ABSTRACT: Often overshadowed by more common genitourinary cancers, such as prostate, testicular, and kidney cancers, penile and urethral cancers nonetheless represent difficult treatment challenges for the clinician. The management of these cancers is slowly evolving. In the past, surgery, often extensive, was the treatment of choice. Recently, however, radiation and chemotherapy have begun to play larger roles as initial therapies, with surgery being reserved for salvage. With these modalities in their treatment armamentarium, oncologists may now be able to spare patients some of the physical and psychological sequelae that often follow surgical intervention without compromising local control and survival. Part 1 of this two-part article, published in last month’s issue, dealt with cancer of the penis. This second part focuses on cancer of the urethra in both females and males. [ONCOLOGY 13(11):1511-1520, 1999]
Penile and urethral cancers, while less common than other genitourinary cancers such as prostate, testicular and kidney carcinomas, nonetheless represent difficult treatment challenges. The management of these cancers is slowly evolving as radiation therapy and chemotherapy begin to play larger roles in treatment. Part 1 of this two-part article, published in last month’s issue, dealt with cancer of the penis. This second part focuses on cancer of the urethra in both females and males.
Epidemiology and Etiology
Carcinoma of the female urethra is a rare tumor, accounting for fewer than 1% of all cancers in the female genitourinary tract. It is most commonly seen during the fifth and sixth decades of life. Only about 1,000 cases have been reported in the literature.
Urethral cancer shows a predilection for women over men (4:1 ratio). The incidence of this cancer is higher in white than in black women.
The human papilloma virus may play a role in the development of urethral cancer in women.
In females, the urethra (Figure 1) is approximately 4 cm long (range, 2 to 6 cm),[2,4] and most of it is buried in the anterior vaginal wall. The urethra is divided into the distal one-third (anterior urethra) and the proximal two-thirds (posterior urethra).
The majority (70%) of neoplasms of the female urethra are squamous cell carcinomas (Figure 2). Other less common histologies that have been reported include transitional cell carcinoma (15%), adenocarcinoma (13%), and undifferentiated carcinoma (2%).
Routes of Spread
The lymphatics from the proximal urethra drain primarily into the pelvic nodes (external iliac, obturator, and presacral),[4,5] whereas those of the distal urethra drain primarily into the inguinal nodes. Unlike the situation in patients with penile carcinoma, palpable inguinal nodes in patients with urethral cancer usually contain metastatic carcinoma. Approximately 14% to 30% of patients with urethral carcinoma have inguinal lymph node metastases at the time of diagnosis.
The most common sites of distant spread are the lungs, liver, and bone.
Clinical Presentation and Diagnostic and Staging Work-up
The most common presenting symptom is urethral bleeding, seen in 56% of cases. Other symptoms include urinary obstructive symptoms, urinary frequency, perineal pain, palpable mass, and urinary incontinence.
The work-up for women with suspected urethral carcinoma includes cystourethroscopy, an excretory urogram, computed tomography (CT) of the pelvis and abdomen, chest x-ray, and magnetic resonance imaging (MRI) of the pelvis (Figure 3).
The TNM staging system for carcinoma of the urethra (in both females and males) is shown in Table 1.
Surgery—Various surgical techniques that maintain continence have been used to treat early carcinomas involving the distal urethra. Procedures range from laser excision to local excision, transurethral excision, and partial urethrectomy. Bladder-sparing procedures have been performed successfully in selected patients with T3 lesions.
