The Real Estate of Gastric Cancer Induction Therapy: Location Versus Intrinsic Molecular Architecture

Abstract

Midstage gastric cancer, although deemed resectable, imparts considerable survival hazards as a result of postoperative disease recurrence. Although local and regional disease control are frequently, but not always, feasible via R0 resection and extended lymphadenectomy, operative treatment cannot affect the extraregional recurrence risks that specifically result from hematogenous (visceral) and transserosal (peritoneal) progression. Several approaches to perioperative adjuvant therapy of gastric cancer have shown benefits in postoperative survival, including postoperative chemoradiation, postoperative systemic chemotherapy, postoperative intraperitoneal chemotherapy, and perioperative systemic chemotherapy. Despite, or perhaps because of, these variable approaches, we have no single standard of adjuvant therapy as of today. Preoperative induction therapy is of particular interest, as it can diminish the disease extent resulting in greater R0 rates; it also provides response assessment with affiliated prognostic implications, as major primary tumor responses have been associated with superior survival. In the current issue of Annals of Surgical Oncology, Reim et al. present data from a high-volume center’s longstanding experience with preoperative chemotherapy of gastric cancer. Postoperative outcomes are superb and confirm the center’s preeminent status of excellence. The specific findings suggest that adenocarcinomas of the esophagogastric junction (AEG) were more likely to respond to preoperative therapy than gastric cancers of the remainder of the stomach (GC). The authors conclude that this may help identify patients who benefit from preoperative therapy. Data from a large patient cohort such as that reported by Reim et al. deserve to be carefully analyzed and assessed for their impact on the discussion regarding preoperative adjuvant therapy, even when based on a retrospective analysis. What can we learn from this experience, and are the findings sufficient to answer questions we have in our current approach to midstage gastric cancer? Location of the primary tumor within the stomach has long been known to carry prognostic information; resection of proximal cancers of equal pathologic stage has resulted in lower survival than distal lesions. Should intragastric location now also be considered as predictor for the likelihood of induction therapy response or benefit, perhaps to the extent of not offering GC lesions preoperative cytotoxic therapy? We are not so certain about the latter aspect. Increasing evidence suggests that we can consider gastric cancer a spectrum of different diseases on the basis of identifiable molecular genetic mechanisms with variable biologic behavior and degrees of therapeutic susceptibility. In light of the complexity of molecular and biologic mechanisms at work, it almost appears too crude to be able to classify gastric cancers within merely two anatomic location groups and expect the response rates to follow suit. In the data presented, lesions in the GC cohort were more frequently advanced (by T category), poorly differentiated, and of nonintestinal type; somewhat surprisingly, more than 20 % of patients overall underwent resection despite M1 disease extent. Does the combination of these adverse prognostic factors within the GC group explain the lesser response rate compared to the AEG cohort, and is the intragastric location therefore a mere surrogate for this unfavorable constellation? For example, the phenotypic Lauren classification, a useful prognostic parameter, has also been linked to induction cytotoxic therapy responses, with complete response rates of 53 % for intestinal and 28 % for nonintestinal tumor. How do the Munich data compare to other studies that have helped establish a role for chemotherapy for gastric cancer, irrespective of the intragastric tumor location? Society of Surgical Oncology 2012