Introduction:In hepatocellular carcinoma (HCC) comorbidities related to decreased liver function or to portal hypertension often limit treatment options. Traditionally, low platelet count has been considered a negative prognostic factor in HCC, especially in early stages. However, recent evidence suggests that elevated platelet count may also predict worse outcomes in advanced stages, suggesting a stage-dependent prognostic impact. Aim:This study evaluated the prognostic role of platelet counts across BCLC stages, adjusted for portal hypertension, to improve individualized patient management. Methods:In this retrospective, multicenter study, platelet count of 1112 patients with HCC in different tumor stages was analyzed. Various platelet count cutoffs (X to Y × 10^9/L) were tested to identify the optimal prognostic threshold. To isolate the effect of platelet levels from portal hypertension, spleen diameter was incorporated as an adjustment variable in multivariate analyses, with variceal status considered when available (in about two thirds of patients). Using an optimized cut-off, survival analysis was performed using univariate and multivariate Cox proportional hazards models. Bootstrapping was performed for internal validation. Results:Platelet count outside 84-200 × 10^9/L was associated with poorer survival (HR = 0.66, 95% CI = 0.57-0.78, p < 0.0001). Bootstrapping showed robustness of the final model. Subgroup analysis revealed worse survival in BCLC stages B and C but not stage A for elevated platelet counts (>200 × 10^9/L) in multivariate analysis (including spleen diameter). Conclusion:Platelet counts showed a stage-dependent prognostic impact in HCC. A platelet count above a cutoff of 200/µL at diagnosis was associated with poorer prognosis. Using this cutoff may improve survival prediction in BCLC B and C patients with potential usage for risk stratification and guidance of treatment decisions. Further external validation is required to confirm these findings and evaluate their clinical applicability.

Introduction: In hepatocellular carcinoma (HCC) comorbidities related to decreased liver function or to portal hypertension often limit treatment options. Traditionally, low platelet count has been considered a negative prognostic factor in HCC, especially in early stages. However, recent evidence suggests that elevated platelet count may also predict worse outcomes in advanced stages, suggesting a stage-dependent prognostic impact. Aim: This study evaluated the prognostic role of platelet counts across BCLC stages, adjusted for portal hypertension, to improve individualized patient management. Methods: In this retrospective, multicenter study, platelet count of 1112 patients with HCC in different tumor stages was analyzed. Various platelet count cutoffs (X to Y x 10<^>9/L) were tested to identify the optimal prognostic threshold. To isolate the effect of platelet levels from portal hypertension, spleen diameter was incorporated as an adjustment variable in multivariate analyses, with variceal status considered when available ( in about two thirds of patients). Using an optimized cut-off, survival analysis was performed using univariate and multivariate Cox proportional hazards models. Bootstrapping was performed for internal validation. Results: Platelet count outside 84-200 x 10<^>9/L was associated with poorer survival (HR = 0.66, 95% CI = 0.57-0.78, p < 0.0001). Bootstrapping showed robustness of the final model. Subgroup analysis revealed worse survival in BCLC stages B and C but not stage A for elevated platelet counts (>200 x 10<^>9/L) in multivariate analysis (including spleen diameter). Conclusion: Platelet counts showed a stage-dependent prognostic impact in HCC. A platelet count above a cutoff of 200/mu L at diagnosis was associated with poorer prognosis. Using this cutoff may improve survival prediction in BCLC B and C patients with potential usage for risk stratification and guidance of treatment decisions. Further external validation is required to confirm these findings and evaluate their clinical applicability.

