Urethral cancer is a rare cancer that occurs in the cells that line the urethra, and accounts for less than 0.1% of all genitourinary (kidney, bladder, penis, prostate, testicles) cancers. The urethra is the tube through which urine exits the body from the bladder; in women the urethra measures 1 1/2 inches long and in men the urethra (passing through the prostate gland and the length of the penis) is about 8 inches long. This disease affects women more often than men.
Types of Urethral Cancer
The type of cancer will depend on which cells the cancer arises in (squamous, carcinoma, transitional, or adenocarcinoma), and the location of the cancer (whether it is closer to the bladder or closer to the outside of the body). Anterior urethral cancer is when the cancer is closest to the outside of the body, and posterior urethral cancer is when the cancer is closest to the bladder.
Risk Factors for Urethral Cancer
Although all of the causes of urethral cancer are not known, the disease sometimes occurs in patients who also have bladder cancer.
Stanford Expertise
When you are being treated for cancer you want a physician who is familiar with your particular disease. However, because urethral cancer is rare it can be difficult to find a doctor who has treated many patients.
As a world-renown center, the Stanford Cancer Center attracts patients with rare cancers, and thus our physicians are more likely to have experience with urethral cancer than doctors at most other hospitals. You can be assured that you will be offered state-of-the-art alternatives for surgery, radiation therapy, and chemotherapy that will take into consideration your age, sex, health, and preferences for diagnosis and therapies.
In addition, your Stanford specialists will discuss with you options for maintaining fertility and for reconstructive surgery if necessary.

Primary
Determine the 4-month progression-free survival rate in patients with progressive regional or metastatic carcinoma of the urothelium treated with sorafenib.
Determine the response rate in patients treated with this drug.
Determine the toxicity of this drug in these patients.
Secondary
Determine time to disease progression and overall survival of patients treated with this drug.
Correlate frequency of raf kinase mutations in tumor specimens with response rate in patients treated with this drug.
Evaluate serum vascular endothelial growth factor levels as potential markers of angiogenesis inhibition in patients treated with this drug.
Determine if there are proteins differentially translated from the genome in patients who respond to treatment with this drug vs patients who do not respond to treatment.
OUTLINE: This is a multicenter study.
Patients receive oral sorafenib twice daily on days 1-56. Courses repeat every 56 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed every 3 months until 2 years from study entry and then every 6 months until 3 years from study entry.
PROJECTED ACCRUAL: A total of 30-53 patients (20-43 with transitional cell carcinoma [TCC] and 10 with non-TCC) will be accrued for this study within 11-16 months.
Eligibility
Ages Eligible for Study: 18 Years and older
Genders Eligible for Study: Both
Accepts Healthy Volunteers: No

Criteria
DISEASE CHARACTERISTICS:
• Histologically confirmed carcinoma of the urothelium (i.e., renal pelvis, ureter, bladder, or urethra) of 1 of the following histologies:
o Transitional cell carcinoma (TCC)
o Mixed histologies containing a component of TCC
o Non-TCC histologies, including adenocarcinoma or squamous cell carcinoma representing > 90% of the specimen
• Regional or metastatic disease
• Measurable disease
o Previously irradiated lesions may only be used as marker lesions provided there is unequivocal evidence of progression by serial imaging studies
• Progressive disease during 1, and only 1, prior systemic chemotherapy regimen for metastatic disease
o Prior adjuvant or neoadjuvant chemotherapy allowed provided it was completed > 12 months before the initiation of the chemotherapy regimen* that the disease progressed on
 Adjuvant or neoadjuvant chemotherapy is not considered 1 prior regimen NOTE: *Administered in the metastatic setting
• No small cell carcinoma, soft tissue sarcoma, or carcinosarcoma
• No previously untreated CNS metastases
o Previously resected and irradiated CNS metastases with evidence of stable disease allowed
PATIENT CHARACTERISTICS:
Age
• 18 and over
Performance status
• ECOG 0-1
Life expectancy
• Not specified
Hematopoietic
• Granulocyte count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• No evidence of bleeding diathesis
Hepatic
• AST ≤ 2.5 times upper limit of normal
• Bilirubin < 1.5 mg/dL
Renal
• Creatinine < 1.5 mg/dL
Cardiovascular
• No uncontrolled hypertension
• No history of American Heart Association class III or IV cardiovascular disease
• No uncontrolled congestive heart failure
• No ventricular dysrhythmias
Other
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No other malignancy within the past 5 years except curatively treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or clinically unsuspected organ-confined prostate cancer found at the time of cystoprostatectomy
• No active unresolved infection requiring parenteral antibiotics within the past 7 days
• No swallowing dysfunction that would preclude ingesting pills
PRIOR CONCURRENT THERAPY:
Biologic therapy
• No prior systemic biologic response modifier therapy
• More than 4 weeks since prior biologic therapy and recovered
Chemotherapy
• See Disease Characteristics
• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered
Endocrine therapy
• More than 4 weeks since prior hormonal therapy and recovered
Radiotherapy
• See Disease Characteristics
• At least 2 weeks since prior radiotherapy and recovered
• No concurrent radiotherapy
Surgery
• See Disease Characteristics
• At least 4 weeks since prior major surgery and recovered
Other
• No concurrent therapeutic anticoagulation
o Concurrent prophylactic anticoagulation (i.e., low-dose warfarin) for venous or arterial access devices allowed provided requirements for PT, INR, or PTT are met
• No concurrent cytochrome P450 enzyme-inducing antiepileptic drugs (e.g., phenytoin, carbamazepine, or phenobarbital)
• No concurrent rifampin
• No concurrent Hypericum perforatum (St. John’s wort)

