Postoperative Chemoradiation or Chemotherapy After Preoperative Chemotherapy for Gastric Cancers

Gastric adenocarcinoma, also known as stomach cancer, is a global health problem. While surgical resection remains the only curative option for patients who develop this disease, because of its aggressive nature and high recurrence rates, all but the lowest stages of gastric cancer require additional, adjuvant therapy in addition to surgery. Currently, two competing standards exist for the adjuvant management of gastric cancer: peri-operative chemotherapy (based upon the MAGIC study), and postoperative combination chemoradiation therapy (based upon the MacDonald Intergroup study). These two standards were arrived at based upon two separate trials that did not directly compare the two approaches, and thus either approach is considered acceptable. Several modifications to the chemotherapy used in the peri-operative approach have been studied and are now accepted as standard as well. Selection oftentimes derives from physician preference and tumor characteristics such as symptoms or nodal stage, and a clear guideline for when to select one adjuvant approach over the other is lacking.

Currently, analysis of patient outcomes from the large, randomized phase III CRITICS trial is ongoing, and will attempt to answer if one approach is clearly favored. Patients enrolled in the CRITICS trial all received preoperative chemotherapy and standardized surgical resection. Patients were then randomized to receive either chemotherapy or chemoradiation therapies postoperatively. Enrollment is closed for the CRITICS trial; preliminary data suggest that neither arm of postoperative treatment is superior. These early data support what practitioners have long suspected, which is that no one adjuvant standard is universally superior, but that tumors from different patients and with different characteristics will respond better to different adjuvant approaches.

Unfortunately, knowing which tumors will respond better to which therapy remains unpredictable. Certain clinical features can help clinicians to make a recommendation for their adjuvant approach. For example, patients who have tumors that are symptomatic, such as with bleeding or gastric obstruction, are less likely to tolerate several months of surgical delay while chemotherapy is administered preoperatively, and thus will typically be offered upfront surgery, followed by adjuvant chemoradiation. For most patients, however, the administration of systemic therapy prior to surgery as a part of a perioperative approach is recommended. This approach is favored because of the local control and reduction in tumor that can result prior to surgery, which is thought to lead to better outcomes in the long term.

However, not all patients will experience a response to preoperative chemotherapy. In those patients whose tumors are found at surgery to remain advanced, with nodal involvement, despite preoperative chemotherapy, long-term outcomes have been shown to be poorer than those whose tumors responded well, with the absence of nodal involvement upon dissection. These data are based upon the retrospective analysis of those patients who were enrolled in the original MAGIC study. Approximately 75% of tumors were found to be in the category of having nodes involved with cancer at resection despite preoperative chemotherapy. Thus, for this majority of patients with gastric cancer who have an inadequate response to preoperative chemotherapy (i.e., who remain node-positive at surgery), an alternative approach to their postoperative adjuvant treatment rather than mere completion of postoperative chemotherapy is apparently necessary.

One reasonable alternative for the management of patients who remain node positive at surgery could be to incorporate radiation into their postoperative adjuvant treatment. There is some evidence for this approach, coming from the South Korean ARTIST trial. In the ARTIST trial, patients who underwent gastrectomy for stomach cancer randomly received either post-operative chemotherapy or chemoradiation therapy. Although no overall survival benefit was seen overall in the ARTIST study, in subset analysis, node positive patients had a significant improvement in disease-free survival with adjuvant chemoradiotherapy versus adjuvant chemotherapy alone.

The disparity in tumor responses to preoperative chemotherapy supports biologic heterogeneity of these tumors. Understanding these biologic differences would be invaluable to the future therapeutic direction of their management. These differences are likely complex, existing as baseline genetic characteristics at diagnosis but also as dynamic changes in these characteristics in response to chemotherapy. Identifying these characteristics could allow clinicians to determine which patients' tumors are unlikely to respond to therapy upfront or how to modify ongoing therapy in response to tumor response and evolution as therapy is administered. Knowing that tumor nodal response to preoperative chemotherapy is a surrogate for outcomes in these patients can provide an important comparator for groups of gene expression and evolution.

Recent work into the characterization of gastric adenocarcinoma suggests that four distinct molecular subtypes exist. These subtypes are characterized as Epstein-Barr virus positive, microsatellite unstable, genomically stable, and chromosome instable. Determination of the genetic features giving rise to each category is based upon analysis of virgin tumor samples, and thus does not consider variations that arise in response to treatment. Nevertheless, each subtype is characterized by the expression or mutation of specific genes or gene categories that can be profiled through routine analysis. Correlating these gene expressions to clinical nodal responses to chemotherapy could potentially offer insights into the biomarker driven determination of adjuvant treatment selection in gastric cancer. Additionally, monitoring these gene expression levels in response to therapy and making similar correlates could provide valuable information into the adaption of adjuvant therapy to the tumor's response to treatment in real time.

The genes associated with these four proposed subtypes of gastric cancer are by no means exhaustive, however, and the expression or alteration of other genes may yield further predictive and therapeutic information for the adjuvant treatment of these cancers. Casting a wider net is increasingly easy to accomplish, with the advent of genomic profiling of tumors. Particularly in the case of profiles that assess for expression of targetable genes, the ability to assess or monitor for their expression as they relate to chemotherapy response could have important implications for being able to incorporate the therapies into the adjuvant treatment process at critical junctures in the treatment sequence.