The Hong Kong consensus statements on unresectable hepatocellular carcinoma: narrative review and update for 2021.

Background and Objective: Hong Kong, like many parts of Asia, faces a high burden of hepatocellular carcinoma (HCC) caused by high endemic rates of hepatitis B virus infection. Hong Kong clinicians have developed a high level of expertise in HCC treatment across surgical, transarterial, ablative, radiotherapeutic and systemic modalities. This publication summarizes the latest evidence-based recommendations on how these modalities should be used. Methods: In two meetings held in 2020, a multidisciplinary panel of surgeons, oncologists and interventional radiologists performed a narrative review of evidence on the management of HCC, with an emphasis on treatment of HCC not amenable to surgical resection. Close attention was paid to new evidence published since the previous version of these statements in 2018. Key Content and Findings: The expert panel has formulated 60 consensus statements to guide the staging and treatment of unresectable HCC. Since the previous version of these statements, considerable additions have been made to the recommendations on use of targeted therapies and immunotherapies because of the large volume of new evidence. Conclusions: Our consensus statements offer guidance on how to select HCC patients for surgical or non-surgical treatment and for choosing among non-surgical modalities for patients who are not candidates for resection. In particular, there is a need for more evidence to aid physicians in the selection of second-line systemic therapies, as currently most data are limited to patients with disease progression on first-line sorafenib.

Suppression of Slit3 induces tumor proliferation and chemoresistance in hepatocellular carcinoma through activation of GSK3ß/ß-catenin pathway.

BACKGROUND: It is essential to understand the mechanisms responsible for hepatocellular carcinoma (HCC) progression and chemoresistance in order to identify prognostic biomarkers as well as potential therapeutic avenues. Recent findings have shown that SLIT3 appears to function as a novel tumor suppressor gene in various types of cancers, yet its clinical correlation and role in HCC has not been understood clearly. METHODS: We determined the transcript levels of Slit3 in tumor and adjacent normal tissues within two cohorts (N = 40 and 25) of HCC patients, and correlated the gene expression with the clinicopathological data. Subsequently, the functional effects and underlying molecular mechanisms of Slit3 overexpression and/or repression were studied using cell-line and mouse models. RESULTS: Our results demonstrated a repression in Slit3 expression in nearly 50% of the HCC patients, while the overall expression of Slit3 inversely correlated with the size of the tumor in both cohorts of patients. Stable down-regulation of Slit3 in HCC cell-lines induced cell proliferation in vitro and tumor growth in vivo, while stable Slit3 overexpression repressed these effects. Molecular investigations showed that the stable Slit3 repression-induced cell proliferation was associated with a higher expression of ß-catenin and a repressed GSK3ß activity. Moreover, Slit3-repression induced chemoresistance to sorafenib, oxaliplatin and 5-FU through impairment of ß-catenin degradation and induction of cyclin D3 and survivin levels. The effects induced by stable Slit3-repression were diminished by transient repression of ß-catenin by siRNA approach. CONCLUSION: This study suggests that Slit3 acts as a tumor suppressor in HCC by repressing the tumor growth and thus tumor progression. Low Slit3 level indicates a poor response of HCC cells to chemotherapy. Restoration or overexpression of Slit3 is a potential therapeutic approach to repress the tumor growth and enhance the efficacy of chemotherapeutic agents.

Serine peptidase inhibitor Kazal type 1 (SPINK1) as novel downstream effector of the cadherin-17/ß-catenin axis in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Previously, we reported that cadherin-17 (CDH17) and its related CDH17/ß-catenin axis may be responsible for inducing HCC in a subset of patients exhibiting CDH17 over-expression. Here we aimed at obtaining a better understanding of the CDH17-related HCC biology and to obtain further indications for the design of targeted therapies in CDH17 over-expressing HCC patients. RESULTS: We found that SPINK1 acts as a downstream effector of the CDH17/ß-catenin axis in HCC. In addition, we found that SPINK1 expression exhibited a positive correlation with CDH17 expression in human HCCs and was over-expressed in up to 70% of the tumors. We identified SPINK1 as a downstream effector of the CDH17/ß-catenin axis using a spectrum of in vitro assays, including gene expression modulation and inhibitor assays, bioinformatics analyses and luciferase reporter assays. These in vitro results were validated in primary human HCCs, including the observation that alteration in ß-catenin expression (a core component of the CDH17/ß-catenin axis) in tumors affects SPINK1 serum levels in HCC patients. Similar to CDH17, SPINK1 expression in HCC cells was found to be associated with specific tumor-related properties via activating the c-Raf/MEK/ERK pathway. CONCLUSIONS: Our current data substantiate our knowledge on the role of CDH17 in the biology of HCC and suggest that components of the CDH17/ß-catenin axis may serve as therapeutic targets in CDH17 over-expressing HCC patients.

