Results of hepatic arterial infusion chemotherapy with 5-FU and leucovorin for unresectable liver metastases from colorectal cancer

PURPOSE: Hepaticarterial infusional(HAI)5-FU chemotherapy, which involves the use of interventional radiology technique, has matured technically in Japan in the 1990's. The antitumor effect of 5-FU is enhanced by combination with leucovorin. This study was performed to evaluate the efficacy and toxicity of HAI 5-FU and leucovorin chemotherapy for patients with unresectable liver metastases from colorectal cancer. METHODS: Treatment was given to 20 patients with unresectable liver metastases from colorectal cancer. The chemotherapy regimen consisted of weekly HAI of 5-FU(1,000 mg/body)and leucovorin(250 mg/body)over five hours. The survival and response rates to the therapy were assessed according to RECIST. Hematologic and non-hematologic toxicity was assessed according to CTCAE v3.0. RESULTS: Combined HAI 5-FU and leucovorin therapy was carried out an average of 27 times. The response rate for liver tumors was 75%, and the median survival time was 22 months. The applied regimen caused only mild adverse events. There was no evidence of myelosuppression except for platelet decrease(grade 3)in a patient with chronic renal failure. CONCLUSION: This HAI approach using 5-FU and leucovorin was effective and the therapy for unresectable liver metastases from colorectal cancer was tolerated well. Therefore the HAI approach should be reconsidered as an effective therapy against this disease in Japan.     

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.     

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.     

Hepatic arterial infusion (HAI) chemotherapy for liver metastases of colorectal cancer using 5-FU

Thirty-three patients with liver metastases of colorectal cancer were treated by intra-arterial 5-FU chemotherapy. The median survival time of all patients was 14 months. A partial remission could be observed in nine patients, and a further 15 patients had stable disease. Patients were treated on an outpatient basis and the toxicity of treatment was mild. We observed no case of sclerosing cholangitis or chemical hepatitis. Intra-arterial 5-FU chemotherapy provided treatment results similar to those reported for FUdR but with less hepatobiliary toxicity.     

Validity of two-hour continuous hepatic arterial infusion chemotherapy with low-dose 5-FU for unresectable liver metastasis from colorectal cancer

The significance of hepatic arterial infusion chemotherapy for unresectable liver metastases from colorectal cancer was evaluated in 50 patients, who received either of the following regimens: 1 shot 5-FU + epirubicin + MMC (FAM group); hepatic arterial infusion of 5-FU for 2 hours + MMC (MF group); hepatic arterial infusion of 5-FU for 2 hours (5-FU group). There were no differences in the clinicopathological backgrounds of the patients among the groups. The mean survival time was 10.3 months, 16.0 months and 16.2 months in the FAM, MF and 5-FU groups. The effective percentages were 0%, 40% and 31% in the FAM, MF and 5-FU groups and the survival time of the effective cases was 18.1 months and 21.8 months in the MF and 5-FU groups. The MF group and 5-FU group showed significant improvement in prognosis. Concerning side effects, myelo-suppression and gastrointestinal toxicity appeared frequently in the MF group. In conclusion, 2-hour continuous hepatic arterial infusion with low-dose 5-FU for unresectable liver metastases from colorectal cancer may be helpful for improvement of prognosis.     

Evaluation of hepatic arterial infusion chemotherapy with levofolinate (l-LV) and 5-fluorouracil (5-FU) for multiple liver metastases from colorectal cancer

We evaluated the effect of hepatic arterial infusion chemotherapy with levofolinate (l-LV) and 5-fluorouracil (5-FU) for multiple liver metastases from colorectal cancer. All patients received drugs on an outpatient basis every six weeks, followed by no medication for two weeks. In this regimen levofolinate (200 mg/m2) was administered for two hours and 5-fluorouracil (500 mg/m2) was administered for thirty minutes as a bolus. A complete response was obtained in five patients and a partial response in five patients; the overall response rate was 40%. All patients could receive this therapy on an outpatient basis because no patient had side effects of Grade 3 or over. It is suggested that our protocol may be useful for improvement of outcome.     