Carlos M.N. de Jesus, P.R. Kawano, H.A. Yamamoto, J.C.S. Trindade Filho, A.D. Agostinho, L.A. Correa

Department of Urology, Botucatu Medical School, Paulista State University, Botucatu, São Paulo, Brazil
Address of Corresponding Author
Urol Int 2004;72:281-283 (DOI: 10.1159/000077678)

Key Words
• Urethral cancer
• Urethral stricture
• Tubular groinskin flap
• Penile carcinoma, treatment
Perineal urethrostomy

Urethral cancer is a disease in which cancerous cells form in the tissues of the urethra. The urethra is the tube that carries urine from the bladder to outside the body. Urethral cancer is a rare genitourinary cancer that occurs more often in women than in men.
Cancer of the urethra may accompany tumors of the bladder. Rarely, tumors of the urethra occur in the absence of tumors elsewhere in the urinary tract. These are more frequently associated with chronic infection and scar tissue.
Treatment Options for Urethral Cancer
Urethral carcinoma may require aggressive surgical removal or less invasive procedures, depending on the location, stage and type of tumor. In these cases, careful surgical planning and a combination of therapies may preserve the bladder and its function. In females, this type of cancer may be related to a pocket or diverticulum which develops in the urethra as a result of chronic infection.
Support Groups
Fox Chase social workers offer a monthly support group for patients who have had a urostomy.

INTRODUCTION — Primary urethral cancer is a rare malignancy in women [1-4]. Unlike other tumors arising in the urinary tract, urethral cancer is more common in women than in men. Differences in anatomy and etiology lead to important differences in the clinical presentation, diagnosis, and treatment of urethral cancer in women compared to men.
The diagnosis and treatment of urethral cancer in women will be reviewed here. Urethral cancer in men is discussed separately. (See “Urethral cancer in men”).
ETIOLOGY AND PATHOGENESIS — Although the etiology of urethral cancer is not well understood, several factors have been associated with its development:
• Transitional cell carcinoma of the proximal urinary tract — Transitional cell carcinoma (TCC) of the urothelium is often multifocal, and similar lesions can develop in the female urethra. Urethral TCC may occur simultaneously with, precede, or follow lesions of the bladder, ureters, or renal pelves.
• Human papillomavirus (HPV) infection — A close association exists between infection with HPV and squamous cancers of the anogenital tract, including cancers of the cervix and anus. (See “Virology of human papillomavirus infections and the link to cancer”, see “Anal squamous intraepithelial lesions (ASIL): Diagnosis, screening, and treatment”, section on HPV infection and see “Cervical intraepithelial neoplasia: Etiology, diagnosis, and natural history”, section on Human papillomavirus infection).
HPV also appears to play a role in causing female urethral cancer. This was illustrated by a series in which HPV was identified in tumors from 11 of 18 patients (61 percent) [5]. HPV 16, which has been causally linked to cervical and anal cancers, was present in 9 of the 11 cases.
• Urethral diverticuli — Cancers can arise in urethral diverticuli. Most typically, these have been clear cell carcinomas, although TCCs and squamous cell carcinomas (SCCs) have also been reported [6,7]. Urinary stasis and infection may be contributing factors.
ANATOMY AND PATHOLOGY — The female urethra averages 3 to 4 cm in length. The proximal 30 percent is composed of transitional epithelium, while the distal 70 percent is stratified squamous epithelium

From:
Southern Medical Journal
Date:
May 1, 2007
Author:
Bilello, Seth; Gomelsky, Alex; Young, Diane
Abstract: There have been less than 100 reported cases of carcinoma in a female urethral diverticulum, with only 10 of these cases being squamous cell carcinoma (SCC). The course of this disease is frequently aggressive, despite multimodality treatment, and most patients die within 2 to 3 years. To our knowledge, carcinoma in situ of the female urethral diverticulum has not been reported to date, and thus, optimal treatment is not well defined. A 41-year-old woman was found to have SCC in situ without evidence of invasive carcinoma after diverticulectomy. She elected close observation and remains disease-free at 2 years. A brief overview is given of the presentation, …

