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Treatment of Radiation or Cyclophosphamide Induced Hemorrhagic Cystitis using Conjugated Estrogen
0022-5347 /90 /l 441-0041$02.00 /0 THE JOURNAL OF UROLOGY Copyright© 1990 by AMERICAN
V oi" 144, July Printed in U.S.A.
UROLOGICAL ASSOCIATION) INC.
TREATMENT OF RADIATION OR CYCLOPHOSPHAMIDE INDUCED HEMORRHAGIC CYSTITIS USING CONJUGATED ESTROGEN YONG K. LIU,* JAMES L HARTY, GREG S. STEINBOCK, HOMER A. HOLT, JR., DAVID H. GOLDSTEIN AND MOHAMMAD AMIN From the Louisville Hematology Clinic and Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky
ABSTRACT
Five patients with severe hemorrhagic cystitis induced by radiation and/or cyclophosphamide were systematically treated with conjugated estrogen. Two patients received conjugated estrogen twice each day (1 mg. per kg.) intravenously, followed on day 3 and thereafter by 5 mg. per day orally. Hematuria decreased markedly 6 to 8 hours after the initial dose and urine color became light yellow within 1 to 3 days. The other 3 patients received 5 mg. conjugated estrogen per day orally and urine color became clear within 4 to 7 days. Hematuria did not recur during 12 to 22 months in 4 patients who received daily conjugated estrogen (1.25 mg.). However, transient episodes of mild hematuria persisted in 1 patient during the 3-month followup despite a higher dose of conjugated estrogen (10 mg. per day). Complications, including thromboembolism and other side effects associated with conjugated estrogen, were not observed in these patients. We postulate that conjugated estrogen controls hematuria in hemorrhagic cystitis by decreasing the fragility of the mucosal microvasculature of the bladder. (J. Ural., 144: 41-43, 1990) 3 had hypertension and 1 also had hypertensive heart disease. One patient had end stage renal failure because of polycystic disease of the kidney and occasional hematuria, and 1 had mild renal failure (serum creatinine 2.5 mg./dl.). Two patients had experienced easy bruising for many years. Radiation-induced proctitis and intermittent rectal bleeding were present in 2 patients and 1 of them underwent colectomy. All patients had normal liver function tests. Methods. Routine blood cell counts were performed with an electronic cell counter. Coagulation tests, including prothrombin time, activated partial thromboplastin time and fibrinogen, were done according to standard techniques. 7- 9 Bleeding time was performed by the modified Ivy method using a simplate Ht device. 10 Platelet aggregation tests using adenosine diphosphate (2 X 10-s M./1.), epinephrine (1 X 10-s M./1.), collagen (0.2 mg./ml.) and ristocetin (1.5 mg./ml.) as inducing agents were performed as recommended. 11
Hemorrhagic cystitis remains a significant complication after systemic cyclophosphamide or local radiation therapy to the pelvic region despite close attention to various preventive measures.1-3 It is associated with significant morbidity and occasionally may lead to death. 4 •5 Effective and conservative therapy for the more severe form of this complication is not available. Although successful in some patients for the control of massive hematuria and irritative voiding symptoms, an aggressive treatment program, such as intravesical instillation of formalin solution, is by itself associated with significant complications. 6 We describe our preliminary experience with conjugated estrogen in the successful management of 5 consecutive patients who had severe hemorrhagic cystitis induced by cyclophosphamide or radiation. Symptoms in all patients responded promptly (completely in 4). PATIENTS AND METHODS
