Weekly hepatic arterial infusion of high dose 5-fluorouracil for liver metastasis from colorectal cancer

A weekly infusion of high dose 5-fluorouracil by way of the hepatic artery has been performed in 23 cases with synchronous metastasis from colorectal cancer since 1993. The prognosis in these cases was compared with 94 cases treated without infusion chemotherapy in 94 cases before 1992. The overall one-year and three-year survival rate was 64.8% and 30.2%, respectively, in cases with infusion chemotherapy. The one-year and three-year survival rate was 42.8% and 18.6%, respectively, in cases without infusion chemotherapy. Overall survival rate was significantly different between cases with and without infusion chemotherapy (p < 0.05). In conclusion, weekly infusion chemotherapy resulted in a better survival rate than without infusion chemotherapy.     

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.     

Prehepatectomy chemotherapy using hepatic artery infusion plus systemic chemotherapy for liver metastases from colorectal cancer

The purpose of this study was to determine the efficacy of hepatic artery infusion (HAI) plus systemic chemotherapy (SYS) as the prehepatectomy chemotherapy for liver metastases from colorectal cancer. Clinicopathologic data were available for 117 patients who were treated with chemotherapy before liver surgery. Response rate of chemotherapy and frequency of liver resection after chemotherapy of patients treated with HAI/SYS (n=26; 65% and 96%, respectively) were higher than those treated with HAI alone (n=63; 41% and 70%) or SYS alone (n=28; 25% and 42%). Histological examination of adjacent nonneoplastic liver confirmed that severe sinusoidal dilatation was less frequent in HAI/SYS group than in SYS group, and moderate to severe steatosis was also less frequent in HAI/SYS group as compared to HAI group. The combination of regional HAI and systemic chemotherapy is an effective prehepatectomy regimen for the treatment of patients with aggressive liver metastases from colorectal cancer.     

Hepatic arterial infusion chemotherapy for liver metastases from colorectal cancer

After randomized studies of hepatic arterial infusion chemotherapy (HAIC) versus systemic chemotherapy for liver metastases from colorectal cancer in the 1980s, the role of HAIC has been unclear and there is still no evidence to support it as the treatment of choice. The high local control, the differences in techniques between Japan and Western countries, the difficulty of detecting pre-treatment extra-hepatic metastases and the fact that HAIC does not control extra-hepatic lesions are the most important points in considering clinical trials of HAIC. Clinical studies on the combination of HAIC using 5-FU and systemic chemotherapy using CPT-11, and then randomized trial of systemic chemotherapy with/without HAIC is required in Japan to reveal the role of HAIC in the management of liver metastases from colorectal cancer. We should understand the importance of our role in this field.     

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.     

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.     

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.     

Indication for hepatic resection after hepatic arterial infusion chemotherapy for multiple liver metastases of colorectal cancer

The indications for hepatic resection after hepatic arterial infusion chemotherapy (HAI) for unresectable metastatic liver tumor of colorectal cancer were analyzed from the surgical outcome of hepatic resections in 23 cases of hepatic resection after HAI. The mean duration of HAI until hepatic resection was 7.4 months (5-14 months). The total dose of 5-FU was 25.7 +/- 8.0 g for a CR + PR group and 14.0 +/- 3.5 g for a NC + PD group. There was a significant difference between two groups (p < 0.01). The group in which serum CEA level normalized after HAI (the normal CEA group) included 7 patients, and the group in which serum CEA level did not normalize (the high CEA level group) had 9 patients. The total dose of 5-FU was 30.0 +/- 7.6 g in the normal CEA level group and 19.1 +/- 6.9 g in the high CEA level group. There was a significant difference between the two groups. The 3-year survival rate was 40.0% in the group with the duration of HAI for longer than 8 months (n = 10) and 0% in the group with the duration of HAI for shorter than 8 months (n = 7). The 3-year survival rate was 66.7% in the normal CEA level group (n = 3) and 0% in the high CEA level group (n = 8). The surgical outcome was better in the HAI for longer than 8 month and normal CEA groups.     

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.     

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.     

Modern insights into hepatic arterial infusion for liver metastases from colorectal cancer

Hepatic arterial infusion (HAI) selectively achieves high drug exposure of liver metastases from colorectal cancer. Such pharmacologic advantage has doubled the response rate of liver metastases on fluoropyrimidines (FP) delivered as HAI rather than intravenously, in a meta-analysis of randomised clinical trials (RCT). However, the improvement in antitumour efficacy did not consistently translate into any significant survival advantage across all randomised studies. However, the results of this meta-analysis should be cautiously interpreted due to the heterogeneity of the studies, inadequate study designs, obsolete therapy and high rate of early treatment discontinuation due to HAI technical failures or hepato-biliary toxicity. Most studies actually were performed before year 2000 and did not integrate the considerable progresses accomplished in the management of CRC, such as multidrug regimens instead of single agent FP and secondary resection of metastases, a major contributing factor for prolonged survival. Furthermore, the systemic exposure of patients given HAI was low without concomitant IV therapy, facilitating extra-hepatic relapses. The role of HAI in liver metastases from CRC should, therefore, be revisited, using modern multidisciplinary therapeutic approaches and appropriate study designs. Recommendations for the design of future RCTs exploring HAI are provided.     

Alternating hepatic arterial infusion and systemic chemotherapy for liver metastases from colorectal cancer: a phase II trial using intermittent percutaneous hepatic arterial access.

