Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089.
OBJECTIVE
In 1990, fluorouracil (FU) plus levamisole for 1 year became standard adjuvant treatment for patients with high-risk stages II and III colon cancer. Intergroup (INT) 0089 assessed the relative contributions of leucovorin and levamisole in such patients.


METHODS
From 1988 to 1992, 3,794 patients were randomly assigned. Experimental treatment consisted of one of three chemotherapy regimens: the low-dose leucovorin plus FU (Mayo Clinic; LDLV) regimen, the high-dose leucovorin plus FU (Roswell Park; HDLV) regimen, and the low-dose leucovorin plus levamisole plus FU (LDLV plus LEV) regimen, each administered for 30 to 32 weeks. The control arm was levamisole plus FU (LEV) for 1 year.


RESULTS
After a median follow-up of 10 years, of 3,561 eligible patients, 1,691 (47%) have died and 1,330 (37%) have experienced disease recurrence; 137 (10%) of those experiencing recurrence are still alive. A total of 481 patients (13%) died without evidence of recurrence, and 1,723 (48%) are alive and disease free. Although there were toxicity differences among the four arms, none was statistically superior in disease-free or overall survival.


CONCLUSIONS
The 6- to 8-month regimens of LDLV and HDLV without levamisole used in this trial, rather than the previous standard regimen of 12 months of LEV, have become widely used. INT-0089 has long-term follow-up of the largest clinical trial of patients with high-risk colon cancer, documenting not only the durability of the treatment effects, but also the natural history of patients with high-risk colon cancer, and analyses of treatment based on age, race, and comorbid conditions such as obesity, diabetes, and second primary cancers.
Haller
Daniel G
DG
University of Pennsylvania, Philadelphia, PA, USA. daniel.haller@uphs.upenn.edu
Catalano
Paul J
PJ
Macdonald
John S
JS
O'Rourke
Mark A
MA
Frontiera
Michael S
MS
Jackson
Don V
DV
Mayer
Robert J
RJ
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000009:adverse effects; D000328:Adult; D000368:Aged; D000380:Agranulocytosis / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D005500:Follow-Up Studies; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D007978:Levamisole / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D010349:Patient Compliance; D012307:Risk Factors; D016019:Survival Analysis; D016896:Treatment Outcome; D014803:Vitamin B Complex / Q000008:administration & dosage / Q000009:adverse effects
D000276:Adjuvants, Immunologic; D014803:Vitamin B Complex; D007978:Levamisole; D002955:Leucovorin; D005472:Fluorouracil