bs_bs_banner
International Journal of Urology (2013) 20, 651–660
Review Article
Therapeutic options for intractable hematuria in advanced
bladder cancer
Dominik Abt, Mirjam Bywater, Daniel Stephan Engeler and Hans-Peter Schmid
Department of Urology, St. Gallen Cantonal Hospital, St. Gallen, Switzerland
Abbreviations & Acronyms
EACA = epsilon-aminocaproic
acid
PGF2 alpha = prostaglandin
F2 alpha
Correspondence: Dominik Abt
M.D., Department of Urology,
St. Gallen Cantonal Hospital,
Rorschacherstrasse 95, St.
Gallen 9007, Switzerland.
Email: dominik01.abt@kssg.ch
Received 12 April 2012;
accepted 14 January 2013.
Online publication 6 February
2013
© 2013 The Japanese Urological Association
doi: 10.1111/iju.12113
Abstract: Intractable hematuria is a common and severe complication in patients with
inoperable bladder carcinoma. The aim was to provide an overview of therapeutic
options for such cases, and analyze their effectiveness and risk profile, so a systematic
literature search of peer-reviewed papers published up to September 2012 was carried
out. Various options are available to treat hematuria in patients with inoperable bladder
cancer; these include orally administered epsilon-aminocaproic acid, intravesical forma-
lin, alum or prostaglandin irrigation, hydrostatic pressure, urinary diversion, radio-
therapy, embolization and intraarterial mitoxantrone perfusion. These treatment options
are associated with different prospects of success, risks and side-effects. Well-designed
and large studies comparing options are completely lacking. Despite various treatment
options, management of intractable hematuria in patients with inoperable bladder
cancer remains a challenge, and most of the reported methods should be seen as
experimental. Interventional radiology and alum instillation seem to be suitable alterna-
tive options for patients who, after critical consideration, cannot be treated by irrigation,
transurethral resection or palliative cystectomy.
Key words: hematuria, interventional radiology, intravesical administration, treat-
ment, urinary bladder neoplasms.
Introduction
Bladder carcinoma often causes recurrent and intractable hematuria. Reasons for bleeding
might be sloughing of tumor mass, side-effects of radiation, cyclophosphamide-induced
hemorrhagic cystitis and other sources of hematuria, such as prostate cancer, simultaneous
ureteropelvic cancer or severe infection. Treatment is often hindered by drugs that dilute the
blood and by comorbidities.
Intractable bleeding in advanced bladder carcinoma is often not curable by irrigation of
the bladder by a catheter. If transurethral resection and coagulation are not able to control
bleeding, palliative cystectomy with urinary diversion is an effective treatment of choice.
However, surgery might not be possible because of comorbidities, or the patient might
refuse it. Alternative palliative methods to reduce bleeding and the frequency of transfusion,
and alleviate pain are required to improve quality of life in such cases.
The present review explores alternative treatments for patients with bleeding complica-
tions of bladder cancer who are not suitable for surgery or who refuse it. Practical experi-
ence with the treatments available, and their effectiveness and risk profiles are discussed.
Methods
A comprehensive literature search for articles published up to September 2012 was carried
out in PubMed using different combinations of the following search terms: “bladder
cancer”, “hematuria”, “epsilon-aminocaproic acid”, “formalin”, “alum”, “prostaglandin”,
“hydrostatic pressure”, “urinary diversion”, “radiotherapy”, “arterial occlusion”, “emboli-
zation”, “mitoxantrone” and “palliative cystectomy”. We reviewed the publications thus
selected, as well as literature cited in these publications.
651
D ABT ET AL.
Table 1 Treatment of intractable hematuria
Orally administered: Epsilon-aminocaproic
acid
Intravesical irrigation: Formalin
Alum
Prostaglandin
Hydrostatic pressure
Urinary diversion
Hypofractionated radiotherapy
Interventional radiology: Embolization/arterial
occlusion
Chemoperfusion with
mitoxantrone
Results
Table 1 gives an overview of the most investigated and most
promising treatments revealed by the literature search. It is
evident that quite a wide range of methods for the manage-
ment of intractable hematuria have been used, a fact that
underlines the difficulty of finding suitable treatment
options for patients not qualifying for or refusing surgery.
However, there is a lack of large, well-controlled trials for all
treatment options described; studies have generally been
limited to descriptions of small numbers of cases, or were of
experimental character.
It should be noted that hyperbaric oxygen therapy,
although used to treat radiation cystitis and
cyclophosphamide-induced hemorrhagic cystitis, was not
used to treat hematuria caused by bladder carcinoma in any
of the articles found. Thus, hyperbaric oxygen therapy is not
further considered in the present review.
Orally administered epsilon-
aminocaproic acid
EACA is a synthetic lysin that competitively inhibits fibri-
nolysis induced by plasminogen and plasmin. When given
orally, the drug is absorbed rapidly and 80% is secreted
unchanged in the urine within 24 h.1 The literature search
found only studies reporting small numbers of cases and one
experimental study on the use of EACA. The patient popu-
lations in these studies were heterogeneous with regard to
the cause of hematuria, which included radiogenic cystitis,
infections, hemorrhagic disorders and urothelial cancer.
There was no empirical data regarding duration and dosage
of EACA treatment.
The use of EACA in hematuria was first described by
Vega et al. in a patient with sickle-cell trait in 1971.2 Ste-
fanini et al. described nine patients with hematuria of
various causes treated with approximately 150 mg/kg/day
EACA for up to 21 consecutive days. The authors reported
that hematuria was controlled effectively in all cases without
overt clinical reactions.3
652
Side-effects of EACA were rare, but serious. Thrombotic
complications, myopathy, rhabdomyolysis, and renal and
hepatic failure were all reported.4,5
Intravesical formalin treatment
Intravesical formalin treatment causes precipitation of cel-
lular proteins of the bladder, and leads to occlusion and
fixation of teleangiectatic tissue and small capillaries.6,7
Treatment of inoperable carcinoma of the bladder by forma-
lin instillation was first described in 1969 by Brown.8 In 24
patients with advanced carcinoma suffering from hematuria
and strangury, a 10% formalin solution was instilled into the
bladder over 15 min. Relief of hematuria was seen in 22
patients within 1–5 days, with a mean duration of 4 months,
without general complications; the method was thus deemed
by Brown to be safe and effective. Subsequently, the method
has been widely used with predominantly good success
rates. For example, Fair reported on 14 patients treated with
1% formalin instillation; 10 patients were responsive to the
first instillation and a further two to the second instillation.
Cessation of hematuria was achieved in the remaining two
patients by another treatment with 2% formalin.9 However,
severe side-effects were subsequently described in other
studies, commonly leading to the discontinuation of forma-
lin instillation in patients with persistent gross hematuria. In
a study of 10 patients, Giannakopoulos et al. reported 40%
renal failure, 40% clinically significant reduction of bladder
capacity (<100 mL), 30% urinary incontinence, 30%
urgency and nocturia, and one case with retroperitoneal
fibrosis.10 A high rate of renal failure (>60%) was also
reported by Ferrie et al.11 According to other reports, forma-
lin treatment caused ureteral stenosis, hydronephrosis and
vesico-ureteric reflux.12 Although the incidence of compli-
cations appears to be lower if formalin solutions of ⱕ4%
are used, the effectiveness of this treatment seems to be
inferior.9,11–13 Furthermore, instillation is painful and
requires general or spinal anesthesia, and a catheter has to be
left in the bladder after the procedure for bleeding control.
There are no studies comparing the effectiveness of formalin
instillation to catheterization alone. Formalin treatment is no
longer common in everyday clinical practice. Cystoscopy
and cystography should always be carried out first to exclude
the existence of blood clots or vesico-ureteric reflux. In the
latter case, if formalin treatment is carried out, prior inser-
tion of a ureteral occlusion catheter is necessary.9,12 Choong
et al. provide a recommendation for the careful use of for-
malin (Table 2).14
Alum irrigation
Alternative approaches to achieve intravesical hemostasis
were investigated as a result of the high complication rate
associated with formalin treatment. The results of alum irri-
© 2013 The Japanese Urological Association
 Therapeutic options for hematuria

