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BACKGROUND: Despite the recent advances in cancer treatment, the therapeutic options for patients with biliary tract cancer are still very limited and the prognosis very poor. More than 50% of newly diagnosed patients with biliary tract cancer are not amenable to curative surgical treatment and thus treated with palliative systemic treatment. Malignant bile duct obstructions in patients with perihilar and/or ductal cholangiocarcinoma (CCA) represents one of the most important challenges in the management of these patients, owning to the risk represented by developing life-threatening cholangitis which, in turn, limits the use of systemic treatment. For this reason, endoscopic stenting and/or bile duct decompression is the mainstay of treatment of these patients. Data on efficacy and safety of adding radiofrequency ablation (RFA) to biliary stenting is not conclusive. The aim of this multicenter, randomized trial is to evaluate the effect of intraductal RFA prior to bile duct stenting in patients with unresectable perihilar or ductal CCA undergoing palliative systemic therapy. METHODS/DESIGN: ACTICCA-2 is a multicenter, randomized, controlled, open-label, investigator-initiated trial. 120 patients with perihilar or ductal CCA with indication for biliary stenting and systemic therapy will be randomized 1:1 to receive either RFA plus bile duct stenting (interventional arm) or bile duct stenting alone (control arm). Patients will be stratified by trial site and tumor location (perihilar vs. ductal). Both arms receive palliative systemic treatment according to the local standard of care determined by a multidisciplinary tumorboard. The primary endpoint is time to first biliary event, which is determined by an increase of bilirubin to > 5 mg/dl and/or the occurrence of cholangitis leading to premature stent replacement and/or disruption of chemotherapy. Secondary endpoints include overall survival, safety according to NCI CTCAE v5, quality of life assessed by questionnaires (EORTC QLQ-C30 and QLQ-BIL21), clinical event rate at 6 months after RFA and total days of over-night stays in hospital. Follow-up for the primary endpoint will be 6 months, while survival assessment will be continued until end of study (maximum follow-up 30 month). All patients who are randomized and who underwent endoscopic stenting will be used for the primary endpoint analysis which will be conducted using a cause-specific Cox proportional hazards model with a frailty for trial site and fixed effects for the treatment group, tumor location, and stent material. DISCUSSION: ACTICCA-2 is a multicenter, randomized, controlled trial to assess efficacy and safety of adding biliary RFA to bile duct stenting in patients with CCA receiving palliative systemic treatment. TRIAL REGISTRATION: The study is registered with ClinicalTrials.gov (NCT06175845) and approved by the local ethics committee in Hamburg, Germany (2024-101232-BO-ff). This manuscript reflects protocol version 1 as of January 9th, 2024.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Ablación por Radiofrecuencia , Stents , Humanos , Colangiocarcinoma/terapia , Colangiocarcinoma/cirugía , Neoplasias de los Conductos Biliares/cirugía , Neoplasias de los Conductos Biliares/terapia , Ablación por Radiofrecuencia/métodos , Ablación por Radiofrecuencia/efectos adversos , Cuidados Paliativos/métodos , Masculino , Femenino , Calidad de Vida , Ablación por Catéter/métodos , Resultado del Tratamiento , AncianoRESUMEN
INTRODUCTION AND OBJECTIVES: Autoimmune liver diseases (AILD) are rare causes hepatocellular carcinoma (HCC). and data on the efficacy and tolerability of anti-tumour therapies are scarce. This pan-European study aimed to assess outcomes in AILD-HCC patients treated with tyrosine kinase inhibitors (TKIs) or transarterial chemoembolization (TACE) compared with patients with more common HCC etiologies, including viral, alcoholic or non-alcoholic fatty liver disease. MATERIALS AND METHODS: 107 patients with HCC-AILD (AIH:55; PBC:52) treated at 13 European centres between 1996 and 2020 were included. 65 received TACE and 28 received TKI therapy. 43 (66%) were female (median age 73 years) with HCC tumour stage BCLC A (34%), B (46%), C (9%) or D (11%). For each treatment type, propensity score matching was used to match AILD to non-AILD-HCC on a 1:1 basis, yielding in a final cohort of 130 TACE and 56 TKI patients for comparative analyses of median overall survival (mOS) and treatment tolerability. RESULTS: HCC-AILD patients showed comparable mOS to controls for both TACE (19.5 vs 22.1 months, p=0.9) and TKI (15.4 vs 15.1 months, p=0.5). Adverse events were less frequent in AILD-HCC patients than controls (33% vs 62%, p=0.003). For TKIs, there were no significant differences in adverse events (73% vs. 86%, p=0.2) or interruption rates (44% vs. 36%, p=0.7). CONCLUSIONS: In summary, this study demonstrates comparable mOS for AILD-HCC patients undergoing local and systemic treatments, with better tolerability than HCC of other causes. TKIs remain important therapeutic options for AILD-HCC patients, particularly given their exclusion from recent immunotherapy trials.
