DOI: 10.25934/pr00008764
title: Competing risk factors in survival analyses for advanced hepatocellular carcinoma outcomes. The key role of liver function and impact of drug class

description: Hepatocellular carcinoma (HCC), the most common form of liver cancer, is a malignancy of global relevance, characterized by poor prognosis. The global burden of HCC is substantial. According to 2020 estimates, liver cancer is the sixth most commonly diagnosed cancer and the third most common cause of cancer death; 905,700 people were diagnosed with and 830,200 people died from liver cancer globally in 2020, while the number of new cases and deaths from liver cancer could rise by >55% by 2040.
The advent of immune checkpoint inhibitors (ICIs), a type of immunotherapy that works by helping the immune system to better find and attack the cancer cells, has drastically changed the landscape of HCC treatment. In particular, the combination of atezolizumab and bevacizumab is now established as the standard of care first- line treatment of advanced-stage HCC based on results of the IMBrave-150 trial, which showed a significantly improved overall survival (OS), progression-free survival (PFS) and quality of life compared to sorafenib. Atezolizumab + Bevacizumab is an ICI-based combination therapy. Sorafenib is a drug of another category (tyrosine-kinase inhibitor -TKI) that has been in use for many years.

Since HCC often occurs in patients with advanced liver fibrosis (which occurs when the healthy tissue of your liver becomes scarred and cannot work as well - fibrosis is the first stage of liver scarring) or cirrhosis (scarring of the liver caused by continuous, long-term liver damage from drinking too much alcohol, a long-term liver infection such as hepatitis B or C, and/or being obese), it is well-known that the functional impairment of the underlying liver disease has a significant impact on survival, independently from the tumour stage and HCC treatment. The risk of liver decompensation (when your cirrhosis has progressed to the point that the liver is having trouble functioning and you start having symptoms of the disease and increasing the risk of death) has never been prospectively assessed as a clinical endpoint in HCC studies evaluating systemic treatments, and could explain the challenge in predicting the prognosis of patients with HCC.

The present proposed study is an individual patient-level post-hoc analysis of a large, randomized phase 3 clinical trial (IMbrave150). This will allow the reanalysis of the individual patient data collected in the trial, rather than relying exclusively on what is reported in the publication, to assess competing risks for death related to tumor progression or liver decompensation in patients with hepatocellular carcinoma.

In hepatocellular carcinoma, events that compete with each other and determine the dutation of a patient’s survival are 1) progression of tumor growth and, 2) liver events, such as digestive bleeds, ascites (fluid collecting in abdomen), liver failure, jaundice. Each of the two can appear independently of the other and compete on the final outcome which is survival. This kind of evaluation requires a specific statistical analysis.