Hepatic Arterial Infusion Of 5-fluorouracil Research Articles

Efficacy and safety of localized concurrent chemoradiation therapy and sorafenib sequential therapy in advanced hepatocellular carcinoma: A prospective phase II trial.

e15678 Background: Patients with advanced hepatocellular carcinoma (HCC) have a particularly poor prognosis of the median overall survival of less than 12 months. Even though sorafenib has been approved for treating advanced stage HCC, the unsatisfactory objective response rate still remain unresolved. In the current study, we aimed to evaluate the efficacy and safety of localized concurrent chemoradiotherapy (CCRT) followed by sequential sorafenib treatment for advanced hepatocellular carcinoma. Methods: This study is an ongoing, phase II trial. Patients with advanced HCC not amenable for curative treatments were eligible. In the course of radiotherapy for 5 weeks, hepatic arterial infusion of 5-fluorouracil (500mg/day) via implanted port was applied during the first 5 days and the last 5 days of radiotherapy. Four weeks after localized CCRT, sorafenib (400mg bid) was maintained. The primary endpoint was overall survival. Results: A total of 47 patients were enrolled. After the completion of localized CCRT, the objective response rate was 31.9%. During the overall treatment course, the objective response rate was 46.8% respectively. Overall, 7 patients (14.9%) underwent curative resection or transplantation after down-staging. The median overall survival was 18.4 months and the progression-free survival was 6.8 months. Adverse events were predictable and manageable with conservative care. Conclusions: Localized CCRT followed by sequential sorafenib treatment in patients with advanced HCC showed significant activity and good tolerability. Furthermore, such a treatment modality, when compared to the use of sorafenib alone, might provide the additional therapeutic benefit through initial tumor reduction, allowing curative treatment after down-staging in 14.9% of patients, Further randomized trial should be required to make the more robust evidence. Clinical trial information: NCT02425605.

Hepatic arterial infusion combined with systemic chemotherapy induced complete response of metachronous liver metastases after resection of pancreatic insulinoma.

Insulinomas are the most common functioning pancreatic neuroendocrine tumors (PNETs). We herein present the case of a 5-year survivor with insulinoma after complete response of postoperative liver metastases to hepatic arterial infusion combined with systemic chemotherapy. A 58-year-old woman was admitted to our hospital following loss of consciousness. Examination revealed a pancreatic tumor, and she underwent distal pancreatectomy following diagnosis of insulinoma. Superparamagnetic iron oxide magnetic resonance imaging (SPIO-MRI) revealed multiple liver metastases 3months after surgery. Therefore, we performed hepatic arterial infusion of 5-fluorouracil (5-FU) combined with systemic gemcitabine infusion. We observed complete ablation of all metastatic liver nodules after 11 cycles of the chemotherapy using MRI. We continued this chemotherapy regimen for 20 cycles, and the patient remains alive without any recurrence 7years after surgery.

Unresectable Colorectal Liver Metastases: The Safety and Efficacy of Conversion Therapy Using Hepatic Arterial Infusion Immunochemotherapy with 5‐Fluorouracil and Polyethylene Glycol‐Interferon α‐2a

