Phase I study of hepatic arterial infusion of floxuridine and dexamethasone with systemic irinotecan for unresectable hepatic metastases from colorectal cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) and dose-limiting toxicities of concurrent systemic irinotecan and hepatic arterial infusion (HAI) of floxuridine (FUDR) and dexamethasone in patients with unresectable hepatic metastases from colorectal cancer, to determine the safety of this combination in patients who have undergone cryosurgery, and to evaluate the pharmacokinetic effects of HAI FUDR on the metabolism of irinotecan. PATIENTS AND METHODS: Forty-six previously treated patients with unresectable liver metastases and no known extrahepatic disease were treated concurrently with intravenous irinotecan weekly for 3 weeks and with HAI of FUDR and dexamethasone for 14 days (both were recycled in 28 days). Parallel cohorts of patients treated with or without cryosurgery were entered at escalating dose levels. RESULTS: The MTD for patients who did not undergo cryosurgery was 100 mg/m2 of irinotecan weekly for 3 weeks every 4 weeks with concurrent HAI FUDR (0.16 mg/kg/d x pump volume/flow rate) plus dexamethasone for 14 days of a 28-day cycle. The dose-limiting toxicities were diarrhea and neutropenia. The response rate (complete and partial) among all patients who did not undergo cryosurgery was 74%. All patients in the cryosurgery group responded, and seven of the eight cryosurgery patients developed normal positron emission tomography scans after chemotherapy. HAI FUDR had no effect on the metabolism of irinotecan. CONCLUSION: Combination therapy with HAI FUDR and dexamethasone plus systemic irinotecan may be safely administered to patients with unresectable hepatic metastases from colorectal cancer. The MTD has been reached for patients with unresectable disease, and we continue to investigate the MTD for patients who have undergone cryosurgery. Although the main objective of this study was to evaluate the toxicity of the combined regimen, a high response rate (74%) was observed.     

Percutaneous hepatic arterial infusion (HAI) of mitomycin C and floxuridine (FUDR): an effective treatment for metastatic colorectal carcinoma in the liver

The response rate of metastatic colorectal carcinoma confined to the liver to HAI of FUDR alone is at the range of 50% and to mitomycin C by hepatic arterial infusion (HAI) at the range of 35%. Mitomycin C was added to FUDR by continuous infusion and given by HAI to 12 patients with colorectal cancer confined to the liver. Catheters were placed subselectively in the hepatic artery, and infusion continued for five to six days when the catheter was removed. Cycles were repeated every 30 days. Chemotherapy consisted of mitomycin C 15 mg/m2 administered on day 1 followed by FUDR 100 mg/m2 by continuous infusion daily for five days. Response to treatment was evaluated by serial determinations of plasma CEA and by imaging techniques consisting of a computerized tomography, sonography, and radionuclide scanning of liver as well as by angiography. In 2 patients, complete remission was achieved; in 4 patients a 75% and in another 4 patients a 50% decrease in liver metastasis was observed, while 2 patients had stable disease. Thus, a response rate of 83% with a median duration of six to seven months was achieved. The median survival of the these patients was 16 months. Eight of the 12 patients have failed previous, i.v. 5-FU containing regimens. Complications related to 45 treatment cycles were the following: catheter displacement in 11.1%, an intimal tear, usually in the hepatic artery in 4.4%, gastric ulcerations in 5.4%, and septicemia in 2.7% of the cycles. In addition, aneurysmal dilation of the hepatic artery occurred in 4 patients (8.8% of the treatment cycles), all of whom continued treatment. Chemotherapy-related complications included primarily thrombocytopenia and stomatitis. Mitomycin C + FUDR by hepatic arterial infusion is an effective treatment for colorectal carcinoma metastatic to the liver. The high response rate justifies the adjuvant treatment of Dukes class C colon cancer patients with this treatment.     

Randomized, multicenter trial of fluorouracil plus leucovorin administered either via hepatic arterial or intravenous infusion versus fluorodeoxyuridine administered via hepatic arterial infusion in patients with nonresectable liver metastases from colorectal carcinoma.

