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- sociated with this drug more elusive and difficult
ter, was synthesised in 1958 as an orally active to control.
transport form of the alkylating agent chiormeth- The wide variety of conditions in which cyclo-
ine (mustine , mechlorethamine) [Bourscaux & phosphamide is employed puts many patients at
Brock 1958]. The fundamental pharmacological risk and the seriousness of cyclophosphamide-in-
activiti es of alkylating agents are disruption of cell duced toxicities dictates the need to limit these ad-
growth, mitot ic activit y and differentiation and verse effects whenever possible. The purpose of this
function , primarily by cross-linking DNA strands. article is to characterise the most important clinical
The capacity of cyclophosphamide to interfere with toxicities associated with cyclophosphamide and to
normal cell division in all rapidly proliferating tis- provide practical recommendations for their
sues provides the basis for its therapeutic effects avoidance . It is not the intention of this article to
and many of its toxicities. be a compreh ensive literature review and, there-
fore, citations of experimental data are limited.
Cyclophospham ide has a wide spectrum of
clinical uses and is an essential component of nu-
1. Common Complications and Toxicities
merous combination chemotherapeutic regimens.
1.1 Bone Marrow Depression
As a single agent, cyclophospham ide is potentially
curative in Burkitt's lymphoma (Ziegler et al. 1970)
and is a highly effective immunosuppressant. Myelosuppression consisting primaril y of leu-
Worldwide, cyclophosphamide is used in around copenia is the most significant of the cyclophos-
phamide-induced toxicities. The nadir (8 to 14 days)
500 000 patients yearly. Organ-specific toxicities
and recovery (I8 to 25 days) times are relatively
and secondary tumours are rare with normal doses.
rapid compared with other antineoplastic agents.
However, doses are often pushed to very high lev-
However, the leucopenia and granulocytopenia
els [240 mg/kg has been reported (Newell & Gore
which occur increase the patient's susceptibility to
1991)] and dose-limiting and life-threatening tox-
pathogenic bacteria or opportunistic microorga-
icities occur in many situations.
nisms. Infectious complications are common in
The crucial factor in the therapeutic and toxic patients treated with high-dose cyclophosphamide,
effects of cyclophosphamide is the requirement for including life-threatening septicaemia (Buckner et
metabolic activation (fig. I). The active metabo- al. 1972; Horn et al. 1990). Although cyclophos-
lites are generated preferentially in the liver, and phamide is generally considered to be platelet-spar-
to a lesser extent in other tissues. It is generally ing, thrombocytopenia can also be a significant
believed that the chlormethine metabolites (in- complication leading to an increased potential for
cluding phosphoramide mustard and nor-nitrogen bleeding episodes.
mustard) are responsible for the therapeutic effects,
and acrolein for the toxic effects of cyclophosph- 1.2 Nausea and Vomiting
amide. While this confers some selectivity upon Nausea and vomiting are promin ent side effects
cyclophosphamide, it also makes the toxicities as~ 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 A frequent manifestation of cyclophosphamide
gastrointestinal tract have a high mitotic index, lo- toxicity is damage to hair follicles (Calabresi &
cal irritation occurs with high doses of cyclophos- Chabner 1990). Extensive alopecia is observed in
phamide. However, this generally does not account at least 50% of patients treated and should be ex-
for the nausea and vomiting which occur in 50% pected, to some degree, in all patients. With long
of the patients treated within minutes of admin- term therapy, axilJary, extremity and pubic hair
istration. Individual patient tolerance to cyclo- may also be lost (Doff & Fritz 1980). Hair loss
phosphamide varies greatly and psychological pre- generally commences 1 to 2 weeks followinga single
conditioning may worsen this toxicity (Doff & Fritz pulse and becomes maximal after I to 2 months.
1980). 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 1966; Rubin & Rubin 1966). Today , sterile hae-
begins even if successive treatments are delivered. morrhagic cystitis is recognised as a major dose-
Regrowth may be atypical initially (unusual tex- limiting side effect of cyclophosphamide usage.
ture; different shade), but this phase is transient Haemorrhagic cystitis is defined as inflamma-
and full recovery to normal is usually achieved after tion characterised by diffuse or insidious vesicle
therapy ends. bleeding within the bladder wall. Cyclophosph-
2. Organ-Specific Toxicities amide-induced haemorrhagic cystitis is considered
2.1 Urotoxicity to be dose-related in animals, but several clinical
studies have failed to establish this correlation in
Numerous reports have appeared since 1959 humans (Lawrence et al. 1975). The incidence of
concerning haemorrhagic cystitis in humans treated cyclophosphamide-induced haemorrhagic cystitis
with cyclophosphamide for various neoplastic and has been reported to be as high as 78% with 4%
non-neoplastic diseases. However, the serious na- mortality from uncontrolled haemorrhage (Grin-
ture of this complication was not realised until a berg-Funes et al. 1990). However, other sources in-
number of cases of severe bladder haemorrhage and dicate the frequency ranges from 2 to 40% in un-
death were reported in the mid-1960s (Pearlman 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 , 28 patients - 200 mg/m 2 weekly or Bladder wall fibros is in 10 (25%) Johnson &
M & F, 300 mg/m 2 every other wk (IV) [slight 3; marked 3; severe 4 (3 Meadows (1971)
Ages not given 3 patients - 50-200 mg/m 2 daily with telangiectasia)]
Leukaemia (26), (orally)
Neuroblastoma (9), 9 patients - both routes
Wilms ' tumour (2),
Lymphosarcoma (1), 18 patients - 3-20 wks
Rhabdomyosarcoma (1), 12 patients - 20-40 wks
Hodgkin 's disease (1) 10 patients - 40-88 wks

Cumulative Dosage
100 patients w/CPHC 46 patients - 18g (IV) over 12 mos 93 microhaematuria Stillwell & Benson
53 M, 47 F 54 patients - 90g (orally) over 38 mos 22 irritative voiding (1988)
5-77 years 29 cystitis and hyperplastic or
Malignant disease (72), ulcerated mucosa
Benign disease (28) 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 785

induced haemorrhagic cystitis developed at sig-

Table II. Cyclophosphamide-induced bladder toxicity
nificantly lower doses and with shorter durations
Clinical symptoms Histopathological features of therapy in patients treated intravenously as op-
posed to orally. Additionally , previous or concur-
Gross haematuria Eccentric nuclei
rent treatment of patients with busulfan or radio-
Irritative voiding Hyperchromatic nuclei
Frequency of urination Nuclear pyknosis therapy, both of which may induce haemorrhagic
Dysuria Vacuolisation cystitis by themselves, may increase the risk of de-
Burning Polymorphonuclear leucocytes veloping this toxicity (Beelen et aI. 1989; Stella et
Urgency Necrotic cystitis
aI. 1990).
