THE
Vol. 118, July, Part 1 Printed in U.S.A.
JOURNAL OF UROLOGY
Copyright © 1977 by The Williams & Wilkins Co.
CYCLOPHOSPHAMIDE HEMORRHAGIC CYSTITIS REQUIRING URINARY DIVERSION ARTHUR L. GOLIN
AND
RALPH C. BENSON, JR.
From the Department of Surgery, Division of Urology, University of Wisconsin Center for Health Sciences, Madison, Wisconsin
ABSTRACT
Hemorrhagic cystitis secondary to cyclophosphamide is a well recognized and unique urologic complication of this widely used agent. Cessation of the drug and supportive care are usually sufficient for management but refractory cases are difficult to treat and potentially life-threatening. A review of the pathology and treatment of this disorder is presented with specific reference to a patient requiring urinary diversion. Hemorrhagic cystitis has been recognized as a complication of cyclophosphamide therapy since 1959. 1•2 The majority of affected patients respond to cessation of the drug and supportive care but protracted episodes of bladder hemorrhage are not uncommon and have even resulted in death. Therefore, a more aggressive approach to these severely affected patients, often including urinary diversion, has been necessary.:¼--5 CASE REPORT
J.P., a 30-year-old white man, presented with an enlarging left clavicular mass, which was proved subsequently to be a Ewing's sarcoma. All laboratory studies were normal. Treatment consisted of local radiotherapy and 2, 8-day courses of 1 mg. actinomycin D daily and 400 mg. cyclophosphamide intravenously. Thereafter, he was maintained on 150 mg. oral cyclophosphamide daily. Occasional dysuria and hematuria were noted after 2½ years of therapy and treatment was discontinued after 5 years owing to anemia. Hematuria persisted and the patient was hospitalized 3 months later. Coagulation studies and an excretory urogram were normal. Urine cultures and cytology were negative. Cystoscopy revealed diffuse patchy areas of hyperemia, which were fulgurated, resulting in cessation ofhematuria. A month later hematuria and urinary retention again necessitated hospitalization. Fulguration, silver nitrate and iced saline bladder irrigations were unsuccessful in controlling the hemorrhage. Bilateral hypogastric arterial embolization with silicone emboli also was ineffective. Formalin instillation was not attempted because of bilateral reflux. A ureterosigmoidostomy was performed after 16 units of blood replacement. Significant bladder hemorrhage persisted after urinary diversion and this was managed successfully with 3 per cent intravesical formalin instillation. The patient has done well subsequently. DISCUSSION
I
r
Hemorrhagic cystitis appears to be a unique urologic complication of cyclophosphamide therapy. Its incidence has been reported as high as 40 per cent in some series and its prevalance will no doubt increase with its expanded use for nonneoplastic diseases, such as the nephrotic syndrome, lupus erythematosis and rheumatoid arthritis. 2 Cyclophosphamide is an alkylating agent that is primarily converted to its active cytotoxic form in the liver. 6 It has been shown that the active metabolites excreted in the urine, rather than the parent compound, are responsible for the effect on the urothelium. 7 The reservoir function of the bladder accounts for the much higher incidence of damage to this organ relative to
the remainder of the urinary tract. Cystoscopic examination reveals various mucosal abnormalities with edema, telangiectasia, hemorrhage and ulceration being most often noted. Microscopically, epithelial loss, capillary dilatation, submucosal hemorrhage, fibrosis and smooth muscle necrosis are seen. 8 •9 The development of hemorrhagic cystitis appears to be doserelated and is more frequent with large dose intravenous therapy. Mucosal changes have been produced in animal models after a single large intravenous dose. However, an individual's risk of developing hemorrhagic cystitis and its severity cannot be correlated with the total amount of cyclophosphamide given. Bennett has found that 100 gm. is the minimum total oral dose causing cystitis in adults. 4 Johnson and Meadows reported histologic evidence of bladder fibrosis in 25 per cent of children who received a total dose greater than 6 gm. per m. 2 of body surface area. 10 All of these patients had received the drug intravenously and only half were clinically symptomatic from the urinary tract at the time of death. Lawrence and associates reported the frequency of bladder symptoms to be doubled in black leukemic children treated with cyclophosphamide. 