Risk profiling of hepatocellular carcinoma occurrence after eradication of hepatitis C virus with direct-acting antiviral agents

Background: Treatment with direct-acting antiviral agents (DAAs) have significantly improved the outcomes of patients with HCV-related cirrhosis. However, the risk of developing hepatocellular carcinoma (HCC) still persists in these patients and predictive models are lacking. The aim of this study is to develop a predictive model including clinical and genetic features for individual risk profiling of HCC occurrence after DAA-induced sustained virologic response (SVR) in patients with HCV cirrhosis. Methods Consecutive patients with HCV cirrhosis achieving SVR after DAA treatment without previous history of HCC were prospectively enrolled and followed-up for HCC occurrence. Clinical and biochemical features were evaluated at the time of DAA start and at the time of SVR. MERTK single-nucleotide polymorphism (SNP) rs6726639 was assessed in all patients. Cox regression model was used to identify risk factors for HCC occurrence. Accuracy was assessed by time-dependent area under the receiver operating characteristic curves (AUROCs) and net benefit was measured by decision curve analysis. Results Four-hundred-seven patients (mean age 67 years, 57% male) were included and followed-up for a mean time of 70 months. HCC occurred in 58 (14.2%) patients. At the time of DAA start, PLT count lower than 120x109/L (HR 2.12, 95%CI 1.15-3.93, p=0.017), albumin levels lower than 3.5 g/dL (HR 2.37, 95%CI 1.38-4.08, p=0.002) and MERTK AA genotype (HR 1.98, 95%CI 1.09-3.62, p=0.026) were independent risk factors for HCC occurrence, by multivariate analysis. At the time of SVR, PLT count lower than 130x109/L (HR 2.14, 95%CI 1.10-4.34, p=0.036), albumin levels lower than 3.8 g/dL (HR 2.21, 95%CI 1.07-4.58, p=0.032) and MERTK AA genotype (HR 2.18, 95%CI 1.01-4.70, p=0.046) were confirmed as independent risk factors for HCC occurrence, by multivariate analysis. Time-dependent AUROCs showed good accuracy and net benefit of this model was confirmed by DCA Conclusions The risk of HCC after DAA-induced SVR persists, although low, also after a long-term follow-up. A risk profiling based on PLT, albumin and MERTK genotype is useful to predict the risk of HCC occurrence after SVR and it could identify a subgroup of patients in which the surveillance schedule for HCC can be personalized and extended

Outcomes of hepatocellular carcinoma patients treated with sorafenib: A meta-analysis of Phase III trials

Aim: To benchmark overall survival (OS) and time to radiological progression (TTP) of patients enrolled in randomized controlled trials (RCTs) assessing sorafenib in advanced hepatocellular carcinoma using individual participant survival data, and to meta-analyze prognostic factors for OS and TTP. Methods: RCTs were identified through literature search until December 2018. Individual participant survival was reconstructed with an algorithm from published Kaplan–Meier curves. Results: Ten RCTs were included. Median OS was 10.0 months (95% CI: 9.6–10.5), and median TTP was 4.1 months (95% CI: 3.8–4.3). Multivariable analyses showed HCV positivity, absence of macrovascular invasion and extra-hepatic disease as predictors of longer OS. Conclusion: We provided a benchmark for future studies on sorafenib. The present results can be used in the decision making for the early shift to second-line strategy

Hepatocellular carcinoma recurrence after direct-acting antiviral therapy: An individual patient data meta-analysis

