Andrew G. Renehan, PhD
In a study reported in The Lancet Oncology, Sekhar and colleagues found that the increasing proportion of lymph node–positive disease associated with enhanced detection techniques has led to nodal stage migration in anal cancer, which may reduce prognostic discrimination on the basis of lymph node positivity. Andrew G. Renehan, PhD, of the University of Manchester, The Christie NHS Foundation Trust, is the corresponding author of The Lancet Oncology article.
The current study aimed to assess the impact of nodal stage migration on survival in squamous cell carcinoma of the anus and evaluate the hypothesis that the phenomenon results in reduced prognostic discrimination. A systematic review and meta-regression analysis of study-level data were performed to quantify changes in lymph node positivity over time and the impact of such change on survival and prognostic discrimination, with the review including studies reported between January 1970 and October 2016. Overall, 62 studies with 10,569 patients reporting lymph node positivity proportions were identified, including 45 studies with 6,302 patients with whole cohort 5-year overall survival, 11 studies with 5-year survival stratified by nodal status, and 20 studies with hazard ratios for analysis of temporal changes in lymph node positivity and outcomes.
Nodal Stage Migration and Outcomes
In the 62 studies, lymph node positivity proportions increased from a mean of 15.3% in 1980 to 37.1% in 2012 (P < .0001). In the analysis of the 45 studies, 5-year overall survival increased from a mean of 64% in 1980 to 75% in 2010. In the 11 studies reporting overall survival by nodal status, prognostic discrimination between lymph node–positive and lymph node–negative patients declined with increasing observed lymph node positivity. Thus, at 20% lymph node positivity, the difference between mean predicted 5-year overall survival for lymph node–negative patients (70%) minus lymph node– positive patients (47%) was 23%, whereas the difference at 35% lymph node positivity was reduced to 15%. The proportion of patients with combined stages T3 and T4 disease remained constant at 41.3% in 1990 and 38.9% in 2012, indicating that nodal stage migration was not associated with a corresponding change in T stage at presentation.
Meta-regression analysis of 20 studies providing hazard ratios for overall survival by nodal status showed that across lymph node positivity proportions increasing from 15% to 40%, the hazard ratios for lymph node–positive vs lymph node–negative disease decreased from 2.5 to 1.3 (P = .014). Simulated scenarios reproduced this effect when the true lymph node positivity proportions were 20% or 25% but not if the true lymph node positivity proportion was 30% or greater.
The investigators concluded: “We describe a consequence of staging misclassification in anal cancer that we have termed reduced prognostic discrimination. We used this new observation to infer that the [lymph node positivity] proportions of more than 30% seen in modern clinical series (11 of 15 studies with a median year since 2007) are higher than the true [lymph node positivity] proportion. The introduction of new staging technologies in oncology might misclassify true disease stage, spuriously informing disease management and ultimately increasing the risk of overtreatment.” ■