Urethral cancer medical therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Medical therapy
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 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. 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 tumor 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 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 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-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.
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 tumors is extrapolated from experience with transitional cell bladder tumors 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. However, the impact of any of these regimens on survival is not known for any stage or setting.
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. Tumor destruction using Nd:YAG or CO2 laser vaporization-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 tumor 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:
- Open excision and organ-sparing conservative surgical therapy.
- Ablative techniques, such as transurethral resection, electroresection and fulguration, or laser vaporization-coagulation (Tis, Ta, T1 lesions).
- External-beam radiation therapy, brachytherapy, or a combination of the two (T1, T2 lesions).
- 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 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 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 tumor, 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:
- Open-excision and organ-sparing conservative, surgical therapy.
- Ablative techniques, such as transurethral resection, electroresection and fulguration, or laser vaporization-coagulation (Tis, Ta, T1 lesions).
- Amputation of the penis (T1, T2, T3 lesions).
- Radiation (T1, T2, T3 lesions, if amputation is refused).
- Combined chemotherapy and radiation therapy.
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 tumors. 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 tumor and decrease local recurrence, in an effort to shrink tumor 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 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 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:
- Preoperative radiation followed by anterior exenteration and urinary diversion with bilateral pelvic node dissection with or without inguinal node dissection.
- For tumors that do not exceed 2 cm in greatest dimension, radiation alone, nonexenterative 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, minimize 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 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.
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.
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:
- Tumor multiplicity.
- Papillary pattern.
- Carcinoma in situ.
- Tumor 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, hemorrhage, and the potential for perineal hernia. Tumors 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 tumor 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 tumors 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:
- In continuity cystourethrectomy.
- Monitor urethral cytology and delayed urethrectomy, if necessary.