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BACKGROUNDAIMS: Unlike other malignancies, hepatic functional reserve competes with tumour progression in determining the risk of mortality from hepatocellular carcinoma (HCC). However, the relative contribution of hepatic decompensation over tumour progression in influencing overall survival (OS) has not been assessed in combination immunotherapy recipients. APPROACHRESULTS: From the AB-real observational study(n=898), we accrued 571 patients with advanced/unresectable HCC, Child-Pugh A class treated with frontline atezolizumab+bevacizumab(AB). Hepatic decompensation and tumour progression during follow-up were studied in relationship to patients' OS using time-dependent Cox model. Baseline characteristics were evaluated as predictors of decompensation in competing risks analysis. During a median follow-up of 11.0 months (95%CI 5.1-19.7), 293 patients(51.3%) developed tumour progression without decompensation and 94(16.5%) developed decompensation. In multivariable time-dependent analysis, decompensation(hazard ratio[HR] 19.04, 95%CI 9.75-37.19), HCC progression(HR 9.91, 95%CI 5.85-16.78), albumin-bilirubin(ALBI) grade 2/3(HR 2.16, 95%CI 1.69-2.77) and number of nodules>3(HR 1.63, 95%CI 1.28-2.08) were independently associated with OS. Pre-treatment ALBI grade 2/3(subdistribution HR [sHR] 3.35, 95%CI 1.98-5.67) was independently associated with decompensation, whereas viral aetiology was protective(sHR 0.55, 95%CI 0.34-0.87). Among patients with viral aetiology, effective antiviral treatment was significantly associated with lower risk of decompensation (sHR 0.48, 95%CI 0.25-0.93). CONCLUSIONS: Hepatic decompensation identifies patients with the worst prognosis following AB and is more common in patients with baseline ALBI>1 and non-viral aetiology. Effective antiviral treatment may protect from decompensation, highlighting the prognostic disadvantage of patients with non-viral aetiologies and the importance of multi-disciplinary management to maximise OS.
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Importance: Whether patients with Child-Pugh class B (CP-B) cancer with unresectable hepatocellular carcinoma (uHCC) benefit from active anticancer treatment vs best supportive care (BSC) is debated. Objective: To evaluate the association of immune checkpoint inhibitor (ICI)-based therapies vs BSC with overall survival (OS) of patients with uHCC and CP-B liver dysfunction. Design, Setting, and Participants: This retrospective, multicenter, international clinical case series examined data of patients with CP-B with uHCC who were receiving first-line ICI-based regimens from September 2017 to December 2022 whose data were extracted from an international consortium and compared with a cohort of patients with CP-B receiving BSC. Patients were treated in tertiary care centers across Europe, US, and Asia in routine clinical practice. After applying the inclusion criteria, 187 and 156 patients were left in the ICI and BSC groups, respectively. The propensity score was calculated for the following variables: age, alpha-fetoprotein levels, Child-Pugh score, extrahepatic spread, portal vein tumor thrombosis, cirrhosis, ascites, and baseline Eastern Cooperative Oncology Group performance status. Exposures: Patients in the ICI group received first-line systemic therapy with either atezolizumab plus bevacizumab (A+B) (n = 141) or nivolumab (n = 46). Main Outcomes and Measures: OS in the inverse probability of treatment weighting (IPTW) populations was the main outcome, and it was estimated with Kaplan-Meier method; univariable Cox regression test was used to make comparisons between the 2 groups. Results: The median age was 66 (IQR, 61-72) and 73 (IQR, 66-81) years in the ICI (33 women [18%]) and BSC groups (41 women [26%]), respectively. In the IPTW populations, median OS was significantly longer in the ICI group (7.50 months; 95% CI, 5.62-11.15) compared with BSC (4.04 months; 95% CI, 3.03-5.03; hazard ratio, 0.59; 95% CI, 0.43-0.80; P < .001). Multivariable analysis confirmed that ICI exposure was associated with a reduction of approximately 50% in the risk of death (hazard ratio, 0.55; 95% CI, 0.35-0.86; P < .001), and the presence of portal vein tumor thrombosis, an Eastern Cooperative Oncology Group performance score of greater than 1, and alpha-fetoprotein levels of 400 ng/mL or greater were associated with increased risk of death. Conclusions and Relevance: The results of this case series provide comparative evidence of improved survival in association with ICI treatment compared with BSC in patients with uHCC with CP-B liver dysfunction.