Background:Immunotherapy-based combinations are currently the standard of care in the systemic treatment of patients with HCC. Recent studies have reported unexpectedly long survival with lenvatinib (LEN), supporting its use in first-line treatment for HCC. This study aims to compare the real-world effectiveness of LEN to atezolizumab/bevacizumab (AZ/BV).Methods:A retrospective analysis was conducted to evaluate the effectiveness and safety of frontline AZ/BV or LEN therapy in patients with advanced HCC across 18 university hospitals in Europe.Results:The study included 412 patients (AZ/BV: n=207; LEN: n=205). Baseline characteristics were comparable between the 2 treatment groups. However, patients treated with AZ/BV had a significantly longer median progression-free survival compared to those receiving LEN. The risk of hepatic decompensation was significantly higher in patients with impaired baseline liver function (albumin-bilirubin [ALBI] grade 2) treated with AZ/BV compared to those with preserved liver function. Patients with alcohol-associated liver disease had poorer baseline liver function compared to other etiologies and exhibited a worse outcome under AZ/BV.Conclusions:In this real-world cohort, survival rates were similar between patients treated with LEN and those treated with AZ/BV, confirming that both are viable first-line options for HCC. The increased risk of hepatic decompensation in patients treated with AZ/BV who have impaired baseline liver function underscores the need for careful monitoring. Future trials should aim to distinguish more clearly between metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease.

TPS574 Background: Escalation of treatment from one to two combined immune checkpoint inhibitors (CPI) has dramatically increased objective and clinical response in advanced hepatocellular carcinoma (HCC) patients. Establishing strategies with more than two CPI agents to further increase response while maintaining a manageable toxicity is therefore a top priority. The upfront simultaneous use of three or more CPI can yield a strong initial response to treatment, but it may also increase treatment-related toxicity. An alternative approach, which prioritizes safety over immediate response, involves utilizing different CPI doublets in a sequential manner. However, this design entails switching to a different combination only after radiological progression is observed, and recurrent progressions may lead to deteriorating liver function and treatment resistance. Trials of immunotherapy of HCC conducted in recent years showed that the efficacy of CPI, when used simultaneously, outweighs the drawbacks of their combined toxicity and that early radiological response to treatment, or the lack thereof, is a predictor of clinical outcome. In addition, failure of trials using broad-spectrum tyrosine kinase inhibitors (TKI) and CPI suggest that antibodies or narrow-spectrum TKI should be used for future CPI-based combinations in HCC studies. Based on these considerations, the MONTBLANC study is the first trial to assess the effectiveness of up-front triple treatment with a combination of the three currently approved immunological agents for HCC and to implement the concept of treatment escalation determined by lack of early radiological response (as opposed to treatment progression). Methods: The MONTBLANC study is a randomized, 2-arm phase II study on the efficacy of combinations of durvalumab, tremelimumab, and bevacizumab in patients with advanced HCC. Patients with preserved liver function (Child-Pugh A) with unresectable tumors or not amenable to local or locoregional treatment are randomized to an early escalation arm (A) or a triple treatment arm (B). Patients in arm A receive combined durvalumab and tremelimumab (STRIDE regimen). Treatment is escalated by the addition of bevacizumab upon detection of disease progression or in the absence of radiological response by the 4th month of treatment. Patients in arm B receive up-front STRIDE and bevacizumab. Treatment will continue until unacceptable toxicity or progression under the Bev-containing regimen. The primary endpoint is overall response rate (ORR). Clinical trial information: NCT05844046 .

