Clinical outcomes of invasive primary urethral cancer: A real world multi-institutional study.
Authors: Garje Rohan , Ganiyani Mohammad Arfat , Barata Pedro C. , Mathew Thomas Vinay , Agarwal Neeraj , Adra Nabil , Kanesvaran Ravindran , Drakaki Alexandra , Cabral Marsenne Y. , Esteban Villarrubia Jorge , Castellano Daniel , Necchi Andrea , Spiess Philippe E. , Apolo Andrea B , Sonpavde Guru P. 
Published: February 2025

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Background:
Primary urethral cancer (PUC) is a rare and highly aggressive malignancy with a spectrum of various histologies without an established treatment approach. Due to the lack of prospective studies in patients with PUC, the clinical outcomes with different treatment modalities are unknown. We aimed to investigate the clinical outcomes based on various treatment approaches and histology.
Methods:
Our retrospective study included patients from 10 international cancer centers in the United States, Europe, and Asia. Eligibility criteria included patients diagnosed with invasive PUC based on the TNM stage (T2-T4, N0-N2). We defined disease free survival (DFS) as time from date of cancer diagnosis to recurrence or death, whichever came first. We utilized Kaplan-Meier survival analysis to study the DFS rate.
Results:
We identified 82 patients diagnosed with PUC, of which 60% were men and 40% were women. The common histologies were urothelial carcinoma (40%), squamous carcinoma (32%), adenocarcinoma (12%). Patients had stage II (30%), III disease (26%) and IV disease (44%). In this cohort 51% underwent surgery only (S), 19% received neoadjuvant chemotherapy f/w surgery (NCT), 11% received concurrent chemoradiation f/w by surgery (CRT), 2% received radiation f/w surgery. In our cohort 43% patients had recurrence of disease. In our study cohort, the DFS rate was 54 % after a median follow up of 15.5 months. The 2-year DFS rates were 64.2% for urothelial carcinoma, 45.7% for adenocarcinoma, and 40.0% for squamous cell carcinoma. Based on treatment, 2-year DFS rates were 68% for NCT, 58.3% for CRT, and 46% for S respectively. Median DFS rate was 41 months in patients with lymph node metastasis (LMN) vs 30 months in patients without LMN. Among 14 patients who underwent genomic testing, the most common gene alterations were seen in PIK3CA (35%), PTEN (21%), ERBB-2 (14%) and CDKN2A/B (28%).
Conclusions:
The management of PUC is complex given the variable histologies. Clinical outcomes appear suboptimal with high rates of recurrence in patients with invasive PUC regardless of histology, treatment, and sex. While our study is limited by its retrospective design, sample size and limited follow up, data suggest that multimodal therapy incorporating chemotherapy with or without radiation may offer better outcomes in invasive PUC. Future large scale prospective studies are needed to optimize treatment approaches in patients with PUC.

2-year DFS based on histology, treatment approach and stage.

Survival rate (%) [95%CI]

DFS (Histology)

Urothelial
64 [43 - 79]

Adenocarcinoma
45 [14 - 72]

Squamous
40 [17 - 61]

DFS (Treatment)

S
46 [29 - 62]

NCT
68 [35 - 86]

CRT
58 [18 - 84]

DFS (Gender)

Male
51 [34 - 66]

Female
51 [31 - 67]

DFS (AJCC stage)

II
62 [39 - 79]

III
50 [29 - 70]

IV
50 [25 - 67]