Hepatic arterial infusion (HAI) or systemic chemotherapy has been used to treat unresectable colorectal liver metastases. The prognosis of the disease in recent years has been improved because chemotherapy is performed before hepatectomy to reduce tumor size (conversion therapy). The purpose of this study was to investigate the safety and efficacy of conversion therapy following HAI immunochemotherapy. Hepatic arterial infusion of 5-fluorouracil (5-FU)/polyethylene glycol (PEG)-IFNα-2a was performed in 21 patients. The primary endpoint was the safety of HAI and hepatectomy. The secondary endpoints were response rate, rate of conversion to hepatectomy, survival rate, and prognostic factors. With regard to side effects, drugs were discontinued temporarily in one patient because of a decrease in white blood cell count; however, other patients continued chemotherapy. The response rate with HAI was 61.9 %, and the conversion rate was 38.1 %. Hepatectomy was completed successfully without mortality. Median progression-free survival (PFS) was 11.5 months (with and without conversion, 16.7 and 4.8 months, respectively; p = 0.021). Median overall survival was 34.6 months (with and without conversion, 48.4 and 26.6 months, respectively; p = 0.003). Prognosis was poor when the number of metastatic tumors was ≥10 [PFS: hazard ratio (HR) 32.21, p = 0.003; overall survival (OS): HR 9.13, p = 0.07], but prognosis improved after hepatectomy (OS: HR 0.08, p = 0.09). Hepatic arterial infusion immunochemotherapy with 5-FU/PEG-IFNα-2a was performed safely without major side effects. Prognosis is expected to improve after successful conversion to hepatectomy.

18F‐fluorodeoxyglucose uptake on positron emission tomography as a prognostic predictor in locally advanced hepatocellular carcinoma

Metabolic activity assessed by (18)F-fluorodeoxyglocuse-positron emission tomography ((18)F-FDG-PET) reflects biological aggressiveness and prognoses in various tumors. The authors present a correlation between tumor metabolic activity and clinical outcomes in patients with hepatocellular carcinoma (HCC). Over a 3-year period (2005-2008), 135 locally advanced HCC patients were treated with localized concurrent chemoradiotherapy (CCRT; external beam radiotherapy at 45 grays for 5 weeks plus concurrent hepatic arterial infusion of 5-fluorouracil during the first and fifth week) followed by repetitive hepatic arterial infusional chemotherapy with 5-fluorouracil and cisplatin. Among them, the authors studied 107 who received (18)F-FDG-PET before CCRT. Maximal standardized uptake values (SUVs) of tumors were calculated. The median maximal tumor SUV was 6.1 (range, 2.4-∼19.2). Patients with low maximal tumor SUVs (<6.1) had a higher disease control rate than those with high maximal tumor SUVs (≥6.1) (86.8% vs 68.5%, respectively, P = .023). Both median progression-free survival (PFS; 8.4 vs 5.2 months; P = .003) and overall survival (OS; 17.9 vs 11.3 months; P = .013) were significantly longer in the low maximal tumor SUV group than in the high maximal tumor SUV group, respectively. In multivariate analysis, low maximal tumor SUV and objective responses to CCRT remained significant for PFS and OS. The high maximal tumor SUV group was more likely to have extrahepatic metastasis within 6 months than the low maximal tumor SUV group (58.1% vs 26.8%, respectively; P < .001). Similar results were obtained for the maximal tumor SUV/normal liver maximal SUV ratio (<2 vs ≥2) concerning progression, death, and extrahepatic metastasis. Metabolic activity may be useful not only in predicting prognosis and treatment responses, but also in establishing optimal treatment plans in locally advanced HCC.

Erratum

In the article titled “Hepatic Arterial Infusion of 5-Fluorouracil for Patients With Liver Metastases From Colorectal Cancer Refractory to Standard Systemic Chemotherapy: A Multicenter, Retrospective Analysis” appearing in Clinical Colorectal Cancer Volume 9, Issue 5, the authors’ institutional affiliations were not listed. The authors and their affiliations are as follows:

Early α-fetoprotein response as a predictor for clinical outcome after localized concurrent chemoradiotherapy for advanced hepatocellular carcinoma