PURPOSE: To assess the efficacy and tolerability of three treatments for patients with documented adenocarcinoma of the colon and/or rectum who have undergone complete resection of primary tumor and have nonresectable liver metastases that do not exceed 75% of the liver volume. PATIENTS AND METHODS: A total of 168 patients at 25 treatment centers were enrolled onto this prospective, multicenter, randomized study. The three treatment arms were as follows: (1) fluorouracil (5-FU)/leucovorin (LV) administered via hepatic arterial infusion (HAI), (2) 5-FU/LV administered via intravenous (IV) infusion, and (3) fluorodeoxyuridine (FUDR) administered via HAI. RESULTS: Median times to disease progression for the three treatment arms were as follows: 9.2 months for patients treated with HAI 5-FU/LV, 6.6 months for IV 5-FU/LV, and 5.9 months for HAI FUDR. Median survival times for patients treated with HAI 5-FU/LV, IV 5-FU/LV, and HAI FUDR were 18.7 months, 17.6 months, and 12.7 months, respectively. There was a nearly two-fold increase in time to progression in addition to a survival benefit among patients with an intrahepatic tumor burden of less than 25% who were treated with HAI 5-FU/LV. The most common adverse events were stomatitis, nausea and vomiting, skin irritation, diarrhea, and elevated serum levels of liver enzymes. Some patients exhibited severe reactions, including biliary sclerosis and chemical hepatitis. CONCLUSION: Although the use of HAI 5-FU/LV as a means of treating liver metastases after resection of colorectal carcinoma warrants further investigation, it cannot be recommended as a routine therapeutic measure at this time.     

Phase I trial of systemic oxaliplatin combination chemotherapy with hepatic arterial infusion in patients with unresectable liver metastases from colorectal cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) of concurrent systemic oxaliplatin (Oxal) combinations plus hepatic arterial infusion (HAI) in patients with unresectable hepatic metastases from colorectal cancer. PATIENTS AND METHODS: Thirty-six patients (89% previously treated) with unresectable liver metastases were treated with concurrent HAI and systemic Oxal plus irinotecan (CPT-11; group A) or Oxal, fluorouracil (FU), and leucovorin (LV; group B). Systemic chemotherapy was administered every 2 weeks concurrent with 2 weeks of HAI floxuridine (FUDR) and dexamethasone (Dex) every 28 days. RESULTS: The MTD for patients in group A was Oxal 100 mg/m(2), CPT-11 150 mg/m(2), and FUDR 0.12 mg/kg x 30 mL divided by pump flow rate. The MTD for group B was Oxal 100 mg/m(2), LV 400 mg/m(2), and FU 1,400 mg/m(2) by continuous infusion over 48 hours, with the same FUDR dose as in group A. Grade 3 or 4 toxicities in groups A and B included diarrhea (24% and 20%), neutropenia (10% and 7%), neurotoxicity (24% and 20%), and bilirubin more than 3 mg/mL (5% and 7%, respectively). The complete and partial response rate totaled 90% for group A and 87% for group B. Median survival time was 36 and 22 months for groups A and B, respectively. Seven patients in group A were ultimately able to undergo liver resection. CONCLUSION: Combination therapy with HAI FUDR and Dex plus systemic Oxal combinations may be safely administered to patients with colorectal cancer. The high response rate (88%) and the possibility of conversion to resectability, despite disease progression on prior systemic regimens, suggest that these combinations should be evaluated in larger studies as first- or second-line therapy in patients with hepatic metastases from colorectal cancer.     

The efficacy and safety of hepatic arterial infusion of oxaliplatin plus intravenous irinotecan,leucovorin and fluorouracil in colorectal cancer with inoperable hepatic metastasis

Hepatic arterial infusion (HAI) was evaluated for different drugs to treat hepatic metastasis from colorectal cancer (CRC). Combination treatment with 5-fluorouracil (5-FU), leucovorin, oxaliplatin and irinotecan (FOLFOXIRI) is effective for CRC. A phase II study was conducted to evaluate concomitant HAI administration of oxaliplatin and intravenous leucovorin, 5-FU and irinotecan (FOLFIRI) for patients with inoperable liver metastasis, which had chemotherapy with oxaliplatin (OX) 85?mg/m² HAI plus systemic intravenous chemotherapy [leucovorin 200?mg/m², 5-FU 2400?mg/m² and irinotecan (IRI) 160?mg/m² in 48 hours]. We treated 24 patients. Neutropaenia was the most frequent toxicity. The main HAI-related toxicity was pain. Two patients (8%) obtained complete response and 17 patients (70%) partial response, giving an objective response rate of 78%. Median follow-up was 22.8 months, and median overall and disease-free survival times were 29 and 20 months, respectively. Therefore, OX HAI and intravenous FOLFIRI is feasible and effective in patients with metastatic CRC.     

