Incidence, outcome and predictors of bleomycin pulmonary toxicity in a university hospital in Oman.

Abstract

OBJECTIVES: To determine the incidence and predictors of bleomycin pulmonary toxicity in a university hospital in Oman. METHODS: This retrospective chart review consisted of 46 patients treated with bleomycin-containing regimes at Sultan Qaboos University Hospital in Oman between January 2007 and December 2010. Data regarding patient age, chemotherapy protocol, cumulative bleomycin dose, smoking history, renal function and concurrent use of granulocyte colony stimulating factor (GCSF) were collected from the hospital's electronic database. Analyses were performed using univariate statistical techniques. RESULTS: Of the 46 patients, 22% (n = 10) experienced bleomycin pulmonary toxicity. There was an overall mortality of 4.3% (n= 2; N = 46), with significantly more deaths in the bleomycin pulmonary toxicity group compared to the cohort that did not have bleomycin pulmonary toxicity (20% versus 0%; p = 0.043). The bleomycin pulmonary toxicity group was significantly older compared to the cohort that did not have bleomycin pulmonary toxicity (48 versus 34 years; p = 0.017). Furthermore, adriamycin, bleomycin, vinblastine, dacarbazine, as front-line chemotherapy, was found to have a trend towards increased risk of bleomycin pulmonary toxicity (90% versus 56%; p = 0.067; power = 31%). There did not seem to be significant differences in bleomycin dose (143 versus 149 units; p = 0.727), smoking status (10% versus 14%; p = 1.000) and systolic blood pressure (133 versus 131 mmHg; p = 0.746) between the two study groups. CONCLUSION: This study confirms a relatively high incidence of bleomycin pulmonary toxicity in a tertiary hospital in Oman. Older patients were significantly more likely to suffer bleomycin pulmonary toxicity compared to younger patients.

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Journal of Oncology Pharmacy Practice
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DOI: 10.1177/1078155212444649
published online 13 April 2012J Oncol Pharm Pract
Bushra M Ahmed and Ibrahim S Al-Zakwani
Incidence, outcome and predictors of bleomycin pulmonary toxicity in a university hospital in Oman


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Oncology
Pharmacy
Practice
Journal of
Original Article
Incidence, outcome and predictors
of bleomycin pulmonary toxicity in
a university hospital in Oman
Bushra M Ahmed
Department of Pharmacy, Sultan Qaboos University Hospital, Sultan Qaboos University, Muscat,
Oman
Ibrahim S Al-Zakwani
Department of Pharmacy, Sultan Qaboos University Hospital, Sultan Qaboos University, Muscat,
Oman; Department of Pharmacology & Clinical Pharmacy, College of Medicine & Health Sciences,
Sultan Qaboos University, Muscat, Oman; Gulf Health Research, Muscat, Oman
Abstract
Objectives: To determine the incidence and predictors of bleomycin pulmonary toxicity in a university hospital in
Oman.
Methods: This retrospective chart review consisted of 46 patients treated with bleomycin-containing regimes at Sultan
Qaboos University Hospital in Oman between January 2007 and December 2010. Data regarding patient age,
chemotherapy protocol, cumulative bleomycin dose, smoking history, renal function and concurrent use of granulocyte
colony stimulating factor (GCSF) were collected from the hospital’s electronic database. Analyses were performed using
univariate statistical techniques.
Results: Of the 46 patients, 22% (n¼10) experienced bleomycin pulmonary toxicity. There was an overall mortality of
4.3% (n¼2; N¼46), with significantly more deaths in the bleomycin pulmonary toxicity group compared to the cohort
that did not have bleomycin pulmonary toxicity (20% versus 0%; p¼0.043). The bleomycin pulmonary toxicity group was
significantly older compared to the cohort that did not have bleomycin pulmonary toxicity (48 versus 34 years;
p¼0.017). Furthermore, adriamycin, bleomycin, vinblastine, dacarbazine, as front-line chemotherapy, was found to
have a trend towards increased risk of bleomycin pulmonary toxicity (90% versus 56%; p¼0.067; power¼31%).
There did not seem to be significant differences in bleomycin dose (143 versus 149 units; p¼0.727), smoking status
(10% versus 14%; p¼1.000) and systolic blood pressure (133 versus 131mmHg; p¼0.746) between the two study
groups.
