Published OnlineFirst July 11, 2017; DOI: 10.1158/1078-0432.CCR-16-0919 Cancer Therapy: Clinical Clinical Cancer Research Sorafenib in Patients with Hepatocellular Carcinoma—Results of the Observational INSIGHT Study Tom M. Ganten1, Rudolf E. Stauber2, Eckardt Schott3, Peter Malfertheiner4, Robert Buder5, Peter R. Galle6, Thomas Gohler€ 7, Matthias Walther8, Ronald Koschny9, and Guido Gerken10 Abstract Purpose: Sorafenib is the only currently approved systemic 13.6, D: 3.1 and A: 6.0, B: 5.5, C: 3.9, and D: 1.7 months, therapy for advanced hepatocellular carcinoma (HCC). We aimed respectively), Child–Pugh liver function (A: 17.6, B: 8.1, C: 5.6 to evaluate the safety and efficacy of sorafenib therapy in patients andA:5.3,B:3.3,C:2.5months,respectively),andperfor- with HCC under real-life conditions regarding patient, tumor mance status of the patient; however, age did not affect prog- characteristics, and any adverse events at study entry and at follow- nosis. Sorafenib-related adverse events at any grade occurred in up visits every 2 to 4 months. 64.9% of patients, with diarrhea (35.4%), hand–foot–skin Experimental Design: The current INSIGHT study is a non- reaction (16.6%), nausea (10.3%), and fatigue (11.2%) occur- interventional, prospective, multicenter, observational study per- ring most frequently. formed in 124 sites across Austria and Germany between 2008 Conclusions: Sorafenib treatment was shown to be effective in and 2014. a real-life setting, in agreement with previously reported clinical Results: Median overall survival and time to progression trial data. The therapy was found to have an acceptable safety (RECIST) were found to be dependent on baseline Barcelona profile, with predominantly mild to moderate side effects. Clinic Liver Cancer (BCLC) tumor stage (A: 29.2, B: 19.6, C: Clin Cancer Res; 1–9. Ó2017 AACR. Introduction and the presence of underlying liver disease. Potentially curative treatment strategies, such as tumor resection, liver transplanta- Liver cancer is the fifth most common cancer worldwide in tion, or percutaneous local ablation, are only possible at an early men, and the ninth most common in women, with incidence stage (7, 8). Once the disease has progressed, transarterial che- expected to increase in the coming years (1–3). Hepatocellular moembolization (TACE) and systemic sorafenib therapy can only carcinoma (HCC) is the most common histologic subtype, prolong survival (9). Sorafenib is a multikinase inhibitor that has accounting for around 80% of liver cancers (4). The main causes demonstrated significant antiproliferative and antiangiogenic of HCC vary across the world, with hepatitis B infection prevailing activity, as well as induction of tumor cell apoptosis in an HCC in the Asia–Pacific (AP) region, while hepatitis C infection and model (10, 11). It acts by disrupting the Raf/MEK/ERK pathway by alcohol abuse are the predominant etiologies in the western world inhibiting Raf-1, in addition to targeting a number of receptor (5–7). The survival rate of patients with HCC is particularly low tyrosine kinases, including VEGFRs (VEGFR-2 and VEGFR-3), owing to late diagnosis, the chemoresistant nature of such tumors, platelet-derived growth factor receptor-b (PDGFR-b), Flt-3, cKIT, and RET. 1Department of Gastroenterology and Oncology, Furst€ Stirum Klinik Bruchsal, In July 2006, sorafenib gained EMA approval for the treatment of Bruchsal, Germany. 2Division of Gastroenterology and Hepatology, Medical HCC, with the FDA following in November 2007. This was as a University Graz, Graz, Austria. 3Department of Hepatology and Gastroenterol- result of a large multicenter, double-blind, placebo-controlled, ogy, CVK, Charite Universitatsmedizin€ Berlin, Berlin, Germany. 4Department of phase III trial involving 602 patients with advanced HCC in Gastroenterology, Hepatology & Infectious Diseases, Otto-von-Guericke Uni- Europe, North and South America, and Australia. The Sorafenib 5 versity of Magdeburg, Magdeburg, Germany. Department of Internal Medicine, Hepatocarcinoma Assessment Randomized Protocol (SHARP, Konventspital Barmherzige Brueder Linz, Linz, Austria. 6First Medical Depart- ment, University Medical Center, Johannes Gutenberg University, Mainz, Ger- NCT00105443) trial demonstrated an increase in median overall many. 7Onkozentrum Dresden, Dresden, Germany. 8Bayer Vital GmbH, Lever- survival time and time to radiologic progression, as well as a kusen, Germany. 9Department of Internal Medicine, University of Heidelberg, manageable safety profile, when patients were treated with sorafe- Heidelberg, Germany. 