Table 2 Protocols for treatment of hematuria by intravesical irrigation or instillation

Formalin • Cystoscopy and cystography are carried out first to exclude the existence of blood clots or
vesico-ureteric reflux. Insertion of a ureteral occlusion catheter is carried out in the case of reflux.
• As spinal or general anesthesia has to be used, coagulation of major bleeding vessels can be carried
out.
• External areas of skin and mucosa are protected with Vaseline. Vagina is packed to prevent catheter
leakage.
• Low initial formalin concentrations (1–2%) should be used.
• Irrigation is carried out for 10 min under gravity at <15 cm H2O.
• Alternatively instillation is carried out under gravity at <15 cm H2O with catheter left open at a level just
above the pubic ramus.
• Contact time should be limited to 15 min.
Alum • Cystoscopy with evacuation of blood clots is recommended before treatment.
• Using a 1% alum solution; 50 g of alum is dissolved in 5 L sterile water and used to irrigate the bladder at
250–300 mL/h.
• Using the 1% solution or a stock solution of 400 g of potash of alum (McCarthy’s) in 4 L sterile hot water,
300 mL of the stock solution is added to 3 L of 0–9% saline through a sterilizing filter and the bladder is
irrigated with up to 30 L of this solution in 24 h.
Prostaglandin • Cystoscopy, clot evacuation and insertion of a three-way catheter are carried out.
• Instillation of the bladder can be carried out using 50 mL of 4–8 mg/L carboprost tromethamine for 1 h.
Bladder is drained and another 50 mL are maintained for 1 h. After draining the bladder it is irrigated
with normal saline now. This can be repeated up to four times a day with a 24 h course consisting of
400 mL carboprost tromethamine administered within 8 h.
• Dosage can be increased to 10 mg/L if there is no improvement.
• Alternatively continuous irrigation of the bladder can be carried out using 8–10 mg/L carboprost
tromethamine at 100 mL/h for 10 h.

