TREATMENT OF CYCLOPHOSPHAMIDE-INDUCED
HEMORRHAGIC CYSTITIS WITH PROSTAGLANDINS
LisaJ. Miller, Sonja W. Chandler, and Cindy M. Ippoliti
OBJECTIVE: To report a case of cyclophosphamide-induced
hemorrhagic cystitis. discuss prevention, and review treatment
options, particularly the use of intravesicular prostaglandins.
DATA SOURCES: Literature obtained through a computerized search,
with subsequent bibliography scanning. Information on the
individual case was obtained from the patient's medical record and
the Pharmacy Clinical Research Specialist.
CASE SUMMARY: A 29-year-old woman who had a postallogeneic
bone marrow transplantation was hospitalized because of graft-
versus-host disease. During hospitalization, she developed a
cyclophosphamide-induced hematuria that, despite hydration and
transfusions of blood products, progressed to refractory hemorrhagic
cystitis. A response was prompted ultimately by a regimen
consisting of continuous bladder irrigation and intermittent
intravesical instillation of carboprost.
DISCUSSION: The best treatment for hemorrhagic cystitis remains
prevention. Therapies for established cystitis are varied; the choice
depends on the degree of hematuria present. Therapies are often
temporary or ineffective, and themselves cause significant
morbidity. One promising treatment option involves the
intravesicular administration of prostaglandins. Reports in the
literature discuss a variety of products, dosages, and treatment
schedules that have been used with some success. The available data
on this technique are presented.
CONCLUSIONS: Prostaglandins appear to be effective in resolving
established hemorrhagic cystitis; however, their place in therapy
remains unclear. Before this class can be employed routinely,
several basic issues remain. These include optimal dosage, dosing
schedule, duration of treatment, and comparative efficacy with other
agents.
Ann Pharmacother 1994;28:590-4.
HEMORRHAGIC CYSTITIS may be defined as inflammation
characterized by diffuse or insidious vesical bleeding. I It is
a common, dose-limiting, potentially life-threatening toxi-
city of the oxazaphosphorines--cyclophosphamide, ifos-
famide, trofosfamide, and sufosfamide. We describe a case
of cyclophosphamide-induced, intractable hemorrhagic
cystitis, which responded to intravesicular instillations of
carboprost.
CASE REPORT
A 29-year-old woman was diagnosed in July 1991, with acute
myeloblastic leukemia. Induction with mitoxantrone and high-
dose cytarabine resulted in a complete remission within 2
months. Two more cycles with the same drugs followed as con-
solidation. The patient relapsed after 14 months, and underwent
an allogeneic bone marrow transplantation (BMT) with marrow
donated from her sibling who was human leukocyte antigen
identical. The conditioning regimen consisted of thiotepa 250
mg/mI/d, administered by intravenous infusion over 4 hours on
LISA J. MILLER, Pharm.D., is a Pharmacy Clinical Practice Specialist. Drug in-
formation. Division of Pharmacy, University of Texas M.D. Anderson Cancer Cen-
ter. Houston, TX 77030. FAX 713/796-8591; SONJA W. CHANDLER, M.S.• is the
Assistant Director. Outpatient Pharmacy Services; and CINDY M. IPPOLlTI, Pharm.
D.• is a Pharmacy Clinical Research Specialist. Bone Marrow Transplantation.
Reprints: Lisa J. Miller. Pharm.D.
590 • The Annals ofPharmacotherapy • 1994 May. Volume 28
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days -9 to -7, busulfan I mg/kg po q6h on days --6 to -4, and
cyclophosphamide 60 mg/kg/d iv infusedover 2 hours on days-3
to -2. Mesna 10 mg/kg ivpb was administered 30 minutes prior to
the first cyclophosphamide dose and continued every 4 hours for a
total of 12 doses. The hospitalization was complicated by episodes
of thrombocytopenia, nausea, vomiting, stomatitis, and a low-
grade fever. The patient was discharged in good condition on day
14 posttransplantation. She was readmitted on day 23 secondary to
severe nausea, vomiting, and diarrhea. A colonoscopy biopsy con-
firmed gastrointestinal graft-versus-host disease (GVHD). On day
38 the patient developed mild hematuria, which partially respond-
ed to hydration with intravenous fluids, intermittent packed red
blood cell (RBC) transfusions, and twice daily platelet transfu-
sions. Persisting, frank hematuria and clots prompted a urology
consult on day 77. Recommended treatment included NaCI 0.9%
continuous bladder irrigation (CBI) and platelet transfusions,
which increased in frequency to every 8 hours. Cystoscopy per-
formed for clot evacuation on day 85 revealed diffuse hemorrhagic
cystitis. Despite administration of alum 0.5-1 % and hydrocorti-
sone 0.1 % bladder irrigations, severe hematuria continued.
