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Management of Severe Reflux in the Patient with Cyclophosphamide Cystitis
0022-534 7/83/1304-0769$02.00/0 THE JOURNAL OF UROLOGY
Vol. 130, October
Copyright© 1983 by The Williams & Wilkins Co.
Printed in U.S.A.
MANAGEMENT OF SEVERE REFLUX IN THE PATIENT WITH CYCLOPHOSPHAMIDE CYSTITIS H. NORMAN NOE* AND H. MICHAEL McSWAIN From the Department of Urology, Division of Pediatric Urology, University of Tennessee Center for the Health Sciences and LeBonheur Children's Medical Center, Memphis, Tennessee
ABSTRACT
Cyclophosphamide cystitis with a high grade of vesicoureteral reflux can lead to rapid renal deterioration. Conventional ureteral reimplantation is inadvisable and urinary diversion, although providing a temporary solution, could lead to long-term complications, particularly in children. We present a case of cyclophosphamide cystitis with vesicoureteral reflux and upper tract deterioration managed successfully with ileocecocystoplasty. This method of management should be considered early in such a patient. Cyclophosphamide is an alkalating agent that has gained wide use in the treatment of many malignant diseases in children. Since its introduction in 1957 side effects of the drug have been studied extensively, the most frequent urologic complications being hemorrhagic cystitis and bladder fibrosis. 1• 2 Another potentially significant complication associated with the use of cyclophosphamide but less well documented in the literature is vesicoureteral reflux3- 5 associated presumably with fibrotic distortion of the ureterovesical anatomy. Herein we present a case of progressive renal deterioration secondary to vesicoureteral reflux following cyclophosphamide administration, which was managed successfully by ileocecocystoplasty. CASE REPORT
and parents strongly wished to avoid urinary diversion. We attempted ureteral reimplantation but a thickened, immobile, friable, freely bleeding bladder was encountered and we were virtually unable to mobilize the ureter. The procedure was abandoned and, except for marked intraoperative blood loss that was replaced, convalescence was uneventful. Creatinine clearance was 61 cc per minute per 1.73 m. 2 • The child was, once again, followed closely, being maintained on intermittent catheterization, continuous medication and frequent double voiding but there was persistent evidence of loss of cortical thickness on the IVP (fig. 3, B) and abdominal ultrasound. Creatinine clearance decreased to 41 cc per minute per 1.73 m. 2 and the voiding cystogram showed persistent severe reflux. In April 1981, approximately 64 months after discovery of the initial tumor, ureteroileocecocystoplasty was performed successfully. Convalescence was uneventful. A followup IVP showed improvement and stabilization of the hydronephrosis (fig. 4). A voiding cystourethrogram showed reflux across the ileocecal valve only at the termination of bladder filling or with marked bladder distension but the IVP and abdominal ultrasound remained improved and stable. Creatinine clearance 18 months postoperatively was 65 cc per minute per 1.73 m. 2 , urine was sterile and the child was totally continent.
K. S., a 3-year-old white girl, was seen in December 1975 for an abdominal mass. Excision of the mass revealed an entodermal sinus tumor arising in the right ovary. She received chemotherapy for 1 year. In March 1977 a 3.5 X 4 cm. mass was noted on routine ultrasound anterior to the right kidney, overlying the aorta and vena cava. No hydronephrosis was noted at this time and the collecting systems were believed to be normal. Excision of the mass revealed recurrent tumor. Followup radiation of 3,910 rad to the upper abdomen and 4,198 rad to the lower abdomen was given. Further chemotherapy was adminDISCUSSION istered in the form of vincristine, actinomycin D, cyclophosThe first case of cyclophosphamide-associated bladder toxphamide and doxorubicin hydrochloride. In February 1978 hematuria occurred. An excretory urogram icity was reported in 1959. 6 Since then, numerous cases have (IVP) showed normal upper tracts (fig. 1) but a voiding cysto- been reported in the literature and the subject has been studied gram revealed grade II reflux bilaterally with changes suggestive extensively. The incidence of bladder toxicity is related to the of cyclophosphamide cystitis. In July hydronephrosis was first duration and cumulative dose of cyclophosphamide, although noted on routine abdominal ultrasound examination but it it has been seen even after a single dose of the drug. There is a resolved immediately upon catheterization of the bladder. A higher reported incidence when the drug is given intravenously. repeat voiding cystogram showed the reflux to be increased in Symptoms of bladder toxicity can become manifest at any time severity with a small capacity bladder (fig. 2). At cystoscopy during the course of treatment. The acute form generally apthe ureteral orifices were significantly abnormal and the typical pears within the first few days of therapy and is heralded by changes of cyclophosphamide cystitis were noted. The child sterile hemorrhagic cystitis of varying degrees of severity. was maintained on antibacterial prophylaxis and double void- Bleeding may be pronounced but in most cases it can be ing, and did well except for some incontinence and occasional managed by cessation of therapy and conservative local measmild hematuria. At this time radiation enteropathy also devel- ures. Chronic bladder toxicity with cyclophosphamide administration is generally seen as recurrent hematuria with progresoped, which was treated successfully. A followup IVP revealed increasing hydronephrosis with sive bladder fibrosis. Bladder fibrosis is said to occur in 25 per globar atrophy and cortical loss, although the child was main- cent of the children receiving cyclophosphamide. 