Overall survival was inferior in octogenarians with early-stage hepatocellular carcinoma undergoing percutaneous radiofrequency ablation. 

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Yi-Hao Yen, Kwong-Ming Kee, Chao-Hung Hung, Chien-Hung Chen, Tsung-Hui Hu, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3880000/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract It is unclear whether overall survival (OS) differs by age for patients with early‐stage hepatocellular carcinoma (HCC) undergoing radiofrequency ablation (RFA). We aim to clarify this issue. All patients diagnosed with early‐stage HCC (i.e., within Milan criteria) and Child–Pugh class A liver disease undergoing RFA between 2011 and 2021 were enrolled. Patients with incomplete ablation were excluded. This study enrolled 791 patients and them divided into four groups by age: <70 years (Group 1, n = 508), 70–74 years (Group 2, n = 122), 75–79 years (Group 3, n = 102), and ≥80 years (Group 4, n = 59). The five-year OS was 65% in Group 1, 60% in Group 2, 53% in Group 3, and 38 % in Group 4 ( p = 0.009). With Group 4 as the reference, multivariate analysis indicated that Groups 1 (HR: 0.496, 95% CI: 0.314–0.785, p = 0.003) and 3 (HR: 0.496, 95% CI: 0.277–0.889, p = 0.018) but not Group 2 (HR: 0.689, 95% CI: 0.403–1.179, p = 0.174) were independent factors associated with superior five-year OS. In conclusion, among patients with early-stage HCC and Child–Pugh class A liver disease undergoing RFA, those aged ≥80 years had inferior five-year OS. Biological sciences/Cancer Biological sciences/Cancer/Cancer therapy Biological sciences/Cancer/Gastrointestinal cancer Hepatocellular carcinoma percutaneous radiofrequency ablation elderly. Figures Figure 1 Figure 2 Figure 3 Introduction According to the Global Cancer Observatory, hepatocellular carcinoma (HCC) is the third most common malignancy worldwide, causing 830,000 deaths annually [ 1 ]. Advances in healthcare have led to increased longevity in the general population of developed countries. For example, from 1960 to 2015, the average life expectancy increased from 66.9 to 76.8 years for males and from 72.3 to 82.6 years for females in Europe [ 2 ]. Similar results were noted in Taiwan. ( https://www.moi.gov.tw/News_Content.aspx?n=2&s=282773 ). Changes in chronic liver disease epidemiology have led to changes in the age of HCC diagnosis in Korea. The proportion of older patients with HCC is increasing [ 3 ]. The term “elderly” has not been conclusively defined. The literature on patients with HCC commonly defines it using a threshold of 70 years [ 4 ]. However, one previous study used a threshold of 75 years [ 5 ]. Among patients with HCC, increased age complicates treatment decisions due to the presence of comorbidities, which can be associated with reduced tolerability and increased risk of severe complications. Physicians should carefully evaluate underlying comorbidities, particularly cardiovascular diseases [ 6 ]. Percutaneous radiofrequency ablation (pRFA) is one curative treatment for early-stage HCC [ 7 ]. A recent Japanese study showed that overall survival (OS) was significantly lower in older (≥ 80 years) than in younger patients undergoing pRFA for early-stage HCC [ 8 ]. However, this study enrolled patients with Child–Pugh class B liver disease [ 8 ]. Life expectancy is limited in patients with decompensated cirrhosis [ 9 ]. Whether there is a survival benefit in patients with HCC and Child–Pugh class B liver disease with treatments other than liver transplant (LT) is unknown [ 7 ]. Therefore, the European Association for the Study of Liver Disease (EASL) guidelines recommend patients with decompensated liver disease and not transplantable HCC should undergo best supportive care [ 7 ]. This study aimed to evaluate whether age affected survival among patients with early-stage HCC and Child–Pugh class A liver disease undergoing pRFA. Materials and methods The Institutional Review Board of Chang Gung Memorial Hospital-Kaohsiung Branch approved this study (reference number: 202201189B0). Informed consents were waived by the IRB due to the retrospective nature of study. Research have been performed in accordance with the Declaration of Helsinki. Data were extracted from the Kaohsiung Chang Gung Memorial Hospital’s HCC registry. Our HCC registry has adopted the original Barcelona Clinic Liver Cancer (BCLC) staging [ 10 ]. BCLC stage 0 is defined as a single tumor of ≤ 2.0 cm without macrovascular invasion or extrahepatic metastasis, with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 and Child–Pugh class of A. BCLC stage A is defined as a single tumor of 2–5 cm or < 3 tumor nodules of ≦ 3 cm without macrovascular invasion or extrahepatic metastasis, with an ECOG-PS of 0 and Child–Pugh class of A or B. Treatment decisions for patients with BCLC stage 0-A and Child–Pugh class A liver disease A multidisciplinary HCC team discussed each patient newly diagnosed with HCC. Ideal surgical candidates (i.e., patients with well-preserved liver function and good PS without severe comorbidities) were referred for liver resection (LR). Tumor location is important in the decision between LR and pRFA. LR is preferred for patients with superficially located tumors. In contrast, pRFA is preferred for patients with centrally located tumors [ 7 ]. Patients with clinically significant portal hypertension are recommended for LT [ 7 ]. However, due to an extreme shortage of deceased donors, very few patients undergo LT as primary treatment for HCC in Taiwan [ 11 , 12 ]. Alternative treatments such as transarterial chemoembolization or radiation therapy were performed for patients not indicated for curative treatments, such as those with a high anesthesia risk due to severe comorbidities or tumor location not indicated for LR and pRFA. The flowchart of patient enrollment is shown in Fig. 1 . This cohort’s raw data are available via the following digital object identifier: https://www.dropbox.com/scl/fi/ynvp7768vhx7psmqapz63/2011-to-2021summary-r1.xlsx?rlkey=1c4ks72b9ly24nzs652tps8oe&dl=0 Tumor size and number were assessed using contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI). OS was defined as the time from the date of pRFA to the last follow-up or death. Recurrence-free survival (RFS) was defined as the time from the date of pRFA to the last follow-up or recurrence. Recurrence was defined according to image studies or pathology diagnosis [ 7 ]. Variables of interest The variables of interest were age, sex, total bilirubin, creatinine, international normalized ratio, Child–Pugh classification [ 13 ], Model for End-Stage Liver Disease (MELD) score [ 14 ], alpha-fetoprotein (AFP), hepatitis B virus surface antigen (HBsAg), anti-hepatitis C virus (HCV) antibody, BCLC stage, and tumor number. Definition of well-preserved liver function in Child–Pugh class A liver disease A retrospective study collected data from 543 patients with chronic liver disease who underwent LR for HCC in a tertiary center in Italy. Postoperative liver decompensation was found to be independently associated with major hepatectomy (odds ratio [OR] = 2.41, 95% confidence interval [CI] = 1.17–4.30, p = 0.010), portal hypertension (OR = 2.20, 95% CI = 1.13–4.30, p = 0.010), and a MELD score of > 9 (OR = 2.26, 95% CI = 1.10–4.58, p = 0.020) [ 15 ]. Therefore, we assumed that compensated liver function could be stratified with additional granularity using a MELD score of > 9 for patients with HCC undergoing LR. pRFA procedure Most patients underwent general anesthesia, but a few underwent sedation. We generally selected patients with BCLC stage 0 HCC without severe comorbidities who underwent sedation. General anesthesia and sedation were described in our previous study [ 16 ]. Under ultrasound guidance, we used a single electrode for pRFA in patients with tumors ≤ 3.0 cm with the Cool-tip™ RF Ablation System (Medtronic, Minneapolis, MN, USA), Big-tip (RF Medical Co., Seoul, Korea), or Viva RF electrode system (STARmed, Seoul, South Korea). We used monopolar RFA with a multiple-electrode switching system (Covidien, Cool-tip™ RF Ablation System) for patients with tumors of 3.0–5.0 cm. We created artificial ascites or pleural effusion for tumors located at the liver dome, which may be obscured by lung air. We created artificial ascites for tumors located near the intestine or stomach to avoid thermal injury. Tumors located near the major biliary tree, gallbladder, major vessels, or heart were not selected for pRFA due to risks of thermal injury or a heat sink effect. Statistical analyses Patient characteristics are presented as the number (%). Categorical variables were