DOI: https://doi.org/10.21203/rs.3.rs-2096398/v1
We investigated the effects of postoperative adjuvant antiviral therapy (AVT) on elderly patients following curative treatment for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC).
A total of 300 elderly patients with HBV-related HCC were recruited, which comprised 123 non-AVT groups and 177 AVT groups. Propensity score matching (PSM) was developed to reduce any bias in patient selection. Independent risk factors were identified by Cox regression analysis.
After PSM, the 1-, 3-, and 5-year OS rates in the AVT group and non-AVT group were 97.5%, 76.0%, 55.0%, and 83.5%, 60.1%, 40.9%, (p = 0.003), respectively. The 1-, 3-, and 5-year RFS rates in the AVT group and non-AVT group were 76.6%, 50.2%, 30.4%, and 63.2%, 42.4%, 26.6% (p = 0.120), respectively. Multivariate Cox analysis revealed that postoperative adjuvant AVT was the independent protective factor associated with mortality (HR = 0.46, 95%CI = 0.31–0.68, p < 0.001).
Among patients who underwent curative hepatectomy for HBV-related elder HCC. Postoperative adjuvant AVT can improve long-term survival and was the independent protective factor associated with survival after PSM.
Hepatocellular carcinoma (HCC) is characterized by low survival and poor prognosis, ranking as the third leading cause of cancer-related mortality in the world[1]. Hepatitis B virus (HBV) infection has been identified as an important etiological factor in hepatocarcinogenesis in Eastern countries (evidence level (EL) 1A)[2]. Nearly 70–90% of HCC cases are associated with HBV infection[2]. Hepatocellular carcinoma (HCC) is the most common malignant tumor in the elderly. Smith et al reported an 88% increase in the incidence of hepatobiliary malignancy among patients ≥ 65 years old compared with an overall 59% increase in the projected incidence[3]. Thus, it is urgent to focus on elderly patients with HCC.
Although hepatic resection is the mainstay of curative therapy for HCC, the high incidence of recurrence remains the major obstacle to improving long-term survival, with almost 70% of patients developing recurrence within 5 years of resection[4, 5]. At present, there is no standard adjuvant treatment for the prevention of recurrence in patients who underwent hepatic resection for HCC. Some studies show that antiviral therapy improves HBV-related HCC survival and reduces tumor recurrence after curative hepatic resection[6–8]. While other studies present different opinions on the efficacy of postoperative anti-HBV therapy[9, 10]. This may be due to different study populations included. Not all patients benefit from receiving postoperative anti-HBV therapy. We note that these present studies were conducted on younger patients (mean age < 65 years), but lack on elderly patients (mean age ≥ 65 years). In addition, basic studies have shown that HBV DNA level is lower in old people[11] and Spontaneous HBsAg seroclearance is higher in patients older than 60 years[12], so there are some differences between young patients and elderly patients in HBV infection.
Based on the above evidence, whether postoperative adjuvant anti-HBV therapy reduces tumor recurrence and improves postoperative survival in elderly HCC is still unclear. Therefore, a multicenter study was conducted to investigate the efficacy of postoperative adjuvant anti-HBV therapy on elderly HCC after R0 hepatic resection.
The multicenter retrospective study was conducted on patients who underwent R0 hepatic resection for HCC from January 2009 to December 2015 were extracted from primary liver cancer big data (PLCBD). The study was performed according to the ethical standards of the Declaration of Helsinki and was approved by the institutional ethics committee. Informed consent was obtained from each patient before surgery.
The inclusion criteria included: (1) HCC diagnosis confirmed by pathology, (2) Age ≥ 65 years, (3) positive hepatitis B surface antigen (HBsAg) and negative hepatitis C antibody, and (4) R0 resection, which was defined as complete resection of the tumor with negative margins. Patients who had (1) extrahepatic metastasis, (2) preoperative anticancer, (3) palliative tumor resection, (4) history of other malignancies, (5) recurrence within 60 days after surgery, (6) incomplete clinical data, (7) perioperative death, and (8) lost to follow-up within 60 days after discharge were excluded.
