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Gastroenterology Research

Original Article

Volume 17, Number 3, June 2024, pages 133-145

The Risk of Infection-Caused Mortality in Gastric Adenocarcinoma: A Population-Based Study

Gastric cancer (GC) is overall the fifth most common cancer. It is the third most common cause of mortality among all cancers. In 2018, approximately one million new cases and more than 780,000 deaths occurred due to GC worldwide [1]. In 2019, the estimated number of new GC cases in the United States was 27,510, with 4,340 deaths [2]. Gastric adenocarcinoma (GAC) is the predominant type of GC, accounting for more than 90% of the cases. GAC has two main types: the most common is the intestinal type, and the other is the diffuse type [3]. Other gastric malignancies include lymphoma and leiomyosarcoma [4, 5]. The incidence and prognosis of GC vary according to demographic and other personal factors; for example, it has more incidence in Asian and Black races than in a White race and in males than females. The incidence increases in older age groups. The median age of GC diagnosis is 70 years for males and 74 for females [2]. Risk factors for GC include various dietary, occupational, and personal characteristics. Dietary risk factors include low vitamins A and C, a high-salt diet, and dietary N-nitroso compounds. Occupational factors include exposure to rubber manufacturing, metal processing, and coal. Other risk factors include smoking, blood group A, exposure to radiation, and gastroesophageal reflux disease (GERD). The latter increases the incidence of adenocarcinoma in the distal esophagus and proximal stomach, including the gastroesophageal junction. Infection with Helicobacter pylori is a definite gastric carcinogen [6-8]. A previous study estimated that H. pylori infection accounts for 6.2% of all GCs [9]. Another study found that GAC incidence in persons with H. pylori colonization is about 3% compared with zero in persons without colonization [10].

GAC is more prevalent in developing countries, but its incidence has decreased in developed countries over the past decades. This is primarily due to the control of risk factors, including lifestyle modification, environmental risk factors, and infection treatment with H. pylori [11-14]. However, the incidence of proximal GAC is increasing in developed countries [15, 16].

Localized stage GAC has a cure rate greater than 50%. However, GAC is an aggressive cancer, and only 10-20% of cases are diagnosed in the early stage of the disease in the United States. At the same time, most patients present with a regional or distant spread [17]. Surgery, including resection and adequate lymphadenectomy, is the only curative intervention in cases with localized disease. In patients with apparently localized proximal GAC, the 5-year survival is still low and ranges from 10% to 15% [6, 18]. Even after complete resection, 20-60% of patients experience the disease’s recurrence [19, 20]. Patients with metastatic GAC receive palliative therapy aiming at improving survival via better tolerance of chemotherapy [18].

The advanced tumor stage is the primary predictive index for survival and mortality in GAC due to the lymphatic and blood spread [4]. Male sex is associated with a higher risk of mortality [2]. Also, postoperative complications are associated with a worse prognosis in gastrointestinal and other malignancies [21-24]. Ma et al (2020) stated that postoperative infections independently affect cancer recurrence and patients’ survival after curative GAC resection surgery [25]. These complications include postoperative infections that independently worsen the prognosis of GAC [26, 27]. Studies suggest prolonged inflammations weaken the patients’ immunity and allow the micro-metastasis to regrow [25]. Perioperative treatment aiming to improve immunity limits postoperative immunosuppression and infections and decreases metastasis progression [25, 28].

Risk factors of mortality due to infections in patients with GAC need to be identified and controlled to reduce the morbidity and mortality related to these infectious diseases. In this retrospective study, we aimed to identify the risk factors associated with increased mortality risk due to infectious diseases in patients with GAC.

Based on the Surveillance, Epidemiology, and End Results (SEER) database, we conducted this retrospective cohort study in patients with stomach adenocarcinoma. The patient’s data, including the treatment field from 1975 to 2016, were extracted using SEER*Stat version 8.3.8.

The dependent variables were executed from the SEER program including: 1) death due to infectious diseases, including pneumonia, influenza, septicemia, tuberculosis, and other infections, i.e., human immunodeficiency virus (HIV); 2) death due to other causes rather than infection; and 3) survivors.

