AFP Response and mRECIST for Unrespectable Hepatocellular Carcinoma after Transarterial Chemoembolization Combined with Sorafenib

Research Article

Austin J Surg. 2019; 6(11): 1189.

AFP Response and mRECIST for Unrespectable Hepatocellular Carcinoma after Transarterial Chemoembolization Combined with Sorafenib

Tian M¹, Huang G², Li J³ and Zhang Y³*

¹Department of Radiology, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, China

²Digestive Disease Center, The Seventh Affiliated Hospital, Sun Yat-sen University, China

³Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-sen University, China

*Corresponding author: Yingqiang Zhang, Department of Interventional Radiology, The Seventh Affiliated Hospital, SunYat-sen University, No 628. Zhenyuan Road, Shenzhen, 518107, P.R. China

Received: April 08, 2019; Accepted: May 07, 2019; Published: May 14, 2019


Background/Aims: The use of Alpha-fetoprotein (AFP) response in unresectable Hepatocellular Carcinoma (HCC) patients undergoing Transarterial Chemoembolization (TACE) combined with sorafenib has not been rigorously evaluated. We defined potential AFP criteria and compared them with modified Response Evaluation Criteria in Solid Tumors (mRECIST) aimed to: a) validate the prognostic role of AFP response, and b) determine the extent of agreement between AFP and imaging criteria.

Methods: In total, 203 unresectable HCC patients with baseline AFP (> 20ng/mL), who underwent combined TACE with sorafenib therapy, were retrospectively enrolled for AFP-imaging correlation analysis. AFP response was classified as complete response, normalization of AFP; partial response, > 50% decrease from baseline; stable disease, -50% to +30% change from baseline; or progressive disease, > 30% increase from baseline. AFP- and mRECIST- based Response Rate (RR) and Disease Control Rate (DCR) was compared, and associations between AFP response and Overall Survival (OS) were evaluated.

Results: The k value for agreement between AFP criteria and mRECIST was 0.47 (moderate), with RR and DCR were 43.3%, 69.0%, and 42.9%, 53.7% (P=0.920, P=0.002), respectively. A higher area under curve for AFP control was observed in receiver operating characteristic curve compared with mRECIST control (0.908 vs. 0.866). The AFP and mRECIST response or control significantly correlated with OS. Both AFP control (Hazard Ratio) [HR]=0.211; 95% CI: 0.132, 0.337; P‹0.001) and mRECIST control was confirmed by multivariate analysis.

Conclusion: The proposed AFP criteria provided accurate predictions in patients with unresectable HCC and positive AFP after TACE combined with sorafenib.

Keywords: Alpha-fetoprotein; Hepatocellular Carcinoma; Response; Sorafenib; Transarterial chemoembolization


Hepatocellular Carcinoma (HCC) is the fifth most common malignancy and the third leading cause of cancer-related death worldwide [1]. Liver resection, liver transplantation, and percutaneous ablation are the main radical treatments for HCC. However, only 30- 40% of early-stage patients are amenable for such curative therapies, and more than 50% of all HCCs are diagnosed at the unresectable stage [2,3]. Sorafenib, an oral inhibitor of multiple kinases involved in HCC proliferation and angiogenesis, and Transarterial Chemoembolization (TACE) are important and common treatments for most patients with unresectable stage HCC [4-7]. Recently, there has been an increasing focus on combining TACE with sorafenib to potentially improve the efficacy for patients with unresectable/ advanced HCC [8-13].

Conventionally, the treatment response of HCC tumors is assessed radiologically. The Response Evaluation Criteria in Solid

Tumors (RECIST) criteria focus on tumor size, has been widely used in the assessment of tumor response to systemic chemotherapy [14]. Whereas, because they include radiologically enhanced criteria, the European Association for the Study of the Liver (EASL) [15] and modified RECIST (mRECIST) [16] criteria can reliably predict the treatment response and survival in patients with HCC undergoing TACE [17-19]. Further, Liu et al concluded that EASL and mRECIST response were a better predictor for OS than RECIST response in HCC patients treated with combination TACE and sorafenib therapy [20]. Therefore, the enhanced radiologic criteria are widely used to assess the tumor response in patients with HCC.

Changes in serum tumor markers are also important for monitoring anticancer treatment response. Alpha-fetoprotein (AFP) is a universally recognized tumor marker for HCC [21]. The diagnostic and prognostic role of AFP in HCC patients has been confirmed [22- 28]. Memon et al [29] and Personeni et al [30] presented their analysis in Journal of Hepatology in which they conclude that AFP response is a reliable prognostic factor for treatment response and survival in HCC patients undergoing TACE or sorafenib alone, respectively. Recently, TACE combined with sorafenib, as a combination of local and systemic therapy, has been a commonly used treatment in multiple, advanced HCC tumors. Therefore, it is needed to identify whether the same holds true for the combination therapy. We present data to support this concept. Meanwhile, we defined potential AFP criteria and compared them with mRECIST to determine the extent of agreement between the tumor maker criteria and imaging criteria.

