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Oral Conjugated Estrogen Therapy for Treatment of Hemorrhagic Cystitis
0022-5347/94/1515-1348$03.00/0 Vol. 151, 1348-1350, May 1994
THE JOURNAL OF UROLOGY Copyright © 1994 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Printed in U.S.A.
ORAL CONJUGATED ESTROGEN THERAPY FOR TREATMENT OF HEMORRHAGIC CYSTITIS J. MILLER, G. D. BURFIELD
AND
K. L. MORETTI
From the Department of Urology, Queen Elizabeth Hospital, Woodville, South Australia
ABSTRACT
We report 7 cases of severe hemorrhagic cystitis that required rep~ated transfusions, sur~ical intervention and oral conjugated estrogens. Of these 7 cases hematuna resolved c~mpletely m 5 during estrogen therapy and decreased sufficiently in 1 to preclude further transfuslO~. W e ~ound conjugated estrogens to be an effective, simple, inexpensive, well tolerated and readily avmlable treatment for hemorrhagic cystitis. KEY WORDS:
hemorrhage; cystitis; bladder; estrogenic substances, conjugated
Hemorrhagic cystitis is a heterogeneous disorder of varying etiology and clinical course. Massive bladder hemorrhage associated with vesical malignancy, radiation or cyclophosphamide therapy is known to cause significant morbidity and in some cases death. Numerous modalities have been proposed to treat such massive vesical hemorrhage but many management options are also associated with significant morbidity and mortality.Hl Encouraged by the recent report of Liu et aP we investigated the use of conjugated estrogens for the treatment of hemorrhagic cystitis. METHODS
Patients. In a 12-month period 7 patients at a mean age of 62 years (range 24 to 74 years) with hemorrhagic cystitis were recruited into our study. Hemorrhage occurred after cyclophosphamide treatment for malignancy in 4 cases (3 hematolog~cal, 1 breast), radiation therapy for carcinoma of the prostate III 2 and a combination of radiation cystitis and active transitional cell bladder cancer in 1. Routine evaluation of each patient consisted of electrolyte, creatinine and liver function measurements, midstream urine microscopy and culture, and complete blood count, platelet function and clotting studies. Prelim~nary excretory urography, subsequent cystourethroscopy and blOpsy completed the diagnostic examination. Presentation and prior therapy. All patients presented with gross hematuria, clot retention and irritative voiding symptoms, and required hospitalization for catheterization and bladder washout which was endoscopic in 4. Of our 7 cases initial treatme~t consisted of cystoscopic washout and bladder instillation of a 4% solution of formalin in 3 and a 1 % instillation of phenol in 1. However, bleeding recurred in these 4 cases before conjugated estrogen therapy was begun. Estrogens were given as primary treatment in 3 cases. All patients required blood transfusions of 3 to 20 units before treatment to maintain a hemoglobin level of more than 8.0 gm. Conjugated estrogen therapy. Therapy began with 2.5 mg. oral conjugated estrogens twice daily and this dosage was maintained until hemorrhaging stopped. After initial stabilization medication was tapered during 2 to 6 weeks and maintained at 625 JIg. daily for the duration of therapy. No patient had a history of major cardiovascular illness or thromboembolic phenomenon that contraindicated estrogen therapy. The patient with terminal disseminated breast carcinoma was started on estrogens after consultation with the oncologist. Response evaluation. Response to therapy was classified into 3 groups: 1) complete response-total cessation of gross ~e maturia within 10 days of the start of therapy, 2) parbal response-persistent gross hematuria but no further transfusions or additional therapy needed, and 3) nonresponse-conAccepted for publication October 15, 1993.