There are limitations in using only radiological criteria to evaluate treatment outcomes in hepatocellular carcinoma (HCC). α-fetoprotein (AFP) is regarded as an indicator of tumour activity in HCC. We present a novel correlation between AFP response and survival outcome in patients treated with localized concurrent chemoradiotherapy (CCRT). From 2005 to 2008, 187 locally advanced HCC patients underwent localized CCRT (external beam radiotherapy at 45 Gy over 5 weeks plus a concurrent hepatic arterial infusion of 5-fluorouracil during the first/fifth week), followed by repetitive hepatic arterial infusional chemotherapy (HAIC) with 5-fluorouracil and cisplatin. Among them, 149 with an elevated baseline AFP level (>20 ng/ml) were finally studied. AFP response was defined as >50% decrease from baseline, 1 month after the completion of localized CCRT. Patients' characteristics were as follows: median age (52 years); Child-Pugh class A/B (n=137/12 respectively); and portal vein thrombosis (n=118). AFP responders (101 patients) had better objective responses than AFP non-responders (48 patients) after CCRT (44.5 vs. 12.5%; P<0.001) and subsequent HAIC (51.5 vs. 16.7%; P<0.001). Both median progression-free survival (PFS, 8.1 vs. 3.9 months; P<0.001) and overall survival (OS, 13.3 vs. 5.9 months; P<0.001) were longer in AFP responders than AFP non-responders. In multivariate analysis, AFP response and objective response were independent factors affecting PFS and OS. Furthermore, AFP non-responders were more likely to have extrahepatic metastasis within 6 months of treatments initiation than AFP responders (59.5 vs. 25.9%; P<0.001). Early AFP response may be useful not only in predicting prognosis and treatment response but also in establishing optimized treatment plans for HCC.

Randomized, phase II study comparing interferon combined 5-fluorouracil plus cisplatin hepatic arterial infusion with interferon combined 5-fluorouracil hepatic arterial infusion in patients with advanced hepatocellular carcinoma

4588 Background: This randomized phase II trial compared the response rate (RR) of interferon (IFN) combined 5-fluorouracil (5FU) plus cisplatin (CDDP) hepatic arterial infusion (HAI) with IFN combined 5FU HAI in advanced hepatocellular carcinoma. Methods: Patients (pts) with measurable histologically or radiologically confirmed advanced hepatocellular carcinoma (major vascular invasion and/or bilobular multiple ≥5 nodules) were randomized into 2 groups. Arm A (n=57): continuous 5FU HAI (300mg/m2 day1–5, day8–12), CDDP HAI (20mg/m2, day 1, day 8 for 1.5 hours). IFN alpha-2b (3M IU/body) was administrated intramuscularly 3 times per week for 4 weeks. The treatment cycles repeated for 6 weeks. Arm B (n=57): IFN combined 5FU HAI with same dose without CDDP infusion. Treatment was continued until disease progression. The primary endpoint was RR. The secondary endpoints were overall survival (OS), time to progression (TTP) and toxicity. Results: Results for responses are presented for 109 pts and toxicity for 114 pts. The best overall response rate (RR) was 46% for group A and 25% for group B. This included 1 (2% of group A) vs. 3 (6% of group B) complete responses, and 25 (44% of group A) vs. 11 (19% of group B) partial responses. Fifteen pts in group A (26%) vs. 19 pts (33%) in group B had stable disease and 13 pts (23%) vs. 22 (39%) in respectively group A and B progressed while on treatment. RR was significantly higher in group A (p=0.02). The median TTP was 6.5 ± 2.0 months (mo) for group A vs. 3.3 ± 2.0 mo for group B (p=0.005). The median OS was 17.6 ± 3.2 mo for group A vs. 10.5 ±2.3 mo for group B (p=0.38). The median OS was 13.7 ± 4.9 mo for both groups. Grade 3/4 toxicity occurred in 65.8% of pts. Hematological toxicity was common and occurred in 53.5%. The thrombocytopenia and infusion port-related toxicity occurred more frequently in group A. Conclusions: IFN combined 5FU plus CDDP HAI shows higher antitumor activity and longer TTP than IFN combined 5FU HAI. Although OS is also longer without significant difference, these results show the clinical efficacy of additional CDDP to IFN combined 5FU HAI. No significant financial relationships to disclose.