Patients. We studied 5 consecutive patients (4 women and 1 man between 40 and 85 years old) during a 2-year period (see table). One patient had rheumatoid arthritis and was treated continuously with oral cyclophosphamide (100 mg. per day), 3 with carcinoma of the uterine cervix received radium implantation and 1 with transitional cell carcinoma of the bladder had external radiation therapy. All patients had episodes of gross hematuria, passage of blood clots in the urine and symptoms of irritative voiding, including dysuria, urgency and frequency of urination as well as suprapubic pain. Four patients had multiple episodes of severe pain that required repeated cystoscopic removal of clots. Repeated cystoscopic examinations were performed in every patient and revealed characteristic multiple hyperemic and telangiectatic areas, bleeding points and mucosal edema of the bladder wall consistent with cyclophosphamide or radiation-induced hemorrhagic cystitis. The bladder mucosa was extremely friable and touching the hyperemic areas with the tip of the cystoscope typically led to immediate bleeding. No tumor was noted on cystoscopic examination at diagnosis of hemorrhagic cystitis. In 2 patients repeated biopsy of the bladder wall revealed no tumor. While no patient had a history of thromboembolic disorders
RESULTS
Mild intermittent hematuria, lasting several hours at a time without irritative voiding symptoms and a recurrence frequency of 1 to 2 episodes per month, began after 6.5 years of continuous oral cyclophosphamide therapy in the patient with rheumatoid arthritis (see table) and cyclophosphamide was continued. Hematuria became more intense, recurring at 1 to 2 episodes per week, with occasional passage of blood clots in the urine and spasmodic suprapubic pain 6 months later when cyclophosphamide was discontinued. However, these symptoms persisted for the next 21 months without improvement despite repeated conservative treatment. Three patients with carcinoma of the uterine cervix had massive hematuria, urinary retention and suprapubic pain 4, 19 and 17 years after radium implantation, respectively. The hematuria in 1 patient remained nearly continuous for 1 month despite conservative intravesical therapy. Two patients had recurrent episodes of hematuria, passage of clots in the urine, occasional urinary retention and suprapubic pain for 12 months. The frequency of these episodes varied from 1 to 4 times monthly. The patient with transitional cell carcinoma of the bladder had hematuria with passage of clots in the urine 1 week after completion of external radiation therapy to the pelvic region. The hematuria became more
Accepted for publication January 10, 1990. * Requests for reprints: Louisville Hematology Clinic, Ste. 502, 225 Abraham Flexner Way, Louisville, Kentucky 40202.
t General Diagnostics, Morris Plaines, New Jersey. 41
42
LIU AND ASSOCIATES
Pertinent clinical data Conjugated Estrogen Therapy*
Hemorrhagic Cystitis Diagnosis
Rheumatoid arthritis Cervical Ca
Transitional cell Ca of bladder
Therapy
Cyclophosphamide Radium implant
External radiation
Mos.
Frequency of Hematuric Episode (per mo.)
Transfusion of Red Blood Cells (units)
21
4-8
11
5
12
1 12 12
Continuous 1-4 1-2 8-10
4
60 5 5 60
22 15 15 2
3
0 0 7
Initial Dose (mg./day)
Mos.
* All patients responded to conjugated estrogen therapy within 4 to 7 days.
intense and frequent 2 months later, recurring at 8 to 10 episodes monthly. All patients underwent repeated local intravesical treatment, including cystoscopic removal of clots, continuous saline or distilled water irrigation and fulguration. One patient also had intravesical instillation of 4 % formalin and 1 received intravesicular instillation of silver nitrate solution. None of these measures provided adequate control of hematuria and urinary symptoms in these patients. Three patients required transfusion of packed red blood cells for anemia because of urinary blood loss (see table). All patients had normal platelet counts, coagulation tests, bleeding time and platelet aggregation responses. Conjugated estrogen was first administered to 3 patients when they were hospitalized for massive hematuria, urinary retention, suprapubic pain and anemia. The other patients were treated on an outpatient basis. Six hours after the initial intravenous dose of conjugated estrogen (1 mg./kg. body weight) the intensity of gross hematuria in 1 patient decreased drastically and the color of the urine became slightly pink. Despite the discontinuation of intravesical saline drip the urine color was light yellow 24 hours later and the urinary sediment showed 10 to 20 red blood cells per high power field. Only a few red blood cells were observed in the urinary sediment on day 3 of therapy when the dose was changed to 5 mg. per day orally. This dose was maintained during the next 6 weeks with no reappearance of symptoms. Thereafter, the