gation treatment were first published by Ostroff and Chen-
ault in 1982.15 Alum (either aluminum ammonium sulfate or
aluminum potassium sulfate), like formalin, also causes
protein precipitation. However, alum has lower cell penetra-
bility than formalin, so that its effect is limited to the cell
surface and interstitial spaces, and cells remain viable. Sys-
temic absorption of alum is also lower.16,17 Alum excretion
proceeds through a renal route, and increased serum levels
can result in prolonged prothrombin times.18
Ostroff and Chenault reported complete cessation of
hematuria over various periods using a 1% alum solution in
six patients with massive bladder hemorrhage (2 due to
carcinoma).15 No side-effects were observed, and treatment
could be given without anesthesia. After this initial publica-
tion, several studies on small numbers of patients were
reported (Table 3),19–22 with success rates between 66% and
100% using 1% alum solutions. Unfortunately, no hard defi-
nitions of success and relapse were provided, except by
Arrizabalaga et al.19 and Goswami et al.18 Also, no compari-
sons to standard bladder irrigation alone were made in any
of the aforementioned studies. Schootstra et al. reported
satisfactory results after treating 16 patients with 0.5% alum
solution (full text not available).23 The lack of well-designed
studies in adequate numbers of patients hampers drawing
overall conclusions on all this data.
Bladder spasms and suprapubic pain are common during
alum treatment. These symptoms are obviously caused by
the acidity of the alum solution, but can be effectively
managed by antispasmodics.19 Serious side-effects of alum
irrigation have only been reported in isolated cases.
Encephalopathy and acute aluminum intoxication occurred
predominantly in patients with renal dysfunction.24–26
Although renal dysfunction is not a clear contraindication,27
Shoskes et al. reported the death of a patient with renal
dysfunction who was treated twice within a 3-month period
with 1% alum given over 48 h.28
To avoid systemic side-effects, serum aluminum can be
monitored during treatment. Signs of clinical toxicity seem
to occur at a mean serum aluminum concentration of
7.4 mmol/L, and surveillance of patients is recommended
when concentrations exceed 3.7 mmol/L.29,30 Goswami et al.
found only a moderate increase of serum aluminum (from
1.68 mmol/L at baseline to 3.36 mmol/L on treatment) in a
prospective study on 12 patients with normal renal function
and without clinical evidence of aluminum toxicity.18
On balance, a 1% alum solution can be considered to be
a treatment option, at least in patients without renal dysfunc-
tion. Measurement of serum aluminum would not appear to
be necessary provided usual concentrations and amounts of
alum irrigation are used. A recommendation for the “ideal”

© 2013 The Japanese Urological Association 653

654
D ABT ET AL.

Table 3 Cases treated with intravesical 1% alum irrigation

Author (Ref.) No. Success rate Mean period of Side-effects Comment
patients irrigation
Ostroff and 6 100% Not reported None observed Rate and period of relapse not reported
Chenault
198215
Arrizabalaga 15 66% complete and 15% 21 h (range Vesical tenesmus and suprapubic pain; Average volume of irrigation fluid: 6 L;
et al. 198719 partial response 3–48 h) no serious or long-term side-effects; clear definition of response
40% without any side-effects
Kennedy et al. 8 100% 3 days 2 cases of suprapubic discomfort, low 2 patients with recurrence after stopping
198420 grade pyrexia and ileus irrigation; up to 30 L solution used in
24 h; 2 moribund patients died within
a few weeks from coincidental disease
Goel et al. 9 100% 49 h None observed during 6 months of Continuous irrigation with 5 mL/min; 3
198517 follow-up patients with recurrence after
stopping irrigation
Nurmi et al. 10 70% complete and 10% Not reported None observed The 2 patients not responding to therapy
198721 partial response suffered from thrombocytopenia
Goswami et al. 12 50% complete and 33% 36.5 h Suprapubic pain in all patients leading to Irrigation rate 3–10 mL/min; irrigation
199318 partial response one dropout; 2 patients with vesical stopped 6 h after cessation of
tenesmus; 3 with spasms leading to bleeding; clear definition of response;
pericatheter leak; mild pyrexia in 4 significant change in serum aluminum
patients levels and thromboplastin time after a
period of 24 h, not associated clinical
side effects; average volume of
irrigation fluid: 10.5 L
Praveen et al.22 9 78% Maximum period Bladder spasms in all patients; Irrigation rate of 5 mL/min;
of 72 h no systemic side effects 3 patients with recurrence of bleeding