Tranexamic acid 750 mg iv q8h on day 95 prompted no addition-
al response. A second cystoscopy was performed on day 96 to fa-
cilitate blood and alum clot evacuation. Immediately following
the procedure, 60 mL of a formalin 5% solution was instilled in-
travesically and retained for 15 minutes. The cystoscopy/forma-
lin treatment was repeated on day 98 with a formalin 10% solu-
tion retained for 20 minutes. Persistent thrombocytopenia and
anemia required that blood products be used continuously; CBI
also was continued. Hematuria reappeared within a few days af-
ter the second cystoscopy/formalin treatment and gradually wors-
ened over the next 6 weeks. On day 142, a solution of carboprost
0.1 mg/IOO mL in 25 mL of NaCi 0.9% was instilled intravesi-
cally q6h with a dwell time of I hour. Oxybutynin 5 mg po qid
was administered as prophylaxis for bladder spasms. The carbo-
prost regimen was continued until day 144, when the concentra-
tion was increased to 0.2 mg/IOO mL. At this time, the urine col-
or was markedly clearer, but remained tinged with blood and
small clots. The carboprost was increased to 0.4 mg/IOO mL in
50 mL of NaCI 0.9% on day 147. Urine was clear following II
days of carboprost therapy. CBI and blood products were contin-
ued. The patient remained free of hematuria until her death on
day 161, caused by multiple organ failure, staphylococcal pneu-
monia, and disseminated herpes simplex virus resulting from
progressive chronic GVHD.
Cyclophosphamide-induced hemorrhagic cystitis was
described first by Cobbins et al. in 1959. 2 Clinical studies
have reported a highly variable incidence, ranging from 2
to 78 percent of unprotected patients. Uncontrolled hemor-
rhage and postcystectomy complications are responsible
for a 4 percent mortality rate.v' Although the cause of toxi-
city is unknown, it has been postulated that the urothelium
is damaged by direct contact with the cyclophosphamide-
active metabolite acrolein. The resulting changes (edema,
necrosis, ulceration, hemorrhage, neovascularization) in
the urothelium are aggravated by chemotherapy-induced
thrombocytopenia.' Patients at risk include those who are
dehydrated, receive cyclophosphamide intravenously, or
have previous or current exposure to busulfan or radiother-
apy.4,5 In addition, virtually all patients conditioned with
cyclophosphamide prior to BMT will be susceptible.' Pro-
phylactic measures to reduce the incidence of cystitis in-

elude catheter bladder drainage, bladder irrigation, hyper-
hydration, forced diuresis, and the administration of mes-
na. Hyperhydration and diuresis dilutes the acrolein in the
urine, thereby reducing exposure to the urothelium. The
procedure may, however, place the patient at risk for fluid
overload and electrolyte imbalance, particularly given the
antidiuretic effect of cyclophosphamide," Mesna, given
orally or parenterally, exerts its preventive action both by
binding acrolein in the urine and by interrupting the degra-
dation of urinary cyclophosphamide to acrolein.v" It ap-
pears that mesna and hyperhydration are equally effective
in preventing cyclophosphamide-induced cystitis in the
BMT population.'?
Despite adequate prevention, urothelial damage is insidi-
ous, and may not present until months after drug exposure.
Our patient first developed hematuria approximately five
weeks after receiving cyclophosphamide. Affected patients
may have symptoms such as gross hematuria, irritative
voiding, increased frequency, dysuria, burning, urgency, in-
continence, and nocturia.' Several methods of treatment for
established hematuria are currently advocated; selection
varies, depending on the severity of bleeding. In all in-
stances, the offending drug should first be discontinued.
Mild cases of hematuria do not result in an acute de-
crease in hematocrit, and can be controlled by simple mea-
sures, such as bladder irrigation with water or NaCl 0.9%.9
Intravesicular instillations with astringents (alum, silver ni-
trate) or systemic administration of antifibrinolytics (amino-
caproic acid, tranexarnic acid) are also effective in these cases.