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[This corrects the article DOI: 10.3389/fimmu.2023.1326078.].
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Background & Aims: Sex-related differences in the immune pathogenesis of hepatocellular carcinoma (HCC), particularly related to oestrogen-dependent secretion of pro-tumourigenic cytokines, are well-known. Whether sex influences the efficacy and safety of immunotherapy is not known. Methods: We performed a restricted maximum likelihood random effects meta-analysis of five phase III trials that evaluated immune checkpoint inhibitors (ICIs) in advanced HCC and reported overall survival (OS) hazard ratios (HRs) stratified by sex to evaluate sex-related differences in OS. In a real-world cohort of 840 patients with HCC from 22 centres included between 2018 and 2023, we directly compared the efficacy and safety of atezolizumab + bevacizumab (A+B) between sexes. Radiological response was reported according to RECIST v1.1. Uni- and multivariable Cox regression analyses were performed for OS and progression-free survival (PFS). Results: In the meta-analysis, immunotherapy was associated with a significant OS benefit only in male (pooled HR 0.79; 95% CI 0.73-0.86) but not in female (pooled HR 0.85; 95% CI 0.70-1.03) patients with HCC. When directly comparing model estimates, no differences in the treatment effect between sexes were observed. Among 840 patients, 677 (81%) were male (mean age 66 ± 11 years), and 163 (19%) were female (mean age 67 ± 12 years). Type and severity of adverse events were similar between the two groups. OS and PFS were comparable between males and females upon uni- and multivariable analyses (aHR for OS and PFS: 0.79, 95% CI 0.59-1.04; 1.02, 95% CI 0.80-1.30, respectively). Objective response rates (24%/22%) and disease control rates (59%/59%) were also similar between sexes. Conclusion: Female phase III trial participants experienced smaller OS benefit following ICI therapy for advanced HCC, while outcomes following A+B treatment were comparable between sexes in a large real-world database. Based on the ambiguous sex-related differences in survival observed here, further investigation of sex-specific clinical and biologic determinants of responsiveness and survival following ICIs are warranted. Impact and implications: While immune checkpoint inhibitors have emerged as standard of care for the treatment of hepatocellular carcinoma, there are conflicting reports on whether the efficacy of cancer immunotherapy differs between females and males. Our study suggests ambiguous sex-related differences in outcomes from immunotherapy in hepatocellular carcinoma. Further investigation of sex-specific clustering in clinicopathologic and immunologic determinants of responsiveness to immune checkpoint inhibitor therapy should be prioritised. Systematic review registration: PROSPERO CRD42023429625.
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BACKGROUND & AIMS: Immune-related liver injury (irLI) is commonly observed in patients with cancer treated with immune checkpoint inhibitors (ICIs). We aimed to compare the incidence, clinical characteristics, and outcomes of irLI between patients receiving ICIs for hepatocellular carcinoma (HCC) vs. other solid tumours. METHODS: Two separate cohorts were included: 375 patients with advanced/unresectable HCC, Child-Pugh A class treated with first-line atezolizumab+bevacizumab from the AB-real study, and a non-HCC cohort including 459 patients treated with first-line ICI therapy from the INVIDIa-2 multicentre study. IrLI was defined as a treatment-related increase of aminotransferase levels after exclusion of alternative aetiologies of liver injury. The incidence of irLI was adjusted for the duration of treatment exposure. RESULTS: In patients with HCC, the incidence of any grade irLI was 11.4% over a median treatment exposure of 4.4 months (95% CI 3.7-5.2) vs. 2.6% in the INVIDIa-2 cohort over a median treatment exposure of 12.4 months (95% CI 11.1-14.0). Exposure-adjusted-incidence of any grade irLI was 22.1 per 100-patient-years in patients with HCC and 2.1 per 100-patient-years in patients with other solid tumours (p <0.001), with median time-to-irLI of 1.4 and 4.7 months, respectively. Among patients who developed irLI, systemic corticosteroids were administered in 16.3% of patients with HCC and 75.0% of those without HCC (p <0.001), and irLI resolution was observed in 72.1% and 58.3%, respectively (p = 0.362). In patients with HCC, rates of hepatic decompensation and treatment discontinuation due to irLI were 7%. Grade 1-2 irLI was associated