|Year : 2022 | Volume
| Issue : 2 | Page : 560-566
Influencing factors related to transcatheter arterial chemoembolization for hepatocellular carcinoma patients achieved tumor response
Hongyan Shao1, Juan Deng2, Luping Xie1, Qiwen Zheng1, Bihui Zou1, Jun Deng2, Tianqi Zhang1, Jingjing He1
1 Department Minimally Invasive Intervention I, Center of Medical Imaging and Minimally Invasive Therapy, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
2 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
|Date of Submission||26-May-2021|
|Date of Acceptance||19-Oct-2021|
|Date of Web Publication||20-May-2022|
Department Minimally Invasive Intervention I, Center of Medical Imaging and Minimally Invasive Therapy, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060
Source of Support: None, Conflict of Interest: None
Objective: To investigate the influencing factors of transcatheter arterial chemoembolization (TACE) on patients with hepatocellular carcinoma (HCC) for tumor response (complete and partial response, CR + PR).
Methods: This research conducted a retrospective study of the hospital charts of patients treated with TACE successfully renewed from October 2014 to December 2015 at Sun Yat-sen University Cancer Center (Guangzhou, China). Univariate analysis (Chi-square test and repeated-measures ANOVA) selected nine influential tumor response factors from 22 core factors. The nine variables were included in a forward multiple logistic regression model predicting patients treated with TACE to achieve tumor response. Overall survival was calculated using the Kaplan–Meier method.
Results: Data of 277 of 282 patients were included in the analysis. Nine variables were analyzed by univariate analysis and independently associated with tumor response (tumor capsule integrity, nausea and vomiting, microwave ablation, liver dysfunction, the absolute value of lymphocyte (LYM), alpha-fetoprotein, and gamma-glutamyl transpeptidase (GGT). By multivariate analysis, GGT (odds ratio [OR] =0.996), liver dysfunction (OR = 0.395), combined with microwave ablation (OR = 0.503), and tumor capsule integrity (OR = 1.894) were the significant predictors of the tumor response group compared with the standard deviation group (P < 0.05).
Conclusions: This study suggests that TACE combined with ablation on patients with complete tumor capsules may have a better prognosis in tumor response and OS; additionally, liver dysfunction and nausea and vomiting were the independent predictors of tumor response.
Keywords: Complete response, hepatocellular carcinoma, partial response, transcatheter arterial chemoembolization, tumor response
|How to cite this article:|
Shao H, Deng J, Xie L, Zheng Q, Zou B, Deng J, Zhang T, He J. Influencing factors related to transcatheter arterial chemoembolization for hepatocellular carcinoma patients achieved tumor response. J Can Res Ther 2022;18:560-6
|How to cite this URL:|
Shao H, Deng J, Xie L, Zheng Q, Zou B, Deng J, Zhang T, He J. Influencing factors related to transcatheter arterial chemoembolization for hepatocellular carcinoma patients achieved tumor response. J Can Res Ther [serial online] 2022 [cited 2022 Jul 7];18:560-6. Available from: https://www.cancerjournal.net/text.asp?2022/18/2/560/345546
| > Introduction|| |
Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related mortality worldwide, and it has been rapidly rising recently. Surgical resection remains the most efficient treatment for patients with HCC.,, However, only 5%–30% of patients with HCC are eligible for surgery., Recent data have shown that transcatheter arterial chemoembolization (TACE) has a significant effect in reducing tumor size and number by blocking the blood supply of tumors.,,, However, TACE's application was limited, because it promotes new blood vessels, making it challenging to effectively clear the tumor focus., Therefore, it is necessary to know what is related to TACE for patients who achieved tumor response. Consequently, we retrospectively investigated efficacy factors among 277 patients with HCC who achieved tumor response after TACE.
| > Methods|| |
Patients and study design
Two hundred and seventy-seven patients with HCC were enrolled in the study. The inclusion criteria were as follows: (1) age >18 years; (2) diagnosis of HCC agrees with the Standards for the Diagnosis and Treatment of Primary Liver Cancer (2011 version); (3) unavailable to resection or refusal to perform TACE; (4) no contraindications related to TACE; (5) Child–Pugh class A or B; and (6) follow-up time >2 months. In addition, the exclusion criteria included the following: (1) patient had gastrointestinal bleeding and (2) medical records were unavailable. This research was approved by the Ethics Committee at Sun Yat-Sen University Cancer Center on December 12, 2019, and deemed exempt because data of this retrospective study come from clinical databases, and there is almost no leakage of patient privacy. Furthermore, the research was conducted following the Declaration of Helsinki (2000) of the World Medical Association.