Purpose To investigate whether automatic 3D visualization of computed tomography (CT) data sets with singular liver tumor compared to 2D images could foster a broader understanding of tumor localization and resectability in the liver within a multidisciplinary team and might therefore be a useful tool in multidisciplinary decision-making. Material and methods The study was configured as a web-based questionnaire. Physicians of all levels of medical training from surgery, radiology, and gastroenterology departments were recruited. A total of seven cases with singular liver tumor CT images with adequate quality were selected. Automatic 3D segmentation was performed using Universal Atlas (Release 5.0) as part of the Brainlab of Elements software suite (Brainlab AG, Munich, Germany). All cases were randomly presented in a 2D and 3D manner. After every case-presentation, multiple choice (single answer) questions concerning tumor extent and resectability were asked. The questions as well as the answers defined to be correct, were evaluated by two senior consultants from the radiology and surgery department. The primary outcome parameters were the correctness of answers stratified for medical specialty and for the level of medical training. The secondary outcome was the time needed for the evaluation of seven liver cases using 2D versus 3D images. Six additional questions were tailored to evaluate the subjective value of the 3D visualization.  Results A total of 92 participants participated in the study, 31.5% of them were abdominal surgeons, 34.8% gastroenterologists, and 33.7% radiologists. Based on the level of medical training, 66 were residents (71.7%) and 26 consultants (28.3%). Only radiologists answered more questions correctly using 2D imaging compared to the 3D method (p = 0.006). There was no statistically significant difference between correctly answered questions when using 2D vs. 3D visualization in the gastroenterologist and surgeon groups (p > 0.05). The resident subgroup showed no statistically significant difference when using the 2D vs. 3D images (p > 0.05), the consultant subgroup answered more questions correctly using 2D imaging (p = 0.009). Physicians with elementary experience of liver pathology also showed no difference in 2D vs. 3D (p = 0.332), physicians with proficient experience of liver pathology answered more questions correctly using 2D imaging (p = 0.010). The median time taken for the evaluation of the seven liver cases was only significantly faster for the gastroenterologist group (p = 0.006) using the 3D analysis (median: 9.1 minutes) than the 2D analysis (median: 10.7 minutes).  Over 80% of the participants found the 3D presentation to be a helpful additional tool for the clinical routine according to the subjective questionnaire. Conclusion In this study 3D visualization of liver tumors was evaluated as helpful within a multidisciplinary team of radiologists, surgeons, and gastroenterologists. However, significantly superior results in the understanding of liver anatomy could not be demonstrated by means of 3D visualization. It may be that more immersive technologies such as augmented reality or virtual reality will lead to a superior understanding compared to conventional presentation of information in 2D cross-sectional images.

Introduction: CT-guided interstitial brachytherapy (iBT) radiotherapy has been established in the treatment of liver tumors. With iBT, hepatocellular carcinoma (HCC) lesions can be treated beyond the limits of thermal ablation (i.e., size and location). However, a comprehensive analysis of the efficacy of iBT in patients within and beyond thermal ablation limits is lacking. Materials and Methods: A total of 146 patients with 216 HCC lesions have been analyzed retrospectively. Clinical and imaging follow-up data has been collected. Lesions were evaluated in terms of suitability for thermal ablation or not. The correlation between local tumor control (LTC), time to progression (TTP), overall survival (OS), and clinical and imaging parameters have been evaluated using univariable and multivariable Cox regression analyses. Results: LTC rates at 12 months, 24 months, and 36 months were 87%, 75%, and 73%, respectively. 65% of lesions (n = 141) were not suitable for radiofrequency ablation (RFA). The median TTP was 13 months, and the median OS was not reached (3-year OS rate: 70%). No significant difference in LTC, TTP, or OS regarding RFA suitability existed. However, in the overall multivariable analysis, lesion diameter >5 cm was significantly associated with lower LTC (HR: 3.65, CI [1.60–8.31], p = 0.002) and shorter TTP (HR: 2.08, CI [1.17–3.70], p = 0.013). Advanced BCLC stage, Child-Pugh Stage, and Hepatitis B were associated with shorter OS. Conclusion: iBT offers excellent LTC rates and OS in local HCC treatment regardless of the limits of thermal ablation, suggesting further evidence of its alternative role to thermal ablation in patients with early-stage HCC.

