Prospective randomised trial on adjuvant hepatic-artery infusion chemotherapy after R0 resection of colorectal liver metastases. Limited but definite efficacy of prophylactic hepatic arterial infusion chemotherapy after curative resection of colorectal liver metastases: A randomized study. Randomized trial of surgery versus surgery followed by adjuvant hepatic arterial infusion with 5-fluorouracil and folinic acid for liver metastases of colorectal cancer. German Cooperative on Liver Metastases (Arbeitsgruppe Lebermetastasen) A prospective, randomized evaluation of the treatment of colorectal cancer metastatic to the liver. Combined-modality treatment for resectable metastatic colorectal carcinoma to the liver: surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy--an intergroup study.
The liver represents the predominant site of cancer relapse after curative resection of hepatic metastases from colorectal carcinoma. Adjuvant intra-arterial chemotherapy was therefore considered a promising therapeutic approach in high-risk patients.
                From July 1984 to December 1985, a total of 42 consecutive patients underwent R0 resection of colorectal liver metastases. Thirty patients with mesenteric lymph-node metastases (Dukes C) were randomised into two groups. In 14 group-A patients, a hepatic artery port catheter was placed during liver resection. Four courses of adjuvant chemotherapy were administered at 4-week intervals, consisting of mitomycin C (8 mg/m2, day 1) and 5-fluorouracil (800 mg/m2, days 1-5). Sixteen group-B patients served as controls. The 12 patients with no mesenteric lymph-node metastases (Dukes A/B) were included in the follow-up program.
                After 5 years, 64% of Dukes A/B patients and 29% of Dukes C patients were alive (P<0.01). The probability of remaining free of recurrent disease after 5 years and 10 years was 55% and 18%, respectively (P<0.01). No significant difference in either 5-year survival (25% vs 31%) or long-term disease-free status (15% vs 23%) was detected between groups A and B. The initial tumour relapse was shifted towards extrahepatic sites in group-A patients, but no difference was obtained regarding the definite distribution of recurrent disease.
                Routine application of adjuvant regional chemotherapy after R0 liver resection is not warranted. Greater than 50% of patients who undergo curative resection of liver metastases from colorectal carcinoma develop recurrent disease in the residual liver. Although several studies have attempted to use hepatic arterial infusion (HAI) chemotherapy to prevent recurrence, to the authors' knowledge the efficacy of the treatment has not yet been determined.
                Nineteen patients who underwent curative hepatectomy for metastatic colorectal carcinoma randomly were assigned into the HAI group (nine patients) or the control group (ten patients). Patients in the HAI group received continuous intraarterial infusion of 5-fluorouracil (5-FU) (500 mg/day) for 4 days followed by a 3-day rest. The treatment was continued for 6 weeks.
                The median follow-up period was 62.2 months. The recurrence was confirmed in three patients in the HAI group and in eight patients in the control group. Of these, recurrence in the remnant liver was observed in one patient and in six patients, respectively. The median disease free interval after hepatectomy was 62.6 months in the HAI group and 13.8 months in the control group. The 1-year, 2-year, and 3-year disease free survival rates were 77.8%, 77.8%, and 66.7%, respectively, in the HAI group and 50.0%, 30.0%, and 20.0%, respectively, in the control group. Significant prolongation of disease free survival was observed in the HAI group (P = 0.045). No patients in the HAI group reported any adverse effect of >/= Grade 2 (according to the National Cancer Institute Common Toxicity Criteria). Two patients in the HAI group and five patients in the control group were dead of disease at the time of last follow-up. The 1-year, 3-year, and 5-year cumulative survival rates for the HAI group were 88.9%, 77.8%, and 77.8%, respectively, whereas those of the control group were 100.0%, 50.0%, and 50.0%, respectively (P = 0.2686).
                This randomized study revealed that short term HAI of 5-FU after curative resection of colorectal hepatic metastases is effective in preventing the recurrence of disease without any serious complications.
                Copyright 2000 American Cancer Society. To determine the impact of adjuvant hepatic arterial infusion (HAI) on survival relative to resection alone in patients with radical resection of colorectal liver metastases.
