Study on the efficacy of adjuvant TACE plus targeted therapy in patients with hepatocellular carcinoma at a high risk of recurrence after hepatectomy

 Corresponding author: Durrani Ahsanullah Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution Liscense 4.0. Study on the efficacy of adjuvant TACE plus targeted therapy in patients with hepatocellular carcinoma at a high risk of recurrence after hepatectomy Durrani Ahsanullah 1, *, Zainab 2, Shukurullah 3, Dhira salsabila 4 and Ulfat Durrani 5 1 Affiliated Hospital of Nantong University. 2 Gastroenterology civil hospital Karachi Pakistan. 3 Zhejiang chines medical university. 4 Affiliated Hospital of Nantong University. 5 Isra Medical university Hyderabad, Pakistan. World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 140-148 Publication history: Received on 25 November 2024; revised on 04 January 2025; accepted on 06 January 2025 Article DOI: https://doi.org/10.30574/wjbphs.2025.21.1.0007 Abstract Objective: Patients with hepatocellular carcinoma (HCC) have a high risk of recurrence after liver resection, and finding effective adjuvant therapy is crucial for improving patient prognosis. The efficacy of transcatheter arterial chemoembolization (TACE) combined with targeted therapy has attracted attention, but there is still insufficient research on its comparison with TACE alone. The aim of this study is to compare the efficacy differences between adjuvant TACE combined with targeted therapy and TACE alone in patients with high risk of recurrence of hepatocellular carcinoma after surgery, and to evaluate the impact of the two treatment regimens on patient survival and recurrence. Methods: This study is a retrospective cohort study that analyzed the prognosis of adjuvant TACE combined with targeted therapy in high-risk hepatocellular carcinoma patients with postoperative recurrence between January 2014 and December 2022. The patients were divided into two groups, one receiving adjuvant TACE combined with targeted therapy, and the other receiving simple TACE treatment. Collect clinical data, treatment plans, and follow-up results of patients, and compare the survival and recurrence rates of two groups of patients. The main research endpoints include overall survival (OS) and recurrence free survival (RFS), and comparisons are made between groups. Apply the COX proportional hazards regression model to conduct univariate and multivariate analyses of OS and RFS, respectively. Result: After adjustment for confounding factors, multivariable analysis identified that TACE + targeted therapy was independently associated with better OS (HR: 0.47; 95% CI: 0.30-0.74; P = 0.001) and RFS (HR: 0.40; 95% CI: 0.20-0.80; P = 0.010) in patients with HCC at a high risk of recurrence after hepatectomy. In addition, BCLC stage-C, Child-Pugh grade B, preoperative extrahepatic metastasis, and surgical margin > 1cm were independent risk factors of OS for patients with HCC at a high risk of recurrence after hepatectomy. Meanwhile, BCLC stage-C, tumor differentiation (moderate versus poor), and preoperative extrahepatic metastasis were independent risk factors of RFS for patients with HCC at a high risk of recurrence after hepatectomy. Conclusion: By analyzing and comparing the prognostic outcomes of adjuvant TACE combined with or without targeted therapy in high-risk hepatocellular carcinoma patients with postoperative recurrence, this study found that adjuvant TACE combined with targeted therapy had a better prognosis than TACE alone: median OS and median RFS were longer. The combination of adjuvant TACE and targeted therapy is an independent influencing factor for better OS and RFS, respectively. World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 140-148 141 Keywords: Hepatocellular Carcinoma (HCC); Recurrence; Trans-arterial Chemoembolization; Targeted Therapy; Liver Resection 1. Introduction Hepatocellular Carcinoma (HCC) stands as a formidable global health challenge, representing the