Clinicopathological characteristics and survival outcomes of younger patients with gastric cancer: a systematic review and meta-analysis
Original Article

Clinicopathological characteristics and survival outcomes of younger patients with gastric cancer: a systematic review and meta-analysis

Penghui Niu1#, Lulu Zhao1#, Rui Ling2#, Dongbing Zhao1, Yingtai Chen1

1National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing, China; 2Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, USA

Contributions: (I) Conception and design: All authors; (II) Administrative support: All authors; (III) Provision of study materials or patients: P Niu, L Zhao, R Ling; (IV) Collection and assembly of data: P Niu, L Zhao; (V) Data analysis and interpretation: L Zhao, R Ling; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

#These authors contributed equally to this work.

Correspondence to: Yingtai Chen. National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan Nanli, Beijing, China. Email: yingtaichen@126.com.

Background: Survival outcomes of gastric cancer in younger patients have been reported in several studies with controversial results. This systematic review and meta-analysis investigated the clinicopathological characteristics, postoperative complications, and survival outcomes between younger and older patients.

Methods: We systematically reviewed clinical researches from PubMed, The Cochrane Library, Embase, and Web of science published up to December 2019. The effect size for the included studies was estimated with the odds ratio (OR). Heterogeneity was investigated using the χ2 test and I2 test, while sensitivity analyses were performed to identify the source of substantial heterogeneity.

Results: A total of 25 clinical studies involving 81,188 gastric cancer patients were included in this meta-analysis, of which one was a prospective study. Younger patients were more likely to be females, pTNM stage IV and peritoneal metastasis. The incidence of postoperative complications, lymph node metastasis, as well as hepatic metastasis of younger patients was significantly lower than that of the older. There was no statistical difference in overall survival (OS) between the younger and older patients with gastric cancer. After stratification for patients with gastrectomy, however, younger patients were associated with a better 5-year OS relative to older patients.

Conclusions: In conclusion, younger patients with gastric cancer were more often diagnosed as poorly differentiation and later pTNM tumor stage. However, younger cancer patients following gastrectomy had a better OS rate than patients in older group. Future large-scale analyses are expected to confirm our findings.

Keywords: Gastric cancer; younger adult; clinicopathological characteristics; survival outcomes; meta-analysis

Submitted May 07, 2020. Accepted for publication Aug 21, 2020.

doi: 10.21037/tcr-20-2024

Introduction

Gastric cancer is an aggressive malignancy and remains the third leading cause of cancer-related death worldwide (1,2). Although the overall incidence of gastric cancer showed a decline worldwide, younger cancer patients had increased obviously during the last decades (3). The growing incidence, as well as its aggressive biological behavior as reported (4,5), has renewed interest in the surgery-based management of younger gastric cancer patients with a focus on therapeutic strategies.

To date, the survival outcomes of younger patients were still controversial. Previous data reported that younger patients had worse survival rates than older (6-9), whereas several studies showed a similar prognosis (10-20). Some studies even expressed that younger patients were associated with improved survival outcomes (21-30). A significant reason for these inconsistent findings from published studies was the different age cutoffs on defining younger patients (6,7,29,30). A published meta-analysis has reported improved 5-year survival in the younger group. However, it was primarily limited to the small sample size and significant heterogeneity (31). Besides, there was currently no randomized clinical trial that targeted the issue.

As such, our study aimed to compare the clinicopathological characteristics, postoperative complications, as well as survival outcomes between younger and older patients with gastric cancer through systematic review and meta-analysis, thus providing evidence for the development of guiding strategies for younger gastric cancer patients. We present the following article in accordance with the PRISMA reporting checklist (available at http://dx.doi.org/10.21037/tcr-20-2024).

Methods

Search strategy

Clinical studies were systematically searched from PubMed, Web of Science, Embase, and The Cochrane Library. The following fields were used for the search: “gastric” or “stomach,” “cancer” or “carcinoma” or “neoplasm” or “tumor,” “young adult” or “younger” or “youth.” These searches were limited to clinical articles published up to December 2019.

Inclusion and exclusion criteria

Studies met the following criteria were included: (I) researches compared gastric cancer in the younger group (≤40 years of age) and older group (>40 years of age); (II) analyses contained quantitative clinicopathological information; (III) researches involved at least one of the mentioned survival outcomes.

Studies were excluded from the analysis as follow: (I) publications were position papers, editorials, case reports, comments, or review articles; (II) literature duplication based on an author or center; (III) research data was inappropriate or cannot be extracted; (IV) studies lacked control group for meta-analysis.

Data extraction

Two independent reviewers extracted predesigned data from the included studies. The extracted information was as follows: Basic characteristics of the study, including authors, country, patient inclusion criteria, sample size, design as well as quality assessment; Clinicopathological characteristics of patients, including gender, tumor location, differentiation, Lauren type, Borrmann classification, pTNM stage, and therapeutic regimens (involving chemotherapy, total/subtotal gastrectomy, curative resection, and lymphadenectomy); Survival outcomes, including metastasis, recurrence, and the short or long-term survival rates on different clinical tumor stage. The stage of gastric cancer was based on the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system. Lymphadenectomy was divided into D1 to D4, depending on the primary tumor location and removal of each lymph node station (32). Gastrectomy was defined as patients received surgery with or without D2 lymphadenectomy, while curative gastrectomy was defined as resection with D2 lymphadenectomy and a negative margin. The disagreement was resolved through discussion among the reviewers.

