Dan Tian,Ting-Ting Chen,Qing Xu,Xiao-Yu Li*,Qian-Zhou Lv*

1Pharmacy department,Zhongshan Hospital,Fudan University,Shanghai 200032,China.

Abstract Background and Objectives:Post embolization fever(PEF)is one of the most common symptoms of post embolization syndrome(PES).This study aimed to determine and validate a model to predict PEF after transcatheter arterial chemoembolization(TACE)in hepatocellular carcinoma(HCC)patients.Methods:Clinical data of HCC patients who underwent TACE with platinum was retrospectively collected in our center from 2017 to 2018.Predictive factors were screened by multivariate logistic regression.The accuracy and discriminative ability of these factors were evaluated by the receiver operating characteristic(ROC)curve using the derivation cohort and an independent validation cohort.Results:A total of 367 patients were included,of whom 53(14.4%)patients had PEF.Fevers were detected in 44 of 252 patients in the derivation cohort and 9 of 115 patients in the validation cohort.Predictors for PEF identified in multivariate logistic regression included Lipiodol emulsion dose(OR,1.081;95%CI,1.006–1.162),number of concomitants uses of hepatoprotectants(OR,0.619;95%CI,0.419–0.914),K+levels(OR,2.992;95%CI,1.225–7.308),and albumin-bilirubin(ALBI)grade(OR,2.249;95%CI,1.040–4.862).Furthermore,the area under the ROC curve of the derivation and validation cohorts were 0.798 and 0.874,respectively.Conclusions:Our study demonstrated that Lipiodol emulsion dose,number of concomitant uses of hepatoprotectants,K+levels,and ALBI grade are independent risk factors for PEF.The multivariate logistic model of these factors shows a discriminative ability to predict PEF in the patients who underwent TACE.

Keywords:post embolization fever;hepatic artery embolization;hepatoprotectants

Introduction

Hepatocellular carcinoma(HCC),the most frequent type of liver cancer,is now the fourth most common malignant tumor and the third most lethal malignant tumor in China to statistics in 2022[1].Several strategies have been demonstrated effective in treating HCC.Surgery is the mainstay of HCC treatment.Other strategies include chemotherapy,chemoembolization,internal radiation,immune therapies,and retinoids.Among them,transcatheter arterial chemoembolization(TACE)is the most widely used primary treatment for unresectable HCC and the recommended first line-therapy for patients at the intermediate stage of the disease[2].TACE has survival benefits in asymptomatic patients with large or multifocal HCCs without vascular invasion or extrahepatic spread[3].According to the current European Association for the Study of Liver guidelines,it has been recommended as the preferred treatment for Barcelona Clinic Liver Cancer patients with stage B HCC[2].However,TACE is associated with transient post embolization syndrome(PES),with an incidence range from 20% to 80%[4–6].Fever,unremitting nausea,vomiting,pain in the liver region,abdominal distention,and poor appetite can be occurred in the patient with PES[7].Among them,post embolization fever(PEF)has been considered to reflect extensive tumor necrosis and represent the efficacy of TACE by physicians.Studies have also validated that PEF may be associated with tumor size and the use of embolic agents[8–10].However,PEF is less predicted by clinical and biochemical indicators,and the few existing conclusions are inconsistent[9].This study aimed to analyze the predictive factors of fever after TACE in patients with HCC who were treated with platinum as the main regimen and to provide clinical evidence for PEF prediction.

Materials and Methods

Inclusion and exclusion criteria

Data were retrospectively collected from patients with HCC who underwent TACE in our center from 2017 to 2018.This study herein was carried out in accordance with the principles of the Declaration of Helsinki and approved by the ethics committee of Zhongshan Hospital,Fudan University(No.B2018-043R).Inclusion criteria included as following:complete medical records and laboratory data for patients before and after TACE,above 14 years old,the survival time of patients above three months,no urinary tract,endocardium,pelvic infection in nearly one month,platinum as the main chemotherapeutic regimen in TACE.Excretion criteria included pregnant or lactating women with an infection and fever before TACE.Furthermore,another cohort of 115 patients who met the same inclusion and exclusion criteria mentioned above were separately collected to be the validation cohort.

