Preliminary efficacy, safety, pharmacokinetics, pharmacodynamics and quality of life study of pegylated recombinant human arginase 1 in patients with advanced hepatocellular carcinoma.

This study was designed to evaluate the efficacy, safety profile, pharmacokinetics, pharmacodynamics and quality of life of pegylated recombinant human arginase 1 (Peg-rhAgr1) in patients with advanced hepatocellular carcinoma (HCC). Patients were given weekly doses of Peg-rhAgr1 (1600 U/kg). Tumour response was assessed every 8 weeks using RECIST 1.1 and modified RECIST criteria. A total of 20 patients were recruited, of whom 15 were deemed evaluable for treatment efficacy. Eighteen patients (90%) were hepatitis B carriers. Median age was 61.5 (range 30-75). Overall disease control rate was 13%, with 2 of the 15 patients achieving stable disease for >8 weeks. The median progression-free survival (PFS) was 1.7 (95% CI: 1.67-1.73) months, with median overall survival (OS) of all 20 enrolled patients being 5.2 (95% CI: 3.3-12.0) months. PFS was significantly prolonged in patients with adequate arginine depletion (ADD) >2 months versus those who had ≤2 months of ADD (6.4 versus 1.7 months; p = 0.01). The majority of adverse events (AEs) were grade 1/2 non-hematological toxicities. Transient liver dysfunctions (25%) were the most commonly reported serious AEs and likely due to disease progression. Pharmacokinetic and pharmacodynamic data showed that Peg-rhAgr1 induced rapid and sustained arginine depletion. The overall quality of life of the enrolled patients was well preserved. Peg-rhAgr1 is well tolerated with a good toxicity profile in patients with advanced HCC. A weekly dose of 1600 U/kg is sufficient to induce ADD. Significantly longer PFS times were recorded for patients who had ADD for >2 months.

A phase 1 dose-escalating study of pegylated recombinant human arginase 1 (Peg-rhArg1) in patients with advanced hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) cells are auxotrophic for arginine, depletion of which leads to tumour regression. The current study evaluated safety, pharmacokinetics (PK)/ pharmacodynamics (PD) parameters, and potential anti-tumor activity of pegylated recombinant human arginase 1 (peg-rhArg1) in advanced HCC patients. METHODS: Eligibility criteria included advanced HCC with measurable lesions, Child-Pugh A or B, and adequate organ function. Initial single IV bolus was followed by weekly doses of peg-rhArgI escalated from 500 U/kg to 2500 U/kg in a 3 + 3 design. RESULTS: Fifteen patients were enrolled at weekly doses of 500 U/kg (n = 3), 1000 U/kg (n = 3), 1600 U/kg (n = 3) and 2500 U/kg (n = 6). The median age was 57 years (33-74); 87% were hepatitis B carriers and 47% had prior systemic treatment. The most commonly reported drug-related non-haematological adverse events (AEs) were diarrhea (13.3%), abdominal discomfort (6.7%) and nausea (6.7%). No drug-related haematological AEs were seen. Only 1 of the six patients that received 2500U/kg peg-rhArg1 experienced DLT (grade 4 bilirubin elevation) and thus the maximum tolerated dose was 2500 U/kg. PK and PD analysis indicated that peg-rhArg1 was efficacious in inducing arginine depletion in a dose-dependent manner. Adequate arginine depletion dose was achieved in the 1,600-2,500 U/kg range and therefore the optimal biological dose was at 1600 U/kg, which was chosen as the recommended dose. The best response was stable disease for >8 weeks in 26.7% of the enrolled patients. CONCLUSION: Peg-rhArg1 has manageable safety profile and preliminary evidence of activity in advanced HCC patients.

Risk factors and prognostic factors of local recurrence after radiofrequency ablation of hepatocellular carcinoma.

