PURPOSE: Systemic bevacizumab (Bev) was added to hepatic arterial infusion (HAI) floxuridine (FUDR)-based chemotherapy in three studies in an attempt to improve outcomes. A specific review of biliary toxicity was carried out. METHODS: This analysis included 203 patients from three prospective studies. The first (study A) was an adjuvant study after liver resection of colorectal metastases in which patients received HAI and systemic chemotherapy (Sys) with or without Bev. Study B comprised unresectable colorectal patients who received HAI and Sys plus Bev. Study C included patients with unresectable cholangiocarcinoma or hepatocellular carcinoma who received HAI plus systematic Bev. The outcome and toxicity of patients in studies B and C were compared with historical controls. RESULTS: In all three studies, the incidence of hyperbilirubinemia and biliary stent placement within 1 year of treatment was increased with the addition of Bev. In the no-Bev versus Bev groups, the placement of biliary stents was as follows: study A, 0 of 38 versus 4 of 35 patients (p = 0.05); study B, 0 of 49 versus 3 of 24 (p = 0.06); and study C, 0 of 34 versus 3 of 22 (p = 0.15). Elevation in bilirubin was noted in the no-Bev versus Bev groups: study A, 0 of 38 versus 5 of 35 patients (p = 0.02); study B, 1 of 49 versus 7 of 24 (p = 0.005); and study C, 2 of 34 versus 5 of 22 (p = 0.10). The addition of Bev did not seem to be associated with improved progression-free or overall survival. CONCLUSIONS: The addition of Bev to HAI FUDR resulted in increased biliary toxicity in three separate studies. Although the sample sizes were small, there was no evidence of improved PFS or OS with the addition of Bev. Bev should not be combined with HAI FUDR.

Very few patients with liver metastases from colorectal cancer can be cured. We have investigated whether a treatment to slow the growth of liver metastases, hepatic-artery infusion of floxuridine, improves palliation in this setting. In a randomised study of 100 patients, we compared quality of life and survival in patients who received hepatic-artery infusion of floxuridine and in those who received conventional symptom palliation. 95% of control patient survival time was spent with normal quality-of-life scores, which suggests that the aim of treatment should be to prolong normal-quality survival rather than merely to sustain quality of life. There was a significant prolongation (p = 0.03) in overall survival in floxuridine-treated patients compared with controls (median 405 vs 226 days). There were similar significant prolongations in normal-quality (ie, normal symptom scores) survival for physical symptoms (p = 0.04), anxiety (p = 0.04), and depression (p = 0.04). This survival benefit was associated with significant reductions in metastasis size on computed tomography (p = 0.001) and in serum carcinoembryonic antigen concentration (p = 0.006) in floxuridine-treated patients. There was no evidence of treatment-related hepatotoxicity as assessed by serum aspartate aminotransferase and bilirubin measurements. This is the first demonstration that survival can be prolonged with normal quality of life in patients with colorectal liver metastases. We conclude that hepatic-artery floxuridine infusion can be recommended for suitable patients.

Seventy-four patients with liver metastasis from proved colorectal primary adenocarcinoma were entered into a prospective, randomized clinical trial to evaluate treatment with intra-arterial floxuridine compared with standard outpatient therapy with fluorouracil delivered by intravenous bolus injection. Eligible patients were randomized to hepatic arterial chemotherapy with an implanted infusion pump or systemic chemotherapy. No crossover between treatment arms was permitted, and patients were followed up to progression and death. Objective tumor response was observed in 48% of patients receiving intra-arterial floxuridine and in 21% of patients receiving intravenous fluorouracil. Time to hepatic progression was significantly longer in the group given intra-arterial therapy: 15.7 vs 6.0 months. However, time to overall progression (6.0 vs 5.0 months) and survival (12.6 vs 10.5 months) were not statistically different. Based on these data, we cannot recommend treatment with intra-arterial floxuridine as given in this study for metastatic colorectal cancer to the liver.

