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- Springer Journals
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- Copyright © The Author(s) 2023
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- 1471-2407
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- 10.1186/s12885-023-10802-9
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Abstract
Background The survival benefit of adjuvant transarterial chemoembolization ( TACE) in patients with hepatectomy for hepatocellular carcinoma (HCC) after hepatectomy remains controversial. We aimed to investigate the survival efficacy of adjuvant TACE after hepatectomy for HCC. Methods 1491 patients with HCC who underwent hepatectomy between January 2018 and September 2021 at four medical centers in China were retrospectively analyzed, including 782 patients who received adjuvant TACE and 709 patients who did not receive adjuvant TACE. Propensity score matching (PSM) (1:1) was performed to minimize selection bias, which balanced the clinical characteristics of the two groups. Results A total of 1254 patients were enrolled after PSM, including 627 patients who received adjuvant TACE and 627 patients who did not receive adjuvant TACE. Patients who received adjuvant TACE had higher disease-free survival (DFS, 1- ,2-, and 3-year: 78%-68%-62% vs. 69%-57%-50%, p < 0.001) and overall survival (OS, 1- ,2-, and 3-year: 96%- 88%-80% vs. 90%-77%-66%, p < 0.001) than those who did not receive adjuvant TACE (Median DFS was 39 months). Among the different levels of risk factors affecting prognosis [AFP, Lymphocyte-to-monocyte ratio, Maximum tumor diameter, Number of tumors, Child-Pugh classification, Liver cirrhosis, Vascular invasion (imaging), Microvascular invasion, Satellite nodules, Differentiation, Chinese liver cancer stage II-IIIa], the majority of patients who received Zhao Wu, Lifeng Cui, Junlin Qian and Laihui Luo contributed equally to this work. *Correspondence: Yongzhu He yongzhuhe@email.ncu.edu.cn Liping Liu liuliping@mail.sustech.edu.cn Kun He hekun80@126.com Wei Shen shenweiniu@163.com Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Wu et al. BMC Cancer (2023) 23:325 Page 2 of 9 adjuvant TACE had higher DFS or OS than those who did not receive adjuvant TACE. More patients who received adjuvant TACE accepted subsequent antitumor therapy such as liver transplantation, re-hepatectomy and local ablation after tumor recurrence, while more patients who did not receive adjuvant TACE accepted subsequent antitumor therapy with TACE after tumor recurrence (All p < 0.05). Conclusions Adjuvant TACE may be a potential way to monitor early tumor recurrence and improve postoperative survival in patients with HCC. Keywords Hepatocellular carcinoma(HCC), Hepatectomy, Prognosis, Adjuvant transarterial chemoembolization ( TACE) Introduction of adjuvant TACE for survival of patients with HCC after Hepatocellular carcinoma(HCC) is the most common hepatectomy remains somewhat controversial. primary malignant tumor of the liver [1, 2]. Almost half Therefore, the purpose of this study was to investigate of the newly diagnosed cases of HCC in the world occur the impact of survival with or without adjuvant TACE in China, resulting in more than 300,000 HCC deaths after hepatectomy in patients with HCC, which hopefully each year. Hepatitis B virus (HBV) infection is the most provides a rational treatment decision for clinical work. important risk factor, and patients with HBV infection slowly progress to the stage of cirrhosis and eventually Methods develop HCC. With the development of medical tech- Patients nology, the current treatment methods for HCC include 1491 patients with hepatocellular carcinoma who under- hepatectomy, radiofrequency ablation, transarterial went hepatectomy at four medical centers in China from chemoembolization(TACE), immune targeted therapy, January 2018 to September 2021 were retrospectively etc. [1–4]. Liver transplantation is often limited by organ evaluated. The above four medical centers are the First shortages, medical technical difficulties and poor medical Affiliated Hospital of Nanchang University (FAHNU), conditions, which makes hepatectomy remain the first- the