Optimization of therapy with radiolabelled somatostatin analogues
(2005)
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- Authors
- Supervisors
- Jamar, François
- Abstract
- This thesis addressed several issues related to the optimisation of peptide targeted radiotherapy with somatostatin analogues in order to minimize the potential toxic effects to the major critical organs: the kidneys and the bone marrow. The main part was dedicated to get further insight into the prevention of renal toxicity. In the first chapter we investigated possible mechanisms of renal uptake of the radiolabelled somatostatin analogues. In particular, we studied the uptake and processing of octreotide by the proximal tubule cell (PTC)-derived opossum kidney (OK) cell line and we concluded that receptor-mediated endocytosis via megalin/cubilin and fluid-phase endocytosis contribute about equally to this uptake. In the second chapter we evaluated in vivo the effect of different regimens of amino acid solutions on the renal uptake of somatostatin analogues and the possible side effects related to the infusion. We presented the results of a phase I study, comparing the effect of different types and amounts of amino acid solutions on 86Y-DOTA-D-Phe1-Tyr3-octreotide renal and tumour uptake measured by PET in 24 patients with somatostatin receptor positive neuroendocrine tumours. The infusion of large amounts of AA reduces renal exposure during peptide-based radiotherapy and allows higher absorbed doses to tumours. The prolongation of the infusion from 4 to 10h further enhances the protective effect on the kidneys. In the third chapter, we reported on efforts directed to improve the estimation of individual absorbed doses in order to predict the impairment of renal function following therapy. The potential risk of kidney toxicity limits the amount of radioactivity that may be administered. An accurate dosimetry method that would provide, prior to therapy, reliable dose estimates to these critical organs and to tumours, would allow the clinician to plan a specific therapeutic regimen and also select those patients who would have the most benefit from the treatment. In this chapter we presented first an overview of the different variables that influence the correct dosimetry estimation. Than we evaluated the contribution of patient-specific adjustments to the standard dosimetric models, such as the renal volume and dose rate, for estimating the renal absorbed dose during therapy with 90Y-DOTA-D-Phe1-Tyr3-octreotide. We showed that radiation nephrotoxicity following 90Y-DOTA-D-Phe1-Tyr3-octreotide therapy is dose-dependent and that the individual renal volume, dose rate and fractionation play an important role in accurate dosimetry estimation that enables to predict the risk of renal function impairment. In chapter 4 we evaluated improved dosimetry approaches for the red marrow as a predictor of haematological toxicity. The main part of this section was however dedicated to study the binding of radioactivity to plasma proteins as a potential mechanism of red marrow irradiation and toxicity during therapy with radiolabelled somatostatin analogues; although quantitatively low, this could contribute to RM toxicity after therapy.
- Affiliations
Citations
Barone, R. (2005). Optimization of therapy with radiolabelled somatostatin analogues. https://hdl.handle.net/2078.5/110652