1 The fibrosis tained on continuous medication and the urine cultures fol- begins in the lamina propria, spreads to the innermost muscle lowed closely in a serial fashion were found to be consistently fibers and generally occurs after at least 3 months of therapy. sterile. In December 1979 she experienced for the first time a The fibrotic bladder becomes small, contracted and fixed. Uresymptomatic break-through urinary tract infection. An IVP teral obstruction and vesicoureteral reflux from altered uretercontinued to show increasing hydronephrosis with cortical loss ovesical junction anatomy have been reported as complications (fig. 3, A). Therapeutic options were discussed, and the patient of the fibrosis. 3- 5 Our case underscores several significant findings of chronic Accepted for publication March 4, 1983. cyclophosphamide-induced bladder changes. The bladder tox* Requests for reprints: LeBonheur Children's Medical Center, 848 icity presented typically with gross hematuria, a finding that is Adams, Suite 403, Memphis, Tennessee 38103. 769
770
NOE AND MCSWAIN
Fm. 1. Initial normaUVP
believed to represent disruption of the suburothelial telangiectatic blood vessels that are involved in the fibrotic process. Our patient also had bilateral grade II vesicoureteral :reflux at the time of presentation, althm.igh no antecedent history of urinary infection or urologic symptoms could be obtained. She received doxorubicin hydrochloride as well as pelvic irradiation, both of which have been shown to potentiate the bladder toxicity of cyclophosphamide. 7•8 Despite maintenance of sterile urine, close followup documented graphically the rather rapid progressive deterioration of the upper urinary tract in our patient. While vesicoureteral reflux is well documented as a complication of cyclophosphamide-associated bladder toxicity, little has been advanced regarding therapeutic options available or long-term effects as they apply to children. No reported experience or- attempts at conventional ureteral reimplantation in these children could be found. An attempt ai conventional ureteral reimplantation in our ,patient failed to correct tbe reflux and prevent subsequent progressive :renal deterioration. Use of bowel either for augmentation o:r diversion seemed to be the only remaining choice. The only Ieported case of bowel usage in a similar situation washy Marshandassociates.3They reported on a 30-year-old woman with cyclophosphamide-,induced necrosis of the bladder with associated contracture, calcification and reflux that was treated successfullywith colocystoplasty. Since urinary diversion was not desired by our patient and her parents, the choice of ureteroileocecocystoplasty appeared most reasonable in an attempt to stop the reflux, provide an improved bladder capacity and low pressure system, and possibly improve the voiding pattern. Risk was believed to be present with the use of the irradiated bowel but the results of our operation have been gratifying with no long-term or shortterm complications. Although some degree of urete:ral reflux remains at the termination of bladder filling the patient has had stabilization and even improvement of the hydronephrosis and creatinine clearance. The urine has remained sterile and total urinary continence has been achieved. Prevention of cyclophosphamide-induced bladder changes leading to cases such as ours would be the optimal situation.
F1G. 2. Voiding cystourethrograms show small bladder .capacity with grade II bilateral :reflux.
The drug, 2-mercaptoethane sulfonate sodium (mesnum), has been demonstrated to prevent isophosphamide..:induced bladder toxicity. 9 The metabolic product of isophosphamide and cyclophosphamide believed responsible for urothelial to:x:icity is acrolein. This compound is inactivated by 2-mercaptoethane sulfonate sodium, which has demonstrated rapid renal excretion
SEVERE JT2fLUX
FIG. 4. IVP 6 months after ureteroileocecocystoplasty shows improvement and stabilization of upper tracts.
of bladder w.o.n,cv,. and perhaps even eliminate associated with cyclophosphamide. For those children who have been treated with cyclophosphamide and have survived the original disease but continue to have reflux and cyclophosphamide cystitis close detailed followup should be performed. It is unknown what percentage of these children will show progression of the reflux with upper tract deterioration. High grades of reflux in this situation can develop and cause renal damage, and we advocate early thers.peut1c intervention when condition and prognosis Conventional antireflux surgery in this situation is our case. When faced with estabas illustrated bladder fibrosis and progresn,"nT'"''" ureteroileocecocystoplasty REFERENCES l apy,
2. Bennett A. Urol., 111: 603, 3. Marsh, F. 1
J, P.: 0-,t,_,i_fic.~'-~:c·r:, conreflux, treated by coiocystoplasty, Brit. J. UroL, 43:
4.