Second Affiliated Hospital of Nanchang Univer - line treatment for patients with early to mid-stage HCC sity (SAHNU), Shenzhen People’s Hospital (SPH) and [2–6]. Because of the majority of HCC in China are diag- Zhongshan People’s Hospital (ZPH). The study was con - nosed at an intermediate or advanced stage, the indica- ducted in accordance with the Declaration of Helsinki tion of surgery is extended to Chinese liver cancer stage (revised in 2013), approved by the ethics committees of (CNLC) II-IIIa [3, 5–7]. However, the survival outcome all medical centers, and informed consent was obtained of most of these intermediate-advanced patients is not from each patient for the data used in the study. Eligible satisfactory [3, 8–10]. patients were screened according to the following inclu- There are two patterns of HCC recurrence after cura - sion criteria: (1) Hepatocellular carcinoma confirmed by tive liver resection: the early-phase and the late-phase [1– postoperative pathology; (2) Tumors were evaluated for 3, 7–10]. The early-phase recurrence occurring in liver CNLC stage I-IIIa; (3) Radical hepatectomy with nega- remnants usually originates from intrahepatic metastasis tive cut margins confirmed by pathology; (4) No antitu - of the primary tumor, whereas the late-phase recurrence mor therapy was given before hepatectomy; (5) No past represents de novo lesions in the liver remnant [1–3, or current history of other malignant tumors; (6) Com- 7–11]. As concern the early recurrence, several authors plete clinical information. Exclusion criteria: (1) Missing believe that during postoperative adjuvant TACE, clinical data or incomplete follow-up; (2) Preoperative residual liver lesions or recurrent tumor lesions can be imaging shows lymph node metastasis or extrahepatic detected early by angiography, and subsequent admin- metastasis; (3) Postoperative pathology confirmed other istration of local chemotherapeutic agents and embolic non-HCC such as bile duct cancer; (4) Patients who have agents that block blood supply can kill and inhibit resid- been diagnosed with other malignant tumors or com- ual or neoplastic tumor cells [12, 13]. However, Chen et bined with serious lesions of the brain, heart, lungs and al. [13]. found that adjuvant TACE does not delay or pre- other organs; (5) Patients who died within 90 days after vent tumor recurrence in patients, and its main role is to operation. A flow chart of the patients enrolled in this detect and treat postoperative residual cancer and early study is shown in Supplementary Fig.S1. recurrent lesions in a timely manner. In addition, the lipi- odol used in TACE can be stably deposited in scattered Hepatectomy and adjuvant TACE microscopic lesions, which indirectly improves the detec- All patients were routinely examined preoperatively with tion rate of microscopic lesions in postoperative com- contrast-enhanced ultrasound, enhanced electron CT, puted tomography (CT) [14]. It is clear that the efficacy and magnetic resonance imaging (MRI), which assessed Wu et al. BMC Cancer (2023) 23:325 Page 3 of 9 tumor status and resectable extent. In addition, liver overall survival (OS) were used as study endpoints. DFS function is assessed with Child-Pugh grading and CT was defined as the time from hepatectomy to diagnosis of volume measurement in all patients. The methods of liver tumor recurrence, while OS was defined as the time from resection include traditional laparotomy, laparoscopic hepatectomy to death or the last follow-up. All patients surgery, anatomic hepatectomy and non-anatomic hepa- were followed up to April 1, 2022. tectomy, and the corresponding surgical methods are adopted according to the location and distribution of the Propensity score matching tumor. Among them, anatomic hepatectomy is the com- To reduce selection bias and confounding factors, pro- plete resection of tumor liver segment or liver segment pensity score matching (PSM) analysis was used to elimi- limited by tumor portal vein branch. Non-anatomic hep- nate imbalances between groups. A 1:1 nearest neighbor atectomy is excision of tumor and partial non-neoplastic matching algorithm was applied with a caliper width of liver parenchyma [15, 16]. 