Hepatotoxicity of targeted therapy for cancer

ABSTRACT

Introduction: Understanding the mechanism of DILI with MTA, and how to avoid and manage these toxicities is essential for minimising inferior cancer treatment outcomes. An organised and comprehensive overview of MTA-associated hepatotoxicity is lacking; this review aims to fill the gap.

Areas covered: A literature review was performed based on published case reports and relevant studies or articles pertaining to the topics on PubMed. Food and Drug Administration drug information documents and search on the US National Library of Medicine LiverTox database was performed for all relevant MTA.

Expert opinion: MTA-associated hepatotoxicity is common but rarely fatal. The pattern of hepatotoxicity is predominantly idiosyncratic. Pharmacogenomics show potential in predicting patients at risk of poorly metabolising or developing immunoallergic responses to MTA, but prospective data is scant. Preventing reactivation of viral hepatitis using anti-viral drugs, and avoidance of drug combinations at high risk of negative interactions are the most readily preventable measures for DILI.

KEYWORDS:

• CYP polymorphisms
• hepatitis reactivation
• hepatotoxicity
• immunotherapy
• molecular targeted therapy
• monoclonal antibodies
• multikinase inhibitors
• pharmacogenomics
• tyrosine kinase inhibitors

Article highlights

• Hepatotoxicity is a common occurrence in approximately a third of patients being treated with a protein kinase inhibitor.

• Hepatotoxicity occur in approximately 10% of patients treated with immune checkpoint inhibitors. Severe hepatotoxicity associated with immune checkpoint inhibitors that warrant high dose corticosteroids should preclude further use of these agents due to the high rates of recurrent hepatotoxicity on rechallenge.

• All patients receiving anti-CD20 monoclonal antibodies should have screening for HBsAg and anti-HBc, and anti-viral prophylaxis started if either is positive to prevent fatal hepatitis B reactivation.

• Clinicians should regularly re-examine FDA updates for guidelines on monitoring liver function tests and potential interacting drugs and food substances when prescribing molecular targeted agents, as side effects may only be detected when new therapies are applied to larger populations of patients subject to less stringent selection outside of clinical trials. Post-marketing reporting and surveillance strategies need to be encouraged, more organised and stringent.

• There is limited data on the clinical application of pharmacogenomics. Further improvement and standardisation of genotyping technology that allow more intensive and accurate investigations in this field holds promise for improving outcomes for oncology patients who are treated with molecular targeted agents.

This box summarizes key points contained in the article

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.