Primary urethral cancer is a rare malignancy in men [1-5]. Differences in anatomy and etiology lead to important differences in the clinical presentation, diagnosis, and treatment of urethral cancer in men compared to women.
Information about the natural history and prognosis of urethral cancer in men is derived from small cases series, and recommendations for treatment are based upon general oncologic principles and extrapolation from other diseases.
The diagnosis, evaluation, and treatment of male urethral cancer will be reviewed here. Female urethral cancer is discussed separately. (See “Urethral cancer in women”).
EPIDEMIOLOGY AND RISK FACTORS
Epidemiology — Urethral cancer is a rare malignancy that accounts for less than 1 percent of urologic cancers diagnosed in the United States and elsewhere [6,7]. Urethral cancer is has its peak incidence between the ages of 75 and 84 years and is more common in African Americans than in whites [8].

A urethral caruncle is a soft, fleshy protrusion of the urethral lining from the urethral opening. The urethra is the tube that drains urine from the bladder. Urethral caruncles are not related to urethral cancer or any other type of cancer.
Urethral caruncles most often occur in girls before puberty and in women after menopause. The exact cause of urethral caruncles isn’t clear, but they are thought to be associated with low levels of female hormones.
A urethral caruncle may cause no signs or symptoms. But some women may have:
• Difficult or painful urination
• Blood in the urine
• Tenderness or irritation around the opening of the urethra
A urethral caruncle is usually found incidentally during an examination done for some other reason. If the caruncle is causing irritation or pain, treatment may include:
• Soaking in a warm bath
• Hormone creams applied directly to the caruncle
• Surgical removal of the caruncle

• Prognosis.
• Cellular classification.
• Staging.
• Treatment options by cancer stage.
This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Some of the reference citations in the 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. Based on the strength of the available evidence, treatment options are described as either standard or under clinical evaluation. These classifications should not be used as a basis for reimbursement determinations.
This summary is available in a patient version, written in less technical language, and in Spanish.

General Information
Transitional cell carcinoma of the renal pelvis, accounting for only 7% of all kidney tumors, and transitional cell cancer of the ureter, accounting for only 1 of every 25 upper tract tumors, are curable in more than 90% of patients if they are superficial and confined to the renal pelvis or ureter. Patients with deeply invasive tumors that are still confined to the renal pelvis or ureter have a 10% to 15% likelihood of cure. Patients with tumors with penetration through the urothelial wall or with distant metastases usually cannot be cured with currently available forms of treatment. The major prognostic factor at the time of diagnosis of upper tract transitional cell cancer is the depth of infiltration into or through the uroepithelial wall. However, even if ureteroscopy and pyeloscopy are successfully implemented, accurate assessment of depth of invasion is difficult. Therefore, total excision of the ureter with a bladder cuff, renal pelvis, and kidney is recommended in an attempt to provide the greatest likelihood of cure.
Most superficial tumors are likely to be well differentiated, while infiltrative tumors are likely to be poorly differentiated. The incidence of synchronous or metachronous contralateral upper tract cancers ranges from 2% to 4%; the incidence of subsequent bladder cancer after prior upper tract transitional cell cancer ranges from 30% to 50%. 1 When involvement of the upper tract is diffuse (involving both the renal pelvis and ureter), the likelihood of subsequent development of bladder cancer increases to 75%. DNA ploidy has not added significant prognostic information beyond that provided by stage and grade. 2
References:
1. Krogh J, Kvist E, Rye B: Transitional cell carcinoma of the upper urinary tract: prognostic variables and post-operative recurrences. Br J Urol 67 (1): 32-6, 1991. [PUBMED Abstract]
2. Corrado F, Ferri C, Mannini D, et al.: Transitional cell carcinoma of the upper urinary tract: evaluation of prognostic factors by histopathology and flow cytometric analysis. J Urol 145 (6): 1159-63, 1991. [PUBMED Abstract]

Cellular Classification
The majority of upper tract uroepithelial tumors are of transitional cell histology. Squamous cell cancer of the urinary tract constitutes less than 15% of the tumors of the renal pelvis and a smaller percentage of ureteral tumors and is often associated with chronic calculus disease and infection.
Grade of transitional cell cancer of the upper tract has generally been found to correlate with stage. Superficial tumors are generally grade I or II, whereas the majority of infiltrative tumors are grades III and IV. Prognosis is worse for patients with high-grade (grades III and IV) tumors than for those with low-grade (grades I and II) tumors.

