Faculty Bibliography

INTRODUCTION/UNASSIGNED:Hepatocellular carcinoma (HCC) is a major health problem worldwide with limited systemic therapy options. Since the approval of sorafenib in 2008, no systemic therapy has provided a sustained/robust/survival benefit for patients with advanced HCC until recently. Many initially promising therapies have been trialed, but survival outcomes remained stagnant. Knowledge concerning previous treatment failures may help inform future therapeutic approaches. AREA COVERED/UNASSIGNED:This article reviews recent advances in the treatment of HCC. Despite some recent success, many systemic and locoregional therapies have failed to produce significant improvements in outcome. These treatment failures are examined and insight into pathways for future success are discussed. EXPERT OPINION/UNASSIGNED:Combination atezolizumab and bevacizumab has changed the landscape of systemic treatment for patients with HCC when it became the first therapy after demonstrating improve outcomes over sorafenib. Clinical trials in patients with advanced HCC have inherent difficulty with challenges to determine if a patient's declining liver function is secondary to disease progression, worsening cirrhosis, or drug toxicity, which may skew results. As we gain more knowledge of underlying genetic alterations behind the pathophysiology of the development of HCC, molecular markers may be identified to assist in predicting which patients would respond to a specific therapy.

Cholangiocarcinoma (CCA) represents nearly 15% of all primary liver cancers and 2% of all cancer-related deaths worldwide. Perihilar cholangiocarcinoma (pCCA) accounts for 50-60% of all CCA. First described in 1965, pCCAs arise between the second-order bile ducts and the insertion of the cystic duct into the common bile duct. CCA typically has an insidious onset and commonly presents with advanced, unresectable disease. Complete surgical resection is technically challenging, as tumor proximity to the structures of the central liver often necessitates an extended hepatectomy to achieve negative margins. Intraoperative frozen section can aid in assuring negative margins and complete resection. Portal lymphadenectomy provides important prognostic and staging information. In specialized centers, vascular resection and reconstruction can be performed to achieve negative margins in appropriately selected patients. In addition, minimally invasive surgical techniques (e.g., robotic surgery) are safe, feasible, and provide equivalent short-term oncologic outcomes. Neoadjuvant chemoradiation therapy followed by liver transplantation provides a potentially curative option for patients with unresectable disease. New trials are needed to investigate novel chemotherapies, immunotherapies, and targeted therapies to better control systemic disease in the adjuvant setting and, potentially, downstage disease in the neoadjuvant setting.

Hepatocellular carcinoma (HCC) is a major cause of mortality worldwide with an increasing incidence due to escalating rates of obesity and non-alcoholic fatty liver disease. Unfortunately, a majority of patients with HCC present with advanced disease. The immune checkpoint inhibitor atezolizumab, a PD-L1 inhibitor, in combination with bevacizumab, anti-VEGF, has become the new standard of care for patients with advanced HCC after demonstrating improved overall and progression free survival over sorafenib. In this review, we discuss the evolving role of immune checkpoint inhibitors in the treatment of HCC and their safety, efficacy, and tolerability.

INTRODUCTION/BACKGROUND:Unfortunately, some hepatocellular carcinoma (HCC) patients do not qualify for curative-intent treatments such as surgical resection or transplantation. Hence, locoregional treatments such as transarterial chemoembolization (TACE) remain instrumental in the treatment of HCC. Systemic therapy has improved over the past decade with the introduction of combination atezolizumab and bevacizumab as the new standard of care for advanced disease. These new therapies are currently under investigation in combination with TACE. AREA COVERED/METHODS:Combination therapies with TACE including systemic therapies, locoregional therapies, and immunotherapies are reviewed. EXPERT OPINION/CONCLUSIONS:There has been limited progress in the management of advanced and intermediate HCC. Recent advances in the management of advanced disease with systemic therapy could be beneficial in combination with TACE for the treatment of intermediate stage disease. Immune based therapies are potentially beneficial in combination with TACE because TACE may produce increased antigen release and immune recognition.

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer behind hepatocellular carcinoma (HCC) and carries a dismal prognosis. Improved genetic analysis has paved the way for a better understanding of the distinct somatic genomic landscapes of ICC. The use of next generation sequencing has paved the way for more personalized medicine through identifying unique mutations which may prove to be therapeutic targets. The ability to identify biomarkers specific to ICC will assist in establishing a diagnosis, monitoring response to therapy, as well as assist in identifying novel therapies and personalized medicine. Herein, we discuss potential biomarkers for ICC and how these markers can assist in diagnosis, monitor response to therapy, and potentially identify novel interventions for the treatment of ICC.