© 2013 The Japanese Urological Association


application is given in the review by Choong et al.
(Table 2).14 All authors recommend cystoscopy with evacu-
ation of blood clots before treatment.
Intravesical instillation of prostaglandin
Prostaglandins can cause constriction of vascular smooth
muscle cells and aggregation of platelets. Only one study
compared the effect of intravesical instillation of PGF2
alpha with alum on hematuria caused by bladder cancer:22
Praveen et al. treated 10 patients with a dose of 1 mg PGF2
alpha daily for a maximum of 5 days. Six patients had com-
plete cessation of macroscopic hematuria; two patients had
partial control. Failure of control was seen in two patients.
There was no significant advantage in efficacy or safety of
PGF2 treatment compared with alum. In both groups,
patients had only local side-effects (bladder spasms, catheter
blockage). The authors concluded that high cost, low avail-
ability and stringent storage conditions are drawbacks for
routine use of PGF2 alpha and recommended it only as an
alternative method where alum treatment is not successful.
A comparison of these treatments to bladder irrigation with
normal saline was not carried out. Several studies have been
carried out on the use of prostaglandin for the treatment of
hemorrhagic cystitis caused by radiation, cyclophosphamide
and bone marrow transplantation. Prostaglandin was effec-
tive in these studies, although the detailed mechanism of
prostaglandin action on the bladder epithelium remains
unclear. A recommendation for the use of prostaglandin also
can be found in Table 2.
Hydrostatic bladder distention
Intravesical hydrostatic pressure for the treatment of
bladder carcinoma was first described by Helmstein.31 In
1972, he reported on 43 patients thus treated to produce
necrosis of the tumor. Holstein et al. were the first to
publish a study using this method for the control of
bladder hemorrhage in 1973.32 Six patients were investi-
gated. Under epidural anesthesia, a balloon was inserted
into the bladder, which was filled with fluid for 6 h to the
level of the systolic blood pressure. Sustained hemostasis
was achieved in three patients; two patients showed tem-
porary improvement and one patient did not respond. In
further studies, similar effectiveness was achieved using
intravesical hydrostatic pressures of 10–20 cm H2O above
diastolic blood pressure, accompanied by a reduced risk of
side-effects as compared with those seen at higher pres-
sures.33,34 In a study on 49 patients treated for urothelial
carcinoma using hydrostatic bladder distention, England
et al. reported a 100% success rate of hemostasis in nine
patients with gross hematuria.35 Likewise, Hammonds
et al. reported successful hemostasis in eight out of eight
patients treated with pressures of 115–145 cm H2O for
© 2013 The Japanese Urological Association
Therapeutic options for hematuria
6 h.34 Over a decade later, in 1986, Antonsen et al. studied
the effect of hydrostatic bladder distention on both hema-
turia and tumor necrosis in 18 patients with severe bleed-
ing.36 A total of 12 patients showed cessation of hematuria
within 1–5 days after treatment, with a recurrence of
bleeding after a mean of 3 months. Despite these good
response rates, no further publications on the Helmstein
bladder distention technique were found by the literature
search. In the initial study, Helmstein observed two cases
of bladder rupture and one perforation through an ulcerat-
ing tumor.31 Bladder rupture was only a very rare compli-
cation when pressure was limited to 10–25 cm H2O
above diastolic blood pressure. Abdominal pain, nausea,
temporary incontinence and pyrexia were reported more
commonly.34,36,37
Information on hydrostatic bladder distention is unfortu-
nately limited to these few studies. In all cases, catheters for
bladder irrigation were inserted after the procedure until the
urine became clear; no studies compared the success rate of
hydrostatic bladder distention followed by bladder irrigation
with bladder irrigation alone. Bearing these limitations in
mind, and in view of the need for anesthesia when using this
technique, hydrostatic pressure treatment of intractable
hematuria is of doubtful value.
Urinary diversion
In their 2009 review, Ghahestani et al. suggested that
urinary diversion might be a treatment option for intractable
hematuria caused by tumor sloughing.38 By excluding the
bladder from the urinary tract, internal blood tamponade can
be carried out. Contact of the bladder mucosa with urine
urokinase, with the enhanced risk of bleeding, is also pre-
vented. This procedure might also make the bladder acces-
sible for other treatment options, such as formalin
instillation, with a reduced risk.
Only one study was found by the literature search where
urinary diversion was used: Pomer et al. treated 16 patients
with severe intractable hemorrhagic cystitis after radio-
therapy (2 of them with bleeding tumors) by cutaneous
ureterostomy.39 A total of 11 patients remained hemorrhage-
free and three had only slight intermittent hematuria. No
cases of relapse requiring treatment were observed during
follow up.
No literature was found where the outcome of urinary
diversion without cystectomy (e.g. ileal conduit, pouch, ure-
terocutaneostomy) was described for cases of intractable
hematuria. The option of urinary diversion alone in high-risk
cases or patients refusing cystectomy is thus debatable, but
retention of large tumor masses in the absence of cystectomy
might also pose a risk of further complications. Palliative
cystectomy with consequent urinary diversion might be a
highly invasive intervention, but it is considerably easier and
faster than curative cystectomy.
655
D ABT ET AL.
Hypofractionated radiotherapy
