ASO Author Reflections: Nodal Downstaging in Gastric Cancer

PAST

We have been experiencing a paradigm shift in gastric cancer treatment over the past decade, from surgery alone to multimodality therapy. Most notably, since the MAGIC trial demonstrated a survival benefit with perioperative therapy, the use of preoperative chemotherapy has sharply increased.¹ This shift necessitated an update in the AJCC staging system, and the new postneoadjuvant ypStage TNM grouping was introduced in the 8th edition.² Although this concept was novel, due to the paucity of the actual survival data of patients who underwent preoperative therapy, the ideal ypTNM grouping is unknown. As part of our programmatic investigation of this topic, we examined the survival impact of downstaging; more specifically, whether patients with clinically node-positive disease (cN+) converted to pathologically N0 (ypN0) status can achieve similar survival to patients with N0 status before preoperative therapy (cN0 and ypN0).³

PRESENT

In our study, 76% of patients underwent preoperative chemoradiation therapy, and 24% patients underwent chemotherapy only, before undergoing R0 gastrectomy.³ We grouped them into three groups: cN0/ypN0, cN+/ypN0, and ypN+ group. Analyses showed that ypN0 patients had significantly better survival compared with ypN+ patients, regardless of cN status, indicating nodal downstaging provides survival benefit, and those patients can achieve “node-negative” survival. Given our previous reports identifying uniformly good survival among ypT0-3N0 patients, we consider ypN0 status is a hallmark of successful preoperative treatment for gastric cancer.^4,5

FUTURE

In this new era of preoperative therapy for gastric cancer, many questions require further research. Staging after preoperative therapy (ypStage) As mentioned above, the ideal ypTNM grouping is unknown. Moreover, because treatment effect on the primary tumor significantly differs depending on the regimen of therapy, we may need a subcategory of ypStage (e.g., for patients who underwent preoperative chemoradiation therapy, or chemotherapy alone). Multi-institutional studies, including variations in practice, are warranted. Impact of tumor regression grade [TRG] Pathologists score TRG based on treatment effect (or proportion of residual viable tumor cell) observed in pathologic evaluation, but its survival impact is unknown. Treatment stratification There is not strong evidence who benefits, and who does not, from perioperative therapy. The current study results indicated that patients with cN+ are the likely the population who benefit the most from preoperative therapy, if they achieved ypN0 disease. Future studies to predict treatment response accurately in advance are warranted. Lastly, Molecular classification of gastric cancer There is a growing science in genomic technologies, such as next-generation sequencing in gastric cancer, that describes the wide heterogeneity of gastric cancer in genetic and epigenetic levels.⁶ Such technologies may provide effective classification of gastric cancer and guide treatment, including molecular-targeted therapies.