PRACTICAL THERAPEUTICS

Drugs 42 (5): 781-795, 1991

0012-6667/91/0011-0781/$07 .50/0
© Adis International Limited. All rights reserved.
CAUl 71

Cyclophosphamide Toxicity
Characterising and Avoiding the Problem

Lucy H. Fraiser, Sarathchandra Kanekal and James P. Kehrer

Division of Pharmacology and Toxicology, College of Pharmacy,
University of Texas at Austin, Austin, Texas, USA

Contents
781 Summary
782 I. Common Complications and Toxicities
782 1.1 Bone Marrow Depression
782 1.2 Nausea and Vomiting
783 1.3 Alopecia
784 2. Organ-Specific Toxicities
784 2.1 Urotoxicity
785 2.2 Pulmonary Toxicity
787 2.3 Cardiac Toxicity
788 3. Long Term Complications and Toxicity
788 3.1 Reproductive Effects
788 3.2 Teratogenic Effects
788 3.3 Oncogenic Effects
790 4. Recommendations for Avoiding Toxicity
790 4.1 Immunosuppression
790 4.2 Nausea and Vomiting
790
4.3 Alopecia
792
4.4 Urotoxicity
792
4.5 Pulmonary Toxicity
793
4.6 Cardiac Toxicity
793
793 4.7 Reproductive Toxicity
793 4.8 Teratogenesis
793 4.9 Oncogenesis
5. Conclusions

Summary Cyclophosphamide, an orally active alkylating agent, is widely used to treat a variety of malig-
nant and nonmalignant disorders . Although it has some tumour selectivity, it also possesses a
wide spectrum of toxicities. The requirement of metabolic activation before cyclophosphamide
exerts either its therapeutic or toxic effects is well established, but has not led to effective counter-
measures. Clinically, damage to the bladder (haemorrhagic cystitis), immunosuppression (when
not desired) and alopecia are the most significant toxicities associated with cyclophosphamide.
Cardiotoxicity is also a possibility when very high doses are given. Preventing these toxicities
has focused on modifications of the treatment regimens and, in the case ofhaemorrhagic cystitis,
782 Drugs 42 (5) 1991

the administration of a drug which is excreted in the urine where it inactivates the bladder-toxic
species. As treatment regimens for cancer become more effective in prolonging a patient' s life,
and as cyclophosphamide receives increasing use for nonm alignant disorders, the potenti al for
cyclophosphamide-induced cancers, part icularly in the bladder, must be recognised. Although the
toxicities associated with cyclophosphamide are serious, this agent remain s a highly effective drug
in man y situati ons. Research on the pathways which play an important role in activating this
drug may improve our ability to target part icular diseases and decrease unwanted side effects.

Cyclophosphamide, a cyclic phosphoramide es-
ter, was synthesised in 1958 as an orally active
transport form of the alkylating agent chiormeth-
ine (mustine , mechlorethamine) [Bourscaux &
Brock 1958]. The fundamental pharmacological
activiti es of alkylating agents are disruption of cell
growth, mitot ic activit y and differentiation and
function , primarily by cross-linking DNA strands.
The capacity of cyclophosphamide to interfere with
normal cell division in all rapidly proliferating tis-
sues provides the basis for its therapeutic effects
and many of its toxicities.
Cyclophospham ide has a wide spectrum of
clinical uses and is an essential component of nu-
merous combination chemotherapeutic regimens.
As a single agent, cyclophospham ide is potentially
curative in Burkitt's lymphoma (Ziegler et al. 1970)
and is a highly effective immunosuppressant.
Worldwide, cyclophosphamide is used in around
500 000 patients yearly. Organ-specific toxicities
and secondary tumours are rare with normal doses.
However, doses are often pushed to very high lev-
els [240 mg/kg has been reported (Newell & Gore
1991)] and dose-limiting and life-threatening tox-
icities occur in many situations.
The crucial factor in the therapeutic and toxic
effects of cyclophosphamide is the requirement for
metabolic activation (fig. I). The active metabo-
lites are generated preferentially in the liver, and
to a lesser extent in other tissues. It is generally
believed that the chlormethine metabolites (in-
cluding phosphoramide mustard and nor-nitrogen
mustard) are responsible for the therapeutic effects,
and acrolein for the toxic effects of cyclophosph-
amide. While this confers some selectivity upon
cyclophosphamide, it also makes the toxicities as~
sociated with this drug more elusive and difficult
to control.
The wide variety of conditions in which cyclo-
phosphamide is employed puts many patients at
risk and the seriousness of cyclophosphamide-in-
duced toxicities dictates the need to limit these ad-
verse effects whenever possible. The purpose of this
article is to characterise the most important clinical
toxicities associated with cyclophosphamide and to
provide practical recommendations for their
avoidance . It is not the intention of this article to
be a compreh ensive literature review and, there-
fore, citations of experimental data are limited.
1. Common Complications and Toxicities
1.1 Bone Marrow Depression
Myelosuppression consisting primaril y of leu-
copenia is the most significant of the cyclophos-
phamide-induced toxicities. The nadir (8 to 14 days)
and recovery (I8 to 25 days) times are relatively
rapid compared with other antineoplastic agents.
However, the leucopenia and granulocytopenia
which occur increase the patient's susceptibility to
pathogenic bacteria or opportunistic microorga-
nisms. Infectious complications are common in
patients treated with high-dose cyclophosphamide,
including life-threatening septicaemia (Buckner et
al. 1972; Horn et al. 1990). Although cyclophos-
phamide is generally considered to be platelet-spar-
ing, thrombocytopenia can also be a significant
complication leading to an increased potential for
bleeding episodes.
1.2 Nausea and Vomiting
Nausea and vomiting are promin ent side effects
of the nitrogen mustards (particularly following
Cyclophosphamide Toxicity 783

intravenous administration) and are presumably a J.3 Alopecia

result of the direct stimulation of the chemorecep-
tor trigger zone. Because the epithelial cells of the
gastrointestinal tract have a high mitotic index, lo-
cal irritation occurs with high doses of cyclophos-
phamide. However, this generally does not account
for the nausea and vomiting which occur in 50%
of the patients treated within minutes of admin-
istration. Individual patient tolerance to cyclo-
phosphamide varies greatly and psychological pre-
conditioning may worsen this toxicity (Doff & Fritz
1980).
A frequent manifestation of cyclophosphamide
toxicity is damage to hair follicles (Calabresi &
Chabner 1990). Extensive alopecia is observed in
at least 50% of patients treated and should be ex-
pected, to some degree, in all patients. With long
term therapy, axilJary, extremity and pubic hair
may also be lost (Doff & Fritz 1980). Hair loss
generally commences 1 to 2 weeks followinga single
pulse and becomes maximal after I to 2 months.
Complete regrowth of hair is possible once cyclo-

H H Ci?
"I \
CICH2CH2

/
N-P~O
\
N -CH2

/
CH2
PHS? Oxidase
/
M-\~O
N-G
\
.9H2
CICH2CH2 0-CH2 P450
0 -CH2
Cyclophosphllmidll 4-Hydroxy.cyclophosphamide 4.Keto:9'cl~sphamide

R-COOH
Carboxyphospharride
H aldehyde
INH2 y ~O oxidase /dehydrogenase

"\~O_ct' I alcohol
dehydrogenase
Aldophosphamide
R-C H20 H
~ Alcophosphamide
Nonenzymatic

HH
CICH2C~2 /NH3+ CH2~e-C~O

CICH2CH2
" ,0-
N-P~O Acrolein

Phosphoramide mustard

CICH2CH2

JH
CICH2CH2
Nor nitrogen mustard

Fig.1. Metabolism of cyclophosphamide to major reactive and nonreactive metabolites . Bold arrows denote pathways leading
to cytotoxic metabolites. The initial 4-hydroxylation step can be catalysed by mixed-function oxidase enzymes and possibly
by cooxidation via the prostaglandin H synthase system. Remaining steps to the therapeutic and toxic metabolites are non-
enzymatic. Further oxidations produce nonreactive species.
784 Drugs 42 (5) 1991

phosphamide is discontinued and hair growth often
begins even if successive treatments are delivered.
Regrowth may be atypical initially (unusual tex-
ture; different shade), but this phase is transient
and full recovery to normal is usually achieved after
therapy ends.
2. Organ-Specific Toxicities
2.1 Urotoxicity
Numerous reports have appeared since 1959
concerning haemorrhagic cystitis in humans treated
with cyclophosphamide for various neoplastic and
non-neoplastic diseases. However, the serious na-
ture of this complication was not realised until a
number of cases of severe bladder haemorrhage and
death were reported in the mid-1960s (Pearlman
1966; Rubin & Rubin 1966). Today , sterile hae-
morrhagic cystitis is recognised as a major dose-
limiting side effect of cyclophosphamide usage.
Haemorrhagic cystitis is defined as inflamma-
tion characterised by diffuse or insidious vesicle
bleeding within the bladder wall. Cyclophosph-
amide-induced haemorrhagic cystitis is considered
to be dose-related in animals, but several clinical
studies have failed to establish this correlation in
humans (Lawrence et al. 1975). The incidence of
cyclophosphamide-induced haemorrhagic cystitis
has been reported to be as high as 78% with 4%
mortality from uncontrolled haemorrhage (Grin-
berg-Funes et al. 1990). However, other sources in-
dicate the frequency ranges from 2 to 40% in un-
protected individuals (Levine & Richie 1989).

Table I. Selected studies implicating cyclophosphamide in urotoxicity

Patient characteristics Cyclophosphamide TOXicity Reference

(sex , age, primary (dose , durat ion)
diagnos is)

314 children, 200 mg/m2 weekly CPHC-25 cases (8%) Lawrence et al.
M & F, Up to 3y [mild 18 cases; (1975)
4 mos-19y severe 5 cases (1 death)]
Leukaemia

40 children ,
M & F,
Ages not given
Leukaemia (26),
Neuroblastoma (9),
Wilms ' tumour (2),
Lymphosarcoma (1),
Rhabdomyosarcoma (1),
Hodgkin 's disease (1)
28 patients - 200 mg/m 2 weekly or Bladder wall fibros is in 10 (25%) Johnson &
300 mg/m 2 every other wk (IV) [slight 3; marked 3; severe 4 (3 Meadows (1971)
3 patients - 50-200 mg/m 2 daily with telangiectasia)]
(orally)
9 patients - both routes
18 patients - 3-20 wks
12 patients - 20-40 wks
10 patients - 40-88 wks

100 patients w/CPHC
53 M, 47 F
5-77 years
Malignant disease (72),
Benign disease (28)
Cumulative Dosage
46 patients - 18g (IV) over 12 mos 93 microhaematuria Stillwell & Benson
54 patients - 90g (orally) over 38 mos 22 irritative voiding (1988)
29 cystitis and hyperplastic or
ulcerated mucosa
5 carcinoma of bladder

1 patient 4800 mg/m 2 as part of BMT Acute haemorrhagic cystitis Efros et al. (1990)
F 29 years conditioning regimen (duration not Acute pyelitis
Hodgkin's disease stated) Death

Abbreviations: CPHC cyclophosphamide-induced haemorrhagic cystitis; BMT = bone marrow transplant; mos months;
wk = week .
Cyclophosphamide Toxicity
Table II. Cyclophosphamide-induced bladder toxicity
Clinical symptoms Histopathological features
Gross haematuria Eccentric nuclei
Irritative voiding Hyperchromatic nuclei
Frequency of urination Nuclear pyknosis
Dysuria Vacuolisation
Burning Polymorphonuclear leucocytes
Urgency Necrotic cystitis
Incontinence Desquamation
Nocturia Mucosa covered by dense
exudate
2.1.1 Mechanism
Several lines of evidence suggest that cyclo-
phosphamide-induced injury to the urinary blad-
der results from contact between the urothelium
and a toxic metabolite present in the urine (Levine
& Ritchie 1989; Phillips et al. 1961). Damage to
the urinary bladder in animals occurs only after
treatment with cyclophosphamide analogues that
are metabolised to acrolein. Thus, this metabolite
is believed to be responsible for cyclophosph-
amide-induced urotoxicity (Cox 1979a), although
chloroacetaldehyde has also been suggested as a
potential bladder toxicant.
2.1.2 Clinical Symptoms
Several retrospective studies have appeared in
the literature in recent years characterising the
clinical features, frequency, contributing factors,
and prognosis of cyclophosphamide-induced hae-
morrhagic cystitis (table I). Symptoms include gross
haematuria, irritative voiding, frequency, dysuria,
burning, urgency, incontinence and nocturia (table
II) [Stillwell & Benson 1988]. Diagnosis of cyclo-
phosphamide-induced haemorrhagic cystitis is
based on: (a) a history of gross haematuria; (b) la-
boratory findings of microscopic haematuria; (c)
platelet counts of greater than 50 000/mm 3; and
(d) lack of significant bacterial growth on urine cul-
tures (Lawrence et al. 1975).
The predisposition of patients to develop cyclo-
phosphamide-induced haemorrhagic cystitis is not
well understood and dehydration is the only un-
disputed risk factor. However, Stillwell and Ben-
son (1988) found evidence that cyclophosphamide-
785
induced haemorrhagic cystitis developed at sig-
nificantly lower doses and with shorter durations
of therapy in patients treated intravenously as op-
posed to orally. Additionally , previous or concur-
rent treatment of patients with busulfan or radio-
therapy, both of which may induce haemorrhagic
cystitis by themselves, may increase the risk of de-
veloping this toxicity (Beelen et aI. 1989; Stella et
aI. 1990).
2.1.3 Histopathological Findings
Cyclophosphamide administration causes a
cytotoxic response in the urothelium of animals and
humans that precedes haemorrhagic cystitis (Forni
et aI. 1964; Koss 1967; Stella et aI. 1990). The most
striking feature of this process is marked but vari-
able cell enlargement. Nuclei are often eccentric and
almost always hyperchromatic with nuclear pyk-
nosis as a common late effect. Cytoplasm shows
vacuolisation and at times contains foreign mater-
ial or is infiltrated with polymorphonuclear leu-
cocytes. Histopathological correlations include
severe necrotic cystitis, desquamation and mucosa
covered with a dense exudate (table II). Ulceration
is followed by an epithelial regenerative process in-
cluding inflammation, haemorrhage and extensive
epithelial hyperplasia.
Although bladder damage is the primary mani-
festation of cyclophosphamide-induced urotoxic-
ity, pathological changes in the upper urinary tracts
have been described in both experimental animals
and humans (Efros et aI. 1990; Koss 1967; Me-
Dougal et aI. 1981 ; Phillips et aI. 1961). It has also
been demonstrated that long term cyclophosph-
amide administration is associated with urinary
bladder fibrosis and telangiectasia (Johnson &
Meadows 1971).
2.2 Pulmonary Toxicity
The incidence of cyclophosphamide-induced
lung injury is much less than haemorrhagic cystitis
and occurs in only about 1% of treated patients
(Cooper et aI. 1986). However, it is often dose-lim-
iting and sometimes life-threatening. Interstitial
pneumonitis and pulmonary fibrosis are the two
786
most common lung conditions associated with cy-
clophosphamide chemotherapy (Burke et al. 1982;
Cooper et al. 1986; Patel et al. 1976; Rodin et al.
1970). Lung injury following treatment with cyclo-
phosphamide was reported as early as 1967 (Andre
et al. 1967) and has been observed both in patients
receiving cyclophosphamide along with other anti-
neoplastic drugs (Dohner et al. 1972; Mark et al.
1978) and in those receiving cyclophosphamide
alone for nonmalignant diseases (table III) [Burke
et al. 1982; Maxwell 1974].
Risk factors for developing lung injury after cy-
clophosphamide are not clear. Dosage, age of the
patient, disease condition, or duration of treatment
do not appear to be predisposing factors (Cooper
et al. 1986). However, a combination of drugs,
radiotherapy or oxygen therapy is known to po-
tentiate cyclophosphamide-induced lung injury
(Cooper et al. 1986; Hakkinen et al. 1982). There
is also convincing evidence that daily doses of cy-
clophosphamide and prednisone contribute to the
development of Pneumocystis carinii pneumonia
which can lead to interstitial pulmonary fibrosis
(Sen et al. 1991).
2.2.1 Mechanism
A single intraperitoneal dose (lOO to 200 mg/
kg) of cyclophosphamide results in reproducible
lung fibrosis in experimental animals (Lee & Keh-
rer 1985; Patel 1990; Patel et al. 1984; Siemann et
al. 1986) that is comparable to the fibrotic lesion
seen in humans. It is generally accepted that lung
damage occurs when a metabolically activated form
of cyclophosphamide interacts covalently with pul-
monary macromolecules. This leads to altered pro-
tein synthesis and ultimately, changes in extracel-
lular matrix components including collagen.
Bioactivation of cyclophosphamide can occur via
the mixed function oxidase enzyme system and re-
cent data suggests that it may also occur through
cooxidation processes involving the prostaglandin
H synthase enzyme system (Smith & Kehrer 1991).
Lung tissue is capable of producing reactive species
from cyclophosphamide (Patel 1990), but it is un-
clear whether metabolism by this organ is solely
responsible for the observed injury.
Drugs 42 (5) 1991
Transient increases of transforming growth fac-
tor {3, in conjunction with other cytokines have
been hypothesised to mediate cyclophosphamide-
induced interstitial pulmonary fibrosis (Lazo &
Hoyt 1990). However, the mechanism by which fi-
brosis is triggered is unclear. Production of reactive
oxygen species (Gurtoo et al. 1981) and lipid per-
oxidation (Patel 1990) have been suggested as pos-
sible causes of the lung injury, but evidence sup-
porting these mechanisms is minimal.
2.2.2 Clinical Symptoms
Table IV lists the common symptoms and his-
topathological findings of interstitial pneumonitis
and pulmonary fibrosis caused by cyclophosph-
amide. Symptoms have occurred after 2 to 3 weeks
(Rodin et al. 1970; Spector et al. 1979) or 3 to 13
years (Abdel Karim et al. 1983; Rodin et al. 1970)
of continuous treatment with cumulative doses
ranging from 30 to 250g. Once lung injury with
cyclophosphamide becomes evident it progresses
rapidly and requires hospitalisation in many cases
(Patel et al. 1976). The temporal variation in the
onset of symptoms may be because cyclophosph-
amide is often used with other antineoplastic agents
and corticosteroids. Several cases have been re-
ported where the symptoms develop or progress
rapidly after cessation of corticosteroids (Spector
et al. 1979, 1980).
General signs of distress such as chest pain, dys-
pnoea, hypoxaemia, cough with expectoration (To-
pilow et al. 1973) and occasional hyperthermia are
common. In one case, auscultation revealed bilat-
eral scattered rales and sibilant bronchi (Patel et
al. 1976). Radiological findings of the chest include
a bibasilar reticular pattern and, in severe cases,
evidence of extensive bilateral fibronodular inter-
stitial infiltrates and pulmonary oedema (Maxwell
1974). Pulmonary function usually shows the typ-
ical changes of restrictive lung disease (Dorr & Fritz
1980).
2.2.3 Histopathological Findings
Histopathological findings in humans are sim-
ilar to those observed with other pulmonary toxi-
cants producing lung fibrosis and include injury to
Cyclophosphamide To xicity 787

Table III. Selected case studies implicating cyclophosphamide in lung toxicity

Patient characteris tics Therapy Toxicity Reference

(age, sex, primary
diagnosis)

52 years Cyclophospham ide Interstitial pulmonary fibrosis Karnofsky (1967)

Chronic myelogenous 200-300 mg/day (250g total) for Pneumocystis carinii
leukaemia approx imately 3 years (orally) Cytomegalovirus infection

66 years, female, Oxygen by mask Interstitial pulmonary fibrosis Case Records of the
carcinoma of breast Cyclophospham ide 50mg daily (3.15g Interstitial pneumonia Massachusett s General
total) Hospital (1972)
Radiotherapy to lungs (1000 R/12
fractions)
[short course I

47 years, male, Cyclophosphamide 10 mg/kg, day 1 and Alveolar and interstit ial infiltrates Dohner et al. (1972)
lymphosar coma 8, one cycle and on day 1 of second Alveolitis
cycle (IV) procarbaz ine, vincristine, Complete resolution upon
prednisone discont inuation
23 years, female, Oxygen therapy Interstitial pneumonia (death) Topilow et al. (1973)
Hodgkin's disease Cyclophospham ide 300 mg/day initially
(unknown duration)
50-150 mg/day (27mo)

74 years, male, chronic Cyclophosphamide 1350mg (IV) and Interstitial pneumonia Patel et al. (1976)
lymphocytic leukaemia vincrist ine 2mg (IV), weekly x 2, Pulmonary fibrosis
prednisone 100 mg/day (orally), x 5 Complete clinical remission upon
discontinuation of
cyclophospham ide and
reinstitution of prednisone (60
mg/day)

56 years, female, Cyclophosphamide 150 mg/ day Pneumocystis carinii (death) Sen et al. (1991)
Wegner's granulomatosis prednisone (duration not stated)

71 years, male Radiotherapy Pneumocystis carinii (death)

malignant thymoma Prednisone, 60 mg/day x 3 mos
Trimethoprim -sulfam ethoxazole
Cyclophosphamide (125mg) and
predn isone (30mg)/day for 2 mos

alveolar cells characterised by type II cell hyper- 2.3 Cardiac Toxicity

plasia, interstitial oedema and hyperplasia, thick-
ening of alveolar septae (Gould & Miller 1975),
fibroblast proliferation (Patel et al. 1976), and in-
terstitial fibrosis (Burke et al. 1982). Although
cyclophospham ide is a powerful imm unosuppres-
sant, lymphocytic and histiocytic interstitial infil-
trat ion is a common histopathological finding
(Burke et al. 1982).
Santos et al. (1971) reported the first case of cy-
clophospham ide-induced cardiom yopath y in hu-
mans. Sin ce then, more than 20 cases of car diac
complications associated with high-dose cyclo-
phosphamide have been described (Hopkins et al.
1982; Mills & Roberts 1979; O'Connell & Beren-
baum 1974), although cyclophosphamide has es-
788
Table IV. Cyclophosphamide-induced pulmonary toxicity
Clinical symptoms Histopathological features
Dyspnoea Endothelial swelling
Cough Type II cell hyperplasia
Fever Interstitial oedema
Pulmonary oedema Thickening of alveolar septae
(noncardiogenic) Lymphocyte and histiocyte
infiltration
Abnormal lung sounds Interstitial fibrosis
sentially no cardiac toxicity at the standard doses
used in most neoplastic diseases.
2.3.1 Mechanism
The precise mechanism by which cyclophos-
phamide produces cardiotoxicity is not known. It
has been postulated that cyclophosphamide (or its
metabolites) directly affects the endothelium with
secondary extravasation of blood containing high
concentrations of cyclophosphamide. The trans-
ient antidiuretic effect of cyclophosphamide may
also contribute to cardiopulmonary failure (Cazin
et al. 1986). No clear risk factors have been iden-
tified for predicting those most at risk, but cardiac
complications are frequent when high-dose cyclo-
phosphamide and total body irradiation are used
in regimens to prepare patients for bone marrow
transplantation (table V). Since heart damage fol-
lowing radiotherapy has been documented, and
there is evidence of enhanced cardiotoxicity with
combination radiation and doxorubicin (adria-
mycin) treatment, prior treatment with anthracy-
clines and/or radiation would appear to be con-
traindications for using high doses of
cyclophosphamide (Tokaz & Von Hoff 1984). Ad-
ditionally, the fact that many patients with cyclo-
phosphamide-induced cardiotoxicity have had
concurrent chemotherapy suggests that combina-
tion chemotherapy may predispose patients to cy-
clophosphamide cardiotoxicity (Baello et al. 1986).
2.3.2 Clinical Symptoms
The clinical picture of cyclophosphamide-in-
duced heart damage appears days or weeks after
treatment. Some indicators of cardiac toxicity are
Drugs 42 (5) 1991
a weight gain of more than 2kg within 48 hours,
abnormal ECG (decrease in the sum of QRS com-
plexes), shortness of breath and other classic signs
of acute congestive heart failure (table VI).
2.3.3 Histopathological Findings
Pathological findings are characterised by ser-
ofibrinous pericarditis and also include interstitial
oedema, haemorrhage, fibrin deposits and multi-
focal necrosis (Cazin et al. 1986). Cyclophosph-
amide-induced complications may include car-
diomyopathies and/or pericarditis, heart failure,
and disturbances in cardiac rhythm (table VI).
3. Long Term Complications and Toxicity
3.1 Reproductive Effects
Azoospermia and ovarian failure are well docu-
mented after long term cyclophosphamide therapy
(Gershwin et al. 1974). Cyclophosphamide causes
reversible azoospermia when used with other agents
(vincristine, prednisone) [Chapman 1984]. Studies
in rodents indicate that cyclophosphamide is ex-
tremely toxic to primordial and antral follicles
(Plowchalk & Mattison 1991). The effects appear
to be dependent on the dose and duration of treat-
ment. Libido and sexual capability are usually not
affected. Azoospermia may be reversible but re-
covery is usually slow and often incomplete. Irreg-
ular menses and amenorrhoea appear to be per-
manent in most patients (Dorr & Fritz 1980).
3.2 Teratogenic Effects
Cyclophosphamide is a well known embryo-
toxin in vivo (Chaube et al. 1967) and teratogenesis
has been reported when large intravenous doses
were administered during the second month of
pregnancy (Toledo et al. 1971). A few reports have
appeared that seem to refute the teratogenic po-
tential of cyclophosphamide. However, since cy-
clophosphamide is an alkylating agent its use dur-
ing pregnancy should be strongly discouraged.
3.3 Oncogenic Effects
Long term continuous therapy with chemother-
apeutic agents is suspected of contributing to the
increased risk of a second malignancy. The potent
Cyclophosphamide Toxicity 789

Table V. Selected studies implicating cyclophosphamide in cardiac tox icity

Patient characteristics (age, sex, Therapy Toxicity Reference

primary diagnosis) (dose duration)

63 BMT patients
15-55 years
Acute leukaemia (21)
Non-Hodgkin's lymphoma (17)
Chronic myelocytic leukaemia (11)
Aplastic anaemia (4)
Hodgkin 's disease (2)
Malignant melanoma (2)
Solid tumours (5)
Multiple myeloma (1)
TACC [39 cases]
TACC + irradiation 8-10 Gy [6 cases]
Cyclophosphamide + irradiation
[6 cases]
Cyclophosphamide, 60 mg/kg/day
Multiple chemotherapeutic agents
[8 cases]
[Cyclophosphamide 60-200 mg/kg,
doxorubicin 65-250 mg/m 2 and/or
duanorubicin 140-2000 mg/m 2]
Fatal cardiomyopathy and/or Cazin et al.
pericarditis, 6 cases (9.5%) (1986)
Nonfatal heart failure , 14 cases
(22%)
x2 Nonfatal pericarditis, 7 cases
(11%)
Disturbance of rhythm , 32 cases
(51%)
[tachycardia 13; bradycardia 14;
atrial arrhythmia 3; ventricular
arrhythmias 2]

25 patients with malignancies

Mediastinum (1) Cyclophosphamide, 60 mg/kg x 2 or 1 death due to myocardial Buckner et al.
120 mg/kg x 1 (IV) + irradiation necrosis (4%) (1972)
[5 cases]
Testicular (4) Cyclophosphamide 60 mg/kg (IV) +
irradiation [2 cases]
Melanoma (3) Cyclophosphamide 60 mg/kg (IV)
[4 cases]
Ovarian (3) Cyclophosphamide 120 mg/kg (IV)
[3 cases]
Lung (5) Cyclophosphamide 120 mg/kg (IV)
x 2 [2 cases]
Colon (3) Cyclophosphamide 60-120 mg/kg (IV)
x 4 [3 cases]
Pancreas (1) Cyclophosphamide 60-120 mg/kg (IV)
x 6 [2 cases]
Skin (2) Cyclophosphamide 240 mg/kg (IV)
[1 case]
Pelvis (1) 5-Fluorouracil + cyclophosphamide
60-120 mg/kg (IV) [3 cases]
Kidney (2) Hydroxyurea + cyclophosphamide
120 mg/kg (IV) [1 case]

Abbreviations: BMT = bone marrow transplant; TACC = cyclophosphamide 45 mg/kg/day x 4; 6-thioguanine 100 mg/m 2 2 X/day
x 7; cytos ine arabinoside 100-200 mg/m 2 2 X/day x 7; CCNU 200-250 mg/m 2 .

alkylating and immunosuppressive activity of cy-
clophosphamide is suggestive of its oncogenic po-
tential, since decreased immunosurveillance and
interactions with DNA are known oncogenic risk
factors. Data demonstrating that cyclophosph-
amide is carcinogenic are extensive. Fairchild et al.
(1979) found a 9-fold increase in the incidence of
bladder cancer in patients treated with cyclophos-
phamide compared to patients treated with other
anticancer agents, while Cox (l979b) summarised
reports indicating that the increase in bladder can-
cer was greater than any other tumour.
The mechanism(s) by which cancer arises fol-
lowing therapy with cyclophosphamide is not clear.
One theory associates the development of bladder
tumours and haemorrhagic cystitis. Upon release
of acrolein into the bladder, damage to the epithe-
lium occurs and is followed by rapid epithelial re-
790 Drugs 42 (5) 1991

Table VI. Cyclophosphamide-induced cardiac toxicity
Clinical symptoms
Serofibrinous pericarditis
Acute congestive heart failure
Weight gain (> 2 kg/48h)
Abnormal ECG
if Cox's (I 979b) theory is correct , patients devel-
oping haemorrhagic cystitis may have a higher
Histopathological features
probability of developing secondary cancer of the
Interstitial oedema bladder or upper urinary tract , particularly if ob-
Haemorrhage struction is present. It is possible that damage of
Fibrin deposits
less severity may be sufficient to promote carcino-
Multifocal necrosis
genesis and there is evidence that men may be at
higher risk than women (McDougal et al. 1981).

generation and hyperplasia. Cox (1979b) proposed
that alkylating agents in the urine interfere with
nucleic acid replication more effectively as an in-
creasing number of cells begin to divide. This leads
to an increased probability of clastogenic and car-
cinogenic changes in the genetic material. Another
possibility is that cyclophosphamide-induced im-
munodeficiency decreases surveillance of spontan-
eously occurring neoplasms and allows tumours to
proliferate.
The development of secondary malignancies in
patients being treated for neoplastic diseases could
be related to the primary tumour. However, re-
ports of neoplasms in patients given cyclophos-
phamide for non-neoplastic diseases suggest that
this factor cannot explain all additional tumours
in cancer patients treated with this drug. Plotz et
al. (1979) reported bladder cancer in 2 patients after
cyclophosphamide therapy for rheumatoid arthri-
tis and systemic lupus erythematosus. Carcinoma
of the urethra and bladder have been reported in
renal allograft patients treated with cyclophosph-
amide and bladder leiomyosarcoma has been re-
ported in patients receiving treatment for lupus ne-
phritis (Lemmers & Barry 1990; Thrasher et al.
1990). McDougal et al. (1981) reported the first case
of renal pelvic carcinoma in a patient treated with
cyclophosphamide for a nonmalignant disease .
Urine stasis due to partial ureterovesical obstruc-
tion probably played a significant role in the patho-
genesis of this tumour. Interestingly, there appears
to be a high incidence of squamous cell carcinoma
after cyclophosphamide, a type which in the gen-
eral population accounts for less than 10% of ur-
inary tract carcinomas (McDougal et al. 1981).
The development of cancer secondary to cyclo-
phosphamide treatment is a rare event. However,
4. Recommendations for Avoiding Toxicity
4.1 Immunosuppression
Loss of immunocompetence is a vital concern
in patients treated with cyclophosphamide. Eval-
uations of bone marrow function is imperative and,
when administered on a long term basis , cyclo-
phosphamide therapy should be guided by the total
leucocyte count which should be kept between 2500
and 4000 cells/nun- of blood. Cyclophosphamide
treatment regimens based on weight, surface area ,
and renal function are designed to prevent exces-
sive bone marrow depression. However, the rate
of cyclophosphamide metabolism varies directly
according to body surface area as opposed to weight,
and toxicity correlates best with surface area
(Gershwin et al. 1974).
Cumulative dose monitoring and scheduling of
chemotherapeutic agents have proven to be very
important with respect to myelosuppression. A
patient's treatment history should be known so that
interactions between past and presently used drugs
can be discovered. For example , bone marrow hy-
poplasias are rare and aplasias virtually non-
existent in patients that have not previously re-
ceived radiotherapy or chemotherapy (Mathe 1974).
Protocols utilising intermittent treatment with
higher doses of cyclophosphamide have been de-
veloped in an attempt to decrease the morbidity
associated with daily cyclophosphamide adminis-
tration. Intermittent cyclophosphamide therapy is
associated with less immunosuppression and a
lower incidence of cancer and bladder toxicity when
compared to the same total dose given as low-dose
daily protocols (Cupps 1990). Recently, the stand-
ard dictum that high-dose intermittent schedule
chemotherapy is better treatment has been ques-
Cyclophosphamide Toxicity
tioned. The theory behind this protocol assumes
that a higher dose of the chemotherapeutic agent
kills a higher percentage of tumour cells or
lymphoc ytes (Dorr & Fritz 1980). It has been dem-
onstrated that intermittent high dose (I g/m 2)
intravenous cyclophosphamide (pulse cyclophos-
phamide) is equally effective as low-dose daily
administration in the treatment of systemic lupus
erythematosus with nephritis (Ballow et al. 1984).
However, when used in the treatment of Wegner's
granulomatosis, a sustained remission was ob-
served in only 21% of the patients treated with pulse
cyclophosphamide (Hoffman et al. 1990). Other
concerns about the use of pulse cyclophosphamide
protocols involve the possibility that the risk of
aplasia may be greater during the induction phase
with the pulse than with low-dose daily cyclo-
phosphamide, and the inability to modify the dose
in response to dail y leucocyte count.
Cycle-dependent drugs such as cyclophos-
phamide should not be administered a second time
until the leucocyte count is restored. Under certain
circumstances, the interval between cycles can be
shortened. Bacillus Calrnette-Guerin (BCG) and
some other agents (androgens and some new cy-
tokines in particular) can indu ce stem cells to cycle
thereby enhancing recovery from leucopenia. Mathe
(1974) demonstrated that BCG has this effect in
mice treated with 250 mg/kg cyclophosphamide and
in humans given pulse cyclophosphamide. An-
other way in which immunocompetence can be
maintained is to treat with several chemothera-
peutic agents that have different primary toxicities
or a different duration or timing of the same tox-
icity. This is the rationale behind the combination
of cyclophosphamide with non-immunosuppres-
sant agents such as corticosteroids and vinca al-
kaloids.
4.2 Nausea and Vomiting
A variety of conditions commonly found in
cancer patients can cause nausea and vomiting and
when possible the underl ying cause should be iden-
tified and corrected. Administering chemothera-
peutic agents at bedtime with a sedative may en-
791
able some patients to sleep through the period of
most intense CNS stimulation and therefore de-
crease or prevent vomiting. However, if vomiting
does occur in an overly sedated patient the chance
of aspiration is enhanced. Oral cyclophosphamide
is better tolerated after a meal and some patients
report decreased nausea when taken with cold foods
such as ice cream (Dorr & Fritz 1980). This may
act to buffer the gut and decrease local irritation.
However, the presence offood in the gut may alter
absorption of the drug. Keeping a patient still in a
relaxed quiet environment may also decrease
nausea and vomiting by counteracting the cyclo-
phosphamide-induced increase in sensitivity of the
labyrinthine system to mot ion (Dorr & Fritz 1980).
Antiemetic drugs are helpful but do not prevent
cyclophosphamide-induced nausea and vomiting.
The antiemetic agents most widely used are the
phenothiazines, difenidol , trimethobenzamide and
benzquinamide. Other agents that have met with
some success include metoclopramide, lorazepam
and thieth ylperazine administered sequentiall y, di-
phenhydram ine, tetrah ydrocannabinol (THC) and
nabilone (Hoffman et al. 1990; Mitchell & Schein
1984).
4.3 Alopecia
The complete prevention of alopecia is not pos-
sible but loss may be minimised by gentle scalp
care during susceptible times. Short term tourni-
quets or ice bags applied to the scalp can be used
to restrict access of chemotherapeutic agents to the
scalp matrix during administration. Scalp tourni-
quet has been shown to significantly reduce hair
loss in several combination regimens containing
cyclophosphamide (Pesce et al. 1978). However,
because of the possibility of creating a sanctuary
for tumours in the scalp, these procedures should
be avoided with widely metastatic tumours such
as leukaemia and lymphoma. If a drug is given by
infusion, a scalp tourniquet is not indicated and
can be deleterious if left in place for long periods.
792
4.4 Urotoxicity
The prognosis in patients who develop cyclo-
phosphamide-induced haemorrhagic cystitis is
generally good due to a variety of relatively suc-
cessful treatment protocols for this complication,
although the best treatment remains prevention.
Induction of frequent voiding may provide pro-
