The Impact of Intervention on Survival of Elderly Patients with Gastric Cancer at IV Stage: A SEER Population-Based Study.

Background The selection of therapeutic regimens for elderly patients with gastric cancer (GC) has attracted much attention. However, few clinical trials have been conducted concerning the subpopulation of patients diagnosed with stage IV disease. In this study, cases from the Surveillance, Epidemiologic and End Results (SEER) database were collected to investigate the effects of surgery and chemotherapy (CT) on the survival benefit in elderly GC patients with stage IV disease. Methods GC patients aged >65 years diagnosed with stage IV disease between 1973 and 2014 in the SEER database were included in the study pool based on strict inclusion and exclusion criteria. Univariate and multivariate analyses were employed to determine prognostic factors for overall survival (OS) and cancer-specific survival (CSS). Kaplan-Meier survival analysis was conducted to investigate the effects of different intervention methods on OS and CSS. Results A total of 9,306 patients were selected from the SEER database. The results showed that patients who received both surgery and chemotherapy significantly obtained OS and CSS benefits (P < 0.0001). Compared with the no surgery and CT group, the CT alone group (P < 0.0001) and the surgery alone group (P < 0.0001) had prolonged survival time. Furthermore, age and grade stratifications served as important indicators for the selection of therapeutic regimens Conclusions Surgery combined with CT outperformed monotherapy or no therapy strategies for elderly patients with stage IV disease.


Abstract
Background The selection of therapeutic regimens for elderly patients with gastric cancer (GC) has attracted much attention. However, few clinical trials have been conducted concerning the subpopulation of patients diagnosed with stage IV disease. In this study, cases from the Surveillance, Epidemiologic and End Results (SEER) database were collected to investigate the effects of surgery and chemotherapy (CT) on the survival benefit in elderly GC patients with stage IV disease.
Methods GC patients aged >65 years diagnosed with stage IV disease between 1973 and 2014 in the SEER database were included in the study pool based on strict inclusion and exclusion criteria.
Univariate and multivariate analyses were employed to determine prognostic factors for overall survival (OS) and cancer-specific survival (CSS). Kaplan-Meier survival analysis was conducted to investigate the effects of different intervention methods on OS and CSS.
Results A total of 9,306 patients were selected from the SEER database. The results showed that patients who received both surgery and chemotherapy significantly obtained OS and CSS benefits (P < 0.0001). Compared with the no surgery and CT group, the CT alone group (P < 0.0001) and the surgery alone group (P < 0.0001) had prolonged survival time. Furthermore, age and grade stratifications served as important indicators for the selection of therapeutic regimens Conclusions Surgery combined with CT outperformed monotherapy or no therapy strategies for elderly patients with stage IV disease.

Background
Gastric cancer (GC) is one of the most common malignancies worldwide. According to a new epidemiological investigation, the incidence and cancer-associated mortality of GC rank fourth and fifth, respectively [2]. GC has been recently identified as a kind of regional disease, whose incidence was found to be high in East Asia, South America and Eastern Europe but lower in America [20,21,24,29]. Despite the tendency of GC patients to be diagnosed at a young age, the disease still mostly occurs in elderly patients, leading to poor prognosis [18]. Furthermore, due to their insensitivity to pain, deficiency of typical symptoms and intolerance of cachexia, elderly patients are usually severely affected by cancer and typically present distant metastasis at diagnosis. More attention should be paid to elderly patients with GC.
Traditional perspectives have shown high risks associated with positive interventions partly due to patient weakness and intolerance to treatment. However, with the development of evidence-based medicine, an increasing number of studies have demonstrated that positive interventions containing surgery or adjuvant chemotherapy (CT) will benefit survival for elderly GC patients. However, elderly patients who are suitable for intervention should meet some criteria, such as high nutrition level, proper physical functioning and some specific serum biomarkers [4,11,15,16,28]. Elderly patients with stage IV disease have always been neglected and designated as a treatment-invalid population.
Little research has focused on this subgroup to evaluate the effects of different therapeutic regimens on prolonging survival.
In this study, we employed the available data from the Surveillance, Epidemiologic and End Results (SEER) database to investigate surgical and therapeutic interventions in elderly GC patients diagnosed at Ⅳ stage to identify the best regimens for this subgroup.

