Non-surgical treatment of primary female urethral cancer.

Primary carcinomas of the female urethra are extremely rare, with an annual incidence of less than ten in one million. Currently, there is no consensus regarding management of this malignancy. However, there have been several case reports demonstrating the efficacy of chemoradiation in the treatment of female urethral cancer. In this report we present two cases of female primary urethral adenocarcinoma that were treated by concomitant chemotherapy and external beam radiotherapy, followed by interstitial brachytherapy.

Introduction

Primary carcinomas of the female urethra are extremely rare, and because most present at an advanced stage the overall prognosis is poor.[1] Owing to the rarity of this disease, there is no consensus on the management of primary female urethral cancer.[2-7] Managed with surgery alone, five-year disease-free survival is only 20–30%. Radiotherapy and chemotherapy have been advocated in combination with surgery to improve treatment outcomes.[2-15]

Several studies have shown that interstitial brachytherapy is an effective modality, used alone or in combination with other treatments.[5,15-17] In a study of 34 women with primary urethral cancer, Milosevic et al. found that adding interstitial brachytherapy to external beam radiation reduced the risk of local recurrence by a factor of 4.2.[5] Foens et al. treated 28 cases of female primary urethral cancer and found that the three-year disease-free survival rates were 29% for those treated with external beam radiation alone, and 57% for those treated with combined external and interstitial radiotherapy.[16] The addition of chemosensitization, for example, cisplatin, to the radiation therapy regimen is also thought to increase local control and survival.[2,18]

In this case report, we describe two cases of female primary urethral adenocarcinoma that have been managed successfully with external beam radiation and concomitant chemotherapy (cisplatin and capecitabine) followed by interstitial brachytherapy.

Materials and Methods

Case #1

A 53-year-old white female presented with progressive dysuria, hematuria, and ultimately urinary retention. On physical examination she had a 4-cm peri-urethral mass. Cystoscopy revealed a urethral tumor involving the entire length of the urethra with extension into, but not invading, the bladder. The biopsy was consistent with a well-to-moderately differentiated adenocarcinoma. T2-weighted magnetic resonance imaging (MRI) demonstrated a mildly hyperintense 7.2×3.0×2.8-cm fungating mass in the proximal urethra with invasion of the anterior wall of the distal vagina. The tumor was staged as stage II (cT2N0M0). Transurethral resection of a small intravesical portion of the tumor was performed. The patient then received external beam radiation therapy with concomitant cisplatin (40 mg/m[2] weekly) and capecitabine (500 mg twice daily, 5 days/week). The whole pelvis received 30 Gy delivered in 15 fractions, followed by an additional 20 Gy delivered in 10 fractions to the lower pelvis. Therapy was given with AP/PA fields using 6 and 15 MV photons on a Varian 2300 linear accelerator. Custom blocks were used to spare normal tissues. The patient tolerated the therapy well, with only mild diarrhea and perineal dermatitis as side-effects.

Approximately two weeks after external beam radiation therapy was completed, interstitial low-dose rate (LDR) brachytherapy was performed using transrectal ultrasound and fluoroscopic guidance. Five interstitial catheters were loaded approximately 1-cm apart with 32 192Ir sources. A 2-cm diameter vaginal cylinder was placed in the vaginal vault, which was loaded with three 5-mg radium equivalent 137Cs sources. The brachytherapy dose was 25 Gy prescribed in addition to the 60 cGy per hour isodose line. Treatment planning was performed on the ROCS planning system, using orthogonal X-ray films. The patient tolerated therapy well, with only dyspareunia as a side-effect. At completion of therapy she had normal urinary voiding function and urinary continence.

Sixteen months later, the patient presented with headache, dizziness, and diplopia. MRI of the brain revealed a heterogeneously enhancing 2.0×2.7×2.7-cm mass in the cerebellum. The biopsy was consistent with metastatic adenocarcinoma, and appeared histologically similar to her urethral tumor. The cerebellar tumor was neurosurgically resected. Postoperative external beam radiation therapy was delivered to the posterior fossa to a prescribed dose of 30 Gy in 10 fractions using 6 MV photons with opposed lateral fields. The patient tolerated therapy well. A follow-up MRI of the brain 15 months after the surgery and radiotherapy showed no recurrence of disease. A follow-up pelvic examination showed no evidence of recurrent disease three years following chemoradiation.

Case #2

A 67-year-old white female presented with recurrent urinary tract infections (UTIs) and urinary retention. On examination, she had a 4-cm peri-urethral mass; the biopsy showed a poorly differentiated adenocarcinoma. MRI of the pelvis revealed an enhancing 4.1×3.5×4.1-cm peri-urethral mass with possible involvement of the inferior bladder. The tumor was staged as a stage II (cT2N0M0) adenocarcin-oma of the urethra. The patient received external beam radiation therapy with concomitant cisplatin (40 mg/m2 weekly) and capecitabine (500 mg twice daily, 5 days/week). A prescribed dose of 46 Gy was delivered in 23 fractions to the tumor, as well as to inguinal and pelvic lymph nodes. Therapy was given with AP/PA fields using 6 and 15 MV photons on a Varian 2300 linear accelerator. Custom blocks were used to spare normal tissues. The patient tolerated external beam therapy well, with only diarrhea, urge incontinence, and superficial ulcerative moist desquamation of the inguinal folds as side-effects. At completion of therapy she had normal urinary voiding function and urinary continence.

