0360-3016/91 $3.00 + .CNl Copyright 0 1991 Pergamon Press plc
hf. J. Radidon Oncology Bid. Pkys. Vol. 21, pp. %I-968 Printed in the U.S.A. AU rights reserved.
??Original Contribution
A COMPARISON OF THE ROLES OF SURGERY AND RADIATION THERAPY IN THE MANAGEMENT OF CARCINOMA OF THE FEMALE URETHRA CASSANDRAS. FOENS, M.D., DAVID H. HUSSEY, M.D., JOHN J. STAPLES, M.D., J. FRED DOORNBOS, M.D., B-CHEN WEN, M.D. AND ANTONIO P. VIGLIOTTI, M.D. Division of Radiation Oncology, Departmentof Radiology, University of Iowa College of Medicine, Iowa City, IA Between 1939 and 1986, 42 patients with carcinoma of the female urethra were treated with surgery and/or radiation therapy at the University of Iowa. Ten patients were treated with surgery alone, 28 with radiation therapy alone, and 4 with combined surgery and radiation therapy. Seventeen patients (40%) developed persistent or recurrent disease at the primary site and 15 (36%) had failures in the inguhuti nodes. The actuarial S-year survival rate was 33.5%. Only 36% (10/28) of patients treated with radiation therapy had iocai failures, compared to 60% (6/10) of those treated with surgery alone. The best results were achieved with combined interstitial and external beam irradiation. Whereas 57% (8/14) of patients who were treated with combined interstitial and external beam irradiation were alive NED at 3 years, none of 7 patients (0%) treated with interstitial implants only and 2 of 7 patients (29%) treated with external beam irradiation alone were alive NED at 3 years. There was a significantly lower inguhtal failure rate in patients who received treatment to the inguhmi nodes (10%) than in those who did not receive htgulnai area treatment (520/o), and this translated into a superior &year survival for those patients (60% vs 18%). Survival rates did not correlate with histopathologic type in this series, although there were differences in the patterns of failure. Survival rates did correlate well with clinical stage. Female urethra, Radiation therapy, Interstitial radiation therapy, External beam radiation therapy.
with the clinical stage of the disease and the histopathologic type.
INTRODUCTION
Carcinoma of the female urethra is a rare tumor, and even large institutions have a relatively limited experience with this disease. It accounts for less than 0.02% of all cancers in women (3, 6, 7, 9). Carcinoma of the urethra is the only urologic malignancy that is more common in women than men (1, 7). Because no single institution has collected a large series of female urethral cancers, there is much that is not known about this disease. This paper is a review of the experience in treating carcinoma of the female urethra at the University of Iowa Hospitals and Clinics, The principal objective is to define the role of radiation therapy in the management of this disease. The specific aims are: a) to compare the effectiveness of surgery, radiation therapy, and combined surgery and radiation therapy in the management of carcinomas of the female urethra; b) to evaluate the effectiveness of interstitial implantation, external beam irradiation, and combined interstitial and external beam irradiation; c) to evaluate the need for elective treatment of the inguinal lymph nodes; and d) to correlate the results of treatment
METHODS
AND MATERIALS
Clinical material Between February 1939 and December 1986, 44 patients with carcinoma of the female urethra were seen at the University of Iowa Hospitals and Clinics. Two of these did not receive treatment with either surgery or radiation therapy and were excluded from the analysis. One of these patients was treated palliatively with chemotherapy, and the other received no treatment. Both died of their disease within 3 months of diagnosis. Forty-one of the remaining 42 patients were white and one was black. Their ages ranged from 34 to 79 years, with a mean of 61 years. Nineteen patients (45%) had squamous cell carcinomas, 10 (24%) transitional cell carcinomas, 8 (19%) adenocarcinomas, 1 (2.4%) a mixed squamous/transitional cell carcinoma, 1 (2.4%) a malignant melanoma, and 3 (7%) had unclassified carcinomas.
Presented at the 32nd Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Miami Beach, FL, 15-19 October 1990. Reprint requests to: David H. Hussey, M.D., Division of Radia961
tion Oncology, Rm. W189Z-GH, University and Clinics, Iowa City, IA 52242-1059. Accepted for publication 29 March 199 1.
of Iowa Hospitals
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The clinical evaluation of these patients included a history and physical examination including a pelvic examination, a complete blood count, liver function tests, a chest X ray, and an intravenous pyelogram. Twelve of the 42 patients were cystoscoped, and all patients had biopsies of the primary tumor. Only one patient had computerized tomography of the abdomen and pelvis. None of the patients had lymphangiograms or magnetic resonance imaging. The patients were staged retrospectively using the Prempree modification of the Chau and Green clinical staging system (4, 9, 10): Stage I: Stage II:
Limited to the distal one-half of the urethra. Involving the proximal urethra, with extension to the periurethral tissues but not involving the vulva or bladder neck. Stage III: Extending to adjacent organs. IIIA: Involving the urethra and vulva. IIIB: Involving the urethra and vagina. IIIC: Involving the urethra and bladder neck. Stage IV: Disease invading the parametrium or paracolpium or with distant metastasis. IVA: Disease involving the parametrium or paracolpium. IVB: Metastasis. IVB 1: Groin nodes. IVB,: Pelvic nodes. IVB-,: Paraaortic nodes. IVB,: Hematogenous metastasis. Twelve patients (28.5%) were classified as having clinical Stage I disease, 7 (16.6%) as Stage II, 15 (35.7%) as Stage III, and 4 (9.5%) as Stage IV. In four patients (9.5%), there was insufficient clinical information for retrospective staging. Thirteen of the patients had lesions that originated in the distal urethra (including 12 Stage I and 1 Stage IIIA patient with disease involving the vulva), and five patients had cancers that originated in the proximal urethra. The remaining 25 patients had tumors that involved the entire length of the urethra. Four of the 42 patients (9.5%) had clinical evidence of inguinal lymph node metastasis at the time of initial diagnosis. None of the 42 patients in this study had paraaortic (Stage IVB,) or hematogenous metastasis (IVB,), although both patients who were excluded from the study had distant spread when first seen.
September 1991, Volume 21, Number 4
excision and an inguinal lymph node dissection, 3 had total urethrectomies, and 3 had pelvic exenterations. Surgery and radiation therapy. Three of the four patients who were treated with combined surgery and radiation therapy received preoperative irradiation. One of these was treated with external beam irradiation followed by a cystourethrectomy, one with colloidal gold instillation followed by a wide local excision, and one with a cystourethrectomy sandwiched between courses of pre- and postoperative external beam irradiation. The fourth patient had a partial resection followed by external beam irradiation and a radium needle implant. Radiation therapy. Seven of the 28 patients who were treated with radiotherapy only were treated with external irradiation alone, 7 with an implant alone, and 14 with both an interstitial implant and external beam irradiation. All of the implants were performed with radium needles, although one patient had interstitial colloidal gold in addition to an implant. There were 24 patients who received external beam radiation therapy, either alone or in combination with surgery or an implant. Nine of these were treated with kilovoltage X rays, 12 with @?o gamma rays, 4 with high energy (> 8 MV) X rays, and 2 with electron beams. Several patients received more than one modality of external beam radiation. The radiation doses for these patients varied considerably. The doses for the patients who were treated with only interstitial irradiation ranged from 2100 to 5472 mg hr (mean = 3177 mg hr). The doses given with external beam irradiation alone ranged from 2400 cGy in 12 fractions to 7020 cGy in 39 fractions (mean = 4507 cGy in 23 fractions). The patients who were treated with both interstitial and external beam irradiation received interstitial doses of 831 to 4700 mg hr plus external beam doses of 600 to 7000 cGy . A wide variety of portal arrangements were used. Fifteen patients were treated with anterior and posterior parallel-opposing portals, five with perineal portals, and four with a combination of anterior/posterior and perineal portals. The treatment portals included the inguinal region in nine patients and excluded the inguinal region in eight patients. In the other seven patients, we were unable to determine whether the inguinal nodes were encompassed. Thus, of the total group of 42 patients, 10 had the inguinal lymph nodes treated (1 with surgery and 9 with external beam irradiation), 25 did not have the inguinal areas treated, and in 7 patients it was uncertain whether the inguinal nodes were irradiated or not.