Stage Information
Though comparable in many respects to staging systems described for bladder cancer, unique structural aspects of the renal pelvis and ureter have led to several differences in the classification schema of tumors that involve the upper tracts. Clinical staging is based on a combination of radiographic procedures (e.g., intravenous pyelogram and computed tomographic scans) and, more recently, ureteroscopy and biopsy.
The advent of rigid and flexible ureteroscopic techniques has permitted endoscopic access to the ureter and renal pelvis. This may permit greater accuracy in preoperative definition of the stage and grade of an upper tract neoplasm. In addition, fulguration and endourological access permit resection or laser coagulation of highly selected low-stage, low-grade lesions of the ureters. 1 However, this approach is still under clinical evaluation since there is the possibility of inaccurate assessment of the stage and extent of disease, and the adequacy and risks of such treatment have not yet been defined. 2 3 4 5
Because of the inaccessibility of ureteral and pelvic anatomy, accurate staging requires pathologic analysis of the surgically excised specimen.
The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification to define carcinoma of the renal pelvis and ureter. 6

TNM Definitions
Primary tumor (T)
• TX: Primary tumor cannot be assessed
• T0: No evidence of primary tumor
o Ta: Papillary noninvasive carcinoma
• Tis: Carcinoma in situ
• T1: Tumor invades subepithelial connective tissue
• T2: Tumor invades the muscularis
• T3: (For renal pelvis only) Tumor invades beyond muscularis into peripelvic fat or the renal parenchyma
• T3: (For ureter only) Tumor invades beyond muscularis into periureteric fat
• T4: Tumor invades adjacent organs or through the kidney into perinephric fat
Regional lymph nodes (N)*
• NX: Regional lymph nodes cannot be assessed
• N0: No regional lymph node metastasis
• N1: Metastasis in a single lymph node, 2 cm or less in greatest dimension
• N2: Metastasis in a single lymph node, more than 2 cm but not more than 5 cm in greatest dimension; or multiple lymph nodes, none more than 5 cm in greatest dimension
• N3: Metastasis in a lymph node more than 5 cm in greatest dimension
* [Note: Laterality does not affect the N classification.]
Distant metastasis (M)
• MX: Distant metastasis cannot be assessed
• M0: No distant metastasis
• M1: Distant metastasis

AJCC Stage Groupings
Stage 0a
• Ta, N0, M0
Stage 0is
• Tis, N0, M0
Stage I
• T1, N0, M0
Stage II
• T2, N0, M0
Stage III
• T3, N0, M0
Stage IV
• T4, N0, M0
• Any T, N1, M0
• Any T, N2, M0
• Any T, N3, M0
• Any T, any N, M1
Patients may also be designated as having localized, regional, or metastatic disease, as follows:
Localized
Patients with localized disease may be classified into three groups:
• Group 1: Low-grade tumor confined to the urothelium without lamina propria invasion (Papilloma Grade I transitional cell cancer).
• Group 2: Grade IIII carcinomas without demonstrable subepithelial invasion or focal microscopic invasion or papillary carcinomas with carcinoma in situ and/or carcinoma in situ elsewhere in the urothelium.
• Group 3: High-grade tumors that have infiltrated the renal pelvic wall or renal parenchyma or both but are still confined to the kidney. Infiltration of muscle in the upper tract may not be associated with as much potential for distant dissemination as appears to be the case for bladder cancer.
Regional
• Group 4: Extension of tumors beyond the renal pelvis or parenchyma and invasion of peripelvic and perirenal fat, lymph nodes, hilar vessels, and adjacent tissues.
Metastatic
• Spread of the tumor to distant tissues.
Each of these classifications has been subclassified into categories of unicentricity or multicentricity. The latter category indicates a more pervasive tumor diathesis and generally a less favorable prognosis.
Although the classifications listed above have prognostic significance, they can only be determined at the time of nephroureterectomy, which is the treatment of choice for patients with this disease. Because of the high incidence of tumor recurrence within the intramural ureter among patients who have had incomplete excision of this area, nephroureterectomy should include the entire ureter and a margin of periureteral orifice mucosa (i.e., bladder cuff).
A TNM system for staging has been established and has demonstrated accurate predictions of survival. The TNM staging system may be a better predictor of prognosis than tumor grade, though both are strongly predictive of survival. Median survival for patients with tumors confined to the subepithelial connective tissue was 91.1 months compared to 12.9 months for patients with tumors invading the muscularis and beyond in one report. Flow cytometry analysis identifies low-stage, low-grade tumors at high risk of recurrence by virtue of their aneuploid histograms. 7 8
References:
1. Grossman HB, Schwartz SL, Konnak JW: Ureteroscopic treatment of urothelial carcinoma of the ureter and renal pelvis. J Urol 148 (2 Pt 1): 275-7, 1992. [PUBMED Abstract]
2. Batata M, Grabstald H: Upper urinary tract urothelial tumors. Urol Clin North Am 3 (1): 79-86, 1976. [PUBMED Abstract]
3. Cummings KB, Correa RJ Jr, Gibbons RP, et al.: Renal pelvic tumors. J Urol 113 (2): 158-62, 1975. [PUBMED Abstract]
4. Nocks BN, Heney NM, Daly JJ, et al.: Transitional cell carcinoma of renal pelvis. Urology 19 (5): 472-7, 1982. [PUBMED Abstract]
5. Heney NM, Nocks BN, Daly JJ, et al.: Prognostic factors in carcinoma of the ureter. J Urol 125 (5): 632-6, 1981. [PUBMED Abstract]
6. Renal pelvis and ureter. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 329-334. [PUBMED Abstract]
7. Huben RP, Mounzer AM, Murphy GP: Tumor grade and stage as prognostic variables in upper tract urothelial tumors. Cancer 62 (9): 2016-20, 1988. [PUBMED Abstract]
8. Blute ML, Tsushima K, Farrow GM, et al.: Transitional cell carcinoma of the renal pelvis: nuclear deoxyribonucleic acid ploidy studied by flow cytometry. J Urol 140 (5): 944-9, 1988. [PUBMED Abstract]