Incontinence Desquamation
Nocturia Mucosa covered by dense
exudate 2.1.3 Histopathological Findings
Cyclophosphamide administration causes a
2.1.1 Mechanism cytotoxic response in the urothelium of animals and
Several lines of evidence suggest that cyclo- humans that precedes haemorrhagic cystitis (Forni
phosphamide-induced injury to the urinary blad- et aI. 1964; Koss 1967; Stella et aI. 1990). The most
der results from contact between the urothelium striking feature of this process is marked but vari-
and a toxic metabolite present in the urine (Levine able cell enlargement. Nuclei are often eccentric and
& Ritchie 1989; Phillips et al. 1961). Damage to almost always hyperchromatic with nuclear pyk-
the urinary bladder in animals occurs only after nosis as a common late effect. Cytoplasm shows
treatment with cyclophosphamide analogues that vacuolisation and at times contains foreign mater-
are metabolised to acrolein. Thus, this metabolite ial or is infiltrated with polymorphonuclear leu-
is believed to be responsible for cyclophosph- cocytes. Histopathological correlations include
amide-induced urotoxicity (Cox 1979a), although severe necrotic cystitis, desquamation and mucosa
chloroacetaldehyde has also been suggested as a covered with a dense exudate (table II). Ulceration
potential bladder toxicant. is followed by an epithelial regenerative process in-
cluding inflammation, haemorrhage and extensive
2.1.2 Clinical Symptoms epithelial hyperplasia.
Several retrospective studies have appeared in Although bladder damage is the primary mani-
the literature in recent years characterising the festation of cyclophosphamide-induced urotoxic-
clinical features, frequency, contributing factors, ity, pathological changes in the upper urinary tracts
and prognosis of cyclophosphamide-induced hae- have been described in both experimental animals
morrhagic cystitis (table I). Symptoms include gross and humans (Efros et aI. 1990; Koss 1967; Me-
haematuria, irritative voiding, frequency, dysuria, Dougal et aI. 1981 ; Phillips et aI. 1961). It has also
burning, urgency, incontinence and nocturia (table been demonstrated that long term cyclophosph-
II) [Stillwell & Benson 1988]. Diagnosis of cyclo- amide administration is associated with urinary
phosphamide-induced haemorrhagic cystitis is bladder fibrosis and telangiectasia (Johnson &
based on: (a) a history of gross haematuria; (b) la- Meadows 1971).
boratory findings of microscopic haematuria; (c)
platelet counts of greater than 50 000/mm 3; and 2.2 Pulmonary Toxicity
(d) lack of significant bacterial growth on urine cul-
tures (Lawrence et al. 1975). The incidence of cyclophosphamide-induced
The predisposition of patients to develop cyclo- lung injury is much less than haemorrhagic cystitis
phosphamide-induced haemorrhagic cystitis is not and occurs in only about 1% of treated patients
well understood and dehydration is the only un- (Cooper et aI. 1986). However, it is often dose-lim-
disputed risk factor. However, Stillwell and Ben- iting and sometimes life-threatening. Interstitial
son (1988) found evidence that cyclophosphamide- pneumonitis and pulmonary fibrosis are the two
786 Drugs 42 (5) 1991

most common lung conditions associated with cy- Transient increases of transforming growth fac-
clophosphamide chemotherapy (Burke et al. 1982; tor {3, in conjunction with other cytokines have
Cooper et al. 1986; Patel et al. 1976; Rodin et al. been hypothesised to mediate cyclophosphamide-
1970). Lung injury following treatment with cyclo- induced interstitial pulmonary fibrosis (Lazo &
phosphamide was reported as early as 1967 (Andre Hoyt 1990). However, the mechanism by which fi-
et al. 1967) and has been observed both in patients brosis is triggered is unclear. Production of reactive
receiving cyclophosphamide along with other anti- oxygen species (Gurtoo et al. 1981) and lipid per-
neoplastic drugs (Dohner et al. 1972; Mark et al. oxidation (Patel 1990) have been suggested as pos-
1978) and in those receiving cyclophosphamide sible causes of the lung injury, but evidence sup-
alone for nonmalignant diseases (table III) [Burke porting these mechanisms is minimal.
et al. 1982; Maxwell 1974].
Risk factors for developing lung injury after cy- 2.2.2 Clinical Symptoms
clophosphamide are not clear. Dosage, age of the Table IV lists the common symptoms and his-
patient, disease condition, or duration of treatment topathological findings of interstitial pneumonitis
do not appear to be predisposing factors (Cooper and pulmonary fibrosis caused by cyclophosph-
et al. 1986). However, a combination of drugs, amide. Symptoms have occurred after 2 to 3 weeks
radiotherapy or oxygen therapy is known to po- (Rodin et al. 1970; Spector et al. 1979) or 3 to 13
tentiate cyclophosphamide-induced lung injury years (Abdel Karim et al. 1983; Rodin et al. 1970)
(Cooper et al. 1986; Hakkinen et al. 1982). There of continuous treatment with cumulative doses
is also convincing evidence that daily doses of cy- ranging from 30 to 250g. Once lung injury with
clophosphamide and prednisone contribute to the cyclophosphamide becomes evident it progresses
development of Pneumocystis carinii pneumonia rapidly and requires hospitalisation in many cases
which can lead to interstitial pulmonary fibrosis (Patel et al. 1976). The temporal variation in the
(Sen et al. 1991). onset of symptoms may be because cyclophosph-
amide is often used with other antineoplastic agents
2.2.1 Mechanism and corticosteroids. Several cases have been re-
A single intraperitoneal dose (lOO to 200 mg/ ported where the symptoms develop or progress
kg) of cyclophosphamide results in reproducible rapidly after cessation of corticosteroids (Spector
lung fibrosis in experimental animals (Lee & Keh- et al. 1979, 1980).