                Nearly 40% to 50% of all patients with colorectal carcinoma develop liver metastases. Curative resection results in a 5-year survival rate of 25% to 30%. Intrahepatic recurrence occurs after a median of 9 to 12 months in up to 60% of patients. The authors hypothesized that adjuvant intraarterial infusion of 5-fluorouracil (5-FU) might decrease the rate of intrahepatic recurrence and improve survival in patients with radical resection of colorectal liver metastases.
                Between April 5, 1991, and December 31, 1996, patients with colorectal liver metastases from 26 hospitals were stratified by the number of metastases and the site of the primary tumor and randomized to resection of the liver metastases followed by adjuvant HAI of 5-FU (1000 mg/m2 per day for 5 days as a continuous 24-hour infusion) plus folinic acid (200 mg/m2 per day for 5 days as a short infusion), or liver resection only.
                The first planned intention-to-treat interim analysis after inclusion of 226 patients and 91 events (deaths) showed a median survival of 34.5 months for patients with adjuvant therapy versus 40.8 months for control patients. The median time to progression was 14.2 months for the chemotherapy group versus 13.7 months for the control group. Grade 3 and 4 toxicities (World Health Organization), mainly stomatitis (57.6%) and nausea (55.4%), occurred in 25.6% of cycles and 62.9% of patients.
                According to this planned interim analysis, adjuvant HAI, when used in this dose and schedule in patients with resection of colorectal liver metastases, reduced the risk of death at best by 15%, but at worst the risk of death was doubled. Thus, the chance of detecting an expected 50% improvement in survival by the use of HAI was only 5%. Patient accrual was therefore terminated. Over a 4-year period (1982 to 1986), 91 patients with solitary or multiple metastases from colorectal cancer were stratified, based on findings at laparotomy, to one of three groups and then prospectively randomized to one of two treatment arms within each group. Group A patients had solitary resectable metastases, group B patients had multiple, resectable metastases, and group C patients had multiple, unresectable metastases. Patients were randomized to one of two treatment arms within a group: group A-arm A1: resection only, arm A2: resection and continuous hepatic artery infusion (CHAI) of fluorodeoxyuridine (FUdR); group B-arm B1: resection and CHAI, arm B2: CHAI only; group C-arm C1: CHAI, arm C2: systemic fluorouracil followed by CHAI. Median time to failure (TTF) was 31.8, 11.1, and 8.8 months for groups A, B, and C, respectively. Arm A2 had an improved TTF when compared with arm A1 (P = .03). Median survival correlated with extent of disease and was 37.3, 22.4, and 13.8 months for groups A, B, and C, respectively. Survival was not changed by treatment variation (arms) within each group. Two- and 5-year cumulative survivals for groups A, B, and C were 72.7% and 45.4%; 45.8% and 16.7%; and 31.7% and 3.2%, respectively. In patients with multiple metastases (groups B and C), those patients whose original tumor was a Dukes' B had a significantly improved TTF and survival over those patients whose tumor was a Dukes' C (P less than or equal to .02). Despite technical improvements that have minimized the morbidity and mortality of hepatic surgery, the long-term outcome of resection of hepatic metastases of colorectal cancer remains poor, with the majority of patients experiencing treatment failure in the liver. Because arterial chemotherapy regimens targeted to the liver have demonstrated high response rates, an intergroup trial of adjuvant therapy for patients undergoing hepatic resection of liver metastases from colorectal cancer was initiated.
                Patients with one to three potentially resectable metastases were randomized preoperatively to receive no further therapy (control arm, 56 patients) or postoperative hepatic arterial floxuridine combined with intravenous continuous-infusion fluorouracil (chemotherapy arm, 53 patients). After exclusion of patients identified as ineligible for the planned treatment at the time of surgery, there were 45 control patients and 30 on the chemotherapy arm. The study was powered to evaluate improvement in time to recurrence and hepatic disease-free survival, not overall survival.
                The 4-year recurrence-free rate was 25% for the control arm and 46% for the chemotherapy group (P =.04). The 4-year liver recurrence-free rate was 43% in the control group and 67% in the chemotherapy group (P =.03). The median survival of the 75 assessable patients was 49 months for the control arm and 63.7 months for the chemotherapy arm (P =.60). The median survival of all 109 patients was 47 months for the control arm compared with 34 months for the chemotherapy arm (P =.19)
                These data demonstrate that adjuvant intra-arterial and intravenous chemotherapy was beneficial in prolonging time to recurrence and pre-venting hepatic recurrence after hepatic resection of colorectal cancer.