Background: Functional germline polymorphisms may contribute to inter-individual differences in response/toxicity to anti-cancer chemotherapy, allowing for the adoption of tailored treatments in clinical practice. Current evidence is often limited to retrospective and not adequately powered studies. Within the frame of the TOSCA (Three Or Six Colon Adjuvant) trial, an ancillary pharmacogenetic study was conducted giving a unique opportunity for a prospective assessment of pharmacogenetic associations for toxicity. Methods: TOSCA is a no-profit, Italian, multicentre, randomized, phase III study conducted in radically resected high risk stage II and III colorectal cancer patients treated with 6 or 3 months of either FOLFOX-4 or XELOX. Patients eligible for the main study were asked to give a further written informed consent for blood sampling and DNA extraction. DNA was used for genotyping 17 polymorphisms in 11 genes related to 5-fluorouracil/oxaliplatin pathways, detoxification, transport and DNA repair (TS, MTHFR, ERCC1, EXRCC1, XRCC3, XPD2, GSTT, GSTP, GSTM, ABCC1, ABCC2). The sample size was calculated assuming a 20% risk of grade 3-4 toxicity and a prevalence of unfavorable genotypes >= 30%. With 531 patients (106 events) the study had a power of 90% to detect an odd ratio = 2 with an alpha error of 5% (two-sided) for the wald test using the logistic regression analysis. Results: From July 2007 to October 2011, 531 patients were enrolled in 26 experimental centres (194 patients in the 6-month FOLFOX-4 arm, 194 patients in the 3-month FOLFOX-4 arm, 74 patients in the 6-month XELOX arm, 69 patients in the 3-month XELOX arm). The proportion of stage II-III patients was balanced according to the two options of adjuvant chemotherapy and treatment duration (three versus six months). Polymorphisms have been already analyzed in 185 patients and the complete data on genotyping and relevant statistics will be available for October 2012. Conclusions: The results of this study may supply a definitive indication on the role of pharmacogenetic analyses for toxicity in this setting.

Pharmacogenetic profiling for toxicity of oxaliplatin and fluoripyrimidines. An Ancillary protocol to the TOSCA trial

RUZZO, ANNAMARIA;MAGNANI, MAURO;
2012-01-01

Abstract

Background: Functional germline polymorphisms may contribute to inter-individual differences in response/toxicity to anti-cancer chemotherapy, allowing for the adoption of tailored treatments in clinical practice. Current evidence is often limited to retrospective and not adequately powered studies. Within the frame of the TOSCA (Three Or Six Colon Adjuvant) trial, an ancillary pharmacogenetic study was conducted giving a unique opportunity for a prospective assessment of pharmacogenetic associations for toxicity. Methods: TOSCA is a no-profit, Italian, multicentre, randomized, phase III study conducted in radically resected high risk stage II and III colorectal cancer patients treated with 6 or 3 months of either FOLFOX-4 or XELOX. Patients eligible for the main study were asked to give a further written informed consent for blood sampling and DNA extraction. DNA was used for genotyping 17 polymorphisms in 11 genes related to 5-fluorouracil/oxaliplatin pathways, detoxification, transport and DNA repair (TS, MTHFR, ERCC1, EXRCC1, XRCC3, XPD2, GSTT, GSTP, GSTM, ABCC1, ABCC2). The sample size was calculated assuming a 20% risk of grade 3-4 toxicity and a prevalence of unfavorable genotypes >= 30%. With 531 patients (106 events) the study had a power of 90% to detect an odd ratio = 2 with an alpha error of 5% (two-sided) for the wald test using the logistic regression analysis. Results: From July 2007 to October 2011, 531 patients were enrolled in 26 experimental centres (194 patients in the 6-month FOLFOX-4 arm, 194 patients in the 3-month FOLFOX-4 arm, 74 patients in the 6-month XELOX arm, 69 patients in the 3-month XELOX arm). The proportion of stage II-III patients was balanced according to the two options of adjuvant chemotherapy and treatment duration (three versus six months). Polymorphisms have been already analyzed in 185 patients and the complete data on genotyping and relevant statistics will be available for October 2012. Conclusions: The results of this study may supply a definitive indication on the role of pharmacogenetic analyses for toxicity in this setting.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11576/2530787
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