Treatment methods
A wide variety of treatment methods were used, as would be expected in a study that spanned 47 years. Ten of the 42 patients were treated with surgery only, 28 with radiation therapy only, and 4 with combined surgery and postoperative radiation therapy. Surgery. Three of the 10 patients who were treated with surgery alone had wide local excisions, 1 had a wide local
RESULTS The patients were treated between February 1939 and December 1986, and the data were analyzed in June 1990. Survival times were computed from the date of histologic diagnosis. The patients were followed for periods ranging from 3 l/2 to 41 years (mean = 23 years). Tabular data
963
Carcinoma of the female urethra 0 C. S. FOENSet al. Percent Falling 166%
60%
0
6
Fig. 1. Cumulative
12
16
Local Failure
24
30
36
TlmehMonths +
42
Groin Fallurs -
46
60
Dlstant Failure
time to failure in 28 patients who developed
were compared using the chi-squared test. Kaplan-Meier survival curves were compared using the Mantel-Haenszel test of significance. Patients were classified as having local failure if there was a persistent or recurrent mass or ulceration in the vicinity of the urethra, with a positive biopsy usually obtainable. Patients were scored as having inguinal failures if they had persistent disease in the groins or they developed metastatic inguinal lymphadenopathy. Those who developed disease beyond the primary site and the groins were classified as having distant metastasis. The patients were scored as having major complications if they developed ulcerations, fistulae, strictures, severe fibrosis, or osteoradionecrosis in areas remote from a site of persistent or recurrent cancer. Patients were reported as dead of intercurrent disease if they had no evidence of cancer on clinical examination performed shortly before the date of death, or if there was no evidence of residual cancer at autopsy. The median time to failure of any kind was 6 months, and all failures were apparent by 39 months (Fig. 1). The data were analyzed in terms of patterns of failure at 3 years, because 95% of the failures occurred within this interval. Fifteen of the total group of 42 patients (36%) were alive with no evidence of disease (NED) at 3 years (Table 1). Seventeen patients (40%) had local failures, 15 (36%) had inguinal failures, and 10 (24%) developed distant metastases. Eleven patients had failures in more than one site. The 3- and 5-year survival rates for the total population were 41% and 33.5%, respectively (Fig. 2). Six patients (14%) developed major complications. These included one patient with a vesicovaginal fistula after surgery alone and one patient with persistent skin ulceration following surgery and postoperative radiation therapy. There were two patients with urethral strictures requiring urinary diversions, one with skin necrosis, and one with a combination of skin necrosis, osteoradionecrosis, and a
64
progressive
disease.
vesicovaginal fistula after combined interstitial and external beam irradiation. Analysis by histopathology
Patient survival did not correlate well with histopathology in this small series. The 5-year survival rates for the major histopathologic types ranged from 29% to 37%. However, the 3-year NED rate for patients with transitional cell carcinomas (600, 60%) was better than the 3-year NED rate for those with squamous (5/19, 26%) or adenocarcinomas (3/8, 37.5%) (Table 2). Likewise, the local control rate for patients with transitional cell carcinomas was superior to the local control rates for those with either of the other major histopathologic types. On the other hand, the control rate in the inguinal lymph nodes was greater with adenocarcinomas than with either squamous or transitional cell carcinomas (Table 2). Although trends were observed, these differences were not statistically sig-
Table 1. Patterns of failure at 3 years Site of failure
No. of pts.
Local Local only Local + other site(s) Inguinal nodes Inguinal nodes only Inguinal + other site(s) Distant metastases Distant only Distant + other site(s)
17 (40%) 6 11 15 (36%) 6 9 lO* (24%) 4* 6 15 (36%)
NEDt
*An additional patient developed distant metastasis at 39 months. tNED = Alive with no evidence of disease at 3 years.
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20%
0% 0
6
12
18
24
30
36
TimehMonths
42
46
64
60
Fig. 2. Actuarial survival for the total population (Kaplan-Meiermethod). The actuarial 3- and S-year survival rates were 41% and 33.5%, respectively.
nificant (local control: x2 = 6.128; p = 0.11; inguinal control: x2 = 6.833; p = 0.09).
Analysis by clinical stage Survival rates correlated to some extent with the clinical stage of the disease. The survival rates for patients with Stage I cancers and for those with unknown stage tumors were slightly greater than the survival rates for patients with Stages II, III, or IV cancers. This suggests that the patients in the unknown stage category had relatively early disease. The actuarial 5-year survival rates for the clinical Stage I, II, III, IV, and unknown stage categories were 41%, 27%, 32%, 25%, and 50%, respectively. The pattern of failure, on the other hand, did not correlate well with the stage of the disease (Table 3). The local
failure rate for Stage I-II cancers (9/19, 47%) was greater than the local failure rate for Stage III-IV disease (6/19, 32%). This was probably because the patients with Stage III-IV cancers were treated more aggressively, for example, with combined interstitial and external beam irradiation or combined surgery and radiation therapy. Similarly, there was a greater incidence of inguinal failures in the patients with Stage I-II tumors (10/19, 53%) than in those with Stage III-IV cancers (5/19, 26%) (Table 3). This was probably because only 1 of 19 patients with Stage I-II cancers had the inguinal lymph nodes treated, compared to 7 of 19 patients with Stage III-IV disease, and 5 other patients with Stage III-IV cancers may have received inguinal irradiation. As expected, the incidence of distant metastasis was greater in the patients with
Table 2. Patterns of failure at 3 years of histology
Site of failure
squamous cell
Transitional cell
Adenocarcinoma
Other
8119 (42%) 3119 5119
l/10 (10%) o/10 1110
S/8 (63%) 318 218
(60%) o/5 315
7119 (37%) 3119 4119
3110 (30%) 2110 l/10
l/8 (12%) O/8 l/8
415 (80%) 115 315
S/19 (26%) 3119 2/19
l/lo* (10%) 1/10* o/10
l/8 (12%) O/8 I/8
(60%) 015 315
s/19 (26%)
6/10 (60%)
318 (37.5%)
l/5 (20%)
LOCd
Local only Local + other site(s) Inguinal nodes Inguinal nodes only Ingninal + other site(s) Distant metastases Distant only Distant + other site(s) NED
*An additional patient developed
distant metastasis
at 39 months.
315
315
Carcinoma of the female urethra 0 C. S. FOENSet al.
