Hepatic Arterial Floxuridine Research Articles

Hepatic artery infusion pump for nasopharyngeal carcinoma with liver metastasis

To evaluate the benefits and risks of hepatic artery infusion (HAI) gemcitabine and floxuridine (FUDR) in patients with nasopharyngeal carcinoma liver metastases. HAI catheter systems were implanted under the guide of digital subtract angiography (DSA) in 16 patients with unresectable nasopharyngeal carcinoma liver metastases. HAI gemcitabine and FUDR in combination with radiotherapy and systemic chemotherapy were delivered. Disease control rate (DCR) of intrahepatic lesions is 100%, objective response rate (ORR) of intrahepatic lesions is 87.5%, including 4 patients (25%) with complete response (CR), 10 patients (62.5%) with partial response (PR) and 2 patients (12.5%) with stable disease (SD). The median overall survival (mOS) was 30 months. There was no significant difference between patients with < 9 intrahepatic lesions and patients with ≥ 9 intrahepatic lesions (31 months vs. 24 months, P = 0.562). Patients without extrahepatic metastases has longer survival than patients with extrahepatic metastases (31 months vs. 17 months, P = 0.005). In all 72 cycles of HAI, the main grade 3/4 toxicities related to HAI include: leukopenia occur in 8 cycles (11.1%), thrombocytopenia in 5 cycles (6.9%), AST/ALT elevation in 12 cycles (16.7). Catheter related complications occurred in 2 patients (12.5%). HAI gemcitabine and FUDR is effective to improve DCR of intrahepatic lesions and prolong mOS for patients with nasopharyngeal carcinoma liver metastases, and is associated with a relative low rate of toxicity.

High-Dose Radiation in Liver-Directed Concurrent Chemoradiotherapy Is Effective for Locally Advanced BCLC Stage C Hepatocellular Carcinoma

Recent advances in radiotherapy (RT) technologies, such as intensity-modulated radiotherapy (IMRT), have enabled the delivery of tumoricidal doses to intrahepatic malignancies while protecting the normal organs. This study evaluated the effects of high-dose RT among patients with locally advanced Barcelona Clinic Liver Cancer stage C hepatocellular carcinoma (BCLC-C HCC). This study retrospectively evaluated data from 637 patients who received RT with concurrent hepatic arterial floxuridine for BCLC-C HCC without distant metastases during 2005–2016. These cases included 514 patients (81%) who were treatment-naïve. Receiver operating characteristic curve analysis showed that the optimal cut-off for the biologically effective dose (BED) was 72 Gy, and the patients were divided into ≥72 Gy (n=101) and BED <72 Gy (n=536). In the BED ≥72 Gy and <72 Gy groups, 94 of 101 patients (93%) and 128 of 536 patients (24%) used IMRT, respectively. The median overall survival (OS) was 16.3 months, with a median follow-up of 12.4 months (19.8 months among patients who were alive). The BED ≥72 Gy and <72 Gy groups had median OSs of 39.7 months and 14.5 months, and 1-year OS rates of 73% and 58%, respectively (P <.001). The 1-year local control (LC) rate was significantly higher in the high-dose group (95% vs. 78%; P <.001). After propensity score matching, 83 matched pairs were created, and the high-dose group still had significantly better 1-year LC rate (95% vs. 82%; P =.006) and 1-year OS rate (71% vs. 62%; P =.01). In the multivariate model, the BED ≥72 Gy was an independent predictor of LC (hazard ratio [HR], 0.26; 95% confidence interval [CI], 0.11–0.61; P =.002) and OS (HR 0.50; 95% CI, 0.33–0.77, P =.002). The surgical conversion rate was significantly higher in the high-dose group (20% vs. 12%, P =.03), with markedly increased median OS among patients who underwent surgery (103.8 months vs. 13.1 months; P <.001). There were no significant differences in gastrointestinal bleeding or radiation-induced liver disease. High-dose RT, which was enabled by IMRT increased LC and OS after liver-directed chemoradiotherapy for locally advanced BCLC-C HCC. It also increased the surgical conversion rate, which contributed to the improved OS.

