Background
Locally advanced gastric cancer with extensive regional and/or para‐aortic lymph node (PAN) metastases is typically unresectable and associated with poor outcomes. This study investigated ...the safety and efficacy of S‐1 plus cisplatin followed by extended surgery with PAN dissection for gastric cancer with extensive lymph node metastasis.
Methods
Patients with gastric cancer with bulky lymph node metastasis along the coeliac artery and its branches and/or PAN metastasis received two or three 28‐day cycles of S‐1 plus cisplatin, followed by gastrectomy with D2 plus PAN dissection. The primary endpoint was the percentage of complete resections with clear margins in the primary tumour (R0 resection). A target sample size of 50 with one‐sided α of 0·105 and β of approximately 0·2 corresponded to an expected R0 rate of 65 per cent and a threshold of 50 per cent.
Results
Between February 2005 and June 2007, 53 patients were enrolled, of whom 51 were eligible. The R0 resection rate was 82 per cent. Clinical and pathological response rates were 65 and 51 per cent respectively. The 3‐ and 5‐year overall survival rates were 59 and 53 per cent respectively. During chemotherapy, grade 3/4 neutropenia occurred in 19 per cent and grade 3/4 non‐haematological adverse events in 15·4 per cent. The incidence of grade 3/4 adverse events related to surgery was 12 per cent. There were no reoperations or treatment‐related deaths.
Conclusion
For locally advanced gastric cancer with extensive lymph node metastasis, 4‐weekly S‐1 plus cisplatin followed by surgery including PAN dissection was safe and effective for some patients. Further investigation of this treatment strategy is warranted.
Merits confirmation in a Western population
Background
It is still unclear whether D2 lymphadenectomy improves the survival of patients with gastric cancer and should therefore be performed routinely or selectively. The aim of this multicentre ...randomized trial was to compare D2 and D1 lymphadenectomy in the treatment of gastric cancer.
Methods
Between June 1998 and December 2006, patients with gastric adenocarcinoma were assigned randomly to either D1 or D2 gastrectomy. Intraoperative randomization was implemented centrally by telephone. Primary outcome was overall survival; secondary endpoints were disease‐specific survival, morbidity and postoperative mortality.
Results
A total of 267 eligible patients were allocated to either D1 (133 patients) or D2 (134) resection. Morbidity (12·0 versus 17·9 per cent respectively; P = 0·183) and operative mortality (3·0 versus 2·2 per cent; P = 0·725) rates did not differ significantly between the groups. Median follow‐up was 8·8 (range 4·5–13·1) years for surviving patients and 2·4 (0·2–11·9) years for those who died, and was not different in the two treatment arms. There was no difference in the overall 5‐year survival rate (66·5 versus 64·2 per cent for D1 and D2 lymphadenectomy respectively; P = 0·695). Subgroup analyses showed a 5‐year disease‐specific survival benefit for patients with pathological tumour (pT) 1 disease in the D1 group (98 per cent versus 83 per cent for the D2 group; P = 0·015), and for patients with pT2–4 status and positive lymph nodes in the D2 group (59 per cent versus 38 per cent for the D1 group; P = 0·055).
Conclusion
No difference was found in overall 5‐year survival between D1 and D2 resection. Subgroup analyses suggest that D2 lymphadenectomy may be a better choice in patients with advanced disease and lymph node metastases. Registration number: ISRCTN11154654 (http://www.controlled‐trials.com).
No difference
Background
The optimal surgical approach for treatment of oesophagogastric junction (OGJ) cancer is controversial. A randomized clinical trial (JCOG9502) comparing transhiatal (TH) and left ...thoracoabdominal (LTA) approaches was stopped after the first interim analysis owing to limited efficacy for LTA resections. Complete 10‐year follow‐up data are now available.
Methods
Patients with histologically proven adenocarcinoma of the OGJ or gastric cardia with oesophageal invasion of 3 cm or less were randomized to a TH or LTA approach. Both groups underwent total gastrectomy and splenectomy with D2 nodal dissection plus para‐aortic lymphadenectomy above the left renal vein. For LTA, a thorough mediastinal lymphadenectomy below the left inferior pulmonary vein was also mandatory. The primary endpoint was overall survival.
Results
A total of 167 patients (82 TH, 85 LTA) were enrolled. The 10‐year overall survival rate was 37 (95 per cent c.i. 26 to 47) per cent for the TH approach and 24 (15 to 34) per cent for the LTA technique (P = 0·060). The hazard ratio for death was 1·42 (0·98 to 2·05) for the LTA technique. Subgroup analysis based on the Siewert classification indicated non‐significant survival advantages in favour of the TH approach.
Conclusion
LTA resections should be avoided in the treatment of adenocarcinoma of the OGJ or gastric cardia. Registration number: NCT00149266 (https://www.clinicaltrials.gov).
No survival benefit from a more extensive operation
The extended lymphadenectomy (D2) was recently introduced in several guidelines as the optimal treatment for gastric cancer, based only on the 15-year follow-up results of the Dutch randomised trial, ...while the British Medical Research Council (MRC) study failed to demonstrate a survival benefit over the more limited D1 dissection. The Italian Gastric Cancer Study Group randomised controlled trial (RCT) was also undertaken to compare D1 versus D2 gastrectomy, and a tendency to improve survival in patients with advanced resectable disease (pT > 1N+) was documented despite negative results in the entire patient population. Now we present the 15-year follow-up results of survival and gastric cancer-related mortality.
