ABSTRACT
Purpose: Bleomycin is a chemotherapeutic agent that causes lung
toxicity. Bleomycin is mostly used in the treatment of germ cell
tumors(GCT) and Hodgkin Lymphoma(HL) in childhood cancers. In this
study, we aimed to detect bleomycin toxicity to the lung in the early
period.
Materials and methods: Pulmonary functions of patients aged 5
years and older who were admitted to the Division of Pediatric Oncology
with germ cell tumors and Hodgkin Lymphoma between 2012 and 2022, who
received bleomycin treatment and were in remission for at least 6 months
were evaluated. The evaluation of respiratory function was based on
history, physical examination, posteroanterior chest radiography and
pulmonary function test.
Results: There were 109 patients with GCT and 122 patients with
HL. The number of patients with GCT who entered follow-up and lived were
59, those with HL were 89]. The number of patients who received
bleomycin treatment, were in remission for at least 6 months and
underwent PFTs were 46 for HL and 12 for GCT. There were 21 patients
with PFT abnormalities. Of these patients, 3 were diagnosed with GCT and
18 were diagnosed with HL. The type of PFT abnormality in the majority
of patients was restrictive disorder.
Conclusion: The absence of respiratory symptoms in 90% of
patients with PFT abnormalities shows the importance of PFT in
asymptomatic patients. Patients who have received bleomycin as part of
treatment should also be followed-up for late pulmonary toxicity.
Keywords: lung toxicity, bleomycin, germ cell tumor, Hodgkin
Lymphoma, pulmonary function test
INTRODUCTION
Bleomycin is an antibiotic agent obtained from a strain of Streptomyces
verticillus in 1966, which shows antitumor activity by inducing free
radicals and is used in the treatment of HL, GCT and squamous carcinomas
in the head and neck region1,2.
Since bleomycin inactivation is low in the lung, bleomycin-induced
toxicity is observed in the lung due to bleomycin
accumulation3. After oxidative damage caused by
bleomycin in the lung, type 1 pneumocytes are destroyed, granulocyte
influx begins, and chemotactic factors, elastase, collagenase and
myeloperoxidase are released4. Vascular and cellular
damage develops due to bleomycin accumulation, an inflammatory process
begins in the lung parenchyma and growth factors released from
macrophages stimulate fibroblasts. Secondary to activated fibroblasts,
lung fibrosis eventually develops. Bleomycin toxicity may occur early or
late and pulmonary fibrosis usually occurs 1 to 6 months after
treatment5,6. Early-onset pulmonary toxicity is
uncommon, occurs as a hypersensitivity reaction and may develop into
interstitial pneumonitis from the first time the drug is administered up
to several months after completion of chemotherapy. Early-onset toxicity
does not have a clear dose relationship to late-onset
toxicity7.
Interstitial pneumonia, also known as hypersensitivity reaction, may
develop at the first dose of chemotherapy or may occur months later.
Methotrexate, bleomycin, procarbazine and carmustine are among the
agents that cause this picture. In most cases the response to drug
withdrawal and steroid treatment is good and normal lung function is
restored. 8,9.
Pulmonary toxicity of chemotherapy may develop as inertstitial lung
pneumonia in the early period and pulmonary fibrosis in the late period.
Toxic effects vary depending on the dose of chemotherapy received,
whether radiation therapy is received, the dose rate of radiation,
duration, pre-existing lung disease and steroid use8.
There are different methods used to determine all these findings, such
as PFT, chest radiography and CT10-12.
This study aimed to investigate lung toxicity in pediatric oncology
patients using bleomycin as part of the treatment and to detect the lung
toxicity of bleomycin in the early period.
MATERIALS and METHODS
This study was conducted on patients diagnosed with HL and GCT who
applied to the Pediatric Oncology outpatient clinic of Cukurova
University Faculty of Medicine between 2012 and 2022. Ethics Committee
of Cukurova University Faculty of Medicine approved the study (meeting
no 2, on 2.4.2021).