Intrahepatic Cholangiocarcinoma

Despite data suggesting a rising worldwide incidence, intrahepatic cholangiocarcinoma (IHC) remains an uncommon disease. This study analyzes changes in IHC frequency, demographics, and treatment outcome in a consecutive and single institutional cohort. Consecutive patients with confirmed IHC seen and treated over a 16-year period were included. The trend in IHC frequency over the study period was compared with that of hilar cholangiocarcinoma patients (HCCA) seen during the same time. Demographics and patient disposition, histopathologic, treatment, recurrence, and survival data were analyzed; changes in these variables over time were assessed. From December 1990 through July 2006, 594 patients were evaluated (IHC = 270, HCCA = 324). Over the study period, the average annual increase in new IHC patients was 14.2% (P < 0.001). Relative to HCCA, the proportional increase in IHC was nearly 3-fold, and new IHC patients have outnumbered those with HCCA by 2:1 over the last 3 years. Conditions associated with IHC were rarely seen, with only 7 patients having a history of sclerosing cholangitis and/or inflammatory bowel disease and none with hepatolithiasis or biliary parasitic disease; however, heavy tobacco use (27%) and diabetes mellitus (16.4%) were particularly prevalent. The majority of patients were not candidates for resection, most commonly because of advanced hepatic disease. After resection (n = 82), median disease-specific survival was 36 months; recurrence was observed in 62.2% of patients at a median follow-up of 26 months, with the liver remnant involved most frequently (62.7%). Multiple hepatic tumors (P < 0.001), regional nodal involvement (P = 0.012), and large tumor size (P = 0.016) independently predicted poor recurrence-free survival. Most patients (n = 115, 73.7%) with unresectable disease were treated with chemotherapy, either systemic alone (n = 75) or combined with regional hepatic arterial floxuridine (FUDR) (n = 28). Compared with the first 10 years of the study (1990-2000), the last 6 years saw an overall improvement in disease-specific survival for all patients (22 vs. 12 months, P = 0.002), which was particularly notable for patients with unresectable disease (15 vs. 6 months, P = 0.003). At Memorial Sloan-Kettering Cancer Center, IHC incidence has increased dramatically in the last 16 years. Resection offers the best opportunity for long-term survival but is possible in the minority, and patients with large, node-positive or multifocal IHC seem to derive little benefit. Establishing and maintaining control of the intrahepatic disease remains the biggest problem for all IHC patients. The recent increase in survival seems largely because of improved nonoperative therapy for unresectable disease.

Phase II Trial of High-Dose Conformal Radiation Therapy With Concurrent Hepatic Artery Floxuridine for Unresectable Intrahepatic Malignancies

A phase II trial was conducted to determine if high-dose radiation with concurrent hepatic arterial floxuridine would improve survival in patients with unresectable intrahepatic malignancies. Three-dimensional conformal high-dose radiation therapy was delivered concurrently with hepatic arterial floxuridine in 128 patients. The radiation dose was based on a normal-tissue complication probability model and subjected the patient to an estimated maximum risk of radiation-induced liver disease of 10% to 15%. The study design provided more than 80% power to detect a two-fold increase in median survival compared with historical controls at a 5% significance level. The median radiation dose delivered was 60.75 Gy (1.5-Gy fractions bid). At a median follow-up time of 16 months (26 months in patients who were alive) the median survival was 15.8 months (95% CI, 12.6 to 18.3 months), significantly longer than in the historical control. The actuarial 3-year survival was 17%. The total dose was the only significant predictor of survival. Primary hepatobiliary tumors had a significantly greater tendency to remain confined to the liver than did colorectal cancer metastases. Overall toxicity was acceptable, with 27 patients (21%) and 11 patients (9%) developing grade 3 and 4 toxicity, respectively, and one treatment-related death. The results suggest that, compared with historical controls, high-dose focal liver irradiation with hepatic artery floxuridine prolongs survival in patients with unresectable chemotherapy-refractory metastatic colorectal cancer and primary hepatobiliary tumors. This provides a rationale for intensification of local therapy for unresectable hepatobiliary cancers and integration of this regimen with newer systemic therapy for patients with colorectal cancer.

Multidetector CT arteriography with volumetric three-dimensional rendering to evaluate patients with metastatic colorectal disease for placement of a floxuridine infusion pump.

