However, there is some evidence that higher activities >500 mCi or myeloablative regimens may be associated with higher response rates. The use of high-specific activity131I-MIBG for therapy seems to reduce side effects. Few data have been published regarding combined chemotherapy with131I-MIBG therapy in patients with PHEO/PGL. Carcinoids are slow-growing NETs that often secrete substances leading to hormonal syndromes. The most frequent sites for carcinoids are the gastrointestinal tract (73.7%) and the bronchopulmonary system (25.1%). Initial staging and follow-up relies on CT and MRI, to evaluate for nodal and metastatic liver disease. Imaging with111 n-pentetreotide or, more recently, with68Ga-somatostatin analogs is performed. Scintigraphy with123I/131I-MIBG is often performed and a published review reported a sensitivity of 70%. At presentation, the best management is surgical removal, 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 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 response greater than 15%. The uptake with consequent accumulation of131I-MIBG in carcinoid raised the possibility of using the radiopharmaceutical therapeutically. Recently, radiolabeled octreotide analogs have been utilized showing a higher overall accumulation in carcinoids than MIBG. Although carcinoid patients rarely have a complete response to131I-MIBG therapy, objective response rates of 11–27.5% have been reported. Symptomatic response rates range from 38 to 92%. Biochemical responses are seen less commonly. Median 5-year survivals of 42–78% have been reported after131I-MIBG therapy in carcinoid. Initial single activities of >14.8 GBq (400 mCi) have been recommended to improve survival and symptomatic improvement. Studies combining131I-MIBG with chemotherapy or biologic therapy are rare. Neuroblastoma is a tumor that arises from primordial neural crest cells and is almost exclusively found in infants and young children. 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 cis-retinoic acid with or without antibody immunotherapy. High-riskpatients often relapse and are resistant to conventional therapy.131I-MIBG therapy has been utilized as palliative therapy for patients with multiple relapses, first-line therapy, and combined therapy with chemotherapy or biologic therapy for consolidation. Several131I-MIBG dosing strategies have been pursued. Most131I-MIBG trials have selected patients with advanced disease that have failed first-line therapy, while others have incorporated131I-MIBG into multiprong dosing strategies. Several trials demonstrated that repeated activities of131I-MIBG could be administered safely. Partial objective responses were reported in up to 40% of patients but complete responses were usually 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 are inconsistent and include survival, overall response, and event free survival (EFS). The most significant toxicity associated with131I-MIBG therapy in both children and adults is hematologic. The nadir in children has been reported to occur at approximately 28 days after a single131I-MIBG administration (range 9–42). When chemotherapy is combined with131I-MIBG therapy, this nadir may occur earlier and is felt to be predominantly driven by the chemotherapy. Patients treated with high activities of131I-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 of131I-MIBG. Second malignancies have been also reported. This occurrence of second malignancy and bone marrow disorders indicates that these patients require close follow-up, especially in those with prolonged survival. Hypothyroidism can also occur. Common systemic/constitutional toxicity associated with large doses of131I-MIBG are ofte observed, including asthenia, nausea, and vomiting. Although131I-MIBG localizes in normal organs such as the heart, lung, kidney, liver, and adrenals, there have been very limited complications related to cardiac, renal, liver or adrenal insufficiency. Pulmonary toxicity is most frequently related to infectious disorders. © Springer Science+Business Media New York 2013. |
