Individual fluorouracil dose adjustment in FOLFOX based on pharmacokinetic follow-up compared with conventional body-area-surface dosing: a phase II, proof-of-concept study.
BACKGROUND
To compare the efficacy and safety of pharmacokinetically (PK) guided fluorouracil (5-FU) dose adjustment vs. standard body-surface-area (BSA) dosing in a FOLFOX (folinic acid, fluorouracil, oxaliplatin) regimen in metastatic colorectal cancer (mCRC).


METHODS
A total of 118 patients with mCRC were administered individually determined PK-adjusted 5-FU in first-line FOLFOX chemotherapy. The comparison arm consisted of 39 patients, and these patients were also treated with FOLFOX with 5-FU by BSA. For the PK-adjusted arm 5-FU was monitored during infusion, and the dose for the next cycle was based on a dose-adjustment chart to achieve a therapeutic area under curve range (5-FU(ODPM Protocol)).


RESULTS
The objective response rate was 69.7% in the PK-adjusted arm, and median overall survival and median progression-free survival were 28 and 16 months, respectively. In the traditional patients who received BSA dosage, objective response rate was 46%, and overall survival and progression-free survival were 22 and 10 months, respectively. Grade 3/4 toxicity was 1.7% for diarrhea, 0.8% for mucositis, and 18% for neutropenia in the dose-monitored group; they were 12%, 15%, and 25%, respectively, in the BSA group.


CONCLUSIONS
Efficacy and tolerability of PK-adjusted FOLFOX dosing was much higher than traditional BSA dosing in agreement with previous reports for 5-FU monotherapy PK-adjusted dosing. Analysis of these results suggests that PK-guided 5-FU therapy offers added value to combination therapy for mCRC.
Oncopharmacology - Pharmacogenetics Department CRCNA INSERM U892, Institut de Cancérologie de l'Ouest, 49933 Angers Cedex, France; Department of Medical Oncology and Clinical Pharmacology, Institut de Cancérologie de l'Ouest, 49933 Angers Cedex, France.
Olivier
O
Capitain
Andreaa
A
Asevoaia
Michele
M
Boisdron-Celle
Anne-Lise
AL
Poirier
Alain
A
Morel
Erick
E
Gamelin
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001830:Body Surface Area; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005500:Follow-Up Studies; D006801:Humans; D002955:Leucovorin / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use; D011379:Prognosis; D011446:Prospective Studies; D015996:Survival Rate; D014018:Tissue Distribution
D000964:Antimetabolites, Antineoplastic; D009944:Organoplatinum Compounds; D002955:Leucovorin; D005472:Fluorouracil