Treatment Option Overview
The rarity of synchronous bilateral renal pelvic neoplasia, the low incidence of asynchronous development of contralateral upper tract tumors, and the increased risk of tumor recurrence in the ipsilateral ureter distal to the original pelvic tumor are the rationale for total nephroureterectomy with bladder cuff for most patients with renal pelvic transitional cell cancers and ureteral cancers.
Contemplation of anything less than total excision must take into account the potential risk for tumor recurrence anywhere in the upper tract unit. In other than unifocal, low-grade, low-stage renal pelvic tumors, the probable extensive involvement of both contiguous and noncontiguous sites would appear to make segmental excision an unnecessary option with a potentially serious risk. However, an operative possibility includes segmental excision of a particular lesion. If the extent of a tumor can be determined by intraoperative assessment, and frozen section histologic diagnosis confirms low-grade, unifocal tumor of limited size, then segmental excision is possible. However, this approach should be reserved for highly selected patients. This includes those patients who have a solitary kidney or those with decreased renal function and who require maximal preservation of renal tissue. The likelihood of tumor recurrence in this setting, and of extension of disease outside the renal pelvis once the pelvis has been violated, is a serious risk that must be heavily weighed in offering a patient this therapeutic option.
Ureteral transitional cell cancer may more readily offer the possibility of segmental excision if the absence of proximal disease can be documented. In this setting, attention is focused on the ease of reconstruction of the ureter and restoration of ureterovesical continuity. This is most feasible if the cancer is in the distal ureter. If partial ureterectomy is possible and proximal disease has been excluded, then segmental excision and ureteral reimplantation can be performed.
Systematic regional lymph node dissection in conjunction with nephroureterectomy or segmental excision has not been found to enhance the effectiveness of surgery if tumors are of high grade or high stage, since in these instances the overall results are so poor. Correspondingly, lymph node involvement is uncommon in low-stage disease, and lymphadenectomy is therefore unlikely to remove additional tumor. Thus, lymph node dissection at the time of nephrectomy may offer prognostic information, but little, if any, therapeutic benefit.

Localized Transitional Cell Cancer of the Renal Pelvis and Ureter
Standard treatment options:
1. Nephroureterectomy with cuff of bladder.
2. Segmental resection of ureter, only if the tumor is superficial and located in the distal third of the ureter.
Treatment options under clinical evaluation:
The development of new instrumentation for endourological treatment of upper tract transitional cell cancer has provided new options for regional management of these cancers. Introduction of electrofulguration and resection instruments or laser probes either transureterally or percutaneously may permit destruction of a primary cancer. Introduction of cytotoxic agents has also been employed. Although a biopsy can be taken for staging purposes, the accuracy of this remains to be determined. The efficacy of treatment by these maneuvers has not been established.
1. Electroresection and fulguration or laser fulguration, if the tumor is superficial.
2. Any parenchymal sparing procedure (segmental resection; ureteroscopic or percutaneous resection/fulguration/laser destruction) if the renal unit is solitary or renal function is depressed.
3. Intrapelvic or intraureteral cytotoxic/immunotherapy. The dramatic successes that have been reported with intravesical cytotoxic (thiotepa, mitomycin, doxorubicin) or immunologic/inflammatory (BCG, interferon) therapy for superficial transitional cell cancers in the bladder have led to the occasional use of these agents in the treatment of upper tract cancers. Long-term follow-up of the results of such treatments has generally not been reported, and the efficacy of this approach cannot be assessed, largely because experience has been limited to those patients whose compromised clinical status (solitary kidney, renal failure, medical risks for surgery) may have influenced clinical outcome. The use of this approach will be limited by the extent of disease in the renal pelvis, the access that these agents may have to the area of disease, the sensitivity of the cancer being treated, and the adequacy and accuracy of initial tumor staging and continued monitoring.
4. Laser vaporization/coagulation. Transurethral and percutaneous access to the upper tract have permitted the use of laser therapy in the control of superficial upper tract transitional cell cancers. This approach is dependent on accurate staging and adequate visualization of the lesions that need to be coagulated. Results of this approach are at present too preliminary to assess. Therapeutic efficacy, however, will depend on staging accuracy on initial treatment and ease of monitoring such patients for disease recurrence and possible progression.

