Abstract
This study aimed to evaluate the efficacy and safety of drug-eluting bead transarterial chemoembolization (DEB-TACE), and to explore its prognostic factors in elderly Chinese hepatocellular carcinoma (HCC) patients. 93 elderly HCC patients undergoing DEB-TACE were prospectively enrolled. Treatment response was assessed by mRECIST criteriaat1 month post DEB-TACE treatment, and progression free survival (PFS) and overall survival (OS) were calculated. Liver function and adverse events (AEs) within 1 month post DEB-TACE were documented. Complete response (CR) rate and objective response rate (ORR) were 18.3% and 87.1%, respectively. Additionally, medians of PFS and OS were 9.0 months and 21.0 months, respectively. Multivariate logistic regression revealed that no factor independently predicted CR achievement, while tumor size ≥5.0 cm and AFP abnormal were independent factors for predicting both shorter PFS and OS, and higher BCLC stage was an independent predictive factor for unfavorable OS. As to safety profiles, the percentages of patients with abnormal TBIL, ALT, AST, and ALP were increased at 1 week, while they were not different at 1 month post DEB-TACE treatment compared with baseline. Most frequent AEs were pain, fever, nausea or vomiting; skin discolorations, myelosuppression, and other AEs were relatively rare. In conclusion, DEB-TACE was efficient and well tolerated in elderly HCC patients, and increased tumor size, abnormal AFP, as well as higher BCLC stage could be independent markers for predicting worse prognosis.
Keywords: Elderly, hepatocellular carcinoma (HCC), drug-eluting beads transarterial chemoembolization (DEB-TACE), efficacy, safety, prognostic factor
Introduction
Liver cancer is a common malignancy, ranking as the sixth most common neoplasm and the second leading cause of cancer death worldwide [1]. According to epidemiologic data, 782,500 new cases and 745,500 deaths of liver cancer occured during 2012 worldwide, with China alone accounting for about 50% of the total number of new cases and deaths [2]. Among all the liver cases, hepatocellular carcinoma (HCC) is the most frequent subtype accounting for about 90% of all primary cases [3]. It’s considered that early diagnosis and early use of comprehensive treatments based on surgical resection are the keys to improve the long-term survival of HCC patients, but the early symptoms of HCC are occult, thus most patients are diagnosed in the intermediate or advanced stages which are not suitable for surgical treatment [4]. In addition, Asian patients tend to have chronic viral hepatitis and cirrhosis, which largely reduces the portion of patients suitable for resection [5,6]. Thus, it is essential to explore more treatment options for HCC patients with intermediate or advanced stages.
Transarterial chemoembolization (TACE) is the most commonly used local-regional treatment for unresectable HCC [7-9]. Drug-eluting beads (DEB)-TACE, as developed in the latest decade, is one type of TACE that uses microbeads as carriers to deliver chemotherapeutic drugs and to embolize tumor feeding arteries [10]. Compared with traditional TACE, DEB-TACE has the unique properties of improving delivery efficiency and eliminating systemic toxicity [11,12]. Several reports observe that DEB-TACE has good efficacy and safety in the treatment of most HCC patients, while studies evaluating its application in treating elderly Chinese HCC patients is rare [13-15]. Therefore, this study aimed to investigate the efficacy and safety of DEB-TACE, and to explore its prognostic factors in elderly Chinese HCC patients.
Materials and methods
Patients
93 elderly Chinese HCC patients about to receive DEB-TACE treatment between Feb 2015 and Mar 2017 in Zhejiang Cancer Hospital were consecutively enrolled in this prospective cohort study. The inclusion criteria were: (1) Diagnosis as primary HCC confirmed by pathologic findings, clinical features, or radiographic examinations according to American Association for the Study of the Liver Diseases (AASLD) guidelines; (2) Age above 65 years; (3) About to receive DEB-TACE treatment with DC Beads® according to clinical needs and personal willingness; (4) Life expectancy more than 12 months. The exclusion criteria were as follows: (1) Contraindication for angiography, embolization procedure or artery punctures; (2) Severe liver dysfunction (Child-Pugh stage C) including jaundice, hepatic encephalopathy, refractory ascites, and hepatorenal syndrome; (3) History of liver transplantation; (4) Renal dysfunction: creatinine >2 mg/dL or creatinine clearance rate <30 mL/min; (5) History of severe infection or hematological malignances; (6) Unlikely to be followed up regularly.
Ethics
This study was approved by the Institution Review Board of Zhejiang Cancer Hospital and conducted in accordance with Declaration of Helsinki. All the patients or their legal guardians provided the written informed consent.
Data collection
Baseline characteristics of demography and clinical pathology were collected from all patients, which included age, gender, history of hepatitis B virus (HBV) and cirrhosis, cycles of TACE treatment, previous cTACE, previous surgery, previous systematic chemotherapy, previous radiofrequency ablation, Barcelona Clinic Liver Cancer (BCLC) stage, Child-Pugh stage, Eastern Cooperative Oncology Group (ECOG) performance status, tumor distribution, tumor size, tumor location, vein invasion, alpha fetoprotein (AFP), carcinoembryonic antigen (CEA) and carbohydrate antigen 199 (CA199).
Procedure of DEB-TACE treatment
In the present study, all patients received DEB-TACE treatment on demand according to clinical conditions and patients’ willing, and the DC Beads (DC-Beads®, British Technology Group, UK) with the diameter of 100 μm to 300 μm were used as carriers, which were loaded with anthracyclines (80 mg). The detailed processes of DEB-TACE were as follows: (1) Loading of chemoembolization reagent: Before the start of loading, the chemoembolization reagent was dissolved to solution (20 mg/ml) and extracted into a 10 ml syringe. One bottle of DC beads was shaken and then the beads suspension was extracted into a 20 ml syringe, which was left at room temperature (RT) for 5 mins, after which the liquid supernatant was pushed out, so the beads remained in the syringe. Subsequently, the chemotherapy reagent solution was mixed with the beads by a tee joint, after which the non-ionic contrast agent was administered into the syringe containing beads and chemotherapy reagent solution at the ratio of 1:1, and the mixture was placed for 30 minutes at RT for further application. Ordinary embolization agents were used if the embolization point was not reached after a bottle of DC Beads was emptied. (2) Implement of DEB-TACE treatment: Digital subtraction angiography (DSA) was performed to exactly define the location of the tumor and its feeding arteries, and then a 2.4 F microcatheter (Merit Maestro®, Merit Medical System, Inc., USA) was inserted into the identified tumor feeding artery leaded by a microwire under the guidance of computer tomography (CT). Subsequently, the prepared beads were delivered at the speed of 1 ml/min through the microcatheter to the artery. As soon as stasis or reflux of the contrast agent was observed during the procedure, the chemoembolization was terminated, which was followed by a second angiography in order to detect the residual blush of tumor. The embolization procedure was repeated if the blush of tumor still occurred and stopped until no more blush of tumor was observed.
