Surgical resection remains the primary curative treatment option in gastric cancer, with five-year survival rates of 58% to 78% and 34% reported for stage I and II disease, respectively (35). Despite this, the overall five-year survival rate for all patients remains poor and ranges between 15% and 38%. Recurrences are frequent after surgery. Recurrence rate and subsequent survival is dependent on the stage at diagnosis.
Prospective randomized trials have evaluated the role of D1 or D2 resection in the management of gastric cancer and they did not show any advantage in terms of overall survival in favor of D2 lymphadenectomy (10,11,36). In an expert consensus report, it has been agreed that at least a D1 resection should be performed and that it is mandatory that at least 15 lymph nodes are removed and recovered (12).
Local or regional recurrence in the gastric or tumor bed, anastomosis, or the regional lymph nodes occurs in 40% to 65% of patients after gastric resection with curative intent (37,38). Metastases occur most often in the liver and the peritoneum. Different strategies have been explored in randomized studies in patients with gastric cancer: adjuvant chemotherapy, adjuvant chemoradiotherapy, and perioperative chemotherapy. In many of the trials, a heterogeneous patient group is studied, including patients with gastric adenocarcinoma and GEJ cancer and patients with less and more advanced stages.
Most of the individual trials studying the effect of postoperative adjuvant chemotherapy do not show a survival advantage compared to surgery alone. These studies often randomized a low number of patients and are clearly underpowered. The trials studied also were predominantly older chemotherapy regimens. Further, the patient populations studied were heterogeneous, including patient populations with both high- and low-risk of recurrence.
Five meta-analyses (or combined analyses) of adjuvant chemotherapy have been published (39-43). Most of the analyses show a small benefit in survival for patients treated with postoperative adjuvant chemotherapy (evidence level 1a). Because of the nature of the data, however, adjuvant chemotherapy is not generally advised for patients who undergo a complete surgical resection of gastric cancer.
A major change in the management of gastric cancer is based on the results of the U.S. GI-Intergroup study, which randomized 556 patients with resected adenocarcinoma of the stomach or GEJ to surgery plus postoperative chemoradiotherapy (bolus 5-FU before, during, and after the irradiation) or surgery alone (44). The median overall survival in the surgery only arm was 27 months, compared to 36 months in the chemoradiotherapy group (P < 0.05). The survival at three years was 50% versus 40% in favor of patients treated with postoperative chemoradio-therapy. After a median follow-up of five years, compared with surgery alone, five-year overall survival was improved by 11.6% (40% vs. 28.4%, respectively; P < 0.001) and the relapse-free survival was increased from 25% to 31%. Patients treated with postoperative chemoradiotherapy had significant less loco-regional recurrences (level 1b evidence). Most patients did not undergo an extensive surgical resection although the protocol recommended a D2 resection. Fifty-four percent of the patients did not even have a D1 resection (44). So it is possible that the adjuvant therapy was simply making up for inadequate surgery. The chemotherapy used in this study was never considered to be a highly effective combination for stomach cancer. Therefore, better chemotherapeutic options should be investigated in this setting, such as infused regimens of 5-FU, which are currently recommended in this combination regimen. The addition of new cytotoxic agents is under investigation.
The Magic trial compared a strategy of surgery alone with perioperative chemotherapy (three cycles of preoperative 5FU/cisplatin-based chemotherapy followed by surgery followed by three cycles of postoperative chemotherapy) in 503 patients with gastric, GEJ, and distal esophageal adenocarcinoma. The patients treated with perioperative chemotherapy had a significantly better survival: 50% versus 41% were alive at two years and 36% versus 23% at five years compared with patients who were treated with surgery only. The progression survival was also significantly improved for patients treated with perioperative chemotherapy: HR 0.66 (95% CI 0.53-0.81; P=0.0001) (level 1b evidence) (45).
It can be concluded that there is growing evidence that (neo)adjuvant treatment improves the outcome of selected patients with gastric cancer. As a general strategy, there is an agreement to recommend postoperative chemoradiotherapy in fit patients who already underwent inadequate surgery or less than D1 resection (12). The strategy of either postoperative chemoradiotherapy or perioperative chemotherapy can be recommended after multidisciplinary team discussions. For both strategies, the evidence is based on data from a large well-performed randomized trial (level 1b evidence). The evidence supporting postoperative chemotherapy is not so strong because of the nature of the randomized trials included in the combined analyses. Generally, either perioperative chemotherapy or postoperative chemoradiotherapy is recommended for patients who have stage T3, T4, or N+ M0 gastric cancer. There is no general agreement whether patients with stage T2bN0 should be offered an adjuvant treatment. In this setting, other factors should be taken into consideration (e.g., factors presented in nomograms).
A neoadjuvant or adjuvant treatment should be offered only to fit patients without important comorbidities. Crucial in good tolerance, especially for the postoperative chemo-radiotherapy, is the ability of the patient to have an adequate calorie intake during the treatment. Adequate measures are therefore necessary, including the administration of enteral nutrition where required.
The strategy of neoadjuvant chemoradiotherapy in gastric cancer has been examined only in relatively small phase II studies. This approach is certainly feasible and promising activity has been suggested. Most patients had in these studies proximal gastric cancers.
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