Phase I/II study of hepatic arterial therapy with floxuridine and dexamethasone in combination with intravenous irinotecan as adjuvant treatment after resection of hepatic metastases from colorectal cancer.

PURPOSE: Patients who undergo resection of liver metastases from colorectal cancer have an average 2-year survival of 65%. With hepatic arterial infusion (HAI) plus systemic fluorouracil and leucovorin, 2-year survival increased to 86%. For further improvement in both local and systemic control, combinations of new systemic drugs with HAI are being explored. The purpose of this study was to determine the maximum-tolerated dose (MTD) of systemic irinotecan (CPT-11) and HAI floxuridine (FUDR) plus dexamethasone (DEX) as combination adjuvant therapy after liver resection. PATIENTS AND METHODS: Ninety-six patients who underwent complete resection of liver metastases from colorectal cancer were treated with six monthly cycles of HAI FUDR plus DEX for 14 days of each 4-week cycle plus escalating doses of systemic CPT-11. The primary end points of the phase I/II study were the MTD and efficacy of this regimen. RESULTS: The MTD for combined systemic CPT-11 and HAI FUDR was CPT-11 at 200 mg/m2 every other week and FUDR at 0.12 mg/kg x pump volume / pump flow rate. The dose-limiting toxicities were diarrhea and neutropenia. With a median follow-up time of 26 months, the 2-year survival rate is 89%. All of the 27 patients who were treated at the MTD are alive. CONCLUSION: In patients who undergo resection of liver metastases from colorectal cancer, adding systemic CPT-11 to HAI therapy in an adjuvant regimen is feasible. This regimen seems to have comparable activity to fluorouracil and leucovorin, but further studies are needed to assess whether it improves local control or decreases extrahepatic recurrences.     

Hepatic arterial infusion of floxuridine and dexamethasone plus high-dose Mitomycin C for patients with unresectable hepatic metastases from colorectal carcinoma

BACKGROUND: In vitro data suggest increased cytotoxicity with Mitomycin C (Mit-C) and Floxuridine (FUDR). Based on these data, we performed a phase II trial of hepatic arterial infusion (HAI) of FUDR and Dexamethasone (Dex) plus high-dose Mit-C for patients with unresectable hepatic metastases from colorectal carcinoma. METHODS: High-dose Mit-C (15 mg/m2) was added via the pump sideport to HAI FUDR and Dex for 14 days of a 28-day cycle. Mit-C was given on days 1 and 29, and FUDR was given indefinitely until disease progression or discontinuation of therapy due to toxicity. RESULTS: Sixty-three patients with unresectable liver metastases were entered. The chemotherapy-na?ve group (n = 26) and those previously treated (n = 37) had similar response and median survival: 73% and 70%, and 23 and 20 months, respectively. The major toxicities were liver bilomas (7.9%), elevation in bilirubin level >3 (22%), and biliary sclerosis (9.5%). Hematologic and gastrointestinal toxicity was less than 2%. CONCLUSION: The addition of high-dose Mit-C to HAI FUDR and Dex produced a high response rate even in previously treated patients. The median survival was 21 months even though half the patients were previously treated with chemotherapy. Biliary toxicity was higher than expected; therefore, alternatives to high dose Mit-C should be investigated when exploring additions to HAI therapy with FUDR and Dex.     

Phase I trial of adjuvant hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone plus systemic oxaliplatin, 5-fluorouracil and leucovorin in patients with resected liver metastases from colorectal cancer

