2009 THE AUTHORS.
JOURNAL COMPILATION 2009 BJU INTERNATIONAL
Mini Reviews
MANAGEMENT OF CYCLOPHOSPHAMIDE-INDUCED HAEMATURIA
MUKHTAR and WOODHOUSE
The management of cyclophosphamide-induced
BJUI BJU INTERNATIONAL
haematuria
Saheel Mukhtar and Christopher Woodhouse*
Departments of Urology, Kent and Canterbury Hospital, Canterbury, Kent, and *Royal Marsden Hospital, London, UK
Accepted for publication 6 October 2009
Haemorrhagic cystitis is a frequent
complication of treatment with
cyclophosphamide. It remains a
difficult clinical problem to treat,
compounded by the frailty of patient.
CYCLOPHOSPHAMIDE
Haemorrhagic cystitis is a frequent
complication of treatment with
cyclophosphamide. It remains a difficult
clinical problem especially as patients may
have metastatic disease, are often elderly and
may be unfit for surgery.
Cyclophosphamide (CP) is an
oxazaphospharine alkylating agent that
acts by cross-linking strands of DNA, thus
preventing the division of cells. It is a
frequently used chemotherapeutic agent for
treating breast cancer, B-cell lymphoma and
leukaemia. The immunosuppressive actions of
CP are used in conditioning before bone-
marrow transplantation, in the treatment of
rheumatoid arthritis and of systemic lupus
erythematosis.
Whilst the use of CP has significant benefits,
acrolein, a hepatic metabolite, is associated
with significant urological side-effects [1].
Excretion of acrolein in the urine produces
oedema, ulceration, haemorrhage and
necrosis of the urothelium [2,3]. In addition,
persistent infection with adenovirus or BK
virus in individuals with bone marrow
suppression might prevent mucosal healing.
Haemorrhagic cystitis (HC) is a frequently
reported complication of CP therapy (2–40%)
[4]. Treatment is difficult and can often be
compounded by significant comorbidities.
The haemorrhage is often worsened by
thrombocytopaenia (inherent in carcinomas,
and induced by CP) and a transfusion-induced
908
Furthermore, the preventative measures and
treatments available for CP-induced
haematuria have their own benefits and
disadvantages.
coagulopathy. Clinicians often become
reluctant to offer advanced treatments which
could exacerbate a difficult situation.
Herein we review the key preventative
measures and treatment options in the
management of CP-induced haematuria.
Preventative measures include the use
of irrigation solution [5], sodium-2-
mercaptoethane sulphonate (Mesna) and
potentially nuclear factor (NF)-κB inhibitors
[6]. The mainstay of treatment currently
consists of bladder irrigation with glycine
solution. This has the aim of reducing overall
bladder inflammation, and preventing
intravesical clot formation, which can
encourage further bleeding.
Other treatments of CP-induced haematuria
include sodium pentosan polysulphate (SPP),
intravesical formalin, intravesical alum
irrigation, hydrostatic pressure embolization,
and intravesical prostaglandins.
PREVENTATIVE MEASURES
BLADDER IRRIGATION
As a prophylactic measure, the insertion of a
catheter and use of continuous bladder
irrigation is no longer used. However, it was
more common before the introduction of new
prophylactic and treatment measures. One
retrospective study in 1995 [5] compared the
use of continuous bladder irrigation with
no bladder irrigation in 199 patients who
received cyclophosphamide ± busulfan
JOURNAL COMPILATION © 2 0 1 0 B J U I N T E R N A T I O N A L | 1 0 5 , 9 0 8 – 9 1 2 | doi:10.1111/j.1464-410X.2009.09132.x
KEYWORDS
cyclophosphamide, haematuria, sodium
pentosan polysulphate, sodium-2-
mercaptoethanesulphonate
in preparation for bone-marrow
transplantation. There was a significant
decrease in haematuria in patients
receiving irrigation (53%) compared with
the non-interventional group (23%,
P < 0.004).
A more recent retrospective non-randomized
study [7] compared patients having bladder
irrigation for 36 h with those who did not.
Both groups of 40 patients also received
treatment with Mesna, hyperhydration and
urinary alkalinization, whilst having
conditioning for bone-marrow
transplantation. The group receiving bladder
irrigation reported improvements across
several variables: a lower incidence of HC
(50% vs 32%; P = 0.11); a significant
reduction in the mean duration of HC (18 vs
10 days; P = 0.02); a shorter duration of
hospitalization (39.6 vs 30.2 days; P < 0.001);
and a lower incidence of late-onset HC
(P = 0.001).
MESNA
The benefit of Mesna in preventing CP-
induced HC is well documented and it is used
routinely in bone marrow treatment centres
as a prophylactic agent. An early prospective
randomized study [8] comparing Mesna
and forced diuresis showed a significant
reduction in the incidence of macroscopic
haematuria in bone marrow recipients in the
Mesna-treated group (61 patients, P < 0.05).
