Thomas Decaens

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.

Brivanib in Patients With Advanced Hepatocellular Carcinoma Who Were Intolerant to Sorafenib or for Whom Sorafenib Failed: Results From the Randomized Phase III BRISK-PS Study

PURPOSE Brivanib is a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor receptors implicated in tumorigenesis and angiogenesis in hepatocellular carcinoma (HCC). An unmet medical need persists for patients with HCC whose tumors do not respond to sorafenib or who cannot tolerate it. This multicenter, double-blind, randomized, placebo-controlled trial assessed brivanib in patients with HCC who had been treated with sorafenib. PATIENTS AND METHODS In all, 395 patients with advanced HCC who progressed on/after or were intolerant to sorafenib were randomly assigned (2:1) to receive brivanib 800 mg orally once per day plus best supportive care (BSC) or placebo plus BSC. The primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), and disease control rate based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) and safety. RESULTS Median OS was 9.4 months for brivanib and 8.2 months for placebo (hazard ratio [HR], 0.89; 95.8% CI, 0.69 to 1.15; P = .3307). Adjusting treatment effect for baseline prognostic factors yielded an OS HR of 0.81 (95% CI, 0.63 to 1.04; P = .1044). Exploratory analyses showed a median time to progression of 4.2 months for brivanib and 2.7 months for placebo (HR, 0.56; 95% CI, 0.42 to 0.76; P < .001), and an mRECIST ORR of 10% for brivanib and 2% for placebo (odds ratio, 5.72). Study discontinuation due to treatment-related adverse events (AEs) occurred in 61 brivanib patients (23%) and nine placebo patients (7%). The most frequent treatment-related grade 3 to 4 AEs for brivanib included hypertension (17%), fatigue (13%), hyponatremia (11%), and decreased appetite (10%). CONCLUSION In patients with HCC who had been treated with sorafenib, brivanib did not significantly improve OS. The observed benefit in the secondary outcomes of TTP and ORR warrants further investigation.

Liver resection for transplantable hepatocellular carcinoma: long-term survival and role of secondary liver transplantation.

Background/Purpose:Liver transplantation (LT) is the best theoretical treatment of hepatocellular carcinoma (HCC) fulfilling the Milan criteria (TNM stages 1–2). However, LT is limited by organ availability and tumor progression on the waiting list. Liver resection (LR) may represent an alternative in these patients. The aim of this study is to report the results of LR in transplantable patients. Patients:From 1990 to 2007, 274 patients underwent liver resection for HCC. Sixty-seven (24%) met the Milan criteria on pathologic study of the specimen. Ten were TNM stage 1 and 57 stage 2 and all had chronic liver disease. There were 56 men and 11 women with a mean age of 63. LR included 12 major hepatectomies, 14 bisegmentectomies, 14 segmentectomies, and 27 nonanatomic resections. Thirty-seven resections were performed through a laparoscopic approach and there were only 8 open resections since 1998. Results:Three patients died postoperatively (4.5%), none after laparoscopic resection. Morbidity rate was 34%. After a mean follow-up of 4.8 years, 36 patients (54%) developed intrahepatic tumor recurrence. Twenty-eight (77%) were again transplantable of which 16 (44%) were transplanted. Two additional patients underwent pre-emptive LT (ie before recurrence). When considering 44 patients <65 years at the time of resection (ie upper age limit for LT), the rates of recurrence, transplantable recurrence, and intention to treat salvage transplantation (patients with transplantable recurrence actually transplanted) were 59%, 80%, and 61%, respectively. Overall and disease free 5-year survival rates were 72% and 44%, respectively. Survival was not influenced by TNM stage 1 or 2, AFP level, tumor differentiation, or the presence microscopic vascular invasion. Survival after salvage LT was 70% and 87% when calculated from the date of LT and LR, respectively. Conclusion:LR for small solitary HCC in compensated cirrhosis yields an overall survival rate comparable to upfront LT. Despite a significant recurrence rate, close imaging monitoring after resection allows salvage LT in 61% of patients with recurrence on intention to treat analysis.

Impact of pretransplantation transarterial chemoembolization on survival and recurrence after liver transplantation for hepatocellular carcinoma.

The actual impact of transarterial chemoembolization before liver transplantation (LT) for hepatocellular carcinoma (HCC) on patient survival and HCC recurrence is not known. Between 1985 and 1998, 479 patients with HCC in 14 French centers were evaluated for LT. Among these 479 patients, this case‐control study included 100 patients who received transarterial chemoembolization before LT (TACE group) and 100 control patients who did not receive chemoembolization (no‐TACE group). Patients and controls were matched for the pre‐LT tumor characteristics, the period of transplantation, the time spent on the waiting list, and pre‐ and posttransplantation treatments. Kaplan‐Meier estimates were calculated 5 years after LT and were compared with the log‐rank test. The mean waiting time before LT was 4.2 ± 3.2 months in the TACE group and 4.3 ± 4.4 months in the no‐TACE group. The median number of TACE procedures was 1 (range: 1‐12). Demographic data, median alpha‐fetoprotein level (21.6 ng/mL and 22.0 ng/mL, respectively), and pre‐ and post‐LT morphologic characteristics of the tumors did not differ in the TACE and no‐TACE groups. Overall 5‐year survival was 59.4% with TACE and 59.3% without TACE (ns). Survival rates did not differ significantly between the two groups with respect to the time on the waiting list, the tumor diameter, or the type of TACE (selective or nonselective). In the TACE group, 30 patients had tumor necrosis ≥80% on the liver explant with a 5‐year survival rate of 63.2%, compared with 54.2% among their matched controls (P = 0.9). In conclusion, with a mean waiting period of 4.2 months and 1 TACE procedure, pre‐LT TACE does not influence post‐LT overall survival and disease‐free survival. (Liver Transpl 2005;11:767–775.)