Background: The purpose of the study was to determine the maximum tolerated dose of systemic oxaliplatin (oxal), 5-fluorouracil (5-FU) and leucovorin (LV) that could be administered with hepatic arterial infusion (HAI) of floxuridine (FUDR) and dexamethasone (Dex) in the adjuvant setting after hepatic resection.Methods: Thirty-five patients with resected liver metastases were entered into a phase I trial using HAI FUDR/Dex with escalating doses of oxal and 5-FU.Results: The initial dose of HAI FUDR was fixed at 0.12 mg/kg × pump volume divided by pump flow rate plus Dex infused over the first 2 weeks of a 5-week cycle. Systemic chemotherapy was delivered on days 15 and 29 with the doses of oxal escalated from 85 to 100 mg/m² and the 5-FU 48-h continuous infusion doses from 1000 to 2000 mg/m². The LV dose was fixed at 400 mg/m². Dose-limiting toxic effects were diarrhea, 8.5%, and elevated bilirubin, 8.5%. With a median follow-up of 43 months, the 4-year survival and progression-free survival were 88% and 50%, respectively.Conclusions: Adjuvant therapy after liver resection with HAI FUDR/Dex plus systemic oxal at 85 mg/m² and 5-FU by continuous infusion at 2000 g/m² with LV at 400 mg/m² is feasible and appears effective. Randomized studies comparing this regimen to systemic FOLFOX are suggested.     

Weekly hepatic arterial infusion of 5-fluorouracil and subsequent systemic chemotherapy for liver metastases from colorectal cancer

OBJECTIVE: To determine the antitumor activity and toxicity of weekly hepatic arterial infusion (HAI) of 5-fluorouracil (5-FU) for liver metastases from colorectal cancer. In addition, the present study also evaluated the efficacy of second-line chemotherapy after termination of HAI. METHODS: A retrospective study was designed to evaluate the clinical outcome in patients treated with HAI. Twenty-six patients with liver metastases from colorectal cancer were treated with 5-FU 1000 mg/m(2) over 5 h once per week on an outpatient basis. The treatment was continued until disease progression, unacceptable toxicity or the patient's refusal to continue treatment occurred. One of three kinds of second-line systemic chemotherapy, irinotecan alone, protracted venous infusion of 5-FU or methotrexate (MTX) and 5-FU, was chosen after termination of HAI. RESULTS: An objective tumor response to HAI was observed in 46% (95% confidence interval, 26.9-65.2%) of 26 patients. The most common adverse events were mild nausea and vomiting (35%) and occurrence of gastroduodenal ulcers (15%). Hematological toxicity was minimal. No responder was observed to improve following second-line chemotherapy after termination of HAI. CONCLUSION: Weekly HAI of 5-FU is both active and well tolerated. However, extrahepatic progression was observed in one-third of patients with termination of HAI and the efficacy of second-line chemotherapy was not demonstrated. Regional treatment with systemic chemotherapy should be conducted to achieve good results in terms of survival.     

Hepatic arterial infusion of floxuridine in patients with liver metastases from colorectal carcinoma: long-term results of a prospective randomized trial.

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.     

The 5-fluorouracil hepato-arterial infusion with oral UFT therapy for the hepatic and extra hepatic metastases of colorectal cancer

BACKGROUND: The 5 fluorouracil hepato-arterial infusion (5-FU HAI) therapy has a good effect on the liver metastases of colorectal cancer. To gain the antitumor effect of the extra-hepatic lesion, an oral UFT was combined with 5-FU HAI (pharmacokinetic modulating chemotherapy, PMC) to enhance the plasma 5-FU concentration. METHODS: UFT (200-400 mg/day) was orally administered daily and a continuous infusion of 5-FU (1,000-1,500 mg/5 h) was given once a week. Eight patients were treated with this regimen. Five of the eight have extra-hepatic lesions with liver metastases when this treatment was started. The response, time to progression, survival, and toxicity were detected. RESULTS: Four of the five patients with extra-hepatic lesion were evaluated. The response rate was 50% (1 CR, 1 PR, and 2 SD). For the liver metastases, the response rate was 62.5% (1 CR, 4 PR, 2 SD, and 1 PD). Grade 2 leukopenia was found in 1 patient. CONCLUSIONS: The 5-FU HAI with an oral UFT therapy had a good effect on the extra-hepatic lesions as well as hepatic metastases of colorectal cancer.     