There was also no specific side-effects of
Mesna.
© 2010 THE AUTHORS

However, Mesna is limited in some regards;
most notably the half-life of Mesna is 90 min,
which is significantly shorter than the half-
life of CP (420 min). Consequently, Mesna
administration must be continuous
throughout the CP treatment. A study in 1991
[9] randomized 100 patients to receive Mesna
or forced saline diuresis. The patients were
undergoing bone-marrow transplant
conditioning with regimens including high-
dose CP. The incidence of severe haematuria
was 33% in the Mesna arm and 20% in the
hyperhydration arm (P = 0.31). This study
showed that Mesna and hyperhydration
are equally effective in preventing
CP-induced HC in bone marrow transplant
patients.
GLUTATHIONE AND AMIFOSTINE
Glutathione and amifostine are
cytoprotective agents which act to protect
normal tissues against the significant
side-effects of chemotherapeutic agents.
Amifostine is metabolized to an active form,
WR-1065, by alkaline phosphatase, which
is found on the plasma membrane. Both
substances act as free-radical scavengers and
provide significant protective effects to
haemopoietic progenitor cells.
It has also been shown that in Swiss male
mice, pre-treatment with amifostine or
glutathione prevents ifosfamide-induced
haematuria in a dose-dependent manner.
Acrolein-induced HC was also prevented
by systemic (intraperitoneal) or local
(intravesicular) pretreatment with glutathione
or amifostine, with the greatest protective
effect seen with local amifostine treatment
(2 mg/kg intravesicular; P < 0.05) [10].
NF-κB INHIBITORS
The inflammatory process in CP-induced
haematuria is mediated by several cytokines,
including TNF-α, interleukin-1 and
cyclooxygenase-2. It is believed that
transcription factors can up-regulate or down
regulate the production of these mediators.
One such transcription factor is NF-κB and so
NF-κB inhibitors such as sesquiterpene
lactone parthenolide might inhibit
inflammation.
A recent study [6] showed that intravesical
pretreatment with parthenolide inhibited
© 2010 THE AUTHORS
JOURNAL COMPILATION © 2010 BJU INTERNATIONAL
MANAGEMENT OF CYCLOPHOSPHAMIDE-INDUCED HAEMATURIA
bladder inflammation and overactivity in rats,
whilst in humans parthenolide has also
been shown to suppress the translocation
and translation of NF-κB, and reduce
cyclooxygenase-2 and interleukin-1
production. As a consequence, NF-κB
inhibitors might be used for preventing CP-
induced haematuria.
TREATMENT OPTIONS
SPP
Oral SPP has been shown to be effective as an
agent in managing interstitial cystitis [11]. A
recent study at the authors’ institution [12]
also showed that SPP is an effective agent in
the treatment of CP-induced haematuria and
haematuria induced by pelvic radiotherapy. In
31 of 51 patients the haematuria stopped and
10 were able to discontinue treatment. The
remaining 20 patients died from their
malignancy before adequate evaluation of
SPP therapy. The regimen suggested by that
report, and others, is 100 mg of SPP three
times daily for 1–8 weeks. Bladder washout
and irrigation are continued as necessary.
Once control is achieved, SPP is continued for
1 year and then gradually reduced.
SPP might exert its effects in several different
ways. These include the replacement of
surface glycosaminoglycans which might
have been lost due to CP treatment;
consequently, the bladder is then less
susceptible to bacterial infection. Another
postulated mechanism is the inhibition of
mast cell degranulation, resulting in a
decrease in the production of NF-κB,
resulting a dampening of the immune
response [13,14]. Oral SPP has been shown
not to have a detectable anticoagulant
activity, is safe and not toxic [15]. SPP has
been associated with thrombocytopenia
and thrombosis [16], the mechanism of
which is thought to be similar to that
associated with a heparin-induced
thrombocytopenia.
INTRAVESICAL FORMALIN
Formalin is used mainly as a histological
fixative but its properties extend to its use as
a preservative, disinfectant and an embalming
agent. It was first used as an intravesical
agent in 1969 and has subsequently been
used successfully to treat severe CP-induced
haematuria, as well as haematuria secondary
to carcinoma and radiotherapy [16–18].
Formalin is thought to cause the precipitation
of cellular proteins in the bladder mucosa.
This has the effect of occluding telangiectatic
vessels and capillaries [19]. If formalin is
absorbed into the systemic circulation it is
modified into formic acid, which results in the
inhibition of anaerobic glycolysis, hexokinase
and cholinesterase [20].
