Transarterial chemoembolization versus sorafenib in patients with hepatocellular carcinoma and extrahepatic disease

BackgroundSorafenib is the recommended treatment for advanced hepatocellular carcinoma (HCC), but transarterial chemoembolization (TACE) is performed in individual cases with limited extrahepatic spread. The aim of this study was to compare the outcome of patients with HCC and extrahepatic disease (EHD) treated with sorafenib and TACE.MethodsA total of 172 patients with HCC and EHD treated with sorafenib (n = 98) or TACE (n = 74) at three German referral centers (Hannover, Mainz and Hamburg) were included in this study. In order to reduce selection bias, patients were matched for significant demographic differences using a propensity score analysis.ResultsPatients with liver cirrhosis, high…

Cisplatin/5-fluorouracil +/- panitumumab for patients with non-resectable, advanced or metastatic esophageal squamous cell cancer : A randomized phase III AIO/EORTC trial with an extensive biomarker program

Drug Treatment for Chronic Hepatitis C Infection and Cancer Risk

BACKGROUND In patients with chronic hepatitis C infection, a sustained virologic response (SVR) to interferon-based therapy markedly decreases the incidence of hepatocellular carcinoma (HCC) over the long term. This is also true for patients who have hepatic cirrhosis, as well as for those with HCC-with or without cirrhosis-who have undergone resection or ablation with curative intent. Recent publications, however, have reported a higher incidence of HCC among patients in both of these subgroups who were treated with direct antiviral agents (DAA) rather than interferon-based therapy. METHODS A selective search for pertinent literature was carried out in the PubMed database with the search t…

Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis.

ObjectiveHomozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants (‘Pi*Z’ and ‘Pi*S’), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse.DesignWe analysed multicentric case–control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed.ResultsThe Pi*Z variant presented in 13.8% of p…

The “RENAISSANCE” Trial: Effect of chemotherapy alone vs. chemotherapy followed by surgical resection on survival and quality of life in patients with limited-metastatic adenocarcinoma of the stomach or esophagogastric junction—A phase III trial of the German AIO/CAO-V/CAOGI.

TPS4140 Background: Recent data indicates that surgical resection may bring a benefit for select patients with metastatic gastric / esophagogastric junction cancer. However, no data obtained in randomized trials is available up to now. The current RENAISSANCE trial investigates this long-lasting question about the role of surgical intervention in limited-metastatic gastric / esophagogastric junction cancer. Methods: This is a prospective, multicenter, randomized, investigator initiated phase III trial. In this study, previously untreated patients with limited metastatic stage (retroperitoneal lymph node metastases only or a maximum of one incurable organ site that is potentially resectable…

Rationale and design of the CRAFT (Continuous ReAssessment with Flexible ExTension in Rare Malignancies) multicenter phase II trial.

Background Approvals of cancer therapeutics are primarily disease entity specific. Current molecular diagnostic approaches frequently identify actionable alterations in rare cancers or rare subtypes of common cancers for which the corresponding treatments are not approved and unavailable within clinical trials due to entity-related eligibility criteria. Access may be negotiated with health insurances. However, approval rates vary, and critical information required for a scientific evaluation of treatment-associated risks and benefits is not systematically collected. Thus clinical trials with optimized patient selection and comprehensive molecular characterization are essential for translati…

Application of patient derived liver cancer cell lines for phenotypic characterization and therapeutic target identification

ASCO-Update 2015 – Neuigkeiten vom 51. Meeting der American Society of Clinical Oncology/ASCO 2015

The field of gastrointestinal oncology is rapidly developing, on the one hand through the identification of novel molecular targets and therapeutic principles, on the other hand through the establishment and improvement of multidisciplinary treatment strategies. The following manuscript summarizes the most important trial results of the ASCO Meeting 2015 for gastrointestinal cancers. Besides trials on perioperative treatment of esophageal-, pancreatic- and colon cancer, we will present impressive data on new therapeutic strategies such as immunotherapy in gastric-, liver and microsatellite instable colorectal cancer. The trials will be put into context by the authors.

Panitumumab in combination with gemcitabine/cisplatin (GemCis) for patients with advanced kRAS WT biliary tract cancer: A randomized phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO).

4082 Background: Biliary tract cancer encompasses a group of genetically heterogeneous tumors. Panitumumab is a human EGFR inhibitor and has shown anti-tumor activity in RAS WT colorectal cancer. M...

Murine liver organoids as a genetically flexible system to study liver cancer in vivo and in vitro.

