Abstract CN03-04: Gastrointestinal and liver toxicities related to targeted therapies
Authors: Tabernero Josep , Markman Ben , Macarulla Teresa , Elez Elena 
Published: May 2019

Major advances with new molecular agents have translated in the last decade in a survival benefit for those patients with advanced stage cancer and in improved cure rates for those treated in the adjuvant setting. Some of these targeted agents have been approved by the regulatory agencies and are now used in daily clinical practice. Globally, this group of drugs includes monoclonal antibodies and tyrosine and non-tyrosine kinase inhibitors. In general, targeted molecular therapies have a good toxicity profile. Nevertheless, new types of toxicities have been reported with the use of these new agents. The spectrum of adverse events is broad and includes gastrointestinal toxic effects; these require careful clinical management. Diarrhea and hepatotoxicity, the most common adverse events experienced with these treatments, can frequently lead to treatment discontinuation and consequently decreased cancer control.

Diarrhea. Diarrhea is one of the most frequent causes of treatment discontinuation with molecular-targeted cancer drugs and it represents a common dose-limiting toxicity. The incidence of drug-induced diarrhea observed with targeted therapies is summarized in the attached table. Diarrhea induced by EGFR tyrosine kinase inhibitors can be easily managed easily by reducing the dose; treatment very rarely has to be ceased entirely. Loperamide is a useful treatment that can decrease intestinal motility, and the guidelines used for irinotecan-related diarrhea can be very well applied.

Hepatotoxicity. Hepatotoxicity is a common cause of discontinuation of treatment for some of the tyrosine kinase inhibitors, this being especially the case of imatinib (see attached table). Moreover there are instances of agents whose clinical development has been curtailed due to this particular toxicity. Hepatotoxicity may comprise different biochemical scenarios including cytolysis, characterized by transaminase increase, and cholostasis, typified by increases in bilirubin, alkaline phosphatase and/or gammaglutamiltranspeptidase. The management of hepatotoxicity must be adapted to each patient according to its severity and impact on the disease. Nevertheless, in all cases, other causes of liver pathology need to be rule out, including progression of the malignancy in this organ. In current practice, treatment with tyrosine kinase inhibitors is interrupted when patients exhibit grade 3 or 4 transaminase elevation. When abnormalities return to grade 1 or less, the treatment can be reintroduced at a reduced dose. If the liver toxic effects do not recur within 6–12 weeks, the initial dose may be re-escalated, accompanied by close monitoring by use of liver function tests. For recurrent grade 3 toxicity, guidelines recommend discontinuation of the drug. If grade 2 transaminase increase is observed, the treatment could be continued with caution and a close follow-up and dose reduction may be considered. A rise in bilirubin levels induced by tyrosine kinase inhibitors can be seen quite frequently, but the drug should only be discontinued in case of grade 3 toxicity. As a general principle, patients taking this class of drugs should avoid alcohol consumption as well as other potential hepatotoxic drugs whenever possible. Phase I studies are evaluating the recommended doses of most of these compounds in patients that have mild to moderate liver function impairment.

Intestinal bleeding and perforation. Several cases of gastrointestinal perforation have been reported in patients treated with bevacizumab and chemotherapy. Although they have been initially described in patients with metastatic colorectal cancer, the relative incidence seems to be extremely low. The Bevacizumab Regimens Investigation of Treatment Effects and Safety (BRiTE) registry reported gastrointestinal perforation in 1.7% of 1,987 patients with metastatic colorectal cancer. The clinical pattern and severity of perforation seen was variable, ranging from asymptomatic to fatal. Most gastrointestinal perforations occurred within the first 3 months after initiation of treatment. The incidence of perforations was greatest in cases where the primary tumor remained in situ, an endoscopic procedure had recently been performed and those with prior radiotherapy. In some trials conducted in patients with advanced ovarian cancer the incidence of this side effect has been shown to be higher.

Elevation of pancreatic enzymes. Some tyrosine kinase inhibitors can rarely induce hyperlipasemia and hyperamylasemia. These abnormalities have been described with sorafenib and sunitinib. In most of the cases this toxicity only deals with biochemical alteration without any clinical effects and can be managed in most cases with close follow-up without discontinuation of the drug.

Conclusions: Targeted therapies have emerged as a new cancer treatment strategy with several currently approved specific indications. Novel targeted agents aim to interfere with specific critical properties of the malignant cells with limited impact on the non-neoplastic host cells thereby increasing the therapeutic index in comparison to conventional cytotoxic agents. However, most targeted agents have the best therapeutic index when they are used in combination with standard chemotherapy. Therefore the specific toxicities related to targeted agents have to be analyzed in combination with the toxicities related to cytotoxic chemotherapy. The most frequent digestive system toxicities include diarrhea and hepatotoxicity, although some patients may present with nausea/vomiting, pancreatic toxicity or very rarely gastrointestinal perforation. Multitargeted agents show a more heterogeneous toxicity profile depending on the different proteins targeted for inhibition. The information emerging from prospective randomized studies is increasingly establishing the toxicity profile related to the administration of these targeted agents.

Toxicities Drug Diarrhea, all grades (grades 3–4) (%) Hepatotoxicity, all grades (grades 3–4) (%) Gefitinib/Erlotinib/Lapatinib 40–60 (3–13) 11 (2) Sorafenib/Sunitinib 33–53 (5–8) 1–52 (1–3) Cetuximab/Panitumumab 20 (2) -

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):CN03-04.