Formalin is a 37–41% solution of
formaldehyde and is diluted when used as an
intravesical agent. Formalin can be used in
varying concentrations but the principle is to
use the smallest possible concentration for
the shortest possible time [21]. Formalin can
be administered with a general anaesthetic or
under spinal anaesthesia, ensuring that the
patient is in a reverse Trendelenburg position.
The regimen advocated by Fair [22] involved
instilling a 1% solution of formalin for
10 min, followed by a washout of the bladder
with distilled water. This schedule was found
to be effective in a trial with 14 patients.
Other regimens have used differing
concentrations for varying lengths of time.
Unfortunately the higher concentrations and
higher duration of treatment have been
associated with several side-effects, ranging
from ureteric fibrosis, anuria and
incontinence, to acute tubular necrosis
leading to renal failure and death [18,22–24].
One of the more common side-effects of
formalin therapy is the development of
bladder fibrosis with subsequent urinary
frequency. Moreover, formalin might be
responsible for triggering bladder spasms in
the neurologically intact bladder, through
sensory stimulation of the bladder mucosa.
In addition, narrowing and rigidity of the
ureteric orifices can occur, leading to
potential hydronephrosis and reflux. Thus,
repeated instillations could lead to the
reflux of formalin into the kidneys. As a
consequence, a cystogram is essential to
exclude ureteric reflux before administering
formalin.
The effectiveness of formalin treatment is not
in doubt, with a high success rate of 80–92%
[16,17]. However, the risks of treatment,
especially with high concentrations, are
significant. Thus, it has been suggested
that it should be used as a treatment when
others have failed, and in individuals where
life-long symptoms will not be a significant
issue.
909
MUKHTAR and WOODHOUSE
HYPERBARIC OXYGEN
The micro-anatomical and pathophysiological
benefits of hyperbaric oxygen have been well
documented. Of these, most notable is the
reduction of inflammation brought about by
several mechanisms, including reduced
production of immunity and inflammatory
cytokines. Hyperbaric oxygen also stimulates
wound repair, increased fibroblast production
and collagen formation and capillary
angiogenesis [25–29]. This in turn creates the
correct circumstances for an ulcerated
bleeding point to heal.
Hyperbaric oxygen therapy is delivered by
inhalation of 100% oxygen in a hyperbaric
chamber with a pressure typically 1.4 to 3
times that of ambient [30]. Each treatment is
for 1 h per exposure and normobaric oxygen
is given between treatments. Treatments are
given with increasing intervals of normal air
between them, to avoid pulmonary oxygen
toxicity [31]. The haemoglobin becomes fully
saturated and the oxygen dissolved in the
plasma increases, which in turn leads to the
physiological changes described above. To
have this treatment the patient must be fit
enough to walk into the chamber and sit for
the duration. In practice, this is difficult when
the patient is sick and having bladder
irrigation.
Hyperbaric oxygen therapy has been shown to
be effective for CP-induced haematuria.
However, much of the research has focused on
the successful treatment of radiation-induced
haematuria and not CP-induced haematuria
[32]. A study in Sprague-Dawley rats showed
that hyperbaric oxygen was effective in
treating HC induced by CP, but it was not
effective as a preventative measure [33].
INTRAVESICAL ALUM IRRIGATION
Alum irrigation was first reported in 1982 in
the treatment of six patients and has been
discussed in several reports [34]. Alum is
thought to act by the inducing protein
precipitation at the cell surface, and in
interstitial spaces. As a result there is
decreased capillary permeability, contraction
of the intercellular space, vasoconstriction,
hardening of the capillary endothelium and a
reduction in oedema, inflammation and
exudate [35].
A 1% aluminium potassium sulphate solution,
made by dissolving potash in sterile distilled
910
water, is administered in a continuous
intravesical lavage of normal saline fluid.
This can be inserted into the bladder with
a whistle-tipped catheter under local
anaesthesia, thus avoiding the need for a
general anaesthetic.
Alum instillation has been found to be
effective in the treatment of HC caused by
TCC, chemotherapy and radiotherapy [36]. In
early work, eight patients aged 57–82 years
and with severe vesical bleeding had irrigation
for a mean of 3 days; the bleeding stopped in
all of them within this time [37].
However, in another report of five patients
who developed CP-induced haematuria,
despite intravenous hydration and diuretics,
only one treatment with alum was successful.
In addition, large hardened clots of blood and
alum precipitate necessitated the use of open
cystotomy for evacuation.
Alum irrigation has limited use in children
with HC. The provisos that a lower
concentration of irrigating solution is used,
that serum aluminium levels are monitored
regularly, and other investigations are
repeated frequently, limits its effectiveness
[38]. This is due to the risk of aluminium
toxicity, which can lead to numerous
symptoms including suprapubic pain and
bladder spasms, related to the acidity of the
irrigation fluid. More profound problems
include respiratory depression, renal failure,
ataxic seizures and even dementia. Whilst
these have not been reported with the use of
alum treatment in adults they remain a
concern in children, and hence the necessary
precautions in this age-group [38]. The
administration of alum irrigation is also
limited by the fact that most hospital
pharmacies might not stock this product and
so obtaining alum might not be possible.