tinued bleeding requiring further transfusion and therapy. Complete and partial responses were considered as favorable results. CASE REPORTS
Case 1. A 69-year-old man with previously diagnosed muscle invasive transitional cell carcinoma who received radical radiotherapy had hemorrhagic cystitis and disseminated metastases 1 year posttreatment. Bleeding responded transiently to multiple cystoscopic diathermies and to instillation of a 4% fo:malin solution but severe hemorrhage recurred that resulted III anemia with a hemoglobin of 7.4 gm. and transfusion on 2 occasions. Conjugated estrogen therapy was begun at 2.5 mg. twice daily and decreased to 1.25 mg. twice daily. No hematuria of note recurred and no further transfusions were needed in the next 2 months until death from disseminated bladder carcinoma. Case 2. A 47-year-old woman with metastatic breast cancer after bilateral mastectomy 9 and 4 years previously had severe irritative voiding symptoms and hemorrhagic cystitis due to cyclophosphamide induced cystitis. Initial therapy with cystoscopic diathermy, washout and hydrodistention failed to control the severe symptoms. After 1.25 mg. oral conjugated estrogens twice daily were administered, gross hematuria ceased and irritative voiding symptoms were greatly improved until death 8 weeks later from cerebral metastases. Case 3. A 68-year-old man had severe hemorrhagic cystitis after receiving radical radiotherapy for clinically localized carcinoma of the prostate. After multiple transfusions hemorrhaging responded transiently to an intravesical 4% formalin instillation. When hematuria recurred 2.5 mg. conjugated estrogens were given twice daily. Hematuria resolved during maintenance therapy but after 6 months the patient refused medication and hematuria recurred in 10 days. Estrogens were resumed and bleeding stopped, and has not recurred on a maintenance dose of 625 JIg. daily. Case 4. A 24-year-old woman had severe thrombocytopenia and hemorrhagic cystitis after receiving cyclophosphamide induction chemotherapy before stem cell transplantation for leukemia. Transfusion of 4 units of blood per day was needed to maintain a hemoglobin of 8 gm. Various therapies, including cystoscopic diathermy and bladder washout, phenol instillation and alum irrigation, and platelet transfusions and oral estrogens failed to control the hemorrhage, which eventually responded to intravenous prostaglandin F2-a infusion. Intermittent hematuria continued but further transfusion was not required. The patient died 4 weeks later of uncertain causes. Case 5. A 74-year-old man who received cyclophosphamide 7 years previously for nonHodgkins lymphoma had 3 episodes of gross hematuria that required repeated cystoscopic washout
1348
ESTROGEN THERAPY FOR HEMORRHAGIC CYSTITIS
and 3 transfusions in 3 weeks. After conjugated estrogen therapy was begun bleeding resolved and no further transfusion was needed. During the next 6 weeks dosage was tapered to a maintenance level of 625 JLg. daily. Hematuria did not recur but the patient died of ischemic heart disease 9 months later. Case 6. A 63-year-old man who received radical radiotherapy for localized prostate cancer 3 years previously presented with disseminated disease and radiation-induced hemorrhagic cystitis that required cystoscopic washout and multiple blood transfusions. A temporary response was gained with instillation of a 4 % formalin solution but bleeding recurred until conjugated estrogens were begun at 2.5 mg. twice daily. Hematuria resolved until death 9 months later from disseminated carcinoma. Case 7. A 43-year-old man who received cyclophosphamide 2 years previously for leukemia had 3 episodes of gross hematuria that required repeated cystoscopic washout and 3 transfusions in 2 weeks. After conjugated estrogen therapy was started bleeding resolved and no further transfusion was needed. During the next 6 weeks dosage was tapered to maintenance therapy of 625 JLg. daily for 3 months. Hematuria did not recur and therapy was withheld. Clinically significant hematuria has not recurred 1 year posttreatment. RESULTS
Of our 7 patients 5 were terminally ill at presentation and died from 6 weeks to 9 months after conjugated estrogen therapy was begun. Death resulted from disseminated breast, transitional cell and prostatic cancer, and leukemia and lymphoma. No hemorrhage recurred in 4 patients. In case 4 cyclophosphamide induced hemorrhagic cystitis was unresponsive to conjugated estrogen therapy but responded to intravenous prostaglandin F2-a and platelet transfusions. The remaining 2 patients were well 36 and 18 months after therapy began, although 1 refused therapy after 6 months. He was hospitalized 10 days later for cystoscopic washout of clot retention secondary to hemorrhagic cystitis. After resumption of conjugated estrogens hemorrhage resolved again. Complete response to treatment occurred in 6 cases and nonresponse in 1. Recurrent hematuria after refusal of therapy was considered a treatment violation, not a treatment failure, and, therefore, was classified as a complete response. DISCUSSION