Regional Transitional Cell Cancer of the Renal Pelvis and Ureter
Treatment of extensive regional disease has thus far not had well-documented success by either radiation or systemic chemotherapy. Patients with extensive regional disease should be considered for clinical trials. Information about ongoing clinical trials is available at the NCI Web site.

Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ® editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic stratgegy. (Refer to the PDQ® summary on Levels of Evidence for more information.)
The prognosis for any patient with metastatic or recurrent transitional cell cancer is poor. The proper management of recurrence depends on the sites of recurrence, extent of prior therapy, and individual patient considerations. Chemotherapy regimens that have been shown effective for metastatic bladder cancer have generally been applied to transitional cell cancers arising from other sites. Patients with distant metastases have a poor prognosis and can be appropriately offered treatment on a clinical trial.
In patients with metastatic or recurrent transitional cell carcinoma of the bladder, combination chemotherapy has produced high response rates and occasional complete responses. 1 2 Results from a randomized trial that compared methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) to single-agent cisplatin in advanced bladder cancer show a significant advantage with M-VAC in both response rate and median survival. The overall response rate with M-VAC in this cooperative group trial was 39%. 3
Other chemotherapy agents that have shown activity in metastatic transitional cell cancer include the following: 4 5 6 7 8[Level of evidence: 3iiiDiii]
• Paclitaxel.
• Ifosfamide.
• Gallium nitrate.
• Gemcitabine.
• Pemetrexed.
Ifosfamide, gallium, and pemetrexed have shown limited activity in patients previously treated with cisplatin. Information about ongoing clinical trials is available at the NCI Web site.
References:
1. Sternberg CN, Yagoda A, Scher HI, et al.: Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium. Efficacy and patterns of response and relapse. Cancer 64 (12): 2448-58, 1989. [PUBMED Abstract]
2. Harker WG, Meyers FJ, Freiha FS, et al.: Cisplatin, methotrexate, and vinblastine (CMV): an effective chemotherapy regimen for metastatic transitional cell carcinoma of the urinary tract. A Northern California Oncology Group study. J Clin Oncol 3 (11): 1463-70, 1985. [PUBMED Abstract]
3. Loehrer PJ Sr, Einhorn LH, Elson PJ, et al.: A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol 10 (7): 1066-73, 1992. [PUBMED Abstract]
4. Roth BJ: Preliminary experience with paclitaxel in advanced bladder cancer. Semin Oncol 22 (3 Suppl 6): 1-5, 1995. [PUBMED Abstract]
5. Witte RS, Elson P, Bono B, et al.: Eastern Cooperative Oncology Group phase II trial of ifosfamide in the treatment of previously treated advanced urothelial carcinoma. J Clin Oncol 15 (2): 589-93, 1997. [PUBMED Abstract]
6. Einhorn LH, Roth BJ, Ansari R, et al.: Phase II trial of vinblastine, ifosfamide, and gallium combination chemotherapy in metastatic urothelial carcinoma. J Clin Oncol 12 (11): 2271-6, 1994. [PUBMED Abstract]
7. Pollera CF, Ceribelli A, Crecco M, et al.: Weekly gemcitabine in advanced bladder cancer: a preliminary report from a phase I study. Ann Oncol 5 (2): 182-4, 1994. [PUBMED Abstract]
8. Sweeney CJ, Roth BJ, Kabbinavar FF, et al.: Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol 24 (21): 3451-7, 2006. [PUBMED Abstract]

Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ® editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic stratgegy. (Refer to the PDQ® summary on Levels of Evidence for more information.)
The prognosis for any patient with metastatic or recurrent transitional cell cancer is poor. The proper management of recurrence depends on the sites of recurrence, extent of prior therapy, and individual patient considerations. Chemotherapy regimens that have been shown effective for metastatic bladder cancer have generally been applied to transitional cell cancers arising from other sites. Patients with distant metastases have a poor prognosis, and can be appropriately offered treatment on a clinical trial.
In patients with metastatic or recurrent transitional cell carcinoma of the bladder, combination chemotherapy has produced high response rates and occasional complete responses. 1 2 Results from a randomized trial that compared methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) to single-agent cisplatin in advanced bladder cancer show a significant advantage with M-VAC in both response rate and median survival. The overall response rate with M-VAC in this cooperative group trial was 39%. 3
Other chemotherapy agents that have shown activity in metastatic transitional cell cancer include the following: 4 5 6 7 8[Level of evidence: 3iiiDiii]
• Paclitaxel.
• Ifosfamide.
• Gallium nitrate.
• Gemcitabine.
• Pemetrexed.
Ifosfamide, gallium, and pemetrexed have shown limited activity in patients previously treated with cisplatin. Information about ongoing clinical trials is available at the NCI Web site.
References:
1. Sternberg CN, Yagoda A, Scher HI, et al.: Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium. Efficacy and patterns of response and relapse. Cancer 64 (12): 2448-58, 1989. [PUBMED Abstract]
2. Harker WG, Meyers FJ, Freiha FS, et al.: Cisplatin, methotrexate, and vinblastine (CMV): an effective chemotherapy regimen for metastatic transitional cell carcinoma of the urinary tract. A Northern California Oncology Group study. J Clin Oncol 3 (11): 1463-70, 1985. [PUBMED Abstract]
3. Loehrer PJ Sr, Einhorn LH, Elson PJ, et al.: A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol 10 (7): 1066-73, 1992. [PUBMED Abstract]
4. Roth BJ: Preliminary experience with paclitaxel in advanced bladder cancer. Semin Oncol 22 (3 Suppl 6): 1-5, 1995. [PUBMED Abstract]
5. Witte RS, Elson P, Bono B, et al.: Eastern Cooperative Oncology Group phase II trial of ifosfamide in the treatment of previously treated advanced urothelial carcinoma. J Clin Oncol 15 (2): 589-93, 1997. [PUBMED Abstract]
6. Einhorn LH, Roth BJ, Ansari R, et al.: Phase II trial of vinblastine, ifosfamide, and gallium combination chemotherapy in metastatic urothelial carcinoma. J Clin Oncol 12 (11): 2271-6, 1994. [PUBMED Abstract]
7. Pollera CF, Ceribelli A, Crecco M, et al.: Weekly gemcitabine in advanced bladder cancer: a preliminary report from a phase I study. Ann Oncol 5 (2): 182-4, 1994. [PUBMED Abstract]
8. Sweeney CJ, Roth BJ, Kabbinavar FF, et al.: Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol 24 (21): 3451-7, 2006. [PUBMED Abstract]
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Cancer of the urethra, a rare type of cancer, is a disease in which cancer (malignant) cells are found in the urethra. The urethra is the tube that empties urine from the bladder, the hollow organ in the lower abdomen that stores urine. In women, the urethra is about 1 1/2 inches long and opens to the outside of the body above the vagina. In men, the urethra is about 8 inches long and goes through the prostate gland and then through the penis to the outside of the body. Cancer of the urethra affects women more often than men.
There may be no symptoms of early cancer of the urethra. A doctor should be seen if there is a lump or growth on the urethra, or pain, bleeding, or other difficulty during urination.
If there are symptoms, a doctor will examine the patient and feel for lumps in the urethra. In men, a thin lighted tube called a cystoscope may be inserted into the penis so the doctor can see inside the urethra. If the doctor finds cells or other signs that are not normal, a small piece of tissue (called a biopsy) may be cut out and looked at under a microscope for cancer cells.
The chance of recovery (prognosis) and choice of treatment depend on the stage of the cancer (whether it is just in one area or has spread to other places) and the patient’s general state of health.
Stage Explanation
Stages of cancer of the urethra
Once cancer of the urethra is found, more tests will be done to find out if cancer cells have spread to other parts of the body (staging). A doctor needs to know the stage of the disease to plan treatment. For cancer of the urethra, patients are grouped into stages depending on where the tumor is and whether it has spread to other places. The following stage groupings are used for cancer of the urethra:
Anterior urethral cancer
The part of the urethra that is closest to the outside of the body is called the anterior urethra, and cancers that start here are called anterior urethral cancers.
Posterior urethral cancer
The part of the urethra that connects to the bladder is called the posterior urethra, and cancers that start here are called posterior urethral cancers. Because the posterior urethra is closer to the bladder and other tissues, cancers that start here are more likely to grow through the inner lining of the urethra and affect nearby tissues.
Urethral cancer associated with invasive bladder cancer
Occasionally, patients who have bladder cancer also have cancer of the urethra. This is called urethral cancer associated with invasive bladder cancer.
Recurrent urethral cancer
Recurrent cancer means that the cancer has come back (recurred) after it has been treated. It may come back in the same place, or in another part of the body.
Treatment Option Overview
How cancer of the urethra is treated
There are treatments for all patients with cancer of the urethra. Three kinds of treatment are used:
• Surgery (taking out the cancer in an operation).
• Radiation therapy (using high-dose x-rays or other high-energy rays to kill cancer cells).
• Chemotherapy (using drugs to kill cancer cells).
Surgery is the most common treatment of cancer of the urethra. A doctor may take out the cancer using one of the following operations:
• Electrofulguration uses an electric current to remove the cancer. The tumor and the area around it are burned away and then removed with a sharp tool.
• Laser therapy uses a narrow beam of intense light to kill cancer cells.
