Adjuvant portal liver infusion in colorectal cancer with 5-fluorouracil/heparin versus urokinase versus control results of a prospective randomized clinical trial (colorectal adenocarcinoma trial I)

Abstract

This prospectively randomized clinical trial was carried out in four Dutch hospitals to reduce the development of metachronous liver metastases and to get a better survival in patients with colorectal malignancies after surgically radical en bloc resection of the primary tumor and the regional lymph nodes. Three hundred seventeen patients were randomized to participate in three trial arms. One group of patients was treated by surgery alone (control group); in the other patients a catheter was placed in the dilated umbilical vein and advanced until the tip was lying in the left branch of the portal vein. Fifty percent of these patients got immediate postoperative portal infusion with 1 g 5-flnorouracil (5-FU) and 5000 U heparin daily for 7 days; the others received portal vein infusion with urokinase 10.000 U/honr for 24 hours only. Three hundred four patients were eligible. Overall hospital mortality was 3.6% (11 patients) and was not influenced by adjuvant treatment. After a median follow-up of 44 months 66 patients have died with relapse and 21 as a result of other causes. The chance of developing liver metastases and other distant metastases after portal infusion with 5-FU/heparin was one third of the chance in the control group (P < 0.001). Only an insignificant reduction of the average death rate in the 5-FU/heparin group was found.In the urokinase group no significant effect in reducing metastases or in survival was noted. Before recommending cytotoxic portal infusion as an adjuvant treatment in patients with colorectal cancer, detailed analysis of other ongoing portal infusion studies has to be awaited and careful calculations have to be made regarding how many patients really can be saved by this treatment.Cancer 65425-432, 1990.N AUTOPSY STUDIES of patients who died from colo-I rectal cancer, liver metastases were found in about 50% to 80%.' At time of surgery up to 25% of patients with primary colorectal cancer already have macroscopic liver metastases2 The number of patients with microscopic metastases is unknown.Tumor invasion into mesenteric veins causes spread of The authors thank Mrs. Mirjam Linskens for help in data collection and preparation of the manuscript, and Mr. P. J. van Assendelft for assistance in data management and analysis. The authors also thank all of the patients who were willing to cooperate in this study and who had the patience to undergo the multiple sometimes unpleasant investigations.Address for reprints: Jack C. J. Wereldsma, MD, PhD, Department of Surgery, Sint Franciscus Gasthuis, Kleiweg 500,3045 PM Rotterdam, The Netherlands.Accepted for publication July 2 1, 1989.circulating malignant cells to the portal vein.3 These tumor cells surrounded by fibrin and platelets may form tumor clots which can adhere at the vascular endothelium of the liver capillaries. These microfoci can develop into macroscopic metastases initiated by, until now, unknown factors. This tumor cell embolus theory sounds reasonable, the unknown factors being the induction of anesthesia, operative stress...

Venous thromboembolism and cancer: Guidelines of the Italian Association of Medical Oncology (AIOM)

“…In the adjuvant setting of colorectal cancer patients, Wereldsma et al reported in a controlled, randomised trial a reduced risk to develop liver metastases in the 5-FU/heparin group compared to surgery alone or intra-portal infusion of urokinase for 24 h (P < 0.01) [79]. Similar results have been reported by Fielding et al [80].…”

Pharmacology and antitumour effects of intraportal pirarubicin on experimental liver metastases

“…These findings are comparable to the results of some clinical trials which have shown a decrease in the number of hepatic recurrences in i.port. treated groups (Taylor et al, 1985;Wereldsma et al, 1990) compared to control groups, but which did not include i.v. treated groups.…”

“…Regional post-operative adjuvant therapy via the portal vein could be an effective means of preventing the development of liver metastases, by delivering higher local drug concentrations to tumour cells at the onset of metastatic invasion. Several clinical trials have been designed to test this hypothesis (Taylor et al, 1985;Gray et al, 1987;Ryan et al, 1988;Wolmark et al, 1990;Metzger et al, 1990;Wereldsma et al, 1990;Beart et al, 1990;Fielding et al, 1992). Most of them used 5-FU alone, or in association with mitomycin C in different schedules.…”

“…Current results are controversial and remain inconclusive. Some trials have shown a reduction in the number of hepatic recurrences with no benefit for overall survival (Wereldsma et al, 1990). Others have demonstrated an increase in overall and disease free survival, although no differences were noted in the number of hepatic recurrences (Wolmark et al, 1990).…”

Quimioterapia complementaria tras resección de metástasis hepáticas en el carcinoma colorrectal

“…Esto hizo que fuera la vía portal la que se empleó con más asiduidad para los primeros tratamientos locorregionales. Este es un procedimiento de cierta complejidad técnica y se ensayó tras resección de tumores primarios en un buen número de ensayos [2][3][4][5][6][7][8] . Aunque en alguno de ellos se detectó un aumento en la supervivencia, en el mayor de ellos 7 fue sin mejorar el control hepático, por lo que se atribuyó su efecto al paso sistémico de la droga.…”