The management of hepatocellular carcinoma. Current expert opinion and recommendations derived from the 24th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2022.

This article summarises expert discussion on the management of patients with hepatocellular carcinoma (HCC), which took place during the 24th World Gastrointestinal Cancer Congress (WGICC) in Barcelona, July 2022. A multidisciplinary approach is mandatory to ensure an optimal diagnosis and staging of HCC, planning of curative and therapeutic options, including surgical, embolisation, ablative strategies, or systemic therapy. Furthermore, in many patients with HCC, underlying liver cirrhosis represents a challenge and influences the therapeutic options.

Association between PD1 mRNA and response to anti-PD1 monotherapy across multiple cancer types.

Background: We hypothesized that the abundance of PD1 mRNA in tumor samples might explain the differences in overall response rates (ORR) observed following anti-PD1 monotherapy across cancer types. Patients and methods: RNASeqv2 data from 10 078 tumor samples representing 34 different cancer types was analyzed from TCGA. Eighteen immune-related gene signatures and 547 immune-related genes, including PD1, were explored. Correlations between each gene/signature and ORRs reported in the literature following anti-PD1 monotherapy were calculated. To translate the in silico findings to the clinical setting, we analyzed the expression of PD1 mRNA using the nCounter platform in 773 formalin-fixed paraffin embedded (FFPE) tumor samples across 17 cancer types. To test the direct relationship between PD1 mRNA, PDL1 immunohistochemistry (IHC), stromal tumor-infiltrating lymphocytes (sTILs) and ORR, we evaluated an independent FFPE-based dataset of 117 patients with advanced disease treated with anti-PD1 monotherapy. Results: In pan-cancer TCGA, PD1 mRNA expression was found strongly correlated (r > 0.80) with CD8 T-cell genes and signatures and the proportion of PD1 mRNA-high tumors (80th percentile) within a given cancer type was variable (0%-84%). Strikingly, the PD1-high proportions across cancer types were found strongly correlated (r = 0.91) with the ORR following anti-PD1 monotherapy reported in the literature. Lower correlations were found with other immune-related genes/signatures, including PDL1. Using the same population-based cutoff (80th percentile), similar proportions of PD1-high disease in a given cancer type were identified in our in-house 773 tumor dataset as compared with TCGA. Finally, the pre-established PD1 mRNA FFPE-based cutoff was found significantly associated with anti-PD1 response in 117 patients with advanced disease (PD1-high 51.5%, PD1-intermediate 26.6% and PD1-low 15.0%; odds ratio between PD1-high and PD1-intermediate/low = 8.31; P < 0.001). In this same dataset, PDL1 tumor expression by IHC or percentage of sTILs was not found associated with response. Conclusions: Our study provides a clinically applicable assay that links PD1 mRNA abundance, activated CD8 T-cells and anti-PD1 efficacy.

New molecular therapies for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a major health problem. Mortality owing to liver cancer has increased in the past 20 years, with recent studies reporting an incidence of 780,000 cases/year. Most patients with hepatocellular carcinoma are still diagnosed at intermediate or advanced disease stages, where curative approaches are often not feasible. Among the treatment options available, the molecular targeted agent sorafenib is able to significantly increase overall survival in these patients. Afterwards, up to 7 randomized phase III clinical trials investigating other molecular therapies in the first-line and second-line settings have failed to improve survival. Potential reasons for this include intertumor heterogeneity, issues with trial design and a lack of predictive biomarkers of response. Advance in our knowledge of the human genome has provided a comprehensive picture of commonly mutated genes in patients with HCC including mutations in the TERT promoter, CTNNB1, TP53 and ARID1A along with other amplifications (FGF19, VEGFA) or homozygous deletions (p16) as the most frequent alterations. This knowledge points toward specific drivers as candidate for druggable therapies. Thus, progressive implementation of proof-of-concept and enrichment might improve results in clinical trials testing of molecular targeted agents. Ultimately, these studies are aimed at long-term to improve current standards of care and influenced clinical decision-making and practice guidelines.

Intrahepatic cholangiocarcinoma: pathogenesis and rationale for molecular therapies.

Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with very poor prognosis. Genome-wide, high-throughput technologies have made major advances in understanding the molecular basis of this disease, although important mechanisms are still unclear. Recent data have revealed specific genetic mutations (for example, KRAS, IDH1 and IDH2), epigenetic silencing, aberrant signaling pathway activation (for example, interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3), tyrosine kinase receptor-related pathways) and molecular subclasses with unique alterations (for example, proliferation and inflammation subclasses). In addition, some ICCs share common genomic traits with hepatocellular carcinoma. All this information provides the basis to explore novel targeted therapies. Currently, surgery at early stage is the only effective therapy. At more advanced stages, chemotherapy regimens are emerging (that is, cisplatin plus gemcitabine), along with molecular targeted agents tested in several ongoing clinical trials. Nonetheless, a first-line conclusive treatment remains an unmet need. Similarly, there are no studies assessing tumor response related with genetic alterations. This review explores the recent advancements in the knowledge of the molecular alterations underlying ICC and the future prospects in terms of therapeutic strategies leading towards a more personalized treatment of this neoplasm.