BACKGROUND: Local recurrence rates after radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC) vary from 2% to 36% in the literature. Limited data were available about the prognostic significance of local recurrence. STUDY DESIGN: Between April 2001 and March 2006, 273 patients with 357 hepatocellular carcinoma nodules underwent RFA, with radiologically complete tumor ablation after a single session of RFA. The risk factors of local recurrence and its impact on overall survival of patients were analyzed. RESULTS: With a median followup period of 24 months, local recurrence occurred in 35 patients (12.8%). By multivariate analysis, tumor size > 2.5 cm was the only independent risk factor for local recurrence. There was no notable difference in overall survival between patients with and without local recurrence. By multivariate analysis, local recurrence more than 12 months after RFA and complete response after additional treatment of local recurrence were associated with better overall survival in patients with local recurrence. CONCLUSIONS: This study demonstrated that tumor size > 2.5 cm was the main risk factor for local recurrence after RFA of hepatocellular carcinoma. Our data suggested that additional aggressive treatment of local recurrence aimed at complete tumor response improves overall survival of patients. Late local recurrence was also associated with better prognosis, suggesting different tumor biology between early and late local recurrent tumors after RFA.

Incomplete ablation after radiofrequency ablation of hepatocellular carcinoma: analysis of risk factors and prognostic factors.

BACKGROUND: Complete ablation rates after a single session of radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC) vary from 48% to 97%. Limited data are available regarding risk factors and prognostic significance of incomplete ablation. METHODS: Between April 2001 and March 2006, 298 patients underwent RFA of 393 HCC nodules with an intent of complete ablation after a single session. Risk factors for incomplete ablation and its effect on overall survival were analyzed. RESULTS: Two hundred seventy-three (91.6%) underwent complete tumor ablation, whereas the other 25 (8.4%) underwent incomplete tumor ablation after a single session of RFA. By multivariate analysis, tumor size > 3 cm (P = .049) was found to be the only independent risk factor for incomplete ablation. There was no statistically significant difference in overall survival between patients with complete and incomplete ablation. By univariate analysis, no previous transarterial chemoembolization (TACE), preoperative serum alfa-fetoprotein < or = 100 microg/mL, and complete response after further treatment of incomplete ablation were associated with better overall survival in patients with incomplete ablation. CONCLUSIONS: This study demonstrated that incomplete ablation after RFA of HCC was associated with tumor size > 3 cm. Our data also suggest that aggressive further treatment of tumors with incomplete ablation aiming at complete tumor response improves overall survival.

Analysis of recurrence pattern and its influence on survival outcome after radiofrequency ablation of hepatocellular carcinoma.

BACKGROUND: Radiofrequency ablation (RFA) is an effective local ablation therapy for hepatocellular carcinoma (HCC) with favorable long-term outcome. There is no data on the analysis of recurrence pattern and its influence on long-term survival outcome after RFA in HCC patients. AIM OF STUDY: To evaluate the tumor recurrence pattern and its influence on long-term survival in patients with HCC treated with RFA. PATIENTS AND METHODS: From April 2001 to January 2005, 209 patients received RFA using internally cooled electrode as the sole treatment modality for HCC. Among them, 117 patients (56%) had unresectable HCC because of bilobar disease, poor liver function, and/or high medical risk for resection; whereas 92 patients (44%) underwent RFA as the primary treatment for small resectable HCC. The ablation procedure was performed through percutaneous (n=101), laparoscopic (n=17), or open approaches (n=91). The tumor recurrence pattern and long-term survival were analyzed. Multivariate analysis was carried out to identify independent prognostic factors affecting the overall survival of patients. RESULTS: The mortality and morbidity rates were 0.9 and 15.7%, respectively. Complete tumor ablation was achieved in 192 patients (92.7%). With a median follow-up period of 26 months, local recurrence occurred in 28 patients (14.5%). Same segment and different segment intrahepatic recurrence occurred in 30 patients (15.6%) and 78 patients (40.6%), respectively. Twenty patients (10.4%) developed distant extrahepatic metastases. The overall 1-, 3-, and 5-year survival rates were 87.2, 66.6, and 42%, respectively. Different segment intrahepatic recurrence and distant recurrence after RFA carried significant poor prognostic influence on overall survival outcome. Using multivariate analysis, Child-Pugh grade (risk ratio [RR]=2.918, 95% confident interval [CI] 1.704-4.998, p=0.000), tumor size (RR=1.231, 95% CI 1.031-1.469, p=0.021), and pattern of recurrence (risk ratio [RR]=1.464, 95% CI 1.156-1.987, P=0.020) were identified as independent prognostic factors for overall survival. CONCLUSION: The tumor recurrence pattern after RFA carries significant prognostic value in relation to overall survival. Long-term regular surveillance and aggressive treatment strategy are required for patients with different segment intrahepatic recurrence to optimize the benefits of RFA.