Background and Objective With the rising importance of precision oncology in biliary tract cancer (BTC), the aim of this retrospective single-center analysis was to describe the clinical and molecular characteristics of patients with BTC who underwent comprehensive genomic profiling (CGP) and were discussed in the CCCMunich LMU molecular tumor board (MTB). Patients and Methods In this single-center observational study, we included BTC patients with intrahepatic cholangiocarcinoma (iCCA), extrahepatic CCA (eCCA), and gallbladder cancer (GB), who had been discussed in the institutional MTB from May 29, 2017, to July 25, 2022. Patients were followed up until 31 January 2023. Data were retrospectively collected by review of medical charts, and MTB recommendation. Results In total, 153 cases were registered to the MTB with a median follow-up of 15 months. Testing was successful in 81.7% of the patients. CGP detected targetable alterations in 35.3% of our BTC patients (most commonly ARID1A/ERBB2/IDH1/PIK3CA/BRAF -mutations and FGFR2 -fusions ). Recommendations for molecularly guided therapy were given in 46.4%. Of those, treatment implementation of targeted therapy followed in 19.4%. In patients receiving the recommended treatment, response rate was 57% and median overall survival was 19 months (vs 8 months in the untreated cohort). The progression-free survival ratio of 1.45 suggest a clinical benefit of molecularly guided treatment. Conclusions In line with previous work, our series demonstrates feasibility and clinical utility of comprehensive genomic profiling in BTC patients. With the growing number of targeted agents with clinical activity in BTC, CGP should become standard of care in the management of this group of patients.

Introduction: Immunotherapy has been established as the standard treatment option for patients with advanced hepatocellular carcinoma (aHCC). Despite the increased efficacy, disease progression occurs in a relevant proportion of patients even after an objective response. Combination concepts with locoregional therapy are currently under investigation for hepatic disease but are also in discussion for the control of distant metastasis. Radiotherapy is a highly effective treatment modality for local tumor control. It is also thought to increase the efficacy of checkpoint inhibition and sensitize distant lesions to the effects of immunotherapy, but may potentially increase adverse effects. In our center, few patients with aHCC treated with immune checkpoint inhibitors (ICIs) received concomitant radiotherapy for symptom or disease control. The aim of this study was to retrospectively analyze adverse effects and efficacy of concomitant radiotherapy in patients with aHCC treated with checkpoint inhibition. Methods: To this aim, patients who received a combination of ICI and radiotherapy in our institution were retrospectively considered for analysis. The predefined inclusion criterion was radiotherapy after initiated checkpoint inhibition and continuation of ICI therapy for at least 8 weeks. Adverse effects and efficacy measurements were performed according to local standards. Results: The database search of 2016–2021 revealed six consecutive patients fulfilling the predefined criteria for concomitant ICI and radiotherapy. Three patients received high-dose-rate brachytherapy (15 Gy) to treat progredient hepatic lesions. Two patients received stereotactic body radiotherapy (SBRT) (25–30 Gy) for symptom control, and 1 patient received brachytherapy and SBRT to treat metastases. No severe adverse events were reported in the period (<6 months) after concomitant radiotherapy. In 5 out of 6 cases, long-term tumor control could be achieved by this therapeutic combination. Conclusion: A good efficacy of concomitant radiotherapy and checkpoint inhibition has been achieved with no safety concerns. Further investigations should evaluate the safety, appropriate clinical context, and efficacy of this promising approach.

PURPOSE:For patients with cancer of unknown primary (CUP), treatment options are limited. Precision oncology, the interplay of comprehensive genomic profiling (CGP) and targeted therapies, aims to offer additional treatment options to patients with advanced and hard-to-treat cancers. We aimed to highlight the use of a molecular tumor board (MTB) in the therapeutic management of CUP patients. METHODS:In this single-center observational study, CUP patients, presented to the MTB of the Comprehensive Cancer Center Munich LMU, a tertiary care center, were analyzed retrospectively. Descriptive statistics were applied to describe relevant findings. RESULTS:Between June 2016 and February 2022, 61 patients with unfavorable CUP were presented to the MTB, detected clinically relevant variants in 74% (45/61) of patients, of which 64% (29/45) led to therapeutic recommendation. In four out of 29 patients (14%), the treatment recommendations were implemented, unfortunately without resulting in clinical benefit. Reasons for not following the therapeutic recommendation were mainly caused by the physicians' choice of another therapy (9/25, 36%), especially in the context of worsening of general condition, lost to follow-up (7/25, 28%) and death (6/25, 24%). CONCLUSION:CGP and subsequent presentation to a molecular tumor board led to a high rate of therapeutic recommendations in patients with CUP. Recommendations were only implemented at a low rate; however, late GCP diagnostic and, respectively, MTB referral were found more frequent for the patients with implemented treatment. This contrast underscores the need for early implementation of CGP into the management of CUP patients.