0.01. SPSS 26.0 statistical(IBM Corp, Armonk, NY, USA) Patients will be recommended to undergo adjuvant software was used for PSM. TACE based on high-risk factors affecting patient prog - nosis, such as concomitant high preoperative tumor Statistical methods marker expression, multiple tumor nodules, tumor The independent sample T-test was used to detect the diameter > 5 cm, positive MVI, satellite nodules, and continuous data conforming to normal distribution, poor tumor differentiation [ 12–14, 17–22]. However, which was expressed as mean ± standard deviation. patients will decide whether to follow the advice based Mann-whitney U test was used to detect continuous on their medical adherence, financial status, or other data with non-normal distribution, which was expressed social factors, which would minimizes patient selec- as median (quartile distance, IQR). Chi-square test was tion bias. Patients will be routinely examined for liver used to detect classified data, which were represented as function, tumor markers, CT and/or MRI to determine numbers (n) and proportions (%). Univariate and multi- tumor recurrence or metastasis before receiving adju- variate analyses were performed in Cox risk models to vant TACE. Patients with normal liver function receive identify independent prognostic factors for DFS and OS, adjuvant TACE about 4 weeks after hepatectomy. The where variables with P values < 0.05 were used in mul- Seldinger technique was used to place the hepatic arte- tivariate analyses in univariate analyses. OS and DFS of rial catheter into the proper hepatic artery through the independent prognostic factors screened after PSM using femoral artery and perform TACE on the entire remnant kaplan-Meier survival analysis, and differences between liver. Detection of any suspicious tumor staining in the curves were estimated by log-rank test. R software (Ver- remnant liver by digital subtraction angiography (DSA) sion 4.2.1 http://www.r-project.org) was used for sta- or CT angiography during operation of PA-TACE. If no tistical analysis of the above data. In addition, x-Tiles tumor staining is found, a mixture of chemotherapeu- 3.6.1 software(http://tissuearray.org/) was used to deter- tic agents (fluorouracil, epirubicin and platinum) and mine the optimal cut-off value for continuous indepen - embolic agents (lipiodol and gelatine sponge) is then dent prognostic factors screened by Cox proportional administered through a catheter to the remaining liver risk model after PSM. All P values were obtained by based on a comprehensive assessment of the patient’s two-tailed test, and P < 0.05 was considered statistically body surface area, physical fitness, and residual liver vol - significant. ume [17–22]. Results Follow-up Clinical characteristics All patients were followed up during outpatient or inpa- A total of 1491 patients with HCC who underwent hep- tient visits. Patients were followed up every 1–2 months atectomy were included, including 782 patients who for six months after discharge and every 3–6 months received adjuvant TACE and 709 patients who did not thereafter. During follow-up, each patient underwent receive TACE. A total of 12 clinical factors [Age, AFP, routine liver function tests, serum alpha-fetoprotein Alanine aminotransferase (ALT), Aspartate aminotrans- (AFP) analysis, and ultrasound examination. When ferase (AST), Alkaline phosphatase (ALP), Platelet- recurrence is suspected, enhanced CT or enhanced MRI to-lymphocyte ratio(PLR), Operation time, Maximum is subsequently used to confirm the diagnosis. Recur - tumor diameter, Anatomical liver resection, Micro- rence was defined as neoplastic nodules confirmed by vascular invasion (MVI), Differentiation, CNLC stage] two imaging studies or by needle biopsy. Treatment of were significantly different between groups before PSM recurrent tumors includes liver transplantation, rehepa- (Table 1, all p < 0.05). 