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Radiotherapy in the Management of Locally Advanced Urethral Squamous Cell Carcinoma
0022-534 7/89/1413-0615$02.00/0 Vol. 141, March
THE JOURNAL OF UROLOGY
Printed in U.S.A.
Copyright© 1989 by The Williams & Wilkins Co.
LOW DOSE COMBINED CHEMOTHERAPY/RADIOTHERAPY IN THE MANAGEMENT OF LOCALLY ADVANCED URETHRAL SQUAMOUS CELL CARCINOMA DOUGLAS W. JOHNSON,* JOHN F. KESSLER, ROBERT G. FERRIGNI
AND
JOHN D. ANDERSON
From the Sections of Radiation Oncology, Medical Oncology and Urology Services, David Grant United States Air Force Medical Center, Travis Air Force Base, California
ABSTRACT
The successful treatment of a patient with bulky squamous cell carcinoma of the urethra using low dose preoperative radiation therapy and concurrent chemotherapy is described. Dramatic rapid tumor response facilitated surgical resection of the remaining microscopic disease. This clinical behavior is remarkably similar to that seen with squamous cell carcinoma of the anal canal and esophagus when a similar regimen is used. At the latter tumor sites the successful use of combination radiotherapy and chemotherapy has reduced the morbidity of subsequent surgery, and in selected cases has obviated the need for a radical operation. Further investigation of such combination treatment is warranted for urethral carcinoma. (J. Ural., 141: 615-616, 1989) Urethral carcinomas represent a rare and challenging subset of genitourinary malignancies. Although 4 times more common in women than men, their rarity and variability have precluded definition of any standard treatment rationale. Numerous investigators have reported treatment techniques ranging from a radical operation to radical radiotherapy, depending upon the size, extent and location of the lesion. 1- 6 Despite the various techniques used recurrence has been frequent for locally advanced or proximal urethral lesions (see table). 1- 5 Recently, improved local control rates have been achieved for squamous cell carcinomas of the anal canal and esophagus by the concurrent use of radiation therapy and chemotherapy. 7-13 We describe a similar regimen used for a patient with locally advanced (stage C) squamous cell carcinoma of the proximal urethra that was followed by a planned radical cystourethrectomy to document tumor response. CASE REPORT
A 56-year-old black female nurse presented to our urology clinic in October 1985 with a 6-month history of progressive urinary outlet obstructive symptoms refractory to antibiotic courses and eventually to self-catheterization. Examination revealed a 2.5 X 6 cm. suburethral mass that extended from the distal urethra up to and involving the bladder neck. There was no inguinal adenopathy. Biopsy of the urethral mass documented a moderately differentiated squamous cell carcinoma (fig. 1). On computerized tomography the lesion completely surrounded the urethra laterally and anteriorly in the retropubic region, without evidence of pelvic or abdominal lymphadenopathy. Serum chemistry studies, a chest radiograph and bone scan failed to reveal distant metastases and the patient was believed to have a bulky stage C lesion. A combined treatment modality regimen was instituted. With a Theratron-80 60cobalt unit the patient received 40 Gy. in 20 fractions during 29 days to the pelvis, perineum and bilateral groin lymph node bearing regions. Mitomycin C (15 mg./m. 2 ) was administered by intravenous push on day 1 of radiation treatment and 5-fluorouracil (1 gm./m. 2) was given by continuous infusion on days 1 to 4. Although treatment was well tolerated the patient had significant moist desquamation in the Accepted for publication August 15, 1988. The opinions expressed herein are solely those of the authors and do not necessarily represent those of the United States Air Force or the United States Government. *Requests for reprints: C. J. Williams Cancer Treatment Center, 800 Prudential Ave., Jacksonville, Florida 32207. 615
inguinal folds beginning 1 week after treatment, which healed within 4 weeks using conservative measures. Re-examination of the patient 4 weeks after completing chemotherapy and radiation revealed dramatic diminution in the size of the mass to a vague, thin 2 cm. long indurated plaque confined to the mid posterior urethral region. On January 16, 1986 the patient underwent anterior pelvic exenteration, bilateral pelvic node dissection and abdominal exploration. Due to the marked diminution in tumor size by this time inferior pubic ramus resection was unnecessary. No gross evidence of disease was seen and the final pathological report revealed only a 3 X 2 X 15 mm. area of fibrous stroma, with scattered submucosal nests of squamous cell carcinoma subjacent to the urethra and evidence of radiation change, including vacuolated cytoplasm and distorted nuclei (fig. 2). The patient had no problems with postoperative wound healing but she did later have an anal stricture that required sphincterotomy. She remained free of disease 28 months after completing treatment. DISCUSSION