rer 1985; Patel 1990; Patel et al. 1984; Siemann et General signs of distress such as chest pain, dys-
al. 1986) that is comparable to the fibrotic lesion pnoea, hypoxaemia, cough with expectoration (To-
seen in humans. It is generally accepted that lung pilow et al. 1973) and occasional hyperthermia are
damage occurs when a metabolically activated form common. In one case, auscultation revealed bilat-
of cyclophosphamide interacts covalently with pul- eral scattered rales and sibilant bronchi (Patel et
monary macromolecules. This leads to altered pro- al. 1976). Radiological findings of the chest include
tein synthesis and ultimately, changes in extracel- a bibasilar reticular pattern and, in severe cases,
lular matrix components including collagen. evidence of extensive bilateral fibronodular inter-
Bioactivation of cyclophosphamide can occur via stitial infiltrates and pulmonary oedema (Maxwell
the mixed function oxidase enzyme system and re- 1974). Pulmonary function usually shows the typ-
cent data suggests that it may also occur through ical changes of restrictive lung disease (Dorr & Fritz
cooxidation processes involving the prostaglandin 1980).
H synthase enzyme system (Smith & Kehrer 1991).
Lung tissue is capable of producing reactive species 2.2.3 Histopathological Findings
from cyclophosphamide (Patel 1990), but it is un- Histopathological findings in humans are sim-
clear whether metabolism by this organ is solely ilar to those observed with other pulmonary toxi-
responsible for the observed injury. 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), Santos et al. (1971) reported the first case of cy-
fibroblast proliferation (Patel et al. 1976), and in- clophospham ide-induced cardiom yopath y in hu-
terstitial fibrosis (Burke et al. 1982). Although mans. Sin ce then, more than 20 cases of car diac
cyclophospham ide is a powerful imm unosuppres- complications associated with high-dose cyclo-
sant, lymphocytic and histiocytic interstitial infil- phosphamide have been described (Hopkins et al.
trat ion is a common histopathological finding 1982; Mills & Roberts 1979; O'Connell & Beren-
(Burke et al. 1982). baum 1974), although cyclophosphamide has es-
788 Drugs 42 (5) 1991

Table IV. Cyclophosphamide-induced pulmonary toxicity a weight gain of more than 2kg within 48 hours,
abnormal ECG (decrease in the sum of QRS com-
Clinical symptoms Histopathological features
plexes), shortness of breath and other classic signs
Dyspnoea Endothelial swelling of acute congestive heart failure (table VI).
Cough Type II cell hyperplasia
Fever Interstitial oedema 2.3.3 Histopathological Findings
Pulmonary oedema Thickening of alveolar septae Pathological findings are characterised by ser-
(noncardiogenic) Lymphocyte and histiocyte ofibrinous pericarditis and also include interstitial
infiltration
oedema, haemorrhage, fibrin deposits and multi-
Abnormal lung sounds Interstitial fibrosis
focal necrosis (Cazin et al. 1986). Cyclophosph-
amide-induced complications may include car-
sentially no cardiac toxicity at the standard doses diomyopathies and/or pericarditis, heart failure,
and disturbances in cardiac rhythm (table VI).
used in most neoplastic diseases.
3. Long Term Complications and Toxicity
2.3.1 Mechanism 3.1 Reproductive Effects
The precise mechanism by which cyclophos-
phamide produces cardiotoxicity is not known. It Azoospermia and ovarian failure are well docu-
has been postulated that cyclophosphamide (or its mented after long term cyclophosphamide therapy
metabolites) directly affects the endothelium with (Gershwin et al. 1974). Cyclophosphamide causes
secondary extravasation of blood containing high reversible azoospermia when used with other agents
concentrations of cyclophosphamide. The trans- (vincristine, prednisone) [Chapman 1984]. Studies
ient antidiuretic effect of cyclophosphamide may in rodents indicate that cyclophosphamide is ex-
also contribute to cardiopulmonary failure (Cazin tremely toxic to primordial and antral follicles
et al. 1986). No clear risk factors have been iden- (Plowchalk & Mattison 1991). The effects appear
tified for predicting those most at risk, but cardiac to be dependent on the dose and duration of treat-
complications are frequent when high-dose cyclo- ment. Libido and sexual capability are usually not
phosphamide and total body irradiation are used affected. Azoospermia may be reversible but re-
in regimens to prepare patients for bone marrow covery is usually slow and often incomplete. Irreg-
transplantation (table V). Since heart damage fol- ular menses and amenorrhoea appear to be per-
lowing radiotherapy has been documented, and manent in most patients (Dorr & Fritz 1980).
there is evidence of enhanced cardiotoxicity with 3.2 Teratogenic Effects
combination radiation and doxorubicin (adria-
mycin) treatment, prior treatment with anthracy- Cyclophosphamide is a well known embryo-
clines and/or radiation would appear to be con- toxin in vivo (Chaube et al. 1967) and teratogenesis
traindications for using high doses of has been reported when large intravenous doses
cyclophosphamide (Tokaz & Von Hoff 1984). Ad- were administered during the second month of
ditionally, the fact that many patients with cyclo- pregnancy (Toledo et al. 1971). A few reports have
phosphamide-induced cardiotoxicity have had appeared that seem to refute the teratogenic po-
concurrent chemotherapy suggests that combina- tential of cyclophosphamide. However, since cy-
tion chemotherapy may predispose patients to cy- clophosphamide is an alkylating agent its use dur-
clophosphamide cardiotoxicity (Baello et al. 1986). ing pregnancy should be strongly discouraged.
3.3 Oncogenic Effects
2.3.2 Clinical Symptoms
The clinical picture of cyclophosphamide-in- Long term continuous therapy with chemother-
duced heart damage appears days or weeks after apeutic agents is suspected of contributing to the
treatment. Some indicators of cardiac toxicity are 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 TACC [39 cases] Fatal cardiomyopathy and/or Cazin et al.
