TACE exploits the preferential hepatic arterial supply of HCC for targeted delivery and embolizes of the feeding artery branches of HCC by lipiodol emulsion, microspheres, polyvinyl alcohol and gelatin sponge with chemotherapeutic drugs. Lipiodol has the unique property of selective uptake and retention in hyperarterialyzed liver tumors (15). Generally, two or three kinds of chemotherapeutic drugs (such as doxorubicin, epirubicin, idarubicin, mitomycin C, or cisplatin), are emulsified in the lipiodol, and then followed by particle embolization to improve the overall survival rate of patients with HCC (16). However, TACE inevitably leads to hypoxic damage to hepatoma cells and surrounding liver tissues. PES is thought to be the result of therapeutic cytotoxicity, tumor ischemia, and intrahepatic and extrahepatic inflammation (9). Studies has showed that PES was associated with a worse survival and a two-fold increased risk of death (7). PEF, a common symptom of PES, was defined as body temperature greater than 38℃ within 3 days after TACE with no evidence of infection (10). Although this fever is self-limiting, which may not be significantly related to the long-term survival rate of patients after TACE (10), and symptomatic interventions can be taken if necessary to achieve satisfactory relief (17), PEF often prolongs hospitalization and leads to unnecessary use of antibiotics.
The incidence of PEF reported in the literature ranged from 20–70% (10–12, 18). This variation was likely attributed to measurement bias derived from differences in the definitions used. Nevertheless, the pathogenesis of PEF is still unclear. Most studies believe that lipiodol-induced embolism may lead to ischemia, hypoxia and necrosis of some normal hepatocytes (10). In addition, TACE itself can lead to inflammatory factors release (19), such stimuli can contribute to stress responses in the human body (10).
Recently, studies have found APRI and ALBI to be predictors of postoperative outcome for patients undergoing liver surgery (20). Hence, the ALBI grade and APRI were introduced in this study to manifest or indicate the hepatic function as well as liver fibrosis and cirrhosis (14).Analysis of 252 patients in this study showed that the incidence of PEF was 17.5%, which was similar to most of previous studies (10, 12). Jun et al. retrospectively analyzed 443 HCC patients who underwent the first session of TACE and found that PEF developed in 117 patients (26.41%). A multivariate analysis using logistic regression showed that ALT value after TACE and the lipiodol dose ≥ 7 mL were independent predictive factors of PEF (10). Shim et al. found that pre-procedure serum bilirubin, ascites, tumor size and female gender predicted PEF in a cohort without background infective hepatitis patient (12). However, more previous study disclosed that a dosage of doxorubicin plus iodized oil > 23 mL during chemoembolization and tumor size > 3 cm were significant predictors associated with the development of PEF (18).
We found the occurrence of PEF was closely related to some clinical and laboratory variables. Among which, Iopiodol emulsion dose, number of hepatoprotectants, K+, and ALBI grade were independent risk factors for PEF. The results of cut-off value indicated that when Iopiodol emulsion dose was greater than 6.5 mL, K+ was greater than 4.25 mmol/L, ALBI grade was more than 1.5, special attention should be paid to the occurrence of PEF in these patients, and good monitoring and prevention should be done. Besides that, our limited data also indicated that the number of hepatoprotectants might be a protect factor for occurrence of PEF. In additon, the area under the ROC curve of validation cohort was 0.874, which indicated comparative stability and discriminative ability of this predictive model.
Here, we performed a single center, retrospective study and the race were limited to Asian, while it is necessary to validate a predict model against external centers with different geography and races. Second, most of our patients were accompanied with infection of HBV and liver cirrhosis which was in accordance with the background of high HBV prevalence rate in China. Detection and controlling for population stratification in association studies of hepatitis patients are needed in the following researches. Third, we did not consider the tumor size’s influence on the PEF for patients’ variant situation for surgical or disease progression. In consideration of situation of hepatoprotectants wide use in China, we added the number of hepatoprotectants in the analysis and found it maybe a potential protect factor for PEF. Further, how the hepatoprotectants actually act in PEF still need further well-designed study.