Conclusion: This study confirms a relatively high incidence of bleomycin pulmonary toxicity in a tertiary hospital in
Oman. Older patients were significantly more likely to suffer bleomycin pulmonary toxicity compared to younger
patients.
Keywords
Bleomycin, pulmonary toxicity, Oman
Introduction
Bleomycin is a polypeptide antibiotic that has been
used in cancer chemotherapy for over 20 years. It is
an attractive addition to combination chemotherapy
regimens because of its broad activity and low myelo-
toxicity.1It is also commonly used as part of cytostatic
treatment for several tumor types such as squamous cell
carcinoma of the head and neck, cervix and esophagus;
germ cell tumors; as well as for both Hodgkin and non-
Hodgkin lymphoma.1
Corresponding author:
Bushra M Ahmed, Department of Pharmacy, Sultan Qaboos University
Hospital, Sultan Qaboos University, P.O. Box 38, Al-Khodh, Muscat,
PC-123, Sultanate of Oman.
Email: bushram@squ.edu.om
J Oncol Pharm Practice
0(0) 1–5
! The Author(s) 2012
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However, bleomycin is sometimes associated with
significant side effects.2Bleomycin-induced toxicity
occurs predominantly in the lungs and the skin due to
the lack of the bleomycin hydrolase in these organs.2
Administration side effects such as fever, chills and
sometimes hypotension are well known.1Other side
effects include dermal hyperpigmentation and fibrosis,
stomatitis and fatigue,1while pulmonary toxicity is the
most feared and dose-limiting side effect of bleomycin.2
In addition, several distinct pulmonary syndromes have
been associated with the use of bleomycin, such as
bronchiolitis obliterans with organizing pneumonia
(BOOP), eosinophilic hypersensitivity and interstitial
pneumonitis.1Bleomycin-induced lung toxicity has
been reported to occur in 2–46% of patients, depending
on criteria used and the presence of risk factors and
mortality occurs in about 1–2% of treated patients.2
The clinical picture of bleomycin pulmonary toxicity
(BPT) is usually non-specific. Dyspnea is present in
70–90% of the cases usually with chest discomfort
and may be associated with non-productive cough.
Moreover, fever and tachypnoea are usually present.
Pulmonary function test may show a restrictive pattern
with a low diffusing capacity for carbon monoxide
(DLCO). In practice, the time course of onset of clinical
manifestations may suggest BPT as it usually develops
sub acutely between one and six months after treatment
with bleomycin.2A number of risk factors for the
development of BPT have been reported in the litera-
ture including cumulative doses of >450 total units, low
glomerular filtration rate (GFR; <80ml/min),3,4older
age (>40 years),3supplemental oxygen exposure,3bolus
drug delivery (as opposed to continuous infusion),1
combination therapy with cyclophosphamide or gran-
ulocyte-colony stimulating factor,5
metastases, prior lung disease and history of smoking.1
Little is known about incidence, outcome and pre-
dictors of BPT in the Gulf region. Furthermore, prac-
tice patterns and patients characteristics in this part of
the World may differ significantly from those observed
in the West. In addition, anecdotal reports have also
suggested an increased number of BPT cases in the
recent years compared to the past. Hence, the aim of
this study was to determine the incidence, outcome and
predictors of BPT in patients treated at Sultan Qaboos
University Hospital in Oman over a 4-year period
between 2007 and 2010.
extent of lung
Methods
A retrospective case-notes review was performed of all
cases of cancers treated with bleomycin-containing
chemotherapy regimens at Sultan Qaboos University
Hospital (SQUH), Oman, during the 4-year period
between January 2007 and December 2010. SQUH is
one of the two centers that use bleomycin in the coun-
try. Inclusion criteria included all patients who received
at least one dose of bleomycin at SQUH during this
period.1As per the internal recommended guidelines
at SQUH, bleomycin is administered as a slow IV
push over 10min. Test dose is not routinely given
unless a patient has previously developed sensitivity
and is re-challenged with bleomycin. However, due to
the possibility of an acute reaction, only physicians are
allowed to administer IV chemotherapy. Cases were
identified by review of the chemotherapy drug records
for inpatients as all patients receiving bleomycin-con-
taining chemotherapy for various types of cancers were
treated as in-patients for the first few days of each cycle.
As there are no internationally accepted guidelines
for the diagnosis of BPT, the criteria used was based on
the presence of pulmonary symptoms with DLCO
reduced by 30–35% from the patient’s baseline, bilat-
eral interstitial infiltrates on chest x-ray or computed
tomography scan and the absence of infection. BPT
was classified as fatal BPT when the primary cause of
death is respiratory failure with no other identifiable
pathology.