The rising incidence of cholangiocarcinoma (CCA) coupled with a low 5-year survival rate that remains below 10% delineates the urgent need for more effective treatment strategies. Although several recent studies provided detailed information on the genetic landscape of this fatal malignancy, versatile model systems to functionally dissect the immediate clinical relevance of the identified genetic alterations are still missing. To enhance our understanding of CCA pathophysiology and facilitate rapid functional annotation of putative CCA driver and tumor maintenance genes, we developed a tractable murine CCA model by combining the cyclization recombination (Cre)-lox system, RNA interference, …

Genetically flexible murine organoids for mechanistic and functional modeling of cholangiocarcinoma

PD-1 targeted immunotherapy in advanced hepatocellular carcinoma: efficacy and safety data from an international multicenter real-world cohort

Treatment with metformin is associated with a prolonged survival in patients with hepatocellular carcinoma

BACKGROUND Hepatocellular carcinoma (HCC) is one of the most lethal cancers. Nutrition- and life style-associated risk factors are increasingly prevalent. Metformin, the mainstay of type 2 diabetes mellitus (T2DM)-treatment, reduces the risk of hepatocarcinogenesis. However, its influence on the prognosis of patients with HCC has not been investigated on a large scale, yet. METHODS Five thousand and ninety-three patients treated for HCC between 2000 and 2016 at three referral centres were included in this retrospective multicentre study. The aim of this study was to assess whether treatment with metformin for T2DM is associated with a prolonged overall survival (OS) in patients diagnosed wi…

Immunotherapy: New Options in Gastrointestinal Cancers?

Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score.

Immunotherapy with atezolizumab plus bevacizumab represents the new standard of care in systemic front-line treatment of hepatocellular carcinoma (HCC). However, biomarkers that predict treatment success and survival remain an unmet need.Patients with HCC put on PD-(L)1-based immunotherapy were included in a training set (n = 190; 6 European centers) and a validation set (n = 102; 8 European centers). We investigated the prognostic value of baseline variables on overall survival using a Cox model in the training set and developed the easily applicable CRAFITY (CRP and AFP in ImmunoTherapY) score. The score was validated in the independent, external cohort, and evaluated in a cohort of patie…

BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update.

Treatment for hepatocellular carcinoma (HCC) has experienced major advancements since the last update of the official Barcelona Clinic Liver Cancer (BCLC) prognosis and treatment strategy published in 2018. Advancements in the field have emerged in all areas, but in this manuscript, we present those that have primed a change in the strategy and comment why some encouraging data in select interventions are still considered immature and in need of further research to gain their incorporation into an evidence-based model for clinicians and researchers. Finally, we describe the critical insight and expert knowledge that is needed to take clinical decisions in individual patients so that the rec…

Immuno-oncology in GI tumours: Clinical evidence and emerging trials of PD-1/PD-L1 antagonists.

The use of immune checkpoint inhibitors constitutes an emerging therapeutic field for the therapy of gastrointestinal (GI) malignancies following the recent FDA approvals of PD-1 inhibitors for esophago-gastric adenocarcinoma, hepatocellular carcinoma and for microsatellite-instable tumors, which are mainly colorectal cancers. This paper reviews the clinical evidence end of 2017 and discusses the clinical development programs of atezolizumab, avelumab, durvalumab, nivolumab and pembrolizumab in GI-tract cancers. Since 2014, these antagonists of the PD-1/PD-L1 axis have gained approval for use in numerous other tumors. Phase II trials and phase I expansion cohorts demonstrate clinical activi…

ASCO- und ESMO-Update 2017 – Neuigkeiten vom 53. Meeting der American Society of Clinical Oncology/ASCO 2017 und European Society for Medical Oncology/ESMO-Congress 2017

ZusammenfassungAuf dem Amerikanischen Krebskongress 2017 und dem Europäischen Krebskongress 2017 wurden eine Reihe von wichtigen Studien vorgestellt, die teilweise zu einer Änderung der aktuellen Therapiestandards in der Viszeralonkologie führen. So gilt nach den Ergebnissen der FLOT4-Studie die Kombination aus Docetaxel, Oxaliplatin und 5-Fluorouracil (FLOT) als der neue Behandlungsstandard in der perioperativen Therapie bei resektablen Adenokarzinomen des gastroösophagealen Übergangs und des Magens. Beim hepatozellulären Karzinom (HCC) hat die selektive interne Radiotherapie (SIRT) in zwei großen Studien keine Verbesserung des Überlebens gegenüber Sorafenib erbracht, sodass ein zunehmende…

PICCA study: panitumumab in combination with cisplatin/gemcitabine chemotherapy in KRAS wild-type patients with biliary cancer—a randomised biomarker-driven clinical phase II AIO study

Abstract Background Combination chemotherapy has shown benefit in the treatment of biliary cancer and further improvements might be achieved by the addition of a biological agent. We report here the effect of chemotherapy with the monoclonal EGFR antibody panitumumab as therapy for KRAS wild-type biliary cancer. Patients and methods Patients with advanced biliary tract cancer were randomised (2:1) to receive cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 on day 1 and day 8/q3w with (arm A) or without panitumumab (arm B; 9 mg/kg BW, i.v q3w). The primary end-point was the evaluation of progression-free survival (PFS) at 6 months. Secondary end-points included objective response rate (ORR), ov…

Role of the GALAD and BALAD-2 Serologic Models in Diagnosis of Hepatocellular Carcinoma and Prediction of Survival in Patients.