Besides, we gathered the independent variables such as: 1) age at diagnosis; 2) sex; 3) race, including White, Black, and others (American Indian/Alaska Native, Asian or Pacific Islander); 4) marital status, including single, married, separated, divorced, and widowed; 5) primary site in the stomach, including the fundus, body, gastric antrum, pylorus, and not otherwise specified (NOS) stomach, cardia, lesser and greater curvature; 6) stage, including localized, regional, distant, and unstaged; and 7) treatment field, including chemotherapy, surgery, and radiation (beam, other types, and none).

We conducted the data analyses using SPSS for Windows version 26.0. The relationships among categorical variables were observed using Pearson’s Chi-square test, and the data were presented as mean and standard deviation (SD) or number and percentage (%). The Cox regression analysis was used in the multivariate analysis to analyze the effect of the variables on the time of death, and the results showed a hazard ratio (HR) and 95% confidence interval (CI). The time to death among the patients was investigated as a univariate analysis by the Kaplan-Meier method, and the data were displayed as mean (months) and 95% CI. The probability of infection was assessed using binary regression analysis, and the results were presented as odds ratio (OR) and 95% CI. The P-value of less than 0.05 means the analysis showed a significant effect.

Ethical and IRB approval are not applicable.

Table 1 shows the clinicopathologic features of the included patients. Overall, 59,580 patients with stomach adenocarcinoma were in our cohort, with a mean age of 68.49 years. The total survival of patients, infectious mortality, and other mortality were 7,427 (12.46%), 854 (1.44%), and 51,299 (86.10%), respectively.

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Table 1. Clinicopathologic Features of Gastric Adenocarcinoma Patients

Higher mean survival month of GAC patients was noted in younger individuals (< 50 years: 60.45 vs. ≥ 50 years: 56.75), female gender vs. males (65.23 vs. 53.24), and other races vs. Whites and Blacks (78.91 vs. 54.01 and 47.21, respectively). Overall, the mean survival in months based on marital status was 33.28 for singles, 62.79 for married, 96.66 for separated, 50.37 for divorced, and 54.18 for widowed subjects. The mean survival months in descending order for the primary site was 77.88 in lesser curvature, NOS vs. 74.63 for pylorus vs. 62.49 for gastric antrum vs. 55.88 for fundus vs. 55.32 for body vs. 53.48 for greater curvature, NOS vs. 52.29 for stomach, NOS and 42.39 for cardia, NOS. Localized stage patients have a higher mean survival month of 76.28 vs. 59.83 for regional vs. 23.90 for unstaged and 15.13 for distant spread stage. The overall survival month was higher, i.e., 68.25 in patients with surgery vs. 14.01 without surgery. Also, the overall survival month was 61.60 for patients receiving chemotherapy vs. 42.23 for patients not receiving/unknown chemotherapy. The overall survival month was 59.47 for patients treated with another type of radiation vs. 45.31 for patients not treated with radiation, and 44 for patients treated by beam radiation. Details of the univariate analysis are shown in Table 2.

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Table 2. Univariate Analysis Using Kaplan-Meier Test

Figures 1-9 show the survival curves of each variable for infection-caused mortality. The multivariate analysis showed that the increased risk of infection-related mortality in patients with age ≥ 50 years (HR: 3.137; 95% CI: 2.178 - 4.517), patients not treated with chemotherapy (HR: 1.669; 95% CI: 1.356 - 2.056), or surgery (HR: 1.412; 95% CI: 1.132 - 1.761) and unstaged patients (HR: 1.699; 95% CI: 1.278 - 2.258). In contrast, a reduced risk of infection-related mortality was noted in females (HR: 0.658; 95% CI: 0.561 - 0.773) and married patients (HR: 0.627; 95% CI: 0.506 - 0.778). Table 3 shows details of the multivariate analysis.

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Figure 1. Survival curve for infection-caused mortality with age.

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Figure 2. Survival curve for infection-caused mortality with sex.

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Figure 3. Survival curve for infection-caused mortality with marital status.

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Figure 4. Survival curve for infection-caused mortality with race.

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Figure 5. Survival curve for infection-caused mortality with primary site.

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Figure 6. Survival curve for infection-caused mortality with stage.

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Figure 7. Survival curve for infection-caused mortality with surgery.