965
Table 3. Patterns of failure at 3 years by clinical stage* Clinical Stage Site of failure Local Local only Local + other site(s) Inguinal nodes Inguinal nodes only Inguinal + other site(s) Distant me&stases Distant only Distant + other site(s) NED
I
II
III
IV
Unknown
6112 (50%) 2112 4112
317 (43%) l/7 217
5/15 (33%) 2115 3115
l/4 (25%) 012 l/4
214 (50%) 112 l/4
5112 (42%) 2112 3112
517 (71%) 317 217
2115 (13%) 0115 2115
314 (75%) l/4 214
o/4 (0%) o/4 o/4
2112 (17%) 0112 2112
l/7 (14%) l/7 o/7
5/15t (33%) 3/15t 2115
l/4 (25%) o/4 l/4
l/4 (25%) o/4 l/4
5112 (42%)
o/7 (0%)
7115 (47%)
l/4 (25%)
214 (50%)
*Prempree modifications of Chau and Green system (9). tAn additional patient developed metastasis at 39 months.
Stage III-IV cancers (6/19, 32%) than in those with Stage I-II tumors (3/19, 16%). Analysis by treatment modality The local failure rate for the group treated with surgery
alone was greater than the local failure rate for the groups treated with radiotherapy alone or combined surgery and irradiation (Table 4). The difference is even greater when one analyzes the data by clinical stage (Table 5). Six of 10 patients (60%) treated with surgery alone developed local recurrences and 5 of these occurred in patients with Stage I-II disease. On the other hand, 10 of the 28 patients (36%)
who were treated with radiation therapy alone developed local failures, and only 3 of these occurred in patients with Stage I-II disease. One of the four patients who was treated with combined surgery and radiation therapy developed a local failure, and that patient’s stage is unknown. Although the patients treated with surgery alone had less advanced cancers, on the average, than those treated with radiotherapy only or combined surgery and radiotherapy, the survival rates for the three groups were similar. The S-year survival rates for the groups treated with surgery only, radiation therapy only, and combined surgery and radiation therapy were 33%, 37%, and 28%, respectively.
Table 4. Patterns of failure at 3 years by treatment modality
Site of failure Local Local only
Local + other site(s) Inguinal nodes Inguinal nodes only Inguinal + other site(s) Distant metastases Distant only Distant + other site(s) NED
Surgery
Radiotherapy (RT)
Surgery + RT
6110 (60%) 3110 3110
10128 (36%) 2l28 8128
l/4 (25%) l/4 o/4
2110 (20%) 0110 2110
13l28 (46%) 6128 7128
o/4 (0%) o/4 014
3llO (30%) 2110 l/10
7/28* (25%) 2/2@ 5128
o/4 (0%) o/4 o/4
2110 (20%)
10128 (36%)
314 (75%)
*An additional patient developed distant metastasis at 39 months.
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Table 5. Local failure rate at 3 years by treatment modality and clinical stage Clinical Stage I
II
III
IV
unknown
Total
Surgery
315
213
l/2
o/o
o/o
6/10 (60%)
Radiation IRT alone ERT alone IRT and ERT
2/l 213
4110
214
II3
l/l
111
o/o
o/3
l/4 o/2 l/l O/l
112 217
l/l o/2
Surgery and
o/o
o/o
o/3
5112 (50%)
317 (43%)
5115 (33%)
O/l
l/2 O/l
lo/28 4/7 417 2/14
(36%) (57%) (57%) (14%)
o/o
l/l
l/4
(25%)
214 (50%)
214 (50%)
radiation Totals
Analysis by radiation therapy technique
17/42 (40%)
The results were significantly better with combined interstitial and external beam irradiation than with either interstitial or external beam irradiation alone. Eight of 14 patients (57%) who were treated with combined interstitial and external beam irradiation were alive NED at 3 years compared to none of 7 patients (0%) treated with interstitial implants alone and only 2 of 7 patients (29%) treated with external beam irradiation alone (Table 6). This difference was statistically significant (x2 = 6.835; p < 0.05). The local control rates were also significantly better with combined interstitial and external beam irradiation. Only 14% (2/14) of the patients in the combined interstitial/external beam group developed local failures, compared to 57% (4/7) of those in each of the other two groups. Likewise, only 21% (3/14) of the patients treated with
both interstitial and external beam irradiation developed groin failures compared to 100% (7/7) of those treated with interstitial irradiation alone, and 43% (3/7) of those treated with external beam irradiation alone (Table 6). These differences were statistically significant (x2 = 11.63; p < 0.005). Four of the 14 patients (29%) developed major complications. However, all of these received high radiation doses, which were estimated to be in the range of 9500-16,000 cGy. The superior local and inguinal control rates for the group that received both interstitial and external beam therapy are reflected in a superior 5-year survival rate. The actuarial 5-year survival rate for the patients who were treated with combined interstitial and external beam irradiation was 42% compared to -26% for the groups treated with either interstitial implantation alone or external beam irradiation alone.
Table 6. Patterns of failure at 3 years by radiotherapy technique
Analysis by inguinal rrearment
Site of failure Local Local only Local + other site(s) Inguinal nodes InguinaI nodes only InguinaI + other site(s) Distant metastases Distant only Distant + other site(s) NED
Interstitial implant (IW
External
417 (57%) o/7 417
417 (57%) l/7 317
2114 (14%) 1114 l/14
717 (100%) 317 417
317 (43%) l/7 217
3114 (21%) 2114 l/14
317 (43%) on 317
217 (29%) o/7 217
2/14* (14%) 2/14* o/14
o/7 (0%)
217 (29%)
8114 (57%)
(:G
ERT+IRT
*An additional patient developed distant metastasis at 39 months.
The data were analyzed to determine the value of treating the inguinal lymph nodes. Of the total group of 42 patients, 10 had the inguinal lymph nodes treated, 25 did not, and in 7 cases there was insufficient information to determine whether or not the inguinal lymph nodes were treated. In general, the patients who received inguinal treatment had more advanced disease. Nevertheless, there was a significantly greater inguinal failure rate in the group that did not receive groin treatment (Table 7). Thirteen of 25 patients (52%) who did not receive groin treatment developed progressive disease in this region, compared to only 1 of 10 patients (10%) who had the inguinal nodes treated and 1 of 7 (14%) who may have received inguinal treatment. These differences were statistically significant (x2 = 6.925; p < .05). The survival rates for these patients showed a similar trend (Fig. 3). The group that received inguinal treatment had a 5-year survival rate of 60% compared to 18% for the group that received no groin treatment and 43% for the group that may have received groin irradiation.
Carcinoma of the female urethra 0 C. S. FOENSet al.
Table 7. Incidence of inguinal node failures by treatment modality Inguinal node treatment Treated
Not treated
Uncertain
Surgery
o/1* (0%)
219 (22%)
o/o (0%)
Radiation
l/7 (14%) o/o l/3 o/4
1 l/14 (79%) 7/l l/l 316
l/7 (14%) o/o l/3 o/4
Surgery and radiation
o/2 (0%)
o/2 (0%)
o/o (0%)
Total
l/10 (10%)
13125 (52%)
l/7 (14%)
Treatment modality
IRT alone ERT alone IRT + ERT
*l patient who had surgery alone had the nodes treated by inguinal node dissection.
