Immunotherapy with atezolizumab plus bevacizumab represents the new standard of care in systemic front-line treatment of hepatocellular carcinoma (HCC). However, biomarkers that predict treatment success and survival remain an unmet need. Patients with HCC put on PD-(L)1-based immunotherapy were included in a training set (n = 190; 6 European centers) and a validation set (n = 102; 8 European centers). We investigated the prognostic value of baseline variables on overall survival using a Cox model in the training set and developed the easily applicable CRAFITY (CRP and AFP in ImmunoTherapY) score. The score was validated in the independent, external cohort, and evaluated in a cohort of patients treated with sorafenib (n = 204). Baseline serum alpha-fetoprotein ≥100 ng/ml (hazard ratio [HR] 1.7; p = 0.007) and C-reactive protein ≥1 mg/dl (HR, 1.7; p = 0.007) were identified as independent prognostic factors in multivariable analysis and were used to develop the CRAFITY score. Patients who fulfilled no criterion (0 points; CRAFITY-low) had the longest median overall survival (27.6 (95% CI 19.5-35.8) months), followed by those fulfilling 1 criterion (1 point; CRAFITY-intermediate; 11.3 (95% CI 8.0-14.6) months), and patients meeting both criteria (2 points; CRAFITY-high; 6.4 (95% CI 4.8-8.1) months; p <0.001). Additionally, best radiological response (complete response/partial response/stable disease/progressive disease) was significantly better in patients with lower CRAFITY score (CRAFITY-low: 9%/20%/52%/20% vs. CRAFITY-intermediate: 3%/25%/36%/36% vs. CRAFITY-high: 2%/15%/22%/61%; p = 0.003). These results were confirmed in the independent validation set and in different subgroups, including Child-Pugh A and B, performance status 0 and ≥1, and first-line and later lines. In the sorafenib cohort, CRAFITY was associated with survival, but not radiological response. The CRAFITY score is associated with survival and radiological response in patients receiving PD-(L)1 immunotherapy. The score may help with patient counseling but requires prospective validation. The immunotherapy-based regimen of atezolizumab plus bevacizumab represents the new standard of care in systemic first-line therapy of hepatocellular carcinoma (HCC). Biomarkers to predict treatment outcome are an unmet need in patients undergoing immunotherapy for HCC. We developed and externally validated a score that predicts outcome in patients with HCC undergoing immunotherapy with immune checkpoint blockers.

The novel CRP–albumin–lymphocyte (CALLY) index is an improved immunonutritive scoring system, based on serum C-reactive protein (CRP), serum albumin, and the lymphocyte count. It has shown promise as a prognostic index for patients with hepatocellular carcinoma (HCC) undergoing resections. This study evaluated the prognostic ability of the CALLY index for patients with HCC undergoing transarterial chemoembolization (TACE). We retrospectively identified 280 treatment-naïve patients with HCC that underwent an initial TACE at our institution, between 2010 and 2020. We compared the CALLY index to established risk factors in univariate and multivariate regression analyses for associations with median overall survival (OS). A low CALLY score was associated with low median OS (low vs. high CALLY: 9.0 vs. 24.0 months, p < 0.001). In the multivariate analysis, the CALLY index remained an independent prognostic predictor (p = 0.008). Furthermore, all factors of the CALLY index reached significance in univariate and in-depth multivariate analyses. However, the concordance index (C-index) of the CALLY index (0.60) was similar to the C-indices of established immunonutritive and inflammation scoring systems (range: 0.54 to 0.63). In conclusion, the CALLY index showed promise as a stratification tool for patients with HCC undergoing TACE. Notably, the CALLY index was not superior to other immunonutritive and inflammation scoring systems in predicting the median OS. Thus, future studies should re-evaluate the mathematical calculation of the index, particularly the contributions of individual parameters.

To compare the overall survival of patients with hepatocellular carcinoma (HCC) who were treated with lipiodol-based conventional transarterial chemoembolization (cTACE) with that of patients treated with drug-eluting bead transarterial chemoembolization (DEB-TACE). By an electronic search of our radiology information system, we identified 674 patients that received TACE between November 2002 and July 2013. A total of 520 patients received cTACE, and 154 received DEB-TACE. In total, 424 patients were excluded for the following reasons: tumor type other than HCC (n = 91), liver transplantation after TACE (n = 119), lack of histological grading (n = 58), incomplete laboratory values (n = 15), other reasons (e.g., previous systemic chemotherapy) (n = 114), or were lost to follow-up (n = 27). Therefore, 250 patients were finally included for comparative analysis (n = 174 cTACE; n = 76 DEB-TACE). There were no significant differences between the two groups regarding sex, overall status (Barcelona Clinic Liver Cancer classification), liver function (Child-Pugh), portal invasion, tumor load, or tumor grading (all p > 0.05). The mean number of treatment sessions was 4 ± 3.1 in the cTACE group versus 2.9 ± 1.8 in the DEB-TACE group (p = 0.01). Median survival was 409 days (95 % CI: 321–488 days) in the cTACE group, compared with 369 days (95 % CI: 310–589 days) in the DEB-TACE group (p = 0.76). In the subgroup of Child A patients, the survival was 602 days (484–792 days) for cTACE versus 627 days (364–788 days) for DEB-TACE (p = 0.39). In Child B/C patients, the survival was considerably lower: 223 days (165–315 days) for cTACE versus 226 days (114–335 days) for DEB-TACE (p = 0.53). The present study showed no significant difference in overall survival between cTACE and DEB-TACE in patients with HCC. However, the significantly lower number of treatments needed in the DEB-TACE group makes it a more appealing treatment option than cTACE for appropriately selected patients with unresectable HCC.

