Urethral Cancer Treatment & Management

Due to the rarity of the disease and the lack of high-quality data, no strong consensus has been reached on treatment modalities of primary urethral cancer (PUC). Large multicentric studies have been reported, providing some insights into PUC management. However, high heterogeneity in treatment regimens and study populations limits the interpretation of the results. ^[18]

A study by Stone et al showed that centralization of care improves clinical outcomes of PUC patients. ^[19] Availability of variations in practice patterns—including multimodal treatment, radical surgery, and regional lymphadenectomy—seems to contribute to the observed improved outcomes in high-volume centers.

The basic principle of treatment is that the patient must understand the potential risks and benefits of the different approaches. After that, physicians in shared decision-making with patients may decide whether to proceed with radical surgery. ^[20] Alternatively, the patient's medical team may advise that radical intervention is relatively contraindicated, based on a risk-benefit analysis.

After accurate staging, the urologist should have a lengthy discussion with the patient regarding the extent and severity of the disease. The issues of reconstruction, urinary diversion, social and family support, and physical therapy are of paramount importance. Educational materials should be provided. For patient education information, see Urethral Cancer.

Therapy for PUC varies with the stage and location of the tumor. If the disease is invasive, extending for more than half of the penile urethra, radiotherapy can be a treatment option for unresectable lesions. Radiotherapy and chemotherapy can be applied to tumors located in the bulbocavernosus urethra, and even for those occurring in the prostatic urethra. For advanced-stage disease, treatment is extensive surgery with chemotherapy and adjuvant radiotherapy. Systemic therapy alone is the only option for cases of extensive metastasis.

Radiation therapy

Radiation therapy has several roles in the management of urethral cancer, including use as primary therapy, in combination with chemotherapy and/or surgery, or as adjuvant treatment for local recurrence after surgery. Radiation therapy includes external beam, brachytherapy, or a combination. Definitive radiation is sometimes used sometimes for advanced-stage tumors, but because monotherapy of large tumors has shown poor tumor control, it is more frequently incorporated into combined modality therapy after surgery or with chemotherapy. The most commonly used tumor doses are in the range of 60 Gy to 70 Gy. ^[2]  

Although the use of radiotherapy in the treatment of PUC demonstrated favorable oncologic outcomes with reported 5-year survival of up to 41%, almost half of the patients suffer from treatment-related adverse effects such as stenosis, fistulas, hemorrhage of the bladder, or necrosis. ^[21] Fistula development is observed more often in the case of large tumors invading the vagina, bladder, or rectum. Severe complication rates for definitive radiation are about 16% to 20%. Toxicity rates increase at doses greater than 65-70 Gy. Intensity-modulated radiation therapy has come into more common use in an attempt to decrease local morbidity from the radiation. ^[2]

Chemotherapy

The literature on chemotherapy for urethral carcinoma is restricted to retrospective, single-center case series or case reports. A wide variety of agents used alone or in combination have been reported over the years, and their use has largely been extrapolated from experience with other urinary tract tumors. ^[2]

Chemotherapy regimens for PUC mainly depend on the underlying histology. Thus, National Comprehensive Cancer Network (NCCN) guidelines recommend cisplatin, gemcitabine, and ifosfamide for squamous cell carcinoma; 5-fluorouracil (5-FU), gemcitabine, and cisplatin-based regimens for adenocarcinoma; and MVAC ( methotrexate, vinblastine, doxorubicin, and cisplatin) for urothelial tumors. In addition, there is a reported efficacy of combined chemoradiation with 5-FU and mitomycin C in a series of male patients with squamous cell carcinoma. ^{[22]   [23]}  

Nevertheless, a correct therapy schedule is difficult to assess for PUC, especially because of a possible overlap in histologic features. ^[24] Platinum-based regimens are the most commonly used chemotherapy in PUC management. ^{[25, 26]} In one review of 44 cases, the overall response rate to platinum-containing chemotherapy was 72%, with median overall survival for the entire cohort of 31.7 months. ^[25]

Gakis et al have shown that, in patients with advanced disease, 3-year overall survival and progression-free survival were significantly improved by neoadjuvant chemotherapy with or without adjuvant systemic therapy, compared with adjuvant therapy alone (P=0.022 and P=0.024, respectively). ^[10] Available data suggest that a combination of chemotherapy with other treatment modalities is preferable to improve survival in patients.

