Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial

Summary

Background

Historical data and recent studies show that standardised extended (D2) lymphadenectomy leads to better results than standardised limited (D1) lymphadenectomy. Based on these findings, the Dutch D1D2 trial, a nationwide prospectively randomised clinical trial, was undertaken to compare D2 with D1 lymphadenectomy in patients with resectable primary adenocarcinoma of the stomach. The aim of the study was to assess the effect of D2 compared with D1 surgery on disease recurrence and survival in patients treated with curative intent.

Methods

Between August, 1989, and July, 1993, patients were entered and randomised at 80 participating hospitals by means of a telephone call to the central data centre of the trial. The sequence of randomisation was in blocks of six with stratification for the participating centre. Eligibility criteria were a histologically proven adenocarcinoma of the stomach without evidence of distance metastasis, age younger than 85 years, and adequate physical condition for D1 or D2 lymphadenectomy. Patients were excluded if they had previous or coexisting cancer or had undergone gastrectomy for benign tumours. Strict quality control measures for pathological assessment were implemented and monitored. Analyses were by intention to treat. This study is registered with the NCI trial register, as DUT-KWF-CKVO-8905, EU-90003.

Findings

A total of 1078 patients were entered in the study, of whom 996 were eligible. 711 patients underwent the randomly assigned treatment with curative intent (380 in the D1 group and 331 in the D2 group) and 285 had palliative treatment. Data were collected prospectively and all patients were followed up for a median time of 15·2 years (range 6·9–17·9 years). Analyses were done for the 711 patients treated with curative intent and were according to the allocated treatment group. Of the 711 patients, 174 (25%) were alive, all but one without recurrence. Overall 15-year survival was 21% (82 patients) for the D1 group and 29% (92 patients) for the D2 group (p=0·34). Gastric-cancer-related death rate was significantly higher in the D1 group (48%, 182 patients) compared with the D2 group (37%, 123 patients), whereas death due to other diseases was similar in both groups. Local recurrence was 22% (82 patients) in the D1 group versus 12% (40 patients) in D2, and regional recurrence was 19% (73 patients) in D1 versus 13% (43 patients) in D2. Patients who had the D2 procedure had a significantly higher operative mortality rate than those who had D1 (n=32 [10%] vs n=15 [4%]; 95% CI for the difference 2–9; p=0·004), higher complication rate (n=142 [43%] vs n=94 [25%]; 11–25; p<0·0001), and higher reoperation rate (n=59 [18%] vs n=30 [8%]; 5–15; p=0·00016).

Interpretation

After a median follow-up of 15 years, D2 lymphadenectomy is associated with lower locoregional recurrence and gastric-cancer-related death rates than D1 surgery. The D2 procedure was also associated with significantly higher postoperative mortality, morbidity, and reoperation rates. Because a safer, spleen-preserving D2 resection technique is currently available in high-volume centres, D2 lymphadenectomy is the recommended surgical approach for patients with resectable (curable) gastric cancer.

Funding

Dutch Health Insurance Funds Council and the Netherlands Cancer Foundation.

Introduction

After several decades of debate on what the optimum surgical treatment of gastric cancer should be, it is now possible to treat patients using evidence-based principles established by well designed and conducted studies. Adequate surgery, the only treatment known to offer cure, is still the cornerstone of gastric-cancer treatment; however, local regional control remains an issue. In western Europe and the USA, optimum local control and survival seemed to be reached with surgery as a single-modality treatment, based mainly on two large European trials, the Dutch Gastric Cancer Trial (DGCT)¹ and the UK Medical Research Council (MRC) randomised trial.² In both trials, standardised extended (D2) lymphadenectomy did not improve survival, and was associated with significantly higher morbidity and mortality compared with standardised limited (D1) lymphadenectomy. The unfavourable outcomes were mostly associated with pancreatico-splenectomy, which was an integral part of the D2 resection in both trials. In 2004, results from a study by Degiuli and colleagues³ suggested a survival benefit after pancreas-preserving D2 resections, and in 2006, a Taiwanese single-institution trial⁴ found that extended lymph-node dissection (D2) led to better results (no postoperative mortality) than D1 lymphadenectomy. More extended resection (D2 plus para-aortic nodal dissection) was not found to be better than D2 resections in Japanese patients.⁵

As a result of the INT0116 trial,⁶ a combination of surgery and postoperative chemoradiotherapy became the standard treatment for curable gastric cancer in the USA. In this trial, fluorouracil plus leucovorin given concomitantly with 45 Gy radiation after potentially curative surgery improved 3-year survival from 41% to 50%, compared with surgery alone. In Europe, following the results of the UK MAGIC trial,⁷ perioperative chemotherapy with the ECF (epirubicin, cisplatin, and fluorouracil) became the new treatment standard for gastric cancer. The MAGIC trial found that perioperative systemic chemotherapy improved 5-year survival from 23% to 36%, compared with surgery alone. Randomised controlled trials in Japanese patients have shown significant improvement in overall survival with postoperative adjuvant chemotherapy with S-1 (an orally active combination of tegafur, gimeracil, and oteracil) after D2 dissection.⁸ Therefore, S-1 after D2 surgery is becoming the standard treatment for patients with gastric cancer in Japan.

Early results from the DGCT showed significantly higher postoperative morbidity and mortality in the D2 group compared with the D1 group.⁹ With the 5-year follow-up results showing no significant survival benefit in the D2 group, a conclusion was drawn that D2 resection could not be advised in patients with curable gastric cancer.¹⁰ However, 11-year follow-up data showed better survival results in exploratory analyses in patients with stage II and IIIa disease who had D2 compared with D1 resections.¹ The current report is the 15-year follow-up data of the DGCT.