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Urethral Cancer

About Urethral Cancer

Incidence and Mortality

Urethral cancer is rare. The annual incidence rates in the surveillance, epidemiology, and end results database over the period from 1973 to 2002 in the United States for men and for women were 4.3 and 1.5 per million, respectively, with downward trends over the three decades. The incidence was twice as high in African Americans as in whites (5 million vs. 2.5 per million). Urethral cancers appear to be associated with infection with human papillomavirus (HPV), particularly HPV16, a strain of HPV known to be causative for cervical cancer.

Because of its rarity, nearly all information about the treatment of urethral cancer and the outcomes of therapy is derived from retrospective, single-centre case series and, therefore, represents a very low level of evidence of 3iiiDiv. The majority of information comes from cases accumulated over many decades at major academic centres.

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 distally to proximally 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 distally to proximally the membranous urethra and the prostatic urethra.

Prognosis

The prognosis of urethral cancer depends on the following factors:

  • Anatomical location.
  • Size.
  • Stage.
  • Depth of invasion.

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

References

  1. Swartz MA, Porter MP, Lin DW, et al.: Incidence of primary urethral carcinoma in the United States. Urology 68 (6): 1164-8, 2006. [PUBMED Abstract]

  2. Wiener JS, Liu ET, Walther PJ: Oncogenic human papillomavirus type 16 is associated with squamous cell cancer of the male urethra. Cancer Res 52 (18): 5018-23, 1992. [PUBMED Abstract]

  3. Wiener JS, Walther PJ: A high association of oncogenic human papillomaviruses with carcinomas of the female urethra: polymerase chain reaction-based analysis of multiple histological types. J Urol 151 (1): 49-53, 1994. [PUBMED Abstract]

  4. Urethra. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 508-9.

  5. Rabbani F: Prognostic factors in male urethral cancer. Cancer 117 (11): 2426-34, 2011. [PUBMED Abstract]

  6. Dalbagni G, Zhang ZF, Lacombe L, et al.: Female urethral carcinoma: an analysis of treatment outcome and a plea for a standardised management strategy. Br J Urol 82 (6): 835-41, 1998. [PUBMED Abstract]

  7. Dinney CP, Johnson DE, Swanson DA, et al.: Therapy and prognosis for male anterior urethral carcinoma: an update. Urology 43 (4): 506-14, 1994. [PUBMED Abstract]

  8. Dalbagni G, Zhang ZF, Lacombe L, et al.: Male urethral carcinoma: analysis of treatment outcome. Urology 53 (6): 1126-32, 1999. [PUBMED Abstract]

  9. Gheiler EL, Tefilli MV, Tiguert R, et al.: Management of primary urethral cancer. Urology 52 (3): 487-93, 1998. [PUBMED Abstract]

Cellular Classification of Urethral Cancer

In an analysis of surveillance, epidemiology, and end results data from 1973 to 2002, the most common histologic types of urethral cancer were:

  • Transitional cell (55%).
  • Squamous cell (21.5%).
  • Adenocarcinoma (16.4%).

Other cell types, such as melanoma, were extremely rare.

The female urethra is lined by transitional cell mucosa proximally and stratified squamous cells distally. Therefore, transitional cell carcinoma is most common in the proximal urethra and squamous cell carcinoma predominates in the distal urethra. Adenocarcinoma may occur in both locations and arises from metaplasia of the numerous periurethral glands.

The male urethra is lined by transitional cells in its prostatic and membranous portion and stratified columnar epithelium to stratified squamous epithelium in the bulbous and penile portions. The submucosa of the urethra contains numerous glands. Therefore, urethral cancer in the male can manifest the histological characteristics of transitional cell carcinoma, squamous cell carcinoma, or adenocarcinoma.

Except for the prostatic urethra, where transitional cell carcinoma is most common, squamous cell carcinoma is the predominant histology of urethral neoplasms. Since transitional cell carcinoma of the prostatic urethra may be associated with transitional cell carcinoma of the bladder and/or transitional cell carcinoma arising in prostatic ducts, it is often treated similarly to these primaries and should be separated from the more distal carcinomas of the urethra.