Results of pharmacokinetic modulating chemotherapy in combination with hepatic arterial 5-fluorouracil infusion and oral UFT after resection of hepatic colorectal metastases

BACKGROUND: Pharmacokinetic modulating chemotherapy (PMC) is a new therapeutic concept in combination with continuous 5-fluorouracil (5-FU) infusion and UFT. UFT enhanced plasma 5-FU concentration and antitumor effects during 5-FU infusion. The authors report on their experiences with arterial 5-FU infusion and UFT after resection of hepatic colorectal secondaries. METHODS: Fifty-eight patients were divided into two groups after hepatectomy. Group A, 30 patients, underwent hepatic arterial infusion (HAI) via implantable port system with perfusion 5-FU for 2 consecutive days per week at 600 mg/m(2)/day, and oral administration of UFT at 400 mg/day for 5-7 days per week, repeated 10 times, and Group B, 28 patients, underwent oral administration of UFT at 400 mg/day for 6 months. All the patients were managed at the outpatient clinic at Hyogo College of Medicine, and recurrence, survival, and toxicity were documented. Plasma 5-FU concentrations during chemotherapy were detected using high performance liquid chromatography. RESULTS: Maximum plasma concentrations of 5-FU in Group A reached 144.0 ng/mL and in Group B 58.7 ng/mL. Cumulative 5-year survival rate after hepatectomy in Group A was 59% and in Group B was 27%. (P = 0.00001) HAI-PMC drastically decreased hepatic recurrence (median hepatic recurrence free times were 34.2 months in Group A vs. 18.4 months in Group B; P = 0.00002). Grade 3 toxicity in Group A was found in 3 patients CONCLUSIONS: Pharmacokinetic modulating chemotherapy was designed as a uracil-related biochemical modulation. HAI-PMC significantly decreased hepatic recurrence after curative resection. This new chemotherapy concept significantly improved prognosis in patients with hepatic colorectal metastases.     

First-line treatment with hepatic arterial infusion plus capecitabine vs capecitabine alone for elderly patients with unresectable colorectal liver metastases

This study aimed to compare the efficacy and safety of HAI fluoropyrimidine (FUDR)/capecitabine or single capecitabine as first-line treatment for elderly patients with unresectable colorectal liver metastases (CLMs). Fifty-one elderly patients with liver-only CLMs were eligible for enrollment. Patients were divided into HAI FUDR /capecitabine group and single capecitabine group randomly. The primary endpoint was median survival time (MST), defined as the time from the date of catheter implantation to the date of death or the date of the last follow-up. The secondary endpoint was objective antitumor response and adverse events. The HAI pump was implanted before chemotherapy. All patients received a 3-week cycle of oral capecitabin. In Group A, the RR and DCR were both 95.8%. In Group B, the RR and DCR were 48.1% and 81.5%, respectively. There was significant difference between the RRs of the 2 groups (P < 0.001). But there was no significant difference between the DCRs of the 2 groups (P = 0.053). There was a statistical difference between the MSTs of the 2 groups (18.5 vs.13 months, P = 0.0312). HAI FUDR combined with oral capecitabine as the first-line treatment for elderly patients with CLMs has promising efficacy and safety.     

Combination chemotherapy with hepatic arterial infusion of 5-fluorouracil (5-FU) and systemic irinotecan (CPT-11) in patients with unresectable liver metastases from colorectal cancer

PURPOSE: Hepatic arterial infusion (HAI) chemotherapy for hepatic metastasis from colorectal cancer has higher response rates compared with systemic chemotherapy, but can not control extrahepatic lesions. So the combination chemotherapy with HAI plus systemic chemotherapy is expected. This study ascertained the efficacy and toxicity of combined chemotherapy with HAI plus systemic CPT-11. METHODS: Seventeen patients were treated with concurrent HAI 5-FU 700-800 mg/m(2) on day 1, 8, 15, 22 and systemic CPT-11 70-80 mg/m(2) on day 1 and 15. Treatment was repeated every 28 days. RESULTS: The objective response rate for all patients was 76.5% (13 of 17 patients), and time to progression was about 10 months. Median survival time was about 20 months, and no difference was seen in the survival of patients without extrahepatic lesions and patients with extrahepatic lesions (21 months vs 18.5 months; p=0.5). The incidence of new extrahepatic metastasis in patients without extrahepatic lesions was 9% (1 of 11 patients). Grade 3 or 4 neutropenia was found in only 2 patients (11.8%). CONCLUSION: Combination therapy with HAI 5-FU plus systemic CPT-11 may be safely administered to patients with colorectal cancer. The incidence of new extrahepatic metastases was low in comparison with reports of HAI monotherapy.     