Data collection

Data were collected and retrieved through the hospital information management system.Demographic information and medical records such as sex,age,diagnosis,concomitant diseases,operation procedures,and medication were recorded.All laboratory examinations before and after TACE were recorded,mainly included blood routine,liver and kidney function parameters(such as total bilirubin(TBIL),direct bilirubin(DBIL),alanine aminotransferase(ALT),aspartate aminotransferase(AST),alkaline phosphatase(ALP),glutamyl transpeptidase(GGT),serum creatinine(sCr),uric acid(UA),etc.),tumor markers(such as alpha fetoprotein(AFP),carcinoembryonic antigen)and coagulation indicators(such as prothrombin time(PT),activated partial thromboplastin time(APTT),fibrinogen(FIB),etc.).The method of collecting preoperative laboratory indicators was collecting venous blood samples within 48 hours before the operation and sending them for examination in the morning.Albumin-bilirubin(ALBI)grade has been reported to be a new tool for evaluating hepatic function in HCC patients compared to the Child-Pugh classification[11].ALBI score was used for grading(≤–2.60=grade 1,greater than–2.60 to≤–1.39=grade 2,greater than–1.39=grade 3).The aspartate aminotransferase/platelet count ratio index (APRI, APRI=[AST(IU/L)/upper limit normal]/PLT(×109/L)]×100),which is thought to be a biomarker of liver fibrosis and cirrhosis[12],was calculated as well.

Statistical analysis

All statistical analyses were performed with the SPSS software(IBM SPSS Statistics 22.0).Values are presented as the mean±standard deviation for data that were normally distributed or median,an inter-quartile range for data that were not normally distributed for continuous variables,and the number(%)for categorical variables.The independent Student's t-test or Mann-Whitney U test was used to determine differences between groups with continuous variables.Chi-squared test or Fisher’s exact test were applied for categorical variables.A multivariate logistic regression model using a forward selection procedure was then constructed to identify the independent predictive factors for PEF.The receiver operating characteristic(ROC)curve was performed to detect the accuracy and discriminative ability of the model using the derivation cohort and a separate validation cohort.All the statistics were a bilateral test,and P＜0.05 was considered statistically significant.

Results

Comparison of general data of patients between fever group and non-fever group

A total of 252 patients were collected,including 209 males and 43 females,aged from 18 to 85 years,with an average age of 57.8±11.3 years.The general data of the fever group(n=44)and non-fever group(n=208)are shown in Table 1.There was no significant difference in demographic characteristics and complications between these two groups(P＞0.05).The number of varieties of hepatoprotectants in the fever group was lower than that in the non-fever group(1.5±0.6 vs 2.4±1.3,P=0.000).In addition,the amount of iodized oil injected in the fever group during TACE was higher than that in the non-fever group(10.5±5.5 vs 7.1±4.6,P=0.000).

Independent factors associated with PEF in the derivation cohort

Univariate analysis showed that Lipiodol emulsion dose,hypertension,number of hepatoprotectants,fluorouracil,platelet(PLT),total protein(TP),albumin(Alb),albumin/globulin ratio(A/G),ALT,AST,ALP,GGT,UREA,K+,AFP,FIB,D-dimer and ALBI grade were associated with PEF(Table 2).After multivariate logistic analysis,three factors including Lipiodol emulsion dose(OR 1.081,95% CI:1.006–1.162,P=0.034),K+(OR 2.992,95% CI:1.225–7.308,P=0.016),and ALBI grade(OR 2.249,95%CI:1.040–4.862,P=0.039)within 48 hours before the operation were positively correlated with fever after TACE,while number of hepatoprotectants(OR 0.619,95%CI:0.419–0.914,P=0.016)was a negatively associated with PEF.ROC curve analysis showed that the AUC of Lipiodol emulsion dose,number of hepatoprotectants,K+,ALBI grade,and predict model ranged from 0.5 to 0.8,and the Cut-off point was 6.5 mL,2.5,4.25 mmol/L,1.5 respectively(Table 3).

Accuracy and discriminative ability of the model

The cohort with 115 patients who met the same inclusion and exclusion criteria mentioned above was selected as a separate validation cohort.Nine out of 115 patients had PEF.There was no significant difference in demographic and complications between the fever cohort and non-fever cohort,shown in Table 4.The number of hepatoprotectants was 1.0±0.5 in the fever cohort and 1.1±0.4 in the non-fever cohort(P=0.370).Lipiodol emulsion dose(mL),K+(mmol/L),and ALBI grade were significantly higher in the fever group,as we expected.The ROC curve was performed to detect the accuracy and discriminative ability of the model.The area under the ROC curve of the derivation cohort and the validation cohort was 0.798 and 0.874,respectively(Figure1).