5. 6. 7. FIG. 3. IVPs. A, increasing hydronephrosis and cortical loss 15 months after discovery of reflux. B, continued cortical loss and hydronephrosis before ureteroileocecocystoplasty.
and low clinical toxicity, and does not interfere with the antitumor metabolite and the parent drug. It is hoped that future use of this agent plus measures already in use will lower the
8.
9.
F. P.,, necrosis
tracture 324, 1971. Renert, W. A., Berdon, W. E. and Baker, D. H.: Hemorrhagic cystitis and vesicouretera! reflux secondary to cytotoxic therapy for childhood malignancies. Amer. J. Roentgen., 117: 664, 1973. Gellman, E., Kissane, J., Frech, R., Vietti, T. and McA!ister, W.: Cyclophosphamide cystitis. J. Canad. Ass. Rad., 20: 99, 1969. Coggins, P. R., Ravdin, R. G. and Eisman, S. H.: Clinical pharmacology and preliminary evaluation of cytoxan (cyclophosphamide). Cancer Chem. Rep., 3: 9, 1959. Jayalakshmamma, B. and Pinke!, D.: Urinary-bladder toxicity following pelvic irradiation and simultaneous cyclophosphamide therapy. Cancer, 38: 701, 1976. Ershler, W. B., Gilchrist, K. W. and Citrin, D. L.: Adriamycin enhancement of cyclophosphamide-induced bladder injury. J. Urol., 123: 121, 1980. Bryant, B. M., Ford, H. T., Jarman, M. and Smith, I.E.: Prevention of isophosphamide-induced urothelial toxicity with 2-mercaptoethane sulphonate sodium (mesnum) in patients with advanced carcinoma. Lancet, 2: 657, 1980.
Vol. 130, October
Copyright© 1983 by The Williams & Wilkins Co.
Printed in U.S.A.
MANAGEMENT OF SEVERE REFLUX IN THE PATIENT WITH CYCLOPHOSPHAMIDE CYSTITIS H. NORMAN NOE* AND H. MICHAEL McSWAIN From the Department of Urology, Division of Pediatric Urology, University of Tennessee Center for the Health Sciences and LeBonheur Children's Medical Center, Memphis, Tennessee
ABSTRACT
Cyclophosphamide cystitis with a high grade of vesicoureteral reflux can lead to rapid renal deterioration. Conventional ureteral reimplantation is inadvisable and urinary diversion, although providing a temporary solution, could lead to long-term complications, particularly in children. We present a case of cyclophosphamide cystitis with vesicoureteral reflux and upper tract deterioration managed successfully with ileocecocystoplasty. This method of management should be considered early in such a patient. Cyclophosphamide is an alkalating agent that has gained wide use in the treatment of many malignant diseases in children. Since its introduction in 1957 side effects of the drug have been studied extensively, the most frequent urologic complications being hemorrhagic cystitis and bladder fibrosis. 1• 2 Another potentially significant complication associated with the use of cyclophosphamide but less well documented in the literature is vesicoureteral reflux3- 5 associated presumably with fibrotic distortion of the ureterovesical anatomy. Herein we present a case of progressive renal deterioration secondary to vesicoureteral reflux following cyclophosphamide administration, which was managed successfully by ileocecocystoplasty. CASE REPORT
and parents strongly wished to avoid urinary diversion. We attempted ureteral reimplantation but a thickened, immobile, friable, freely bleeding bladder was encountered and we were virtually unable to mobilize the ureter. The procedure was abandoned and, except for marked intraoperative blood loss that was replaced, convalescence was uneventful. Creatinine clearance was 61 cc per minute per 1.73 m. 2 • The child was, once again, followed closely, being maintained on intermittent catheterization, continuous medication and frequent double voiding but there was persistent evidence of loss of cortical thickness on the IVP (fig. 3, B) and abdominal ultrasound. Creatinine clearance decreased to 41 cc per minute per 1.73 m. 2 and the voiding cystogram showed persistent severe reflux. In April 1981, approximately 64 months after discovery of the initial tumor, ureteroileocecocystoplasty was performed successfully. Convalescence was uneventful. A followup IVP showed improvement and stabilization of the hydronephrosis (fig. 4). A voiding cystourethrogram showed reflux across the ileocecal valve only at the termination of bladder filling or with marked bladder distension but the IVP and abdominal ultrasound remained improved and stable. Creatinine clearance 18 months postoperatively was 65 cc per minute per 1.73 m. 2 , urine was sterile and the child was totally continent.