Like radical surgery, radiation therapy alone in high doses usually is successful in controlling early stage urethral carcinoma, especially when an interstitial radioactive implant is used. 3- 6 However, bulky proximal lesions involving the bladder neck often are refractory to the latter approach, since the implant is unable to cover all disease adequately. For bulky proximal stage C lesions the treatment approach usually recommended includes 50 Gy. preoperative radiation therapy followed by a radical pelvic operation. Despite this aggressive approach local and distant failures remain a problem, and treatment complications can be significant. 1 Combinations of low dose radiation (30 to 40 Gy.) and concurrent chemotherapy have been shown to have synergistic antineoplastic effects in anal canal and esophageal squamous cell carcinoma. 7 - 13 The combination appears to allow the use of lower doses of radiation without compromising efficacy. With this chemotherapy plus radiation approach a radical operation often can be avoided at these sites when pathological complete response is obtained. Morbidity in patients who require an operation due to persistent disease after the combined approach does not appear to be significantly increased. Similarly, squamous cell carcinoma of the urethra might represent a site worthy of study for the combined chemotherapy and radiation treatment approach. Although residual nests of malignant cells were still present in the pathological specimen
616
JOHNSON AND ASSOCIATES
Curative therapy for urethral carcinoma No. Pts Treated for Cure
Stage
Modes of Therapy
Mayer and associates'
16
All
Johnson and O'Connell'
24
All
Hopkins and associates'
15
All
Prempree and associates:i
14
All
Radiation therapy, surgery, radiation therapy plus surgery Radiation therapy, surgery, radiation therapy plus surgery Radiation therapy, surgery, radiation therapy plus surgery Radiation therapy with or without
Klein and associates 1
12
C
Reference
Local Control
% Long-Term Survival
31
25
%
62
20
13
78
77
Comments
Short av. followup
5-yr. followup
surgery
Radiation therapy plus surgery
86
Only 5-mo. followup, high morbidity
Although case reports do not support conclusions, we believe that concurrent chemotherapy and radiotherapy may have synergistic antitumor activity in squamous cell carcinoma of the urethra similar to that seen at other disease sites. The role of this approach relative to radical surgery awaits further detailed clinical investigation. REFERENCES
FIG. 1. Low and high power photomicrographs of initial biopsy specimen show dense sheets of moderately differentiated squamous cell carcinoma. A, reduced from X32. B, reduced from Xl28.
FIG. 2. Low and high power photomicrographs of post-treatment specimen show marked evidence of radiation effect. A, markedly decreased cellularity in fibrous stroma. Reduced from X32. B, few scattered nests of residual malignant cells with bizarre and pyknotic nuclei. Reduced from Xl28.
from our patient, an intriguing report by Shah and associates outlined a similar chemotherapy plus radiotherapy approach in a 74-year-old woman with a 6 cm. stage C squamous cell carcinoma of the urethra who refused an operation. She remained without evidence of disease with 30 months of followup at the time of the report. 14
1. Klein, F. A., Whitmore, W. F., Jr., Herr, H. W., Morse, M. J. and Sogani, P. C.: Inferior pubic rami resection with en bloc radical excision for invasive proximal urethral carcinoma. Cancer, 51: 1238, 1983. 2. Mayer, R., Fowler, J. E., Jr. and Clayton, M.: Localized urethral cancer in women. Cancer, 60: 1548, 1987. 3. Prempree, T., Amornmarn, R. and Patanaphan, V.: Radiation therapy in primary carcinoma of the female urethra. II. An update on results. Cancer, 54: 729, 1984. 4. Johnson, D. E. and O'Connell, J. R.: Primary carcinoma of female urethra. Urology, 21: 42, 1983. 5. Hopkins, S. C., Vider, M., Nag, S. K., Tai, D. L. and Soloway, M. S.: Carcinoma of the female urethra: reassessment of modes of therapy. J. Urol., 129: 958, 1983. 6. Prempree, T., Wizenberg, M. J. and Scott, R. M.: Radiation treatment of primary carcinoma of the female urethra. Cancer, 42: 1177, 1978. 