Key points

Introduction

Gastric cancer showed a long-term decreasing trend for both incidence and mortality in Japan, mainly due to decreased incidence of Helicobacter pylori infection and a Westernized diet of less salty food. The Intergroup Study 0116 was one of the earliest positive adjuvant therapy trials in gastric cancer, proving the efficacy of postoperative chemoradiation therapy. Its subgroup analysis, together with a small study comparing D1 versus D2 resection, ended the argument that advanced gastric cancer is already a systemic disease and does not benefit from adjuvant therapy. Now it is widely accepted that a good local control is essential to cure gastric cancer. In the guidelines of the Japan Gastric Cancer Association (JGCA), standard surgery for resectable gastric cancer is defined as resection of at least two-thirds of the stomach with a D2 lymph node dissection. Thus, a high degree of local control is achieved by surgery in East Asian countries. After D2 surgery, the 5-year survival rates for pathologic stage IA and stage IB according to the JGCA classification (13th edition) were 92.3% and 84.7%, respectively. Contrary to these high survival rates, those for pathologic stages II, IIIA, and IIIB were not adequate—72.1%, 52.8%, and 31.0%, respectively. Thus, patients with stages II–III gastric cancer often have recurrence even after curative surgery, which indicates additional treatment is warranted to improve the prognosis of these patients. This review outlines the Eastern perspective on the surgical and adjuvant management of gastric cancer.

Introduction

Gastric cancer showed a long-term decreasing trend for both incidence and mortality in Japan, mainly due to decreased incidence of Helicobacter pylori infection and a Westernized diet of less salty food. The Intergroup Study 0116 was one of the earliest positive adjuvant therapy trials in gastric cancer, proving the efficacy of postoperative chemoradiation therapy. Its subgroup analysis, together with a small study comparing D1 versus D2 resection, ended the argument that advanced gastric cancer is already a systemic disease and does not benefit from adjuvant therapy. Now it is widely accepted that a good local control is essential to cure gastric cancer. In the guidelines of the Japan Gastric Cancer Association (JGCA), standard surgery for resectable gastric cancer is defined as resection of at least two-thirds of the stomach with a D2 lymph node dissection. Thus, a high degree of local control is achieved by surgery in East Asian countries. After D2 surgery, the 5-year survival rates for pathologic stage IA and stage IB according to the JGCA classification (13th edition) were 92.3% and 84.7%, respectively. Contrary to these high survival rates, those for pathologic stages II, IIIA, and IIIB were not adequate—72.1%, 52.8%, and 31.0%, respectively. Thus, patients with stages II–III gastric cancer often have recurrence even after curative surgery, which indicates additional treatment is warranted to improve the prognosis of these patients. This review outlines the Eastern perspective on the surgical and adjuvant management of gastric cancer.

Standard surgery for resectable gastric cancer in the East

In Japan, the standard surgery for resectable gastric cancer has been gastrectomy with a D2 lymph node dissection. Although the Dutch randomized controlled trial (RCT) comparing D1 and D2 dissection could not show a significant survival benefit of D2 dissection in the primary analysis, it demonstrated a significant reduction in the locoregional recurrence rate and cancer-related deaths after long-term follow-up. In addition, a Taiwanese RCT demonstrated a significant survival benefit of D2 or more extensive lymph node dissection compared with D1 dissection. These findings led to the recent revision of the European Society for Medical Oncology guidelines for gastric cancer and the National Comprehensive Cancer Network guidelines for gastric cancer, and they now recommend D2 lymph node dissection for resectable gastric cancer similar to the JGCA guidelines. The Japan Clinical Oncology Group (JCOG) conducted a phase III trial (JCOG9501) to investigate the survival benefit of para-aortic nodal dissection (D3 dissection) compared with standard D2 for cT2b-T4 gastric cancer. A total of 523 patients were randomly assigned to either D2 or D3 dissection. D2 plus para-aortic nodal dissection was associated with a longer operation time ( P <.001), greater blood loss ( P <.001), and a significant increase in minor complications ( P <.001). Nevertheless, there was no significant difference in OS and recurrence-free survival (RFS) between the 2 groups. Thus, a clinical benefit of prophylactic para-aortic lymph node dissection for resectable gastric cancer was not shown. Therapeutic para-aortic lymph node dissection for patients with clinically involved para-aortic node metastasis is still considered a recommended surgery in Japan.