References

Swartz MA, Porter MP, Lin DW, et al.: Incidence of primary urethral carcinoma in the United States. Urology 68 (6): 1164-8, 2006. [PUBMED Abstract]

Stage Information for Urethral Cancer

Prognosis and treatment decisions are both determined by:

  • The anatomical location of the primary tumour.
  • The size of the tumour.
  • The stage of the cancer.
  • The depth of invasion of the tumour.

The histology of the primary tumour is of less importance in estimating response to therapy and survival. Endoscopic examination, urethrography, and magnetic resonance imaging are useful in determining the local extent of the tumour.

Distal Urethral Cancer

These lesions are often superficial.

  • Female: Lesions of the distal third of the urethra.
  • Male: Anterior, or penile, portion of the urethra, including the meatus and pendulous urethra.

Proximal Urethral Cancer

These lesions are often deeply invasive.

  • Female: Lesions not clearly limited to the distal third of the urethra.
  • Male: Bulbomembranous and prostatic urethra.

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.

Stage Definitions by Depth of Invasion

  • Stage 0 (Tis, Ta): Limited to mucosa.
  • Stage A (T1): Submucosal invasion.
  • Stage B (T2): Infiltrating periurethral muscle or corpus spongiosum.
  • Stage C (T3): Infiltration beyond periurethral tissue.
    • Female: Vagina, labia, muscle.
    • Male: Corpus cavernosum, muscle.
  • Stage D1 (N+): Regional nodes; pelvic and inguinal.
  • Stage D2 (N+, M+): Distant nodes; visceral metastases.

Definitions of TNM

The American Joint Committee on Cancer has designated staging by TNM classification to define urethral cancer.

References

  1. Urethra. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 508-9.
  2. Grigsby PW, Corn BW: Localized urethral tumours in women: indications for conservative versus exenterative therapies. J Urol 147 (6): 1516-20, 1992. [PUBMED Abstract]
  3. Ryu J, Kim B: MR imaging of the male and female urethra. Radiographics 21 (5): 1169-85, 2001 Sep-Oct. [PUBMED Abstract]
  4. Pavlica P, Barozzi L, Menchi I: Imaging of male urethra. Eur Radiol 13 (7): 1583-96, 2003. [PUBMED Abstract]
  5. Trabulsi DJ, Gomella LG: Cancer of the urethra and penis. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1272-79.
  6. Erckert M, Stenzl A, Falk M, et al.: Incidence of urethral tumour involvement in 910 men with bladder cancer. World J Urol 14 (1): 3-8, 1996. [PUBMED Abstract]

Urethral Cancer Treatments

Information about the treatment of urethral cancer and the outcomes of therapy is derived from retrospective, single-centre case series and represents a very low level of evidence of 3iiiDiv. The majority of this information comes from the small numbers of cases accumulated over many decades at major academic centres. Therefore, the treatment in these reports is usually not standardised and the treatment also spans eras of shifting supportive care practices. Because of the rarity of urethral cancer, its treatment may also reflect extrapolation from the management of other urothelial malignancies, such as bladder cancer in the case of transitional cancers, and anal cancer in the case of squamous cell carcinomas.

Role of Surgery

Surgery is the mainstay of therapy for urethral cancers in both women and men. The surgical approach depends on tumour stage and anatomic location, and tumour grade plays a less important role in treatment decisions. Although the traditional recommendation has been to achieve a 2-cm tumour-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. Radiation therapy and/or chemotherapy may be added in some cases in patients with extensive disease or in an attempt at organ preservation; but there are no clear guidelines for patient selection, and the low level of evidence precludes confident conclusions about their incremental benefit.