Impact of UCSF criteria according to pre‐ and post‐OLT tumor features: Analysis of 479 patients listed for HCC with a short waiting time

Orthotopic liver transplantation (OLT) indication for hepatocellular carcinoma (HCC) is currently based on the Milan criteria. The University of California, San Francisco (UCSF) recently proposed an expansion of the selection criteria according to tumors characteristics on the explanted liver. This study: 1) assessed the validity of these criteria in an independent large series and 2) tested for the usefulness of these criteria when applied to pre‐OLT tumor evaluation. Between 1985 and 1998, 479 patients were listed for liver transplantation (LT) for HCC and 467 were transplanted. According to pre‐OLT (imaging at date of listing) or post‐OLT (explanted liver) tumor characteristics, patients were retrospectively classified according to both the Milan and UCSF criteria. The 5‐yr survival statistics were assessed by the Kaplan‐Meier method and compared by the log‐rank test. Pre‐OLT UCSF criteria were analyzed according to an intention‐to‐treat principle. Based on the pre‐OLT evaluation, 279 patients were Milan+, 44 patients were UCSF+ but Milan− (subgroup of patients that might benefit from the expansion), and 145 patients were UCSF− and Milan−. With a short median waiting time of 4 months, 5‐yr survival was 60.1 ± 3.0%, 45.6 ± 7.8%, and 34.7 ± 4.0%, respectively (P < 0.001). The 5‐yr survival was arithmetically lower in UCSF+ Milan− patients compared to Milan+ but this difference was not significant (P = 0.10). Based on pathological features of the explanted liver, 5‐yr survival was 70.4 ± 3.4%, 63.6 ± 7.8%, and 34.1 ± 3.1%, in Milan+ patients (n = 184), UCSF+ Milan− patients (n = 39), and UCSF− Milan− patients (n = 238), respectively (P < 0.001). However, the 5‐yr survival did not differ between Milan+ and UCSF+ Milan− patients (P = 0.33). In conclusion, these results show that when applied to pre‐OLT evaluation, the UCSF criteria are associated with a 5‐yr survival below 50%. Their applicability is therefore limited, despite similar survival rates compared to the Milan criteria, when the explanted liver is taken into account. Liver Transpl 12:1761‐1769, 2006.

Stabilization of β‐catenin affects mouse embryonic liver growth and hepatoblast fate

During hepatogenesis, after the liver has budded out of the endoderm, the hepatoblasts quickly expand and differentiate into either hepatocytes or biliary cells, the latter of which arise only within the ductal plate surrounding the portal vein. Because the Wnt/β‐catenin pathway is involved in liver homeostasis and regeneration and in liver carcinogenesis, we investigated here a role for Wnt/β‐catenin signaling in the embryonic liver. A cyclization recombination (Cre)/locus of X‐over P1 (loxP) strategy was chosen to perform adenomatous polyposis coli (Apc) invalidation in order to activate ectopic β‐catenin signaling in hepatoblasts; an appropriate transgenic model expressing the Cre recombinase was used. Phenotypic and immunolocalization studies, together with messenger RNA analyses, by microarray and real‐time quantitative polymerase chain reaction approaches were performed on this model during normal hepatogenesis. The loss of Apc allowed β‐catenin activation in the hepatoblasts after the formation of the liver bud and led to embryonic lethality. In this model, the liver became hypoplastic, and hepatocyte differentiation failed, whereas β‐catenin–activated ducts developed and gave rise to fully differentiated bile ducts when transplanted into adult recipient livers. Microarray analyses suggested that β‐catenin plays a role in repressing the hepatocyte genetic program and remodeling the ductal plate. According to these data, in normal embryonic livers, β‐catenin was transiently activated in the nascent bile ducts. Conclusion: We demonstrated a key role for the Wnt/β‐catenin pathway in liver embryonic growth and in controlling the fate of hepatoblasts, preventing them from differentiating toward the hepatocyte lineage, and guiding them to biliary ductal morphogenesis. (HEPATOLOGY 2007.)