Abstract Objective The benefit of direct-acting antivirals (DAAs) against HCV following successful treatment of hepatocellular carcinoma (HCC) remains controversial. This meta-analysis of individual patient data assessed HCC recurrence risk following DAA administration. Design We pooled the data of 977 consecutive patients from 21 studies of HCV-related cirrhosis and HCC, who achieved complete radiological response after surgical/locoregional treatments and received DAAs (DAA group). Recurrence or death risk was expressed as HCC recurrence or death per 100 person-years (100PY). Propensity score-matched patients from the ITA.LI.CA. cohort (n=328) served as DAA-unexposed controls (no-DAA group). Risk factors for HCC recurrence were identified using random-effects Poisson. Results Recurrence rate and death risk per 100PY in DAA-treated patients were 20 (95% CI 13.9 to 29.8, I2=74.6%) and 5.7 (2.5 to 15.3, I2=54.3), respectively. Predictive factors for recurrence were alpha-fetoprotein logarithm (relative risk (RR)=1.11, 95% CI 1.03 to 1.19; p=0.01, per 1 log of ng/mL), HCC recurrence history pre-DAA initiation (RR=1.11, 95% CI 1.07 to 1.16; p<0.001), performance status (2 vs 0, RR=4.35, 95% CI 1.54 to 11.11; 2 vs 1, RR=3.7, 95% CI 1.3 to 11.11; p=0.01) and tumour burden pre-HCC treatment (multifocal vs solitary nodule, RR=1.75, 95% CI 1.25 to 2.43; p<0.001). No significant difference was observed in RR between the DAA-exposed and DAA-unexposed groups in propensity score-matched patients (RR=0.64, 95% CI 0.37 to 1.1; p=0.1). Conclusion Effects of DAA exposure on HCC recurrence risk remain inconclusive. Active clinical and radiological follow-up of patients with HCC after HCV eradication with DAA is justified

What is the benefit of prophylaxis to prevent HBV reactivation in HBsAg-negative anti-HBc-positive patients? Meta-analysis and decision curve analysis

Background and aims: Patients with overt or occult hepatitis B virus (HBV) infection receiving immunosuppressive treatments have a wide risk of HBV reactivation (HBVr). We performed meta-analysis with decision curve analyses (DCA) to estimate the risk of HBVr in HBsAg-negative anti-HBc-positive patients naïve to nucleos(t)ide analogues (NAs) receiving immunosuppressive treatments. Approach and results: Studies were identified through literature search until October 2022. Pooled estimates were obtained using random-effects model. Subgroup analyses were performed according to underlying disease and immunosuppressive treatments. DCA was used to identify the threshold probability associated with the net benefit of antiviral prophylaxis in HBsAg-negative anti-HBc-positive patients. We selected 68 studies (40 retrospective and 28 prospective), including 8034 patients with HBsAg negative anti-HBc positive. HBVr was 4% (95% CI 3%-6%) in HBsAg-negative anti-HBc-positive patients, with a significantly high heterogeneity (I2 69%; p &lt; .01). The number-needed-to-treat (NNT) by DCA ranged from 8 to 24 for chemotherapy plus rituximab, from 12 to 24 for targeted therapies in cancer patients and from 13 to 39 for immune-mediated diseases. Net benefit was small for monoclonal antibodies. Conclusions: Our DCA in HBsAg-negative anti-HBc-positive patients provided evidence that NA prophylaxis is strongly recommended in patients treated with chemotherapy combined with rituximab and could be appropriate in patients with cancer treated with targeted therapies and in patients with immune-mediated diseases. Finally, in patients with cancer treated with monoclonal antibodies or with chemotherapy without rituximab, the net benefit is even lower

The Evolving Scenario in the Assessment of Radiological Response for Hepatocellular Carcinoma in the Era of Immunotherapy: Strengths and Weaknesses of Surrogate Endpoints

Hepatocellular carcinoma (HCC) is a challenging malignancy characterised by clinical and biological heterogeneity, independent of the stage. Despite the application of surveillance programs, a substantial proportion of patients are diagnosed at advanced stages when curative treatments are no longer available. The landscape of systemic therapies has been rapidly growing over the last decade, and the advent of immune-checkpoint inhibitors (ICIs) has changed the paradigm of systemic treatments. The coexistence of the tumour with underlying cirrhosis exposes patients with HCC to competing events related to tumour progression and/or hepatic decompensation. Therefore, it is relevant to adopt proper clinical endpoints to assess the extent of treatment benefit. While overall survival (OS) is the most accepted endpoint for phase III randomised controlled trials (RCTs) and drug approval, it is affected by many limitations. To overcome these limits, several clinical and radiological outcomes have been used. For instance, progression-free survival (PFS) is a useful endpoint to evaluate the benefit of sequential treatments, since it is not influenced by post-progression treatments, unlike OS. Moreover, radiological endpoints such as time to progression (TTP) and objective response rate (ORR) are frequently adopted. Nevertheless, the surrogacy between these endpoints and OS in the setting of unresectable HCC (uHCC) remains uncertain. Since most of the surrogate endpoints are radiology-based (e.g., PFS, TTP, ORR), the use of standardised tools is crucial for the evaluation of radiological response. The optimal way to assess the radiological response has been widely debated, and many criteria have been proposed over the years. Furthermore, none of the criteria have been validated for immunotherapy in advanced HCC. The coexistence of the underlying chronic liver disease and the access to several lines of treatments highlight the urgent need to capture early clinical benefit and the need for standardised radiological criteria to assess cancer response when using ICIs in mono- or combination therapies. Here, we review the most commonly used clinical and radiological endpoints for trial design, as well as their surrogacy with OS. We also review the criteria for radiological response to treatments for HCC, analysing the major issues and the potential future perspectives