compared between groups using the chi-square test. OS and RFS were compared between groups using the Kaplan–Meier estimator and log-rank test. To identify prognostic factors, a multivariate regression analysis was performed using univariate Cox proportional hazards analysis, with p < 0.05 as the significance level. All p -values were two-tailed, and a p < 0.05 was considered statistically significant. All statistical analyses were performed using the SPSS Statistics software (version 25; IBM Corp., Armonk, NY, USA). Results Baseline characteristics of patients with early-stage HCC undergoing pRFA stratified by age This study enrolled 791 patients and divided them into four groups by age: <70 years (Group 1, n = 508), 70–74 years (Group 2, n = 122), 75–79 years (Group 3, n = 102), and ≥ 80 years (Group 4, n = 59). The proportion of men was highest in Group 1 ( p = 0.001), the HBsAg-positive proportion was highest in Group 1 ( p 9 did not differ significantly between groups (Table 1 ). Table 1 Baseline characteristics of each group of patients with early-stage hepatocellular carcinoma undergoing percutaneous radiofrequency ablation. < 70 years, n = 508 70–74 years, n = 122 75–79 years, n = 102 ≥ 80 years, n = 59 p Men 344 (67.7%) 70 (57.4%) 51 (50.0%) 30 50.8%) 0.001 Pathology diagnosis of HCC 240 (47.2%) 60 (49.2%) 50 (49.0%) 28(47.5%) 0.974 Tumor number 0.128 Single 394 (77.6%) 102 (83.6%) 88 (86.3%) 45 (76.3%) Multiple 114 (22.4%) 20 (16.4%) 14 (13.7%) 14(23.7%) BCLC stage 0.187 0 192 (37.8%) 47(38.5%) 36(35.3%) 14(23.7%) A 316(62.2%) 75(61.5%) 66(64.7%) 45(76.3%) AFP ≧ 20ng/ml 181(35.9%) 41(33.6%) 46(45.1%) 21(35.6%) 0.288 MELD score > 9 196(38.9%) 51(41.8%) 52(51.0%) 19(32.2%) 0.073 HBsAg positive 247(48.6%) 35(28.7%) 25(24.5%) 23(39.0%) < 0.001 Anti-HCV positive 220(43.3%) 68(55.7%) 64(62.7%) 24(40.7%) 0.001 Key: AFP, alpha-fetoprotein; MELD, model for end-stage liver disease; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; BCLC, Barcelona clinic liver cancer; HCC, hepatocellular carcinoma Causes of death in each age-based group of patients with early-stage HCC undergoing pRFA The causes of death did not differ significantly among groups ( p = 0.389; Table 2 ). Table 2 Causes of death in each group of patients with early-stage hepatocellular carcinoma undergoing percutaneous radiofrequency ablation. < 70 years, n = 508 70–74 years, n = 122 75–79 years, n = 102 ≥ 80 years, n = 59 p = 0.389 HCC, n (%) 89(17.5%) 24(19.7%) 20(19.6%) 13(22.0%) Unknown, n (%) 8(1.6%) 2(1.6%) 0(0.0%) 1(1.7%) Non-HCC: n (%) 54(10.6%) 18(14.8%) 11(10.8%) 12(20.3%) HCC, hepatocellular carcinoma The five-year OS and RFS in each age-based group of patients with early-stage HCC undergoing pRFA The media follow-up period was 2.32 years (interquartile range = 0.85–4.93), during which 252 (31.9%) patients died, and 369 (46.6%) developed recurrent tumors. The five-year OS was 65% in Group 1, 60% in Group 2, 53% in Group 3, and 38% in Group 4 ( p = 0.009; Fig. 2 ). The five-year RFS was 40% in Group 1, 18% in Group 2, 33% in Group 3, and 30% in Group 4 ( p = 0.259; Fig. 3 ). Univariate and multivariate Cox proportional hazards analyses for five-year OS Univariate analyses showed that age < 70 years (hazard ratio [HR] = 0.477, 95% CI = 0.303–0.752, p = 0.001), age 75–79 years (HR = 0.522, 95% CI = 0.294–0.926, p = 0.026) were associated with superior five-year OS compared to age ≥ 80 years. In addition, they showed that male vs. female sex (HR = 1.362, 95% CI = 1.014–1.831, p = 0.040), BCLC stage A vs. 0 (HR = 1.531, 95% CI = 1.141–2.056, p = 0.005), AFP ≥ 20 vs. 9 vs. ≤9 (HR = 1.76, 95% CI = 1.33–2.32, p < 0.001), and HBsAg positive vs. negative (HR = 0.716, 95% CI = 0.538–0.955, p = 0.023) were associated with inferior five-year OS. Similarly, multivariate analysis showed that age < 70 years (HR = 0.496, 95% CI = 0.314–0.785, p = 0.003), age 75–79 years (HR = 0.496, 95% CI = 0.277–0.889, p = 0.018) were associated with superior five-year OS compared to age ≥ 80 years. In addition, it showed that BCLC stage A vs. 0 (HR = 1.420, 95% CI = 1.053–1.913, p = 0.021), AFP ≥ 20 vs. 9 vs. ≤9 (HR = 1.63, 95% CI = 1.225–2.169, p = 0.001) were associated with inferior five-year OS (Table 3 ). Table 3 Univariate and multivariate Cox proportional hazards analysis for five-year overall survival. Univariate Multivariate HR (95%CI) p HR (95%CI) p Age ≧ 80 as reference < 70 0.477(0.303–0.752) 0.001 0.496(0.314–0.785) 0.003 70–74 0.644(0.379–1.095) 0.104 0.689(0.403–1.179) 0.174 75–79 0.522(0.294–0.926) 0.026 0.496(0.277–0.889) 0.018 Men vs women 1.362(1.014–1.831) 0.040 1.365(0.999–1.864) 0.050 BCLC stage A vs. 0 1.531(1.141–2.056) 0.005 1.420(1.053–1.913) 0.021 AFP ≧ 20 vs 9 vs ≦ 9 1.76(1.33–2.32) 0.000 1.63(1.225–2.169) 0.001 HBsAg positive vs negative 0.716(0.538–0.955) 0.023 0.809(0.596-1.100) 0.176 Anti-HCV positive vs negative 1.016(0.773–1.336) 0.909 AFP, alpha-fetoprotein; MELD, model for end-stage liver disease; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; BCLC, Barcelona clinic liver cancer. Univariate and multivariate Cox proportional hazards analyses for five-year RFS Univariate analyses showed that BCLC stage A vs. 0 (HR = 1.486, 95% CI = 1.193–1.852, p < 0.001), AFP ≥ 20 vs. <20 ng/mL (HR = 1.355, 95% CI = 1.099–1.671, p = 0.004), and HBsAg positive vs. negative (HR = 0.808, 95% CI = 0.655–0.998, p = 0.048) were associated with inferior five-year RFS. Multivariate analysis showed that BCLC stage A vs. 0 (HR = 1.472, 95% CI = 1.180–1.836, p = 0.001), and AFP ≥ 20 vs. <20 ng/mL (HR = 1.347, 95% CI = 1.091–1.663, p = 0.006) were associated with inferior five-year RFS (Table 4 ). Table 4 Univariate and multivariate Cox proportional hazards analysis for five-year recurrence-free survival. Univariate Multivariate HR (95%CI) p HR (95%CI) p Men vs women 0.899(0.728–1.109) 0.319 BCLC stage A vs. 0 1.486(1.193–1.852) 0.000 1.472(1.180–1.836) 0.001 AFP ≧ 20 vs 9 vs ≦ 9 1.20(0.976–1.485) 0.082 HBsAg positive vs negative 0.808(0.655–0.998) 0.048 0.854(0.690–1.056) 0.145 Anti-HCV positive vs negative 1.158(0.943–1.423) 0.161 Age ≧ 80 as reference < 70 1.037(0.681–1.580) 0.866 70–74 1.353(0.849–2.155) 0.203 75–79 1.152(0.705–1.884) 0.573 Key: AFP, alpha-fetoprotein; MELD, model for end-stage liver disease; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; BCLC, Barcelona clinic liver cancer. Discussion This study enrolled a large cohort of patients with early-stage HCC and Child–Pugh class A liver disease undergoing pRFA, who were stratified into four groups by age. Tumor numbers, BCLC stages, AFP level ≥ 20 ng/mL, and MELD score > 9 did not differ significantly between groups. The proportion of men was highest in Group 1 ( p = 0.001), the HBsAg-positive proportion was highest in Group 1 ( p < 0.001), and the anti-HCV-positive proportion was highest in Group 3 ( p = 0.001). However, whether sex and chronic liver disease etiology were associated with OS among patients with early-stage HCC remains unclear. 7 In contrast, tumor burden (i.e., tumor number and BCLC stage), AFP level, and liver function reserve (i.e., MELD score) are well-known factors associated with OS of patients with HCC [ 7 ]. We can assume that characteristics related to OS were similar between groups. Therefore, we did not perform propensity score matching between them. We found that five-year OS was lowest in those aged ≥ 80 years ( p = 0.009). In addition, multivariate analysis showed that age ≥ 80 years was independently associated with inferior five-year OS. Therefore, we can conclude that age ≥ 80 years was associated with inferior five-year OS in patients with early-stage HCC and Child–Pugh class A liver disease undergoing pRFA. In contrast, age ≥ 80 years was not associated with five-year RFS. Multiple studies have associated being elderly with inferior OS in patients with early-stage HCC undergoing pRFA. Takahashi et al. enrolled 461 patients with early-stage HCC and showed that OS was similar between elderly (i.e., aged ≥ 75 years) and non-elderly patients with HCC undergoing pRFA [ 17 ]. Similarly, Hiraoka et al. enrolled 206 patients with early-stage HCC and showed that OS was similar between elderly (i.e., aged ≥ 75 years) and non-elderly patients with HCC undergoing pRFA [ 18 ]. However, Nishikawa et al. enrolled 368 patients with early-stage HCC and showed that OS was inferior in elderly (i.e., aged ≥ 75 years) compared to non-elderly patients with HCC undergoing pRFA ( p = 0.001) [ 19 ]. Nonetheless, Tateishi et al. showed no difference in three-year survival between patients aged > 68 years (76%) and < 68 years (79.2%) among 1000 patients treated with RFA [ 20 ]. Finally, Ochi et al. enrolled 1079 patients