Radiolabeled metaiodobenzylguanidine for the treatment of neuroblastoma

https://doi.org/10.1016/j.nucmedbio.2008.05.002Get rights and content

Abstract

Introduction

Neuroblastoma is the most common pediatric extracranial solid cancer. This tumor is characterized by metaiodobenzylguanidine (MIBG) avidity in 90% of cases, prompting the use of radiolabeled MIBG for targeted radiotherapy in these tumors.

Methods

The available English language literature was reviewed for original research investigating in vitro, in vivo and clinical applications of radiolabeled MIBG for neuroblastoma.

Results

MIBG is actively transported into neuroblastoma cells by the norepinephrine transporter. Preclinical studies demonstrate substantial activity of radiolabeled MIBG in neuroblastoma models, with 131I-MIBG showing enhanced activity in larger tumors compared to 125I-MIBG. Clinical studies of 131I-MIBG in patients with relapsed or refractory neuroblastoma have identified myelosuppression as the main dose-limiting toxicity, necessitating stem cell reinfusion at higher doses. Most studies report a response rate of 30–40% with 131I-MIBG in this population. More recent studies have focused on the use of 131I-MIBG in combination with chemotherapy or myeloablative regimens.

Conclusions

131I-MIBG is an active agent for the treatment of patients with neuroblastoma. Future studies will need to define the optimal role of this targeted radiopharmaceutical in the therapy of this disease.

Introduction

Neuroblastoma is the most common extracranial malignant solid tumor of childhood. The peak incidence occurs during early childhood and approximately 650 new cases are diagnosed in the United States each year [1]. The tumor is derived from the sympathetic nervous system. The most common site of origin is within the adrenal medulla, although the tumor also commonly arises elsewhere along the sympathetic chain.

Neuroblastoma is notable for its heterogeneous clinical behavior. Several key clinical and biological prognostic features have been identified that appear to influence the behavior of these tumors. The two most important clinical features are age and stage. Younger patients have a lower risk of developing recurrent disease and therefore improved overall survival. The threshold at which a patient is considered “young” has shifted in recent years from less than 1 year to less than 18 months of age at initial diagnosis [2], [3]. All patients with newly diagnosed neuroblastoma undergo a series of staging studies to evaluate the extent of disease. Approximately 50% of patients have distant hematogenous metastases at the time of diagnosis, most commonly to the bone or bone marrow [4]. These patients will undergo dedicated imaging of the primary tumor and bone marrow biopsies. As a tumor derived from the sympathetic nervous system, these tumors typically express the norepinephrine transporter which mediates active intracellular uptake of radiolabeled metaiodobenzylguanidine (MIBG) in approximately 90% of patients [5], [6]. Patients with newly diagnosed neuroblastoma therefore typically also have a diagnostic MIBG scan performed to identify sites of bone metastasis or diffuse bone marrow involvement [7]. The results of these staging studies are used to assign a patient a stage based upon the International Neuroblastoma Staging System (INSS) [8]. In addition to these clinical features, several biological prognostic factors have also been identified. The most important biological prognostic factor is amplification of the MYCN oncogene, which has consistently been reported as an independent adverse prognostic factor [9]. Tumor histopathologic grading according to the Shimada classification system, tumor ploidy, gain of chromosome 17q and deletions of 1p and 11q are other biological prognostic factors evaluated in these tumors [10], [11], [12], [13].

The treatment of neuroblastoma depends upon a patient's estimated risk of relapse, based upon these identified clinical and biological prognostic features. For those patients with low-stage localized tumors (INSS 1 and 2) and favorable biological features, surgical resection alone is almost always curative. For patients with locally aggressive tumors (INSS 3) but favorable biology, the combination of chemotherapy and surgical resection is the standard approach with excellent outcomes [14]. Patients with metastatic disease at initial diagnosis who are greater than 18 months of age and patients with MYCN-amplified locoregional tumors are treated with intensive multimodal therapy with chemotherapy, surgical resection, local radiation and consolidation with high-dose therapy with autologous hematopoietic stem cell rescue [15]. These patients also benefit from 13-cis-retinoic acid given post-consolidation as a differentiating agent for minimal residual disease [15], [16]. While this intensive approach has been shown to improve outcome, patients with high-risk disease frequently relapse and fewer than 50% of these patients will be long-term survivors [15], [16].

The poor outcome in patients with high-risk disease and the observation that 90% of tumors are MIBG avid provide the rationale for utilizing MIBG as a targeted radionuclide in these patients. This review will summarize the available preclinical and clinical experience of using MIBG as a therapeutic agent for neuroblastoma. The review will include a discussion of approaches that combine MIBG with other active agents for neuroblastoma. The review will conclude with an overview of the reported late effects of MIBG therapy in this patient population as well as the practical considerations involved in administering MIBG therapy to young patients.