Assessment and definition of treatment response
One month after DEB-TACE treatment, all patients underwent enhanced magnetic resonance imaging (MRI) or CT examination. And the modified Response Evaluation Criteria in Solid Tumors (mRECIST) was used to assess treatment response of DEB-TACE treatment. The mRECIST embraced the following four response categories: Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD), which were defined as follows: (1) CR: no existence of arterial enhancement of targeted tumors; (2) PR: the decrease in diameter of targeted tumor (with arterial enhancement) ≤30%; (3) SD: the decrease in diameter of targeted tumor (with arterial enhancement) did not achieve PR or less than PD; (4) PD: the increase in diameter of targeted tumor (with arterial enhancement) ≥20% or new tumor existed. Moreover, objective response rate (ORR) was defined as the percentage of patients with CR plus patients with PR.
Assessment of survival
Progression free survival (PFS) and overall survival (OS) were analyzed in this study. PFS was calculated from the date of DEB-TACE treatment to the date of progression or death from any cause, and OS was calculated from the date of DEB-TACE treatment to the date of death from any cause. The median follow-up duration was 16.0 months (range: 2.0-32.0 months) and the last follow up date was Oct 30th, 2017.
Liver function assessments and adverse events
Examinations of liver function indexes including total bilirubin (TBIL), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were performed before DEB-TACE treatment, at 1 week and 1 month post DEB-TACE treatment to evaluate the influence of DEB-TACE on liver function. Assessments of liver function were based on the treatment records of DEB-TACE (N=121). In addition, adverse events (AEs) occurring within 1 month post DEB-TACE treatment were also recorded.
Statistics
Statistical analysis was performed using SPSS 22.0 software (IBM, USA), and graphs were drawn by Graphpad Prism 6.01 software (GraphPad Software Inc, USA). Data were mainly presented as mean value ± standard deviation or count (percentage). Kaplan-Meier (K-M) curve was used to describe the PFS and OS, and then comparison of PFS and OS between/among subgroups was determined by log-rank test. Univariate and multivariate logistic regression analysis was performed to determine the predicting value of baseline factors for CR achievement. Univariate and multivariate Cox regression analysis was used to evaluate the predictive factors for PFS and OS. P<0.05 was considered significant.
Results
Baseline characteristics of elderly HCC patients
As listed in Table 1, 93 elderly HCC patients (75 male and 18 female) with mean age 70.4±4.6 years were enrolled in this study. 76 (81.7%) cases had history of HBV and 58 (62.4%) cases had history of cirrhosis. There were 60 (64.5%) patients who had multifocal disease, 46 (49.5%) patients had tumor size ≥5.0 cm, and 29 (31.2%) patients had vein invasion. The numbers of patients in ECOG performance status 0, 1, 2 and 3 were 60 (64.5%), 31 (33.3), 1 (1.1%) and 1 (1.1%), respectively. 80 (86.0%) patients were at Child-Pugh stage A and 13 (14.0%) patients were at stage Child-Pugh B. In addition, there were 24 (25.8%), 38 (40.9%) and 31 (33.3%) patients at BCLC stage A, B and C, respectively. The other detailed clinicopathological characteristics, biochemical indexes and treatment history of elderly HCC patients were presented in Table 1.
Table 1.
Baseline characteristics of elderly patients with HCC who underwent DEB-TACE treatment
| Measurement | Elderly HCC Patients (N=93) |
|---|---|
| Age (years) | 70.4±4.6 |
| Gender (male/female) | 75/18 |
| History of HBV (n/%) | 76 (81.7) |
| History of cirrhosis (n/%) | 58 (62.4) |
| Number of tumors (n/%) | |
| Unifocal | 33 (35.5) |
| Multifocal | 60 (64.5) |
| Tumor location (n/%) | |
| Unilobar | 70 (75.3) |
| Bilobar | 23 (24.7) |
| Tumor size ≥5.0 cm (n/%) | 46 (49.5) |
| Vein invasion (n/%) | 29 (31.2) |
| ECOG performance status (n/%) | |
| 0 | 60 (64.5) |
| 1 | 31 (33.3) |
| 2 | 1 (1.1) |
| 3 | 1 (1.1) |
| Child-Pugh stage (n/%) | |
| A | 80 (86.0) |
| B | 13 (14.0) |
| BCLC stage (n/%) | |
| A | 24 (25.8) |
| B | 38 (40.9) |
| C | 31 (33.3) |
| Cycles of DEB-TACE treatment (n/%) | |
| 1 cycle | 75 (80.6) |
| ≥2 cycles | 18 (19.4) |
| AFP (n/%) | |
| Normal | 29 (31.2) |
| Abnormal | 51 (54.8) |
| Unknown | 13 (14.0) |
| CEA (n/%) | |
| Normal | 55 (59.1) |
| Abnormal | 17 (18.3) |
| Unknown | 21 (22.6) |
| CA199 (n/%) | |
| Normal | 47 (50.5) |
| Abnormal | 25 (26.9) |
| Unknown | 21 (22.6) |
| Previous treatments (n/%) | |
| cTACE | 34 (36.6) |
| Surgery | 20 (21.5) |
| Systematic chemotherapy | 2 (2.2) |
| Radiofrequency ablation | 10 (10.8) |
Data are presented as mean ± standard deviation or count (percentage). HCC, hepatocellular carcinoma; DEB-TACE, drug-eluting bead transarterial chemoembolization; HBV, hepatitis B virus; cTACE, conventional transarterial chemoembolization; ECOG, Eastern Cooperative Oncology Group; BCLC, Barcelona Clinic Liver Cancer; AFP, alpha fetoprotein; CEA, carcinoembryonic antigen; CA199, carbohydrate antigen 199.
Treatment response to DEB-TACE in elderly HCC patients
As displayed in Figure 1, after DEB-TACE treatment, 17 (18.3%) patients achieved CR and 64 (68.8%) patients achieved PR, and the ORR was 87.1%. Additionally, the numbers of patients were SD and PD were 7 (7.5%) and 5 (5.4%), respectively.
Figure 1.
Treatment responses of DEB-TACE treatment in elderly HCC patients. The percentages of patients achieving CR, PR, ORR, SD and PD in elderly HCC patients 1 month after DEB-TACE treatment were 18.3%, 68.8%, 87.1%, 7.5% and 5.4%, respectively. DEB-TACE, drug-eluting bead transarterial chemoembolization; HCC, hepatocellular carcinoma; CR, complete response; PR, partial response; ORR, objective response rate; SD, stable disease; PD, progressive disease.