with early-stage HCC treated with RFA and found that those aged ≥ 80 years had significantly shorter OS than the other groups ( p < 0.05) [ 8 ]. All these studies enrolled patients with Child–Pugh class A or B liver disease [ 8 , 17 – 20 ]. Since decompensated cirrhosis may be a competing risk more strongly associated with death than older age, in this study, we only enrolled patients with Child–Pugh class A liver disease to clarify whether older age was associated with inferior OS in patients with early-stage HCC undergoing pRFA. Similar to Ochi et al., [ 8 ] non-HCC-related deaths were most common among those aged ≥ 80 years in our study, although the difference was not statistically significant ( p = 0.389). A recent population-based study evaluated about 3.9 million patients in seven high-income Western countries with seven primary cancers (esophagus, stomach, colon, rectum, pancreas, lung, and ovary). It showed that the survival benefit was limited in elderly patients, whereas a significant improvement in the OS was noted in younger patients [ 21 ]. Although they did not assess HCC, their findings are consistent with ours regarding HCC. Age ≥ 80 years was not associated with five-year RFS in our study, consistent with Ochi et al. [ 8 ] A MELD score of > 9 was associated with inferior five-year OS in our study. A recent review paper showed that the MELD score is commonly used in patients with HCC undergoing LR to predict postoperative liver failure and survival; it is also commonly used in patients with HCC undergoing LT to predict survival on the waiting list. The albumin-bilirubin (ALBI) score is used to predict survival in patients with HCC undergoing LR and non-surgical therapies [22]. However, the lack of albumin data in our HCC registry dataset precluded us from using the ALBI score to estimate patients’ liver functional reserve. In addition, while a MELD score of > 9 was originally used to predict postoperative liver decompensation in patients with HCC undergoing LR, [ 15 ] our findings suggest that it can also predict OS in patients with HCC undergoing pRFA. Our study associated an AFP level of ≥ 20 ng/mL with inferior five-year OS and RFS. This cutoff was set according to the American Association for the Study of Liver Diseases guidelines, which recommend that among patients at risk of HCC and undergoing surveillance for HCC, those with an AFP level of ≥ 20 ng/mL should be examined using contrast-enhanced CT or MRI [23]. The strength of our study is that it only enrolled patients with Child–Pugh class A liver disease to clarify whether older age is associated with inferior OS in patients with early-stage HCC undergoing pRFA. However, it had some limitations. First, it was a retrospective single-center study. Second, the number of patients aged ≥ 80 years was limited. Future studies are needed to evaluate which treatment is most appropriate for patients with early-stage HCC and Child–Pugh class A liver disease. Stereotactic body radiotherapy (SBRT) may offer advantages in patients with early-stage HCC aged ≥ 80 years because it does not require general anesthesia. Future studies should also compare survival outcomes and treatment complications between pRFA and SBRT in patients with early-stage HCC aged ≥ 80 years. Conclusion Among patients with early-stage HCC and Child–Pugh class A liver disease undergoing pRFA, those aged ≥ 80 years had inferior five-year OS. Declarations Not applicable Funding: This study was supported by Grant CMRPG8N1131 from the Chang Gung Memorial Hospital-Kaohsiung Medical Center, Taiwan. Conflict of interest: The authors have no conflicts of interest to disclose for all authors. Data availability: all data is available Ethics approval: The Institutional Review Board of Kaohsiung Chang Gung Memorial Hospital approved this study (Reference number: 202201189B0) Consent to participate. Written consents were waived by the IRB due to the retrospective nature of study. Consent for publication. All authors agree to publication if the paper is accepted Acknowledgement The authors thank Cancer Center, Kaohsiung Chang Gung Memorial Hospital for the provision of HCC registry data. The authors thank Chih-Yun Lin and Nien-Tzu Hsu and the Biostatistics Center, Kaohsiung Chang Gung Memorial Hospital for statistics work. This study was supported by Grant CMRPG8N1131 from the Chang Gung Memorial Hospital-Kaohsiung Medical Center, Taiwan. No conflict of interests. Authors’ Contributions Study conception and design: YHY Acquisition of data: all authors Analysis and interpretation of data: CYL Drafting of manuscript: YHY Critical revision of manuscript: all authors Approval of manuscript: all authors Data availability statement The raw data for the cohort are available via the following digital object identifier: https://www.dropbox.com/scl/fi/ynvp7768vhx7psmqapz63/2011-to-2021summary-r1.xlsx?rlkey=1c4ks72b9ly24nzs652tps8oe&dl=0 Additional Information (including a Competing Interests Statement) The authors have no conflicts of interest to disclose for all authors. References Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. 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Efficacy and safety of radiofrequency ablation for elderly hepatocellular carcinoma patients. Hepatol Res. 2010;40:997-1005. doi: 10.1111/j.1872-034X.2010.00713.x. Hiraoka A, Michitaka K, Horiike N, Hidaka S, Uehara T, Ichikawa S, et al. Radiofrequency ablation therapy for hepatocellular carcinoma in elderly patients. J Gastroenterol Hepatol. 2010;25:403-7. doi: 10.1111/j.1440-1746.2009.06037.x. Nishikawa H, Osaki Y, Iguchi E, Takeda H, Ohara Y, Sakamoto A, et al. Percutaneous radiofrequency ablation for hepatocellular carcinoma: clinical outcome and safety in elderly patients. J Gastrointestin Liver Dis. 2012;21:397-405. Tateishi R, Shiina S, Teratani T, Obi S, Sato S, Koike Y, Fujishima T, et al. Percutaneous radiofrequency ablation for hepatocellular carcinoma. An analysis of 1000 cases. Cancer. 2005 Mar 15;103:1201-9. doi: 10.1002/cncr.20892. Arnold M, Rutherford MJ, Bardot A, Ferlay J, Andersson TM, Myklebust TÅ, et al. Progress in cancer survival, mortality, and incidence in seven high-income countries 1995-2014 (ICBP SURVMARK-2): a population-based study. Lancet Oncol. 2019;20:1493-1505. doi: 10.1016/S1470-2045(19)30456-5. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3880000","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":269768110,"identity":"1aab9b28-b0a5-4588-9c5f-478ca4109586","order_by":0,"name":"Yi-Hao Yen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9klEQVRIiWNgGAWjYNCCAgsgwXyAgbGBaC0GEkCCLQFJSwJRWngMiNPC33788YcPBhKJ/dI93yR+7rCRY2A/fHQD44/DOLVInMkxk5wB1DJzztltkr1n0owZeNLSbjAk4NZiwJDDxswD1LLhRu42Cd62w4kNEjxmQC23cWvhf/748x+glv03cp5J/iVKi0SCgTQDyBaJHDZpomyRuPHGTLLHQMJ4xo00Y2vZtjRjNpBfEtL+49TC35/++MOPChvZ/hnJD2++bbOR42c/fOzGB5s0nFpgwLGBgYEFFDsMbCAigaAGBgZ7IGb+QITCUTAKRsEoGIEAALsOVFTD8tg8AAAAAElFTkSuQmCC","orcid":"","institution":"Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Yi-Hao","middleName":"","lastName":"Yen","suffix":""},{"id":269768111,"identity":"13badee3-8344-435e-bf1d-5dfff3cbac0e","order_by":1,"name":"Kwong-Ming Kee","email":"","orcid":"","institution":"Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Kwong-Ming","middleName":"","lastName":"Kee","suffix":""},{"id":269768112,"identity":"1cf82332-53b1-49f7-94fd-974e7a4d37c6","order_by":2,"name":"Chao-Hung Hung","email":"","orcid":"","institution":"Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Chao-Hung","middleName":"","lastName":"Hung","suffix":""},{"id":269768113,"identity":"75ca8c90-1eaf-46d9-a4e1-54fab0dd89dc","order_by":3,"name":"Chien-Hung Chen","email":"","orcid":"","institution":"Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Chien-Hung","middleName":"","lastName":"Chen","suffix":""},{"id":269768114,"identity":"80da7bb8-0ff4-4198-abc8-329bfd2a1193","order_by":4,"name":"Tsung-Hui Hu","email":"","orcid":"","institution":"Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Tsung-Hui","middleName":"","lastName":"Hu","suffix":""},{"id":269768115,"identity":"f4b68296-236d-4085-8b03-fc539cf0aa42","order_by":5,"name":"Jing-Houng Wang","email":"","orcid":"","institution":"Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jing-Houng","middleName":"","lastName":"Wang","suffix":""},{"id":269768116,"identity":"e7c05052-b2ee-453b-ad59-aadd497a8ac2","order_by":6,"name":"Chih-Yun Lin","email":"","orcid":"","institution":"Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Chih-Yun","middleName":"","lastName":"Lin","suffix":""}],"badges":[],"createdAt":"2024-01-19 22:17:25","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3880000/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3880000/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":50389960,"identity":"d71d7d69-599b-4555-8efe-b1249b04d603","added_by":"auto","created_at":"2024-01-30 18:39:05","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":358119,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of patient enrollment.