Predictors of survival and toxicity in patients on adjuvant therapy with 5-fluorouracil for colorectal cancer.
The present study aimed at investigating whether the simultaneous evaluation of pharmacokinetic, pharmacogenetic and demographic factors could improve prediction on toxicity and survival in colorectal cancer patients treated with adjuvant 5-fluorouracil (5FU)/leucovorin therapy. One hundred and thirty consecutive, B2 and C Duke's stage colorectal cancer patients were prospectively enrolled. 5FU pharmacokinetics was evaluated at the first cycle. Thymidylate synthase (TYMS) 5'UTR and 3'UTR polymorphisms and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms were assessed in peripheral leukocytes. Univariate and multivariate analyses were applied to evaluate which variables could predict chemotherapy-induced toxicity, disease-free survival (DFS) and overall survival (OS). Multivariate analysis showed that: (a) low 5FU clearance was an independent predictive factor for severe toxicity (OR=7.32; P<0.0001); (b) high-5FU clearance predicted poorer DFS (HR=1.96; P=0.041) and OS (HR=3.37; P=0.011); (c) advanced age was associated with shorter DFS (HR=3.34; P=0.0008) and OS (HR=2.66; P=0.024); (d) the C/C genotype of the MTHFR C677T polymorphism was protective against grade 3-4 toxicity (P=0.040); (e) none of the TYMS polymorphisms could explain 5FU toxicity or clinical outcome.
Gusella
M
M
Laboratory of Pharmacology and Molecular Biology, Oncology Department, Azienda-ULSS 18-Rovigo, Trecenta, Italy. milenagusella@libero.it
Frigo
A C
AC
Bolzonella
C
C
Marinelli
R
R
Barile
C
C
Bononi
A
A
Crepaldi
G
G
Menon
D
D
Stievano
L
L
Toso
S
S
Pasini
F
F
Ferrazzi
E
E
Padrini
R
R
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002277:Carcinoma / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D064420:Drug-Related Side Effects and Adverse Reactions / Q000175:diagnosis / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000627:therapeutic use*; D005838:Genotype; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016019:Survival Analysis; D013940:Thymidylate Synthase / Q000235:genetics
D000964:Antimetabolites, Antineoplastic; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; D002955:Leucovorin; D005472:Fluorouracil