PURPOSE: A multicentric randomized study that compared patients who received intrahepatic arterial infusion (HAI) to a group of patients who did not receive HAI (control group) was performed for unresectable hepatic metastases from primary colorectal carcinoma. PATIENTS AND METHODS: One hundred sixty-six patients were assigned randomly to HAI of floxuridine (5 fluoro-2'deoxyuridine [FUDR]) 0.3 mg/kg/d for 14 days every 4 weeks or to the control group; this latter group, depending on the investigator's choice, was either under observation or received systemic fluorouracil (5-FU). The same regimen of systemic 5-FU also was administered to the HAI group in the event of extrahepatic progression. No crossover from the control group to the HAI group was permitted. The mean duration of follow-up was 54 months (range, 31 to 72), and 163 patients were analyzed. RESULTS: A significant improvement was observed in the survival rate for the 81 patients assigned to HAI group (P less than .02) with a 1-year survival rate of 64% versus 44% in the control group (82 patients). The 2-year survival rate was 23% versus 13%. The median survival was 15 months versus 11 months for the HAI group and the control group, respectively. Survival was better for patients with a less than 30% liver involvement, and for those treated in more specialized centers. The hepatotoxic effects of HAI were observed in 47 patients (chemical hepatitis [n = 28], and biliary sclerosis [n = 19]). The 1-year rate of sclerosing cholangitis was equal to 25%. Gastrointestinal toxicity was infrequent and consisted of gastritis or diarrhea. CONCLUSIONS: Therapy with HAI of FUDR improves the survival of patients with liver metastases over colorectal carcinoma. However, the methods that are used to diminish the toxicity of HAI and efficient systemic chemotherapy, such as a combination of 5-FU and leucovorin, are required to prevent extrahepatic metastases.

In 1983, the Northern California Oncology Group (NCOG) instituted a randomized trial of intravenous (IV) versus intraarterial (IA) floxuridine (FUDR) administered via an implantable pump for patients with colorectal cancer metastatic to the liver. The study objectives were to compare the hepatic response rate, time to hepatic progression, and toxicity for the two treatment arms. The study design, which allowed patients failing IV FUDR to crossover to the IA arm, prevents a meaningful comparative analysis of survival. Patients with liver-only metastases (N = 143) were randomized, 76 to the IV arm and 67 to the IA arm, and 115 patients (65 IV, 50 IA) were fully evaluable. Of the 65 patients in the IV arm, 28 crossed over to IA treatment after failing IV FUDR. The dose-limiting toxicity of IV FUDR was diarrhea, whereas biliary toxicity limited both the dose and duration of IA FUDR therapy. Of the first 25 patients treated with IA FUDR at a dose of .3 mg/kg/day, 10 developed radiographically evident biliary strictures, and three developed permanent jaundice. With reduction of the initial IA FUDR dose to .2 mg/kg/day, and adoption of a policy of early dosage reduction, treatment interruption, or termination of therapy for persistent elevations in alkaline phosphatase, only two further cases of serious biliary toxicity occurred. However, 26 of the 50 IA FUDR patients ultimately had therapy terminated because of drug toxicity rather than disease progression. When compared with systemic infusion, infusion into the hepatic artery greatly enhanced the antitumor activity of FUDR against colorectal liver metastases. Although biliary toxicity is the most serious limitation of this form of therapy, biliary stricture and jaundice usually can be averted through careful monitoring of liver enzymes and early dosage reduction.

BACKGROUND: The purpose of this study was to evaluate the toxicity of immediate postoperative intraperitoneal (IP) floxuridine (FUdR) and leucovorin (LV) after resection of high risk colon cancer, and to determine the appropriate dose of intravenous fluorouracil (FU) plus levamisole during concurrent intraperitoneal therapy. METHODS: The authors conducted a tertiary referral Comprehensive Cancer Center Phase I Trial in patients with resected colon cancer at high risk for recurrence. After resection of all gross disease, intraperitoneal treatment was administered twice daily for 3 days every 2 weeks for three cycles (Days 1-3, 15-17, 29-31). Intravenous FU daily for 5 days was administered on days 29-33 concurrently with the third cycle of intraperitoneal therapy. Fluorouracil doses during the last cycle of intraperitoneal therapy were escalated; intraperitoneal FUdR and LV doses and weekly intravenous FU doses (starting on Day 58) were fixed. RESULTS: Twenty-six patients with resected high risk colon cancer were treated. Three had Dukes' B2, 16 Dukes' C, and 7 Dukes' D (M1) resected tumors. Intraperitoneal therapy was well tolerated with no increase in operative morbidity and no operative mortality. Two patients had > or = Grade 3+ toxicity during IP therapy alone. There were no treatment related deaths. During concurrent intraperitoneal and intravenous chemotherapy, the maximum tolerated dose of FU was 300 mg/m2/day for 5 days. The recommended dose for Phase II or III trials is 200 mg/m2/day for 5 consecutive days. Pharmacokinetic analysis indicated that using the doses used in this trial, measurable systemic concentrations of FUdR and LV were obtained during IP therapy. This may have contributed to observed toxicity with intravenous FU doses of 300-400 mg/m2. With a median duration of follow-up of 18 months, four patients had recurrence of disease. No peritoneal recurrences have been noted to date. CONCLUSIONS: Immediate postoperative IP FUdR and LV are well tolerated after resection of high risk colon cancer. The recommended dose of intravenous FU beginning on Day 29 (concurrent with the last dose of IP therapy) is 5FU 200 mg/m2 for 5 consecutive days. The remaining year of adjuvant fluorouracil and levamisole can be administered with standard dose attenuation. Although follow-up is short, the lack of recurrent peritoneal metastases is encouraging. Additional trials with this approach are warranted in patients with high risk colorectal cancer.