Database
The SEER database is an authoritative resource of available cancer cases that can be utilized to investigate demographic, geographic and survival characteristics. The SEER research data include patient-associated clinical information, such as age, sex, race/ethnicity, marital status, insurance status and age/year of diagnosis, as well as large amounts of pathologic features, such as TNM classification, cancer grade, treatment method and survival data. The SEER*Stat software was used to search and download available data from the SEER database. The dataset in SEER was called "18 Regs Custom Data (with additional treatment fields), Nov 2016 Sub (1973-2014 varying)". Patients diagnosed with stage IV GC who were older than 65 years were selected for the initial patient pool.
The age range in this study was based on that in previous studies that defined elderly patients [3,28,33]. Additionally, the behavioral type of tumors used for analysis was confined to "Malignant". To investigate the effect of different intervention methods on elderly GC patients with stage IV disease, information on relevant terms in this sample pool was extracted, which could be summarized as four aspects, including demographic information, clinicopathological features, therapeutic regimens and survival information. The collected data were further arranged and analyzed.

Variables
Variable information included sex, age, race, living region, marital status, median household income, insurance status, histologic type according to ICD-O-3, therapeutic records (surgery, CT and radiation), survival time and cause of death (COD) to site recode. The AJCC 6th edition TNM stage was collected for subsequent analysis rather than the AJCC 7th edition TNM stage because there was a lack of information on TNM stage based on the AJCC 7th edition in the patients diagnosed before 2010.
Demographic information was reorganized for convenience of analysis. The age at diagnosis was divided into five subgroups with intervals of 5 years, including "65-69", "70-74", "75-79", "80-84" and " 85". Race was classified as "White, Black and Other (American Indian/AK Native, Asian/Pacific Islander)". The rural-urban living region was defined as three classified areas according the following groups: "Comp rural lt 2,500 urban pop, adjacent/not adjacent to a metro area" and "Fringe counties of metropolitan areas ge 1 million pop" were clustered together as "rural". "Counties in metropolitan areas of 250,000 to 1 million pop or lt 250 thousand pop" was classified as "county". "Urban pop of ge 20,000 adjacent/not adjacent to a metropolitan area" and "Urban pop of 2,500 to 19,999, adjacent/not adjacent to a metro area" were classified as "urban". Marital status included 6 items: "Married (including common law)" was classified as "married". The not married cases were divided into two groups. One group included "Single (never married)", "Divorced", "Separated" and "Unmarried or Domestic Partner" cases. "Widowed" was grouped separately because it has been reported that widowed GC patients are at the highest risk of death compared with patients with other marital statuses [25]. Median household income was marked as "1-4" by quartile from lowest to highest for convenience of further investigations. For insurance status, the "Insured" and "Insured/No specifics" groups were clustered together as the "insured" group. The other cases were divided into "Medicaid", "Uninsured" and "Unknown" groups.
Clinicopathological features included AJCC 6th TNM stage, histologic type and grade. For the T stage, "T2a", "T2b" and "T2NOS" were all included in the "T2" group. Histologic type in the SEER database was determined according to ICD-O-3. The histologic type was defined as "Epithelial", "Adenocarcinoma" or "Other". The "Other" group included some rare kinds of GC, including squamous and complex epithelial types.
Therapeutic regimens were the main factors in this study. Patients who underwent surgery for primary tumor sites within the stomach or metastatic organs and tissues were all defined as having surgical intervention. Patients who received radiation were excluded from the study cohort to eliminate the effects of interventions unrelated to surgery and CT on survival time.
For survival information, the survival months of each patient and related COD information were rearranged for analysis of overall survival (OS) and cancer-specific survival (CSS), which were the primary outcomes in this study. The date of the last contact was regarded as the censored value for patients still alive.

Patient population
The selection criteria were key in this study. The inclusion criteria were as follows: a) patients diagnosed with GC pathologically; b) patients with an age of diagnosis over 65 years old; and c) patients diagnosed at stage IV. The exclusion criteria were as follows: a) patients with a lack of demographic information; b) patients with a lack of important clinical characteristics and treatment records; c) patients who were lost to follow-up; and d) patients who underwent radiotherapy. The pool of metastatic GC patients was utilized for further analysis.

