Efficacy and Safety of Surgical Resection in Elderly Patients with Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

Jin-Soo Lee; Dong Ah Park; Seungeun Ryoo; Jungeun Park; Gi Hong Choi; Jeong-Ju Yoo

doi:10.5009/gnl230485

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Efficacy and Safety of Surgical Resection in Elderly Patients with Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

Jin-Soo Lee¹ , Dong Ah Park² , Seungeun Ryoo² , Jungeun Park² , Gi Hong Choi³ , Jeong-Ju Yoo¹

Author Info ⁺

¹Department of Internal Medicine, Soonchunhyang University School of Medicine, Asan, Korea; ²Division of Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency, Seoul, Korea; ³Department of General Surgery, Yonsei University School of Medicine, Seoul, Korea

Correspondence to: Dong Ah Park
ORCID https://orcid.org/0000-0001-7225-3152
E-mail pda124@neca.re.kr

Jeong-Ju Yoo
ORCID https://orcid.org/0000-0002-7802-0381
E-mail puby17@naver.com

Jin-Soo Lee and Dong Ah Park contributed equally to this work as first authors.

Received: November 22, 2023; Revised: January 17, 2024; Accepted: January 29, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut Liver 2024;18(4):695-708. https://doi.org/10.5009/gnl230485

Published online May 7, 2024, Published date July 15, 2024

Abstract

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Abstract
Graphical Abstract
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
CONFLICTS OF INTEREST
AUTHOR CONTRIBUTIONS
SUPPLEMENTARY MATERIALS
References

Background/Aims: With increased life expectancy, the management of elderly hepatocellular carcinoma (HCC) patients became a crucial issue, yet it is still challenging due to comorbidities and high surgical risks. While surgical resection is considered as primary treatment for eligible HCC patients, systematic evidence on its outcomes in elderly patients remains scarce. In this review, we aimed to analyze the efficacy and safety outcomes of surgical resection in elderly HCC patients.
Methods: The studies included in this meta-analysis were selected from Ovid-MEDLINE, Ovid-Embase, CENTRAL, KoreaMed, KMbase, and KISS databases following a predefined protocol. Efficacy outcomes included overall survival and disease-free survival, while the safety outcomes included postoperative mortality and complications.
Results: Patients in the elderly group (≥65 years) who underwent surgery exhibited non-inferior overall survival (hazard ratio [HR], 1.26; 95% confidence interval [CI], 0.92 to 1.74) and disease-free survival (HR, 1.03; 95% CI, 0.99 to 1.08) compared to the non-elderly group. Overall postoperative mortality exhibited no statistical difference (odds ratio [OR], 1.07; 95% CI, 0.87 to 1.31), but 30-day, 90-day, and in-hospital mortality were higher in the elderly group. The incidence of overall complications was higher in the elderly group (OR, 1.44; 95% CI, 1.22 to 1.69). Sensitivity analysis for the super elderly group (≥80 years) showed significantly higher in-hospital mortality compared to the non-super elderly group (OR, 2.51; 95% CI, 1.16 to 5.45).
Conclusions: The efficacy outcome of surgical resection in the elderly HCC patients was not worse than that in the non-elderly HCC patients, while in-hospital mortality and complications rates were higher. Therefore, surgical resection should be purposefully considered in the elderly population, with careful candidate selection.

Keywords: Hepatocellular carcinoma, Aged, Surgery, Treatment

Graphical Abstract

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Abstract
Graphical Abstract
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
CONFLICTS OF INTEREST
AUTHOR CONTRIBUTIONS
SUPPLEMENTARY MATERIALS
References

INTRODUCTION

Go to

Abstract
Graphical Abstract
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
CONFLICTS OF INTEREST
AUTHOR CONTRIBUTIONS
SUPPLEMENTARY MATERIALS
References

According to the World Health Organization, hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer-related deaths worldwide, in 2020, with an annual estimate of 830,000 deaths.¹ Deaths caused by HCC are particularly frequent in Asia, where HCC is the second cause of cancer-related death.² Due to the increase in life expectancy and advancements in medical technology, the number of elderly patients with HCC has been rising and the treatment selection for elderly HCC patients has become increasingly important.^3,4

Surgical resection is considered the gold standard for curative treatment of early to intermediate-stage HCC patients.⁵ Owing to recent advances in surgical techniques and perioperative management, recent studies have shown that surgical resection shows better outcomes than other treatment options such as radiofrequency ablation, transarterial chemoembolization, and systemic chemotherapy.^6,7 However, recommending surgical resection as a primary treatment for elderly HCC patients (≥65 years) is significantly challenged by their higher comorbidity rates, increased surgical risks, and the lack of objective data.^8,9 Moreover, most patients aged 80 and above are typically excluded from research designs, further exacerbating the scarcity of data for this specific age group. Here arises a demand for guidelines addressing the safety and feasibility of surgical resection in this specific patient age range, necessitating large-scale studies comparing the efficacy and safety outcomes of surgical resection between elderly and non-elderly patients.¹⁰