Emergence of CD26+ Cancer Stem Cells with Metastatic Properties in Colorectal Carcinogenesis.

Colorectal cancer results from genetic aberrations which accumulate over a long period of time, with malignant and metastatic properties acquired at a relatively late stage. A subpopulation of CD26+ colorectal cancer stem cells are known to be implicated in metastasis. We quantified CD26+ cancer cells in 11 primary tumor samples by flow cytometry, and showed that tumors having confirmed or suspected metastases harbored a relatively high CD26+ level in these samples. We hypothesized that this subpopulation of cancer stem cells arises in the late stage of carcinogenesis from the bulk of tumor daughter cells which are CD26-. The manipulation of PIK3CA and TP53, two genes commonly deregulated in the late stage, had an effect on the maintenance of the CD26+ cell population. When CD26- tumor daughter cells were sorted and cultured, the emergence of tumor spheres containing CD26+ cells occurred. These findings shed light to the origin of colorectal cancer stem cells with metastatic properties, which has an implication on conventional treatments by surgery or adjuvant chemotherapy for tumor debulking.

Differences in health-related quality of life between European and Asian patients with hepatocellular carcinoma.

AIM: The aim of this study is to explore the possible effects of clinical and cultural characteristics of hepatocellular carcinoma on patients' health-related quality of life (HRQoL). METHODS: Patients with hepatocellular carcinoma from Asian and European countries completed the EORTC QLQ-C30 and the EORTC QLQ-HCC18. Comparisons were made using Student's t-test and Wilcoxon rank-sum test with method of false discovery to correct multiple comparisons. Multiway analysis of variance and model selection were used to assess the effects of clinical characteristics and geographic areas. RESULTS: Two hundred and twenty-seven patients with hepatocellular carcinoma completed questionnaires. After adjusting for demographic and clinical characteristics, Asian patients still had significantly better HRQoL scores in emotional functioning, insomnia, (QLQ-C30) and in sexual interest (QLQ-HCC18). We also found an interaction in physical functioning (QLQ-C30) and fatigue (QLQ-HCC18) between geographic region and marital status, married European had worse HRQoL scores than Asian singles. CONCLUSIONS: Both clinical characteristics and geographic areas affected the HRQoL in with hepatocellular carcinoma. Cultural differences and clinical differences in the pattern of disease due to active surveillance of Asian countries may explain the results.

TSC1/2 mutations define a molecular subset of HCC with aggressive behaviour and treatment implication.

OBJECTIVE: We investigated the mutational landscape of mammalian target of rapamycin (mTOR) signalling cascade in hepatocellular carcinomas (HCCs) with chronic HBV background, aiming to evaluate and delineate mutation-dependent mechanism of mTOR hyperactivation in hepatocarcinogenesis. DESIGN: We performed next-generation sequencing on human HCC samples and cell line panel. Systematic mutational screening of mTOR pathway-related genes was undertaken and mutant genes were evaluated based on their recurrence. Protein expressions of tuberous sclerosis complex (TSC)1, TSC2 and pRPS6 were assessed by immunohistochemistry in human HCC samples. Rapamycin sensitivity was estimated by colony-formation assay in HCC cell lines and the treatment was further tested using our patient-derived tumour xenograft (PDTX) models. RESULTS: We identified and confirmed multiple mTOR components as recurrently mutated in HBV-associated HCCs. Of significance, we detected frequent (16.2%, n=18/111) mutations of TSC1 and TSC2 genes in the HCC samples. The spectrum of TSC1/2 mutations likely disrupts the endogenous gene functions in suppressing the downstream mTOR activity through different mechanisms and leads to more aggressive tumour behaviour. Mutational disruption of TSC1 and TSC2 was also observed in HCC cell lines and our PDTX models. TSC-mutant cells exhibited reduced colony-forming ability on rapamycin treatment. With the use of biologically relevant TSC2-mutant PDTXs, we demonstrated the therapeutic benefits of the hypersensitivity towards rapamycin treatment. CONCLUSIONS: Taken together, our findings suggest the significance of previously undocumented mutation-dependent mTOR hyperactivation and frequent TSC1/2 mutations in HBV-associated HCCs. They define a molecular subset of HCC having genetic aberrations in mTOR signalling, with potential significance of effective specific drug therapy.

