The patterns and timing of recurrence after curative resection for gastric cancer in China

Background The recurrence of gastric cancer after curative resection had adverse effects on patients’ survival. The treatment presence varied from different countries. The aims of this study were to understand the recurrence incidence, patterns, and timing and to explore the risk factors in China. Methods One thousand three hundred four patients who undergoing curative resection from more than 100 hospitals between January 1st 1986 and September 1st 2013, were surveyed in detail. Clinical pathological factors were examined as potential risk factors of each recurrence pattern using univariate and multivariate analyses. Recurrence timing was also analyzed based on disease-free survival. Results Among 1304 gastric cancer patients, 793 patients (60.8%) experienced recurrence and 554 patients (42.5%) experienced recurrence within 2 years after operation. The median disease-free survival was 29.00 months (interquartile range [IQR] 12.07, 147.23). Receiving operation in general hospitals was one of independent risk factors of local-regional recurrence (OR = 1.724, 95% CI 1.312 to 2.265) and distant metastasis (OR = 1.496, 95% CI 1.164 to 1.940). Patients would suffer lower risk of distant metastasis if they received no more than 3 cycles adjuvant chemotherapy (OR = 0.640, 95% CI 0.433 to 0.943). Adjuvant radiotherapy could reduce the risk of recurrence (OR 0.259, 95% CI 0.100 to 0.670), especially distant metastasis (OR = 0.260, 95% CI 0.083 to 0.816). Conclusions More than 60% patients experienced recurrence after curative resection for gastric cancer, especially within 2 years after surgery. Risk factors were clarified between various recurrence patterns. Advanced gastric cancer and undergoing operation in general hospitals contributed to increased recurrence risk and worse survival. Enough number of lymph nodes harvest and standard D2 lymphadenectomy could reduce recurrence. Chinese patients would benefit from adjuvant chemotherapy and radiotherapy.


Background
Gastric cancer is the fourth common malignant tumor in the world, and China is one of countries with high gastric cancer incidence [1,2]. So far, curative resection has been considered as the only way to cure gastric cancer. Recurrence after curative resection contributes to the limited survival of patients. Recurrence patterns generally include local-regional recurrence, distant or hematogenous metastasis, and peritoneum implanting. Recurrence patterns have related to adjuvant treatment modes. For example, in America, local-regional recurrence and hematogenous metastasis were fairly common, and patients could benefit from adjuvant radiochemotherapy [3][4][5]. While, in Japan and South Korea, where distant metastasis and peritoneum implanting were regular, patients could benefit from adjuvant chemotherapy, rather than adjuvant radio-chemotherapy [6][7][8][9]. Moreover, recurrence timing could provide information of postoperative follow-up, in order to find recurrence timely. In China, several small sample singlecenter studies had reported the recurrence patterns and relative risk factors [10][11][12], but little large sample and multiple centers analysis had reported recurrence timing and survival. And the level of gastric cancer treatment varied from different hospitals, sites, and times. So, that exploring the actual recurrence patterns and timing was necessary. It was the first large sample of multiplecenter retrospective analysis for recurrence patterns and timing after curative gastric cancer resection in China. We specifically analyzed the relationship between surgical hospitals and recurrence. It would provide more information for clinicians in choosing individual treatment schedules and predicting prognosis.

Patients
There were 1646 patients, who underwent operation for gastric malignant tumors between January 1st 1986 and September 1st 2013, in more than 100 Chinese hospitals, screened for this analysis. All of them finally received postoperative treatment in Gastrointestinal Tumor Department of Beijing Cancer Hospital and Radiotherapy Department of Fudan University Shanghai Cancer Center. Three hundred forty-two patients were excluded for the following reasons: (1) 192 patients underwent palliative tumor resection (including both primary and non-local regional metastasis lesions totally resected) or experienced microscopically/visible positive (R1/R2) margin status, (2) 67 patients whose postoperative histological examinations turned out not to be gastric adenocarcinoma, and (3) 83 patients experienced death whose recurrence time and patterns were unclear. Finally, 1304 gastric adenocarcinoma patients were included in this study for recurrence patterns and timing after curative resection (Fig. 1).

