Similar to China, Europe has a predominance of advanced gastric cancer, with more than 50% of patients in stages III and IV. Likewise, they share similar views with us in terms of treatment, with European colleagues promoting D2 radical surgery and perioperative chemotherapy, while reserving their views on radiotherapy. Therefore, the European guidelines may be of particular interest to us.
The 2010 ESMO Clinical Practice Guidelines for the Diagnosis, Treatment, and Follow-up of Gastric Cancer (hereinafter referred to as “the Guidelines”) have updated the diagnosis, staging, treatment, and follow-up of gastric cancer based on the results of numerous clinical trials, and these recommendations are undoubtedly of great value in guiding our clinical practice work.
Treatment of localized gastric cancer
Surgical treatment
Surgical resection remains the only effective means to potentially eradicate early gastric cancer, and the extent of surgical resection depends on preoperative staging.
The clear indications for endoscopic mucosal resection (EMR) are intramucosal carcinoma without ulceration, well differentiated tumor tissue and tumor diameter ≤2 cm [Class III evidence, Grade A recommendation].
Radical gastric cancer surgery is indicated for patients with stage Ib to III gastric cancer. Subtotal gastrectomy is feasible if the distance between the proximal cut margin and the esophagogastric junction is 5 cm or more under the naked eye, and total gastrectomy should be performed in the rest of cases [Class III evidence, Level A recommendation].
The results of an observational study and randomized trial in East Asia showed that D2 lymph node dissection with resection of N1 and N2 lymph nodes was superior to D1 lymph node dissection [Class II evidence, Level B recommendation]. The current consensus is that D2 lymph node dissection should be performed as standard treatment for appropriate patients by surgical specialists in treatment centers experienced in surgical and postoperative management. It follows that for surgeons in the West, especially in Europe, as for us, D2 surgery is advocated as the standard of care for patients with resectable gastric cancer.
Perioperative chemotherapy
In terms of chemotherapy, a UK randomized trial confirmed that 3 cycles of preoperative and postoperative epirubicin + cisplatin + continuous intravenous infusion of 5-fluorouracil (ECF regimen) improved the 5-year survival (OS) of patients with limited gastric cancer to 36.3%, significantly better than the 23.0% with surgery only. The advantage of perioperative ECF regimen treatment over surgery alone in significantly improving patient survival was further confirmed in the FFCD trial [Class I evidence, Level A recommendation]. ECF perioperative regimens are now the standard of care in the UK and parts of Europe.
Given that the efficacy of capecitabine in advanced gastric cancer is not inferior to that of 5-fluorouracil, and that capecitabine is administered orally without central venous placement, most medical centers use epirubicin + cisplatin + capecitabine (ECX regimen) as the perioperative chemotherapy regimen of choice [Class IV evidence, Level C recommendation].
Postoperative chemoradiotherapy
In terms of chemoradiotherapy, a North American study confirmed that 5 cycles of postoperative chemotherapy with 5-fluorouracil + calcium folinic acid given before, during and after radiotherapy (45 Gy/25 doses/5 weeks) improved patients’ 5-year OS by approximately 15% [Class I evidence, Level A recommendation]. This postoperative radiotherapy regimen has become standard in the United States, but it has not been widely accepted in Europe given the potential toxic effects of abdominal chemoradiotherapy and the impact on surgical outcomes.
Notably, only about 10% of patients in this North American study had D2 lymph node dissection, the remaining 36% had D1 lymph node dissection, and 54% had D0 lymph node dissection, and those with D0/D1 lymph node dissection benefited more from postoperative radiotherapy, although there was no significant difference [Class II evidence, Class B recommendation]. The results of this study suggest that the improved survival with postoperative radiotherapy may be a compensation for incomplete surgical resection.
A study of cisplatin in combination with capecitabine ± radiotherapy (ARTIST) is currently underway in Korea to investigate the role of radiotherapy in the postoperative treatment of gastric cancer. The safety results have confirmed that radiotherapy did not increase the incidence of adverse effects, and the final survival outcome is worthy of expectation.
Adjuvant chemotherapy
A recent meta-analysis has shown that adjuvant chemotherapy has a survival advantage for postoperative gastric cancer patients, with adjuvant chemotherapy showing a significant clinical benefit in 5 studies conducted in Asia (HR=0.74, 95% CI 0.64-0.8) compared to 14 studies conducted outside Asia (HR=0.90, 95% CI 0.85-0.96).
Neoadjuvant radiotherapy
In theory, neoadjuvant radiotherapy is more effective than postoperative treatment strategies, but neoadjuvant radiotherapy for gastric cancer is still in the exploratory phase of trials, and randomized controlled clinical trials are needed to further explore its therapeutic value in gastric cancer.