most prevalent primary liver malignancy and ranking as the fourth leading cause of cancer-related mortality worldwide [1]. Characterized by its association with chronic liver diseases, such as cirrhosis, HCC poses a complex clinical scenario requiring a multi-faceted understanding for effective management. Hepatectomy, or surgical removal of the tumorbearing portion of the liver, stands as a primary curative option for HCC. However, the postoperative landscape is marked by the persistent threat of recurrence, necessitating a comprehensive examination of its incidence, contributing factors, and the associated challenges in management [2-3]. Of all liver primary tumors, hepatocellular carcinoma (HCC) accounts for about 90% of cases. About 85% of patients with cirrhosis are also diagnosed with hepatocellular carcinoma. Currently, HCC ranks as the fifth most frequent cause of cancer globally. HCC is the second most common cause of cancer-related mortality in men, after lung cancer [2-4]. HCC has an 18% five-year survival rate, second only to pancreatic cancer. Hepatitis caused by viruses (hepatitis B and hepatitis C), alcoholic liver disease, and non-alcoholic fatty liver disease/steatohepatitis are important risk factors for hepatocellular cancer. In 80%–90% of cirrhosis patients, HCC develops. In patients with cirrhosis, the annual incidence of HCC is 2-4% [5]. Large margins have been recommended for non-anatomic resections of small (<5 cm) HCCs, as well as HCCs with microvascular invasion, cirrhosis-free, or high levels of alpha-fetoprotein (AFP) [6]. Other studies, however, showed that postoperative recurrence rates and patterns were unaffected by tumor-negative margins of ≤1 mm and margins <1 cm [7]. High-risk recurrence not only poses challenges to the clinical management of HCC but also significantly impacts patient prognosis and quality of life. The delicate balance between aggressive intervention and preserving patients' overall well-being underscores the complexity of managing recurrent HCC [8]. A comprehensive understanding of HCC, including its propensity for recurrence after Hepatectomy, is essential for advancing therapeutic strategies. The subsequent sections will delve into the specific challenges posed by high-risk recurrence and explore the limitations of current therapies, highlighting the critical need for innovative approaches to enhance the overall management of HCC [9]. Tran’s catheter arterial chemoembolization (TACE) is a widely utilized postoperative adjuvant therapy for hepatocellular carcinoma (HCC). TACE combines the administration of chemotherapeutic agents directly into the tumor-feeding arteries with subsequent embolization. This dual approach aims to achieve localized chemotherapy delivery while inducing ischemia in the tumor, effectively targeting residual cancer cells [10]. Advancements in understanding the molecular pathways involved in HCC have led to the development of targeted therapies. Sorafenib and lenvatinib, both multi-kinase inhibitors, have demonstrated efficacy in postoperative settings by inhibiting angiogenesis and tumor cell proliferation [11]. Immunotherapeutic agents, such as nivolumab and pembrolizumab, have demonstrated potential in the postoperative setting by harnessing the immune system to target residual cancer cells. Early clinical trials have shown encouraging results, suggesting a role for immunotherapy in preventing HCC recurrence [12]. Loco-regional therapies, including radiofrequency ablation (RFA) and microwave ablation (MWA), play a crucial role in managing postoperative HCC recurrence. These techniques offer targeted destruction of small residual tumors, improving outcomes in select patient populations [13]. 