11 The relationship of hemorrhagic cystitis to duration of cyclophosphamide therapy is less clear, and many patients do not have symptoms until months after therapy has been discontinued. Increased diuresis and regular voiding is thought to reduce the possibility of developing cystitis by decreasing the concentration and contact time of the active metabolites of cyclophosphamide with the bladder mucosa. 7 Patients on cyclophosphamide should be encouraged to maintain a high fluid intake and to void at frequent intervals. Most authors now agree that the development of sterile cystitis in a patient on cyclophosphamide therapy is an indication for permanent discontinuation of the drug. The majority of patients who have hemorrhag{c cystitis will respond to cessation of therapy and adequate drainage. Reynolds and associates have advocated bilateral ureteral catheterization in the management of these patients in order to prevent contact of active metabolites with the bladder mucosa. 12 Short-term prednisone may be of benefit in reducing the associated edema and inflammation. Cystoscopic examination should be performed in all of these patients and we agree with Lapides that in many cases the hemorrhage may be controlled with ajudicious fulguration oftelangiectatic bleeding areas. 13 Continuous bladder irrigation with silver nitrate has been reported to be of benefit for some patients. Hypogastric artery ligation (as in our case with embolization) is, at best, a temporizing measure owing to the extensive collateral vasculature. 14 Formalin instillation has been shown to be effective in a number of patients with uncontrolled bladder hemorrhage. 15 •16 Before using formalin the possibility of ureteral reflux should be determined since its incidence is
Accepted for publication February 11, 1977. Read at annual meeting of North Central Section, American Urological Association, Palm Beach, Florida, October 17-24, 1976. 110
CYCLOPHOSPHAMIDE HEMORRHAGIC CYSTITIS REQUIRING URINARY DIVERSION
high in these patients. Although an actual incidence of reflux has not been reported in patients experiencing hemcystitis the pathological changes present in the bladder are nearly identical to those of radiation cystitis, a condition frequently associated with ureteral reflux. Despite repeated attempts at conservative therapy most patients with life-threatening hemorrhage require some form of urinary diversion as did our patient. Nephrostomy, ureterostomy, ileal diversion and ureterosigmoidoscopy have all been used. Diversion of the urinary stream is usually sufficient to control the hemorrhage by preventing bladder distension. In a few cases cystectomy has been performed at the time of diversion. Our is the first to be reported with continued bladder hemorrhage after diversion, which was managed with formalin instillation. Successful management of hemorrhagic does not obviate the need for urological followup. A per cent increased incidence of carcinoma has been demonstrated in mice on long-term, high-dose cyclophosphamide. 17 In 1971 Worth and in 1974 Dale and Smith raised the question of an association of transitional carcinoma in the bladder in patients treated with cyclophosphamide. 18 ''" More recently, Wall and Clausen reported 5 cases of invasive bladder carcinoma (4 squamous and 1 undifferentiated) in patients treated previously with cyclophosphamide who had hemorrhagic cystitis. 20 This apparent association of bladder cancer plus our lack of knowledge concerning the carcinogenic potential of the metabolites of cyclophosphamide in man underscores the necessity for yearly cystoscopy in all patients experiencing cyclophosphamide cystitis. REFERENCES
1. Coggins, P. R., Ravdin, R. G. and Eisman, S. H.: Clinical
pharmacology and preliminary evaluation of Cytoxan (cyclophosphamide). Cancer Chemother. Rep., 3: 9, 1959. 2. Sweeney, M. J., Tuttle, A.H., Etteldorf, J. N. and Whittington, G. L.: Cyclophosphamide in the treatment of common neoplastic diseases of childhood. J. Pediat., 61: 702, 1962. 3. Anderson, E. E., Cobb, 0. E. and Glenn, J. F.: Cyclophosphamide hemorrhagic cystitis. J. Urol., 97: 857, 1967. 4. Bennett, A.H.: Cyclophosphamide and hemorrhagic cystitis. J. Urol., 111: 603, 1974.