Approximately four weeks after external beam radiation was completed, interstitial high-dose rate (HDR) brachytherapy was performed using transvaginal ultrasound with a perineal template for needle guidance (Figure 1). Seven interstitial brachytherapy flexi-needles were placed in the tumor. A treatment planning CT of the pelvis was then performed, and the CT images were transferred to the treatment planning system (Brachyvision 7.1, Varian Inc, Sunnyvale CA). The tumor and urethra were contoured, and the indwelling times in each catheter were adjusted manually to deliver an optimized dose of 5 Gy/fraction to the tumor, for a total of 20 Gy (Figures 2 and 3), given over three days.

Figure 1

Transverse ultrasound image of the tumor for case #2.

Figure 2

Computer tomography images of the tumor (red contour) and urethra (yellow contour) along with the interstitial needles for case # 2.

Figure 3

Computer tomography images of the tumor with the 5 Gy isodose line (blue) for case #2.

After interstitial HDR treatments had been completed, the template was removed (with the needles kept in place) so that an MRI could be performed. The MR images were transferred to the treatment planning system and fused with the treatment planning CT images, using the needle locations as the registration points. The tumor was more easily visualized on the MRI data set than on the CT data set. The tumor and urethra were contoured on the MR image set for comparison with those structures on the CT image set (Figure 4). The fused images showed that the tumor was adequately treated. A follow-up MRI, performed three months after the brachytherapy treatment, showed no residual tumor mass. Fourteen months after treatment, the patient has no evidence of disease recurrence, radiographically or on a physical examination.

Figure 4

Contours from the fused computer tomography and magnetic resonance images for Case #2. The magnetic resonance tumor volume is in green, the computed tomography tumor volume is in red, the magnetic resonance urethra is in blue, the computed tomography urethra is in yellow.

Results and Discussion

Primary urethral cancer is rare, comprising less than 1% of all malignancies.[4] A recent review of the National Cancer Institute Surveillance, Epidemiology, and End Results database showed that 1,075 men and 540 women were diagnosed with primary urethral cancer in the United States from 1973 to 2002, the major histological types being transitional cell carcinoma (55%), squamous cell carcinoma (21.5%), and adenocarcinoma (16.4%).[1] The histology of the neoplasm, however, does not seem to affect prognosis.[2,4,5]

Multiple factors have been correlated with the outcome in women with urethral cancer. This is well illustrated in a series of 72 women treated at Memorial Sloan-Kettering over a period of 36 years.[12] In this study, multivariate analysis showed that the stage of the primary tumor, the presence or absence of regional lymph node involvement, and the site of disease (proximal versus distal urethra) were all independent risk factors for survival. For example, patients with tumors ≤2 cm in size in the distal urethra had a 60% five-year survival rate, while those with lesions >4 cm in size in the proximal urethra had a five-year survival rate of only 13%. Others have also demonstrated that small, distal tumors have relatively good prognoses, whereas larger, proximal tumors carry relatively poor prognoses.[2-14] Overall prognosis, however, remains relatively poor, with a five-year overall survival rate of approximately 35–45%.[2-5]

Multiple small case studies have suggested that single modality treatment (surgery or radiation therapy) is effective for small, distal tumors; on the other hand, multimodal treatment has been recommended for larger and more proximal tumors.[3-5,7,8,15] Other case reports have suggested that brachytherapy is an effective component of multimodality treatment of primary urethral cancer.[5,8,16,17] Our case report corroborates the assertion that larger, proximal tumors may be effectively treated with chemoradiotherapy, and that interstitial brachytherapy appears to be a significant component of this treatment approach.

The use of advanced imaging technologies, including transvaginal ultrasound to guide the placement of interstitial needles along with MRI and CT scans, allows for improved diagnosis and treatment of urethral cancer.[19-25] Further advancement of the treatment planning can be made by the utilization of ultrasound-based planning (Vitesse, Varian). Vitesse allows the capture of ultrasound data and its conversion to DICOM RT, which can then be exported to the BrachyVision treatment planning system. The use of ultrasound in planning would shorten the work flow by eliminating the need for a CT scan, and would also provide excellent imaging of the tumor along with the implanted needles.

Conclusions

There are no consensus recommendations for the treatment of primary female urethral cancer owing to the rarity of this disease and the paucity of information in the literature. As such, the reporting of all cases of primary urethral cancer is necessary to better determine optimal management. Many authors have suggested a combination of surgery, chemosensitization, and radiation therapy. This case report supports the assertion that interstitial brachytherapy after chemoradiation is an effective and well-tolerated treatment option for female primary urethral adenocarcinoma. In the two patients presented in this case study, the responses to therapy have been excellent with only relatively mild side-effects.