The PFS and OS of elderly HCC patients underwent DEB-TACE
K-M curve illustrated that the median PFS of elderly HCC patients was 9.0 months with 95% confidence interval (CI): 7.4-10.6 months (Figure 2A), and the median OS was 21.0 months with 95% CI: 18.4-23.6 months (Figure 2B).
Figure 2.
PFS and OS of DEB-TACE treatment. Median PFS was 9.0 months (95% CI: 7.4-10.6 months) (A), and median OS was 21.0 months (95% CI: 18.4-232.6 months) (B) in elderly HCC patients post DEB-TACE treatment. The PFS and OS were evaluated by K-M curve. PFS, progression free survival; OS, overall survival; DEB-TACE, drug-eluting beads transcatheter hepatic arterial chemoembolization; K-M, Kaplan-Meier.
Correlation of baseline characteristics with PFS and OS by K-M curve analysis
In order to investigate the correlation of baseline characteristics with PFS and OS, patients were divided into subgroups according to their baseline parameters, and K-M curves were drawn and log-rank test was performed. As listed in Figure 3, tumor size ≥5 cm (P<0.001, Figure 3A), vein invasion (P=0.025, Figure 3B), higher BCLC stage (P<0.001, Figure 3C), Child-Pugh stage B (P=0.003, Figure 3D), AFP abnormal (P=0.035, Figure 3E) and previous radiofrequency ablation (P=0.014, Figure 3F) were associated with worse PFS.
Figure 3.
Comparison of PFS between/among subgroups. Elderly HCC patients with tumor size ≥5.0 cm (A), vein invasion (B), higher BCLC stage (C), Child-Pugh stage B (D), AFP abnormality (E) and previous radiofrequency ablation (F) had shorter PFS. Comparison of PFS between/among groups was determined by K-M curve and Log-rank test. P<0.05 was considered significant. HCC, hepatocellular carcinoma; PFS, progression free survival; BCLC, Barcelona Clinic Liver Cancer; AFP, alpha fetoprotein; K-M, Kaplan-Meier.
As to OS (Figure 4), tumor size ≥5 cm (P<0.001, Figure 3A), vein invasion (P<0.001, Figure 4B), higher BCLC stage (P<0.001, Figure 3C), Child-Pugh stage B (P=0.047, Figure 4D) and AFP abnormal (P=0.035, Figure 4E) were correlated with unfavorable OS. No correlation of other baseline characteristics with PFS and OS was observed.
Figure 4.
Comparison of OS between/among subgroups. Elderly HCC patients with tumor size ≥5.0 cm (A), vein invasion (B), BCLC stage B/C (C), Child-Pugh stage B (D) and AFP abnormality (E) were discovered to have poorer OS. Comparison of OS between/among groups was determined by K-M curve and Log-rank test. P<0.05 was considered significant. OS, overall survival; HCC, hepatocellular carcinoma; BCLC, Barcelona Clinic Liver Cancer; AFP, alpha fetoprotein; K-M, Kaplan-Meier.
Factors affecting CR achievement in elderly HCC patients
As listed in Table 2, univariate logistic regression and multivariate logistic regression analysis was used to detect the factors affecting CR achievement and the results showed that multifocal (P=0.031), vein invasion (P=0.035) and higher BCLC stage (P=0.014) were factors that predicted absence of CR, but no independent predictive factor for CR achievement was found according to multivariate logistic regression analysis.
Table 2.
Factors affecting CR achievement by univariate and multivariate logistic regression analysis
| Measurement | Univariate logistic regression | Multivariate logistic regression | ||||||
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| P value | OR | 95% CI | P value | OR | 95% CI | |||
|
|
|
|||||||
| Lower | Higher | Lower | Higher | |||||
| Age (≥70 years vs <70 years) | 0.512 | 0.700 | 0.241 | 2.031 | 0.481 | 0.562 | 0.113 | 2.798 |
| Gender (male vs female) | 0.388 | 2.000 | 0.414 | 9.662 | 0.601 | 2.034 | 0.142 | 29.115 |
| History of HBV | 0.448 | 1.844 | 0.380 | 8.952 | 0.394 | 0.345 | 0.030 | 3.998 |
| History of cirrhosis | 0.441 | 1.565 | 0.501 | 4.895 | 0.069 | 6.303 | 0.868 | 45.764 |
| Number of tumors (multifocal vs unifocal) | 0.031 | 0.304 | 0.103 | 0.897 | 0.649 | 0.636 | 0.091 | 4.458 |
| Tumor location (bilobar vs unilobar) | 0.899 | 0.923 | 0.268 | 3.174 | 0.545 | 1.908 | 0.236 | 15.432 |
| Tumor size ≥5.0 cm | 0.451 | 0.664 | 0.229 | 1.927 | 0.848 | 0.834 | 0.130 | 5.352 |
| Vein invasion | 0.035 | 0.107 | 0.013 | 0.852 | 0.275 | 0.238 | 0.018 | 3.128 |
| Higher ECOG performance status | 0.843 | 1.095 | 0.444 | 2.703 | 0.639 | 1.535 | 0.256 | 9.194 |
| Child-Pugh stage (B vs A) | 0.308 | 0.333 | 0.040 | 2.756 | 0.704 | 0.433 | 0.006 | 32.641 |
| Higher BCLC stage | 0.014 | 0.388 | 0.182 | 0.828 | 0.265 | 0.408 | 0.085 | 1.973 |
| DEB-TACE treatment (≥2 cycles vs 1 cycle) | 0.631 | 1.363 | 0.386 | 4.813 | 0.420 | 2.491 | 0.270 | 22.941 |
| AFP abnormal | 0.299 | 0.563 | 0.190 | 1.668 | 0.948 | 0.944 | 0.167 | 5.341 |
| CEA abnormal | 0.079 | 0.152 | 0.019 | 1.247 | 0.219 | 0.150 | 0.007 | 3.093 |
| CA199 abnormal | 0.273 | 0.498 | 0.143 | 1.731 | 0.371 | 0.448 | 0.077 | 2.602 |
| Previous cTACE | 0.905 | 0.935 | 0.312 | 2.805 | 0.862 | 1.165 | 0.207 | 6.541 |
| Previous surgery | 0.384 | 1.694 | 0.517 | 5.550 | 0.254 | 3.428 | 0.413 | 28.463 |
| Previous systematic chemotherapy | 0.284 | 4.687 | 0.278 | 78.946 | - | - | - | - |
| Previous radiofrequency ablation | - | - | - | - | - | - | - | - |
Data are presented as P value, OR (odds ratio) and 95% CI (confidence interval). BCLC stage was scored as: A=1, B=2, C=3. For the variable “Previous radiofrequency ablation”, “-” indicated that there was no statistical effectiveness in univariate and multivariate logistic regression model analysis due to the lack of effective events. For the variable “Previous systematic chemotherapy”, “-” indicated that there was no statistical effectiveness in multivariate logistic regression model analysis due to the lack of effective events. P value <0.05 was considered significant. CR, complete response; DEB-TACE, drug-eluting bead transarterial chemoembolization; cTACE, conventional transarterial chemoembolization; ECOG, Eastern Cooperative Oncology Group; BCLC, Barcelona Clinic Liver Cancer; AFP, alpha fetoprotein; CEA, carcinoembryonic antigen; CA199, carbohydrate antigen 199.