The reported frequency of bladder hemorrhage ranges from 2.5 to 12% after pelvic irradiation2,a and 2 to 40% after cyclophosphamide therapy.4,l2 Often there is no correlation between the extent of therapy and development of severe hematuria. Although most oncologists attempt to prevent this complication by using forced diuresis, multiport radiation therapy and detoxifying agents, such as N-acetylcysteine, disulfiram and sodium-2-mercaptoethane-sulfonate, severe hemorrhagic cystitis still occurs. The exact pathogenesis remains unknown but direct urothelial toxicity and microvascular damage are considered the final common pathways regardless of etiology. Current management involves 3 stages: l)-prevention, 2)minimally invasive therapy and 3)-invasive or operative treatment. Prevention includes adequate oral or intravenous hydration and active diuresis during treatment. Catheter drainage to decrease epithelial contact time with toxins adjuvant to the use of standard detoxification agents has been recommended during cyclophosphamide therapy. Minimally invasive measures involve correction of any bleeding diathesis and bladder washouts or irrigation using large bore catheters. Some cases resolve with no additional treatment but if bleeding continues other approaches are possible. Low irritant agents, such as aluminum sulfates9- 11 and E1, E2 and F2-a prostaglandins/a-l6 may be intravesically instilled at bedside, or balloon dilation l7 or instillation of the more irritant solutions, including silver nitrate,a,5 pheno14,6 and formalin,2,a,7,s may be performed cystoscopically in the operating room with the patient under general
1349
anesthesia. Vasopressin,18 prostaglandinsl5 and conjugated estrogens l may also be given orally. Phenol or silver nitrate cautery of the vesical mucosa has been recommended in life threatening hemorrhagic cystitis but the brief response and the need to anesthetize the patient make cautery a less than attractive option. A 1 to 10% intravesical solution of formalin has been widely used for hemorrhagic cystitis since its effectiveness was reported in 1969 by Brown. 7 Donahue and Frank reported complete response rates of 83 %, 78% and 71 % in 245 cases treated by instillation of formalin at 10%, 5% and 1% concentrations, respectively.s Most response occurred within 48 hours of treatment with a 3 to 4-month average duration of response before recurrence. However, major complications occurred at all levels of formalin concentrations. Death resulted in 2.2% of patients treated with 5% formalin and in 5.7% of those treated with 10%. Many complications and deaths were related to unsuspected vesicoureteral reflux alone or in combination with multiple instillations. Therefore, preoperative cystograms or balloon occlusion of the ureters is suggested to decrease the incidence of reflux nephropathy. Instillation of formalin, phenol or silver nitrate into the bladder induces severe pain and, therefore, regional or general anesthesia is recommended before therapy. A number of reports describe bedside intravesical instillation of 1% alum solution, using aluminum ammonium sulfate or aluminum potassium sulfate with moderate success. 9- 11 Response is transient in more than 30% of cases and hemorrhage usually recurs when instillation is discontinued. Furthermore, alum readily forms thick precipitates that block catheters and coat the urothelium, which creates difficulties in subsequent intravesical therapy should alum fail to control the bleeding. Epsilon aminocaproic acid has been used at our institution as a bedside instillation to control vesical hemorrhage but it proved unsatisfactory in many cases, because clot retention developed that required cystoscopic washout. The use of prostaglandins has been reported to prevent and treat hemorrhagic cystitis. In 5 cases prostglandin F2-a given intravesically for 4 to 5 days successfully stopped vesical hemorrhage and provided long-term resolution with no recurrence at 6 to 14 months. la ,l5 The mode of action is unclear but it is thought to relate to the stimulation of smooth muscle contraction and subsequent hemostasis by normal hemostatic and coagulation mechanisms. Increases in renal blood flow and urine production caused by prostaglandins are also thought to contribute to resolution. Major drawbacks of this therapy are the development of severe bladder spasms and the cost of prostaglandins. Invasive or operative treatment is used in cases that do not respond to less aggressive therapy. Radiographic or operative arterial occlusion of the vesical arteries/ 9 open bladder diathermy and/or packing,20 urinary diversion 2l and in extreme cases