amount of conjugated estrogen was decreased to 2.5 mg. per day and 10 days later gross hematuria with urinary retention and suprapubic pain recurred. Treatment was reinstated with intravenous conjugated estrogen (1 mg./kg. body weight) for 2 days, followed by 5 mg. per day orally. The intensity of hematuria again decreased promptly and the urine color returned to light yellow 48 hours later. The patient experienced no hematuria during the ensuing 22 months when maintained at this dose. Conjugated estrogen then was discontinued with no recurrence during a 6-month period. Another patient also responded promptly to intravenous conjugated estrogen (1 mg.jkg. body weight). Gross hematuria decreased in intensity within 8 hours and the urine was light yellow by day 3 even though the urinary sediment still had 25 to 30 red blood cells per high power field. The dosage of conjugated estrogen was changed to 5 mg. per day orally on day 3 but mild intermittent hematuria recurred 2 weeks later. The dosage of conjugated estrogen was increased to 10 mg. daily but mild hematuria continued for another 2 weeks. There were 4 episodes of asymptomatic mild hematuria during the 3 months that the patient received daily conjugated estrogen (10 mg.). Ureteral obstruction secondary to radiation cystitis required placement of a double pigtail ureteral catheter before treatment. Repeat cystoscopy showed minimal bladder bleeding only at sites abraded by the stent. The patient with cyclophosphamide-induced hemorrhagic cystitis was hospitalized for persistent massive hematuria, urinary retention, passage of clots in the urine, recurrent spasmodic suprapubic pain and anemia for 2 weeks. Instillation of 4% formalin intravesically failed to relieve the urinary symp-
toms or decrease the intensity of hematuria. The intensity of hematuria decreased noticeably 1 day after the initiation of oral conjugated estrogen therapy (5 mg. per day) and the urine color was yellow on day 4 of treatment. Urinalysis showed 2 to 3 red blood cells per high power field 1 week later. Hematuria did not recur during the ensuing 12 months since the conjugated estrogen was decreased to 1.25 mg. daily. Two patients had gross hematuria when outpatient treatment with conjugated estrogen (5 mg. per day) was begun. The urine color became normal, that is light yellow, approximately 1 week later. There were 1 to 4 red blood cells per high power field in the urinary sediment after 1 month of conjugated estrogen therapy. Neither patient had recurrent hematuria during the next 14 months, at which time the dose of conjugated estrogen was decreased to 1.25 mg. daily. All patients tolerated the conjugated estrogen well without untoward effect. None of them suffered thromboembolic complications or received blood transfusion during the therapy period. Cystoscopic examinations were repeated in 3 patients after a minimum of 4 months of absence of hematuria. Local areas of pale edematous mucosa and regions of telangiectasia still were present but there was no bleeding. Furthermore, bleeding did not occur when the mucosa, including the regions with dilated vessels, was touched gently by the cystoscope. DISCUSSION
Clinical manifestations of hemorrhagic cystitis after radiation therapy to the pelvic region or systemic cyclophosphamide vary from asymptomatic and transient microscopic hematuria on one hand to recurrent episodes of massive hematuria marked by severe irritative voiding symptoms, including urinary retention and suprapubic pain, on the other. 12• 13 The mild form of this disease usually ceases without treatment. However, severe forms frequently require multiple blood transfusions for anemia caused by urinary blood loss as well as repeated cystoscopy to remove the blood clots and relieve urinary retention. Diagnosis requires a history of exposure to radiation to the pelvic region or systemic cyclophosphamide therapy, hematuria with or without irritative voiding symptoms and typical cystoscopic findings, including areas of mucosal edema, telangiectasia and multiple hemorrhagic points. 