Diagnosis and staging of hepatocellular carcinoma
HCC was diagnosed by pathological tumor biopsy or clinical diagnosis (at least combined with two kinds of imaging examination), a combination of tests for specific serum tumor markers, such as alpha-fetoprotein (AFP), and imaging procedures, such as computed tomography (CT) and magnetic resonance imaging (MRI). In this study, HCC was classified using the BCLC staging system based on dynamic CT or MRI findings.
Transcatheter arterial chemoembolization procedure
In this study, an associate professor with 15 years of interventional technology experience performed all TACE operations.
TACE was performed on the celiac and common hepatic arteries, which were catheterized using a 5Fr catheter (Terumo, Tokyo, Japan) into the femoral artery by the Seldinger's method, and digital subtraction angiography was performed using a nonionic iodine contrast agent. After evaluating the tumor-located segment by cone-beam CT, super-selective intubation of segmental or sub-segment target arteries was performed using a 0.035 mm ultra-slip microcatheter (Terumo, Tokyo, Japan) and verified by DSA inspection. Next, the ultra-slip microcatheter was advanced toward the tumor-feeding artery. Then, chemotherapeutic drugs and embolic agents were manually injected into a tumor-feeding artery, depending on the size and number of tumors, blood supply, and hepatic function of the patient. Pirarubicin or Lobaplatin (50 mg/m2) and absorbable gelatin sponge particles (Nanjing, China) were prepared by mixing 5–10 ml lipiodol (Guerbet, France).
We evaluated TACE's tumor responses through Modified Response Evaluation Criteria in Solid Tumors assessment by CT after 1 month. In addition, a follow-up system at our center monitored the survival status. Therefore, the TACE procedure could be repeated according to the tumor response and the patient's liver function.
All statistical analyses were conducted using the Statistical Package for the Social Sciences (SPSS v. 26.0, Chicago, IL, USA). Demographic and disease-related information care presented as mean ± standard deviation (SD) or frequency (percentage) depending on the data type. Twenty-two core factors with HCC patients were analyzed by univariate and multivariate logistic regression. Overall survival was calculated using the Kaplan–Meier method and analyzed by the log-rank test. A two-tailed P < 0.05 was considered statistically significant.
| > Results|| |
The outcome for the 277 patients with HCC was tumor response in 136 (49.1%), SD in 106 (38.3%), and PD in 35 (12.6%). The influencing factors were analyzed by single-factor analysis from 22 factors in [Table 1] and [Table 2]; the parameters with P < 0.05 were analyzed with multiple logistic regression, as shown in [Table 3] and [Table 4]. The odds ratio (OR) provides the degree of change in odds linked between a one-unit change and an explanatory variable.
|Table 3: Multivariate logistic regression to identify the significant predictors of transcatheter arterial chemoembolization for hepatocellular carcinoma (The reference category is standard deviation group)|
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|Table 4: Multivariate logistic regression to identify the significant factors of transcatheter arterial chemoembolization for hepatocellular carcinoma (The reference category is progressive disease group)|
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Demographic and clinical characteristics of the patients
Patients' median age was 52.7 years, ranging from 21 to 80 years, and 257 patients (92.7%) were male. Patients in this study at BCLC stage C were 168 (60.6%), with HBV infection in 234 (84.5%); 42.2% of the patients presented with cirrhosis, 32.9% presented combined with microwave ablation, and 43.0% had vascular invasion. Moreover, to assess laboratory indicators among the tumor response, SD, and PD groups, repeated-measures ANOVAs are used in [Table 2]. Overall, the univariate analysis indicated that nine factors significantly influence the efficacy of TACE [Table 1] and [Table 2].