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3880000/v1/951a152fe085aa9923a2dd1f.jpg"},{"id":50389963,"identity":"090b3b02-b6d2-451b-82df-c9370f5f1f87","added_by":"auto","created_at":"2024-01-30 18:39:05","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":4026505,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves for overall survival (OS) after initial radiofrequency ablation (RFA) in each group of patients with early‐stage hepatocellular carcinoma (HCC): Group1, \u0026lt;70 years; Group 2, 70–74 years; Group 3, 75–79 years; Group 4, ≥80 years\u003c/p\u003e","description":"","filename":"Fig.2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3880000/v1/e21d05046bf8525a470c7f63.jpg"},{"id":50389961,"identity":"971a240d-b193-4a75-81ef-251050b719f1","added_by":"auto","created_at":"2024-01-30 18:39:05","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":4111877,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves for recurrence‐free survival after initial RFA in each group of patients with early‐stage HCC: Group 1, \u0026lt;70 years; Group 2, 70–74 years; Group 3, 75–79 years; Group 4, ≥80 years.\u003c/p\u003e","description":"","filename":"Fig.3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3880000/v1/432d5217b810cd0074cd95c3.jpg"},{"id":60070075,"identity":"fac5cf5e-c433-46fd-a672-fa1809d8561c","added_by":"auto","created_at":"2024-07-11 10:45:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":9208973,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3880000/v1/aadef807-6798-4ae1-ad42-fc1ecff38c45.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Overall survival was inferior in octogenarians with early-stage hepatocellular carcinoma undergoing percutaneous radiofrequency ablation. ","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAccording to the Global Cancer Observatory, hepatocellular carcinoma (HCC) is the third most common malignancy worldwide, causing 830,000 deaths annually [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Advances in healthcare have led to increased longevity in the general population of developed countries. For example, from 1960 to 2015, the average life expectancy increased from 66.9 to 76.8 years for males and from 72.3 to 82.6 years for females in Europe [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Similar results were noted in Taiwan. (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.moi.gov.tw/News_Content.aspx?n=2\u0026amp;s=282773\u003c/span\u003e\u003cspan address=\"https://www.moi.gov.tw/News_Content.aspx?n=2\u0026amp;s=282773\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eChanges in chronic liver disease epidemiology have led to changes in the age of HCC diagnosis in Korea. The proportion of older patients with HCC is increasing [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe term \u0026ldquo;elderly\u0026rdquo; has not been conclusively defined. The literature on patients with HCC commonly defines it using a threshold of 70 years [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, one previous study used a threshold of 75 years [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Among patients with HCC, increased age complicates treatment decisions due to the presence of comorbidities, which can be associated with reduced tolerability and increased risk of severe complications. Physicians should carefully evaluate underlying comorbidities, particularly cardiovascular diseases [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePercutaneous radiofrequency ablation (pRFA) is one curative treatment for early-stage HCC [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. A recent Japanese study showed that overall survival (OS) was significantly lower in older (\u0026ge;\u0026thinsp;80 years) than in younger patients undergoing pRFA for early-stage HCC [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, this study enrolled patients with Child\u0026ndash;Pugh class B liver disease [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Life expectancy is limited in patients with decompensated cirrhosis [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Whether there is a survival benefit in patients with HCC and Child\u0026ndash;Pugh class B liver disease with treatments other than liver transplant (LT) is unknown [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Therefore, the European Association for the Study of Liver Disease (EASL) guidelines recommend patients with decompensated liver disease and not transplantable HCC should undergo best supportive care [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis study aimed to evaluate whether age affected survival among patients with early-stage HCC and Child\u0026ndash;Pugh class A liver disease undergoing pRFA.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003e The Institutional Review Board of Chang Gung Memorial Hospital-Kaohsiung Branch approved this study (reference number: 202201189B0). Informed consents were waived by the IRB due to the retrospective nature of study. Research have been performed in accordance with the Declaration of Helsinki.\u003c/p\u003e \u003cp\u003eData were extracted from the Kaohsiung Chang Gung Memorial Hospital\u0026rsquo;s HCC registry.\u003c/p\u003e \u003cp\u003eOur HCC registry has adopted the original Barcelona Clinic Liver Cancer (BCLC) staging [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. BCLC stage 0 is defined as a single tumor of \u0026le;\u0026thinsp;2.0 cm without macrovascular invasion or extrahepatic metastasis, with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 and Child\u0026ndash;Pugh class of A. BCLC stage A is defined as a single tumor of 2\u0026ndash;5 cm or \u0026lt;\u0026thinsp;3 tumor nodules of ≦\u0026thinsp;3 cm without macrovascular invasion or extrahepatic metastasis, with an ECOG-PS of 0 and Child\u0026ndash;Pugh class of A or B.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eTreatment decisions for patients with BCLC stage 0-A and Child\u0026ndash;Pugh class A liver disease\u003c/h2\u003e \u003cp\u003eA multidisciplinary HCC team discussed each patient newly diagnosed with HCC. Ideal surgical candidates (i.e., patients with well-preserved liver function and good PS without severe comorbidities) were referred for liver resection (LR). Tumor location is important in the decision between LR and pRFA. LR is preferred for patients with superficially located tumors. In contrast, pRFA is preferred for patients with centrally located tumors [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Patients with clinically significant portal hypertension are recommended for LT [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, due to an extreme shortage of deceased donors, very few patients undergo LT as primary treatment for HCC in Taiwan [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Alternative treatments such as transarterial chemoembolization or radiation therapy were performed for patients not indicated for curative treatments, such as those with a high anesthesia risk due to severe comorbidities or tumor location not indicated for LR and pRFA.\u003c/p\u003e \u003cp\u003eThe flowchart of patient enrollment is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. This cohort\u0026rsquo;s raw data are available via the following digital object identifier:\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cspan class=\"ExternalRef\"\u003e \u003cspan class=\"RefSource\"\u003ehttps://www.dropbox.com/scl/fi/ynvp7768vhx7psmqapz63/2011-to-2021summary-r1.xlsx?rlkey=1c4ks72b9ly24nzs652tps8oe\u0026amp;dl=0\u003c/span\u003e \u003cspan address=\"https://www.dropbox.com/scl/fi/ynvp7768vhx7psmqapz63/2011-to-2021summary-r1.xlsx?rlkey=1c4ks72b9ly24nzs652tps8oe\u0026amp;dl=0\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e \u003c/span\u003e \u003c/p\u003e \u003cp\u003eTumor size and number were assessed using contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI). OS was defined as the time from the date of pRFA to the last follow-up or death. Recurrence-free survival (RFS) was defined as the time from the date of pRFA to the last follow-up or recurrence. Recurrence was defined according to image studies or pathology diagnosis [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eVariables of interest\u003c/h2\u003e \u003cp\u003eThe variables of interest were age, sex, total bilirubin, creatinine, international normalized ratio, Child\u0026ndash;Pugh classification [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], Model for End-Stage Liver Disease (MELD) score [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], alpha-fetoprotein (AFP), hepatitis B virus surface antigen (HBsAg), anti-hepatitis C virus (HCV) antibody, BCLC stage, and tumor number.