12' 13 Our patients had a severe form of hemorrhagic cystitis: 1 case was induced by cyclophosphamide while the others were caused by radiation. Several methods have been advocated for the control of bleeding in radiation or cyclophosphamide-induced hemorrhagic cystitis, including light fulguration; local or systemic administration of epsilon aminocaproic acid or vitamin E; intravesical instillation of water, aluminum hydroxide, silver nitrate solution, phenol or formalin; application of a Helmstein hydrostatic pressure balloon; urinary diversion and internal iliac artery ligation or embolization, and cystectomy. 4 • 6 • 13 • 14 The more conservative local measures are preferred but generally ineffective, and more aggressive treatments are associated with significant morbidity and mortality. 1• 4• 6 • 13 ' 14 Intravesical instillation of formalin and Helmstein hydrostatic balloon application have provided satisfactory control of hematuria. 4 •6 How-
TREATI'1ENT OF HEivIOl=tH,I'lAGIC c:lSTITI3 USit~G CO]\J"JUGATED ESTFtOGEI\J
ever, both 111.easures may cause as well. Suprapubic pain, dysuria, urinary incontinence, decreased bladder capacity because of fibrosis, renal papillary necrosis, hydronephrosis, bladder rupture and even death have been reported after instillation of formalin into the bladder. 6 Intravesical application of a Helmstein pressure balloon may cause necrosis of bladder mucosa, damage to detrusor function and rupture of the bladder. 4 It has long been evident that an effective and conservative method for the treatment of radiation or cyclophosphamide-induced hemorrhagic cystitis is urgently needed. Our patients had no relief from recurrent episodes of massive hematuria and irritating voiding symptoms after repeated treatment with normal saline bladder irrigation and fulguration of bleeding points in the bladder mucosa. Intravesical instillation of silver nitrate solution and 4 % formalin failed therapeutically. However, all patients, responded promptly to intravenous or oral administration of conjugated estrogen with complete disappearance of even microscopic hematuria. Furthermore, hematuria has not recurred in 4 of the 5 patients during the 12 to 22-month followup while receiving lower doses of oral conjugated estrogen. The pharmacological mechanism of action of conjugated estrogen is unclear. However, conjugated estrogen has been shown to normalize the prolonged bleeding time and improve hemostasis in patients with advanced renal failure. 15 • 16 The same pharmacological action does not appear to be responsible for control of hematuria in hemorrhagic cystitis. Our patients had a normal bleeding time and other coagulation parameters during the hematuric episodes. Repeated cystoscopic examinations showed little difference in the appearance of bladder mucosa between the time of the initial episode and remission. Gentle touching of the hyperemic region of the bladder mucosa with the tip of a cystoscope caused no bleeding during remission, whereas similar action at the time of a hematuric episode typically led to profuse bleeding. These observations suggest that conjugated estrogen may have an effect on the capillary wall resulting in decreased vascular fragility. ~·c,H'-HV•-ACV
VVHAJJ>>>V•~v,vo,cv
Danette Lockhart and Melissa Bullock provided technical assistance. Dr. Arnold Belker supplied valuable suggestions. REFERENCES
1. McGuire, E. J., Weiss, R. M., Schiff, M., Jr. and Lytton, B.:
Hemorrhagic radiation cystitis treatment. Urology, 3: 204, 1974. 2. Brugieres, L., Hartmann, 0., Travagli, J.P., Benhamou, E., Pico,
3.
4. 5.
6. 7.
8.
9. 10. lL 12. 13. 14. 15. 16.
43
t'..L L.i Valteau, D.i Kalifa, C.J Patte, C., Flar.nant, F. and Lernerle, J.: Hemorrhagic cystitis following high-dose chemotherapy and bone marrow transplantation in children with malignancies: incidence, clinical course and outcome. J. Clin. Oncol., 7: 194, 1989. Shaw, P. J., Hugh-Jones, K., Hobbs, J. R., Downie, C. J. C. and Barnes, R.: Busulfan and cyclophosphamide cause little early toxicity during displacement bone marrow transplantation in fifty children. Bone Marrow Transplant., 1: 193, 1986. Klein, F. A. and Smith, M. J. V.: Urinary complications of cyclophosphamide therapy: etiology, prevention and management. South. Med. J., 76: 1413, 1983. Pyeritz, R. E., Droller, M. J., Bender, W. L. and Sarai, R.: An approach to the control of massive hemorrhage in cyclophosphamide-induced cystitis by intravenous