Patient baseline characteristics included demographic information, surgical factors, laboratory parameters, and tumor characteristics. Blood samples were obtained within 14 days before surgery for routine laboratory tests for blood cells, liver function, a-fetoprotein (AFP), hepatitis B virus, hepatitis B e antigen, and hepatitis B virus deoxyribonucleic acid (HBV-DNA) load. The albumin–bilirubin (ALBI) grade was calculated by the formula, 0.66 × log10 (bilirubin, µmol/L)-0.085 × (albumin, g/l). According to the previously described cutoff results in two grades: ALBI grade 1 (≤ 2.63), and grade 2 (> 2.63). Tumor characteristics were obtained from postoperative pathological reports.
All patients were followed up once every 3–4 months for the first 2 years after discharge from hospitals and every 4–6 months in subsequent years. The follow-up examination included serum AFP, liver function, and at least one abdomen image scan, including abdomen ultrasonography, magnetic resonance imaging (MRI), or abdominal computed tomography scan (CT).
The diagnosis and management of tumor recurrence relied on the evidence of imaging findings according to the current guidelines[13]. Primary end-points were overall survival (OS) and recurrence-free survival (RFS). OS was defined as the interval between the date of surgery and the date of patient death or the date of the last follow-up. RFS was the interval between the date of surgery and the date when tumor recurrence was diagnosed or the date of patient death or the date of the last follow-up. The follow-up was censored on 31st May 2022.
The definition of “elderly” varies in published work, ranging from 60–80 years old. Smith et al reported an 88% increase in the incidence of hepatobiliary malignancy among patients ≥ 65 years old compared with an overall 59% increase in the projected incidence[3]. Therefore, the age threshold for old people is ≥ 65 years old in our study.
Postoperative adjuvant AVT was defined as continuously using at least one type of AVT drug for more than 3 months after hepatic resection within 3 months. The indications of AVT were mainly according to the contemporary guidelines for the management of patients with HBV infection. The nucleoside and nucleotide analogs were used for AVT in this study, including lamivudine (100 mg per day) adefovir (10 mg per day), and entecavir (0.5 mg per day).
Propensity score matching (PSM) was developed to reduce any bias in patient selection. Possible unbalanced variables in baseline between non-AVT and AVT groups were matched by a 1:1 ratio nearest neighbor match with a caliber of 0.3.
Categorical variables were grouped based on a normal reference value or clinical judgment and were presented as n (%) and compared using the chi-square test or Fisher exact test. Continuous variables were adopted by Student’s t-test or Mann–Whitney U-test for comparison and demonstrated with a mean (standard deviation, SD). Univariate and multivariate Cox proportional hazard regression was performed to detect the independent factors of OS and RFS after PSM. Kaplan–Meier method was used to estimate OS and RFS rates before and after PSM, and the difference between the two groups was analyzed by the log-rank test.
All statistical tests were two-tailed, and a p-value of less than 0.05 was considered statistically significant. All statistical analysis was performed with R version 4.0.4(http://www.r-project.org/). The R packages of “Table 1”, “Matchit”, “glmnet”, “survminer”, and “survival” were used in this study.
During the study period, there were a total of 361 patients with HBV-related elderly HCC patients who received R0 hepatic resection. 61 patients were excluded because of extrahepatic metastasis (n = 7), preoperative anticancer (n = 6), palliative tumor resection (n = 7), history of other malignancies (n = 5), recurrence within 60 days after surgery (n = 3), incomplete clinical data (n = 11), perioperative death (n = 8), and lost to follow-up within 60 days after discharge (n = 14). Finally, the study consisted of 300 patients, which comprises 123 non-AVT groups and 177 AVT groups. The flow chart of patient’s selection was shown in Fig. 1.
As summarized in Table 1, AVT groups had lower rates of HBeAg positive (78.0% vs 93.5%), and smaller tumor sizes (5.17 vs 6.19 cm). Other variables didn’t exist a difference between the two groups.