EMBOLIZATION
The vasculature of the bladder is derived from
the internal iliac arteries, and attempts to
control intractable haematuria by using
embolization have had some success. It was
first reported in 1974 by Hald and Mygiand
[39] and a subsequent review of reports
showed successful control of severe
haematuria in 32 of 35 patients (92%) [40].
The internal iliac artery and its main branches
can be catheterized via the ipsilateral or
contralateral femoral artery, or from the left
JOURNAL COMPILATION
axillary artery. Embolization can then be
applied by the use of Gelfoam or coils [41,42].
It has also been done using a blood clot and
isobutyl-2-cyanoacrylate [43,44]. Selective
embolization works on the same principle as
embolization, but there is a greater degree of
control of specific blood vessels.
More recently, superselective embolization
has been used to treat severe intractable
haematuria. By using a microcatheter (2.5 F)
instead of an angiographic catheter (4 F),
together with a guidewire (≈1 mm) and using
a polyvinyl acetate embolization suspension
in the bladder arteries, a centre in Rome [44]
reported that it is a feasible technique. In
addition, it was reported that superselective
embolization is associated with a lower
recurrence rate of haematuria and a lower
degree of postembolization gluteal pain,
claudication or tissue necrosis [45,46].
However, the efficacy of embolization is
variable. In a short series of seven patients
who had embolization of the internal iliac
artery, with a follow-up was 6–12 months
[47], the haematuria was controlled in
four patients ‘permanently’, while three
had further episodes of haematuria
necessitating admission. Two of these
patients were managed conservatively,
whilst the third required a repeated course
of embolization.
In the authors’ limited experience,
embolization has never worked. The blood
supply of the bladder is so extensive that
adequate devascularization is difficult.
PROSTAGLANDINS
Several case reviews and case reports have
suggested a potential role for prostaglandins
in the treatment of severe HC, but the exact
mechanism of action is unclear. It might
act through several different mechanisms.
These include the induction of haemostasis
with platelet aggregation or by causing
vasoconstriction of vessels in the mucosa
and submucosa, through membrane
stabilization. Topical prostaglandin E2
(dinoprostone) has been shown to be
effective in controlling severe chronic HC
after CP therapy [48]. In addition, another
prostaglandin analogue, prostaglandin-F2α
(carboprost tromethamine) has been
reported to be effective in the treatment of
this HC. The occurrence of spasms as a side-
© 2010 THE AUTHORS
© 2010 BJU INTERNATIONAL

effect shows their potent effect on smooth
muscle in the bladder wall, and a similar
effect on vascular smooth muscle might
decrease blood flow locally. Promotion of
platelet aggregation by prostaglandin-E2
analogues or low concentrations of
carboprost might also reduce bleeding. In
addition, prostaglandins are thought to have
a protective effect against mucosal injury
mediated by oxidants.
HELMSTEIN’S BLADDER HYDRODISTENSION
The concept of bladder hydrodistension was
first reported in 1966 [49]. It was initially
described for the treatment of bladder
carcinomas but was adapted for use in
treatment in radiation-induced haematuria. It
has never been used in the treatment of CP-
induced haematuria and is probably only of
historical and theoretical interest.
CONCLUSION
There are several available preventative
measures and treatments available for CP-
induced haematuria. Each one has benefits
and disadvantages there is no ideal
management option. This is worsened by the
fact that patients could have metastatic
disease, or be elderly and unfit for surgery. Of
all the preventative options that are available
Mesna appears to have the greatest
effectiveness in the treatment of CP-induced
HC. Mesna is used routinely in bone marrow
treatment centres as a prophylactic agent.
However, it is limited by its shorter half-life
(90 min) than that of CP (7 h). Oral SPP and
supportive measures until it is effective
should always be the first line treatment. All
of the other treatments have major side-
effects or are difficult to instigate, or both.
CONFLICT OF INTEREST
None declared.
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Correspondence: Saheel Mukhtar, Department
of Urology, Kent and Canterbury Hospital,
Canterbury, Kent CT1 3NG, UK.
e-mail: smukhtar2005@googlemail.com
Abbreviations: CP, cyclophosphamide;
HC, haemorrhagic cystitis; Mesna,
sodium-2-mercaptoethane sulphonate; NF,
nuclear factor; SPP, sodium pentosan
polysulphate.
© 2010 THE AUTHORS
© 2010 BJU INTERNATIONAL