Multiple logistic regression analysis
Multiple logistic regression modeling in the developmental data set resulted in a model containing nine variables: Tumor capsule integrity, nausea and vomiting, combined with microwave ablation, liver dysfunction, lymphocyte (LYM), AFP, GCT, TPO, and PLT.
[Table 3] presents the estimated logistic regression coefficients. The OR estimates the probability of tumor response, associated with an increase of 1 unit, controlling for all other variables in the model. In this study, multiple logistic regression modeling shows that liver dysfunction, combined with microwave ablation, tumor capsule integrity, and gamma-glutamyl transpeptidase (GGT) had an OR of 0.395, 0.503, 1.894, and 0.996, respectively. This means that compared with patients with stable curative effects, patients with normal liver function were 0.395 times more likely to achieve complete or partial remission than patients with impaired liver function with stable efficacy. Patients without combined ablation were 0.503 times more likely to achieve complete or partial remission. Compared with patients with an incomplete capsule, patients with a complete capsule were 1.894 times more likely to achieve complete or partial remission than those with stable efficacy. Furthermore, complete or partial remission probability was 0.996 times higher in HCC patients with GCT and increased by 1 unit.
Compared with the patients with progressive disease, the probability of complete or partial response (CR or PR) in HCC patients with GGT increased by 1 unit and was 0.996 times. The probability of achieving a CR or PR in HCC patients with a complete capsule was 3.168 times that of progressive disease compared with the patients with incomplete capsules. The probability of achieving a CR or PR in HCC patients without nausea and vomiting was 0.381 times of progressive disease compared with the patients with nausea and vomiting [Table 4]. However, no significant relationship was found for the SD group. GGT, LYM, AFP, and PLT at a presentation of three groups are shown in [Figure 1].
|Figure 1: Gamma-glutamyl transpeptidase, lymphocyte, alpha-fetoprotein, and PLT at a presentation of the three groups|
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Kaplan–Meier curves of cumulative survival for patients underwent transcatheter arterial chemoembolization
In this study, Kaplan–Meier analysis showed that the patients who underwent TACE combined with microwave ablation had a longer OS than those who did not [P < 0.001, [Figure 2]a]. The Kaplan–Meier survival curve suggests no significant difference in OS between patients with liver dysfunction before TACE [P > 0.05, [Figure 2]b]. The survival curve shows no significant difference in OS between patients with nausea and vomiting after TACE [P > 0.005, [Figure 3]a]. Furthermore, [Figure 3]b indicates that patients with complete tumor capsules had longer OS than patients with incomplete capsules (P = 0.001). The means for survival time of CR + PR, SD, and PD groups were 30.702, 23.716, and 19,535 months, respectively. The CR + PR group had a significantly longer OS than the SD and PD groups [P < 0.005, [Figure 4]].
|Figure 2: (a) Comparison of transcatheter arterial chemoembolization combined with microwave ablation in OS after transcatheter arterial chemoembolization. The Kaplan–Meier survival curve shows that the patients who underwent transcatheter arterial chemoembolization combined with microwave ablation had a longer OS than that not (P < 0.001). (b) A comparison of liver dysfunction in OS after transcatheter arterial chemoembolization. The Kaplan–Meier survival curve suggests that no significant difference in OS between the two groups (P > 0.05)|
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|Figure 3: (a) The Kaplan–Meier survival curve shows that no significant difference in OS between patients with nausea and vomiting after transcatheter arterial chemoembolization (P > 0.005). (b) The Kaplan–Meier survival curve indicates that patients with complete tumor capsule had longer OS than patients with incomplete capsule (P = 0.001)|
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|Figure 4: A comparison of OS among CR + PR, SD, and PD groups. The Kaplan–Meier survival curve reveals that the CR + PR group had longer OS than SD and PD groups (P < 0.05)|
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| > Discussion|| |
In this study, multivariate analyses revealed that GCT, combined ablation, complete tumor capsule, and liver dysfunction were the significant factors contributing to CR and PR, compared with SD. However, HGG meeting the statistical standard might not be applicable because of the OR value (OR = 0.996). Conversely, combined ablation, complete tumor capsule, and liver dysfunction were beneficial for achieving tumor response (CR + PR). It may be a complete liver capsule, which is more likely to be completely embolized, and liver dysfunction enhances M-CSF production via a cytokine cascade, resulting in the proliferation of liver macrophages in vivo and leading to a better treatment effect.