K. S., a 3-year-old white girl, was seen in December 1975 for an abdominal mass. Excision of the mass revealed an entodermal sinus tumor arising in the right ovary. She received chemotherapy for 1 year. In March 1977 a 3.5 X 4 cm. mass was noted on routine ultrasound anterior to the right kidney, overlying the aorta and vena cava. No hydronephrosis was noted at this time and the collecting systems were believed to be normal. Excision of the mass revealed recurrent tumor. Followup radiation of 3,910 rad to the upper abdomen and 4,198 rad to the lower abdomen was given. Further chemotherapy was adminDISCUSSION istered in the form of vincristine, actinomycin D, cyclophosThe first case of cyclophosphamide-associated bladder toxphamide and doxorubicin hydrochloride. In February 1978 hematuria occurred. An excretory urogram icity was reported in 1959. 6 Since then, numerous cases have (IVP) showed normal upper tracts (fig. 1) but a voiding cysto- been reported in the literature and the subject has been studied gram revealed grade II reflux bilaterally with changes suggestive extensively. The incidence of bladder toxicity is related to the of cyclophosphamide cystitis. In July hydronephrosis was first duration and cumulative dose of cyclophosphamide, although noted on routine abdominal ultrasound examination but it it has been seen even after a single dose of the drug. There is a resolved immediately upon catheterization of the bladder. A higher reported incidence when the drug is given intravenously. repeat voiding cystogram showed the reflux to be increased in Symptoms of bladder toxicity can become manifest at any time severity with a small capacity bladder (fig. 2). At cystoscopy during the course of treatment. The acute form generally apthe ureteral orifices were significantly abnormal and the typical pears within the first few days of therapy and is heralded by changes of cyclophosphamide cystitis were noted. The child sterile hemorrhagic cystitis of varying degrees of severity. was maintained on antibacterial prophylaxis and double void- Bleeding may be pronounced but in most cases it can be ing, and did well except for some incontinence and occasional managed by cessation of therapy and conservative local measmild hematuria. At this time radiation enteropathy also devel- ures. Chronic bladder toxicity with cyclophosphamide administration is generally seen as recurrent hematuria with progresoped, which was treated successfully. A followup IVP revealed increasing hydronephrosis with sive bladder fibrosis. Bladder fibrosis is said to occur in 25 per globar atrophy and cortical loss, although the child was main- cent of the children receiving cyclophosphamide. 1 The fibrosis tained on continuous medication and the urine cultures fol- begins in the lamina propria, spreads to the innermost muscle lowed closely in a serial fashion were found to be consistently fibers and generally occurs after at least 3 months of therapy. sterile. In December 1979 she experienced for the first time a The fibrotic bladder becomes small, contracted and fixed. Uresymptomatic break-through urinary tract infection. An IVP teral obstruction and vesicoureteral reflux from altered uretercontinued to show increasing hydronephrosis with cortical loss ovesical junction anatomy have been reported as complications (fig. 3, A). Therapeutic options were discussed, and the patient of the fibrosis. 3- 5 Our case underscores several significant findings of chronic Accepted for publication March 4, 1983. cyclophosphamide-induced bladder changes. The bladder tox* Requests for reprints: LeBonheur Children's Medical Center, 848 icity presented typically with gross hematuria, a finding that is Adams, Suite 403, Memphis, Tennessee 38103. 769
770
NOE AND MCSWAIN
Fm. 1. Initial normaUVP
believed to represent disruption of the suburothelial telangiectatic blood vessels that are involved in the fibrotic process. Our patient also had bilateral grade II vesicoureteral :reflux at the time of presentation, althm.igh no antecedent history of urinary infection or urologic symptoms could be obtained. She received doxorubicin hydrochloride as well as pelvic irradiation, both of which have been shown to potentiate the bladder toxicity of cyclophosphamide. 7•8 Despite maintenance of sterile urine, close followup documented graphically the rather rapid progressive deterioration of the upper urinary tract in our patient. While vesicoureteral reflux is well documented as a complication of cyclophosphamide-associated bladder toxicity, little has been advanced regarding therapeutic options available or long-term effects as they apply to children. No reported experience or- attempts at conventional ureteral reimplantation in these children could be found. An attempt ai conventional ureteral reimplantation in our ,patient failed to correct tbe reflux and prevent subsequent progressive :renal deterioration. Use of bowel either for augmentation o:r diversion seemed to be the only remaining choice. The only Ieported case of bowel usage in a similar situation washy Marshandassociates.3They reported on a 30-year-old woman with cyclophosphamide-,induced necrosis of the bladder with associated contracture, calcification and reflux that was treated successfullywith colocystoplasty. Since urinary diversion was not desired by our patient and her parents, the choice of ureteroileocecocystoplasty appeared most reasonable in an attempt to stop the reflux, provide an improved bladder capacity and low pressure system, and possibly improve the voiding pattern. Risk was believed to be present with the use of the irradiated bowel but the results of our operation have been gratifying with no long-term or shortterm complications. Although some degree of urete:ral reflux remains at the termination of bladder filling the patient has had stabilization and even improvement of the hydronephrosis and creatinine clearance. The urine has remained sterile and total urinary continence has been achieved. Prevention of cyclophosphamide-induced bladder changes leading to cases such as ours would be the optimal situation.