Quality assessment

The quality of the included studies was evaluated using The Newcastle-Ottawa Quality Assessment Scale (NOS) (33). The NOS checklist consisted of three major categories (selection, comparability, and outcome) with a maximum of nine stars. Each included study achieving six or more number of stars was graded high quality. Any disagreement was discussed to reach a consensus.

Statistical analysis

We conducted the review and meta-analysis using Revman software, version 5.3 (Cochrane Collaboration, Oxford, United Kingdom). Categorical variables were analyzed by the odds ratio (OR), while the corresponding 95% confidence interval (CI) was recorded. The Z test was conducted to determine the OR, with P<0.05 considered statistical significance. Heterogeneity was investigated using the χ2 test and the I2 test. If significant heterogeneity existed, we employed the random effect model; otherwise, the fixed effects model was adopted (34,35). Sensitivity analyses were undertaken to investigate sources of substantial heterogeneity.

Results

Studies selection

Our initial search strategy generated a total of 8,686 relevant clinical studies. After a screening of titles and abstracts, 108 articles were scrutinized by a full-text review. Eighty-three studies were eventually excluded by following the exclusion criteria and inclusion criteria. In total, the eligible 25 clinical studies (4,5,8-30) involving 81,188 gastric cancer patients were entered into the review and meta-analysis, of which one was a prospective study (17), three were multicenter studies (16,19,21), and the rest were all retrospective studies. Figure 1 showed the flow chart of the search process. The NOS scores and essential characteristics of the eligible studies were shown in Table 1.

Figure 1 The flow chart of the research process until December 2019.

Table 1

Basic characteristics of the included 25 studies

Authors Country Patient criteria Document type NOS Group No. Age Gender Tumor location pTNM stage
Male Female Upper Middle Lower I II III IV
Song et al. (4) China GC underwent surgery (2007–2011) Retrospective Study 7 YG ≤40 112 – 59 53 12 21 64 5 30 59 18
OG ≥70 358 – 274 84 61 64 208 25 89 206 38
Cormedi et al. (5) Brazil GC (2011–2013) Retrospective Study 8 YG ≤40 71 37 34 37 – – – 4 5 23 36
OG >40 223 63.74 135 88 – – – 35 29 52 89
Tavares et al. (8) Portugal GC with surgery (2000–2005) Retrospective Study 7 YG ≤40 23 – 12 11 – – – 6 6 4 6
OG >40 360 – 207 153 – – – 76 43 105 97
Guan et al. (9) the United States GC (1973–2014) Retrospective Study 8 YG <35 1,369 – 728 641 338 133 275 51 59 119 385
OG ≥65 46,521 – 28,104 18,417 11,839 3,617 12,243 3,838 3,407 3,604 4,358
Isobe et al. (10) Japan GAC (1977–2006) Retrospective Study 8 YG ≤40 169 34.5±4.8 79 90 34 70 40 68 30 23 48
OG >40 3,649 64.5±10.0 2,518 1,131 790 1,047 1,341 1,765 471 628 782
Kim et al. (11) Korea GC (1986–2000) Retrospective Study 8 YG ≤35 137 30.6±5.1 63 74 23 50 56 41 21 36 39
OG >70 194 73.3±3.1 131 63 16 41 130 60 41 55 38
Kunisaki et al. (12) Japan GC underwent curative surgery (1985–1999) Retrospective Study 8 YG ≤40 131 35.2±5.0 64 67 44 65 19 79 16 24 12
