Intra-arterial chemotherapy using an implantable infusion pump and liver irradiation for the treatment of hepatic metastases

Liver metastases are a common cause of death in colon carcinoma. The dual blood supply of the liver permits regional perfusion while hepatic catabolism fo 5-fluorouracil (FU), floxuridine (FUdR) permit higher drug exposures than systemic (IV) administration. We have studied the effect of continuous intra-arterial chemotherapy (FU: 5-10 mg/kg/day and FUdR: 0.2 mg/kg/day) and whole liver irradiation (1000 rad every 4 weeks, total dose of 3000 rad) for metastatic colon carcinoma to liver. Eighteen patients with metastases to liver only are reported using this combination therapy. Seven patients had percutaneous placement of a catheter via the brachial artery, two had operative placement of a catheter via the gastroduodenal artery, all of which were connected to the Cormed infusor system, nine had operative placement of the Infusaid implantable pump with catheter placement into the hepatic artery via the gastroduodenal artery. The median survival for the entire group was 241 days. In those patients whose liver function tests (bilirubin and alkaline phosphatase) were less than two times normal, the median survival was 770 days. The median survival of the patients with greater than two times normal LFT's was 178 days. Two patients died of complications of the treatment. One who developed irreversible radiation hepatitis but at autopsy had only two areas of microscopic tumor foci in the liver and another who had received only 15 days of infusion and 1000 rad to liver. This patient developed irreversible chemical enteritis secondary to chemotherapy infusion into the superior mesenteric artery. Three patients have undergone abdominal reexploration and one at autopsy, who were found to have no gross evidence of tumor in the liver despite previous pathologic confirmation. It appears that some patients with minimal tumor burdens can have sterilization of their tumors. There were three cases of reversible liver function abnormalities. Complications associated with conventional intra-arterial chemotherapy (artery thrombosis, catheter sepsis and dislodgement, pump infusion variation and pump failure) were not seen with the Infusaid delivery system. The pump is refilled every 2-3 weeks via percutaneous puncture. All therapy was given on an outpatient basis. Pump acceptance and tolerance was 100%. Intra-arterial chemotherapy can now be accomplished without the morbidity associated with it in the past. The combination of chemotherapy and liver irradiation may offer improved survival in selected 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.     

Intra-arterial infusion chemotherapy for unresectable hepatocellular carcinoma using an implantable reservoir]

Arterial infusion therapy using implantable reservoirs was used in 44 patients with hepatocellular carcinoma which was unresectable for severe liver dysfunction or advanced tumor. The prognosis for patients with whom the double lumen reservoir developed by our department which can occlude the hepatic artery, was compared with that of patients for whom the conventional reservoir was employed. We also evaluated the reduction surgery previous to infusion therapy for tumor-advanced unresectable HCC. The six-month survival rates (Kaplan-Meier method) of the double lumen reservoir cases were significantly higher than for conventional reservoir cases. The survival rates of the cases of reduction surgery and infusion therapy (within only one year) were higher than for infusion therapy cases. Not only the use of the double lumen reservoir but the reduction surgery for unresectable HCC increases the effectiveness of infusion therapy and improves the prognosis.     

Significance of radionuclide examination in hepatic arterial infusion chemotherapy using implantable reservoir

Technetium 99m macroaggregated albumin (Tc-MAA) perfusion scintigraphy has been performed during hepatic arterial infusion chemotherapy using implantable reservoir. A total of 40 radionuclide (RI) studies were performed on 25 patients with liver metastasis of colorectal origin. Of 40 RI studies, 12 (30%) showed impaired liver perfusion. Three studies showed no perfusion of the liver, 3 increased radiotracer accumulations at liver hilus, 2 extrahepatic distributions, 2 catheter occlusions, 1 extravasation and 1 unilobar distribution. The accumulation of Tc-MAA in the tumor was graded from Grade I (tumor uptake decreased or similar relative to liver) to Grade III (tumor uptake remarkably increased). The response to chemotherapy was evaluable in 14 cases. A case with Grade I resulted in NC. Of 6 cases with Grade II, 1 resulted in MR, 3 in NC and 1 in PD. Of 8 cases with Grade III, 2 resulted in PR, 1 in MR and 5 in NC. Tumor response was observed in cases showing increased uptake of Tc-MAA. SPECT was performed in 7 cases, and revealed that hepatic tumors were hypervascular. We concluded that RI examination reveals not only hepatic perfusion, but also tumor microcirculation.     

