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

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 radio-chemotherapy [3‐5]. 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 [6‐9]. Moreover, recurrence timing could provide information of postoperative follow-up, in order to find recurrence timely. In China, several small sample single-center studies had reported the recurrence patterns and relative risk factors [10‐12], 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 multiple-center 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.

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 [10‐12], 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.

As this analysis noted, 60.8% patients experienced recurrence after curative resection for gastric cancer, which was similar with previous results [10, 12, 15]. The incidence of distant metastasis was comparably high (30–45%) all over the world [3, 5, 7, 8, 10‐12, 17, 18]. Patients in Japan and South Korea suffered lower local-regional recurrence compared with China (7-10 vs. 32.4%) [7‐9]. But American patients suffered higher local-regional recurrence in contrast with the Chinese (44.1 vs. 32.4%) [3]. However, peritoneum implanting in China was obviously lower than in Japan, South Korea, and USA (13.7 vs. 30–45.9%) [3, 7, 8, 18, 19]. It might associate with less sensitive imaging examination (even MRI/CT with only 56% sensitivity for peritoneum implanting) [20], less laparoscopic exploration, and cytological examination of peritoneal lavage fluid. The actual incidence of peritoneum implanting would be higher in China.

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 lymphadenectomy ratio in general hospital. Although the time span of this study was as long as 27 years and D2 lymphadenectomy was just generalized in the past 15 years, specialist hospitals had higher lymph nodes harvest ≧15 rate D2 lymphadenectomy rate at every period (from Jan. 1986 to Dec. 1999, 40.7 and 34.0% vs. 19.5 and 13.3%; from Jan. 2000 to Dec. 2006, 69.0 and 58.1% vs. 33.2 and 29.9%; from Jan. 2007 to Sept. 2013, 77.3 and 73.6% vs. 59.1 and 57.4%). It might relate to less volume of curative gastric cancer resection in general hospitals [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.

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.