Alum (potassium aluminum sulfate) can be delivered over
2-4 days as a CBI in a concentration of 0.5-2%.11 It acts as
a superficial astringent, leading to protein precipitation
over the bleeding surface. Unfortunately, alum precipitate
frequently clogs catheters and coats the urothelium, mak-
ing it difficult to attempt other therapies. Reports of en-
cephalopathy and seizures secondary to aluminum toxicity
in patients receiving intravesicular alum and concomitant
cyclosporine therapy make this method less desirable.
Also noted in the literature is the fact that alum only tem-
porarily decreases transfusion requirements and rarely
stops bleeding entirely." Silver nitrate is instilled into the
bladder in a concentration of 0.5-1.0% and retained there
for 10-20 minutes." Its mechanism of action is similar to
that of alum-silver ions interact with proteins, causing de-
naturing and precipitation. As with alum, reports indicate
that control of bleeding may be only temporary. In addi-
tion, a precipitate of silver chloride crystals in the urinary
tract has been attributed to a functional urinary obstruc-
tion.!' Hemostatic agents such as aminocaproic acid and
tranexarnic acid concentrate in the bladder and inhibit local
fibrinolysis.P:" With aminocaproic acid, a loading dose of
5 g is administered parenterally, followed by an infusion of
1.0-1.25 g'h.15 In most cases, a maximal response is achieved
within 8-12 hours. Tranexamic acid is 7-10 times more
potent than aminocaproic acid,16,17 and is administered in-
travenously 10-15 mg/kg tid. Adverse effects attributable
to the antifibrinolytics include ureteral obstruction, renal
colic, and acute renal failure secondary to clot formation.
In addition, these agents may produce potentially fatal
thrombus formation in patients with disseminated intravas-
cular coagulation."
Moderate bladder hemorrhage produces a decrease in
hematocrit over several days and requires 6 units or less of
The Annals ofPharmacotherapy
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Case Reports
transfused, packed RBCs. Initially, cystoscopy should be
undertaken to evacuate the bladder of clots and CBI initiat-
ed to prevent recurrent clot formation. Treatment can then
be attempted with the above-mentioned chemical irrigants
or hemostatics. DeVries and Freiha recommend the use of
intravesicular prostaglandins as an alternative in moderate
cases of hematuria, following astringent therapy, and in
conjunction with hemostatics and transfusions," Other re-
searchers have advocated that prostaglandins be used ini-
tially, in addition to bladder irrigations and transfusions.P"
Severe hematuria can be defined as hemorrhage refrac-
tory to simple irrigations, instillations, or aminocaproic
acid. More than 6 units of packed RBC transfusions are
needed to maintain hemodynamic stability. Following cys-
toscopy, treatment begins with intravesicular formalin or
phenol and proceeds to surgical intervention. Formalin (the
aqueous solution of formaldehyde) has a desiccating ef-
fect, which hydrolyzes proteins and coagulates tissues."
Regeneration of the urothelium occurs in approximately 3
weeks. Formalin is instilled at a concentration of 1-10%
with a 15-30 minute dwell time; up to four treatments may
be required. Although formalin is up to 80 percent effec-
tive, it must be instilled under general anesthesia because
of the intense pain associated with the procedure. Compli-
cations of treatment appear to be dose related and include
vesicoureteral reflux, papillary necrosis, bladder and ureter-
al fibrosis, and fatal intraperitoneal extravasation. Intraves-
icular phenol has been used with some success in pediatric
patients." As with formalin, the procedure is conducted un-
der anesthesia with 30 rnL of glycerin and 30 rnL of a phe-
nol 100% solution instilled for 1 minute. This is followed
by an instillation of 60 mL of absolute alcohol for 1 min-
ute, suctioning, and irrigation. Treatment with phenol has the
advantage of causing less permanent damage to the blad-
der than does formalin,
One of the first reports describing the use of intravesicu-
lar prostaglandins in the treatment of hemorrhagic cystitis
involved an l S-year-old man with acute myeloid leukemia.
His BMT conditioning regimen consisted of cyclophos-
phamide 60 mg/kg and mesna 12 mg/kg (dosing schedule
not indicated). On day 21 following BMT, he developed
macroscopic hematuria, verified by biopsy to be secondary
to hemorrhagic cystitis. He was originally treated with
multiple transfusions, tranexamic acid, and cystoscopy.