PURPOSE: To determine the maximum tolerated dose (MTD) and preliminary efficacy of concurrent hepatic arterial infusion (HAI) of floxuridine (FUDR) and systemic modified oxaliplatin, 5-fluorouracil and leucovorin (m-FOLFOX6) in Chinese patients with unresectable hepatic metastases from colorectal cancer. PATIENTS AND METHODS: Thirty-five patients with unresectable liver metastases with or without extrahepatic disease were treated with concurrent HAI and systemic m-FOLFOX6. HAI FUDR was delivered in a 14-day infusion with escalating dose levels, and each cycle was repeated every 4 weeks. RESULTS: The MTD for FUDR was 0.12 mg/kg/day when combined with systemic m-FOLFOX6. The dose-limited toxicities were neutropenia (8.6 %), alanine aminotransferase/aspartate aminotransferase elevation (5.7 %) and diarrhea (11.4 %). The overall response rate was 68.6 % for hepatic metastases and 14.3 % for extrahepatic metastases. The median progression-free survival and overall survival were 8.23 and 25 months, respectively. CONCLUSION: The recommended dose of FUDR was 0.12 mg/kg/day when combined with systemic m-FOLFOX6. This combination achieved a high response rate in hepatic disease and a high control rate in extrahepatic disease. Further study is needed to assess the potential additional value of HAI therapy in converting patients with hepatic metastases to candidates for resection.

ANTECEDENTES: Aunque los tratamientos locorregionales como la infusión arterial hepática (IAH) tienen la ventaja, en comparación con la quimioterapia sistémica (QTS), de aplicar dosis mayores de agentes anticancerosos directamente en el órgano metastásico, su beneficio en cuanto a la supervivencia general (SG) es incierto. Se resumieron cuantitativamente los resultados de los ensayos controlados aleatorios (ECA) que compararon IAH con QTS para el tratamiento de la enfermedad hepática metastásica no resecable del cáncer colorrectal (CCR). OBJETIVOS: El objetivo de este trabajo es resumir cuantitativamente los resultados de los ECA que compararon IAH con QTS para el tratamiento de las metástasis hepáticas no resecables del CCR. ESTRATEGIA DE BÚSQUEDA: Se realizó una revisión sistemática de los informes publicados hasta setiembre de 2008 sobre los resultados de ECA que compararon IAH con QTS para el tratamiento de las metástasis hepáticas no resecables del CCR, mediante búsquedas efectuadas en las bases de datos electrónicas MEDLINE, Embase, Cancerlit, Cochrane y GoogleScholar, así como otros bancos de datos que recopilan información sobre ensayos clínicos. CRITERIOS DE SELECCIÓN: Los criterios de inclusión fueron pacientes con metástasis hepáticas no resecables del CCR incluidos en ECA que compararon IAH con QTS. Las medidas de resultado fueron la tasa de respuesta tumoral y la supervivencia general. RECOPILACIÓN Y ANÁLISIS DE DATOS: Dos autores independientes realizaron la selección de estudios y la evaluación de la calidad metodológica. Un tercer autor realizó un análisis de concordancia para desentrañar los posibles sesgos sistemáticos. RESULTADOS PRINCIPALES: Se identificaron 10 ECA que cumplieron con los criterios de elegibilidad. Los regímenes de IAH se basaron en la floxuridina, el 5-fluorouracilo o una de estas dos fluoropirimidinas en ocho ECA y un ECA, respectivamente. La QTS consistió en floxuridina o 5-fluorouracilo en tres y siete ECA, respectivamente. Al agrupar los datos de resumen, la tasa de respuesta tumoral resultó del 42,9% y del 18,4% para la IAH y la QTS, respectivamente (RR = 2,26; IC del 95%: 1,80 a 2,84; < 0,0001). Las medias ponderadas de las medianas del tiempo de SG fueron de 15,9 y 12,4 meses para la IAH y QTS, respectivamente: el metarriesgo de muerte no fue estadísticamente diferente entre los dos grupos de tratamiento (CRI = 0,90; IC del 95%: 0,76 a 1,07; = 0,24). CONCLUSIONES DE LOS AUTORES: LAS PRUEBAS ACTUALMENTE DISPONIBLES NO APOYAN EL USO CLÍNICO O INVESTIGACIONAL DE LA IAH DE FLUOROPIRIMIDINAS SOLA PARA EL TRATAMIENTO DE LOS PACIENTES CON METÁSTASIS HEPÁTICAS NO RESECABLES DEL CCR: la mayor tasa de respuesta tumoral obtenida con este régimen de IAH no se traduce en una ventaja de supervivencia sobre la QTS con fluoropirimidinas únicamente.