627 patients in each group matched tectomy, local ablation, TACE, chemoradiotherapy, and by PSM, which resulted in no significant differences in immunotargeted therapy. Disease free survival (DFS) and clinical factors between groups (Table 1, all p > 0.05). Wu et al. BMC Cancer (2023) 23:325 Page 4 of 9 Table 1 Clinical characteristics of patients with HCC who underwent adjuvant TACE or not Clinical characteristics Before PSM After PSM Total P Total P Adjuvant TACE Adjuvant TACE (n = 1491) (n = 1254) No (n = 709) Yes (n = 782) No (n = 627) Yes (n = 627) Age (years) 56.00 (47.00, 57.00 (48.00, 55.00 (47.00, 0.007 56.00 (47.00, 56.00 (47.00, 56.00 (48.00, 0.908 64.00) 66.00) 63.00) 64.00) 65.00) 64.00) AFP (ng/mL) 53.05 (6.30, 38.40 (5.00, 77.200 (7.68, 0.003 47.38 (6.00, 38.66 (5.01, 67.50 (7.05, 0.107 879.63) 526.68) 1000.00) 718.00) 620.10) 812.75) ALT (U/L) 30.80 (22.00, 29.00 (21.00, 32.86 (23.00, 0.001 30.00 (21.20, 29.00 (21.05, 31.00 (21.45, 0.238 45.66) 43.00) 48.00) 44.58) 44.00) 44.90) AST (U/L) 35.00 (26.99, 33.21 (26.00, 37.00 (28.00, < 0.001 34.00 (26.00, 33.21 (26.00, 34.55 (26.58, 0.106 50.00) 46.82) 52.97) 48.00) 46.73) 50.00) GGT (U/L) 53.00 (30.14, 53.47 (30.00, 52.59 (30.53, 0.608 50.06 (29.01, 54.63 (30.24, 46.54 (29.00, 0.083 104.31) 104.90) 104.00) 99.11) 106.50) 92.00) ALP (U/L) 96.00 (75.00, 93.00 (72.00, 98.13 (77.29, 0.034 95.00 (75.00, 93.23 (73.42, 96.50 (76.71, 0.327 123.00) 122.55) 124.80) 122.97) 122.90) 122.94) TB (mol/L) 14.60 (10.80, 14.10 (10.40, 14.80 (11.19, 0.106 14.40 (10.70, 14.20 (10.40, 14.60 (11.07, 0.236 19.77) 19.80) 19.68) 19.74) 19.77) 19.63) WBC (10 /L) 5.30 (4.27, 6.53) 5.24 (4.22, 5.34 (4.33, 0.738 5.30 (4.30, 6.50) 5.30 (4.33, 5.30 (4.26, 0.346 6.59) 6.50) 6.65) 6.44) CR (µmol/L) 72.80 (62.40, 72.70 (62.40, 72.86 (62.45, 0.829 73.00 (63.00, 73.00 (62.45, 73.10 (63.13, 0.453 82.90) 82.95) 82.86) 83.00) 82.64) 83.35) PT (s) 11.90 (11.30, 11.90 (11.30, 11.90 (11.30, 0.892 11.90 (11.30, 11.90 (11.30, 11.90 (11.30, 0.700 12.60) 12.60) 12.60) 12.60) 12.60) 12.70) NLR 2.20 (1.61, 3.22) 2.20 (1.59, 2.22 (1.62, 0.194 2.22 (1.61, 3.23) 2.24 (1.60, 2.20 (1.62, 0.678 3.12) 3.28) 3.22) 3.26) LMR 3.42 (2.59, 4.77) 3.50 (2.59, 3.40 (2.59, 0.687 3.45 (2.60, 4.85) 3.47 (2.56, 3.44 (2.64, 0.495 4.90) 4.72) 4.89) 4.83) PLR 110.20 (82.18, 104.20 (78.01, 113.51 (86.96, < 0.001 109.78 (82.30, 107.20 111.71 (85.50, 0.153 153.29) 148.57) 158.14) 150.50) (80.34, 151.93) 150.00) Operation time (mins) 220.00 (165.00, 215.00 (160.00, 220.00 (176.25, 0.044 220.00 (170.00, 220.00 220.00 (175.00, 0.680 280.00) 270.00) 280.00) 280.00) (165.00, 280.00) 280.75) Maximum tumor diameter 44.00 (27.00, 40.00 (25.00, 49.00 (29.25, < 0.001 43.00 (27.00, 43.00 (27.00, 43.000 (27.00, 0.934 (mm) 71.00) 65.00) 76.00) 68.00) 69.00) 67.50) Gender male 1263 (84.71) 600 (84.63) 663 (84.78) 0.991 1064 (84.85) 534 (85.17) 530 (84.53) 0.813 [n(%)] female 228 (15.29) 109 (15.37) 119 (15.22) 190 (15.15) 93 (14.83) 97 (15.47) HBV [n(%)] Negative 199 (13.35) 107 (15.09) 92 (11.76) 0.070 169 (13.48) 94 (14.99) 75 (11.96) 0.137 Positive 1292 (86.65) 602 (84.91) 690 (88.24) 1085 (86.52) 533 (85.01) 552 (88.04) Child–Pugh A 1424 (95.51) 673 (94.92) 751 (96.04) 0.362 1199 (95.61) 596 (95.06) 603 (96.17) 0.408 classifica - B 67 (4.49) 36 (5.08) 31 (3.96) 55 (4.39) 31 (4.94) 24 (3.83) tion [n(%)] Liver No 373 (25.02) 178 (25.11) 195 (24.94) 0.988 306 (24.40) 155 (24.72) 151 (24.08) 0.844 cirrhosis Yes 1118 (74.98) 531 (74.89) 587 (75.06) 948 (75.60) 472 (75.28) 476 (75.92) [n(%)] Number single 1307 (87.66) 630 (88.86) 677 (86.57) 0.207 1104 (88.04) 556 (88.68) 548 (87.40) 0.542 of tumors multiple 184 (12.34) 79 (11.14) 105 (13.43) 150 (11.96) 71 (11.32) 79 (12.60) [n(%)] Tumor left 472 (31.66) 232 (32.72) 240 (30.69) 0.648 402 (32.06) 207 (33.01) 195 (31.10) 0.768 location right 945 (63.38) 444 (62.62) 501 (64.07) 793 (63.24) 391 (62.36) 402 (64.11) [n(%)] double 74 (4.96) 33 (4.65) 41 (5.24) 59 (4.70) 29 (4.63) 30 (4.78) Tumor mar- Non-smooth 376 (25.22) 181 (25.53) 195 (24.94) 0.839 313 (24.96) 161 (25.68) 152 (24.24) 0.602 gin [n(%)] Smooth 1115 (74.78) 528 (74.47) 587 (75.06) 941 (75.04) 466 (74.32) 475 (75.76) Vascular Negative 1362 (91.35) 653 (92.10) 709 (90.66) 0.372 1161 (92.58) 575 (91.71) 586 (93.46) 0.281 invasion Positive 129 (8.65) 56 (7.90) 73 (9.34) 93 (7.42) 52 (8.29) 41 (6.54) (imaging) [n(%)] Wu et al. BMC Cancer (2023) 23:325 Page 5 of 9 Table 1 (continued) Clinical characteristics