We sought to evaluate the usefulness of multidetector CT (MDCT) arteriography with volumetric three-dimensional (3D) rendering to depict the hepatic vascular anatomy. Our study population was patients who had undergone arterial mapping in preparation for placement of a hepatic arterial floxuridine infusion pump for treatment of metastatic hepatic colorectal carcinoma. We retrospectively reviewed the medical records of 26 patients with hepatic colorectal metastases who had been scheduled for implantation of a hepatic artery pump. Before surgery, all patients underwent MDCT arteriography with volumetric 3D rendering of the hepatic vessels. The axial and 3D arteriograms were evaluated for their usefulness in depicting hepatic arterial anatomy. Subsequently, three patients also underwent catheter angiography. Twenty-two of the 26 patients imaged had a hepatic artery floxuridine infusion pump implanted. Results of the CT arteriography were correlated with findings at surgery or on catheter angiography if surgery was not performed. MDCT arteriography correctly revealed hepatic arterial anatomy in all 25 patients with angiographic or surgical confirmation. One patient with aberrant hepatic arterial anatomy did not have angiographic or surgical confirmation. Classic hepatic arterial anatomy was identified in 16 (64%) of 25 patients. The following hepatic arterial variants were found in one patient each: the common hepatic artery arising directly from the aorta; a replaced left hepatic artery; an accessory right hepatic artery; a replaced left hepatic artery and accessory right hepatic artery; a replaced right hepatic artery; a right hepatic arterial branch arising early (before the origin of the gastroduodenal artery); and replaced right and left hepatic arteries. Three patients were not suitable candidates for placement of a hepatic artery floxuridine pump. The patient who had no angiographic or surgical confirmation was also not considered a good surgical candidate because of replaced right and left hepatic arteries. Two patients (8%) had an accessory left hepatic artery. MDCT arteriography with volumetric 3D rendering is an accurate, noninvasive method of depicting hepatic arterial anatomy and, therefore, of selecting patients with colorectal metastatic disease who could benefit from hepatic artery pump implantation. Catheter angiography provides no additional information, and we have eliminated it as a routine preoperative imaging examination.

Management of symptomatic locoregional recurrence during regional chemotherapy for colorectal liver metastases.

The incidence of symptomatic locoregional recurrence is doubled in patients receiving regional chemotherapy with hepatic arterial floxuridine infusion (HAI) compared with that in those with colorectal liver metastases treated by symptom control. This study assessed the management of symptomatic locoregional recurrence in HAI-treated patients with colorectal liver metastases. A retrospective review of all patients with colorectal liver metastases treated by HAI in one hospital over a 10-year period was carried out and the management of those who developed symptomatic locoregional recurrence was studied. Twenty-three (14 per cent) of 166 HAI-treated patients with colorectal liver metastases developed symptoms of locoregional recurrence. Liver metastases were responding to HAI at the onset of symptoms in 19 (ten abdominal, nine pelvic recurrence) of the 23 patients. Resection of abdominal recurrence was possible in seven of the ten patients, with a median hospital stay of 14 days; there was one perioperative death. Resected patients survived a median of 15 months after resection of the recurrence, with five of seven remaining free of symptoms of locoregional recurrence. In contrast, six of nine HAI-responding patients with pelvic recurrence treated by external beam radiotherapy died from uncontrolled symptomatic pelvic disease. Resection of abdominal recurrence achieved worthwhile palliation in patients with HAI-controlled liver metastases, but palliation of pelvic recurrence by irradiation was unsatisfactory.

Combined-Modality Treatment for Resectable Metastatic Colorectal Carcinoma to the Liver: Surgical Resection of Hepatic Metastases in Combination With Continuous Infusion of Chemotherapy—An Intergroup Study

