Somatostatin-based radiotherapy with [ 90 Y-DOTA]-TOC in neuroendocrine tumors: long-term outcome of a phase I dose esca
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RESEARCH
Open Access
Somatostatin-based radiotherapy with [90Y-DOTA]-TOC in neuroendocrine tumors: long-term outcome of a phase I dose escalation study Nicolas Marincek1*, Ann-Catherine Jörg1*, Philippe Brunner1, Christian Schindler2, Michael T Koller3, Christoph Rochlitz4, Jan Müller-Brand1, Helmut R Maecke5, Matthias Briel3,6 and Martin A Walter1,7
Abstract Background: We describe the long-term outcome after clinical introduction and dose escalation of somatostatin receptor targeted therapy with [90Y-DOTA]-TOC in patients with metastasized neuroendocrine tumors. Methods: In a clinical phase I dose escalation study we treated patients with increasing [90Y-DOTA]-TOC activities. Multivariable Cox regression and competing risk regression were used to compare efficacy and toxicities of the different dosage protocols. Results: Overall, 359 patients were recruited; 60 patients were enrolled for low dose (median: 2.4 GBq/cycle, range 0.9-7.8 GBq/cycle), 77 patients were enrolled for intermediate dose (median: 3.3 GBq/cycle, range: 2.0-7.4 GBq/cycle) and 222 patients were enrolled for high dose (median: 6.7 GBq/cycle, range: 3.7-8.1 GBq/cycle) [90Y-DOTA]-TOC treatment. The incidences of hematotoxicities grade 1–4 were 65.0%, 64.9% and 74.8%; the incidences of grade 4/5 kidney toxicities were 8.4%, 6.5% and 14.0%, and the median survival was 39 (range: 1–158) months, 34 (range: 1–118) months and 29 (range: 1–113) months. The high dose protocol was associated with an increased risk of kidney toxicity (Hazard Ratio: 3.12 (1.13-8.59) vs. intermediate dose, p = 0.03) and a shorter overall survival (Hazard Ratio: 2.50 (1.08-5.79) vs. low dose, p = 0.03). Conclusions: Increasing [90Y-DOTA]-TOC activities may be associated with increasing hematological toxicities. The dose related hematotoxicity profile of [90Y-DOTA]-TOC could facilitate tailoring [90Y-DOTA]-TOC in patients with preexisting hematotoxicities. The results of the long-term outcome suggest that fractionated [90Y-DOTA]-TOC treatment might allow to reduce renal toxicity and to improve overall survival. (ClinicalTrials.gov number NCT00978211). Keywords: Radiopeptide therapy, DOTATOC, DOTA-TOC, Survival, Neuroendocrine tumor
Background Neuroendocrine tumors comprise a spectrum of different malignancies with a yearly increasing incidence and prevalence [1]. Most of these tumors express subtypes of the somatostatin receptor [2], which permits binding and internalization of the natural ligand, the 14 amino acid peptide somatostatin (Figure 1A). Stepwise modifications of the somatostatin sequence led to the development of the * Correspondence: [email protected]; Ann-Catherine.Joerg@stud. unibas.ch 1 Institute of Nuclear Medicine, University Hospital Basel, CH Full list of author information is available at the end of the article
biologically more stable 8 amino acid somatostatin analogue Octreotide [3,4] (OC, Figure 1B), which nowadays has become a valuable tool for the treatment of symptomatic neuroendocrine tumors [5,6]. Introduction of a tyrosine into the th
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