A Multicenter Retrospective Study on Clinical Characteristics, Treatment Patterns, and Outcome in Elderly Patients with Hepatocellular Carcinoma

Background. There is a paucity of information on the clinical presentation and outcome of elderly hepatocellular carcinoma (HCC) patients. We performed a multicenter retrospective comparative study to assess the impact of age on potential differences in clinical characteristics, treatment patterns, and outcome in HCC patients. Methods. We retrospectively analyzed HCC patients treated at two U.S. tertiary institutions from 1998 to 2008. Demographics, tumor parameters, etiology and severity of cirrhosis, treatment, and survival from diagnosis were collected and analyzed. After exclusion of transplanted patients, survival analyses were performed using the Kaplan-Meier method with log-rank tests and Cox proportional hazards models. Results. Three hundred thirty-five HCC patients were divided into two groups: “elderly” (95 patients, age ≥70 years) and “younger” (240 patients, aged <70 years). The male/female (M/F) ratio was 5.8:1 and 1.7:1 in the younger and elderly groups, respectively (p < .0001). Hepatitis C virus (HCV) infection rate was 48.3% in younger and 21.1% in elderly patients (p < .0001); Child class B and C cirrhosis accounted for 35.8% in younger and 25.3% in elderly patients (p = .063). Compared with younger patients, the elderly received transplant less frequently (19.6% versus 5.3%, p = .0002) and were more likely to receive supportive care only (22.9% versus 36.8%, p = .01). No significant differences between the two age groups were seen in tumor parameters or other treatments received. Overall (p = .47) and HCC-specific survival rates (p = .38) were similar in both age groups. Conclusions. Characteristics that distinguish elderly from younger HCC patients include lower M/F ratio, worse performance status, lower rate of HCV infection, and less advanced underlying cirrhosis. Elderly patients were less likely to have a liver transplant and more likely to receive supportive care only. However, overall and HCC-specific survival were similar between the two groups

Differential Effects of Sorafenib on Liver Versus Tumor Fibrosis Mediated by Stromal-Derived Factor 1 alpha/C-X-C Receptor Type 4 Axis and Myeloid Differentiation Antigen-Positive Myeloid Cell Infiltration in Mice

Sorafenib—a broad kinase inhibitor—is a standard therapy for advanced hepatocellular carcinoma (HCC) and has been shown to exert antifibrotic effects in liver cirrhosis, a precursor of HCC. However, the effects of sorafenib on tumor desmoplasia—and its consequences on treatment resistance—remain unknown. We demonstrate that sorafenib has differential effects on tumor fibrosis versus liver fibrosis in orthotopic models of HCC in mice. Sorafenib intensifies tumor hypoxia, which increases stromal-derived factor 1 alpha (SDF-1α) expression in cancer and stromal cells and, subsequently, myeloid differentiation antigen–positive (Gr-1+) myeloid cell infiltration. The SDF-1α/C-X-C receptor type 4 (CXCR4) pathway directly promotes hepatic stellate cell (HSC) differentiation and activation through the mitogen-activated protein kinase pathway. This is consistent with the association between SDF-1α expression with fibrotic septa in cirrhotic liver tissues as well as with desmoplastic regions of human HCC samples. We demonstrate that after treatment with sorafenib, SDF-1α increased the survival of HSCs and their alpha-smooth muscle actin and collagen I expression, thus increasing tumor fibrosis. Finally, we show that Gr-1+ myeloid cells mediate HSC differentiation and activation in a paracrine manner. CXCR4 inhibition, using AMD3100 in combination with sorafenib treatment, prevents the increase in tumor fibrosis—despite persistently elevated hypoxia—in part by reducing Gr-1+ myeloid cell infiltration and inhibits HCC growth. Similarly, antibody blockade of Gr-1 reduces tumor fibrosis and inhibits HCC growth when combined with sorafenib treatment. Conclusion: Blocking SDF-1α/CXCR4 or Gr-1+ myeloid cell infiltration may reduce hypoxia-mediated HCC desmoplasia and increase the efficacy of sorafenib treatment. (Hepatology 2014;59:1435-1447

Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial

Background: Immune checkpoint blockade therapy has shown promising results in patients with advanced hepatocellular carcinoma. We aimed to assess the efficacy and safety of pembrolizumab in this patient population. Methods: KEYNOTE-224 is a non-randomised, multicentre, open-label, phase 2 trial that is set in 47 medical centres and hospitals across ten countries. Eligible patients had pathologically confirmed hepatocellular carcinoma; had previously been treated with sorafenib and were either intolerant to this treatment or showed radiographic progression of their disease after treatment; an Eastern Cooperative Oncology Group performance status of 0–1; adequate organ function, and were Child-Pugh class A. Participants received 200 mg pembrolizumab intravenously every 3 weeks for about 2 years or until disease progression, unacceptable toxicity, patient withdrawal, or investigator decision. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response in all patients who received at least one dose of pembrolizumab, which was radiologically confirmed by use of the Response Evaluation Criteria in Solid Tumors version 1.1 by central review. Safety was also assessed in all treated patients. This trial is ongoing but closed to enrolment and is registered with ClinicalTrials.gov number NCT02702414. Findings: Between June 7, 2016, and Feb 9, 2017, we screened 169 patients with advanced hepatocellular carcinoma, of whom 104 eligible patients were enrolled and treated. As of data cutoff on Feb 13, 2018, 17 (16%) patients were still receiving pembrolizumab. We recorded an objective response in 18 (17%; 95% CI 11–26) of 104 patients. The best overall responses were one (1%) complete and 17 (16%) partial responses; meanwhile, 46 (44%) patients had stable disease, 34 (33%) had progressive disease, and six (6%) patients who did not have a post-baseline assessment on the cutoff date were considered not to be assessable. Treatment-related adverse events occurred in 76 (73%) of 104 patients, which were serious in 16 (15%) patients. Grade 3 treatment-related events were reported in 25 (24%) of the 104 patients; the most common were increased aspartate aminotransferase concentration in seven (7%) patients, increased alanine aminotransferase concentration in four (4%) patients, and fatigue in four (4%) patients. One (1%) grade 4 treatment-related event of hyperbilirubinaemia occurred. One death associated with ulcerative oesophagitis was attributed to treatment. Immune-mediated hepatitis occurred in three (3%) patients, but there were no reported cases of viral flares. Interpretation: Pembrolizumab was effective and tolerable in patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib. These results indicate that pembrolizumab might be a treatment option for these patients. This drug is undergoing further assessment in two phase 3, randomised trials as a second-line treatment in patients with hepatocellular carcinoma. Funding: Merck & Co, Inc.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

An orthotopic mouse model of hepatocellular carcinoma with underlying liver cirrhosis

Subcutaneous xenografts have been used for decades to study hepatocellular carcinoma (HCC). These models do not reproduce the specific pathophysiological features of HCCs, which occur in cirrhotic livers showing pronounced necroinflammation, abnormal angiogenesis, and extensive fibrosis. As these features are critical for studying the role of the pathologic host microenvironment in tumor initiation, progression, and treatment response, alternative HCC models are desirable. Here, we describe a syngeneic orthotopic HCC model in immunocompetent mice with liver cirrhosis induced by carbon tetrachloride (CCl4) that recapitulates key features of human HCC. Induction of significant hepatic fibrosis requires 12 weeks of CCl4 administration. Intrahepatic implantation of murine HCC cell lines requires 30 minutes per mouse. Tumor growth varies by tumor cell line and mouse strain used. Alternatively, tumors can be induced in a genetically engineered mouse model. In this setting, CCl4 is administered for 12 weeks after tail-vein injection of Cre-expressing adenovirus in Mst1–/–Mst2F/– mice and results in development of HCC tumors (hepatocarcinogenesis) concomitantly to liver cirrhosis

