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ORIGINAL ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 4  |  Page : 941-946

Establishment of a predictive model for short-term efficacy of transcatheter arterial chemoembolization treatment in hepatocellular carcinoma and its clinical application


Department of Interventional Radiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China

Date of Web Publication14-Aug-2019

Correspondence Address:
Zhenchang Wang
Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Beijing
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_52_19

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 > Abstract 


Objective: This study aimed to establish a predictive model for the presence of transcatheter arterial chemoembolization (TACE) resistance in hepatocellular carcinoma (HCC) Barcelona Clinic Liver Cancer classification stage B or stage C4 (BCLC B/C) and further verify its accuracy, enabling clinicians to accurately predict the efficacy of TACE and propose individualized therapy to further optimize multidisciplinary team plans.
Materials and Methods: A retrospective database review was performed, including 191 patients (39 females and 152 males; aged 50–76 years with a mean age of 55 ± 10 years) who received three consecutive TACE sessions for treating HCC (BCLC B/C) in 1 month apart, for a total of 3 months. After three TACE treatments, a total of 95 patients among the 191 patients showed TACE resistance, 112 cases were randomly selected to build the modeling group, and the remaining 79 cases formed a verification group. Some prognostic risk factors were obtained through clinical observation. Then, univariate and multivariate analyses were performed using the logistic proportional hazard regression model. Based on multivariate analysis results, a risk-index model was established and its effects on predicting the incidence of TACE resistance of those patients were evaluated.
Results: Based on the results of the multivariate analysis, to show that were four-independent factors affecting a prognosis of patients with TACE resistance after three consecutive TACE treatment in 3 months, which were red blood cell (RBC), neutrophil count (NC), model for end-stage liver disease (MELD), and Apoprotein A1. The risk index model established according to the above factors was expressed as a predictive indice (PI), and PI = −3.79 + 4.916 × RBC − 1.547 × NC − 4.142 × MELD + 10.789 × ApoA1. The area under the receiver operating characteristic curves (AUROC) of PI of the modeling group was 0.986, which was significantly higher than that of each component index in the equation. The specificity of the modeling group was 86.3%, and the sensitivity was 70.4%, and 43 of 61 patients with PI ≤ 5.36 (70.5%) had a good outcome 3 months after consecutive TACE. From of the PI, among 51 patients with TACE resistance after consecutive TACE, 32 (62.7%) had a PI > 5.36, and only 19 patients were misidentified as having TACE resistance because of their PI > 5.36. The accuracy was 82.1%. The specificity of the validation group was 85.9%, and the sensitivity was 77.9%. The disease was under control in 29 of the 35 patients with PI ≤ 5.36 (82.9%) after consecutive TACE. According to PI, among the 44 patients with TACE resistence after consecutive TACE, 38 (86.4%) had PI > 5.36, and only 6 patients were misidentified as TACE resistance due to their PI > 5.36, with an accuracy of 87.3%, respectively.
Conclusions: According to the PI of this study, we investigated the risk factors and protective factors to estimate the presence of TACE resistance after three consecutive TACE treatment, so as it could help doctors to evaluate the patientet condition and choose more reasonable treatment methods.

Keywords: Efficacy, hepatocellular carcinoma, the predictive index, transcatheter arterial chemoembolization resistance


How to cite this article:
Wei J, Wang Z. Establishment of a predictive model for short-term efficacy of transcatheter arterial chemoembolization treatment in hepatocellular carcinoma and its clinical application. J Can Res Ther 2019;15:941-6

How to cite this URL:
Wei J, Wang Z. Establishment of a predictive model for short-term efficacy of transcatheter arterial chemoembolization treatment in hepatocellular carcinoma and its clinical application. J Can Res Ther [serial online] 2019 [cited 2019 Sep 18];15:941-6. Available from: http://www.cancerjournal.net/text.asp?2019/15/4/941/264291