Data collection
All patients' clinical pathological characteristics, including age, sex, tumor location, surgical hospitals (general and specialist hospitals), depth of tumor invasion, number of positive lymph nodes, extent of lymphadenectomy, histological type, neo-adjuvant treatment, adjuvant treatment, and recurrence and survival information were retrospectively reviewed based on operative notes and medical records.

Pathological identification
Cardia and fundus tumors were identified as gastroesophageal junction (GEJ) adenocarcinoma. Tumors located in the rest sites of gastric were identified as nongastroesophageal junction (non-GEJ) adenocarcinoma. The lymphadenectomy extent was defined according to the 2010 Japanese gastric cancer treatment guidelines [13]. The tumors' stages were classified based on the postoperative tissues, according to the 7th edition American Joint Committee on Cancer (AJCC) staging system of gastric adenocarcinoma. Histological classification was in accordance with the World Health Organization (WHO) classification of tumors of the digestive system [14]. Well-differentiated tumors included highly and moderately differentiated papillary carcinoma. And poorly differentiated included low differentiated papillary carcinoma, mucinous adenocarcinoma, and hepatoid adenocarcinoma. Recurrence was defined as biopsy and imaging highly suspicious of recurrence. Recurrence patterns included local-regional recurrence (gastric or nodal), distant metastasis (organs and distant lymph nodes), and peritoneum implanting (peritoneum nodules, ascites, and Krukenberg tumors).

Postoperative follow-up
All patients were followed from the date of surgery to death or emigration. The last follow-up of all recurrence Fig. 1 The screening progress for analysis patients and survival information was January 7th 2015. Recurrence and survival data were obtained from patients' medical records and telephone follow-up.
The recurrence free survival (RFS) was defined as the time from surgery to recurrence or death of any other causes. The overall survival (OS) was defined as the time from operation to death. The recurrence occurred within 2 years after surgery was defined as early recurrence. Recurrence patterns were classified based on the site of the first recurrence. The recurrence inspected within 3 months after the first recurrence was regarded as synchronous recurrence.

Statistical analysis
Fifteen clinical relative characteristics were examined as potential risk factors of recurrence. Differences between two groups were assessed by the chi-square or Fisher exact tests. The association of clinical pathological factors with the extent of recurrence was assessed using logistic models. Back-Wald method of multivariate analysis model was used to avoid possible interaction factors for recurrence patterns. Survival curves were analyzed by Kaplan-Meier method and compared by the log-rank test. All analyses were carried out by SPSS version 22.0. The prognostic powers of covariates were recorded by odds ratios (ORs) and 95% confidence internals (CIs). All p values <0.05 were considered statistically significant. Based on this database, several clinical pathological factors were independent risk factors of recurrence in any site (Table 2). Specially, patients who underwent radical surgery in general hospitals (OR 1.632, 95% CI 1.238 to 2.151) and suffered signet ring cell cancer (OR 1.881, 95% CI 1.108 to 3.193) were more likely to experience recurrence. Patients receiving adjuvant radiotherapy (OR 0.259, 95% CI 0.100 to 0.670) contributed to lower recurrence risk.

Risk factors of each recurrence pattern
In exploring risk factors of recurrence patterns, different clinical pathological factors contributed to specific recurrence patterns (    (Fig. 3a).  (Fig. 3b).