OG ≥55 918 60.2±3.2 658 260 340 386 168 510 123 174 111
Liu et al. (13) China GC underwent surgery; no chemotherapy; no metastasis. (2008–2014) Retrospective Study 7 YG ≤40 198 – 115 83 – – – – – – –
OG ≥55 1,096 – 895 201 – – – – – – –
Okamoto et al. (14) Japan GC underwent laparotomy
(1960–1984)		 Retrospective Study 6 YG <30 34 24.9 10 24 3 13 7 – – – –
OG ≥75 132 77.9 97 35 12 37 66 39 7 31 55
Takatsu et al. (15) Japan GC underwent surgical resection (2000–2010) Retrospective Study 8 YG ≤40 136 36 [16–39] 72 64 25 70 35 65 21 28 22
OG ≥60 1,435 65 [60–69] 1,024 411 385 581 416 786 206 253 190
Tekesin et al. (16) Turkey GC (1990–2014) Retrospective Cohort Study 7 YG ≤40 92 36 [22–40] 53 39 17 – – 5 4 17 52
OG >40 774 60 [41–75] 553 221 141 – –– 25 46 195 372
Wang et al. (17) China GC underwent gastrectomy (1998–2006) Prospective Study 7 YG ≤40 21 34.9±1.1 9 12 1 7 13 – – – –
OG >55 36 67.1±0.8 22 14 4 7 25 11 9 15 1
Hsieh et al. (18) Japan GAC underwent curative gastrectomy (1981–1992) Retrospective Study 7 YG ≤40 115 – 46 69 14 27 68 23 22 56 14
OG >60 1,009 – 626 373 194 160 626 293 160 467 89
Ma et al. (19) China GC underwent curative surgery (2009–2011) Retrospective Study 7 YG ≤40 125 – 76 49 – – – 30 24 71 –
OG >40 1,752 – 1,341 411 – – – 403 400 946 –
Mitsudomi et al. (20) Japan GC (1970–1984) Retrospective Study 7 YG <40 128 – 66 62 13 58 31 – – – –
OG ≥50 1,275 – 863 412 131 379 550 – – – –
Kulig et al. (21) Poland GC (1977–1998) Retrospective Study 6 YG ≤40 214 35.0 119 95 24 56 56 24 14 25 63
OG >40 3,217 61.0 2,277 940 387 733 677 315 251 380 770
Bani-Hani et al. (22) Jordan GAC (1991–2001) Retrospective Study 7 YG ≤40 17 36.3±0.9 7 10 5 3 3 4 2 4 7
OG >40 159 63.8±0.7 104 55 26 39 83 11 39 55 46
Kim et al. (23) Korea GC underwent surgery (1993–2000) Retrospective Study 7 YG ≤40 175 34.58±4.26 100 75 19 67 83 79 20 49 37
OG >40 1,124 59.25±9.17 765 359 120 364 624 439 145 304 236
Lai et al. (24) Korea GC underwent curative surgery (1987–2004) Retrospective Study 8 YG ≤40 883 35 476 407 125 – – 444 135 213 91
OG >40 6,071 58.7 4,195 1,876 720 – – 2,850 1,057 1,567 597
Maehara et al. (25) Japan GC underwent surgery (1965–1991) Retrospective Study 6 YG <40 174 38.8±4.9 89 85 31 58 63 – – – –
OG >70 356 74.8±3.9 247 109 90 86 152 – – – –
Silva et al. (26) Brazil GAC (1988–2005) Retrospective Study 7 YG ≤40 62 – 38 24 9 – 50 21 – 35 –
OG >40 453 – 288 165 68 – 385 127 – 280 –
Zhou et al. (27) China GC resections (2004–2014) Retrospective Study 7 YG ≤40 152 33.7±5.54 53 99 8 57 75 39 32 66 15
OG >40 250 62.9±10.4 178 72 75 53 115 141 35 52 22
Adachi et al. (28) Japan GC underwent surgery (1981–1990) Retrospective Study 7 YG <40 36 – 20 16 – – 6 16 5 8 7
OG >60 68 – 43 25 – – 27 25 13 16 14
Bautista et al. (29) the United States Non-cardia GAC (2000–2010) Retrospective Cohort Study 8 YG <40 46 34.1±4.1 24 22 1 10 14 – – – –
OG ≥50 1,208 71.5±3.8 714 494 65 379 426 – – – –
Wang et al. (30) China GC underwent curative gastrectomy (2005–2010) Retrospective Study 8 YG ≤40 342 34.1±5.2 198 144 53 79 177 82 97 137 26
OG >40 3,588 61.4±10.1 2,448 1,140 841 741 1,783 876 927 1,522 263