Background & Aims: 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. Methods: 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. Results: Of 994 ICI-treated patients screened, a total of 58 patients (male, n = 41; 71%) with a mean age of 65.0 & PLUSMN;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 3.37.0) 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. Conclusions: 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. Impact and implications: 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 pre-treated with immunotherapy in a retrospective, international, multicenter study. Our data provide the rationale for pro-spective trials investigating the role of ICI-based regimens in patients who have progressed on first-line immunotherapy. & COPY; 2022 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

TPS492 Background: Atezolizumab and bevacizumab is the first approved immunotherapeutic regimen for first-line treatment of patients with advanced hepatocellular carcinoma (HCC). The efficacy and tolerability of this regimen suggests that its use could be extended to the treatment of patients with intermediate-stage HCC in combination with transarterial chemoembolization (TACE). The effect of TACE combined with atezolizumab and bevacizumab could improve response and tumor control as well as prevent disease progression in non-responders to TACE. Response to the early use of immunotherapy could also reduce the number and extent of TACE cycles needed to achieve tumor control, thereby contributing to the prevention of collateral damage to the liver parenchyma and preservation of liver function. Initiating immunotherapy first may also promote the access of circulating lymphocytes into tumor lesions. The DEMAND study investigates the efficacy and ideal sequence of TACE and immunotherapy in intermediate stage HCC. Methods: This investigator-initiated, multi-center, randomized, open-label phase 2 trial is the first study to evaluate the safety and efficacy of atezolizumab and bevacizumab prior to, or in combination with TACE in patients with unresectable HCC. 106 patients (Barcelona Clinic Liver Cancer Stage A not amenable to curative therapy or B, Child-Pugh A or B7, Eastern Cooperative Oncology Group performance status 0 or 1, no prior TACE) will be randomized in a 1:1 ratio to receive either up-front atezolizumab and bevacizumab followed by TACE selectively directed against progressive lesions (Arm A, 53 patients), or TACE and synchronous treatment with atezolizumab and bevacizumab (Arm B, 53 patients). Patients receive study treatment until loss of clinical benefit or unacceptable toxicity for up to 24 months. The use of local ablation is allowed for the treatment of lesions which cannot be targeted sufficiently selectively by TACE, or of de-novo lesions. The primary endpoint is the 24-month survival rate; secondary endpoints include objective response rate, progression-free survival, safety and quality of life. Translational analyses aim at identifying predictive biomarkers and focus on immune cell phenotyping in tumor and peripheral blood, circulating tumor DNA and changes in the diversity of the gut microbiome. Recruitment is ongoing in 15 German centers with 21 of 106 patients randomized. Clinical trial information: NCT04224636.

The optimal treatment sequence of tyrosine kinase inhibitor (TKI)-based therapy in patients with hepatocellular carcinoma (HCC) remains unclear. Therefore, sequential systemic therapy after first-line therapy with sorafenib or lenvatinib was compared in a retrospective real-world cohort. In total, 164 patients with HCC were included. Child B cirrhosis was present in 26 patients (16.5%), whereas 132 patients (83.5%) had preserved liver function. In total, 72 patients (44%) discontinued systemic therapy after first-line therapy while 51 (31%) and 31 (19%) patients received 2 or more treatment lines. Most notably, median overall survival (mOS) was influenced by liver functional status and patient performance status at the beginning of first-line therapy. Patients receiving a sequential therapy regimen had significantly longer mOS compared to patients that discontinued systemic therapy after omitting first-line treatment. The choice of the initial TKI did not impact mOS. A clear deterioration of liver function could be observed during the course of TKI-based treatment.

