Gastric cancer (GC) is an aggressive malignancy with significant prevalence and mortality rate in Asia (1, 2). Young adults with GC are regarded as a different clinical entity from carcinogenesis to prognosis (1). The OS of GC in young adults remains poor (1–5). Considering a significant loss of life-years in young patients with GC, decreasing GC mortality needs more extensive studies on this disease.

Clinical stage and treatment are two strong predictors of OS in young patients with GC (2, 5–8). Despite many attempts to characterize the clinical differences between younger and older people with GC (9–12), few studies focused on young adults with GC who were initially diagnosed with advanced GC (YAAGC). One believes that young patients with less comorbidity can tolerate more aggressive treatment (1, 2, 7); however, the prognostic factors are poorly understood. The survival benefit of early detection of GC in young people has come to a consensus (1, 3–6, 8); however, near-universal findings in young patients with GC have seen a female predominance, higher frequency of advanced lesions, and poor-differentiated tumors at presentation in comparison with older patients (1, 3–6, 8). Surgical resection (radical or palliative gastrectomy) is often performed for patients with potentially resectable lesions in practice, which is associated with a favorable outcome in advanced GC (13). Nevertheless, the role of survival benefits after surgical resection remains unknown in general treatment practice for advanced GC in young adults. In addition, laboratory findings (14) such as alkaline phosphatase (ALP) and hemoglobin (Hb), and some well-known prognostic markers (15–17), such as neutrophil–lymphocyte ratio (NLR), still need to be validated in the population of YAAGC.

In this study, we aimed to identify baseline patient- or tumor-related prognostic factors and to devise a prediction model for survival and risk stratification in a large sample size of YAAGC. The devised applicable prognostic index for YAAGC would be valuable for assessing survival prognosis of individual patients, aiding in risk stratification, and guiding decisions for optimal treatment strategies.

Between January 2006 and December 2019, we identified a consecutive cohort of 282 young inpatients with GC treated at our institution. After the exclusion criteria were applied, a total of 220 YAAGC patients were included in the analysis ( Figure 1 ). After a median of 10.5 months follow-up, 143 (65%) patients died ( Figure 2 ). The estimated median OS time was 16.3 months, ranging from 0.5 to 102.7 months. One-year survival and 2-year survival rate was 43.6% (95% CI: 36.5 to 50.7) and 18.2% (95% CI: 11.1 to 25.3), respectively. Figure 2 shows the OS for the whole group.

Table 1 summarizes patient baseline characteristics and the results of the univariate analyses for patient- and tumor-related factors. There was a female predominance (71.4%, n = 157) in young patients with advanced GC. One-fifth of the patients (n = 46) reported a family history of any cancer (p = 0.070). Few patients presented with a poor performance status (ECOG ≥2) at admission. The median NLR ratio was 3.12 (range 0.81 to 21.33). A significant number of this population included patients with peritoneal metastasis (60.5%, n = 133), poorly differentiated tumors (95.9%, n = 211), and bone metastasis (12.7%, n = 28). Indeed, high NLR level (≥3.12), hypoproteinemia (albumin < 40 g/L), presence of peritoneal or bone metastases, and previous gastrectomy of primary site or radical gastrectomy were significant for OS in univariate analyses.

The final multivariable stepwise Cox regression with age, gender, and all significant univariate predictors identified three independent prognostic factors ( Table 2 ). Although abnormally low blood levels of albumin (HR 1.522, 95% CI 1.085 to 2.137, p = 0.015) and abnormally high levels of NLR (HR 1.446, 95% CI 1.022 to 2.047, p = 0.021) were two independent predictive factors of poor prognosis, a previous radical gastrectomy was associated with a significant OS benefit (HR 0.345, 95% CI 0.205 to 0.583, p = 0.000).

Since the risks (as measured by HRs) of these three independent prognostic factors had a similar magnitude, except radical gastrectomy, which was counted twice due to its relative size of HR being the square of others, we then created a simple prognostic score without losing too much information for each patient by calculating the score of prognostic factors. Accordingly, the prognostic score ranged from 0 to 4 ( Table 3 ). A prognostic index was devised using prognostic scores as follows: good-risk group, that is, YAAGC patients with zero to one prognostic score; intermediate-risk group, that is, YAAGC patients with two prognostic scores; and poor-risk group, that is, YAAGC patients with three to four prognostic scores. Of 220 YAAGC patients with complete data for the three variables, 30 YAAGC patients were categorized as good-risk group, 54 YAAGC patients as intermediate-risk group, and 136 YAAGC patients as poor-risk group. The Kaplan–Meier survival curves according to the prognostic model are provided in Figure 3 . Median OS for good-, intermediate-, and poor-risk groups were 36.43 months (95% CI 22.80–49.99), 17.87 months (95% CI 10.63–25.16), and 11.27 months (95% CI 9.41–13.18), respectively. Survival differences among groups achieved statistical significance (p < 0.0001).