vasopressin: a case report. J. Urol., 120: 253, 1978. Donahue, L. A. and Frank, I. N.: Intravesical formalin for hemorrhagic cystitis: analysis of therapy. J. Urol., 141: 809, 1989. Hougie, C.: One-stage prothrombin time. In: Hematology, 3rd ed. Edited by W. J. Williams, E. Beutler, A. J. Erslev and M. A. Lichtman. New York: McGraw Hill Book Co., pp. 1665-1667, 1983. Hougie, C.: Recalcification time test and its modifications (partial thromboplastin time, activated partial thromboplastin time, and expanded partial thromboplastin time). In: Hematology, 3rd ed. Edited by W. J. Williams, E. Beutler, A. J. Erslev and M. A. Lichtman. New York: McGraw Hill Book Co., pp. 1662-1665, 1983. Ellis, B. C. and Stransky, A.: A quick and accurate method for the determination of fibrinogen in plasma. J. Lab. Clin. Med., 58: 477, 1961. Kumar, R., Ansell, J. E., Canoso, R. T. and Deykin, D.: Clinical trial of a new bleeding-time device. Amer. J. Clin. Path., 70: 642, 1978. Weiss, H.J.: Platelet aggregation. In: Hematology, 3rd ed. Edited by W. J. Williams, E. Beutler, A. J. Erslev and M.A. Lichtman. New York: McGraw Hill Book Co., pp. 1673-1675, 1983. Pool, T. L.: Irradiation cystitis: diagnosis and treatment. Surg. Clin. N. Amer., 39: 947, 1959. Stillwell, T. J. and Benson, R. C., Jr.: Cyclophosphamide-induced hemorrhagic cystitis. A review of 100 patients. Cancer, 61: 451, 1988. Jerkins, G. R., Noe, H. N. and Hill, D.: Treatment of complications of cyclophosphamide cystitis. J. Urol., 139: 923, 1988. Liu, Y. K., Kosfeld, R. E. and Marcum, S. G.: Treatment of uraemic bleeding with conjugated oestrogen. Lancet, 2: 887, 1984. Livio, M., Mannucci, P. M., Vigano, G., Mingardi, G., Lombardi, R., Mecca, G. and Remuzzi, G.: Conjugated estrogens for the management of bleeding associated with renal failure. New Engl. J. Med., 315: 731, 1985.
V oi" 144, July Printed in U.S.A.
UROLOGICAL ASSOCIATION) INC.
TREATMENT OF RADIATION OR CYCLOPHOSPHAMIDE INDUCED HEMORRHAGIC CYSTITIS USING CONJUGATED ESTROGEN YONG K. LIU,* JAMES L HARTY, GREG S. STEINBOCK, HOMER A. HOLT, JR., DAVID H. GOLDSTEIN AND MOHAMMAD AMIN From the Louisville Hematology Clinic and Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky
ABSTRACT
Five patients with severe hemorrhagic cystitis induced by radiation and/or cyclophosphamide were systematically treated with conjugated estrogen. Two patients received conjugated estrogen twice each day (1 mg. per kg.) intravenously, followed on day 3 and thereafter by 5 mg. per day orally. Hematuria decreased markedly 6 to 8 hours after the initial dose and urine color became light yellow within 1 to 3 days. The other 3 patients received 5 mg. conjugated estrogen per day orally and urine color became clear within 4 to 7 days. Hematuria did not recur during 12 to 22 months in 4 patients who received daily conjugated estrogen (1.25 mg.). However, transient episodes of mild hematuria persisted in 1 patient during the 3-month followup despite a higher dose of conjugated estrogen (10 mg. per day). Complications, including thromboembolism and other side effects associated with conjugated estrogen, were not observed in these patients. We postulate that conjugated estrogen controls hematuria in hemorrhagic cystitis by decreasing the fragility of the mucosal microvasculature of the bladder. (J. Ural., 144: 41-43, 1990) 3 had hypertension and 1 also had hypertensive heart disease. One patient had end stage renal failure because of polycystic disease of the kidney and occasional hematuria, and 1 had mild renal failure (serum creatinine 2.5 mg./dl.). Two patients had experienced easy bruising for many years. Radiation-induced proctitis and intermittent rectal bleeding were present in 2 patients and 1 of them underwent colectomy. All patients had normal liver function tests. Methods. Routine blood cell counts were performed with an electronic cell counter. Coagulation tests, including prothrombin time, activated partial thromboplastin time and fibrinogen, were done according to standard techniques. 7- 9 Bleeding time was performed by the modified Ivy method using a simplate Ht device. 10 Platelet aggregation tests using adenosine diphosphate (2 X 10-s M./1.), epinephrine (1 X 10-s M./1.), collagen (0.2 mg./ml.) and ristocetin (1.5 mg./ml.) as inducing agents were performed as recommended. 11