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 artery infusion of chemotherapy as a treatment for hepatic metastases from colorectal cancer

Hepatic artery infusion (HAI) of chemotherapy as a treatment for hepatic metastases from colorectal cancer has become more commonly used after the introduction of the totally implantable hepatic artery pump in the early 1970s. Floxuridine (FUDR) is the generally used chemotherapy agent in the pump because of its high solubility and high extraction rates by the liver on the first pass of the chemotherapy through the hepatic circulation. HAI has been used mainly to treat unresectable liver metastases in patients who have liver metastases only. The other scenario for pump use has been as an adjuvant therapy after resection of all metastatic disease inthe liver. The rationale for HAI includes the unique dual blood supply of the liver allowing chemotherapy given into the artery and sparing the normal cells, which get their predominant blood supply from the portal vein. The details of pump design will be reviewed. Complications from HAI are specific for this therapy and will be reviewed. Treatment of unresectable liver metastases with HAI has been the subject of a number of prospective randomized studies. These will be presented, along with newer phase II studies. Three randomized studies on the usefulness of HAI after hepatic resection will be presented.     

Intra-arterial infusion chemotherapy for locally advanced breast cancer using implantable reservoir connected with catheter inserted in recurrent radial artery

Intra-arterial infusion chemotherapy through a catheter incubated at the recurrent radial artery and connected to an implantable reservoir was performed in eight patients with supraclavicular lymph node metastasis including four locally advanced recurrent breast cancers and two inflammatory breast cancer. Clinical response in breast cancer patients was 1 CR, 3 PR, 1 NC, and 1 PD. There was no complication related with catheter insertion. Therefore from the aspect of quality of life, this system was considered useful for treatment of advanced breast cancer, especially locally advanced recurrent breast cancer.     

Intra-arterial infusion chemotherapy for advanced bladder cancer and prostate cancer using reservoir system

Eight patients with bladder cancer and two patients with prostate cancer were given intra-arterial infusion chemotherapy using the reservoir system. The tip of the catheter was inserted through the femoral artery to the common iliac artery and we compressed both femoral arteries during infusion. Five patients with locally advanced bladder cancer and two patients with prostate cancer were evaluated for the clinical and pathological efficacy of the treatment. Clinically, the efficacy of four of the five patients with bladder cancer was CR or PR and pathologically (according to Shimosato's criteria), the efficacy was two in IVb or III, and three in IIb. Clinically, the efficacy in two patients with prostate cancer was CR or PR, and pathologically the efficacy was IVb or IIb. Three patients had complications of the reservoir system. These results suggest that good therapeutic efficacy and an improved quality of life can be obtained by intra-arterial chemotherapy using the reservoir system.     

Current strategies using hepatic arterial infusion chemotherapy for the treatment of colorectal cancer

In recent years, a number of phase III clinical trials have reported median survival times approaching 20 months using modern combination chemotherapy for metastatic colorectal cancer (CRC). Despite the advances in systemic therapy, this approach is still considered palliative because long-term survival or cure is extremely rare. Surgery or the use of ablative techniques may result in prolonged survival for patients with liver metastases, but only a minority of cases are suitable for local therapy. Hepatic arterial infusion (HAI) therapy involves local delivery of drug to liver metastases, resulting in higher intrahepatic drug levels and a consequent doubling in response rates compared with systemic chemotherapy. Despite higher response rates, demonstrating a survival advantage for HAI has been more challenging. Recently, a number of studies have been published that appear to address some of the inadequacies of earlier trials and have demonstrated encouraging results. This review assimilates the current data on HAI for CRC and includes an assessment of new chemotherapeutic agents delivered via HAI, neoadjuvant HAI, HAI combined with systemic chemotherapy, the use of HAI for early-stage colorectal cancer, and future trials. Continued progress in the field of HAI therapy may reduce the morbidity and mortality associated with CRC, so continued research in this area should be encouraged.     