To minimize the effect of potential confounders, we generated 120 pairs of patients by propensity score matching. Of the 120 pairs of propensity score-matched patients, the non-AVT and AVT groups did not differ significantly in baseline characteristics (Table 1).
|
Variables |
Before PSM |
After PSM |
||||
|---|---|---|---|---|---|---|
|
non-AVT (n = 123) |
AVT (n = 177) |
p-value |
non-AVT (n = 120) |
AVT (n = 120) |
p-value |
|
|
Gender |
||||||
|
Female |
19 (15.4%) |
25 (14.1%) |
0.879 |
15 (12.5%) |
18 (15.0%) |
0.708 |
|
Male |
104 (84.6%) |
152 (85.9%) |
105 (87.5%) |
102 (85.0%) |
||
|
HBeAg |
||||||
|
Negative |
8 (6.5%) |
39 (22.0%) |
< 0.001 |
8 (6.7%) |
8 (6.7%) |
1.000 |
|
Positive |
115 (93.5%) |
138 (78.0%) |
112 (93.3%) |
112 (93.3%) |
||
|
AFP, ng/mL |
||||||
|
< 400 |
93 (75.6%) |
132 (74.6%) |
0.946 |
90 (75.0%) |
93 (77.5%) |
0.762 |
|
≥ 400 |
30 (24.4%) |
45 (25.4%) |
30 (25.0%) |
27 (22.5%) |
||
|
HBVDNA, IU/mL |
||||||
|
≤ 1000 |
16 (13.0%) |
30 (16.9%) |
0.442 |
20 (16.7%) |
16 (13.3%) |
0.588 |
|
> 1000 |
107 (87.0%) |
147 (83.1%) |
100 (83.3%) |
104 (86.7%) |
||
|
PLT, 109 /L |
||||||
|
< 100 |
22 (17.9%) |
41 (23.2%) |
0.337 |
26 (21.7%) |
22 (18.3%) |
0.628 |
|
≥ 100 |
101 (82.1%) |
136 (76.8%) |
94 (78.3%) |
98 (81.7%) |
||
|
ALB, g/L |
||||||
|
Mean (SD) |
41.1 (3.79) |
41.1 (3.62) |
0.946 |
41.5 (3.47) |
41.2 (3.78) |
0.581 |
|
TBIL, µmol/L |
||||||
|
Mean (SD) |
14.3 (4.91) |
14.4 (4.92) |
0.922 |
14.7 (4.75) |
14.4 (4.92) |
0.633 |
|
GGT, IU/L |
||||||
|
Mean (SD) |
78.5 (59.8) |
76.2 (79.8) |
0.782 |
79.9 (78.1) |
77.3 (59.9) |
0.775 |
|
ALP, IU/L |
||||||
|
Mean (SD) |
89.1 (35.6) |
89.3 (39.5) |
0.977 |
89.6 (40.6) |
88.3 (35.5) |
0.796 |
|
ALBI grade |
||||||
|
1 |
88 (71.5%) |
123 (69.5%) |
0.799 |
89 (74.2%) |
87 (72.5%) |
0.884 |
|
2 |
35 (28.5%) |
54 (30.5%) |
31 (25.8%) |
33 (27.5%) |
||
|
Margin |
||||||
|
< 1cm |
107 (87.0%) |
142 (80.2%) |
0.168 |
97 (80.8%) |
104 (86.7%) |
0.294 |
|
> 1cm |
16 (13.0%) |
35 (19.8%) |
23 (19.2%) |
16 (13.3%) |
||
|
Transfusion |
||||||
|
No |
110 (89.4%) |
165 (93.2%) |
0.339 |
111 (92.5%) |
109 (90.8%) |
0.815 |
|
Yes |
13 (10.6%) |
12 (6.8%) |
9 (7.5%) |
11 (9.2%) |
||
|
Blood loss, ml |
||||||
|
< 800ml |
116 (94.3%) |
167 (94.4%) |
1.000 |
112 (93.3%) |
115 (95.8%) |
0.568 |
|
≥ 800ml |
7 (5.7%) |
10 (5.6%) |
8 (6.7%) |
5 (4.2%) |
||
|
Tumor size, cm |
||||||
|
Mean (SD) |
6.19 (3.11) |
5.17 (2.41) |
0.003 |
5.69 (2.52) |
6.00 (2.89) |
0.377 |
|
Tumor number |
||||||
|
Single |
108 (87.8%) |
144 (81.4%) |
0.181 |
98 (81.7%) |
106 (88.3%) |
0.206 |
|
Multiple |
15 (12.2%) |
33 (18.6%) |
22 (18.3%) |
14 (11.7%) |
||
|
MVI |
||||||
|
No |
93 (75.6%) |
126 (71.2%) |
0.474 |
83 (69.2%) |
91 (75.8%) |
0.312 |
|
Yes |
30 (24.4%) |
51 (28.8%) |
37 (30.8%) |
29 (24.2%) |
||
|
Differentiation |
||||||
|
I-II |
22 (17.9%) |