Continuous bleeding prompted the use of prostaglandin E 2
(dinoprostone) on day 138. A dose of 0.75 mg/IOO rnL in
200 mL of NaCl 0.9% was instilled into the bladder and
retained for 4 hours. The treatment was repeated daily for
5 days, at which time the hematuria ceased." Because in-
travesicular dinoprostone has been studied previously in
the treatment of schistosomal ulcers," it was suggested that
this drug's cytoprotective actions might be responsible for
the healing effect on the urothelium following cyclophos-
phamide injury,"
A lack of product availability caused Trigg et al. to sub-
stitute intravesicular prostaglandin E I (alprostadil) for
dinoprostone in a small trial consisting of six pediatric
BMT patients. Four of five leukemia patients underwent
conditioning with high-dose etoposide, cytosine arabi-
noside, and cyclophosphamide (90 mg/kg). One of the leu-
kemia patients did not receive etoposide. The sixth patient,
who had Fanconi's anemia, was given a modified busul-
fan, cytosine arabinoside, and cyclophosphamide (dosage
• 1994 May, Volume 28 • 591
not indicated) regimen. The leukemia patients each had
prior chemotherapy exposure with no incidence of hemor-
rhagic cystitis. Onset of hematuria ranged from 19 to 57
days after BMT. All patients received aggressive fluid hy-
dration and forced diuresis with furosemide as initial thera-
py; however, symptoms persisted. All patients were inter-
mittently platelet dependent. Based on past failure rates ex-
perienced with other methods (phenol, formalin, alum), the
authors instituted therapy with intravesicular alprostadil. A
dose of 0.75 mg/100 mL diluted in 55 mL of NaCl 0.9%
was instilled into the bladder (over 5 minutes), and re-
tained for 1 hour. The regimen was then repeated daily for
at least 7 days. In five of six patients, alprostadil successful-
ly controlled the hemorrhagic cystitis by elimination of all
gross hematuria; occasional microscopic hematuria persist-
ed. One leukemia patient's cystitis failed to respond and ul-
timately resulted in death. The authors speculate that this
failure may have been related to premature discontinuation
of the prostaglandin. No systemic adverse effects were ob-
served, although patients did experience localized pain
caused by bladder distension and spasms. The alprostadil
dosage was selected empirically; it was suggested that a
lower dosage might have been equally effective."
Intravesicular alprostadil was studied later in 13 pedi-
atric patients after allogeneic BMT for a variety of hemato-
logic disorders. Most patients received conditioning with
high-dose etoposide, cytosine arabinoside, and cyclophos-
phamide (dosage not indicated). Two of the 13 patients
with Fanconi's anemia received a modified busulfan and
cyclophosphamide regimen. Gross hematuria manifested
in all patients, ranging from 14 to 124 days following
BMT. They were treated initially with aggressive fluid hy-
dration and forced diuresis. The need for blood products
was not mentioned. When gross hematuria with clots per-
sisted, alprostadil bladder instillations were begun at a dose
of 0.75 mg/lOO mL in 50-100 mL of NaCl 0.9%. This so-
lution was instilled over 5 minutes and retained for 1 hour.
The regimen was continued daily for 1 week. Gross hema-
turia resolved in 11 of 13 patients; however, 3 of the 11 re-
sponders developed a recurrence of symptoms requiring
retreatment. The only adverse reaction noted by the au-
thors was bladder spasms."
Intravesicular prostaglandin F 2-alpha analog (carbo-
prost) was first used successfully in a 59-year-old man
with lymphoma with hemorrhagic cystitis secondary to 11
months of treatment with oral cyclophosphamide (dosage
not indicated). The urine cleared initially following conser-
vative treatment with periodic irrigation and increased oral
fluid intake. Two weeks later, however, the patient present-
ed with severe hemorrhage and clot retention. A cystosto-
my was performed for clot removal and to permit CBI.
The hematuria persisted, necessitating multiple transfu-
sions. Prostaglandin bladder irrigation was instituted: 200
mL of 0.7 mg/IOO mL solution of carboprost in NaCl
0.9% was retained for 4 hours daily. Hematuria resolved
by day 5 of treatment. No hematologic, systemic, or con-
stitutional adverse effects were noted."