Hemorrhagic cystitis remains a significant complication after systemic cyclophosphamide or local radiation therapy to the pelvic region despite close attention to various preventive measures.1-3 It is associated with significant morbidity and occasionally may lead to death. 4 •5 Effective and conservative therapy for the more severe form of this complication is not available. Although successful in some patients for the control of massive hematuria and irritative voiding symptoms, an aggressive treatment program, such as intravesical instillation of formalin solution, is by itself associated with significant complications. 6 We describe our preliminary experience with conjugated estrogen in the successful management of 5 consecutive patients who had severe hemorrhagic cystitis induced by cyclophosphamide or radiation. Symptoms in all patients responded promptly (completely in 4). PATIENTS AND METHODS
Patients. We studied 5 consecutive patients (4 women and 1 man between 40 and 85 years old) during a 2-year period (see table). One patient had rheumatoid arthritis and was treated continuously with oral cyclophosphamide (100 mg. per day), 3 with carcinoma of the uterine cervix received radium implantation and 1 with transitional cell carcinoma of the bladder had external radiation therapy. All patients had episodes of gross hematuria, passage of blood clots in the urine and symptoms of irritative voiding, including dysuria, urgency and frequency of urination as well as suprapubic pain. Four patients had multiple episodes of severe pain that required repeated cystoscopic removal of clots. Repeated cystoscopic examinations were performed in every patient and revealed characteristic multiple hyperemic and telangiectatic areas, bleeding points and mucosal edema of the bladder wall consistent with cyclophosphamide or radiation-induced hemorrhagic cystitis. The bladder mucosa was extremely friable and touching the hyperemic areas with the tip of the cystoscope typically led to immediate bleeding. No tumor was noted on cystoscopic examination at diagnosis of hemorrhagic cystitis. In 2 patients repeated biopsy of the bladder wall revealed no tumor. While no patient had a history of thromboembolic disorders
RESULTS
Mild intermittent hematuria, lasting several hours at a time without irritative voiding symptoms and a recurrence frequency of 1 to 2 episodes per month, began after 6.5 years of continuous oral cyclophosphamide therapy in the patient with rheumatoid arthritis (see table) and cyclophosphamide was continued. Hematuria became more intense, recurring at 1 to 2 episodes per week, with occasional passage of blood clots in the urine and spasmodic suprapubic pain 6 months later when cyclophosphamide was discontinued. However, these symptoms persisted for the next 21 months without improvement despite repeated conservative treatment. Three patients with carcinoma of the uterine cervix had massive hematuria, urinary retention and suprapubic pain 4, 19 and 17 years after radium implantation, respectively. The hematuria in 1 patient remained nearly continuous for 1 month despite conservative intravesical therapy. Two patients had recurrent episodes of hematuria, passage of clots in the urine, occasional urinary retention and suprapubic pain for 12 months. The frequency of these episodes varied from 1 to 4 times monthly. The patient with transitional cell carcinoma of the bladder had hematuria with passage of clots in the urine 1 week after completion of external radiation therapy to the pelvic region. The hematuria became more
Accepted for publication January 10, 1990. * Requests for reprints: Louisville Hematology Clinic, Ste. 502, 225 Abraham Flexner Way, Louisville, Kentucky 40202.
t General Diagnostics, Morris Plaines, New Jersey. 41
42
LIU AND ASSOCIATES
Pertinent clinical data Conjugated Estrogen Therapy*
Hemorrhagic Cystitis Diagnosis
Rheumatoid arthritis Cervical Ca
Transitional cell Ca of bladder
Therapy
Cyclophosphamide Radium implant
External radiation
Mos.
Frequency of Hematuric Episode (per mo.)
Transfusion of Red Blood Cells (units)
21
4-8
11
5
12
1 12 12
Continuous 1-4 1-2 8-10
4
60 5 5 60
22 15 15 2
3
0 0 7
Initial Dose (mg./day)
Mos.