INTRODUCTION/BACKGROUND:Cholangiocarcinomas (CCA) are rare, highly invasive tumors often diagnosed at an advanced disease stage with an associated poor prognosis. Surgery represents the only chance for curative-intent treatment, but recurrence rates remain high. Neoadjuvant or adjuvant chemotherapy are options for patients with resectable CCA to increase recurrence-free survival and overall survival, while palliative chemotherapy represents the treatment for unresectable disease. Global efforts are currently focused on the development of novel more effective therapies. AREAS COVERED/METHODS:A review was conducted in August 2021 using the PubMed database with the following keywords: 'cholangiocarcinoma,' 'chemotherapy,' and 'therapy.' Manuscripts reporting on first- and second-line chemotherapy, neoadjuvant and adjuvant treatment regimens, and targeted therapies currently being tested or employed in the management of CCA were examined. EXPERT OPINION/CONCLUSIONS:The prognosis of CCA is negatively affected by several factors including a lack of reliable biomarkers leading to delayed diagnoses, high inter- and intra-tumoral heterogeneity, and few effective chemotherapy regimens. In pursuit of more effective therapies, ongoing trials are testing both conventional and targeted drugs.

INTRODUCTION/BACKGROUND:HCC comprises roughly 60 to 80% of all primary liver cancers and exhibits wide geographical variability. Appropriate treatment allocation needs to include both patient and tumor characteristics. AREAS COVERED/METHODS:Current HCC classification systems to guide therapy are either liver function-centric and evaluate physiologic liver function to guide therapy or prognostic stratification classification systems broadly based on tumor morphologic parameters, patient performance status, and liver reserve assessment. This review focuses on different classification systems for HCC, their strengths, and weaknesses, as well as the use of artificial intelligence in improving prognostication in HCC. EXPERT OPINION/CONCLUSIONS:Future HCC classification systems will need to incorporate clinic-pathologic data from a multitude of sources and emerging therapies to develop patient-specific treatment plans targeting a patient's unique tumor profile.

OBJECTIVES:To compare the efficacy and safety of algenpantucel-L [HyperAcute-Pancreas algenpantucel-L (HAPa); IND# 12311] immunotherapy combined with standard of care (SOC) chemotherapy and chemoradiation to SOC chemotherapy and chemoradiation therapy alone in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (PDAC). SUMMARY BACKGROUND DATA:To date, immunotherapy has not been shown to benefit patients with borderline resectable or locally advanced unresectable PDAC. HAPa is a cancer vaccine consisting of allogeneic pancreatic cancer cells engineered to express the murine α(1,3)GT gene. METHODS:A multicenter, phase 3, open label, randomized (1:1) trial of patients with borderline resectable or locally advanced unresectable PDAC. Patients received neoadjuvant SOC chemotherapy (FOLFIRINOX or gemcitabine/nab-paclitaxel) followed by chemoradiation (standard group) or the same standard neoadjuvant regimen combined with HAPa immunotherapy (experimental group). The primary outcome was overall survival. RESULTS:Between May 2013 and December 2015, 303 patients were randomized from 32 sites. Median (interquartile range) overall survival was 14.9 (12.2-17.8) months in the standard group (N = 158) and 14.3 (12.6-16.3) months in the experimental group (N = 145) [hazard ratio (HR) 1.02, 95% confidence intervals 0.66-1.58; P = 0.98]. Median progression-free survival was 13.4 months in the standard group and 12.4 months in the experimental group (HR 1.33, 95% confidence intervals 0.72-1.78; P = 0.59). Grade 3 or higher adverse events occurred in 105 of 140 patients (75%) in the standard group and in 115 of 142 patients (81%) in the experimental group (P > 0.05). CONCLUSIONS:Algenpantucel-L immunotherapy did not improve survival in patients with borderline resectable or locally advanced unresectable PDAC receiving SOC neoadjuvant chemotherapy and chemoradiation. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT01836432.

INTRODUCTION:Intrahepatic cholangiocarcinoma (ICC) incidence continues to rise worldwide, and overall survival remains poor. Complete surgical resection remains the only opportunity for cure in patients with ICC yet only one-third of patients present with resectable disease. AREAS COVERED:While the low incidence rate of ICC hinders accrual of patients to large, randomized control trials, larger database and long-term institutional studies provide evidence to guide surgical management of ICC. These studies demonstrate feasibility, safety, and efficacy of aggressive surgical management in appropriately selected patients with ICC. Recent advances in the management of ICC, with a focus on surgical considerations, are reviewed. EXPERT OPINION:Historically, little progress has been made in the management of ICC with stagnant mortality rates and poor long-term outcomes. However, regionalization of care to centers with experienced multidisciplinary teams, advances in minimally invasive surgical techniques, discovery and development of targeted and immunotherapy agents, and combination locoregional and systemic therapies offer signs of progress in the management of ICC.