The role of adjuvant radiation therapy in nonmetastatic gastric cancer: an evolving paradigm.

Although gastric cancer is decreasing in incidence in the United States, it remains one of the most commonly diagnosed and most lethal cancers worldwide. Surgery remains the mainstay of treatment for localized disease. However, the persisting contribution of locoregional and distant recurrences to the low overall survival rates at 5 years has argued for the use of radiation therapy and chemotherapy in addition to curative resection. The argument for consideration of an additional locoregional treatment is further strengthened by recent data showing that even with improved surgical techniques, patients with higher Maruyama indices (constituting a majority of resected patients) have isolated locoregional failure rates of 21% on autopsy, a figure that closely parallels that of earlier re-operation and autopsy series. Furthermore, as any component of relapse, locoregional failure rates in these patients ranged between 57% and 88%, with failures noted in the gastric bed, regional nodes, gastric remnant, anastomosis, and duodenal stump, all of which can be encompassed in a regional radiation field. The review by McCloskey and Yang in this issue of Gastrointestinal Cancer Research elegantly and succinctly highlights the role of radiation therapy, employed preoperatively or postoperatively, in the multimodality treatment of nonmetastatic resectable gastric cancer. The authors also illustrate technical issues related to the delineation of targets, improvements in radiation field design, and the challenges faced during implementation of newer treatment delivery techniques. To frame these recommendations for radiation therapy for gastric cancer in the current context of multimodality treatment of resectable disease, it is instructive to consider the predominant treatment options available to patients. POSTOPERATIVE THERAPY As highlighted by the authors, a clear role for postoperative adjuvant combinedmodality therapy for resected gastric cancers was first established by the INT 0116 trial. Adjuvant chemoradiotherapy improved disease-free and overall survival, and the benefit of chemoradiotherapy seemed to be largely due to reduction in locoregional recurrences rather than reduction of distant recurrences. Despite these convincing results from a welldesigned trial, issues have been raised about its universal applicability because of the low rate (10%) of D2 lymphadenectomy, raising the possibility that chemoradiotherapy may merely be compensating for suboptimal surgery. Multiple lines of evidence suggest that is unlikely to be the case. First, in a subset analysis of this trial, there was no evidence that the benefit of adjuvant treatment was different based on the extent of lymphadenectomy. Second, randomized Western trials have failed to identify a survival benefit with D2 lymphadenectomy over D1 lymphadenectomy, similar to the finding that more extensive surgeries did not reduce locoregional failure rates in the reoperation series. Third, more extensive nodal dissections may be confounded by stage migration, where up to 75% of stage IIB patients undergoing D1 lymphadenectomy are upstaged to stage IV on D2 dissection. Last, a large (albeit nonrandomized) comparison of patients undergoing D2 lymphadenectomies who received similar adjuvant therapy vs. no additional therapy after resection confirmed a locoregional control and overall survival benefit for adjuvant therapy. Taken together, these findings argue strongly that the benefit derived from adjuvant therapy in the INT 0116 trial was unlikely to be merely due to such therapy compensating for inadequate surgery. Indeed, the results of this trial probably reflect a scenario most commonly encountered in clinical practice in the United States, where D2 lymphadenectomies performed frequently in the community are the exception rather than the rule. The high incidence (34%) of radiation therapy protocol violations that needed to be rectified before administration of treatment remains a valid critique of the trial’s broad applicability to routine practice. Moreover, it underscores the need for greater training of radiation oncologists regarding treatment of gastric cancer, a disease that is decreasing in incidence nationwide and fewer radiation oncologists are encountering in their practice. As McCloskey and Yang point out, there are multiple parallel efforts to educate the radiation oncology community via lectures, workshops, and development of consensus guidelines.