Background & Aims GALAD and BALAD-2 are statistical models for estimating the likelihood of the presence of hepatocellular carcinoma (HCC) in individual patients with chronic liver disease and the survival of patients with HCC, respectively. Both models use objective measures, particularly the serum markers α-fetoprotein (AFP), AFP-L3, and des-γ-carboxyprothrombin. We aimed to validate these models in an international cohort of patients with HCC and assess their clinical performance. Methods We collected data on cancer diagnosis and outcomes of 6834 patients (2430 with HCC and 4404 with chronic liver disease) recruited from Germany, Japan, and Hong Kong. We also collected data from 229 pati…

The GALAD Score as Potential Screening Test for Hepatocellular Carcinoma in Nonalcoholic Steatohepatitis: An International Multicenter Study

The prevalence of nonalcoholic steatohepatitis (NASH) is rising rapidly and is currently the most common chronic liver disease in Western populations. Hepatocellular carcinoma (HCC) is a major complication of NASH and the current performance of screening approaches based on ultrasound shows limitations. To facilitate earlier diagnosis, this international multicenter study, with eight German and one Japanese center participating, tests the potential benefit of applying the biomarkers AFP, AFP-L3, DCP and related scores for HCC screening in NASH patients. In the retrospective German cohort, 126 NASH patients with newly diagnosed HCC and 231 NASH control patients without HCC were enrolled. In …

Ramucirumab in elderly patients with hepatocellular carcinoma and elevated alpha-fetoprotein after sorafenib in REACH and REACH-2.

Background & Aims: Limited data on treatment of elderly patients with hepatocellular carcinoma (HCC) increase the unmet need. REACH and REACH-2 were global phase III studies of ramucirumab in patients with HCC after prior sorafenib, where patients with alpha-fetoprotein (AFP) ≥400 ng/mL showed an overall ssurvival (OS) benefit for ramucirumab. These post-hoc analyses examined efficacy and safety of ramucirumab in patients with HCC and baseline AFP ≥ 400 ng/mL by three prespecified age subgroups (<65, ≥65 to <75 and ≥75 years). Methods: Individual patient data were pooled from REACH (baseline AFP ≥400 ng/mL) and REACH-2. Kaplan-Meier and Cox proportional hazards regression methods …

Risk estimation for biliary tract cancer: Development and validation of a prognostic score.

Background & Aims Biliary tract cancer is a rare tumour entity characterized by a poor prognosis. We aimed to identify prognostic factors and create a prognostic score to estimate survival. Methods Clinical data of the training set, consisting of 569 patients treated from 2000 to 2010 at Hannover Medical School, were analysed. A prognostic model defining three prognostic risk groups was derived from Cox regression analyses. The score was applied and validated in an independent cohort of 557 patients from four different German centres. Results Median overall survival (OS) was 14.5 months. If complete resection was performed, the patients had a significantly improved OS (23.9 months; n=242) a…

Cisplatin and 5-Fluorouracil with or Without Epidermal Growth Factor Receptor Inhibition Panitumumab for Patients with Non-Resectable, Advanced or Metastatic Esophageal Squamous Cell Cancer: A Prospective, Open-Label, Randomised Phase 3 AIO/EORTC Trial (Power)

Background: Advanced unresectable esophageal squamous cell cancer (ESCC) is treated with palliative chemotherapy of cisplatin and 5-fluorouracil (CF). Targeting epidermal growth factor receptor (EGFR) with antibodies panitumumab (P) or cetuximab with chemotherapy enhanced overall survival (OS) in metastatic colorectal cancer or squamous cell cancer of head and neck. With prospective serum and tumour biomarkers, we tested if P added to CF (CFP) improved OS in confirmed advanced ESCC. Methods: 146 patients, not curatively resectable and not qualified for definitive radio-chemotherapy were randomised 1:1 to CF (cisplatin [100 mg/m² i.v., day 1] and 5-fluorouracil [1000 mg/m²/day i.v., days 1-4…

Application of Patient-Derived Liver Cancer Cells in Personalized Treatment Approach: Phenotypic Characterization and Therapeutic Target Identification

