Adjuvant regional chemotherapy and systemic chemotherapy versus systemic chemotherapy alone in patients with stage II-III colorectal cancer: a multicentre randomised controlled phase III trial.
BACKGROUND
Systemic adjuvant chemotherapy can improve overall survival and reduce the incidence of distant metastases for patients with advanced colon cancer. This study aimed to investigate whether regional chemotherapy (given by intraperitoneal or intraportal methods) combined with systemic chemotherapy was more effective than was systemic chemotherapy alone in terms of survival and recurrence for patients with stage II-III colorectal cancer. The study also compared systemic chemotherapy with fluorouracil and folinic acid with that of fluorouracil and levamisole.


METHODS
During surgery, 753 patients with stage II-III colorectal cancer were randomly assigned to systemic chemotherapy alone (379 with fluorouracil and folinic acid, and 374 with fluorouracil and levamisole), and 748 to postoperative regional chemotherapy with fluorouracil followed by systemic chemotherapy with fluorouracil and folinic acid (n=368) or with fluorouracil and levamisole (n=380). Regional chemotherapy was given intraperitoneally (n=415) or intraportally (n=235) according to institution. The primary endpoint was 5-year overall survival. Secondary endpoints were 5-year disease-free survival and toxic effects. Analyses were by intention to treat.


RESULTS
Median follow-up was 6.8 years (range 0.0-10.1). 5-year overall survival was 72.3% (95% CI 69.0-75.6) for patients assigned regional and systemic chemotherapy, compared with 72.0% (68.7-75.3) for those assigned systemic chemotherapy alone (hazard ratio [HR] 0.97 [0.81-1.15], p=0.69). 5-year overall survival for all patients assigned fluorouracil and levamisole was 72.0% (68.7-75.2) compared with 72.3% (69.0-75.6) for all those assigned fluorouracil and folinic acid (HR 0.98 [0.82-1.17], p=0.81). The hazard ratios for 5-year disease-free survival were 0.94 (0.80-1.10) for regional versus non-regional treatment, and 0.92 (0.79-1.08) for all fluorouracil and levamisole versus fluorouracil and folinic acid. Grade 3-4 toxic effects were low in all groups.


CONCLUSIONS
Fluorouracil-based regional chemotherapy adds no further benefit to that obtained with systemic chemotherapy alone in patients with advanced colorectal cancer.
Hospital Ambroise Pare, Assistance Publique Hôpitaux de Paris, 9 Avenue Charles de Gaulle, Boulogne-Billancourt Cedex 92104, France. bernard.nordlinger@apr.aphr.fr
Bernard
B
Nordlinger
Philippe
P
Rougier
Jean-Pierre
JP
Arnaud
Muriel
M
Debois
Jaques
J
Wils
Jean-Claude
JC
Ollier
Olivier
O
Grobost
Philippe
P
Lasser
Jacob
J
Wals
Jerome
J
Lacourt
Jean-François
JF
Seitz
Jose
J
Guimares dos Santos
Harry
H
Bleiberg
Rémy
R
Mackiewickz
Thierry
T
Conroy
Olivier
O
Bouché
Thierry
T
Morin
Liliana
L
Baila
Eric
E
van Cutsem
Laurent
L
Bedenne
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D010478:Chemotherapy, Cancer, Regional Perfusion; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D007978:Levamisole / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D016019:Survival Analysis
D007978:Levamisole; D002955:Leucovorin; D005472:Fluorouracil