 > Introduction Top


In terms of tumor incidence, hepatocellular carcinoma (HCC) ranks fifth worldwide and fourth in China. Transcatheter arterial chemoembolization (TACE) is an indispensable approach in the treatment of liver cancer, especially in the middle or advanced stage. In some patients, sequential TACE failed to produce ideal outcomes. Patients could not benefit from TACE in terms of survival, and some could not even tolerate TACE treatment, and such clinical manifestations are referred to as TACE resistance. A Japanese scholar Kudo et al.[1] suggested that liver cancer patients who receive TACE once a month for 2 consecutive months and show <50% of tumor necrosis, or new lesions and vascular invasion, are considered to have developed TACE resistance. European scholar Raou et al.[2] have a different understanding of TACE resistance, defining it as the forced discontinuation of sequential TACE due to the presence of adverse drug reactions, liver function damage, and decreased physical strength after the treatment. For patients with liver cancer of middle or advanced stage who developed TACE resistance, clinicians should develop a comprehensive therapeutic regimen by means of multidisciplinary team (MDT) meetings to maximize the survival of patients, in a timely and effective manner. Therefore, the prediction of the efficacy of sequential TACE and rational choices of treatment are crucial for the prognosis of patients with liver cancer but are seldom elaborated in China and abroad. This study aimed to establish a predictive model for the presence of TACE resistance in HCC (BCLC B/C) and further verify its accuracy, enabling clinicians to accurately predict the efficacy of TACE and propose individualized therapy to further optimize MDT plans, in a timely manner.


 > Materials and Methods Top


Study design

Patient data

A total of 191 patients with chronic hepatitis B, cirrhosis, and primary HCC admitted to Beijing Ditan Hospital affiliated to Capital Medical University from July 2016 to June 2018 were retrospectively analyzed. The 95 cases of TACE resistance in a total of 191 patients were showed after three times TACE treatment. The European Association for the Study of Liver and the American Association for the Study of Liver Disease guidelines [3] served as reference for the diagnostic criteria for primary HCC. The Japan Society of Hepatology defined TACE failure or refractoriness (resistance) as ineffective response (viable HCC lesions >50%) even after two or more consecutive TACE sessions. The consecutive TACE (three times) treatment was approved by the ethics committee of the aforementioned hospital. The consents were signed by the patients before operations, including TACE and anesthesia and the complications, were proved. The study was approved by the Local Ethics Committee. This study was performed in accordance with the Declaration of Helsinki.

Inclusion criteria

  1. With Barcelona Clinic Liver Cancer classification stage B or stage C
  2. With liver function Child-Pugh class A or class B
  3. a
  4. With Eastern Cooperative Oncology Group score 0–1
  5. Without evidence of extrahepatic metastasis
  6. Who reject or cannot tolerate surgery were included
  7. With the Japan Society of Hepatology defined TACE failure or refractoriness (resistance).


Exclusion criteria

  1. Liver cancer patients who have undergone surgical resection of tumors or liver transplantation
  2. Patients who received targeted therapy such as sorafenib or systemic chemotherapy, radiofrequency ablation, microwave ablation, or radioactive seed implantation of iodine-125
  3. Patients who underwent surgical resection, liver transplantation, or radioactive seed implantation of iodine-125 after TACE or physical ablation
  4. Patients with complications or history of severe cardiac insufficiency, renal insufficiency, coagulopathy (prothrombin activity <40%), thrombocytopenia (platelet count <30 × 109/l), and malignant tumors other than primary liver cancer were excluded
  5. Patients who were unable to tolerate consecutive TACE treatment due to deterioration of liver function.


Consecutive transcatheter arterial chemoembolization treatment (three times)

The Seldinger technique was used to puncture the right femoral artery. The vascular sheath was placed, and the 5F hepatic catheter (COOK, US) was inserted into the celiac trunk. The proper hepatic artery and left and right hepatic arteries were selected for angiography to identify the tumor location, blood supply, etc. The superior mesenteric artery and the inferior phrenic artery were selected for angiography to show whether there were abnormal blood vessels outside the liver. For each case, target vessels were ultra-selected with 2.8F microcatheter (Progreat, Terumo, Tokyo, Japan). For each kilogram of body weight, patients were perfused with 20–30 mg of lobaplatin and 20–40 mg of epirubicin. The commonly used embolic agents were ethiodized poppy-seed oil (5–15 ml) and embosphere (100–300 um/300–500 um). The target vessels were completely embolized, and postembolization angiography of hepatic arteries showed the absence of tumor staining.

Follow-up

All patients underwent a review of abdominal-enhanced magnetic resonance imaging (MRI), liver function, electrolytes, renal function, blood routine, coagulation function, alpha-fetoprotein (AFP), and other laboratory indicators 1 month after the first TACE treatment. According to the modified Response Evaluation Criteria in Solid Tumors (mRECIST), patients were classified as having complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Patients with PR, SD, and PD (three of them had a Child-Pugh class C liver function and could not tolerate a second TACE [TACE2]) received the TACE2 treatment. One month after TACE2, abdominal enhanced MRI and routine laboratory indicators were reviewed. Patients with PR, SD, and PD (four of them had a Child-Pugh class C liver function and could not tolerate a TACE2) received the third TACE treatment (TACE3). Abdominal-enhanced MRI and routine laboratory indicators were reviewed 1 month after TACE3, and patients were again classified as having a CR, PR, SD, and PD according to the mRECIST. This study found 142 patients with TACE resistance (Tumor necrosis volume <50% after TACE/vascular invasion/distant metastasis/alpha-fetoprotein AFP continuously increased) in according to the definition of the Liver Cancer Study Group of Japan.