30 (16.9%) |
0.955 |
17 (14.2%) |
22 (18.3%) |
0.484 |
|
III-IV |
101 (82.1%) |
147 (83.1%) |
103 (85.8%) |
98 (81.7%) |
||
|
Tumor capsular |
||||||
|
No |
13 (10.6%) |
24 (13.6%) |
0.551 |
14 (11.7%) |
13 (10.8%) |
1.000 |
|
Yes |
110 (89.4%) |
153 (86.4%) |
106 (88.3%) |
107 (89.2%) |
||
|
Liver cirrhosis |
||||||
|
No |
37 (30.1%) |
45 (25.4%) |
0.448 |
32 (26.7%) |
34 (28.3%) |
0.885 |
|
Yes |
86 (69.9%) |
132 (74.6%) |
88 (73.3%) |
86 (71.7%) |
||
|
Abbreviations: AVT, antiviral therapy; AFP, alpha-fetoprotein; HBeAg, hepatitis B e antigen; HBVDNA, hepatitis B virus deoxyribonucleic acid; PLT, platelet count; ALB, albumin; TBIL, total bilirubin; GGT, gamma-glutamyl transpeptidase; ALP, alkaline phosphatase; ALBI grade, albumin-bilirubin grade; MVI, microvascular invasion; SD, standard deviation; PSM, propensity score matching. |
||||||
Before PSM, the median OS in the AVT and non-AVT groups was 5.23 (95%CI = 4.85–6.50) years and 3.92 (95%CI = 3.01–5.19) years, respectively. The 1-, 3-, and 5-year OS rates in the AVT group and non-AVT group were 96.6%, 74.9%, 52.2%, and 83.1%, 60.1%, 41.2% (p = 0.003), respectively (Fig. 2). The median RFS in the AVT and non-AVT groups was 2.90 (95%CI = 2.16–3.62) years and 2.17 (95%CI = 1.06–3.06) years, respectively. The 1-, 3-, and 5-year RFS rates in the AVT group and non-AVT group were 77.8%, 47.3%, 28.2%, and 62.5%, 42.2%, 26.9% (p = 0.170), respectively (Fig. 3).
After PSM, the median OS in the AVT and non-AVT groups was 5.83 (95%CI = 4.88–NA) years and 3.92 (95%CI = 3.01–5.19) years, respectively. The 1-, 3-, and 5-year OS rates in the AVT group and non-AVT group were 97.5%, 76.0%, 55.0%, and 83.5%, 60.1%, 40.9%, (p = 0.003), respectively (Fig. 4). The median RFS in the AVT and non-AVT groups was 3.14 (95%CI = 2.13–4.33) years and 2.17 (95%CI = 1.06–3.06) years, respectively. The 1-, 3-, and 5-year RFS rates in the AVT group and non-AVT group were 76.6%, 50.2%, 30.4%, and 63.2%, 42.4%, 26.6% (p = 0.120), respectively (Fig. 5).
After PSM, the multivariate Cox analyses for determining the risk factors associated with OS and RFS were shown in Tables 2–3. Multivariate Cox analysis revealed that serum PLT levels (HR = 0.55, 95%CI = 0.38–0.81, p = 0.003), tumor size levels (HR = 1.14, 95%CI = 1.07–1.21, p < 0.001), and MVI (HR = 1.89, 95%CI = 1.30–2.75, p = 0.001) were factors associated with tumor recurrence by multivariate analysis (Table 2). Multivariate Cox analysis revealed that serum AFP levels (HR = 1.74, 95%CI = 1.14–2.67, p = 0.011), serum PLT levels (HR = 0.41, 95%CI = 0.26–0.65, p < 0.001), tumor size levels (HR = 1.13, 95%CI = 1.05–1.22, p = 0.002), MVI (HR = 2.80, 95%CI = 1.80–4.37, p < 0.001), and postoperative adjuvant AVT (HR = 0.46, 95%CI = 0.31–0.68, p < 0.001) were factors associated with OS by multivariate analysis (Table 3).