BACKGROUND:Cholangiocarcinoma (CCA) is a highly aggressive malignancy, and its incidence seems to be increasing over the last years. Given the high rate of irresectability at the time of initial diagnosis, new treatment approaches are important to achieve better patient outcomes. Our review provides an overview of current multimodal therapy options across different specialties of gastroenterology/oncology, surgery, and interventional radiology.SUMMARY:CCA is subdivided into clinically and molecularly distinct phenotypes. Surgical treatment currently is the only potentially curative therapy, but unfortunately, the majority of all patients are not eligible for resection at the time of initial diagnosis due to anatomic location, inadequate hepatic reserve, metastatic disease, or limiting comorbidities. However, multimodal treatment options are available to prolong survival, relieve symptoms, and maintain life quality.KEY MESSAGES:The treatment of CCA is complex and requires close interdisciplinary collaboration and individualized treatment planning to ensure optimal patient care at specialized centers. Molecular profiling of patients and inclusion into clinical trials is highly recommended.

Objective: Evaluation of the efficacy and safety of atezolizumab/bevacizumab in a real-world HCC cohort, including patients with impaired liver function and prior systemic therapy. Methods: Retrospective analysis of 147 HCC patients treated with atezolizumab/bevacizumab at six sites in Germany and Austria. Results: The overall response rate and disease control rate were 20.4% and 51.7%, respectively. Seventy-three patients (49.7%) met at least one major exclusion criterion of the IMbrave150 trial (IMbrave-OUT), whereas 74 patients (50.3%) were eligible (IMbrave-IN). Median overall survival (mOS) as well as median progression-free survival (mPFS) was significantly longer in IMbrave-IN versus IMbrave-OUT patients [mOS: 15.0 months (95% confidence interval (CI): 10.7–19.3] versus 6.0 months (95% CI: 3.2–8.9; p < 0.001) and mPFS: 8.7 months (95% CI: 5.9–11.5) versus 3.7 months (95% CI: 2.7–4.7; p < 0.001)]. Prior systemic treatment did not significantly affect mOS [hazard ratio (HR): 1.32 (95% CI: 0.78–2.23; p = 0.305)]. mOS according to ALBI grades 1/2/3 were 15.0 months (95% CI: not estimable), 8.6 months (95% CI: 5.4–11.7), and 3.2 months (95% CI: 0.3–6.1), respectively. ALBI grade and ECOG score were identified as independent prognostic factors [ALBI grade 2 versus 1; HR: 2.40 (95% CI: 1.34 – 4.30; p = 0.003), ALBI grade 3 versus 1; HR: 7.28 (95% CI: 3.30–16.08; p < 0.001), and ECOG ⩾2 versus 0; HR: 2.09 (95% CI: 1.03 – 4.23; p = 0.042)], respectively. Sixty-seven patients (45.6%) experienced an adverse event classified as CTCAE grade ⩾3. Patients in the IMbrave-OUT group were at increased risk of hepatic decompensation with encephalopathy (13.7% versus 1.4%, p = 0.004) and/or ascites (39.7% versus 9.5%; p < 0.001). Conclusion: In this real-world cohort, efficacy was comparable to the results of the IMbrave150 study and not affected by prior systemic treatment. ALBI grade and ECOG score were independently associated with survival. IMbrave-OUT patients were more likely to experience hepatic decompensation.