Irradiation has been examined for the control of hematuria
in patients with bladder carcinoma since the late 1960s.40 In
1979, Chan et al. reported on seven patients, five with
intractable hemorrhage and two with ureteral obstruction,
whose medical conditions prevented surgery.41 Using up to
three doses of 10 Gy with 12 ¥ 12 cm portals, they found
prompt cessation of bleeding in all cases for 2–8 months
(mean 5 months). Side-effects were mild (diarrhea, nausea
and vomiting for 3–4 days after therapy), and there were no
long-term complications. Fossa and Hosbach treated 39
patients with advanced bladder carcinoma with radiotherapy
(3 Gy ¥ 10 over 2 weeks) palliatively, and reported a marked
improvement of hematuria.42
In 1999, Jose et al. treated 65 patients with weekly 6-Gy
fractions up to a total of 30–36 Gy while investigating a low
toxicity regimen for palliative bladder radiotherapy in
patients with poor performance status. There was good
tumor response and local control, but just seven of 14
patients with hematuria were controlled by the treatment.
The main acute toxicity was urinary frequency (up to hourly
at the peak of the reaction) in seven patients, and urinary
obstruction in one. Late toxicity amongst the 16 patients
who were evaluable after 1 year included four patients with
persistent frequency, one with severe hematuria and one
with a bladder capacity <100 mL. One patient experienced
late bowel and bladder morbidity.43
Information on the use of low-dose radiotherapy for the
treatment of intractable hematuria is restricted to these few
studies. The rate of success is unclear: while tumor control
should lead to control of hematuria, the latter can also be a
side-effect of the irradiation itself. Additionally, the method
seems too elaborate to come into routine use.
Embolization
In 1974, Hald and Mygind were the first to report on uni-
lateral hypogastric artery embolization for the treatment of
intractable hematuria in a patient with bladder carcinoma.44
They occluded the hypogastric artery and stopped bleeding
using pieces of the patient’s vastus lateralis muscle. They
reported disappearance of the tumor at cystoscopy and only
moderate side-effects (tenderness and induration of the
gluteal region and the back of the thigh, and transient
urgency). Subsequent studies using embolization were
reviewed by McIvor in 1982, who described 35 patients with
an overall response rate of 92% regardless of time to
relapse.45 In 1988 Appleton et al. reported results on eight
patients with bladder hemorrhage as a result of carcinoma
who were treated with selective embolization. Effective
control was achieved in six patients and partial control in
two patients, without clinically relevant side-effects.46
Selective embolization now appears to be a widely used
method of treating persistent hematuria caused by carcino-
656
mas of the bladder. Its popularity might be a result of the
perceived low risk of serious side-effects, although infor-
mation on the frequency of complications is lacking. There
have only been a few reports of severe complications:
Hietala47 and Sieber48 reported necrosis of the bladder after
embolization of an internal iliac artery in patients with
severe pelvic trauma, but similar complications were not
seen after treatment of hematuria. The risk of gluteal
necrosis, particularly known by patients undergoing
embolization for pelvic trauma, can be avoided by selec-
tive embolization of the anterior trunk of the internal iliac
artery, sparing the gluteal branches.49–51 The most common
problems are pain in the gluteal region and the back of the
thigh, as well as transient voiding dysfunction, as initially
reported by Hald and Mygind.44 The complication rate
appears to have been further reduced by selective and
super-selective embolization brought about by technical
improvement of catheters and occlusion.46,52–54 Rand-
omized or prospective studies have still to be carried out,
however.
Intra-arterial chemoperfusion
with mitoxantrone
Mitoxantrone is a chemotherapeutic agent that causes DNA
cross-linking and blocking of the cell cycle. Mitoxantrone
perfusion for the treatment of intractable hematuria was
described by Textor et al. in 2000.55 In a non-randomized
clinical trial, 15 patients treated with standard arterial
embolization were compared with 15 patients treated by
selective and super-selective perfusion of the tumor-
supplying vessels with 20 mg/m2 body surface area mitox-
antrone over 1–2 h, with a mean of two applications each.
Complete control of the hemorrhage was achieved in 12/15 of
the patients with embolization and 14/15 of the patients with
chemoperfusion. Hemorrhage stopped within 24 h in
embolization patients and after 4–15 days (mean 10 days) in
chemoperfusion patients. The authors reported recurrence of
hemorrhage in 4/13 embolization patients and 3/14 of che-
moperfusion patients. Major complications were only
observed in embolized patients (7/22). Side-effects of mitox-
antrone were temporary nausea, vomiting and pyrexia. The
authors described a significantly reduced occurrence of post-
therapeutic pain as a major advantage of mitoxantrone che-
moperfusion (6/31 compared with 20/22 in the embolization
group) and concluded that intra-arterial chemoperfusion
using mitoxantrone is an effective therapy in patients with
intractable gross hematuria. However, because of the delayed
effect of chemoperfusion, they recommended standard
embolization therapy in patients with life-threatening bleed-
ing, which might have led to selection bias in this non-
randomized study. Mitoxantrone chemoperfusion seems to
be a valuable therapeutic option, and it is therefore all the
more surprising that the literature search did not find
© 2013 The Japanese Urological Association
 Therapeutic options for hematuria