No., number of patients; pTNM, pathological (p), primary tumor (T), lymph nodes (N) and distant metastases (M); GC, gastric cancer; GAC, gastric adenocarcinoma.

Clinicopathological characteristics

The clinicopathologic characteristics of the gastric cancer patients were presented in Tables 2 and S1. Compared with the older group, younger patients with gastric cancer were more often female from pooled 25 studies (OR =2.09, 95% CI: 1.81–2.41, P<0.001, I2=76%) (Figure S1). Younger patients were more likely to be a diffuse type (OR =4.29, 95% CI: 3.15–5.85, P<0.001, I2=82%), pTNM stage IV (OR =1.21, 95% CI: 1.08–1.35, P<0.001, I2=0), poorly differentiation (OR =3.59, 95% CI: 2.89–4.47, P<0.001, I2=82%), and a signet ring cell carcinoma (OR =4.81, 95% CI: 4.33–5.33, P<0.001, I2=0) (Figure S2).

Table 2

Subgroup meta-analysis of clinicopathological characteristics and survival outcomes between the younger group and older group

Subgroup Included studies Included patients I2 (%) Effect model OR/WMD 95% CI P
Female 25 81,188 76 Random 2.09 1.81–2.41 <0.001
Diffuse type 10 56,335 82 Random 4.29 3.15–5.85 <0.001
pTNM stage IV 16 26,202 0 Fixed 1.21 1.08–1.35 <0.001
Poorly differentiation 19 75,349 82 Random 3.59 2.89–4.47 <0.001
SRCC 5 52,262 0 Fixed 4.81 4.33– 5.33 <0.001
Therapeutic regimen
   Subtotal gastrectomy 9 14,427 39 Fixed 0.88 0.79–0.99 0.03
   Curative gastrectomy 14 18,159 10 Fixed 0.93 0.82–1.06 0.30
   D1 lymphadenectomy 4 7,387 25 Fixed 0.59 0.48–0.73 <0.001
   ≥ D2 lymphadenectomy 4 7,387 27 Fixed 1.77 1.44–2.18 <0.001
   Chemotherapy 6 8,750 43 Fixed 1.79 1.49–2.16 <0.001
   Postoperative complications 5 6,309 73 Random 0.44 0.24–0.79 0.006
Recurrence/metastasis
   Peritoneal recurrence 4 1,965 11 Fixed 1.93 1.31–2.84 0.001
   Lymph node metastasis 8 3,901 0 Fixed 0.83 0.69–0.98 0.03
   Hepatic metastasis 9 11,126 0 Fixed 0.68 0.47–0.98 0.04
   Peritoneal metastasis 9 11,695 63 Random 1.63 1.16–2.27 0.004
5-year OS 9 59,647 60 Random 1.01 0.79–1.30 0.92
5-year OS underwent surgery 18 26,770 56 Random 1.35 1.16–1.57 <0.001
   Stage I-OS 8 6,536 11 Fixed 2.38 1.56–3.61 <0.001
   Stage II-OS 8 3,347 46 Fixed 1.28 0.98–1.66 0.07
   Stage III-OS 7 5,702 27 Fixed 1.36 1.14–1.63 <0.001
   Stage IV-OS 7 1,483 0 Fixed 1.93 1.30–2.85 0.001
5-year OS underwent curative surgery 12 19,012 60 Random 1.39 1.12–1.72 0.002
   Stage I-OS 4 5,261 51 Random 1.73 0.86–3.49 0.13
   Stage II-OS 4 2,771 51 Random 0.95 0.60–1.51 0.83
   Stage III-OS 4 4,639 0 Fixed 1.29 1.05–1.58 0.01
   Stage IV-OS 3 1,016 0 Fixed 1.86 1.20–2.89 0.006

pTNM, pathological (p), primary tumor (T), lymph nodes (N) and distant metastases (M); SRCC, signet ring cell carcinoma; OS, overall survival.

Concerning to therapeutic regimen, six studies showed that younger group had a higher chemotherapy rate when compared to older group (OR =1.79, 95% CI: 1.49–2.16, P<0.001, I2=43%). In addition, the proportions of younger patients underwent subtotal gastrectomy or D1 resection were significantly lower than those of the older (OR =0.88, 95% CI: 0.79–0.99, P=0.03, I2=39%; OR =0.59, 95% CI: 0.48–0.73, P<0.001, I2=25%, respectively). However, there were no statistical differences in curative resection rate between the two groups (OR =0.93; 95% CI: 0.82–1.06, P=0.30, I2=10%) (Figure S3).

Postoperative complications

A total of 6,309 patients from five studies were enrolled in postoperative complications. The result revealed that the proportion of complications in younger patients was significantly lower compared to the older (OR =0.44, 95% CI: 0.24–0.79, P=0.006), and the heterogeneity between the younger and older group was significant (I2=73%) (Figure S4).

Survival outcomes

Figure 2 presented the meta-analysis of the 5-year overall survival (OS) with total patients, gastrectomy group, and only curative gastrectomy group, respectively. There was no significant difference for total patients based on the nine included studies (OR =1.01, 95% CI: 0.79–1.30, P=0.92, I2=60%). However, the pooled 18 and 12 studies respectively showed that younger adults in gastrectomy group and only curative gastrectomy group were associated with better survival relative to that of the older (OR =1.35, 95% CI: 1.16–1.57, P<0.001, I2=56%; OR =1.39, 95% CI: 1.12–1.72, P=0.002, I2=60%).

Figure 2 The 5-year overall survival for gastric cancer between younger and older group. (A) The 5-year overall survival of total patients; (B) the 5-year overall survival of patients underwent gastrectomy; (C) the 5-year overall survival of patients underwent curative gastrectomy.

Moreover, further survival analyses between younger and older patients were done under the different pTNM tumor stage. Four of the studies provided survival rates for gastrectomy group, and the meta-analysis showed that younger patients at pTNM stage I, stage III, and stage IV were associated with better 5-year OS than older (OR =2.38, 95% CI: 1.56–3.61, P<0.001, I2=11%; OR =1.36, 95% CI: 1.14–1.63, P<0.001, I2=27%; OR =1.93, 95% CI: 1.30–2.85, P=0.001, I2=0%, respectively) (Figure 3). For the only curative gastrectomy group, three of the included studies revealed that younger patients at pTNM stage III and stage IV also had improved survival (OR =1.29, 95% CI: 1.05–1.58, P=0.01, I2=0%; OR =1.86, 95% CI: 1.20–2.89, P=0.006, I2=0%, respectively), but there was no statistical difference in gastric cancer at stage I (OR =1.73, 95% CI: 0.86–3.49, P=0.13, I2=51%) (Figure 4). The short-term (including the 1-, 2-, 3-year) survival rates were presented in Table S2.

Figure 3 The 5-year overall survival of gastric cancer underwent gastrectomy between younger and older group. (A) Meta-analysis of patients at pTNM stage I; (B) meta-analysis of patients at pTNM stage II; (C) meta-analysis of patients at pTNM stage III; (D) meta-analysis of patients at pTNM stage IV.
Figure 4 The 5-year overall survival of gastric cancer underwent curative gastrectomy between younger and older group. (A) Meta-analysis of patients at pTNM stage I. (B) meta-analysis of patients at pTNM stage II; (C) meta-analysis of patients at pTNM stage III; (D) meta-analysis of patients at pTNM stage IV.

