A phase II and pharmacologic study of fluorouracil given by a 1-hour infusion daily for 5 days with leucovorin and interferon alpha-2a in adenocarcinoma of the large bowel.
We have reported that increasing the length of infusion from 5 min to 1 h appeared to substantially reduce the toxicity associated with fluorouracil (5-FU) modulated by leucovorin (LV) and interferon alpha-2a (IFN-alpha). This phase II study assessed the antitumor efficacy of this regimen. Patients (n=38) with colorectal cancer received IFN-alpha 5 MU/m(2) SC on days 1-6; on days 2-6, LV 200 mg/m(2) IV was given with 5-FU at initial doses of 370-425 mg/m(2)/h. The regimen was well-tolerated with no grade 4 toxicity. At 425 mg/m(2) 5-FU, grade 3 toxicities included diarrhea (8.6%), anorexia, fever and fatigue (5.7% each), neutropenia and nausea/vomiting (2.9% each). Individuals tolerated 5-FU doses up to 644 mg/m(2). Objective responses occurred in 27% of 37 patients; median time to progression and survival were 6.1 and 12.9 months. Only 1 of 25 informative tumor samples had high-frequency microsatellite instability (MSI), while 7 of 23 assessable patients (30%) with MSI-negative tumors had an objective response. With 425 mg/m(2), the average 5-FU Cp and AUC(0-1 h) were 37.4 microM and 1161 microM/h. Some 6 patients had extended sampling, and the half-lives of 5-FU and FBAL (apparent) were 8.6 and 100.0 min, respectively. A 1-h infusion of 5-FU is well tolerated; individual dose escalation of 5-FU allows each patient to receive the maximum tolerable dose.
Ismail
Abdel Salam Attia
AS
Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute-Navy, National Naval Medical Center, Bethesda, MD 20889-5105, USA.
Quinn
Mary G
MG
Wright
Maurice A
MA
Ernst
Aaron
A
Kao
Vivian
V
Grogan
Liam
L
Parr
Allison
A
Grollman
Frank
F
Kirsch
Ilan R
IR
Grem
Jean L
JL
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage; D007420:Intestine, Large / Q000378:metabolism / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011994:Recombinant Proteins; D015996:Survival Rate; D013940:Thymidylate Synthase / Q000378:metabolism; D016896:Treatment Outcome
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D013940:Thymidylate Synthase; D005472:Fluorouracil