Table 4 Summary of therapeutic options for intractable hematuria

Treatment Reported Reported duration Anestheia required Complications
response of treatment (incidence and
rate (%) severity combined)
EACA 66–100 3–21 days No Mild
Formalin 71–100 1–5 days Yes Severe
Alum 50–100 1–3 days No Mild
Prostaglandin 60 1–5 days No Mild
Hydrostatic pressure 50–100 1–5 days Yes Severe
Urinary diversion 69 Single treatment Depending on method Severe
Hypofractionated radiotherapy 50–100 Up to several weeks No Mild
Embolization/arterial occlusion 75–100 Single treatment Local anesthetics Mild
Chemoperfusion (Mitoxantrone) 93 Single treatment Local anesthetics Mild

any other studies evaluating this method for treatment of
hemostasis.
Discussion
Alternative techniques for hemostasis in advanced bladder
cancer have been poorly studied in patients who cannot be
treated with the well-established methods of irrigation,
endoscopic coagulation and cystectomy. The reasons might
lie in the sporadic use of these treatments and the short life
expectancy of the patients. Even so, it is remarkable that all
nine methods reviewed above have not been systematically
investigated in studies comparing them with the efficacy and
safety of the well-established approaches, in particular with
irrigation alone.
Comparison of the success rates of the different published
studies is limited by the lack of generally accepted defini-
tions of success and relapse, and the difficulty in assessing
the severity and cause of bleeding. Table 4 attempts to sum-
marize published response rates, treatment periods and
complications.
Alternative methods for hemostasis in intractable hema-
turia are almost always described as options for patients
where anesthesia and surgery pose a high risk. However,
invasiveness, complexity and risks of some of the alternative
approaches do not always seem to be lower. Thus, intravesi-
cal formalin treatment and hydrostatic bladder distention
cannot be carried out without anesthesia, are time-
consuming, must frequently be carried out more than once
and carry substantial risks. For these reasons, they are rarely
used in routine clinical practice.
The use of orally administered EACA appears at first
sight to be practicable and simple. However, its effectiveness
in treating recurrent hematuria is uncertain based on the
results of the available studies, and its possible risks should
not be underestimated in view of the fact that the relevant
patient population is very susceptible both to thromboem-
bolic events and to renal complications. Thus, screening for
risk factors and seeking advice from a hematologist are
necessary for every patient for whom administration of
EACA is considered.
Hypofractionated radiotherapy has been reported by some
authors to result in almost complete cessation of hematuria
caused by bladder carcinoma. Critical examination of the
literature showed, however, that several applications are
usually necessary, and that treatment might be required for
up to several weeks. This might be suitable for treatment of
subacute and recurrent hematuria, and prophylaxis of bleed-
ing, but would not seem appropriate for cases of acute bleed-
ing, or for patients receiving palliative cancer therapy.
Alum instillation seems to be a promising therapeutic
option for treatment of intractable hematuria. Alum can be
easily instilled without anesthesia and can thus be used to
supplement bladder irrigation, which is carried out routinely
in almost every case of gross hematuria. The success of
alum instillation appears very promising and is associated
with low risk, except for patients with renal dysfunction,
where caution is required. In contrast, prostaglandin instil-
lation for the treatment of hematuria caused by bladder
carcinoma has hardly been investigated. However, because
of its advantageous risk profile, prostaglandin instillation
might be considered as an alternative for alum where
response is inadequate or in patients with renal dysfunction.
In the case of inoperable patients with acute or hyperacute
hematuria, the possibility of interventional radiology seems
to be a very interesting option. No anesthesia is required,
and cessation of bleeding occurs quickly and can be main-
tained. Although embolization has been reported to have
serious side-effects, the complication rate (particularly post-
interventional pain) appears to have been reduced by selec-
tive and super-selective embolization brought about by
technical improvement of catheters and occlusion. Intra-
arterial chemoperfusion with mitoxantrone might be a
promising variant of conventional embolization, although it

© 2013 The Japanese Urological Association 657

D ABT ET AL.

Hematuria in
advanced CHRONIC Radiotherapy
bladder cancer

ACUTE
Chemoperfusion
(mitoxantrone)
Oral epsilon-
Irrigation Additionally aminocaproic
acid Urinary diversion
Persistent or with cystectomy
recurrent

Transurethral TUR-B not

possible Cystectomy
resection
not possible
Persistent or
recurrent
Urinary diversion
without
Renal cystectomy
insufficiency

Alum Prostaglandin Persistent or

recurrent

Persistent or
recurrent

Embolization / Fig. 1 Decision tree for the treatment

arterial occlusion Formalin
of intractable hematuria.

has been insufficiently studied. Based on the results to date,
it would not appear to be the method of choice in hyperacute
bleeding because of the greater time required to achieve
hemostasis as compared with embolization. However, there
are fewer side-effects associated with this treatment.
The present discussion shows that relevant alternative
treatment options for intractable hematuria are available.
However, the effectiveness and risk profiles of these
methods remain uncertain because of the lack of informa-
tion. Thus, standard treatment procedures for recurring or
intractable gross hematuria always have to be considered
during the process of treatment. Patients initially refusing
surgery might reconsider this option in the face of prolonged
hospitalization or repeated, painful bladder tamponade.
Patients initially classified as inoperable because of their
poor general state condition might be optimized by adequate
medical therapy and prepared for surgery. Thus, our pro-
posed decision tree (Fig. 1) for the treatment of hematuria in
advanced bladder cancer also includes standard treatments.
In summary, treatment of intractable hematuria in patients
with inoperable bladder carcinoma is still a challenging and
often frustrating matter. We suppose the decision to use
alternative treatment options must be suited to each patient,
and their particular problems and risks. In our opinion, alum
instillation and interventional radiological treatment seem to
be the most reasonable solutions where, after critical con-
sideration, the patient cannot be treated by irrigation,
transurethral resection or palliative cystectomy.
References
1 Mc Nichol GP, Fletcher AP, Alkjaersig N, Sherry S. The
absorption, distribution, and excretion of
epsilon-aminocaproic acid following oral or intravenous
administration to man. J. Lab. Clin. Med. 1962;
59: 15.
2 Vega R, Shanberg AM, Malloy TR. The use of epsilon
aminocaproic acid in sickle cell trait hematuria. J. Urol.
1971; 105: 552–3.
3 Stefanini M, English HA, Taylor AE. Safe and effective,
prolonged administration of epsilon aminocaproic acid in
bleeding from the urinary tract. J. Urol. 1990; 143:
559–61.
4 Biswas CK, Milligan DA, Agte SD, Kenward DH, Tilley
PJ. Acute renal failure and myopathy after treatment with
aminocaproic acid. Br. Med. J. 1980; 28:
115–16.
5 Manjunath G, Fozailoff A, Mitcheson D, Sarnak MJ.
Epsilon-aminocaproic acid and renal complications: case
report and review of the literature. Clin. Nephrol. 2002; 58:
63–7.
6 Whittaker JR, Freed SZ. Effects of formalin on bladder
urothelium. J. Urol. 1975; 114: 866–70.

