Patients with gastric cancer (GC) and patients with locally advanced and node-positive disease can benefit from adjuvant therapy following resection (1). At present, adjuvant treatment recommendations are made in light of risk stratification guidelines based upon the American Joint Committee on Cancer (AJCC) staging classification system (2). The eighth revision of the AJCC staging system in 2017 reclassified tumors that invade the subserosa as T3 disease, whereas these tumors were previously classified as stage T2b disease (2). To date, the majority of randomized trials conducted to evaluate the value of adjuvant therapy in patients with GC have been focused on patients with stage II/III disease (3,4). To the best of our knowledge, no randomized trials have specifically assessed whether adjuvant therapy offers survival benefits to those with stage T2N0 disease. Thus, the appropriate adjuvant therapy of choice for the treatment of these patients remains a matter of controversy. The Japanese gastric cancer treatment guidelines (JGCG) do not recommend adjuvant therapy for those with stage IB (T1N1 and T2N0) GC (5), whereas the European Society of Medical Oncology (ESMO) guidelines recommend postoperative adjuvant chemotherapy or chemoradiotherapy for those with stage IB GC (6). The National Comprehensive Cancer Network (NCCN) (7) and the Chinese Society of Clinical Oncology (CSCO) (8) have also provided recommendations regarding the administration of adjuvant chemotherapy only to patients exhibiting specific findings associated with high-risk disease, such as younger age (≤50 or ≤40 years, respectively), poorly differentiated/high grade cancer, lymphovascular invasion, neural invasion or <D2 lymph node dissection. These inconsistencies have been further complicated by nation-to-nation differences in lymph node dissection strategies. Currently, adjuvant therapy is not thought to be appropriate for all patients with stage T2N0 GC following radical tumor resection; instead, this treatment is only administered to those with high-risk disease (9). In the present review, the features of stage T2N0 disease that may assist with the identification of patients who are most likely to benefit from the application of adjuvant chemotherapy were discussed.

In the North American Intergroup-0116 trial, a total of 556 patients with resected adenocarcinoma of the stomach or gastroesophageal junction were evaluated as a single cohort of individuals with stage IB or higher resectable GC. In the trial, a 10-year follow-up confirmed that postoperative chemoradiotherapy was associated with sustained and robust benefits in overall survival time (9,10). As a result, adjuvant chemoradiotherapy is the standard regimen used to treat patients with GC, who have undergone curative surgical resection and have stage T3 or higher disease and/or positive nodal disease in the USA. The patients classified with stage T2a/bN0 disease according to the sixth edition AJCC staging criteria (11) were reclassified with stage T2N0 (stage IB) or stage T3N0 (stage IIA) disease using the 8th edition revision of this staging system (2). A retrospective examination suggested that very few patients who met the revised criteria for stage T2N0 GC were included in the North American Intergroup-0116 trial, and these results cannot be interpreted as demonstrating the benefits of chemotherapy in patients with T2N0 disease. Only 10% of patients had undergone formal D2 dissection in the trial, while 90% had undergone D0 or D1 lymph node dissection (10). Therefore, the trial lacked the power to reliably determine whether postoperative chemoradiotherapy was beneficial to patients with D2 lymph node dissection.

The adjuvant chemoradiation therapy in stomach cancer (ARTIST) trial analyzed 458 patients with GC, higher than stage IB (excluding those with T2aN0 disease) who had undergone D2 lymph node dissection (12). Patients in this trial were randomized into chemotherapy and chemoradiotherapy groups. No differences in disease-free survival (DFS) or overall survival (OS) times were detected between these two groups upon 3 and 7-year follow-up (12,13). In light of these results, the ESMO guidelines suggested that postoperative chemoradiotherapy was not necessary for patients with stage IB or higher GC following appropriate surgical resection, including D2 lymph node dissection (6). A subgroup-based analysis of the trial results suggested that adjuvant chemoradiotherapy similarly afforded no notable benefits relative to adjuvant chemotherapy alone in patients with stage IB disease (14). This analysis did not include patients with stage T2N0 (muscularis propria) disease; therefore, we hypothesized that these patients would similarly not benefit from postoperative radiotherapy, as this stage of the disease was even earlier compared with those included in the ARTIST trial. A retrospective analysis also suggested that patients with stage III/IV GC would benefit from radiotherapy, whereas patients with stage IB and II tumors would not (15). Therefore, chemoradiotherapy would not be required for all patients with T2N0 GC following D2 gastrectomy.