Comparison of percutaneous and surgical approaches for radiofrequency ablation of small and medium hepatocellular carcinoma.

HYPOTHESIS: Radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) can be performed by percutaneous or surgical approach. Tumor size is an important consideration while deciding the treatment approach. DESIGN: Case series with prospective data collection. SETTING: A tertiary referral center. PATIENTS: A total of 228 patients who underwent RFA of small ( .99). Complication rate (P < .001) and hospital stay (P < .001) were higher with the surgical approach. One-year and 3-year survival rates were 91% and 71%, respectively, in the percutaneous group, and 89% and 57%, respectively, in the surgical group (P = .30). In patients with medium HCC, the complete ablation rate was similar between the surgical and the percutaneous groups (92% vs 95%; P = .48), and the complication rate was also comparable (P = .17). The 1-year and 3-year survival rates were 92% and 68%, respectively, in the surgical group, significantly superior to the corresponding rates of 81% and 42% in the percutaneous group (P = .03). CONCLUSIONS: In patients with small HCC, the percutaneous approach achieved similar tumor control with lower morbidity compared with the surgical approach and should be the preferred approach provided that tumor location is suitable. For medium HCC, the surgical approach seems to achieve better overall survival and may be a preferred option.

Duodenopleural fistula formation after percutaneous radiofrequency ablation for recurrent hepatocellular carcinoma.

Radiofrequency ablation (RFA) is a treatment option in the management of unresectable or recurrent hepatocellular carcinoma (HCC). It can be performed either through laparotomy or in a minimally invasive manner by percutaneous, laparoscopic or thoracoscopic routes. Percutaneous RFA is associated with reduced surgical trauma and thus can be performed in patients with significant comorbidities. The procedure can be repeated after short intervals for sequential ablation of multiple liver lesions. However, the associated risks should not be underestimated. This is the first report of a rare complication of duodeno-pleural fistula after percutaneous RFA of a recurrent subcapsular HCC. The risk of bowel perforation during the ablation of subcapsular HCC requires special attention, since only the position of the tip of the electrode, but not the zone of ablation, can be assessed accurately by imaging during the procedure. Our case demonstrated that there was leakage of bowel content from the duodenal injury site into the pleural cavity through the RFA track. Subsequent uncontrolled infection resulted in empyema thoracis and led to the death of the patient.

High serum vascular endothelial growth factor levels predict poor prognosis after radiofrequency ablation of hepatocellular carcinoma: importance of tumor biomarker in ablative therapies.

BACKGROUND: Radiofrequency ablation (RFA) is a recently developed treatment for hepatocellular carcinoma (HCC). Thus far, the prognostic impact of tumor biomarkers has not been evaluated in this treatment. High serum level of vascular endothelial growth factor (VEGF) has been shown to predict microscopic vascular invasion and metastasis in HCC. This study investigated the prognostic significance of pre-treatment serum VEGF level in patients with HCC undergoing RFA treatment. METHODS: Serum VEGF levels were measured using enzyme-linked immunosorbent assay in 120 patients with HCC undergoing RFA, and in 15 healthy controls. Serum VEGF levels were correlated with clinicopathological features of the HCC patients. The prognostic significance of serum VEGF levels was assessed by univariate and multivariate analyses. RESULTS: The median serum VEGF level in the HCC patients was 240 pg/mL (range 17-1162), significantly higher than that of healthy controls (p = .024). The serum VEGF levels were significantly correlated with platelet counts (r = .487, p < .001) but not other clinicopathological features. Patients with serum VEGF level > 240 pg/mL had worse overall and recurrence-free survival compared with those with serum VEGF level > 240 pg/mL (p = .005 and .002, respectively). By multivariate analysis, serum VEGF level was a significant prognostic factor of both overall and recurrence-free survival. CONCLUSIONS: High pre-treatment serum VEGF levels predict poor prognosis after RFA of HCC. This study highlights the importance of tumor biomarker as a prognostic predictor in ablative therapy for HCC, which has an intrinsic problem of unavailability of histopathological prognostic features.