Concerning to the metastasis status of gastric cancer, nine of the 25 studies showed that younger group was predominant in peritoneal metastasis (OR =1.63, 95% CI: 1.16–2.27, P=0.004, I2=63%). Some included studies reported the lymph node metastasis and hepatic metastasis of gastric cancer, and our result showed that both lymph node metastasis and hepatic metastasis ratio was lower in younger group compared with those of the older (OR =0.83, 95% CI: 0.69–0.98, P=0.03, I2=0%; OR =0.68, 95% CI: 0.47–0.98, P=0.04, I2=0%). In addition, 4 related studies indicated that the incidence of peritoneal recurrence was significantly higher in younger group (OR =1.93, 95% CI: 1.31–2.84, P=0.001, I2=11%) (Figure S5 and Table S3).

Discussion

The review and meta-analysis involved 24 retrospective comparative trails and one prospective study with 81,188 patients with gastric cancer. Our findings demonstrated that the younger group after gastrectomy or only curative gastrectomy was correlated with a better OS, but there was no significant difference for total patients between the two groups. To our best knowledge, this analysis was the most extensive evaluation to compare the clinicopathological feature and prognosis between the younger and older group.

Several findings regarding the clinicopathological characteristics in the meta-analysis were in agreement with previous researches, including a higher proportion of female, poorly differentiation, signet ring cell carcinoma, diffuse histology, and pTNM tumor stage IV in younger adults (8-21). Our survey revealed that younger patients had a higher proportion of females, while male predominance was mostly seen in the older group. Although the reasons for female predominance in younger patients were not clear, some potential explanations had been identified. Several studies considered hormonal factors, such as estrogens and higher percentages of estrogen receptor-positive cells might be associated with the predominance of younger females (36,37). Compared to older patients, younger patients with gastric cancer had been believed to be related to genetic changes rather than environmental factors (38). Thereby more frequent exposure to environmental carcinogens, such as cigarettes, might lead to the dominance among older male patients (39). Concerning to histological type, our analysis revealed that poorly differentiation, diffuse-type, and signet ring cell carcinoma were predominant in the younger group. In comparison, more patients in the older group were diagnosed as intestinal type and mucous adenocarcinoma. The primary reason may be germline mutations, specifically in the CDH1 gene, as reported in some researches (26,40,41). While the included studies rarely capture the duration of symptoms before initial diagnosis, other researches have reported delayed diagnosis, and hereditary factors may be closely correlated with advanced gastric cancer (42,43).

Surgery, especially curative resection, was an important approach for patients with gastric cancer (44). There were higher proportions of chemotherapy and ≥ D2 lymphadenectomy in the younger group compared with the older. However, the percentages of total gastrectomy and curative resection revealed no statistical differences between younger and older groups, while subtotal gastrectomy was frequently performed in older patients. These results may be due to the significant comorbidities and impairment of functional status in older patients (45-47). Moreover, a previous study demonstrated that the ratio of older patients who had other synchronous or previous malignancies at initial diagnosis was up to 21% based on Munich Cancer Registry data (48). In our review, postoperative complications were more prevalent in the older group, which also reflected a worse tolerance for surgery or chemotherapy. Several studies investigated that the incidence of postoperative complications was closely correlated with poor prognosis (49,50), thus providing a survival advantage for the younger group.

In this analysis, a tendency of peritoneal metastasis in the younger group may reflect the genetic susceptibility, such as CDH1 and RhoA, that could lead to more aggressive biological behaviors (40,51). Moreover, the infiltration of poorly differentiated gastric cancer was more pronounced in the vertical direction, thus conferring lymph node involvement and peritoneal dissemination. Metastasis was the leading cause of recurrence, and it had been thought that peritoneal metastasis was the most common form of repetition in gastric carcinoma (15). Our finding indicated a higher incidence of peritoneal recurrence in younger patients, which was similar to the other conclusion (12).

Younger gastric cancer patients as a group revealed similar long-term OS compared to older, and this finding was consistent with previous studies (5,10,11,20). In the subgroups of gastrectomy and only curative gastrectomy, both the short-term (including the 1-, 2-, 3-year) and long-term (including the 5-year) OS for older group was more miserable than those of the younger group, possibly due to a more significant percentage of comorbidities and complications. When the 5-year OS under different pTNM stages was evaluated, the results differed substantially between the younger and older group. A trend towards better long-term survival in the younger group may reflect a higher tolerance for the patients given a younger age and fewer comorbidities. Moreover, the shorter life expectancy of the older group compared to the younger may also be responsible.

