Long-term clinicopathological prognosis on 609 cases after gastrectomy: A 10-year follow up single-institutional retrospective analysis

Objective: This retrospective study focused on relevant factors about gastric cancer patients who underwent gastrectomy after 10 years, which showed great significance of prolonging survival time of gastric cancer patients. Methods: 609 gastric cancer patients after surgery were recruited from January, 2005 to December, 2007. They were perfectly followed and their clinicopathological data were collected. Univariate analysis was performed using Log-rank test in order to compare survival rates between or among groups. The outcomes with statistical significance (P<0.05) were screened out. Cox regression model was employed for survival multivariate analysis. Forward stepwise LR analysis was used to screen the factors influencing survival qualities of relevant patients after surgery. Results: Univariate analysis indicated that prognosis was correlated with age, pT stage, pN stage, pM stage, tumor size, location, type of gastrectomy, degree of differentiation, vascular invasion, nerve invasion, radical treatment, chemotherapy, radiotherapy, pTNM stage and BMI (P0.05). Multivariate analysis showed that pT stage, pN stage, pM stage, degree of differentiation, vascular invasion, nerve invasion, radical treatment, chemotherapy, radiotherapy, pTNM stage were independent prognostic factors of GC patients (P0.05). Conclusions: The 10-year survival rates of gastric cancer patients are primarily determined by tumor progression. Appropriate treatment can improve prognosis of patients. Early diagnosis of gastric cancer and prompt implementation of radical surgery and adjuvant chemotherapy are essential for increasing survival rates. This study provides a promising direction for future basic researches. properties of and effective approaches are diagnosis, prompt radical treatment and adjuvant chemotherapy. They are crucial for increasing survival rates after gastrectomy. this study provides a promising access to establishing a bridge between basic and clinical studies.


Introduction
Gastric cancer (GC) is one of the most prevalent malignancies worldwide, whose incidence ranks the fifth only to lung cancer, breast cancer, colorectal cancer and prostate cancer based on GLOBOCAN published in 2018 [1]. Approximately one third of worldwide cases of GC took place in China. Chinese date of malignancy registration showed that the incidence of GC ranks the second in new cases and the third in cases whose deaths were caused by malignancies [2]. As the major treatment method, surgery is considered as the sole way to People's Liberation Army of China, including 454 men and 155 women, whose ages ranged from 23 to 83 years old. Their followed-up information were completed. Data in case history were recorded in detail. The clinicopathological information included age, sex, pT stage, pN stage, pM stage, tumor size, location, type of gastrectomy, degree of differentiation, the amount of dissected lymph nodes, vascular invasion, nerve invasion, radical treatment, selected approach and therapeutic number of chemoradiotherapy, pTNM stage and body mass index (BMI). Also, patients whose death were not due to GC were excluded in this study.

Follow-up
The patients were followed through telephone interview or review in outpatient clinic. The follow-up surveys were implemented every 3 months within 2 years after the end of treatment, every 6 months within 3 to 5 years and every year after 5 years, the end point of which was until December 25, 2017. The overall survival time should be from the day after surgery to the outcome or the end of survey. The follow-up of these patients were from less than 1 month to 155 months. All the cases included were followed. Multivariate Cox regression analysis:

Statistical analysis
In order to adjust the relationships among variables and remove confounding factors, the outcomes with statistical significance in univariate analysis were included into Cox proportional hazards regression models. Forward stepwise LR method was employed in multivariate analysis. PTNM stage, separated with pT, pN and pM, was included in the other regression model analysis since TNM stage should be dependent on the tumor, the number of involved regional lymph nodes and metastasis. Moreover, polytomous variables were included as dummy variables. The system encoded dummy variables in the way that the last dummy variable served as the baseline level. The results showed that these outcomes were independent prognostic factors of GC patients after surgery, including age, pT stage, pN stage, pM stage, degree of differentiation, vascular invasion, nerve invasion, radical treatment, chemotherapy, radiotherapy and pTNM stage (All P0.05, Table.2).
Survival curves are respectively shown in Figure.2, Figure 3 and Figure 4. Studies have reported inconsistent results about relationship between age and prognosis [4][5], which may result from the absence of unified criterion of age groups. The elderly are identified as old people who are more than 65 years old by World Health Organization (WHO). In this study, the elderly accounted for 34.3% (209/609). Univariate and multivariate analysis both demonstrated that age was significantly correlated with GC prognosis (P 0.05), which was consistent with results of former studies [6]. Survival curves showed that long-term survival rates of patients who were over 65 years old were obviously lower than the ones of patients who were below 65 years old. This result might be partially due to deterioration of physical condition and increasing incidence of Multivariate analysis showed that the depth of tumor invasion could serve as an independent prognostic factor. This conclusion was consistent with Orman's study [7]. This logical method is displayed as the thinking of "Precision Medicine".
pTNM stage was proved as an important independent prognostic factor of GC patients [9].
This study found that 10-year cumulative survival rates apparently decreased with more advanced stages. Univariate and multivariate analysis indicated that pTNM systematic stage could serve as an important and independent prognostic factor. The same conclusion was drawn in studies of western and developing countries [10][11]. 10-year survival rates of IA and IV stages were respectively 47.9% and 2.9%. 10-year survival rate was generally low in this study because of a small proportion of patients at early stage.
Most patients were diagnosed as GC at advanced stage. Therefore, it is concluded that prognosis is greatly dependent on GC clinical stage. Thus, surgery at early stage can promote prognosis.
There are abundant blood vessels, lymphatic vessels and nerves in the gastric wall layer from mucosa to serosa. The more deep tumors invade gastric wall, the more chances tumor cells will have to spread to vicinity of tumors through vessels and nerves, resulting in lymphatic and hematogenous metastasis. This is the major way of GC metastasis [12].
Scartozzi and his colleagues collected 734 patients who had undergone radical cancer gastrectomy at advanced stage and found that vessel and nerve invasion were independent prognostic factors of influencing recurrence and long-term survival of GC patients [13]. Univariate and multivariate analysis in this study both demonstrated that lymph node metastasis was an independent prognostic factor. Consequently, vessel and nerve invasion are determined to play important roles in tumor metastasis.
Tumors are likely to recur for GC patients, especially those at advanced stage, because of macroscopically invisible remnants in surgical areas even when the visible tumors are clearly dissected. Postoperative chemoradiotherapy is an effective approach to killing remaining tumor cells. It was reported that increasing survival rates of GC patients after surgery were mainly attributed to the improved capability of postoperative chemotherapy [14]. Two large clinical randomized controlled trials proved that postoperative chemotherapy could contribute to better prognosis than surgery alone [15][16]. However, there are no studies about the relationship between numbers of chemotherapy and prognosis. Univariate and multivariate analysis in this study showed that postoperative chemotherapy was an independent prognostic factor. According to survival curves, survival rates of six cycles of chemotherapy were the highest, and the ones of over 6 cycles were statistically lower (p = 0.028). This difference proved that 6 cycles of chemotherapy was the best choice in the condition that patients could have good physical endurance. Over 6 cycles of chemotherapy is regarded as a kind of overtreatment and cannot improve survival rates. Patients who underwent 2 cycles of chemotherapy had the lowest 10-year survival, reasons of which may be concluded as three aspects: a) sample errors can be huge based on small number of patients who underwent 2 cycles of chemotherapy; b) the compliance of chemotherapy can be not optimal; c) it is widely accepted that weak patients cannot tolerate more cycles of chemotherapy. The influence of physical weakness on survival is much bigger than the one of numbers of chemotherapeutic cycles.
Conventional radiotherapy had mostly served as palliative treatment in GC until New England Journal published a study of Macdonald in 2001. Since this event, radiotherapy, as a kind of adjuvant therapy, has received wide attention in multidisciplinary treatment [17]. However, the application of radiotherapy in GC owns less clinical studies and acceptance than other kinds of tumors, because there have been long-term conventional concept and different features in GC treatment between China and western countries.
Univariate and multivariate analysis in this study showed postoperative radiotherapy was an independent prognostic factor. However, 10-year survival rates of patients who underwent radiotherapy were lower than those who did not receive radiotherapy, which might be attributed to degrees of tumor differentiation. The influence of poor differentiation on prognosis is much severer than the one of radiotherapy. Mohsen and his colleagues drew the similar conclusion that survival rates of patients who received radiotherapy and did not receive radiotherapy were 9% and 19%, respectively (P = 0.59).
There was no statistical difference between them [18]. Otherwise, univariate and multivariate analysis both indicated that the degree of differentiation and radical treatment were two independent prognostic factors of GC, consistent with previous studies [19][20].
Univariate analysis showed that sex was not an independent prognostic factor of GC, which was keeping with previous studies [20][21]. We indicated that prognosis was associated with tumor size, location, type of gastrectomy and BMI. Survival curves was shown in Fig. 5. Whereas multivariate analysis showed that these outcomes were not independent prognostic factors in GC, inconsistent with some studies [7,20,21]. The type of gastrectomy mainly depends on tumor location and size in clinical practice. It can take on relative distributions of patients in subgroups. Therefore, the conclusion about tumor size, location, type of gastrectomy is the same as other studies. There still exist controversies about the relationship between BMI and prognosis [23]. Some scholars claimed that high BMI led to more difficult surgery, higher chances of complications, more residual involved lymph nodes, higher rates of recurrence and metastasis [24]. In this way, high BMI can decrease survival rates of GC patients. Some other scholars claimed that the surgical and adjuvant therapeutic duration of patients with high BMI was better than the ones with low BMI. Dystrophic patients, which is also called patients with abnormally low BMI, were easy to suffer systemic inflammation. This physiopathological process could promote malignant biological behaviors [25]. It seems that high BMI may increase survival rates of patients. However, opposite results may be partly due to different races, different regions, different numbers of samples and mutual effects of prognostic factors. The correct conclusion needs further studies. studies are confined to mucosa microenvironment [26]. It is reported that Periostin, an extracellular matrix molecule, was closely associated with the genesis, progression and prognosis of GC [27]. The author's previous basic studies found that Periostin could interfere with tumor plasticity through induction of stem-like potential, promoting malignant biological behaviors of tumor cells. This study strongly indicated that the molecules that acted as essential roles of GC were probably located in subserosa. It is not clear that whether Periostin took the leading position of plasticity of tumor cells. The exploration of concrete molecular mechanisms and confirmation of key molecules will provide more reliable theoretical proof for monitoring the processes of GC and choose individualized treatment regimens in future basic studies.
This study will provide not only references for diagnosis, treatment, and evaluation of GC prognosis, but also an access to future basic studies through clinical phenomena and problems. This amazing advancement will lead the direction of basic medicine and assist to overcome clinical challenges more specifically, which is also displayed as the thinking of "Precision Medicine". The process is exactly the authentic value of basic studies.

Funding
This study was funded in part by National Natural Science Foundation of China     The survival curves of tumor size(a), location(b), type of gastrectomy(c) and BMI(d)