Updates in the Management of Gastric Cancer

Prof Yasuhiro Kodera
Prof. Winnie Yeo
Department of Clinical Oncology
Chinese University of Hong Kong
23 Jul 2019
Updates in the Management of Gastric Cancer
Globally, gastric cancer is the third leading cause of cancer death.1 Its primary treatment is gastrectomy with adjuvant chemotherapy or chemoradiotherapy to improve survival. Although neoadjuvant chemotherapy or adjuvant chemoradiation is preferred in Western countries, postoperative adjuvant chemotherapy is still the mainstream therapeutic strategy in Asia.2 At a recent symposium in Hong Kong, experts discussed updates in the treatment and management of gastric cancer, with a focus on the use of S-1 (TS-ONE®; Taiho Pharma Singapore), a combination of tegafur, gimeracil, and oteracil potassium.

Treatment Stratergy of Gastric Cancer
Although early stage, localized gastric cancer may be treated with surgery alone with high survival rates, once tumour cells have spread through the submucosa, survival rates drastically diminish.3 Surgery is able to remove visible cancer and the surrounding lymphatic tissues, but adjuvant therapy is needed to eradicate micrometastases.

Several approaches to adjuvant therapy have been developed in different regions around the world; postoperative chemoradiation therapy in the United States (US), perioperative combination chemotherapy in Europe, and postoperative chemotherapy in Asia.5 The landmark INT-0116 study instituted the use of postoperative chemoradiation in the US.4,5 In Europe, the MAGIC trial established perioperative epirubicin, cisplatin, and 5-FU (ECF) as a standard treatment for resectable gastroesophageal cancer.3,5 Neoadjuvant therapies are also becoming increasingly common in Western countries.6 In contrast, primary surgery followed by adjuvant chemotherapy is the mainstream strategy in Asia. According to Prof Kodera, postoperative chemotherapy is the standard of care in Asia because most patients are diagnosed at an early stage when tumour shrinkage is not required, and D2 lymphadenectomy is usually performed as it gives superior local control.

Capecitabine with oxaliplain
The CLASSIC study, a pivotal Asian Study, randomized 1,035 patients with stage II or III gastric cancer (based on TNM classification and UICC staging) who had undergone curative D2 gastrectomy to either observation or 6 months of capecitabine and oxaliplatin (CapeOX).7 The study recruited patients from South Korea, China and Taiwan. The 3-year disease-free survival was 74 percent in the CapeOX group and 59 percent in the surgery-only group (hazard ratio [HR], 0.56, 95 confidence interval [CI], 0.44–0.72).7 Significant survival advantage was also shown in this trial, with the estimated 5-year overall survival rate of 78 percent in the CapeOX group and 69 percent in the surgery-alone group (HR, 0.66, 95 percent CI, 0.51–0·85; p=0.0015).7

S-1 monotheraphy
The Adjuvant Chemotherapy Trial of S-1 in Gastric Cancer (ACTS-GC) study, another pivotal Japanese trial, randomized 1,059 patients with stage II or III gastric cancer (based on Japanese classification; 75 patients were stage IV patients based on TNM classification) who had undergone curative D2 gastrectomy to either observation or 1-year of S-1.8 The study was terminated at the first interim analysis due to a highly significant difference of survival in favour of chemotherapy.8 The 5-year overall survival (OS) rate was 71.7 percent in the postoperative adjuvant S-1 group and 61.1 percent in the surgery-only group, (HR, 0.67, 95 percent CI, 0.54–0.83).9 The relapse-free survival (RFS) rate at 5 years was 65.4 percent in the adjuvant S-1 group and 53.1 percent in the surgery-only group (HR, 0.65, 95 percent CI, 0.54–0.79).9 The rates of local, lymph node, peritoneal and haematogenous recurrence were lower in the S-1 group than the surgery-only group, with a HR of 0.572, 0.505, 0.687, and 0.784, respectively.9 Subgroup analyses showed that treatment was equally effective regardless of disease stage, sex, age, and histologic type.

The hazard ratio for OS observed with the use of S-1 monotherapy in the ACTS-GC study was similar with that observed in the comparison between CapeOX combination regimen and surgery alone. So far, however, there is no data on direct comparison between S-1 and CapeOX. As a consequence of these results, S-1 alone for 1 year is currently considered as the standard postoperative adjuvant chemotherapy for Stage II/III gastric cancer in Japan and Asian countries, whereas CapeOX for 6 months could also be considered for Stage III disease.