7. Michaelson, R. A., Magill, G. B., Quan, S. H. Q., Leaming, R. H., Nikrui, M. and Stearns, M. W.: Preoperative chemotherapy and radiation therapy in the management of anal epidermoid carcinoma. Cancer, 51: 390, 1983. 8. Meeker, W. R., Jr., Sickle-Santanello, B. J., Philpott, G., Kenady, D., Bland, K. I., Hill, G. H. and Popp, M. B.: Combined chemotherapy, radiation, and surgery for epithelial cancer of the anal canal. Cancer, 57: 525, 1986. 9. John, M. J., Flam, M., Lovalvo, L. and Mowry, P.A.: Feasability of non-surgical definitive management of anal canal carcinoma. Int. J. Rad. Oncol. Biol. Phys., 13: 299, 1987. 10. Leichman, L., Steiger, Z., Seydel, H. G., Dindogru, A., Kinzie, J., Tohen, S., MacKenzie, G. and Shell, J.: Preoperative chemotherapy and radiation therapy for patients with cancer of the esophagus: a potentially curative approach. J. Clin. Oncol., 2: 75, 1984. 11. Coia, L. R., Engstrom, P. F. and Paul, A.: Nonsurgical management of esophageal cancer: report of a study of combined radiotherapy and chemotherapy. J. Clin. Oncol., 5: 1783, 1987. 12. Lokich, J. J., Shea, M. and Chaffey, J.: Sequential infusional 5fluorouracil followed by concomitant radiation for tumors of the esophagus and gastroesophagealjunction. Cancer, 60: 275, 1987. 13. Poplin, E., Fleming, T., Leichman, L., Seydel, H. G., Steiger, Z., Taylor, S., Vance, R., Stuckey, W. J. and Rivkin, S. E.: Combined therapies for squamous-cell carcinoma of the esophagus, a Southwest Oncology Group study (SWOG-8037). J. Clin. Oncol., 5: 622, 1987. 14. Shah, A. B., Katra, J. K., Silber, L. and Molho, L.: Squamous cell cancer of female urethra. Successful treatment with chemoradiotherapy. Urology, 25: 284, 1985.
THE JOURNAL OF UROLOGY
Printed in U.S.A.
Copyright© 1989 by The Williams & Wilkins Co.
LOW DOSE COMBINED CHEMOTHERAPY/RADIOTHERAPY IN THE MANAGEMENT OF LOCALLY ADVANCED URETHRAL SQUAMOUS CELL CARCINOMA DOUGLAS W. JOHNSON,* JOHN F. KESSLER, ROBERT G. FERRIGNI
AND
JOHN D. ANDERSON
From the Sections of Radiation Oncology, Medical Oncology and Urology Services, David Grant United States Air Force Medical Center, Travis Air Force Base, California
ABSTRACT
The successful treatment of a patient with bulky squamous cell carcinoma of the urethra using low dose preoperative radiation therapy and concurrent chemotherapy is described. Dramatic rapid tumor response facilitated surgical resection of the remaining microscopic disease. This clinical behavior is remarkably similar to that seen with squamous cell carcinoma of the anal canal and esophagus when a similar regimen is used. At the latter tumor sites the successful use of combination radiotherapy and chemotherapy has reduced the morbidity of subsequent surgery, and in selected cases has obviated the need for a radical operation. Further investigation of such combination treatment is warranted for urethral carcinoma. (J. Ural., 141: 615-616, 1989) Urethral carcinomas represent a rare and challenging subset of genitourinary malignancies. Although 4 times more common in women than men, their rarity and variability have precluded definition of any standard treatment rationale. Numerous investigators have reported treatment techniques ranging from a radical operation to radical radiotherapy, depending upon the size, extent and location of the lesion. 1- 6 Despite the various techniques used recurrence has been frequent for locally advanced or proximal urethral lesions (see table). 1- 5 Recently, improved local control rates have been achieved for squamous cell carcinomas of the anal canal and esophagus by the concurrent use of radiation therapy and chemotherapy. 7-13 We describe a similar regimen used for a patient with locally advanced (stage C) squamous cell carcinoma of the proximal urethra that was followed by a planned radical cystourethrectomy to document tumor response. CASE REPORT
A 56-year-old black female nurse presented to our urology clinic in October 1985 with a 6-month history of progressive urinary outlet obstructive symptoms refractory to antibiotic courses and eventually to self-catheterization. Examination revealed a 2.5 X 6 cm. suburethral mass that extended from the distal urethra up to and involving the bladder neck. There was no inguinal adenopathy. Biopsy of the urethral mass documented a moderately differentiated squamous cell carcinoma (fig. 1). On computerized tomography the lesion completely surrounded the urethra laterally and anteriorly in the retropubic region, without evidence of pelvic or abdominal lymphadenopathy. Serum chemistry studies, a chest radiograph and bone scan failed to reveal distant metastases and the patient