* All patients responded to conjugated estrogen therapy within 4 to 7 days.
intense and frequent 2 months later, recurring at 8 to 10 episodes monthly. All patients underwent repeated local intravesical treatment, including cystoscopic removal of clots, continuous saline or distilled water irrigation and fulguration. One patient also had intravesical instillation of 4 % formalin and 1 received intravesicular instillation of silver nitrate solution. None of these measures provided adequate control of hematuria and urinary symptoms in these patients. Three patients required transfusion of packed red blood cells for anemia because of urinary blood loss (see table). All patients had normal platelet counts, coagulation tests, bleeding time and platelet aggregation responses. Conjugated estrogen was first administered to 3 patients when they were hospitalized for massive hematuria, urinary retention, suprapubic pain and anemia. The other patients were treated on an outpatient basis. Six hours after the initial intravenous dose of conjugated estrogen (1 mg./kg. body weight) the intensity of gross hematuria in 1 patient decreased drastically and the color of the urine became slightly pink. Despite the discontinuation of intravesical saline drip the urine color was light yellow 24 hours later and the urinary sediment showed 10 to 20 red blood cells per high power field. Only a few red blood cells were observed in the urinary sediment on day 3 of therapy when the dose was changed to 5 mg. per day orally. This dose was maintained during the next 6 weeks with no reappearance of symptoms. Thereafter, the amount of conjugated estrogen was decreased to 2.5 mg. per day and 10 days later gross hematuria with urinary retention and suprapubic pain recurred. Treatment was reinstated with intravenous conjugated estrogen (1 mg./kg. body weight) for 2 days, followed by 5 mg. per day orally. The intensity of hematuria again decreased promptly and the urine color returned to light yellow 48 hours later. The patient experienced no hematuria during the ensuing 22 months when maintained at this dose. Conjugated estrogen then was discontinued with no recurrence during a 6-month period. Another patient also responded promptly to intravenous conjugated estrogen (1 mg.jkg. body weight). Gross hematuria decreased in intensity within 8 hours and the urine was light yellow by day 3 even though the urinary sediment still had 25 to 30 red blood cells per high power field. The dosage of conjugated estrogen was changed to 5 mg. per day orally on day 3 but mild intermittent hematuria recurred 2 weeks later. The dosage of conjugated estrogen was increased to 10 mg. daily but mild hematuria continued for another 2 weeks. There were 4 episodes of asymptomatic mild hematuria during the 3 months that the patient received daily conjugated estrogen (10 mg.). Ureteral obstruction secondary to radiation cystitis required placement of a double pigtail ureteral catheter before treatment. Repeat cystoscopy showed minimal bladder bleeding only at sites abraded by the stent. The patient with cyclophosphamide-induced hemorrhagic cystitis was hospitalized for persistent massive hematuria, urinary retention, passage of clots in the urine, recurrent spasmodic suprapubic pain and anemia for 2 weeks. Instillation of 4% formalin intravesically failed to relieve the urinary symp-
toms or decrease the intensity of hematuria. The intensity of hematuria decreased noticeably 1 day after the initiation of oral conjugated estrogen therapy (5 mg. per day) and the urine color was yellow on day 4 of treatment. Urinalysis showed 2 to 3 red blood cells per high power field 1 week later. Hematuria did not recur during the ensuing 12 months since the conjugated estrogen was decreased to 1.25 mg. daily. Two patients had gross hematuria when outpatient treatment with conjugated estrogen (5 mg. per day) was begun. The urine color became normal, that is light yellow, approximately 1 week later. There were 1 to 4 red blood cells per high power field in the urinary sediment after 1 month of conjugated estrogen therapy. Neither patient had recurrent hematuria during the next 14 months, at which time the dose of conjugated estrogen was decreased to 1.25 mg. daily. All patients tolerated the conjugated estrogen well without untoward effect. None of them suffered thromboembolic complications or received blood transfusion during the therapy period. Cystoscopic examinations were repeated in 3 patients after a minimum of 4 months of absence of hematuria. Local areas of pale edematous mucosa and regions of telangiectasia still were present but there was no bleeding. Furthermore, bleeding did not occur when the mucosa, including the regions with dilated vessels, was touched gently by the cystoscope. DISCUSSION