Statistical methods
In general, demographic information, clinicopathological features, therapeutic regimens and survival information were summarized and rearranged for statistical comparisons. The differences in continuous variables were analyzed by Student's t test. The differences in categorical variables were analyzed by the c 2 test. This study aimed to investigate the potential risk factors of different therapeutic interventions. Kaplan-Meier curves and the log-rank test were employed to determine the effects of variables on OS and CCS. The independent prognostic factors were revised by the Cox proportional hazards model and used to select the potential bias for the relationship between survival benefits and intervention methods. All statistical analyses were performed using SPSS 25.0. Statistical significance was set at a two-sided P < 0.05.

Results
Cohort description and patient characteristics A total of 11,967 patients were initially selected from the SEER database in this study. After the exclusion of patients with a lack of information concerning basic demographic data, clinicopathological features and survival time, 10,968 patients remained for further investigation. To accurately analyze surgical and chemotherapeutic effects in GC, patients who had received radiotherapy were excluded to keep the intervention methods comparable. Ultimately, 9,306 patients were selected for statistical analysis. The selection procedure is shown in Fig. 1.
This pool was divided into four groups according to therapeutic regimens: 1) patients who received neither surgery nor CT (n = 4,674); 2) patients who received surgery alone (n = 1,097); 3) patients who received CT alone (n = 2,969); and 4) patients who received both surgery and CT (n = 566). The percentages of the groups were 50.23%, 11.79%, 31.90% and 6.08%, respectively. The clinical features of this cohort are presented in Table 1. There were significant differences between the four intervention groups regarding sex, age, ethnicity, marital status, median income, insurance status, T stage, N stage, histologic type and grade (P < 0.05).    (Fig. 2). The results showed that the patients who