5. Watson, N. A. and Notley, R. G.: Urologic complications Gf cyclophosphamide. Brit. J. Urol., 45: 606, 1973. 6. Brock, N. and Hohorst, H.. J.: Metabolism of cyclophosphamid2. Cancer, 20: 900, 1967. 7. Philips, F. S., Sternberg, S. S., Cronin, A. P. and Vidal, P. NL. Cyclophosphamide and urinary bladder toxicity. Cancer Res., 21: 1577, 1961. 8. Bonikos, D. S. and Koss, L. G.: Acute effects of cyclophosphamide on rat urinary bladder muscle. Arch. Path., 97: 242, 19U. 9. Goldman, R. L. and Warner, N. E.: Hemorrhagic cystitis and cytomegalic inclusions in the bladder associated with phosphamide therapy. Cancer, 25: 7, 1970. 10. Johnson, W. W. and Meadows, D. C.: Urinary bladder fibrosis and telangiectasia associated with long-term cyclophospha-· mide therapy. New Engl. J. Med. 284: 290, 1971. R. J. A.: 11. Lawrence, H. J., Simone, J. and mide-induced hemorrhagic cystitis in children Cancer, 36: 1572, 1975. 12. Reynolds, R. D., Simerville, J. J., O'Hara, D. D., Parkinson, J. E.: Hemorrhagic cystitis due to cy,cwµuu~1aca,~mide. J. Urol., 101: 45, 1969. 13. Lapides, J.: Treatment of delayed intractable hemorrhagic tis following radiation or chemotherapy. J. Urol., 104-: 1970. 14. Nagel, R. and Baumgartel, H.: Zur Behandlug der lebensbedrohlichen Blasenblutung unter cystostatischer Therapie. Urologe, 7: 94, 1968. 15. Shah, B. C. and Albert, D. J.: Intravesical instillation of formalin for the management of intractable hematuria. J. U roL, 110: 519, 1973. 16. Firlit, C. F.: Intractable hemorrhagic cystitis se(:on,da,rv tensive carcinomatosis: management with formalin J. Urol., 110: 57, 1973. 17. Walker, S. E. and Bole, G. G.: Augmented incidence in female New Zealand black-New Zealand white mice treated with long-term cyclophosphamide. J. Lab. Clin. Med., 78: 978, 1971. 18. Worth, P.H.: Cyclophosphamide and the bladder. (Letter to Editor.) Brit. Med. J., 3: 182, 1971. 19. Dale, G. A. and Smith, R. B.: Transitional cell carcinoma of the bladder associated with cyclophosphamide. J. Urol., U2: 603, 1974. 20. Wall, R. L. and Clausen, K. P.: Carcinoma of the der in patients receiving cyclophosphamide. New Med., 293: 271, 1975.
Vol. 118, July, Part 1 Printed in U.S.A.
JOURNAL OF UROLOGY
Copyright © 1977 by The Williams & Wilkins Co.
CYCLOPHOSPHAMIDE HEMORRHAGIC CYSTITIS REQUIRING URINARY DIVERSION ARTHUR L. GOLIN
AND
RALPH C. BENSON, JR.
From the Department of Surgery, Division of Urology, University of Wisconsin Center for Health Sciences, Madison, Wisconsin
ABSTRACT
Hemorrhagic cystitis secondary to cyclophosphamide is a well recognized and unique urologic complication of this widely used agent. Cessation of the drug and supportive care are usually sufficient for management but refractory cases are difficult to treat and potentially life-threatening. A review of the pathology and treatment of this disorder is presented with specific reference to a patient requiring urinary diversion. Hemorrhagic cystitis has been recognized as a complication of cyclophosphamide therapy since 1959. 1•2 The majority of affected patients respond to cessation of the drug and supportive care but protracted episodes of bladder hemorrhage are not uncommon and have even resulted in death. Therefore, a more aggressive approach to these severely affected patients, often including urinary diversion, has been necessary.:¼--5 CASE REPORT
J.P., a 30-year-old white man, presented with an enlarging left clavicular mass, which was proved subsequently to be a Ewing's sarcoma. All laboratory studies were normal. Treatment consisted of local radiotherapy and 2, 8-day courses of 1 mg. actinomycin D daily and 400 mg. cyclophosphamide intravenously. Thereafter, he was maintained on 150 mg. oral cyclophosphamide daily. Occasional dysuria and hematuria were noted after 2½ years of therapy and treatment was discontinued after 5 years owing to anemia. Hematuria persisted and the patient was hospitalized 3 months later. Coagulation studies and an excretory urogram were normal. Urine cultures and cytology were negative. Cystoscopy revealed diffuse patchy areas of hyperemia, which were fulgurated, resulting in cessation ofhematuria. A month later hematuria and urinary retention again necessitated hospitalization. Fulguration, silver nitrate and iced saline bladder irrigations were unsuccessful in controlling the hemorrhage. Bilateral hypogastric arterial embolization with silicone emboli also was ineffective. Formalin instillation was not attempted because of bilateral reflux. A ureterosigmoidostomy was performed after 16 units of blood replacement. Significant bladder hemorrhage persisted after urinary diversion and this was managed successfully with 3 per cent intravesical formalin instillation. The patient has done well subsequently. DISCUSSION
