Treatment of liver metastases with a combination of chemotherapy and hyperfractionated external radiation therapy

Twelve patients with liver metastases from colorectal cancer were treated with 5-FUdR hepatic artery, or 5-FU i.v. infusion therapy and hyperfractionated whole liver irradiation (2,100 rad in 14 fractions, two fractions/day over a period of 9 days). All 12 patients tolerated treatments well and no unusual toxicity was noted from this therapy. Response was assessed on completion of treatment and on follow-up examinations by physical examination, repeat liver function tests (LFTS), and CT scans. Symptomatic relief was achieved in all patients. Decreased liver size and improved LFTS were noted in 10/12 (83%) of patients. CT scans showed decrease in size of metastases. Survivals ranged from 16 to 120 weeks. Infusion therapy was given either by implanted infusion pump or continuous i.v. infusion therapy, 5-FUdR 0.3 mg/kg of body weight/day or 5-FU 1,000 mg/m2/day. Hyperfractionated external radiotherapy with concomitant 5-FUdR hepatic artery of 5-FU i.v. infusion therapy for liver metastases was well-tolerated, and both subjective and objective response and quality of survival were noted. Hyperfractionated external beam irradiation with concurrent chemotherapy can be effective in palliating patients with liver metastases.     

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.     

Continuous systemic 5-fluorouracil infusion in advanced colorectal cancer: results in 91 patients

Ninety-one patients with metastatic colorectal cancer were treated with continuous ambulatory 5-fluorouracil (5FU) infusion 250-300 mg/m2/day through a chronic indwelling central venous catheter. Twenty-six of the 91 patients (29%) had received previous bolus 5FU. Fifty-eight of the 91 patients (64%) had two or more sites of disease, and 74 of 91 patients (81%) had liver metastases. Results were complete remission in 5 of 91 (6%), partial remission in 25 of 91 (27%), stable disease in 33 of 91 (36%), and progressive disease in 28 of 91 (31%), for an overall response rate of 30 of 91 (33%); median duration of response was 7 months. Twenty-six of 65 previously untreated patients (40%) experienced objective response. Median survival from initiation of treatment for all patients was 11 months. Forty-one percent of patients experienced no significant toxicity and were able to continue therapy without treatment interruption. Toxicities necessitating treatment interruption included stomatitis in 35 patients (39%), hand-foot syndrome in 33 patients (36%), and diarrhea in 10 patients (11%). No significant myelosuppression or serious catheter-related complications were encountered. We conclude that continuous systemic venous infusion of 5FU produces a higher response rate than traditional bolus 5FU schedules, with apparent enhancement of survival and easily managed toxicity.     

肝动脉药盒灌注氟脲苷联合全身化疗治疗不可切除老年结直肠癌肝转移

目的 探讨经肝动脉药盒灌注（HAI）氟脲苷（FUDR）联合全身化疗治疗不可切除老年结直肠癌肝转移患者的疗效及安全性.方法 对18例不可手术切除的老年结直肠癌肝转移回顾性分析.所有患者采用一种改进的介入方法植入肝动脉药盒,术后第2天开始接受HAI FUDR联合全身化疗.对治疗疗效、毒副反应及随访结果进行分析.结果 18例患者的总有效率为94.4%,其中完全缓解1例（5.6%）,部分缓解16例（88.9%）,疾病进展1例（5.6%）.8例患者转化为可手术切除,转化率为44.4%.中位无进展生存时间为26.0个月,中位总生存时间为30.2个月.结论 HAI FUDR联合全身化疗是治疗不可切除老年结直肠癌肝转移的一种安全有效的方法,可获得较高的手术切除率.     

Central venous access port-related complications in outpatient chemotherapy for colorectal cancer