The Co‐mutational Spectrum Determines the Therapeutic Response in Murine FGFR2 Fusion‐Driven Cholangiocarcinoma

Background and aims Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer and a highly lethal malignancy. Chemotherapeutic options are limited, but a considerable subset of patients harbors genetic lesions for which targeted agents exist. Fibroblast growth factor receptor 2 (FGFR2) fusions belong to the most frequent and therapeutically relevant alterations in ICC, and the first FGFR inhibitor was recently approved for the treatment of patients with progressed, fusion-positive ICC. Response rates of up to 35% indicate that FGFR-targeted therapies are beneficial in many but not all patients. Thus far, no established biomarkers exist that predict resistance or r…

Application of patient-derived liver cancer cells for phenotypic characterization and therapeutic target identification.

Primary liver cancer (PLC) ranks among the most lethal solid cancers worldwide due to lack of effective biomarkers for early detection and limited treatment options in advanced stages. Development of primary culture models that closely recapitulate phenotypic and molecular diversities of PLC is urgently needed to improve the patient outcome. Long-term cultures of 7 primary liver cancer cell lines of hepatocellular and cholangiocellular origin were established using defined culture conditions. Morphological and histological characteristics of obtained cell lines and xenograft tumors were analyzed and compared to original tumors. Time course analyses of transcriptomic and genomic changes were…

Genetic Variation in HSD17B13 Reduces the Risk of Developing Cirrhosis and Hepatocellular Carcinoma in Alcohol Misusers.

Background and aims Carriage of rs738409:G in patatin-like phospholipase domain containing 3 (PNPLA3) is associated with an increased risk for developing alcohol-related cirrhosis and hepatocellular carcinoma (HCC). Recently, rs72613567:TA in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) was shown to be associated with a reduced risk for developing alcohol-related liver disease and to attenuate the risk associated with carriage of PNPLA3 rs738409:G. This study explores the risk associations between these two genetic variants and the development of alcohol-related cirrhosis and HCC. Approach and results Variants in HSD17B13 and PNPLA3 were genotyped in 6,171 participants, including 1,03…

Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with intermediate and advanced/relapsed hepatocellular carcinoma: a TOS–ESMO initiative endorsed by CSCO, ISMPO, JSMO, KSMO, MOS and SSO

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of hepatocellular carcinoma (HCC) was published in 2018, and covered the diagnosis, management, treatment and follow-up of early, intermediate and advanced disease. At the ESMO Asia Meeting in November 2018 it was decided by both the ESMO and the Taiwan Oncology Society (TOS) to convene a special guidelines meeting immediately after the Taiwan Joint Cancer Conference (TJCC) in May 2019 in Taipei. The aim was to adapt the ESMO 2018 guidelines to take into account both the ethnic and the geographic differences in practice associated with the treat…

Cisplatin and 5-fluorouracil with or without epidermal growth factor receptor inhibition panitumumab for patients with non-resectable, advanced or metastatic oesophageal squamous cell cancer: a prospective, open-label, randomised phase III AIO/EORTC trial (POWER).

Background Palliative chemotherapy of advanced oesophageal squamous cell cancer (ESCC) consists of cisplatin/5-fluorouracil (CF) to target epidermal growth factor receptor (EGFR) with panitumumab (P); chemotherapy enhanced overall survival (OS) in advanced colorectal or squamous cell head and neck cancers. With prospective serum and tumour biomarkers, we tested if P added to CF (CFP) improved OS in advanced ESCC. Patients and methods Eligible patients with confirmed ESCC that was not curatively resectable or did not qualify for definitive radiochemotherapy, were randomised 1 : 1 to receive CF [cisplatin (C) 100 mg/m2 i.v., day 1; 5-fluorouracil (F) 1000 mg/m2 i.v., days 1–4] or CF plus P (9…

GALAD Score Detects Early Hepatocellular Carcinoma in an International Cohort of Patients With Nonalcoholic Steatohepatitis

Background & Aims The prevalence of nonalcoholic steatohepatitis (NASH) associated hepatocellular carcinoma (HCC) is increasing. However, strategies for detection of early-stage HCC in patients with NASH have limitations. We assessed the ability of the GALAD score, which determines risk of HCC based on patient sex; age; and serum levels of α-fetoprotein (AFP), AFP isoform L3 (AFP-L3), and des-gamma-carboxy prothrombin (DCP), to detect HCC in patients with NASH. Methods We performed a case-control study of 125 patients with HCC (20% within Milan Criteria) and 231 patients without HCC (NASH controls) from 8 centers in Germany. We compared the performance of serum AFP, AFP-L3, or DCP vs GALAD …