There were several limitations in the analysis because of the characteristics of the included studies identified. Firstly, only one of the trials we identified was a prospective study. Secondly, most of the included studies were from Eastern Asia, which might not have a great representative and guiding value across the globe, especially in Western countries. Thereby, more related researches were expected to evaluate in gastric cancer patients at a younger age. Thirdly, there were inevitable heterogeneities, such as female ratio, diffuse type, as well as several survival variables in the analysis. The contribution of each included study to the pooled estimate was evaluated in the sensitivity analyses, and the result showed that sources of these heterogeneities were mainly from the selection bias. Furthermore, the lack of available patient data did not allow our analysis to assess disease-specific survival and disease-free survival. Despite these limitations, the study to our knowledge was the most extensive analysis evaluating the clinicopathological characteristics and survival outcomes in the younger and older patients, which may overcome the limitation of small sample size and single-institution targeted the field. Besides, all of the clinical studies involved in the meta-analysis had a high quality and met our inclusion criteria, thus might provide more valuable resources for the clinicians in patients' management and decision-making.

Conclusions

In conclusion, younger patients with gastric cancer were more often diagnosed as poorly differentiation and later pTNM tumor stage. However, younger cancer patients following gastrectomy had a better OS rate than patients in older group. Future large-scale analyses are expected to confirm our findings.

Figure S1 Meta-analysis of female ratio between younger and older group.
Figure S2 The proportion of clinicopathologic feature between younger and older group. (A) Meta-analysis of diffuse type; (B) meta-analysis of pTNM stage IV; (C) meta-analysis of poorly differentiation; (D) meta-analysis of signet ring cell carcinoma.
Figure S3 The proportion of therapeutic regimen between younger and older group. (A) Meta-analysis of subtotal gastrectomy; (B) meta-analysis of D1 lymphadenectomy; (C) meta-analysis of chemotherapy; (D) meta-analysis of curative resection.
Figure S4 Meta-analysis of the proportion of postoperative complications between younger and older group.
Figure S5 The proportion of metastasis and recurrence between younger and older group. (A) Meta-analysis of peritoneal recurrence; (B) meta-analysis of peritoneal metastasis; (C) meta-analysis of lymph node metastasis; (D) meta-analysis of hepatic metastasis.

Table S1

Clinicopathological characteristics of the included 25 studies

Authors Group No. Tumor size ± SD (cm) Pain Bleeding Cardiopulmonary disease Differentiation SRCC Mucinous Lauren type Borrmann classification
Well Poor Intestinal Diffuse Mixed I II III IV
Song et al. (4) YG 112 ≤6 n=70; >6 n=42 – – – 6 106 – – – – – – – – –
OG 358 ≤6 n=239; >6 n=119 – – – 83 275 – – – – – – – – –
Cormedi et al. (5) YG 71 – – – – – – – – 3 57 3 – – – –
OG 223 – – – – – – – – 78 74 14 – – – –
Tavares et al. (8) YG 23 – 12 3 – 4 12 – – 8 15 0 – – – –
OG 360 – 160 100 – 56 89 – – 255 105 0 – – – –
Guan et al. (9) YG 1,369 5.00±3.00 – – – 31 916 558 25 668 652 – – – – –
OG 46,521 4.00±1.47 – – – 2493 22,616 5756 990 37,799 7,021 – – – – –
Isobe et al. (10) YG 169 – – – – – 66 75 4 – – – – – – –
OG 3,649 – – – – – 943 600 82 – – – – – – –
Kim et al. (11) YG 137 5.07±3.23 – – – – – 25 4 – – – 5 13 93 26
OG 194 5.16±3.45 – – – – – 6 10 – – – 10 43 128 13
Kunisaki et al. (12) YG 131 <5 n=76; ≥5 n=55 – – – 30 101 – – – – – – – – –
OG 918 <5 n=536; ≥5 n=382 – – – 479 439 – – – – – – – – –
Liu et al. (13) YG 198 – – – 0 7 164 – – – – – – – – –
OG 1,096 – – – 29 123 587 – – – – – – – – –
Okamoto et al. (14) YG 34 – – – – – 22 2 0 – – – 0/20 0 12 4
OG 132 – – – – – 51 1 5 – – – 3/85 25 34 14
Takatsu et al. (15) YG 136 – – – – 13 123 – – – – – – – – –
OG 1,435 – – – – 662 773 – – – – – – – – –
Tekesin et al. (16) YG 92 – 22 6 – – – – – 39 45 7 – – – –
OG 774 – 191 52 – – – – – 526 220 21 – – – –
Wang et al. (17) YG 21 <5 n=13; ≥5 n=8 – – – 4 10 4 1 – – – 1 6 12 2
OG 36 <5 n=23; ≥5 n=13 – – – 10 4 2 5 – – – 2 13 19 1
Hsieh et al. (18) YG 115 4.80±3.50 – – – 17 98 – – 17 64 13 – – – –
OG 1,009 4.50±3.00 – – – 453 556 – – 491 279 103 – – – –
Ma et al. (19) YG 125 – – – – 3 111 – – – – – – – – –
OG 1,752 – – – – 93 1,228 – – – – – – – – –
Mitsudomi et al. (20) YG 128 – 48 6 3 5 94 – – – – – 2 11 28 20
OG 1,275 – 20 3 14 600 449 – – – – – 20 175 347 106
Kulig et al. (21) YG 214 – 90 12 2 – – – – 42 80 18 – – – –
OG 3,217 – 1831 186 293 – – – – 1,106 623 207 – – – –
Bani-Hani et al. (22) YG 17 – 12 2 – – 8 – – 6 11 – – – – –
OG 159 – 109 23 – – 41 – – 121 18 – – – – –
Kim et al. (23) YG 175 – – – – 42 133 – – – – – – – – –
OG 1,124 – – – – 608 516 – – – – – – – – –
Lai et al. (24) YG 883 ≤4 n=586; >4 n=288 – – – 135 711 – – – – – 10 114 297 75
OG 6,071 ≤4 n=354; >4 n=2,488 – – – 2,661 3,232 – – – – – 665 812 2,039 405
Maehara et al. (25) YG 174 7.10±4.20 – – – 39 135 – – – – – – – – –
OG 356 6.30±3.80 – – – 225 129 – – – – – – – – –
Silva et al. (26) YG 62 ≤5 n=31; >5 n=27 – – – – – – – 15 36 11 – – – –
OG 453 ≤5 n=179; >5 n=259 – – – – – – – 230 146 77 – – – –
Zhou et al. (27) YG 152 – 73 19 – – – – – 14 120 18 – – – –
OG 250 – 98 11 – – – – – 156 73 21 – – – –
Adachi et al. (28) YG 36 6 23 – 0 – 33 – – – – – – – – –
OG 68 6.05 16 – 21 – 35 – – – – – – – – –
Bautista et al. (29) YG 46 – – – 3 0 37 – – 14 32 – – – – –
OG 1,208 – – – 564 40 759 – – 754 494 – – – – –
Wang et al. (30) YG 342 – – – – 16 258 86 16 64 166 112 18 114 156 54
OG 3,588 – – – – 172 2,244 534 233 790 2,049 1,027 272 1,252 1,756 308