with improved overall survival only in patients with HCC (hazard ratio 0.53, 95% CI 0.29-0.96). CONCLUSIONS: Despite higher incidence and earlier onset, irLI in patients with HCC is characterised by higher rates of remission and lower requirement for corticosteroid therapy (vs. irLI in other solid tumours), low risk of hepatic decompensation and treatment discontinuation, not negatively affecting oncological outcomes. IMPACT AND IMPLICATIONS: Immune-related liver injury (irLI) is common in patients with cancer receiving immune checkpoint inhibitors (ICIs), but whether irLI is more frequent or it is associated with a worse clinical course in patients with hepatocellular carcinoma (HCC), compared to other tumours, is not known. Herein, we compared characteristics and outcomes of irLI in two prospective cohorts including patients treated with ICIs for HCC or for other oncological indications. irLI is significantly more common and it occurs earlier in patients with HCC, also after adjustment for duration of treatment exposure. However, outcomes of patients with HCC who developed irLI are not negatively affected in terms of requirement for corticosteroid therapy, hepatic decompensation, treatment discontinuation and overall survival.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Estudios Prospectivos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/epidemiología , Inmunoterapia/efectos adversos , CorticoesteroidesRESUMEN
Hepatocellular carcinoma (HCC) has high recurrence rates exceeding 50% despite curative resection. The serum biomarker alpha-fetoprotein (AFP) is a well-known prognostic marker for HCC. EpCAM-positive circulating tumor cells (CTC) have a high predictive value for early HCC recurrence after curatively intended resection, most likely indicating micro-metastases at the time of resection. However, sensitivity remains low. The objective of this study was to evaluate a composite test comprising both CTC and AFP to identify patients at high risk for early HCC recurrence. We prospectively enrolled 58 patients undergoing curative intended resection for HCC at a tertiary referral center. Blood specimens were obtained prior to resection and analyzed for EpCAM-positive CTC and serum AFP levels. A positive result was defined as either detection of CTC or AFP levels ≥ 400 ng/ml. Eight patients tested positive for CTC, seven for AFP, and two for both markers. A positive composite test was significantly associated with shorter early recurrence-free survival (5 vs. 16 months, p = 0.005), time to recurrence (5 vs. 16 months, p = 0.011), and overall survival (37 vs. not reached, p = 0.034). Combining CTC and AFP identified patients with poor outcome after surgical resection, for whom adjuvant or neoadjuvant therapies may be particularly desirable.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Células Neoplásicas Circulantes , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/cirugía , Neoplasias Hepáticas/patología , alfa-Fetoproteínas , Molécula de Adhesión Celular Epitelial , Pronóstico , Recurrencia Local de Neoplasia/diagnóstico , Biomarcadores de TumorRESUMEN
BACKGROUND: Since the introduction of the combination treatment of anti-programmed death-ligand 1 antibody atezolizumab and anti-VEGF antibody bevacizumab (AB), median overall survival in HCC has drastically improved. However, evidence on the efficacy and safety of the novel treatment standard in patients with prior exposure to systemic treatment is scarce. The aim of this global, multicenter, observational study was to evaluate the efficacy and safety of AB in patients after previous systemic therapy. METHODS: We screened our global, multicenter, prospectively maintained registry database for patients who received any systemic therapy before AB. The primary end point was overall survival; secondary end points were time-to-progression, progression-free survival, objective response rate, and safety (rate and severity of adverse events). RESULTS: Among 493 patients who received AB for unresectable HCC, 61 patients received prior systemic therapy and were included in this analysis. The median age of the study population was 66 years, with 91.8% males. Predominant risk factors for HCC were viral hepatitis (59%) and alcohol (23%). Overall survival for AB was 16.2 (95% CI, 14.5-17.9) months, time-to-progression and progression-free survival were 4.1 (95% CI, 1.5-6.6) and 3.1 (95% CI, 1.1-5.1) months, respectively. The objective response rate was 38.2% (7.3% with complete and 30.9% with partial response). Overall survival was not influenced by treatment line (2nd vs. >2nd) or previous systemic treatment modality (tyrosine kinase inhibitors vs. immune checkpoint inhibitors). Treatment-related adverse events of all grades according to Common Terminology Criteria for Adverse Events were documented in 42.6% of patients, with only 13.1% of grade ≥3, including one death. CONCLUSION: In this observational study, AB emerges as a safe and efficacious treatment option in patients with HCC previously treated with other systemic therapy.