Negative Lymph Nodes Predict Survival in Stage III Colon Ca

SAN FRANCISCO—The number of negative lymph nodes identified during surgical resection of stage III colorectal cancer predicts long-term survival independently of the number of positive nodes identified, new data show. Lead author Nancy N. Baxter, MD, PhD, a colon and rectal surgeon at St. Michael's Hospital, Toronto, presented the study results at the 2006 Gastrointestinal Cancers Symposium (abstract 219).

Studies of the association between total number of lymph nodes evaluated and survival in stage III colorectal cancer have yielded inconsistent results, Dr. Baxter said. "This is likely because total number of nodes is a factor, of course, of both number of positive nodes and number of negative nodes," she noted. "We know that a higher number of positive nodes is associated with a worse prognosis, where—as we think it's potentially possible that the number of negative nodes is associated with a better prognosis, so you have two competing factors that add up to the total number of nodes."

Dr. Baxter and her colleagues analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database from patients with invasive adenocarcinoma of the colon or rectum that was stage III based on AJCC staging criteria. All of the patients had undergone radical surgery, and none had received preoperative radiation therapy. The cancer had been diagnosed between 1988 and 1997, and follow-up was conducted through 2002. In analyses, patients were stratified into quartiles based on the number of negative lymph nodes identified (≤ 3, 4-7, 8-12, and ≥ 13).

The study included 24,289 patients with stage III disease; the substage was IIIA in 10%, IIIB in 58%, and IIIC in 32%. The mean age of the population was 68 years; researchers identified a median of seven negative nodes and two positive nodes. "The correlation between the total number of positive lymph nodes and the total number of negative lymph nodes was negligible-to-weak for our substages, ranging from -0.03 to -0.13," Dr. Baxter noted.

Incidence of Death

During the mean 5.1-year follow-up, the incidence of death from colorectal cancer was 16%, 34%, and 47% in the stage IIIA, IIIB, and IIIC groups, respectively. Cancer-specific survival did not differ by quartile of number of negative lymph nodes among patients with stage IIIA disease, but increased significantly with quartile among patients with stage IIIB and IIIC disease.

Comparing patients in the highest quartile of negative lymph nodes (≥ 13) with those in the lowest (≤ 3), the 5-year cumulative survival was essentially the same in stage IIIA disease (88% vs 87%), but differed substantially in stage IIIB disease (73% vs 56%) and in stage IIIC disease (61% vs 39%).

In a multivariate model that included age, sex, race, tumor grade, tumor location, registry, and both positive and negative lymph node counts, patients in the highest quartile of number of negative lymph nodes were significantly less likely than their counterparts in the lowest quartile to die in the stage IIIB group (hazard ratio [HR] 0.54, P < .0001) and the stage IIIC group (HR 0.49, P < .0001).

In addition, patients in the lowest quartile of number of positive lymph nodes were significantly less likely than their counterparts in the highest quartile to die in the stage IIIB group (HR 0.69, P < .0001) and the stage IIIC group (HR 0.56, P < .0001). In the stage IIIA group, only lowest quartile of positive lymph nodes was associated with a reduced risk of death (HR 0.61). Dr. Baxter noted there was no significant interaction between number of negative and number of positive nodes.

In a final analysis considering the combined influence of both negative and positive lymph node counts, cancer-specific survival in the stage IIIB and IIIC groups was best among patients who simultaneously had the most negative nodes and the fewest positive nodes, and was poorest among patients who simultaneously had the fewest negative nodes and the most positive nodes. Survival was intermediate among patients with some combination of these categories.

"Number of negative lymph nodes predicts survival in the majority of patients with stage III disease," Dr. Baxter concluded. Moreover, not only is this effect independent of the effect of positive lymph nodes, but it also appears to be of the same magnitude. "So it's an important factor to consider when assessing an individual patient's probability of recurrence," she asserted.

As for the mechanism linking negative lymph node count to survival, Dr. Baxter said, "undoubtedly, some of this is due to stage migration—if you identify only a very small number of lymph nodes, you are likely missing many lymph nodes, and some of them may be positive. However, this effect is significant even at the extremes of staging." A second mechanism could be quality of pathology, she said, but this is unlikely because the association was still evident in stage IIIC disease, in which large numbers of nodes were harvested. A third mechanism could be the quality of surgery, Dr. Baxter said, but this also is unlikely because the association was stronger for colon cancer than for rectal cancer, whereas quality of surgery is known to be more important for the latter.

"So we are left with a question of whether this is a marker of host immunologic status or a marker of tumor-host interaction or antigenicity of the tumor," she said. "I think this is an area that deserves more research because it potentially could be targeted for therapy."