The objective of this study was to provide systematic evidence that supports the decision for surgical resection in elderly patients with HCC. There have been several studies comparing the outcomes of surgical resection between elderly and non-elderly patients, but most of them were limited to single institution,¹¹ or had a small number,¹² or were restricted to the domestic population.¹³ Therefore, we conducted a systematic review and meta-analysis on outcomes of surgical resection, including the super elderly population.

MATERIALS AND METHODS

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Abstract
Graphical Abstract
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
CONFLICTS OF INTEREST
AUTHOR CONTRIBUTIONS
SUPPLEMENTARY MATERIALS
References

This article was registered at the International Prospective Register of Systematic Reviews (CRD42023469975) for adequate protocol. Systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and Meta-analysis of Observational Studies in Epidemiology checklists. Ethics approval was waived from the Institutional Review Board of the National Evidence-based Healthcare Collaborating Agency and the current study conformed to the ethical guidelines of the World Medical Association Declaration of Helsinki.

1. Study selection and subgroup design

The study selection algorithm is characterized in Fig. 1. Articles were mainly identified and searched from databases and registers in 2021 and an updated search was conducted in 2022. Ovid-MEDLINE, Ovid-Embase, and CENTRAL were the international databases used, and KoreaMed, KMbase, and KISS were the domestic databases. In primary study screening, title-based selection and exclusion were conducted and 9,601 studies were excluded. Furthermore, abstract-based screening was done, and 2,511 studies were excluded. A total of 225 studies were selected for full-text review. After considering the relevance to our study design, a final set of 56 studies was selected for systemic analysis (Fig. 1). Since all the studies included in the meta-analysis were retrospective design, they are inherently more susceptible to selection bias and confounding factors. To address this limitation, we conducted subgroup analyses based on various classification such as age cutoff, publication year, country, and methodological index for non-randomized studies (MINORS) score. Additionally, sensitivity analysis was performed specifically for the super elderly population. The primary meta-analysis of our study focused on comparing the elderly group, defined as individuals aged 65 and above, with the non-elderly group, defined as those under 65, and presenting the analysis results. However, considering the increasing prevalence of very elderly patients in clinical practice, we conducted an additional sensitivity analysis specifically for the super elderly group, defined as individuals aged 80 and above, in studies where this age category was separately classified.

Figure 1.Selection flowchart of the studies included in meta-analysis.

2. Study outcome

The purpose of the study was to compare efficacy and safety outcomes between elderly and non-elderly patients with HCC. Efficacy-related outcomes included overall survival (OS) and disease-free survival (DFS), while safety-related outcomes included postoperative mortality and postoperative complications.

3. Methodological quality and risk of bias assessment

The assessment of bias risk was conducted independently by two researchers, and consensus was reached through discussion with a third party. For randomized controlled trials, the Cochrane Risk of Bias 1.0 tool was used whereas the MINORS (a valid instrument designed to assess the methodological quality of non-randomized surgical studies, consisting of 12 questions with a total of 24 points¹⁴ was used for non-randomized controlled trials (Supplementary Fig. 1).

4. Statistical analysis

Efficacy-related outcomes, OS and DFS, were evaluated using median value, interquartile range (IQR), and range. Meta-analysis was primarily done with a random effects model, using the following methods: (1) inverse variance method for survival and consecutive data and (2) Mantel-Haenszel method for binary data. The binary outcomes were presented as odds ratio (OR), and for survival outcomes, hazard ratio (HR) with a 95% confidence interval (CI). Statistical inter-study heterogeneity of meta-analysis was primarily assessed by Forest plot and Cochrane Q statistics (p<0.10) with I² statistics (≥50%). Moreover, subgroup analysis was conducted to find factors contributing to heterogeneity and those factors included age threshold, disease stage, country of study, publication year, quality assessment scores, and the number of adjusted variables. Also, sensitivity analysis was conducted on super elderly patients, independently (≥80 years). Publication bias was assessed using funnel plots and Egger’s test (Supplementary Fig. 2). Meta-analysis was conducted using RevMan 5.3, and statistical significance for differences between groups was assessed at a significance level of 5%.