Data collected for patients included previously
described risk factors for BPT. Each case was reviewed
with respect to the total bleomycin dose received by the
patient, age at diagnosis, treatment with radiotherapy
before or during chemotherapy, previous lung disease,
smoking history and the lowest GFR of any cycle at the
time of treatment with bleomycin. Measurement of the
GFR had been performed by using the modification of
diet in renal disease (MDRD) equation for measure-
ment of creatinine clearance. Mortality, and its associ-
ation with BPT, was based on the documentation in the
electronic patient record (EPR).
Statistical analysis
Descriptive statistics were used to describe the data.
For categorical variables, frequencies and percentages
were reported. Differences between the two groups
(BPT; yes/no) were analyzed using Pearson’s ?2tests
(or Fisher’s exact tests for cells <5). For continuous
variables, mean and standard deviation were used to
summarize the data while analysis was performed
using Student’s t-test. An a priori two-tailed level of
significance was set at the 0.05 level. Statistical analyses
were conducted using STATA version 11.1 (STATA
Corporation, College Station, TX).
Results
Review of bleomycin database revealed that there
were a total of 46 patients treated at SQUH during
the 4-year study period (2007–2010) that met the
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inclusion criteria. BPT was seen in 22% (n¼10) of the
patients. Furthermore, there were a total of two deaths
seen in the study cohort representing an overall mortal-
ity of 4.3% (N¼46). However, mortality was signifi-
cantly higher in the BPT group compared to the cohort
without BPT (20% versus 0%; p¼0.043). The observed
deaths were in patients aged 48 and 53 years, cumula-
tive bleomycin dose of 60 and 128 units, and both
patients had GFR >90ml/min.
The demographic and clinical characteristics of the
study cohort are listed in Table 1. The overall mean age
of the cohort was 37?17 years ranging from 14 to 69
years. The BPT group was, however, significantly older
compared to the cohort that did not have BPT (48
versus 34 years; p¼0.017). The observed rate of BPT
was 41% (7 of 17 patients) and 10% (3 of 29 patients)
in patients >40 years old and patients less than 40 years
old, respectively. There were a total of 43% (n¼20)
female patients. There did not seem to be a significant
difference in bleomycin dose (143 versus 149 units;
p¼0.727),
p¼1.000) and systolic blood pressure (133 versus
131mmHg; p¼0.746) in the two study groups.
It appeared that GFR was not a significant predictor
of BPT, however, this statement should be interpreted
with caution due to low study power (14% instead of
the usual of at least 80%).
In all, 67% (n¼31) of patients had a diagnosis of
Hodgkin’s lymphoma (HL).
Adriamycin, bleomycin, vinblastine, dacarbazine
(ABVD) was the major intervention in our study
(n¼29; 63%). The front-line chemotherapy (ABVD)
had a tendency of an increased risk of BPT compared
smokingstatus (10%versus14%;
to other chemotherapy regimens (90% versus 56%;
p¼0.067; power¼31%). In addition, the BPT group
had a higher proportion of patients using GCSF than
the non-BPT cohort (60% versus 53%; p¼0.685;
power¼3%). When the data was analyzed for each
year separately, it was noted that most of the cases
were in 2008 and 2009, where approximately 37% of
patients on bleomycin developed BPT. However, in
2007, no case of BPT was observed while there was
only one case that was observed in 2010 (Table 2).
Discussion
This retrospective study demonstrates for the first time
the incidence of BPT in a tertiary hospital in Oman.
A pulmonary toxicity rate of 22% (10/46) was identi-
fied in patients treated with bleomycin. In all, 20%
(2/10) of patients with BPT [4.3% (2/46) of the total
cohort] had fatal BPT. Martin et al. reported a
relatively similar incidence of 18% (25/141) and
mortality rate of 4.2% (6/141) in HL patients treated
with bleomycin-containing regimens.6
Age seems to play a significant role in the develop-
ment of BPT. In our study, the rate of BPT was
increased by a factor of 4 in patients’ ?40 years old
compared with younger patients (41% versus 10%,
respectively). Martin et al. reported a similar age
effect presented as higher rate of pulmonary toxicity
in patients ?40 years old compared with younger
patients (33% versus 11%, respectively).6Age in asso-
ciation with BPT also had an impact on mortality, as
the two patients who died in this study were >40 years
Table 1. Demographic and clinical characteristics.
