In the current study, we developed and externally validated a nomogram to predict 3- and 5-year OS for primary GC patients after surgical resection. We identified age, race, location, tumor size, T stage, N stage, M stage, and chemotherapy as independent prognostic factors, among which the number of metastatic LNs held the most weight. Compared with the 8th AJCC TNM classification, our nomogram performed better in both the training and external validation sets. To some extent, the 8th AJCC staging system did not perform poorly. Nevertheless, our nomogram can predict individualized survival probability more precisely.
Some nomograms classified GC location into the upper, middle, and lower third [8, 15]. In this study, we divided all GC types into cardia and non-cardia (the survival curves of the middle third and lower third were similar in our cohort; data not shown). As a result, we found that cardia GC had a worse prognosis than non-cardia GC (P<0.001). Our finding is consistent with a systematic review that found patients with upper third GC had significantly increased all-cause mortality [19]. When the gastroesophageal junction (GEJ) was removed, the prognosis of pure cardia GC was even worse. Our data also show that sex was not an independent prognostic factor, which is inconsistent with previous findings [8, 10, 14, 15, 20]. Although males and females differ in terms of incidence rate, their prognoses appear to be similar.
Previously, Kim et al. found that age had nonlinear effects on HR [10]. Another study also found that patients older than 70 years had the lowest 5-year OS compared with younger and middle-aged patients [21]. Their results are consistent with our analysis using X-tile software, so we chose to convert age into a categorical variable at 70. Although grade is closely associated with malignant behavior and distant metastasis, it does not seem to be an independent factor affecting prognosis in our study. Therefore, when we performed multivariate analysis, the P value became insignificant.
Another discrepancy in this study pertains to chemotherapy. Recent studies have proven that adjuvant chemotherapy after surgery could benefit patients in terms of survival probability [22]. A meta-analysis showed that compared with surgery alone, fluorouracil-based postoperative adjuvant chemotherapy significantly reduced the mortality of GC patients [23]. Another phase III randomized controlled trial (RCT) revealed that chemotherapy using capecitabine plus oxaliplatin for half a year after D2 gastrectomy improved the 3-year disease-free survival of GC compared with surgery alone (74% vs 59%, HR: 0.56, P<0.001) [24]. The results of our multivariate analysis further demonstrated that chemotherapy acted as a protective factor against poor outcomes (Figure 3). We believe its failure to show statistical significance in the univariate analysis was largely due to some confounding factors. To the best of our knowledge, we are the first to finally include chemotherapy in the nomogram construction of GC.
Similar to most previous studies, we excluded patients with fewer than 16 examined LNs [8]. This helps to ensure surgical quality and prevent the stage migration effect [8, 25]. In our study, the median examined LN numbers were 23 and 24 in the training and validation sets, respectively.
Quite a few studies have used a randomly assigned (data-splitting) method to create a validation set [8, 16, 17]. However, this method theoretically is more of internal validation and will lead to sample wasting as well as insufficient power for evaluation. In contrast, our external validation set was established according to year at diagnosis (training set, 2004-2012; validation set, 2013-2016). In the calibration plot, the predicted survival corresponded closely with the actual 3- and 5-year OS (Figure 6).
Notably, 655 patients had distant metastasis (M1) but underwent surgery. Among them, 58.6% (384/655) received chemotherapy, and 15.1% (99/655) received radiotherapy. A growing number of studies have shown that patients with unresectable stage IV GC can achieve good survival outcomes if they undergo radical gastrectomy after responding to several combined chemotherapy regimens [26]. This novel strategy is called conversion surgery, a treatment approach in which initially unresectable tumors become curable after chemotherapy response. If R0 resection is achieved, conversion surgery can significantly improve the patient survival rate [26]. We thus did not exclude such patients and hope that our nomogram can be used with these patients to predict OS after surgery. Nevertheless, this concept is still controversial, and current cancer guidelines do not recommend surgery for stage IV patients.
Regarding the surgical approach, one study revealed that distal gastrectomy had comparable long-term survival to total gastrectomy for middle and lower third GC when R0 resection was achieved [27]. Apart from conventional open surgery, laparoscopic gastrectomy has also been performed in recent years [28]. RCTs comparing laparoscopic with open distal gastrectomy showed that the former had noninferior 3-year survival in both early and advanced GC [29, 30]. For early gastric cancer (EGC), endoscopic treatments such as endoscopic submucosal dissection (ESD) are becoming increasingly popular, with advantages of minimized invasion and low postoperative complications [31]. Researchers in Japan analyzed 1956 patients with EGC undergoing curative ESD and found that the 5-year OS rate was 92.6% [31]. Another study predicting the risk of lymph node metastasis (LNM) in EGC after radical ESD suggested that a predicted risk of less than 3% may avoid subsequent gastrectomy, which could ultimately improve patient quality of life.
There are some striking strengths in our study. First, we used the SEER database, a standardized and relatively comprehensive database with a large sample size. Data from 2004 were collected, and more than 6000 patients were ultimately included in our study. Second, to the best of our knowledge, we are the first to classify GC according to cardia/non-cardia in a nomogram and found good discrimination in survival outcomes. We are also the first to finally include chemotherapy in the nomogram for GC as an independent prognostic factor. Third, our nomogram is based on the existing 8th AJCC staging system; thus, it is widely available and highly convenient for clinical application. The performance of our nomogram was excellent, with a C-index of 0.748 in the external validation set.
Our study also has some limitations that should be noted. First, patients who did not receive chemotherapy and those with missing information were included in the SEER database, which added difficulty in determining the significance of chemotherapy. However, the actual role of chemotherapy in patient prognosis could be underestimated because of this limitation. Second, we did not further divide T4 and N3 stages in our results because 893 cases had T4 or N3 stage but lacked specific details. This may have sacrificed some precision but simplified the model.