The Phenomenon of “Therapeutic” Nodal Yield at Cystectomy for Bladder Cancer: Do Not Discount the Will Rogers Effect

The role of lymphadenectomy and lymph node (LN) yield during radical cystectomy (RC) for patients with urothelial cell carcinoma (UCC) remains a point of ongoing debate. Multiple retrospective studies have demonstrated a survival advantage when more, compared with fewer, LNs are removed [, ]. Multiple potential mechanisms for the improvement in outcomes with higher LN yield have been proposed: (1) a direct therapeutic benefit of removal of cancerous LNs; (2) modification of treatments and earlier intensification of adjuvant treatments on identification of pN+ disease; and (3) LN yield acting as a surrogate marker for surgeon or institutional factors associated with a higher quality of care across the disease continuum []. While the effect of these factors on patient survival is a matter of debate, the influence of stage migration, also known as the Will Rogers effect, is an often-underappreciated and yet simpler (and arguably more likely) explanation of these findings. The origin of the term in the medical vernacular has been attributed to Dr. Michael McFarlane referencing the following Will Rogers quote: “When the Oakies left Oklahoma and moved to California, they raised the average intelligence level in both states” []. In the context of bladder cancer and increasing LN yield, surgeons are shifting patients with low-volume pN+ disease (Oakies moving to California), which would have been indexed as pN0 (Oklahoma residents), to the pN+ state (California residents). Thus, removal of pN+ contamination from the pN0 cohort leads to an apparent improvement in outcomes for the pN0 group. Furthermore, the pN+ cohort also “benefits” by appearing to have superior outcomes when more nodes are removed, as patients with the lowest volume of pN+ disease, who have a more favorable prognosis than those with high-volume pN+ disease, are now included in the pN+ group. Thus, because of migration of individuals between states (of the USA or of an oncologic condition), both groups appear to benefit from Oakie migration and higher-volume LN dissection, despite the fact no individual has gained intelligence or lived longer and the outcome for the population as a whole did not change.

To illustrate the influence of the Will Rogers effect on outcomes, we provide an analysis of how greater LN yield, even when all resected LNs are negative, is associated with better outcomes. By including only patients with pN0 disease, we aimed to mitigate other hypothesized effects of lymphadenectomy such as a direct therapeutic effect of debulking of cancerous LNs or a change in management or treatment intensification on detection of pN+ disease.

We reviewed the National Cancer Database (NCDB) for patients diagnosed with cTany N0 M0 UCC from 2004 to 2016 who underwent RC and lymphadenectomy. Patients with non-UCC histology and those with pathologically positive disease (pN+) were excluded. The main independent variable was LN yield. The primary dependent variable was overall survival (OS). OS probability was estimated using the Kaplan-Meier method and survival curves were compared using the log-rank test. We fitted multivariable Cox proportional-hazard models with robust standard errors clustered by hospital and adjusted for multiple factors, including use of neoadjuvant or adjuvant systemic therapy, to assess for an adjusted association between LN yield and OS. LN yield was treated as both an unordered categorical variable (1–5, 6–10, 11–15, 16–20, 21–25, and ≥26 LNs) and a continuous variable. Kaplan-Meier curves were stratified using three different LN thresholds (greater or less than 5, 15, or 25 LNs). Subgroup analyses included patients with and without neoadjuvant systemic therapy among patients with muscle-invasive bladder cancer (MIBC).

We identified 19 939 patients with pN0 UCC who underwent RC and pelvic LN dissection, of whom 5154 had non–muscle-invasive bladder cancer (NMIBC) and 14 775 had MIBC (Supplementary Table 1). Median follow-up was 34 mo (interquartile range [IQR] 15–64) and the median LN yield was 14 (IQR 8–22). There were 7410 deaths during follow-up. LN yield was associated with better OS in the overall cohort (Fig. 1; p < 0.001), in the subgroups of patients with NMIBC (p < 0.001) and MIBC (p < 0.001) disease, and in the MIBC subgroups treated with (Fig. 1B; p < 0.001) and without (Fig. 1C; p < 0.001) neoadjuvant systemic therapy. After adjustment for multiple covariates, LN yield remained associated with better OS (Fig. 1A) when treated as both a categorical and a continuous variable. Patients with an LN yield of ≥26 had a 34% lower risk of death in comparison to patients with an LN yield of ≤5, despite the fact that none of the resected nodes harbored cancer. Furthermore, when we increased the LN threshold from 5 to 15 to 25 LNs for dichotomization, median OS increased from 83 to 95 to 103 mo, respectively (Fig. 1D).

Although we cannot discount the possibility that other potential mechanisms are at play, the marked and orderly “therapeutic effect” of resecting LNs that are negative for cancer very strongly points to the Will Rogers phenomenon as the explanation for the effect observed. Resection of a greater number of nodes means that the pN0 cohort evaluated is simply of higher fidelity and is less likely to be contaminated by patients with oligometastatic pN+ disease. Despite the fact that no patient’s therapeutic destiny may have been altered when more LNs were resected, the pN0 group with higher LN yield appears to live longer in this analysis because of the artifact of how patients are indexed.

Despite numerous retrospective series demonstrating an improvement in oncological outcomes with larger and more extensive LN dissections, level 1 evidence is absent. The one published randomized trial assessing standard versus extended lymphadenectomy failed to demonstrate statistically significant differences in recurrence-free survival, cancer-specific survival, or OS between the standard and extended lymphadenectomy groups []. However, the trial results do not fit the classic narrative and thus its findings have been criticized. Results from SWOG 1011, which randomized more than 650 patients to extended or standard lymphadenectomy, are yet to be reported and are likely to shed more light on the debate.

In addition to the nonrandomized nature of our analysis, which may introduce selection bias, this analysis is limited by the lack of centralized pathology review, which is not feasible in the NCDB.

These data provide a plausible explanation for the therapeutic yield phenomenon seen in the management of not only bladder cancer but also urothelial cancer of the upper urinary tract, prostate cancer, and kidney cancer. The persisting narrative that a greater number of resected LNs results in better outcomes is likely to find itself down for the count as the often-discounted Will Rogers effect may prevail with the maturation of definitive prospective trials.

Author contributions: Kevin B. Ginsburg had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Ginsburg, Kutikov, Magee, Schober, Bukavina.

Acquisition of data: Ginsburg, Kutikov.

Analysis and interpretation of data: Ginsburg, Kutikov.

Drafting of the manuscript: Ginsburg, Bell, Kutikov.

Critical revision of the manuscript for important intellectual content: Ginsburg, Bell, Kutikov, Bukavina, Schober, Magee.

Statistical analysis: Ginsburg.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Kutikov.

Other: None.

Financial disclosures: Kevin B. Ginsburg certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.

Funding/Support and role of the sponsor: None.