Despite technical improvements that have minimized the morbidity and mortality of hepatic surgery, the long-term outcome of resection of hepatic metastases of colorectal cancer remains poor, with the majority of patients experiencing treatment failure in the liver. Because arterial chemotherapy regimens targeted to the liver have demonstrated high response rates, an intergroup trial of adjuvant therapy for patients undergoing hepatic resection of liver metastases from colorectal cancer was initiated. Patients with one to three potentially resectable metastases were randomized preoperatively to receive no further therapy (control arm, 56 patients) or postoperative hepatic arterial floxuridine combined with intravenous continuous-infusion fluorouracil (chemotherapy arm, 53 patients). After exclusion of patients identified as ineligible for the planned treatment at the time of surgery, there were 45 control patients and 30 on the chemotherapy arm. The study was powered to evaluate improvement in time to recurrence and hepatic disease-free survival, not overall survival. The 4-year recurrence-free rate was 25% for the control arm and 46% for the chemotherapy group (P =.04). The 4-year liver recurrence-free rate was 43% in the control group and 67% in the chemotherapy group (P =.03). The median survival of the 75 assessable patients was 49 months for the control arm and 63.7 months for the chemotherapy arm (P =.60). The median survival of all 109 patients was 47 months for the control arm compared with 34 months for the chemotherapy arm (P =.19) These data demonstrate that adjuvant intra-arterial and intravenous chemotherapy was beneficial in prolonging time to recurrence and pre-venting hepatic recurrence after hepatic resection of colorectal cancer.

P53 mutation and response to hepatic arterial floxuridine in patients with colorectal liver metastases.

To establish the relationship between the number and site of p53 genomic mutations in metastatic colorectal cancer, and the response to hepatic arterial floxuridine. Liver metastasis biopsies were collected, at the time of laparotomy for hepatic arterial cannulation. in 28 patients with metachronous colorectal liver metastases. p53 Gene mutations were assessed using reverse transcription, nested polymerase chain reaction, single strand conformational polymorphism and gene sequencing. Chemotherapy response was determined from computerised liver tomograms after 4 months of treatment. Liver metastasis p53 mutation was identified in 21 (75%), and p53 "hot spot" mutation in 11 (39%) patients. There was a significantly lower prevalence (Fisher's, P=0.001) of patients with p53 "hot spot"-mutated liver metastases in stable disease and partial response (5/22) than in progressive (6/6) disease groups. Significantly fewer (Mann-Whitney U, P=0.002) p53 "hot spot" mutations/biopsy were observed in liver metastases from stable disease and partial response (median 0, iqr. 0-0) than in progressive (median 1, iqr 1-2) disease patients. p53 "Hot spot"-mutated liver metastases were associated with significantly shorter survival times (logrank P=0.05) after hepatic arterial floxuridine. Significant response or survival-time differences by total or L2/L3 zinc-binding site p53 mutations were not detected. The results support a role for p53 "hot spot" mutations in colorectal liver metastasis resistance to fluorinated pyrimidines, and suggest that the presence of such mutations may be a contra-indication to treatment of colorectal liver metastases with hepatic arterial floxuridine.

Systemic Irinotecan or Regional Floxuridine Chemotherapy Prolongs Survival After Hepatic Cryosurgery in Patients with Metastatic Colon Cancer Refractory to 5-Fluorouracil

Most colorectal cancers metastatic to the liver are resistant to chemotherapy and are not amenable to surgical resection. This study evaluated our 6-year experience (July 1992—July 1998) in treating patients with unresectable hepatic colorectal metastases refractory to systemic 5-fluorouracil (5-FU). One hundred fifty-three patients underwent cryosurgical ablation (CSA) of 5-FU—resistant hepatic metastases. The patients then received either hepatic arterial floxuridine (FUDR), systemic CPT-11, or no postoperative adjuvant chemotherapy. Number, size, and location of hepatic metastases, carcinoembryonic antigen (CEA) levels, and type of postoperative treatment were analyzed. One to 15 lesions were frozen (median number, 3; median size, 6 cm), for a total of 73 synchronous and 80 metachronous lesions. Overall median survival was 28.4 months from the date of diagnosis of liver metastases and 16.1 months from the time of CSA. After cryosurgery alone, median survival was 13 months, which was significantly shorter than the post-CSA survival of 23.6 months with adjuvant CPT-11 and 21.2 months with hepatic FUDR ( P = 0.007). Predictors of survival included preoperative CEA, postoperative reduction in CEA, and adjuvant chemotherapy ( P < 0.05). Neither size, number of lesions, nor tumor location impacted survival. At a median follow-up of 13 months, 67% of patients have recurred (35% hepatic, 16% extrahepatic, and 49% both). Twenty percent of the recurrences were in the lobe of the CSA site. The 25 patients who underwent a second CSA had a median survival of 28.4 months from CSA and 40 months from the date of diagnosis of liver metastases. These data indicate that CSA offers an effective alternative for unresectable patients resistant to 5-FU. Systemic CPT-11 or regional FUDR may further prolong survival after CSA.