Statistical analysis

Statistical analysis was performed using the SPSS software version 19.0 (SPSS Inc, Chicago, IL, USA). The baseline characteristics of the modeling group and the verification group were statistically described separately to test whether the two groups had statistical differences and whether they were comparable. Univariate analysis was performed on all variables of the modeling groups of the three interventional treatments, and then the variables with significance were introduced into the logistic proportional hazard regression model for multivariate analysis using the forward selection method. The significance level for entry was a = 0.05, and a value of P < 0.05 was considered statistically significant.

According to the regression model obtained by multivariate analysis, the predictive indices (PI) of three consecutive TACE treatments were established, the PI values of the modeling group and the verification group for each intervention were calculated respectively, and the ROC curves were drawn, respectively. The cutoff value corresponding to the maximum Youden's index (sensitivity + specificity-1) was selected. Combining the positive predictive value, negative predictive value, and accuracy, the risk index was evaluated in terms of its predictive value of short-term efficacy of TACE in primary liver cancer.


 > Results Top


Patients' baseline information

Among the 191 patients who underwent three times consecutive TACE treatment, 152 (80%) were men and 39 (20%) were women. The age range was 50–76 years and the average age was 55 ± 10 years, as shown in [Table 1]. There was no significant difference in age, gender, major biochemical, and immunological parameters between the modeling group and the validation group (P > 0.05), indicating that they were comparable. Univariate logistic regression analysis of the consecutive TACE modeling group about 12 of the 35 covariates had an effect on the short-term efficacy of TACE in primary liver cancer (P < 0.05). Multivariate logistic regression analysis of the consecutive TACE modeling group. A multivariate analysis was performed by introducing the variables with significance in univariate analysis into the logistic proportional hazard regression model. The results showed that four prognostic factors were affecting the short-term efficacy of consecutive TACE in primary liver cancer after 3 months of treatment: The neutrophil count (NC) and model for end-stage liver disease (MELD) were risk factors for TACE resistance after treatment, and the relative risks [exp(ß)] were 0.714 and 0.143, respectively; red blood cell (RBC) count and apolipoprotein A1 (ApoA1) were protective factors for effective treatment (P < 0.05), and the relative risks [exp(ß)] were 16.932 and 2.859, respectively [Table 2].
Table 1: Influencing factors of short-term efficacy of transcatheter arterial chemoembolization in patients with Barcelona clinic liver cancer stage B/C liver cancer and their assignment

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Table 2: Cox multivariate analysis of short-term efficacy of transcatheter arterial chemoembolization 1 in the modeling group

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Based on the results of the multivariate analysis, a predictive index model (PI) was established, and PI = −3.79 + 4.916 × RBC − 1.547 × NC − 4.142 × MELD + 10.789 × ApoA1. The larger the PI value, the better the efficacy of consecutive TACE 3 months after treatment. [Figure 1] shows the ROC curves of PI of the modeling group and component indicators predicting the efficacy of consecutive TACE 3 months after treatment in primary liver cancer. [Table 3] shows the corresponding AUROC. The AUROC of PI of the modeling group was 0.986, which was significantly higher than that of each component index in the equation. The cutoff value corresponding to the maximum of the Youden's index (sensitivity + specificity-1) was selected. The cutoff value was 5.36. PI ≤ 5.36 was used as a marker of good efficacy of consecutive TACE in patients with primary liver cancer 3 months after treatment. PI > 5.36 was used as TACE resistance after the intervention. [Table 3] shows that the positive predictive value of the modeling group was 86.3%, and the specificity was 86.3%. In other words, 43 of 61 patients with PI > 5.36 (70.5%) had a good outcome 3 months after consecutive TACE. We can tell from the PI, among 51 patients with TACE resistance after consecutive TACE, 32 (62.7%) had a PI ≤ 5.36, and only 19 patients were misidentified as having TACE resistance because of their PI > 5.36. The accuracy was 82.1%. [Table 4] shows that the PPV of the validation group was 86.8%, and the specificity was 85.9%. That is, the disease was under control in 29 of the 35 patients with PI > 5.36 (82.9%) 3 months after TACE. According to PI, among the 44 patients with TACE resistance after consecutive TACE, 38 (86.4%) had a PI ≤ 5.36, and only 6 were misidentified as TACE resistance due to their PI > 5.36, with an accuracy of 87.3%.
Figure 1: Operating characteristic curves curves of PI of the modeling group and component indices predicting the presence of transcatheter arterial chemoembolization resistence after the three time of consecutive transcatheter arterial chemoembolization