In this analysis, to the best of our knowledge, we focused so far on the largest series of YAAGC. In multivariate analysis, we identified previous radical gastrectomy, serum albumin level, and NLR as significant prognostic factors. Of note, we devised a simple prognostic index for YAAGC based on easily available variables. In this model, patients in different risk groups had varying survival.

In our cohort, the positive prognostic role of previous radical gastrectomy on primary tumor is probably linked to a more favorable disease course, even though they already have had a stage IV disease. In the current knowledge, surgery is still the only chance for long-term survival for GC that can be curatively resected (7). Indeed, some reports suggested that young GC patients would benefit from curative resection or palliative debulking surgery (7, 18–20). Recently, a study by Medrano-Guzmán et al. consisting of a cohort of 588 consecutive cases supported the idea that young patients aged under 45 years who have undergone complete resection of their cancer have a better survival rate after two disease-free years, despite advanced presentation of the disease (18). Similarly, Park et al. reported a significantly higher 5-year survival rate in curatively resected young patients than older groups with GC (21). In addition, a retrospective cohort study suggested surgery as independent covariates associated with OS in young patients with non-metastatic GC (22). Furthermore, the positive status of resection margins is an unfavorable independent prognostic factor of GC in the young group (23). In fact, immediate surgery may significantly reduce the tumor burden and avoid otherwise frequent complications in YAAGC, such as obstruction, bleeding, and perforation, thus favorably affecting patient conditions and treatment tolerability (1). Given the advantage of less comorbidities, young GC patients may be better candidates to receive aggressive surgery following chemoradiation (1). Interestingly, the prognosis of young GC patients may be better than that in older patients after radical gastrectomy when matched for baseline characteristics (24). Nevertheless, whether a radical gastrectomy on primary tumor would benefit YAAGC is worth verifying in future prospective clinical research.

The NLR is a cost-effective method and a potential inflammation-based prognostic indicator for several types of cancer (16, 25, 26). In this study, NLR was an independent prognostic factor affecting the survival in YAAGC. Indeed, NLR was considered as a prognostic indicator in resectable (27), unresectable (15, 16, 28), and advanced clinical stage in GC (15, 29). NLR is also related to more aggressive tumor characteristics. In line with other study (29), NLR is associated with the occurrence of peritoneal metastases and bone metastases, as well as other markers of platelet–lymphocyte ratio (PLR) in YAAGC ( Supplementary Table 1 ). This ratio thus may be used to assist in individualized follow-up and treatment (25), with a better diagnostic value than the traditional tumor markers CA19-9 and CEA (16, 29). However, we did not observe any correlation between tumor differentiation (16) and NLR for YAAGC. In contrast to previous findings (16, 29), we proposed that NLR is also a valuable predictor of prognoses in young female patients with advanced GC.

In this study, multivariate analysis indicated that hypo-albuminemia was an independent prognostic factor for YAAGC. Indeed, it is known that preoperative low serum albumin is an independent negative prognostic factor for resectable (17, 30) or advanced clinical stage in GC (31). In our cohort, a significant number of YAAGC with peritoneal metastases were included, and the accumulation of albumin in peritoneum activity may thus have a role in hypoalbuminemia. Indeed, serum albumin level was correlated to the occurrence of peritoneal metastases in YAAGC ( Supplementary Table 1 ). We found that the serum albumin level was negatively correlated to both the systemic inflammatory markers NLR and PLR ( Supplementary Table 1 ). Controversially, the relation between hypoalbuminemia and poor survival may be secondary to that of the systemic inflammatory response (32). Additionally, studies on the mechanism of hypoproteinemia in GC found that a massive leakage of serum albumin into the stomach occurs often in GC as well as other gastric disease (33, 34). Besides, hypoalbuminemia is reported to predict venous thromboembolism in metastatic GC patients (35) and postoperative complications after GC surgery (36). Though those are beyond the aim of this study, the relation of hypoalbuminemia and venous thromboembolisms seems a good project for a future study.

However, some limitations exist in our study. In statistical methods, dichotomization and categorization of continuous variables cause loss of information, but simplify the implementation of the analyses and interpretation of the results. In addition, the simple prognostic index based on retrospective data did require validation in an external cohort of YAAGC. Furthermore, an analysis of confounding variables may be needed to exclude possible interference in the relevant prognostic factors. Moreover, relevant histopathological parameters that affect the laboratory parameters may need to be considered for clinical application of this model.

In conclusion, three prognostic factors have been identified in young patients with advanced GC. A simple prognostic index has been developed with distinct survival rates among the different risk groups. This simple prognostic model may help in designing future trials.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Fudan University Shanghai Cancer Center (1503144-8). The patients/participants provided their written informed consent to participate in this study.

Conceptualization, data curation and collection, and manuscript review and editing: WZ and G-LC. Investigation, methodology, data analysis, and original draft preparation: G-LC and YH. Data collection and investigation: G-LC, YH, XP, W-JF, X-YZ, X-DZ, W-HL, MH, Z-YC, W-JG, and WZ. All authors contributed to the article and approved the submitted version.

This study was supported by a grant from the National Natural Science Foundation of China (No. 81802362).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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