A Phase I/II Multicenter Study of Single-Agent Foretinib as First-Line Therapy in Patients with Advanced Hepatocellular Carcinoma.

Purpose: This phase I/II single-arm study evaluated the safety, pharmacokinetics, pharmacodynamics, and activity of foretinib, an oral multikinase inhibitor of MET, ROS, RON, AXL, TIE-2, and VEGFR2, in the first-line setting in advanced hepatocellular carcinoma patients.Experimental Design: In the phase I part, advanced hepatocellular carcinoma patients were dose escalated on foretinib (30-60 mg) every day using the standard 3+3 design. Once the maximum tolerated dose (MTD) was determined, an additional 32 patients were dosed at the MTD in the phase II expansion cohort for assessment of efficacy and safety. Exploratory analyses were conducted to assess potential biomarkers that might correlate with clinical efficacy and survival.Results: The MTD of foretinib was established as 30 mg every day. The most frequent adverse events were hypertension, decreased appetite, ascites, and pyrexia. When dosed at 30 mg every day in the first-line setting, foretinib demonstrated promising antitumor activity. According to the modified mRECIST, the objective response rate was 22.9%, the disease stabilization rate 82.9%, and the median duration of response 7.6 months. The median time to progression was 4.2 months and the median overall survival (OS) was 15.7 months. Fifteen candidate biomarkers whose levels in the circulation were significantly altered in response to foretinib treatment were elucidated. Multivariate analyses identified IL6 and IL8 as independent predictors of OS.Conclusions: Foretinib demonstrated promising antitumor activity and good tolerability in the first-line setting in Asian advanced hepatocellular carcinoma patients. Baseline plasma levels of IL6 or IL8 might predict the response to foretinib. Clin Cancer Res; 23(10); 2405-13. ©2016 AACR.

Integrative biomarker analyses indicate etiological variations in hepatocellular carcinoma.

BACKGROUND & AIMS: The purpose of this study was to determine whether biomarkers from baseline plasma and archival tissue specimens collected from patients enrolled in the EVOLVE-1 trial - a randomized phase 3 study of everolimus in hepatocellular carcinoma (HCC) - were associated with prognosis, etiology or ethnicity. METHODS: Circulating plasma levels of bFGF, PLGF, VEGF, VEGF-D, c-Kit, collagen IV, sVEGFR1 and VEGFR2 were measured by ELISA (N=503). Protein levels of IGF-1R, c-Met, mTOR, Tsc2 were assayed by immunohistochemistry (N=125). Genomic DNA sequencing was conducted on a panel of 287 cancer-related genes (N=69). RESULTS: Patients with baseline plasma concentrations of VEGF or sVEGFR1 above the cohort median had significantly shorter overall survival. These plasma biomarkers retained prognostic significance in a multivariate Cox regression model with geographic region, macroscopic vascular invasion and alpha fetoprotein AFP levels. Membranous c-Met protein levels were significantly lower for Asian patients, as well as for hepatitis B viral etiology. The prevalence of genetic changes were similar to previous reports, along with a trend towards higher PTEN and TSC2 mutations among Asians. CONCLUSIONS: The angiogenesis biomarkers VEGF and sVEGFR1 were independent prognostic predictors of survival in patients with advanced HCC. Potential differences in c-Met and mTOR pathway activation between Asian and non-Asian patients should be considered in future clinical trials. LAY SUMMARY: Our study demonstrates that circulating angiogenesis biomarkers can predict the survival outcome in patients with advanced hepatocellular carcinoma independent of the clinical variables. There is etiology and ethnicity variation in molecular pathway activation in hepatocellular carcinoma, which should be considered for future clinical trial design of targeted therapy. CLINICAL TRIAL REGISTRATION NUMBER: NCT01035229.