DISCUSSION The results of this study are similar to those reported in the literature. Thirty-six percent (W42) of the patients were alive with no evidence of disease at 3 years, and the actuarial 5-year survival rate was 33.5%. Bracken et al. (3) reported a 5-year survival rate of 32% in a series of 81 patients seen at M.D. Anderson Hospital, and Antoniades (2) observed a 28% 5-year survival rate in 31 patients from Princess Margaret Hospital. Prempree et al. (9) reported slightly better results in a series of patients treated primarily with radiotherapy. In their study, 43% (9/21) of the patients treated definitively or palliatively survived 5 years. Thus, the overall 5-year survival rates in most series are in the range of 30-40%.
0
6
12
---
18
24
967
Carcinomas of the female urethra come in a variety of histopathologic types. Squamous cell carcinomas are most common, followed by transitional cell carcinomas and adenocarcinomas . Melanomas, mixed transitional/squamous carcinomas, and undifferentiated carcinomas are occasionally seen. Cell type has not been found to be of prognostic value by most authors, nor has it been useful as a means for selecting a treatment modality. The 5-year survival rates in our series ranged from 29% to 37% for the major histopathologic types. Nevertheless, there was a difference in the pattern of failure. Patients with transitional cell carcinomas had a lower failure rate at the primary site, and adenocarcinoma patients had a lower failure rate in the inguinal lymph nodes. These differences are probably due to the small number of patients available for analysis or to differences in the treatment methods employed. A variety of classifications have been used to stage carcinomas of the female urethra. Most authors have used the pathologic staging system of Grabstald et al. (5), which is based on depth of invasion, extension to adjacent structures, and the presence or absence of metastatic disease. Others have used the clinical staging system originally proposed by Chau and Green (4), which is based on the location of the primary tumor as well as the extent of the disease. Although the two staging systems differ in the early stages, Stages III and IV in the Chau and Green classification correspond well to Stages C and D in the Grabstald system. In contrast to cell type, staging has been found to be of prognostic value. In this series, 41% of patients with Stage I disease survived 5 years, compared to only 25-32% of those with Stage II-IV cancers. Similarly, Bracken et al. (3) found 5-year survival rates of 40-45% in patients with Stage A-B cancers and 20-25% in patients with Stage C-D tumors. However, there was a discrepancy in the patterns of failure for early and advanced cancers in our series.
30
36
TlmehMonths ++Notlbtod
42
48
54
60
-ufEaMh
Fig. 3. Actuarial survival as a function of whether the inguinal nodes were treated. Ten patients had the inguinal nodes treated, 25 patients did not, and in 7 patients it was uncertain whether the inguinal nodes were treated. (Kaplan-Meier method.)
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There were more local and inguinal failures in Stages I-II in our study than in Stages III-IV. This is probably because the patients with more advanced tumors were treated with combined interstitial and external beam irradiation and the treatment portals encompassed the inguinal lymph nodes. The data show that radiation therapy is an effective means of treating carcinoma of the female urethra, particularly when the radiotherapy is delivered with combined interstitial and external beam irradiation. Although, 60% (600) of the patients treated with surgery alone in this series developed local failures, only 36% (10/28) of those treated with radiation therapy did. And within the radiation therapy group, only 14% (2/14) of those treated with combined interstitial and external beam irradiation had local failures. These results are even more impressive if one considers the stage of the disease. Most of the patients treated with surgery alone had Stage I-II cancers, and most of the those treated with combined interstitial and external beam irradiation had Stage III-IV disease. Carcinomas of the female urethra metastasize predominantly through the lymphatics. The primary lymphatic drainage of the distal urethra is to the inguinal lymph nodes, whereas the primary lymphatic drainage of the proximal urethra is to the deep pelvic nodes (3, 6). Four of the patients in our series (9%) had inguinal lymph node metastasis at the time of diagnosis. Others have reported inguinal lymphadenopathy in 22-33% of patients at presentation (2, 8). The results of this study demonstrate the value of treating the inguinal lymph nodes. Only 10% (l/10) of the patients who received inguinal treatment in this series developed groin failures, compared to 52% ( 13/25) of those who did not receive inguinal treatment. The only patient who developed a groin failure in the group that received inguinal treatment had massive disease at both the primary
September 1991, Volume 21, Number 4
site and the regional lymph nodes (Stage IVB). The groins were treated with 4000 cGy tumor dose in 22 fractions, a low dose for gross disease. In contrast, another patient with gross inguinal lymphadenopathy was treated with 7000 cGy in 7 weeks to the inguinal region and survived 9 years NED. The patients who received treatment to the inguinal lymph nodes also had a significantly greater 5-year survival rate (60%) than those who did not (18%). On the basis of these results, we currently treat patients with carcinoma of the female urethra with combined interstitial and external beam irradiation regardless of the clinical stage and histology. For elective treatment, a dose of 4000-4500 cGy in 4 l/2-5 weeks is delivered through portals which encompass the frst echelon of lymph node drainage. Following this, an additional 2000-3000 cGy is delivered to the primary tumor with an interstitial implant.
CONCLUSIONS 1. Radiation therapy was an effective means of treating
carcinoma of the female urethra, particularly when it was delivered with combined interstitial and external beam irradiation. 2. The local and inguinal control rates with combined interstitial and external beam irradiation were superior to those achieved with either interstitial or external beam irradiation alone. 3. The inguinal failure rate in our series was significantly lower in patients who received inguinal treatment, and this translated into improved survival for patients in this group. 4. Survival rates did not correlate with histopathologic type in this series, although there were differences in the patterns of failure. Survival rates did correlate with clinical stage.
REFERENCES 1. Ali, M. M.; Klein, F. A.; Hazra, T. A. Primary female urethra carcinoma: a retrospective comparison of different treatment techniques. Cancer 6254-57; 1988. 2. Antoniades, J. Radiation therapy in carcinoma of the female
urethra. Am. J. Roentgenol. 114:145-151; 1972. 3. Bracken, R. B.; Johnson, D. E.; Miller, L. S.; Ayala, A. G.; Gomez, J. J.; Rutledge, F. N. Primary carcinoma of the female urethra. J. Ural. 116:188-192; 1976. 4. Chau, P. M.; Green, A. E. Radiotherapeutic management of malignant tumors of the vagina. In: Ariel, I. M., ed. Progress in clinical cancer, Vol 1. New York: Gune & Stratton; 1965: 728-750. 5. Grabstald, H.; Hilaris, B.; Henshike, J.; Whitmore, W. F. Cancer of the female urethra. JAMA 197:835-842; 1966.
Johnson, D. E.; O’Connell, J. R. Primary carcinoma of the female urethra. Urol. 21:42-45; 1983. Johnson, D. E.; O’Connell, J. R.; Delclos, L. Carcinoma of the urethra. In: Javadpour, N., ed. Principles and management of urologic cancer, 2nd edition. Baltimore: Williams & Wilkins; 1983:569X)9. Mayer, R.; Fowler, J. E.; Clayton, M. Localized urethral cancer in women. Cancer 60:1548-1551; 1987. Prempree, T.; Amornmarn, R.; Patanaphan, V. Radiation therapy in primary carcinoma of the female urethra II. An update on results. Cancer 543729-733; 1983. 10. Taggart, C. G.; Castro, J. R.; Rutledge, F. N. Carcinoma of the female urethra. Am. J. Roentgenol. 114:145-151; 1972.
hf. J. Radidon Oncology Bid. Pkys. Vol. 21, pp. %I-968 Printed in the U.S.A. AU rights reserved.
