ARTIST 2: Interim results of a phase III trial involving adjuvant chemotherapy and/or chemoradiotherapy after D2-gastrectomy in stage II/III gastric cancer (GC).

Abstract

4001 Background: Adjuvant chemotherapy and/or chemoradiotherapy have been the standard of care in GC for years, supported by randomized trials. We compared the efficacy of different chemotherapy regimens and chemoradiotherapy in patients with D2-resected, stage II/III, node-positive GC. Methods: From Feb 2013 through Nov 2018, we randomly assigned, in a 1:1:1 ratio, patients with pathologically-staged II or III, node-positive, D2-resected GC, to receive adjuvant S-1 (40-60 mg twice daily 4-weeks-on/2-weeks-off) for one year, S-1 (2-weeks-on/1-week-off) plus oxaliplatin 130 mg/m2 (SOX) for six months, or SOX plus chemoradiotherapy 45 Gy (SOXRT). Randomization was stratified according to the type of surgery (total or subtotal gastrectomy), stage (II or III), and Lauren histologic classification (diffuse or intestinal). The primary endpoint was disease-free survival (DFS). A total of 900 patients had to be enrolled to demonstrate superiority of SOX or SOXRT to S-1 (hazard ratio [HR] 0.667), with 90% power at a two-sided significance level of 5%. Results: A total of 538 patients were included for this interim efficacy analysis. Median age was 58 years, men constituted 65%, and stage II and III were 31% and 69%, respectively. Baseline tumor and patient characteristics were balanced between treatment arms. Adverse events were as anticipated in each arm, generally well-tolerated and manageable. DFS in the control arm (S-1) were significantly shorter than in SOX and SOXRT arms (stratified HR for recurrence): S-1 vs. SOX, 0.617 (P = 0.016) and S-1 vs. SOXRT, 0.686 (P = 0.057). The DFS at 3-years was found to be 65%, 78% and 73% in S-1, SOX and SOXRT arms, respectively. No difference in DFS between SOX and SOXRT was found (HR 0.910, P = 0.667). Based on the results after the observation of 145 recurrence events at the cutoff date of Dec 27, 2018, the independent data monitoring committee considered the results sufficient to meet the endpoint of the trial and recommended early stopping of the trial. Conclusions: In patients with curatively D2-resected, stage II/III, node-positive GC, adjuvant SOX or SOXRT was effective in prolonging DFS, when compared to S-1 monotherapy. Clinical trial information: NCT0176146.

Comparison of S‐1 plus oxaliplatin (SOX) and capecitabine plus oxaliplatin (XELOX) as adjuvant chemotherapies for stage II and III gastric cancer after D2 resection: A single‐center retrospective study

“…In a retrospective investigation conducted in Korea, patients with stage III GC in the XELOX group demonstrated no improvement in survival compared with the S‐1 group; however, subgroup analysis suggested that XELOX may be associated with a better 3‐year OS rate for patients with stage IIIC GC (55.2% vs 39%; HR = 0.5; 95% CI, 0.23–1.10; P = 0.075) 18 . In the ARTIST 2 study, 3‐year DFS rate in the S‐1 group was shorter than that in the SOX group for patients with stage II and III GC with lymph node metastasis (64% vs 78%; HR = 0.617; P = 0.0157); 19 however, its effects on OS are yet to be reported. In this study, the 3‐year OS rate of patients with stage IIIC disease in the SOX group was 65.8%, which was higher than that of 59.1% reported for patients with locally advanced disease receiving S‐1 monotherapy in the ACTS‐GC study 14 .…”

Perioperative chemotherapy for locally advanced gastric cancer in Japan: current and future perspectives

“…However, subset analysis indicated the potential benefit of adjuvant chemoradiotherapy in node-positive locally advanced gastric cancer [41], and the ARTIST 2 trial was conducted to investigate the superiority of S-1 plus oxaliplatin or S-1 plus oxaliplatin with chemoradiotherapy to S-1 monotherapy in patients with node-positive stage II/III gastric cancer. The results showed the superiority of S-1 plus oxaliplatin (HR 0.617; p = 0.016) and S-1 plus oxaliplatin with chemoradiotherapy (HR 0.686; p = 0.057), but did not show an additional effect of radiotherapy on the doublet regimen [42].…”

Recent Developments of Systemic Chemotherapy for Gastric Cancer

“…As first reported at the American Society of Clinical Oncology annual meeting in 2019, post-operative SOX significantly prolonged DFS over S-1 with well tolerated toxicities at interim analysis. This was sufficient evidence for the independent data monitoring committee to stop the trial [48]. Despite post-operative chemoradiotherapy's promising benefit for patients with LN-positive GC in the preceding ARTIST trial, no other benefit was observed in the SOX+RT arm in the ARTIST-II trial [48].…”

“…At present, the guidelines in Europe and the USA recommend D1 resection, with D2 resection being an option that should be used sparingly and only by expert surgeons in specialized and high-volume centers [39,40]. The reported frequencies of patients receiving D2 gastrectomy for resectable GC in clinical trials of adjuvant therapy were 10-55% in the West [41][42][43] and 98-100% in the East [44][45][46][47][48][49][50] (Table 1). The 5-year OS rate of patients receiving curative gastrectomy without adjuvant treatment was reported at approximately 70% in Japanese and Korean trials [51,52] and 23-35% in Western trials [36,41,42].…”