RESULTS

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Abstract
Graphical Abstract
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
CONFLICTS OF INTEREST
AUTHOR CONTRIBUTIONS
SUPPLEMENTARY MATERIALS
References

1. Characteristics of studies included in the systemic review

As mentioned above, a total of 56 articles were included in the final analysis. The baseline characteristics of the enrolled studies including baseline liver function and cancer status are presented in Table 1.^11-13,15-62 When classified by continent, the majority of studies, 47 (83.9%), were from Asia, while nine studies (16.0%) were from Europe. Forty-six studies (82.1%) were conducted by a single institution, and 10 studies (17.8%) involved multi-institutions. All 56 studies were retrospective cohort studies. An age threshold of 70 years for elderly patients was used in 24 studies (42.8%), followed by 75 years in 14 studies (25%), and 65 years in five studies (8.9%).

Table 1

Demographics and Characteristics of Studies Included in the Systematic Review: Elderly versus Non-Elderly

Study (year)	Country	Institution	Recruitment period	Matching	Objective	Age cutoff, yr	No. of elderly	No. of non-elderly	Baseline liver function, %		Tumor size, mm
Study (year)	Country	Institution	Recruitment period	Matching	Objective	Age cutoff, yr	No. of elderly	No. of non-elderly	Elderly Child A/B	Non-elderly Child A/B	Elderly	Non-elderly
Fujio (2022)¹²	Japan	Single	2012–2016	NR	HR for HCC	75	22	39	95/5	87/13	53.6	52
Pu (2022)¹⁵	China	Multicenter	2007–2019	PSM	R0 HR for HCC	70	140	140	94/6	94/6	NA	NA
Harada (2021)¹¹	Japan	Single	2001–2012	PSM	HR for HCC	70	234	234	97/3	95/5	30	31
Liu (2021)¹⁶	Taiwan	Registry	2007–2017	NR	HR for HCC	75	96	908	NA	NA	41.5	NA
Tan (2021)¹⁷	Singapore	Single	2000–2018	NR	HR for HCC	70	278	764	94/6	95/5	45	38
Chen (2020)¹³	China	Multicenter	2006–2016	NR	HR for HCC	65	92	738	91/9	89/11	105	108
Shin (2020)¹⁸	Korea	Single	2012–2018	NR	HR for HCC	70	49	184	NA	NA	NA	NA
Shimada (2020)¹⁹	Japan	Single	2000–2017	NR	HR for HCC	65	363	384	NA	NA	57	61
Yasuda (2020)²⁰	Japan	Single	2000–2013	NR	Major HR for HCC	70	23	18	100/0	100/0	54	78
Xing (2020)²¹	China	Multicenter	2003–2016	NR	HR for HCC	70	259	1,875	96/4	90/10	NA	NA
Famularo (2019)²²	Italy	Multicenter	2005–2015	PSM	HR for HCC	75	92	92	92/8	96/4	35	41
Jiang (2019)²³	China	Registry	2004–2015	NR	HR for HCC	65	956	1,392	NA	NA	NA	NA
Kaibori (2019)²⁴	Japan	Registry	2000–2007	NR	HR for HCC	75	2,020	10,567	92/8	90/10	38	NA
Okamura (2018)²⁵	Japan	Single	2002–2014	PSM	HR for HCC	75	72	72	99/1	99/1	NA	NA
Chen (2018)²⁶	China	Single	2010–2016	NR	HR for HCC	65	256	886	91/9	82/18	NA	84
Goh (2018)²⁷	Singapore	Single	2007–2016	PSM	LMH for HCC	70	40	94	NA	NA	30	25
Hsu (2018)²⁸	Taiwan	Single	2003–2014	NR	HR for large HCC (>5 cm)	70	79	178	92/8	89/11	86	90
Wang (2018)²⁹	China	Single	2011–2016	NR	HR for HCC	70	48	97	NA	NA	NA	NA
Yu (2018)³⁰	China	Single	2003–2013	NR	HR for HCC	70	23	58	83/17	91/9	47	37
Santambrogio (2017)³¹	Italy	Single	1998–2015	NR	HR for HCC	75	53	115	100/0	100/0	NA	NA
Bauschke (2016)³²	Germay	Single	1995–2014	NR	HR for HCC	70	63	81	87/13	77/23	NA	NA