Acute leukaemia (21) TACC + irradiation 8-10 Gy [6 cases] pericarditis, 6 cases (9.5%) (1986)
Non-Hodgkin's lymphoma (17) Cyclophosphamide + irradiation Nonfatal heart failure , 14 cases
Chronic myelocytic leukaemia (11) [6 cases] (22%)
Aplastic anaemia (4) Cyclophosphamide, 60 mg/kg/day x2 Nonfatal pericarditis, 7 cases
Hodgkin 's disease (2) (11%)
Malignant melanoma (2) Multiple chemotherapeutic agents Disturbance of rhythm , 32 cases
Solid tumours (5) [8 cases] (51%)
Multiple myeloma (1) [Cyclophosphamide 60-200 mg/kg, [tachycardia 13; bradycardia 14;
doxorubicin 65-250 mg/m 2 and/or atrial arrhythmia 3; ventricular
duanorubicin 140-2000 mg/m 2] 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- anticancer agents, while Cox (l979b) summarised
clophosphamide is suggestive of its oncogenic po- reports indicating that the increase in bladder can-
tential, since decreased immunosurveillance and cer was greater than any other tumour.
interactions with DNA are known oncogenic risk The mechanism(s) by which cancer arises fol-
factors. Data demonstrating that cyclophosph- lowing therapy with cyclophosphamide is not clear.
amide is carcinogenic are extensive. Fairchild et al. One theory associates the development of bladder
(1979) found a 9-fold increase in the incidence of tumours and haemorrhagic cystitis. Upon release
bladder cancer in patients treated with cyclophos- of acrolein into the bladder, damage to the epithe-
phamide compared to patients treated with other lium occurs and is followed by rapid epithelial re-
790 Drugs 42 (5) 1991

Table VI. Cyclophosphamide-induced cardiac toxicity if Cox's (I 979b) theory is correct , patients devel-
oping haemorrhagic cystitis may have a higher
Clinical symptoms Histopathological features
probability of developing secondary cancer of the
Serofibrinous pericarditis Interstitial oedema bladder or upper urinary tract , particularly if ob-
Acute congestive heart failure Haemorrhage struction is present. It is possible that damage of
Weight gain (> 2 kg/48h) Fibrin deposits
less severity may be sufficient to promote carcino-
Abnormal ECG 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 4. Recommendations for Avoiding Toxicity
that alkylating agents in the urine interfere with 4.1 Immunosuppression
nucleic acid replication more effectively as an in-
creasing number of cells begin to divide. This leads Loss of immunocompetence is a vital concern
to an increased probability of clastogenic and car- in patients treated with cyclophosphamide. Eval-
cinogenic changes in the genetic material. Another uations of bone marrow function is imperative and,
possibility is that cyclophosphamide-induced im- when administered on a long term basis , cyclo-
munodeficiency decreases surveillance of spontan- phosphamide therapy should be guided by the total
eously occurring neoplasms and allows tumours to leucocyte count which should be kept between 2500
proliferate. and 4000 cells/nun- of blood. Cyclophosphamide
The development of secondary malignancies in treatment regimens based on weight, surface area ,
patients being treated for neoplastic diseases could and renal function are designed to prevent exces-
be related to the primary tumour. However, re- sive bone marrow depression. However, the rate
ports of neoplasms in patients given cyclophos- of cyclophosphamide metabolism varies directly
phamide for non-neoplastic diseases suggest that according to body surface area as opposed to weight,
this factor cannot explain all additional tumours and toxicity correlates best with surface area
in cancer patients treated with this drug. Plotz et (Gershwin et al. 1974).
al. (1979) reported bladder cancer in 2 patients after Cumulative dose monitoring and scheduling of
cyclophosphamide therapy for rheumatoid arthri- chemotherapeutic agents have proven to be very
tis and systemic lupus erythematosus. Carcinoma important with respect to myelosuppression. A
of the urethra and bladder have been reported in patient's treatment history should be known so that
renal allograft patients treated with cyclophosph- interactions between past and presently used drugs
amide and bladder leiomyosarcoma has been re- can be discovered. For example , bone marrow hy-
ported in patients receiving treatment for lupus ne- poplasias are rare and aplasias virtually non-
phritis (Lemmers & Barry 1990; Thrasher et al. existent in patients that have not previously re-
1990). McDougal et al. (1981) reported the first case ceived radiotherapy or chemotherapy (Mathe 1974).
of renal pelvic carcinoma in a patient treated with Protocols utilising intermittent treatment with
cyclophosphamide for a nonmalignant disease . higher doses of cyclophosphamide have been de-
Urine stasis due to partial ureterovesical obstruc- veloped in an attempt to decrease the morbidity
tion probably played a significant role in the patho- associated with daily cyclophosphamide adminis-
genesis of this tumour. Interestingly, there appears tration. Intermittent cyclophosphamide therapy is
to be a high incidence of squamous cell carcinoma associated with less immunosuppression and a
after cyclophosphamide, a type which in the gen- lower incidence of cancer and bladder toxicity when
eral population accounts for less than 10% of ur- compared to the same total dose given as low-dose
inary tract carcinomas (McDougal et al. 1981). daily protocols (Cupps 1990). Recently, the stand-
The development of cancer secondary to cyclo- ard dictum that high-dose intermittent schedule
phosphamide treatment is a rare event. However, chemotherapy is better treatment has been ques-
Cyclophosphamide Toxicity 791

tioned. The theory behind this protocol assumes able some patients to sleep through the period of
that a higher dose of the chemotherapeutic agent most intense CNS stimulation and therefore de-
kills a higher percentage of tumour cells or crease or prevent vomiting. However, if vomiting
lymphoc ytes (Dorr & Fritz 1980). It has been dem- does occur in an overly sedated patient the chance
onstrated that intermittent high dose (I g/m 2) of aspiration is enhanced. Oral cyclophosphamide
intravenous cyclophosphamide (pulse cyclophos- is better tolerated after a meal and some patients
phamide) is equally effective as low-dose daily report decreased nausea when taken with cold foods
administration in the treatment of systemic lupus such as ice cream (Dorr & Fritz 1980). This may
erythematosus with nephritis (Ballow et al. 1984). act to buffer the gut and decrease local irritation.
However, when used in the treatment of Wegner's However, the presence offood in the gut may alter
granulomatosis, a sustained remission was ob- absorption of the drug. Keeping a patient still in a
served in only 21% of the patients treated with pulse
relaxed quiet environment may also decrease
cyclophosphamide (Hoffman et al. 1990). Other
nausea and vomiting by counteracting the cyclo-
concerns about the use of pulse cyclophosphamide
phosphamide-induced increase in sensitivity of the
protocols involve the possibility that the risk of
labyrinthine system to mot ion (Dorr & Fritz 1980).
aplasia may be greater during the induction phase
Antiemetic drugs are helpful but do not prevent
with the pulse than with low-dose daily cyclo-
cyclophosphamide-induced nausea and vomiting.
phosphamide, and the inability to modify the dose
The antiemetic agents most widely used are the
in response to dail y leucocyte count.