Multimodal treatment 

Multimodality therapy appears to be the mainstay treatment to achieve the longest survival without evidence of disease. Although patients with low-stage disease show good survival with single-modality therapy, patients with higher-stage cancer fared much better after multimodality therapy in the form of either chemotherapy with radiation therapy or neoadjuvant chemotherapy with radiation therapy prior to surgery. ^[27] Several studies have reported promising overall survival of up to 83% after 1 year of chemoradiotherapy. ^[1]

Resection of the primary tumor together with perioperative chemotherapy resulted in longer overall survival than chemotherapy alone (P=0.02).  ^[25] Chemotherapy in combination with surgery demonstrated median overall survival of 25.6 months from chemotherapy initiation. It has been shown that, if systemic chemotherapy is provided before surgery, response to this treatment is essential for sustained overall survival. ^[28] In the follow-up of combined radiotherapy and concurrent chemotherapy with 5-FU and mitomycin, all non-responders died during follow-up, even those who underwent salvage surgery.

Primary melanoma of the urethra presents a unique challenge compared with other histologic types. Oliva et al found that, despite distal locations and urethral confinement at the time of surgery, 9 of 15 patients survived less than 5 years. ^[29] Perhaps combination therapy, consisting of radical surgery and adjuvant chemotherapy and radiation therapy, may improve these rates by destroying cancer cells that evaded the surgical treatment. Chemotherapy may have a particularly good effect on primary melanoma of the urethra, considering the brisk mitotic activity of this histologic subtype.

Despite promising results of multimodal treatment in some patients, outcomes for patients with advanced PUC are still relatively poor. Further well-designed prospective studies are needed to assess the optimal treatment strategy, and benefits and shortcomings of combined treatment modalities.

Surgical excision remains the standard as a primary mode of treatment for non-metastatic urethral cancer for both male and female patients, conferring a survival advantage. ^[30] The extent of surgery depends on the location of the tumor within the urethra and the clinical stage. Considering the notoriously aggressive nature of the disease, radical surgery is generally recommended to improve survival. Minimally invasive urethra-sparing techniques have been gaining acceptance in highly selected patients in whom superficial disease is detected. This less aggressive approach preserves body image and cosmesis, as well as sexual and reproductive function; however, aggressive, careful, and frequent follow-up is mandatory in these cases.

Accurate staging of the tumor is essential prior to definitive surgery, particularly if significant reconstruction is required. The patient should have already been to the operating room at least once for a transurethral biopsy and examination under anesthesia. Based on these findings, an imaging modality such as MRI or CT scanning should be performed to predict the extent of local invasion.

Surgery in male patients

The literature describes the following four modalities of surgical management in male urethral cancer:

• Urethra-sparing management
• Partial penectomy
• Radical penectomy
• Pelvic lymphadenectomy and en bloc resection including penectomy and cystoprostatectomy with the removal of the anterior pubis

Dalbangi et al retrospectively identified 46 patients who were treated with surgery (all 4 modalities). They found that 38% of 18 patients with anterior urethral tumors survived, whereas only 14% of 28 patients with posterior urethral malignancies remained alive. These studies indicate that surgery alone can be used as definitive therapy in selected cases, namely low-grade or low-stage malignancies; however, it is an ineffective treatment in advanced urethral carcinomas. ^[15]

Urethra-sparing management

Conservative procedures can be acceptable in selected patients with superficial involvement, papillary tumors, or low-grade tumors. Endoscopic treatment could be performed with either transurethral electroresection or fulguration or transurethral laser therapy. Minimally invasive surgeries should be followed by intraurethral chemotherapy or bacillus Calmette-Guérin (BCG) immunotherapy. This technique tends to work for patients with localized low-grade disease (clinical stage lower than T2), in whom the location allows adequate visualization and reduces the risk of iatrogenic incontinence. However, this approach carries the highest risk of recurrence and the potential for the development of urethral stricture disease. ^[31]

Segmental resection with reconstruction is another alternative for localized disease. The urethra can be surgically removed with clean margins for very distal urethral tumors in men, and the healthy urethra can be mobilized and advanced to create a new urethral meatus. In general, segmental resection is not reasonable in women except for very distal tumors. If the length of resected segment prevents advancing of the urethra, several options exist for reconstruction.