Comparable survival in patients with unresectable hepatocellular carcinoma treated by radiofrequency ablation or transarterial chemoembolization.

HYPOTHESIS: The survival benefits of radiofrequency ablation (RFA) and transarterial chemoembolization (TACE) are similar for patients with unresectable hepatocellular carcinoma amenable to either treatment. DESIGN: Retrospective comparative study. SETTING: Tertiary care institution. PATIENTS: From February 22, 2001, to March 10, 2004, 91 patients with unresectable hepatocellular carcinoma (tumor diameter <5 cm and <4 tumor nodules) treated by either TACE or RFA were analyzed from a prospective database. MAIN OUTCOME MEASURES: The treatment-related morbidity, mortality, overall survival, and time to disease progression. RESULTS: Forty patients received TACE and 51 patients received RFA during the study period. Demographic data were comparable in both groups of patients. The treatment-related morbidities of TACE and RFA were 10% and 28%, respectively (P = .04). There was no treatment-related mortality in either group. There was 1 patient (2%) with complete tumor remission in the TACE group, and the complete ablation rate in the RFA group was 96%. The time to disease progression was similar in both groups (P = .95). The overall survival rates at 1 and 2 years were 80% and 58%, respectively, in the TACE group and 82% and 72%, respectively, in the RFA group (P = .21). CONCLUSIONS: The overall survival and time for disease progression were similar in both groups of patients. In terms of the survival result, the efficacies of RFA and TACE were comparable for patients with unresectable hepatocellular carcinoma.

Radiofrequency ablation for hepatocellular carcinoma and metastatic liver tumors: a comparative study.

BACKGROUND: This study compared the effectiveness of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) and liver metastases. METHODS: We compared the outcomes of 240 patients with HCC and 44 patients with liver metastases treated with RFA. Data were prospectively collected and retrospectively analyzed. Effects of different variables on recurrences were studied. RESULTS: A total of 406 tumor nodules were treated. The median size of the largest ablated tumor was 2.5 cm, and the median tumor number was 1. Complete tumor ablation was achieved in 91.2%. Local recurrence rate was 15.4% after a median follow-up of 24.5 months. There was no significant impact of tumor pathology on local recurrence. However, patients with liver metastasis had higher extrahepatic recurrence rate (P = 0.019) and shorter disease-free survival (P = 0.007). Patients with multiple tumors had higher local (P = 0.047) and extrahepatic (P = 0.019) recurrence rates than those with a solitary tumor. Tumor size had an impact on local recurrence rate only in patients with liver metastasis with a higher rate in those with tumor > 2.5 cm in diameter (P = 0.028). CONCLUSIONS: Tumor pathology does not appear to have a significant impact on local recurrence rates. RFA is effective in local tumor control for both HCC and liver metastasis.

Effectiveness of radiofrequency ablation for hepatocellular carcinomas larger than 3 cm in diameter.

HYPOTHESIS: Radiofrequency ablation is a safe and effective treatment for hepatocellular carcinomas 3.1 to 8.0 cm in diameter. DESIGN: Case series with prospective data collection. SETTING: Tertiary referral center. PATIENTS: Eighty-six patients with hepatocellular carcinoma treated with radiofrequency ablation from May 1, 2001, to December 31, 2002, were placed into categories of those with tumors 3 cm or smaller (group 1, n = 51) and those with tumors 3.1 to 8.0 cm (group 2, n = 35) in diameter. INTERVENTIONS: Radiofrequency ablation was performed with a single or cluster cool-tip electrode. The choice of treatment route was based on tumor size and position. MAIN OUTCOME MEASURES: Complication, treatment mortality, and complete ablation rates. RESULTS: Radiofrequency ablation was performed percutaneously in 26 patients in group 1 and 9 patients in group 2, with laparoscopy in 2 patients in group 1 and 1 patient in group 2, and with open operation in 23 patients in group 1 and 25 patients in group 2. The complication rates were 12% and 17% in group 1 and group 2, respectively (P =.48); treatment mortality rates were 0% and 3%, respectively (P =.41). Complete ablation rates after a single session of ablation assessed by means of computed tomography 1 month after treatment were 94% and 91% in group 1 and group 2, respectively (P =.68). CONCLUSION: Radiofrequency ablation is a safe and effective treatment for patients with hepatocellular carcinomas 3.1 to 8.0 cm in diameter.