Efficacy of 5-FU hepatic arterial infusion with l-leucovorin for patients with unresectable colorectal liver metastasis

We investigated the efficacy of 5-FU hepatic artery infusion (HAI)for patients with unresectable colorectal liver metastasis. Fifteen patients who received HAI between June 2004 and December 2006 were studied. HAI was attempted as first-line chemotherapy in seven patients(Group A)and as second-line or more in eight(Group B). The response rate, time to progression, survival and toxicity were compared with those of 39 patients treated with systemic chemotherapy(18 as first-line: Group C, 21 as second-line or more: Group D). Response rate was 85.7%, 35.7%, 50.0%, and 4.8% in Groups A, B, C, and D, respectively. Time to progression was 12.5 months, 4.7 months, 5.8 months, and 2.3 months, in Groups A, B, C, and D, respectively, and significantly longer in Group A compared with Group C, as well as in Group B compared with Group D. Median survival was 15.4 months, 9.1 months, 11.3 months, and 8.0 months in Groups A, B, C, and D, respectively, and significantly longer in Group B compared with Group D. Grade 3 or 4 non-hematological toxicity was not observed in Group A and B. HAI was effective for the control of unresectable colorectal liver metastasis and improved survival as second-line chemotherapy or more.     

A clinical study of hepatic arterial infusion chemotherapy with 5-FU and leucovorin for liver metastases

We followed patients who underwent hepatic arterial infusion chemotherapy (HAI) with 5-FU and Leucovorin for liver metastases. Since CR (complete response) and PR (partial response) were achieved, this therapy seems to be effective. 5-FU metabolized on its first pass through the liver, and the hepatic extraction with rapid HAI is lower than that with slow HAI. It is suggested that control of extrahepatic lesions thought rapid HAI is useful for life prolongation.     

Continuous hepatic arterial infusion of 5-fluorouracil with leucovorin for unresectable liver metastases from colorectal cancer

Twenty-three patients with liver metastases from colorectal cancer were treated by continuous hepatic arterial infusion chemotherapy with 5-FU and Leucovorin. The regimen was that 500 mg/body of 5-FU with 30 mg/body of Leucovorin was administered continuously for 5 days, followed by no medication for 16 days. The effect of this therapy was evaluated and the relationship between this therapy and the overexpression of vascular endothelial growth factor (VEGF) or microvessel density (MVD) was also studied. Complete response was obtained in 4 patients and partial response in 3 patients; the response rate was 32%. The response rate was 60% in patients who underwent more than 7 courses. The response rate was 44% in patients with positive VEGF and 33% in patients with negative VEGF. The response rate was 50% in patients with an MVD of more than 30 and 33% in patients with an MVD of less than 30. The 3-year survival rate for patients who underwent more than 7 courses was 37.5%. This therapy had to be abandoned in 6 patients due to occlusion of the catheter. Skillful maintenance of the catheter is necessary for a high response rate and satisfactory prognosis using this therapy.     

Second-look hepatectomy after 5FU arterial infusion in patients with primary unresectable hepatic colorectal metastases

We treated primary unresectable hepatic colorectal metastases by hepatic arterial chemotherapy (HAC) combined with resection of the tumor. Patients underwent a resection of the primary colorectal tumor and a placement of HAC system, and received a 5-fluorouracil (5FU) administration once a week (320 mg/m(2)/day). Five patients underwent a 'second-look' hepatectomy in this series. Their shrinkage rate of the primary lesion ranged from 80-99%, as seen by computed tomography. The resected liver tumors were characterized as p53-positive and proliferating cell nuclear antigen-positive. The levels of fluorodeoxyuridylate (FdUMP) and thymidylate synthetase inhibition were low in the tumor tissue. These results might reflect a kind of resistance to 5FU therapy. Hepatectomy is one of the possible options to eradicate the residual SFU-resistant component of the malignancy. Our preliminary experience possibly indicates longer survival from combination approach than from HAC alone.     

Concentration of 5-FU after hepatic artery infusion chemotherapy for liver metastases of colorectal cancer

AIM: Hepatic artery infusion chemotherapy (HAI) using 5-FU is a good method of treating patients with liver metastases from colorectal cancer. We investigated the toxicity and the response in relation to the concentration of 5-FU after HAI, and examined various factors that would have an effect on the 5-FU concentration. RESULTS: The mean 5-FU concentration was 480 ng/ml. The most frequent complication of HAI was anorexia. Three of 14 patients suffered from grade 2 or 1 anorexia. The 5-FU concentration of these patients was higher (1,010, 721, 642 ng/ml) than that of the others. The response rate of HAI was 36%. The 5-FU concentration of responders tended to be lower than that of non-responders. None of the following was related to the 5-FU concentration: whether or not the gallbladder was resected, whether or not co-lateral blood flow was recognized, or the volume of the patients' liver. CONCLUSION: 5-FU concentration after HAI has some effect on anti-tumor response and gastrointestinal toxicity.     