was believed to have a bulky stage C lesion. A combined treatment modality regimen was instituted. With a Theratron-80 60cobalt unit the patient received 40 Gy. in 20 fractions during 29 days to the pelvis, perineum and bilateral groin lymph node bearing regions. Mitomycin C (15 mg./m. 2 ) was administered by intravenous push on day 1 of radiation treatment and 5-fluorouracil (1 gm./m. 2) was given by continuous infusion on days 1 to 4. Although treatment was well tolerated the patient had significant moist desquamation in the Accepted for publication August 15, 1988. The opinions expressed herein are solely those of the authors and do not necessarily represent those of the United States Air Force or the United States Government. *Requests for reprints: C. J. Williams Cancer Treatment Center, 800 Prudential Ave., Jacksonville, Florida 32207. 615
inguinal folds beginning 1 week after treatment, which healed within 4 weeks using conservative measures. Re-examination of the patient 4 weeks after completing chemotherapy and radiation revealed dramatic diminution in the size of the mass to a vague, thin 2 cm. long indurated plaque confined to the mid posterior urethral region. On January 16, 1986 the patient underwent anterior pelvic exenteration, bilateral pelvic node dissection and abdominal exploration. Due to the marked diminution in tumor size by this time inferior pubic ramus resection was unnecessary. No gross evidence of disease was seen and the final pathological report revealed only a 3 X 2 X 15 mm. area of fibrous stroma, with scattered submucosal nests of squamous cell carcinoma subjacent to the urethra and evidence of radiation change, including vacuolated cytoplasm and distorted nuclei (fig. 2). The patient had no problems with postoperative wound healing but she did later have an anal stricture that required sphincterotomy. She remained free of disease 28 months after completing treatment. DISCUSSION
Like radical surgery, radiation therapy alone in high doses usually is successful in controlling early stage urethral carcinoma, especially when an interstitial radioactive implant is used. 3- 6 However, bulky proximal lesions involving the bladder neck often are refractory to the latter approach, since the implant is unable to cover all disease adequately. For bulky proximal stage C lesions the treatment approach usually recommended includes 50 Gy. preoperative radiation therapy followed by a radical pelvic operation. Despite this aggressive approach local and distant failures remain a problem, and treatment complications can be significant. 1 Combinations of low dose radiation (30 to 40 Gy.) and concurrent chemotherapy have been shown to have synergistic antineoplastic effects in anal canal and esophageal squamous cell carcinoma. 7 - 13 The combination appears to allow the use of lower doses of radiation without compromising efficacy. With this chemotherapy plus radiation approach a radical operation often can be avoided at these sites when pathological complete response is obtained. Morbidity in patients who require an operation due to persistent disease after the combined approach does not appear to be significantly increased. Similarly, squamous cell carcinoma of the urethra might represent a site worthy of study for the combined chemotherapy and radiation treatment approach. Although residual nests of malignant cells were still present in the pathological specimen
616
JOHNSON AND ASSOCIATES
Curative therapy for urethral carcinoma No. Pts Treated for Cure
Stage
Modes of Therapy
Mayer and associates'
16
All
Johnson and O'Connell'
24
All
Hopkins and associates'
15
All
Prempree and associates:i
14
All
Radiation therapy, surgery, radiation therapy plus surgery Radiation therapy, surgery, radiation therapy plus surgery Radiation therapy, surgery, radiation therapy plus surgery Radiation therapy with or without
Klein and associates 1
12
C
Reference
Local Control
% Long-Term Survival
31
25
%
62
20
13
78
77
Comments
Short av. followup
5-yr. followup
surgery
Radiation therapy plus surgery
86
Only 5-mo. followup, high morbidity
Although case reports do not support conclusions, we believe that concurrent chemotherapy and radiotherapy may have synergistic antitumor activity in squamous cell carcinoma of the urethra similar to that seen at other disease sites. The role of this approach relative to radical surgery awaits further detailed clinical investigation. REFERENCES
FIG. 1. Low and high power photomicrographs of initial biopsy specimen show dense sheets of moderately differentiated squamous cell carcinoma. A, reduced from X32. B, reduced from Xl28.