Utility of neutrophil-to-lymphocyte ratio to identify long-term survivors among HCC patients treated with sorafenib

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Validation and refinement of PROSASH model using the neutrophil‐to‐lymphocyte ratio in patients with HCC receiving sorafenib

AbstractThe recently developed PROSASH model is proving to be a useful tool in risk‐group discrimination in hepatocellular carcinoma (HCC) patients treated with sorafenib. Several studies highlighted that the neutrophil‐to‐lymphocyte ratio (NLR) is one of the most important predictors of survival in HCC patients treated with sorafenib. The aims of the present study were to validate the PROSASH model and determine whether the incorporation of inflammatory markers can improve risk stratification. This study included 438 patients. According to the four categories of the PROSASH model, median overall survival (OS) was 20.0, 14.9, 8.5 and 3.0 months respectively (P < .001). The Harrell's c for this categorized model was 0.621. NLR (cut‐off 3) stratified OS in each of the PROSASH categories. After reclassification, median OS was 21.0, 15.1, 8.2 and 4.1 months (P < .001). The Harrell's c increased from 0.621 to 0.673 (P = .001). Integrating NLR into the PROSASH model allowed a more accurate classification of the patients in the risk groups

Mechanisms of Resistance to Immunotherapy in Hepatocellular Carcinoma

: Systemic treatment for advanced hepatocellular carcinoma (HCC) has been revolutionized over the last few years following the approval of immune checkpoint inhibitors (ICI). Despite the promising survival extension seen with ICI combination regimens, responses are not universally seen and the optimal partner for programmed cell death 1 pathway inhibitors remains to be identified. Even fewer encouraging results have been demonstrated with ICI used for monotherapy. Several mechanisms of resistance have been described so far, involving characteristics of cancer cells (intrinsic mechanisms) and of the surrounding tumor microenvironment (extrinsic mechanisms). Factors related to therapy may also contribute to the development of resistance. Increasing research efforts are being dedicated to the discovery of novel approaches and targets to overcome resistance, some of which may be introduced into clinic in the future. Herein we describe a selection of resistance mechanisms that have been involved in impairing response to ICI and propose potential therapeutic approaches to overcome resistance

The role of PNI to predict survival in advanced hepatocellular carcinoma treated with Sorafenib

Background and aims: The present study aims to investigate the role of the prognostic nutritional index (PNI) on survival in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. Methods: This multicentric study included a training cohort of 194 HCC patients and three external validation cohorts of 129, 76 and 265 HCC patients treated with Sorafenib, respectively. The PNI was calculated as follows: 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (per mm3). Univariate and multivariate analyses were performed to investigate the association between the covariates and the overall survival (OS). Results: A PNI cut-off value of 31.3 was established using the ROC analysis. In the training cohort, the median OS was 14.8 months (95% CI 12-76.3) and 6.8 months (95% CI 2.7-24.6) for patients with a high (&gt;31.3) and low (&lt;31.3) PNI, respectively. At both the univariate and the multivariate analysis, low PNI value (p = 0.0004), a 1-unit increase of aspartate aminotransferase (p = 0.0001), and age &gt; 70 years (p&lt; 0.0038) were independent prognostic factors for OS. By performing the same multivariate analysis of the training cohort, the PNI &lt;31.3 versus &gt;31.3 was found to be an independent prognostic factor for predicting OS in all the three validation cohorts. Conclusions: PNI represents a prognostic tool in advanced HCC treated with first-line Sorafenib. It is readily available and low-cost, and it could be implemented in clinical practice in patients with HCC