Clinical manifestations of hemorrhagic cystitis after radiation therapy to the pelvic region or systemic cyclophosphamide vary from asymptomatic and transient microscopic hematuria on one hand to recurrent episodes of massive hematuria marked by severe irritative voiding symptoms, including urinary retention and suprapubic pain, on the other. 12• 13 The mild form of this disease usually ceases without treatment. However, severe forms frequently require multiple blood transfusions for anemia caused by urinary blood loss as well as repeated cystoscopy to remove the blood clots and relieve urinary retention. Diagnosis requires a history of exposure to radiation to the pelvic region or systemic cyclophosphamide therapy, hematuria with or without irritative voiding symptoms and typical cystoscopic findings, including areas of mucosal edema, telangiectasia and multiple hemorrhagic points. 12' 13 Our patients had a severe form of hemorrhagic cystitis: 1 case was induced by cyclophosphamide while the others were caused by radiation. Several methods have been advocated for the control of bleeding in radiation or cyclophosphamide-induced hemorrhagic cystitis, including light fulguration; local or systemic administration of epsilon aminocaproic acid or vitamin E; intravesical instillation of water, aluminum hydroxide, silver nitrate solution, phenol or formalin; application of a Helmstein hydrostatic pressure balloon; urinary diversion and internal iliac artery ligation or embolization, and cystectomy. 4 • 6 • 13 • 14 The more conservative local measures are preferred but generally ineffective, and more aggressive treatments are associated with significant morbidity and mortality. 1• 4• 6 • 13 ' 14 Intravesical instillation of formalin and Helmstein hydrostatic balloon application have provided satisfactory control of hematuria. 4 •6 How-
TREATI'1ENT OF HEivIOl=tH,I'lAGIC c:lSTITI3 USit~G CO]\J"JUGATED ESTFtOGEI\J
ever, both 111.easures may cause as well. Suprapubic pain, dysuria, urinary incontinence, decreased bladder capacity because of fibrosis, renal papillary necrosis, hydronephrosis, bladder rupture and even death have been reported after instillation of formalin into the bladder. 6 Intravesical application of a Helmstein pressure balloon may cause necrosis of bladder mucosa, damage to detrusor function and rupture of the bladder. 4 It has long been evident that an effective and conservative method for the treatment of radiation or cyclophosphamide-induced hemorrhagic cystitis is urgently needed. Our patients had no relief from recurrent episodes of massive hematuria and irritating voiding symptoms after repeated treatment with normal saline bladder irrigation and fulguration of bleeding points in the bladder mucosa. Intravesical instillation of silver nitrate solution and 4 % formalin failed therapeutically. However, all patients, responded promptly to intravenous or oral administration of conjugated estrogen with complete disappearance of even microscopic hematuria. Furthermore, hematuria has not recurred in 4 of the 5 patients during the 12 to 22-month followup while receiving lower doses of oral conjugated estrogen. The pharmacological mechanism of action of conjugated estrogen is unclear. However, conjugated estrogen has been shown to normalize the prolonged bleeding time and improve hemostasis in patients with advanced renal failure. 15 • 16 The same pharmacological action does not appear to be responsible for control of hematuria in hemorrhagic cystitis. Our patients had a normal bleeding time and other coagulation parameters during the hematuric episodes. Repeated cystoscopic examinations showed little difference in the appearance of bladder mucosa between the time of the initial episode and remission. Gentle touching of the hyperemic region of the bladder mucosa with the tip of a cystoscope caused no bleeding during remission, whereas similar action at the time of a hematuric episode typically led to profuse bleeding. These observations suggest that conjugated estrogen may have an effect on the capillary wall resulting in decreased vascular fragility. ~·c,H'-HV•-ACV
VVHAJJ>>>V•~v,vo,cv
Danette Lockhart and Melissa Bullock provided technical assistance. Dr. Arnold Belker supplied valuable suggestions. REFERENCES
1. McGuire, E. J., Weiss, R. M., Schiff, M., Jr. and Lytton, B.:
Hemorrhagic radiation cystitis treatment. Urology, 3: 204, 1974. 2. Brugieres, L., Hartmann, 0., Travagli, J.P., Benhamou, E., Pico,
3.
4. 5.
6. 7.
8.
9. 10. lL 12. 13. 14. 15. 16.
43
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