PURPOSE: To evaluate the objective response to a short course of hepatic arterial infusion (HAI) using temporary, percutaneously placed catheters alternating with systemic prolonged continuous infusion fluorouracil (ci 5-FU) and daily oral leucovorin (L). PATIENTS AND METHODS: Eligible patients were previously untreated (except for adjuvant therapy) adults with liver-predominant metastases, with Eastern Cooperative Oncology Group performance status of 0 to 2. Treatment regimen included HAI with fluorodeoxyuridine (FUDR) 60 mg/m2/d and L 15 mg/m2/d continuously infused daily for 4 days. After a 1-week rest, ci 5-FU was administered through a central venous access device using a dose of 180 mg/m2/d with a fixed dose of oral L at 5 mg/m2/d for 21 out of 28 days. Cycles were repeated every 6 weeks. After four cycles of therapy, patients were maintained on ci 5-FU and daily oral L until evidence of progression. RESULTS: Forty-three patients were enrolled onto this trial. One patient was ineligible. The objective response rate for all patients (17 partial, zero complete) was 41% (95% confidence interval [CI], 26% to 56%). Five patients were not able to receive at least one complete cycle of HAI. Among patients who received at least one complete cycle of HAI, the response rate was 46% (95% CI, 30% to 62%). Five patients underwent a liver resection after enrolling onto the protocol. At the time of analysis, estimated median time to progression was 6 months, and estimated median overall survival was 13 months. CONCLUSION: The objective response rate was comparable to that achieved with more prolonged and more frequent HAI using FUDR. This approach should be studied as an acceptable alternative to surgically placed hepatic arterial catheters/pumps and may have a role as neoadjuvant therapy for liver metastases that are unresectable, as well as an adjuvant role for patients with resected hepatic metastatic colorectal cancer.     

Hepatic arterial infusion of 5-fluorouracil for patients with liver metastases from colorectal cancer refractory to standard systemic chemotherapy: a multicenter, retrospective analysis

IntroductionThis retrospective study evaluated the safety and efficacy of hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil (5-FU) for patients with liver metastases from colorectal cancer refractory to standard systemic chemotherapy.Patients and MethodsFifty-five patients who had shown disease progression during the prior standard systemic chemotherapy with oxaliplatin, irinotecan, and 5-FU were enrolled. The treatment was weekly HAIC with 5-FU 1000 mg/m²/5 hours through an indwelling catheter-port system.ResultsNo major adverse reaction was observed other than grade 3 leukocytopenia (3.6%) and hyperbilirubinemia (1.8%). The overall response rate and disease control rate were 18.2% and 70.9%, respectively. The median progression-free survival and median overall survival (OS) were 2.8 months, and 6.7 months, respectively. The initial sites of disease progression were liver in 14, other than liver in 27, and both in 6. Multivariate analysis identified Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1 and number of extrahepatic metastatic sites (NMS) ≤1 as favorable prognostic factors for OS (hazard ratio [HR], 8.277; 95% CI, 3.60-19.0; P = .000 for ECOG PS; and HR, 2.456; 95% CI, 1.30-4.61; P = .005 for NMS).ConclusionHAIC with 5-FU may be a safe and effective treatment for patients with colorectal liver metastases refractory to standard systemic chemotherapy.     

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.     

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.     

The efficacy and limitation of hepatic arterial infusion chemotherapy for colorectal liver metastases

We investigated the efficacy and limitation of hepatic arterial infusion (HAI) chemotherapy for colorectal liver metastases. In terms of prophylactic HAI following curative resection of liver, the 5-year disease-free survival of HAI group (12 g of 5-FU administered in 6 weeks) was 66.7%, whereas that of randomly selected control group was 20.0%. The difference was statistically significant (p = 0.045). Recurrent disease was confirmed in three cases of HAI group (one in liver) and in 8 patients of the control group (6 in liver). However, the overall survival was not significantly different between the groups. Thus, the short-term HAI of 5-FU is effective in decreasing the recurrence of disease. As for the treatment of unresectable liver metastases, some patients received HAI of 5-FU (1,000-1,500 mg/w) showed prolonged survival with partial remission of the disease. However, the 1-, 2-, and 3-year cumulative survival of HAI group (n = 27) was 69.3, 34.1 and 11.4%, respectively, against 61.3, 22.6 and 9.4%, respectively, in the transarterial embolization (TAE) group (n = 31). Therefore it is important to estimate the effect in the early phase of HAI, and aggressively continue the treatment in selected patients for whom it is suitable.     

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.     

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.     

Effects and complications of continuous hepatic arterial infusion chemotherapy using implantable reservoir for liver metastases from colorectal cancer

Continuous arterial infusion chemotherapy using implantable reservoir was performed for unresectable liver metastases from colorectal cancer and the therapeutic effects, side effects and complications were evaluated. Eleven patients were treated with four kinds of arterial infusion courses that mainly consisted of 5-FU. The arterial infusion courses were discontinued in 2 patients because of nausea and vomiting, and in one patient because of diarrhea. The catheters were dislocated in 2 patients and another 2 developed fistulous between the hepatic artery and bile duct. Three patients developed duodenal ulcer. Serum CEA was reduced in 4 patients (36%). After all, response rate was 9% (1/11). The one-year survival rates of all cases and cases treated with more than 4 courses were 36.3% and 80.0%, respectively.     

A case of resection of synchronous multiple liver metastases from colorectal cancer after hepatic infusion chemotherapy and systemic chemotherapy

A 70-year-old man was admitted for tranverse colon cancer with multiple liver metastases. Hepatic arterial infusion chemotherapy and systemic chemotherapy (FOLFOX 4) were conducted postoperatively. Thirteen months after the first surgery, liver metastases became resectable and hepatectomy was performed. Though multiple liver metastases were unresectable at the time of the first examination, hepatectomy was possible followed by hepatic arterial infusion chemotherapy and systemic chemotherapy.