Personalized dosing via pharmacokinetic monitoring of 5-fluorouracil might reduce toxicity in early- or late-stage colorectal cancer patients treated with infusional 5-fluorouracil-based chemotherapy regimens.
BACKGROUND
Therapeutic plasma 5-fluorouracil (5-FU) levels are achieved in only 20% to 30% of patients with the current practice of administering 5-FU doses based on body surface area (BSA). Alternatively, 5-FU doses can be adjusted based on 5-FU pharmacokinetic (PK) monitoring. Although benefits of PK monitoring of 5-FU in metastatic colorectal cancer (CRC) have been reported, its utility among patients with early stage disease has not been reported.


METHODS
We retrospectively examined the effect of 5-FU PK monitoring in 84 CRC patients (49 stage IV and 35 stage II/III) receiving mFOLFOX6 (modifiedFOLFOX6; modified 5-fluorouracil, leucovorin, oxaliplatin protocol) or mFOLFIRI (modified 5-fluorouracil, leucovorin, irinotecan protocol). Forty-six of the 84 patients received 5-FU doses based on BSA and 38 received doses that were adjusted with PK monitoring. 5-FU plasma levels were measured using a nanoparticle immunoassay method.


RESULTS
5-fluorouracil PK monitoring significantly improved disease-free survival in stage II/III patients (P = .0429). There was also a trend towards improved progression-free survival among stage IV patients who had their 5-FU levels PK-monitored (P = .16). Moreover, 5-FU PK monitoring significantly reduced (P = .0437) and delayed (P = .0144) adverse effects in stage II/III patients. Toxicity occurred after the second 5-FU dose in the BSA group and after the sixth to seventh dose in the PK monitoring group. In stage IV patients, the onset of toxicities was also delayed with PK monitoring (P = .0605).


CONCLUSIONS
We provide evidence that PK monitoring of 5-FU is potentially beneficial for late stage and early stage CRC. These results contribute to the growing body of evidence regarding patient benefit when treatment decisions are based on the individual patient characteristics, in this case, a patients' 5-FU levels.
Hematology/Oncology Division, Department of Medicine, Penn State College of Medicine, Hershey, PA.
Christina Leah B
CL
Kline
Hematology/Oncology Division, Department of Medicine, Penn State College of Medicine, Hershey, PA.
Angelique
A
Schiccitano
Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA.
Junjia
J
Zhu
Hematology/Oncology Division, Department of Medicine, Penn State College of Medicine, Hershey, PA.
Cheryl
C
Beachler
Hematology/Oncology Division, Department of Medicine, Penn State College of Medicine, Hershey, PA.
Hassan
H
Sheikh
Hematology/Oncology Division, Department of Medicine, Penn State College of Medicine, Hershey, PA.
Harold A
HA
Harvey
Hematology/Oncology Division, Department of Medicine, Penn State College of Medicine, Hershey, PA; Division of Radiation Oncology, Department of Radiology, Penn State College of Medicine, Hershey, PA.
Heath B
HB
Mackley
Department of Surgery, Penn State College of Medicine, Hershey, PA.
Kevin
K
McKenna
Department of Surgery, Penn State College of Medicine, Hershey, PA.
Kevin
K
Staveley-O'Carroll
Department of Surgery, Penn State College of Medicine, Hershey, PA.
Lisa
L
Poritz
Department of Surgery, Penn State College of Medicine, Hershey, PA.
Evangelos
E
Messaris
Department of Surgery, Penn State College of Medicine, Hershey, PA.
David
D
Stewart
Department of Pharmacology, Penn State College of Medicine, Hershey, PA.
Jeffrey
J
Sivik
Hematology/Oncology Division, Department of Medicine, Penn State College of Medicine, Hershey, PA. Electronic address: weldeiry@hmc.psu.edu.
Wafik S
WS
El-Deiry
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods*; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D057285:Precision Medicine; D012189:Retrospective Studies
D009944:Organoplatinum Compounds; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin
5-FU; Chemotherapy; FOLFOX; OnDose; Personalized cancer therapy