Patients and Methods

Patient selection

The study protocol was approved by the ethics committees of the institution. Written informed consent was obtained from each participant in accordance with the Declaration of Helsinki. Patients with unresectable HCC who underwent TACE combined with sorafenib as initial treatment at our center, between January 2010 and December 2014, were retrospectively analysed. The HCC diagnosis was made according to the EASL guideline [3].

The inclusion criteria were: (a) age between 18-75 years; (b) Barcelona Clinic Liver Cancer stage B or C; (c) Child-Pugh class A or B liver function; (d) Eastern Cooperative Oncology Group (ECOG) performance scores = 2; (e) no previous treatments; (f) HCC with elevated baseline AFP (> 20 ng/mL); and (g) availability of radiologic imaging and serum AFP data. Patients were excluded for any of the following: (a) HCC with normal baseline serum AFP (< 20 ng/mL); (b) inadequate target lesion (diffuse pattern or largest lesion < 1 cm); (c) Child-Pugh class C liver function or massive ascites, esophageal gastric variceal bleeding, or hepatic encephalopathy; (d) obstructive jaundice; (e) secondary malignancy; (f) missing data.

Treatment protocol

The treatment protocol was performed according to our previous report [12,13]. Briefly, 10 to 20 mL lipiodol (Guerbet, Paris, France) was mixed with 20–40 mg epirubicin (Pfizer, New York, USA) to create an emulsion. Depending on the tumor size and liver function, 2–20 mL of the emulsion was infused into the liver tumor through a catheter. Subsequently, embolization using gelfoam was carried out. When blood flow slowed or a vascular cast was observed, the injection was stopped. sorafenib treatment was started 1–3 days after TACE. The initial dose of oral sorafenib was 400 mg given twice daily. Doses were modified depending on the toxicity according to National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) 3.0.


Standard follow-up evaluations protocol of treatment for HCC described previously [13,31] including dynamic contrast-enhanced CT scans and laboratory tests, were performed to evaluate the efficacy at 4-6 weeks after initiation of therapy and every 2 months thereafter. Laboratory tests included hematologic analyses, liver function test, serum AFP assay, and hepatitis serologic test. Complications and adverse events were recorded.


Serum AFP levels were measured using a microparticle enzyme immunoassay (Abbott Laboratories, Chicago, IL). AFP response was classified as follows: Complete Response (CR), normalization of AFP; Partial Response (PR), >50% decrease from baseline; Stable Disease (SD), -50% to +30% change from baseline; or Progressive Disease (PD), >30% increase from baseline. Tumor response evaluation criteria were based on radiologic evaluation according to the mRECIST guideline [16] as: CR: disappearance of any intratumoral arterial enhancement in total lesions; PR: =30% decrease in tumor size; SD, neither PR nor PD; or PD: =20% increase in tumor size or the appearance of new lesion(s). The overall response assessment of target and nontarget lesions was determined based on the mRECIST criteria. All measurements were performed by an independent observer (.., who had >15 years of experience) who was blinded to clinical data to minimize the possibility of false categorizations. Whenever response categorization was not obvious, final classification was made by consensus (.. and .., who had >20 years of experience). The interval between AFP measurement and CT scan was up to 2 days.

Because the initial response is a robust predictor for favorable outcome, the concept was applied in the present study. The initial response was defined as the first assessment after initial therapy [32- 34]. Objective response was defined as sum of CR and PR, disease control was a sum of CR, PR and SD. whereas PD was defined nonresponse. The primary endpoint was Overall Survival (OS). OS was defined as the time from the date of treatment initiation until the date of death or last follow-up. The correlation of response and OS was analyzed.

Statistical analyses

All statistical analyses were performed using SPSS software (SPSS version 16.0, SPSS, Chicago, IL). For baseline characteristics, continuous variables are described as medians±standard deviations and categorical variables are expressed as frequencies and percentages. Intermethod agreement between the two methods was assessed using Cohen’s kappa (k) coefficient. A k coefficient >0.75 represented excellent intermethod agreement and a k coefficient of ‹0.21 represented poor intermethod agreement [35]. The Kaplan– Meier method and log-rank test were used to calculate and compare survival differences, respectively. Univariate analyses were performed using the log-rank test. Variables with a P value ‹0.1 were entered into a multivariate analysis using the Cox proportional hazards model to identify risk factors associated with OS. All statistical tests were two-sided, and P ‹0.05 was considered statistically significant.


Study population

Among 577 consecutive newly diagnosed patients with unresectable HCC who underwent TACE plus sorafenib as initial treatment, 374 were excluded because they had normal serum AFP (n=139), diffuse HCC (n=8), Child-Pugh class C liver function (n=63) or massive ascites (n=16), esophageal gastric variceal bleeding (n=10), or hepatic encephalopathy (n=6), obstructive jaundice (n=11); or secondary malignancy (n=10). In addition, 112 patients were excluded because their data were not available. The analysis cohort included 203 patients. The baseline characteristics of all patients are detailed shown in Table 1. The mean duration of sorafenib treatment was 12.8 months (range 1-56 months). The mean follow-up duration was 15.7 months (range 3-63 months).