Carboprost bladder instillations have been studied most
extensively by Levine and Krane, In their initial study, the
drug was evaluated in four BMT patients, all of whom had
received conditioning regimens containing cyclophos-
phamide 3.8-15.6 g. Patient 1, an 8-year-old boy with
acute myeloblastic leukemia, developed gross hematuria on
592 • The Annals ofPharmacotherapy • 1994 May, Volume 28
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hospital day 20, progressing to clot retention on day 41. Ini-
tial treatment included cystoscopy with clot evacuation, in-
travesicular administration of formalin, and CBI. On hospi-
tal day 51, 25 mL of carboprost 0.1 mg/100 mL was instilled
and retained for 45 minutes. This was repeated four times
daily for 5 days. To achieve complete resolution of symp-
toms, the patient required an additional 3 days of therapy at
a dose of 0.2 mg/100 mL. Patient 2 was a 38-year-old man
with irnmunoblastic lymphoma. On hospital day 31, he de-
veloped clot retention necessitating CBI. Twenty-four hours
later, 50 mL of a carboprost 0.2 mg/100 mL solution was
instilled for I hour, the bladder was drained, and the proce-
dure immediately was repeated. This was followed with
NaCl 0.9% CBI for 2 hours. The carboprost/CBI regimen
was duplicated 4 times daily for 5 days. Although the pa-
tient initially showed some improvement, severe bladder
spasms and continuous hematuria prompted discontinua-
tion of prostaglandin therapy. A complete response was
seen with intravesical formalin 2.5 mg/100 mL. 12
Patient 3 was a 27-year-old breast cancer patient who
developed hematuria on hospital day 5. Three days of hy-
dration followed. Clot retention developed in the bladder
on hospital day 8. After clot evacuation, 100 mL of carbo-
prost 0.2 mg/100 mL was instilled 4 times daily for 1 day.
The patient began to experience severe bladder spasms. To
treat this, the fluid volume was divided in half and the pa-
tient given a carboprost/CBI regimen similar to that of pa-
tient 2. Hematuria persisted, however, and the dose of car-
boprost was increased to 0.4 mg/100 mL for an additional
2 days. The hematuria cleared completely following 10
days of carboprost therapy.
Patient 4 was a 35-year-old man with mixed cellularity
Hodgkin's disease. He presented 4 weeks after transplanta-
tion with complaints of gross hematuria and passage of
large blood clots. He initially received 100 mL of a 0.4
mg/100 mL carboprost solution to his bladder. However,
because of severe spasms, he too was placed on the carbo-
prost/CBI regimen. Hematuria resolved following comple-
tion of treatment. With the exception of bladder spasms, no
patients in this report experienced prostaglandin-induced
adverse effects. In three patients, the spasms were alleviat-
ed by oral administration of oxybutynin chloride 10 mg
qid. The investigators speculate that therapy failure seen in
patient 2 may have been caused by retained bladder clots,
which prevented contact between the bladder wall and the
carboprost solution.'! Of interest in this study was the dos-
ing schedule, which differed considerably from that of the
other reports. The clinical significance of divided dosing
was not addressed.
Most recently, Levine and Jarrad reported on their expe-
rience with 18 patients (aged 9-44) who had received one
or more courses of cyclophosphamide 3.6-15.8 g. Two pa-
tients had received the drug as cytotoxic therapy alone; 16
others were given cyclophosphamide for BMT condition-
ing. Mesna, in doses of 80 percent that of the cyclophos-
phamide, was administered prophylactically to 12 patients.
All patients had been treated initially for gross hematuria
with forced diuresis or NaCl 0.9% CBI. Prostaglandin
therapy was instituted only after significant transfusion re-
quirements (> 1 unit packed RBCs/d) and/or numerous clot
evacuation procedures were documented. In 12 patients,
the following protocol was implemented: 50 mL of carbo-
prost 0.2-1.0 mg/100 mL was instilled into the bladder and

retained for 1 hour. The bladder was then drained and the
procedure immediately repeated. cm with NaCl 0.9% fol-
lowed. Carboprost was administered four times during a
l6-hour period with cm instituted during the remaining 8
hours. Generally, if no improvement was noted after four
to six courses, the initial dose of carboprost was increased.