Targeting the mTOR pathway in hepatocellular carcinoma: Current state and future trends

Mechanistic target of rapamycin (mTOR) regulates cell growth, metabolism and aging in response to nutrients, cellular energy stage and growth factors. mTOR is frequently up-regulated in cancer including hepatocellular carcinoma (HCC) and is associated with bad prognosis, poorly differentiated tumors, and earlier recurrence. Blocking mTOR with rapamycin and first generation mTOR inhibitors, called rapalogs, has shown promising reduction of HCC tumor growth in preclinical models. Currently, rapamycin/rapalogs are used in several clinical trials for the treatment of advanced HCC, and as adjuvant therapy in HCC patients after liver transplantation and TACE. A second generation of mTOR pathway inhibitors has been developed recently and is being tested in various clinical trials of solid cancers, and has been used in preclinical HCC models. The results of series of clinical trials using mTOR inhibitors in HCC treatment will emerge in the near future.

Comparison of two techniques of transarterial chemoembolization before liver transplantation for hepatocellular carcinoma : A case-control study

Supraselective transarterial chemoembolization (STACE) more efficiently targets chemotherapy delivered via the feeding arterial branches of the tumor than does conventional transarterial chemoembolization (TACE). However, the hypothesis of its greater efficacy compared with the latter is subject to controversy. The aim of the present study was to compare STACE to conventional TACE in a controlled study of candidates for liver transplantation (LT) for hepatocellular carcinoma (HCC). Patients were matched for factors associated with HCC recurrence and survival. Sixty patients were included: 30 who were treated with STACE and 30 treated with conventional TACE. The 2 groups were similar in terms of matched criteria. In the overall population (uni‐ and multinodular HCC), there was no marked difference between the 2 groups in 5‐year disease‐free survival: 76.8% vs. 74.8%. In sensitivity analysis of patients considered to be the best candidates for TACE (uninodular HCC ≤5 cm), there was a trend toward significance between STACE and TACE in 5‐year disease‐free survival: 87% vs. 64% (P = 0.09). The only factor associated with complete tumor necrosis was STACE in the overall population (30.8% vs. 6.9%, P = 0.02), with a similar trend in the subgroup of patients with a single nodule (33.3% vs. 6.7%, P = 0.06), whereas the mean number of procedures was similar in the 2 groups (mean, 1.3 procedures; range 1‐5 procedures; P = NS). STACE is more efficient at inducing complete tumor necrosis in the liver. This study observed trends toward improvement in the disease‐free survival of patients with uninodular HCC ≤5 cm. Future studies focusing on such patients are warranted. Liver Transpl, 2007.

Objective response by mRECIST as a predictor and potential surrogate end-point of overall survival in advanced HCC

BACKGROUND & AIMS The Modified Response Evaluation Criteria in Solid Tumors (mRECIST) was developed to overcome the limitations of standard RECIST criteria in response assessment of hepatocellular carcinoma (HCC). We aimed to investigate whether objective response by mRECIST accurately predicted overall survival (OS) in patients with advanced HCC treated with systemic targeted therapies and also to preliminarily assess this end-point as a potential surrogate of OS. METHODS Individual patient data from the BRISK-PS randomized phase III trial comparing brivanib vs. placebo (the first to prospectively incorporate mRECIST) were used to analyze objective response as a predictor of OS in a time-dependent covariate analysis. Patients with available imaging scans during follow-up were included (n=334; 85% of those randomized). Moreover, a correlation of the survival probability in deciles vs. the observed objective response was performed to evaluate its suitability as a surrogate end-point. RESULTS Objective response was observed in 11.5% and 1.9% of patients treated with brivanib and placebo respectively, and was associated with a better survival (median OS 15.0 vs. 9.4months, p<0.001). In addition, objective response had an independent prognostic value (HR=0.48; 95% confidence interval [CI], 0.26-0.91, p=0.025) along with known prognostic factors. Finally, objective response showed promising results as a surrogate of OS in this trial (R=-0.92; 95% CI, -1 to -0.73, p<0.001). It was an early indicator of the treatment effect (median time to objective response was 1.4months). CONCLUSIONS Objective response by mRECIST in advanced HCC predicts OS and thus can be considered as a candidate surrogate end-point. Further studies are needed to support this finding. LAY SUMMARY There is a need to identify surrogate end-points for overall survival in advanced hepatocellular carcinoma. We studied patients from the phase III BRISK trial, comparing brivanib treatment with placebo after sorafenib progression. We demonstrate that objective response is an independent predictor of survival and qualifies as a potential surrogate end-point for overall survival in this patient population. CLINICAL TRIAL NUMBER NCT00825955.

Natural history and therapeutic management of recurrent hepatocellular carcinoma after liver transplantation

While the natural history and appropriate diagnostic and management practices are relatively well defined for hepatocellular carcinoma (HCC), data are scarce concerning the characteristic features and treatment modalities for recurrent HCC after liver transplantation. The time of recurrence appears to impact survival more significantly than localization, but to date, guidelines for therapeutic management of recurrent HCC have not been established. Data in the literature shows that late and unifocal recurrence has a better prognosis when treated by surgery or radiofrequency. In the event of early recurrence, surgery cannot be recommended due to the lack of evidence and the high risk of advanced disease. Systemic therapy can be discussed in a situation of multifocal recurrence. Proliferative signal inhibitors exhibit both immunosuppressive and antiproliferative properties and liver transplantation teams tend to introduce such treatment despite the lack of extensive data.