Although the incidence of gastric cancer was gradually decreased year by year, gastric cancer is still the third leading cause of cancer-related deaths all over the world because of poor biological behavior. Node-negative GC patients carry a significantly better prognosis than node-positive GC. However, a subset of these patients eventually died due to recurrence. Chou et al. reported the cumulative RFS rate and OS rate were 83.2% and 84.3%, respectively, in node-negative AGC patients underwent gastrectomy (R0) at five-year. Correspondingly, Zhao et al. investigated the cumulative RFS rate and OS rate were 71.1% and 63.5%, respectively. In the present study, With the median follow-up period of 57.5 months, 47 (15.3%) of 307 patients had tumor recurrences. The entire 307 patients with node-negative AGC who underwent D2 lymphadenectomy with the cumulative RFS rate and OS rate were 84.9% and 77.2% at five-year, respectively. In consideration of the high recurrence rate for node-negative AGC and the situation that these patients lacking independent prognosis factors except for the depth of invasion, it is necessary to find predictive outcome indicators that may complement TNM staging system and guide clinicians not only to choose appropriate postoperative treatment strategy but also to construct individual follow-up schedule to improve prognosis of GC[6, 16].
In this study, we excluded patients with T1 and T4b stage, on account of early gastric cancer (T1N0) associated with favorable prognosis who had low lymph node metastatic rate. On the contrary, T4b patients who had lower 5-year survival rate usually received postoperative chemotherapy by reason of the malignant biological behavior of gastric cancer. To some extent, it can reduce their confounding effect in the research.
Implementing appropriate adjuvant therapy is vital for gastric cancer patients after complete tumor resection to prevent recurrence and improve overall survival. Sasako et al. reported the adjuvant chemotherapy of S-1 can prolong curatively resected GC patients’ overall survival. Combination of fluoropyrimidines and platinum is remaining the first line treatment of AGC. Sakamoto et al. put forward capecitabine plus cisplatin were effective to patients with early relapse. The 1-year RFS rates of stage II patients (n = 41) and stage III patients (n = 59) were 87% and 84% respectively found in JCLASSIC-PII. In conclusion, capecitabine plus oxaliplatin was beneficial following resection of GC in Japanese patients. However, we didn’t find that a statistically significant association between improved prognosis and postoperative chemotherapy. Although 230 patients (74.9%) were received chemotherapy, only 148 patients (64.3%) patients finished > 80% of the scheduled cycles, the other patients owing to the side effects of the chemotherapy and economic reasons didn’t receive chemotherapy or complete it, which might affect the conflicting results.
Of note, different patterns of recurrence correspond to different postoperative adjuvant therapy regimens. Hence, it is significant to predict the recurrence pattern to scheme personalized therapy. Previously, Huang et al. reviewed the medical records of 317 node-negative GC patients and the results showed that 51 patients had recurred, the population patients with locoregional recurrence, peritoneal seeding accounted for 51.0% separately and 21 (41.1%) patients had hematogenous metastasis. Chou et al. indicated that the main pattern of recurrence in node-negative patients was locoregional disease. This study is not in accordance with previous results that the main pattern were locoregional (n = 28, 48.9%) and hematogenous (n = 28, 48.9%) recurrence. This difference might be out of with/without receiving chemotherapy after surgery, regional difference and the variability of tumor biology. Tumor size, the depth of tumor invasion (T stage), Lauren type and the presence of lymphatic vessel invasion have been identified as risk factors for recurrence in this series. Furthermore, we demonstrated that tumor size, T stage and histological differentiation were significant risk indicators for locoregional recurrence in node-negative GAC. T stage, tumor differentiation, Lauren type and lymphatic vessel invasion were associated with higher risks of peritoneal seeding. Of these factors, the depth of tumor invasion and the presence of lymphatic vessel invasion were relevant to hematogenous spread. Actually, in regard to the predictors of recurrence patterns in GC have been explored previously, but few in node-negative[23–25]. Interestingly, pT stage had been confirmed as a risk predictor in any of recurrence patterns in relevant research fields[26, 27]. The depth of tumor invasion was also the most unanimous significant prognostic parameter of node-negative GC patients, which was consistent with the multivariate analysis (P = 0.007) of independent factors related to OS in this study. In the aspect of tumor size, it is no consistency for the prognostic significance in node-negative AGC, unlike breast and lung cancer[28, 29]. Chou et al. demonstrated that bigger tumor was correlated with hematogenous metastasis, but we only observed tumor size was related to Locoregional recurrence. The discrepancy may be explained by enrolling T4b patients who had dismal prognosis in their research that was not included ours. Although several studies found tumor size increased the hazard for recurrence and survival in advanced node-negative GC underwent R0 resection, this result was not repeated in other researches[30–32]. Univariate analysis revealed tumor size was significantly associated with 5-year OS (P = 0.045) in our series but it lost any significance in the multivariate analysis with the Cox proportional hazards model (P = 0.082). In terms of the presence of lymphatic vessel invasion, it was a predictive marker both for peritoneal seeding and hematogenous spread. On the other hand, it was an important poor prognostic indicator to shorten the time of OS. Noteworthily, The above results of lymphatic vessel invasion were consistent with this study. Zhao et al. hypothesized lymphatic vessel invasion was the startup phase based on it was associated with lymph node micrometastasis. Unfortunately, we have not observed it had prognostic value in recurrence-free survival.
In general, the combined use of the pathological cancer markers, has more complex and more heterogeneous, might has more advantages than that of single markers for GC patients in the prognostic value. p53 is a tumor-suppressor gene that located on chromosome 17p and encoded a 53-kDa protein. The p53 gene plays an important role in the cell cycle by G1 arrest checkpoint cell cycle to modulate cell proliferation and suppress the development of tumor. However, during the development of GC, the functions of p53 protein are often blocked because it has undergone mutation. Compare to normal p53 protein, mutated p53 protein prolong its half-life on account of changing configuration and increasing stability. Therefore, it can be detected by immunohistochemical staining. Several studies have reported that overexpression of p53 were independent risk factors for EGC patients[35, 36]. Ki67 is a nuclear proliferation-associated antigen, which encodes two protein isoforms with molecular weights of 345 and 395 kDa. In addition, it is universally expressed throughout the cell cycle in proliferating (late G1, S, G2 and M-phases), but is absent in quiescent cells. The prognostic value of pKi67 has been investigated as a reliable marker having been shown in several types of cancer, such as colorectal and breast cancer, according to activating the trigger of downregulation for the gene of apoptosis[38, 39]. Whereas, some analyses found the expression of Ki67 was correlated with survival in gastric cancer, others found no significant difference between Ki67 expression and oncological outcomes[40, 41]. In a word, p53 and Ki67 are important biomarkers for cancer progression. However, little research reported on whether the combination of p53 and Ki67 is an independent prognosis factor in node-negative AGC after D2 curative resection. The whole patients were divided into 3 groups: Group1 (negative for both Ki67 and P53), Group2 (positive for either biomarker), Group3 (positive for both biomarkers). We found Group3 was a significant prognostic parameter in terms of RFS and OS compared with Group1, P = 0.002 and P = 0.030 respectively. Meanwhile, Group 3 had shorter recurrence-free survival compared with Group1 and Group2 in the multivariate analysis with the Cox proportional hazards model (P = 0.037), but do not find the significant difference between Group 3 and OS.
Several limitations of the present study should be acknowledged. Firstly, on account of the retrospective nature of this study, all the result may be influenced. Secondly, it was single institutional research with the limitation of the number of patients. On the side, our observations are necessary to be confirmed by more large-scale prospective studies with more longer follow-up time.