Cycle-dependent drugs such as cyclophos- phenothiazines, difenidol , trimethobenzamide and
phamide should not be administered a second time benzquinamide. Other agents that have met with
until the leucocyte count is restored. Under certain some success include metoclopramide, lorazepam
circumstances, the interval between cycles can be and thieth ylperazine administered sequentiall y, di-
shortened. Bacillus Calrnette-Guerin (BCG) and phenhydram ine, tetrah ydrocannabinol (THC) and
some other agents (androgens and some new cy- nabilone (Hoffman et al. 1990; Mitchell & Schein
tokines in particular) can indu ce stem cells to cycle 1984).
thereby enhancing recovery from leucopenia. Mathe
(1974) demonstrated that BCG has this effect in
mice treated with 250 mg/kg cyclophosphamide and 4.3 Alopecia
in humans given pulse cyclophosphamide. An-
other way in which immunocompetence can be
The complete prevention of alopecia is not pos-
maintained is to treat with several chemothera-
sible but loss may be minimised by gentle scalp
peutic agents that have different primary toxicities
or a different duration or timing of the same tox- care during susceptible times. Short term tourni-
icity. This is the rationale behind the combination quets or ice bags applied to the scalp can be used
of cyclophosphamide with non-immunosuppres- to restrict access of chemotherapeutic agents to the
sant agents such as corticosteroids and vinca al- scalp matrix during administration. Scalp tourni-
kaloids. quet has been shown to significantly reduce hair
loss in several combination regimens containing
4.2 Nausea and Vomiting cyclophosphamide (Pesce et al. 1978). However,
because of the possibility of creating a sanctuary
A variety of conditions commonly found in for tumours in the scalp, these procedures should
cancer patients can cause nausea and vomiting and be avoided with widely metastatic tumours such
when possible the underl ying cause should be iden- as leukaemia and lymphoma. If a drug is given by
tified and corrected. Administering chemothera- infusion, a scalp tourniquet is not indicated and
peutic agents at bedtime with a sedative may en- can be deleterious if left in place for long periods.
792 Drugs 42 (5) 1991

4.4 Urotoxicity with continuous irrigation of the bladder or intra-

vesicle instillation of formalin or alum to prevent
The prognosis in patients who develop cyclo- clot retent ion (Levine & Krane 1990; Levine & Ri-
phosphamide-induced haemorrhagic cystitis is chie 1989). When these measures fail, ligation of
generally good due to a variety of relatively suc- the hypogastric arteries, urinary diversion with
cessful treatment protocols for this complication, cystotomy and bladder packing, or cystectomy have
although the best treatment remains prevention. been advocated (Andriole et al. 1990; Eigner &
Induction of frequent voiding may provide pro- Freiha 1990). Alternativel y, prostaglandins and
phylaxis by diluting acrolein and reducing uroth- their analogues have been shown to be effective in
elial exposure. It should be noted , however, that the control of cyclophosphamide-induced haemor-
cyclophosphamide produces a direct effect on renal rhagic cystitis. However, this is not an established
tubules , inducing a state of inappropriate water re- method of treatment and it is recommended that
tention. Therefore, excessive hydration may put the informed consent be obtained prior to its use (Lev-
patient at risk for fluid overload and possible ine & Krane 1990).
hyponatraemia, seizures and death (DeFronzo et
al. 1973). 4.5 Pulmonary Toxicity
Attempts to decrease the urothelial toxicity of
cyclophosphamide have led to the development of Currently, there are no known parameters for
thiol compounds that inactivate acrolein in the identifying patients predisposed to lung injury.
bladder. The most useful agent is sodium 2-mer- Suggestions for prevention include proph ylactic
captoethane-sulfonate (mesna). Mesna can be given treatment with antimicrobials in immunosup-
orally or parenterall y and is oxidised to a stable pressed patients being treated with cyclophosph-
inactive disulphide within minutes. It becomes ac- amide (to prevent opportunistic infections ), limi-
tive when excreted into the urine where it binds tation of the use of daily cyclophosphamide/
acrolein (DeVries & Freiha 1990). Mesna has the predn isone, and thorough knowledge of the patient
added benefit of inhibiting the release of acrolein including previous therapies and characteristics of
from 4-hydroxycyclophosphamide in the urine their lifestyle which might increase the risk of pul-
(Levine & Richie 1989). N-AcetyIcysteine, which monary complications.
binds to the carbon-to-carbon double bond of ac- Cyclophosphamide must be immediately with-
rolein forming a stable and nontoxic compound drawn from the treatment regimen upon diagnosis
(Kaye 1973; Primack 1971), has also been used. of pulmonary injury. Alternative drugs with less
However, this agent does not provide upper tract toxicity toward the lung can be used. Although cor-
protection since it must be instilled directly into ticosteroids have been effective in mild cases (Ad-
the bladder in order to avoid decreasing the chem- amson 1984; Burke et al. 1982) they failed to pre-
otherapeutic activity of cyclophosphamide and to vent mortality in more serious incidents (Cooper
reach effective local concentrations. et al. 1986; Rodin et al. 1970) and it has been sug-
Periodic urine cytologies on patients receiving gested they potentiate some types of lung injury
cyclophosphamide may aid in the early detection (Kehrer et al. 1984). Recurrence of pulmonary
of bladder toxicity (Fairchild et al. 1979). Once symptoms associated with renewed cyclophosph-
haemorrhagic cystitis develops, treatment varies amide therapy in patients who showed rapid re-
depending on the degree haematuria. Most cases covery after stopping previous cyclophosphamide
resolve spontaneously after stopping cyclophos- treatment is not common (Spector et al. 1980; To-
phamide and the drug can often be reinstated later pilow et al. 1973). The prognosis is favourable for
(Lawrence et al. 1975). In mild cases, suprah ydra- patients diagnosed at an early stage and is variable
tion to maintain elevated urinary output is indi- in patients showing signs of severe pulmonary in-
cated. In more severe cases, patients may be treated sufficiency.