Hepatocellular carcinoma treated by continuous hepatic arterial infusion of etoposide, CDDP and 5-FU

Fifteen patients with advanced hepatocellular carcinoma were treated by hepatic arterial infusion (HAI). Treatment consisted of a 24-hour continuous HAI of etoposide (60 mg/day, day 1-5), CDDP (30 mg/day, day 1-5) and 5-fluorouracil (250 mg/day, day 1-26). Three patients had two series of infusions. Five patients were treated by transcatheter arterial embolization following HAI. Among 13 evaluable patients, one showed a complete remission and five patients had a partial response. We obtained a response rate of 46.2%. Toxicity included hematologic toxicity, alopecia, nausea and vomiting. The major toxicity was myelosuppression, but it was well tolerated. These results indicate that continuous HAI of etoposide, CDDP and 5-FU is effective for advanced hepatocellular carcinoma.     

Complications of hepatic artery infusion

Purpose: The resurgence of hepatic artery infusion (HAI) for the treatment of colorectal liver metastases has been dampened by concern over its complications. We have reviewed the incidence and frequency of complications associated with HAI and discussed the factors associated with these complications. Methods: A PUBMED search was conducted from 1950–2001 using various combinations of these keywords: hepatic arterial infusion, colorectal carcinoma, complications, and trials. The main inclusion criterion was the reporting of HAI complications. The main exclusion criterion was duplicated patients. Extracted data included chemotherapeutic agents, catheter technique, drug toxicities, and catheter related complications. Relative risks and 95% confidence intervals were calculated. Results: We reviewed 437 articles/abstracts and included 101 studies. 4580 patients with 4582 toxicities and complications were reported. The mortality rate was 1%. The most common toxicities were: GI symptoms 22%, chemical hepatitis 19%, and bone marrow toxicity 8%. 5-fluorouracil (5-FU) HAI had statistically significant risk for GI symptoms and bone marrow toxicity. Floxuridine (FUDR) HAI had statistically significant risk for chemical hepatitis, sclerosing cholangitis, and biliary toxicity. The most common catheter complications were: hepatic artery occlusion 6%, catheter thrombosis 5%, and catheter displacement 7%. Conclusions: This literature review of the complications of HAI confirms a low mortality associated with HAI. Sclerosing cholangitis and chemical hepatitis are associated with the use of FUDR, while the use of 5-FU is associated with bone marrow toxicity. Our observations support the development of hepatic cytoprotective agents and other effective anti-tumor agents to improve the results and morbidity of HAI for colorectal liver metastases.     

Hepatic arterial infusion and systemic chemotherapy after multiple metastasectomy in patients with colorectal carcinoma metastatic to the liver: a North Central Cancer Treatment Group (NCCTG) phase II study, 92-46-52

BackgroundPatients with multiple liver metastases from colorectal cancer are at high risk of recurrence after resection. Hepatic artery infusion (HAI) alternating with systemic therapy after surgical resection may improve survival after surgery.MethodsPatients with liver-only metastases from colorectal cancer amenable to resection/cryoablation were eligible. Previous adjuvant chemotherapy for a completely resected primary tumor was allowed. Alternating courses of HAI and systemic therapy included floxuridine (FUDR) by HAI. Systemic chemotherapy consisted of bolus leucovorin (LV) plus 5-fluorouracil (5-FU).ResultsForty-nine patients had complete resection of their liver metastases, with 44% having more than 4 hepatic metastases and 78% having bilobar disease. Thirty-six patients had HAI FUDR alternating with systemic therapy. Patients received a median of 3.5 cycles (range, 1-4) and 3 cycles (range, 0-6) of therapy with HAI FUDR and systemic therapy, respectively. At the time of final analysis the estimated median disease-free survival and hepatic disease-free survival was 1.2 years (95% confidence interval [CI], 0.9-2.1) and 1.8 years (95% CI, 1.8-not available), respectively. Eleven patients (31%) were alive at this writing. All surviving patients had a minimum of 5.5 years of follow-up.ConclusionThis trial of adjuvant chemotherapy in patients who underwent complete resection with unfavorable characteristics demonstrates apparent improvement in outcome compared with historical series treated with surgery alone. However the results of this trial and other randomized trials of HAI do not appear to support its use at this time because of the development of more effective systemic options.     

Hepatic arterial infusion plus systemic irinotecan in patients with unresectable hepatic metastases from colorectal cancer previously treated with systemic oxaliplatin: a retrospective analysis.