Before PSM After PSM Total P Total P Adjuvant TACE Adjuvant TACE (n = 1491) (n = 1254) No (n = 709) Yes (n = 782) No (n = 627) Yes (n = 627) Anatomical No 457 (30.65) 245 (34.56) 212 (27.11) 0.002 384 (30.62) 208 (33.17) 176 (28.07) 0.058 liver resec- Yes 1034 (69.35) 464 (65.44) 570 (72.89) 870 (69.38) 419 (66.83) 451 (71.93) tion [n(%)] Laparo- No 898 (60.23) 422 (59.52) 476 (60.87) 0.632 735 (58.61) 365 (58.21) 370 (59.01) 0.819 scopic Yes 593 (39.77) 287 (40.48) 306 (39.13) 519 (41.39) 262 (41.79) 257 (40.99) surgery [n(%)] MVI [n(%)] Negative 839 (56.27) 450 (63.47) 389 (49.74) < 0.001 741 (59.09) 372 (59.33) 369 (58.85) 0.909 Positive 652 (43.73) 259 (36.53) 393 (50.26) 513 (40.91) 255 (40.67) 258 (41.15) Satellite Negative 1268 (85.04) 607 (85.61) 661 (84.53) 0.607 1072 (85.49) 527 (84.05) 545 (86.92) 0.173 nodules Positive 223 (14.96) 102 (14.39) 121 (15.47) 182 (14.51) 100 (15.95) 82 (13.08) [n(%)] Differentia - High-medium 1231 (82.56) 604 (85.19) 627 (80.18) 0.013 1038 (82.78) 528 (84.21) 510 (81.34) 0.204 tion [n(%)] low 260 (17.44) 105 (14.81) 155 (19.82) 216 (17.22) 99 (15.79) 117 (18.66) CNLC stage I 1259 (84.43) 615 (86.74) 644 (82.35) 0.026 1077 (85.89) 540 (86.12) 537 (85.65) 0.162 [n(%)] II 103 (6.91) 37 (5.22) 66 (8.44) 84 (6.70) 35 (5.58) 49 (7.81) III a 129 (8.65) 57 (8.04) 72 (9.21) 93 (7.42) 52 (8.29) 41 (6.54) HCC, Hepatocellular carcinoma; PSM, Propensity score matching; TACE, Transarterial chemoembolization; AFP, Alpha-fetoprotein; ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; GGT, Gamma-glutamyltransferase; ALP, Alkaline phosphatase; TB, Total bilirubin; WBC, White blood cell; CR, Creatinine; PT, Prothrombin time; NLR, Neutrophil-to-lymphocyte ratio; LMR, Lymphocyte-to-monocyte ratio; PLR, Platelet-to-lymphocyte ratio; HBV, Hepatitis B virus; MVI, Microvascular invasion; CNLC, Chinese liver cancer Risk factors for DFS and OS after PSM Critical values of continuous variables in risk factors 10 clinical factors [Fig. 1A; AFP, p = 0.001; Lymphocyte- Among continuous variables, only AFP was an indepen- to-monocyte ratio (LMR), p = 0.021; Maximum tumor dent risk factor for DFS, so X-Tiles software was used diameter, p < 0.001; Number of tumors, p = 0.007; Vascu- to determine the optimal cut-off value of AFP at 996.7 lar invasion (imaging), p = 0.020; MVI, p < 0.001; Satellite ng/mL (Supplementary Fig. S2 ABC). Maximum tumor nodules, p < 0.001; Differentiation, p < 0.001; Adjuvant diameter and LMR were the common independent risk TACE, p < 0.001; CNLC stage, p = 0.013, p = 0.005] were factors for DFS and OS among the continuous variables found to be independent risk factors for DFS, while after multi-factor analysis. Therefore, it was determined 10 clinical factors [Fig. 1B; LMR, p = 0.024; Maximum by x-Tiles software that 2.7 and 2.5 were the cut-off val - tumor diameter, p < 0.001; Child-Pugh classification, ues of LMR (Supplementary Fig. S3 ABCDEF), while 55 p = 0.038; Liver cirrhosis, p = 0.009; Vascular invasion and 57 mm were the cut-off values of maximum tumor (imaging), p = 0.013; MVI, p < 0.001; Satellite nodules, diameter (Supplementary Fig. S4 ABCDEF). For the con- p < 0.001; Differentiation, p < 0.001; Adjuvant TACE, venience of calculation, 2.6 (average) was taken as the p < 0.001; CNLC stage, p = 0.041, p = 0.017] were found to optimal cut-off value of LMR, and 55 mm was taken as be independent risk factors for OS. During the follow-up the best cut-off value of maximum tumor diameter. period, there were 452 tumor recurrences and 226 deaths after hepatectomy in patients with HCC. Patients who Kaplan-Meier analysis of DFS and OS after PSM received adjuvant TACE had higher DFS (Fig. 1C- ,2-, The results of the subgroup Kaplan-Meier survival analy - and 3-year: 78%-68%-62% vs. 69%-57%-50%, p < 0.001) sis at 1, 2, and 3 years were as follows (Fig. 2): Patients and OS (Fig. 1D- ,2-, and 3-year: 96%-88%-80% vs. 90%- at different CNLC stages who received adjuvant TACE 77%-66%, p < 0.001) than those who did not receive adju- had significantly higher DFS [Figs. 2A and I and 83%- vant TACE (Median DFS was 39 months). There were 70%-63% vs. 75%-61%-55%, p = 0.001; II (Median of 30 significant