Characteristic All (N¼46)
37?17
20 (43%)
148?70
6 (13%)
132?17
BPT (n¼10; 22%)
48?15
5 (50%)
143?41
1 (10%)
133?11
No BPT (n¼36; 78%)
34?16
15 (42%)
149?77
5 (14%)
131?18
p Value
Age, mean?SD, years
Female gender, n (%)
Bleo dose, mean?SD, mg
Smoking, n (%)
SBP, mean?SD, mmHg
GFR, ml/min, n (%)
>90
80–90
0.017
0.638
0.727
1.000
0.746
39 (85%)
4 (9%)
9 (90%)
0 (0%)
30 (83%)
1 (10%)0.515
30–59
<30
2 (4%)
1 (2%)
1 (10%)
0 (5%)
1 (3%)
1 (3%)
HL, n (%)
ABVD protocol, n (%)
GCSF, n (%)
31 (67%)
29 (63%)
25 (54%)
9 (90%)
9 (90%)
6 (60%)
22 (61%)
20 (56%)
19 (53%)
0.132
0.067
0.685
ABVD: adriamycin, bleomycin, vinblastine, dacarbazine; bleo: bleomycin; GCSF: granulocyte colony stimulating factor; GFR: glomerular filtration rate;
HL: Hodgkin’s lymphoma; SD: standard deviation; SBP: systolic blood pressure.
Ahmed and Al-Zakwani3
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Page 5

old. However, the numbers were too small to derive any
meaningful definitive association.
High cumulative doses of bleomycin of >400mg
have been shown to put patients at higher risk for
developing BPT.2However, the maximum dose used
in this study was 252 units with a mean dose of 148
units. This is significantly lower than the dose asso-
ciated with higher rates of toxicity. As a result, no
significant differenceswere
between BPT and non-BPT patients in terms of cumu-
lative bleomycin dose. Simpson et al. described 180
patients with germ cell tumours treated with bleo-
mycin and they did not find a significant difference
in the cumulative dose between patients who died
from BPT and patients who did not.7This was also
in line with findings from the study by Martin et al.
where bleomycin dose did not significantly increase
the risk of BPT in patients with HL.6
BPT was reported even with low doses of bleomycin.
Iacovino et al. described two cases of fatal BPT in
patients who received 100 and 165 units of bleomycin.8
Bechard et al. reported a case of fatal BLT after 20
units of bleomycin.9In our study, BPT developed
after cumulative doses ranging between 90 and 216
units. During treatment with ABVD, pulmonary tox-
icity was seen anytime between the second and the sixth
chemotherapy cycle (2–6 months) while one patient
developed BPT after the third dose of the first cycle
while being treated with BEP protocol. Real et al. sug-
gested that a hypersensitivity response to bleomycin
may be sometimes confused with BPT especially in
patients who received low doses of bleomycin.10
However, there are no criteria to differentiate these con-
ditions from each other where the radiologic and func-
tional pulmonary changes will be similar.10
Considering patients’ renal function and BPT,
although it has been suggested that high creatinine
level is the most important risk factor for predicting
BPT, this conclusion could not be proven in this
studydue tolimitednumber
GFR<80ml/min. Of the three patients with impaired
renal function in our study, one patient who was 66
years old and had a calculated GFR of ?44ml/min
had developed thepulmonary
foundinthisstudy
of patientswith
toxicityaftera
cumulative dose of 216 units. The other two patients
aged 58 and 59 years with GFR levels of 35 and 18ml/
min, respectively, received
bleomycin of 26 units and 10 units, respectively.
(Treatmentwasstopped
Similarly, six patients had a history of smoking in our
study, hence its association with BPT could not be
elucidated.
With regard to front line chemotherapy as a risk
factor for BPT, it was shown that ABVD had a ten-
dency of higher rate of pulmonary toxicity compared to
MOPP/AVD in the treatment of HL. In this study,
22% of ABVD-patients developed BPT compared to
4% of MOPP/AVD-patients.6Another cohort study
of 60 HL patients treated with ABVD showed that
37% of patients had a declined pulmonary function,
where bleomycin was discontinued in 23% of patients
and 1% had fatal BPT.11In our study, of the 29
patients who were treated with ABVD chemotherapy,
31% (9/29) developed BPT. Out of these, two had
already completed their treatment protocol when BPT
wasdiagnosed,21% (6/29)
bleomycin from further chemotherapy cycles and 3%
(1/29) had fatal BPT. In comparison, only 6% (1/17) of
patients on non-ABVD regimens developed BPT.