Figure 1 ROC curves determining model performance for prediction of PEF in a derivation cohort(n=252)and b validation cohort(n=115).AUC,Area Under Curve.

Table 1 Comparison of demographic and clinical data between two groups before TACE

Table 2 Univariate and multivariate logistic regression showing independent factors associated with fever after TACE(Continued)

Table 2 Univariate and multivariate logistic regression showing independent factors associated with fever after TACE

Table 3 ROC curve analysis of predicted factors

Table 4 Demographic and clinical data of validation cohort

Discussion

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 hyper-arterialized liver tumors[13].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[14].However,TACE inevitably leads to hypoxic damage to hepatoma cells and surrounding liver tissues.Hepatoprotectants are used strategically to protect liver function in patients receiving chemotherapy.PES is thought to be the result of therapeutic cytotoxicity,tumor ischemia,and intrahepatic and extrahepatic inflammation[7].Studies have shown that PES was associated with worse survival and a two-fold increased risk of death[4].PEF,a common symptom of PES,was defined as self-limiting fever with body temperature greater than 38℃within three days after TACE with no evidence of infection,was significantly related to the long-term survival rate of patients after TACE[8].and symptomatic interventions can be taken if necessary to achieve satisfactory relief[15],PEF often prolongs hospitalization and leads to unnecessary use of antibiotics.

The incidence of PEF reported in the literature ranged from 20% to 70 %[8–10,16].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[8].In addition,TACE itself can lead to inflammatory factors release[17]and contribute to stress responses in the human body[8].Sabre et al.found that patients with a preprocedural platelet count less than 336×103/uL were less likely to have PES[18].

The latest studies have found that APRI and ALBI are predictors ofpostoperative outcomes for patients undergoing liver surgery[19].Hence,the ALBI grade and APRI were introduced in this study to manifest or indicate hepatic function and liver fibrosis,and cirrhosis[12].It showed that the incidence of PEF was 17.5%by analyzing the 252 patients in this study,insistent with most previous studies[8–10].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 %).They revealed that the ALT value after TACE and the lipiodol dose≥7 mL were independent predictive factors of PEF after multivariate analysis by logistic regression[8].Shim et al.found that pre-procedure serum bilirubin,ascites,tumor size,and female gender predicted PEF in a cohort without background infective hepatitis patients[10].However,a 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 developing PEF[16].

We found that the occurrence of PEF was closely related to some clinical and laboratory variables.Among these,Lipiodol emulsion dose,number of hepatoprotectants,K+,and ALBI grade were independent risk factors for PEF.Special attention should be paid to the occurrence of PEF in the patients with Lipiodol emulsion dose was greater than 6.5 mL,K+was greater than 4.25 mmol/L,and ALBI grade was more than 1.5,according to the results of the cut-off value,and measures should be taken for further monitoring and prevention.

Besides,our limited data also indicated that the number of hepatoprotectants might be a protective factor for the occurrence of PEF.Furthermore,the area under the ROC curve of the validation cohort was 0.874,which indicated the comparative stability and discriminative ability of this predictive model.

Here,we performed a single center retrospective study,and the race was limited to Asians.At the same time,it is necessary to validate a prediction model against external centers with different geography and races.Second,most of our patients were accompanied by an infection of HBV and liver cirrhosis which was in accordance with the background high HBV prevalence rate in China.Detection and control for population stratification in association studies of hepatitis patients are needed in the following research.Third,we did not consider the tumor size's influence on the PEF for patients'variant situations for surgical or disease progression.Considering the situation of hepatoprotectants wide use in China,we added the number of hepatoprotectants in the analysis and found it a potential protective factor for PEF.Further,how the hepatoprotectants act in PEF still needs further well-designed study.

Conclusion

PEF is a common complication in patients with advanced,unresectable HCC.We found that Lipiodol emulsion dose,number of hepatoprotectants,K+,and ALBI grade are strong predictors for PEF.Moving forward,the multivariate logistic model of these factors shows a discriminative ability to predict PEF in the validation cohort.