• Cystourethrectomy removes the bladder and the urethra.
In men, the part of the penis containing the urethra that has cancer may be removed in an operation called a partial penectomy. Sometimes the entire penis is removed (penectomy). A patient may need plastic surgery to make a new penis if all or part of the penis is removed. The bladder and prostate may also be removed in an operation called cystoprostatectomy. Lymph nodes in the pelvis may also be removed (lymph node dissection). Lymph nodes are small bean-shaped structures that are found throughout the body. They produce and store infection-fighting cells.
In women, surgery to remove the urethra, the bladder, and the vagina (anterior exenteration) may also be done. Lymph nodes in the pelvis may be removed (lymph node dissection). Plastic surgery may be needed to make a new vagina after this operation.
If the urethra is removed, the doctor will need to make a new way for the urine to pass from the body. This is called urinary diversion.
If the bladder is removed, the doctor will need to make a new way for the patient to store and pass urine. There are several ways to do this. Sometimes the doctor will use part of the small intestine to make a tube through which urine can pass out of the body through an opening (stoma) on the outside of the body. This is sometimes called an ostomy or urostomy. If a patient has an ostomy, a special bag will need to be worn to collect urine. This special bag, which sticks to the skin around the stoma with a special glue, can be thrown away after it is used. This bag does not show under clothing, and most people take care of these bags themselves. The doctor may also use part of the small intestine to make a new storage pouch (a continent reservoir) inside the body where the urine can collect. The patient would then need to use a tube (catheter) to drain the urine through a stoma.
Radiation therapy uses x-rays or other high-energy rays to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external radiation therapy) or from putting materials that produce radiation (radioisotopes) through thin plastic tubes (internal radiation therapy) in the area where cancer cells are found. Radiation may be used alone or with surgery and/or chemotherapy.
Chemotherapy uses drugs to kill cancer cells. Chemotherapy may be taken by mouth, or it may be put in the body through a needle in a vein or muscle. Chemotherapy is called a systemic treatment because the drug enters the bloodstream, travels through the body and can kill cancer cells outside the urethra.
Treatment by stage
Treatment depends on where the cancer is found, whether it has spread to other areas in the body, and the patient’s sex, age, and overall health.
Standard treatment may be considered because of its effectiveness in patients in past studies, or participation in a clinical trial may be considered. Not all patients are cured with standard therapy and some standard treatments may have more side effects than are desired. For these reasons, clinical trials are designed to find better ways to treat cancer patients and are based on the most up-to-date information. Clinical trials are going on in many parts of the country for patients with cancer of the urethra. To learn more about clinical trials, call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237); TTY at 1-800-332-8615.
Anterior Urethral Cancer
Treatment is different for men and women.
For women, treatment may be one of the following:
1. Electrofulguration.
2. Laser therapy.
3. External and/or internal radiation therapy.
4. Radiation therapy followed by surgery or surgery alone to remove the urethra and the organs in the lower pelvis (anterior exenteration), or the tumor only, if it is small. A new way is made for urine to pass out of the body (urinary diversion).
For men, treatment may be one of the following:
1. Electrofulguration.
2. Laser therapy.
3. Surgery to remove a part of the penis (partial penectomy).
4. Radiation therapy.
Posterior Urethral Cancer
Treatment is different for men and women.
For women, treatment will probably be radiation therapy followed by surgery or surgery alone to remove the urethra, the organs in the lower pelvis (anterior exenteration), or the tumor only, if it is small. Lymph nodes in the pelvis are usually removed (lymph node dissection), and lymph nodes in the upper thigh may or may not be removed. A new way is made for urine to pass out of the body (urinary diversion).
For men, treatment will probably be radiation therapy followed by surgery or surgery alone to remove the bladder and prostate (cystoprostatectomy) and the penis and urethra (penectomy). Lymph nodes in the pelvis are usually removed (lymph node dissection), and lymph nodes in the upper thigh may or may not be removed. A new way is made for urine to pass out of the body (urinary diversion).
Urethral Cancer Associated With Invasive Bladder Cancer
Because people with bladder cancer sometimes also have cancer of the urethra, the urethra may be removed at the same time the bladder is taken out (cystourethrectomy). If the urethra is not removed during surgery for bladder cancer, the doctor may follow the patient closely so treatment can be started if cancer of the urethra develops.
Recurrent Urethral Cancer
Treatment depends on what treatment the patient received before. If the patient had surgery, treatment may be radiation therapy and surgery to remove the cancer. If the patient had radiation therapy, treatment may be surgery to remove the cancer. Clinical trials are testing chemotherapy for cancer of the urethra that has spread to other parts of the body.
Changes to This Summary (08/19/2005)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Links to the NCI Dictionary of Cancer Terms were added to this summary.
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About PDQ
PDQ IS A COMPREHENSIVE CANCER DATABASE AVAILABLE ON NCI’S WEB SITE.
PDQ is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. Most of the information contained in PDQ is available online at NCI’s Web site. PDQ is provided as a service of the NCI. The NCI is part of the National Institutes of Health, the federal government’s focal point for biomedical research.
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Before starting treatment, patients may want to think about taking part in a clinical trial. A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about new treatments, the risks involved, and how well they do or do not work. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.”
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