658 © 2013 The Japanese Urological Association


7 Kumar S. Effect of intravesical formalin on the urothelium.
Br. J. Urol. 1979; 51: 375–7.
8 Brown RB. A method of management of inoperable
carcinoma of the bladder. Med. J. Aust. 1969;
1: 23–4.
9 Fair WR. Formalin in the treatment of massive bladder
hemorrhage. Techniques, results, and complications.
Urology 1974; 3: 573–6.
10 Giannakopoulos X, Grammeniatis E, Chambilomatis P,
Baltogiannis D. Massive haemorrhage of inoperable bladder
carcinomas: treatment by intravesical formalin solution. Int.
Urol. Nephrol. 1997; 29: 33–8.
11 Ferrie BG, Rundle JS, Kirk D, Paterson PJ, Scott R.
Intravesical formalin in intractable haematuria. J. Urol.
1985; 91: 33–5.
12 Godec CJ, Gleich P. Intractable hematuria and formalin.
J. Urol. 1983; 130: 688–91.
13 Spiro LH, Hecht H, Horowitz A, Orkin L. Formalin
treatment for massive bladder hemorrhage. Complications.
Urology 1973; 2: 669–71.
14 Choong SK, Walkden M, Kirby R. The management
of intractable haematuria. BJU Int. 2000; 86:
951–9.
15 Ostroff EB, Chenault OW Jr. Alum irrigation for the
control of massive bladder hemorrhage. J. Urol. 1982; 128:
929–30.
16 Gosselin RE, Hodge HC, Smith RP, Gleason MN.
Clinical Toxicology of Commercial Products. Acute
Poisoning. Toxicity Information About Selected
Ingredients. The Williams & Wilkins Co., Baltimore, MD,
1976.
17 Goel AK, Rao MS, Bhagwat AG, Vaidyanathan S,
Goswami AK, Sen TK. Intravesical irrigation with alum for
the control of massive bladder hemorrhage. J. Urol. 1985;
133: 956–7.
18 Goswami AK, Mahajan RK, Nath R, Sharma SK.
How safe is 1% alum irrigation in controlling
intractable vesical hemorrhage? J. Urol. 1993; 149:
264–7.
19 Arrizabalaga M, Extramiana J, Parra JL, Ramos C,
Díaz González R, Leiva O. Treatment of massive
haematuria with aluminous salts. Br. J. Urol. 1987; 60:
223–6.
20 Kennedy C, Snell ME, Witherow RO. Use of alum to
control intractable vesical haemorrhage. Br. J. Urol. 1984;
56: 673–5.
21 Nurmi M, Puntala P, Torniainen K. Alum irrigation in the
treatment of severe haemorrhage from the bladder. Ann.
Chir. Gynaecol. 1987; 76: 173–5.
22 Praveen BV, Sankaranarayanan A, Vaidyanathan S. A
comparative study of intravesical instillation of 15(s) 15 Me
alpha and alum in the management of persistent hematuria
of vesical origin. Int. J. Clin. Pharmacol. Ther. Toxicol.
1992; 30: 7–12.
23 Schootstra R, van Driel MF, Hassankhan R et al. The use
of an alum irrigation in the treatment of massive bladder
haemorrhage. Pharm. Weekbl. Sci. 1989; 11: 175–8 (fulltext
not available).
© 2013 The Japanese Urological Association
Therapeutic options for hematuria
24 Phelps KR, Naylor K, Brien TP, Wilbur H, Haqqie SS.
Encephalopathy after bladder irrigation with alum: case
report and literature review. Am. J. Med. Sci. 1999; 318:
181–5.
25 Murphy CP, Cox RL, Harden EA, Stevens DA, Heye MM,
Herzig RH. Encephalopathy and seizures induced by
intravesical alum irrigations. Bone Marrow Transplant.
1992; 10: 383–5.
26 Perazella M, Brown E. Acute aluminum toxicity and alum
bladder irrigation in patients with renal failure. Am. J.
Kidney Dis. 1993; 21: 44–6.
27 Modi KB, Paterson PJ. Alum irrigation in massive bladder
hemorrhage in severe renal failure. Am. J. Kidney Dis.
1988; 12: 233–5.
28 Shoskes DA, Radzinski CA, Struthers NW, Honey RJ.
Aluminum toxicity and death following intravesical alum
irrigation in a patient with renal impairment. J. Urol. 1992;
147: 697–9.
29 Roberts NB, Williams P. Serum aluminium measurement
by DC plasma emission spectrometry. Ann. Clin. Biochem.
1988; 2: 169–75.
30 Fleming LW, Steward WK, Fell GS, Halls DJ. The effect of
oral aluminium therapy on plasma aluminium levels in
patients with chronic renal failure in an area with low water
aluminium. Clin. Nephrol. 1982; 17: 222–7.
31 Helmstein K. Treatment of bladder carcinoma by a
hydrostatic pressure technique. Report on 43 cases. Br. J.
Urol. 1972; 44: 434–50.
32 Holstein P, Jacobsen K, Pedersen JF, Sorensen JS.
Intravesical hydrostatic pressure treatment: new method for