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eDefinition of well-preserved liver function in Child\u0026ndash;Pugh class A liver disease\u003c/h2\u003e \u003cp\u003eA retrospective study collected data from 543 patients with chronic liver disease who underwent LR for HCC in a tertiary center in Italy. Postoperative liver decompensation was found to be independently associated with major hepatectomy (odds ratio [OR]\u0026thinsp;=\u0026thinsp;2.41, 95% confidence interval [CI]\u0026thinsp;=\u0026thinsp;1.17\u0026ndash;4.30, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.010), portal hypertension (OR\u0026thinsp;=\u0026thinsp;2.20, 95% CI\u0026thinsp;=\u0026thinsp;1.13\u0026ndash;4.30, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.010), and a MELD score of \u0026gt;\u0026thinsp;9 (OR\u0026thinsp;=\u0026thinsp;2.26, 95% CI\u0026thinsp;=\u0026thinsp;1.10\u0026ndash;4.58, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.020) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Therefore, we assumed that compensated liver function could be stratified with additional granularity using a MELD score of \u0026gt;\u0026thinsp;9 for patients with HCC undergoing LR.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003epRFA procedure\u003c/h2\u003e \u003cp\u003eMost patients underwent general anesthesia, but a few underwent sedation. We generally selected patients with BCLC stage 0 HCC without severe comorbidities who underwent sedation. General anesthesia and sedation were described in our previous study [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Under ultrasound guidance, we used a single electrode for pRFA in patients with tumors\u0026thinsp;\u0026le;\u0026thinsp;3.0 cm with the Cool-tip\u0026trade; RF Ablation System (Medtronic, Minneapolis, MN, USA), Big-tip (RF Medical Co., Seoul, Korea), or Viva RF electrode system (STARmed, Seoul, South Korea). We used monopolar RFA with a multiple-electrode switching system (Covidien, Cool-tip\u0026trade; RF Ablation System) for patients with tumors of 3.0\u0026ndash;5.0 cm. We created artificial ascites or pleural effusion for tumors located at the liver dome, which may be obscured by lung air. We created artificial ascites for tumors located near the intestine or stomach to avoid thermal injury. Tumors located near the major biliary tree, gallbladder, major vessels, or heart were not selected for pRFA due to risks of thermal injury or a heat sink effect.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003ePatient characteristics are presented as the number (%). Categorical variables were compared between groups using the chi-square test. OS and RFS were compared between groups using the Kaplan\u0026ndash;Meier estimator and log-rank test. To identify prognostic factors, a multivariate regression analysis was performed using univariate Cox proportional hazards analysis, with p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 as the significance level. All \u003cem\u003ep\u003c/em\u003e-values were two-tailed, and a \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. All statistical analyses were performed using the SPSS Statistics software (version 25; IBM Corp., Armonk, NY, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eBaseline characteristics of patients with early-stage HCC undergoing pRFA stratified by age\u003c/h2\u003e \u003cp\u003eThis study enrolled 791 patients and divided them into four groups by age: \u0026lt;70 years (Group 1, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;508), 70\u0026ndash;74 years (Group 2, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;122), 75\u0026ndash;79 years (Group 3, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;102), and \u0026ge;\u0026thinsp;80 years (Group 4, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;59). The proportion of men was highest in Group 1 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), the HBsAg-positive proportion was highest in Group 1 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and the anti-HCV-positive proportion was highest in Group 3 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001). Pathological HCC diagnosis, tumor number, BCLC stage, AFP level\u0026thinsp;\u0026ge;\u0026thinsp;20 ng/mL, and MELD score\u0026thinsp;\u0026gt;\u0026thinsp;9 did not differ significantly between groups (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of each group of patients with early-stage hepatocellular carcinoma undergoing percutaneous radiofrequency ablation.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;70 years, n\u0026thinsp;=\u0026thinsp;508\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70\u0026ndash;74 years, n\u0026thinsp;=\u0026thinsp;122\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e75\u0026ndash;79 years, n\u0026thinsp;=\u0026thinsp;102\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;80 years, n\u0026thinsp;=\u0026thinsp;59\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e344 (67.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e70 (57.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e51 (50.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e30 50.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathology diagnosis of HCC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e240 (47.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e60 (49.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e50 (49.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e28(47.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.974\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor number\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.128\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSingle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e394 (77.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e102 (83.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e88 (86.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e45 (76.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultiple\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e114 (22.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20 (16.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14 (13.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e14(23.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBCLC stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.187\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e192 (37.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e47(38.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e36(35.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e14(23.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e316(62.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e75(61.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e66(64.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e45(76.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAFP\u0026thinsp;≧\u0026thinsp;20ng/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e181(35.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e41(33.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e46(45.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e21(35.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.288\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMELD score\u0026thinsp;\u0026gt;\u0026thinsp;9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e196(38.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e51(41.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e52(51.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e19(32.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.073\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHBsAg positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e247(48.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e35(28.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e25(24.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e23(39.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-HCV positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e220(43.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e68(55.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e64(62.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e24(40.