Randomized, open-label phase 2 study comparing frontline dovitinib versus sorafenib in patients with advanced hepatocellular carcinoma.

UNLABELLED: Angiogenesis inhibition by the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) inhibitor sorafenib provides survival benefit in hepatocellular carcinoma (HCC); however, angiogenic escape from sorafenib may occur due to angiogenesis-associated fibroblast growth factor receptor (FGFR) pathway activation. In addition to VEGFR and PDGFR, dovitinib inhibits FGFR. Frontline oral dovitinib (500 mg/day, 5 days on, 2 days off; n = 82) versus sorafenib (400 mg twice daily; n = 83) was evaluated in an open-label, randomized phase 2 study of Asian-Pacific patients with advanced HCC. The primary and key secondary endpoints were overall survival (OS) and time to tumor progression (TTP) as determined by a local investigator, respectively. Patients included in the study were ineligible for surgical and/or locoregional therapies or had disease progression after receiving these therapies. The median OS (95% confidence interval [CI]) was 8.0 (6.6-9.1) months for dovitinib and 8.4 (5.4-11.3) months for sorafenib. The median TTP (95% CI) per investigator assessment was 4.1 (2.8-4.2) months and 4.1 (2.8-4.3) months for dovitinib and sorafenib, respectively. Common any-cause adverse events included diarrhea (62%), decreased appetite (43%), nausea (41%), vomiting (41%), fatigue (35%), rash (34%), and pyrexia (30%) for dovitinib and palmar-plantar erythrodysesthesia syndrome (66%) and decreased appetite (31%) for sorafenib. Subgroup analysis revealed a significantly higher median OS for patients in the dovitinib arm who had baseline plasma soluble VEGFR1 (sVEGFR1) and hepatocyte growth factor (HGF) below median levels versus at or above the median levels (median OS [95% CI]: sVEGFR1, 11.2 [9.0-13.8] and 5.7 [4.3-7.0] months, respectively [P = .0002]; HGF, 11.2 [8.9-13.8] and 5.9 [5.0-7.6] months, respectively [P = 0.0002]). CONCLUSION: Dovitinib was well tolerated, but activity was not greater than sorafenib as a frontline systemic therapy for HCC. Based on these data, no subsequent phase 3 study has been planned. (Hepatology 2016;64:774-784).

Efficacy of radiofrequency ablation compared with transarterial chemoembolization for the treatment of recurrent hepatocellular carcinoma: a comparative survival analysis.

BACKGROUND: This study aims to assess if radiofrequency ablation (RFA) has any oncological superiority over transarterial chemoembolization (TACE) on post-hepatectomy recurrence. METHODOLOGY: From 2002 to 2011, 60.15% of 823 patients developed recurrence after hepatectomy for Hepatocellular carcinoma (HCC). 102 patients with recurrence underwent RFA (n = 42) or TACE (n = 60) for tumor size ≤5 cm and number of lesion ≤3 when tumors were not resectable or transplantable. Those with renal impairment, portal vein thrombosis and poor liver reserve were excluded. Primary outcome was overall survival, which was determined using log-rank test and Kaplan Meier plots performed. Categorical data were analyzed using Chi-square test and continuous variable were analyzed using Mann-U Whitney test. RESULTS: Demographics and primary tumor characteristics were similar in both groups (p > 0.05). Overall survival after initial hepatectomy and salvage treatment for recurrence was similar (p > 0.05) in both groups with 5-year OS after salvage treatment for RFA and TACE at 24.1% and 25.7%, respectively. For patients with second recurrence after salvage treatment, an interchangeable treatment strategy of RFA and TACE conferred a better survival outcome than a stand-alone treatment with RFA or TACE (p < 0.05). CONCLUSIONS: RFA and TACE may be equally effective for intrahepatic recurrence after hepatectomy when tumor size is ≤5 cm and ≤3 lesion when re-resection or salvage transplantation is not considered feasible.