Section snippets

Preclinical studies of radiolabeled MIBG in neuroblastoma

A relatively small number of studies have evaluated radiolabeled MIBG in preclinical models of neuroblastoma. Most of these studies have focused on MIBG uptake into neuroblastoma cells, though other groups have also investigated mechanisms of the cytotoxicity of this agent in neuroblastoma. Early investigators observed that only a subset of neuroblastoma cell lines demonstrated specific uptake of radiolabeled MIBG, while other neuroblastoma cell lines showed only passive diffusion of the drug

Clinical determinants of MIBG uptake in patients with neuroblastoma

Only 90% of patients with neuroblastoma have MIBG-avid tumors [5], [6]. The clinical determinants of MIBG avidity remain largely unclear, though two studies have begun to address this issue. In the first study, researchers attempted to correlate the intensity of 123I-MIBG tumor uptake on diagnostic scans with clinical and biologic features in 26 patients with neuroblastoma [50]. Aside from a suggestion of increased 123I-MIBG uptake in larger tumors, none of the other variables correlated with

Pharmacokinetics

Relatively few data describe the clearance of radiolabeled MIBG in children with neuroblastoma. In one study, six children with neuroblastoma received 100–200 mCi of 131I-MIBG and had urinary MIBG levels measured following the infusion [51]. A median of 57% and 70% of the administered dose was excreted in the urine by 24 and 48 h post-infusion, respectively. The elimination half-life during the first 44 h post-infusion was 10.6 h, which was slightly faster than in adult patients with

Use of multiple MIBG treatments in patients with neuroblastoma

Most of the studies described above included patients who received multiple courses of MIBG therapy. While these studies have demonstrated the feasibility of this strategy, only two reports have specifically studied multiple treatments with 131I-MIBG. The first study retrospectively reported on the experience with multiple 131I-MIBG treatments at our institution in 28 patients with relapsed or refractory neuroblastoma [73]. Patients in this series typically received approximately 18 mCi/kg 131

MIBG in combination with other therapies in neuroblastoma

Given the success of radiolabeled MIBG monotherapy in treating patients with relapsed or refractory neuroblastoma, several groups have evaluated this agent in combination with other active agents for neuroblastoma (Table 3). An Italian group has reported on their experience using 131I-MIBG in combination with cisplatin, an active agent against neuroblastoma and a radiation sensitizer [75], [76]. Five patients with relapsed or refractory disease were treated with cisplatin on the first day of

MIBG as a component of myeloablative therapy in neuroblastoma

As myeloablative therapy has been demonstrated to improve the outcomes for newly diagnosed patients with advanced neuroblastoma [15], [80], [81], several groups have evaluated 131I-MIBG in combination with myeloablative regimens. One of the first reports of this strategy treated five patients with relapsed or refractory neuroblastoma with a median of 300 mCi 131I-MIBG on Day 0 [82]. Patients then received high-dose chemotherapy on Days 7–12 using carboplatin and melphalan with or without

MIBG therapy for newly diagnosed patients with neuroblastoma

With the success of 131I-MIBG in treating patients with relapsed or refractory neuroblastoma, several studies have incorporated this agent into the treatment of patients with newly diagnosed neuroblastoma. At one center in Amsterdam, patients with Stage 4 neuroblastoma were eligible to enroll in a study of 131I-MIBG given at a fixed dose of 200 mCi followed 4–6 weeks later by a second infusion of 100 mCi [88], [89]. If the primary tumor was resectable after these two courses, patients proceeded

Use of dosimetry and post-treatment scans in MIBG therapy for neuroblastoa

Dosimetry has been evaluated in therapeutic MIBG studies for several indications. Several groups have utilized dosimetry either from a tracer MIBG dose or from an initial therapeutic MIBG dose in order to prescribe a 131I-MIBG activity calculated to produce a given whole-body radiation dose [69], [74], [78], [92]. This strategy has been effective, with calculated 131I-MIBG doses typically yielding the desired whole-body radiation dose. For example, one study treated eight patients with two

Acute toxicity and late effects of MIBG therapy in patients with neuroblastoma

Hematologic toxicity, most notably thrombocytopenia, has been reported as the main toxicity in nearly all studies of 131I-MIBG therapy. The hematologic toxicity of 53 patients with relapsed or refractory neuroblastoma treated with 18 mCi/kg of 131I-MIBG has been described in detail by our group [98]. In this series, 36% of patients required stem cell support for prolonged myelosuppression. Those patients who did not meet the criteria for stem cell reinfusion nevertheless required platelet

Practical aspects of administering 131I-MIBG therapy to children

Neuroblastoma is a tumor that peaks in incidence in toddlers. As such, most of the patients with neuroblastoma who receive 131I-MIBG therapy are children. Use of high-dose 131I-MIBG in this patient population poses challenges resulting from the radiation safety requirements associated with the administration of this therapy. These treatments require close collaboration between pediatric oncologists, nuclear medicine physicians and technologists, nursing staff, radiation safety officers, social

Future directions

Both preclinical and clinical data demonstrate the substantial activity of radiolabeled MIBG in neuroblastoma. Recent studies have evaluated more novel approaches. These approaches include combinations of 131I-MIBG with myeloablative regimens, with chemotherapy agents with radiation sensitizing properties, or with biologic agents. As additional experience with these combination approaches is obtained, the use of these combination strategies will need to be rationally incorporated into the

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