|
Characteristics |
Univariate |
Multivariate |
||||
|---|---|---|---|---|---|---|
|
HR |
95%CI |
P-value |
HR |
95%CI |
P-value |
|
|
Gender male vs female |
1.40 |
0.87–2.27 |
0.165 |
|||
|
HBeAg positive vs negative |
0.85 |
0.46–1.58 |
0.613 |
|||
|
AFP positive vs negative |
1.45 |
1.03–2.03 |
0.031 |
1.19 |
0.83–1.71 |
0.341 |
|
HBVDNA, IU/mL |
||||||
|
> 1000 vs ≤ 1000 |
1.17 |
0.71–1.93 |
0.528 |
|||
|
PLT, 109 /L > 100 vs ≤ 100 |
0.62 |
0.43–0.89 |
0.010 |
0.55 |
0.38–0.81 |
0.003 |
|
ALB, g/L |
0.96 |
0.92-1.00 |
0.075 |
|||
|
TBIL, µmol/L |
1.00 |
0.97–1.03 |
0.952 |
|||
|
GGT, IU/L |
1.00 |
1.00–1.00 |
0.172 |
|||
|
ALP, IU/L |
1.00 |
1.00-1.01 |
0.402 |
|||
|
ALBI grade, 2 vs 1 |
1.41 |
1.00–2.00 |
0.050 |
|||
|
Margin, >1cm vs ≤ 1cm |
0.68 |
0.44–1.05 |
0.082 |
|||
|
Transfusion yes vs no |
2.42 |
1.45–4.04 |
0.001 |
1.54 |
0.68–3.49 |
0.302 |
|
Blood loss ≥ 800mL vs < 800mL |
2.14 |
1.15–3.97 |
0.016 |
0.88 |
0.35–2.27 |
0.799 |
|
Tumor size, cm |
1.13 |
1.07–1.19 |
< 0.001 |
1.14 |
1.07–1.21 |
< 0.001 |
|
Tumor number multiple vs solitary |
1.55 |
1.03–2.31 |
0.034 |
1.44 |
0.93–2.22 |
0.101 |
|
MVI yes vs no |
2.33 |
1.65–3.29 |
< 0.001 |
1.89 |
1.30–2.75 |
0.001 |
|
Differentiation III-IV vs I-II |
1.87 |
1.17–2.97 |
0.008 |
1.53 |
0.94–2.52 |
0.090 |
|
Tumor capsular yes vs no |
0.90 |
0.56–1.45 |
0.660 |
|||
|
Liver cirrhosis yes vs no |
1.29 |
0.90–1.85 |
0.163 |
|||
|
AVT yes vs no |
0.78 |
0.57–1.07 |
0.123 |
|||
|
Abbreviations: AVT, antiviral therapy; AFP, alpha-fetoprotein; HBeAg, hepatitis B e antigen; HBVDNA, hepatitis B virus deoxyribonucleic acid; PLT, platelet count; ALB, albumin; TBIL, total bilirubin; GGT, gamma-glutamyl transpeptidase; ALP, A LKaline phosphatase; ALBI grade, albumin-bilirubin grade; MVI, microvascular invasion; SD, standard deviation; PSM, propensity score matching; RFS, recurrence-free survival. |
||||||
|
Characteristics |
Univariate |
Multivariate |
||||
|---|---|---|---|---|---|---|
|
HR |
95%CI |
P-value |
HR |
95%CI |
P-value |
|
|
Gender male vs female |
1.02 |
0.59–1.75 |
0.953 |
|||
|
HBeAg positive vs negative |
0.75 |
0.36–1.53 |
0.424 |
|||
|
AFP positive vs negative |
1.74 |
1.17–2.58 |
0.006 |
1.74 |
1.14–2.67 |
0.011 |
|
HBVDNA, IU/mL |
||||||
|
> 1000 vs ≤ 1000 |
1.40 |
0.70–2.79 |
0.345 |
|||
|
PLT, 109 /L, > 100 vs ≤ 100 |
0.52 |
0.34–0.78 |
0.002 |
0.41 |
0.26–0.65 |
< 0.001 |
|
ALB, g/L |
0.94 |
0.89–0.99 |
0.026 |
0.99 |
0.91–1.07 |
0.763 |
|
TBIL, µmol/L |
1.02 |
0.98–1.05 |
0.419 |
|||
|
ALBI grade, 2 vs 1 |
1.63 |
1.09–2.44 |
0.017 |
1.27 |
0.68–2.39 |
0.454 |
|
Margin, >1cm vs ≤ 1cm |
0.72 |
0.43–1.20 |
0.206 |
|||
|
Transfusion yes vs no |
2.25 |
1.23–4.12 |
0.008 |
1.05 |
0.52–2.09 |
0.897 |
|
Blood loss ≥ 800mL vs < 800mL |
2.35 |
1.19–4.67 |
0.014 |
|||
|
Tumor size, cm |
1.14 |
1.06–1.22 |
< 0.001 |
1.13 |
1.05–1.22 |
0.002 |
|
Tumor number multiple vs solitary |
1.07 |
0.64–1.80 |
0.785 |
|||
|
MVI yes vs no |
2.70 |
1.81–4.03 |
< 0.001 |
2.80 |
1.80–4.37 |
< 0.001 |
|
Differentiation III-IV vs I-II |
1.81 |
1.03–3.19 |
0.039 |
1.20 |
0.66–2.18 |
0.560 |
|
Tumor capsular yes vs no |
0.66 |
0.39–1.13 |
0.128 |
|||
|
Liver cirrhosis yes vs no |
1.34 |
0.86–2.09 |
0.190 |
|||
|
AVT yes vs no |
0.57 |
0.39–0.83 |
0.003 |
0.46 |
0.31–0.68 |
< 0.001 |
|