cystectomy20 have varying rates of success and significant side effects or life threatening complications, and may not be appropriate for terminally ill patients. In 1990 Liu et al reported on the use of oral conjugated estrogens for hemorrhagic cystitis, and introduced an effective, simple and readily available treatment option. l In their study 5 patients remained free of hematuria and complications at 12 to 22 months of followup. Initially 2 cases were treated with intravenous estrogens but equally good responses were noted with oral estrogens. Of our 7 patients 6 responded completely to 2.5 mg. oral estrogens twice daily with long lasting response in those patients still living. Because most of our patients were terminally ill, the ease of estrogen therapy and the avoidance of more aggressive or invasive measures were of great benefit. The recurrence of bleeding in 1 patient 10 days after the withdrawal of low dose estrogens introduces the issue of treatment duration. The increased cardiovascular complication rate in men with prostate cancer who are treated with estrogens at moderate to high doses is well known. However, the long-term
1350
ESTROGEN THERAPY FOR HEMORRHAGIC CYSTITIS
effect of low dose therapy is unknown. After an initial loading period we were able to reduce dosage rapidly to a low level and still prevent hemorrhagic cystitis. The duration of therapy and ideal initiating and maintenance doses have not been established by this or the previous study by Liu et al. Additional clinical studies are needed to confirm these encouraging results, develop the ideal dosage regimen and establish the mechanism of action for estrogen therapy. Although Liu et al have suggested that decreased vascular, that is capillary, fragility is a possible mechanism, basic research into this area is lacking and may reveal alternative explanations, such as bladder mucous secretion, or alteration in coagulation or hemostatic mechanisms. In addition, new studies may lead to other treatments for hemorrhagic cystitis that are based on a better understanding of the underlying pathophysiology. Conjugated estrogens are an effective, simple, inexpensive, well tolerated and readily available treatment for hemorrhagic cystitis that is unresponsive to conservative therapy. We support the use of oral conjugated estrogens as first line treatment in this serious disorder. However, we advise against the longterm use of high doses of estrogens in those patients at risk for thromboembolic, cardiac or cerebrovascular disease, or in those with reasonable life expectancy until further studies establish the long-term safety of this treatment. REFERENCES 1. Liu, Y. K., Harty, J. I., Steinbock, G. S., Holt, H. A., Jr., Goldstein, D. H. and Amin, M.: Treatment of radiation or cyclophosphamide induced hemorrhagic cystitis using conjugated estrogen. J. Urol., 144: 41, 1990. 2. Behnam, K., Pati!, U. B. and Mariano, E.: Intravesical instillation of Formalin for hemorrhagic cystitis secondary to radiation for gynecologic malignancies. Gynec. Oncol., 16: 31, 1983. 3. McGuire, E. J., Wiess, R M., Schiff, M., Jr. and Lytton, B.: Hemorrhagic radiation cystitis: treatment. Urology, 3: 204, 1974. 4. Duckett, J. W., Jr., Peters, P. C. and Donaldson, M. H.: Severe cyclophosphamide hemorrhagic cystitis controlled with phenol. J. Ped. Surg., 8: 55, 1973. 5. Kumar, A. P. M., Wren, E. L., Jr., Jayalakshmamma, B., Conrad, L., Quinn, P. and Cox, C.: Silver nitrate irrigation to control bladder hemorrhage in children receiving cancer therapy. J. Urol., 116: 85, 1976.
6. Susan, L. P. and Marsh, R J.: Phenolization of bladder in treatment of massive intractable hematuria. Urology, 5: 119, 1975. 7. Brown, R B.: A method of management of inoperable carcinoma of the bladder. Med J. Aust., 1: 23, 1969. 8. Donahue, L. A. and Frank, I. N.: Intravesical formalin for hemorrhagic cystitis: analysis of therapy. J. Urol., 141: 809, 1989. 9. Ostroff, E. B. and Chenault, O. W., Jr.: Alum irrigation for the control of massive bladder hemorrhage. J. Urol., 128: 929, 1982. 10. Goel, A. K., Rao, M. S., Bhagwat, A. G., Vaidyanathan, S., Goswami, A. K. and Sei, T. K.: Intravesical irrigation with alum for the control of massive bladder hemorrhage. J. Urol., 133: 956,1985. 11. Kennedy, C., Snell, M. E. and Witherow, R 0.: Use of alum to control intractable vesical haemorrhage. Brit. J. Urol., 56: 673, 1984. 12. Foad, B. S. I. and Hess, E. V.: Urinary bladder complications with CY therapy. Arch. Intern. Med., 136: 616, 1976. 13. Levine, L. A. and Kranc, D. M.: Evaluation of carboprost tromethamine in the treatment of cyclophosphamide-induced hemorrhagic cystitis. Cancer, 66: 242, 1990. 14. Gray, K. J., Engelmann, U. H., Johnson, E. H. and Fishman, I. J.: Evaluation of misoprostol cytoprotection of the bladder with cyclophosphamide (Cytoxan) therapy. J. Urol., 136: 497, 1986. 