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Masculino , Humanos , Anciano , Femenino , Bevacizumab/efectos adversos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/inducido químicamente , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/inducido químicamente , Anticuerpos Monoclonales Humanizados/efectos adversosRESUMEN
BACKGROUND: Atezolizumab plus bevacizumab (Atezo/Bev) is first line-treatment for unresectable hepatocellular carcinoma (HCC). Body mass index (BMI) has demonstrated predictive value for response to immunotherapy in non-HCC cancer types. Our study investigated the effect of BMI on safety and efficacy of real-life use of Atezo/Bev for unresectable HCC. METHODS: 191 consecutive patients from seven centres receiving Atezo/Bev were included in the retrospective study. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) defined by RECIST v1.1 were measured in overweight (BMI ≥ 25) and non-overweight (BMI < 25) patients. Treatment-related adverse events (trAEs) were evaluated. RESULTS: Patients in the overweight cohort (n = 94) had higher rates of non-alcoholic fatty liver disease (NAFLD) and lower rates of Hepatitis B compared to non-overweight cohort (n = 97). Baseline Child-Pugh class and Barcelona Clinic Liver Cancer stage were similar between cohorts, with lower rates of extrahepatic spread in the overweight group. Overweight patients had similar OS compared to non-overweight (median OS 15.1 vs. 14.9 months; p = 0.99). BMI did not influence median PFS (7.1 vs. 6.1 months; p = 0.42), ORR (27.2% vs. 22.0%; p = 0.44) and DCR (74.1% vs. 71.9%; p = 0.46). There were higher rates of atezolizumab-related fatigue (22.3% vs. 10.3%; p = 0.02) and bevacizumab-related thrombosis (8.5% vs. 2.1%; p = 0.045) in the overweight patients, but overall trAEs and treatment discontinuation were comparable between cohorts. CONCLUSION: Atezo/Bev has comparable efficacy in overweight HCC patients, with an increase in treatment-related fatigue and thrombosis. Combination therapy is safe and efficacious to use in overweight patients, including those with underlying NAFLD.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Humanos , Índice de Masa Corporal , Bevacizumab/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Estudios Retrospectivos , Neoplasias Hepáticas/tratamiento farmacológico , Fatiga , Ubiquitina-Proteína LigasasRESUMEN
During metastasis, cancer cells invade, intravasate, enter the circulation, extravasate, and colonize target organs. Here, we examined the role of interleukin (IL)-22 in metastasis. Immune cell-derived IL-22 acts on epithelial tissues, promoting regeneration and healing upon tissue damage, but it is also associated with malignancy. Il22-deficient mice and mice treated with an IL-22 antibody were protected from colon-cancer-derived liver and lung metastasis formation, while overexpression of IL-22 promoted metastasis. Mechanistically, IL-22 acted on endothelial cells, promoting endothelial permeability and cancer cell transmigration via induction of endothelial aminopeptidase N. Multi-parameter flow cytometry and single-cell sequencing of immune cells isolated during cancer cell extravasation into the liver revealed iNKT17 cells as source of IL-22. iNKT-cell-deficient mice exhibited reduced metastases, which was reversed by injection of wild type, but not Il22-deficient, invariant natural killer T (iNKT) cells. IL-22-producing iNKT cells promoting metastasis were tissue resident, as demonstrated by parabiosis. Thus, IL-22 may present a therapeutic target for prevention of metastasis.
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Interleucinas , Neoplasias Hepáticas , Células T Asesinas Naturales , Animales , Ratones , Células Endoteliales/metabolismo , Interleucinas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/secundario , Ratones Endogámicos C57BL , Células T Asesinas Naturales/metabolismo , Neoplasias Colorrectales/metabolismo , Interleucina-22RESUMEN
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±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. 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 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.