Treatment interruptions and complications with two continuous hepatic artery floxuridine infusion systems in colorectal liver metastases

Continuous hepatic artery floxuridine infusion benefits patients with colorectal liver metastases. Implanted infusion pumps are more expensive but may result in fewer treatment interruptions than when using an external pump connected to a port. We have assessed device-related complications, treatment interruptions and added nurse interventions in 95 patients undergoing a total of 959 treatment cycles via either implanted pump (64 patients) or port (31 patients). Compared with the implanted pump, the port was associated with a significant increase (P < 0.003) in catheter blockage (24/31 vs 2/64 patients), treatment interruption (15/265 vs 12/694 treatments) and added nurse intervention (80/265 vs 20/694 treatments). Survival in patients with colorectal liver metastases is limited and the complications of treatment should be kept to a minimum. An implanted subcutaneous infusion pump offers the benefit of a 3-fold lower incidence of treatment interruption and a 30-fold lower incidence of catheter blockage than when continuous infusion chemotherapy is given via an external infusion device.

Hepatic artery dexamethasone infusion inhibits colorectal hepatic metastases: A regional antiangiogenic therapy

A randomized trial treating colorectal hepatic metastases demonstrated that hepatic arterial floxuridine (FUdR) with dexamethasone increased tumor response compared with hepatic arterial FUdR alone (Cancer 1992;69:327-34). The mechanism of this improvement is unclear. We investigated the effect of hepatic arterial dexamethasone with or without FUdR on the growth of colorectal hepatic metastases in an animal model. BD-IX rats were inoculated intrasplenically with 10(7) K12/TRb colon cancer cells on day 0. On day 14, the hepatic metastases were counted and hepatic arterial catheters placed for chemotherapy. Forty-eight animals were randomized to 4 groups for 14 days of infusion with heparinized saline alone (group A), heparinized saline with dexamethasone 0.03 mg/kg/d (group B), heparinized saline with FUdR 2 mg/kg/d (group C), or heparinized saline with dexamethasone 0.03 mg/kg/d plus FUdR 2 mg/kg/d (group D). The hepatic metastases were recounted by laparotomy on day 28. Response in each rat was expressed in terms of percentage change in number of hepatic nodules between the number of hepatic nodules seen on days 14 and 28. In vitro chemosensitivity of K12/TRb to dexamethasone with or without FUdR was examined using an MTT (3-(4,5-dimethylthiazole-2-yl-2,5-diphenyltetrazolium bromide; Sigma, St. Louis, MO, U.S.A.) assay. The effect of dexamethasone on tumor-induced angiogenesis was tested using an in vivo assay. The mean percentage change in tumor nodules was +129% in group A, +17% in group B, -4% in group C, and -29% in group D (p = 0.002 A vs. B, p = 0.04 C vs. D). The MTT assay showed that dexamethasone had no direct effect on K12/TRb growth or on tumor FUdR sensitivity. Dexamethasone inhibited K12/TRb-induced angiogenesis in vivo. Hepatic arterial dexamethasone is effective in treating colorectal hepatic metastases and is more effective when combined with hepatic arterial FUdR. The antiangiogenic activity of dexamethasone may partially contribute to its efficacy.

Hepatobiliary Toxicity of 5-Fluoro-2??-Deoxyuridine

Biliary sclerosis remains the dose-limiting toxicity in a subset of patients receiving hepatic arterial (HA) floxuridine (FUDR) for the treatment of hepatic malignancy. To investigate the etiology of FUDR-associated sclerosing cholangitis, portal vein catheters were placed in mixed-breed hounds (N = 4) and connected to an implanted infusion pump system. Floxuridine 0.3 mg/kg/day was infused for 49 to 77 days each, as a continuous infusion. Cholangiograms were performed before and after infusion, and weekly liver function tests were obtained. The results were compared to dogs (N = 6) that received HA FUDR 0.3 mg/kg/d x 30 days, and dogs (N = 5) that received HA saline for 100 days. Elevation in the serum glutamic pyruvic transaminase and alkaline phosphatase, indistinguishable from the HA group, was seen in all four dogs with portal vein infusion. Maximum bilirubin levels ranged from 0.6 to 3.0 (mean 1.7), compared to a range of 6.4 to 28 (mean 13.4) for the HA dogs. Cholangiograms demonstrated hepatic volume loss consistent with hepatocellular injury, but no biliary sclerosis. These data suggest that sclerosing cholangitis resulting from intra-arterial infusion of FUDR is unlikely to be due to metabolites of the drug excreted in the bile, but due to direct toxicity to the biliary tree.

