Characteristics, Treatment and Outcomes of Patients with Primary Urethral Cancer: A Multi-Center Review over Two Decades

Abstract

<h3>Purpose/Objective(s)</h3> Primary urethral cancer is an uncommon and aggressive malignancy that accounts for less than 1% of all genitourinary malignancies. Due to its rarity, no prospective trials exist to formally guide treatment. Current approaches are informed by retrospective series and extrapolation from other genitourinary cancers. In this study, we sought to characterize the management trajectory of consecutive patients with urethral cancer in our hospital system over the past 2 decades. <h3>Materials/Methods</h3> The medical records of all adult patients who had received treatment for urethral cancer between January 2000 and December 2021 within a multi-center academic hospital system were queried. Baseline clinicopathologic features, treatment details, and progression were recorded and stratified by histology. Survival analysis was performed using multivariable Cox proportional hazards regression. <h3>Results</h3> There were 37 females and 31 males with urethral cancer included in this analysis, of whom 45 (66%) presented with at least stage III disease. Median age at diagnosis was 69 years (IQR 59–74) and median follow-up was 24 months (IQR 7–48). The most common histologies consisted of squamous cell carcinoma (SCC, 29%), urothelial carcinoma (UC, 28%), and adenocarcinoma (AC, 28%). Compared to all other histologies, SCCs were more likely to present in the distal urethra (85% vs. 35%, <i>P</i><0.001) and with regional nodal involvement (50% vs. 19%, <i>P</i>=0.020), while UCs were more often diagnosed in males (74% vs. 35%, <i>P</i>=0.011). ACs tended to feature larger primary tumors with more frequent indication for exenteration in resectable settings (41% vs. 12%, <i>P</i>=0.041). Receipt of any neoadjuvant therapy (N=11), rather than any adjuvant therapy (N=14) or surgery alone (N=26), was associated with a trend toward longer distant recurrence-free survival among patients who underwent curative-intent resection (median not reached vs. 72 months, HR 0.22, 95% CI 0.04–1.10, <i>P</i>=0.065) after adjustment for age, sex, and stage. Among patients who received curative-intent external beam radiation (N=27), additional high-dose rate (HDR) brachytherapy (N=10) conferred superior locoregional control (median 48 vs. 19 months, HR 0.21, 95% CI 0.05–0.91, <i>P</i>=0.038). Urethral stricture requiring operative dilation was noted in 3 patients, of whom 2 had received HDR brachytherapy. <h3>Conclusion</h3> Urethral cancer is an uncommon malignancy with sparse evidence to guide treatment, especially for rarer histologies including neuroendocrine carcinoma, sarcoma, and mucosal melanoma. While further prospective studies are warranted, the addition of neoadjuvant chemotherapy and/or radiotherapy prior to surgery, as well as HDR brachytherapy following external beam radiation, may be considered in the multi-disciplinary management of urethral cancer.