Between June 1998 and December 2006, eligible patients with gastric cancer who signed the informed consent were randomised at 5 centres to either D1 or D2 gastrectomy. Intraoperative randomisation was implemented centrally by phone call. Primary outcome was overall survival (OS); secondary end-points were disease-specific survival, postoperative morbidity and mortality. Analyses were by intention to treat. Strict quality control measures for surgery, lymph node removal, pathology and patient follow-up were implemented and monitored. Registration number: ISRCTN11154654 (http://www.controlled-trials.com).
A total of 267 eligible patients were assigned to either D1 (133 patients) or D2 (134) procedure. Median follow-up time was 16.76 years. Analyses were done both in overall patient population and in pT > 1N+. One hundred patients (38.5) were alive without recurrence. OS and disease-specific survival (DSS) were very high in both arms. In overall population, they were not different between D1 and D2 arm (51.3% vs. 46.8% and 65% vs. 67% respectively, p = 0.31 and p = 0.94). DSS was significantly higher after D2 in pT > 1N+ patients (29.4% vs. 51.4%, p = 0.035). OS and DSS were better after D1 in patients older than 70 years (p = 0.003 and p = 0.006). DSS was higher after D1 also in early stages (p = 0.01).
After 15-year follow up, despite no relevant difference in overall population, DSS and gastric cancer-related mortality of patients with advanced disease and lymph node metastases are improved by D2 procedure. Further data available from this trial suggest that D1 procedure should be preferably used in older patients and in early disease. As accurate detection of advanced diseases can be currently provided by adequate preoperative workup in referral centres, D2 procedure should be recommended in these cases.
Piedmont Regional fund for Finalized Healthy Research Project, Application 2003 for data collection.
•In overall population, the survival benefit of D2 dissection is not evident.•In resectable locally advanced GC, D2 dissection improves disease-specific survival.•Preoperative staging could identify locally advanced disease in referral centres.•D2 dissection is not necessary in early gastric cancer.•In older patients, D2 procedure is not superior and can be dangerous.
Interleukin-22 (IL-22) has been recently highlighted owing to its biological significance in the modulation of tissue responses during inflammation. However, the role of IL-22 in carcinogenesis has ...remained unclear. Here, we investigated the pathophysiological significance of IL-22 expression in gastric cancer tissues and examined the mechanism by which IL-22 promotes gastric cancer cell invasion.
Human gastric cancer specimens were analysed by immunohistochemistry for expression of IL-22 and IL-22 receptor 1 (IL-22R1). The effects of IL-22-induced STAT3 and ERK signalling on invasive ability of gastric cancer cells were examined using a small-interfering RNA system and specific inhibitors. AGS cells were co-cultured with cancer-associated fibroblasts (CAFs) from human gastric cancer tissues and assessed by invasion assay.
Interleukin-22 and its receptor were expressed in α-smooth muscle actin-positive stromal cells and tumour cells at the invasive front of gastric cancer tissues, respectively. The expression of IL-22 and IL-22R1 was significantly related to lymphatic invasion. Interleukin-22 treatment promoted the invasive ability of gastric cancer cells through STAT3 and ERK activation. The invasive ability of gastric cancer cells was significantly enhanced by co-culture with IL-22-expressing CAFs.
Interleukin-22 produced by CAFs promotes gastric cancer cell invasion via STAT3 and ERK signalling.
Background
Total gastrectomy for gastric cancer is associated with excessive weight loss and decreased calorie intake. Nutritional support using eicosapentaenoic acid modulates immune function and ...limits catabolism in patients with advanced cancer, but its impact in the perioperative period is unclear.
Methods
This was a randomized phase III clinical trial of addition of eicosapentaenoic acid‐rich nutrition to a standard diet in patients having total gastrectomy for gastric cancer. Patients were randomized to either a standard diet or standard diet with oral supplementation of an eicosapentaenoic acid (ProSure®), comprising 600 kcal with 2·2 g eicosapentaenoic acid, for 7 days before and 21 days after surgery. The primary endpoint was percentage bodyweight loss at 1 and 3 months after surgery.
Results
Of 127 eligible patients, 126 were randomized; 124 patients (61 standard diet, 63 supplemented diet) were analysed for safety and 123 (60 standard diet, 63 supplemented diet) for efficacy. Across both groups, all but three patients underwent total gastrectomy with Roux‐en‐Y reconstruction. Background factors were well balanced between the groups. Median compliance with the supplement in the immunonutrition group was 100 per cent before and 54 per cent after surgery. The surgical morbidity rate was 13 per cent in patients who received a standard diet and 14 per cent among those with a supplemented diet. Median bodyweight loss at 1 month after gastrectomy was 8·7 per cent without dietary supplementation and 8·5 per cent with eicosapentaenoic acid enrichment (P = 0·818, adjusted P = 1·000). Similarly, there was no difference between groups in percentage bodyweight loss at 3 months (P = 0·529, adjusted P = 1·000).
Conclusion
Immunonutrition based on an eicosapentaenoic acid‐enriched oral diet did not reduce bodyweight loss after total gastrectomy for gastric cancer compared with a standard diet. Registration number: UMIN000006380 (
http://www.umin.ac.jp/)
Immunonutrition of no benefit
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