Seung Woon Paik

Brivanib Versus Sorafenib As First-Line Therapy in Patients With Unresectable, Advanced Hepatocellular Carcinoma: Results From the Randomized Phase III BRISK-FL Study

PURPOSE Brivanib is a dual inhibitor of vascular-endothelial growth factor and fibroblast growth factor receptors that are implicated in the pathogenesis of hepatocellular carcinoma (HCC). Our multinational, randomized, double-blind, phase III trial compared brivanib with sorafenib as first-line treatment for HCC. PATIENTS AND METHODS Advanced HCC patients who had no prior systemic therapy were randomly assigned (ratio, 1:1) to receive sorafenib 400 mg twice daily orally (n = 578) or brivanib 800 mg once daily orally (n = 577). Primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), disease control rate (DCR) based on modified Response Evaluation Criteria in Solid Tumors (mRECIST), and safety. RESULTS The primary end point of OS noninferiority for brivanib versus sorafenib in the per-protocol population (n = 1,150) was not met (hazard ratio [HR], 1.06; 95.8% CI, 0.93 to 1.22), based on the prespecified margin (upper CI limit for HR ≤ 1.08). Median OS was 9.9 months for sorafenib and 9.5 months for brivanib. TTP, ORR, and DCR were similar between the study arms. Most frequent grade 3/4 adverse events for sorafenib and brivanib were hyponatremia (9% and 23%, respectively), AST elevation (17% and 14%), fatigue (7% and 15%), hand-foot-skin reaction (15% and 2%), and hypertension (5% and 13%). Discontinuation as a result of adverse events was 33% for sorafenib and 43% for brivanib; rates for dose reduction were 50% and 49%, respectively. CONCLUSION Our study did not meet its primary end point of OS noninferiority for brivanib versus sorafenib. However, both agents had similar antitumor activity, based on secondary efficacy end points. Brivanib had an acceptable safety profile, but was less well-tolerated than sorafenib.

HBeAg and hepatitis B virus DNA as outcome predictors during therapy with peginterferon alfa-2a for HBeAg-positive chronic hepatitis B

The aims of this study were to evaluate the usefulness of quantitative hepatitis B e antigen (HBeAg) values for predicting HBeAg seroconversion in patients treated with peginterferon alfa‐2a and to assess the dynamic changes in quantitative HBeAg during therapy, compared with conventional measures of serum hepatitis B virus DNA. Data were analyzed from a large, randomized, multinational phase III registration trial involving 271 HBV‐infected HBeAg‐positive patients who received peginterferon alfa‐2a plus oral placebo for 48 weeks. HBeAg levels were measured serially during therapy using a microparticle enzyme immunoassay validated with in‐house reference standards obtained from the Paul Ehrlich Institute (PEIU/mL). In patients who achieved HBeAg seroconversion, levels of HBeAg consistently decreased during treatment and remained at their lowest level during the 24 weeks of posttreatment follow‐up. After 24 weeks of treatment, 4% of patients with the highest levels of HBeAg (≥100 PEIU/mL) achieved HBeAg seroconversion, yielding a negative predictive value of 96%, which was greater than that obtained for levels of HBV DNA (86%). Late responders to peginterferon alfa‐2a could also be differentiated from nonresponders by continued decrease in HBeAg values, which were not evident by changes in HBV DNA. Conclusion: These analyses suggest quantitative HBeAg is a useful adjunctive measurement for predicting HBeAg seroconversion in patients treated with peginterferon when considering both sensitivity and specificity compared with serum HBV DNA. (HEPATOLOGY 2008;47:428–434.)

Clinical usefulness of carbohydrate antigen 19-9 as a screening test for pancreatic cancer in an asymptomatic population.

Background and Aim:  Although the prognosis for pancreatic cancer is generally poor, it is well known that the survival rate for resected pancreatic cancer is much higher than that for more conservative treatment. The importance of early detection is emphasized for resection of pancreatic cancer. Measurement of serum carbohydrate antigen (CA) 19‐9 has shown satisfactory sensitivity and predictive value in symptomatic patients, but no available data has been found on healthy asymptomatic subjects. Thus, the authors aimed to determine the clinical usefulness of CA 19‐9 as a screening tool for pancreatic cancer in asymptomatic subjects.