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

Role of Radiation Therapy

Radiation therapy with external beam, brachytherapy, or a combination is sometimes used for the primary therapy of early-stage proximal urethral cancers, particularly in women. Brachytherapy may be delivered with low-dose-rate iridium-192 sources using a template or urethral catheter. Definitive radiation is also sometimes used for advanced-stage tumours, but because monotherapy of large tumours has shown poor tumour control, it is more frequently incorporated into combined modality therapy after surgery or with chemotherapy. There are no head-to-head comparisons of these various approaches, and patient selection may explain differences in outcomes among the regimens.

The most commonly used tumour doses are in the range of 60 Gy to 70 Gy. Severe complication rates for definitive radiation are about 16% to 20% and include fistula development, especially for large tumours 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 come into more common use in an attempt to decrease local morbidity of the radiation.

Role of Chemotherapy

The literature on chemotherapy for urethral carcinoma is anecdotal in nature and restricted to retrospective, single-centre 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 tumours.

For squamous cell cancers, agents that have been used in penile cancer or anal carcinoma include:

  • Cisplatin.
  • 5-Fluorouracil.
  • Bleomycin.
  • Methotrexate.
  • Irinotecan.
  • Gemcitabine.
  • Paclitaxel.
  • Docetaxel.
  • Mitomycin-C

Chemotherapy for transitional cell urethral tumours is extrapolated from experience with transitional cell bladder tumours and, therefore, usually contains the following:

  • Methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC).
  • Paclitaxel.
  • Carboplatin.
  • Ifosfamide, with occasional complete responses.

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 in an attempt at organ preservation. [3] However, the impact of any of these regimens on survival is not known for any stage or setting.

References

  1. Trabulsi DJ, Gomella LG: Cancer of the urethra and penis. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1272-79.
  2. Karnes RJ, Breau RH, Lightner DJ: Surgery for urethral cancer. Urol Clin North Am 37 (3): 445-57, 2010. [PUBMED Abstract]
  3. Cohen MS, Triaca V, Billmeyer B, et al.: Coordinated chemoradiation therapy with genital preservation for the treatment of primary invasive carcinoma of the male urethra. J Urol 179 (2): 536-41; discussion 541, 2008. [PUBMED Abstract]
  4. Koontz BF, Lee WR: Carcinoma of the urethra: radiation oncology. Urol Clin North Am 37 (3): 459-66, 2010. [PUBMED Abstract]
  5. Trabulsi EJ, Hoffman-Censits J: Chemotherapy for penile and urethral carcinoma. Urol Clin North Am 37 (3): 467-74, 2010. [PUBMED Abstract]
  6. VanderMolen LA, Sheehy PF, Dillman RO: Successful treatment of transitional cell carcinoma of the urethra with chemotherapy. Cancer Invest 20 (2): 206-7, 2002. [PUBMED Abstract]
  7. Lin CC, Hsu CH, Huang CY, et al.: Phase II trial of weekly paclitaxel, cisplatin plus infusional high dose 5-fluorouracil and leucovorin for metastatic urothelial carcinoma. J Urol 177 (1): 84-9; discussion 89, 2007. [PUBMED Abstract]

Distal Urethral Cancer

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. Tumour destruction using Nd: YAG or CO2 laser vaporisation-coagulation represents an alternative option. For large lesions and more invasive lesions (stage A and stage B, T1 and T2, respectively), brachytherapy or a combination of brachytherapy and external-beam radiation therapy 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 nodes are palpable, frozen section confirmation of tumour should be obtained. If positive for malignancy, ipsilateral node dissection is indicated. If no inguinal adenopathy exists, node dissection is not generally performed, and the nodes are followed clinically.

Standard treatment options:

  1. Open excision and organ-sparing conservative surgical therapy.
  2. Ablative techniques, such as transurethral resection, electroresection and fulguration, or laser vaporisation-coagulation (Tis, Ta, T1 lesions).
  3. External-beam radiation therapy, brachytherapy, or a combination of the two (T1, T2 lesions).
  4. Anterior exenteration with or without preoperative radiation and diversion (T3 lesions or recurrent lesions).