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Introduction: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of many malignancies in recent years. However, immune-related adverse events (irAE) are a frequent concern in clinical practice. The safety profile of ICI for the treatment of malignancies in patients diagnosed with autoimmune and cholestatic liver disease (AILD) remains unclear. Due to this uncertainty, these patients were excluded from ICI clinical trials and ICI are withheld from this patient group. In this retrospective multicenter study, we assessed the safety of ICI in patients with AILD. Methods: We contacted tertiary referral hospitals for the identification of AILD patients under ICI treatment in Europe via the European Reference Network on Hepatological Diseases (ERN RARE-LIVER). Fourteen centers contributed data on AILD patients with malignancies being treated with ICI, another three centers did not treat these patients with ICI due to fear of irAEs. Results: In this study, 22 AILD patients under ICI treatment could be identified. Among these patients, 12 had primary biliary cholangitis (PBC), five had primary sclerosing cholangitis (PSC), four had autoimmune hepatitis (AIH), and one patient had an AIH-PSC variant syndrome. Eleven patients had hepatobiliary cancers and the other 11 patients presented with non-hepatic tumors. The applied ICIs were atezolizumab (n=7), durvalumab (n=5), pembrolizumab (n=4), nivolumab (n=4), spartalizumab (n=1), and in one case combined immunotherapy with nivolumab plus ipilimumab. Among eight patients who presented with grade 1 or 2 irAEs, three demonstrated liver irAEs. Cases with grades ≥ 3 irAEs were not reported. No significant changes in liver tests were observed during the first year after the start of ICI. Discussion: This European multicenter study demonstrates that PD-1/PD-L1 inhibitors appear to be safe in patients with AILD. Further studies on the safety of more potent dual immune checkpoint therapy are needed. We conclude that immunotherapy should not categorically be withheld from patients with AILD.
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Colestasis , Hepatitis Autoinmune , Neoplasias , Humanos , Receptor de Muerte Celular Programada 1 , Nivolumab/efectos adversos , Antígeno B7-H1 , Hepatitis Autoinmune/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/efectos adversosRESUMEN
Hepatocellular carcinoma (HCC) ranks among the five most common cancer entities worldwide and leads to hundred-thousands of deaths every year. Despite some groundbreaking therapeutical revelations during the last years, the overall prognosis remains poor. Although the immune system fights malignant transformations with a robust anti-tumor response, certain immune mediators have also been shown to promote cancer development. For example, interleukin (IL)-22 has been associated with HCC progression and worsened prognosis in multiple studies. However, the underlying mechanisms of the pathological role of IL-22-signaling as well as the role of its natural antagonist IL-22 binding protein (IL-22BP) in HCC remain elusive. Here, we corroborate the pathogenic role of IL-22 in HCC by taking advantage of two mouse models. Moreover, we observed a protective role of IL-22BP during liver carcinogenesis. While IL-22 was mainly produced by CD4+ T cells in HCC, IL-22BP was abundantly expressed by neutrophils during liver carcinogenesis. Hepatocytes could be identified as a major target of this pathological IL-22-signaling. Moreover, abrogation of IL-22 signaling in hepatocytes in IL22ra1flox/flox × AlbCre+ mice reduced STEAP4 expression-a known oncogene-in HCC in vivo. Likewise, STEAP4 expression correlated with IL22 levels in human HCC samples, but not in healthy liver specimens. In conclusion, these data encourage the development of therapeutical approaches that target the IL-22-IL-22BP axis in HCC.
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Systemic inflammation is a key risk factor for hepatocellular carcinoma (HCC) progression and poor outcomes. Inflammatory markers such as the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) may have prognostic value in HCC treated with standard of care atezolizumab plus bevacizumab (Atezo-Bev). We conducted a multicenter, international retrospective cohort study of patients with unresectable HCC treated with Atezo-Bev to assess the association of NLR and PLR with overall survival (OS), progression-free survival (PFS), and objective response rates. Patients with NLR ≥ 5 had a significantly shorter OS (9.38 vs. 16.79 months, p < 0.001) and PFS (4.90 vs. 7.58 months, p = 0.03) compared to patients with NLR < 5. NLR ≥ 5 was an independent prognosticator of worse OS (HR 2.01, 95% CI 1.22−3.56, p = 0.007) but not PFS. PLR ≥ 300 was also significantly associated with decreased OS (9.38 vs. 15.72 months, p = 0.007) and PFS (3.45 vs. 7.11 months, p = 0.04) compared to PLR < 300, but it was not an independent prognosticator of OS or PFS. NLR and PLR were not associated with objective response or disease control rates. NLR ≥ 5 independently prognosticated worse survival outcomes and is worthy of further study and validation.