Does hepatitis B seroconversion affect survival outcome in patients with hepatitis B related hepatocellular carcinoma?

BACKGROUND: Little is known about whether hepatitis B surface antigen (HBsAg) seroconversion (SC) contributes to any survival benefits for patients with hepatocellular carcinoma (HCC). METHODS: All patients with hepatitis B-related HCC and HBsAg seroclearance between 1989 and 2013 were identified. Case- and control-groups were matched according to their stage of disease and mode of treatment. Baseline demographics, liver function, and overall survivals (OS) were compared between these two groups. RESULTS: Thirty-nine HCC cases with HBsAg SC were identified, and 312 non-seroconversion (NSC) HCC cases were matched. Forty-eight percent of patients had curative resections, 14% were treated with ablation and 38% were for palliation. Age of patients in SC group was older than those in NSC group (P=0.026). Although there was significantly better liver function in SC vs. NSC groups in terms of bilirubin (P=0.027), albumin (P=0.003), AST (P=0.001) and ALT (P<0.001), there was no overall difference in Child-Pugh grade among the two groups. In regarding tumour pathology, SC commonly presented with solitary tumour nodule as compared to multiple nodules in NSC (P=0.027), and was also frequently associated with a normal background liver parenchyma (P<0.001). Although no survival benefit was confirmed in log-rank analysis between SC and NSC, the absolute 5-year survival of SC group was better in resection (72.2% vs. 55.3%), ablation (83.3% vs. 57.4%) and palliation (24.4% vs. 14.4%). CONCLUSIONS: HCC patients with HBsAg SC are associated with a better background liver parenchyma and function, and might contribute to an improved long-term survival.

Pure Laparoscopic Versus Open Left Lateral Sectionectomy for Hepatocellular Carcinoma: A Single-Center Experience.

INTRODUCTION: Laparoscopic left lateral sectionectomy has been proven to be a safe and effective treatment for liver lesions. However, most of the literatures only reported this treatment method on benign lesion or colorectal metastases. The data on long-term outcome of laparoscopic left lateral section resection in patients with HCC and cirrhosis are still limited. The aim of this study is to analyze the survival outcome of laparoscopic left lateral sectionectomy when compared to open approach in patients with HCCs. METHOD: Between January 2004 and September 2014, 967 patients had primary HCC with hepatectomy performed. Twenty-four patients had undergone pure laparoscopic left lateral sectionectomy for hepatocellular carcinoma (HCC). Twenty-nine patients with case-matched tumor characteristics and liver functions but received open left lateral sectionectomy for HCC were included for comparison. RESULTS: Comparing laparoscopic group to open resection group, the median operation time was 190.5 versus 195 min (P = 0.734); the median blood loss was 100 versus 300 ml (P < 0.001). Hospital stay was 5 days in laparoscopic group versus 6 days in the open group (P = 0.057). There was no difference between the two groups in terms of complications (P = 0.495). The median survival in laparoscopic group was >115 months versus >125 months in the open group (P = 0.853). CONCLUSION: Laparoscopic left lateral sectionectomy for HCC is a safe and simple procedure associated with less blood loss. The survival outcome is comparable with conventional open approach. It is becoming a more favorable treatment option even for patients with HCC and cirrhosis.

Retrospective study of metachronous lung metastases from primary hepatocellular carcinoma.

BACKGROUND: This study investigates whether there has been any survival improvement for hepatocellular carcinoma patients with resectable and unresectable lung metastases over time. METHODS: The data of 280 hepatocellular carcinoma patients who developed metachronous lung metastases after hepatectomy with curative intent were analysed. Overall survival was compared in patients with resectable and unresectable lung metastases and in different periods (Era I: 1989-1995, Era II: 1996-2010). RESULTS: The median overall survival of patients with unresectable and resectable diseases was 7.46 and 40.36 months, respectively (P < 0.0001). In Era I, the median overall survival of patients with unresectable and resectable diseases was 5.59 and 43.15 months, respectively (P < 0.0001). The corresponding figures in Era II were 8.38 and 32.90 months (P < 0.0001). The overall survival of patients with resectable disease did not differ significantly in the two eras but there was a significant improvement in survival of patients with unresectable disease in Era II. Their 1-year, 3-year and 5-year survival rates in Era I versus Era II were 11.1% versus 38.4%, 5.6% versus 9.1% and 2.8% versus 3.5%, respectively (P = 0.041). The corresponding figures for their counterparts in the resectable group were 90% versus 85.8%, 80% versus 45.9% and 40% versus 29.5%, respectively (P = 0.443). CONCLUSIONS: Patients with resectable lung metastases had better overall survival than those with unresectable lung metastases. Notably, patients with unresectable lung metastases had significant improvement in survival over the years.

