Wednesday, 6 June 2018

Preoperative Chemo Improves Outcomes in Node-Negative Gastric Cancer

In patients with gastric cancer who receive chemotherapy before gastrectomy, resulting in downstaged disease (cN+ ypN0), overall survival is similar to that of patients with natural node-negative disease (cN0 ypN0), according to a recent study. The report is the first to shine a light on this clinical question.
“In this retrospective cohort study, ypN status is a significant prognostic factor for overall survival [OS]. However, there is no survival difference between natural N0 and downstaged N0 patients,” said lead author Naruhiko Ikoma, MD, MS, a surgeon at the University of Texas MD Anderson Cancer Center, in Houston. He presented the study results at the 2018 Society for Surgical Oncology Annual Cancer Symposium (abstract 4).
In the United States, the standard of care for localized gastric cancer is preoperative chemotherapy followed by gastrectomy, based on data from multiple clinical trials showing that preoperative chemotherapy increases survival (N Engl J Med 2008[1];358:36-46; J Clin Oncol 2011;29[13]:1715-1721). Today, more than half of patients receive preoperative chemotherapy before gastrectomy (Cancer 2018;124[5]:998-1007).
This treatment shift brought about a need for changes to staging, and in 2018, the yp stage was introduced for gastric cancer patients who undergo preoperative chemotherapy or chemoradiation therapy in the American Joint Committee on Cancer’s AJCC Cancer Staging Manual, Eighth Edition. The staging manual uses the TNM system for gastric cancer staging, based on the size of the tumor (T), spread to nearby lymph nodes (N) and metastases to distant sites (M). In a previous analysis of patients at MD Anderson Cancer Center, those with node-negative disease on final pathology had uniformly good outcomes among patients with a status of ypT0-3, with no differences in survival (Gastric Cancer2018;21[1]:74-83). Because of limited data, the TNM group designation of ypT0 patients has not yet been defined. In addition, whether downstaged N0 patients (cN+ ypN0 disease) and natural N0 patients (cN0ypN0 disease) have similar survival is unknown.
Dr. Ikoma and his colleagues conducted a retrospective cohort study using a prospectively maintained database of patients with gastric cancer treated at MD Anderson Cancer Center. They included 316 patients with gastric adenocarcinoma, including Siewert type III gastroesophageal junction tumors, who underwent R0 resection for nonmetastatic disease after preoperative chemotherapy or chemoradiation therapy. The majority of the study population was male (62%) and white (56%); 23% had gastroesophageal junction tumors, and 76% received chemoradiation.
The researchers categorized patients into three groups based on nodal status: natural N0 (cN0/ypN0; n=94), downstaged N0 (cN+/ypN0; n=93), or node-positive (ypN+; n=129). Compared with the natural N0 disease group, the downstaged N0 disease group was more likely to have advanced clinical T category cases (P<0.001), to receive preoperative radiation therapy (90% vs. 76%), and to undergo total gastrectomy (61% vs. 39%). “The ypT category was grossly similar between those two groups,” Dr. Ikoma said.
With a median follow-up of 3.1 years, the median OS was 7.7 years, and the five-year OS was 60.3%. “There is no survival difference between natural N0 and downstaged N0 group, even though the downstaged N0 group had a more advanced baseline clinical T category,” Dr. Ikoma said. “As expected, node-positive patients had worse overall survival.” In a sensitivity analysis stratified by ypT category (ypT0-2 or ypT3-4; P=0.936 and P=608, respectively) and in a Cox regression analysis that adjusted for various factors that could influence survival, outcomes were similar in the natural N0 and downstaged N0 groups.
“ypN0 status is an important hallmark representing a successful preoperative treatment, regardless of pretreatment clinical nodal status in gastric cancer patients,” Dr. Ikoma said. The results can be generalized to other institutions, he said.
During a question-and-answer session after the presentation, Daniel Coit, MD, FACS, a surgeon at Memorial Sloan Kettering Cancer Center, in New York City, asked for further data. “Patients who get radiation therapy have an exaggerated local response that may impact both T and N downstaging, but may have a less impact on systemic disease, as opposed to those patients who are downstaged by chemotherapy alone,” he said. “Did you find any difference in outcome of those patients who achieved ypN0 status, depending on whether they got chemotherapy or chemoradiation?”
Dr. Ikoma responded that there was a distinction between those preoperative treatment groups. “Patients who had a complete response after chemoradiation had worse outcomes compared with if they received chemotherapy alone.”
This answer, Dr. Coit said, highlights the difference between assessing response at the primary and assessing the effect of a treatment on survival. “If you get a complete response after chemotherapy, that is likely to impact long-term survival. On the other hand, if you get a complete response after chemoradiation, where radiation exaggerates the complete response, you don’t see quite the same advantage. It is a subtle, but very important difference,” Dr. Coit said. “A lot of people advocate for chemoradiation therapy by saying there is a much higher local response rate and complete resection rate. That may be true, but it may be irrelevant to survival. People die of systemic disease, and that is what the treatment should be aimed at.” - Kate O’Rourke
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