Patients with advanced disease of the entire urethra extending to bladder and vagina may be treated surgically with anterior exenteration. This involves removal of the pelvic lymph nodes, entire urethra, and uterus with appendages, along with en bloc resection of the pubic symphysis and inferior rami (Figure 4 and Figure 5). Anterior exenteration alone, however, has been reported to produce a 5-year survival rate of less than 20% in patients with invasive carcinoma, with a significant incidence of local failure (> 66%).[2,7]
Radiation therapy is an alternative to local surgery for patients with low-stage urethral carcinoma.[8-13] In such patients, definitive radiation therapy produces cure rates averaging about 75% (Table 2).[8,13,14] In general, patients treated with radiation have received brachytherapy either alone or combined with external-beam radiation therapy. The doses in the various series range from 5,000 to 6,000 cGy for brachytherapy alone to 4,000 to 4,500 cGy of external radiation to the whole pelvis followed by a brachytherapy boost of 2,000 to 2,500 cGy over 2 to 3 days. As most of these lesions are distal in location, the inguinal nodes are at risk. Thus, if whole-pelvis radiation is delivered, care must be taken to include the inguinal nodes, as well as the iliac, obturator, and presacral nodes. The pelvis, groins, and primary lesion receive 4,500 cGy in 25 fractions. External-beam therapy is followed by a brachytherapy boost, for a total tumor dose of 6,500 to 7,000 cGy.[14,15]
In patients with advanced urethral cancer, radiation therapy alone offers 5-year survival rates ranging from 5% to 57% and averaging approximately 34% (Table 3). The studies in this table represent a heterogeneous group of patients with varying stages of diseases and radiation approaches. Patients with lesions involving the bladder neck probably should be excluded from this group because of the higher incidence of local failure after definitive radiation therapy.
Surgery Plus Radiation Therapy—In the past, because of the overall poor results with either radiation or surgery alone in advanced carcinoma of the urethra, some authors recommended a combined-modality treatment approach involving preoperative radiation and surgery.[1,2,7,16] Various radiation schedules were used preoperatively, ranging from 2,000 cGy in 5 fractions to 4,500 to 5,000 cGy in 25 fractions.[10,14]
In the relatively small numbers of patients treated, the combination of radiation and surgery may have offered some improvement over radiation alone for advanced lesions (Table 4). However, with the advent of fluorouracilmitomycin (Mitomycin)-radiation combinations (see “Chemotherapy” below), surgery may change from being an upfront therapy to a salvage modality for patients with advanced squamous cell urethral carcinomas.
Complications—The rate of complications of radiation therapy in females with cancer of the urethra has been reported to range from 0% to 42% (mean, approximately 20%). Urethral strictures and stenosis are the most commonly reported complications. Urethrovaginal fistulas, incontinence, and necrosis have also been reported, depending on the size of the tumor, the total dose of radiation, and whether or not surgery is combined with radiation.
In 1988, Sailer, Shipley, and Wang described the effective use of neoadjuvant chemotherapy in two patients with advanced transitional cell tumors. These patients received two cycles of methotrexate, a platinum agent, and vinblastine prior to radiation therapy and the platinum every 3 weeks during radiation (60 to 65 Gy). The treatment was satisfactorily tolerated.
Chemoradiation—More recently, a number of case reports have appeared in the literature documenting dramatic results with fluorouracil, mitomycin, and external-beam radiation[17-21] in patients with advanced squamous cell carcinomas of the urethra.
Johnson et al reported a dramatic response to fluorouracil, mitomycin, and low-dose radiation (40 Gy) in a patient with advanced squamous cell carcinoma of the urethra, in which the initial 2.5 × 6 cm lesion shrunk to a thin 2-cm plaque. When the patient underwent a subsequent anterior exenteration, no evidence of gross disease was seen and according to pathologic analysis, only a 3 × 2 × 15 mm area of fibrous stroma with scattered nests of squamous cell carcinoma was seen.
Kalra et al treated 15 patients with advanced squamous cell carcinoma of the female genital tract, including 1 patient with urethral cancer, with fluorouracil, mitomycin, and radiation. The patient with urethral cancer was reported to be free of disease at 36+ months of follow-up..
Tran and Krieg described the case of a patient with a 6 × 6 cm squamous cell carcinoma of the urethra presenting with a urethrovaginal fistula. The only surgery done was biopsy and urinary diversion. The patient received fluorouracil and mitomycin along with 5,580 cGy of external-beam radiation. She is now disease free for over 5 years with recent negative biopsies.
Similarly, Licht et al et al reported on 2 female patients treated with fluorouracil-mitomycin and modest doses of external-beam radiation (5,000 and 4,320 cGy, respectively). Both patients have been free of disease for more than 94 months.
Thus, the combination of fluorouracil and mitomycin (as in squamous cell carcinoma of the anus) and external-beam radiation, with surgery reserved for salvage, appears to offer a very promising alternative to upfront radical surgery for women with squamous cell carcinoma of the urethra. Further investigation of this approach is clearly warranted.
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