15. Shurafa, M., Shumaker, E. and Cronin, S.: Prostaglandin F2-alpha bladder irrigation for control of intractable cyclophosphamideinduced hemorragic cystitis. J. Urol., 137: 1230, 1987. 16. Mohuiddon, J., Prentice, H. G., Schey, S., Blacklock, H. and Dandona, P.: Treatment of cyclophosphamide-induced cystitis with prostaglandin E2. Ann. Intern. Med., 101: 142, 1984. 17. Holstein, P., Jacobsen, K., Pedersen, J. F. and Sorensen, J. S.: Intravesical hydrostatic pressure treatment: new method for control of bleeding from the bladder mucosa. J. Urol., 109: 234, 1973. 18. Pyeritz, R E., Droller, M. J., Bender, W. L. and Saral, R: An approach to the control of massive hemorrhage in cyclophosphamide-induced cystitis by intravenous vasopressin: a case report. J. Urol., 120: 253, 1978. 19. Appleton, D. S., Sibley, G. N. and Doyle, P. T.: Internal iliac artery embolisation for the control of severe bladder and prostate haemorrhage. Brit. J. Urol., 61: 45, 1988. 20. McGuire, E. J., Weiss, R M., Schiff, M., Jr. and Lytton, B.: Hemorrhagic radiation cystitis. Treatment. Urology, 3: 204, 1974. 21. Pomer, S., Karcher, G. and Simon, W.: Cutaneous ureterostomy as last resort treatment of intractable haemorrhagic cystitis following radiation. Brit. J. Urol., 55: 392, 1983.
THE JOURNAL OF UROLOGY Copyright © 1994 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Printed in U.S.A.
ORAL CONJUGATED ESTROGEN THERAPY FOR TREATMENT OF HEMORRHAGIC CYSTITIS J. MILLER, G. D. BURFIELD
AND
K. L. MORETTI
From the Department of Urology, Queen Elizabeth Hospital, Woodville, South Australia
ABSTRACT
We report 7 cases of severe hemorrhagic cystitis that required rep~ated transfusions, sur~ical intervention and oral conjugated estrogens. Of these 7 cases hematuna resolved c~mpletely m 5 during estrogen therapy and decreased sufficiently in 1 to preclude further transfuslO~. W e ~ound conjugated estrogens to be an effective, simple, inexpensive, well tolerated and readily avmlable treatment for hemorrhagic cystitis. KEY WORDS:
hemorrhage; cystitis; bladder; estrogenic substances, conjugated
Hemorrhagic cystitis is a heterogeneous disorder of varying etiology and clinical course. Massive bladder hemorrhage associated with vesical malignancy, radiation or cyclophosphamide therapy is known to cause significant morbidity and in some cases death. Numerous modalities have been proposed to treat such massive vesical hemorrhage but many management options are also associated with significant morbidity and mortality.Hl Encouraged by the recent report of Liu et aP we investigated the use of conjugated estrogens for the treatment of hemorrhagic cystitis. METHODS
Patients. In a 12-month period 7 patients at a mean age of 62 years (range 24 to 74 years) with hemorrhagic cystitis were recruited into our study. Hemorrhage occurred after cyclophosphamide treatment for malignancy in 4 cases (3 hematolog~cal, 1 breast), radiation therapy for carcinoma of the prostate III 2 and a combination of radiation cystitis and active transitional cell bladder cancer in 1. Routine evaluation of each patient consisted of electrolyte, creatinine and liver function measurements, midstream urine microscopy and culture, and complete blood count, platelet function and clotting studies. Prelim~nary excretory urography, subsequent cystourethroscopy and blOpsy completed the diagnostic examination. Presentation and prior therapy. All patients presented with gross hematuria, clot retention and irritative voiding symptoms, and required hospitalization for catheterization and bladder washout which was endoscopic in 4. Of our 7 cases initial treatme~t consisted of cystoscopic washout and bladder instillation of a 4% solution of formalin in 3 and a 1 % instillation of phenol in 1. However, bleeding recurred in these 4 cases before conjugated estrogen therapy was begun. Estrogens were given as primary treatment in 3 cases. All patients required blood transfusions of 3 to 20 units before treatment to maintain a hemoglobin level of more than 8.0 gm. Conjugated estrogen therapy. Therapy began with 2.5 mg. oral conjugated estrogens twice daily and this dosage was maintained until hemorrhaging stopped. After initial stabilization medication was tapered during 2 to 6 weeks and maintained at 625 JIg. daily for the duration of therapy. No patient had a history of major cardiovascular illness or thromboembolic phenomenon that contraindicated estrogen therapy. The patient with terminal disseminated breast carcinoma was started on estrogens after consultation with the oncologist. Response evaluation. Response to therapy was classified into 3 groups: 1) complete response-total cessation of gross ~e maturia within 10 days of the start of therapy, 2) parbal response-persistent gross hematuria but no further transfusions or additional therapy needed, and 3) nonresponse-conAccepted for publication October 15, 1993.