I
r
Hemorrhagic cystitis appears to be a unique urologic complication of cyclophosphamide therapy. Its incidence has been reported as high as 40 per cent in some series and its prevalance will no doubt increase with its expanded use for nonneoplastic diseases, such as the nephrotic syndrome, lupus erythematosis and rheumatoid arthritis. 2 Cyclophosphamide is an alkylating agent that is primarily converted to its active cytotoxic form in the liver. 6 It has been shown that the active metabolites excreted in the urine, rather than the parent compound, are responsible for the effect on the urothelium. 7 The reservoir function of the bladder accounts for the much higher incidence of damage to this organ relative to
the remainder of the urinary tract. Cystoscopic examination reveals various mucosal abnormalities with edema, telangiectasia, hemorrhage and ulceration being most often noted. Microscopically, epithelial loss, capillary dilatation, submucosal hemorrhage, fibrosis and smooth muscle necrosis are seen. 8 •9 The development of hemorrhagic cystitis appears to be doserelated and is more frequent with large dose intravenous therapy. Mucosal changes have been produced in animal models after a single large intravenous dose. However, an individual's risk of developing hemorrhagic cystitis and its severity cannot be correlated with the total amount of cyclophosphamide given. Bennett has found that 100 gm. is the minimum total oral dose causing cystitis in adults. 4 Johnson and Meadows reported histologic evidence of bladder fibrosis in 25 per cent of children who received a total dose greater than 6 gm. per m. 2 of body surface area. 10 All of these patients had received the drug intravenously and only half were clinically symptomatic from the urinary tract at the time of death. Lawrence and associates reported the frequency of bladder symptoms to be doubled in black leukemic children treated with cyclophosphamide. 11 The relationship of hemorrhagic cystitis to duration of cyclophosphamide therapy is less clear, and many patients do not have symptoms until months after therapy has been discontinued. Increased diuresis and regular voiding is thought to reduce the possibility of developing cystitis by decreasing the concentration and contact time of the active metabolites of cyclophosphamide with the bladder mucosa. 7 Patients on cyclophosphamide should be encouraged to maintain a high fluid intake and to void at frequent intervals. Most authors now agree that the development of sterile cystitis in a patient on cyclophosphamide therapy is an indication for permanent discontinuation of the drug. The majority of patients who have hemorrhag{c cystitis will respond to cessation of therapy and adequate drainage. Reynolds and associates have advocated bilateral ureteral catheterization in the management of these patients in order to prevent contact of active metabolites with the bladder mucosa. 12 Short-term prednisone may be of benefit in reducing the associated edema and inflammation. Cystoscopic examination should be performed in all of these patients and we agree with Lapides that in many cases the hemorrhage may be controlled with ajudicious fulguration oftelangiectatic bleeding areas. 13 Continuous bladder irrigation with silver nitrate has been reported to be of benefit for some patients. Hypogastric artery ligation (as in our case with embolization) is, at best, a temporizing measure owing to the extensive collateral vasculature. 14 Formalin instillation has been shown to be effective in a number of patients with uncontrolled bladder hemorrhage. 15 •16 Before using formalin the possibility of ureteral reflux should be determined since its incidence is
Accepted for publication February 11, 1977. Read at annual meeting of North Central Section, American Urological Association, Palm Beach, Florida, October 17-24, 1976. 110
CYCLOPHOSPHAMIDE HEMORRHAGIC CYSTITIS REQUIRING URINARY DIVERSION