Discussion
Most studies had noted that curative resection for gastric cancer focused largely on prognosis [15,16]. In China, most recurrence pattern data was based on small sample, single-center database [10][11][12], which could not actually reflect the presence of gastric cancer treatment. And little studies noted recurrence timing and took the surgical hospitals' influence on recurrence into consideration. This study was important, because it firstly aimed to identify the incidence, patterns, and timing of recurrence after curative resection for gastric cancer in a large sample and multiple-center cohort of Chinese patients. The outcomes not only provided Chinese presence of curative resection for gastric cancer but also informed the points, which clinicians should focus during the postoperative follow-up.
Based on this analysis, the difference between surgical hospitals and recurrence was specifically analyzed. Receiving operation in general hospitals contributed to higher recurrence risk and shorter RFS (Fig. 3c, p < 0.001). It partly related less lymph nodes harvest and lower D2    [21] and earlier D2 lymphadenectomy generalization in specialist hospitals. It also referred that standard D2 lymphadenectomy training of clinicians should be continued in China. And increased T stage was the most important independently risk factor of recurrence and with worse RFS (Fig. 3d, p < 0.001). Several studies had noted that postoperative recurrence associated with factors, such as T stage, extent of lymph node invasion, and tumor location [3, 7, 10-12, 17, 19, 22-26], which were consistent with this study. Based on this database, female and signet ring cell cancer contributed to increased incidence of peritoneum implanting, which reported in previous results [17,27]. However, we did not find that lymph node invasion related to peritoneum implanting [22]. The age of patients closely associated with distant metastasis and peritoneum implanting. Patients older than 65 years old had higher risk of distant metastasis and lower risk of peritoneum implanting. In further study, in the group of patients older than 65 years old, less patients were signet ring cell cancer (5.9 vs. 13.0%, p < 0.001) and more patients did not receive adjuvant chemotherapy (22.6 vs. 12.9%, p < 0.001), comparing with the group of patients no more than 65 years old. It might explain the results. In addition, among patients with signet ring cell cancer, compared with subtotal gastrectomy, patients with total gastrectomy contribute to slightly lower risk of peritoneum implanting (10.0 vs. 15.2%) and multiple patterns recurrence (23.3 vs. 33.0%). It might be better to underwent total gastrectomy for signet ring cell cancer patients. The overall median RFS noting in this analysis was 29.00 months, which was similar to the results in USA [3]. Of note was the further study that the median RFS among patients with recurrence was much shorter, at a little more than 1 year (14.73 months), as the previous study reported [17,19]. Single local-regional recurrence occurred later than any other recurrence types and had better overall survival. The overall 3-and 5-year survival rates were 63.8 and 44.8%, respectively, which were higher than previous American study (50.9 and 39.3%) [3]. In further study, the median survival after recurrence was only 13.97 months (IQR 7.03, 24.67), which was consistent with the results of Koizumi W and colleague (13.0 months) [28]. And early recurrence patients had worse survival after recurrence than late recurrence patients (13.50 vs. 16.30 months, p = 0.023), which did not show in American analysis [3].
In this study, Chinese patients had more multiple pattern recurrence than patients in America and South Korea (42.5 vs. 33.2 vs. 16.3-27.4%) [3,19,29]. It partly reflected the lack of regular postoperative follow-up in China. A large part of recurrence was early recurrence and 5-year DFS was only 5.2%. So, that receiving operative examination every 3 months within 2 years and every 6 months within 5 years after surgery were recommended [30,31], especially for patients with such risk factors.
There were also several limitations in this study. At first, as the patients undergoing surgery in more than 100 hospitals in China, selection bias was unavoidable. Nevertheless, in China, it was general for patients receiving radical resection and adjuvant treatment in different hospitals. Secondly, several other factors previously reported as associated with the recurrence, such as tumor size, vascular tumor thrombus, and Lauren classification did not include this study. Thirdly, the relationship of D2 lymphadenectomy and lymph nodes harvest ≧15 to recurrence were different, which associated with long time span of surgery and loss of detail surgical records. And then, in this study, we only found had no more than 3 cycles of adjuvant chemotherapy could reduce the recurrence, with statistical significance. More cycles of adjuvant chemotherapy also potential to reduce recurrence. It might associate with different chemotherapy regimens and bias in retrospective study. However, we could not find the association between neo-adjuvant chemotherapy, adjuvant chemotherapy regimens, and recurrence. And although we found that adjuvant radiotherapy could reduce postoperative recurrence and distant metastasis, the results were lower reliability because of small samples. Last but not the least, some patients were lost during follow-up, without information on recurrence or death. All these issues might have led to potential bias in the analysis of recurrence patterns and timing after curative gastric cancer resection.

Conclusions
In brief, this multiple-center retrospective analysis noted that postoperative recurrence of gastric cancer was common, especially early recurrence. Advanced tumor stage and large tumor burden contributed to increased recurrence risk and worse survival. Enough lymph nodes harvest and standard D2 lymphadenectomy could reduce the postoperative recurrence. Patients might benefit from adjuvant chemotherapy and radiotherapy in China.