Refining the Role for Adjuvant Radiotherapy in Gastric Cancer: Risk Stratification Is Key

Adjuvant therapy for gastric cancer has been investigated in successive clinical trials over the last four decades, ultimately leading us closer to more effective and risk-stratified therapies after gastric resection. The international efforts to improve outcomes for gastric cancer and to define the appropriate adjuvant regimen are a testament to the global impact of this disease, with approximately one million patients diagnosed per year and almost 750,000 deaths annually worldwide. The final report of the Adjuvant Chemoradiotherapy Trial in Stomach Tumors (ARTIST) trial accompanying this editorial presents updated analyses that may help us to better tailor adjuvant therapies after gastric resection. The investigators of the ARTIST trial who conducted this study in Korea are to be commended for their well-designed and wellexecuted clinical trial, and for building on the results of previous European, Japanese, and American trials, addressing the longstanding question of what constitutes effective adjuvant therapy for gastric cancer. Early attempts to identify active adjuvant regimens in phase III randomized trials were unsuccessful, and a meta-analysis of 14 trials published after 1980 failed to demonstrate any benefit of adjuvant therapy after surgical resection. It was not until the US Gastric Surgical Adjuvant Trial (INT-0116), a large, phase III, randomized trial of 556 patients with resected stage IB through IV (M0) gastric or gastroesophageal junction adenocarcinoma was reported in 2001 that a clear survival advantage could be demonstrated with the use of adjuvant therapy. This study demonstrated an improvement in 3-year overall survival from 41% with surgery alone to 50% with surgery and adjuvant fluorouracil and leucovorin combined with radiotherapy, thus, supporting a major role for radiotherapy in the adjuvant treatment of this disease. Updated results, with more than 10 years of follow-up, have shown a sustained benefit in progressionfree and overall survival with adjuvant chemoradiotherapy. The sites of local and regional relapse were 2% and 22%, respectively, in the treatment arm and 8% and 39% in the control arm, suggesting that adjuvant chemoradiotherapy sterilized subclinical locoregional failure sites. This study established postoperative chemoradiotherapy as a standard of care for patients with resected gastric cancer with high risk for locoregional failure. However, the INT-0116 study was highly criticized for the limited lymph node dissections performed on the patients enrolled on the study. Gastric resection with an extensive (D2) lymphadenectomy was recommended, but patients were not excluded on the basis of the extent of lymph node dissection. After a review of the surgical records, only 54 (10%) patients had undergone a formal D2 dissection. A D1 dissection (removal of perigastric nodes) had been performed in 36%, and most patients (54%) had undergone a D0 resection, signifying that there was less than a complete dissection of the involved nodes. The extent of surgical resection was not found to be a predictor of outcome in the INT-0116 trial, nor in several large randomized trials comparing D1 and D2 lymph node dissections in gastric cancer. Nonetheless, a D2 lymphadenectomy has become the standard surgical approach in Asia and Europe. As such, there was a concern that the benefit of the postoperative chemoradiotherapy in the INT-0116 trial might have been due to the higher locoregional failure risk after suboptimal surgery and thus would not have an impact in the setting of more extensive D2 lymph node dissections. A retrospective review compared outcomes from several Dutch phase I/II studies of adjuvant chemoradiotherapy after D1 or D2 resection versus outcomes from the Dutch Gastric Cancer Group Trial that randomly assigned patients between D1 and D2 lymphadenectomy without adjuvant therapy. Dikken et al reported that after D1 surgery, the addition of postoperative chemoradiotherapy significantly reduced local recurrence rates but not in the D2 resection population. This question of the benefit of radiotherapy in the setting of more extensive surgery parallels the uncertainty about the role of radiotherapy for rectal cancer in the setting of a more total mesorectal excision (TME). As in rectal cancer, for which the Dutch Colorectal Cancer Group initiated the TME trial to evaluate the role of preoperative short-course radiotherapy in the setting of a TME for rectal cancer, it was necessary to evaluate the impact of radiotherapy in the setting of a D2 lymphadenectomy for gastric cancer. This was the unique feature of the ARTIST trial, which randomly assigned only patients who underwent a D2 resection for pathologically staged IB to IV (M0) gastric cancer to adjuvant chemotherapy involving six cycles of capecitabine and cisplatin (XP) or 2 cycles of XP before and after concurrent capecitabine and radiotherapy (XPRT). While the first publication of the results of the ARTIST trial was interpreted as a negative study because there was no difference in the primary end point of 3-year disease-free survival (DFS) between the two arms (78.2% in the XPRT arm and 74.2% in the XP arm, P .0862), there was some indication of a benefit for radiotherapy. In an unplanned subgroup analysis, node-positive patients in the XPRT arm had a better DFS (77.5% in the XPRT arm and 72.3% in the XP arm; P .0365). In this final report of the ARTIST trial, with a median of 7 years of follow-up, there is still not a significant difference in DFS and no difference in overall survival for JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 28 OCTOBER 1 2015