Book cme 0703

Radionuclide therapy in children with

C.A. Hoefnagel (Amsterdam)

Specific targeting of neuroblastoma may be achieved either via the metabolic route (MIBG), via receptor binding (peptides) or via the immunological route (antibodies). A good concentration and relatively long retention of the selected agent at tumor sites, shown by a tracer study, enable radionuclide therapy.
An active uptake-1 mechanism at the cell membrane and neurosecretory storage granules in the cytoplasm of neural crest tumors are responsible for the specific uptake and retention of 131I-MIBG respectively. As nonadrenergic tissues rely on passive diffusion only, this results in high tumor/nontumor ratio’s. A number of drugs may interfere with the uptake and/or retention of 131I-MIBG (Table 1). Somatostatine analogues target peptide receptors on the cell surface. Unlike MIBG and antibodies, peptides are not specific for neural crest tumors but for the peptide receptor. The high uptake of 111In-pentetreotide in kidneys, liver and spleen is less favorable for therapy. After high doses of 111In-pentetreotide were initially used for therapy of endocrine tumors, phase I and II studies using 90Y- and 177Lu-labeled octreotide or lanreotide currently are being conducted in adults. Monoclonal antibodies target antigens on the cell surface of some neural crest tumors. In the eighties murine monoclonal antibodies 131I-UJ13A and 131I-3F8 were used for treatment of neuroblastoma. More recently, chimeric antibodies have been developed yielding high specific tumor uptakes in neuroblastoma-bearing nude mice and initial results of scintigraphy in patients are promising.
Since 1984 therapeutic doses of 131I-MIBG have been administered to children with metastatic or recurrent neuroblastoma failing conventional treatment. Pooled results of major centres indicate an objective response rate of 51% (Table 2). Most patients had stage IV, progressive and intensely pretreated disease and were only treated with 131I-MIBG when other treatment modalities had failed. Both the 131I-MIBG therapy and the isolation are generally well tolerated by children; hematological side effects may occur. For patients with recurrent and progressive disease after conventional treatment 131I-MIBG therapy is probably the best palliative treatment, as its invasiveness and toxicity compare favorably with that of chemotherapy and external beam radiotherapy.
The therapeutic effect of 131I-MIBG may be increased by combining it with chemotherapy and/or total body irradiation, but this is associated with severe toxicity. Less toxic is the combination of 131I-MIBG therapy with oxygen treatment under hyperbaric conditions, by which the tumor cell is exposed to the toxic effect of hydroxyl radicals in addition to the radiation effect.
More recently, 131I-MIBG therapy has been integrated in the treatment protocol as the initial therapy instead of preoperative combination chemotherapy in children presenting with advanced disease/inoperable neuroblastoma. The objective is to reduce the tumor volume, enabling adequate surgical resection and to avoid toxicity and the induction of early drug resistance. Chemotherapy is reserved to treat minimal residual disease postoperatively. Initial results demonstrated the feasibility and effecti-veness of this approach: a higher objective response rate (>70%) and considerably less toxicity compared to 131I-MIBG therapy after conventional treatment. 131I-MIBG is equally effective as chemotherapy in attaining operability of neuroblastoma and the 5 year survival rate is not worse. Two new multicenter studies integrate upfront 131I-MIBG therapy in the treatment protocol of neuroblastoma: patients with unresectable stage II and III neuroblastoma receive 2 cycles of 131I-MIBG only prior to surgery; in patients with stage IV and unfavorable prognostic parameters (high risk group) the 131I-MIBG therapy is intensified and combined with the topoisomerase I inhibitor Topotecan to enhance the radiation induced cytotoxicity.
Phase I studies of radioimmunotherapy using 131I-UJ13A or 131I-3F8 in small series of patients with stage IV neuroblastoma resulted in few objective responses and stabilization of disease, but this was associated with severe side effects and the induction of HAMA response limited the usefulness of repeated application. New developments in radioimmunotherapy of neuroblastoma include the use of chimeric antibodies, such as chCE7 and ch14.18. In nude mice with SK-N-SH neuroblastoma xenografts ANNUAL CONGRESS OF THE EUROPEAN ASSOCIATION OF NUCLEAR MEDICINE
the therapeutic efficacy of 131I-labeled anti-L1-CAM antibody chCE7 compared to 131I-MIBG was demonstrated; the complementarity of these agents, as shown by comparative scintigraphic studies in patients, underline the heterogeneity of this disease and may have implications for radionuclide therapy of neuroblastoma in the future. Suggested reading
Hoefnagel CA and Lewington VJ 1998 MIBG therapy. In: Murray IPC and Ell PJ, Eds. Nuclear medicine in
clinical diagnosis and treatment, 2nd edition. Edinburgh, Churchill Livingstone, pp 1067-1081.
Hoefnagel CA 1999 Nuclear medicine therapy of neuroblastoma. Q J Nucl Med 43: 336-343.
Hoefnagel CA, Rutgers M, Buitenhuis CKM, et al 2001 A comparison of targetting neuroblastoma with
mIBG and anti L1-CAM antibody mAB chCE7: therapeutic efficacy in a neuroblastoma xenograft model
and imaging of neuroblastoma patients. Eur J Nucl Med 28: 359-368.
Troncone L and Galli G, Eds 1991 Proceedings International Workshop on The Role of [131I]metaiodobenz
ylguanidine in the Treatment of Neural Crest Tumors. J Nucl Biol Med 35: 177-362.
Adrenergic blocking agents [b]:e.g. bretylium, guanethidine Sympathicomimetics [b]:e.g. amphetamine,Dopamine, isoproterenol, terbutaline Table 1. Medication interfering with MIBG-uptake and/or retention [mechanism: a = uptake-1 inhibition, b = depletion, c = transport inhibition, d = uncertain] Objective response: Objective response: Subjective response:Tumor volume Table 2. Pooled results of 131I-MIBG therapy in neural crest tumors (EANM Radionuclide Therapy Committee Workshop, Barcelona, October 1999)


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