In a total gastrectomy with D2 lymph node dissection, the role of splenectomy has been an important topic of debate. A phase III trial (JCOG0110) was conducted to compare D2 with and without splenectomy for proximal gastric cancer that did not invade the greater curvature. The reason for exclusion of tumors invading the great curvature is possible microscopic invasion into the gastrosplenic ligament and 3 times higher incidence of nodal metastasis in the splenic hilum. A total of 505 patients were randomly assigned to either the splenectomy or spleen preservation group. The splenectomy group had higher morbidity ( P <.01) and larger blood loss ( P = .025) than the spleen preserving group. The 5-year OS rates were 75.1% and 76.4% in the splenectomy and spleen preservation groups, respectively, and the noninferiority of spleen preservation was demonstrated ( P = .025). Based on these results, splenectomy should be avoided in total gastrectomy for proximal gastric cancer that does not invade the greater curvature even in Japan.

Evidence for postoperative adjuvant therapy in the East

Postoperative adjuvant therapy aims to eradicate micrometastasis that exists even after surgery. Accurate staging before surgery in gastric cancer is impossible, whereas the postoperative strategy can select only patients who have high risk of recurrence based on an accurate pathologic diagnosis. This, together with a high incidence of early-stage disease, limits the broader application of neoadjuvant treatment in Korea and Japan. On the other hand, the biggest drawback of adjuvant therapy is drug compliance, which is decreased by surgical morbidity and sequelae after gastrectomy, such as body weight loss or malnutrition. Therefore, the development of adjuvant therapy needs both the consideration of the intensity of the regimen required and the ability to achieve drug compliance.

Several RCTs investigating the efficacy and safety of adjuvant chemotherapy for gastric cancer have been conducted in the East since the 1990s ( Table 1 ). In the 1990s, the JCOG9206-1 trial investigated adjuvant chemotherapy using mitomycin, 5-fluorouracil (5-FU), and cytarabine followed by oral 5-FU for 18 months. A total of 252 patients with clinically serosa-negative gastric cancer after curative surgery (except for clinical T1N0 tumor) were randomly assigned to either adjuvant chemotherapy or surgery alone. Although RFS tended to be better in the adjuvant chemotherapy group than the surgery-alone group (5-year RFS rates, 88.8% vs 83.7%, respectively; P = .14), this trial did not show statistical significance due to small sample size. The JCOG9206-2 trial focused on clinically serosa-positive gastric cancer and investigated adjuvant chemotherapy using a combination of intraperitoneal injection of cisplatin soon after abdominal closure, postoperative intravenous injection of cisplatin and 5-FU, and oral administration of uracil-tegafur (UFT) for 12 months. A total of 268 patients were randomly assigned to either adjuvant chemotherapy or surgery alone. Due to the toxicity or progressive disease, 61.5% of the patients in the adjuvant chemotherapy group discontinued the treatment. In results, this study failed to show survival benefit of adjuvant chemotherapy compared with surgery alone (5-year OS rates, 62.0% vs 60.9%, respectively; P = .48).

In 1990s, an RCT (Intergroup Study 0116) was conducted to evaluate the survival benefit of adjuvant chemoradiotherapy using 5-FU plus leucovorin after R0 lymph node dissection in the United States. A total of 556 patients with resected adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to either chemoradiotherapy or surgery alone. Chemoradiotherapy reduced local recurrence by 10%, and the chemoradiotherapy group achieved a significant improvement in OS ( P = .005) if patients underwent D0 or D1 surgery. The clinical benefit of chemoradiotherapy after D2 dissection, however, had not been investigated, so the Adjuvant Chemoradiation Therapy in Stomach Cancer (ARTIST) trial was conducted in a Korean single institution to evaluate the clinical benefit of the addition of radiation therapy to adjuvant chemotherapy after D2 surgery. A total of 458 gastric cancer patients with pathologic stages IB–IV (except for M1 lymph node or distant metastases) were randomized to either the adjuvant chemotherapy group using capecitabine plus cisplatin or the adjuvant chemoradiotherapy group using capecitabine plus cisplatin. The final analysis showed similar disease-free survival (DFS) and OS between the 2 groups ( P = .092 and P = .527, respectively). This trial demonstrated that adjuvant chemoradiotherapy is not effective in the East, where good local control of tumor can be achieved by D2 lymph node dissection.

