Urethral Cancer Treatment (PDQ®)–Health Professional Version

Incidence and Mortality

Urethral cancer is rare. The annual incidence rate for urethral cancer in the Surveillance, Epidemiology, and End Results (SEER) Program database from 1973 to 2002 in the United States was 4.3 per million for men and 1.5 per million for women, with downward trends over the three decades.[1] The incidence was twice as high in African American individuals as in White individuals (5 per million vs. 2.5 per million). Urethral cancers appear to be associated with human papillomavirus (HPV) infection, particularly HPV16, a strain known to cause cervical cancer.[2,3]

Because urethral cancer is rare, nearly all information about its treatment and the outcomes of therapy is derived from retrospective, single-center case series, which represents a very low Level of evidence C3. Most information comes from cases accumulated over many decades at major academic centers.

Anatomy

The female urethra is largely contained within the anterior vaginal wall. In adults, it is about 4 cm in length.

The male urethra, which averages about 20 cm in length, is divided into distal and proximal portions. The distal urethra, which extends from the tip of the penis to just before the prostate, includes the meatus, the fossa navicularis, the penile or pendulous urethra, and the bulbar urethra. The proximal urethra, which extends from the bulbar urethra to the bladder neck, includes the membranous urethra and the prostatic urethra.

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Prognosis

The prognosis of urethral cancer depends on the following factors:[4-6]

Superficial tumors in the distal urethra in both women and men are generally curable. However, deeply invasive lesions are rarely curable by any combination of therapies. In men, the prognosis of tumors in the distal (pendulous) urethra is better than for tumors of the proximal (bulbomembranous) and prostatic urethra, which tend to present at more advanced stages.[7,8] Likewise, distal urethral tumors tend to occur at earlier stages in women and to have a better prognosis than proximal tumors.[9]

Distal Urethral Cancer

These lesions are often superficial.

Proximal Urethral Cancer

These lesions are often deeply invasive.

Urethral Cancer Associated With Invasive Bladder Cancer

Approximately 5% to 10% of men with cystectomy for bladder cancer may have or may develop urethral cancer distal to the urogenital diaphragm.[5,6]

American Joint Committee on Cancer (AJCC) Stage Groupings and TNM Definitions

The AJCC has designated staging by TNM (tumor, node, metastasis) classification to define urethral cancer.[1]

Surgery

Surgery is the mainstay of therapy for urethral cancers in both women and men.[Level of evidence C3] The surgical approach depends on tumor stage and anatomic location, and tumor grade plays a less important role in treatment decisions.[1,2] Although the traditional recommendation has been to achieve a 2-cm tumor-free margin, the optimal surgical margin has not been rigorously studied and is not well defined. The role of lymph node dissection is not clear in the absence of clinical involvement, and the role of prophylactic dissection is controversial.[2] Radiation therapy and/or chemotherapy may be added in some cases in patients with extensive disease or in an attempt at organ preservation. However, there are no clear guidelines for patient selection, and the low level of evidence precludes confident conclusions about their incremental benefit.[2,3]

Ablative techniques, such as transurethral resection, electroresection and fulguration, or laser vaporization-coagulation, are used to preserve organ function in cases of superficial anterior tumors, although the supporting literature is scant.[2]

Radiation Therapy

External-beam radiation therapy, brachytherapy, or a combination is sometimes used as the primary therapy for early-stage proximal urethral cancers, particularly in women.[Level of evidence C3] Brachytherapy may be delivered with low-dose-rate iridium Ir 192 sources using a template or urethral catheter. Definitive radiation is also sometimes used 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.[4] There are no head-to-head comparisons of these various approaches, and patient selection may explain differences in outcomes among the regimens.[Level of evidence C3]

The most commonly used tumor doses are in the range of 60 Gy to 70 Gy. Severe complication rates for definitive radiation therapy are about 16% to 20% and include fistula development, especially for large tumors invading the vagina, bladder, or rectum. Urethral strictures also occur in the setting of urethral-sparing treatment. Toxicity rates increase at doses greater than 65 Gy to 70 Gy. Intensity-modulated radiation therapy has become more common in an attempt to decrease local morbidity of the radiation.[4]

Chemotherapy

The literature on chemotherapy for urethral carcinoma is anecdotal in nature and restricted to retrospective, single-center case series or case reports.[5][Level of evidence C3] 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.

For squamous cell cancers, agents that have been used in penile cancer or anal carcinoma include the following:[3,5]

Chemotherapy for transitional cell urethral tumors is extrapolated from experience with transitional cell bladder tumors and, therefore, usually contains the following:[1,4-7]

Chemotherapy has been used alone for metastatic disease or in combination with radiation therapy and/or surgery for locally advanced urethral cancer. It may be used in the neoadjuvant setting with radiation therapy in an attempt to increase the resectability rate or to preserve organs.[3] However, the impact of any of these regimens on survival is not known for any stage or setting.