2. Material and methods 2.1. Study Design and Participants This study was a retrospective cohort analysis designed to evaluate the efficacy of adjuvant TACE plus targeted therapy versus TACE alone in patients with HCC at a high risk of recurrence after Hepatectomy. Patients who underwent Hepatectomy for HCC between January 2014 and December 2022 from Nantong University Affiliated Hospital were retrospectively analyzed. The diagnosis of HCC was confirmed by postoperative histopathological examination of the resected specimens. Targeted therapy used in this study included Lenvatinib (12 mg/d for bodyweight ≥ 60 kg or 8 mg/d for bodyweight < 60 kg orally once daily), (400 mg twice a day) or lapatinib (250-500 mg orally once daily). World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 140-148 142 2.2. Inclusive Criteria The inclusion criteria were as follows: (a) patients diagnosed with HCC at a high risk of recurrence after Hepatectomy; (b) undergone Hepatectomy as the primary treatment for HCC; (c) treated with adjuvant TACE plus targeted therapy or TACE alone; (d) Child-Pugh A or B liver function; (e) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and (f) available imaging and clinical follow-up data. 2.3. Exclusive Criteria The exclusion criteria were as follows: (a) a history of other malignancies within the past 5 years; (b) incomplete medical records or insufficient follow-up data; (c) undergone loco regional therapy other than TACE for their HCC; (d) Child-Pugh class C liver cirrhosis; (e) severe underlying cardiac, pulmonary, or renal disease. 2.4. Statistical Analysis Statistical analysis was performed using the IBM SPSS version 26.0. Continuous variables were expressed as mean ± standard deviations or medians (range) and interquartile ranges as appropriate. Categorical variables were reported as numbers and proportions. Continuous variables were compared using the student’s t test and categorical variables were compared using the Fisher’s exact test or the χ2 test with Yate’s continuity correction, as appropriate. Survival curves were generated using the Kaplan-Meier method and compared using the log-rank test. All variables with a P value < 0.1 in the Univariable analyses were included in the multivariable Cox-regression analyses. Hazard ratios (HRs) for OS and RFS were calculated with 95% confidence intervals (CIs). All statistical tests were two-tailed, and a P value < 0.05 was considered statistically significant. 3. Results 3.1. Comparisons of Baseline Characteristics A total of 171 high-risk recurrent HCC patients after liver resection were included in the study, including 102 cases in the TACE group and 69 cases in the TACE + targeted therapy group. Comparison of baseline patient characteristics and operative variables among the groups are noted in Table 1. There is no significant difference in most variables between the two groups. Table 1 Baseline Characteristics TACE group （n = 102） TACE + targeted therapy（n = 69） P Sex (male) 82 (80.4%) 57 (82.6%) 0.715 Age (years) 59±9 58±10 0.415 ECOG PS (1) 44 (43.1%) 37 (53.6%) 0.178 BCLC stage 0.269 0 9 (8.8%) 13 (18.8%) A 79 (77.5%) 46 (66.7%) B 6 (5.9%) 5 (7.2%) C 8 (7.8%) 5 (7.2%) Cirrhosis 63 (61.8%) 54 (78.3%) 0.023 Child–Pugh grade (B) 6 (5.9%) 2 (2.9%) 0.351 Preoperative extrahepatic metastasis 2 (2.0%) 0 (0.0%) 0.149 Microvascular invasion 28 (27.5%) 14 (20.3%) 0.286 World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 140-148 143 Preoperative AFP (> 400μg/l) 81 (79.4%) 56 (81.2%) 0.779 Largest tumor size (> 5 cm) 43 (42.2%) 23 (33.3%) 0.245 Tumor number (multiple) 16 (15.7%) 10 (14,5%) 0.831 Satellite nodules (yes versus no) 10 (9.8%) 9 (13.0%) 0.508 Tumor differentiation 0.572 poor 46 (45.1%) 26 (37.7%) moderate 45 (44.1%) 36 (52.2%) 3.2. Comparisons of Long-term Outcomes Comparison of long-term outcomes among the three groups are noted in Table 2. The TACE + targeted therapy group had better OS (median: 79.7 vs. 45.9 months, P = 0.002) and RFS (median: 36.5 vs. 15.0 months, P ＜ 0.001) versus the TACE group. The OS and RFS curves among the groups are shown in Figure 1 and Figure 2, respectively. Figure 1 KaplanMeier Analysis of overall survival World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 140-148 144 