F1G. 2. Voiding cystourethrograms show small bladder .capacity with grade II bilateral :reflux.
The drug, 2-mercaptoethane sulfonate sodium (mesnum), has been demonstrated to prevent isophosphamide..:induced bladder toxicity. 9 The metabolic product of isophosphamide and cyclophosphamide believed responsible for urothelial to:x:icity is acrolein. This compound is inactivated by 2-mercaptoethane sulfonate sodium, which has demonstrated rapid renal excretion
SEVERE JT2fLUX
FIG. 4. IVP 6 months after ureteroileocecocystoplasty shows improvement and stabilization of upper tracts.
of bladder w.o.n,cv,. and perhaps even eliminate associated with cyclophosphamide. For those children who have been treated with cyclophosphamide and have survived the original disease but continue to have reflux and cyclophosphamide cystitis close detailed followup should be performed. It is unknown what percentage of these children will show progression of the reflux with upper tract deterioration. High grades of reflux in this situation can develop and cause renal damage, and we advocate early thers.peut1c intervention when condition and prognosis Conventional antireflux surgery in this situation is our case. When faced with estabas illustrated bladder fibrosis and progresn,"nT'"''" ureteroileocecocystoplasty REFERENCES l apy,
2. Bennett A. Urol., 111: 603, 3. Marsh, F. 1
J, P.: 0-,t,_,i_fic.~'-~:c·r:, conreflux, treated by coiocystoplasty, Brit. J. UroL, 43:
4.
5. 6. 7. FIG. 3. IVPs. A, increasing hydronephrosis and cortical loss 15 months after discovery of reflux. B, continued cortical loss and hydronephrosis before ureteroileocecocystoplasty.
and low clinical toxicity, and does not interfere with the antitumor metabolite and the parent drug. It is hoped that future use of this agent plus measures already in use will lower the
8.
9.
F. P.,, necrosis
tracture 324, 1971. Renert, W. A., Berdon, W. E. and Baker, D. H.: Hemorrhagic cystitis and vesicouretera! reflux secondary to cytotoxic therapy for childhood malignancies. Amer. J. Roentgen., 117: 664, 1973. Gellman, E., Kissane, J., Frech, R., Vietti, T. and McA!ister, W.: Cyclophosphamide cystitis. J. Canad. Ass. Rad., 20: 99, 1969. Coggins, P. R., Ravdin, R. G. and Eisman, S. H.: Clinical pharmacology and preliminary evaluation of cytoxan (cyclophosphamide). Cancer Chem. Rep., 3: 9, 1959. Jayalakshmamma, B. and Pinke!, D.: Urinary-bladder toxicity following pelvic irradiation and simultaneous cyclophosphamide therapy. Cancer, 38: 701, 1976. Ershler, W. B., Gilchrist, K. W. and Citrin, D. L.: Adriamycin enhancement of cyclophosphamide-induced bladder injury. J. Urol., 123: 121, 1980. Bryant, B. M., Ford, H. T., Jarman, M. and Smith, I.E.: Prevention of isophosphamide-induced urothelial toxicity with 2-mercaptoethane sulphonate sodium (mesnum) in patients with advanced carcinoma. Lancet, 2: 657, 1980.