BACKGROUND: Response rates to systemic chemotherapy are low after tumor progression on oxaliplatin regimens. Hepatic arterial infusion (HAI) therapy in patients with tumor progression is a viable alternative. PATIENTS AND METHODS: Thirty-nine heavily pre-treated patients (all receiving prior oxaliplatin) with unresectable colorectal hepatic metastases were treated with systemic CPT-11 and concurrent HAI floxuridine (FUDR) and dexamethasone (DEX). RESULTS: Partial responses were seen in 44% of patients. Median time to hepatic progression was 8.6 months, and median time to overall progression was 6.5 months. Median survival from time of initiation of HAI was 20.1 months [95% confidence interval (CI) 16.9-21.4] and from the initiation of treatment of metastatic disease, 32.01 months (95% CI 29.1-34.6). After a median follow-up of 19.1 months, seven patients (18%) proceeded to potentially curative surgery. Grade 3/4 toxic effects included neutropenia (13%), diarrhea (15%), intra-abdominal hemorrhage (2%), and bleeding duodenal ulcer (2%). Elevated liver function tests were seen, including bilirubin concentration >3 mg/dl (7%), alkaline phosphatase 2X baseline (20%), and aspartate aminotransferase >3X baseline (26%). CONCLUSIONS: HAI FUDR/DEX plus systemic CPT-11 achieves a response rate of 44% and a median overall survival of 20 months in heavily pre-treated patients with colorectal hepatic metastases all receiving previous oxaliplatin; 18% of patients proceeded to surgical resection or ablation.     

Hepatic arterial infusion of low-dose leucovorin/5-FU chemotherapy for unresectable hepatic metastases from colorectal cancer

Hepatic arterial infusion (HAI) chemotherapy for unresectable liver metastases from colorectal cancer (CRC) is generally indicated to patients without extrahepatic lesions. This study was performed to examine whether or not it was possible to obtain a comparable survival time, response rate (RR) and modest toxicity combining low-dose LV and 5-FU (LV/5-FU) with HAI for the patients with unresectable liver metastases from CRC. Twenty two patients with unresectable multiple liver metastases were enrolled in the study. These were patients who had been admitted from 1994 to 2003 in our hospital. Patients were given LV at 25 mg/body immediately followed by 5-FU at 500 mg/body as a 2-hour HAI daily for 5 consecutive days every 5 weeks. The median survival time (MST) of HAI patients was 24.5 months. According to the treatment in the HAI patients, one patient was CR, 6 were PR, 9 were NC, 6 were PD, and the response rate (RR) was 31.8% (7 of 22 patients). The toxicities to this regimen on HAI were observed in 12 patients, and grades 3 or 4 were in 3 patients only. These results suggested that HAI with LV/5-FU can be useful for unresectable liver metastases from CRC.     

Good tolerance to high-dose hepatic arterial infusion therapy

A pilot study was designed to evaluate the efficacy of high-dose FUDR administered through the hepatic artery for the treatment of cancer involving the liver. Three dose schedules were used beginning with a dose of 0.5 mg FUDR/kg/day for 2 weeks followed by normal saline infusion for 2 weeks (schedule A). Elevation of serum bilirubin was the sole indication to deescalate to schedule B (0.3 mg FUDR/kg/day for two weeks followed by saline infusion for 4 weeks). Tolerance to this schedule escalated the patient to schedule C (0.5 mg FUDR/kg/day for 2 weeks followed by normal saline infusion for 4 weeks). Eighteen patients were treated, sixteen with metastatic colon cancer, one with metastatic leiomyosarcoma, and one with hepatoma. The patient with hepatoma developed progressive disease after one cycle of therapy. Of the 17 patients with metastatic cancer only 5 patients failed therapy yielding a 70% response rate. High-dose FUDR was well tolerated with only six patients requiring deescalation to schedule B. Elevation of alkaline phosphatase and glutamic oxaloacetic transaminase was universal. Two patients developed peptic ulceration. Sclerosing cholangitis was not observed. We conclude that high-dose FUDR administered through the hepatic artery is as safe as conventional dose infusion therapy but probably not more effective. The safety of high-dose FUDR infusion therapy suggests that sclerosing cholangitis is association with hepatic arterial infusion therapy is not related to the FUDR dose.