In 6 patients, a slightly different protocol was followed: pa-
tients received carboprost 0.8-1.0 mg/lOO mL as a CBI at
a rate of 100 mL/h for 10 hours. CBI with NaCI 0.9% was
used for the remainder of the day,"
Responses were divided into three groups: (1) complete
response (resolution of hematuria) within seven days, (2)
partial response (decreased clot formation and transfusion
requirements with partial clearing of urine) requiring fur-
ther therapy, and (3) no response. Nine patients had a com-
plete response with carboprost, while 8 individuals partial-
ly responded. One patient failed to respond to four days of
the intermittent carboprost regimen and required formalin
therapy. Equivalent results were seen with both the inter-
mittent and continuous infusion methods of carboprost ad-
ministration; however, optimal dosages were not addressed.
Several factors were assessed to determine whether the
severity of hemorrhagic cystitis or response to carboprost
could be predicted. Lower cyclophosphamide dosages, no
prophylactic mesna, allogeneic BMT, and decreased trans-
fusion requirements were characteristics of the complete
responders. Prior cyclophosphamide exposure, time of onset
of hemorrhagic cystitis, and platelet counts appeared to have
no bearing on response. Adverse effects were limited to
bladder spasms, occurring in 14 of 18 patients. Long-term
evaluation was difficult to assess, as 12 of the patients died
of malignant disease or other complications."
Prostaglandins ~, F2, 12, and thromboxane A2 are secret-
ed by the kidney and bladder.26,27 Prostaglandins are known
to have a variety of roles in bladder function: maintaining
tone, modulating sensation, and assisting in voiding." In
addition, they offer cytoprotection against infection, ulcer-
ation, and carcinogenesis. The prostaglandins' effect on
hemorrhagic cystitis may be related to their ability to in-
hibit platelet aggregation." Another theory involves the ca-
pability of these agents to cause membrane strengthening,
thereby reducing edema and extravasation of RBCs.28
Bladder spasms encountered in these reports most likely
are caused by prostaglandin-stimulated detrusor contrac-
tions.P The spasms can be prevented or minimized with
the concurrent use of smooth muscle relaxants. Other sys-
temic adverse effects are notably absent, suggesting that
little prostaglandin is absorbed systemically.
Given our particular patient's dependence on blood
products, her cystitis could have been categorized as se-
vere. The hemorrhaging did not respond to formalin instil-
lations and the patient undoubtedly would have undergone
surgery if her overall clinical status had improved. It is im-
possible to predict whether or not she would have respond-
ed to additional formalin therapy, or if she would have
continued to be symptom-free following carboprost ad-
ministration. It is also unknown if her urine would have
cleared while receiving the carboprost at a lower concen-
tration. However, the patient did tolerate the treatment
well, and experienced no bladder spasms while receiving
prophylactic oxybutynin.
In summary, moderate-to-severe hemorrhagic cystitis
does respond to local prostaglandin therapy. However,
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Case Reports
product availability, optimal dosages, dosing schedules,
and duration of treatment all remain uncertain variables in
the decision to administer these agents intravesicularly. In
addition, comparative trials with proven therapies, i.e., for-
malin, are lacking. The high incidence of prostaglandin-in-
duced bladder spasms also must be considered and pro-
phylactic measures implemented. Until more defmitive in-
formation is accrued, the role of prostaglandins in the
treatment of hemorrhagic cystitis will remain an alterna-
tive to be used when more conventional methods fail. ~
References
I. Fraiser LH, Kanekal S, Kehrer JP. Cyclophosphamide toxicity: char-
acterizing and avoiding the problem. Drugs 1991;42:781-5.
2. Coggins PR, Ravdin RG, Eisman SH. Clinical pharmacology and pre-
liminary evaluation of cytoxan (cyclophosphamide). Cancer Chemo-
therRep 1959;3:9-11.
3. Goldman RL, Warner NE. Hemorrhagic cystitis and cytomegalic in-
clusions in the bladder associated with cyclophosphamide therapy.
Cancer 1970;25:7-11.
4. Stillwell TJ, Benson RC. Cyclophosphamide-induced hemorrhagic cys-
titis: a review of 100 patients. Cancer 1988;61:451-7.
5. Beelen DW, Quabeck K, Graeven U, Sayer HG, Mahmoud HK,
Schaefer VW. Acute toxicity and first clinical results of intensive post-
induction therapy using a modified busulfan and cyclophosphamide
regimen with autologous bone marrow rescue in first remission of
acute myeloid leukemia. Blood 1989;74:1507-16.
6. Letendre L, Hoagland HC, Gertz MA. Hemorrhagic cystitis complicat-
ing bone marrow transplantation. MayoClin Proc 1992;67: 128-30.