No., number of patients; Pain, abdominal pain; SRCC, signet ring cell carcinoma; YG, younger group; OG, older group.

Table S2

Subgroup meta-analysis of overall survival comparison between the younger group and older group

Subgroup Included studies Included patients I2 (%) Effect model OR/WMD 95% CI P
OS
   1-year OS 8 59,132 81 Random 1.08 0.80–1.45 0.63
   2-year OS 8 59,132 78 Random 1.04 0.79–1.36 0.79
   3-year OS 8 59,132 74 Random 1.01 0.78–1.32 0.93
   5-year OS 9 59,647 60 Random 1.01 0.79–1.30 0.92
OS underwent gastrectomy
   1-year OS 15 18,442 0 Fixed 1.20 1.04–1.39 0.01
   2-year OS 15 18,442 56 Random 1.31 1.08–1.58 0.005
   3-year OS 15 18,442 1 Fixed 1.33 1.19–1.48 <0.001
   5-year OS 18 26,770 56 Random 1.35 1.16–1.57 <0.001
Stage I-OS underwent gastrectomy1
   1-year OS 5 5,437 0 Fixed 5.18 1.03–26.03 0.05
   2-year OS 5 5,437 0 Fixed 2.29 1.11–4.71 0.02
   3-year OS 5 5,437 0 Fixed 3.32 1.72–6.40 <0.001
   5-year OS 8 6,536 11 Fixed 2.38 1.56–3.61 <0.001
Stage II-OS underwent gastrectomy
   1-year OS 5 2,735 0 Fixed 1.54 0.72–3.33 0.27
   2-year OS 5 2,735 0 Fixed 1.25 0.80–1.94 0.33
   3-year OS 5 2,735 45 Fixed 1.47 1.01–2.14 0.04
   5-year OS 8 3,347 46 Fixed 1.28 0.98–1.66 0.07
Stage III-OS underwent gastrectomy
   1-year OS 5 4,499 61 Random 1.41 0.81–2.45 0.22
   2-year OS 5 4,499 55 Random 1.53 1.07–2.20 0.02
   3-year OS 5 4,499 60 Random 1.62 1.14–2.31 0.007
   5-year OS 7 5,702 27 Fixed 1.36 1.14–1.63 <0.001
Stage IV-OS underwent gastrectomy
   1-year OS 5 1,341 74 Random 1.18 0.54–2.58 0.68
   2-year OS 5 1,341 83 Random 3.46 1.26–9.56 0.02
   3-year OS 5 1,341 41 Fixed 1.77 1.23–2.54 0.002
   5-year OS 7 1,483 0 Fixed 1.93 1.30–2.85 0.001
OS underwent curative surgery
   1-year OS 11 12,660 0 Fixed 1.35 1.05–1.72 0.02
   2-year OS 11 12,660 33 Fixed 1.22 1.03–1.45 0.02
   3-year OS 11 12,660 0 Fixed 1.36 1.17–1.58 <0.001
   5-year OS 12 19,012 60 Random 1.39 1.12–1.72 0.002
Stage I-OS underwent curative surgery
   5-year OS 4 5,261 51 Random 1.73 0.86–3.49 0.13
Stage II-OS underwent curative surgery
   5-year OS 4 2,771 51 Random 1.07 0.80–1.43 0.67
Stage III-OS underwent curative surgery
   5-year OS 4 4,639 0 Fixed 1.29 1.05–1.58 0.01
Stage IV-OS underwent curative surgery
   5-year OS 3 1,016 0 Fixed 1.86 1.20–2.89 0.006
OS underwent Non-curative surgery
   1-year OS 3 268 70 Random 1.31 0.40–4.29 0.66
   2-year OS 3 268 38 Fixed 0.92 0.49–1.71 0.87
   3-year OS 3 268 0 Fixed 1.37 0.72–2.61 0.34
   5-year OS 3 268 0 Fixed 1.14 0.56–2.36 0.72

1stage, pTNM stage. OS, overall survival.