??Original Contribution
A COMPARISON OF THE ROLES OF SURGERY AND RADIATION THERAPY IN THE MANAGEMENT OF CARCINOMA OF THE FEMALE URETHRA CASSANDRAS. FOENS, M.D., DAVID H. HUSSEY, M.D., JOHN J. STAPLES, M.D., J. FRED DOORNBOS, M.D., B-CHEN WEN, M.D. AND ANTONIO P. VIGLIOTTI, M.D. Division of Radiation Oncology, Departmentof Radiology, University of Iowa College of Medicine, Iowa City, IA Between 1939 and 1986, 42 patients with carcinoma of the female urethra were treated with surgery and/or radiation therapy at the University of Iowa. Ten patients were treated with surgery alone, 28 with radiation therapy alone, and 4 with combined surgery and radiation therapy. Seventeen patients (40%) developed persistent or recurrent disease at the primary site and 15 (36%) had failures in the inguhuti nodes. The actuarial S-year survival rate was 33.5%. Only 36% (10/28) of patients treated with radiation therapy had iocai failures, compared to 60% (6/10) of those treated with surgery alone. The best results were achieved with combined interstitial and external beam irradiation. Whereas 57% (8/14) of patients who were treated with combined interstitial and external beam irradiation were alive NED at 3 years, none of 7 patients (0%) treated with interstitial implants only and 2 of 7 patients (29%) treated with external beam irradiation alone were alive NED at 3 years. There was a significantly lower inguhtal failure rate in patients who received treatment to the inguhmi nodes (10%) than in those who did not receive htgulnai area treatment (520/o), and this translated into a superior &year survival for those patients (60% vs 18%). Survival rates did not correlate with histopathologic type in this series, although there were differences in the patterns of failure. Survival rates did correlate well with clinical stage. Female urethra, Radiation therapy, Interstitial radiation therapy, External beam radiation therapy.
with the clinical stage of the disease and the histopathologic type.
INTRODUCTION
Carcinoma of the female urethra is a rare tumor, and even large institutions have a relatively limited experience with this disease. It accounts for less than 0.02% of all cancers in women (3, 6, 7, 9). Carcinoma of the urethra is the only urologic malignancy that is more common in women than men (1, 7). Because no single institution has collected a large series of female urethral cancers, there is much that is not known about this disease. This paper is a review of the experience in treating carcinoma of the female urethra at the University of Iowa Hospitals and Clinics, The principal objective is to define the role of radiation therapy in the management of this disease. The specific aims are: a) to compare the effectiveness of surgery, radiation therapy, and combined surgery and radiation therapy in the management of carcinomas of the female urethra; b) to evaluate the effectiveness of interstitial implantation, external beam irradiation, and combined interstitial and external beam irradiation; c) to evaluate the need for elective treatment of the inguinal lymph nodes; and d) to correlate the results of treatment
METHODS
AND MATERIALS
Clinical material Between February 1939 and December 1986, 44 patients with carcinoma of the female urethra were seen at the University of Iowa Hospitals and Clinics. Two of these did not receive treatment with either surgery or radiation therapy and were excluded from the analysis. One of these patients was treated palliatively with chemotherapy, and the other received no treatment. Both died of their disease within 3 months of diagnosis. Forty-one of the remaining 42 patients were white and one was black. Their ages ranged from 34 to 79 years, with a mean of 61 years. Nineteen patients (45%) had squamous cell carcinomas, 10 (24%) transitional cell carcinomas, 8 (19%) adenocarcinomas, 1 (2.4%) a mixed squamous/transitional cell carcinoma, 1 (2.4%) a malignant melanoma, and 3 (7%) had unclassified carcinomas.
Presented at the 32nd Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Miami Beach, FL, 15-19 October 1990. Reprint requests to: David H. Hussey, M.D., Division of Radia961
tion Oncology, Rm. W189Z-GH, University and Clinics, Iowa City, IA 52242-1059. Accepted for publication 29 March 199 1.
of Iowa Hospitals
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The clinical evaluation of these patients included a history and physical examination including a pelvic examination, a complete blood count, liver function tests, a chest X ray, and an intravenous pyelogram. Twelve of the 42 patients were cystoscoped, and all patients had biopsies of the primary tumor. Only one patient had computerized tomography of the abdomen and pelvis. None of the patients had lymphangiograms or magnetic resonance imaging. The patients were staged retrospectively using the Prempree modification of the Chau and Green clinical staging system (4, 9, 10): Stage I: Stage II:
Limited to the distal one-half of the urethra. Involving the proximal urethra, with extension to the periurethral tissues but not involving the vulva or bladder neck. Stage III: Extending to adjacent organs. IIIA: Involving the urethra and vulva. IIIB: Involving the urethra and vagina. IIIC: Involving the urethra and bladder neck. Stage IV: Disease invading the parametrium or paracolpium or with distant metastasis. IVA: Disease involving the parametrium or paracolpium. IVB: Metastasis. IVB 1: Groin nodes. IVB,: Pelvic nodes. IVB-,: Paraaortic nodes. IVB,: Hematogenous metastasis. Twelve patients (28.5%) were classified as having clinical Stage I disease, 7 (16.6%) as Stage II, 15 (35.7%) as Stage III, and 4 (9.5%) as Stage IV. In four patients (9.5%), there was insufficient clinical information for retrospective staging. Thirteen of the patients had lesions that originated in the distal urethra (including 12 Stage I and 1 Stage IIIA patient with disease involving the vulva), and five patients had cancers that originated in the proximal urethra. The remaining 25 patients had tumors that involved the entire length of the urethra. Four of the 42 patients (9.5%) had clinical evidence of inguinal lymph node metastasis at the time of initial diagnosis. None of the 42 patients in this study had paraaortic (Stage IVB,) or hematogenous metastasis (IVB,), although both patients who were excluded from the study had distant spread when first seen.
September 1991, Volume 21, Number 4
excision and an inguinal lymph node dissection, 3 had total urethrectomies, and 3 had pelvic exenterations. Surgery and radiation therapy. Three of the four patients who were treated with combined surgery and radiation therapy received preoperative irradiation. One of these was treated with external beam irradiation followed by a cystourethrectomy, one with colloidal gold instillation followed by a wide local excision, and one with a cystourethrectomy sandwiched between courses of pre- and postoperative external beam irradiation. The fourth patient had a partial resection followed by external beam irradiation and a radium needle implant. Radiation therapy. Seven of the 28 patients who were treated with radiotherapy only were treated with external irradiation alone, 7 with an implant alone, and 14 with both an interstitial implant and external beam irradiation. All of the implants were performed with radium needles, although one patient had interstitial colloidal gold in addition to an implant. There were 24 patients who received external beam radiation therapy, either alone or in combination with surgery or an implant. Nine of these were treated with kilovoltage X rays, 12 with @?o gamma rays, 4 with high energy (> 8 MV) X rays, and 2 with electron beams. Several patients received more than one modality of external beam radiation. The radiation doses for these patients varied considerably. The doses for the patients who were treated with only interstitial irradiation ranged from 2100 to 5472 mg hr (mean = 3177 mg hr). The doses given with external beam irradiation alone ranged from 2400 cGy in 12 fractions to 7020 cGy in 39 fractions (mean = 4507 cGy in 23 fractions). The patients who were treated with both interstitial and external beam irradiation received interstitial doses of 831 to 4700 mg hr plus external beam doses of 600 to 7000 cGy . A wide variety of portal arrangements were used. Fifteen patients were treated with anterior and posterior parallel-opposing portals, five with perineal portals, and four with a combination of anterior/posterior and perineal portals. The treatment portals included the inguinal region in nine patients and excluded the inguinal region in eight patients. In the other seven patients, we were unable to determine whether the inguinal nodes were encompassed. Thus, of the total group of 42 patients, 10 had the inguinal lymph nodes treated (1 with surgery and 9 with external beam irradiation), 25 did not have the inguinal areas treated, and in 7 patients it was uncertain whether the inguinal nodes were irradiated or not.