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eKey: AFP, alpha-fetoprotein; MELD, model for end-stage liver disease; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; BCLC, Barcelona clinic liver cancer; HCC, hepatocellular carcinoma\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eCauses of death in each age-based group of patients with early-stage HCC undergoing pRFA\u003c/h2\u003e \u003cp\u003eThe causes of death did not differ significantly among groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.389; Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCauses of death in each group of patients with early-stage hepatocellular carcinoma undergoing percutaneous radiofrequency ablation.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;70 years, n\u0026thinsp;=\u0026thinsp;508\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70\u0026ndash;74 years, n\u0026thinsp;=\u0026thinsp;122\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e75\u0026ndash;79 years, n\u0026thinsp;=\u0026thinsp;102\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;80 years, n\u0026thinsp;=\u0026thinsp;59\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.389\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHCC, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e89(17.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e24(19.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20(19.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e13(22.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8(1.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2(1.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0(0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1(1.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-HCC: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e54(10.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18(14.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11(10.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e12(20.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eHCC, hepatocellular carcinoma\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eThe five-year OS and RFS in each age-based group of patients with early-stage HCC undergoing pRFA\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe media follow-up period was 2.32 years (interquartile range\u0026thinsp;=\u0026thinsp;0.85\u0026ndash;4.93), during which 252 (31.9%) patients died, and 369 (46.6%) developed recurrent tumors. The five-year OS was 65% in Group 1, 60% in Group 2, 53% in Group 3, and 38% in Group 4 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The five-year RFS was 40% in Group 1, 18% in Group 2, 33% in Group 3, and 30% in Group 4 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.259; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eUnivariate and multivariate Cox proportional hazards analyses for five-year OS\u003c/h2\u003e \u003cp\u003eUnivariate analyses showed that age\u0026thinsp;\u0026lt;\u0026thinsp;70 years (hazard ratio [HR]\u0026thinsp;=\u0026thinsp;0.477, 95% CI\u0026thinsp;=\u0026thinsp;0.303\u0026ndash;0.752, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), age 75\u0026ndash;79 years (HR\u0026thinsp;=\u0026thinsp;0.522, 95% CI\u0026thinsp;=\u0026thinsp;0.294\u0026ndash;0.926, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.026) were associated with superior five-year OS compared to age\u0026thinsp;\u0026ge;\u0026thinsp;80 years. In addition, they showed that male vs. female sex (HR\u0026thinsp;=\u0026thinsp;1.362, 95% CI\u0026thinsp;=\u0026thinsp;1.014\u0026ndash;1.831, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.040), BCLC stage A vs. 0 (HR\u0026thinsp;=\u0026thinsp;1.531, 95% CI\u0026thinsp;=\u0026thinsp;1.141\u0026ndash;2.056, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005), AFP\u0026thinsp;\u0026ge;\u0026thinsp;20 vs. \u0026lt;20 ng/mL (HR\u0026thinsp;=\u0026thinsp;1.606, 95% CI\u0026thinsp;=\u0026thinsp;1.220\u0026ndash;2.115, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), MELD score\u0026thinsp;\u0026gt;\u0026thinsp;9 vs. \u0026le;9 (HR\u0026thinsp;=\u0026thinsp;1.76, 95% CI\u0026thinsp;=\u0026thinsp;1.33\u0026ndash;2.32, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and HBsAg positive vs. negative (HR\u0026thinsp;=\u0026thinsp;0.716, 95% CI\u0026thinsp;=\u0026thinsp;0.538\u0026ndash;0.955, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.023) were associated with inferior five-year OS. Similarly, multivariate analysis showed that age\u0026thinsp;\u0026lt;\u0026thinsp;70 years (HR\u0026thinsp;=\u0026thinsp;0.496, 95% CI\u0026thinsp;=\u0026thinsp;0.314\u0026ndash;0.785, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003), age 75\u0026ndash;79 years (HR\u0026thinsp;=\u0026thinsp;0.496, 95% CI\u0026thinsp;=\u0026thinsp;0.277\u0026ndash;0.889, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.018) were associated with superior five-year OS compared to age\u0026thinsp;\u0026ge;\u0026thinsp;80 years. In addition, it showed that BCLC stage A vs. 0 (HR\u0026thinsp;=\u0026thinsp;1.420, 95% CI\u0026thinsp;=\u0026thinsp;1.053\u0026ndash;1.913, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.021), AFP\u0026thinsp;\u0026ge;\u0026thinsp;20 vs. \u0026lt;20 ng/mL (HR\u0026thinsp;=\u0026thinsp;1.620, 95% CI\u0026thinsp;=\u0026thinsp;1.225\u0026ndash;2.143, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), and MELD score\u0026thinsp;\u0026gt;\u0026thinsp;9 vs. \u0026le;9 (HR\u0026thinsp;=\u0026thinsp;1.63, 95% CI\u0026thinsp;=\u0026thinsp;1.225\u0026ndash;2.169, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) were associated with inferior five-year OS (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate and multivariate Cox proportional hazards analysis for five-year overall survival.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnivariate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMultivariate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR (95%CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHR (95%CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u0026thinsp;≧\u0026thinsp;80 as reference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.477(0.303\u0026ndash;0.752)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.496(0.314\u0026ndash;0.785)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e70\u0026ndash;74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.644(0.379\u0026ndash;1.095)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.104\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.689(0.403\u0026ndash;1.179)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.174\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e75\u0026ndash;79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.522(0.294\u0026ndash;0.926)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.026\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.496(0.277\u0026ndash;0.889)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.018\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMen vs women\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.362(1.014\u0026ndash;1.831)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.040\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.365(0.999\u0026ndash;1.864)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.050\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBCLC stage\u003c/p\u003e \u003cp\u003eA vs. 0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.531(1.141\u0026ndash;2.056)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.420(1.053\u0026ndash;1.913)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.021\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAFP\u0026thinsp;≧\u0026thinsp;20 vs\u0026thinsp;\u0026lt;\u0026thinsp;20 ng/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.606(1.220\u0026ndash;2.115)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.620(1.225\u0026ndash;2.143)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMELD score\u0026thinsp;\u0026gt;\u0026thinsp;9 vs\u0026thinsp;≦\u0026thinsp;9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.76(1.33\u0026ndash;2.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.63(1.225\u0026ndash;2.169)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHBsAg positive vs negative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.716(0.538\u0026ndash;0.955)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.809(0.596-1.100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.176\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-HCV positive vs negative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.016(0.773\u0026ndash;1.336)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.909\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAFP, alpha-fetoprotein; MELD, model for end-stage liver disease; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; BCLC, Barcelona clinic liver cancer.