Evaluation of hepatic arterial infusion chemotherapy with low-dose leucovorin and 5-FU from reservoir for multiple liver metastases by colorectal cancer

5 patients with colorectal cancer with multiple liver metastases underwent resection of primary lesions. We then evaluated the effects of hepatic arterial infusion chemotherapy with low-dose leucovorin and 5-FU. Weekly, dl-leucovorin of 30 mg/body or l-leucovorin of 25 mg/body was administered as a bolus, then 5-FU of 500 mg/body was administered for 1 hour through the hepatic artery from the subcutaneous reservoir on an outpatient basis. 2 of 5 patients achieved a CR of liver metastases, but later 1 of these 2 cases had metastases of bone and lung. No adverse effects, such as nausea, vomiting, diarrhea or bone marrow suppression, were seen after this treatment in any of the patients.     

A clinical study of hepatic arterial infusion chemotherapy with low-dose CDDP and 5-FU for liver metastases

We followed patients who underwent hepatic arterial infusion chemotherapy with low-dose CDDP+5-FU for liver metastases from colorectal cancer in the outpatient setting. A catheter was inserted from the femoral artery into the proper hepatic artery using the interventional technique. Two complete response (CR) and seven partial response (PR) were achieved, but later 2 of these patients had lung metastases. We conclude that this therapy may be effective, but control of extrahepatic lesions is necessary for life prolongation.     

Evaluation of hepatic resection following hepatic arterial infusion chemotherapy for colorectal liver metastases

We evaluated the significance of hepatectomy following hepatic arterial infusion (HAI) chemotherapy for colorectal liver metastases. The prognosis of 4 cases with initially resectable tumors was discouraging, indicating no benefit of preoperative HAI for resectable tumors. The 2- and 3-year survival of patients who underwent hepatectomy after downstaging by HAI of originally unresectable metastases were 100% and 67%, respectively, suggesting that hepatectomy combined with HAI is a promising modality for those patients. However, it seems that the control of extrahepatic disease and decision making for the timing for surgical therapy are issues requiring improvement.     

Five-hour hepatic arterial infusion of high-dose 5-FU on weekly schedule for liver metastases from colorectal cancer

The study of 5-hour hepatic arterial infusion of high-dose 5-FU on a weekly schedule (weekly high-dose 5-FU HAI: WHF) was conducted to reveal a new pump-free regimen to avoid the reduction of QOL due to continuous infusion pumps. By the phase I study, the recommended dose was determined to be 1.000 mg/m2/5 hrs qw. Thus far, 20 cases entered the phase II study of this regimen, and 1 CR and 10 PRs were observed in 15 evaluated cases without major toxicity. This regimen is highly effective for liver metastases from colorectal cancer without reduction of QOL in patients by pumps. A study of this regimen involving a large number of cases is required.     

Hepatic arterial infusion of chemotherapy for hepatic metastases from colorectal cancer.

BACKGROUND: Sixty percent of colon cancer patients develop liver metastasis. Only 25% of those have potentially resectable hepatic metastases, and approximately 58% of those patients relapse. METHODS: We review the indications and the technical aspects of hepatic artery infusion (HAI) of chemotherapy, as well as the efficacy, morbidity, and outcomes. RESULTS: HAI of chemotherapy has been used following hepatic metastasectomy, in patients with unresectable metastases, or in combination with other agents. Floxuridine, the chemotherapeutic agent most studied, is administered through an implantable subcutaneous infusion pump connected to a surgically placed hepatic artery catheter, which delivers the chemotherapeutic agents at a slow fixed rate. Treatment-related toxicities include chemical hepatitis, biliary sclerosis, and peptic ulceration. Some trials report a survival benefit for HAI over systemic chemotherapy with acceptable toxicity. CONCLUSIONS: Regional perfusion chemotherapy can be logistically and technically complicated to deliver. The development of newer systemic agents with superior efficacy in the treatment of metastatic colorectal cancer will likely diminish the role of regional perfusion therapy in the future.     

Efficacy comparison between hepatic arterial infusion chemotherapy plus systemic chemotherapy used as first-line and non-first-line treatments for the patients of colorectal cancers with unresectable hepatic metastases

Objective:The combination of hepatic arterial chemotherapy (HAIC) and systemic chemotherapy (SYC) has potential ef ect on colorectal cancer (CRC) patients with unresectable hepatic metastasis. The aim of this retrospective study was to investigate the ef icacy and safety of this combined therapeutic regimen on Chinese patients based on single institute experiences. Methods:Al 54 patients of this retrospective analysis were diagnosed with CRC with unresectable liver metas-tasis and received combined HAIC and SYC. Among the patients, 23 of them received HAIC plus SYC when they developed liver metastases as first-line treatment (Group 1), and 31 patients received HAIC plus SYC as non-first-line treatment (Group 2). The dif erent ef icacy in two groups was analyzed by SPSS 19.0. Results:The overal response rate (ORR) were 52.2%and 25.8%respectively in Groups 1 and 2 (P=0.047), and the disease control rate (DCR) were 65.2%and 35.5%respec-tively in Groups 1 and 2 (P=0.031). The median progression-free survival (PFS) were 6.8 and 3.3 months (P=0.002), the median hepatic progression-free survival (H-PFS) were 8.8 and 3.7 months (P=0.001), and the median overal survival (OS) were 18.8 and 13.7 months (P=0.121) in Groups 1 and 2, respectively. No fatal reaction was observed and no significant dif erence of adverse reaction was found in two groups. Grade 3/4 toxic ef ects included neutropenia (9.7%in Group 2 only), gastrointestinal reaction (8.7%in Group 1 and 6.5%in Group 2), stomatitis (6.5%in Group 2 only) and hyperbilirubinemia (4.3%in Group 1 only). Conclusion:HAIC combined with SYC showed promising ef icacy and safe profiles on CRC patients with unresectable liver metastases.     

