Interventions in 131I-MIBG treatment of neuroendocrine tumours

Full text: Specific targeting of neuroendocrine tumours for therapy may be achieved either via the metabolic route (MIBG), via receptor binding (peptides) or via the immunological route (antibodies). Any malignant neural crest tumour, showing sufficient uptake and retention of 131I-meta-odobenzylguanidine (MIBG) on a diagnostic tracer study is a candidate for therapy using this agent. The principle indications for 131I-MIBG therapy are malignant pheochromocytoma and paraganglioma, neuroblastoma stage III and IV, medullary thyroid carcinoma and symptomatic, metastatic carcinoid tumors. At an EANM Radionuclide Therapy Committee workshop on 131IMIBG therapy in 1999 the results of treatment in 534 patients with neural crest tumours were gathered, showing cumulative objective response rates of 51% for malignant pheochromocytoma, 48% for paraganglioma, 51% for neuroblastoma, 23% for medullary thyroid carcinoma and 8% for carcinoid tumors. Moreover, symptomatic palliation occurred in more than 60% of the patients. These results compare favorably with the best reported results of combination chemotherapy. An active uptake-1 mechanism at the cell membrane and neurosecretory storage granules in the cytoplasm of neural crest tumours are responsible for the uptake and retention of 131I-MIBG, respectively, resulting in high tumour/nontumour ratio's. Many drugs are known or may be expected to interfere with (i.e. have a negatively effect on) the uptake and/or retention of 131I-MIBG by the tumour cell. In contrast, there are also factors which may influence either the uptake/retention of 131I-MIBG or the results of therapy in a positive way. Possible interventions: 1. Use of other labels, for example 125I-MIBG, 211At-MABG and 76Br-MBBG, which, in view of their ultrashort pathway, may have a role in the treatment of micrometastases and bone marrow infiltration, particularly as the results of 131I-MIBG therapy under these circumstances are poor. 2. By increasing the specific activity and the production of non-carrier-added 131I-MIBG tumour uptake may be improved, although. the optimal specific activity may vary with the tumour type. 3. Prolonging retention, e.g. by calcium channel antagonists. Blake et al. showed that Nifedipine (Adalat) altered the kinetics of 131131I-MIBG therapy in some patients: the observed increased uptake and retention led to a higher absorbed radiation dose to the tumour. 4. Alternative routes of administration may enhance the tumour uptake, for instance via the intra-arterial or intraperitoneal route. When the metastases of a neural crest tumour are confined to the liver, administration of 131I-MIBG therapy via hepatic arterial catheter is feasible. 5. Combination with other treatment modalities, e.g. chemotherapy and/or total body irradiation, myeloablative chemotherapy requiring autologous bone marrow or stem-cell rescue, accepting additional toxicity. In neuroblastoma 131I-MIBG therapy has been combined with oxygen treatment under hyperbaric conditions and high doses vitamine C, resulting in the formation of hydroxyl radicals, which are toxic to the neuroblastoma cell on top of the 131I-MIBG radiation effect to which it is exposed. 6. Changing the order of treatments: 131I-MIBG therapy as the initial therapy instead of preoperative combination chemotherapy in children presenting with advanced disease/inoperable neuroblastoma. Initial results have demonstrated the feasibility and effectiveness of upfront 131I-MIBG therapy: a higher objective response rate (>70%) and considerably less toxicity compared to 131I-MIBG therapy after conventional treatment. 7. Prevention of tumour cell repair: in high risk euroblastoma (stage IV, >1 year of age), upfront 131I-MIBG therapy has been combined with Topotecan, a topoisomerase I inhibitor, which may enhance the radiation induced cytotoxicity by interfering with repair of damaged cells. 8. Combining radionuclide targeting mechanisms: as in nude mice with SK-N-SH neuroblastoma xenografts the therapeutic efficacy of 131I-labelled anti-L1-CAM antibody chCE7 in comparison with 131I-MIBG and in patients the complementarity of these agents in targeting neuroblastoma was demonstrated, combined or alternating MIBG- and radioimmunotherapy may be a future approach. 9. Induction of tumour cell differentiation, e.g. using retinoic acid or interferon, may increase the specific uptake and retention of 131I-MIBG in tumours. The successful transfection of the noradrenalin transporter gene (NAT) into NAT negative neuroblastoma cell lines offers another possibility to improve the efficacy of MIBG therapy. 10. Blocking extratumoural specific uptake by unlabelled ('cold') MIBG. In nude mice with PC-12 pheochromocytoma xenografts excess unlabelled MIBG leads to significant reduction of tumour uptake of 125I-MIBG, but in patients with carcinoid tumors treated with unlabelled MIBG favourable changes in the biodistribution of 131I-MIBG were observed, increasing the tumour/non-tumour ratio by a factor 1.1-2.1 in 70% of the patients. Combined therapy of high dose unlabelled MIBG followed by 7.4 GBq 131I-MIBG may result in a greater biochemical response and palliative effect than each of the treatments alone. I conclude that 131I-MIBG therapy is effective in several neural crest tumours, attaining 50% objective response in pheochromocytoma, paraganglioma and neuroblastoma and providing excellent palliation to most patients. The tumour targeting and therapy effectiveness may be enhanced by pharmacological interventions and by combination with other treatment modalities. (author)