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Cholangiocarcinoma (CCA) is an aggressive tumor associated with a high rate of recurrence after resection. An important risk factor for recurrence is the presence of occult metasta-ses, which are not radiologically detectable at the time of diagnosis. There are currently no biomarkers for the preoperative assessment of micrometastases. A previous study demonstrated the prognostic relevance of circulating tumor cells (CTC) in patients with advanced CCA but the potential of CTCs as a preoperative marker for detecting occult metastases has not been investigated so far. In this two-phase study, we first recruited a cohort of 27 patients with histologically proven, metastatic CCA or gallbladder cancer (GBCA) to assess feasibility (feasibility cohort, FC). CTCs were measured in the peripheral blood using the CellSearch System (CSS) between October 2012 and January 2017. Subsequently, in 11 patients undergoing curative-intended resection for CCA (intrahepatic CCA: n =4; extrahepatic CCA n= 6; gallbladder cancer: n=1), peripheral and central venous blood specimens were obtained to improve detection rate by simultaneous measurement and to elucidate distribution of CTCs in different venous compartments. Presence of CTCs detection was correlated with postoperative TNM-status. In the FC, CTCs (range 1-3 cells, median: 1) were detected in 40% (11/27) patients and were signifi-cantly associated with worse overall survival (hazard ratio: 3.59; 95% CI: 1.79- 7.1; p = 0.04). By combined peripheral and central measurement, CTC detection was increased to 54% (6/11) in the resection cohort (RC) and was associated with metastases that were only identified during the surgical procedure (peritoneal carcinoma: n = 1; infiltration of the duodenum: n = 1) or immediately after surgery (evidence of pulmonary metastases by CT scan two days after resection, not evident on initial tumor staging prior resection). Taken together, in this single center pilot study, we demonstrated that CTCs are detectable in CCA patients and are associated with significantly impaired survival in patients at metastatic stage. Detection rate prior to surgery was improved to >50% by combined peripheral and central measurement. Moreover, preoperative CTC detection may indicate existing metastases and could help to stratify patients more accurately.
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BACKGROUND: IMbrave150 has established the superiority of atezolizumab plus bevacizumab over sorafenib in patients with unresectable hepatocellular carcinoma (HCC). METHODS: We generated a prospectively maintained database including patients treated with atezolizumab plus bevacizumab for unresectable HCC across Europe, Asia and USA. Clinico-pathologic characteristics were assessed for their prognostic influence on overall survival (OS) and progression-free survival (PFS) in univariable and multivariate analyses. Overall response rate by RECIST v1.1 and treatment-related adverse events (TRAEs) per CTCAE v.5.0 were reported. RESULTS: Out of 433 patients, 296 Child-Pugh A and ECOG performance status01 patients received atezolizumab plus bevacizumab in first line and were included. Patients were mostly male (82.7%), cirrhotic (75%) with history of viral hepatitis (65.9%). Overall, 68.9% had Barcelona Clinic Liver Cancer C-stage HCC with portal vein tumour thrombosis (PVTT, 35%) and extrahepatic spread (EHS, 51.7%). After a median follow-up of 10.0 months (95% confidence interval (CI): 9.4-10.4), median OS and PFS were 15.7 (95% CI: 14.5-NE) and 6.9 months (95% CI: 6.1-8.3), respectively. In the response-evaluable patients (n = 273), overall response rate was 30.8%. Overall, 221 patients (74.6%) developed TRAEs, with 70 (23.6%) reporting grade 3 or higher TRAEs; 25 (8.4%) patients had bleeding events. OS was independently associated with baseline Albumin-bilirubin (ALBI) grade and PVTT. Shorter PFS was associated with AFP≥ 400 ng/ml, worse ALBI and presence of EHS. CONCLUSION: This global observational study confirms the reproducible safety and efficacy of atezolizumab plus bevacizumab in routine clinical practice. Within Child-Pugh-A criteria, the presence of PVTT and higher ALBI grade identify patients with poorer survival.
