Several bodies of evidence both from the West and the East currently recommend that some form of adjuvant therapy should be delivered in addition to surgery in patients with potentially curable advanced gastric cancer. Progress in surgical technique to dissect cancer with wide resection margin may have reached a plateau,¹ and development of perioperative adjuvant therapy is the only way to improve the outcome. This chapter describes the history and recent advances in the multimodality treatment in the Far East where the incidence of this disease remains high.

Rationale and Brief History

Surgeons are capable of removing macroscopic disease by gastrectomy, and could additionally remove occult microscopic lymphatic spread through en bloc nodal dissection. However, cancer cells that entered the blood stream or were exfoliated from the serosal surface and shed into the peritoneal cavity could develop into recurrences. It is well documented that micrometastases are more vulnerable to chemotherapy than gross metastases, and adjuvant therapy after surgical resection could theoretically be recommended. Administration of intravenous mitomycin and/or oral fluoropyrimidines became the community standard in Japan after the positive result of a phase III trial with surgery alone as a control.² However, the study, conducted between 1964 and 1973, was found later to be of insufficient quality to merit universal recognition. Since the late 1980s, therefore, several randomized trials comparing adjuvant chemotherapy with surgery alone were conducted by the Japan Clinical Oncology Group (JCOG), a study group funded by the Japanese government, which consistently failed to prove a survival benefit. A history before the current standard of care was established has been summarized in Table 99-1. Some trials failed due to inclusion criteria by which only patients with relatively early-stage cancer were deemed eligible.^3,4 One of these trials was criticized as underpowered because it failed to detect marginal benefit that might have existed.⁴ Another trial explored a treatment that was eventually found to be unsuitable both in terms of efficacy and feasibility.⁵ The final attempt during this era was a pivotal phase III trial exploring high-dose UFT (360 mg/m²/day) for 16 months among patients with node-positive pT2~3 cancer.⁶ Unfortunately, the accrual for this study was extremely poor due to rarity of the disease that fell into these disease categories and small number of institutions that were invited to participate, and the trial had to be stopped well before the planned number of patients was enrolled.

A phase II trial exploring S-1 (1 M tegafur-0.4 M gimestat-1 M otastat potassium), a novel oral fluoropyrimidine, at a dose of 40 mg/m² twice daily for 4 weeks with 2 weeks of rest resulted in a response rate of 49%.⁷ This drug was also found to be relatively safe and tolerable in the postoperative adjuvant setting by a prospective feasibility study.⁸ These encouraging results prompted researchers to abandon the aforementioned UFT trial⁶ and turn to S-1 for a new trial.

In this trial, patients with stage II and III gastric cancer as defined by the second edition of the Japanese Classification of Gastric Carcinoma (almost similar population with the stage II/III cancer by the TNM Classification, 6th ed.) who underwent R0 resection by D2 dissection were randomized to be treated either by S-1 for 12 months or surgery alone. The primary endpoint was overall survival, and accrual of 1000 patients was required to show a hazard ratio for death of 0.70 in the S-1 group. Between 2001 and 2004, 1059 patients were accrued and superiority of the S-1 group was proven at the first interim analysis.⁹ Final analysis at 5 years confirmed significant survival benefit, with >10% difference in the 5-year survival rate and a hazard ratio for death of 0.669 (95% confidence interval [CI], 0.540 to 0.828%)¹⁰ despite the fact that the treatment was tolerated for 12 months in only 66% of patients. Most frequent grade 3 or 4 adverse events were anorexia, nausea, and diarrhea. Due to polymorphic differences in the CYP2A6 gene, S-1 at the same dosage causes severe diarrhea and is not tolerated by the Caucasians. At a reduced dose of 50 mg/m²/day, the S-1/CDDP combination has shown more favorable safety profile in a randomized comparison with the conventional combination of CDDP and infusional 5-FU in the advanced/metastatic setting while survival was apparently noninferior.¹¹ However, the safety and efficacy of S-1 in the adjuvant setting among non-Asian patients, either alone or in combination, remain unknown.