BACKGROUND: The current standard chemotherapy for advanced or metastatic colorectal cancer in Japan is FOLFOX or FOLFIRI therapy. Although both therapies include continuous infusion of 5-fluorouracil (5-FU), outpatient home chemotherapy is possible by placing a central venous access port (CV-port) and using a portable disposable pump. The port system has been placed more frequently since the approval of FOLFOX. Consequently, more complications involving ports and pumps have been encountered. METHODS: At our hospital, 232 patients with colorectal cancer underwent outpatient home chemotherapy by placing a CV-port and using a portable disposable pump for continuous infusion of 5-FU between 1998 and 2005. Incidence and contents of complications involving ports and pumps were investigated retrospectively. RESULTS: A total of 54 incidents of complications involving ports and pumps were identified in 3142 treatments (1.72%) from among 34 of the 232 patients (14.7%). In 2005, when FOLFOX was introduced, 31 incidents occurred in 1903 treatments (1.63%) for 19 of 149 patients (12.8%). Incidents involved port placement (n = 6), catheter and port system-related complications (n = 15), puncture needle-related complications (n = 3), skin complications related to tape fixation (n = 20) and pump-related complications (n = 10). In 10 patients (4.3%), system-related complications made therapy difficult to continue and system exchange was required. CONCLUSIONS: Technical troubles involving ports and pumps occurred at a certain rate, and skin incision was required for system exchange in some cases. When performing outpatient chemotherapy using ports and pumps, thorough prior guidance and double-checking must be implemented, and proper countermeasures must be established.     

Hepatic arterial infusion of high dose 5-FU in weekly schedule for liver metastases from colorectal cancer employing a newly developed pump "Koken Infusor"

Seventeen patients with unresectable liver metastases from colorectal cancer were treated with 5 hour infusion of 1,000 mg/m2 of 5-FU in weekly schedule, employing a newly developed portable pump "Koken-Infusor". This pump is operated by batteries. It is small, light and easy to use. And five hundred cycles of treatments were performed, but the pump induced no major complications. The response evaluated by a CT-scan was 73% (11/15) without major toxicities. In conclusion "Koken-Infusor" is very useful for this treatment, especially for out patients. It appears that this therapy is one of the effective treatments for liver metastases from colorectal cancer.     

Hepatic chemoinfusion of 5-FU in metastasis of gastrointestinal cancer and advanced primary hepatocellular carcinoma.

From 1 January 1983 to 1 January 1988, 38 patients were treated for hepatic cancer in the HEINZ-KALK-Hospital. Thirty-one of these had liver metastases due to gastrointestinal cancer and seven had advanced primary hepatocellular cancer. In all patients more than 50% of the liver volume was involved with the tumour or the metastases. Eleven patients with liver metastases of gastrointestinal cancer (excepting colorectal cancer) were treated by intra-arterial hepatic bolus infusion of 750-1000 mg 5-fluorouracil (5-FU) by selective catheterisation of the hepatic or superior mesenteric artery after puncture of the right or left femoral artery. The median survival was 13.4 months. In seven patients with advanced primary hepatocellular carcinoma the same therapeutic regime was used. The median survival was 10 months. In the 21 patients with disseminated metastases of previously resected colorectal cancer a catheter was inserted into the gastro-duodenal artery and connected to a subcutaneously placed port. Brief infusions of 750-1000 mg 5-FU were administered for 14 days with a day interruption and thereafter 2 month interruption. There were few side effects and 80% of the patients continued to work or carry on a normal life. The median survival was 14.4 months. Based on this experience we consider hepatic chemoinfusion with 5-FU in gastrointestinal cancer and advanced primary hepatocellular carcinoma is capable of improving quality of life and possibly expectancy.     

Hepatic artery infusion chemotherapy for metastatic colorectal cancer to the liver at the lahey clinic: comparison between two methods of treatment, surgical versus percutaneous catheter placement

This study updates our experience with hepatic artery infusion chemotherapy for colorectal liver metastases at the Lahey Clinic. It compares surgical versus percutaneous catheter methods, employing an external pump. The surgical series (SS) consisted of 58 patients (1970-1995) treated with floxuridine (FUDR), 20 mg/d for 4 to 5 weeks (modified in 1985; 2-week cycles). Percutaneous series (PS) consisted of 42 patients (1976-1995) treated with fluorouracil (5-FU), 20 mg/d for 10 days followed by a floxuridine (FUDR) schedule as with SS. Analysis consisted of tumor response, survival, and toxicity data between the two methods. Response rates showed no significant difference, SS (34%) and PS (48%) (P = 0.22). There were no significant differences in survival from treatment until death in SS (n = 58) of 13 months versus PS (n = 42) of 10.6 months (P = 0.39), from diagnosis until death, SS being 28.4 months versus PS of 26.4 months (P = 0.71) and from metastases until death, SS being 17.4 months versus PS of 22.2 months (P = 0.35). Hepatic toxicity was similar, but there was increased bone marrow toxicity, mucositis, and diarrhea for the PS. Response rates are similar for both our SS and PS and to that reported in recently randomized surgical trials. Hepatic artery infusion chemotherapy with FUDR by percutaneous catheter placement may be as effective as surgical catheter placement for colorectal liver metastases, but further study is needed.     