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Table 3: Verification of the predictive value of the predictive index of the modeling group

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Table 4: Verification of the predictive value of the predictive index of the verification group

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 > Discussion Top


Interventional therapy for primary liver cancer often requires multiple TACE procedures. Timely evaluation of the efficacy of the consecutive TACE to avoid treatment failure is a clinical issue that needs to be solved urgently, and this is of great significance for further MDT meetings aiming to maximize the treatment efficacy. For the patients with TACE resistance, the Liver Cancer Study Group of Japan (70.8% of the scholars) recommends that the efficacy of TACE should be evaluated after two or more TACE treatments. To further explore the risk factors associated with TACE resistance and the protective factors to improve the efficacy, in this study, a total of three TACE were performed separately in patients, and the short-term efficacy of the three times of consecutive TACE was evaluated.

Three months after the consecutive TACE treatment, the efficacy was evaluated in patients with primary liver cancer. A formula of PI was established and consisted of four indicators: MELD, NC, RBC count, and ApoA1. Since its establishment, MELD has been widely used to evaluate the liver reserve function of end-stage liver disease and is considered an important risk factor for the prognosis of patients with liver cancer. Therefore, a full evaluation of MELD before the consecutive TACE will help clinicians to understand the patient's condition and take more reasonable measures to improve the prognosis of patients. Changes in NC after the consecutive TACE reflected the release of systemic chemokines and interleukins, resulting in a sustained inflammatory response. There is already a tissue inflammatory response before further malignant progression of solid tumors.[4] After localized embolization, substantial necrotic tumor tissues further promote the progression of inflammation in the inflammatory microenvironment. In turn, the inflammatory response may provide a favorable microenvironment for the occurrence, development, and metastasis of tumor cells.[5] Neutrophils recruited by the inflammatory response secrete a large number of cytokines such as vascular endothelial growth factor, tumor necrosis factor, and interleukin 1/4 to promote tumor occurrence and development, serving as an important mediator of tumor progression.[6] In addition, neutrophils can also inhibit T lymphocyte activity by producing nitric oxide, reactive oxygen species, arginase, etc., thereby weakening the T lymphocyte-based immune response and resulting in a weakened T lymphocyte-mediated tumor-killing effect.[7] The main function of RBC is to transport oxygen and carbon dioxide produced by tissues. In 1981, Siegel proposed a new concept of RBC immune system. RBC can eliminate circulatory, immune complexes through phagocytosis and resemble effector cells to inhibit tumor growth and metastasis. The liver is the main organ synthesizing ApoA1; the latter is the main structural protein of high-density lipoprotein cholesterol (HDL-C). Therefore, ApoA1 reflects the synthesis function of hepatocytes. The hepatocyte function of liver cancer patients is impaired, and various blood lipids and lipoproteins are decreased. A progressive decline in HDL-C and total cholesterol is a marker of progression and exacerbation of liver cancer. Jiang et al. reported that plasma ApoA1 is a good indicator for evaluating the protein synthesis function of the liver after hepatectomy, which can be used to evaluate liver function damage caused by liver cancer.[8] Combining the above four indicators, the predictive index model for the evaluation of the efficacy of the consecutive TACE in liver cancer patients was established. The AUROC of the modeling group was as high as 0.986, and the accuracy was 82.1%. The AUROC of the validation group was as high as 0.991, with an accuracy of 87.3%. The model has high accuracy and good repeatability, providing a reference value for predicting the efficacy of the consecutive TACE in liver cancer patients.