Partial penectomy

Partial penectomy involves the excision of the malignant lesion with 2-cm margins. This treatment modality can be used only for infiltrative lesions of the distal penile urethra. If the proximal half of the penile urethra is involved with infiltrating tumor, then a total penectomy is indicated. Ilioinguinal node dissection is performed only if the nodes are palpable. In contrast to penile cancer, no apparent benefit is associated with prophylactic groin dissection.

Radical penectomy

Total penectomy involves the removal of the penis, urethra, and penile root. This surgery is used primarily for lesions that are not amenable to partial penectomy (ie, infiltrative proximal penile urethral carcinomas). ^[12]  The calculated local recurrence rate in patients with posterior disease who underwent exenteration, with or without lymph node dissection, decreased from 68% to 24% with the addition of en bloc pubectomy. ^[1]  

Pelvic lymphadenectomy and en bloc resection

En bloc resection is reserved for patients with T2/Nx/M0 or higher tumors in the bulbomembranous or prostatic urethra. Although poor survival figures are associated with these lesions, radical en bloc excision offers the best chance for long-term disease control and prevention of disease recurrence.

This surgery includes a pelvic lymphadenectomy with an en bloc total penectomy, cystoprostatectomy, urinary diversion, and in-continuity resection of the pubic rami and urogenital diaphragm. Portions of the scrotal and perineal skin and soft tissues may require excision with bulky tumor involvement of these structures. Similarly, the pubic symphysis is resected if bulky disease involves the presymphyseal tissues. Inguinal lymphadenectomy is performed only if palpable disease is present. The most common form of urinary diversion in the event of cystectomy is an ileal conduit.

Kaplan et al reported results of this procedure in 28 patients with bulbomembranous urethral tumors. Of those patients, 16 died of the disease, 6 survived longer than 5 years, 3 developed local recurrences but did not die, and 3 were lost to follow-up. ^[32]  

Dinney et al described 5 patients with bulbomembranous urethral cancer who were treated with radical cystoprostatectomy, penectomy, urethrectomy, scrotectomy, and resection of the inferior pubic rami. One patient was cured, but the other 4 died—3 from local recurrence and 1 from heart disease. Because these patients had high-stage disease, consider selection bias when evaluating the efficacy of this therapy. ^[26]

Surgery in female patients

In women with urethral carcinoma, to provide the highest chance of local cure, primary radical urethrectomy should remove all the periurethral tissue from the bulbocavernosus muscle up to the bladder neck and pelvic bone. ^[33] Segmental resection with or without additional radiotherapy might be considered only in the case of very distal tumors and if complete tumor resection can be guaranteed. If the length of resected segment prevents advancing of the urethra, several options exist for reconstruction. Local recurrence rates in women undergoing partial urethrectomy with intraoperative frozen section analysis were 22–60%. ^{[34, 35]}

Minimally invasive surgical techniques, used for small distal urethral tumors, might be also considered. They resulted in considerable local failure rates of 16%. However, strict local tumor control in women treated with urethra-sparing treatment should be performed to prevent local and systemic progression. ^[34]

Postoperative care

General postoperative precautions that are paramount to reducing complications include the following:

• Hemodynamic support with intravenous fluids, both crystalloid and colloid
• Intravenous antibiotics
• Incentive spirometry and aggressive pulmonary toilet
• Deep venous thrombosis prophylaxis

Strict measurement of 24-hour input and output from all drains should be carefully and clearly recorded in order to manage fluid status appropriately and determine whether spontaneous diuresis is progressing. Use of diuretic agents may be required based on these recordings.

Stoma nurse care and teaching are necessary, particularly for when the patient is discharged home, because they will likely need to record their output initially. Initial teaching of stomal appliance care and/or intermittent catheterization provides the patient with much-needed autonomy and leads to the development of a positive and proactive self-image. Visiting nurse assistance may be necessary if the patient cannot initially meet the high demands these procedures require.

Physical therapy is often required, particularly if portions of the pubic rami have been resected.