tinued bleeding requiring further transfusion and therapy. Complete and partial responses were considered as favorable results. CASE REPORTS
Case 1. A 69-year-old man with previously diagnosed muscle invasive transitional cell carcinoma who received radical radiotherapy had hemorrhagic cystitis and disseminated metastases 1 year posttreatment. Bleeding responded transiently to multiple cystoscopic diathermies and to instillation of a 4% fo:malin solution but severe hemorrhage recurred that resulted III anemia with a hemoglobin of 7.4 gm. and transfusion on 2 occasions. Conjugated estrogen therapy was begun at 2.5 mg. twice daily and decreased to 1.25 mg. twice daily. No hematuria of note recurred and no further transfusions were needed in the next 2 months until death from disseminated bladder carcinoma. Case 2. A 47-year-old woman with metastatic breast cancer after bilateral mastectomy 9 and 4 years previously had severe irritative voiding symptoms and hemorrhagic cystitis due to cyclophosphamide induced cystitis. Initial therapy with cystoscopic diathermy, washout and hydrodistention failed to control the severe symptoms. After 1.25 mg. oral conjugated estrogens twice daily were administered, gross hematuria ceased and irritative voiding symptoms were greatly improved until death 8 weeks later from cerebral metastases. Case 3. A 68-year-old man had severe hemorrhagic cystitis after receiving radical radiotherapy for clinically localized carcinoma of the prostate. After multiple transfusions hemorrhaging responded transiently to an intravesical 4% formalin instillation. When hematuria recurred 2.5 mg. conjugated estrogens were given twice daily. Hematuria resolved during maintenance therapy but after 6 months the patient refused medication and hematuria recurred in 10 days. Estrogens were resumed and bleeding stopped, and has not recurred on a maintenance dose of 625 JIg. daily. Case 4. A 24-year-old woman had severe thrombocytopenia and hemorrhagic cystitis after receiving cyclophosphamide induction chemotherapy before stem cell transplantation for leukemia. Transfusion of 4 units of blood per day was needed to maintain a hemoglobin of 8 gm. Various therapies, including cystoscopic diathermy and bladder washout, phenol instillation and alum irrigation, and platelet transfusions and oral estrogens failed to control the hemorrhage, which eventually responded to intravenous prostaglandin F2-a infusion. Intermittent hematuria continued but further transfusion was not required. The patient died 4 weeks later of uncertain causes. Case 5. A 74-year-old man who received cyclophosphamide 7 years previously for nonHodgkins lymphoma had 3 episodes of gross hematuria that required repeated cystoscopic washout
1348
ESTROGEN THERAPY FOR HEMORRHAGIC CYSTITIS
and 3 transfusions in 3 weeks. After conjugated estrogen therapy was begun bleeding resolved and no further transfusion was needed. During the next 6 weeks dosage was tapered to a maintenance level of 625 JLg. daily. Hematuria did not recur but the patient died of ischemic heart disease 9 months later. Case 6. A 63-year-old man who received radical radiotherapy for localized prostate cancer 3 years previously presented with disseminated disease and radiation-induced hemorrhagic cystitis that required cystoscopic washout and multiple blood transfusions. A temporary response was gained with instillation of a 4 % formalin solution but bleeding recurred until conjugated estrogens were begun at 2.5 mg. twice daily. Hematuria resolved until death 9 months later from disseminated carcinoma. Case 7. A 43-year-old man who received cyclophosphamide 2 years previously for leukemia had 3 episodes of gross hematuria that required repeated cystoscopic washout and 3 transfusions in 2 weeks. After conjugated estrogen therapy was started bleeding resolved and no further transfusion was needed. During the next 6 weeks dosage was tapered to maintenance therapy of 625 JLg. daily for 3 months. Hematuria did not recur and therapy was withheld. Clinically significant hematuria has not recurred 1 year posttreatment. RESULTS
