What Can We Expect from Sorafenib in the Treatment of Liver Cancer Affected by Nonalcoholic Fatty Liver Disease?
Ubiquitous and increasingly common obesity is a risk factor for many cancers. Over the past 20 years, studies have linked obesity to higher incidences of breast and colorectal cancers, as well as hepatocellular carcinoma (HCC) associated with nonalcoholic fatty liver disease (NAFLD). What is the efficacy and safety of sorafenib in this patient population, and does it differ from patients with liver cancers caused by viral infection or alcohol abuse? This intrigued a team of researchers from Melbourne, Australia.
Liver damage through fat accumulation
Nonalcoholic liver steatosis is a common finding in patients with metabolic syndrome – that is, individuals with obesity, hypertension, hyperlipidemia, and insulin resistance. The increasing prevalence of metabolic syndrome is also elevating the number of patients with fatty liver disease (NAFLD) across various stages.
Simple steatosis can progress to steatohepatitis (NASH) and further to fibrosis and cirrhosis. Malignant transformation to hepatocellular carcinoma (HCC) most often occurs on the background of liver cirrhosis, but a certain portion of patients with NAFLD can develop it earlier. The presence of liver inflammation is already a risk. Globally, the incidence is reported at 0.1‒1.3 cases of HCC per 1,000 patients with non-cirrhotic NAFLD per year.
Support for carcinogenesis
A significant pathophysiological mechanism is likely insulin resistance. This condition increases the release of free fatty acids from adipose tissue, and their breakdown through β-oxidation generates reactive oxygen species (ROS), damaging mitochondria and triggering the secretion of pro-inflammatory cytokines. Chronic inflammation activates pro-oncogenic transcription factors, and the released ROS damage anti-tumor CD4+ and CD8+ T lymphocytes. Mild systemic inflammation, reduced immune surveillance, and changes in gut microbiota then support liver inflammation and accelerate carcinogenesis.
Targeted treatment of HCC with sorafenib
One of the targeted drugs used for HCC is sorafenib. According to recommended guidelines, it represents a potential first-line therapy for advanced stage C or upon progression with locally ablative methods in intermediate stage B. As with other cancers, monitoring the efficacy of used drugs depending on the disease's etiology or biological characteristics can be crucial for HCC as well.
An observational study attempted to do just that, analyzing data from 5,201 patients with HCC treated in Western and Central Europe and North America. Its aim was to compare overall survival (OS), survival duration on sorafenib treatment, and the drug's toxicity in patients with HCC based on NAFLD (183 individuals; 3.6% of the study population) versus those with HCC from other etiologies.
Etiology of HCC and clinical outcomes of treatment
The NAFLD group was slightly older (median 65.8 vs. 63.0 years) and had a higher proportion of women (10.4 vs. 2.3%). After accounting for known prognostic factors, no difference was found in OS between the two groups (19.3 vs. 17.6 months; hazard ratio [HR] 0.99; 95% confidence interval [CI] 0.84‒1.18; p = 0.98). There was also no difference in survival duration on sorafenib treatment (HR 0.96; 95% CI 0.79‒1.17; p = 0.96), despite patients with NAFLD having more advanced HCC (stage C and D 70.9 vs. 58.9%; p < 0.01) and initiating therapy with lower doses of sorafenib (51.4 vs. 36.4%; p < 0.01).
Additionally, no difference was observed in the frequency of common adverse events, with diarrhea and fatigue being the most common. Severe hypertension manifested similarly – in 6.3% of NAFLD patients and 5.8% of those with HCC from other causes. An interesting result was observed with palmoplantar erythrodysesthesia (hand-foot syndrome), which occurred less frequently in NAFLD patients (3.8 vs. 12.4%; p = 0.03). This could have been related to the initial administration of lower doses of sorafenib in this group.
Conclusion
Although patients with NAFLD are primarily at risk for cardiovascular events, we should not neglect oncological risks. One of the basic targeted drugs for HCC, sorafenib, according to the presented observational study, is just as effective in patients whose cancer developed on the basis of NAFLD as in those with liver cancer caused by alcohol damage or viral infections.
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Sources:
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3. Primary tumors of the liver, gallbladder, and bile ducts (C22‒C24). In: Kiss I. (ed.). The Blue Book of the Czech Oncology Society. 28th update. Masaryk Oncology Institute, Brno, 1. 3. 2022. Available at: www.linkos.cz/files/modra-kniha/21/803.pdf
4. Howell J., Samani A., Mannan B. et al. Impact of NAFLD on clinical outcomes in hepatocellular carcinoma treated with sorafenib: an international cohort study. Therap Adv Gastroenterol 2022; 15: 17562848221100106, doi: 10.1177/17562848221100106.
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