The adjuvant chemotherapy trial of TS-1 for gastric cancer (ACTS-GC) incorporated 1,059 patients who were randomly assigned to either undergo surgery only or with S-1 adjuvant chemotherapy (3). The patients included in the study had histologically-confirmed stage II (excluding T1), IIIA, or IIIB GC (defined based on the 13th edition of JCGC criteria) (16) and had undergone R0 gastrectomy with extended D2 lymphadenectomy. Postoperative S-1 adjuvant chemotherapy could improve OS and relapse-free survival (RFS) times in individuals with stage II/III GC who had undergone D2 gastrectomy (3,17). This phase III trial was the first to conclusively demonstrate that adjuvant chemotherapy was an effective means of treating GC, following D2 gastrectomy. The capecitabine and oxaliplatin adjuvant study in stomach cancer (CLASSIC) trial was designed in an effort to assess the DFS benefits of capecitabine and oxaliplatin-based adjuvant chemotherapy following D2 gastrectomy in patients with GC (4). This trial enrolled patients with histologically-confirmed stage II (T2N1, T1N2 and T3N0), IIIA (T3N1, T2N2 and T4N0), or IIIB (T3N2) gastric adenocarcinoma (based on the 6th edition AJCC staging system). The results of the CLASSIC trial demonstrated that postoperative capecitabine and oxaliplatin treatment improved OS and DFS times compared with that in surgery alone in patients with advanced GC (4,18).

The Global Advanced/Adjuvant Stomach Tumor Research International Collaboration group performed a meta-analysis of the findings from 17 trials based on individual patient data and determined that adjuvant chemotherapy was associated with significant improvements in OS [hazard ratio (HR), 0.82; P<0.001] and DFS times (HR, 0.82; P<0.001) compared with that in surgery alone (19). However, the vast majority of the data in the study was focused on patients with stage II/III disease. Therefore, there were too few patients with T2N0 GC included in the trials to conduct a conclusive assessment of the relative benefits of adjuvant chemotherapy in these patients. The CLASSIC and ACTS-GC trials did not include patients with stage T2N0 GC, according to 8th edition of the AJCC criteria. At present, to the best of our knowledge, no randomized prospective clinical trials have specifically evaluated the relative benefits of adjuvant chemotherapy in patients with stage T2N0 GC.

A retrospective analysis of 2,229 patients with (stage I–IV) in the 2001–2008 California Cancer Registry determined that 29% of these patients exhibited N0 disease, while 70% exhibited T1-T2 tumors (20). Multivariate analyses indicated that surgery alone was associated with improved survival outcomes compared with that in adjuvant therapy in this study cohort; therefore, adjuvant therapy was not beneficial to patients with stage IB disease. A separate evaluation of the Surveillance Epidemiology of End Results (SEER) database similarly examined adjuvant therapy-related outcomes in patients with stage IB GC from 1988 to 2008 (21). The analysis suggested that survival rates were highest among patients with stage IB GC, who had received chemoradiotherapy compared with that in patients receiving surgery alone, when patients with stage IA disease were omitted. Therefore, these results supported adjuvant therapy administration to patients with stage IB GC (21). Another retrospective assessment of 23,461 patients with stage IB-II GC in the National Cancer Database (1998–2011) revealed that the risk-adjusted mortality rates among patients with stage IB GC were notably higher when patients did not undergo adjuvant therapy, although no OS benefit to adjuvant chemoradiotherapy was detected when adequate lymph node dissection was conducted in patients with node-negative disease (22). These findings suggested that the benefit of adjuvant therapy for patients with stage T2N0 GC, following adequate lymphadenectomy remains uncertain. These retrospective studies also have numerous limitations, including the fact that they included patients that would now be classified with T1N1 or T3N0 stage disease based on the current AJCC staging system (2). Further randomized trials would be important to adequately evaluate the benefits of adjuvant therapy in patients with stage T2N0 GC. These patients typically have a favorable prognosis; however, several retrospective studies suggested that specific subgroups of high-risk patients with T2N0 GC had poorer prognosis (7,8,23–25). Therefore, prognostic markers should be identified to assist with identifying which patients with stage T2N0 GC would benefit from adjuvant chemotherapy.

According to the ESMO guidelines, postoperative adjuvant chemotherapy is recommended in patients with T2N0 disease, that have undergone surgery without administration of preoperative chemotherapy (6). However, under the JGCG guidelines, these patients are recommended to only undergo observation without adjuvant treatment following curative surgical resection (5). In addition, the NCCN and CSCO have published guidelines describing these high-risk characteristics; adjuvant chemotherapy may reduce the risk of metastasis in the following groups of patients with T2N0: Younger age (≤40 or ≤50), poorly differentiated/higher grade cancer, lymphovascular invasion, neural invasion or < D2 lymph node dissection (3,4).

At present, no prospective randomized trials have firmly established whether adjuvant chemotherapy provides any survival benefit to patients with stage T2N0 GC. Typically, the addition of radiotherapy, as an adjuvant chemotherapy regimen is unnecessary in such patients following D2 gastrectomy. Retrospective analyses have found that adjuvant chemotherapy would not be appropriate for all patients with T2N0 GC and should instead be restricted to high-risk patients (23–25). However, these prior trials were sub-optimally designed. At the Affiliated Kunshan Hospital to Jiangsu University, evidence-based guidelines established in light of the NCCN and CSCO recommendations would be followed and patients would be encouraged to participate in clinical trials as appropriate. Future guidelines have the potential to refine current clinical guidance for the treatment of patients with stage T2N0 GC by incorporating additional markers and prospective studies.