Factors affecting PFS in elderly HCC patients
To explore the factors for predicting PFS, univariate Cox regression was performed, and tumor size ≥5.0 cm (P<0.001), vein invasion (P=0.013), higher BCLC stage (P<0.001), Child-Pugh stage B (P=0.007), AFP abnormality (P=0.050), and previous radiofrequency ablation (P=0.022) were disclosed to be correlated with worse PFS, while multivariate Cox regression revealed that only tumor size ≥5.0 cm (P=0.002) and AFP abnormality (P=0.038) were independent factors for predicting shorter PFS (Table 3).
Table 3.
Factors affecting PFS by univariate and multivariate Cox proportional hazards regression model analysis
| Measurement | Univariate Cox’s regression | Multivariate Cox’s regression | ||||||
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| P value | HR | 95% CI | P value | HR | 95% CI | |||
|
|
|
|||||||
| Lower | Higher | Lower | Higher | |||||
| Age (≥70 years vs <70 years) | 0.867 | 1.037 | 0.677 | 1.589 | 0.871 | 0.950 | 0.508 | 1.773 |
| Gender (male vs female) | 0.735 | 0.905 | 0.507 | 1.615 | 0.846 | 1.085 | 0.476 | 2.472 |
| History of HBV | 0.729 | 1.102 | 0.638 | 1.903 | 0.922 | 0.949 | 0.327 | 2.747 |
| History of cirrhosis | 0.918 | 0.977 | 0.627 | 1.523 | 0.689 | 0.865 | 0.424 | 1.762 |
| Number of tumors (multifocal vs unifocal) | 0.207 | 1.334 | 0.852 | 2.090 | 0.682 | 0.871 | 0.449 | 1.690 |
| Tumor location (bilobar vs unilobar) | 0.102 | 1.522 | 0.920 | 2.519 | 0.777 | 1.130 | 0.485 | 2.630 |
| Tumor size ≥5.0 cm | <0.001 | 2.594 | 1.650 | 4.079 | 0.002 | 3.179 | 1.504 | 6.716 |
| Vein invasion | 0.013 | 1.856 | 1.142 | 3.017 | 0.981 | 0.991 | 0.466 | 2.109 |
| Higher ECOG performance status | 0.144 | 1.317 | 0.910 | 1.908 | 0.651 | 1.144 | 0.639 | 2.047 |
| Higher BCLC stage | <0.001 | 1.775 | 1.327 | 2.375 | 0.060 | 1.759 | 0.977 | 3.167 |
| Child-Pugh stage (B vs A) | 0.007 | 2.336 | 1.265 | 4.315 | 0.087 | 2.840 | 0.858 | 9.398 |
| DEB-TACE treatment (≥2 cycles vs 1 cycle) | 0.729 | 1.102 | 0.636 | 1.910 | 0.576 | 1.273 | 0.547 | 2.963 |
| AFP abnormality | 0.050 | 1.614 | 1.000 | 2.607 | 0.038 | 2.026 | 1.038 | 3.951 |
| CEA abnormality | 0.256 | 0.701 | 0.379 | 1.294 | 0.253 | 0.588 | 0.236 | 1.463 |
| CA199 abnormality | 0.966 | 0.989 | 0.585 | 1.669 | 0.884 | 1.053 | 0.524 | 2.117 |
| Previous cTACE | 0.500 | 1.164 | 0.749 | 1.810 | 0.412 | 1.300 | 0.695 | 2.433 |
| Previous surgery | 0.782 | 1.075 | 0.643 | 1.798 | 0.339 | 1.516 | 0.646 | 3.554 |
| Previous systematic chemotherapy | 0.592 | 1.474 | 0.357 | 6.077 | 0.263 | 0.233 | 0.018 | 2.982 |
| Previous radiofrequency ablation | 0.022 | 2.213 | 1.122 | 4.364 | 0.849 | 1.121 | 0.345 | 3.639 |
Data are presented as P value, HR (hazards ratio) and 95% CI (confidence interval). BCLC stage was scored as: A=1, B=2, C=3. P value <0.05 was considered significant. PFS, progression free survival; DEB-TACE, drug-eluting bead transarterial chemoembolization; cTACE, conventional transarterial chemoembolization; ECOG, Eastern Cooperative Oncology Group; BCLC, Barcelona Clinic Liver Cancer; AFP, alpha fetoprotein; CEA, carcinoembryonic antigen; CA199, carbohydrate antigen 199.
Factors affecting OS in elderly HCC patients
As shown in Table 4, univariate Cox regression analysis was performed showing that tumor size ≥5.0 cm (P<0.001), vein invasion (P<0.001), higher BCLC stage (P<0.001) and AFP abnormality (P=0.005) were associated with poorer OS. Multivariate Cox regression analysis revealed that tumor size ≥5.0 cm (P=0.001), higher BCLC stage (P=0.022), and AFP abnormality (P=0.001) were independent factors for predicting worse OS.
Table 4.