Ten-year outcomes of percutaneous radiofrequency ablation as first-line therapy of early hepatocellular carcinoma: Analysis of prognostic factors

BACKGROUND & AIMS The aim was to assess 10-year outcomes of radiofrequency ablation as a first-line therapy of early-stage hepatocellular carcinoma with an analysis of prognostic factors. METHODS From April 1999 to April 2011, 1305 patients (male:female=993:312; mean age, 58.4 years) with 1502 early-stage hepatocellular carcinomas (mean size, 2.2 cm) were treated with percutaneous radiofrequency ablation as a first-line option. Follow-up period ranged from 0.4 to 146.6 months (median, 33.4 months). We assessed the 10-year follow-up results of recurrences and survival with the analyses of prognostic factors. RESULTS Recurrences occurred in 795 patients (1-17 times), which were managed with various therapeutic modalities. The cumulative local tumor progression rates were 27.0% and 36.9% at 5 and 10 years, respectively, for which the only significant risk factor was large tumor size (B=0.584, p=0.001). Cumulative intrahepatic distant and extrahepatic recurrence rates were 73.1% and 88.5%, and 19.1% and 38.2% at 5 and 10 years, respectively. Corresponding overall survival rates were 59.7% and 32.3%, respectively. Poor survival was associated with old age (B=0.043, p=0.010), Child-Pugh class B (B=-1.054, p<0.001), absence of antiviral therapy during follow-up (B=-0.699, p=0.034), and presence of extrahepatic recurrence (B=0.971, p=0.007). CONCLUSIONS Ten-year survival outcomes after percutaneous radiofrequency ablation as a first-line therapy of hepatocellular carcinoma were excellent despite frequent tumor recurrences. Overall survival was influenced by age, Child-Pugh class, antiviral therapy, or extrahepatic recurrence.

Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: The SPACE trial

BACKGROUND & AIMS Transarterial chemoembolization with doxorubicin-eluting beads (DC Bead®; DEB-TACE) is effective in patients with Barcelona clinic liver cancer stage B hepatocellular carcinoma (HCC). The multikinase inhibitor sorafenib enhances overall survival (OS) and time-to-tumor progression (TTP) in patients with advanced HCC. This exploratory phase II trial tested the efficacy and safety of DEB-TACE plus sorafenib in patients with intermediate stage HCC. METHODS Patients with intermediate stage multinodular HCC without macrovascular invasion (MVI) or extrahepatic spread (EHS) were randomized 1:1 to DEB-TACE (150 mg doxorubicin) plus sorafenib 400 mg twice daily or placebo. The primary endpoint was TTP by blinded central review. Secondary endpoints included time to MVI/EHS, OS, overall response rate (ORR) using modified response evaluation criteria in solid tumors, disease control rate (DCR), time to unTACEable progression (TTUP), and safety. RESULTS Of 307 patients randomized, 154 received sorafenib and 153 received placebo. Median TTP for subjects receiving sorafenib plus DEB-TACE or placebo plus DEB-TACE was similar (169 vs. 166 days, respectively; hazard ratio (HR) 0.797, p=0.072). Median time to MVI/EHS (HR 0.621, p=0.076) and OS (HR 0.898, p=0.29) had not been reached. The ORRs for patients in the sorafenib and placebo groups with post-baseline scans were 55.9% and 41.3%, respectively, and the DCRs were 89.2% and 76.1%, respectively. TTUP was lower with sorafenib than with placebo (HR 1.586; 95% confidence intervals, 1.200-2.096; median 95 vs. 224 days). No unexpected adverse events related to sorafenib were observed. CONCLUSION Sorafenib plus DEB-TACE was technically feasible, but the combination did not improve TTP in a clinically meaningful manner compared with DEB-TACE alone.

Twenty‐four‐week clevudine therapy showed potent and sustained antiviral activity in HBeAg‐positive chronic hepatitis B

Clevudine is a pyrimidine analogue with potent and sustained antiviral activity against HBV. The present study evaluated the safety and efficacy of 30 mg clevudine once daily for 24 weeks and assessed the durable antiviral response for 24 weeks after cessation of dosing. A total of 243 hepatitis B e antigen (HBeAg)‐positive chronic hepatitis B patients were randomized (3:1) to receive clevudine 30 mg once daily (n = 182) or placebo (n = 61) for 24 weeks. Patients were followed for a further 24 weeks off therapy. Median serum HBV DNA reductions from baseline at week 24 were 5.10 and 0.27 log10 copies/mL in the clevudine and placebo groups, respectively (P < 0.0001). Viral suppression in the clevudine group was sustained off therapy, with 3.73 log10 reduction at week 34 and 2.02 log10 reduction at week 48. At week 24, 59.0% of patients in the clevudine group had undetectable serum HBV DNA levels by Amplicor PCR assay (less than 300 copies/mL). The proportion of patients who achieved normalization of alanine aminotransferase (ALT) levels was 68.2% in the clevudine group and 17.5% in the placebo group at week 24 (P < 0.0001). ALT normalization in the clevudine group was well maintained during post‐treatment follow‐up period. The incidence of adverse events (AEs) was similar between the clevudine group and the placebo group. No resistance to clevudine was detected with 24 weeks of administration of drug. Conclusion: A 24‐week clevudine therapy was well tolerated and showed potent and sustained antiviral effect without evidence of viral resistance during treatment period in HBeAg‐positive chronic hepatitis B. (HEPATOLOGY 2007;45:1172–1178.)