Cucchetti (2016)³³	Italy	Single	1997–2013	NR	HR for HCC with LC	70	229	690	NA	NA	NA	NA
Harimoto (2016)³⁴	Japan	Single	2004–2013	NR	HR for HCC	70	139	157	94/6	96/4	40	40
Kim (2015)³⁵	Korea	Single	2006–2010	NR	HR for HCC	70	60	219	NA	NA	49	49
Kishida (2015)³⁶	Japan	Single	2005–2010	NR	HR for HCC	75	22	82	91/9	99/1	35	30
Motoyama (2015)³⁷	Japan	Single	1990–2013	NR	HR for HCC	75	113	499	95/5	94/6	33	30
Nozawa (2015)³⁸	Japan	Single	2000–2010	NR	HR for HCC	70	192	239	86/14	85/15	NA	30
Sato (2015)³⁹	Japan	Single	2000–2010	NR	HR for HCC	75	34	195	74/26	83/17	49	54
Faber (2014)⁴⁰	Germany	Single	2000–2010	NR	HR for HCC with LC	70	63	78	NA	NA	50	50
Liu (2014)⁴¹	Taiwan	Single	2002–2013	PSM	HR for HCC	75	118	118	93/7	93/7	NA	NA
Mori (2014)⁴²	Japan	Single	2000–2012	NR	HR for HCC with PHT	70	64	131	78/22	71/29	41	33
Ueno (2014)⁴³	Japan	Single	2001–2010	NR	HR for HCC	75	66	186	91/9	91/9	50	40
Wang (2014)⁴⁴	China	Single	2007–2012	NR	HR for HBV related HCC	65	207	1,336	NA	NA	NA	NA
Wang (2014)⁴⁵	China	Single	2007–2012	Paired matched	Major hepatectomy for HCC with LC	70	56	152	86/14	80/20	75	89
Hirokawa (2013)⁴⁶	Japan	Single	2000–2011	NR	HR for HCC	70	100	120	88/12	82/18	35	30
Ide (2013)⁴⁷	Japan	Single	2000–2010	NR	HR for HCC	75	64	192	89/11	88/12	49	49
Murillo (2013)⁴⁸	Spain	Single	2000–2011	NR	HR for HCC	70	22	14	NA	NA	38	47
Nishikawa (2013)⁴⁹	Japan	Single	2004–2012	NR	HR for HCC	75	92	206	98/2	96/4	46	48
Taniai (2013)⁵⁰	Japan	Single	1990–2010	NR	HR for HCC	75	63	353	89/11	75/24/1	NA	NA
Lee (2012)⁵¹	Korea	Single	2000–2010	NR	HR for HCC	70	61	90	NA	NA	45	43
Nanashima (2011)⁵²	Japan	Single	1994–2009	NR	HR for HCC	70	69	119	93/7	89/11	NA	NA
Portolani (2011)⁵³	Italy	Single	1992–2009	NR	HR for HCC	70	175	276	92/8	93/7	48	49
Mirici-Cappa (2010)⁵⁴	Italy	Multicenter	1987–2004	PSM	HR for HCC	70	32	32	93/7	82/13	34	41
Tan (2021)¹⁷^*	Singapore	Single	2000–2018	NR	HR for HCC	80	50	1,042	92/8	94/6	80	NA
Sanyal (2020)⁵⁵	England	Single	2005–2015	NR	HR for HCC	80	19	181	NA	NA	NA	NA
Shimada (2020)¹⁹^†	Japan	Single	2000–2017	NR	HR for HCC	80	49	757	NA	NA	64	NA
Inoue (2019)⁵⁶	Japan	Single	2001–2017	PSM	HR for HCC	80	45	485	100/0	93/7	41	32
Lee (2019)⁵⁷	Taiwan	Single	1986–2015	NR	HR for HCC	80	77	3,309	96/4	96/4	59	42
Wu (2019)⁵⁸	Taiwan	Single	1992–2016	NR	HR for HCC	85	31	1,858	87/10/3	87/11/2	56	65
Chen (2018)²⁶^†	China	Single	2010–2016	NR	HR for HCC	80	32	1,110	94/6	84/16	69	NA
Hamaoka (2017)⁵⁹	Japan	Single	2004–2013	NR	HR for HCC	80	60	565	93/7	93/7	33	27
Nozawa (2015)³⁸^‡	Japan	Single	2000–2010	NR	HR for HCC	80	20	411	95/5	85/15	41	NA
Katsuta (2014)⁶⁰^§	Japan	Single	2000–2012	NR	HR for HCC	80	29	457	83/17	91/9	NA	NA
Tsujita (2012)⁶¹	Japan	Multicenter	1995–2008	NR	HR for HCC	80	23	385	NA	NA	NA	NA
Yamada (2012)⁶²	Japan	Multicenter	1992–2009	NR	HR for HCC	80	11	267	82/18	92/8	52	48
Nanashima (2011)⁵²^∥	Japan	Single	1994–2009	NR	HR for HCC	80	12	167	100/0	90/10	NA	NA

NR, not reported; PSM, propensity score matching; HR, hepatic resection; HCC, hepatocellular carcinoma; LC, liver cirrhosis; LMH, laparoscopic minor hepatectomy; PHT, portal hypertension; HBV, hepatitis B virus; NA, not applicable.