Factors affecting OS by univariate and multivariate Cox proportional hazards regression model analysis
| Measurement | Univariate Cox regression | Multivariate Cox regression | ||||||
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| P value | HR | 95% CI | P value | HR | 95% CI | |||
|
|
|
|||||||
| Lower | Higher | Lower | Higher | |||||
| Age (≥70 years vs <70 years) | 0.433 | 1.255 | 0.712 | 2.214 | 0.301 | 1.547 | 0.677 | 3.539 |
| Gender (male vs female) | 0.270 | 0.682 | 0.345 | 1.347 | 0.810 | 1.150 | 0.368 | 3.593 |
| History of HBV | 0.834 | 0.930 | 0.473 | 1.829 | 0.188 | 0.433 | 0.124 | 1.505 |
| History of cirrhosis | 0.945 | 1.021 | 0.566 | 1.842 | 0.489 | 0.691 | 0.242 | 1.971 |
| Number of tumors (multifocal vs unifocal) | 0.494 | 1.236 | 0.673 | 2.270 | 0.433 | 0.659 | 0.232 | 1.870 |
| Tumor location (bilobar vs unilobar) | 0.123 | 1.703 | 0.865 | 3.353 | 0.979 | 0.982 | 0.246 | 3.917 |
| Tumor size ≥5.0 cm | <0.001 | 3.058 | 1.643 | 5.693 | 0.001 | 6.454 | 2.057 | 20.248 |
| Vein invasion | <0.001 | 3.770 | 1.921 | 7.400 | 0.410 | 1.570 | 0.537 | 4.589 |
| Higher ECOG performance status | 0.303 | 1.312 | 0.782 | 2.200 | 0.409 | 1.467 | 0.591 | 3.643 |
| Higher BCLC stage | <0.001 | 2.436 | 1.635 | 3.629 | 0.022 | 2.606 | 1.151 | 5.898 |
| Child-Pugh stage (B vs A) | 0.057 | 2.252 | 0.976 | 5.196 | 0.330 | 2.229 | 0.445 | 11.164 |
| DEB-TACE treatment (≥2 cycles vs 1 cycle) | 0.818 | 1.090 | 0.523 | 2.270 | 0.751 | 1.233 | 0.339 | 4.483 |
| AFP abnormality | 0.005 | 2.816 | 1.366 | 5.805 | 0.001 | 7.180 | 2.205 | 23.385 |
| CEA abnormality | 0.532 | 1.274 | 0.596 | 2.727 | 0.495 | 1.467 | 0.488 | 4.408 |
| CA199 abnormality | 0.768 | 1.108 | 0.561 | 2.191 | 0.969 | 1.021 | 0.362 | 2.878 |
| Previous cTACE | 0.576 | 0.839 | 0.453 | 1.553 | 0.922 | 0.953 | 0.359 | 2.527 |
| Previous surgery | 0.752 | 1.116 | 0.566 | 2.198 | 0.769 | 1.108 | 0.558 | 2.200 |
| Previous systematic chemotherapy | 0.853 | 1.207 | 0.165 | 8.837 | 0.889 | 1.154 | 0.154 | 8.643 |
| Previous radiofrequency ablation | 0.360 | 1.637 | 0.570 | 4.706 | 0.406 | 0.496 | 0.095 | 2.592 |
Data were presented as P value, HR (hazards ratio) and 95% CI (confidence interval). BCLC stage was scored as: A=1, B=2, C=3. P value <0.05 was considered significant. OS, overall survival; DEB-TACE, drug-eluting bead transarterial chemoembolization; cTACE, conventional transarterial chemoembolization; ECOG, Eastern Cooperative Oncology Group; BCLC, Barcelona Clinic Liver Cancer; AFP, alpha fetoprotein; CEA, carcinoembryonic antigen; CA199, carbohydrate antigen 199.
Influence of DEB-TACE treatment on liver function in elderly HCC patients
In this study, the liver function related laboratory indexes of 121DEB-TACE records before, after 1 week and 1 month of treatment DEB-TACE were documented, and the results are shown in Table 5. The percentage of patients with TBIL abnormality (P=0.002), ALT abnormality (P<0.001), AST abnormality (P<0.001) and ALP abnormality (P<0.001) were all increased at 1 week post DEB-TACE treatment compared with baseline, while no difference of the percentage of patients with abnormal TBIL, ALT, AST and ALP at 1 month after DEB-TACE treatment compared to baseline was found (all P>0.05).
Table 5.
Liver function before and after DEB-TACE treatment (121 DEB-TACE records)
| Baseline | 1 week post DEB-TACE | 1 months post DEB-TACE | P value* | P value# | |
|---|---|---|---|---|---|
| TBIL abnormal (n/N/%) | 40/120 (33) | 53/105 (51) | 28/113 (25) | 0.002 | 0.064 |
| ALT abnormal (n/N/%) | 23/120 (19) | 59/105 (56) | 18/113 (16) | <0.001 | 0.383 |
| AST abnormal (n/N/%) | 50/120 (42) | 67/102 (66) | 42/112 (38) | <0.001 | 0.281 |
| ALP abnormal (n/N/%) | 41/119 (35) | 61/112 (55) | 42/102 (41) | <0.001 | 0.143 |
Data are presented as count (percentage). Comparison was determined by McNemar test. P<0.05 was considered significant.
P value: 1 week post DEB-TACE vs baseline;
P value: 1 months post DEB-TACE vs baseline.
DEB-TACE, drug-eluting bead transarterial chemoembolization; TBIL, total bilirubin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase.
Safety assessment
The AEs of 121 DEB-TACE records during 1 month post DEB-TACE treatment were recorded, and the results exhibited that 83 (68.6%) cases had pain, 51 (42.1%) cases presented with fever, and 38 (31.4%) cases had nausea or vomiting (Table 6). In addition, there were 3 (3.0%), 2 (2.0%) and 10 (8.3%) cases presented with skin discoloration, myelosuppression, and other AEs, respectively.
Table 6.
Adverse events occurring within one month after DEB-TACE treatment (121 DEB-TACE records)
| Items | n (%) |
|---|---|
| Pain | 83 (68.6) |
| Fever | 51 (42.1) |
| Nausea or vomiting | 38 (31.4) |
| Skin discoloration | 3 (3) |
| Myelosuppression | 2 (2) |
| Others | 10 (8.3) |
Data are presented as count (percentage). DEB-TACE, drug-eluting bead transarterial chemoembolization.
Discussion
This study illuminated that: (1) DEB-TACE treatment achieved 18.3% CR rate and 87.1% ORR in elderly HCC patients. (2) Elderly HCC patients had median PFS 9.0 months (95% CI: 7.4-10.6 months) and median OS 21.0 moths (95% CI: 18.4-23.6 months) post DEB-TACE. (3) Subgroup analysis of PFS and OS exhibited that elderly HCC patients with tumor size ≥5.0 cm, vein invasion, higher BCLC stage, Child-Pugh stage B, and AFP abnormal had both shorter PFS and OS, and the patients with previous radiofrequency ablation had worse PFS. The multivariate Cox regression analysis elucidated that tumor size ≥5.0 cm and AFP abnormal were independent predicting factors for both poorer PFS as well as OS, and higher BCLC stage was an independent factor for predicting worse OS. (4) Compared with baseline, elderly HCC patients’liver function related laboratory indexes deteriorated after 1 week of DEB-TACE treatment, while no change in liver function related laboratory indexes was observed after 1 moth of treatment. (5) The most common AEs within 1 month after treatment were pain, fever, nausea and vomiting, while skin discoloration and myelosuppression were rare in our study.