Many studies have proved TACE's effectiveness combined with ablative therapies to treat unresectable HCC.,,,, A meta-analysis that included eight randomized controlled trials showed that combining RFA with TACE has advantages in improving the overall survival rate and provides a better prognosis for patients with intermediate- and large-size HCC. However, some studies reveal that TACE combined radiofrequency ablation (RFA) may result in more discomfort symptoms, complications, and longer hospital stay more than TACE or RFA. Considering all evidence, it seems that applying TACE-combined microwave ablation could further improve the therapeutic effect of unresectable HCC. In addition, several studies have shown that HAIC may be the first-line therapy for patients with advanced HCC., For HCC patients without tumor capsule integrity who may lead to poor prognosis after TACE, combined RFA and microwave ablation may be a good attempt. An Asia-Pacific Primary Liver Cancer Expert Consensus Statement recommended targeted therapy as first-line treatment for TACE-unsuitable patients. Furthermore, 90Y-radioembolization (TARE) or sorafenib, TACE + sorafenib, or other modalities may be considered alternative options in TACE-unsuitable patients who are not candidates for targeted therapy., Patients in this study at BCLC stage C were 60.6%, the anti-tumoural treatment formally recommended by Western guidelines is systemic therapy with sorafenib.
Among patients with complete tumor capsules, nausea, and vomiting, a better tumor response (CR + PR) was observed in patients who underwent TACE than patients who received PD [Table 4]. In a previous study, Shi-Ying et al. have shown the correlation between alkaline phosphatase, serum alanine transferase, and nausea and vomiting. However, the study did not report any associations between nausea and vomiting and survival rates, even though nausea and vomiting are common in patients with HCC after TACE. Previous studies have shown that nausea and vomiting can result in postembolization syndrome (PES) after TACE, which may lead to an increased duration of hospitalization and decreased quality of life in patients treated with TACE. A randomized, double-blinded, placebo-controlled study suggests that preventive dexamethasone before TACE could alleviate PES. It is helpful for medical staff to explain patients' symptoms after TACE clinically and guide them to maintain an optimistic treatment attitude. It embodies humanistic medical care.
In this research, the OS of the CR + PR group was significantly longer than that of the SD and PD group, consistent with the results of Kudo, M. In addition, the OS of patients undergoing TACE combined with microwave ablation and complete tumor envelope was significantly longer than patients without microwave ablation and complete tumor capsule. Liu et al. also agreed that TACE combined with MWA would be a better alternative for large (>5.0 cm) HCCs. In contrast, there was no significant difference in OS between patients with liver dysfunction and nausea and vomiting after TACE. This means that TACE combined with microwave and patients with complete tumor capsules were independent and effective predictors of OS. While liver dysfunction and nausea and vomiting could not independently predict OS. In multivariate regression analysis, liver dysfunction and nausea and vomiting were used only as auxiliary factors to predict the possibility of patients to achieve CR + PR.
In this material, these variables were unassociated with tumor response from the event: HBV infection, liver cirrhosis, ALBI grade, BCLC stage, vascular invasion, and tumor extension are assumed to be useful. However, some studies show a piece of evidence between the factors described above and survival.,
Notably, this study exhibits certain limitations. Initially, the sample size was relatively not big enough to reduce the statistical power of the analysis. Second, since the patient was discharged from the hospital when we collected the information, some of our information, such as embolization method, and degree could not be collected; this will be the next research step. Finally, this study is a single-institution and retrospective research; multiple institutions and prospective studies are required to clarify its effectiveness further.
| > Conclusions|| |
This study suggests that patients with HCC treated with TACE, combined with ablation, complete tumor capsule, liver dysfunction, and nausea and vomiting, are more likely to achieve a CR or PR. Patients underwent TACE combined with ablation, and patients with complete tumor capsules might have longer OS. In addition, liver dysfunction and nausea and vomiting are probably adjunct predictors of longer OS. However, multiple institutions and prospective studies are required to clarify its effectiveness further.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]