BACKGROUND:Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths, and radiological imaging and locoregional therapies are essential for the management of patients with HCC.SUMMARY:In cirrhotic patients, a characteristic imaging pattern establishes the noninvasive diagnosis of HCC with acceptable sensitivity and high specificity. In addition to diagnosis, imaging is used in the staging of patients and treatment allocation. Multiparametric MRI with hepatospecific contrast agents improves lesion detection, characterization, and treatment allocation; recently described imaging criteria allow identification of precursor lesions. Radiofrequency ablation (RFA) and transarterial chemoembolization (TACE) have been established in the treatment of patients with HCC at the early and intermediate stages, respectively. Microwave ablation has been described as an alternative to RFA in selected cases. Imaging-guided brachytherapy, a catheter-based radiotherapy technique, offers advantages to overcome some limitations of the aforementioned therapies, including the tumor location and size. Currently, no adjuvant therapy is recommended after RFA or TACE, but several new drugs are under evaluation. Furthermore, although the exact role of selective internal radiation therapy (SIRT) in HCC still needs to be defined, it is an alternative to systemic agents in patients with intolerance, and additional benefit has been shown in selected subgroups. Additionally, SIRT offers an alternate to TACE with higher objective response rates in patients who needs bridging before transplantation.KEY MESSAGES:New imaging criteria improved lesion detection in patients at a risk for HCC, and advances in interventional therapies expanded the range of patients eligible for locoregional treatments.

The combination of the anti-PD-L1 antibody atezolizumab and the anti-VEGF bevacizumab is the first approved immunotherapeutic regimen for first-line therapy in patients with unresectable hepatocellular carcinoma (HCC), currently approved in more than 80 countries. The efficacy and tolerability of this regimen suggest that the use of atezolizumab bevacizumab could be extended to the treatment of patients with intermediate-stage HCC in combination with transarterial chemoembolization (TACE). The authors describe the rationale and design of the DEMAND study. This investigator-initiated, multicenter, randomized phase 2 study is the first trial to evaluate the safety and efficacy of atezolizumab bevacizumab prior to or in combination with TACE in patients with intermediate-stage HCC. The primary end point is the 24-month survival rate; secondary end points include objective response rate, progression-free survival, safety and quality of life.

Immune checkpoint inhibitor (ICI)-based regimens are transforming the landscape of hepatocellular carcinoma (HCC) treatment. We describe the effect of combined ipilimumab and nivolumab in patients with advanced HCC after the failure of prior ICI-based combination treatments. The clinical course of patients with advanced HCC who received combined ipilimumab and nivolumab after prior ICI-based combination therapies was assessed. Progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) per RECIST v1.1 and mRECIST, overall survival (OS), and safety were analyzed. Of 109 patients treated with atezolizumab and bevacizumab or other ICI-based combination treatments, ten patients received subsequent therapy with ipilimumab and nivolumab. The majority of patients had Barcelona Clinic Liver Cancer (BCLC) Stage C (80