The incidence of non-alcoholic steatohepatitis (NASH) is increasing worldwide and a poorly defined subset of patients develops end-stage liver disease and hepatocellular carcinoma (HCC). Differences in the biological behaviour, tumour characteristics, associated risk factors, treatment outcomes and overall survival of patients with NASH-HCC remain poorly defined. The aim of this study was to determine and analyze these differences in a large clinical cohort to guide treatment decisions. 1119 patients with HCC treated in an 11 year period at the University Medical Centre of the Johannes Gutenberg University Mainz were retrospectively analyzed. Patients with NASH-HCC (n = 45) were older (67.6 vs. 65 years), had an increased frequency of the metabolic syndrome and complications with a higher incidence of obesity (31.1% vs. 14.7%), type II diabetes mellitus (66.7% vs. 37.85%), a higher rate of myocardial infarction (13.3% vs. 4.8%) and apoplectic stroke (8.9% vs. 2.1%) (all p < 0.05). Interestingly, liver function was preserved to a higher extent and MELD scores were significantly lower in NASH-HCC. Nonetheless, resection or orthotopic liver transplantation was performed only in 17.8% and 4.4% of NASH-HCC respectively. Overall survival was lower compared to HCC of other aetiologies. Independent of the underlying aetiology BMI exhibited a positive correlation with overall survival. Despite retained liver function, patients with NASH-associated HCC showed a decreased overall survival. With regards to the expected increasing prevalence of NASH, it will be necessary to improve screening and surveillance strategies to identify HCC in NASH early and improve survival.

We investigated the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with hepatocellular carcinoma (HCC) who received ICI-based therapies in a previous systemic line. In this international, retrospective multicenter study, patients with HCC who received at least two lines of ICI-based therapies (ICI-1, ICI-2) at 14 institutions were eligible. The main outcomes included best overall response and treatment-related adverse events. Of 994 ICI-treated patients screened, a total of 58 patients (male, n = 41; 71%) with a mean age of 65.0±9.0 years were included. Median systemic treatment lines of ICI-1 and ICI-2 were 1 (range, 1-4) and 3 (range, 2-9), respectively. ICI-based therapies used at ICI-1 and ICI-2 included ICI alone (ICI-1, n = 26, 45%; ICI-2, n = 4, 7%), dual ICI regimens (n = 1, 2%; n = 12, 21%), or ICI combined with targeted therapies/anti-VEGF (n = 31, 53%; n = 42, 72%). Most patients discontinued ICI-1 due to progression (n = 52, 90%). Objective response rate was 22% at ICI-1 and 26% at ICI-2. Responses at ICI-2 were also seen in patients who had progressive disease as best overall response at ICI-1 (n = 11/21; 52%). Median time-to-progression at ICI-1 and ICI-2 was 5.4 (95% CI 3.0-7.7) months and 5.2 (95% CI 3.3-7.0) months, respectively. Treatment-related adverse events of grade 3-4 at ICI-1 and ICI-2 were observed in 9 (16%) and 10 (17%) patients, respectively. ICI rechallenge was safe and resulted in a treatment benefit in a meaningful proportion of patients with HCC. These data provide a rationale for investigating ICI-based regimens in patients who progressed on first-line immunotherapy in prospective trials. Therapeutic sequencing after first-line immune checkpoint inhibitor (ICI)-based therapy for advanced hepatocellular carcinoma (HCC) remains a challenge as no available second-line treatment options have been studied in immunotherapy-pretreated patients. Particularly, the role of ICI rechallenge in patients with HCC is unclear, as data from prospective trials are lacking. We investigated the efficacy and safety of ICI-based regimens in patients with HCC pretreated with immunotherapy in a retrospective, international, multicenter study. Our data provide the rationale for prospective trials investigating the role of ICI-based regimens in patients who have progressed on first-line immunotherapy.

Background Lenvatinib is approved as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). The efficacy of lenvatinib in Caucasian real-world patients is insufficiently defined. The purpose of this study was to evaluate the efficacy of lenvatinib in a multi-center cohort (ELEVATOR) from Germany and Austria. Methods A retrospective data analysis of 205 patients treated with first-line systemic lenvatinib at 14 different sites was conducted. Overall survival, progression free survival, overall response rate and adverse event rates were assessed and analyzed. Results Patients receiving lenvatinib in the real-world setting reached a median overall survival of 12.8 months, which was comparable to the results reported from the REFLECT study. Median overall survival (mOS) and progression free survival (mPFS) was superior in those patients who met the inclusion criteria of the REFLECT study compared to patients who failed to meet the inclusion criteria (mOS 15.6 vs 10.2 months, HR 0.55, 95% CI 0.38-0.81, p=0.002; mPFS 8.1 vs 4.8 months HR 0.65, 95% CI 0.46-0.91, p=0.0015). For patients with an impaired liver function according to the Albumin-Bilirubin (ALBI) grade, or reduced ECOG performance status ≥2, survival was significantly shorter compared to patients with sustained liver function (ALBI grade 1) and good performance status (ECOG performance status 0), respectively (HR 1.69, 95% CI 1.07-2.66, p=0.023; HR 2.25, 95% CI 1.19-4.23, p=0.012). Additionally, macrovascular invasion (HR 1.55, 95% CI 1.02-2.37, p=0.041) and an AFP ≥200 ng/mL (HR 1.56, 95% CI 1.03-2.34, p=0.034) were confirmed as independent negative prognostic factors in our cohort of patients with advanced HCC. Conclusion Overall, our data confirm the efficacy of lenvatinib as first-line treatment and did not reveal new or unexpected side effects in a large retrospective Caucasian real-world cohort, supporting the use of lenvatinib as meaningful alternative for patients that cannot be treated with IO-based combinations in first-line HCC.