Treatment methods
A wide variety of treatment methods were used, as would be expected in a study that spanned 47 years. Ten of the 42 patients were treated with surgery only, 28 with radiation therapy only, and 4 with combined surgery and postoperative radiation therapy. Surgery. Three of the 10 patients who were treated with surgery alone had wide local excisions, 1 had a wide local
RESULTS The patients were treated between February 1939 and December 1986, and the data were analyzed in June 1990. Survival times were computed from the date of histologic diagnosis. The patients were followed for periods ranging from 3 l/2 to 41 years (mean = 23 years). Tabular data
963
Carcinoma of the female urethra 0 C. S. FOENSet al. Percent Falling 166%
60%
0
6
Fig. 1. Cumulative
12
16
Local Failure
24
30
36
TlmehMonths +
42
Groin Fallurs -
46
60
Dlstant Failure
time to failure in 28 patients who developed
were compared using the chi-squared test. Kaplan-Meier survival curves were compared using the Mantel-Haenszel test of significance. Patients were classified as having local failure if there was a persistent or recurrent mass or ulceration in the vicinity of the urethra, with a positive biopsy usually obtainable. Patients were scored as having inguinal failures if they had persistent disease in the groins or they developed metastatic inguinal lymphadenopathy. Those who developed disease beyond the primary site and the groins were classified as having distant metastasis. The patients were scored as having major complications if they developed ulcerations, fistulae, strictures, severe fibrosis, or osteoradionecrosis in areas remote from a site of persistent or recurrent cancer. Patients were reported as dead of intercurrent disease if they had no evidence of cancer on clinical examination performed shortly before the date of death, or if there was no evidence of residual cancer at autopsy. The median time to failure of any kind was 6 months, and all failures were apparent by 39 months (Fig. 1). The data were analyzed in terms of patterns of failure at 3 years, because 95% of the failures occurred within this interval. Fifteen of the total group of 42 patients (36%) were alive with no evidence of disease (NED) at 3 years (Table 1). Seventeen patients (40%) had local failures, 15 (36%) had inguinal failures, and 10 (24%) developed distant metastases. Eleven patients had failures in more than one site. The 3- and 5-year survival rates for the total population were 41% and 33.5%, respectively (Fig. 2). Six patients (14%) developed major complications. These included one patient with a vesicovaginal fistula after surgery alone and one patient with persistent skin ulceration following surgery and postoperative radiation therapy. There were two patients with urethral strictures requiring urinary diversions, one with skin necrosis, and one with a combination of skin necrosis, osteoradionecrosis, and a
64
progressive
disease.
vesicovaginal fistula after combined interstitial and external beam irradiation. Analysis by histopathology
Patient survival did not correlate well with histopathology in this small series. The 5-year survival rates for the major histopathologic types ranged from 29% to 37%. However, the 3-year NED rate for patients with transitional cell carcinomas (600, 60%) was better than the 3-year NED rate for those with squamous (5/19, 26%) or adenocarcinomas (3/8, 37.5%) (Table 2). Likewise, the local control rate for patients with transitional cell carcinomas was superior to the local control rates for those with either of the other major histopathologic types. On the other hand, the control rate in the inguinal lymph nodes was greater with adenocarcinomas than with either squamous or transitional cell carcinomas (Table 2). Although trends were observed, these differences were not statistically sig-
Table 1. Patterns of failure at 3 years Site of failure
No. of pts.
Local Local only Local + other site(s) Inguinal nodes Inguinal nodes only Inguinal + other site(s) Distant metastases Distant only Distant + other site(s)
17 (40%) 6 11 15 (36%) 6 9 lO* (24%) 4* 6 15 (36%)
NEDt
*An additional patient developed distant metastasis at 39 months. tNED = Alive with no evidence of disease at 3 years.
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20%
0% 0
6
12
18
24
30
36
TimehMonths
42
46
64
60
Fig. 2. Actuarial survival for the total population (Kaplan-Meiermethod). The actuarial 3- and S-year survival rates were 41% and 33.5%, respectively.
nificant (local control: x2 = 6.128; p = 0.11; inguinal control: x2 = 6.833; p = 0.09).
Analysis by clinical stage Survival rates correlated to some extent with the clinical stage of the disease. The survival rates for patients with Stage I cancers and for those with unknown stage tumors were slightly greater than the survival rates for patients with Stages II, III, or IV cancers. This suggests that the patients in the unknown stage category had relatively early disease. The actuarial 5-year survival rates for the clinical Stage I, II, III, IV, and unknown stage categories were 41%, 27%, 32%, 25%, and 50%, respectively. The pattern of failure, on the other hand, did not correlate well with the stage of the disease (Table 3). The local
failure rate for Stage I-II cancers (9/19, 47%) was greater than the local failure rate for Stage III-IV disease (6/19, 32%). This was probably because the patients with Stage III-IV cancers were treated more aggressively, for example, with combined interstitial and external beam irradiation or combined surgery and radiation therapy. Similarly, there was a greater incidence of inguinal failures in the patients with Stage I-II tumors (10/19, 53%) than in those with Stage III-IV cancers (5/19, 26%) (Table 3). This was probably because only 1 of 19 patients with Stage I-II cancers had the inguinal lymph nodes treated, compared to 7 of 19 patients with Stage III-IV disease, and 5 other patients with Stage III-IV cancers may have received inguinal irradiation. As expected, the incidence of distant metastasis was greater in the patients with
Table 2. Patterns of failure at 3 years of histology
Site of failure
squamous cell
Transitional cell
Adenocarcinoma
Other
8119 (42%) 3119 5119
l/10 (10%) o/10 1110
S/8 (63%) 318 218
(60%) o/5 315
7119 (37%) 3119 4119
3110 (30%) 2110 l/10
l/8 (12%) O/8 l/8
415 (80%) 115 315
S/19 (26%) 3119 2/19
l/lo* (10%) 1/10* o/10
l/8 (12%) O/8 I/8
(60%) 015 315
s/19 (26%)
6/10 (60%)
318 (37.5%)
l/5 (20%)
LOCd
Local only Local + other site(s) Inguinal nodes Inguinal nodes only Ingninal + other site(s) Distant metastases Distant only Distant + other site(s) NED
*An additional patient developed
distant metastasis
at 39 months.
315
315
Carcinoma of the female urethra 0 C. S. FOENSet al.