high in these patients. Although an actual incidence of reflux has not been reported in patients experiencing hemcystitis the pathological changes present in the bladder are nearly identical to those of radiation cystitis, a condition frequently associated with ureteral reflux. Despite repeated attempts at conservative therapy most patients with life-threatening hemorrhage require some form of urinary diversion as did our patient. Nephrostomy, ureterostomy, ileal diversion and ureterosigmoidoscopy have all been used. Diversion of the urinary stream is usually sufficient to control the hemorrhage by preventing bladder distension. In a few cases cystectomy has been performed at the time of diversion. Our is the first to be reported with continued bladder hemorrhage after diversion, which was managed with formalin instillation. Successful management of hemorrhagic does not obviate the need for urological followup. A per cent increased incidence of carcinoma has been demonstrated in mice on long-term, high-dose cyclophosphamide. 17 In 1971 Worth and in 1974 Dale and Smith raised the question of an association of transitional carcinoma in the bladder in patients treated with cyclophosphamide. 18 ''" More recently, Wall and Clausen reported 5 cases of invasive bladder carcinoma (4 squamous and 1 undifferentiated) in patients treated previously with cyclophosphamide who had hemorrhagic cystitis. 20 This apparent association of bladder cancer plus our lack of knowledge concerning the carcinogenic potential of the metabolites of cyclophosphamide in man underscores the necessity for yearly cystoscopy in all patients experiencing cyclophosphamide cystitis. REFERENCES
1. Coggins, P. R., Ravdin, R. G. and Eisman, S. H.: Clinical
pharmacology and preliminary evaluation of Cytoxan (cyclophosphamide). Cancer Chemother. Rep., 3: 9, 1959. 2. Sweeney, M. J., Tuttle, A.H., Etteldorf, J. N. and Whittington, G. L.: Cyclophosphamide in the treatment of common neoplastic diseases of childhood. J. Pediat., 61: 702, 1962. 3. Anderson, E. E., Cobb, 0. E. and Glenn, J. F.: Cyclophosphamide hemorrhagic cystitis. J. Urol., 97: 857, 1967. 4. Bennett, A.H.: Cyclophosphamide and hemorrhagic cystitis. J. Urol., 111: 603, 1974.
5. Watson, N. A. and Notley, R. G.: Urologic complications Gf cyclophosphamide. Brit. J. Urol., 45: 606, 1973. 6. Brock, N. and Hohorst, H.. J.: Metabolism of cyclophosphamid2. Cancer, 20: 900, 1967. 7. Philips, F. S., Sternberg, S. S., Cronin, A. P. and Vidal, P. NL. Cyclophosphamide and urinary bladder toxicity. Cancer Res., 21: 1577, 1961. 8. Bonikos, D. S. and Koss, L. G.: Acute effects of cyclophosphamide on rat urinary bladder muscle. Arch. Path., 97: 242, 19U. 9. Goldman, R. L. and Warner, N. E.: Hemorrhagic cystitis and cytomegalic inclusions in the bladder associated with phosphamide therapy. Cancer, 25: 7, 1970. 10. Johnson, W. W. and Meadows, D. C.: Urinary bladder fibrosis and telangiectasia associated with long-term cyclophospha-· mide therapy. New Engl. J. Med. 284: 290, 1971. R. J. A.: 11. Lawrence, H. J., Simone, J. and mide-induced hemorrhagic cystitis in children Cancer, 36: 1572, 1975. 12. Reynolds, R. D., Simerville, J. J., O'Hara, D. D., Parkinson, J. E.: Hemorrhagic cystitis due to cy,cwµuu~1aca,~mide. J. Urol., 101: 45, 1969. 13. Lapides, J.: Treatment of delayed intractable hemorrhagic tis following radiation or chemotherapy. J. Urol., 104-: 1970. 14. Nagel, R. and Baumgartel, H.: Zur Behandlug der lebensbedrohlichen Blasenblutung unter cystostatischer Therapie. Urologe, 7: 94, 1968. 15. Shah, B. C. and Albert, D. J.: Intravesical instillation of formalin for the management of intractable hematuria. J. U roL, 110: 519, 1973. 16. Firlit, C. F.: Intractable hemorrhagic cystitis se(:on,da,rv tensive carcinomatosis: management with formalin J. Urol., 110: 57, 1973. 17. Walker, S. E. and Bole, G. G.: Augmented incidence in female New Zealand black-New Zealand white mice treated with long-term cyclophosphamide. J. Lab. Clin. Med., 78: 978, 1971. 18. Worth, P.H.: Cyclophosphamide and the bladder. (Letter to Editor.) Brit. Med. J., 3: 182, 1971. 19. Dale, G. A. and Smith, R. B.: Transitional cell carcinoma of the bladder associated with cyclophosphamide. J. Urol., U2: 603, 1974. 20. Wall, R. L. and Clausen, K. P.: Carcinoma of the der in patients receiving cyclophosphamide. New Med., 293: 271, 1975.
