Dissertation

Exploiting Radiosensitivity in the Modern Management of Neuroblastoma

Armour, Alison A

1997

Overview

Neuroblastoma is a biologically diverse and clinically challenging tumour. At one end of the clinical spectrum, children with localised, low risk disease, can survive with little or no therapy. Spontaneous resolution of this tumour has been seen and children have survived despite residual macroscopic tumour remaining at the end of therapy. In contrast, the majority of children present with widespread metastatic disease and are rarely curable. Paradoxically this is an aggressive form of disease despite appearing sensitive to both chemotherapy and radiotherapy. The majority of these patients relapse and only 20% survive 2 years. This thesis is concerned only with the management of stage 4 patients and concentrates on 3 main areas. Firstly, the role of control of the primary tumour was considered, in this essentially systemic disease. It was shown that complete surgical resection of the primary reduces local relapse and improves survival. Prognostic factors for stage 4 patients were examined during this analysis and the identification of prognostic subgroups was possible. Secondly a retrospective analysis of all stage 4 patients treated within this centre was completed, to determine the usefulness of external beam radiotherapy in the palliation of advanced disease. The final part of this thesis is experimentally based. Factors that may improve the clinical effectiveness of 131I-meta-iodobenzylguanidine (131I-mIBG) were investigated. This molecule is a targeting agent, which, when administered systemically, is selectively accumulated by tumours of neural crest origin. In clinical practice the individual tumour uptake can be variable and the optimum timing of administration is still undetermined. Initially a new formulation of 131I-mIBG was investigated. This 'no carrier added' (nca) formulation meant that smaller quantities of drug could be administered and tumour specific accumulation increased. Before clinical studies could be contemplated, laboratory investigations had to be completed, to determine if this new preparation behaved similarly to the traditional formulation. The work documented in this thesis confirms this is the case. Another aim of this thesis was to examine biological factors that may modulate specific tumour accumulation of this agent. The effect of pre-dosing neuroblastoma cells in culture, with chemotherapy agents, resulted in a 2-5 fold increase in specific type 1 tumour accumulation. This may be a very significant finding for the future administration of 131I-mIBG in combination therapy regimens. Unfortunately the combination of elevated temperature and 131I-mIBG exposure resulted in decreased tumour accumulation of 131I-mIBG.

• Publisher: ProQuest Dissertations & Theses
• Subject: Medicine / Nuclear physics
• ISBN: 9780438748170, 0438748174