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Annals of Oncology Advance Access published online on December 12, 2008
Annals of Oncology, doi:10.1093/annonc/mdn667
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© The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Pharmacogenetic analyses of hematotoxicity in advanced gastric cancer patients receiving biweekly fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT): a translational study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)

E. Goekkurt1, S.-E. Al-Batran2, U. Mogck1, C. Pauligk2, J. T. Hartmann3, M. Kramer1, E. Jaeger2, G. Ehninger1 and J. Stoehlmacher1,*

1 Department of Internal Medicine I, University Hospital Carl Gustav Carus, University of Dresden, Dresden
2 Department of Oncology and Hematology, Krankenhaus Nordwest, Frankfurt
3 Department of Medical Oncology, Hematology, Immunology, Rheumatology, Pneumology, Eberhard-Karls-University, Tuebingen, Germany

* Correspondence to: Dr J. Stoehlmacher, University Hospital Carl Gustav Carus, Department of Internal Medicine I, Fetscherstr. 74, 01307 Dresden, Germany. Tel: +49-351-458-2311; Fax: +49-351-449-210-630; E-mail: jan.stoehlmacher{at}uniklinikum-dresden.de

Background: Docetaxel-based chemotherapy regimens have demonstrated activity in advanced gastric cancer (AGC). However, a high rate of grade 3/4 hematotoxicity was reported with these regimens. Our purpose was to identify pharmacogenetic markers with potential to detect patients with increased risk to encounter severe hematotoxicity following treatment with 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT).

Patients and methods: Polymorphisms of genes involved in DNA repair, drug transport and metabolism were determined in 50 AGC patients receiving FLOT within a phase II trial. DNA was extracted from peripheral blood. Genotyping was carried out using PCR-based techniques.

Results: Patients possessing TS-group A genotypes (2R/2R, 2R/3RC, 3RC/3RC) were at increased risk for grade 3/4 hematotoxicity compared with patients harboring a TS-group B genotype (2R/3RG, 3RC/3RG, 3RG/3RG). In all, 59% (20 of 34) of patients with TS-group A genotypes developed grade 3/4 hematotoxicity compared with 25% (4 of 16) of those having TS-group B genotypes (P = 0.035). Grade 3/4 neutropenia occurred in 53% (18 of 34) of TS-group A patients compared with 19% (3 of 16) in TS-group B patients (P = 0.032). Multivariate analyses identified TS-group A genotypes as significant predictors of grade 3/4 overall hematotoxicity {odds ratio (OR) 4.62 [95% confidence interval (CI) 1.22; 17.44], P = 0.024} and neutropenia [OR 5.74 (95% CI 1.03; 32.08), P = 0.047].

Conclusion: TS-promoter polymorphisms may be associated with hematotoxicity in AGC patients receiving FLOT.

advanced gastric cancer, docetaxel, 5-fluorouracil, hematotoxicity, oxaliplatin, polymorphism

Received for publication September 8, 2008. Revision received September 8, 2008. Accepted for publication September 9, 2008.


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