PURPOSE: The primary aim of this study was to characterize the 6-month overall survival and toxicity associated with second-line capecitabine treatment of advanced pancreatic cancer patients harboring the TYMS *2/*2 allele. The secondary aim was to analyze the response rate and pharmacokinetics of capecitabine-based therapy in this patient population. Lastly, TYMS, ATM and RecQ1 single nucleotide polymorphism were analyzed relative to overall survival in patients screened for study participation. METHODS: Eighty patients with stage IV pancreatic cancer were screened for the *2/*2 TYMS allele. Patients with the *2/*2 TYMS polymorphism were treated with capecitabine, 1,000 mg/m2 twice daily for 14 consecutive days of a 21 day cycle. Screened patients not possessing TYMS *2/*2 were monitored for survival. Pharmacokinetic analysis was done during Cycle 1 of the therapy. RESULTS: Sixteen of the 80 screened patients tested positive for *2/*2 TYMS variant. Four out of the 16 eligible patients were treated on study. The study was terminated early due to poor accrual and increased toxicity. Three patients experienced grade 3 non-hematologic toxicities of palmer-plantar erythrodysesthesia, diarrhea, nausea and vomiting. Grade 2 toxicities were similar and occurred in all patients. Only one patient was evaluable for response after completion of three cycles of therapy. The presence of the *2/*2 TYMS genotype in all of the screened patients trended toward a decreased overall survival. CONCLUSION: To our knowledge, this study represents the first genotype-directed clinical trial for patients with pancreatic adenocarcinoma. Although the study was closed early, it appears capecitabine therapy in pancreatic cancer patients harboring the TYMS *2/*2 variant may be associated with increased non-hematologic toxicity. This study also demonstrates the challenges performing a genotype-directed study in the second-line setting for patients with advanced pancreatic cancer.
PURPOSE: The primary aim of this study was to characterize the 6-month overall survival and toxicity associated with second-line capecitabine treatment of advanced pancreatic cancerpatients harboring the TYMS *2/*2 allele. The secondary aim was to analyze the response rate and pharmacokinetics of capecitabine-based therapy in this patient population. Lastly, TYMS, ATM and RecQ1 single nucleotide polymorphism were analyzed relative to overall survival in patients screened for study participation. METHODS: Eighty patients with stage IV pancreatic cancer were screened for the *2/*2 TYMS allele. Patients with the *2/*2 TYMS polymorphism were treated with capecitabine, 1,000 mg/m2 twice daily for 14 consecutive days of a 21 day cycle. Screened patients not possessing TYMS *2/*2 were monitored for survival. Pharmacokinetic analysis was done during Cycle 1 of the therapy. RESULTS: Sixteen of the 80 screened patients tested positive for *2/*2 TYMS variant. Four out of the 16 eligible patients were treated on study. The study was terminated early due to poor accrual and increased toxicity. Three patients experienced grade 3 non-hematologic toxicities of palmer-plantar erythrodysesthesia, diarrhea, nausea and vomiting. Grade 2 toxicities were similar and occurred in all patients. Only one patient was evaluable for response after completion of three cycles of therapy. The presence of the *2/*2 TYMS genotype in all of the screened patients trended toward a decreased overall survival. CONCLUSION: To our knowledge, this study represents the first genotype-directed clinical trial for patients with pancreatic adenocarcinoma. Although the study was closed early, it appears capecitabine therapy in pancreatic cancerpatients harboring the TYMS *2/*2 variant may be associated with increased non-hematologic toxicity. This study also demonstrates the challenges performing a genotype-directed study in the second-line setting for patients with advanced pancreatic cancer.
Authors: Theresa Pluth Yeo; Ralph H Hruban; Steven D Leach; Robb E Wilentz; Taylor A Sohn; Scott E Kern; Christine A Iacobuzio-Donahue; Anirban Maitra; Michael Goggins; Marcia I Canto; Ross A Abrams; Daniel Laheru; Elizabeth M Jaffee; Manuel Hidalgo; Charles J Yeo Journal: Curr Probl Cancer Date: 2002 Jul-Aug Impact factor: 3.187
Authors: T A Sohn; C J Yeo; J L Cameron; L Koniaris; S Kaushal; R A Abrams; P K Sauter; J Coleman; R H Hruban; K D Lillemoe Journal: J Gastrointest Surg Date: 2000 Nov-Dec Impact factor: 3.452
Authors: S T Pullarkat; J Stoehlmacher; V Ghaderi; Y P Xiong; S A Ingles; A Sherrod; R Warren; D Tsao-Wei; S Groshen; H J Lenz Journal: Pharmacogenomics J Date: 2001 Impact factor: 3.550
Authors: E Villafranca; Y Okruzhnov; M A Dominguez; J García-Foncillas; I Azinovic; E Martínez; J J Illarramendi; F Arias; R Martínez Monge; E Salgado; S Angeletti; A Brugarolas Journal: J Clin Oncol Date: 2001-03-15 Impact factor: 44.544
Authors: J Schüller; J Cassidy; E Dumont; B Roos; S Durston; L Banken; M Utoh; K Mori; E Weidekamm; B Reigner Journal: Cancer Chemother Pharmacol Date: 2000 Impact factor: 3.333
Authors: Thomas H Cartwright; Allen Cohn; Jerry A Varkey; Yin-Miao Chen; Ted P Szatrowski; John V Cox; Joseph J Schulz Journal: J Clin Oncol Date: 2002-01-01 Impact factor: 44.544
Authors: Eric Van Cutsem; Walter L Vervenne; Jaafar Bennouna; Yves Humblet; Sharlene Gill; Jean-Luc Van Laethem; Chris Verslype; Werner Scheithauer; Aijing Shang; Jan Cosaert; Malcolm J Moore Journal: J Clin Oncol Date: 2009-03-23 Impact factor: 44.544