Association of chemotherapy with survival in node-positive penile squamous cell carcinoma stratified by nodal burden: A National Cancer Database analysis.

Abstract

e17033 Background: Node-positive penile squamous cell carcinoma (PSCC) carries a poor prognosis, yet the survival benefit of systemic chemotherapy remains uncertain given the lack of completed randomized trials and reliance on limited phase II and retrospective data. Although NCCN guidelines recommend chemotherapy for patients with ≥3 positive lymph nodes, whether chemotherapy benefit differs by pathologic nodal burden has not been formally evaluated using interaction analysis. We hypothesized that chemotherapy is associated with improved overall survival (OS) among patients with high nodal burden (≥3 nodes) but not among those with low nodal burden (1–2 nodes). Methods: Using the National Cancer Database (2004–2022), we identified adults with pathologically node-positive, nonmetastatic PSCC who underwent regional lymph node dissection with numeric nodal counts available. Heterogeneity of treatment effect by nodal burden was formally assessed using a chemotherapy × nodal burden interaction term. Nodal burden was classified as low (1–2 positive nodes) or high (≥3 positive nodes). OS was estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariable Cox proportional hazards regression adjusted for age, race, ethnicity, Charlson-Deyo comorbidity score, T stage, tumor grade, primary tumor surgery, radiotherapy, facility type, insurance status, and year of diagnosis. A 90-day landmark analysis was performed to mitigate immortal time bias. Results: Among 1,300 patients, 589 (45%) received chemotherapy. A statistically significant chemotherapy × nodal burden interaction was observed (p = 0.009), indicating differential survival associations by nodal burden. In the overall cohort, chemotherapy was not associated with OS (log-rank p = 0.47). Among patients with high nodal burden, chemotherapy was associated with improved OS (adjusted HR 0.76, 95% CI 0.59–0.98, p = 0.03; log-rank p = 0.002), with median OS of 35.9 months compared with 20.6 months for those not receiving chemotherapy. In contrast, among patients with low nodal burden, chemotherapy was not associated with improved OS (adjusted HR 1.19, 95% CI 0.95–1.49, p = 0.13; median OS 59.0 vs 65.7 months; log-rank p = 0.79). Findings were consistent in landmark analyses (interaction p = 0.008). Conclusions: In this large national cohort, the association between chemotherapy and survival in node-positive, nonmetastatic PSCC differed significantly by pathologic nodal burden. Chemotherapy was associated with improved survival among patients with ≥3 positive lymph nodes but not among those with limited nodal involvement. These findings demonstrate clinically meaningful heterogeneity in chemotherapy benefit and may inform more precise patient selection for systemic therapy in node-positive PSCC.