Of our 7 patients 5 were terminally ill at presentation and died from 6 weeks to 9 months after conjugated estrogen therapy was begun. Death resulted from disseminated breast, transitional cell and prostatic cancer, and leukemia and lymphoma. No hemorrhage recurred in 4 patients. In case 4 cyclophosphamide induced hemorrhagic cystitis was unresponsive to conjugated estrogen therapy but responded to intravenous prostaglandin F2-a and platelet transfusions. The remaining 2 patients were well 36 and 18 months after therapy began, although 1 refused therapy after 6 months. He was hospitalized 10 days later for cystoscopic washout of clot retention secondary to hemorrhagic cystitis. After resumption of conjugated estrogens hemorrhage resolved again. Complete response to treatment occurred in 6 cases and nonresponse in 1. Recurrent hematuria after refusal of therapy was considered a treatment violation, not a treatment failure, and, therefore, was classified as a complete response. DISCUSSION
The reported frequency of bladder hemorrhage ranges from 2.5 to 12% after pelvic irradiation2,a and 2 to 40% after cyclophosphamide therapy.4,l2 Often there is no correlation between the extent of therapy and development of severe hematuria. Although most oncologists attempt to prevent this complication by using forced diuresis, multiport radiation therapy and detoxifying agents, such as N-acetylcysteine, disulfiram and sodium-2-mercaptoethane-sulfonate, severe hemorrhagic cystitis still occurs. The exact pathogenesis remains unknown but direct urothelial toxicity and microvascular damage are considered the final common pathways regardless of etiology. Current management involves 3 stages: l)-prevention, 2)minimally invasive therapy and 3)-invasive or operative treatment. Prevention includes adequate oral or intravenous hydration and active diuresis during treatment. Catheter drainage to decrease epithelial contact time with toxins adjuvant to the use of standard detoxification agents has been recommended during cyclophosphamide therapy. Minimally invasive measures involve correction of any bleeding diathesis and bladder washouts or irrigation using large bore catheters. Some cases resolve with no additional treatment but if bleeding continues other approaches are possible. Low irritant agents, such as aluminum sulfates9- 11 and E1, E2 and F2-a prostaglandins/a-l6 may be intravesically instilled at bedside, or balloon dilation l7 or instillation of the more irritant solutions, including silver nitrate,a,5 pheno14,6 and formalin,2,a,7,s may be performed cystoscopically in the operating room with the patient under general
1349
anesthesia. Vasopressin,18 prostaglandinsl5 and conjugated estrogens l may also be given orally. Phenol or silver nitrate cautery of the vesical mucosa has been recommended in life threatening hemorrhagic cystitis but the brief response and the need to anesthetize the patient make cautery a less than attractive option. A 1 to 10% intravesical solution of formalin has been widely used for hemorrhagic cystitis since its effectiveness was reported in 1969 by Brown. 7 Donahue and Frank reported complete response rates of 83 %, 78% and 71 % in 245 cases treated by instillation of formalin at 10%, 5% and 1% concentrations, respectively.s Most response occurred within 48 hours of treatment with a 3 to 4-month average duration of response before recurrence. However, major complications occurred at all levels of formalin concentrations. Death resulted in 2.2% of patients treated with 5% formalin and in 5.7% of those treated with 10%. Many complications and deaths were related to unsuspected vesicoureteral reflux alone or in combination with multiple instillations. Therefore, preoperative cystograms or balloon occlusion of the ureters is suggested to decrease the incidence of reflux nephropathy. Instillation of formalin, phenol or silver nitrate into the bladder induces severe pain and, therefore, regional or general anesthesia is recommended before therapy. A number of reports describe bedside intravesical instillation of 1% alum solution, using aluminum ammonium sulfate or aluminum potassium sulfate with moderate success. 