title: Preliminary observations indicate variable patterns of plasma 5-fluorouracil (5-FU) levels during dose optimization of infusional 5-FU in colorectal cancer patients.
abstract: Efforts to improve efficacy and minimize toxicity have led to pharmacokinetic monitoring of plasma 5-Fluorouracil (5-FU) levels in colorectal cancer patients undergoing chemotherapy. We observed variation in basal 5-FU levels in 21 patients and significant variation during subsequent dose optimization. Tumor KRAS, BRAF mutations and TS mRNA levels were determined. Regimens included FOLFOX6 + Avastin (N = 8), FOLFOX6 (N = 11), FOLFIRI (N = 1) and FOLFOX4 (N = 1). Mutations identified in tumors included G12V KRAS (N = 2), G12A KRAS (N = 1), and V600E BRAF (N = 3). Six-of-eleven patients with normalized tumor TS mRNA levels < 4.0 had a 5-FU AUC of 20 mg.h/L or greater, and 80% of patients (4 of 5) with TS levels > 4.0 had a plasma 5-FU AUC of less than or equal to 20 mg.h/L. Approximately 2/3 of patients achieved therapeutic 5-FU AUC levels with 0-2 dose adjustments while a sub-group of ~1/3 of patients slowly achieved therapeutic levels (> 3-4 dose increases leading to supra-therapeutic 5-FU and subsequent reductions to lesser than original doses). Liver metastases and tumor TS levels did not fully account for variable 5-FU AUC optimization patterns. The 5-FU level during continuous infusion was half-therapeutic in one patient who received FOLFOX4. The observed heterogeneous patterns at baseline and during dose optimization of 5-FU levels suggest variations in 5-FU metabolism among treated patients. Physiological and/or genetic differences underlying heterogeneity in 5-FU levels during dose optimization require further study of patient demographics, single nucleotide polymorphisms in Dihydropyrimidine Dehydrogenase (DPD), TS, or other genes that impact 5-FU metabolism and gene expression changes in liver after 5-FU therapy.
authors.affiliation: Hematology/Oncology Division, Penn State Hershey Cancer Institute, Hershey, PA, USA.
authors.forename: Christina Leah
authors.initials: CL
authors.lastname: Kline
authors.forename: Hassan S
authors.initials: HS
authors.lastname: Sheikh
authors.forename: Angelique
authors.initials: A
authors.lastname: Scicchitano
authors.forename: Rebecca
authors.initials: R
authors.lastname: Gingrich
authors.forename: Cheryl
authors.initials: C
authors.lastname: Beachler
authors.forename: Niklas K
authors.initials: NK
authors.lastname: Finnberg
authors.forename: Jason
authors.initials: J
authors.lastname: Liao
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Sivik
authors.forename: Wafik S
authors.initials: WS
authors.lastname: El-Deiry
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000097:blood* / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D019540:Area Under Curve; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D013940:Thymidylate Synthase / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D000964:Antimetabolites, Antineoplastic; C117307:KRAS protein, human; D009944:Organoplatinum Compounds; D011518:Proto-Oncogene Proteins; D013940:Thymidylate Synthase; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin