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Incidence and prevention of bladder toxicity from cyclophosphamide in the treatment of rheumatic diseasesA data-driven review.

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ARTHRITIS & RHEUMATISM
Vol. 62, No. 1, January 2010, pp 9–21
DOI 10.1002/art.25061
© 2010, American College of Rheumatology
REVIEW
Incidence and Prevention of Bladder Toxicity From
Cyclophosphamide in the Treatment of Rheumatic Diseases
A Data-Driven Review
Paul A. Monach, Lindsay M. Arnold, and Peter A. Merkel
agents in carrying an increased risk of both common and
opportunistic infections, teratogenicity, sterility, and
secondary hematologic malignancy. Cyclophosphamide,
and the related agent ifosfamide, can also cause toxicity
to the urinary bladder, including hemorrhagic cystitis
and bladder cancer (10,11). The prospect of preventing
these serious bladder toxicities with mesna (2mercaptoethanesulfonic acid) has led to the common
use of this agent, which is considered safe and is
frequently recommended in textbooks and clinical
guidelines for routine use (5,12–14).
Thus, it is relevant and timely to review the data
on the bladder toxicity of cyclophosphamide, with a
focus on the rheumatic diseases, in order to review the
rationale and evidence for prescribing mesna to prevent
such bladder toxicity and to outline practical recommendations for the use of mesna in the rheumatology setting.
Introduction
Cyclophosphamide has been used since the 1960s
to treat severe manifestations of autoimmune inflammatory diseases such as systemic lupus erythematosus,
systemic vasculitis, and systemic sclerosis (scleroderma)
(1–4). This alkylating agent, which is considered to be
the “strongest” medication commonly used by rheumatologists, has well-established efficacy in lupus nephritis
and systemic necrotizing vasculitis, conditions for which
it became regarded as the standard of care by the 1980s
(1,2,5). Cyclophosphamide continues to be used regularly, in clinical practice and in clinical trials, to treat
other severe manifestations of lupus, lung disease in
scleroderma, many types of vasculitis, and other systemic
inflammatory diseases (4,6–9). Despite the development
of and interest in other agents to treat severe inflammatory disease, cyclophosphamide is unlikely to be consigned to the status “of historic interest only” any time
soon.
Although the doses of cyclophosphamide prescribed in autoimmune diseases are lower than the doses
typically prescribed for cancer chemotherapy, in rheumatic diseases the drug is often used for extended
periods of time and, due to a high rate of clinical relapse,
treatment often requires repeated courses. Cyclophosphamide resembles many other chemotherapeutic
Medical literature search strategy
Articles related to the association of cyclophosphamide with hemorrhagic cystitis and bladder cancer were initially identified using the following search
parameters in PubMed (www.ncbi.nlm.nih.gov): [cyclophosphamide AND (cystitis OR bladder cancer) AND
(vasculitis OR arteritis OR granulomatosis OR rheumatoid OR lupus OR scleroderma OR non-Hodgkin’s)].
This search yielded 157 articles, the abstracts of which
were reviewed, yielding 19 articles that either contained
primary data on more than a few patients or reviewed
older literature. A review of the references in these 19
articles revealed only 2 other studies containing additional primary data.
Articles related to the use of mesna to prevent
cystitis were initially identified using the following
search parameters in PubMed: [(cyclophosphamide OR
Dr. Monach’s work was supported in part by an Arthritis
Investigator Award from the Arthritis Foundation.
Paul A. Monach, MD, PhD, Lindsay M. Arnold, PharmD,
BCPS, Peter A. Merkel, MD, MPH: Boston University School of
Medicine and Boston Medical Center, Boston, Massachusetts.
Address correspondence and reprint requests to Paul A.
Monach, MD, PhD, Vasculitis Center, E5, Boston University School of
Medicine, 72 East Concord Street, Boston, MA 02118. E-mail:
pmonach@bu.edu.
Submitted for publication February 24, 2009; accepted in
revised form September 25, 2009.
9
10
MONACH ET AL
ifosfamide) AND cystitis AND mesna]. This search
yielded 164 articles, the abstracts of which were reviewed, yielding 15 articles that included primary data or
reviewed the data (much of it unpublished) related to
US Food and Drug Administration (FDA) approval of
oral mesna (15). An evaluation of the articles referenced
in this latter review as well as in a clinical practice
guideline for the use of chemotherapy and radiotherapy
protectants (16) yielded only 2 articles containing additional primary data. A search of the Cochrane Database
of Systematic Reviews using “mesna” as a key word
yielded 4 articles, none of which was related to cyclophosphamide or ifosfamide and bladder toxicity. A
search using “cyclophosphamide” as a key word yielded
101 articles, only 1 of which focused on adverse events
(secondary malignancies); a review of this article did not
identify additional studies relevant to the present topic.
Information pertaining to the pharmacology of
cyclophosphamide, its metabolites, and mesna was obtained from textbooks and reviews and from references
obtained from these sources.
Cyclophosphamide pharmacology
Cyclophosphamide is an oxazophosphorine alkylating agent that causes crosslinking of DNA strands,
thereby preventing cell division and causing cell death.
Cyclophosphamide has major activity against rapidly
proliferating cells that is not cell cycle specific, and its
mechanism in treating autoimmune disease is not well
understood. Mechanisms postulated include apoptosis
induction, decreased IgG production due to B cell
suppression, and decreased production of adhesion molecules and cytokines (17).
Cyclophosphamide is a prodrug metabolized via
the hepatic P450 enzymatic system to both active and
inactive metabolites, as outlined in Figure 1. Among
these, the inactive (nonalkylating) metabolite acrolein
(18) is presumed to be the cause of cystitis, based on its
subsequent excretion into and concentration in the urine
and on direct evidence of acute bladder toxicity in
animals (19–21). Acrolein is considered likely to be the
cause of bladder cancer as well, although there is no
direct evidence to support this. The great majority of
bladder cancers that arise following cyclophosphamide
treatment, as with idiopathic bladder cancers, are transitional cell carcinomas, but rare cases of sarcomas and
other types of bladder carcinoma have been reported
(22–24).
Oral and intravenous (IV) administration of cyclophosphamide have been reported to produce similar
Figure 1. Chemical structures, metabolism, and interactions of cyclophosphamide and mesna. Phosphoramide mustard is the main active
(alkylating) metabolite of cyclophosphamide, and acrolein is the
inactive metabolite thought to be responsible for bladder toxicity.
Conversion of aldophosphamide to phosphoramide mustard and acrolein occurs in the plasma. Acrolein is then excreted into the urine,
and phosphoramide mustard undergoes spontaneous degradation.
Both mesna and dimesna are excreted in the urine, and one-third of
excreted dimesna is converted back to mesna in the renal tubule. The
periods of time listed with mesna and dimesna indicate the length of
time after administration that these agents appear in the bladder.
peak concentrations (25), with oral bioavailability of
75–100%. Cyclophosphamide is primarily cleared
through the liver, with only 10–15% of the drug excreted
unchanged in the urine, although urine is the site of
excretion of numerous inactive metabolites (17,18). Tubular reabsorption is high given its nonionized nature,
resulting in significant elimination via hepatic metabolism. No change in the rate of toxicity among patients
with liver disease has been reported (17). A low level of
alkylating activity from unbound metabolites is typically
observed in the plasma for at least 24 hours, but this may
be significantly prolonged in patients with severe renal
failure. However, the necessity for dose adjustments in
CYCLOPHOSPHAMIDE AND MESNA
11
Table 1. Incidence of hemorrhagic cystitis following treatment with daily oral cyclophosphamide (CYC)*
No. of patients
Total CYC
dose, gm‡
CYC duration,
months‡
Author, year (ref.)
Disease(s)
CYC dose
Mesna
Total
Cystitis†
Mean
Range
Mean
Range
Aptekar et al, 1973 (37)
Townes et al, 1976 (39)
Plotz et al, 1979 (35)§
Austin et al/Carette et al,
1986/1983 (1/36)
Stillwell et al, 1988 (32)
Pederson-Bjergaard et al, 1988 (10)
Silver et al, 1993 (31)
Radis et al, 1995 (38)§
Talar-Williams et al, 1996 (33)
Reinhold-Keller et al, 2000 (34)
SLE, WG, RA
RA
SLE, RA
SLE
1.3–1.5 mg/kg
2 mg/kg
1–4 mg/kg
1–4 mg/kg
No
No
No
No
46
24
54
40
10
4
7
6
28
26
48
ND
6–74
19–34
2–152
ND
15
7
28
ND
3–41
5–9
1–91
ND
WG
NHL
SSc
RA
WG
WG
1–2 mg/kg
100 mg/m2
1–2 mg/kg
50–150 mg
2 mg/kg
2 mg/kg
No
No
No
No
No
Yes
111
471
14
119
145
142
17/45¶
33#
2
14
42/51**
17††
101
ND
ND
53
124
129
5–531
ND
ND
ND
ND
42–350
38
ND
9
32
37
29
4–144
ND
6–12
ND
ND
9–77
* There was some overlap of patients in the studies by Plotz et al, Austin et al, and Carette et al. SLE ⫽ systemic lupus erythematosus; WG ⫽
Wegener’s granulomatosis; RA ⫽ rheumatoid arthritis; ND ⫽ no data; NHL ⫽ non-Hodgkin’s lymphoma; SSc ⫽ systemic sclerosis.
† The definition of cystitis differed between studies; cystoscopy was not required for the diagnosis, except as noted otherwise.
‡ Among the subset of patients with cystitis, unless noted otherwise.
§ Data for CYC dose and duration were based on all patients in the study; no data were available for the subset of patients with cystitis.
¶ In the smaller number of patients (n ⫽ 17), cystitis was defined by gross hematuria or was confirmed by cystoscopy; the larger number of patients
(n ⫽ 45) was calculated based on the percent of patients with hematuria in whom cystitis was confirmed by cystoscopy (65%).
# Defined by gross hematuria or confirmed by cystoscopy.
** In the smaller number of patients (n ⫽ 42), cystitis was confirmed by cystoscopy; the larger number of patients (n ⫽ 51) was calculated based
on the percent of patients with hematuria in whom cystitis was confirmed by cystoscopy (70%).
†† Confirmed by cystoscopy.
patients with renal dysfunction is not well documented
but is commonly advised (5,17,18,26).
For the treatment of autoimmune diseases, cyclophosphamide dosing is typically 1.5–2 mg/kg/day when it
is provided orally or 500–1,000 mg/m2 IV in monthly or
biweekly pulse-dose regimens (3,5,7,8,27–30). For comparison, treatment of malignancies often involves doses
⬎1,000 mg/m2 administered on weekly or biweekly
schedules in combination with other drugs or radiation
therapy. It is thus difficult to extrapolate outcomes and
toxicities from the oncology literature to patients given
cyclophosphamide for the treatment of autoimmune
diseases.
Association between treatment with daily oral
cyclophosphamide and hemorrhagic cystitis
The mode of cyclophosphamide administration
that has generated the most concern with regard to
bladder toxicity is daily oral dosing, because the duration
of treatment and the total cumulative exposure are
generally higher compared with intermittent IV dosing,
and hydration and bladder evacuation cannot be assured.
The development of hemorrhagic cystitis during
treatment with oral cyclophosphamide has been evaluated in 3 large cohorts of patients with Wegener’s
granulomatosis (WG) and in additional cohorts of patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), or non-Hodgkin’s lymphoma
(NHL) (1,10,31–39) (Table 1). The strategy of encouraging patients to drink large volumes of fluids was
specifically mentioned in a few studies (32,35,37), but
compliance with these directions was not assessed. The
methods of diagnosing hemorrhagic cystitis differed
somewhat among these studies, but in all cases the initial
screening involved routine urinalyses during the period
of treatment. In the studies in which the diagnosis was
usually (32,33) or always (34) confirmed by cystoscopy,
the incidence of hemorrhagic cystitis ranged from 12%
to 41%. The mean cyclophosphamide exposure of patients who had hemorrhagic cystitis was ⬎100 gm over a
mean of ⬎30 months, with a wide range of both the total
dose and the duration of treatment (Table 1). Few
studies provide any information about the severity of
hemorrhagic cystitis, in terms of either the degree or
duration of discomfort or the need for transfusion. From
these limited data, cystitis severe enough to require
transfusion appears to be uncommon (occurring in 3 of
69 patients in 3 studies) (32,33,37). Although many
patients with WG or SLE had renal involvement, no
data relating the risk of cystitis to renal dysfunction were
reported in any study.
12
MONACH ET AL
Table 2. Incidence of bladder cancer following treatment with daily oral cyclophosphamide (CYC)*
No. of patients
CYC treatment
Bladder
cancer
Latency,
years
46
54
40
0
2
1
NA
6–7
4
NA
100
ND
1–2 mg/kg
100 mg/m2
111
471
3
7
1–14
5–12
ND
6.8
RA
WG
50–150 mg
2 mg/kg
119
145
9
7
4–23
0.6–15
WG, MPA
WG
2 mg/kg
2 mg/kg
123
142
3
1
WG
ND
1,065
WG
1–2 mg/kg
293
Author, year (ref.)
Disease(s)
CYC dose
Aptekar et al, 1973 (37)
Plotz et al, 1979 (35)
Austin et al/Carette et al,
1983/1986 (1/36)
Stillwell et al, 1988 (32)
Pederson-Bjergaard et al,
1988 (10)
Radis et al, 1995 (38)
Talar-Williams et al, 1996
(33)
Westman et al, 1998 (40)
Reinhold-Keller et al,
2000 (34)
Knight et al, 2004/2002
(42,43)
Faurschou et al, 2008 (41)
SLE, WG, RA
SLE, RA
SLE
1.3–1.5 mg/kg
1–4 mg/kg
1–4 mg/kg
WG
NHL
Total
Duration,
years
Total
dose, gm†
Followup,
years‡
NA
2–4
4
NA
ND
ND
ND
4.5
7.1
3.2–14.2
1–12
2.8–4.2
56–531
83–129
6.0
3.8
22
31
8.8–56
13–65
5§
0.6–5.1
120 ⫾ 56
19–251
13.1
8.5
⬎5
7
4.8
ND
1.0–13.9
⬎1
6
ND
350
4.6
7.0
11
4–15
4.8
2.6–8.1
7.2¶
0–234
ND
5
7–18
3.6
1.2–8.3
⬎1#
⬎36#
6.0
OR
95% CI
ND
* There is some overlap of patients in the studies by Plotz et al, Austin et al, and Carette et al. Latency is defined as the time between beginning
cyclophosphamide treatment and the diagnosis of bladder cancer. In the study by Reinhold-Keller et al, oral mesna was also given routinely. Odds
ratios (ORs) and 95% confidence intervals (95% CIs) for the development of bladder cancer represent the comparison of CYC-treated patients with
control subjects. SLE ⫽ systemic lupus erythematosus; WG ⫽ Wegener’s granulomatosis; RA ⫽ rheumatoid arthritis; NA ⫽ not applicable; ND ⫽
no data; NHL ⫽ non-Hodgkin’s lymphoma; MPA ⫽ microscopic polyangiitis.
† Values are the range or mean ⫾ SD, for patients in whom bladder cancer developed.
‡ For the studies by Aptekar et al, Plotz et al, Austin et al, Carette et al, Stillwell et al, Pederson-Bjergaard et al, and Radis et al, values are the means;
for all other studies, values are the medians.
§ Value is the mean.
¶ Value is the median.
# Values are for 4 of 5 patients with bladder cancer.
Association of daily oral cyclophosphamide with an
increased risk of bladder cancer
The incidence of bladder cancer following treatment with daily oral cyclophosphamide has been reported for many of the same cohorts used to investigate
hemorrhagic cystitis (1,10,32–38) and for several separate cohorts that were used to measure the incidence of
multiple types of cancer (40–43) (Table 2). Most of the
analyses were based on single-center cohorts, with odds
ratios (ORs) for the development of bladder cancer
usually calculated in comparison with registry data.
Although the number of cases of cancer observed
in each cohort was small (range 0–11), resulting in large
confidence intervals (CIs) for the ORs for cancer risk, a
substantially elevated risk of bladder cancer associated
with cyclophosphamide treatment was observed in all
studies (OR range 3.6–100). The total cumulative doses
of cyclophosphamide given to patients in whom bladder
cancer subsequently developed varied widely but were
⬎100 gm in the majority of cases and ⬎30 gm in the
great majority (missing data preclude the calculation of
percentages) (Table 2). An elevated risk of bladder
cancer in association with cyclophosphamide treatment
for WG, RA, and NHL was clearly observed; an analogous risk was not identified with certainty among patients with SLE, but a smaller number of patients with
SLE was studied (Table 2). In 3 studies, 2 of which
involved WG (31,40) and 1 of which involved NHL (10),
time-dependent analyses demonstrated that the prevalence of bladder cancer reached 10% between 11 years
and 16 years after the beginning of treatment with
cyclophosphamide. The largest study of bladder cancer
following cyclophosphamide treatment described 31
cases among 6,171 patients with NHL (5.0%) (44).
Results of this study are more difficult to compare with
those of the other studies (and thus are not included in
Table 2) due to the variety of cyclophosphamide regimens used and the frequent concomitant use of radiation therapy (an independent risk factor for bladder
cancer).
The yearly incidence of bladder cancer among
white persons in the US has been estimated at 40 per
100,000 men and 10 per 100,000 women (45). This
incidence rises with age; therefore, the baseline risk for
patients with WG, as used to calculate ORs as described
above (10,40,41), is somewhat higher: 58–67 per
CYCLOPHOSPHAMIDE AND MESNA
13
Table 3. Association of bladder cancer with a prior diagnosis of hemorrhagic cystitis in patients treated
with daily oral cyclophosphamide*
Bladder cancer
Author, year (ref.)/
cystitis definition
Stillwell et al, 1988 (32)
Cystoscopy
Pedersen-Bjergaard et al, 1988 (10)
No data
Radis et al, 1995 (38)
Nonglomerular hematuria
Cystoscopy
Talar-Williams et al, 1996 (33)
Nonglomerular hematuria
Cystoscopy
Reinhold-Keller et al, 2000 (34)
Cystoscopy
Total
Nonglomerular hematuria
Cystoscopy
Disease
No bladder
cancer
Cystitis
No
cystitis
Cystitis
No
cystitis
P†
3
0
14
94
0.003
2
5
31
433
0.08
5
3
4
6
13
11
97
99
0.004
0.07
6
5
1
2
45
46
93
92
0.008
0.10
1
0
16
125
0.12
17
14
10
13
119
118
842
843
⬍0.0001
⬍0.0001
WG
NHL
RA
WG
WG
* In the study by Reinhold-Keller et al, oral mesna was also given routinely. Cystitis was defined by the
presence of nonglomerular hematuria or was proven by cystoscopy. Both definitions were used separately
to calculate statistics, and 2 separate totals were calculated and analyzed due to the use of both definitions
in 2 of the studies. WG ⫽ Wegener’s granulomatosis; NHL ⫽ non-Hodgkin’s lymphoma; RA ⫽
rheumatoid arthritis.
† For the association of cystitis with bladder cancer, using Fisher’s exact test for each study individually
and the Mantel-Haenszel test for the total, stratified by study.
100,000. Smoking is the best-documented environmental
risk factor for bladder cancer and increases the risk
⬃3-fold (46). Among the studies referenced above in
which tobacco use was reported, more than half of the
patients in whom bladder cancer developed were smokers or former smokers (10,32,33,35,38).
Thus, treatment with oral cyclophosphamide confers an independent, substantial, and probably doserelated increased risk of bladder cancer, with an effect
that may be delayed for many years after the medication
has been discontinued.
Probable association of hemorrhagic cystitis with
increased future risk of bladder cancer
In most studies examining the risk of bladder
cancer following treatment with daily oral cyclophosphamide, bladder cancer was associated with previous hematuria during cyclophosphamide treatment
and/or with documented cystitis (32–34) (Table 3). Similarly, the available data appear to confirm a strong
association between prior cystitis and the subsequent
risk of developing bladder cancer, with an OR of 7.2
(95% CI 1.9–27) obtained using the Mantel-Haenszel
estimator. However, because both cystitis and bladder
cancer are associated with the cumulative dose of cyclophosphamide and the duration of treatment, a causeand-effect relationship between cystitis and cancer cannot be firmly established.
There are 2 caveats to this apparent association.
First, it is possible that selection bias influenced these
studies: patients in whom hematuria develops early in
the course of treatment are much more likely to be
evaluated later—by history, urinalysis, urine cytology,
and/or screening cystoscopy—than are patients who
never had such abnormalities. Second, a registry-based
case–control study does not support the conclusion that
bladder cancer is associated with a history of cystitis.
Knight et al (42) reported that only 1 of 11 patients with
bladder cancer (all of whom had been treated for WG
with oral cyclophosphamide) had a history of cystitis
documented by cystoscopy, and that hematuria in the
other 10 patients was first noted shortly before the
diagnosis of cancer. In contrast, 18 of 25 control subjects
had a history of microscopic hematuria (42). However, it
is unclear whether a uniform screening strategy was
used, or whether a distinction between glomerular (i.e.,
associated with red blood cell casts or declining renal
function) and nonglomerular hematuria could be made.
14
MONACH ET AL
Table 4.
Incidence of hemorrhagic cystitis following treatment with intermittent IV cyclophosphamide (CYC) for rheumatic diseases*
No. of patients
Author, year (ref.)
Disease(s)
CYC dose
2
Mesna
No
Austin et al, 1986 (1)
SLE
0.5–1.0 gm/m every 3 mos
Hoffman et al, 1990 (48)
WG
1.0 gm/m2 every 1–3 mos
No
2
Gourley et al, 1996 (3)
SLE
0.75 gm/m every 1–3 mos
Yes
Martin et al, 1997 (50)
SLE, vasc
0.5–1.0 gm/m2 every mo
No
Guillevin et al, 1997 (53)
WG
0.7–1.0 gm/m2 every 3–6 wks
No
Adu et al, 1997 (54)
WG, MPA, PAN
15 mg/kg every 2–6 wks
Yes
Martin-Suarez et al, 1997 (55) SLE, vasc, myo
0.5 gm every 1–4 wks
Yes/no
Koldingsnes et al, 1998 (51)
WG
15 mg/kg every 2–8 wks
No
Haubitz et al, 1998 (52)
WG, MPA
0.75 gm/m2 every mo ⫻ 12
No
2
Ginzler et al, 2005 (6)
SLE
0.5–1.0 gm/m every mo ⫻ 6
No
Hoyles et al, 2006 (8)
SSc
0.6 gm/m2 every mo ⫻ 6
No
Goransson et al, 2008 (49)
SLE, WG, myo
15 mg/kg every mo
No
Total
Cystitis
20
14
55
75
27
24
90
11
22
69
22
42
0
1†
0
0
1
0
1‡
0
0
0
0
0
Total CYC
dose, gm
Mean Range
ND
ND
ND
5
28
ND
3
ND
16
ND
6
10
ND
ND
⬍15
ND
ND
⬍30
1–25
12–88
⬍20
⬍9
ND
1–52
CYC duration,
years
Mean
Range
4
0.8
ND
0.5
ND
ND
0.3
3.3
ND
ND
ND
1.2
ND
0.1–1.8
⬍3
ND
ND
⬍1.5
0.0–3.7
1.0–8.2
⬍1
0.1–0.5
0.1–0.5
0.0–8.8
* The total cyclophosphamide dose and the duration of therapy were based on all patients in the study. IV ⫽ intravenous; SLE ⫽ systemic lupus
erythematosus; ND ⫽ no data; WG ⫽ Wegener’s granulomatosis; vasc ⫽ vasculitis; MPA ⫽ microscopic polyangiitis; PAN ⫽ polyarteritis nodosa;
myo ⫽ myositis; SSc ⫽ systemic sclerosis.
† Patient also had a history of cystitis with oral cyclophosphamide.
‡ Patient was 1 of 8% of patients in this case series who were not treated with mesna.
In summary, the available data indicate, with
some caveats, that antecedent hemorrhagic cystitis is
associated with a future increased risk of bladder cancer.
Lack of evidence for a strong association of periodic
IV cyclophosphamide with hemorrhagic cystitis or
bladder cancer
Periodic, usually IV, dosing of cyclophosphamide
has been the standard of care for lupus nephritis for ⬎20
years (1,3,6), and similar regimens have been used for
other severe rheumatic diseases (8,28,47). Mesna is used
more frequently in this setting than is daily oral therapy,
likely due to convenience or by the adoption of a
practice that is common in oncology. However, even
when mesna has not been routinely used, few cases of
hemorrhagic cystitis have been reported in clinical trials
or additional case series of patients treated with periodic
IV cyclophosphamide for rheumatic diseases. Three
cases were identified among 471 treated patients in the
studies listed in Table 4, and the great majority of these
patients did not receive mesna (1,3,6,8,48–55). The
development of bladder cancer after pulse regimens has
been described in only a few case reports (56–58).
It is important to note that cystitis and bladder
cancer were not the primary topics of investigation in
these studies; thus, there are no descriptions of strategies for systematic screening for hematuria or subsequent cystoscopy, and the duration of followup was
likely too short (median ⬍5 years) to detect many
bladder cancers. Even if one assumes that the reported
difference in bladder toxicity between daily oral and
periodic IV cyclophosphamide regimens is real, it is
possible that this finding simply reflects the total dose of
cyclophosphamide rather than the timing or route of
administration. Few patients in studies of periodic IV
cyclophosphamide have received more than 30 gm, in
marked contrast to studies of bladder toxicity in patients
given daily oral cyclophosphamide (compare the total
doses in Tables 1, 2, and 4). Regardless of the reason,
however, it is clear that the risk of hemorrhagic cystitis
with periodic IV dosing of cyclophosphamide as used in
rheumatology is quite low, in contrast to the experience
with high-dose IV cyclophosphamide and ifosfamide as
used in oncology (see discussion below).
Additional, although indirect, support for a low
risk of bladder cancer with periodic IV cyclophosphamide comes from observational studies. Unselected patients with lupus do not appear to be at
elevated risk of bladder cancer (OR 1.23, 95% CI
0.66–2.11), based on a multicenter cohort study of 9,547
patients followed up for an average of 8 years (59).
Exposure to cyclophosphamide was not reported in this
study; however, based on the frequency of severe nephritis in SLE and the near-universal use of this treatment
during the period of study (59), one can expect that at
least 30% of the patients received periodic IV cyclophosphamide for at least 6 months. Several smaller
studies have also consistently failed to document an
excess risk of bladder cancer in patients with lupus
(60–65).
CYCLOPHOSPHAMIDE AND MESNA
Mesna pharmacology
Mesna is a thiol compound, completely lacking in
antineoplastic activity, that is used in conjunction with
oxazophosphorine alkylating agents as a uroprotective
agent. Mesna is thought to decrease the incidence of
cystitis and bladder cancer by counteracting the toxic
effects of acrolein (16,66,67). The administration of
mesna with cyclophosphamide for the prevention of
bladder toxicity is a practice derived primarily from
investigations with ifosfamide, a structural analog of
cyclophosphamide.
Following either oral or IV administration,
mesna undergoes rapid dimerization within plasma to
the inactive disulfide compounds dimesna, mesnacysteine, mesna-glutathione, and others (67). Both
mesna and dimesna are cleared quickly by the kidneys.
Dimesna undergoes filtration by the glomerulus, and
roughly one-third is then converted back to mesna in the
renal tubules by glutathione reductase (66). Mesna then
binds to acrolein within the urine. The free sulfhydryl
group found in mesna combines directly with the double
bond of acrolein as well as other urotoxic
4-hydroxyoxazaphosphorine metabolites (16,66) (Figure
1). The conversion of 4-hydroxycyclophosphamide to
acrolein may also be inhibited by mesna (68). Both of
these factors contribute to the inhibition of acrolein
binding to cell-surface proteins in the bladder, thereby
potentially limiting cyclophosphamide-associated toxicities. Urinary mesna concentrations greatly exceed
plasma concentrations, allowing for rapid clearance of
acrolein from the urinary system. However, mesna does
not protect against nonurologic toxicities associated with
the oxazaphosphorines.
Mesna has 50–75% bioavailability after oral administration and is not affected by food intake (16,66).
Urinary thiol concentrations following oral administration are approximately one-half those observed after IV
administration. Oral administration is associated with
delayed peak urinary concentrations (3 hours after
dosing compared with 1 hour following IV administration [67]) and prolonged excretion. When oral doses of
mesna are doubled, peak urinary thiol concentrations
are unchanged but are maintained for longer periods of
time (67).
The recommended dosing of IV mesna is a total
dose equal to 20% (weight/weight) of the total cyclophosphamide dose, in the form of 3 equal doses of
mesna, with the first dose administered 15–30 minutes
prior to cyclophosphamide and the others administered
4 hours and 8 hours following cyclophosphamide (67).
15
When mesna is given orally, the dose should be equal to
40% of the cyclophosphamide dose (oral or IV), based
on the 50% oral bioavailability of mesna. For convenience, a combination of IV and oral doses can be given:
an initial IV dose (equal to 6.8% of the cyclophosphamide dose) followed by 2 oral doses (each equal
to 13.3% of the cyclophosphamide dose). If the first dose
of mesna is administered orally, it should be given 2
hours before cyclophosphamide (oral or IV), but the
second and third oral doses can still be given 4 hours and
8 hours after cyclophosphamide, as with IV mesna
dosing.
Two forms of mesna are available for oral use.
The IV solution, at a concentration of 10 mg/ml, can be
ordered by outpatient pharmacies in the US, at a
wholesale cost of approximately $0.55 per typical daily
dose of 60 mg. A tablet is available but at a cost of
approximately $4.50 per 60 mg, and the only strength
sold is 400 mg, making dosing for patients with rheumatic diseases both expensive and technically challenging. The principal disadvantage of using the IV solution
orally is the strong sulfurous odor and taste; mixing with
a carbonated beverage or juice drink is recommended.
Beyond the issues of taste and inconvenience, mesna is
generally well tolerated, with mild gastrointestinal toxicity being the most common side effect. Allergic reactions to mesna have been reported but are considered
rare (69).
Although renal dysfunction might theoretically
increase the risk of systemic cyclophosphamide toxicity
due to a decreased rate of elimination of the drug and its
metabolites, renal insufficiency seems unlikely to lead to
an increased rate of bladder toxicity, because the delivery of acrolein to the bladder is also reduced. Similarly,
because mesna requires active glomerular filtration and
tubular secretion in order to reach the urine, use of
mesna in patients with significant renal dysfunction is
unlikely to be beneficial. However, the relative urinary
concentrations of mesna and acrolein have never been
measured in the setting of renal insufficiency, and
oliguria could lead to prolonged exposure of the bladder
to whatever amount of acrolein arrives there; thus, one
cannot regard use of mesna in patients with renal
insufficiency as having been addressed conclusively.
Efficacy of mesna for the prevention of hemorrhagic
cystitis
Data for the use of mesna to prevent hemorrhagic cystitis caused by cyclophosphamide in the treatment of rheumatic diseases are not conclusive. This
16
topic is best approached in a broader context that
includes strategies for hydration, data on the use of
mesna in patients with cancer, and insights from animal
models. These data were obtained with the use of
periodic high-dose IV cyclophosphamide or ifosfamide,
both of which are associated with high risks of cystitis. It
is unclear whether these results are more applicable, in
rheumatic diseases, to periodic IV dosing (in which the
route and schedule of administration are similar but the
baseline risk is much lower) or to daily oral dosing (in
which the route and schedule are very different, but the
baseline risk is similarly high).
Hydration. Hydration with IV fluids immediately
prior to and for several hours after IV administration of
cyclophosphamide, as well as oral hydration for 72 hours
following the cyclophosphamide dose, is typically recommended to aid in the prevention of hemorrhagic cystitis.
When oral cyclophosphamide is given, patients are
instructed to drink fluids at the time of dosing and for
several hours thereafter and to take cyclophosphamide
in the morning to limit retention of metabolites in the
urine overnight. It should be noted that since the time
when bladder toxicities of oxazophosphorines were first
recognized, the effectiveness of hydration per se has
never been formally evaluated, having been regarded as
the standard of care against which all other strategies for
bladder protection are to be compared.
Mesna in animal models of cystitis. Studies in
rodents support the effectiveness of mesna in preventing
acute bladder toxicity from cyclophosphamide or acrolein (21,70–74). These studies typically involved the brief
use of high doses of cyclophosphamide and thus provide
better support for the use of mesna in patients with
malignancies than in patients with rheumatic disease.
Mesna and cystitis in rheumatic diseases. The
prospect of preventing cystitis and/or bladder cancer by
coadministering mesna to patients receiving daily oral
cyclophosphamide has never been addressed in a systematic manner. Among the studies of patients with
WG, the incidence of cystitis may have been lower in the
single cohort that routinely received oral mesna (12%)
(34) than in the 2 others that did not receive oral mesna
(35–41%) (30,31) (Table 1). However, the possibility of
important differences in the dosing schedules, total
cumulative doses, and clinical characteristics, particularly renal dysfunction, makes a direct comparison problematic. Similarly, differing approaches to screening for
and the diagnosis of cystitis among these 3 studies
introduce another source of uncertainty. However, because these studies provide the only data relevant to the
question of whether mesna prevents cystitis in patients
MONACH ET AL
receiving daily oral cyclophosphamide, and interpretation and comparison of these studies are the subject of
debate (34,75), a detailed review of the controversy is
warranted.
Reinhold-Keller et al (34) diagnosed all cases of
cystitis by cystoscopy, and all cases of nonglomerular
hematuria were investigated in this way; therefore, their
report of a 12% incidence appears accurate. TalarWilliams et al (33) reported nonglomerular hematuria in
73 of 145 patients (50%). Cystoscopy was performed in
only 60 of these 73 patients, with confirmation of cystitis
in 42 (i.e., 70% of those undergoing cystoscopy), giving
a minimum prevalence of cystitis in the cohort of 29%.
Both “50%” and “29%” have been used to describe the
incidence of cystitis in this study (34,75). However, the
most appropriate estimate is probably neither of these
figures but instead is the percent of confirmed cases (42
of 60 [70%]) multiplied by the percent with hematuria
(50%), resulting in an incidence of 35% (Table 1).
Stillwell et al (32) diagnosed cystitis either on the basis
of gross hematuria (11 patients) or by cystoscopy performed for the followup of new microscopic hematuria.
However, only a minority of patients with microscopic
hematuria were investigated by cystoscopy (20 of 52),
and because the percent of patients in whom cystitis was
confirmed by cystoscopy was 65% (which notably is
similar to the incidence of 70% reported by TalarWilliams), one could reasonably extrapolate that the
true incidence of cystitis in the study by Stillwell et al is
41% (11 ⫹ [0.65 ⫻ 52] ⫽ 45 of 111 patients). Despite the
difficulty of directly comparing these 3 studies, it is
worth noting that the study showing the lowest incidence
of cystitis (in the setting of routine mesna therapy) used
the most thorough screening strategy (34), which should
have biased toward a higher rather than lower incidence.
Although routine treatment with mesna has recently been incorporated into some protocols that have
used periodic IV dosing of cyclophosphamide (28), data
on the efficacy of mesna in preventing cystitis are
lacking, because the baseline risk of cystitis with such
regimens appears to be quite low (Table 4).
Mesna and cystitis with high-dose cyclophosphamide or ifosfamide. Mesna as prophylactic therapy against bladder toxicity has been tested only in a
randomized, controlled manner among patients receiving high-dose IV cyclophosphamide or ifosfamide as
part of bone marrow transplantation (BMT) protocols
or as chemotherapy for solid malignancies. Mesna treatment (with maintenance hydration of 1.5–3 liters/day)
has been compared with IV hyperhydration (either 6
liters/day with a diuretic or 3 liters/m2/day), with similar
CYCLOPHOSPHAMIDE AND MESNA
but incomplete effectiveness in preventing short-term
bladder toxicity caused by high-dose IV cyclophosphamide in BMT (76,77). By pooling the results
from these 2 studies, hematuria of any degree was
observed in 41 (57%) of 72 patients receiving mesna and
in 44 (67%) of 66 patients receiving hyperhydration;
macroscopic hematuria was observed in 17 (24%) of 72
patients receiving mesna and in 17 (26%) of 66 patients
receiving hyperhydration. In patients also receiving hydration during high-dose IV cyclophosphamide treatment, the addition of mesna was more effective than the
addition of continuous bladder irrigation in preventing
acute bladder toxicity (78).
Mesna is routinely used (and is FDA-approved in
both IV and oral forms) as prophylaxis against cystitis in
ifosfamide-containing regimens (16), based on 4 small
controlled trials of IV mesna (79–82), 3 subsequent
trials showing equivalent rates of cystitis comparing IV
with oral mesna (15,83), and additional uncontrolled but
often larger series (84–90) that made comparisons with
the high rate of hemorrhagic cystitis (⬃50%) noted in
early studies of ifosfamide (11). Even with mesna prophylaxis, however, the rates of acute urotoxicity ranged
from 1% to 10% in these studies (16). In addition,
among 15 patients without clinical evidence of bladder
toxicity 24 hours after receiving ifosfamide and mesna,
the bladder mucosa was macroscopically (10 of 15
patients) and microscopically (100%) abnormal, with
mucosal alterations including edema, exocytosis, and
hemorrhage (91).
Summary. Direct evidence for the effectiveness
of mesna in preventing cystitis comes only from its use
with ifosfamide in patients with cancer and on data from
animal models, both of which are of uncertain relevance
to the use of cyclophosphamide in patients with rheumatic diseases. The data from rheumatology series are
consistent with a protective effect but are inadequate to
draw a firm conclusion.
Paucity of data on the efficacy of mesna for the
prevention of bladder cancer in patients treated with
cyclophosphamide or ifosfamide
No study has compared the incidences of bladder
cancer resulting from the use of cyclophosphamide with
or without mesna. Among studies describing long-term
followup after treatment with daily oral cyclophosphamide (10,32–34,38,40–42), the only study in
which mesna was routinely used revealed a low rate of
bladder cancer (1 of 142 treated patients) despite one of
the longest average followup times (see Table 2) and
17
perhaps the most comprehensive (or at least the bestdocumented) screening strategy (34). However, with
such small numbers of events, a comparison among
studies or pooling of these data is even more problematic than it is for comparing the incidences of cystitis.
There are no published data regarding the effect of
mesna on the rate of secondary bladder cancer in
patients treated for malignancies with high-dose IV
cyclophosphamide or ifosfamide; the prospect and need
for such studies have been noted (92).
A single study in rodents supports the effectiveness of mesna in preventing bladder cancer induced by
prolonged exposure to cyclophosphamide. Cyclophosphamide administered orally at a dosage of 2.5 mg/kg/day
for 5 days per week produced bladder tumors in 24 of 80
treated rats (30%); the incidence of tumors was reduced
to 22% (8 of 36) in rats given low-dose mesna (5
mg/kg/day) and to 7% (3 of 41) in rats given high-dose
mesna (15 mg/kg/day) (93).
Evidence-based consensus guidelines on the use of
mesna
Evidence-based consensus guidelines on the use
of mesna have not addressed its value in patients with
rheumatic diseases. Given the low reported incidence of
hemorrhagic cystitis with standard doses of IV cyclophosphamide in patients with cancer, the American
Society of Clinical Oncology does not recommend the
routine use of mesna for patients receiving cyclophosphamide and states that mesna should be used only
in conjunction with the administration of high-dose
cyclophosphamide, typically defined as 50 mg/kg or 2
gm/m2 (16,94).
In the rheumatology literature, guidelines for the
use of mesna vary and are not detailed. Guidelines from
the British Society for Rheumatology for the management of antineutrophil cytoplasmic antibody–associated
vasculitis have recommended that mesna be “considered
for patients on IV cyclophosphamide therapy” (95).
Similarly, guidelines on vasculitis from the European
League Against Rheumatism recommend that “patients
receiving pulse cyclophosphamide should also be given
oral or IV mesna” and add that “mesna may also be
beneficial in patients receiving continuous oral cyclophosphamide” (5). In contrast, consensus guidelines for
management of lupus have made no mention of mesna
(30,96). Rheumatology textbooks and other resources
regularly recommend use of mesna for patients receiving
IV cyclophosphamide, with little or no comment on the
use of mesna with oral cyclophosphamide (12–14).
18
MONACH ET AL
Overall, the paucity of evidence supporting the
use of mesna is striking in light of recommendations for
its use and the common adoption of such guidelines in
rheumatology practice. However, there is also no evidence against the effectiveness of mesna and little
prospect of the issue being definitively addressed in a
trial. With uncertain and unquantifiable risks and benefits, patient and physician preference can and should
play important roles, and thus, recommendations to
“consider” use of mesna are fully consistent with the
evidence. However, the conclusions of this review diverge from most recommendations in one important
respect: on the basis of the much clearer risks of bladder
toxicity with daily oral cyclophosphamide, the inclination to use mesna should be much stronger with daily
oral dosing compared with periodic IV dosing.
Summary and recommendations
The conclusions of this literature review are as
follows: 1) daily oral cyclophosphamide is associated
with an increased risk of both hemorrhagic cystitis and
bladder cancer, in a dose-dependent and/or durationdependent manner; 2) hemorrhagic cystitis that occurs
during cyclophosphamide treatment is associated with
an increased risk of bladder cancer years later; 3) IV
cyclophosphamide therapy, as prescribed for rheumatic
diseases, carries a low risk of cystitis and probably also of
bladder cancer; 4) evidence for the effectiveness of
mesna in preventing cystitis is based largely on its use
with ifosfamide in patients with cancer and on data from
animal models, both of which are of uncertain relevance
to the use of cyclophosphamide in patients with rheumatic diseases; 5) there is no direct evidence for the
effectiveness of mesna in preventing bladder cancer in
humans.
On the basis of the current evidence, the following recommendations for use of mesna in the rheumatology setting are proposed:
1. Explain to patients that the evidence for the benefit
of mesna in rheumatologic diseases is not strong.
2. Upon starting a first course of oral or IV cyclophosphamide, discuss the issues with the patient; if
the patient expresses no strong preference, do not
use mesna.
3. Additional factors to consider when deciding on
the use of mesna are as follows:
a. the expense of mesna, especially oral tablet
form;
b. the inconvenience of the relatively complex dos-
ing regimen for mesna, particularly for daily
dosing;
c. the ability to tolerate hydration during either
daily oral or pulse IV therapy with cyclophosphamide;
d. the total cumulative dose of cyclophosphamide
for patients requiring a repeat course.
4. Upon starting a second course of cyclophosphamide (i.e., more than 4–6 months of total
treatment), particularly with oral dosing, consider
recommending mesna.
Cyclophosphamide remains an important treatment for patients with various rheumatic diseases. Although additional study of the usefulness of mesna in
patients with rheumatic diseases would be welcomed,
such research is unlikely to occur, especially given the
trend toward developing non–cyclophosphamide-based
therapies. Given the uncertainties outlined in this review, decisions regarding the use of mesna will need to
be made on an individual basis, taking into consideration
the varying attitudes of both physicians and patients
toward risk reduction.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved
the final version to be published.
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