differences in DFS [Fig. 1E; I vs. II, p < 0.001; months vs. Median of 11 months), 70%-51%-47% vs. II (Median of 19 months) vs. IIIa (Median of 7 months), 44%-31%-31%, p = 0.011; IIIa (Median of 17 months vs. p = 0.012; I vs. IIIa, p < 0.001] and OS [Fig. 1F; I vs. II, Median of 4 months), 53%-47%-47% vs. 29%-19%-15%, p = 0.025; II vs. IIIa (Median of 29 months), p = 0.006; I p = 0.003] and OS [Figs. 2B and I and 97%-89%-83% vs. vs. IIIa, p < 0.001] among patients with different CNLC 93%-81%-70%, p < 0.001; II (No median OS vs. Median stages. of 26 months), 95%-90%-85% vs. 78%-52%-42%, p < 0.001; IIIa (Median of 33 months vs. Median of 18 months), 87%-67%-46% vs. 75%-46%-32%, p = 0.029] than those Wu et al. BMC Cancer (2023) 23:325 Page 6 of 9 Negative, p = 0.003; Positive, p < 0.001), Differentiation (Supplementary Fig. S9 AC; High-medium vs. Low, p < 0.001; High-medium, p = 0.001; Low, p < 0.001)] or OS [Fig. 2D; LMR (Supplementary Fig. S3 HJ; ≤ 2.6 vs. > 2.6, p = 0.005; ≤ 2.6, p < 0.001; > 2.6, p = 0.045), Maximum tumor diameter (Supplementary Fig. S4 HJ; ≤ 55 mm vs. > 55 mm, p < 0.001; ≤ 55 mm, p < 0.001; > 55 mm, p = 0.001), Child-Pugh classification (Supplementary Fig. S5 CD; A vs. B, p < 0.001; A, p < 0.001; B, p = 0.016), Liver cirrhosis (Supplementary Fig. S5 EF; No vs. Yes, p = 0.007; No, p = 0.073; Yes, p < 0.001), Vascular inva- sion (imaging, Supplementary Fig. S6 BD; Negative vs. Positive, p < 0.001; Negative, p < 0.001; Positive, p = 0.029), MVI (Supplementary Fig. S7 BD; Negative vs. Positive, p < 0.001; Negative, p = 0.163; Positive, p < 0.001), Satellite nodules (Supplementary Fig. S8 BD; Negative vs. Positive, p < 0.001; Negative, p < 0.001; Positive, p < 0.001), Differ - entiation (Supplementary Fig. S9 BD; High-medium vs. Low, p < 0.001; High-medium, p < 0.001; Low, p = 0.046)] than those who did not receive adjuvant TACE. Follow-up antitumor therapy More patients who received adjuvant TACE accepted subsequent antitumor therapy such as liver transplan- tation (Before PSM, p = 0.037; After PSM, p = 0.017), Fig. 1 Univariate and multifactorial analysis of Cox regression models for re-hepatectomy (Before PSM, p = 0.103; After PSM, DFS (A) and OS (B) in patients with HCC undergoing hepatectomy after PSM; Kaplan-Meier analysis of DFS (C) and OS (D) for patients with HCC p = 0.036) and local ablation (Before PSM, p < 0.001; who received adjuvant TACE or not; Kaplan-Meier analysis of DFS (E) and After PSM, p = 0.001) after tumor recurrence, while more OS (F) for patients with different CNLC stages. DFS, Disease-free survival; patients who did not receive adjuvant TACE accepted OS, Overall survival; HCC, Hepatocellular carcinoma; PSM, Propensity subsequent antitumor therapy with TACE (Before PSM, score matching; TACE, Transarterial chemoembolization; CNLC, Chinese p < 0.001; After PSM, p < 0.001) after tumor recurrence liver cancer; HR, Hazard ratio; Cl, Confidence interval; AFP, Alpha-feto- protein; ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; (Table 2). GGT, Gamma-glutamyltransferase; ALP, Alkaline phosphatase; TB, Total bilirubin; WBC, White blood cell; CR, Creatinine; PT, Prothrombin time; Discussion NLR, Neutrophil-to-lymphocyte ratio; LMR, Lymphocyte-to-monocyte Barcelona Clinic Liver Cancer (BCLC) stage has long ratio; PLR, Platelet-to-lymphocyte ratio; HBV, Hepatitis B virus; MVI, Mi- been a widely used clinical guideline for HCC in interna- crovascular invasion tional clinical practice [5]. In order to benefit the survival who did not receive adjuvant TACE. Among the differ - of more patients with intermediate to advanced HCC, the ent levels of risk factors affecting prognosis, the majority surgical indications of CNLC stage have been expanded of patients who received adjuvant TACE had higher DFS compared with BCLC stage [3]. Although the expanded [Fig. 2C; AFP (Supplementary Fig. S2 DE; ≤ 996.7ng/mL indications for surgery have led to better outcomes for vs. > 996.7ng/mL, p < 0.001; ≤ 996.7ng/mL, p < 0.001; > more patients with HCC, these patients inevitably have 996.7ng/mL, p = 0.001), LMR (Supplementary Fig. S3 GI; a higher recurrence rate [3, 8–10]. Therefore, post-hepa - ≤ 2.6 vs. > 2.6, p = 0.018; ≤ 2.6, p = 0.129; > 2.6, p < 0.001), tectomy adjuvant therapy is more necessary for patients Maximum tumor diameter (Supplementary Fig. S4 GI; with high-risk recurrent tumors. ≤ 55 mm vs. > 55 mm, p < 0.001; ≤ 55 mm, p = 0.002; > In recent years, adjuvant TACE has been the most 55 mm, p = 0.001), Number of tumors (Supplementary commonly applied treatment modality for patients with Fig. S5 AB; Single vs. Multiple, p < 0.001; Single, p < 0.002; high rates of postoperative tumor recurrence [18–20]. Multiple, p = 0.002); Vascular invasion (imaging, Supple- However, adjuvant TACE after hepatectomy has not been mentary Fig. S6 AC; Negative vs. Positive, p < 0.001; Neg- fully accepted by experts internationally, and its efficacy ative, p < 0.001; Positive, p = 0.003), MVI (Supplementary is still controversial to some extent. An earlier prospec- Fig. S7 AC; Negative vs. Positive, p < 0.001; Negative, tive randomized trial found a significant benefit of liver p = 0.259; Positive, p < 0.001), Satellite nodules (Supple- resection combined with adjuvant TACE in terms of mentary Fig. S8 AC; Negative vs. Positive, p < 0.001; recurrence and survival of patients [21]. In this study, Wu et al. BMC Cancer (2023) 23:325 Page 7 of 9 Fig. 2 Subgroup Kaplan-Meier analysis of DFS (A) and OS (B) for patients with different CNLC stages who received adjuvant TACE or not; Subgroup forest plots of DFS (C) and OS (D) at 1, 2, and 3 years for patients with different risk factors who received adjuvant TACE or not. DFS, Disease-free survival; OS, Overall survival; CNLC, Chinese liver cancer; TACE, Transarterial chemoembolization; AFP, Alpha-fetoprotein; LMR, Lymphocyte-to-monocyte ratio; MVI, Microvascular invasion; CNLC, Chinese liver cancer Table 2 Follow-up antitumor therapy after confirmation of tumor recurrence in patients who received adjuvant TACE or not Anti-tumor therapy Before PSM After PSM P P Adjuvant TACE Adjuvant TACE No (n = 275) Yes (n = 274) No (n = 255) Yes (n = 197) Liver transplantion 4 12 0.037 4 11 0.017 Re-hepatectomy 10 18 0.103 10 17 0.036 Local ablation 111 147 < 0.001 105 112 0.001 TACE 86 42 < 0.001 79 22 < 0.001 chemoradiotherapy 15 8 0.155 14 5 0.125 immunotargeted therapy 49 47 0.954 43 30 0.668 TACE, Transarterial chemoembolization patients who received adjuvant TACE had a significantly improved, whereas the prognosis of patients with nega- improved prognosis, which makes the results consistent tive MVI who received adjuvant TACE was not affected. with the views of some scholars [18–21]. However, the In addition, patients accompanied by satellite nodules follow-up period of this study was only 3 years, and the and high-medium-differentiated tumors also obtained efficacy of adjuvant TACE on the long-term survival of better survival effects after receiving adjuvant TACE. patients still needs to be further explored. However, patients with Low differentiated tumors in Wang et al. [18] found that the prognosis of patients this study who received adjuvant TACE did not have a with MVI who received adjuvant TACE was significantly longer survival. This result above may be related to the Wu et al. BMC Cancer (2023) 23:325 Page 8 of 9 overpowering invasive and metastatic ability of Low dif- clinical guidelines for adjuvant TACE, and the drugs and ferentiated tumors [22]. u Th s, it seems that the postop - doses may vary from one medical center to another; (3) erative pathological findings are highly informative for Ultrasound combined with AFP was used as the initial patients to choose adjuvant TACE or not. monitoring tool for follow-up in this study, which had an Whether the indication for postoperative adjuvant impact on the rate of early recurrence of missed tumors. TACE depends exclusively on the high-risk recurrence It is hoped that more large, multi-center, prospective tri- population. It is well known that vascular tumor invasion als will be conducted in the future to verify the findings is a high-risk factor that severely affects patient prognosis of this study. [23, 24]. In this study, patients with or without vascular Overall, adjuvant TACE is not only an invasive diag- tumor invasion had better survival results after receiving nostic procedure