Patients with chronic hepatitis B treated with oral antiviral therapy retain a higher risk for HCC compared with patients with inactive stage disease

Background It is generally stated that oral antiviral therapy in patients with chronic hepatitis B (CHB) decreases the risk of developing hepatocellular carcinoma (HCC). Although oral nucleos(t)ide analogues (NUCs) may induce a state similar to inactive stage CHB, the long-term risk for HCC in patients treated with NUCs compared with inactive CHB is unclear. Methods A total of 1378 patients who were treatment naïve and started NUC therapy and 1014 patients with inactive stage CHB who were HBeAg-negative and continuously had hepatitis B DNA <2000 IU/mL during follow-up were enrolled. The NUC group was divided into two groups by continuous viral suppression: NUC complete responder (CR) group and NUC incomplete responder (IR) group. Cumulative HCC incidence rates were compared between the groups. Results The risk of developing HCC was significantly higher in the NUC CR group compared with the inactive CHB group, regardless of the presence of baseline liver cirrhosis (p<0.001). Risk factors associated with the development of HCC were treatment groups (p<0.001), age (p<0.001), sex (p<0.001) and the presence of liver cirrhosis at baseline (p=0.005). Of the NUC group, the cumulative incidence of HCC in the NUC IR group was significantly higher compared with the NUC CR group (p=0.028). Conclusions The use of potent oral antiviral therapy can effectively suppress HBV replication in patients with CHB. However, the risk of HCC development in patients treated with oral antiviral agent is still significantly higher than patients with inactive stage CHB.

Role of cyclooxygenase-2 and inducible nitric oxide synthase in pancreatic cancer

Abstract Background and Aim: Recently, it has been recognized that both cyclooxygenase‐2 (COX‐2) and inducible nitric oxide synthase (iNOS) produce important endogenous factors of human tumor progression. However, the clinicopathological and biological significance of the expression of COX‐2 and iNOS in pancreatic cancer remains unclear. The objective of this study is to find the possible roles and clinical significance of COX‐2 and iNOS expression in pancreatic cancer.

A 12‐week clevudine therapy showed potent and durable antiviral activity in HBeAg‐positive chronic hepatitis B

Clevudine is a nucleoside analog with an unnatural β‐L configuration. In a phase I/II clinical trial, once daily doses ranging from 10 to 200 mg for 28 days were well tolerated, and produced significant antiviral activity. The present study was conducted to assess the degree and durability of the antiviral response to 12 weeks of clevudine treatment, and to investigate its safety and tolerability. A total of 98 patients with HBeAg‐positive chronic hepatitis B were randomized to placebo (n = 32), 30‐mg clevudine (n = 32), and 50‐mg clevudine (n = 34) groups. Patients were followed up after 12 weeks of treatment for a further 24 weeks off‐therapy. Median serum hepatitis B virus DNA reductions from baseline at week 12 were 0.20, 4.49, and 4.45 log10 copies/mL in the placebo, 30‐mg clevudine, and 50‐mg clevudine groups, respectively (P < .0001). Posttreatment antiviral activities were sustained, with 3.32 and 2.99 log10 reductions at week 12 off‐therapy and 2.28 and 1.40 log10 reductions at week 24 off‐therapies in the 30‐ and 50‐mg clevudine groups, respectively. Median serum alanine aminotransferase (ALT) levels decreased markedly from baseline during clevudine treatment and were maintained below the upper limit of normal throughout the 24 weeks off‐therapy in the two clevudine‐treated groups. The incidences of adverse events and treatment‐emergent grade 3 or 4 laboratory abnormalities were similar for the three groups. In conclusion, clevudine showed potent antiviral activity during therapy and induced a sustained posttreatment antiviral effect for 6 months after a 12‐week treatment period, and this was associated with a sustained normalization of ALT levels. (HEPATOLOGY 2006;43:982–988.)

Healing rate of EMR-induced ulcer in relation to the duration of treatment with omeprazole.

BACKGROUND Although EMR-induced ulcers heal faster and recur less often than noniatrogenic gastric ulcers, there is no consensus regarding the duration of therapy for these ulcers. This study prospectively evaluated healing of EMR-induced ulcers according to the duration of omeprazole therapy. METHODS A total of 69 patients were randomly assigned, after EMR, to treatment with omeprazole (20 mg per day) for 7 days (1-week group) or with omeprazole (20 mg per day) for 28 days (4-week group). Four weeks after EMR, ulcer size and stage were compared with those of the initial EMR-induced ulcer. Each patient kept a daily diary of drugs consumed and ulcer-related symptoms during the 4-week period after EMR. RESULTS Thirty-four patients were randomized to the 4-week group, and 26 were randomized to the 1-week group. No significant differences were observed between the two groups at 4 weeks after EMR in terms of ulcer reduction ratio (p=0.29) or stage (p=0.11). In addition, no difference was observed between the two groups with respect to ulcer-related symptoms or use of additional gastric-coating medication (p=0.48). CONCLUSIONS For EMR-induced ulcer, treatment with omeprazole for 1 week is equivalent to treatment for 4 weeks. Short-term therapy with omeprazole can be considered for EMR-induced ulcer.