Cyclophosphamide Toxicity 793

4.6 Cardiac Toxicity morrhagic cystitis (hydration; N-acetylcysteine;

mesna) [Cox 1979b). Patients being considered for
There is no specific prophylactic or sympto- long term cyclophosphamide therapy should also
matic treatment available for cyclophosphamide- be evaluated for obstructive uropathy in order to
induced cardiotoxicity. Considering the poor effi- diminish the risk of developing upper urinary tract
cacy of cardiac stimulants, it may be desirable to cancers (McDougal et al. 1981).
limit the use of high-dose cyclophosphamide in
preparation of leukaemic patients for marrow
transplant. This may be accomplished by giving 5. Conclusions
preference, when possible, to total body irradiation
over chemotherapy regimens containing cyclo- The acute toxicities of cyclophosphamide are
phosphamide, or by using the lowest dose of cy- related to its cytotoxicity. Like other alkylating
clophosphamide that is effective in conditioning a agents, cyclophosphamide is most toxic to rapidly
patient for transplant (Beelen et al. 1989). proliferating tissues such as the haematopoietic
system, epithelial cells of the gastrointestinal tract,
4.7 Reproductive Toxicity hair follicles and gonads. Immunosuppression
(when not desired) is the most significant expected
There is some evidence suggesting that pulse cy- complication of cyclophosphamide use. However,
clophosphamide therapy may lessen the degree of the availability of aseptic units to enhance the im-
amenorrhoea in women by comparison to those re- munocompromised patient's safety during the in-
ceiving prolonged treatment with daily cyclophos- duction phase, as well as leucocyte and platelet
phamide (Hoffman et al. 1990). Additionally, it transfusions, allow many of the complications of
would be prudent to avoid combining cyclophos- aplasia to be overcome; As a result, specific organ
phamide therapy with other agents known to cause
toxicities often dictate the dose and duration of
reproductive effects, such as busulfan and corti-
treatment. The most common of these toxicities is
costeroids .
bladder cystitis which occurs in approximately 10%
of the patients treated with standard doses of cy-
4.8 Teratogenesis
clophosphamide. Because of improvements in can-
cer treatment and organ transplantation, an in-
Teratogenic effects of chemotherapeutic agents
creasing number of patients are achieving prolonged
generally appear to be less pronounced when given
late in pregnancy. However, there is a sound basis survival. Therefore, late complications of cyclo-
for the absolute avoidance of chemotherapeutic phosphamide, such as reproductive failure and on-
agents in pregnant women unless the patient's life cogenesis, are becoming more important. More
is endangered. consideration should be given to reducing these late
complications.
4.9 Oncogenesis In view of the numerous toxicities associated
with cyclophosphamide, most of which can be life-
In view of the expanding evidence suggesting an threatening, the decision to use cyclophosphamide
association between cyclophosphamide therapy and in clinical settings must weigh known complica-
subsequent urinary tract neoplasms, it may be pru- tions against potential benefits. Cyclophosphamide
dent to re-evaluate the use of cyclophosphamide in is frequently used to treat conditions which are not
nonneoplastic disorders. Prophylactic measures that necessarily fatal and, on an individual basis, its use
should be taken to prevent bladder cancer in may be justified. However, physicians should be
patients who must be treated with cyclophosph- alert to the possibility of inducing malignancies and
amide are those which diminish the risk of hae- toxicities that may threaten the life of the patient.
794 D rugs 42 (5) 1991

the causative agent. Biochemical Pharm acology 28: 2045-2049,

Acknowledgements 1979a
Cupps TR. Cyclophosphamide: to pulse or not to pulse? Amer-
This wo rk was su p po rt ed by N IH gran t HL 356 89 a nd ican Jo urnal of Medicine 89: 399-402, 1990
DeFronzo RA, Braine H, Colvin M. Water intoxication in man
th e Gustavus a nd Louise P fe itTe r R esea rch F oundatio n . after cyclophosphamide therapy: time course and relation to
drug activation. Annals oflnternal Medicine 78: 86 1-869, 1973
DeVries CR, Freiha FS. Hemorrhagic cystitis: a review. Journ al
References of Uro logy 143: 1-7, 1990
Dohner VA, Ward HP, Standard RE. Alveolitis dur ing procar-
bazine, vincristi ne and cyclophosphamide therapy. Chest 62:
Abdel Karim FW, Ayash RE, Allam C, Salem PA. Pulmonary 636-639, 1972
fibrosis after prolonged treatm ent with low-dose cyclophos-
Dorr RT, Fritz WL (Eds). Cancer chemot herapy handbook, El-
pham ide: a case report. Oncology 40: 174-176, 1983
sevier, New Yor k, 1980
Adamso n IYR. Drug induced pulmon ary fibrosis. Enviro nmental
Efros M, Ahmed T, Choudhury M. Cyclophosphami de-induced
Health Perspectives 55: 25-36, 1984
hemorrh agic pyelitis and ureteritis associated with cystitis in
Andre R, Rochant H, Dreyfus B, Duham el G, Pecheri J. Fibrose
marrow transplantation. Journ al of Uro logy 144: 1231-1232,
interstitielle diffuse du poumon au cours d'un e maladie de
1990
Hodgkin traitee par des doses elevees d'End oxan . Bulletin de
Eigner EB, Freiha FS. Th e fate of the remain ing bladd er following
la Societe Medical L'Hopital Paris 118: 1133-1141, 1967
supravesical diversion. Journal of Urology 144: 31-33, 1990
Andr iole G L, Yuan JJ, Catalona WJ. Cystotomy, temp orary ur-
Fairchild WV, Spence CR, Solomon HD , Ga ngai MP. The in-
inary diversion and bladde r packing in the management of
severe cyclophosphamide-induced hemorrh agic cystitis. Jour- cidence of bladder cancer after cyclophosphamid e therapy.