Continuous infusion chemotherapy using an infusional port in colorectal cancer with liver metastases

Chemotherapy for colorectal cancer with liver metastases following surgical operation for primary tumor should be selected following surgical intervention. Continuous infusion chemotherapy using an infusional port was selected for unresectable metastasis due to colorectal cancer in our department. The catheter was placed in the hepatic artery through a gastroduodenal by operative procedure. 5-fluorouracil (5-FU) and mitomycin C (MMC) were used as chemotherapeutic agents. After MMC was given at 10 mg/body by bolus, administration of 5-FU was continuously infused at 250 mg/day for 2 weeks, followed by a 2-week interval. Drug administration was done by implanted pump hepatic arterial infusion. Seventeen of the patients with liver metastasis underwent this chemotherapy from 1986 through 1990. Results of the infusion chemotherapy were as follows. Value of serum CEA decreased until two courses were given in all cases. In 11 cases, the tumor size on CT was remarkably smaller. In these patients, however, there were many complications due to the catheter used for catheter replacement, drug leakage, drug extravasation and so on. We concluded that although this chemotherapy was very effective, the method should be improved in terms of the material, the location of catheter tip and the like.     

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.     

Hepatic arterial bolus chemotherapy for colorectal metastases using an implantable port

Twenty-one patients with isolated colorectal liver metastases underwent hepatic artery infusion (HAI) port implantation for regional chemotherapy with bolus injections of 5-FU, LV and fast drip of cisplatin. Ten of the 21 patients had previously failed systemic chemotherapy before HAI. Toxicity was moderate and no need for modulation of the chemotherapeutic dose was required. The objective response rate of the whole group was 52.4%. The patients, who had not previously received systemic chemotherapy, had a significantly higher response rate of 81.8% compared to patients treated previously by systemic chemotherapy, who had a response rate of 20% (p=0.0089). In addition, there was a difference in cumulative survival between these two groups. The HAI combined chemotherapy with 5-FU, LV and cisplatin given by bolus injection through an implantable port is effective therapy with similar response rate but considerable reduced toxicity compared to continuous HAI with FUdR. We assume that this therapy might prolong survival significantly especially in patients not treated before by systemic chemotherapy.     

Role of intra-arterial hepatic chemotherapy in the treatment of colorectal cancer metastases

Hepatic metastases are common with colorectal cancer. The primary blood supply to hepatic metastases is the hepatic artery. Regional chemotherapy utilizing the hepatic artery is one treatment option for liver metastases. The advantage of hepatic arterial chemotherapy is that high concentrations of the therapeutic drug are obtained in the liver with minimal systemic toxicity. Recently, systemic chemotherapy regimens have been added to hepatic arterial infusional chemotherapy to treat hepatic metastases. Due to the high response rates in the liver, resection rates are increasing in patients originally thought to have unresectable liver disease. Hepatic arterial chemotherapy has also been used in the adjuvant setting after resection of all liver metastases in order to minimize hepatic recurrences. The role of hepatic arterial infusional therapy in treating hepatic colorectal metastases includes treating patients with both resectable and unresectable metastases in the adjuvant, neoadjuvant, or palliative settings.     