7. Hows JM, Mehta A, Ward L. Comparison ofmesna with forced diure-
sis to prevent cyclophosphamide-induced haemorrhagic cystitis in
marrow transplantation: a prospective randomised study. Br J Cancer
1984;50:753-6.
8. Levine LA, Ritchie JP. Urologic complications of cyclophosphamide. J
Uro/1989;141:1063-9.
9. De Vries CR, Freiha FS. Hemorrhagic cystitis: a review.] Uro/1990;
143:1-9.
10. Shepherd JD, Pringle LE, Barnett MJ, Klingemann HG, Reece DE,
Phillips GL. Mesna versus hyperhydration for the prevention of cy-
clophosphamide-induced hemorrhagic cystitis in bone marrow trans-
plantationJ Clin Oncoll99I;9:2016-20.
II. Goel AK, Rao MS, Bhagwat AG, Vaidyanathan S, Goswami AK,
Sen TK. Intravesical irrigation with alum for the control of massive
bladder hemorrhage. ] Uro11985; 133:956-7.
12. Levine LA, Krane DM. Evaluation of carboprost tromethamine in the
treatment of cyclophosphamide-induced hemorrhage cystitis. Cancer
1990;66:242-5.
13. Kumar APM, Wrenn EL Jr, Jayalakshmamma B, Conrad L,
Quinn P, Cox C. Silver nitrate irrigation to control bladder hemor-
rhage in children receiving cancer therapy. J Urol 1976; 116:85-6.
14. Raghavaiah NV, Soloway MS. Anuria following silver nitrate for in-
tractable bladder hemorrhage.] Uro/1977;118:681-2.
15. Aroney RS, Dalley DN, Levi JA. Haemorrhagic cystitis treated with ep-
silon-arninocaproicacid. Med J Aust 1980;2:92.
16. Ro JS, Knutrud 0, Stormorken H. Antifibrinolytic treatment with
tranexamic acid (AMCA) in pediatric urinary tract surgery. J Pediatr
Surg 1970;5:315-20.
17. Verstraete M. Clinical application of inhibitors of fibrinolysis. Drugs
1985;29:236-61.
18. Mohiuddin J, Prentice HG, Schey S, Blacklock H, Dandona P. Treat-
ment of cyclophosphamide-induced cystitis with prostaglandin ~ (let-
ter). Ann Intern Med 1984;101:142.
19. Trigg ME, O'Reilly J, Rumelhart S. Morgan D, Holida M, DeAlar·
con P. Prostaglandin E. bladder instillations to control severe hemor-
rhagic cystitis (abstracn.J UroI199O;143:92-4:
20. Comito M, Peters G, Giller R, DeAlarcon P, Morgan D, Trigg M.
Use of alprostadil (pGE.) bladder instillations for severe hemorrhagic
cystitis (abstract). ProcAnnu Am Soc Clin Oncoll99I;IO:A811.
21. Shurafa M, Shumaker E, Cronin S. Prostaglandin Fj-alpha bladder ir-
rigation for control of intractable cyclophosphamide-induced hemor-
rhagic cystitis.Z UroI1987;137:1230-1.
• 1994 May, Volume 28 • 593
22. Shrom SH, DonaldsonMH, Duckett JW Jr, Wein AJ. Formalin treat-
mentfor intractable hemorrhagic cystitis. Cancer 1976;38: 1785-9.
23. Susan LP, Marsh RJ. Phenolization of bladderintreatment of massive
intractable hematuria. Urology 1975;5: 119-21.
24. EI-GendiMA, Nassar SH, Toppozada M, Abdel-RaheemF. Phanna-
cotherapeutics of prostaglandin E2 and 15 (S) 15-methylprostaglandin
F2 alpha in chronic schistosomal bladder ulcer: a c1inico-endoscopic
study. Prostaglandins 1982;24:97-104.
25. Levine LA, Jarrad OF. Treatment of cyclophosphamide-induced hem-
orrhage cystitis with intravesical carboprost tromethamine. J Urol
1993;149:719-23.
26. Frolich JC, WilsonTW, Sweetman BJ, Smigel M, Nies AS,Carr K,
et al. Urinaryprostaglandins: identification and origin. J Clin Invest
1975;55:763-70.
27. Brown WW, Zenser TV, DavisBB. Prostaglandin production by rabbit
urinary bladder. Am J PhysioI1980;239:F452-8.