TACE is one of the most commonly used treatments for HCC patients who are not suitable for surgery. It aims to realize tumor necrosis effect by blocking the tumor supplying vessel and delivering antitumor drugs [8,9]. Conventional TACE involves the use of lipiodol, chemotherapy drugs, and embolization of the tumor-supplying vessel with gel-foam or particles [16]. However, the liquid motility of lipiodol reduces the effective concentration of antitumor drugs, and the inability to control drug release precisely renders the conventional TACE ineffective in many cases [17-19]. DEB-TACE, a modified version of conventional TACE, uses antitumor drug loaded microbeads with diameter of 100-1000 μm to slowly release drugs to the targeted tumor and meanwhile blocks the tumor-supplying vessel, achieving increased and more sustained drug concentration and less systemic toxicity in HCC patients compared with conventional TACE [20]. Cumulative studies show that DEB-TACE has a good efficacy in treating patients with HCC. For example, a single-center, prospective cohort study reveals a midterm CR rate of 28.6% and an ORR of 71.4% in 28 HCC patients treated with DEB-TACE [21]. Another prospective cohort study illuminates that the ORR is 60% at 1 month post DEB-TACE treatment in 57 HCC patients [22]. In a study aimed to evaluate the efficacy of DEB-TACE as bridge therapy for HCC patients undergoing liver transplantation, 40% and 73% of the patients achieves CR and ORR, respectively [23]. However, since these previous studies did not enroll entirely elderly HCC patients, to our knowledge, there is still no study aiming to evaluate the treatment response of elderly HCC patients to DEB-TACE. In the present study, we found that the CR and ORR were 18.3% and 87.1% to DEB-TACE treatment in elderly Chinese HCC patients. The discrepancy of treatment response rates between our study and previous studies might be derived from the distinct eligibility criteria, different patients with distinctive disease conditions, and the different time of response assessment among studies.
As for survival profiles, a retrospective cohort study enrolling 143 HCC patients who underwent DEB-TACE treatment disclosed that DEB-TACE treatment realizes a median OS of 12.53 months [24]. Another retrospective cohort study conducted in 147 unresectable HCC patients revealed that the median survival by single-drug DEB-TACE treatment was 15.00±1.50 months [25]. Also, a retrospective cohort study showed that the median PFS and OS of patients who underwent DEB-TACE were 5.1 months and 13.3 months in 80 advanced stage HCC patients, respectively [26]. These results from the prior studies suggest that DEB-TACE could achieve a good efficacy regarding patients’ survival in HCC patients. In this study, we found that the median PFS of elderly Chinese HCC patients post DEB-TACE treatment was 9.0 months (95% CI: 7.4-10.6 months), and the median OS was 21.0 months (95% CI: 18.4-23.6 months). Compared with previous studies, the PFS and OS of in our study were numerically increased. This disparity might mainly result from the follow-up time in our study being longer and the technology skills were improved along with time, as well as the disease conditions that differed.
In clinical practice, a proportion of elderly HCC patients appear to have a poor response to DEB-TACE, hence, investigating prognostic factors in elderly HCC patients undergoing DEB-TACE treatment is necessary. However, few studies explored the prognostic factors in elderly HCC patients undergoing DEB-TACE therapy until now. The published reports only evaluated the prognostic factors in general HCC patients but not in the elderly HCC patients specifically. For instance, a previous cohort study reports that higher Child-Pugh stage and portal vein invasion are independent factors for predicting unfavorable OS in HCC patients treated by DEB-TACE [27]. Another prospective cohort study discloses that higher ECOG performance score, elevated serum albumin, and multifocal disease independently correlate with worse OS in both DEB-TACE and cTACE treated HCC patients [28]. In addition, a retrospective cohort study reveals that multifocal disease and maximum tumor diameter above 3.5 cm are associated with shorter OS in early/intermediate HCC patients [29]. To our best knowledge, this was the first study evaluating the predictive factors for efficacy in elderly HCC patients receiving DEB-TACE, and we found that tumor size ≥5.0 cm as well as AFP abnormality were independently correlated with unfavorable PFS, and tumor size ≥5.0 cm, higher BCLC stage as well as AFP abnormality were independent factors for predicting worse OS in elderly patients treated by DEB-TACE. Several possible explanations for our results were as follows: (1) largest tumor size ≥5.0 cm and higher BCLC stage indicated more severe disease and decreased liver function, which might lead to a poorer prognosis and a less favorable tolerance to the treatment. (2) AFP, secreted by HCC cells, is a typical biomarker of HCC, and it is reported that early increased serum AFP level is associated with disease progression in advanced HCC patients treated with sorafenib [30]. AFP also participates in the pathogenesis of HCC by promoting HCC cells growth, proliferation, metastasis, repressing cell apoptosis, and evading immune surveillance through a variety of mechanisms [31-35]. Therefore, high AFP level was detrimental to elderly HCC patients’ prognosis.
Liver function assessment is routine in patients with HCC before performing resections, transplantation, chemotherapy, radiotherapy or TACE treatments. The results in our study showed that the proportions of patients with abnormal liver function related indexes were elevated at 1 week while they were similar to that of baseline at 1 month after DEB-TACE treatment, which indicated that there was a rapid worsening of the liver function in elderly HCC patients treated by DEB-TACE in our study. However, their liver function recovered at 1 month post treatment, suggesting that DEB-TACE did not cause long-term damage of liver function in elderly HCC patients. For the purpose of evaluating the safety of DEB-TACE in treating elderly HCC patients, we also recorded the AEs occurred within one month post DEB-TACE. According to previous studies, the most common AE in HCC patients treated by DEB-TACE is embolization syndrome, including pain, fever, nausea and vomiting [25,26,36]. Unfortunately, there are very limited studies aiming to evaluate safety in the elderly HCC patients receiving DEB-TACE. In our study, the most common AEs in elderly HCC patients who underwent DEB-TACE were pain, fever, nausea and vomiting, which were mainly mild and manageable. There were only a few severe AEs associated with chemotherapeutic agents such as skin discoloration, myelosuppression and other AEs, which suggested that DEB-TACE was well tolerable in elderly HCC patients.
There were several limitations in this study: (1) The sample size of this study was relatively small, which might cause insufficient statistical power, thus, it is necessary to include more patients in future studies. (2) The treatment response in our study was assessed at 1 month post DEB-TACE, therefore, the long-term response was not evaluated, which should be performed in future studies. (3) The single center design of our study might cause selection bias, thus a future study should be conducted in multiple centers in different areas.
In conclusion, DEB-TACE was efficient and well tolerated in elderly HCC patients, and increased tumor size, abnormal AFP, and higher BCLC stage could be independent markers for adverse prognosis.
Acknowledgements
We gratefully acknowledge the help of Shanghai QeeJen Bio-Tech Co., Ltd., who have helped me improve the data analysis.
Disclosure of conflict of interest
None.