9- 11 Response is transient in more than 30% of cases and hemorrhage usually recurs when instillation is discontinued. Furthermore, alum readily forms thick precipitates that block catheters and coat the urothelium, which creates difficulties in subsequent intravesical therapy should alum fail to control the bleeding. Epsilon aminocaproic acid has been used at our institution as a bedside instillation to control vesical hemorrhage but it proved unsatisfactory in many cases, because clot retention developed that required cystoscopic washout. The use of prostaglandins has been reported to prevent and treat hemorrhagic cystitis. In 5 cases prostglandin F2-a given intravesically for 4 to 5 days successfully stopped vesical hemorrhage and provided long-term resolution with no recurrence at 6 to 14 months. la ,l5 The mode of action is unclear but it is thought to relate to the stimulation of smooth muscle contraction and subsequent hemostasis by normal hemostatic and coagulation mechanisms. Increases in renal blood flow and urine production caused by prostaglandins are also thought to contribute to resolution. Major drawbacks of this therapy are the development of severe bladder spasms and the cost of prostaglandins. Invasive or operative treatment is used in cases that do not respond to less aggressive therapy. Radiographic or operative arterial occlusion of the vesical arteries/ 9 open bladder diathermy and/or packing,20 urinary diversion 2l and in extreme cases cystectomy20 have varying rates of success and significant side effects or life threatening complications, and may not be appropriate for terminally ill patients. In 1990 Liu et al reported on the use of oral conjugated estrogens for hemorrhagic cystitis, and introduced an effective, simple and readily available treatment option. l In their study 5 patients remained free of hematuria and complications at 12 to 22 months of followup. Initially 2 cases were treated with intravenous estrogens but equally good responses were noted with oral estrogens. Of our 7 patients 6 responded completely to 2.5 mg. oral estrogens twice daily with long lasting response in those patients still living. Because most of our patients were terminally ill, the ease of estrogen therapy and the avoidance of more aggressive or invasive measures were of great benefit. The recurrence of bleeding in 1 patient 10 days after the withdrawal of low dose estrogens introduces the issue of treatment duration. The increased cardiovascular complication rate in men with prostate cancer who are treated with estrogens at moderate to high doses is well known. However, the long-term
1350
ESTROGEN THERAPY FOR HEMORRHAGIC CYSTITIS
effect of low dose therapy is unknown. After an initial loading period we were able to reduce dosage rapidly to a low level and still prevent hemorrhagic cystitis. The duration of therapy and ideal initiating and maintenance doses have not been established by this or the previous study by Liu et al. Additional clinical studies are needed to confirm these encouraging results, develop the ideal dosage regimen and establish the mechanism of action for estrogen therapy. Although Liu et al have suggested that decreased vascular, that is capillary, fragility is a possible mechanism, basic research into this area is lacking and may reveal alternative explanations, such as bladder mucous secretion, or alteration in coagulation or hemostatic mechanisms. In addition, new studies may lead to other treatments for hemorrhagic cystitis that are based on a better understanding of the underlying pathophysiology. Conjugated estrogens are an effective, simple, inexpensive, well tolerated and readily available treatment for hemorrhagic cystitis that is unresponsive to conservative therapy. We support the use of oral conjugated estrogens as first line treatment in this serious disorder. However, we advise against the longterm use of high doses of estrogens in those patients at risk for thromboembolic, cardiac or cerebrovascular disease, or in those with reasonable life expectancy until further studies establish the long-term safety of this treatment. REFERENCES 1. Liu, Y. K., Harty, J. I., Steinbock, G. S., Holt, H. A., Jr., Goldstein, D. H. and Amin, M.: Treatment of radiation or cyclophosphamide induced hemorrhagic cystitis using conjugated estrogen. J. Urol., 144: 41, 1990. 2. Behnam, K., Pati!, U. B. and Mariano, E.: Intravesical instillation of Formalin for hemorrhagic cystitis secondary to radiation for gynecologic malignancies. Gynec. Oncol., 16: 31, 1983. 3. McGuire, E. J., Wiess, R M., Schiff, M., Jr. and Lytton, B.: Hemorrhagic radiation cystitis: treatment. Urology, 3: 204, 1974. 4. Duckett, J. W., Jr., Peters, P. C. and Donaldson, M. H.: Severe cyclophosphamide hemorrhagic cystitis controlled with phenol. J. Ped. Surg., 8: 55, 1973. 5. Kumar, A. P. M., Wren, E. L., Jr., Jayalakshmamma, B., Conrad, L., Quinn, P. and Cox, C.: Silver nitrate irrigation to control bladder hemorrhage in children receiving cancer therapy. J. Urol., 116: 85, 1976.
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