结直肠癌肝转移经肝动脉栓塞及持续灌注化疗的临床疗效

背景与目的：结直肠癌肝转移患者经肝动脉介入栓塞或静脉持续滴注化疗药物,治疗效果有所提高,但尚存肿瘤局部化疗药物浓度不够高,化疗药物对肿瘤细胞的杀伤力不够强,晚期结肠直肠癌的治疗效果仍然不够好的缺陷。本文将动脉介入与持续灌注化疗药物两种方法相结合,观察结直肠癌肝转移患者经肝动脉介入栓塞或持续灌注化疗的临床疗效。方法：对26例结直肠癌肝转移患者经肝动脉介入治疗93次,单用肝动脉持续灌注化疗42次,肝动脉介入栓塞联合持续灌注化疗51次。化疗药物选用阿霉素（ADM）、顺铂（DDP）、丝裂霉素（MMC）、醛氢叶酸（CF）和5-氟尿嘧啶（5-FU）。先将ADM30mg/m^2和MMC6mg/m^2加入超液化碘油10-30ml中进行肝动脉灌注栓塞,然后留置导管进行持续动脉滴注。方案为CF200mg/m^2,d1-3,静脉滴注;DDP80mg/m^2d1,如肾功能改变则改用Vp-1660mg/m^2,d1-3,应用电动输液泵动脉滴注;5-FU2500mg/m^2,采用便携式输液泵将5-FU持续动脉滴注72h。结果：近期疗效以实体瘤疗效评价标准评价,CR1例,CR率3.85%;PR14例,PR率53.84%,总有效率为57.69%。本组0.5、1、2、3和5年生存率分别为92.31%、76.92%、38.46%、23.07%和3.85%,肝转移后中位生存期为11.5个月。全组病人出现的不良反应主要有肝功能损害、胃肠道反应和骨髓抑制,经护肝、制酸、止呕、水化和应用升白细胞药物对症治疗后可缓解。结论：经肝动脉持续灌注化疗及栓塞是治疗结直肠癌肝转移瘤的较好方法,能提高治疗效果。     

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.     

Continuous intrahepatic infusion of floxuridine and leucovorin through an implantable pump for the treatment of hepatic metastases from colorectal carcinoma

Based on laboratory studies showing enhanced cytotoxicity of floxuridine (FUDR) when used with high doses of leucovorin (LV), a pilot study of FUDR and LV through an implantable pump was initiated for the treatment of hepatic metastases from colorectal cancer. The highest dose of LV that could be administered, taking into account the constraints of the capacity of the pump and the solubility of LV, was 120 mg/m2/d. Due to the possibility of added toxicity, 25% of this dose was initially used. Twenty-four patients were treated at three dose levels. Eight patients were treated with the combination of LV (30 mg/m2/d) and FUDR (0.3 mg/kg/d) for a 14-day infusion through the pump, alternating with 2 weeks of saline. All eight patients had a greater than 50% decrease in measurable disease (PR) and a greater than 50% decrease in carcinoembryonic antigen (CEA) value; however, sclerosing cholangitis developed in two of these patients within 4 months. The next seven patients were treated with a lower dose of FUDR (0.2 mg/kg/d) and the same dose of LV, both for 14 days. Four of seven patients had a PR, and toxicity was decreased with no biliary sclerosis. A third regimen explored the combination of FUDR (0.3 mg/kg/d) and LV (30 mg/m2/d) for 7 days, alternating with 1 week of saline, to evaluate a shorter interval of treatment with the same overall dose intensity. Six of nine patients had a PR and all patients had a greater than 50% decrease in CEA value; sclerosing cholangitis developed in three of these patients. The overall response rate was 72%, with 18 of 25 patients alive after 1 year. The median survival time has not been determined, but it is greater than 27 months. FUDR with LV appeared to be effective in the treatment of hepatic metastases from colorectal carcinoma, but hepatic toxicity appeared to be greater than that previously reported with FUDR alone.     

Evaluation of continuous intra-arterial infusion chemotherapy after hepatic resection of liver metastases in colorectal cancer

We retrospectively evaluated continuous intra-arterial infusion chemotherapy after hepatic resection for hepatic metastases of colorectal cancer. From 1982 to 1990, we treated 22 patients with continuous intra-arterial infusion chemotherapy after hepatic resection, and 43 patients with only hepatic resection. 5-FU (250 mg/day) was administered continuously through implantable reservoir immediately after hepatic resection, and continued as long as possible. The total dose of 5-FU administered was 1.75-46.0 g (mean 17.4 g). We divided the patients into three groups: the first was administered a total dose of 5-FU more than 15 g, the next with less than 15 g, and the last with only hepatic resection was not given 5-FU. The 5-FU group receiving more than 15 g showed the lowest rate of hepatic metastasis recurrence. We compared the group showing recurrence within six months after hepatic resection (early recurrent group) with the group evidencing recurrence on and after six months (late recurrent group). In the former group, extra-hepatic recurrence significantly increased, whereas in the latter group hepatic recurrence significantly increased (p less than 0.05). In the early recurrent group, moderately or poorly differentiated adenocarcinoma significantly increased (p less than 0.01). According to the pathological result of pre-operative biopsy, one should check for extra-hepatic lesion as much as possible, and choose systemic chemotherapy for the early recurrent group.     