28. Gray KJ, Engelmann UH, Johnson EH, Fishman IJ. Evaluation of
misoprostol cytoprotection of the bladder withcyclophosphamide ther-
apy. J UroI1986;136:497-5oo.
EXTRACfO
OBJETIVO: Describir un caso de cistitis hemomigica inducida por
ciclofosfamida,discutir la prevenci6n,y revisar las opciones de
tratarniento, en especial, la utilizaci6nde prostaglandinas intravesicales.
FUENTES DE INFORMACION: Artfculosseleccionadosde una amplia
bibliograffa obtenida por ordenador y datos del paciente obtenidos de la
historia medica del mismo y del especialistaen farmacia clfnica.
RESUMEN DEL CASO: Mujer de 29 alios con un trasplante alogenicode
medula 6sea es hospitaiizadadebido a enferrnedaddel injerto contra el
huesped, Durante la hospitaiizaci6n, la paciente desarroll6hematuria
inducida por ciclosfosfamidaque a pesar de hidrataci6ny
administraci6nde sangre y concentradosde eritrocitosy plaquetas
progres6 a cistitis hemorragica refractariaque mejor6 con un regimen de
irrigaci6ncontinua de vejiga e instilaci6nintravesical interrnitente de
carboprost.
DISCUSION: Aunque eI mejor tratarnientode la cistitis hemorragicasigue
siendo la prevenci6nexisten terapias variadas para cistitis establecidas,
dependiendola elecci6n de una u otra del grado de hematuria presente.
Con frecuenciaestas terapias acnian solo temporalmente 0 son
ineficacesy pueden causar morbilidadsignificativa. La administraci6n
594 • The Annals ofPharmacotherapy • 1994 May, Volume 28
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intravesical de carboprostparece una opci6n prometedorayaqui se
describenlos datos disponiblessobre esta tecnica.
CONCLUSIONES: Las prostaglandinas parecen eficacesen el tratamientode
la cistitis hemorragica, pero su lugar en la terapiade esta enferrnedad
aun no esta definitivamenteestablecido.Antes de utilizarlas de manera
rutinaria,habrfaque establecer:dosis optima, intervalode dosificaci6n,
duraci6n de tratamiento, y eficacia comparativacon OlrOS agentes.
CARMENCAO
RESUME
OBJECIlF: Rapporterun cas de cystite hemorragiqueinduitepar la
cyclophosphamide; discuter des methodes de preventionet reviser les
possibilitesde traitements,plus particulierement de I'utilisationdes
prostaglandines (PG) par voie intravesicale,
REVUE DE LA LI1TERATURE: Une revue de la litteraturefut obtenue par
recherche inforrnatisee et par une recherchede la bibliographie.
L'inforrnation relative au cas presentefut obtenue par la revue du
dossier medical du patient et par Ie pharmacienresponsable du patient
en question.
PRESENTATION DE CAS: Une femme de 29 ans et statut post-greffede
moelle allogeniquefut hospitaliseepour une GVHD (Graft-Versus-Host
Disease). Durant I'hospitalisation, elle a developpe une hematurie
secondaire11 la cyclosphosphamide qui, malgre I'hydratationet
I'administrationde produits sanguins,degenera en une cystite
hemorragiquerefractaire, Une reponse fut fmalementobtenue suite 11
I'irrigation vesicalecontinueet I'instillationintravesicale interrnittente
de carboprost,une PG.
DISCUSSION: La therapie la plus efficace contre la cystite hemorragique
demeure toujours la prophylaxiede celle-ci.Cependant, lorsquecette
complicationsurvient,plusieurschoix de therapiesont possibles,
dependant du degre d'hematurie present chez Ie patient. Les therapies
sont souvent temporaireset inefficacesen plus de pouvoir causer
plusieurscomplications. Une therapieprometteuseserait I'instillation
vesicalede PG. La litteraturerapporte plusieurschoix d'agents dans
cette classe ainsi que plusieursposologiespossibles. Les donnees de ces
techniquesy sont presentees.
CONCLUSIONS: Les PG semblent efficacespour traiter la cystite
hemorragiquememe si leur efficacitereste 11 etre demontree, De plus,
quelques questions demeurentquant 11 leur utilisation: posologie
optimale,duree d'utilisation, et efficacitecomparee 11 d'autres
alternatives.
ERIC MASSON