Fever is not good after transarterial chemoembolization for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related death in Taiwan. Based on current guidelines, transarterial chemoembolization (TACE) is recommended as the standard care for intermediate-stage HCC or early-stage HCC, which is ineligible for curative therapy, namely, surgical resection and local ablation. However, the heterogeneity of intermediate-stage HCC has been well documented, so several scoring systems and prognostic factors have been developed to help predict the clinical outcomes of HCC patients receiving TACE. Fever following TACE, termed postembolization fever (PEF), is a very common symptom in HCC patients receiving TACE. It usually occurs within 3 days after TACE. In the past few years, PEF has attracted wide interest because several studies associated it with the overall survival after TACE. However, the relationship between PEF and TACE treatment response remains unclear. In addition, the incidence of PEF in Taiwan has also not yet been formally reported. In this issue of AIDM, Jeng et al investigated the incidence of PEF and its association with TACE treatment response in a large cohort of 525 HCC patients. Interestingly, they found that PEF occurred in approximately one third (35.2%) of patients, with a median time of one day post-TACE. They also identified several factors prior to TACE that were associated with PEF, including a more advanced stage of HCC, higher tumor burden (beyond up-to-seven), higher alanine transferase (ALT) level, higher Albumin-Bilirubin (ALBI) grade and greater lipiodol dose. Importantly, they found that PEF was associated with a higher complete response (CR) rate of TACE treatment. In addition, they showed that a higher Hepatoma arterial-embolisation prognostic (HAP) score, a predictive scoring system for TACE treatment of HCC, was associated with PEF. The analysis demonstrates the clear and interesting association between PEF and tumor burden and liver reserve. It has an important clinical implication. Because PEF is a simple observable and measurable parameter, its potential to serve as a sole biomarker or one of a scoring system/model for predicting treatment response of TACE should be further evaluated in a large prospective study. The results from the study of Jeng et al are very interesting but somewhat not surprising. Theoretically, PEF results from either infection or inflammation. Nevertheless, only three cases of PEF in this TACE/HCC cohort could be attributed to bacterial infection. In other words, most PEFs identified in this study were due to noninfectious inflammatory reactions. Although the underlying mechanisms that cause noninfectious PEF are still not fully understood, a prior study showed that the release of cytokines from necrotic tumor tissues likely contributed to PEF and affected the outcomes of HCC patients receiving TACE. Thus, it is reasonably assumed that TACE applied to treat larger tumor volume or burden may cause more tumor necrosis and the release of more pyretic factors that induce PEF as a result. Therefore, the occurrence of PEF can be considered an indirect indicator that probes the tumor burden of HCC. As it is usually more difficult to achieve CR by TACE for a larger tumor burden, it is not surprising that the presence of PEF was associated with less likelihood of CR. However, it is notable that PEF was also associated with poor liver reserve, which was indicated by higher ALBI grade. This implies that the intrahepatic environmental changes in a liver of poor reserve may also influence the inflammatory process and fever following TACE. Whether and how the released cytokines from necrotic tumors influence the tumor growth or control by host antitumor immunity in the HCC immune microenvironment are currently unknown. Unfortunately, no studies had ever performed a comprehensive investigation on the dynamic changes of the immune microenvironment of HCC following TACE. This is particularly relevant in the era of tumor immunotherapy. The combination of locoregional therapy and immunotherapy is an emerging concept and strategy for the treatment of HCC, particularly for unresectable HCC. It has been known that an inflamed tumor microenvironment is associated with better response to immunotherapy. As fever is often considered a sign of inflammation, the observation that PEF indicates an unfavorable outcome of TACE for HCC is actually against the concept of immune control for tumor growth. This seemingly contradictory observation urges the need for further Received: 17 May 2020 Accepted: 21 May 2020