A prospective feasibility study of respiratory-gated proton beam therapy for liver tumors

Purpose To evaluate the feasibility of a respiratory-gated proton beam therapy for liver tumors. Materials and Methods Fifteen patients were enrolled on a prospective IRB-approved protocol. Eligibility criteria included Childs-Pugh A/B cirrhosis, unresectablebiopsy-proven hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), or metastatic disease (solid tumors only), 1-3 lesions, and tumor size of ≤6 cm. Patients received 15 fractions to a total dose of 45-75 GyE using respiratory-gated proton beam therapy. Gating was performed with an external respiratory position monitoring (RPM) based system. Results Of the15 patients enrolled on this clinical trial, 11 had HCC, 3 had ICC, and 1had metastasis from another primary. Ten patients had a single lesion, 3 patients had 2 lesions, and 2 patients 3 lesions. Toxicities were: Gr 3 bilirubinemia- 2, Gr 3 gastrointestinal bleed- 1, and Gr 5 stomach perforation-1. One patient had a marginal recurrence, 3 had hepatic recurrences elsewhere in the liver, and 2 had extrahepatic recurrence. With a median follow-up for survivors of 69 months, 1-yr, 2-yr, 3-yr OS is 53%, 40%, and 33% respectively. PFS is 40%,33% and 27% at 1, 2, and 3 years, respectively. Conclusion Respiratory-gated proton beam therapy for liver tumors is feasible. Phase II studies for primary liver tumors and metastatic tumorsare underway

Updated efficacy and safety of KEYNOTE-224: a phase II study of pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib

Objective: Pembrolizumab, a PD-1 inhibitor, demonstrated anti-tumour activity and tolerability in patients treated with sorafenib and with advanced hepatocellular carcinoma in KEYNOTE-224. Longer-term efficacy and safety after ∼2.5 years of additional follow-up are reported. Patients and methods: Adults with confirmed hepatocellular carcinoma who experienced progression after or intolerance to sorafenib treatment received pembrolizumab 200 mg every 3 weeks for ≤35 cycles or until confirmed progression, unacceptable toxicity, withdrawal of consent or investigator decision. The primary end-point was objective response rate assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumours v1.1. The secondary end-points included duration of response, disease control rate, time to progression, progression-free survival, overall survival and adverse events. Results: Efficacy and safety were assessed in 104 patients. The median time from first dose to data cutoff was 45.1 months (range, 41.3–49.3). Objective response rate was 18.3% (95% CI: 11.4–27.1), and median duration of response was 21.0 months (range, 3.1 to 39.5+). Disease control rate was 61.5%, and median time to progression was 4.8 months (95% CI: 3.9–7.0). Median progression-free survival was 4.9 months (95% CI: 3.5–6.7) and median overall survival was 13.2 months (95% CI: 9.7–15.3). Of 104 patients, 76 (73.1%) patients reported treatment-related adverse events; most were low grade in severity (grade 3–4, n = 26 [25.0%]; grade 5, n = 1 [1.0%]). Immune-mediated hepatitis occurred in 3 patients (all grade 3). No viral-induced hepatitis flares occurred. Conclusions: After ∼2.5 years of additional follow-up, pembrolizumab continued to provide durable anti-tumour activity and no new safety concerns were identified. ClinicalTrials.gov identifier: NCT02702414.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial

