title: Factors predicting the response to oral fluoropyrimidine drugs: a phase II trial on the individualization of postoperative adjuvant chemotherapy using oral fluorinated pyrimidines in stage III colorectal cancer treated by curative resection (ACT-01 Study).
abstract: We evaluated the predictive relevance of several biomarkers on the survival of patients with stage III colorectal cancer treated with adjuvant chemotherapy of oral fluoropyrimidines. This was a multicenter phase II trial on adult patients with histologically confirmed resected stage III (Dukes' C) colorectal cancer. Patients received oral doxifluridine (800 mg/m2/day) in 3 divided doses, or oral uracil/tegafur (UFT) (400 mg/m2/day) in 2 divided doses for 5 days, every 7 days for 12 months with a 5-year follow-up. Outcome measures were disease-free survival and tissue markers [thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD) protein levels and TP, DPD, thymidylate synthase (TS) and orotate phosphoribosyltransferase (OPRT) mRNA levels in tumor samples and TS tandem-repeat type in blood samples]. There was a significant association between the intratumoral TP/DPD enzyme ratio and disease-free survival when the model included the drug, the parameter and the interactions between them [hazard ratio (HR)=2.76; P=0.00469]. The 5-year disease-free survival rate was statistically significantly higher in patients with high TP/DPD ratios [median ≥2.63: 71.9%; 95% confidence interval (CI) 61.4-80.0] compared to patients with low TP/DPD ratios (<2.63: 57.0%; 95% CI 46.3-66.3) (log-rank P=0.0277) following adjuvant therapy with oral fluoropyrimidines. No significant association was observed between the intratumoral TP/DPD enzyme ratio (cut-off value 2.0) and the disease-free survival rate in the doxifluridine group; primary endpoint (log-rank P=0.6850). The magnitude of the intratumoral TP/DPD enzyme ratio may be a potential indicator for the individualization of postoperative adjuvant chemotherapy with oral fluoropyrimidines for stage III colorectal cancer.
authors.affiliation: Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital, Tokyo, Japan. m.takeo@cick.jp
authors.forename: Takeo
authors.initials: T
authors.lastname: Mori
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ohue
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Takii
authors.forename: Tadashi
authors.initials: T
authors.lastname: Hashizume
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kato
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kotake
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Sato
authors.forename: Toshiro
authors.initials: T
authors.lastname: Tango
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D016001:Confidence Intervals; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D005467:Floxuridine / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009962:Orotate Phosphoribosyltransferase / Q000235:genetics; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000378:metabolism; D005641:Tegafur / Q000009:adverse effects / Q000627:therapeutic use*; D013939:Thymidine Phosphorylase / Q000235:genetics / Q000378:metabolism; D013940:Thymidylate Synthase / Q000235:genetics
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D005467:Floxuridine; D005641:Tegafur; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D009962:Orotate Phosphoribosyltransferase; D013939:Thymidine Phosphorylase; C025034:doxifluridine