phylaxis by diluting acrolein and reducing uroth-
elial exposure. It should be noted , however, that
cyclophosphamide produces a direct effect on renal
tubules , inducing a state of inappropriate water re-
tention. Therefore, excessive hydration may put the
patient at risk for fluid overload and possible
hyponatraemia, seizures and death (DeFronzo et
al. 1973).
Attempts to decrease the urothelial toxicity of
cyclophosphamide have led to the development of
thiol compounds that inactivate acrolein in the
bladder. The most useful agent is sodium 2-mer-
captoethane-sulfonate (mesna). Mesna can be given
orally or parenterall y and is oxidised to a stable
inactive disulphide within minutes. It becomes ac-
tive when excreted into the urine where it binds
acrolein (DeVries & Freiha 1990). Mesna has the
added benefit of inhibiting the release of acrolein
from 4-hydroxycyclophosphamide in the urine
(Levine & Richie 1989). N-AcetyIcysteine, which
binds to the carbon-to-carbon double bond of ac-
rolein forming a stable and nontoxic compound
(Kaye 1973; Primack 1971), has also been used.
However, this agent does not provide upper tract
protection since it must be instilled directly into
the bladder in order to avoid decreasing the chem-
otherapeutic activity of cyclophosphamide and to
reach effective local concentrations.
Periodic urine cytologies on patients receiving
cyclophosphamide may aid in the early detection
of bladder toxicity (Fairchild et al. 1979). Once
haemorrhagic cystitis develops, treatment varies
depending on the degree haematuria. Most cases
resolve spontaneously after stopping cyclophos-
phamide and the drug can often be reinstated later
(Lawrence et al. 1975). In mild cases, suprah ydra-
tion to maintain elevated urinary output is indi-
cated. In more severe cases, patients may be treated
Drugs 42 (5) 1991
with continuous irrigation of the bladder or intra-
vesicle instillation of formalin or alum to prevent
clot retent ion (Levine & Krane 1990; Levine & Ri-
chie 1989). When these measures fail, ligation of
the hypogastric arteries, urinary diversion with
cystotomy and bladder packing, or cystectomy have
been advocated (Andriole et al. 1990; Eigner &
Freiha 1990). Alternativel y, prostaglandins and
their analogues have been shown to be effective in
the control of cyclophosphamide-induced haemor-
rhagic cystitis. However, this is not an established
method of treatment and it is recommended that
informed consent be obtained prior to its use (Lev-
ine & Krane 1990).
4.5 Pulmonary Toxicity
Currently, there are no known parameters for
identifying patients predisposed to lung injury.
Suggestions for prevention include proph ylactic
treatment with antimicrobials in immunosup-
pressed patients being treated with cyclophosph-
amide (to prevent opportunistic infections ), limi-
tation of the use of daily cyclophosphamide/
predn isone, and thorough knowledge of the patient
including previous therapies and characteristics of
their lifestyle which might increase the risk of pul-
monary complications.
Cyclophosphamide must be immediately with-
drawn from the treatment regimen upon diagnosis
of pulmonary injury. Alternative drugs with less
toxicity toward the lung can be used. Although cor-
ticosteroids have been effective in mild cases (Ad-
amson 1984; Burke et al. 1982) they failed to pre-
vent mortality in more serious incidents (Cooper
et al. 1986; Rodin et al. 1970) and it has been sug-
gested they potentiate some types of lung injury
(Kehrer et al. 1984). Recurrence of pulmonary
symptoms associated with renewed cyclophosph-
amide therapy in patients who showed rapid re-
covery after stopping previous cyclophosphamide
treatment is not common (Spector et al. 1980; To-
pilow et al. 1973). The prognosis is favourable for
patients diagnosed at an early stage and is variable
in patients showing signs of severe pulmonary in-
sufficiency.
Cyclophosphamide Toxicity
4.6 Cardiac Toxicity
There is no specific prophylactic or sympto-
matic treatment available for cyclophosphamide-
induced cardiotoxicity. Considering the poor effi-
cacy of cardiac stimulants, it may be desirable to
limit the use of high-dose cyclophosphamide in
preparation of leukaemic patients for marrow
transplant. This may be accomplished by giving
preference, when possible, to total body irradiation
over chemotherapy regimens containing cyclo-
phosphamide, or by using the lowest dose of cy-
clophosphamide that is effective in conditioning a
patient for transplant (Beelen et al. 1989).
4.7 Reproductive Toxicity
There is some evidence suggesting that pulse cy-
clophosphamide therapy may lessen the degree of
amenorrhoea in women by comparison to those re-
ceiving prolonged treatment with daily cyclophos-
phamide (Hoffman et al. 1990). Additionally, it
would be prudent to avoid combining cyclophos-
phamide therapy with other agents known to cause
reproductive effects, such as busulfan and corti-
costeroids .
4.8 Teratogenesis
Teratogenic effects of chemotherapeutic agents
generally appear to be less pronounced when given
late in pregnancy. However, there is a sound basis
for the absolute avoidance of chemotherapeutic
agents in pregnant women unless the patient's life
is endangered.
4.9 Oncogenesis
In view of the expanding evidence suggesting an
association between cyclophosphamide therapy and
subsequent urinary tract neoplasms, it may be pru-
dent to re-evaluate the use of cyclophosphamide in
nonneoplastic disorders. Prophylactic measures that
should be taken to prevent bladder cancer in
patients who must be treated with cyclophosph-
amide are those which diminish the risk of hae-
793
morrhagic cystitis (hydration; N-acetylcysteine;
mesna) [Cox 1979b). Patients being considered for
long term cyclophosphamide therapy should also
be evaluated for obstructive uropathy in order to
diminish the risk of developing upper urinary tract
cancers (McDougal et al. 1981).
5. Conclusions
The acute toxicities of cyclophosphamide are
related to its cytotoxicity. Like other alkylating
agents, cyclophosphamide is most toxic to rapidly
proliferating tissues such as the haematopoietic
system, epithelial cells of the gastrointestinal tract,
hair follicles and gonads. Immunosuppression
(when not desired) is the most significant expected
complication of cyclophosphamide use. However,
the availability of aseptic units to enhance the im-
munocompromised patient's safety during the in-
duction phase, as well as leucocyte and platelet
transfusions, allow many of the complications of
aplasia to be overcome; As a result, specific organ
toxicities often dictate the dose and duration of
treatment. The most common of these toxicities is
bladder cystitis which occurs in approximately 10%
of the patients treated with standard doses of cy-
clophosphamide. Because of improvements in can-
cer treatment and organ transplantation, an in-
creasing number of patients are achieving prolonged
survival. Therefore, late complications of cyclo-
phosphamide, such as reproductive failure and on-
cogenesis, are becoming more important. More
consideration should be given to reducing these late
complications.
In view of the numerous toxicities associated
with cyclophosphamide, most of which can be life-
threatening, the decision to use cyclophosphamide
in clinical settings must weigh known complica-
tions against potential benefits. Cyclophosphamide
is frequently used to treat conditions which are not
necessarily fatal and, on an individual basis, its use
may be justified. However, physicians should be
alert to the possibility of inducing malignancies and
toxicities that may threaten the life of the patient.
794
Acknowledgements
This wo rk was su p po rt ed by N IH gran t HL 356 89 a nd
th e Gustavus a nd Louise P fe itTe r R esea rch F oundatio n .
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