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Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Trombosis de la Vena , Albúminas/uso terapéutico , Anticuerpos Monoclonales Humanizados , Antineoplásicos/uso terapéutico , Bevacizumab/efectos adversos , Bilirrubina , Carcinoma Hepatocelular/patología , Femenino , Humanos , Neoplasias Hepáticas/patología , Masculino , Sorafenib/uso terapéutico , alfa-FetoproteínasRESUMEN
BACKGROUND AND AIMS: Combination atezolizumab/bevacizumab is the gold standard for first-line treatment of unresectable hepatocellular carcinoma (HCC). Our study investigated the efficacy and safety of combination therapy in older patients with HCC. METHODS: 191 consecutive patients from eight centres receiving atezolizumab and bevacizumab were included. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) defined by RECIST v1.1 were measured in older (age ≥ 65 years) and younger (age < 65 years) age patients. Treatment-related adverse events (trAEs) were evaluated. RESULTS: The elderly (n = 116) had higher rates of non-alcoholic fatty liver disease (19.8% vs. 2.7%; p < .001), presenting with smaller tumours (6.2 cm vs 7.9 cm, p = .02) with less portal vein thrombosis (31.9 vs. 54.7%, p = .002), with fewer patients presenting with BCLC-C stage disease (50.9 vs. 74.3%, p = .002). There was no significant difference in OS (median 14.9 vs. 15.1 months; HR 1.15, 95% CI 0.65-2.02 p = .63) and PFS (median 7.1 vs. 5.5 months; HR 1.11, 95% CI 0.54-1.92; p = .72) between older age and younger age. Older patients had similar ORR (27.6% vs. 20.0%; p = .27) and DCR (77.5% vs. 66.1%; p = .11) compared to younger patients. Atezolizumab-related (40.5% vs. 48.0%; p = .31) and bevacizumab-related (44.8% vs. 41.3%; p = .63) trAEs were comparable between groups. Rates of grade ≥3 trAEs and toxicity-related treatment discontinuation were similar between older and younger age patients. Patients 75 years and older had similar survival and safety outcomes compared to younger patients. CONCLUSIONS: Atezolizumab and bevacizumab therapy is associated with comparable efficacy and tolerability in older age patients with unresectable HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab/efectos adversos , Carcinoma Hepatocelular/patología , Humanos , Neoplasias Hepáticas/patologíaRESUMEN
BACKGROUND AND AIMS: Atezolizumab plus bevacizumab (AtezoBev) is the standard of care for first-line treatment of unresectable HCC. No evidence exists as to its use in routine clinical practice in patients with impaired liver function. APPROACH AND RESULTS: In 216 patients with HCC who were consecutively treated with AtezoBev across 11 tertiary centers, we retrospectively evaluated treatment-related adverse events (trAEs) graded (G) according to Common Terminology Criteria for Adverse Events v5.0, including in the analysis all patients treated according to label (n = 202, 94%). We also assessed overall survival (OS), progression-free survival (PFS), overall response (ORR), and disease control rates (DCR) defined by Response Evaluation Criteria in Solid Tumors v1.1. Disease was mostly secondary to viral hepatitis, namely hepatitis C (n = 72; 36%) and hepatitis B infection (n = 35, 17%). Liver function was graded as Child-Pugh (CP)-A in 154 patients (76%) and CP-B in 48 (24%). Any grade trAEs were reported by 143 patients (71%), of which 53 (26%) were G3 and 3 (2%) G4. Compared with CP-A, patients with CP-B showed comparable rates of trAEs. Presence and grade of varices at pretreatment esophagogastroduodenoscopy did not correlate with bleeding events. After a median follow-up of 9.0 months (95% CI, 7.8-10.1), median OS was 14.9 months (95% CI, 13.6-16.3), whereas median PFS was 6.8 months (95% CI, 5.2-8.5). ORR and DCR were respectively 25% and 73%, with no difference across CP classes. CONCLUSIONS: This study confirms reproducible safety and efficacy of AtezoBev in routine practice. Patients with CP-B reported similar tolerability compared with CP-A, warranting prospective evaluation of AtezoBev in this treatment-deprived population.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Anticuerpos Monoclonales Humanizados , Bevacizumab/efectos adversos , Carcinoma Hepatocelular/patología , Humanos , Cirrosis Hepática/complicaciones , Neoplasias Hepáticas/patología , Estudios RetrospectivosRESUMEN
Palliative treatment of elderly patients with hepatocellular carcinoma (HCC) is often challenging due to comorbidities or frailty, and data about the outcome and overall survival (OS) in these patients are limited. This was a retrospective single centre study. Patients were grouped according to their age as young (<60 years; YP), intermediate (60-70 years; IP) or elderly (>70 years; EP). Administration of chemotherapy or transarterial chemoembolization (TACE) was defined as palliative treatment. Therapy-related adverse events (AE) were assessed via CTCAE 5.0. Out of 656 patients analyzed, n = 359 received palliative treatment: YP: n = 90; IP: n = 127 and EP: n = 142. The median OS (months) in patients receiving TACE (n = 254) was 17 vs. 18 vs. 20 months for YP, IP, and EP, respectively (p = 0.44) and 15 vs. 16 vs. 17 months (p = 0.56), respectively, in patients receiving chemotherapy (n = 105). AEs differed non-significantly between the subgroups. Multivariate analysis revealed impaired liver function and advanced tumor stage as significant factors for impaired OS. In this study, the mOS and rate of AEs were equal between elderly and younger HCC patients receiving palliative treatment. Therefore, we propose regular palliative treatment stratification in spite of the high age of patients.