control of bleeding from the bladder mucosa. J. Urol. 1973;
109: 234–6.
33 Hansen RI, Djurhuus JC, Nerstrom B. Hydrostatic pressure
treatment for carcinoma of the bladder. A clinical and
urodynamic evaluation of the effect on bladder hemorrhage
and fibrosis in irradiated patients. Scand. J. Urol. Nephrol.
1976; 10: 209–13.
34 Hammonds JC, Williams JL, Fox M. The control of severe
bleeding from the bladder by intravesical hyperbaric
therapy. Br. J. Urol. 1974; 46: 309–12.
35 England HR, Rigby C, Shepheard BG, Tresidder GC,
Blandy JP. Evaluation of Helmstein’s distension method
for carcinoma of the bladder. Br. J. Urol. 1973; 45:
593–9.
36 Antonsen HK, Lose G, Højensgård JC. The Helmstein
bladder distension treatment for tumours and severe
bleeding. Int. Urol. Nephrol. 1986; 18: 421–7.
37 Glashan RW. A critical review of the management of
bladder neoplasia using a modified form of Helmstein’s
pressure therapy. Br. J. Urol. 1975; 47: 57–66.
38 Ghahestani SM, Shakhssalim N. Palliative treatment of
intractable hematuria in context of advanced bladder
cancer: a systematic review. Urol. J. 2009; 6:
149–56.
39 Pomer S, Karcher G, Simon W. Cutaneous ureterostomy
as last resort treatment of intractable haemorrhagic
cystitis following radiation. Br. J. Urol. 1983; 55:
392–4.
659
D ABT ET AL.
40 Silber I, Bowles WT, Cordonnier JJ. Palliative treatment of
carcinoma of the urinary bladder. Cancer 1969; 23:
586–8.
41 Chan RC, Bracken RB, Johnson DE. Single dose whole
pelvis megavoltage irradiation for palliative control of
hematuria or ureteral obstruction. J. Urol. 1979; 122:
750–1.
42 Fosså SD, Hosbach G. Short-term moderate-dose pelvic
radiotherapy of advanced bladder carcinoma. A
questionnaire-based evaluation of its symptomatic effect.
Acta Oncol. 1991; 30: 735–8.
43 Jose CC, Price A, Norman A et al. Hypofractionated
radiotherapy for patients with carcinoma of the
bladder. Clin. Oncol. (R. Coll. Radiol.) 1999; 11:
330–3.
44 Hald T, Mygind T. Control of life-threatening vesical
hemorrhage by unilateral hypogastric artery muscle
embolization. J. Urol. 1974; 112: 60–3.
45 McIvor J, Williams G, Southcott RD. Control of severe
vesical haemorrhage by therapeutic embolisation. Clin.
Radiol. 1982; 33: 561–7.
46 Appleton DS, Sibley GN, Doyle PT. Internal iliac artery
embolisation for the control of severe bladder and prostate
haemorrhage. Br. J. Urol. 1988; 61: 45–7.
47 Hietala SO. Urinary bladder necrosis following selective
embolization of the internal iliac artery. Acta Radiol.
Diagn. 1978; 19: 316–20.
48 Sieber PR. Bladder necrosis secondary to pelvic artery
embolization: case report and literature review. J. Urol.
1994; 151: 422.
660
49 Yasumura K, Ikegami K, Kamohara T, Nohara Y. High
incidence of ischemic necrosis of the gluteal muscle after
transcatheter angiographic embolization for severe pelvic
fracture. J. Trauma 2005; 58: 985–90.
50 Silberzweig JE, Khorsandi AS. Occurrence of massive
gluteal muscle necrosis following transcatheter
angiographic embolization (TAE) to control pelvic
hemorrhage in 6 patients. J. Trauma 2006; 60:
686–7.
51 Auerbach AD, Rehman S, Kleiner MT. Selective
transcatheter arterial embolization of the internal iliac
artery does not cause gluteal necrosis in pelvic trauma
patients. J. Orthop. Trauma 2012; 26: 290–5.
52 Hayes MC, Wilson NM, Page A, Harrison GS. Selective
embolization of bladder tumours. Br. J. Urol. 1996; 78:
311–12.
53 Anand AK, Gupta SK, Ravi K, Ghosh D. Selective
embolization of internal iliac artery for massive
haemorrhage from bladder secondary to carcinoma. Clin.
Oncol. (R. Coll. Radiol.) 1991; 3: 348–50.
54 Olliff S, Thomas S, Karani J, Walters H. Superselective
embolization using a coaxial catheter technique. Br. J.
Radiol. 1990; 63: 197–201.
55 Textor HJ, Wilhelm K, Strunk H, Layer G, Dölitzsch C,
Schild HH. Locoregional chemoperfusion with
mitoxantrone for palliative therapy in bleeding bladder
cancer compared with embolization. Rofo 2000; 172:
462–6.
© 2013 The Japanese Urological Association