Intraperitoneal 5-fluorouracil in the management of colorectal liver cancer.

Twenty-five patients with colorectal liver metastases had a subcutaneous portal connection with a peritoneal catheter implanted for the intraperitoneal (i.p.) administration of 5-fluorouracil (5-FU). In five patients, the malignant disease rapidly progressed and the implanted catheter system was never used. Among the remaining 20 patients, seven patients had i.p. 5-FU as adjuvant treatment following liver resection and 13 patients received palliative chemotherapy (5-FU) owing to unresectable liver metastases. 5-FU was administered on a regular basis every 4 to 6 weeks by continuous infusion of 1000 mg/day (approximately 15 mg/kg/day) for 5 days. In seven patients, i.p. chemotherapy was managed on an outpatient basis. In general, i.p. 5-FU treatment was well tolerated with only minor abdominal complaints during the initial treatments. No definite effect on survival has been noted. All patients (n = 13) receiving palliative i.p. 5-FU died after a median of 4 (range 1.5-18) months. Two patients receiving adjuvant chemotherapy died owing to recurrence after 20 and 23 months, while five patients are alive, two with recurrent disease and three without, after 14-35 months.     

皮下埋植式药泵动脉灌注化疗治疗大肠癌肝转移

[目的]探讨采用经皮下埋植式药泵肝动脉栓塞化疗治疗大肠癌肝转移的近期疗效、生存期及并发症。[方法]泵内化疗组24例采用经皮下埋植式药泵肝动脉栓塞化疗 ,对照组20例采用静脉化疗。[结果]泵内化疗组近期疗效 (CR +PR)为79.1% ,静脉化疗组为15% ,经检验两组差异有显著性 (P<0.05) ;泵内化疗组6个月、12个月、24个月的生存率分别为83.7%、63.5%、41.9% ,而静脉化疗组6个月、12个月、24个月的生存率分别为54.5%、29.7 %、14.6% ,经检验两组差异有显著性 (P<0.05)。[结论]采用经皮下埋植式药泵肝动脉栓塞化疗是治疗大肠癌肝转移安全、有效的方法之一 ,较静脉化疗能提高疗效及生存期     

A case of unresectable multiple hepatic metastases from colorectal cancer successfully treated with panitumumab therapy on third-line

In a patient with multiple liver metastases of colorectal cancer in whom tumor response had been achieved by 5-FU hepatic arterial infusion, the catheter for arterial infusion chemotherapy was occluded resulting in re-elevation of tumor marker levels. Second-line IRIS therapy using S-1 and CPT-11 was started. IRIS therapy reduced tumor marker levels to a degree greater than that previously achieved with 5-FU hepatic arterial infusion, and diagnostic imaging allowed a judgment of partial response. But tumor marker levels increased gradually. After all, diagnostic imaging allowed a judgment of progressive disease and an eminent elevation of tumor marker levels in one year. Third-line panitumumab therapy was started. Panitumumab therapy reduced tumor marker levels to a degree greater than that previously achieved with 5-FU hepatic arterial infusion and IRIS therapy, and diagnostic imaging allowed a judgment of partial response. We report herein a successful case. Hepatic arterial infusion therapy is one of the treatment methods characterized by a lower incidence of adverse reactions, relatively low cost, and expectation of high anti-tumor efficacy as compared to chemotherapy such as FOLFIRI. IRIS therapy does not require a port insertion and pump carrying, and its cost is about half of FOLFIRI therapy. When used as second-line therapy for unresectable colorectal cancer, non-inferiority of IRIS therapy to FOLFIRI therapy has been demonstrated in a phase II/III clinica (l FIRIS) study. We may say that IRIS therapy is promising as an equivalent to hepatic arterial infusion therapy in the treatment of liver metastases of colorectal cancer. In addition, we may say that panitumumab therapy is promising as an equivalent to hepatic arterial infusion therapy and IRIS therapy.     

Alternating hepatic intra-arterial floxuridine and fluorouracil: a less toxic regimen for treatment of liver metastases from colorectal cancer.