10Department for Gastroenterology and Hepatology, nib (12, 13). A separate trial in the AP region gave similar promising University Hospital Essen, Essen, Germany. results. The AP trial involved a total of 226 patients with unresect- Corresponding Author: Tom M. Ganten, Department of Gastroenterology and able or metastatic HCC and demonstrated significantly longer Oncology, Furst€ Stirum Klinik Bruchsal, Gutleutstrasse 1-14, Bruchsal 76646, overall survival for those who were treated with sorafenib (14, 15). Germany. Phone: 4972-51708-57301; Fax: 4972-51708-57309; E-mail: Noninterventional studies are important postapproval trials [email protected] designed to characterize the safety and effectiveness of new doi: 10.1158/1078-0432.CCR-16-0919 therapies in a real-life setting. They have the advantage of includ- Ó2017 American Association for Cancer Research. ing patient populations that are not usually enrolled in controlled www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst July 11, 2017; DOI: 10.1158/1078-0432.CCR-16-0919 Ganten et al. daily, some patients were also started on a lower daily dose of 200, Translational Relevance 400, or 600 mg. The current INSIGHT study is a noninterventional, prospec- tive, multicenter, observational study performed in 124 sites Documentation across Austria and Germany between 2008 and 2014. A total of At each follow-up visit during sorafenib therapy, tumor and 788 patients were included. Noninterventional studies are patient status evaluation, and the occurrence of AEs were important postapproval trials designed to characterize the documented. Data were collected at the start of sorafenib safety and effectiveness of new therapies in a real-life setting. treatment, and then at intervals of 2 to 4 months. AEs were They have the advantage of including patient populations that categorized according to the Common Terminology Criteria for are not usually enrolled in controlled clinical trials, and the Adverse Events (CTCAE) v.3.0. A serious AE (SAE) was classed collected results are very important for the use in everyday as an event that resulted in death, hospitalization, disability/ clinical practice. With this study, we aimed to evaluate the incapacity, was life threatening, or was assessed to be an safety and efficacy of sorafenib therapy in patients with hepa- important medical event. tocellular carcinoma under real-life conditions outside the framework of a randomized clinical trial. In agreement with Statistical analysis previously reported clinical trial data, sorafenib treatment was Data are given as percentages or means with SDs. Variables shown to be effective. The therapy was found to have an were considered on an available case basis, and the number of acceptable safety profile, with predominantly mild to moder- documentations available for each is noted in the results tables. ate side effects. Overall survival and time to progression are represented by Kaplan–Meier curves to illustrate outcomes over time. Univar- iate and multivariate Cox regression analyses were used to identify baseline characteristics associated with overall survival clinical trials, such as those with Child–Pugh B status or of an and time to progression. Factors included were age, gender, older age. Here, we report on INSIGHT, a large multicenter, extrahepatic spread, and vascular invasion. Alpha-fetoprotein noninterventional study of sorafenib treatment in a broad HCC was excluded from the analysis owing to the high number of population. We describe the baseline characteristics of the missing values. patients, and their influence on safety and efficacy under real-life clinical conditions. Results During the study period, 791 patients were enrolled in the trial. Patients and Methods Of these, one patient received no treatment, and two patients had The INSIGHT study is a noninterventional, prospective, mul- missing documentation. This resulted in a total of 788 patients for ticenter, observational study performed in 124 sites across Austria the safety analysis set. Another six patients were excluded from the fi and Germany. The study ran from April 2008 to April 2014, with ef cacy analysis set: one patient had no written informed consent, the final data collection cutoff for primary output being October one patient was misdiagnosed, and for four patients, no follow-up 2013. Written informed consent was provided and ethical approv- information was available. Therefore, a total of 782 patients were fi fi al was obtained from the Ethical Committee of University Clinic nally evaluated regarding ef cacy. Duisburg, Germany (no. 08-3611). The study was conducted in The end of the study observation period was a result of disease accordance with the Declaration of Helsinki. progression for 284 patients (36.0%), death for 212 patients (26.9%), and unacceptable AEs leading