Efficacy of radiofrequency ablation compared with transarterial chemoembolization for the treatment of recurrent hepatocellular carcinoma: a comparative survival analysis.

BACKGROUND: This study aims to assess if radiofrequency ablation (RFA) has any oncological superiority over transarterial chemoembolization(TACE) on post-hepatectomy recurrence. METHODS: From 2002 to 2011, 60.15% of 823 patients developed recurrence after hepatectomy for HCC. One hundred and two patients with recurrence underwent RFA (n = 42) or TACE (n = 60) for tumour size ≤5 cm and number of lesions ≤ 3 when tumours were not resectable or transplantable. Those with renal impairment, portal vein thrombosis and poor liver reserve were excluded. The primary outcome was overall survival, which was determined using log-rank test and Kaplan-Meier plots performed. Categorical data were analysed using the chi-square test and continuous variable were analysed using the Mann-Whitney U-test. RESULTS: Demographics and primary tumour characteristics were similar in both groups (P > 0.05). Overall survival (OS) after an initial hepatectomy and salvage treatment for recurrence was similar (P > 0.05) in both groups with a 5-year OS after salvage treatment for RFA and TACE at 24.1% and 25.7%, respectively. For patients with the second recurrence after salvage treatment, an interchangeable treatment strategy of RFA and TACE conferred a better survival outcome than a stand-alone treatment with RFA or TACE (P < 0.05). CONCLUSIONS: RFA and TACE may be equally effective for intrahepatic recurrence after hepatectomy when the tumour size is ≤ 5 cm and ≤ 3 lesions when re-resection or salvage transplantation is not considered feasible.

Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial.

BACKGROUND: There is no standard of care for adjuvant therapy for patients with hepatocellular carcinoma. This trial was designed to assess the efficacy and safety of sorafenib versus placebo as adjuvant therapy in patients with hepatocellular carcinoma after surgical resection or local ablation. METHODS: We undertook this phase 3, double-blind, placebo-controlled study of patients with hepatocellular carcinoma with a complete radiological response after surgical resection (n=900) or local ablation (n=214) in 202 sites (hospitals and research centres) in 28 countries. Patients were randomly assigned (1:1) to receive 400 mg oral sorafenib or placebo twice a day, for a maximum of 4 years, according to a block randomisation scheme (block size of four) using an interactive voice-response system. Patients were stratified by curative treatment, geography, Child-Pugh status, and recurrence risk. The primary outcome was recurrence-free survival assessed after database cut-off on Nov 29, 2013. We analysed efficacy in the intention-to-treat population and safety in randomly assigned patients receiving at least one study dose. The final analysis is reported. This study is registered with ClinicalTrials.gov, number NCT00692770. FINDINGS: We screened 1602 patients between Aug 15, 2008, and Nov 17, 2010, and randomly assigned 1114 patients. Of 556 patients in the sorafenib group, 553 (>99%) received the study treatment and 471 (85%) terminated treatment. Of 558 patients in the placebo group, 554 (99%) received the study treatment and 447 (80%) terminated treatment. Median duration of treatment and mean daily dose were 12·5 months (IQR 2·6-35·8) and 577 mg per day (SD 212·8) for sorafenib, compared with 22·2 months (8·1-38·8) and 778·0 mg per day (79·8) for placebo. Dose modification was reported for 497 (89%) of 559 patients in the sorafenib group and 206 (38%) of 548 patients in the placebo group. At final analysis, 464 recurrence-free survival events had occurred (270 in the placebo group and 194 in the sorafenib group). Median follow-up for recurrence-free survival was 8·5 months (IQR 2·9-19·5) in the sorafenib group and 8·4 months (2·9-19·8) in the placebo group. We noted no difference in median recurrence-free survival between the two groups (33·3 months in the sorafenib group vs 33·7 months in the placebo group; hazard ratio [HR] 0·940; 95% CI 0·780-1·134; one-sided p=0·26). The most common grade 3 or 4 adverse events were hand-foot skin reaction (154 [28%] of 559 patients in the sorafenib group vs four [<1%] of 548 patients in the placebo group) and diarrhoea (36 [6%] vs five [<1%] in the placebo group). Sorafenib-related serious adverse events included hand-foot skin reaction (ten [2%]), abnormal hepatic function (four [<1%]), and fatigue (three [<1%]). There were four (<1%) drug-related deaths in the sorafenib group and two (<1%) in the placebo group. INTERPRETATION: Our data indicate that sorafenib is not an effective intervention in the adjuvant setting for hepatocellular carcinoma following resection or ablation.