Max Seidensticker consults, advises, and has received grants from Bayer, Cook, and Sirtex. Daniel Roessler advises for Bayer and advises and has received grants from Ipsen. Najib Ben Khaled has received a travel grant from Eisai and lecture honoraria from Falk. Prof. De Toni has served as a paid consultant for AstraZeneca, Bayer, BMS, Eisai, Eli Lilly, Pfizer, Ipsen and Roche. He has received reimbursement of meeting attendance fees and travel expenses from Arqule, BMS, Bayer, Celsion and Roche, and lecture honoraria from BMS, Falk and Roche. He has received third‐party funding for scientific research from Arqule, AstraZeneca, BMS, Bayer, Eli Lilly and Roche. TO THE EDITOR: We read with interest the article by Bhangui et al. who provide a model of prediction of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) from a living donor.(1) The still frequent post‐LT recurrence of HCC raises the controversial issue of the use of immunotherapy in LT recipients, a topic that has gained exceptional relevance after the combination of atezolizumab/bevacizumab has been approved for the treatment of HCC. Checkpoint‐inhibitor based combination regimens have been shown high efficacy in advanced HCC,(2) but little is known about the activity and safety of immunotherapy after LT. The availability of these immunotherapeutic agents for treatment of HCC will cause clinicians to be increasingly called to weigh the potential oncological benefits of immunotherapy in transplant recipients against the odds of a fatal treatment outcome owing to the potential occurrence of organ rejection. We recently used atezolizumab/bevacizumab in analogy to the Imbrave150 study as a salvage treatment for a 35‐year‐old male patient with a recurrence of fibrolamellar HCC 4 years after LT.(2) Treatment was initiated after multiple surgical and local interventions and after the failure of 2 regimens of systemic therapy (gemcitabine/oxaliplatin and fluorouracil/interferon alfa‐2b). A positron emission tomography–computed tomography scan conducted after 3 months of treatment showed a marked decrease of [18F]fludeoxyglucose uptake as a possible sign of response (Fig. 1). Because therapy was well tolerated, and, notably, no signs of organ rejection were evident, atezolizumab/bevacizumab was continued for an additional 6 months until diffuse disease progression and clinical deterioration became evident. The patient died 10 months after treatment initiation as a result of tumor progression without signs of immune‐mediated liver toxicity (Supporting Fig. 1 and Table 1).FIG. 1: [18F]fludeoxyglucose positron emission tomography/computed tomography scans (A,C) before and (B,D) 3 months after initiation of atezolizumab/bevacizumab. Arrows indicate representative lesions with decreasing metabolic activity.The approval of atezolizumab/bevacizumab marked a breakthrough in the therapy of HCC. However, the experience on the use of these agents in the post‐LT setting is limited to case series.(3) This is the first report on the use of combined atezolizumab/bevacizumab, the now standard first‐line treatment of advanced HCC, in a LT recipient. This case shows that organ rejection does not invariably occur in LT recipients receiving immunotherapy even when used in combinations intended to enhance immune response. Immunotherapy cannot be recommended in LT recipients. Nevertheless, after the approval of atezolizumab/bevacizumab, an increasingly frequent use of these agents as a salvage treatment of post‐LT HCC recurrence is to be expected. Until biomarkers capable of predicting response or liver toxicity will become available, we propose that an international registry is established to collect evidence from single‐case experiences on the effects of immunotherapy in the posttransplant setting to guide future clinical studies.

We have read with interest the paper by Gerbes et al ,1 which highlights the current developments in the treatment of hepatocellular carcinoma (HCC). Fibrolamellar HCC (FL-HCC) is, in contrast to HCC,2 an infrequent tumour, most often occurring in adolescents or young adults without underlying liver disease.3 Chemotherapy-based regimens are typically used to treat FL-HCC based on studies in small patients’ cohorts and case series.3 Despite anecdotal reports of response to systemic treatment, the prognosis of advanced FL-HCC is poor.4 The development of immune checkpoint inhibitors (ICP) is drastically changing the approach to the treatment of HCC. In particular, recent trials showed that immunoncological treatment can be potentiated if ICP are used in combination.5 6 This is exemplified by the use of nivolumab/ipilimumab,7 and by the results of the phase III IMBRAVE 150 trial, which recently marked …

Immune checkpoint inhibitors (ICIs) belong to the therapeutic armamentarium in advanced hepatocellular carcinoma (HCC). However, only a minority of patients benefit from immunotherapy. Therefore, we aimed to identify indicators of therapy response. This multicenter analysis included 99 HCC patients. Progression-free (PFS) and overall survival (OS) were studied by Kaplan-Meier analyses for clinical parameters using weighted log-rank testing. Next-generation sequencing (NGS) was performed in a subset of 15 patients. The objective response (OR) rate was 19% median OS (mOS)16.7 months. Forty-one percent reached a PFS > 6 months; these patients had a significantly longer mOS (32.0 vs. 8.5 months). Child-Pugh (CP) A and B patients showed a mOS of 22.1 and 12.1 months, respectively. Ten of thirty CP-B patients reached PFS > 6 months, including 3 patients with an OR. Tumor mutational burden (TMB) could not predict responders. Of note, antibiotic treatment within 30 days around ICI initiation was associated with significantly shorter mOS (8.5 vs. 17.4 months). Taken together, this study shows favorable outcomes for OS with low AFP, OR, and PFS > 6 months. No specific genetic pattern, including TMB, could identify responders. Antibiotics around treatment initiation were associated with worse outcome, suggesting an influence of the host microbiome on therapy success.