nal of Uro logy 143: 1006-1007, 1990 Journ al of Urology 122: 163-164, 1979
Baello EB, Eansberg ME, Ferguson DW, Kugler JW, Gingrich JO, Forni AM, Koss LG, Geller W. Cytological study of the effect of
et al. Effect of high-dose cyclophosphamide and total-body ir- cyclophosphamide on the epithelium of the urin ary bladder in
radiat ion on left ventricular function in adu lt patients with man. Cancer 17: 1348-1355, 1964
leukemia undergoing allogenic bone marrow tra nsplantation. Gershwin ME, Goe tzl EJ, Steinberg AD. Cyclophosphamide: use
Cancer Treat ment Reports 70: 1187-1193, 1986 in practice. Annals of Internal Medicine 80: 531-540, 1974
Ballow J E, Austin HA, Muenz LR, et al. Effect of treatment on Gould VE. Miller J. Sclerosing alveolitis induced by cyclophos-
the evaluatio n of renal abnorma lities in lupus nephr itis. New pham ide. America n Jo urna l of Pathology 81: 513-528, 1975
England Jou rnal of Medicine 311: 491-495, 1984 Grinberg-Funes D, Sheldon C, Weiss M. Th e use of prostaglandin
Beelen DW, Quabeck K, Graeven U, Sayer HG, Mahmoud HK, Fz alpha for the prophylaxis of cyclophosphamide ind uced cys-
et al. Acute toxicit y and first clinical results of intensive post- titis in rats. Jou rnal of Urology 144: 1500-1504, 1990
induction therapy using a modified busulfan and cyclophos- G urtoo HL, Hipkens JH , Sharma SD. Role of glutathione me-
phamide regimen with autologous bone marrow rescue in first tabolis m depe ndent toxicity and chemotherapy of cyclophos-
remissio n of acute myeloid leukemia. Blood 74: 1507- 1516, phamide. Cancer Research 4 1: 3584-3591, 1981
1989 Hakkinen PJ, Whiteley JW, Witschi HP. Hyperoxia, but not thor-
Bourscaux F, Brock N. Chemotherapeutic action of a cyclic ni- acic X-radiation, potentiates bleom ycin and cyclophosph-
trogen mustard phospham ide ester (B518-ASTA) in experi- amide-induced lung damage in mice. American Review of
mental tumours in the rat. Nat ure 181: 931, 1958 Respiratory Disease 126: 281-285, 1982
Buckner CD, Rudolph RH, Fefer A, Clift RA, Epstein RB, et al. Hoffman GS, Leavitt RY, Fleisher TA, Minor JR , Fauci AS.
High-dose cyclophosphamide thera py for malignant disease: Treatment of Wegener's granulomatosis with intermittent high-
toxicity, tumor response, and the effects of stored autologous dose int ravenous cyclophosphamide. American Journ al of
marr ow. Cancer 29: 357-365, 1972 Medicine 89: 403-410, 1990
Burke DA, Stoddart JC, Ward MK, Simpson CGB. Fatal pul- Hopk ins HA, Betsill WL, Hobson AS, Looney WB. Cyclophos-
monary fibrosis occurring durin g treatment with cyclophos- phamid e indu ced cardio myopathy in the rat. Cancer Treat-
phami de. British Medical Journ al 285: 696, 1982 ment Reports 66: 1521-1527, 1982
Calabresi P, Chabner BA. Chemotherapy of neoplastic diseases. Horn M, Phebus C, Blatt J. Cancer chemoth erap y after solid or-
In Gilman et al. (Eds) The pharmacological basis of therap eu- gan tran splantat ion. Cancer 66: 1468-1471, 1990
tics, 8th ed., pp. 1202-1263, MacMillan, New York, 1990 Johnson WW, Meadows DC. Urinary -bladder fibrosis and telan-
Case Record s of the Massachusetts General Hospital (Case 26- giectasia associated with long term cycloph osphamide therapy.
1972). New England Journ al of Medicine 286: 1405-1411, 1972 New England Journ al of Medicine 284: 290-294, 1971
Cazin B, Gorin C, Laprote P, Gallet B, Douay L, et al. Cardiac Karnofsky DA. Late effects of immunosuppressive anticancer
complications after bone marro w tran splant ation: a report on drugs. Federation Proceedings 26: 925-932, 1967
a series of 63 consecutive transplantations. Cancer 57: 206 1- Kaye CM. Biosynthesis of mercaptu ric acids from allyl alcohol,
2069, 1986 allyl esters and acrolein. Biochemical Journ al 134: 1093-110I,
Chapman RM. Effect of cytotoxic therapy on sexuality and gon- 1973
ada l function . In Perry MC & Yarbro JW (Eds) Toxicity of Kehrer JP , Klein-Szanto AJP, Sorensen EMB, Pearl man R, Ros-
chemo therapy, pp. 343-363, Grune & Stratto n, Orlando, 1984 ner MH. Enhanced acute lung damage following corticosteroi d
Chaube S, Kurg G, Murp hy ML. Teratogenic effects of cyclo- treatm ent. American Review of Respiratory Disease 130: 256-
phosphamide (NSC-2627 1) in the rat. Cancer Chemotherapy 261, 1984 I
Reports 51: 363-376, 1967 Koss LG. A light and electron microscopic study of the effect of
Coo per AJD, White DA, Matthay RA. Drug-induced pulmonary a single dose of cyclophosphamide on vario us organs in the
disease. American Review of Respiratory Disease 133: 321- rat. Laboratory Invest igation 16: 44-65, 1967
340, 1986 Lawrence HJ, Simone J, Aur JA. Cyclophosphami de-induced
Cox PJ. Cyclophosp hamide cystitis and bladder cancer: a hy- hemorrhagic cystitis in children with leukemia. Cancer 36: 1572-
pothesis. European Journ al of Cancer 15: 1071-1072, 1979b 1576, 1975
Cox PJ. Cyclophosphami de cystitis-identificatio n of acrolein as Lazo JS, Hoyt DG. The molecular basis of interstitial pulmonary
Cyclophosphamide Toxicit y 795

fibrosis by anti neoplastic agents. Cancer Treatment Reviews patients receiving cyclophosphamide for systemic lupus ery-
17: 165- 167, 1990 thematosus or rheum atoid arthritis. Annals of Internal Med-
Lee Y -CC, Kehrer JP . Increased pulmonary collagen syntheses icine 91: 221-223, 1979
in mice treated with cyclophosphamide . Drug and Chemica l Plowchalk DR, Matt ison DR. Phosphoram ide mustard is re-
Toxicology 8: 503-512, 1985 sponsible for the ovarian toxicity of cyclophosphamide. Tox-
Lemmers MJ, Barry JM . Denovo carcinoma of the lower urinary icology and Applied Pharmacology 107: 472-481, 1991
tract in renal allograft recipients. Journal of Urology 144: 1233- Primack A. Amelioration of cyclophosphamide-ind uced cystitis.
