Since 1984, therapeutic doses of ¹³¹I-MIBG have been administered to children with metastatic or recurrent neuroblastoma failing conventional treatment. In 1991, pooled results of the major centers (273 patients) indicated an objective response rate of 35% [15]; that rate increased to 51% (Table 1) [2]. Most of these patients had stage IV, progressive, and intensely pretreated disease and were only treated with ¹³¹I-MIBG after other treatment modalities failed. Both the ¹³¹I-MIBG therapy and isolation are generally well tolerated by children; hematological side effects may occur. Apart from objective response, the palliative effect was often impressive. For patients with recurrent and progressive disease after conven tional treatment, ¹³¹I-MIBG therapy is probably the best palliati ve treatment, as the invasiveness and toxicity of this therapy compare favorably with those of chemotherapy and external-beam radiotherapy [23].

Some groups combined ¹³¹I-MIBG therapy with chemotherapy and/or total body irradiation, accepting more toxicity, and with myeloablative chemotherapy requiring autologous bone marrow or stem cell rescue [24]. Voûte et al. [25] combined 131I-MIBG therapy with oxygen treatment under hyperbaric conditions, aiming to improve survival in patients with recurrent stage IV neuroblastoma by adding the toxic effect of hydroxyl radicals to the radiation effect. Subsequently, high-dose vitamine C therapy was added to this regimen.

¹³¹I-MIBG therapy has been integrated into the treatment protocol as the initial therapy instead of preoperative combina tion chemo therapy in children presenting with advanced disease/inoperable neuroblastoma. The objective is to reduce tumor volume, enabling adequate surgi cal resection, and avoiding toxicity and induction of multiple drug resis tance. Chemotherapy is reserved to treat minimal residual disease postoperatively. Initial results demonstrate the feasibility and effecti veness of this appro ach: a higher objective response rate (>70%) and considerably less toxicity compared with 131I-MIBG therapy after conventional treatment [26]. By 2001, results in 56 patients showed that ¹³¹I-MIBG is equally as effective as chemotherapy in attaining operability of neuroblastoma: 43 of 56 evaluable patients (77%) had complete or >95% resection of the primary tumor or did not require surgery at all. At follow-up (13–144 months), the 5-year survival rate was 37% [2]. Based upon these results, upfront 131I-MIBG therapy was integrated into the treatment of neuroblastoma in two ways: patients with favorable parameters receive a less aggressive therapy, consisting of two cycles of ¹³¹I-MIBG followed by surgery, whereas patients with unfavorable parameters (high-risk group) receive intensified ¹³¹I-MIBG therapy combined with the topoisomerase I inhibitor topotecan to enhance radiation-induced cytotoxicity.

Compared to ¹³¹I-MIBG therapy after chemotherapy, upfront ¹³¹I-MIBG therapy has significantly less toxicity, the most frequent side effect now being nausea/vomiting (21%) and grade IV hematological toxicity in less than 5% of patients [27].

In 21 children with unresectable neuroblastoma, the contribution of ¹³¹I-MIBG therapy in the treatment regimen was acclaimed once more: the objective response rate was 95.2%, and the 10-year overall and event-free survival rate was 90.5% [28].

In the abdomen, MTC may present with liver metastases. Results of combination chemothe rapy are disappointing. Radionu clide therapy using ¹³¹I-MIBG or ¹³¹I-anti-CEA antibo dies may provide both tumor regression and palliation. Pooled results in 29 patients with MTC treated with ¹³¹I-MIBG (Table 1) show an objective response rate of only 23% and a tumor-marker response of 60%; nevertheless, palliative effects, which may be quite meaningful, occurred in 60% of patients. However, only a minority of patients demonstrate sufficient ¹³¹I-MIBG uptake [2].

More patients may be amenable to radioimmunotherapy. In a phase I/II study of treatment using bispecific anti- DTPA/anti-CEA immunoconjugates followed by 131Ihapten in a two-step procedure in 26 MTC patients, some mixed responses, disease stabilization, and palliation were attained with limited hematological toxicity, but human anti-murine antibody (HAMA) response occurred in more than half of the patients [29]. As patients may require several of these treatments, the use of chimeric or humanized immunoconjugates would be more appropriate.

Palliative treatment for metastatic carcinoid tumors include long-acting somatostatin analogs (Sandostatin), alpha- interferon (IFN-α), hepatic artery embolization, ¹³¹I-labeled and -unlabeled MIBG, and ⁹⁰Y- or ¹⁷⁷Lu-labeled octreotide therapy. Cumulative re sults of ¹³¹I-MIBG therapy in 159 patients with symptomatic metastatic disease show an objective response rate of only 8% and >50% decrease in 5-hydroxyindoleacetic acid (HIAA) excretion in 24% (Table 1). Despite the absence of objective response, palliation occurs in 60% of patients, without producing significant side effects [30]. In view of the often indolent character of this disease, the value of a prolonged symptomatic response should not be underestimated: in a study at Duke University Medical Center involving 98 patients with metastatic carcinoid treated with 131I-MIBG, subjective response was correlated with prolonged survival [31].

In carci noid tumors not qualifying for ¹³¹I-MIBG therapy because of no or insufficient tumor uptake, palliative treatment with high doses of unlabeled MIBG also proved beneficial in 60% of cases, albeit with a shorter mean duration [32]. Improved biochemical and palliative effects of ¹³¹I-MIBG treatment due to enhanced tumor/nontumor ratios by predosing with non-labeled MIBG have also been reported [33]. Combination of higher doses of ¹³¹I-MIBG and unlabeled MIBG is used for therapy whenever comparative scintigraphy demonstrates a >20% increase in T/NT ratio by adding unlabeled MIBG.

Despite the results described above, over recent years, a decline in the use of ¹³¹I-MIBG for NET therapy has occurred, possibly related to the development of radio-labeled peptides for diagnosis and therapy. In the individual patient, combined imaging of NETs using MIBG and octreotide is the key to selecting the therapy with the best dosimetric characteristics. Nevertheless, in clinical practice, in the literature, and at congresses, we see the use of radiolabeled peptides for therapy appearing more prominently. Although the indications for both therapies do not overlap completely, in radiolabeled peptide therapy, the objective response rates are relative low (up to 30%) and metabolic and palliative effects are more pronounced, with the latter also having bearing on patient survival, as was observed in ¹³¹I-MIBG therapy of carcinoid tumors.