Definition of elderly: *<70/70–79/≥80 yr; ^†<65/65–79/≥80; ^‡<70/70–80/≥81 yr; ^§<50/50–79/≥80; ^∥<50/50–69/70–79/≥80 yr.

2. Overall survival

Forty-eight articles reported the results of the OS. In the elderly group meta-analysis, at the 3-year postoperative point, the median OS of the elderly group was 70.0% (IQR, 62.7% to 75.1%) and 74.3% (IQR, 66.8% to 77.9%) in the non-elderly group. The median survival periods were similar between the two groups: the elderly group had a median of 69 months (IQR, 52.5 to 77.0 months), while the non-elderly group had a median of 73.3 months (IQR, 60.0 to 89.7 months). In the analysis of the super elderly group (≥80 years), the 3-year median OS rates were 67.7% (IQR, 53.3% to 79.3%) for the super elderly and 70.9% (IQR, 46.0% to 76.8%) for the non-super elderly, respectively. Similar to the elderly group analysis, median survival periods were similar between the super elderly and non-super elderly; 64.8 months in super elderly and 79.4 months in non-super elderly (Supplementary Table 1).

We conducted a meta-analysis on OS between elderly and non-elderly groups. Univariate analysis showed that the OS of the elderly group was worse than that of the non-elderly group (HR, 1.18; 95% CI, 1.09 to 1.27; I²=67%) (Fig. 2A), whereas, in multivariate analysis, there was no significant difference between the two groups (HR, 1.26; 95% CI, 0.92 to 1.74; I²=71%). In subgroup analysis, studies that used 75 years as the age threshold for the elderly showed lower heterogeneity, and the overall mortality of the elderly group was higher than that of the non-elderly group (HR, 1.29; 95% CI, 1.17 to 1.42; I²=23%) (Table 2).

Figure 2.Forest plots. (A) Overall mortality between elderly versus non-elderly. (B) Disease-free survival between elderly versus non-elderly. (C) Postoperative mortality between elderly versus non-elderly. (D) Post operative mortality between super elderly versus non-super elderly. (E) Postoperative complication between elderly versus non-elderly. (F) Postoperative complication between super elderly versus non-super elderly. SE, standard error; IV, inverse variance; CI, confidence interval; M-H, Mantel-Haenszel.

Table 2

Meta-Analysis on Overall Survival: Elderly versus Non-Elderly

Variable	Univariate analysis			Multivariate analysis
Variable	No. of studies	Random, IV HR (95% CI)	I², %	No. of studies	Random, IV HR (95% CI)	I², %
Overall mortality	32	1.18 (1.09–1.27)	67	4	1.26 (0.92–1.74)	71
Using data					NA
Calculated data	23	1.13 (1.04–1.22)	52		NA
Reported data	9	1.26 (1.07–1.49)	79		NA
Age cutoff
65–70 yr	18	1.09 (1.00–1.19)	66	1	1.08 (0.49–2.36)	NA
75 yr	14	1.29 (1.17–1.42)	23	2	1.39 (0.69–2.81)	89
Publication year
2016–2022	20	1.19 (1.08–1.31)	70	4	1.26 (0.92–1.74)	71
2010–2015	13	1.19 (1.02–1.40)	61	0	-	-
Country
Asia	26	1.15 (1.07–1.24)	65	2	1.23 (0.90–1.69)	0
Non-Asia	6	1.46 (0.96–2.20)	77	2	1.39 (0.69–2.81)	89
MINORS score
Over median value (20)	15	1.32 (1.15–1.50)	70	2	1.39 (0.69–2.81)	89
Under median value (20)	17	1.10 (0.99–1.22)	67	2	1.23 (0.90–1.69)	0

IV HR, inverse variance hazard ratio; CI, confidence interval; NA, not applicable; MINORS, methodological index for non-randomized studies.

Sensitivity analysis between the super elderly (≥80 years) and the non-super elderly group showed higher overall mortality in the super elderly group (HR, 1.32; 95% CI, 1.04 to 1.67; I²=79%), but had higher heterogeneity between studies. In subgroup analysis, studies published between 2010 and 2015 showed lower heterogeneity and the risk of death for the super elderly group was higher than that for the non-super elderly group (HR, 1.59; 95% CI, 1.00 to 2.53; I²=0%). Furthermore, in studies with high MINORS score, there was no statistical heterogeneity, and the overall mortality for the super elderly group was also higher (HR, 1.22; 95% CI, 1.03 to 1.44; I²=0%) (Supplementary Table 2).

