7. DISEASE MANAGEMENT
7.1. Treatment of primary urethral carcinoma in males
Previously, treatment of male distal urethral carcinoma followed the procedure for penile cancer, with surgical excision of the primary lesion with a wide safety margin . Distal urethral tumours exhibit significantly improved survival rates compared with proximal tumours . Therefore, in the treatment of distal urethral carcinoma the focus of clinicians has shifted towards improving functional outcomes and quality of life (QoL), while preserving oncological safety. A retrospective series found no evidence of local recurrence, even with
< 5 mm resection margins (median follow-up: 17–37 months), in men with pT1–3N0–2 distal urethral carcinoma treated with well-defined penile-preserving surgery and additional iliac/inguinal lymphadenectomy (LND) for clinically suspected LN disease . Similar results for the feasibility of penile-preserving surgery have also been reported in recent series [71,72]. However, a series on patients treated with penile-preserving surgery for distal urethral carcinoma reported a higher risk of progression in patients with positive proximal margins, which was also more frequently observed in cases with lymphovascular and peri-neural invasion of the primary tumour .
7.1.1. Summary of evidence and guidelines for the treatment of primary urethral carcinoma in males
Summary of evidence
In distal urethral tumours performing a partial urethrectomy with a minimal safety margin does not increase the risk of local recurrence.
Offer distal urethrectomy as an alternative to penile amputation in localised distal urethral tumours, if negative surgical margins can be achieved intra-operatively.
Ensure complete circumferential assessment of the proximal urethral margin if penile preserving surgery is intended.
7.2. Treatment of localised primary urethral carcinoma in females
7.2.1. Urethrectomy and urethra-sparing surgery
In women with localised urethral carcinoma, to provide the highest chance of local cure, primary radical urethrectomy should include removal of all the peri-urethral tissue from the bulbocavernosus muscle bilaterally and distally, with a cylinder of all adjacent soft tissue up to the pubic symphysis and bladder neck. Bladder neck closure and appendicovesicostomy for primary distal urethral lesions has been shown to provide satisfactory functional results .
Previous series have reported outcomes in women with mainly distal urethral tumours undergoing primary treatment with urethra-sparing surgery, with or without additional radiotherapy (RT) compared to primary urethrectomy with the aim of maintaining integrity and function of the lower urinary tract [74,75]. In longer-term series with a median follow-up of 153–175 months, local recurrence rates in women undergoing partial urethrectomy with intra-operative frozen section analysis were 22–60%, and distal sleeve resection of > 2 cm resulted in secondary urinary incontinence in 42% of patients who subsequently required additional reconstructive surgery [74,75].
Ablative surgical techniques, i.e., transurethral resection (TUR) or laser, used for small distal urethral tumours, have also resulted in considerable local failure rates of 16%, with a CSS rate of 50%. This emphasises the critical role of local tumour control in women with distal urethral carcinoma to prevent local and systemic progression .
In women, RT was investigated in several older series with a medium follow up of 91–105 months . With a median cumulative dose of 65 Gy (range 40–106 Gy), the 5-year local control rate was 64% and 7-year CSS was 49% . Most local failures (95%) occurred within the first two years after primary treatment . The extent of urethral tumour involvement was found to be the only parameter independently associated with local tumour control but the type of RT (EBRT vs. interstitial brachytherapy) was not . In one study, the addition of brachytherapy to EBRT reduced the risk of local recurrence by a factor of 4.2 . Of note, pelvic toxicity in those achieving local control was considerable (49%), including urethral stenosis, fistula, necrosis, cystitis and/or haemorrhage, with 30% of the reported complications graded as severe .
7.2.3. Summary of evidence and guidelines for the treatment of localised primary urethral carcinoma in females
Summary of evidence
In females with distal urethral tumours, urethra-sparing surgery and local RT represent alternatives to primary urethrectomy but are associated with increased risk of tumour recurrence and local toxicity.
Offer urethra-sparing surgery, as an alternative to primary urethrectomy, to females with distal urethral tumours, if negative surgical margins can be achieved intra-operatively.