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Figure 8. Survival curve for infection-caused mortality with radiation.

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Figure 9. Survival curve for infection-caused mortality with chemotherapy.

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Table 3. Multivariate Analysis Using Cox Regression Test

The probability of infection in adenocarcinoma patients increased in patients with age ≥ 50 years (OR: 2.094; 95% CI: 1.453 - 3.018), other races vs. White and Black races (OR: 1.226; 95% CI: 1.006 - 1.494), lesser curvature, NOS as a primary site (OR: 1.325; 95% CI: 1.02 - 1.721) and patients without chemotherapy (OR: 1.258; 95% CI: 1.029 - 1.538). The probability of infection decreased in females (OR: 0.789; 95% CI: 0.671 - 0.928), married patients (OR: 0.715; 95% CI: 0.574 - 0.89), patients not treated by surgery (OR: 0.549; 95% CI: 0.447 - 0.673), regional (OR: 0.561; 95% CI: 0.478 - 0.66) and distant stage (OR: 0.354; 95% CI: 0.284 - 0.442). Table 4 shows details of the binary regression analysis.

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Table 4. The Probability of Infection Using Binary Regression Test

This study analyzed 59,580 patients with GAC registered in the SEER database. The factors associated with higher mortality rates due to infections in patients with GAC included older age at diagnosis (age > 50 years), male sex, no or unknown history of chemotherapeutic treatment, patients without surgery, and unstaged disease.

In contrast, younger age at diagnosis, female sex, and married status appear to have a protective effect with reduced mortality. Race, other marital statuses (single, separated, divorced, and widowed), disease’s primary site, radiation therapy, and regional and distant spread had no significant effect on mortality.

The binary regression analysis showed that patients with older age at diagnosis, male sex, and those with no or unknown history of exposure to chemotherapy had a higher risk of infection.

However, females and married status were associated with lower infection rates. Also, patients not recommended for surgery and patients with regional and distant disease stages had a lower risk of infection. Race (White and Black), other marital statuses (single, separated, divorced, and widowed), other primary cancer sites, radiation exposure, and unstaged have no significant risk for infection. Races other than Black and White, i.e., Asians and other races, had a higher risk for infection but not for death due to infection. Prior studies have reported that Asians have better survival after diagnosis of GAC compared to Whites, which may be related to earlier diagnosis [29-31].

Prior studies [29, 31] have reported better survival in patients with surgical intervention for GAC due to operability feasibility in early-stage cancers. Married status in patients with GC is associated with lower mortality, as reported in prior studies [32]. It may be indirectly related to lower psychosocial burden and better social support available for these patients, as reported in other studies [33, 34].

Cancer patients are more vulnerable to hospitalization with severe sepsis [35]. Previous studies have reported that severe sepsis has a higher risk of mortality in cancer patients, especially those with a distant spread, compared to concomitant chronic medical conditions, i.e., liver disease, renal failure, obstructive pulmonary diseases, and diabetes [35, 36]. There is a need to evaluate the risk factors for infection in GAC and the risk of increased mortality, which may help choose appropriate therapy for such patients and help improve patient outcomes.

Among patients with GAC, those with older age, unmarried status, male gender, unstaged cancer, history of chemotherapy, and not recommended for surgery have a higher risk of mortality due to infections.

This study is based on large database registered in the SEER database and follow-up information. Death-related information of the study population is well documented in the SEER database. We have considered a wide variety of infections, including tuberculosis, pneumonia, influenza, septicemia, and other infections, including HIV infection, not only sepsis. However, the limitations of this study persist. There is no record of genetic and personal factors that may have affected the liability to infection and mortality due to infectious diseases. Data regarding tumor differentiation and histological subtypes of GAC were not included in analysis.

Acknowledgments

None to declare.

Financial Disclosure

None to declare.

Conflict of Interest

The authors declare no conflict of interest.

Informed Consent

Not applicable.

Author Contributions

Adnan Malik: supervision, date curation, data analysis, writing and editing the manuscript. Farman Ali: writing and editing the manuscript. Muhammad Imran Malik: data curation, writing and editing the manuscript. Shahbaz Qureshi: writing and editing the manuscript.

Data Availability

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

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