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 (stage 0/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 tumours. Penile amputation is used for infiltrating lesions. Traditionally, a 2-cm margin proximal to the tumour 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 the male is not well defined. Some anterior urethral cancers have been cured with radiation alone or a combination of chemotherapy and radiation therapy.

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

Standard treatment options:

  1. Open-excision and organ-sparing conservative, surgical therapy.
  2. Ablative techniques, such as transurethral resection, electroresection and fulguration, or laser vaporisation-coagulation (Tis, Ta, T1 lesions).
  3. Amputation of the penis (T1, T2, T3 lesions).
  4. Radiation (T1, T2, T3 lesions, if amputation is refused).
  5. Combined chemotherapy and radiation therapy.

The level of evidence for these treatment options is 3iiiDiv.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with distal urethral cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

References

  1. Davis JW, Schellhammer PF, Schlossberg SM: Conservative surgical therapy for penile and urethral carcinoma. Urology 53 (2): 386-92, 1999. [PUBMED Abstract]
  2. Trabulsi DJ, Gomella LG: Cancer of the urethra and penis. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1272-79.
  3. Karnes RJ, Breau RH, Lightner DJ: Surgery for urethral cancer. Urol Clin North Am 37 (3): 445-57, 2010. [PUBMED Abstract]
  4. Koontz BF, Lee WR: Carcinoma of the urethra: radiation oncology. Urol Clin North Am 37 (3): 459-66, 2010. [PUBMED Abstract]
  5. Cohen MS, Triaca V, Billmeyer B, et al.: Coordinated chemoradiation therapy with genital preservation for the treatment of primary invasive carcinoma of the male urethra. J Urol 179 (2): 536-41; discussion 541, 2008. [PUBMED Abstract]

Proximal Urethral Cancer

Female Proximal Urethral Cancer

Lesions of the proximal or 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 tumours. The best results have been achieved with exenterative surgery and urinary diversion with 5-year survival rates ranging from 10% to 20%.

To increase the resectability rate of gross tumour and decrease local recurrence, in an effort to shrink tumour margins, it is reasonable to recommend adjunctive, preoperative, radiation therapy. Pelvic lymphadenectomy is performed concomitantly. Ipsilateral inguinal node dissection is indicated only if biopsy specimens of ipsilateral palpable adenopathy are positive on frozen section. For tumours that do not exceed 2 cm in greatest dimension, radiation alone, non-exenterative 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 less than 2 cm in diameter, a 60% 5-year survival can be anticipated; for those greater than 4 cm in diameter, the 5-year survival falls to 13%.

Standard treatment options:

1. Preoperative radiation followed by anterior exenteration and urinary diversion with bilateral pelvic node dissection with or without inguinal node dissection.

2. For tumours that do not exceed 2 cm in greatest dimension, radiation alone, non-exenterative surgery alone, or the combination may be sufficient to provide an excellent outcome.

Male Proximal Urethral Cancer

Lesions of the bulbomembranous urethra require radical cystoprostatectomy and en bloc penectomy to achieve adequate margins of resection, minimise local recurrence, and achieve long-term, disease-free survival. Pelvic lymphadenectomy is also performed because of the high incidence of positive 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 can be expected in only 15% to 20% of patients. In an effort to shrink tumour 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.

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

Standard treatment options:

  • Preoperative radiation or combined chemotherapy and radiation therapy followed by cystoprostatectomy, urinary diversion, and penectomy with bilateral pelvic node dissection with or without inguinal node dissection.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with proximal urethral cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

References

  1. Koontz BF, Lee WR: Carcinoma of the urethra: radiation oncology. Urol Clin North Am 37 (3): 459-66, 2010. [PUBMED Abstract]
  2. Grigsby PW, Corn BW: Localised urethral tumours in women: indications for conservative versus exenterative therapies. J Urol 147 (6): 1516-20, 1992. [PUBMED Abstract]
  3. Su LM, Smith JA Jr.: Laparoscopic and robotic-assisted laparoscopic radical prostatectomy and pelvic lymphadenectomy. In: Wein AJ, Kavoussi LR, Novick AC, et al.: Campbell-Walsh Urology. 10th ed. Philadelphia, Pa, Elsevier Saunders, 2012, pp 2830-2849.
  4. Karnes RJ, Breau RH, Lightner DJ: Surgery for urethral cancer. Urol Clin North Am 37 (3): 445-57, 2010. [PUBMED Abstract]