Phase I/II study of irinotecan, UFT and leucovorin with hepatic arterial infusion using 5-FU in colorectal cancer patients with unresectable liver metastases

Purpose

To evaluate the efficacy and tolerability of systemic chemotherapy with irinotecan (CPT-11), UFT and leucovorin (LV) combined with hepatic arterial infusion (HAI) consisting of 5-fluorouracil (5-FU) in colorectal cancer patients with unresectable liver metastases.

Methods

Patients were treated concurrently with escalating doses of intravenous CPT-11 (100, 120, and 140?mg/m²) on day 1 of each 14-day treatment cycle, with oral UFT (300?mg/m² per day) and LV (75?mg/body per day) on days 1?C7 of each cycle, and with HAI 5-FU (2,000?mg/week) on days 8?C14 of each cycle.

Results

Twelve patients were enrolled in the phase I study. The maximum-tolerated dose was not reached. Consequently, the recommended dose of CPT-11 for the phase II study was determined to be 140?mg/m². Twenty-two patients were evaluated in the phase II study. Five patients experienced grade 3 neutropenia, two experienced grade 3 anorexia, two experienced nausea, and two experienced vomiting. An overall response was observed in 19 out of 22 patients (86.4%). The median progression-free survival period was 11.2?months, and the 3-year survival rate was 50.6%. Fourteen patients (63.6%) were ultimately able to undergo a complete liver resection.

Conclusions

Chemotherapy with CPT-11 and UFT/LV combined with HAI yielded a high response rate and enabled a significant proportion of patients with initially unresectable liver metastases to undergo surgical resection. Further trials are warranted.     

Hepatic arterial infusion chemotherapy for colorectal liver metastases

Hepatic metastases are a frequent complication of colorectal cancer. Resection of liver metastases can result in long-term survival. However, the majority of patients have unresectable disease. Alternative methods in Japan for treating these patients are hepatic arterial infusion (HAI) chemotherapy with administration of 1,000 mg/m2 of 5-FU over 5 hours. We summarize the status of HAI chemotherapy in terms of colorectal hepatic metastases today. HAI chemotherapy produced higher response rates compared with systemic chemotherapy, but did not demonstrate elongation of survival time in many trials. Important problems remaining to be solved are the technical aspects of percutaneous implantation of intraarterial catheters connected to a subcutaneous infusion reservoir and studies of combined therapy with systemic chemotherapy. Furthermore, in order to finally determine the position of HAI for colorectal liver metastases, it is necessary to conduct a comparative study versus systemic chemotherapy, using the survival time as the primary end point.     

Hepatic arterial infusion chemotherapy with oxaliplatin in unresectable liver metastases from colorectal cancer after systemic chemotherapy failure

We report 5 cases of colorectal liver metastases (CRLM) with hepatic arterial infusion (HAI) oxaliplatin after systemic infusion chemotherapy failure. Patients with unresectable CRLM and history of systemic chemotherapy failure were treated with HAI oxaliplatin (L-OHP 100 mg/body, 2 hours) combined with intravenous (iv) levofolinate calcium (175 mg/body, 2 hours) and iv bolus 5-FU (500 mg/body) every 2 weeks. RESULT: An average age was 58 years. All patients had previously received FOLFOX. Lung metastases had already existence before HAI oxaliplatin in 4 patients. A median of 10 treatments were administered (range 5-14). Serum level of CEA was decreased in 4 cases. In 2 patients, lung metastasis developed while a PR was obtained in the liver metastasis. Progress disease (PD) was confirmed in other 3 patients. No major toxicity was presented. The median time to progression free survival was 3.0 months and the median overall survival was 7.1 months. CONCLUSION: HAI oxaliplatin might be beneficial as a salvage therapy for CRLM without extrahepatic metastasis, which demonstrated an acceptable tolerability and maintenance of QOL.