965
Table 3. Patterns of failure at 3 years by clinical stage* Clinical Stage Site of failure Local Local only Local + other site(s) Inguinal nodes Inguinal nodes only Inguinal + other site(s) Distant me&stases Distant only Distant + other site(s) NED
I
II
III
IV
Unknown
6112 (50%) 2112 4112
317 (43%) l/7 217
5/15 (33%) 2115 3115
l/4 (25%) 012 l/4
214 (50%) 112 l/4
5112 (42%) 2112 3112
517 (71%) 317 217
2115 (13%) 0115 2115
314 (75%) l/4 214
o/4 (0%) o/4 o/4
2112 (17%) 0112 2112
l/7 (14%) l/7 o/7
5/15t (33%) 3/15t 2115
l/4 (25%) o/4 l/4
l/4 (25%) o/4 l/4
5112 (42%)
o/7 (0%)
7115 (47%)
l/4 (25%)
214 (50%)
*Prempree modifications of Chau and Green system (9). tAn additional patient developed metastasis at 39 months.
Stage III-IV cancers (6/19, 32%) than in those with Stage I-II tumors (3/19, 16%). Analysis by treatment modality The local failure rate for the group treated with surgery
alone was greater than the local failure rate for the groups treated with radiotherapy alone or combined surgery and irradiation (Table 4). The difference is even greater when one analyzes the data by clinical stage (Table 5). Six of 10 patients (60%) treated with surgery alone developed local recurrences and 5 of these occurred in patients with Stage I-II disease. On the other hand, 10 of the 28 patients (36%)
who were treated with radiation therapy alone developed local failures, and only 3 of these occurred in patients with Stage I-II disease. One of the four patients who was treated with combined surgery and radiation therapy developed a local failure, and that patient’s stage is unknown. Although the patients treated with surgery alone had less advanced cancers, on the average, than those treated with radiotherapy only or combined surgery and radiotherapy, the survival rates for the three groups were similar. The S-year survival rates for the groups treated with surgery only, radiation therapy only, and combined surgery and radiation therapy were 33%, 37%, and 28%, respectively.
Table 4. Patterns of failure at 3 years by treatment modality
Site of failure Local Local only
Local + other site(s) Inguinal nodes Inguinal nodes only Inguinal + other site(s) Distant metastases Distant only Distant + other site(s) NED
Surgery
Radiotherapy (RT)
Surgery + RT
6110 (60%) 3110 3110
10128 (36%) 2l28 8128
l/4 (25%) l/4 o/4
2110 (20%) 0110 2110
13l28 (46%) 6128 7128
o/4 (0%) o/4 014
3llO (30%) 2110 l/10
7/28* (25%) 2/2@ 5128
o/4 (0%) o/4 o/4
2110 (20%)
10128 (36%)
314 (75%)
*An additional patient developed distant metastasis at 39 months.
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Table 5. Local failure rate at 3 years by treatment modality and clinical stage Clinical Stage I
II
III
IV
unknown
Total
Surgery
315
213
l/2
o/o
o/o
6/10 (60%)
Radiation IRT alone ERT alone IRT and ERT
2/l 213
4110
214
II3
l/l
111
o/o
o/3
l/4 o/2 l/l O/l
112 217
l/l o/2
Surgery and
o/o
o/o
o/3
5112 (50%)
317 (43%)
5115 (33%)
O/l
l/2 O/l
lo/28 4/7 417 2/14
(36%) (57%) (57%) (14%)
o/o
l/l
l/4
(25%)
214 (50%)
214 (50%)
radiation Totals
Analysis by radiation therapy technique
17/42 (40%)
The results were significantly better with combined interstitial and external beam irradiation than with either interstitial or external beam irradiation alone. Eight of 14 patients (57%) who were treated with combined interstitial and external beam irradiation were alive NED at 3 years compared to none of 7 patients (0%) treated with interstitial implants alone and only 2 of 7 patients (29%) treated with external beam irradiation alone (Table 6). This difference was statistically significant (x2 = 6.835; p < 0.05). The local control rates were also significantly better with combined interstitial and external beam irradiation. Only 14% (2/14) of the patients in the combined interstitial/external beam group developed local failures, compared to 57% (4/7) of those in each of the other two groups. Likewise, only 21% (3/14) of the patients treated with
both interstitial and external beam irradiation developed groin failures compared to 100% (7/7) of those treated with interstitial irradiation alone, and 43% (3/7) of those treated with external beam irradiation alone (Table 6). These differences were statistically significant (x2 = 11.63; p < 0.005). Four of the 14 patients (29%) developed major complications. However, all of these received high radiation doses, which were estimated to be in the range of 9500-16,000 cGy. The superior local and inguinal control rates for the group that received both interstitial and external beam therapy are reflected in a superior 5-year survival rate. The actuarial 5-year survival rate for the patients who were treated with combined interstitial and external beam irradiation was 42% compared to -26% for the groups treated with either interstitial implantation alone or external beam irradiation alone.
Table 6. Patterns of failure at 3 years by radiotherapy technique
Analysis by inguinal rrearment
Site of failure Local Local only Local + other site(s) Inguinal nodes InguinaI nodes only InguinaI + other site(s) Distant metastases Distant only Distant + other site(s) NED
Interstitial implant (IW
External
417 (57%) o/7 417
417 (57%) l/7 317
2114 (14%) 1114 l/14
717 (100%) 317 417
317 (43%) l/7 217
3114 (21%) 2114 l/14
317 (43%) on 317
217 (29%) o/7 217
2/14* (14%) 2/14* o/14
o/7 (0%)
217 (29%)
8114 (57%)
(:G
ERT+IRT
*An additional patient developed distant metastasis at 39 months.
The data were analyzed to determine the value of treating the inguinal lymph nodes. Of the total group of 42 patients, 10 had the inguinal lymph nodes treated, 25 did not, and in 7 cases there was insufficient information to determine whether or not the inguinal lymph nodes were treated. In general, the patients who received inguinal treatment had more advanced disease. Nevertheless, there was a significantly greater inguinal failure rate in the group that did not receive groin treatment (Table 7). Thirteen of 25 patients (52%) who did not receive groin treatment developed progressive disease in this region, compared to only 1 of 10 patients (10%) who had the inguinal nodes treated and 1 of 7 (14%) who may have received inguinal treatment. These differences were statistically significant (x2 = 6.925; p < .05). The survival rates for these patients showed a similar trend (Fig. 3). The group that received inguinal treatment had a 5-year survival rate of 60% compared to 18% for the group that received no groin treatment and 43% for the group that may have received groin irradiation.
Carcinoma of the female urethra 0 C. S. FOENSet al.
Table 7. Incidence of inguinal node failures by treatment modality Inguinal node treatment Treated
Not treated
Uncertain
Surgery
o/1* (0%)
219 (22%)
o/o (0%)
Radiation
l/7 (14%) o/o l/3 o/4
1 l/14 (79%) 7/l l/l 316
l/7 (14%) o/o l/3 o/4
Surgery and radiation
o/2 (0%)
o/2 (0%)
o/o (0%)
Total
l/10 (10%)
13125 (52%)
l/7 (14%)
Treatment modality
IRT alone ERT alone IRT + ERT
*l patient who had surgery alone had the nodes treated by inguinal node dissection.