Early detection of cancer: ideas for a debate.

Even if the overall number of cancer is increasing, the mortality has started to decrease in the Western World. The role of early detection in this decrease is a matter of debate. To assess its impact on mortality it is important to distinguish between diagnosis of cancer in symptomatic patients, and early detection in asymptomatic individuals who may self-refer or who may be offered ad hoc or systematic screening. The policies for early detection and screening vary greatly between European countries, despite many similarities in their cancer burden, and this partly reflects the uncertainties surrounding asymptomatic testing for cancer. A Task Force of European expert, held in Azzate (VA), Italy, established to address these issues, acknowledged the need for more research in the field of individual risk assessment since general statistics are more and more perceived as inadequate to design personal early detection plans. The group also recognised that combinations of early detection and screening will enforce the effectiveness of new treatments in curbing mortality curves, although policies will vary with different cancers.

New aspects of diagnosis and therapy of hepatocellular carcinoma.

Hepatocellular carcinoma is one of the major cancer killers. It affects patients with chronic liver disease who have established cirrhosis, and currently is the most frequent cause of death in these patients. The main risk factors for its development are hepatitis B and C virus infection, alcoholism and aflatoxin intake. If acquistion of risk factors is not prevented and cirrhosis is established, the sole option to improve survival is to detect the tumor at an early stage when effective therapy may be indicated. Early detection plans should be based on hepatic ultrasonography every 6 months, whereas determination of tumor markers is not efficient. Upon detection of a hepatic nodule, there is a need to establish unequivocal diagnosis, either through biopsy or through the application of non-invasive criteria based on the specific radiology appearance of the tumor: fast arterial uptake of contrast followed by venous washout. Effective treatment for liver cancer includes surgical resection, liver transplantation and percutaneous ablation. These options provide a high rate of complete responses and are assumed to improve survival that should exceed 50% at 5 years. If the tumor is diagnosed at an advanced stage, the sole option that improves survival is transarterial chemoembolization. Ongoing research should further advance the time at diagnosis and identify new and effective options targeting molecular pathways governing tumor progression.

Systematic review: evidence-based management of hepatocellular carcinoma--an updated analysis of randomized controlled trials.

The treatment strategy of hepatocellular carcinoma applied following scientific guidelines is only supported by 77 randomized controlled trials published so far, a figure that clearly pinpoints hepatocellular carcinoma as an 'orphan' cancer in terms of clinical research when compared with other high-prevalent cancers worldwide. A systematic review analysing 61 randomized controlled trials (1978-2002) showed a modest survival benefit from chemoembolization in patients with intermediate tumours, and the lack of an effective first-line treatment option for patients with advanced disease. These conclusions have been endorsed by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. The present updated evidence-based approach includes 16 randomized controlled trials published from 2002 to 2005 assessing percutaneous ablation (seven), other loco-regional therapies (three) and systemic therapies (six). Eight showed high-quality methodological profiles. Four randomized controlled trials demonstrated a better local hepatocellular carcinoma control in tumours larger than 2 cm treated by radiofrequency ablation compared with ethanol injection. No survival advantages were obtained from systemic treatments in patients with advanced hepatocellular carcinoma, an area that is an unmet need. Therefore, there is an urgent request to conduct well-designed phase III investigations in hepatocellular carcinoma patients.

Is microbubble-enhanced ultrasonography sufficient for assessment of response to percutaneous treatment in patients with early hepatocellular carcinoma?

The objective of this study was to assess the efficacy of contrast-enhanced ultrasonography (CEUS) with SonoVue to evaluate the response to percutaneous treatment (ethanol injection/radiofrequency) of hepatocellular carcinoma in comparison with spiral computed tomography (CT) immediately and 1 month after treatment. Forty-one consecutive cirrhotic patients with early stage tumor (not suitable for resection) were included. Spiral CT and CEUS were performed in all patients before treatment, in the following 24 h, and 1 month later. The results of each examination were compared with the 1-month spiral CT, considered the gold standard technique. The 24-h CEUS and the 24-h spiral CT sensitivity to detect residual disease were 27% and 20%, respectively. The 24-h CEUS and the 24-h spiral CT positive predictive value of persistent vascularization detection were 75% and 66%, respectively. The 1-month CEUS detected partial responses in ten out of 11 cases (91% sensitivity, 97% specificity, 95% accuracy). Spiral CT and CEUS performed in the 24 h following treatment are slightly useful to evaluate therapeutic efficacy. The 1-month CEUS has a high diagnostic accuracy compared with spiral-CT in the usual assessment of percutaneous treatment response.