BACKGROUND: Two years after undergoing resection of liver metastases from colorectal cancer, about 65 percent of patients are alive and 25 percent are free of detectable disease. We tried to improve these outcomes by treating patients with hepatic arterial infusion of floxuridine plus systemic fluorouracil after liver resection. METHODS: We randomly assigned 156 patients at the time of resection of hepatic metastases from colorectal cancer to receive six cycles of hepatic arterial infusion with floxuridine and dexamethasone plus intravenous fluorouracil, with or without leucovorin, or six weeks of similar systemic therapy alone. Patients were stratified according to previous treatment and the number of liver metastases identified at operation. The study end points were overall survival, survival without recurrence of hepatic metastases, and survival without any metastases at two years. RESULTS: The actuarial rate of overall survival at two years was 86 percent in the group treated with local plus systemic chemotherapy and 72 percent in the group given systemic therapy alone (P=0.03). The median survival was 72.2 months in the combined-therapy group and 59.3 months in the monotherapy group, with a median follow-up of 62.7 months. After two years, the rates of survival free of hepatic recurrence were 90 percent in the monotherapy group and 60 percent in the monotherapy group (P<0.001), and the respective rates of progression-free survival were 57 percent and 42 percent (P=0.07). At two years, the risk ratio for death was 2.34 among patients treated with systemic therapy alone, as compared with patients who received combined therapy (95 percent confidence interval, 1.10 to 4.98; P=0.027), after adjustment for important variables. The rates of adverse effects of at least moderate severity were similar in the two groups, except for a higher frequency of diarrhea and hepatic effects in the combined-therapy group. CONCLUSIONS: For patients who undergo resection of liver metastases from colorectal cancer, postoperative treatment with a combination of hepatic arterial infusion of floxuridine and intravenous fluorouracil improves the outcome at two years.

PURPOSE: The treatment of unresectable liver-confined metastatic disease from colorectal cancer (CRC) is a challenging issue. Although locoregional treatments such as hepatic arterial infusion (HAI) claim the advantage of delivering higher doses of anticancer agents directly into the affected organ, the benefit in terms of overall survival (OS) is unclear. We quantitatively summarized the results of randomized controlled trials (RCT) comparing HAI with systemic chemotherapy (SCT). METHODS: To date, 10 RCTs have been published, for a total of 1,277 patients enrolled. For tumor response rates, relative risks (RR) and their 95% CIs were obtained from raw data; for OS, hazard ratios (HRs) and their 95% CIs were extrapolated from the Kaplan-Meier survival curves. RESULTS: HAI regimens were based on floxuridine (FUDR) in nine of 10 RCTs, whereas in one RCT, fluorouracil (FU) + leucovorin was used. SCT consisted of FUDR, FU, FU + leucovorin, or a miscellany of FU and best supportive care in three, one, four, and two studies, respectively. Pooling the data, tumor response rate was 42.9% and 18.4% for HAI and SCT, respectively (RR = 2.26; 95% CI, 1.80 to 2.84; P < .0001). Mean weighted median OS times were 15.9 and 12.4 months for HAI and SCT, respectively; the meta-risk of death was not statistically different between the two study groups (HR = 0.90; 95% CI, 0.76 to 1.07; P = .24). CONCLUSION: Currently available evidence does not support the clinical or investigational use of fluoropyrimidine-based HAI alone for the treatment of patients with unresectable CRC liver metastases, at least as a first-line therapy.