1235, 1990 Journ al of the Natio nal Cancer Institute 47: 223-227, 1971
Levine LA. Krane OM. Evaluation of carboprost tro met hamine Rodin AE, Haggard ME, Travis LB. Lung changes and chemo-
in the treatmen t of cyclophosphamide-induced hemorrha gic therapeuti c agents in childhood. American Journal of Diseases
cystitis. Cancer 66: 242-245, 1990 in Children 120: 337-340, 1970
Levine LA. Richie JP. Uro logical complications of cyclophos- Rubin JS, Rubin RT. Cyclophosphamide hemorrhagic cystitis.
phamide. Journ al of Uro logy 141: 1063-1069, 1989 Journal of Uro logy 96: 313-3 16, 1966
Mark GJ, Lehimgar-zadeh A, Ragsdale BD. Cyclophosphamide Sant os GW, Sensenbrenner L, Burke PJ, Colvin M, Ownen Jr
pneumonit is. Th orax 33: 89-93, 1978 AH, et al. Marrow transplantation in man following cyclo-
Mathe G. Prevention of chemotherapy complications: time, tox- phosph amid e. Transplantati on Proceedings 3: 400-404, 1971
icity, pharmacokinetic, pharm acodynamic and logistic factors. Sen RP, Walsh TE, Fisher W, Brock N. Pulmonary complications
In Mathe and Oldham (Eds) Complications of cancer chemo- of comb ination therapy with cyclophosphamide and predni-
therapy, pp. 124-139, Springer-Verlag, New York, 1974 sone. Chest 99: 143-146, 1991
Maxwell I. Reversible pulmonary edema following cyclophos- Siemann OW, Macler L, Penney DP. Cyclophosphamide- indu ced
phamid e treatment. Journal of the American Medical Asso- pulm ona ry toxicity. British Journal of Cancer 53 (Suppl. VII):
ciation 229: 137-138, 1974 343-346, 1986
McDougal WS, Cramer SF, Miller R. Invasive carcinoma of the Smith RD, Kehrer JP. Cooxidat ion of cyclophosphamide as an
renal pelvis following cyclophosphamide therapy for nonma- alternative pathway for its bioactivat ion and lung toxicity.
lignant disease. Cancer 48: 691-695, 1981 Cancer Research 51: 542-548, 1991
Mills BA, Roberts RW. Cyclophosphamide-induced cardio myo- Spector IJ, Zimbler H, Ross JS. Cyclophosphamide and intersti-
pathy: a report of two cases and review of the English litera- tial pneum onitis. Journal of the American Medical Association
ture. Cancer 43: 2223-2226, 1979 243: 1133, 1980
Mitchell EP, Schein PS. Gastroi ntestinal toxicity of chemother- Spector IJ, Zimbler H, Ross JS. Early onset of cyclophosphami de-
apeutic agents. In Yarbro et al. (Eds) Toxicity of chemother- induced interstitial pneum onitis. Jou rnal of the American
apy, pp. 269-295, Gr une & Stratto n, New York, 1984 Medical Associatio n 242: 2852-2853, 1979
Newell DR, Gore ME. Toxicity of alkylating agents: clinical char- Stella F, Batt istelli S, Marcheggiani F, De Santis M, Gia rdi ni C,
acter istics and pharm acokinetic determinants. In Powis G & et al. Urothe lial cell changes due to busulfan and cyclophos-
Hacker MP (Eds) Toxicit y of ant icancer drugs, pp. 44-62, Per- pham ide treat ment in bone marrow transplantation. Acta Cy-
tologica 34: 885-890, 1990
gamon Press, New York, 1991
Stillwell TJ, Benson RC Cyclophosphamide-induced hemor-
O'Con nell TX, Berenbaum MC Cardiac and pulmonary effects
rhagic cystitis. Cancer 61: 451-457, 1988
of high doses of cyclophosphamide and isophosphamide. Can-
Th rasher JB, Miller GJ, Wettlaufer I N. Bladder leiomyosarcoma
cer Research 34: 1586-1591, 1974
following cyclophosphamide therapy for lupus neph ritis. Jou r-
Patel AR, Shah PC, Rhee HL, Sassoon H, Rao KP. Cyclophos- nal of Uro logy 143: 119-121, 1990
pham ide therapy and interstitial pulmonary fibrosis. Cancer Tokaz LK, Von Hoff DO. Th e cardio toxicity of antica ncer agents.
38: 1542-1549, 1976
In Yarbro et al. (Eds) Toxicity of chemotherapy, pp. 199-226,
Patel JM, Block ER, Hood CI. Biochemical indices of cyclo- Gru ne & Statio n Inc, New York, 1984
phospham ide-induced lung toxicity. Toxicology and Applied Toledo TM, Harper RC, Mosser RH. Fetal effects during cyclo-
Pharmacology 76: 128-138, 1984 phosphamide and irradiatio n therapy. Annals ofi nternal Med-
Patel JM. Metabolism and pulm onary toxicity of cyclophosph- icine 74: 87-9 1, 1971
ami de. Pharmacology and Th erapeutics 47: 137-146, 1990 Topilow AA, Rothenberg SP, Cottrell TS. Interstitial pneum onia
Pearlm an CK. Cystitis due to cytoxa n-Case report. Journal of'U r- after prolonged treatmen t with cyclophosphamide. American
ology 95: 713-7 15, 1966 Review of Respiratory Disease 108: 114-117, 1973
Pesce A, Cassuto JP , Joyner MV, Path MRC, DuJardin P, et al. Ziegler JL, Morrow RH, Fass L, et al. Treatm ent of Burkitt's
Scalp tourn iquet in the preventi on of chemotherapy-induced tumo r with cyclophosphamide. Cancer 26: 474-484, 1970
alopecia. New England Journal of Medicine 298: 1204-1205,
1978
Phillips FS, Sternbe rg SS, Cronin AP, Vidal PM. Cyclophosph-
amide and urin ary bladd er toxicity. Cancer Research 21: 1577- Correspondence and reprints: Dr James P. Kehrer, Division of
1589, 1961 Pharm acology and Toxico logy, College of Pharmacy, The Uni-
Plotz PH, Klippel JH , Decker JL, et al. Bladder complications in versity of Texas at Austin, Austin, TX 78712-1074, USA.