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eUnivariate and multivariate Cox proportional hazards analyses for five-year RFS\u003c/h2\u003e \u003cp\u003eUnivariate analyses showed that BCLC stage A vs. 0 (HR\u0026thinsp;=\u0026thinsp;1.486, 95% CI\u0026thinsp;=\u0026thinsp;1.193\u0026ndash;1.852, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), AFP\u0026thinsp;\u0026ge;\u0026thinsp;20 vs. \u0026lt;20 ng/mL (HR\u0026thinsp;=\u0026thinsp;1.355, 95% CI\u0026thinsp;=\u0026thinsp;1.099\u0026ndash;1.671, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004), and HBsAg positive vs. negative (HR\u0026thinsp;=\u0026thinsp;0.808, 95% CI\u0026thinsp;=\u0026thinsp;0.655\u0026ndash;0.998, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.048) were associated with inferior five-year RFS. Multivariate analysis showed that BCLC stage A vs. 0 (HR\u0026thinsp;=\u0026thinsp;1.472, 95% CI\u0026thinsp;=\u0026thinsp;1.180\u0026ndash;1.836, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), and AFP\u0026thinsp;\u0026ge;\u0026thinsp;20 vs. \u0026lt;20 ng/mL (HR\u0026thinsp;=\u0026thinsp;1.347, 95% CI\u0026thinsp;=\u0026thinsp;1.091\u0026ndash;1.663, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006) were associated with inferior five-year RFS (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate and multivariate Cox proportional hazards analysis for five-year recurrence-free survival.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnivariate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMultivariate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR (95%CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHR (95%CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMen vs women\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.899(0.728\u0026ndash;1.109)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.319\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBCLC stage\u003c/p\u003e \u003cp\u003eA vs. 0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.486(1.193\u0026ndash;1.852)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.472(1.180\u0026ndash;1.836)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAFP\u0026thinsp;≧\u0026thinsp;20 vs\u0026thinsp;\u0026lt;\u0026thinsp;20 ng/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.355(1.099\u0026ndash;1.671)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.347(1.091\u0026ndash;1.663)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMELD score\u0026thinsp;\u0026gt;\u0026thinsp;9 vs\u0026thinsp;≦\u0026thinsp;9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.20(0.976\u0026ndash;1.485)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.082\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHBsAg positive vs negative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.808(0.655\u0026ndash;0.998)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.048\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.854(0.690\u0026ndash;1.056)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.145\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-HCV positive vs negative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.158(0.943\u0026ndash;1.423)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.161\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u0026thinsp;≧\u0026thinsp;80 as reference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.037(0.681\u0026ndash;1.580)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.866\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e70\u0026ndash;74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.353(0.849\u0026ndash;2.155)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.203\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e75\u0026ndash;79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.152(0.705\u0026ndash;1.884)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.573\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eKey: AFP, alpha-fetoprotein; MELD, model for end-stage liver disease; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; BCLC, Barcelona clinic liver cancer.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study enrolled a large cohort of patients with early-stage HCC and Child–Pugh class A liver disease undergoing pRFA, who were stratified into four groups by age. Tumor numbers, BCLC stages, AFP level ≥ 20 ng/mL, and MELD score \u0026gt; 9 did not differ significantly between groups. The proportion of men was highest in Group 1 (\u003cem\u003ep\u003c/em\u003e = 0.001), the HBsAg-positive proportion was highest in Group 1 (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001), and the anti-HCV-positive proportion was highest in Group 3 (\u003cem\u003ep\u003c/em\u003e = 0.001). However, whether sex and chronic liver disease etiology were associated with OS among patients with early-stage HCC remains unclear.\u003csup\u003e7\u003c/sup\u003e In contrast, tumor burden (i.e., tumor number and BCLC stage), AFP level, and liver function reserve (i.e., MELD score) are well-known factors associated with OS of patients with HCC [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. We can assume that characteristics related to OS were similar between groups. Therefore, we did not perform propensity score matching between them. We found that five-year OS was lowest in those aged ≥ 80 years (\u003cem\u003ep\u003c/em\u003e = 0.009). In addition, multivariate analysis showed that age ≥ 80 years was independently associated with inferior five-year OS. Therefore, we can conclude that age ≥ 80 years was associated with inferior five-year OS in patients with early-stage HCC and Child–Pugh class A liver disease undergoing pRFA. In contrast, age ≥ 80 years was not associated with five-year RFS.\u003c/p\u003e \u003cp\u003eMultiple studies have associated being elderly with inferior OS in patients with early-stage HCC undergoing pRFA. Takahashi et al. enrolled 461 patients with early-stage HCC and showed that OS was similar between elderly (i.e., aged ≥ 75 years) and non-elderly patients with HCC undergoing pRFA [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Similarly, Hiraoka et al. enrolled 206 patients with early-stage HCC and showed that OS was similar between elderly (i.e., aged ≥ 75 years) and non-elderly patients with HCC undergoing pRFA [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. However, Nishikawa et al. enrolled 368 patients with early-stage HCC and showed that OS was inferior in elderly (i.e., aged ≥ 75 years) compared to non-elderly patients with HCC undergoing pRFA (\u003cem\u003ep\u003c/em\u003e = 0.001) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Nonetheless, Tateishi et al. showed no difference in three-year survival between patients aged \u0026gt; 68 years (76%) and \u0026lt; 68 years (79.2%) among 1000 patients treated with RFA [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Finally, Ochi et al. enrolled 1079 patients with early-stage HCC treated with RFA and found that those aged ≥ 80 years had significantly shorter OS than the other groups (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAll these studies enrolled patients with Child–Pugh class A or B liver disease [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e–\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Since decompensated cirrhosis may be a competing risk more strongly associated with death than older age, in this study, we only enrolled patients with Child–Pugh class A liver disease to clarify whether older age was associated with inferior OS in patients with early-stage HCC undergoing pRFA.\u003c/p\u003e \u003cp\u003eSimilar to Ochi et al., [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] non-HCC-related deaths were most common among those aged ≥ 80 years in our study, although the difference was not statistically significant (\u003cem\u003ep\u003c/em\u003e = 0.389).\u003c/p\u003e \u003cp\u003eA recent population-based study evaluated about 3.9\u0026nbsp;million patients in seven high-income Western countries with seven primary cancers (esophagus, stomach, colon, rectum, pancreas, lung, and ovary). It showed that the survival benefit was limited in elderly patients, whereas a significant improvement in the OS was noted in younger patients [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Although they did not assess HCC, their findings are consistent with ours regarding HCC.