A research group consisting of 37 centers from South Korea, China, and Taiwan conducted the CLASSIC trial, another postoperative adjuvant chemotherapy trial in which XELOX regimen, a combination of oral capecitabine (1000 mg/m² twice daily for 14 days, with 7 days of rest) and intravenous oxaliplatin (130 mg/m² on day one of each cycle), was compared with a surgery alone arm.¹² Patients with stage II and III gastric cancer as defined by the TNM classification 6th ed. were eligible and 1035 patients were registered. Significant difference in 3-year disease-free survival, the primary endpoint, was observed at the first interim analysis (hazard ratio 0.56; 95% CI, 0.44 to 0.72, P<0.0001). After further follow-up, the overall survival at 5 years was also reported to be significantly in favor of the XELOX arm.¹³ Most common adverse events were nausea, neutropenia, and loss of appetite, and grade 3 or 4 adverse events were reported in 56% of the chemotherapy group. Compliance to the treatment (67% tolerated the planned eight cycles of XELOX) was as good as that for the single agent S-1 in the ACTS-GC trial, but this needs to be interpreted with caution since the median age of patients who were treated with XELOX was 56 years old as opposed to 63 years old in the ACTS-GC trial (Table 99-2). However, tolerability of the XELOX regimen among Japanese patients in terms of relative drug intensities of the two drugs was considered satisfactory in an age-adjusted analysis of a feasibility study, and the regimen was eventually approved in Japan.

In both of these studies, stage II and III gastric cancer of Asian patients treated by D2 dissection benefitted significantly from postoperative chemotherapy. However, analyses of the pattern of recurrence have shown contrasting results in that S-1 is more effective in preventing peritoneal disease while XELOX effectively suppressed the incidence of distant hematogenic metastases. Thus, either of the two regimens could in future be selected considering the biology of the cancer.

In the ACTS-GC trial, the risk ratio increased substantially in a step-by-step fashion as the disease progressed from stage II to stage IIIB (Table 99-2), and there is room for improvements in the adjuvant therapy against stage III cancer. One way to move forward in Japan could be to explore the S-1/CDDP combination, which was found to be superior to S-1 in the advanced/metastatic setting.¹⁴ Use of CDDP at a dose of 60 mg/m² requires hydration to prevent renal toxicity, which is usually accomplished by an admission overnight even among physically fit patients. This combination results in gastrointestinal and bone marrow toxicities and was found to be too toxic for use in patients who have lost their appetite due to gastrectomy and are still recovering from the surgical stress. A prospective feasibility study reported that only 30% of the planned doses were administered in an attempt to deliver five courses of S-1/CDDP postoperatively.¹⁵ The compliance was substantially improved when the treatment was handled exclusively by expert medical oncologists in another feasibility study. In this study, S-1 was given as a single agent in the first course, and CDDP was coadministered only in the subsequent three courses. A promising 3-year recurrence-free survival rate of 74% was reported for 63 Stage III patients in this particular feasibility study.¹⁶

More recently, however, XELOX, another combination of oral fluoropyrimidine and platinum explored in the CLASSIC trial, was also shown to have a higher risk ratio among Stage III cancer (Table 99-2).¹³ From this view point, there is little reason to assume that the S-1/CDDP combination given postoperatively would result in better outcomes compared with S-1 monotherapy. A randomized comparison between postoperative S-1 and postoperative S-1/docetaxel,¹⁷ a marginally less effective but less toxic combination than S-1/CDDP, is currently ongoing in Japan by another study group as a final and desperate attempt to establish a novel postoperative adjuvant therapy for Stage III cancer. Meanwhile, JCOG decided to change the strategy and turn to neoadjuvant chemotherapy for clinically Stage III gastric cancer. The details of the new study will be discussed later in this chapter. Sufficient diagnostic accuracy is crucial so as to avoid unnecessary use of toxic agents for patients with stage I disease, and this issue is currently being addressed in a preparatory prospective study to confirm the diagnostic accuracy of modern endoscopic and imaging modalities for preoperative staging of gastric cancer.

Duration of adjuvant chemotherapy is an intriguing issue, because there is no way of knowing the optimal length of treatment or dose intensity which is sufficient to eliminate micrometastases, the potential targets of postoperative adjuvant chemotherapy. Evidence-based postoperative adjuvant therapies for several types of cancer are delivered over 6 months, including the XELOX regimen explored in the Korean CLASSIC trial. The Japanese have historically used postoperative chemotherapies that are continued for more than 12 months.^3–6 Although the duration of adjuvant S-1 proposed in the ACTS-GC trial eventually settled at 12 months (eight courses) of treatment, it is still longer than other globally accepted regimens. The excellent outcome of the Stage II subset prompted the JCOG investigators to launch a phase III trial to prove non-inferiority of the 6 months (four courses) of postoperative treatment with S-1 to 12 months (eight courses). The primary endpoint is relapse-free survival, and enrollment of 1,000 patients is need.