Evaluating the role of treatment-related toxicities in the challenges facing targeted therapies for advanced hepatocellular carcinoma

Abstract

Advanced hepatocellular carcinoma (aHCC) is a complex disease beset by underlying liver dysfunction and high molecular heterogeneity. Sorafenib, introduced in 2007, is considered the standard systemic therapy for aHCC, yet only a minority of patients show objective evidence of a response radiologically, and median overall survival is still under 1 year. Other targeted drugs for the treatment of aHCC have failed to reach their primary endpoints of improved/non-inferior overall survival in comparison with sorafenib in recent phase 3 trials. Toxicity was a significant problem, raising the question as to whether outcomes in aHCC trials are being hindered by high levels of adverse events (AEs), particularly in populations with underlying cirrhosis. This is true of six recently failed phase 3 studies involving sunitinib, erlotinib, linifanib, brivanib (two trials), and everolimus, as well as ongoing phase 2 and 3 trials of other drugs that work through similar molecular pathways. This article reviews these drugs' toxicities, with a focus on AEs as a reason for their failure in phase 3 trials of patients with aHCC. We also review completed and ongoing phase 3 studies of combination therapies with sorafenib, as well as toxicities of many of the targeted agents in aHCC, including geographic/ethnic differences, measures of toxicity, and strategies to improve management.

The albumin–bilirubin grade improves hepatic reserve estimation post‐sorafenib failure: implications for drug development

“…Furthermore, as an improved marker of functional reserve, the ALBI grade might be useful to facilitate patient stratification according to their risk of toxicity from systemic anti‐cancer treatment, a non‐negligible concern in patients with underlying impairment of hepatic drug clearance …”

“…16 Furthermore, as an improved marker of functional reserve, the ALBI grade might be useful to facilitate patient stratification according to their risk of toxicity from systemic anti-cancer treatment, a non-negligible concern in patients with underlying impairment of hepatic drug clearance. 17 We therefore conducted a study to ascertain the prognostic value of the ALBI grade in patients who permanently discontinued sorafenib treatment in a large collaborative study including patients from Europe, and Asia.…”

Prognostic value of microRNAs in hepatocellular carcinoma: a meta-analysis

“…HCC is one of the most common tumors, over 700,000 new cases are reported yearly, and HCC is considered as the third primary etiology of tumor-associated mortality rate globally [ 222 – 224 ]. In spite of enormous process in diagnosis and comprehensive therapy over the last few decades, HCC patients still have poor prognosis, primarily due to its high rate of recurrence [ 225 ] and metastasis [ 226 ].…”

Oncological Impact of M-Tor Inhibitor Immunosuppressive Therapy after Liver Transplantation for Hepatocellular Carcinoma: Review of the Literature

“…The median time to progression (TTP) was 2.96 months vs. 2.6 months (Everolimus vs. placebo). Therefore, no benefit in the median TTP, in the overall population or in any of the pre-stratified subgroups was demonstrated (Zhu et al, 2014 ; Chuma et al, 2015 ; Deng et al, 2015 ; Palmer and Johnson, 2015 ).…”