Offer local radiotherapy, as an alternative to urethral surgery, to females with localised urethral tumours but discuss local toxicity.
7.3. Multimodal treatment in locally-advanced urethral carcinoma in both males and females
Multimodal therapy in primary urethral carcinoma consists of definitive surgery plus chemotherapy with additional RT . Multimodal therapy was often underutilised as shown by Cahn and colleagues in locally-advanced disease (only 16%) notwithstanding promising results [78-81]. In a recent study monotherapy was associated with decreased local recurrence-free survival after adjusting for stage, histology, sex, and year of treatment (p = 0.017). Its use has decreased over time . Treatment in academic centres was reported to result in higher utilisation of neoadjuvant- and multimodal treatment and improved OS in patients with locally-advanced urothelial- and SCC primary urethral carcinoma .
7.3.2. Preoperative cisplatin-based chemotherapy
Retrospective studies reported that modern cisplatin-based combination chemotherapy regimens can be effective in advanced primary urethral carcinoma providing prolonged survival even in LN-positive disease. Moreover, they emphasised the critical role of surgery after chemotherapy to achieve long-term survival in patients with locally-advanced urethral carcinoma. In a study using the National Cancer Database in men with primary urothelial carcinoma, NAC was reported to decrease the risk of all-cause mortality, while AC was not associated with an OS benefit, as compared to no chemotherapy in men, with primary urothelial carcinoma neoadjuvant chemotherapy (NAC) was reported to exhibit improved OS compared with adjuvant chemotherapy .
In a series of 124 patients, 39 (31%) were treated with peri-operative platinum-based chemotherapy for advanced primary urethral carcinoma (twelve patients received NAC, six received neoadjuvant chemoradiotherapy and 21 adjuvant chemotherapy). Patients who received NAC or chemoradiotherapy for locally-advanced primary urethral carcinoma (> cT3 and/or cN+) appeared to demonstrate improved survival compared to those who underwent upfront surgery with or without adjuvant chemotherapy . Another retrospective series including 44 patients with advanced primary urethral carcinoma, reported outcomes on 21 patients who had preoperatively received cisplatin-based combination chemotherapy according to the underlying histologic subtype. The overall response rate for the various regimens was 72% and the median OS 32 months .
7.3.3. Chemoradiotherapy in locally-advanced squamous cell carcinoma of the urethra
The clinical feasibility of local RT with concurrent chemotherapy as an alternative to surgery in locally-advanced SCC has been reported in several series. This approach offers a potential for genital preservation [85-89]. The largest, and recently updated, retrospective series reported outcomes in 25 patients with primary locally-advanced SCC of the urethra treated with two cycles of 5-fluorouracil and mitomycin C with concurrent EBRT. A complete clinical response was observed in ~80% of patients. The 5-year OS and disease-specific survival was 52% and 68%, respectively. In this updated series, salvage surgery, initiated only in non-responders or in case of local failure, was not reported to be associated with improved survival .
A large retrospective cohort study in patients with locally-advanced urethral carcinoma treated with adjuvant RT and surgery vs. surgery alone demonstrated that the addition of RT improved OS .
7.3.4. Salvage treatment in recurrent primary urethral carcinoma after surgery for primary treatment
A multicentre study reported that patients who were treated with surgery as primary therapy and underwent surgery or RT-based salvage treatment for recurrent solitary or concomitant urethral disease, demonstrated similar survival rates compared to patients who never developed recurrence after primary treatment .
7.3.5. Treatment of regional lymph nodes
Nodal control in urethral carcinoma can be achieved either by regional lymph node (LN) dissection , RT  or chemotherapy . Currently, there is still no clear evidence supporting prophylactic bilateral inguinal and/or pelvic LND in all patients with urethral carcinoma . However, in patients with clinically enlarged inguinal/pelvic LNs or invasive tumours, regional LND should be considered as initial treatment since cure might still be achievable with limited disease . It was recently shown that in patients with invasive urethral SCC and cN1–2 disease, inguinal LND conferred an OS benefit .