Abbreviations: AVT, antiviral therapy; AFP, alpha-fetoprotein; HBeAg, hepatitis B e antigen; HBVDNA, hepatitis B virus deoxyribonucleic acid; PLT, platelet count; ALB, albumin; TBIL, total bilirubin; GGT, gamma-glutamyl transpeptidase; ALP, A LKaline phosphatase; ALBI grade, albumin-bilirubin grade; MVI, microvascular invasion; SD, standard deviation; PSM, propensity score matching; OS, overall survival. |
||||||
Hepatocellular carcinoma (HCC) is the most common malignant tumor in the elderly, and the highest age-specific rates of HCC are observed among persons over age 70 years in developed countries[14]. The mean age of HCC patients at first diagnosis is increasing[15], possibly due to the aging of the population, increase in life expectancy, improvement in overall health conditions, as well as the use of antiviral therapy in high prevalence regions, which may delay the occurrence of HCC[16, 17].
HBV infection is regarded as an important risk factor for tumor recurrence and is associated with poor prognosis in HCC patients[7, 18, 19]. In contrast, some clinical studies found no significant correlation between the HBV DNA levels or HBeAg status and the development of HBV-related HCC[20, 21]. Basic studies showed that HBV DNA level was lower in old people[11] and Spontaneous HBsAg seroclearance was higher in patients older than 60 years[12]. A study in paradigms for HBV-related human carcinogenesis found that epigenetic pathways (transactivation, insertional mutagenesis, chromosomic arrangements) were more obvious in the elderly[22]. In addition, there are other non-viral causes of HCC in the elderly. Old age seems to favor non-alcoholic fatty liver disease (NAFLD), NASH, and ultimately HCC [23]. Therefore, the role of HBV infection is unclear in HBV-related HCC recurrence for the elderly.
Several studies showed that postoperative adjutant AVT benefits HBV-related HCC patients by decreasing tumor recurrence[6–8]. However, patients were from a single department, the sample size was limited in the RCT, and the including patients were not widely representative in these studies. In contrast, other studies showed that there was no significant effect of postoperative AVT on HBV-related HCC recurrence. The study of Li N et al. found no significant effect of postoperative AVT on HBV-related HCC recurrence in the two groups (76.7 vs. 91.7%; P = 0.077) after the follow-up period[9]. Another study by Kuzuya et al reported that the 1- and 2-year disease-free survival rates were 23.3 and 2.3%, respectively, for the treatment group, and 8.3% and 0%, respectively, for the control group (P = 0.072)[10]. To the best of our knowledge, there are no relevant studies on anti-HBV therapy to prevent postoperative recurrence of HBV-related HCC in the elderly. Based on our respective cohort study, we found that postoperative adjuvant AVT was not significantly associated with a decrease in tumor recurrence after curative hepatic resection for HBV-related elderly HCC patients, which was consistently observed in propensity score matching. Moreover, multivariate Cox analysis also revealed that postoperative adjuvant AVT was not an independent protected factor associated with tumor recurrence after curative hepatic resection for HBV-related elderly HCC patients.