3. Disease-free survival

DFS was reported in 34 studies. In the elderly group analysis, at the 3-year postoperative point, the median DFS rate for the elderly group was 40.6% (IQR, 36.0% to 50.9%), while the non-elderly group showed a rate of 44.9% (IQR, 35.7% to 54.5%). Five-year median DFS rate was 33.0% in both elderly and non-elderly groups (IQR, 25.6% to 36.9% and IQR, 25.6% to 39.8%, respectively). The median DFS periods were similar between the two groups, with the elderly group having 27.8 months (IQR 20.3 to 35.8 months) and the non-elderly group having 33.4 months (IQR, 18.6 to 42.6 months) (Supplementary Table 1). According to the univariate analysis for DFS, there was no statistically significant difference between elderly and non-elderly groups (HR, 1.03; 95% CI, 0.99 to 1.08; I²=0%) (Table 3, Fig. 2B).

Table 3

Meta-Analysis on Disease-Free Survival: Elderly versus Non-Elderly

Variable	Univariate analysis
Variable	No. of studies	Random, IV HR (95% CI)	I², %
Overall estimate	21	1.03 (0.99–1.08)	0
Using data
Calculated data	15	1.04 (0.96–1.13)	17
Reported data	6	1.03 (0.97–1.10)	0
Age cutoff
65–70 yr	10	1.05 (0.97–1.14)	0
75 yr	11	1.02 (0.96–1.08)	0
Publication year
2016–2022	13	1.04 (0.99–1.09)	0
2010–2015	8	1.17 (0.92–1.49)	34
Country
Asia	18	1.02 (0.98–1.07)	0
Non-Asia	3	1.43 (1.02–2.01)	0
MINORS score
Over median value (20)	10	1.06 (0.91–1.24)	33
Under median value (20)	11	1.04 (0.99–1.10)	0

IV HR, inverse variance hazard ratio; CI, confidence interval; MINORS, methodological index for non-randomized studies.

In sensitivity analysis for the super elderly group (≥80 years), 3-year median DFS were 38.1% (IQR, 34.1% to 46.2%) and 46.3% (IQR, 38.8% to 47.9%) for super elderly and non-super elderly respectively. Five-year median DFS rates were 35.1% (IQR, 19.4% to 40.2%) and 32.3% (IQR, 28.7% to 35.2%) respectively. Median DFS periods were 26.3 months (IQR, 24.0 to 31.3 months) in super elderly and 28.4 months (IQR, 20.5 to 33.2 months) in non-super elderly (Supplementary Table 1).

4. Postoperative mortality

Overall postoperative mortality, 30 days postoperative mortality, 90 days postoperative mortality, in-hospital mortality, and mortality related to hepatic failure were analyzed (Table 4). Fourteen studies reported overall postoperative mortality and there was no significant difference between elderly and non-elderly groups (OR, 1.07; 95% CI, 0.87 to 1.31; I²=51%) (Fig. 2C). Whereas the elderly group showed significantly higher 30 days, 90 days mortality, and in-hospital mortality rates compared to the non-elderly group with OR of 2.13, 1.65, and 1.78, respectively. However, hepatic failure-related mortality showed no significant difference between the two groups (OR, 1.28; 95% CI, 0.76 to 2.16; I²=0%). Within the super elderly (≥80 years) group versus non-super elderly group analysis, the super elderly group showed significantly higher in-hospital mortality (OR, 2.51; 95% CI, 1.16 to 5.45). However, there were no significant differences in overall postoperative mortality (OR, 0.91; 95% CI, 0.33 to 2.50) (Fig. 2D), 30 days, and 90 days mortality between the two groups (Table 4).

Table 4

Postoperative Mortality: Elderly versus Non-Elderly, Super Elderly versus Non-Super Elderly

Outcome variable	No. of studies	Elderly		Non-elderly		Random, M-H pooled OR	95% CI	I², %
Outcome variable	No. of studies	No. of participants	Events	No. of participants	Events	Random, M-H pooled OR	95% CI	I², %
Elderly vs non-elderly
Overall mortality rate	14	1,813	734	4,525	2,057	1.07	0.87–1.31	51
30-Day mortality rate	10	1,740	24	5,921	58	2.13	1.28–3.54	0
90-Day mortality rate	13	1,738	47	5,841	115	1.65	1.09–2.49	8
In-hospital mortality rate	10	1,055	31	3,175	47	1.78	1.03–3.09	14
Hepatic failure-related mortality rate	11	1,463	28	2,976	45	1.28	0.76–2.16	0
Super elderly vs non-super elderly
Overall mortality rate	4	137	39	2,304	929	0.91	0.33–2.50	75
30-Day mortality rate	6	287	6	6,954	92	2.27	0.99–5.18	0
90-Day mortality rate	4	149	3	3,828	55	2.05	0.76–5.57	0
In-hospital mortality rate	5	143	6	4,548	102	2.51	1.16–5.45	0
Hepatic failure-related mortality rate	0	-				-	-	-

M-H, Mantel-Haenszel; OR, odds ratio; CI, confidence interval.