Hepatic resection plus hepatic artery infusion with implantable port for colorectal metastases

Hepatic resection of metastatic colorectal carcinoma offers a chance for long term survival and is being performed with increasing frequency. The aim of this study is to reduce the re relapse in the residual liver after curative hepatectomy. Nineteen patients with hepatic metastases from colorectal carcinoma who underwent hepatic resection plus hepatic artery infusion therapy using an implantable port (HR-HAI) were analyzed. As hepatic resection, lobectomies were performed in 6 patients, segmentectomies in 8 patients and wedge resection in 5 patients. As chemotherapeutic agents, adriamycin in 8 patients, mitomycin C in 7 patients and OK-432 in 4 patients were used. The drugs were administered through hepatic artery via a port every one month for one year at the out patient clinic. Eight out of 19 patients had no complication by HR-HAI therapy, but 3 patients had catheter obstruction within one year, 4 had gastrointestinal discomfort, 3 fever up and 1 liver tissue necrosis. The serious hepatotoxicity such as sclerosing cholangitis was not observed. Re-relapses were appeared in 15 patients and the sites were the residual liver in 10 patients, and 5 in the other organs. The 3-year survival rate of 19 treated patients was 40.0% higher than 33.3% of 52 patients undergone hepatic resection alone, but the difference was not statistically significant.     

Intra-arterial infusion chemotherapy of hepatic carcinoma using a totally-implantable Infusaid pump

Three patients with primary carcinoma of the liver and 11 patients with metastatic carcinoma of the liver were treated by hepatic arterial infusion of 5-FU and Mitomycin C (MMC), using a totally-implantable, percutaneously-refillable infusion pump: INFUSAID 210, 400. The infusion cannulae were placed into the hepatic arteries under direct vision on laparotomy, and the pumps were placed in subcutaneous pockets. The implanted pumps were well tolerated in these patients, who received chemotherapy as outpatients; the only adverse effects noted were related to 5-FU and MMC toxicity. The cumulative duration of successful infusion exceeded 104 months (for individual patients: range 2 to 20 months; average 7.4 months). Complications associated with conventional intraarterial chemotherapy (artery thrombosis, catheter sepsis and dislodgement, pump infusion variation and pump failure) were not seen with the INFUSAID delivery system. The pump is refilled every two weeks via percutaneous puncture. All therapy was given on an outpatient basis. Pump acceptance and tolerance was 100%. Our study using this infusion pump to deliver 5-FU and MMC has shown response rates of 66% (2/3) for primary carcinoma of the liver with cirrhosis and 82% (9/11) for metastatic carcinoma of the liver. The average survival for the primary and metastatic carcinomas of the liver were 6.0 months and 8.4 months respectively. Utilization of the totally-implantable INFUSAID pump provides a convenient, cost-effective, and safe administration technique for patients with primary and metastatic carcinomas of the liver.     

Regional chemotherapy: a focus on hepatic artery infusion for colorectal cancer liver metastases

Regional infusion strategies have been used as a treatment modality in multiple cancers, including ovarian, appendiceal, and colorectal cancers. Perhaps the most illustrative use of regional therapy is that of hepatic arterial infusion (HAI) for liver metastases from colorectal cancer. The administration of chemotherapy by HAI is logical and has theoretic advantages over systemic chemotherapy for the treatment of hepatic metastases from colorectal cancer. With the use of an appropriately chosen chemotherapy agent, HAI can generate an increase in hepatic tumor drug exposure as compared with intravenous delivery of the same agent. This article reviews the pharmacologic benefits of HAI therapy and the contemporary trials performed and underway.