References
- 1.Gelband H, Chen CJ, Chen W, Franceschi S, Hall SA, London WT, McGlynn KA, Wild CP. Liver cancer. In: Gelband H, Jha P, Sankaranarayanan R, Horton S, editors. Cancer: disease control priorities. 3rd edition (volume 3) Washington (DC): 2015. [Google Scholar]
- 2.Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391:1301–1314. doi: 10.1016/S0140-6736(18)30010-2. [DOI] [PubMed] [Google Scholar]
- 3.Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–386. doi: 10.1002/ijc.29210. [DOI] [PubMed] [Google Scholar]
- 4.Bruix J, Sherman M American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–1022. doi: 10.1002/hep.24199. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Bertuccio P, Turati F, Carioli G, Rodriguez T, La Vecchia C, Malvezzi M, Negri E. Global trends and predictions in hepatocellular carcinoma mortality. J Hepatol. 2017;67:302–309. doi: 10.1016/j.jhep.2017.03.011. [DOI] [PubMed] [Google Scholar]
- 6.El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142:1264–1273. e1261. doi: 10.1053/j.gastro.2011.12.061. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Fu Y, Zhao X, Yun Q, Zhu X, Zhu Y, Li Q, Hu K, Wang J, Qiao Z. Transarterial chemoembolization (TACE) plus percutaneous ethanol injection (PEI) for the treatment of unresectable hepatocellular carcinoma: a meta-analysis of randomized controlled trials. Int J Clin Exp Med. 2015;8:10388–10400. [PMC free article] [PubMed] [Google Scholar]
- 8.Ha Y, Lee JB, Shim JH, Kim KM, Lim YS, Yoon HK, Shin YM, Lee HC. Validation and reappraisal of the assessment for retreatment with transarterial chemoembolization score for unresectable non-metastatic hepatocellular carcinoma in a hepatitis b virus-endemic region. Eur Radiol. 2016;26:3510–3518. doi: 10.1007/s00330-015-4185-2. [DOI] [PubMed] [Google Scholar]
- 9.Li XL, Guo WX, Hong XD, Yang L, Wang K, Shi J, Li N, Wu MC, Cheng SQ. Efficacy of the treatment of transarterial chemoembolization combined with radiotherapy for hepatocellular carcinoma with portal vein tumor thrombus: a propensity score analysis. Hepatol Res. 2016;46:1088–1098. doi: 10.1111/hepr.12657. [DOI] [PubMed] [Google Scholar]
- 10.Raoul JL, Heresbach D, Bretagne JF, Ferrer DB, Duvauferrier R, Bourguet P, Messner M, Gosselin M. Chemoembolization of hepatocellular carcinomas. A study of the biodistribution and pharmacokinetics of doxorubicin. Cancer. 1992;70:585–590. doi: 10.1002/1097-0142(19920801)70:3<585::aid-cncr2820700308>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]
- 11.Imai N, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Hayashi K, Hirooka Y, Goto H. Transarterial chemoembolization for hepatocellular carcinoma: a review of techniques. World J Hepatol. 2014;6:844–850. doi: 10.4254/wjh.v6.i12.844. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Zou JH, Zhang L, Ren ZG, Ye SL. Efficacy and safety of cTACE versus DEB-TACE in patients with hepatocellular carcinoma: a meta-analysis. J Dig Dis. 2016;17:510–517. doi: 10.1111/1751-2980.12380. [DOI] [PubMed] [Google Scholar]
- 13.Rostas J, Tam A, Sato T, Kelly L, Tatum C, Scoggins C, McMasters K, Martin RC 2nd. Imageguided transarterial chemoembolization with drug-eluting beads loaded with doxorubicin (DEBDOX) for unresectable hepatic metastases from melanoma: technique and outcomes. Cardiovasc Intervent Radiol. 2017;40:1392–1400. doi: 10.1007/s00270-017-1651-z. [DOI] [PubMed] [Google Scholar]
- 14.Arabi M, BenMousa A, Bzeizi K, Garad F, Ahmed I, Al-Otaibi M. Doxorubicin-loaded drugeluting beads versus conventional transarterial chemoembolization for nonresectable hepatocellular carcinoma. Saudi J Gastroenterol. 2015;21:175–180. doi: 10.4103/1319-3767.157571. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Rahman FA, Naidu J, Ngiu CS, Yaakob Y, Mohamed Z, Othman H, Jarmin R, Elias MH, Hamid NA, Mokhtar NM, Ali RR. Conventional versus doxorubicin-eluting beads transarterial chemoembolization for unresectable hepatocellular carcinoma: a tertiary medical centre experience in malaysia. Asian Pac J Cancer Prev. 2016;17:4037–4041. [PubMed] [Google Scholar]
- 16.Ono Y, Yoshimasu T, Ashikaga R, Inoue M, Shindou H, Fuji K, Araki Y, Nishimura Y. Longterm results of lipiodol-transcatheter arterial embolization with cisplatin or doxorubicin for unresectable hepatocellular carcinoma. Am J Clin Oncol. 2000;23:564–568. doi: 10.1097/00000421-200012000-00006. [DOI] [PubMed] [Google Scholar]
- 17.Varela M, Real MI, Burrel M, Forner A, Sala M, Brunet M, Ayuso C, Castells L, Montana X, Llovet JM, Bruix J. Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J Hepatol. 2007;46:474–481. doi: 10.1016/j.jhep.2006.10.020. [DOI] [PubMed] [Google Scholar]
- 18.Lewis AL, Taylor RR, Hall B, Gonzalez MV, Willis SL, Stratford PW. Pharmacokinetic and safety study of doxorubicin-eluting beads in a porcine model of hepatic arterial embolization. J Vasc Interv Radiol. 2006;17:1335–1343. doi: 10.1097/01.RVI.0000228416.21560.7F. [DOI] [PubMed] [Google Scholar]
- 19.Poon RT, Tso WK, Pang RW, Ng KK, Woo R, Tai KS, Fan ST. A phase I/II trial of chemoembolization for hepatocellular carcinoma using a novel intra-arterial drug-eluting bead. Clin Gastroenterol Hepatol. 2007;5:1100–1108. doi: 10.1016/j.cgh.2007.04.021. [DOI] [PubMed] [Google Scholar]