5. Postoperative complications

The overall postoperative complication was reported in 26 studies (Table 5). The elderly group had a higher incidence of postoperative complications than that of the non-elderly group (OR, 1.44; 95% CI, 1.22 to 1.69; I²=51%) (Fig. 2E). The elderly group also had a higher incidence of major postoperative complications (OR, 1.30; 95% CI, 1.11 to 1.53; I²=26%), whereas no significant difference in postoperative hepatic failure was observed between the two groups (OR, 1.20; 95% CI, 0.79 to 1.82; I²=0%). In sensitivity analysis, the super elderly group had a higher incidence of complications than the non-super elderly group (OR, 2.02; 95% CI, 1.35 to 3.02; I²=65%) (Fig. 2F) whereas major postoperative complications and postoperative hepatic failure did not show a statistical difference between groups.

Table 5

Postoperative Complications: Elderly versus Non-Elderly, Super Elderly versus Non-Super Elderly

Outcome variable	No. of studies	Elderly		Non-elderly		Random, M-H pooled OR	95% CI	I², %
Outcome variable	No. of studies	No. of participants	Events	No. of participants	Events	Random, M-H pooled OR	95% CI	I², %
Elderly vs non-elderly
Overall postoperative complications	26	2,943	1,184	8,629	2,762	1.44	1.22–1.69	51
Major postoperative complications	24	2,476	411	8,360	1,041	1.30	1.11–1.53	26
Postoperative hepatic failure	13	1,154	33	3,914	100	1.20	0.79–1.82	0
Super elderly vs non-super elderly
Overall postoperative complications	9	359	171	9,457	2,940	2.02	1.35–3.02	65
Major postoperative complications	7	197	28	3,516	328	1.25	0.66–2.39	47
Postoperative hepatic failure	8	197	5	5,147	83	2.25	0.96–5.27	0

M-H, Mantel-Haenszel; OR, odds ratio; CI, confidence interval.

DISCUSSION

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Through this meta-analysis, several meaningful results regarding the efficacy and safety of surgery in elderly HCC patients were obtained. These results can be of great help to clinicians in decision-making in a recent trend where the number of elderly HCC patients is increasing.

The first finding of our study was that there was no statistically significant difference in the efficacy outcomes, namely OS and DFS, between the elderly and non-elderly groups (Tables 2 and 3). Univariate analysis for OS showed a difference between the elderly and non-elderly groups (HR, 1.18; 95% CI, 1.09 to 1.27). However, in multivariate analysis, no statistically significant difference was observed between the two groups (HR, 1.26; 95% CI, 0.92 to 1.74). Therefore, it is suggested that factors other than surgery might have had a greater influence on the difference in OS between the elderly and non-elderly groups.^24,63 One possible interpretation of this result may be that relative to the past, the overall health status has improved owing to recent advancements in medical technology, which led to an increase in average lifespan and improved performance among the elderly population.⁶⁴ Another speculation is that the likelihood of undergoing surgery in selected patients, particularly those with good performance status, is higher in actual clinical practice. Patients with poor performance status often undergo other procedures such as radiofrequency ablation rather than surgery.⁶⁵ Therefore, the patients analyzed in this study might have had similar initial pre-operative conditions compared to the non-elderly group. The last hypothesis is that the overall advancement in surgical techniques and postoperative management might have contributed to improved surgical outcomes in elderly HCC patients.⁶⁶ To investigate this hypothesis further, subgroup analyses were conducted according to the year of publication which indicated no significant differences in results across different study periods (Table 2).

The second finding is that in the Asian region, the difference in OS and DFS between elderly and non-elderly groups had a less pronounced trend compared to the non-Asian regions, although not statistically significant (Tables 2 and 3). This is thought to be due to the differences in HCC etiology and surgical methods between Asia and non-Asian countries. In Asia, the proportion of HCC due to viral hepatitis such as hepatitis B virus or hepatitis C virus is significantly higher compared to the predominance of nonalcoholic fatty liver disease-associated HCC in the West.^2,67-69 It is known that the average age of nonalcoholic fatty liver disease-associated HCC patients is about 5 to 10 years older than that of viral hepatitis-associated HCC patients.^70-72 Therefore, it is assumed that the median age of Asia's HCC is lower than that of the West, potentially resulting in improved postoperative survival. Moreover, the incidence of HCC is higher in Asia compared to non-Asian countries, and the difference in surgical experience and techniques due to the higher incidence in Asia may have contributed to better surgical outcomes in elderly Asian HCC patients compared to non-Asian patients.^69,73