In theory, AVT may affect long-term survival by directly modulating the remnant liver function which improves the patient’s tolerance to various treatments for tumor recurrence[10, 24]. In our study, we found that postoperative adjuvant AVT was statistically significantly associated with an increase in long-term survival after curative hepatic resection for HBV-related elderly HCC patients, which was consistently observed in propensity score matching. And, multivariate Cox analysis also revealed that postoperative adjuvant AVT was an independent protected factor associated with long-term survival after curative hepatic resection for HBV-related elderly HCC patients. These results are agreed with previous studies[6, 9, 25].
There are some limitations in our study. First, part of the patients who were treated in the early period of this study failed to receive AVT, though they might meet the treatment criteria of AVT. Second, this study was a retrospective study, which may be subject to bias and confounding. To overcome this issue, we conducted propensity score matching to minimize the differences. We also did not investigate the type of AVT due to the variety in medications and the limited sample size of patients who received a distinct drug, all of which made effective statistical analysis difficult. Third, in this study, it was difficult to evaluate the effect of the HBV genotype, which is likely to affect HCC incidence and NA efficacy.
In conclusion, among patients who underwent curative hepatic resection for HBV-related elderly HCC. Postoperative adjuvant AVT can improve long-term survival, but was not the independent protective factor associated with tumor recurrence. At present, there is no standard adjuvant treatment for the prevention of HCC recurrence in patients who undergo hepatic resection. Given the benefits of improving long-term survival, improving remnant liver function, and affordable and convenient treatment. We still recommended that HBV-related elderly HCC patients receive adjuvant AVT after curative hepatic resection.
HCC, hepatocellular carcinoma
HBV, hepatitis B virus
AVT, antiviral therapy;
AFP, alpha-fetoprotein;
HBeAg, hepatitis B e antigen;
HBVDNA, hepatitis B virus deoxyribonucleic acid;
PLT, platelet count;
ALB, albumin;
TBIL, total bilirubin;
GGT, gamma-glutamyl transpeptidase;
ALP, A LKaline phosphatase;
ALBI grade, albumin-bilirubin grade;
MVI, microvascular invasion;
OS, overall survival
RFS, recurrence-free survival
SD, standard deviation;
PSM, propensity score matching.
Acknowledgments
We would like to thank Mengchao Hepatobiliary Hospital of Fujian Medical University, the First Affiliated Hospital of Fujian Medical University, and Eastern Hepatobiliary Surgery Hospital for providing valuable clinical data. We thank our patients who silently provided data, Finally, we are grateful to Editage (https://app.editage.com/) for its excellent polishing work.
Author contributions
Conception and design: Jinyu Zhang, Qionglan Wu, Jingfeng Liu.
Administrative support: Jingfeng Liu, Jinhua Zeng.
Collection and assembly of data: Jinyu Zhang, Qionglan Wu, Jianxing Zeng.
Data analysis and interpretation: Jinyu Zhang, Qionglan Wu, Jianxing Zeng.
Manuscript writing: All authors.
Funding
This study was supported by the Medical Innovation Project of Fujian Province (2020CXA055), the Natural Science Foundation of Fujian Province (2020J011160), Fujian Provincial Clinical Research Center for Hepatobiliary and Pancreatic Tumors (2020Y2013), Key Clinical Specialty Discipline Construction Program of Fuzhou (201912002), and the Scientific Foundation of Fuzhou Municipal Health commission(2021-S-wp1).
Availability of data and materials
Data from this study are available to any interested researchers upon reasonable request to the corresponding author.
Ethics approval and consent to participate
This study was approved by the Medical Ethics Committee of Mengchao Hepatobiliary Hospital of Fujian Medical University and complies with the Declaration of Helsinki. At the same time, this study has obtained the exemption of informed consent application from the Ethics Committee of Mengchao Hepatobiliary Hospital of Fujian Medical University.
Consent for publication
Not applicable.
Competing interests
The authors disclose no conflicts of interest.