Background: Cabozantinib has shown clinical activity in combination with checkpoint inhibitors in solid tumours. The COSMIC-312 trial assessed cabozantinib plus atezolizumab versus sorafenib as first-line systemic treatment for advanced hepatocellular carcinoma. Methods: COSMIC-312 is an open-label, randomised, phase 3 trial that enrolled patients aged 18 years or older with advanced hepatocellular carcinoma not amenable to curative or locoregional therapy and previously untreated with systemic anticancer therapy at 178 centres in 32 countries. Patients with fibrolamellar carcinoma, sarcomatoid hepatocellular carcinoma, or combined hepatocellular cholangiocarcinoma were not eligible. Tumours involving major blood vessels, including the main portal vein, were permitted. Patients were required to have measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), Barcelona Clinic Liver Cancer stage B or C disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, adequate organ and marrow function, and Child-Pugh class A. Previous resection, tumour ablation, radiotherapy, or arterial chemotherapy was allowed if more than 28 days before randomisation. Patients were randomly assigned (2:1:1) via a web-based interactive response system to cabozantinib 40 mg orally once daily plus atezolizumab 1200 mg intravenously every 3 weeks, sorafenib 400 mg orally twice daily, or single-agent cabozantinib 60 mg orally once daily. Randomisation was stratified by disease aetiology, geographical region, and presence of extrahepatic disease or macrovascular invasion. Dual primary endpoints were progression-free survival per RECIST 1.1 as assessed by a blinded independent radiology committee in the first 372 patients randomly assigned to the combination treatment of cabozantinib plus atezolizumab or sorafenib (progression-free survival intention-to-treat [ITT] population), and overall survival in all patients randomly assigned to cabozantinib plus atezolizumab or sorafenib (ITT population). Final progression-free survival and concurrent interim overall survival analyses are presented. This trial is registered with ClinicalTrials.gov, NCT03755791. Findings: Analyses at data cut-off (March 8, 2021) included the first 837 patients randomly assigned between Dec 7, 2018, and Aug 27, 2020, to combination treatment of cabozantinib plus atezolizumab (n=432), sorafenib (n=217), or single-agent cabozantinib (n=188). Median follow-up was 15·8 months (IQR 14·5–17·2) in the progression-free survival ITT population and 13·3 months (10·5–16·0) in the ITT population. Median progression-free survival was 6·8 months (99% CI 5·6–8·3) in the combination treatment group versus 4·2 months (2·8–7·0) in the sorafenib group (hazard ratio [HR] 0·63, 99% CI 0·44–0·91, p=0·0012). Median overall survival (interim analysis) was 15·4 months (96% CI 13·7–17·7) in the combination treatment group versus 15·5 months (12·1–not estimable) in the sorafenib group (HR 0·90, 96% CI 0·69–1·18; p=0·44). The most common grade 3 or 4 adverse events were alanine aminotransferase increase (38 [9%] of 429 patients in the combination treatment group vs six [3%] of 207 in the sorafenib group vs 12 [6%] of 188 in the single-agent cabozantinib group), hypertension (37 [9%] vs 17 [8%] vs 23 [12%]), aspartate aminotransferase increase (37 [9%] vs eight [4%] vs 18 [10%]), and palmar-plantar erythrodysaesthesia (35 [8%] vs 17 [8%] vs 16 [9%]); serious treatment-related adverse events occurred in 78 (18%) patients in the combination treatment group, 16 (8%) patients in the sorafenib group, and 24 (13%) in the single-agent cabozantinib group. Treatment-related grade 5 events occurred in six (1%) patients in the combination treatment group (encephalopathy, hepatic failure, drug-induced liver injury, oesophageal varices haemorrhage, multiple organ dysfunction syndrome, and tumour lysis syndrome), one (<1%) patient in the sorafenib group (general physical health deterioration), and one (<1%) patient in the single-agent cabozantinib group (gastrointestinal haemorrhage). Interpretation: Cabozantinib plus atezolizumab might be a treatment option for select patients with advanced hepatocellular carcinoma, but additional studies are needed. Funding: Exelixis and Ipsen.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Standardization and harmonization of distributed multi-center proteotype analysis supporting precision medicine studies

Distributed multi-omic digitization of clinical specimen across multiple sites is a prerequisite for turning molecular precision medicine into reality. Here, the authors show that coordinated proteotype data acquisition is feasible using standardized MS data acquisition and analysis strategies