However, due to small sample size, a significant
verysmalldoses of
or continued abroad).
hadto discontinue
Table 2. Overview of the number of bleomycin pulmonary
toxicity (BPT) cases for the years 2007 through 2010.a
YearBPT (percent)No BPTTotal
2007
2008
2009
0
4 (36%)
5 (38%)
11
7
8
11
11
13
20101 (9%) 1011
aPercents are row percentages.
Table 3. Chemotherapy protocols used in the study.
ProtocolDescription
ABVD Doxorubicin 25mg/m2IV bolus Days 1 and 15
Bleomycin 10mg/m2IV Days 1 and 15
Vinblastine 6mg/m2IV Days 1 and 15
Dacarbazine 375mg/m2IV Days 1 and 15
Bleomycin 30mg Days 1, 8 and 15
Etoposide 100mg/m2Days 1–5
Cisplatin 20mg/m2Days 1–5
Mitoxantrone 7mg/m2IV Day 1
Cyclophosphamide 300mg/m2IV Day 1
Etoposide 150mg/m2IV Day 1
Vincristine 1.4mg/m2(max 2mg) IV Day 8
Bleomycin 10mg/m2IV Day 8
Prednisolone 50mg PO once daily on weeks 1–4,
then 50mg PO on alternate days from
week 5 to end of treatment
ABVD in standard dose
Rituximab 375mg/m2IV weekly starting
from Day 1 of ABVD
Cyclophosphamide 650mg/m2IV Day 1
Doxorubicin 25mg/m2Day1
Etoposide 100mg/m2Days 1–3
Procarbazine 100mg/m2PO Days 1–7
Prednisone 40mg/m2PO Days 1–14
Vincristine 1.4mg/m2(max 2mg) IV Day 8
Bleomycin 10mg/m2IV Day 8
BEP
PMitCEBO
ABVD-R
BEACOP
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difference could not be observed between BPT and
non-BPT patients treated with different chemotherapy
protocols. Table 3 outlines all the chemotherapy proto-
cols used in the current study.
The concomitant administration of GCSF with bleo-
mycin-containing chemotherapy was not found to
increase risk of BPT in our study. This finding was
also observed by Bastion and Coiffier in 278 patients
treated with bleomycin?GCSF and no pulmonary
complicationsoccurred
Moreover, in a two-group study, 29 patients received
bleomycin+GCSF and 57 patients received only bleo-
mycin. No difference in BPT between the two groups
was observed (p¼1.000).13
It has been observed by the treating oncologists that
the incidence of BPT has increased in recent years com-
pared to the past. We analyzed the data for four con-
secutive years from 2007 to 2010. It was found that the
main cases of BPT had occurred in 2008 and 2009. No
obvious reason was found for this finding as bleomycin
brand has not been changed in the hospital over the
4-year study period, as well as the method of aseptic
preparation and the laminar flow cabinet. Bearing in
mind that the overall incidence of toxicity was compar-
able to previous studies,3,4,6–13this finding may be
coincidental.
This study has some limitations including its type,
being retrospective might lead to bias. In addition, its
small sample size might affect detection of some clinic-
ally significant meaningful
However, the study outcome might provide meaningful
information in pooled meta-analysis.
in thestudy group.12
predictors forBPT.
Conclusion
BPT contributed to significant co-morbidity and mor-
tality. Knowledge about the incidence of this condition
in our institution and the risk factors associated with it
will allow physicians to be more vigilant including pro-
viding regular screening for BPT. As a value-added
benefit, employing a specialized chemotherapy pharma-
cist to check the appropriateness of therapy as well as
any dosage modification necessary, e.g. in renal impair-
ment, is warranted. In fact, at the writing of this manu-
script, the Hospital Administration had approved a
grade for such a service.
Funding
This research received no specific grant from any funding
agency in the public, commercial, or not-for-profit sectors.
Acknowledgement
We thank the medicine information centre for their kind sup-
port. Also, a special thanks goes to Dr Ikram Burney, Senior
Oncology Consultant at SQUH, and Ph. Mafiana Rose,
Oncology Clinical Pharmacist, for their valuable advice.
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