\u003c/p\u003e \u003cp\u003eAge ≥ 80 years was not associated with five-year RFS in our study, consistent with Ochi et al. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] A MELD score of \u0026gt; 9 was associated with inferior five-year OS in our study. A recent review paper showed that the MELD score is commonly used in patients with HCC undergoing LR to predict postoperative liver failure and survival; it is also commonly used in patients with HCC undergoing LT to predict survival on the waiting list. The albumin-bilirubin (ALBI) score is used to predict survival in patients with HCC undergoing LR and non-surgical therapies [22]. However, the lack of albumin data in our HCC registry dataset precluded us from using the ALBI score to estimate patients’ liver functional reserve. In addition, while a MELD score of \u0026gt; 9 was originally used to predict postoperative liver decompensation in patients with HCC undergoing LR, [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] our findings suggest that it can also predict OS in patients with HCC undergoing pRFA.\u003c/p\u003e \u003cp\u003eOur study associated an AFP level of ≥ 20 ng/mL with inferior five-year OS and RFS. This cutoff was set according to the American Association for the Study of Liver Diseases guidelines, which recommend that among patients at risk of HCC and undergoing surveillance for HCC, those with an AFP level of ≥ 20 ng/mL should be examined using contrast-enhanced CT or MRI [23].\u003c/p\u003e \u003cp\u003eThe strength of our study is that it only enrolled patients with Child–Pugh class A liver disease to clarify whether older age is associated with inferior OS in patients with early-stage HCC undergoing pRFA. However, it had some limitations. First, it was a retrospective single-center study. Second, the number of patients aged ≥ 80 years was limited. Future studies are needed to evaluate which treatment is most appropriate for patients with early-stage HCC and Child–Pugh class A liver disease. Stereotactic body radiotherapy (SBRT) may offer advantages in patients with early-stage HCC aged ≥ 80 years because it does not require general anesthesia. Future studies should also compare survival outcomes and treatment complications between pRFA and SBRT in patients with early-stage HCC aged ≥ 80 years.\u003c/p\u003e \u003cp\u003e\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAmong patients with early-stage HCC and Child–Pugh class A liver disease undergoing pRFA, those aged ≥ 80 years had inferior five-year OS.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis study was supported by\u0026nbsp;Grant CMRPG8N1131\u0026nbsp;from the\u0026nbsp;Chang Gung Memorial Hospital-Kaohsiung Medical Center, Taiwan.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest:\u0026nbsp;\u003c/strong\u003eThe authors have no conflicts of interest to disclose for all authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u0026nbsp;\u003c/strong\u003eall data is available\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u003c/strong\u003e The Institutional Review Board of Kaohsiung Chang Gung Memorial Hospital approved this study (Reference number: 202201189B0)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate.\u003c/strong\u003e Written consents were waived by the IRB due to the retrospective nature of study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication.\u0026nbsp;\u003c/strong\u003eAll authors agree to publication if the paper is accepted\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank Cancer Center, Kaohsiung Chang Gung Memorial Hospital for the provision of HCC registry data. The authors thank Chih-Yun Lin and Nien-Tzu Hsu and the Biostatistics Center, Kaohsiung Chang Gung Memorial Hospital for statistics work. This study was supported by Grant CMRPG8N1131 from the Chang Gung Memorial Hospital-Kaohsiung Medical Center, Taiwan. No conflict of interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy conception and design:\u0026nbsp;YHY\u003c/p\u003e\n\u003cp\u003eAcquisition of data: all authors\u003c/p\u003e\n\u003cp\u003eAnalysis and interpretation of data: CYL\u003c/p\u003e\n\u003cp\u003eDrafting of manuscript: YHY\u003c/p\u003e\n\u003cp\u003eCritical revision of manuscript: all authors\u003c/p\u003e\n\u003cp\u003eApproval of manuscript: all authors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe raw data for the cohort are available via the following digital object identifier:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ehttps://www.dropbox.com/scl/fi/ynvp7768vhx7psmqapz63/2011-to-2021summary-r1.xlsx?rlkey=1c4ks72b9ly24nzs652tps8oe\u0026amp;dl=0\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional Information (including a Competing Interests Statement)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest to disclose for all authors.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. 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Hierarchic Interaction of Factors Associated With Liver Decompensation After Resection for Hepatocellular Carcinoma. JAMA Surg. 2016;15:846-53. doi: 10.1001/jamasurg.2016.1121.\u003c/li\u003e\n\u003cli\u003eLiu YW, Yen YH, Li WF, Wang CC, Lu SN, Kee KM, et al. Minimally invasive surgery versus percutaneous radiofrequency ablation for early-stage hepatocellular carcinoma: Results from a high-volume liver surgery center in East Asia. Surg Oncol. 2022;42:101769. doi: 10.1016/j.suronc.2022.101769.\u003c/li\u003e\n\u003cli\u003eTakahashi H, Mizuta T, Kawazoe S, Eguchi Y, Kawaguchi Y, Otuka T, et al. Efficacy and safety of radiofrequency ablation for elderly hepatocellular carcinoma patients. Hepatol Res. 2010;40:997-1005. doi: 10.1111/j.1872-034X.2010.00713.x.\u003c/li\u003e\n\u003cli\u003eHiraoka A, Michitaka K, Horiike N, Hidaka S, Uehara T, Ichikawa S, et al. Radiofrequency ablation therapy for hepatocellular carcinoma in elderly patients. J Gastroenterol Hepatol. 2010;25:403-7. doi: 10.1111/j.1440-1746.2009.06037.x.\u003c/li\u003e\n\u003cli\u003eNishikawa H, Osaki Y, Iguchi E, Takeda H, Ohara Y, Sakamoto A, et al. Percutaneous radiofrequency ablation for hepatocellular carcinoma: clinical outcome and safety in elderly patients. J Gastrointestin Liver Dis. 2012;21:397-405.\u003c/li\u003e\n\u003cli\u003eTateishi R, Shiina S, Teratani T, Obi S, Sato S, Koike Y, Fujishima T, et al. Percutaneous radiofrequency ablation for hepatocellular carcinoma. An analysis of 1000 cases. Cancer. 2005 Mar 15;103:1201-9. doi: 10.1002/cncr.20892.\u003c/li\u003e\n\u003cli\u003eArnold M, Rutherford MJ, Bardot A, Ferlay J, Andersson TM, Myklebust T\u0026Aring;, et al. Progress in cancer survival, mortality, and incidence in seven high-income countries 1995-2014 (ICBP SURVMARK-2): a population-based study. Lancet Oncol. 2019;20:1493-1505. doi: 10.1016/S1470-2045(19)30456-5.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Hepatocellular carcinoma, percutaneous radiofrequency ablation, elderly.","lastPublishedDoi":"10.21203/rs.3.rs-3880000/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3880000/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIt is unclear whether overall survival (OS) differs by age for patients with early‐stage hepatocellular carcinoma (HCC) undergoing radiofrequency ablation (RFA). We aim to clarify this issue. All patients diagnosed with early‐stage HCC (i.e., within Milan criteria) and Child–Pugh class A liver disease undergoing RFA between 2011 and 2021 were enrolled. Patients with incomplete ablation were excluded. This study enrolled 791 patients and them divided into four groups by age: \u0026lt;70 years (Group 1, \u003cem\u003en\u003c/em\u003e = 508), 70–74 years (Group 2, \u003cem\u003en\u003c/em\u003e = 122), 75–79 years (Group 3, \u003cem\u003en\u003c/em\u003e = 102), and ≥80 years (Group 4, \u003cem\u003en\u003c/em\u003e = 59). The five-year OS was 65% in Group 1, 60% in Group 2, 53% in Group 3, and 38 % in Group 4 (\u003cem\u003ep\u003c/em\u003e = 0.009). With Group 4 as the reference, multivariate analysis indicated that Groups 1 (HR: 0.496, 95% CI: 0.314–0.785, \u003cem\u003ep\u003c/em\u003e = 0.003) and 3 (HR: 0.496, 95% CI: 0.277–0.889, \u003cem\u003ep\u003c/em\u003e= 0.018) but not Group 2 (HR: 0.689, 95% CI: 0.403–1.179, \u003cem\u003ep\u003c/em\u003e = 0.174) were independent factors associated with superior five-year OS. In conclusion, among patients with early-stage HCC and Child–Pugh class A liver disease undergoing RFA, those aged ≥80 years had inferior five-year OS.\u003c/p\u003e","manuscriptTitle":"Overall survival was inferior in octogenarians with early-stage hepatocellular carcinoma undergoing percutaneous radiofrequency ablation. 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