Urethral Cancer Associated with Invasive Bladder Cancer

Approximately 10% (range, 4%–17%) of patients who undergo cystectomy for bladder cancer can be expected to have or to later develop clinical neoplasm of the urethra distal to the urogenital diaphragm. Factors associated with the risk of urethral recurrence after cystectomy include:

  • Tumour multiplicity.
  • Papillary pattern.
  • Carcinoma in situ.
  • Tumour location at the bladder neck.
  • Prostatic urethral mucosal or stromal involvement.

The benefits of urethrectomy at the time of cystectomy need to be weighed against the morbidity factors, which include added operating time, haemorrhage, and the potential for perineal hernia. Tumours found incidentally on pathologic examination are much more likely to be superficial or in situ in contrast to those that present with clinical symptoms at a later date when the likelihood of invasion within the corporal bodies is high. The former lesions are often curable, and the latter are only rarely so. Indications for urethrectomy in continuity with cystoprostatectomy are:

  • Visible tumour in the urethra.
  • Positive swab cytology of the urethra.
  • Positive margins of the membranous urethra on frozen section taken at the time of cystoprostatectomy.
  • Multiple in situ bladder tumours that extend onto the bladder neck and proximal prostatic urethra.

If the urethra is not removed at the time of cystectomy, follow-up includes periodic cytologic evaluation of saline urethral washings.

Standard treatment options:

1. In continuity cystourethrectomy.

2. Monitor urethral cytology and delayed urethrectomy, if necessary.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with urethral cancer associated with invasive bladder cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

References

1. Trabulsi DJ, Gomella LG: Cancer of the urethra and penis. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1272-79.

2. Sherwood JB, Sagalowsky AI: The diagnosis and treatment of urethral recurrence after radical cystectomy. Urol Oncol 24 (4): 356-61, 2006 Jul-Aug. [PUBMED Abstract]

Recurrent or Metastatic Urethral Cancer

Local recurrences of urethral cancer may be amenable to local modality therapy with radiation or surgery, with or without chemotherapy. (Refer to the treatment option overview section of this summary for more information). Metastatic disease may be treated with regimens in common use for other urothelial transitional cell or squamous cell carcinomas, or anal carcinomas, depending upon the histology.

Treatment options:

1. Locally recurrent urethral cancer after radiation therapy should be treated by surgical excision, if feasible.

2. Locally recurrent urethral cancer after surgery alone should be considered for combination radiation and wider surgical resection.

3. Metastatic urethral cancer should be considered for clinical trials using chemotherapy. Transitional cell cancer of the urethra may respond favourably to the same chemotherapy regimens employed for advanced transitional cell cancer of the bladder.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with recurrent urethral cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

References

1. Trabulsi DJ, Gomella LG: Cancer of the urethra and penis. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1272-79.

2. Trabulsi EJ, Hoffman-Censits J: Chemotherapy for penile and urethral carcinoma. Urol Clin North Am 37 (3): 467-74, 2010. [PUBMED Abstract]

3. Lin CC, Hsu CH, Huang CY, et al.: Phase II trial of weekly paclitaxel, cisplatin plus infusional high dose 5-fluorouracil and leucovorin for metastatic urothelial carcinoma. J Urol 177 (1): 84-9; discussion 89, 2007. [PUBMED Abstract]

4. VanderMolen LA, Sheehy PF, Dillman RO: Successful treatment of transitional cell carcinoma of the urethra with chemotherapy. Cancer Invest 20 (2): 206-7, 2002. [PUBMED Abstract]