Table S3

Therapeutic regimens and survival outcomes of the included studies

Authors Group No. Type of gastrectomy Resection margin Lymphadenectomy Chemotherapy Complication Peritoneal recurrence Metastasis
Subtotal Total R0 R1/R2 D0 D1 ≥D2 Lymph node Vessel Hepatic Peritoneal
Song et al. (4) YG 112 – – 85 27 – – – – – – – – – –
OG 358 – – 260 98 – – – – – – – – – –
Cormedi et al. (5) YG 71 – – – – – – – 21 – – – – – –
OG 223 – – – – – – – 59 – – – – – –
Tavares et al. (8) YG 23 4 19 – – – – – 9 – 3 – – 1 –
OG 360 133 227 – – – – – 86 – 10 – – 21 –
Guan et al. (9) YG 1,349 – – – – – – – – – – – – – –
OG 46,521 – – – – – – – – – – – – – –
Isobe et al. (10) YG 169 – 52 112 – 3 30 119 69 – – – – 4 33
OG 3,649 – 936 2,728 – 217 988 2,205 1,180 – – – – 203 414
Kim et al. (11) YG 137 78 47 101 – – – – – – – 70 – 5 21
OG 194 122 52 157 – – – – – – – 106 – 6 18
Kunisaki et al. (12) YG 131 93 25 121 – – 24 107 – – 18 48 34 2 6
OG 918 644 274 827 – – 280 638 – – 61 397 332 22 44
Liu et al. (13) YG – – – – – – – – – – – – – – –
OG – – – – – – – – – – – – – – –
Okamoto et al. (14) YG 34 – – 15 – 10 – – – – – 19 – 2 13
OG 132 – – 73 – 23 – – – – – 64 – 10 20
Takatsu et al. (15) YG 126 – 32 114 22 – – – – 14 6 – – 1/114 –
OG 1,435 – 445 1,241 194 – – – – 276 58 – – 33/1,241 –
Tekesin et al. (16) YG 92 17 32 – – – – – – – – – 29 – 26
OG 774 185 260 – – – – – – – – – 254 – 230
Wang et al. (17) YG 21 – – 19 – – – – – 4 – – 20 – 76
OG 36 – – 33 – – – – – 153 – – 155 – 461
Hsieh et al. (18) YG 115 84 31 101 14 – – – 82 – – 12 – – –
OG 1,009 753 256 893 116 – – – 590 – – 25 – – –
Ma et al. (19) YG 125 – – – – – – – 96 – – – 43 – –
OG 1,752 – – – – – – – 1,023 – – – 451 – –
Mitsudomi et al. (20) YG 128 13 29 103 – – – – – 9 – – – – –
OG 1,275 90 236 1,076 – – – – – 15 – – – – –
Kulig et al. (21) YG 214 89 63 78 74 – 39 113 – 65 – – – – –
OG 3,217 1,195 898 1,146 947 – 641 1,452 – 1,058 – – – – –
Bani-Hani et al. (22) YG 17 – – 7 – – – – – – – – – – –
OG 159 – – 66 – – – – – – – – – – –
Kim et al. (23) YG 175 – – 144 31 – – – – – – 86 – – –
OG 1,124 – – 888 236 – – – – – – 566 – – –
Lai et al. (24) YG 883 612 262 – – – – – – – – – – – –
OG 6,071 4,491 1,519 – – – – – – – – – – – –
Maehara et al. (25) YG 174 112 62 125 – – 32 141 – – 15 95 15 2 23
OG 356 212 139 255 – – 119 237 – – 25 207 81 16 23
Silva et al. (26) YG – – – – – – – – – – – 38 – – –
OG – – – – – – – – – – – 342 – – –
Adachi et al. (28) YG2 36 – – – – – – – – 7 – 17 – 1/7 4/7
OG3 68 – – – – – – – – 25 – 33 – 3/24 7/24
Bautista et al. (29) YG 46 – – – – – – – 31 – – – – – –
OG 1,208 – – – – – – – 475 – – – – – –
Wang et al. (30) YG 342 – – 327 15 – – – 267 – – – – 16 13
OG 3,588 – – 3,406 182 – – – 2,856 – – – – 165 173

No., number of patients; YG, younger group; OG, older group; R, resection margin.

Acknowledgments

Funding: This study was funded in part by the National Key R&D Program of China (Grant No. 2017YFC0908300).

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at http://dx.doi.org/10.21037/tcr-20-2024

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr-20-2024). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Cite this article as: Niu P, Zhao L, Ling R, Zhao D, Chen Y. Clinicopathological characteristics and survival outcomes of younger patients with gastric cancer: a systematic review and meta-analysis. Transl Cancer Res 2020;9(10):6026-6038. doi: 10.21037/tcr-20-2024

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