Figure 2 KaplanMeier Analysis of Recurrence free survival 3.3. Univariable and multivariable analysis of OS and RFS Univariable and multivariable Cox-regression analyses were used to identify independent risk factors of OS and RFS (Tables 2 and Table 3). After adjustment for confounding factors, multivariable analysis identified that TACE + targeted therapy was independently associated with better OS (HR: 0.47; 95% CI: 0.30-0.74; P = 0.001) and RFS (HR: 0.40; 95% CI: 0.20-0.80; P = 0.010) in patients with HCC at a high risk of recurrence after Hepatectomy. In addition, BCLC stage-C, Child-Pugh grade B, preoperative extrahepatic metastasis, and surgical margin > 1cm were independent risk factors of OS for patients with HCC at a high risk of recurrence after Hepatectomy. Meanwhile, BCLC stage-C, tumor differentiation (moderate versus poor), and preoperative extrahepatic metastasis were independent risk factors of RFS for patients with HCC at a high risk of recurrence after Hepatectomy. Table 2 Univariable and Multivariable Analysis of OS Univariable Analysis Multivariable Analysis HR (95% CI) P HR (95% CI) P TACE + targeted therapy versus TACE 0.48 (0.32-0.72) <0.001 0.47 (0.30-0.74) 0.001 Sex (male versus female) 1.80 (0.76-4.25) 0.181 Age (years) 1.01 (0.98-1.04) 0.584 ECOG PS (1versus 0 ) 1.03 (0.57-1.84) 0.934 BCLC stage 0 1.00 1.00 A 1.23 (0.48-3.21) 0.666 0.92 (0.32-2.65) 0.875 B 3.70 (0.98-13.9) 0.053 2.39 (0.49-11.70) 0.283 C 6.02 (2.04-17.76) 0.001 4.03 (1.13-14.41) 0.032 Cirrhosis (yes versus no) 0.72 (0.38-1.35) 0.306 Child–Pugh grade (B versus A) 4.39 (1.70-11.34) 0.002 3.67 (1.26-10.67) 0.017 Preoperative extrahepatic metastasis (yes versus no) 27.56 (5.91-128.4) <0.001 15.14 (2.52-90.98) 0.003 Microvascular invasion (yes versus no) 2.11 (1.11-4.01) 0.023 0.96 (0.45-2.07) 0.920 World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 140-148 145 Preoperative AFP (> 400 versus ≤ 400μg/l) 1.99 (1.06-3.74) 0.031 1.26 (0.58-2.74) 0.558 Largest tumor size (> 5 versus ≤ 5 cm) 1.94 (1.08-3.47) 0.026 1.77 (0.89-3.53) 0.106 Renewal 2 Univariable Analysis Multivariable Analysis HR (95% CI) P HR (95% CI) P Tumor number (multiple versus solitary) 1.68 (0.78-3.63) 0.186 Satellite nodules (yes versus no) 1.93 (1.12-3.33) 0.018 0.91 (0.35-2.39) 0.851 Tumor differentiation poor 1.00 moderate 0.40 (0.21-0.75) 0.004 0.50 (0.24-1.01) 0.052 well 0.43 (0.16-1.17) 0.098 0.98 (0.31-3.12) 0.971 Surgical approach (laparoscopic versus open ) 1.05 (0.41-2.69) 0.916 Surgical margin (> 1 versus ≤ 1 cm) 0.58 (0.31-1.09) 0.092 0.41 (0.19-0.88) 0.022 Table 3 Univariable and Multivariable Analysis of RFS Univariable Analysis Multivariable Analysis HR (95% CI) P HR (95% CI) P TACE + targeted therapy versus TACE 0.39 (0.21-0.73) 0.004 0.40 (0.20-0.80) 0.010 Sex (male versus female) 0.61 (0.36-1.04) 0.071 0.70 (0.40-1.22) 0.209 Age (years) 1.00 (0.97-1.03) 0.636 ECOG PS (1versus 0 ) 0.96 (0.64-1.42) 0.957 BCLC stage 0 1.00 1.00 A 1.58 (0.83-2.98) 0.162 1.42 (0.72-2.81) 0.309 B 2.72 (1.05-7.06) 0.040 2.03 (0.77-5.40) 0.154 C 3.41 (1.49-7.78) 0.004 2.58 (1.06-6.33) 0.038 Cirrhosis (yes versus no) 0.80 (0.52-1.22) 0.292 Child–Pugh grade (B versus A) 1.34 (0.54-3.31) 0.527 Preoperative extrahepatic metastasis (yes versus no) 12.33 (2.86-53.2) 0.001 5.51 (1.22-24.83) 0.026 Microvascular invasion (yes versus no) 1.72 (1.12-2.64) 0.013 1.18 (0.73-1.91) 0.506 Preoperative AFP (> 400 versus ≤ 400μg/l) 1.60 (1.01-2.55) 0.045 1.28 (0.78-2.13) 0.330 Largest tumor size (> 5 versus ≤ 5 cm) 1.43 (0.96-2.13) 0.076 1.15 (0.74-1.81) 0.530 Tumor number (multiple versus solitary) 1.14 (0.65-2.02) 0.645 Satellite nodules (yes versus no) 1.48 (0.86-2.58) 0.161 Tumor differentiation poor 1.00 1.00 World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 140-148 146 Renewal 3 Univariable Analysis Multivariable Analysis HR (95% CI) P HR (95% CI) P moderate 0.38 (0.250.58) <0.001 0.44 (0.280.70) <0.001 well 0.49 (0.250.99) 0.045 0.66 (0.311.42) 0.286 Surgical approach (laparoscopic