Pilot clinical trial of localized concurrent chemoradiation therapy for locally advanced hepatocellular carcinoma with portal vein thrombosis

Patients with advanced hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT) have a particularly grave prognosis. In the current study, an attempt was made to localize chemoradiation therapy (CCRT) followed by hepatic arterial infusion chemotherapy (HAIC) in patients with locally advanced HCC with PVT and good reserve liver function. The objective of the current study was to evaluate the therapeutic effect of localized CCRT followed by HAIC as a new treatment modality for these patients. Between January 1998 and December 2003, 40 patients were recruited. Concurrent regional chemotherapy using an intra-arterial implanted port plus localized external beam radiotherapy was performed with a total of 45 gray (Gy) over 5 weeks with conventional fractionation and hepatic arterial infusion of 5-fluorouracil (5-FU), which was administered during the first and fifth weeks of radiotherapy. One month after localized CCRT, HAIC with 5-FU and cisplatin was administered every 4 weeks. One month after localized CCRT, an objective response was observed on the intention-to-treat analysis in 18 of 40 patients (45%). The actuarial 3-year overall survival rate was 24.1% and the median survival time was 13.1 months from the start of radiation treatment. Responders after localized CCRT demonstrated significantly better survival (P = .033) than nonresponders. The substantial response rate as well as median survival time noted in the current study encourages the use of this new approach in patients with locally advanced HCC with PVT.

Complete remission of hepatocellular carcinoma with portal vein tumor thrombus and lymph node metastases by arterial infusion of 5-fluorouracil and interferon-α combination therapy following hepatic resection

We report two cases of hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) and lymph node (LN) metastases successfully treated by hepatic arterial infusion of 5-fluorouracil (5-FU) combined with systemic injection of interferon (IFN)-alpha following hepatic resection for the liver tumor. Complete remission was obtained. Case 1 was a 51-year-old man who had HCC in the right lobe of the liver with PVTT and multiple intrahepatic metastases. He also had abdominal and mediastinal LN metastases. Case 2 was a 53-year-old man who had diffuse-type HCC in the right lobe of the liver with PVTT and intrahepatic metastases. A chest computed tomography scan revealed lymph nodes enlarged to 1.0 cm from the mediastinum to the left supraclavicular space. Both patients underwent the hepatectomy to reduce the tumor volumes and remove the PVTT to relieve portal vein obstruction. Following the surgery, the patients underwent IFN-alpha/5-FU combination therapy. Three months after this combined therapy, tumor markers (both alpha-fetoprotein and protein induced by vitamin K absence or antagonist II) returned to the normal range and residual tumors in the liver disappeared. The patients are alive without any recurrence more than 1 year after initial treatment. IFN-alpha/5-FU combined therapy following hepatic resection is a promising modality for the treatment of advanced HCC with LN metastasis.

Phase II trials of pancreatic and hepatic arterial infusion of 5-fluorouracil (5-FU) and cisplatin (CDDP) in patients with advanced pancreatic cancer with or without liver metastasis

4140 Background: Liver metastasis is a common progression of pancreatic cancer. The purpose of this study was to examine the efficacy and safety of a modality therapy consisting of pancreatic and hepatic arterial infusion of 5-FU and CDDP in patients with advanced pancreatic cancer with or without liver metastasis. Methods: 12 patients with unresectable pancreatic cancer were enrolled in this study. 8 patients had locally advanced pancreatic cancer with no distant metastases (Group A). 4 patients had advanced pancreatic cancer with no distant metastases except to the liver (Group B). To restrict the blood flow into the pancreas and the liver, the peripancreatic artery (ex. dorsal pancreatic artery) were embolized superselectively with microcoils. The tip of the catheter was placed in the proper hepatic artery and the side hole was placed in the gastroduodenal artery for the patients of pancreas head cancer. The splenic artery and the common hepatic artery were used for the patients of pancreas body or tail cancer. The patients of Group A received both hepatic and pancreatic arterial injection chemotherapy to prevent liver metastasis. The arterial infusion chemotherapy consisted of 5-FU 250 mg/sqm administration as a 24-hr continuous arterial infusion and a bolus injection of CDDP 5mg/sqm three times a week for two weeks to all 12 patients. Consequently, 8 of 12 patients were administered 5-FU 600mg/sqm as a 5-hr continuous arterial infusion weekly. Results: 3 patients of Group A had PR (Overall response was 37.5%). None of Group B had CR or PR. Median survival time was 16.3 months for Group A and 6.1 months for Group B. One of Group A had liver metastasis after this treatment. Toxicity was predictable and in general manageable. One patient had the grade 4 hematotologic toxicity but recovered. Conclusions: In patients with unresectable pancreatic cancer, hepatic and pancreatic arterial injection chemotherapy after hemodynamic change is effective to treat main pancreatic tumor and to prevent liver metastasis. No significant financial relationships to disclose.