Treatment of metastatic gastric cancer
First-line treatment
For patients with stage IV gastric cancer, palliative chemotherapy should be given because it significantly improves patient quality of life and survival compared with best supportive care [Class I evidence, Level A recommendation].
Two-drug regimens containing platinum and fluorouracil are the most widely used regimens, and there is still controversy regarding three-drug combinations. A meta-analysis confirmed that a three-drug combination regimen with an anthracycline in addition to a two-drug regimen of platinum and fluorouracil provides a significant survival benefit [Class I evidence, Level A recommendation], with the ECF regimen being the most efficacious and well-tolerated regimen.
A three-drug regimen combined with docetaxel on top of a two-drug regimen of 5-fluorouracil and cisplatin (PF) was more efficacious than the PF regimen, but the toxic effects of the 3-week docetaxel regimen were greater, with an incidence of neutropenia of up to 29%. Another randomized phase II study showed that cisplatin + 5-fluorouracil or capecitabine combined with weekly docetaxel regimens achieved similar efficacy to the 3-week regimen with lower toxic effects.
Irinotecan combined with 5-fluorouracil + calcium folinic acid has similar efficacy to the PF regimen and may also be a treatment option for selective patients.
Regarding the ECF regimen, a non-inferiority trial in the UK compared the efficacy and safety of the ECF regimen with its three alternatives (EOF, ECX, EOX) in the first-line treatment of advanced gastric cancer using capecitabine (X) instead of 5-fluorouracil (F) and/or oxaliplatin (O) instead of cisplatin (C). The results showed that the efficacy of the ECX, EOF (epirubicin + oxaliplatin + 5-fluorouracil) and EOX (epirubicin + oxaliplatin + capecitabine) regimens were not inferior to that of the ECF regimen. the EOX regimen had a significantly longer OS than the ECF regimen (11.2 months versus 9.9 months, HR=0.80, 95% CI 0.66-0.97, P=0.02). Concomitant regimens with oxaliplatin instead of cisplatin resulted in a significant decrease in the incidence of thromboembolism (7.6% versus 15.1%, P=0.0003). Moreover, the ECX regimen is a suitable option for patients with advanced gastric cancer because it avoids central venous placement and reduces hospitalization and associated costs.
Other studies have also confirmed that capecitabine can replace 5-fluorouracil [Class I evidence, Level A recommendation] and oxaliplatin can replace cisplatin [Class I evidence, Level A recommendation], and that this substitution does not compromise efficacy but also reduces toxic effects. A meta-analysis showed that capecitabine improved OS better than intravenous infusion of 5-fluorouracil in two- and three-drug regimens for the treatment of advanced gastric cancer [Class I evidence, Level A recommendation].
Targeted therapies
In targeted therapy, the addition of trastuzumab to cisplatin combined with fluorouracil significantly improved remission rates, median progression-free survival and median OS in patients with human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (13.8 months versus 11.1 months, HR=0.74, 95% CI 0.60-0.91, P=0.0048) [Class I evidence, Grade B Recommended]. Therefore, targeted therapy in combination with trastuzumab should be given to patients with HER2-positive gastric cancer.
Several studies are under further investigation regarding the role of other molecularly targeted agents such as cetuximab, panitumumab or bevacizumab in combination with chemotherapy in the treatment of advanced gastric cancer.
Second-line treatment
For patients with advanced gastric or combined gastroesophageal cancer who progress within 6 months after first-line chemotherapy, one study showed that irinotecan significantly prolonged the median OS of patients compared with best supportive therapy (4.0 months versus 2.4 months, HR=0.48, 95% CI 0.25-0.92, P=0.023) [Class II evidence, Grade B recommendation]; for patients with advanced disease progression after first-line therapy, they should be actively considered for participation in clinical trials; for patients with relapse >3 months after first-line treatment, patients may be considered for treatment with their prior chemotherapy regimen.
Elderly patients
Older patients aged ≥70 years are often excluded from clinical studies; however, a pooled analysis showed that the efficacy and tolerability of palliative chemotherapy were not significantly reduced in older patients. Therefore, older age is not a contraindication to palliative chemotherapy [Class II evidence, Level B recommendation], but factors such as comorbidities, organ functional status, and physical fitness status of older patients must be fully considered.
■ Summary
As seen from the updated recommendations of the Guideline, capecitabine shows an important position in the chemotherapy of both limited gastric cancer and metastatic gastric cancer. It is believed that the role of capecitabine in the treatment of gastric cancer will be supported by more evidence-based medical evidence as clinical practice progresses and ECX and EOX regimens are widely promoted in the clinic.