In the 2000s, more feasible regimens using oral fluoropyrimidines were applied to adjuvant therapy. The National Surgical Adjuvant Study Group for Gastric Cancer (NSAS-GC) trial compared OS between adjuvant chemotherapy using UFT for 16 months and surgery alone for patients with pathologic T2 N1-2 tumor. Because the accrual speed was slower than expected, it was terminated at the time of the registration of 190 patients (38% of the projected sample size). Although 7% of the patients in the adjuvant chemotherapy group experienced recurrence by 16 months, 51% of the patients could complete adjuvant chemotherapy using UFT for 16 months. OS was significantly better in the adjuvant chemotherapy group than the surgery-alone group (5-year OS rates, 86% vs 73%, respectively; P = .017). Although the efficacy of UFT for moderately locally advanced gastric cancer patients was demonstrated in this trial, further confirmatory studies were needed because of the small number of enrolled patients and poor OS of the control arm compared with Japanese standard results in that period.

After the NSAS-GC trial, the Adjuvant Chemotherapy for Gastric Cancer with S-1 (ACTS-GC) trial was conducted to investigate the efficacy and safety of adjuvant chemotherapy using an oral fluoropyrimidine agent that combines tegafur, gimeracil, and oteracil (S-1). A total of 1059 patients with pathologic stages II–III gastric cancer (except for pathologic T1 tumor) were randomly assigned to either S-1 for 1 year or surgery alone. On the adjuvant chemotherapy arm, 65.8% of the patients completed S-1 for 1 year. In the interim analysis, OS was significantly better in the adjuvant chemotherapy group than the surgery-alone group (3-year OS rates, 80.1% vs 70.1%, respectively; P = .003). The survival difference was maintained after long-term follow-up period (5-year OS rates, 71.7% vs 61.1%, respectively). Based on these results, adjuvant chemotherapy using S-1 for 1 year after D2 dissection was established as the standard treatment of stages II–III gastric cancer patients in Japan.

To develop more effective treatments, the significance of sequential agents was also investigated in a large-scale RCT. The Stomach Cancer Adjuvant Multi-Institutional Group Trial (SAMIT) compared DFS between adjuvant chemotherapy with sequential combination (paclitaxel for 11 weeks followed by UFT or S-1 for 36 weeks) and monotherapy (UFT or S-1 for 48 weeks) for clinically T4a or T4b gastric cancer after D2 dissection. This trial also investigated the noninferiority of UFT compared with S-1 in a 2-by-2 factorial design. A total of 1495 patients were randomly assigned to 1 of 4 treatment groups. Comparing DFS between the sequential group and the monotherapy group, the 3-year DFS rate was 57.2% in the sequential group and 54.0% in the monotherapy group, which did not show statistical significance ( P = .27). In comparison between the UFT group and the S-1 group, DFS was significantly better in the S-1 group than in the UFT group (3-year DFS rates, 58.2% vs 53.0%, respectively; P = .0048). This result demonstrated that adjuvant chemotherapy using sequential agents did not improve DFS and that S-1 was better than UFT as the monotherapy regimen for resectable gastric cancer.

Another large-scale RCT of adjuvant chemotherapy was conducted in East Asia outside Japan. The Capecitabine and Oxaliplatin Adjuvant Study in Gastric Cancer (CLASSIC) trial investigated adjuvant chemotherapy using capecitabine plus oxaliplatin for 6 months. A total of 1035 patients with pathologic stages II–III gastric cancer after D2 dissection were enrolled from Korea, China, and Taiwan and randomly assigned to either adjuvant chemotherapy or surgery alone. On the adjuvant chemotherapy arm, 66.5% of the patients completed the treatment. The interim analysis showed a significant improvement in DFS in the adjuvant chemotherapy group compared with the surgery-alone group (3-year DFS rates, 74% vs 59%, respectively; P <.0001). In the updated results, the OS was also significantly better in the adjuvant chemotherapy group than the surgery-alone group (5-year OS rates, 78% vs 69%, respectively; P = .0029). This result indicated that adjuvant chemotherapy with capecitabine plus oxaliplatin could be one of the standard treatments for stages II–III gastric cancer patients.