Steatosis is not associated with increased risk of chemotherapy induced liver injury in metastatic colorectal cancer

Background

Chemotherapy associated liver injury (CALI), a form of drug induced liver injury (DILI), is associated with higher morbidity, mortality, treatment disruption, poorer future chemotherapy tolerance and surgical outcomes. Pre-existing steatosis was shown to be associated with disordered Azathioprine hepatic metabolism, increasing the risk of thiopurine related hepatitis. This study aimed to determine if steatosis was associated with increased risk of CALI that would warrant pre-treatment screening. Metastatic colorectal carcinoma (CRC) was chosen to analyse this relationship as its treatment, namely 5-Flurouracil, Irinotecan and Oxaliplatin are all recognised causes of CALI.

Methods

Regional tertiary referrals for CRC were examined over a four year period between Jan 2016 and Dec 2019. The outcome of interest was evidence of CALI following the first cycle of chemotherapy over a 3 month period. CALI was defined as a rise in ALT >3-times upper limit of normal or histological evidence of DILI, including sinusoidal obstruction syndrome, steatohepatitis and nodular regenerative hyperplasia. MRI and PET-CT modalities were used to objectively determine pre-existing steatosis prior to treatment. Demographic data collected included age, sex, alcohol consumption, BMI, pre-existing liver disease and concordant drugs that also induce steatosis.

Results

376 patients were treated for metastatic CRC between 5th Jan 2016 and 27th Dec 2019. 122 patients had pre-treatment imaging to determine presence of steatosis. Median age was 66.0 years (IQR 57 – 74 years); 63.9% female (n=78/122). Median BMI 25.6kg/m2 (IQR 23.0 – 30.5kg/m2). None of the patients had a formal diagnosis of liver disease. 5 patients had hazardous or harmful alcohol consumption. 82.8% (n=101/122) had liver metastases prior to commencing chemotherapy. The commonest chemotherapy regimen received was Capecitabine and Oxaliplatin (54.1%; n=66/122). Based on MRI and PET-CT imaging, 19.6% (n=24/122) of patients had pre-existing steatosis prior to treatment. 9.8% (n=12/122) had biochemical or histological evidence of CALI, only one of which had pre-existing steatosis (p=0.30; chi2 = 1.08). None of these patients had previously received adjuvant oxaliplatin for colorectal carcinoma. A diagnosis of CALI was not associated with delays to subsequent surgery or chemotherapy. 8 patients had histological evidence of new steatosis post chemotherapy with no adverse features.

Conclusion

Almost 1 in 10 patients developed CALI following treatment for metastatic CRC. Simple steatosis does not appear to be associated with CALI and should not impact treatment decisions related to metastatic colorectal carcinoma. This study cannot comment on the relationship between CALI and pre-existing liver fibrosis and cirrhosis.