Studies have explored the addition of other chemotherapeutic agents to S-1, such as cisplatin or docetaxel, as postoperative adjuvant therapy for curatively resected gastric cancer.

S-1 with cisplatin
Although the SPIRITS trial showed survival benefits of adding cisplatin to S-1 over S-1 alone in the treatment of unresectable or metastatic gastric cancer,10 a feasibility study (CCOG0703) in the postoperative adjuvant setting showed that the combination of cisplatin and S-1 was not well tolerated, with only seven patients (22 percent) completing all five cycles.11 A subsequent study (CCOG1106) markedly improved the completion rate to 60.6 percent by the insertion of one cycle of S-1 monotherapy, delaying administration of cisplatin by 6 weeks.12 Nevertheless, the expected completion rate of 70 percent was not achieved.12

S-1 with docetaxel
The START trial in advanced metastatic gastric cancer showed that docetaxel plus S-1 significantly improved median OS and median PFS when compared with S-1 alone.13 The combination of docetaxel and S-1 vs S-1 alone in the postoperative adjuvant setting was explored in the JACCRO GC-07 trial.14 Following curative resection by D2 gastrectomy, pStage III gastric cancer patients were randomly assigned to receive either S-1 with docetaxel (S-1/docetaxel) or S-1 alone. At the planned second interim analysis, the independent data and safety monitoring committee recommended termination of the trial because the 3-year RFS of the S-1/docetaxel arm (65.9 percent) was significantly superior to that of the S-1 arm (65.9 percent vs 49.6 percent, HR, 0.632, 99 percent CI, 0.400–0.998; p=0.0007).14 This benefit in 3-year RFS was seen amongst all stage IIIA, IIIB and IIIC subset of patients.15

Importantly, S-1/docetaxel suppressed all types of recurrences, with marked reductions in lymph node (4.8 percent vs 11.3 percent) and haematogenous recurrences (5.3 percent vs 9.8 percent) compared with the S-1 arm. Postoperative S-1/docetaxel was safe and manageable, where more than two-thirds of patients (71 percent) were able to complete the full six cycles of docetaxel.15 Although leukopenia, neutropenia, anorexia, malaise, and alopecia occurred more frequently than in the S-1 arm, similar compliance (49 vs 56 percent) and dose reduction (39 vs 30 percent) rates demonstrated that the addition of a taxane did not interfere with S-1 chemotherapy.15 Owing to these positive results, the study researchers recommend postoperative adjuvant S-1/docetaxel after D2 gastrectomy as a potential new standard of care in patients with pStage III gastric cancer.14

In summary, the preferred treatment strategy for locally advanced gastric cancer is postoperative adjuvant chemotherapy following curative resection in Asia. The current standard of care is S-1 monotherapy for 1 year based on the ACTS-GC trial, although recent data from the JACCRO GC-07 study indicates that postoperative S-1/docetaxel is superior to S-1 alone, yielding a superior RFS and reduced haematogenous, lymphatic and peritoneal recurrences.

Local Experience in Adjuvant Gastric Cancer
A multicentre retrospective study was conducted to assess the toxicity profile of S-1 in Chinese patients with gastric cancer who had received adjuvant S-1 chemotherapy.16 Of the 30 patients studied, 19 (63 percent) patients completed eight cycles. The most common grade 3–4 adverse events included septic episode (16.7 percent), neutropenia (10 percent), anaemia (6.7 percent), diarrhoea (6.7 percent), hyperbilirubinaemia (6.7 percent), and syncope (6.7 percent). Dose reductions were required in 22 (73.3 percent) patients and 12 (40.0 percent) patients had dose delays. Patients who underwent total gastrectomy were more likely to experience adverse haematological events than those who underwent partial gastrectomy (p=0.034). Non-haematological adverse events occurred more commonly in patients with nodal involvement (p=0.031). Patients with a history of regular alcohol intake were more likely to have earlier treatment withdrawal (p=0.044). Lower body weight (p=0.007) and lower body surface area (p=0.017) were associated with dose interruptions.16

Overall, adjuvant S-1 therapy has a tolerable toxicity profile among Chinese patients who have undergone curative resection for gastric cancer, with a tolerability profile similar to that of other Asian populations. Patients who have identifiable risk factors for adverse events should be closely monitored during treatment as this may enable earlier intervention with supportive therapy to optimize treatment outcome.
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