for early monitoring of tumor recur- adjuvant TACE. In addition, patients in different CNLC rence, but may also be a potential treatment to improve stages also have a survival benefit with adjuvant TACE. the survival of patients with HCC after hepatectomy. It follows that the population suitable for adjuvant TACE is not limited to such patients. Meanwhile, some scholars Supplementary Information The online version contains supplementary material available at https://doi. believe that tumor recurrence in patients with cirrhosis org/10.1186/s12885-023-10802-9. may be a new tumor rather than an intrahepatic metas- tasis of the tumor, which may be the result of surgery Supplementary Material 1 to remove only the primary tumor but not the sclerotic Supplementary Material 2 liver with cancerous potential [25, 26]. Marasco et al. [26] Supplementary Material 3 showed that cirrhosis is a risk factor for late recurrence of Supplementary Material 4 HCC and is directly related to the degree of liver disease and portal hypertension. Patients with cirrhosis in this Supplementary Material 5 study had a significantly lower OS rate than those with - Supplementary Material 6 out cirrhosis. Interestingly, OS improved in patients with Supplementary Material 7 and without cirrhosis who received adjuvant TACE. It Supplementary Material 8 is worth considering whether patients without high-risk Supplementary Material 9 factors should receive adjuvant TACE. It should not be overlooked that adjuvant TACE is not Supplementary Material 10 only a treatment but also an invasive diagnostic pro- cedure. If tumor staining is detected during adjuvant Acknowledgements TACE, it may be considered a diagnostic tool to monitor Not applicable. tumor recurrence rather than an adjuvant treatment [27]. Authors’ contributions On the other hand, more patients who received adjuvant Zhao Wu, Lifeng Cui, Junlin Qian, Laihui Luo: Concept, design, data collection, TACE underwent subsequent curative treatment (liver analysis, manuscript preparation, editing. Shuju Tu, Fei Cheng, Lebin Yuan, WenJian Zhang, Wei Lin, Hongtao Tang, Xiaodong Li: Data collection, analysis, transplantation, re-hepatectomy, or local ablation) after manuscript preparation, editing. Hui Li, Yang Zhang, Jisheng Zhu, Yong Li, the diagnosis of tumor recurrence, which may have led Yuanpeng Xiong, Zemin Hu, Peng Peng: Analysis, manuscript preparation, to longer overall survival for them. Earlier monitoring of editing. Yongzhu He, Liping Liu, Kun He, Wei Shen: Guarantees the integrity of the entire study and manuscript review. All authors have read and approved tumor recurrence during adjuvant TACE may result in the final version to be submitted. lesions that are usually localized and controllable, which further affects subsequent antitumor therapy. In contrast, Funding This work was funded by Natural Science Foundation of Jiangxi Provincial more patients who did not receive adjuvant TACE under- (Project Number: 20171BAB205064) and National Natural Science Foundation went subsequent palliative treatment (TACE), which may of China (Project Number: 81860432) that have no role in the collection, be related to the greater extent of tumor recurrence and analysis, interpretation of results or writing of the manuscripts. unfavorable factors such as large vessel cancer throm- Data availability bosis and extrahepatic metastases [28]. In conclusion, The datasets generated and analyzed during the current study are not the effect of adjuvant TACE on recurrence patterns and publicly available due to privacy and ethical concerns, but are available from the corresponding author on reasonable request. the direct therapeutic effect of adjuvant TACE itself may together contribute to the survival benefit in this patient Declarations population. This may explain why the majority of patients in this study had a significant survival benefit after receiv - Ethics approval and consent to participate ing adjuvant TACE. 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Journal
BMC Cancer – Springer Journals
Published: Apr 7, 2023
Keywords: Hepatocellular carcinoma(HCC); Hepatectomy; Prognosis; Adjuvant transarterial chemoembolization (TACE)