Development of a radioimmunoassay for neurone specific enolase (NSE) and its application in the study of patients receiving intra hepatic arterial streptozotocin and floxuridine

A radioimmunoassay has been developed for neurone specific enolase (NSE) and used to measure serum NSE levels in patients with neuroendocrine and non-neuroendocrine tumours following intra hepatic arterial chemotherapy. Ten patients were studied, 7 receiving streptozotocin and floxuridine for neuroendocrine tumours and three receiving cisplatinum for non-neuroendocrine neoplasms. All ten patients had liver metastases. In patients with tumours of neuroendocrine origin, a significant increase in serum NSE was recorded within 24 h of therapy. Slight increases in serum NSE levels were also recorded in three patients with non neuroendocrine tumours. These increases may reflect lysis of neuroendocrine cells within the tumour. Raised levels in non-neuroendocrine tumour patients may reveal damage done to healthy neuronal and neuroendocrine cells during treatment. NSE may be a useful marker of the extent of cell death following chemotherapy.

Floxuridine-Associated Sclerosing Cholangitis A Dog Model

The authors developed a dog model for the biliary sclerosis that occurs as a severe complication of protracted hepatic arterial floxuridine (FUDR) infusions (using implanted drug delivery systems) in patients with hepatic cancers. Infusaid pumps attached to hepatic arterial catheters were used for protracted infusions in ten mixed breed hounds. To allow repeated cholangiograms, the animals' gallbladders were removed and catheters connected to subcutaneous infusion ports were positioned in the cystic ducts. Five treated dogs received FUDR 0.3 mg/kg/day through the pump for a total of 30 days. Five control dogs received only saline through the pump. Cholangiograms were obtained before and after treatment in all animals. In the control group, serum liver function test results and the cholangiographic appearance of the biliary tree remained within normal limits. By contrast, in the FUDR-treated group, serum glutamic-pyruvic transaminase and alkaline phosphatase progressively rose above normal, starting 2-3 weeks into FUDR infusion, followed by hyperbilirubinemia (7-28 mg/dl peak levels) beginning 4 to 6 weeks after initiation of the drug infusion. Cholangiograms revealed focal strictures involving the central bile ducts (five dogs) and diffuse attenuation of the intrahepatic ducts (four dogs). Thus, the liver function abnormalities and the cholangiographic findings in this dog model mimic the hepatobiliary toxicity in sensitive patients receiving similar treatment.

Treatment of metastatic colorectal cancer with hepatic artery combination chemotherapy.

Treatment of patients with hepatic metastases from colorectal cancer using hepatic artery floxuridine (FUDR) has been reported to induce high partial remission rates and perhaps prolonged survival. However, several investigators, including our own group, have obtained response rates of only 30%. Alkylating agents can increase the efficacy of antimetabolites. Based on clinical data and pharmacokinetic considerations the authors have combined FUDR with mitomycin C and carmustine (BCNU) by the arterial route. Thirty-six patients with hepatic metastases from colorectal cancer received FUDR 0.3 mg/kg/day 2 weeks of 4, mitomycin C 15 mg/M2 over 1 hour every 8 weeks, and BCNU 150 mg/M2 over 1 hour every 8 weeks--all via the hepatic artery using Infusaid pumps (Infusaid, Sharon, MA). The mitomycin C and BCNU were alternated monthly at the start of each FUDR cycle. The patient characteristics were as follows: 78% hepatomegaly, 44% also extrahepatic tumor, 42% prior systemic 5-fluorouracil. Combined partial and complete response rates were independent of prior chemotherapy: 71% if untreated, 67% with prior 5-fluorouracil. Median survival for the combined response/stable disease group was 13.7 months from the start of hepatic artery chemotherapy, and 4.5 months for the six nonresponders. Based on these data the authors have begun a randomized trial comparing single-agent FUDR to the FUDR, mitomycin C, BCNU combination.