Treatment Options for Female Distal Urethral Cancer

If the malignancy is at or just within the meatus and superficial parameters (stage 0/Tis, Ta), open excision or electroresection and fulguration may be possible. Tumor destruction using neodymium:yttrium-aluminum-garnet (Nd:YAG) or CO₂ laser vaporization-coagulation represents an alternative option. For large lesions (T1) and more invasive lesions (T2), brachytherapy or a combination of brachytherapy and external-beam radiation therapy (EBRT) are alternatives to surgical resection of the distal third of the urethra. Patients with T3 distal urethral lesions or lesions that recur after treatment with local excision or radiation therapy require anterior exenteration and urinary diversion.

If inguinal lymph nodes are palpable, frozen section confirmation of a tumor should be obtained. If positive for malignancy, ipsilateral lymph node dissection is indicated. If no inguinal adenopathy exists, lymph node dissection is not generally performed, and the nodes are monitored clinically.

Treatment options for female distal urethral cancer include the following:

The level of evidence for these treatment options is Level of evidence C3.

Treatment Options for Male Distal Urethral Cancer

If the malignancy is in the pendulous urethra and is superficial, there is potential for long-term disease-free survival. In the rare cases that involve mucosa only (Tis, Ta), resection and fulguration may be used. For infiltrating lesions in the fossa navicularis, amputation of the glans penis may be adequate treatment. For lesions involving more proximal portions of the distal urethra, excision of the involved segment of the urethra, preserving the penile corpora, may be feasible for superficial tumors. Penile amputation is used for infiltrating lesions. Traditionally, a 2-cm margin proximal to the tumor is used, but the optimal margin has not been well studied. Local recurrences after amputation are rare.

The role of radiation therapy in the treatment of anterior urethral carcinoma in men is not well defined. Some anterior urethral cancers have been cured with radiation alone or a combination of chemotherapy and radiation therapy.[4,5]

If inguinal lymph nodes are palpable, ipsilateral node dissection is indicated after frozen section confirmation of a tumor because a cure is still achievable with limited regional nodal metastases. If no inguinal adenopathy exists, lymph node dissection is not generally performed, and the nodes are monitored clinically.

Treatment options for male distal urethral cancer include the following:

The level of evidence for these treatment options is Level of evidence C3.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Treatment Options for Female Proximal Urethral Cancer

Lesions of the proximal urethra or the entire length of the urethra are usually associated with invasion and a high incidence of pelvic nodal metastases. The prospects for cure are limited except in the case of small tumors. The best results have been achieved with exenterative surgery and urinary diversion, with 5-year survival rates ranging from 10% to 20%.

In an effort to shrink tumor margins, increase the resectability rate of gross tumor, and decrease local recurrence, adjunctive preoperative radiation therapy is a reasonable option. Pelvic lymphadenectomy is performed concomitantly. Ipsilateral inguinal lymph node dissection is indicated only if biopsy specimens of ipsilateral palpable adenopathy are positive on a frozen section. For tumors that do not exceed 2 cm in greatest dimension, radiation alone, nonexenterative surgery alone, or a combination of the two may be sufficient to provide an excellent outcome.

It is reasonable to consider removal of part of the pubic symphysis and the inferior pubic rami to maximize the surgical margin and reduce local recurrence. The perineal closure and vaginal reconstruction can be accomplished with the use of myocutaneous flaps.

The prognosis of female urethral cancer is related to the size of the lesion at presentation. For lesions smaller than 2 cm in diameter, a 5-year survival rate of 60% can be anticipated. For lesions larger than 4 cm in diameter, the 5-year survival rate falls to 13%.

Treatment options for female proximal urethral cancer include the following:

The level of evidence for these treatment options is Level of evidence C3.

Treatment Options for Male Proximal Urethral Cancer

Lesions of the bulbomembranous urethra require radical cystoprostatectomy and en bloc penectomy to achieve adequate margins of resection, minimize local recurrence, and achieve long-term, disease-free survival. Pelvic lymphadenectomy is also performed because of the high incidence of positive lymph nodes and the limited added morbidity.

Despite extensive surgery, local recurrence is common, and this event is invariably associated with eventual death from the disease. Five-year survival rates are only 15% to 20%. In an effort to shrink tumor margins, the use of preoperative adjunctive radiation therapy may be considered. In an effort to increase the surgical margins of dissection, resection of the inferior pubic rami and the lower portion of the pubic symphysis has been used. Urinary diversion is required.[3]

Ipsilateral inguinal lymph node dissection is indicated if palpable ipsilateral inguinal adenopathy is found on physical examination and confirmed to be neoplasm by frozen section.

Treatment options for male proximal urethral cancer include the following:

The level of evidence for these treatment options is Level of evidence C3.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of urethral cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Urethral Cancer Treatment are:

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Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Urethral Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/urethral/hp/urethral-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389356]

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