Radiofrequency ablation for subcapsular hepatocellular carcinoma.

BACKGROUND: Limited data from recent studies suggested an increased risk of bleeding complications, needle-track seeding, and local recurrence after radiofrequency ablation (RFA) of subcapsular hepatocellular carcinoma (HCC). METHODS: Between May 2001 and October 2002, 80 patients underwent RFA of 104 HCC nodules. Forty-eight patients had subcapsular HCC (group I), whereas the other 32 patients did not have subcapsular HCC (group II). RFA was performed via celiotomy, laparoscopy, or a percutaneous approach. Subcapsular HCCs were ablated by indirect puncture through nontumorous liver, and the needle track was thermocoagulated. RESULTS: There were no significant differences between groups in treatment morbidity (14.6% vs. 15.6%; P =.898), mortality (2.1% vs. 0%; P = 1.000), complete ablation rate after a single session (89.4% vs. 96.9%; P =.392), local recurrence rate (4.3% vs. 12.5%; P =.216), recurrence-free survival (1 year: 60.9% vs. 49.2%; P =.258), or overall survival (1 year: 88.3% vs. 79.4%; P =.441). After a median follow-up of 13 months, no needle-track seeding or intraperitoneal metastasis was observed. CONCLUSIONS: This study shows that the results of RFA for subcapsular HCCs are comparable to those of RFA for nonsubcapsular HCCs. Subcapsular HCC should not be considered a contraindication for RFA treatment.

Learning curve for radiofrequency ablation of liver tumors: prospective analysis of initial 100 patients in a tertiary institution.

OBJECTIVE: This study aims to evaluate the effect of operator experience on the treatment outcomes of radiofrequency ablation (RFA) for malignant liver tumors. SUMMARY BACKGROUND DATA: RFA is gaining popularity as the ablative therapy of choice for liver tumors. It is generally considered a simple and safe technique, and little attention has been paid to the importance of operator experience in this treatment. A learning curve in this treatment modality has not been documented before. PATIENTS AND METHODS: The clinical data and treatment outcomes of the initial 100 patients undergoing RFA for liver tumors (hepatocellular carcinoma, n = 84; metastasis, n = 15; cholangiocarcinoma n = 1) were collected prospectively. All patients were managed by a single team of surgeons and interventional radiologists. The data of the first 50 patients (group I) and the second 50 patients (group II) were compared. RESULTS: RFA was performed by percutaneous (group I, n = 22; group II, n = 19), open (group I, n = 26; group II, n = 30) or laparoscopic (group I, n = 2; group II, n = 1) approach. In group I, 30 patients (60%) had a solitary tumor and 20 (40%) had multiple tumors; in group II, 35 patients (70%) had a solitary tumor and 15 (30%) had multiple tumors (P = 0.295). The size of the largest tumor was comparable between groups I and II (median, 2.8 cm in both groups; P = 0.508). Group II had significantly shorter hospital stay (median, 4.0 versus 5.5 days; P = 0.048), lower morbidity rate (4% versus 16%; P = 0.046) and higher complete ablation rate (100% versus 85.7%; P = 0.006) than group I. There was 1 hospital death (2%) in group I and 0 in group II. By multivariate analysis, treatment period (group I versus group II) was an independent significant factor affecting the morbidity rate and complete ablation rate. CONCLUSIONS: A low complication rate and a high complete ablation rate could be achieved with the accumulated experience from the first 50 cases of RFA for liver tumors by a specialized team. This study demonstrates that there is a significant learning curve in RFA for liver tumors.