versus open ) 1.30 (0.742.31) 0.363 Surgical margin (> 1 versus ≤ 1 cm) 0.872 (0.571.33) 0.524 4. Discussion There is a clear relationship between the severity of the disease and the prognosis, as seen by the decreasing RFS and OS as BCLC staging becomes intermediate from low. This is in line with the clinical suspicion that hepatocellular carcinoma in its advanced stages may have worse prognoses. Improved clinical outcomes have resulted from the study's experimental settings, which may point the way for better postoperative care and longer patient survival rates [14]. Patients with HCC and maintained liver function typically undergo curative Hepatectomy. There is a high rate of recurrence following Hepatectomy, which makes the long-term survival rate unsatisfactory. Among the many unfavorable factors linked to recurrence and very poor RFS and OS after curative resection, MVI stands out [15-16]. Preliminary research found that MVI raised recurrence probabilities [17-18] and lowered survival odds (4.70%, 95% CI: 1.24-17.80). A meta-analysis and thorough assessment of randomized trials revealed that adjuvant TACE therapy did not seem to be helpful for patients with low-risk recurrent HCC. Adjuvant therapy based on standardized antiviral and hepatoprotective treatments is advised for patients at high risk of HCC recurrence (i.e., tumor diameter > 5 cm, combined vascular invasion, multiple tumors or satellite lesions, and residual lesions). This may improve disease-free survival (DFS), RFS, and OS.[19-20]. Due to the fact that MVI mostly disseminate by portal venous branches and can move in both directions when portal venous blood flows, this anatomical state is thought to be required for tumor dissemination in circulation[21]. The presence of MVI is correlated with a number of factors, such as the size, shape, and degree of differentiation of hepatic neoplasms [22]. the invasion of a vessel that is at least 1 cm away from the tumor capsule[23]. The effect of choosing the right margin for anatomic resection on the postoperative course of patients with HCC has been the subject of numerous studies; nevertheless, the significance of this discovery has been called into question. A 2 cm margin safely lowers the postoperative recurrence rate and improves survival outcomes when compared to resection margins between 1 and 2 cm, according to research [24]. A few studies suggest that in order to eradicate microscopic lesions and reduce the chance of recurrence, the majority of patients should have a resection margin of at least 1.0 cm.[25]. In order to remove microscopic lesions, a broader resection margin is preferred, according to a small number of studies [26]. However, the majority of patients in these cohorts had cirrhosis. Preserving nontumorous liver parenchyma in cirrhotic patients is essential to prevent postoperative liver failure. As of right now, no adjuvant treatment for HCC has been approved to prevent recurrence. Many adjuvants therapy have been investigated for HCC after curative resection with the goal of reducing recurrence and extending OS. These treatments consist of TACE, immunological therapies, molecularly targeted medicines, and radiation therapy (RT). However, these therapies don't always yield the expected outcomes.[27-28]. 5. Conclusion By analyzing and comparing the prognostic outcomes of adjuvant TACE combined with or without targeted therapy in high-risk hepatocellular carcinoma patients with postoperative recurrence, this study found that adjuvant TACE combined with targeted therapy had a better prognosis than TACE alone: median OS and median RFS were longer. The combination of adjuvant TACE and targeted therapy is an independent influencing factor for better OS and RFS, respectively. World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 140-148 147 Compliance with ethical standards Disclosure of conflict of interest No conflict of interest to be disclosed. 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