7.3.6. Summary of evidence and guidelines for multimodal treatment in advanced urethral carcinoma in both males and females
Summary of evidence
In locally-advanced urethral carcinoma, cisplatin-based chemotherapy with curative intent prior to surgery might improve survival compared to chemotherapy alone, or surgery followed by chemotherapy.
In locally-advanced SCC of the urethra, treatment with chemoradiotherapy might be an alternative to surgery.
In locally-advanced urothelial- and SCC of the urethra, treatment in academic centres improves OS.
Refer patients with advanced urethral carcinoma to academic centres.
Discuss treatment of patients with locally-advanced urethral carcinoma within a multidisciplinary team of urologists, radiation-oncologists, and oncologists.
In locally-advanced urethral carcinoma, use cisplatin-based chemotherapeutic regimens with curative intent prior to surgery.
In locally-advanced squamous cell carcinoma (SCC) of the urethra, offer the combination of curative radiotherapy (RT) with radiosensitising chemotherapy for definitive treatment and genital preservation.
Offer salvage surgery or RT to patients with urethral recurrence after primary treatment.
Offer inguinal lymph node (LN) dissection to patients with limited LN-positive urethral SCC.
7.4. Treatment of urothelial carcinoma of the prostate
Local conservative treatment with extensive TUR and subsequent BCG instillation is effective in patients with Ta or Tis prostatic urethral carcinoma . A systematic review reported patients treated with TURP before BCG show a better local response in the prostatic urethra with a higher disease-free survival (80–100% vs. 63–89%) and progression free survival (PFS) (90–100% vs. 75–94%) than patients in studies in which no TURP was performed . Risk of understaging local extension of prostatic urethral cancer at TUR is high in patients with ductal or stromal involvement . Some earlier series have reported superior oncological results for the initial use of radical cystoprostatectomy as a primary treatment option in patients with ductal involvement [93,94]. In 24 patients with prostatic stromal invasion treated with radical cystoprostatectomy, a LN mapping study found that twelve patients had positive LNs, with an increased proportion located above the iliac bifurcation .
7.4.1. Summary of evidence and guidelines for the treatment of urothelial carcinoma of the prostate
Summary of evidence
Patients undergoing TUR of the prostate for prostatic urothelial carcinoma prior to BCG treatment show superior complete response rates compared to those who do not.
Offer a urethra-sparing approach with transurethral resection (TUR) and bacillus-Calmette Guérin (BCG) to patients with non-invasive urethral carcinoma or carcinoma in situ of the prostatic urethra and prostatic ducts.
In patients not responding to BCG, or in patients with extensive ductal or stromal involvement, perform a cystoprostatectomy with extended pelvic lymphadenectomy.
7.5. Metastatic disease
A recent analysis of the SEER database reported that patients with M1 disease who underwent primary site surgery did not exhibit any survival benefit . Systemic therapy in metastatic disease should be selected based on the histology of the tumour. The EAU Guidelines on Muscle-invasive and Metastatic Bladder Cancer can be followed if UC is the predominant histology . Even though urethral carcinoma patients have been included in large clinical trials on immunotherapy, so far, in terms of response rates, no subgroup analyses are available .
In addition, there is an urgent clinical need to better address the role of local palliative treatment strategies in primary urethral carcinoma including surgery, which has shown to impact positively on QoL aspects in selected
patients with advanced genital cancers .
Figure 7.1: Management of primary urethral carcinoma
* Ensure complete circumferential assessment if penile-preserving/urethra-sparing surgery or partial urethrectomy is intended.
** Squamous cell carcinoma.
*** Regional lymphadenectomy should be considered in clinically enlarged lymph nodes.
**** Consider neoadjuvant chemotherapy.
***** In extensive or BCG-unresponsive disease: consider (primary) cystoprostatectomy +/- urethrectomy + lymphadenectomy.
BCG = bacillus Calmette-Guérin; CT = computed tomography; MRI = magnetic resonance imaging; PUC = primary urethral carcinoma; TUR = transurethral resection.