Discussion
The selection of therapeutic regimens for elderly GC patients has been a hot topic in clinical practice.
Compared with younger GC patients, elderly individuals mostly have poor prognosis and short survival [18]. Traditional thoughts have suggested that surgery and CT are not suitable for elderly patients given considerations of quality of life and the cost-benefit ratio. However, recent studies have shown that appropriate interventions for elderly patients can significantly improve survival [3,11,15]. Clarification of the significance of positive interventions in elderly patients seems necessary.
This study focused on the relationship between survival and therapeutic regimens in a specific subgroup of elderly GC patients, those with cancer metastasis. Information on elderly GC patients with stage IV disease from the SEER database was extracted, including demographic information, clinicopathological features, therapeutic regimens and survival information. The cohort consisted of 9,603 patients after a strict selection procedure. OS and CSS were the primary outcomes. Modification of the multivariate analysis showed that age, the second lowest income bracket, grade and therapeutic method were independent prognostic factors.
Surgical intervention for elderly GC patients has always been controversial. There are two purposes of surgical intervention for elderly patients with stage IV disease: prolonging survival time and alleviating cancer-associated symptoms. Although Katai et al [10] reported nonideal short-term survival after surgery in elderly patients ten years ago, some recent studies have demonstrated that the postoperative morbidity and mortality in elderly patients are comparable with those in younger patients [19,22], which may be attributable to advances in nutritional support, anesthesia, surgical instruments and skills. The benefits of surgery plus CT for the survival of GC patients with stage IV disease were also clearly identified [12,26,27,32]. The postoperative complication rate was not different between elderly populations of different ages, which suggested that the benefits of surgical intervention would not decrease with age. CT has been recommended as the main method for treating stage IV GC [1]. Its efficacy for metastatic GC has been proven by many clinical trials.
In this study, the therapeutic methods were the main factors for patient survival. Patients who underwent treatment with both surgery and CT acquired the best OS and CSS values. Conversely, the no surgery or CT group had the shortest OS and CSS values. Surgery and CT decreased the risks of OS and CSS by 72% and 71%, respectively. Only surgery or CT obtained survival benefits compared with no treatment. The advantages of Surgery plus CT for survival outcomes were consistent with those identified in previous studies [8,23]. Furthermore, the OS and CSS values associated with CT alone were significantly better than those associated with surgery alone. This suggests that CT is a better choice than surgery for elderly patients with stage IV disease who cannot receive both, which may be due to the noninvasive methods and relief of stress associated with CT.
However, in the cohort of this study, only 6.1% patients received surgery and CT. The percentages of patients who received surgery or CT alone were 11.8% and 31.9%, respectively. Nearly half of the patients received neither surgery nor CT. Moreover, the number of patients who received surgery decreased with increasing age, which was consistent with a previous study [22]. Few elderly patients choose positive interventions, especially combined surgical and chemotherapeutic interventions, due to their physical status and the risk-benefit ratio. Pre-existing views of patients and their families about the side effects of surgery and CT might be another reason that positive intervention was not chosen.
To classify the most appropriate subpopulation who can benefit from positive intervention, a stratified analysis according to age and grade was conducted. For age, the effects of the four therapeutic methods on OS and CSS were similar to those seen in the unstratified results. Patients who underwent surgery and CT achieved the best survival, while the no treatment group had the worst survival. With increasing age, patients received less survival benefit from both or single intervention methods, as previous studies have reported [17,30]. Moreover, an increase in age also narrowed the survival gap between the surgery alone and CT alone groups. The OS and CSS hazards associated with surgery alone generally declined, while those associated with CT alone increased. There are two possible reasons for these results. The SEER database is an authoritative database, whose cancer incidence data from population-based cancer registries covers approximately 34.6% of the U.S. population. Some published articles from SEER data have investigated the relationships of elderly GC patients and therapeutic efficacy [5,13,14,33]. This study first focused on the evaluation of the effects of surgical and chemotherapeutic methods in elderly GC patients with stage IV disease from the SEER database. The subpopulation of GC patients had features similar to those of young patients or all elderly patients. However, this study also revealed unique characteristics of elderly patients with stage IV disease. First, for the general survival and stratified analysis, the results were concluded as "surgery plus CT > CT alone > surgery alone > no surgery or CT". Second, the efficacy of CT alone was significantly superior to that of surgery alone, but the survival gap narrowed and even faded away with increasing age. Third, the GC grade was an important indicator of the success of the intervention methods and thus could be used for the prediction of therapeutic efficacy and the selection of the most appropriate regimens.
Undoubtedly, shortcomings existed in the study: elderly patients who received surgery could have had better physical status and health-care conditions than those who did not receive surgery, which might lead to selection bias in the survival outcomes; another limitation was the lack of detailed information in the recorded data, such as surgical methods and CT drugs. This missing information could have caused potential biases in the final results.

Conclusions
Our findings show that the surgery + CT regimen is the most effective method in terms of survival Availability of data and materials The datasets generated and/or analysed during the current study are available in the SEER database repository, https://seer.cancer.gov/.

Competing interests
The authors declare that they have no competing interests. Authors' contributions BC was responsible for acquisition of data, further analysis and mainly drafting the manuscript. WL and WZ were responsible for design of the work and revising the manuscript critically. CW was responsible for curation of the data and revising the manuscript critically. YS and XZ were responsible for interpretation of data and partly drafting the work. BW was responsible for the conception of the work and revising it critically. All authors read and approved the final manuscript.

Additional Files
Additional files 1-Stratified analysis of age concerning effects of therapeutic method on OS.
This table provides the detailed data of hazard ratios of OS by four intervention methods based on age stratification.
Additional files 2-Stratified analysis of grade concerning effects of therapeutic method on OS.
This table provides the detailed data of hazard ratios of OS by four intervention methods based on grade stratification.
Additional files 3-Stratified analysis of age concerning effects of therapeutic method on CSS.
This table provides the detailed data of hazard ratios of CSS by four intervention methods based on age stratification.

Additional files 4-Stratified analysis of grade concerning effects of therapeutic method on CSS.
This table provides the detailed data of hazard ratios of CSS by four intervention methods based on grade stratification.

Additional files 5-PRISMA checklist
The PRISMA checklist can help authors check the content integrity and be useful for critical appraisal of this manuscript. Figure 1 Flow chart of study enrollment and exclusions.