Three months after the three consecutive TACE treatment, every time of efficacy was evaluated according to the mRECIST. Except for patients with CR, other patients with PR, SD, and PD underwent the consecutive TACE procedure. Patients with poor liver function and progressive jaundice would not receive further TACE treatment. One month after each TACE, the abdominal enhanced MRI was reviewed, and the efficacy was evaluated according to the mRECIST. A multivariate analysis was performed by introducing the variables with significance in univariate analysis into the logistic proportional hazard regression model. The results showed that four prognostic factors were affecting the short-term efficacy of TACE in primary liver cancer. The predictive index model for PI was established based on four indicators: RBC, NC, and MELD, ApoA1. For patients with abnormally enhanced tumor lesions in the liver who also met the indications for further interventional therapy; hence, three times TACE was performed. We found that the predictive index model for PI included four indicators: RBC, NC, MELD, and ApoA1. Studies have confirmed that the progression and prognosis of liver cancer are closely related to the local microenvironment and systemic immune function. The tumor antigens released after hepatocarcinoma tissue necrosis can induce specific antitumor T lymphocyte immune response.[9] Recurrence is the main cause of postoperative death in patients with HCC. The adaptive immune cells in and adjacent to tumor tissues participate in the formation of the tumor immune microenvironment.[10] The immune function of RBCs is closely related to that of tumors. RBCs can inhibit tumor growth and diversion through to clear the circulation of immune complexes, effector cell-like effect, and phagocytosis adducts.[11] On the one hand, normal RBCs can increase the activity of lymphocyte activated killer cells and promote the latter's killing effect on tumor cells and on the other hand, they can enhance the activity of NK cells by releasing natural killer cell activation factors, thereby increasing the killing effect of NK cells on tumor cells.[12] The patient is prone to upper gastrointestinal bleeding due to portal hypertension, resulting in hemorrhagic anemia. The hypersplenic function can cause RBCs to be destroyed by mononuclear macrophages. Increased neutrophils also affect liver cancer risk factors for prognosis. The elevated neutrophils cause systemic chemokines and the release of interleukin causes a continuous inflammatory reaction and promotes swelling Tumor proliferation and angiogenesis leading to poor prognosis.[13] The liver is the main synthesis site of apolipoprotein, which is the main structural protein of HDL-C and can directly reflect the level of HDL-C.[14] The level of plasma ApoA1 is a good indicator to evaluate the liver protein synthesis ability during the perioperative period after hepatectomy and can be regarded as an indicator to evaluate the degree of liver damage caused by liver cancer. Due to the deterioration of liver function in liver cancer patients, many kinds of blood lipids and lipoproteins have been reduced. The progressive reduction of HDL-C and total cholesterol concentrations is a criterion for the progression of liver cancer. Low-density lipoprotein cholesterol (LDL-C) was negatively correlated with the prognosis of liver cancer. Studies show plasma LDL-C in patients with liver cancer have increased significantly, the latter possibly by association with fibrinogen Competitive binding sites to inhibit fibrinolysis and promote platelet adhesion attachment and thrombosis, and elevated LDL-C can help promote tumor cell proliferation.[15],[16] It was reported that the increased MELD score had a role in determining the prognosis of cirrhosis and upper gastrointestinal hemorrhage and evaluating the risk of recurrence of hemorrhage. However, in patients with HCC, upper gastrointestinal hemorrhage was related to portal hypertension caused by cirrhosis. It may also be related to portal hypertension caused by tumor compression portal vein or portal vein cancer embolismand hence, a simple MELD score may underestimate the risk of death in HCC patients.[17],[18] For the treatment of advanced HCC, argon-helium cryoablation combined with TACE is obviously effective and safe. The ages, tumor diameter, tumor periportal location, and grade of liver function (Child-Pugh) have obviously impacted the treatment effectiveness.[19]

Primary liver cancer is regulated by a variety of genes. The pathogenesis of liver cancer is extremely complicated. Therefore, we can also think of liver cancer as a disease group. In summary, the prognostic factors of liver cancer vary in different stages during interventional treatment. Given such conclusion, clinicians may further investigate TACE resistance from the perspective of clinical parameters, and actively apply clinical interventions according to the risk factors and protective factors affecting the therapeutic efficacy, to maximize the therapeutic efficacy. In this study, there were more HCC patients with BCLC C, which belongs to advanced liver cancer and it may increase the incidence of TACE resistance to some extent.


 > Conclusions Top


According to the PI of this study, we investigated the risk factors and protective factors to estimate the presence of TACE resistance after three consecutive TACE treatment, so as it could help doctors to evaluate the patient's condition and choose more reasonable treatment methods.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Zhong JH, Rodríguez AC, Ke Y, Wang YY, Wang L, Li LQ, et al. Hepatic resection as a safe and effective treatment for hepatocellular carcinoma involving a single large tumor, multiple tumors, or macrovascular invasion. Medicine (Baltimore) 2015;94:e396.  Back to cited text no. 10
    
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Pinato DJ, Sharma R. An inflammation-based prognostic index predicts survival advantage after transarterial chemoembolization in hepatocellular carcinoma. Transl Res 2012;160:146-52.  Back to cited text no. 13
    
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Tietge UJ, Boker KH, Bahr MJ, Weinberg S, Pichlmayr R, Schmidt HH, et al. Lipid parameters predicting liver function in patients with cirrhosis and after liver transplantation. Hepatogastroenterology 1998;45:2255-60.  Back to cited text no. 14
    
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