Phase II trials of pancreatic and hepatic arterial infusion of 5-fluorouracil (5-FU) and cisplatin (CDDP) in patients with advanced pancreatic cancer with or without liver metastasis

4140 Background: Liver metastasis is a common progression of pancreatic cancer. The purpose of this study was to examine the efficacy and safety of a modality therapy consisting of pancreatic and hepatic arterial infusion of 5-FU and CDDP in patients with advanced pancreatic cancer with or without liver metastasis. Methods: 12 patients with unresectable pancreatic cancer were enrolled in this study. 8 patients had locally advanced pancreatic cancer with no distant metastases (Group A). 4 patients had advanced pancreatic cancer with no distant metastases except to the liver (Group B). To restrict the blood flow into the pancreas and the liver, the peripancreatic artery (ex. dorsal pancreatic artery) were embolized superselectively with microcoils. The tip of the catheter was placed in the proper hepatic artery and the side hole was placed in the gastroduodenal artery for the patients of pancreas head cancer. The splenic artery and the common hepatic artery were used for the patients of pancreas body or tail cancer. The patients of Group A received both hepatic and pancreatic arterial injection chemotherapy to prevent liver metastasis. The arterial infusion chemotherapy consisted of 5-FU 250 mg/sqm administration as a 24-hr continuous arterial infusion and a bolus injection of CDDP 5mg/sqm three times a week for two weeks to all 12 patients. Consequently, 8 of 12 patients were administered 5-FU 600mg/sqm as a 5-hr continuous arterial infusion weekly. Results: 3 patients of Group A had PR (Overall response was 37.5%). None of Group B had CR or PR. Median survival time was 16.3 months for Group A and 6.1 months for Group B. One of Group A had liver metastasis after this treatment. Toxicity was predictable and in general manageable. One patient had the grade 4 hematotologic toxicity but recovered. Conclusions: In patients with unresectable pancreatic cancer, hepatic and pancreatic arterial injection chemotherapy after hemodynamic change is effective to treat main pancreatic tumor and to prevent liver metastasis. No significant financial relationships to disclose.

Weekly Hepatic Arterial Infusion of 5-Fluorouracil and Subsequent Systemic Chemotherapy for Liver Metastases from Colorectal Cancer

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

Hepatic arterial infusion of 5-fluorouracil and cisplatin for unresectable or recurrent hepatocellular carcinoma with tumor thrombus of the portal vein.