- 20.Lammer J, Malagari K, Vogl T, Pilleul F, Denys A, Watkinson A, Pitton M, Sergent G, Pfammatter T, Terraz S, Benhamou Y, Avajon Y, Gruenberger T, Pomoni M, Langenberger H, Schuchmann M, Dumortier J, Mueller C, Chevallier P, Lencioni R Investigators PV. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol. 2010;33:41–52. doi: 10.1007/s00270-009-9711-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Kloth C, Thaiss WM, Kargel R, Grimmer R, Fritz J, Ioanoviciu SD, Ketelsen D, Nikolaou K, Horger M. Evaluation of texture analysis parameter for response prediction in patients with hepatocellular carcinoma undergoing drug-eluting bead transarterial chemoembolization (DEBTACE) using biphasic contrast-enhanced ct image data: correlation with liver perfusion CT. Acad Radiol. 2017;24:1352–1363. doi: 10.1016/j.acra.2017.05.006. [DOI] [PubMed] [Google Scholar]
- 22.Kokabi N, Ludwig JM, Camacho JC, Xing M, Mittal PK, Kim HS. Baseline and early mr apparent diffusion coefficient quantification as a predictor of response of unresectable hepatocellular carcinoma to doxorubicin drug-eluting bead chemoembolization. J Vasc Interv Radiol. 2015;26:1777–1786. doi: 10.1016/j.jvir.2015.08.023. [DOI] [PubMed] [Google Scholar]
- 23.Yu CY, Ou HY, Weng CC, Huang TL, Chen TY, Leung-Chit L, Hsu HW, Chen CL, Cheng YF. Drug-eluting bead transarterial chemoembolization as bridge therapy for hepatocellular carcinoma before living-donor liver transplantation. Trans Plant Proc. 2016;48:1045–1048. doi: 10.1016/j.transproceed.2015.12.078. [DOI] [PubMed] [Google Scholar]
- 24.Cheung AH, Lam CS, Tam HS, Cheung TT, Pang R, Poon RT. Nine-year experience of doxorubicin-eluting beads chemoembolization for hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2016;15:493–498. doi: 10.1016/s1499-3872(16)60133-9. [DOI] [PubMed] [Google Scholar]
- 25.Gomes AS, Monteleone PA, Sayre JW, Finn RS, Sadeghi S, Tong MJ, Britten CD, Busuttil RW. Comparison of triple-drug transcatheter arterial chemoembolization (TACE) with single-drug tace using doxorubicin-eluting beads: longterm survival in 313 patients. AJR Am J Roentgenol. 2017;209:722–732. doi: 10.2214/AJR.17.18219. [DOI] [PubMed] [Google Scholar]
- 26.Kalva SP, Pectasides M, Liu R, Rachamreddy N, Surakanti S, Yeddula K, Ganguli S, Wicky S, Blaszkowsky LS, Zhu AX. Safety and effectiveness of chemoembolization with drug-eluting beads for advanced-stage hepatocellular carcinoma. Cardiovasc Intervent Radiol. 2014;37:381–387. doi: 10.1007/s00270-013-0654-7. [DOI] [PubMed] [Google Scholar]
- 27.Kloeckner R, Weinmann A, Prinz F, Pinto dos Santos D, Ruckes C, Dueber C, Pitton MB. Conventional transarterial chemoembolization versus drug-eluting bead transarterial chemoembolization for the treatment of hepatocellular carcinoma. BMC Cancer. 2015;15:465. doi: 10.1186/s12885-015-1480-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Golfieri R, Giampalma E, Renzulli M, Cioni R, Bargellini I, Bartolozzi C, Breatta AD, Gandini G, Nani R, Gasparini D, Cucchetti A, Bolondi L, Trevisani F Precision Italia Study Group. Randomised controlled trial of doxorubicin-eluting beads vs conventional chemoembolisation for hepatocellular carcinoma. Br J Cancer. 2014;111:255–264. doi: 10.1038/bjc.2014.199. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Facciorusso A, Mariani L, Sposito C, Spreafico C, Bongini M, Morosi C, Cascella T, Marchiano A, Camerini T, Bhoori S, Brunero F, Barone M, Mazzaferro V. Drug-eluting beads versus conventional chemoembolization for the treatment of unresectable hepatocellular carcinoma. J Gastroenterol Hepatol. 2016;31:645–653. doi: 10.1111/jgh.13147. [DOI] [PubMed] [Google Scholar]
- 30.Nakazawa T, Hidaka H, Takada J, Okuwaki Y, Tanaka Y, Watanabe M, Shibuya A, Minamino T, Kokubu S, Koizumi W. Early increase in alpha-fetoprotein for predicting unfavorable clinical outcomes in patients with advanced hepatocellular carcinoma treated with sorafenib. Eur J Gastroenterol Hepatol. 2013;25:683–689. doi: 10.1097/MEG.0b013e32835d913b. [DOI] [PubMed] [Google Scholar]
- 31.Mizejewski GJ. Does alpha-fetoprotein contribute to the mortality and morbidity of human hepatocellular carcinoma? A commentary. J Hepatocell Carcinoma. 2016;3:37–40. doi: 10.2147/JHC.S114198. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Mitsuhashi N, Kobayashi S, Doki T, Kimura F, Shimizu H, Yoshidome H, Ohtsuka M, Kato A, Yoshitomi H, Nozawa S, Furukawa K, Takeuchi D, Suda K, Miura S, Miyazaki M. Clinical significance of alpha-fetoprotein: involvement in proliferation, angiogenesis, and apoptosis of hepatocellular carcinoma. J Gastroenterol Hepatol. 2008;23:e189–197. doi: 10.1111/j.1440-1746.2008.05340.x. [DOI] [PubMed] [Google Scholar]
- 33.Li MS, Ma QL, Chen Q, Liu XH, Li PF, Du GG, Li G. Alpha-fetoprotein triggers hepatoma cells escaping from immune surveillance through altering the expression of Fas/FasL and tumor necrosis factor related apoptosis-inducing ligand and its receptor of lymphocytes and liver cancer cells. World J Gastroenterol. 2005;11:2564–2569. doi: 10.3748/wjg.v11.i17.2564. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Li MS, Li PF, Chen Q, Du GG, Li G. Alpha-fetoprotein stimulated the expression of some oncogenes in human hepatocellular carcinoma Bel 7402 cells. World J Gastroenterol. 2004;10:819–824. doi: 10.3748/wjg.v10.i6.819. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Li MS, Li PF, He SP, Du GG, Li G. The promoting molecular mechanism of alpha-fetoprotein on the growth of human hepatoma Bel7402 cell line. World J Gastroenterol. 2002;8:469–475. doi: 10.3748/wjg.v8.i3.469. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Megias Vericat JE, Garcia Marcos R, Lopez Briz E, Gomez Munoz F, Ramos Ruiz J, Martinez Rodrigo JJ, Poveda Andres JL. Trans-arterial chemoembolization with doxorubicin-eluting particles versus conventional trans-arterial chemoembolization in unresectable hepatocellular carcinoma: a study of effectiveness, safety and costs. Radiologia (Roma) 2015;57:496–504. doi: 10.1016/j.rx.2015.01.008. [DOI] [PubMed] [Google Scholar]