Hepatic intra-arterial (HIA) infusion of floxuridine (FUDR) via an implanted pump has shown promise in the treatment of colorectal cancer metastasized to the liver. However, the potential benefit of this therapy may be offset by the high incidence of treatment-limiting biliary toxicity. Although weekly HIA bolus of fluorouracil (5-FU) is effective against metastatic colorectal cancer to the liver with no biliary toxicity, it is limited by systemic side effects. In December 1986, we began a phase II trial of alternating HIA FUDR and 5-FU via the implanted pump in an attempt to extend the duration of treatment by obviating the limiting biliary (FUDR) and systemic (5-FU) drug toxic effects. Patients received continuous HIA FUDR at 0.1 mg/kg of body weight per day on days 1 through 8 followed by an HIA bolus of 5-FU at 15 mg/kg given via the pump sideport on days 15, 22, and 29, with the cycle repeated every 35 days. Sixty-eight patients were enrolled in this trial, and 64 were fully evaluable. Of the 64 patients, 30 (47%) previously had received chemotherapy. Major response (complete response plus partial response) was observed in 32 (50%) of 64 patients, and the median survival from pump implantation in all patients was 22.4 months. In contrast to the experience with the single-agent HIA FUDR regimen, no patient had treatment terminated because of drug toxicity. Alternating HIA FUDR and 5-FU has efficacy similar to that of HIA FUDR given alone, but when closely monitored and adjusted appropriately, is not associated with toxic effects requiring treatment termination.     

Evaluation of a totally implanted venous access port and portable pump in a continuous chemotherapy infusion schedule on an outpatient basis

In this study we evaluated the feasibility of a totally implanted vascular access port (VAP) and portable infusion pump for cytostatic drug administration on an outpatient basis, in a 21-day continuous infusion schedule with 4-epidoxorubicin (phase I and phase II study) and mitoxantrone (phase I study). Patients were instructed to dissolve their own drugs at home. Fifty patients were treated with 114 cycles (2394 infusion days). The complication rate was low. In one patient thrombosis of the subclavian and superior caval vein resulted in the termination of treatment. One patient developed pulmonary embolism during treatment. Needle dislocation was observed in two patients. No septicaemia and no irreversible catheter occlusion were seen. Pump functioning was efficient and pump arrest (9 ×) never lasted longer than 24 h. We conclude that a VAP and portable pump are a safe and reliable route of administration for cytostatic drugs on an outpatient basis and that patients are capable of preparing their own drugs at home without increase of complications.     

Continuous venous infusion of vindesine in metastatic breast cancer: experience with a subcutaneously implanted system and portable pump

Fourteen patients with advanced pretreated breast cancer were treated with vindesine in continuous venous infusion (1.5 mg/sm/24 hours for 72 hours every 3 weeks). A totally implanted venous access and a portable pump were used. A total of 33 courses was administered. No objective response was observed and treatment was stopped. Drug-related toxicity consisted mainly of alopecia (64% of patients), nausea and vomiting (29%) and mucositis (29%). Catheter - related toxicity was observed in 6 patients (43%) and consisted of infection of the skin pocket in 4 patients and dislodging of the needle and catheter break in one patient. The feasibility of continuous venous infusion of vesicant drugs in outpatients is discussed.     

Occlusion of the left superficial femoral artery during hepatic arterial infusion of chemotherapy for liver metastases from colon cancer 18 months after the implantation of a port system: a case report

We report a case of complication of a catheter port system. A 67-year-old male who had undergone left hemicolorectomy and partial hepatectomy for liver metastases from colon cancer underwent hepatic arterial infusion (HAI) of chemotherapy by a percutaneously implanted catheter port system to prevent recurrence. Eighteen months after the implantation of a port system he complained of intermittent claudication. Intravenous digital subtraction angiography (IV-DSA) showed occlusion of the left superficial femoral artery. The catheter was removed and a femoro-popliteal bypass with an artificial graft was constructed. Thrombus was found around the indwelling catheter at the insertion site. After the operation his complaint disappeared and has been alive without recurrence for 6 years.     