In patients treated with radiation therapy, the overall risk of complication is roughly 20%. ^[14] Complications include the following:

• Urethral stricture
• Radiation cystitis/urethritis
• Bowel irritation
• Fibrosis
• Infection
• Bleeding
• Fistula formation (rare)

Patients treated with urethrectomy or partial penectomy have a lower risk of complications from urethral stricture formation or development of urethral fistulae, but these risks should be addressed with the patient prior to surgery. Urinary incontinence may result from bladder overactivity and severe urgency or from damage to the external sphincter, which may lead to stress incontinence or progress to total urinary incontinence.

Tumor recurrence may lead to erosion or abscess of the penile, scrotal, and perineal skin. Necrotic tissue at these sites may lead to poor wound healing and the development of fistulae and abscesses, culminating in sepsis.

In patients treated with radical cystoprostatectomy, complications include bowel obstruction, infection, and leakage, primarily due to the use of intestinal or colonic conduits for urinary diversion.

Consultations with a plastic surgeon and orthopedic surgeon should be requested prior to surgery, and their presence should be readily available in the operating room. Social interaction should be monitored because patients with this disease may require a psychiatric consultation liaison. Social support services may provide the patient with much-needed empathy.

On follow-up visits, carefully obtain a history, with particular attention to new symptoms such as the following:

• Hematuria
• Decreased urine output
• Voiding symptoms (if the urethra has been preserved)
• Gastrointestinal symptoms
• Changes in bowel habits
• Weight loss and other constitutional symptoms
• Bone, back, or flank pain
• Neurologic symptoms

Periodically examine the remaining urethra, pelvis, and inguinal regions. Perform urinalysis, urine cytology, and cystoscopy periodically. Significant hematuria, urinary tract infections, and malignant cells noted in the urine all should be addressed promptly and appropriately. If lesions are noted upon cystoscopy, they should be subsequently biopsied. Fistulae should be identified and treated quickly to minimize morbidity. Further investigation into tumor recurrence should be initiated if fistulae are identified. ^[36]

Imaging studies of the pelvis (ie, CT scanning with intravenous contrast) should be performed every 6 months to a year to check for local recurrence or hydronephrosis.

Perform periodic chest radiography and comprehensive metabolic panel blood tests every 3 months initially for the first 2 years, then every 6 months for up to 5 years, and annually thereafter. Rising serum urea nitrogen and creatinine levels may suggest an obstructive process or some element of kidney toxicity. A new lesion noted on a chest radiograph would require CT scanning to further characterize it and possibly obtaining a CT-guided biopsy specimen. If metastatic disease is confirmed, systemic therapy should be strongly considered.

Local or distant recurrence after initial therapy occurs in up to 71% of patients after 5 years; median 5-year recurrence-free survival varies from 24% to 63%. ^{[1, 34]} Recurrence occurs more often with proximal lesions compared with distal ones (50–57% and 8–33%, respectively). ^{[15, 26]} Clinical lymph node metastasis is also a risk factor for recurrence. ^[37]

Gakis et al reported that patients treated with surgery as primary therapy who underwent surgery or radiation-based salvage treatment for recurrent solitary or concomitant urethral disease demonstrated similar survival rates compared with patients who never experienced recurrence after primary treatment. Only extra-urethral recurrence significantly affected overall survival compared with no recurrence (48.5% and 86.5% [P = 0.002], respectively). There was no difference in survival between different salvage therapies. ^[38] No specific recommendations can yet be given regarding the best therapeutic modality in recurrence management.

Metastatic disease may be treated with chemotherapy regimens in common use for other urothelial carcinomas, depending on the histology. In a review of primary urethral cancer cases from the the Surveillance, Epidemiology and End Results (2004-2016) database that included 181 patients with metastatic disease, Wenzel et al reported that chemotherapy is associated with a survival benefit in adenocarcinoma, urothelial carcinoma, and other variant histology subtypes, but not in squamous cell carcinoma. ^[39]

Besides chemotherapy, immune checkpoint inhibitors (eg, pembrolizumab) might be considered as subsequent-line therapy in metastatic PUC patients. ^[22] However, it has been evaluated only in patients with urothelial histology. Moreover, even though urethral carcinoma patients have been included in large clinical trials of immunotherapy, no subgroup analyses are available.