Modified Anterior Approach for the ALPPS Procedure: How We Do It.

BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a highly complex operation that demands a thorough understanding of the intrahepatic vascular anatomy and skills in parenchymal transection for the in situ split procedure. In order to minimize adhesion formation after the stage I operation and to avoid iatrogenic tumor rupture during right liver mobilization in large tumors, anterior approach appears to be a logical approach for the in situ split procedure. However, in contrast to the anterior approach adopted for the usual right hepatectomy, the right hepatic artery and biliary pedicle remain intact and undivided during the first operation. To address this issue, we hereby reported our experience of the modified 'anterior approach' for the ALPPS procedure that facilitates a complete in situ parenchymal split. METHODS: Prospectively collected data of 13 patients who underwent the ALPPS procedure by the modified anterior approach for hepatocellular carcinoma from October 2013 to October 2014 were reviewed. RESULTS: The baseline future liver remnant volume (FLR) was 286 ml. The median tumor size was 6.0 cm. After a median of 8 days from stage I operation, the left FLR hypertrophied by 52.7 % in volume to 482 ml. All patients proceeded to second stage hepatectomy (extended right hepatectomy, n = 5; right hepatectomy, n = 6; right trisectionectomy, n = 2) without significant adhesion encountered. The overall morbidity and mortality rates were 7.7 % (n = 1) and 7.7 % (n = 1), respectively. CONCLUSION: The modified anterior approach is safe and feasible for complete in situ split in the ALPPS procedure.

Comparison of Survival Outcomes Between Right Posterior Sectionectomy and Right Hepatectomy for Hepatocellular Carcinoma in Cirrhotic Liver: A Single-Centre Experience.

BACKGROUND: Right hepatectomy (RH) instead of right posterior sectionectomy (RPS) is commonly performed for hepatocellular carcinoma (HCC) in cirrhotic livers located lateral to the right hepatic vein in order to ensure adequate resection margin. This potentially increased the risk of postoperative liver failure. This study aims to compare survival outcomes and surgical morbidities between RH and RPS. METHODS: All patients between 2003 and 2013 with resection for solitary HCC in cirrhotic livers at segment 6/7 were reviewed. Baseline demographics, liver function, perioperative outcomes, and overall (OS) and disease-free survival (DFS) were compared between RH and RPS. RESULTS: Eighty-one patients were included in this study. Thirty-two patients had RH and forty-nine with RPS were selected as controls. Majority of the HCC patients (91.4 %) suffered from chronic hepatitis B. There was no significant difference in age, gender and Child-Pugh grade between the two groups. The median tumour size of RH group was 6 vs. 4 cm in the RPS group (p < 0.0001). Both groups had no statistical difference in resection margin and their associated morbidities. The 5-year OS for RH and RPS was 76 and 83.8 %, respectively (p = 0.766), whereas their corresponding DFS was 52.6 and 52.2 % (p = 0.859). Despite the discrepancy of tumour size among the two groups, there was no statistical difference in subgroup analysis based on their corresponding stage of disease. CONCLUSION: RPS can achieve similar OS and DFS as RH for HCC, and should be considered as the treatment of choice in order to optimise the postoperative remnant parenchymal liver functions.