FIG. 2. Low and high power photomicrographs of post-treatment specimen show marked evidence of radiation effect. A, markedly decreased cellularity in fibrous stroma. Reduced from X32. B, few scattered nests of residual malignant cells with bizarre and pyknotic nuclei. Reduced from Xl28.
from our patient, an intriguing report by Shah and associates outlined a similar chemotherapy plus radiotherapy approach in a 74-year-old woman with a 6 cm. stage C squamous cell carcinoma of the urethra who refused an operation. She remained without evidence of disease with 30 months of followup at the time of the report. 14
1. Klein, F. A., Whitmore, W. F., Jr., Herr, H. W., Morse, M. J. and Sogani, P. C.: Inferior pubic rami resection with en bloc radical excision for invasive proximal urethral carcinoma. Cancer, 51: 1238, 1983. 2. Mayer, R., Fowler, J. E., Jr. and Clayton, M.: Localized urethral cancer in women. Cancer, 60: 1548, 1987. 3. Prempree, T., Amornmarn, R. and Patanaphan, V.: Radiation therapy in primary carcinoma of the female urethra. II. An update on results. Cancer, 54: 729, 1984. 4. Johnson, D. E. and O'Connell, J. R.: Primary carcinoma of female urethra. Urology, 21: 42, 1983. 5. Hopkins, S. C., Vider, M., Nag, S. K., Tai, D. L. and Soloway, M. S.: Carcinoma of the female urethra: reassessment of modes of therapy. J. Urol., 129: 958, 1983. 6. Prempree, T., Wizenberg, M. J. and Scott, R. M.: Radiation treatment of primary carcinoma of the female urethra. Cancer, 42: 1177, 1978. 7. Michaelson, R. A., Magill, G. B., Quan, S. H. Q., Leaming, R. H., Nikrui, M. and Stearns, M. W.: Preoperative chemotherapy and radiation therapy in the management of anal epidermoid carcinoma. Cancer, 51: 390, 1983. 8. Meeker, W. R., Jr., Sickle-Santanello, B. J., Philpott, G., Kenady, D., Bland, K. I., Hill, G. H. and Popp, M. B.: Combined chemotherapy, radiation, and surgery for epithelial cancer of the anal canal. Cancer, 57: 525, 1986. 9. John, M. J., Flam, M., Lovalvo, L. and Mowry, P.A.: Feasability of non-surgical definitive management of anal canal carcinoma. Int. J. Rad. Oncol. Biol. Phys., 13: 299, 1987. 10. Leichman, L., Steiger, Z., Seydel, H. G., Dindogru, A., Kinzie, J., Tohen, S., MacKenzie, G. and Shell, J.: Preoperative chemotherapy and radiation therapy for patients with cancer of the esophagus: a potentially curative approach. J. Clin. Oncol., 2: 75, 1984. 11. Coia, L. R., Engstrom, P. F. and Paul, A.: Nonsurgical management of esophageal cancer: report of a study of combined radiotherapy and chemotherapy. J. Clin. Oncol., 5: 1783, 1987. 12. Lokich, J. J., Shea, M. and Chaffey, J.: Sequential infusional 5fluorouracil followed by concomitant radiation for tumors of the esophagus and gastroesophagealjunction. Cancer, 60: 275, 1987. 13. Poplin, E., Fleming, T., Leichman, L., Seydel, H. G., Steiger, Z., Taylor, S., Vance, R., Stuckey, W. J. and Rivkin, S. E.: Combined therapies for squamous-cell carcinoma of the esophagus, a Southwest Oncology Group study (SWOG-8037). J. Clin. Oncol., 5: 622, 1987. 14. Shah, A. B., Katra, J. K., Silber, L. and Molho, L.: Squamous cell cancer of female urethra. Successful treatment with chemoradiotherapy. Urology, 25: 284, 1985.