A safe and simple method of percutaneous transfemoral implantation of a port-catheter access system for hepatic artery chemotherapy infusion]

The purpose of this study was to perform a simple percutaneous transfemoral implantation of a portcatheter access system using a new catheter coating for hepatic artery chemotherapy infusion, and to evaluate the complications of transfemoral infusion port implantation. The methods of treatment for complications were also studied. The port-catheter system was percutaneously implanted via femoral artery access in 180 patients with malignant liver tumors. Blood flow redistribution was performed using embolization coils. An unfixed 5 Fr catheter was placed in a hepatic artery, and connected to a port implanted subcutaneously below the level of the inguinal ligament. The success rate of implantation was 99%. Complications after placement were observed as follows: port system obstruction (9.6%); dislocation of the catheter tip (8.4%); drug toxicity (4.5%); and infection (3.4%). Notable is the avoidance of cerebral infarcts. In 3 of 17 patients with port obstruction, recanalization of the port was achieved. In 11 of 15 patients with catheter dislocation, replacement of the catheter-port system was successful. In 5 patients with hepatic artery occlusion, the replacement of a microcatheter-port access system was achieved, and hepatic artery chemotherapy infusion was resumed. This percutaneous transfemoral implantation of a catheter-port access system would seem to be a very simple and useful method for many clinical doctors, and it may improve the quality of life in patients with an unresectable malignant liver tumor.     

Reasonable approach for prophylactic hepatic arterial infusion chemotherapy after potentially curative surgery for colorectal liver metastases

The authors discuss the reasonable management of implantable ports and catheters after cessation of adjuvant hepatic arterial infusion (HAI) chemotherapy following curative resection of colorectal liver metastases. Local recurrence in the residual liver was observed in only 4 patients of thirty-two patients (13%). Although heparin administration into the port was regularly performed in 17 patients to prevent its occlusion, the ports were successfully maintained in only 9 patients at a median time of 11.8 months postoperatively, and only one patient received further regional chemotherapy for recurrent disease. These findings indicate that heparin administration to maintain the port brings little benefit. In the most recent 3 cases, we used a new Piolax W Spiral catheter and removed the catheter and port after cessation of adjuvant chemotherapy. No complication related to the procedure occurred, and patients' quality of life was well preserved, suggesting that this approach for HAI is reasonable and beneficial.     

Phase II evaluation of treatment of complete resection of hepatic metastases from colorectal cancer and adjuvant hepatic arterial infusion of floxuridine: an Eastern Cooperative Oncology Group Study (PB083).

This study was designed to evaluate hepatic arterial infusion of floxuridine (FUDR) in patients with resected hepatic metastases from colorectal cancer. Patients who met eligibility criteria had an Infusaid pump (Infusaid Corporation, Sharon, MA, U.S.A.) implanted for intraarterial administration of chemotherapy. After complete surgical resection of hepatic metastases, FUDR (0.2 mg/kg/day) was given in 28-day cycles consisting of 14 days of treatment followed by 14 days of rest. Of 11 patients enrolled, one was ineligible, one received no treatment because of a blocked pump, and nine were treated per protocol. Of the nine treated patients, all are dead: one from hepatic toxicity, one from unrelated causes, and seven from progressive disease. Grade 3-4 toxicity included three cases of gastritis and two cases of hepatotoxicity from FUDR. Although this regimen was not successful, in part because of toxicity, the patient population studied here should be considered for future studies of adjuvant therapy.     

Outcomes of hepatic artery infusion therapy for hepatic metastases from colorectal carcinoma after radiological placement of infusion catheters.

AIM: The aim of this study is to evaluate the safety and efficacy of hepatic artery infusion (HAI) of 5-fluorouracil (5FU) for patients with liver metastases from colorectal carcinoma after radiological placement of infusion catheters. METHODS: Forty-two patients with liver metastases from colorectal carcinoma received radiological placement of infusion catheters using the distal fixation method. They received continuous HAI of 5FU 1,000-1,500mg for 5h weekly or biweekly. Tumor status was assessed by chest-abdominal computed tomography (CT) scan after every 10 infusions. Hepatic perfusion was checked by CT arteriography via the infusion port after every 10 infusions. RESULTS: Radiological placements of catheters were performed successfully in all cases. Each patient received an average of 36 treatments (range: 10-98). Catheter failure was found in 3 patients (7.1%). Nine incidents of grade 1 toxicity were observed in 8 patients (19.0%). There was a complete response in 6 patients, partial remission in 18, stable disease in 9, and progression of disease in 9 (response rate: 57.1%). Overall median survival time was 29.1 months. Using Cox's proportional hazard model, lymph node metastases in primary colorectal carcinoma and pre-treatment serum CEA affected overall survival (P=0.011, P=0.005). CONCLUSIONS: HAI after radiological placement of infusion catheters is a safe and effective treatment particularly for patients with no lymph node metastasis in primary carcinoma or with a low pre-treatment serum CEA level.