This study was designed to evaluate the efficacy of hepatic arterial infusion of 5-fluorouracil (5-FU) and cisplatin (CDDP) for unresectable or recurrent hepatocellular carcinoma (HCC) with tumor thrombus of the trunk or first branches of the portal vein (PVTT). Seven unresectable or recurrent HCC patients with PVTT were enrolled in this study. A one-week course of chemotherapy consisted of intraarterial administration of CDDP (10 mg on days 1-5) for 1 h and 5-FU (250 mg on days 1-5) for 24 h, followed by cessation of administration for the subsequent 2 days (days 6 and 7). Three or more sequential courses of chemotherapy were given through an implanted reservoir. Serum alpha-fetoprotein (AFP) levels before the chemotherapy were >20 ng/ml in six of the seven patients. Serum AFP levels were decreased in four of the six patients after chemotherapy, including two patients (cases 1 and 7) whose AFP levels later returned to normal. Six of the seven patients had measurable lesions in the liver, with a response rate of 33%. In three of the seven patients (43%), PVTTs decreased in size or disappeared after chemotherapy. The mean and median survival periods of all patients were 8.0 and. 7.5 months, respectively. The chemotherapy described in this report is beneficial in terms of survival for HCC patients with PVTT for whom transcatheter arterial embolization or surgical treatment is contraindicated.

Continuous hepatic arterial infusion of 5-fluorouracil for unresectable colorectal liver metastases: Phase II study

Although hepatic arterial infusion therapy (HAIT) with 5-fluoro-2'-deoxyuridine for colorectal liver metastases yielded a good response, the treatment may be limited by hepatic toxicities. This study was designed to evaluate HAIT by using 5-fluorouracil (5-FU), with the expectation of a good response with little hepatic toxicities. HAIT was begun at a dose of 360 mg/m2 of 5-FU for 7 days by using an extracorporeal infusion pump, followed by 180 mg/m2 of 5-FU for 21 days. After a 7-day interval, 180 mg/m2 of 5-FU was infused for 7 days; this 7-day infusion/7-day no infusion cycle was repeated. Fifty-three of the 68 patients who were referred to this study were evaluable. Complete response was observed in two patients and partial response in 25 (response rate of 50.9%), with a median survival time of 11 months: 18 months for 27 responders and 7 months for 26 nonresponders. Gastrointestinal complications were observed in 18 patients: abdominal pain in nine, vomiting in five, and bleeding in four. No hepatobiliary or hematologic toxicities occurred. Infusion-related complications occurred in 20 patients. HAIT with 5-FU may provide an effect similar to HAIT with fluoro-2' deoxyuridine but without hepatobiliary complications.

A 10-year survivor with unresectable hepatic metastases from sigmoid colon carcinoma treated with regional chemotherapy

We treated a man with unresectable hepatic metastases from sigmoid colon carcinoma who has since survived for more than 10 years. A sigmoidectomy with lymph node dissection was performed and a continuous hepatic arterial infusion of 5-fluorouracil (5-FU) with intermittent infusion of mitomycin C (MMC) was administered for about 3 months after this operation. The total doses of 5-FU and MMC were 16 g and 84 mg, respectively. Tegafur also was administered orally at a dose of 600 mg/day for about 8 months. The carcinoembryonic antigen (CEA) level (which had reached 4,409 ng/ml preoperatively) normalized 4 months after surgery, and still remains normal. Very few patients with unresectable hepatic metastases survive for 5 or more years. However, regional chemotherapy can be effective in some patients.

Continuous hepatic artery infusion of 5‐fluorouracil for metastatic colorectal cancer localised to the liver

Continuous regional delivery of chemotherapeutic agents offers the prospect of maximising dose intensity at the site of localised disease, while minimising systemic toxicity. This prospective phase II study evaluates the efficacy and toxicity of hepatic arterial infusion of 5-Fluorouracil (5-FU) via an implantable Infusaid pump in previously untreated patients with localised but unresectable hepatic metastases from colorectal cancer. In 25 patients the response rate was 56% and median survival was 15 months, comparable to previous reports utilising fluorodeoxyuridine (FUDR). Twenty per cent of patients (all responders) survived longer than three years. Systemic toxicity was trivial, and the practice of reducing the intensity of therapy when nausea or a rise in alkaline phosphatase occurred avoided the previously described local toxicity of biliary sclerosis seen frequently with FUDR. In selected patients, particularly those with more limited disease, this form of therapy is effective and well tolerated and warrants further evaluation as an alternative to FUDR.