The third finding of our study revealed a higher postoperative mortality in the elderly group compared to the non-elderly group, with a particularly high in-hospital mortality noted in the super elderly group (≥80 years). While it was somewhat predictable that postoperative mortality would be higher in the elderly, our study was able to objectively quantify this.⁷⁴ Therefore, it is essential to consider longer in-hospital monitoring periods for elderly HCC patients, especially for the super elderly after surgery. Additionally, both the elderly and super elderly groups exhibited higher rates of postoperative complications, with a notably increased risk of major postoperative complications observed in the elderly group. This highlights the need for greater attention to postoperative management in elderly patients.³¹ Although there were no significant differences in hepatic failure-related deaths, it is important to note that this could be due to the inclusion of patients with remaining liver reserve functions suitable for surgery, emphasizing the need for careful interpretation of the results.

Our study has several limitations. First, the individual comorbidities were not considered. This study conducted a meta-analysis of the entire cohort without adjusting for comorbidities. However, the reported comorbidities varied across studies, and studies with objectively quantifiable measures suitable for meta-analysis, such as the Charlson comorbidity index score, were limited. Therefore, adjusting for comorbidities to derive conclusive results proved challenging. The comorbidities frequently mentioned and adjusted from several studies were as follows: hypertension, diabetes, hyperlipidemia, chronic kidney disease, cerebrovascular disease, cerebrovascular accident, pulmonary disease, and Charlson comorbidity index score. To make up for this shortcoming, a multivariate analysis adjusting for other variables was conducted in regard to the OS, but it still had some limitations. Second, in our meta-analysis, we did not perform sub-analyses according to baseline liver function or cancer status. However, considering that the majority of surgical candidates were likely to be Child-Pugh class A with stage I patients, we believe there may have been some level of homogeneity between the two groups. Furthermore, the included studies were all retrospective design and focused only on patients who underwent surgery, which may have resulted in selection bias. Fourth, in sensitivity analysis for the super elderly group (≥80 years), the efficacy outcomes did not demonstrate consistent results compared to those of elderly versus non-elderly analysis. Due to the small number of studies and patients, as well as high heterogeneity among the literature, accurate evaluation was restricted, hence further detailed research is required for the super elderly patient population.^{17,19,38,52,55-59,61,62,75} Fifth, our study did not differentiate between different surgical methods (open surgery vs laparoscopic surgery), which could influence both efficacy and safety outcomes. Lastly, while our study evaluated OS and DFS, it lacks a comprehensive analysis of other relevant outcomes such as quality of life, postoperative functional status, and patient-reported outcomes. These factors are crucial for an assessment of the impact of surgical resection on elderly patients and further research should consider these aspects of efficacy outcome.

In conclusion, through careful and multidisciplinary patient selection for surgical candidates among elderly HCC patients, both OS and DFS would not be worse than those of the non-elderly group. Thus, it is imperative to actively consider surgical treatment in the selected elderly HCC patients. Future studies that adjust for differences in comorbidity and surgical method might be crucial to determine the respective weights of variables affecting efficacy and safety outcomes. Ultimately, deriving a scoring system or a guideline to assist the decision-making process for surgical treatment in elderly HCC patients is required in the clinical setting. In our meta-analysis results, factors that could be included in the scoring system may consist of age 65 and above, age 80 and above, geographic location (Asia vs non-Asia). Further research should consider incorporating additional factors such as sex, cancer stage, cancer size, CTP score, performance status, comorbidities, surgical method, and hospital size into the scoring system.^76,77

ACKNOWLEDGEMENTS

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MATERIALS AND METHODS
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DISCUSSION
ACKNOWLEDGEMENTS
CONFLICTS OF INTEREST
AUTHOR CONTRIBUTIONS
SUPPLEMENTARY MATERIALS
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This study was supported by the National Evidence-based Healthcare Collaborating Agency (NECA) (NA21-008; NA22-006) and the Soonchunhyang University Research Fund.

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No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTIONS

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Study concept and design: D.A.P., G.H.C. Data acquisition: D.A.P., S.R., J.P. Data analysis and interpretation: D.A.P., J.J.Y. Drafting of the manuscript: J.S.L., J.J.Y. Critical revision of the manuscript for important intellectual content: J.J.Y., D.A.P. Statistical analysis: J.J.Y., D.A.P. Approval of final manuscript: all authors.

SUPPLEMENTARY MATERIALS

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Supplementary materials can be accessed at https://doi.org/10.5009/gnl230485.

References

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References

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Article

Original Article

Gut and Liver 2024; 18(4): 695-708

Published online July 15, 2024 https://doi.org/10.5009/gnl230485