Assessment of the external validity of the AJCC 8^th staging system for small intestinal adenocarcinoma: A time to reconsider the role of tumor location?

Background: The current study evaluates the validity and performance of the 8th edition of the American Joint Committee on Cancer (AJCC) staging system for small intestinal adenocarcinoma patients. Methods: Surveillance, Epidemiology and End Results (SEER) database [2004-2015] was explored and AJCC 6th, 7th, and 8th versions were assigned for each patient. Through Kaplan-Meier estimates, overall survival analyses were conducted. Cox regression analysis (adjusted for age, race, gender, sub-site, grade and surgical treatment) was conducted for cancer-specific survival and additionally, pairwise hazard ratio comparisons were performed. Results: A total of 2,997 small intestinal adenocarcinoma patients were eligible and included in the analysis. Overall survival was compared according to the three AJCC staging systems. For the three versions, the P value for the trend in overall survival was significant (P<0.0001). Cancer-specific Cox regression hazard was calculated for the three staging systems. Pairwise hazard ratio comparisons between different AJCC 6th stages were conducted and all P values for comparisons were significant (P<0.0001). Pairwise hazard ratio comparisons between different AJCC 7th and 8th stages were also performed, and all comparisons were significant (P<0.05) except for stage IIB vs. IIIA. C-statistic (using death from small intestinal adenocarcinoma as the dependent variable) for AJCC 6th staging system was: 0.645 [standard error (SE): 0.011; 95% CI: 0.623-0.668]; for c-statistic for AJCC 7th staging system was 0.658 (SE: 0.011; 95% CI: 0.637-0.680); while c-statistic for AJCC 8th staging system was 0.660 (SE: 0.011; 95% CI: 0.638-0.682). Multivariate analysis of factors affecting cancer-specific survival suggested that older age (P=0.005), higher lymph node ratio (P<0.0001) and duodenal localization of the primary are associated with worse outcomes (P=0.008). Conclusions: There is no evidence that AJCC 8th system provided better prognostic characterization compared to previous AJCC staging systems for small intestinal adenocarcinoma. Subsite-specific staging paradigms should be explored in future editions of the staging system.