Cisplatin plus weekly CPT-11/docetaxel in advanced esophagogastric cancer: a phase I study with pharmacogenetic assessment of XPD, XRCC3 and UGT1A1 polymorphisms.
OBJECTIVE
A multicenter phase I trial to establish the recommended dose of CPT-11/docetaxel plus cisplatin in advanced esophagogastric cancer patients and to correlate the efficacy and toxicity with genetic polymorphisms in DNA repair genes (XPD and XRCC3) and the UGT1A1 gene.


METHODS
Four dose levels with a fixed dose of cisplatin (60 mg/m(2)), day 1, and dose-escalation of CPT-11 (50-70 mg/m(2)) and docetaxel (25-30 mg/m(2)), days 1 and 8, every 3 weeks were planned. Polymorphisms of XPD (Asp312Asn and Lys751Gln), XRCC3 (Thr241Met) and UGT1A1*28 were examined in baseline peripheral blood.


RESULTS
Twenty-eight patients were included at three different dose levels. Dose-limiting toxicities were febrile neutropenia and diarrhea; the recommended dose was established at CPT-11 60 mg/m(2) and docetaxel 25 mg/m(2) plus cisplatin 60 mg/m(2). Objective response was observed in 13 patients (50%). Median time to progression was 6.6 months, and median survival was 11.3 months. Median time to progression was 9.7 months for patients harboring the XRCC3 Met241Met genotype versus 8.4 months for patients with Thr241Met and 3.1 months for those with Thr241Thr (P = .04).


CONCLUSIONS
CPT-11/docetaxel plus cisplatin is active in patients with advanced esophagogastric cancer. XRCC3 Met241Thr polymorphisms could be a useful marker to predict prognosis in patients treated with a cisplatin-based chemotherapy. However, these results are required to be confirmed with a great number of patients.
Font
Albert
A
Medical Oncology Service, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Crta Canyet s/n, 08916, Badalona, Barcelona, Spain. afont@ico.scs.es
Salazar
Ramon
R
Maurel
Joan
J
Taron
Miquel
M
Ramirez
Jose Luis
JL
Tabernero
Josep
J
Gallego
Rosa
R
Casado
Esther
E
Manzano
Jose Luis
JL
Carcereny
Enric
E
Guix
Marta
M
Fernández-Llamazares
Jaume
J
Rosell
Rafael
R
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002945:Cisplatin / Q000008:administration & dosage; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D003967:Diarrhea / Q000139:chemically induced; D018450:Disease Progression; D018572:Disease-Free Survival; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000502:physiology; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics* / Q000502:physiology; D009503:Neutropenia / Q000139:chemically induced; D020641:Polymorphism, Single Nucleotide; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016019:Survival Analysis; D043823:Taxoids / Q000008:administration & dosage; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics* / Q000502:physiology; D000099148:UGT1A1 Enzyme
D002166:Camptothecin; D002945:Cisplatin; D004268:DNA-Binding Proteins; D000077143:Docetaxel; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D009363:Neoplasm Proteins; D043823:Taxoids; D051759:Xeroderma Pigmentosum Group D Protein; D000099148:UGT1A1 Enzyme; C110901:X-ray repair cross complementing protein 3; C497292:ERCC2 protein, human