DISCUSSION The results of this study are similar to those reported in the literature. Thirty-six percent (W42) of the patients were alive with no evidence of disease at 3 years, and the actuarial 5-year survival rate was 33.5%. Bracken et al. (3) reported a 5-year survival rate of 32% in a series of 81 patients seen at M.D. Anderson Hospital, and Antoniades (2) observed a 28% 5-year survival rate in 31 patients from Princess Margaret Hospital. Prempree et al. (9) reported slightly better results in a series of patients treated primarily with radiotherapy. In their study, 43% (9/21) of the patients treated definitively or palliatively survived 5 years. Thus, the overall 5-year survival rates in most series are in the range of 30-40%.
0
6
12
---
18
24
967
Carcinomas of the female urethra come in a variety of histopathologic types. Squamous cell carcinomas are most common, followed by transitional cell carcinomas and adenocarcinomas . Melanomas, mixed transitional/squamous carcinomas, and undifferentiated carcinomas are occasionally seen. Cell type has not been found to be of prognostic value by most authors, nor has it been useful as a means for selecting a treatment modality. The 5-year survival rates in our series ranged from 29% to 37% for the major histopathologic types. Nevertheless, there was a difference in the pattern of failure. Patients with transitional cell carcinomas had a lower failure rate at the primary site, and adenocarcinoma patients had a lower failure rate in the inguinal lymph nodes. These differences are probably due to the small number of patients available for analysis or to differences in the treatment methods employed. A variety of classifications have been used to stage carcinomas of the female urethra. Most authors have used the pathologic staging system of Grabstald et al. (5), which is based on depth of invasion, extension to adjacent structures, and the presence or absence of metastatic disease. Others have used the clinical staging system originally proposed by Chau and Green (4), which is based on the location of the primary tumor as well as the extent of the disease. Although the two staging systems differ in the early stages, Stages III and IV in the Chau and Green classification correspond well to Stages C and D in the Grabstald system. In contrast to cell type, staging has been found to be of prognostic value. In this series, 41% of patients with Stage I disease survived 5 years, compared to only 25-32% of those with Stage II-IV cancers. Similarly, Bracken et al. (3) found 5-year survival rates of 40-45% in patients with Stage A-B cancers and 20-25% in patients with Stage C-D tumors. However, there was a discrepancy in the patterns of failure for early and advanced cancers in our series.
30
36
TlmehMonths ++Notlbtod
42
48
54
60
-ufEaMh
Fig. 3. Actuarial survival as a function of whether the inguinal nodes were treated. Ten patients had the inguinal nodes treated, 25 patients did not, and in 7 patients it was uncertain whether the inguinal nodes were treated. (Kaplan-Meier method.)
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There were more local and inguinal failures in Stages I-II in our study than in Stages III-IV. This is probably because the patients with more advanced tumors were treated with combined interstitial and external beam irradiation and the treatment portals encompassed the inguinal lymph nodes. The data show that radiation therapy is an effective means of treating carcinoma of the female urethra, particularly when the radiotherapy is delivered with combined interstitial and external beam irradiation. Although, 60% (600) of the patients treated with surgery alone in this series developed local failures, only 36% (10/28) of those treated with radiation therapy did. And within the radiation therapy group, only 14% (2/14) of those treated with combined interstitial and external beam irradiation had local failures. These results are even more impressive if one considers the stage of the disease. Most of the patients treated with surgery alone had Stage I-II cancers, and most of the those treated with combined interstitial and external beam irradiation had Stage III-IV disease. Carcinomas of the female urethra metastasize predominantly through the lymphatics. The primary lymphatic drainage of the distal urethra is to the inguinal lymph nodes, whereas the primary lymphatic drainage of the proximal urethra is to the deep pelvic nodes (3, 6). Four of the patients in our series (9%) had inguinal lymph node metastasis at the time of diagnosis. Others have reported inguinal lymphadenopathy in 22-33% of patients at presentation (2, 8). The results of this study demonstrate the value of treating the inguinal lymph nodes. Only 10% (l/10) of the patients who received inguinal treatment in this series developed groin failures, compared to 52% ( 13/25) of those who did not receive inguinal treatment. The only patient who developed a groin failure in the group that received inguinal treatment had massive disease at both the primary
September 1991, Volume 21, Number 4
site and the regional lymph nodes (Stage IVB). The groins were treated with 4000 cGy tumor dose in 22 fractions, a low dose for gross disease. In contrast, another patient with gross inguinal lymphadenopathy was treated with 7000 cGy in 7 weeks to the inguinal region and survived 9 years NED. The patients who received treatment to the inguinal lymph nodes also had a significantly greater 5-year survival rate (60%) than those who did not (18%). On the basis of these results, we currently treat patients with carcinoma of the female urethra with combined interstitial and external beam irradiation regardless of the clinical stage and histology. For elective treatment, a dose of 4000-4500 cGy in 4 l/2-5 weeks is delivered through portals which encompass the frst echelon of lymph node drainage. Following this, an additional 2000-3000 cGy is delivered to the primary tumor with an interstitial implant.
CONCLUSIONS 1. Radiation therapy was an effective means of treating
carcinoma of the female urethra, particularly when it was delivered with combined interstitial and external beam irradiation. 2. The local and inguinal control rates with combined interstitial and external beam irradiation were superior to those achieved with either interstitial or external beam irradiation alone. 3. The inguinal failure rate in our series was significantly lower in patients who received inguinal treatment, and this translated into improved survival for patients in this group. 4. Survival rates did not correlate with histopathologic type in this series, although there were differences in the patterns of failure. Survival rates did correlate with clinical stage.
REFERENCES 1. Ali, M. M.; Klein, F. A.; Hazra, T. A. Primary female urethra carcinoma: a retrospective comparison of different treatment techniques. Cancer 6254-57; 1988. 2. Antoniades, J. Radiation therapy in carcinoma of the female
urethra. Am. J. Roentgenol. 114:145-151; 1972. 3. Bracken, R. B.; Johnson, D. E.; Miller, L. S.; Ayala, A. G.; Gomez, J. J.; Rutledge, F. N. Primary carcinoma of the female urethra. J. Ural. 116:188-192; 1976. 4. Chau, P. M.; Green, A. E. Radiotherapeutic management of malignant tumors of the vagina. In: Ariel, I. M., ed. Progress in clinical cancer, Vol 1. New York: Gune & Stratton; 1965: 728-750. 5. Grabstald, H.; Hilaris, B.; Henshike, J.; Whitmore, W. F. Cancer of the female urethra. JAMA 197:835-842; 1966.
Johnson, D. E.; O’Connell, J. R. Primary carcinoma of the female urethra. Urol. 21:42-45; 1983. Johnson, D. E.; O’Connell, J. R.; Delclos, L. Carcinoma of the urethra. In: Javadpour, N., ed. Principles and management of urologic cancer, 2nd edition. Baltimore: Williams & Wilkins; 1983:569X)9. Mayer, R.; Fowler, J. E.; Clayton, M. Localized urethral cancer in women. Cancer 60:1548-1551; 1987. Prempree, T.; Amornmarn, R.; Patanaphan, V. Radiation therapy in primary carcinoma of the female urethra II. An update on results. Cancer 543729-733; 1983. 10. Taggart, C. G.; Castro, J. R.; Rutledge, F. N. Carcinoma of the female urethra. Am. J. Roentgenol. 114:145-151; 1972.