Actitud a seguir ante una lesión hepática focal / Approaching focal liver lesions

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[Adult living donor liver transplantation. Analysis of the first 30 cases]. / Trasplante hepático de donante vivo en adultos. Análisis de los 30 primeros casos.

INTRODUCTION: In the last 2-3 years, adult living donor liver transplantation (ALDLT) has been developed on an international scale, multiplying the number of procedures performed. Despite this, analysis of the results is still incomplete. The aim of the present study was to perform a descriptive analysis of the results after the first 3 years of the initiation of the program. MATERIAL AND METHODS: During this period, 30 ALDLT were performed. In all procedures, right lobe grafts were used. The mean age of donors and recipients was 31.8 and 52.7 years, respectively. The main indication for liver transplantation was liver cirrhosis due to hepatitis C virus (70%) and 38% of recipients were stage C in the Child-Pugh classification. A total of 46.7% of recipients had hepatocellular carcinoma. RESULTS: Donors: The mean volume of the remnant liver was 632 cc (40.5% of the previous hepatic mass). Ten donors (33%) presented complications. The most frequent complication was biliary fistula (20%) and three patients required reintervention. The mean length of hospital stay among donors was 11.7 days. Recipients: The mean weight of the graft was 775 g, with a mean difference between graft weight and that of the recipient of 1.11. Fifteen recipients (50%) presented biliary leaks and nine of these (30%) required reintervention. There were no graft losses for technical reasons. Four patients died. With a median follow-up of 14 months, actuarial survival at 18 months was 92.9%. CONCLUSION: ALDLT is an effective method for reducing the number of patients on the waiting list. The probability of survival is similar to that of cadaveric transplantation. Biliary complications in the recipient constitute a problem, the long-term repercussions of which remain to be resolved.

Review article: natural history and prognostic prediction of patients with hepatocellular carcinoma.

The knowledge of the natural history of patients with hepatocellular carcinoma is important to estimate the prognosis at diagnosis and indicate the best therapy. Prognosis is related to tumour stage at diagnosis, degree of liver function impairment induced either by the tumour itself or by the underlying cirrhosis, general physical condition of the patients, and potential impact of therapy. Prognostic estimation should take into account all four aspects. Treatment is very relevant to be considered in patients with early stage tumours since surgical resection, transplantation or percutaneous ablation provide a high rate of complete responses and thus, improve survival. This might be as high as 50-75% at 5 years. Patients diagnosed at an intermediate/advanced stage will receive palliative treatment and prospective studies have recently redefined the outcome predictors of this stratum. Asymptomatic patients in whom the tumour has not invaded vessels or disseminated may reach a 50% survival at 3 years, while those with adverse predictors do not reach this time point. These data have to be taken into account not only in the conventional clinical practice, but also in the design and evaluation of prospective investigations that should be properly powered to reach an informative sample size. To achieve both aims, within the Barcelona Clinic Liver Cancer Group we have developed a staging system that combines prognosis prediction with decision making, thus becoming a useful tool both for practice and research.

Cost effectiveness of adjuvant therapy for hepatocellular carcinoma during the waiting list for liver transplantation.

BACKGROUND: Survival after liver transplantation for early hepatocellular carcinoma (HCC) is worsened by the increasing dropout rate while waiting for a donor. AIMS: To assess the cost effectiveness of adjuvant therapy while waiting for liver transplantation in HCC patients. METHOD: Using a Markov model, a hypothetical cohort of cirrhotic patients with early HCC was considered for: (1) adjuvant treatment-resection was limited to Child-Pugh's A patients with single tumours, and percutaneous treatment was considered for Child-Pugh's A and B patients with single tumours unsuitable for resection or with up to three nodules < 3 cm; and (2) standard management. Length of waiting time ranged from six to 24 months. RESULTS: Surgical resection increased the transplantation rate (>10%) and provided gains in life expectancy of 4.8-6.1 months with an acceptable cost ($40,000/ year of life gained) for waiting lists > or = 1 year whereas it was not cost effective ($74,000/life of year gained) for shorter waiting times or high dropout rate scenarios. Percutaneous treatment increased life expectancy by 5.2-6.7 months with a marginal cost of approximately $20,000/year of life gained in all cases, remaining cost effective for all waiting times. CONCLUSIONS: Adjuvant therapies for HCC while waiting for liver transplantation provide moderate gains in life expectancy and are cost effective for waiting lists of one year or more. For shorter waiting times, only percutaneous treatment confers a relevant survival advantage.