Patients treated and is being followed-up with a diagnosis of HL or GCT,
who are in remission for at least 6 months after completion treatment,
who are 5 years old or older (for compliance with PFT), received
bleomycin treatment, accepted to enroll into the study and signed an
informed consent were included into the study.
231 files of patients diagnosed with HL and GCT were scanned. There were
109 patients diagnosed with GCT and 122 patients diagnosed with HL. 15
of the patients diagnosed with GCT and 17 of the patients with HL were
excluded because they were exitus. While 35 of the 94 living patients
diagnosed with GHT were excluded from follow-up, 16 of the 105 living
patients diagnosed with HL were excluded because they were never
followed-up. The number of patients with GCT who were followed-up and
alive were 59, that of HL were 89.
The number of patients who received bleomycin treatment, were in
remission for at least 6 months and could be reached and underwent PFT
were 46 for HL and 12 for GHT and the total number of patients were 58.
All living and reachable patients diagnosed with HL and GCT were
prospectively
subjected to PFT and chest radiography. Those with PFT disorders were
evaluated as obstructive type, restrictive type and mixed type. Chest
radiographs were evaluated as normal or pathological (interstitial
fibrosis findings) were present.
Obstructive disorder was defined when FEV1/FVC is decreased
(<80%) and/or FEV1 is decreased (<80%),
FEF25-75(MEF25-75) is decreased (<70%), FVC is normal,
restrictive disorder; situations where FEV1/FVC is normal or increased
(> 80%), FVC is decreased (< 80%), mixed
disorder; FEV1/FVC decreased (<80%) and FVC decreased
(<80%) conditions were considered13. In
PFT, values are determined as a percentage based on the values in
healthy individuals for a certain age, gender, height, body weight and
race.
In our study, the bleomycin dose was calculated as
units/m2. Fort the calculation of body surface area
[(Body weightx4)+7]/( Body weight + 90) formula was used.
In our study, the abnormalities in the lung functions of GHT and HL
patients who were in remission for at least 6 months and who received
bleomycin treatment was eveluated by PFT, chest radiography, thorax CT.
Bleomycin cumulative dose, chronic respiratory symptoms, RT, height,
body weight, stage, histopathological subtype, family history
recurrence, and smoking status were also recorded.
The relationship between the patients with PFT disorder and the
variables such age at diagnosis, duration of remission, chemotherapy
protocols of the patients, whether they received radiotherapy,
cumulative dose of bleomycin received, smoking, gender, whether
pathology was detected in chest radiography and thorax tomography,
presence of symptoms, and histopathological subtype were examined.
Statistical Analysis
When performing statistical analysis, chi square test statistics were
used to compare categorical measurements between groups. In comparing
numerical measurements between groups, t-test was used in independent
groups if the assumptions were met and Mann-Whitney U test was used if
the assumptions were not met. Categorical measurements were summarized
as numbers and percentages and numerical measurements were summarized as
mean and standard deviation (median and minimum-maximum where
necessary). IBM SPSS Statistics Version 20.0 package program was used in
the statistical analysis of the data. In all tests, the statistical
significance level was taken as 0.05.
RESULTS
148 patients who were diagnosed with HLand GCT, were followed-up, who
remission for at least 6 months were evaluated in the study.
The number of patients with GCT was 59 (40%) and the number of patients
with HL was 89 (60%).
114 of 148 patients (77%) received bleomycin treatment, and 58 patients
who were in remission for at least 6 months, were under regular
follow-up, and wanted to undergo examination and PFT were included in
the study. PFT was performed in 12 patients diagnosed with GCT and in 46
patients diagnosed with HL.
Of the 58 patients who underwent PFT, 7 (12,1%) had cough, 5 (8,6%)
had sputum, 8 (13,8%) had shortness of breath, and 4 (6,9%) had
wheezing. Among those who underwent PFT, smoking prevalence was 3,4%.
Of the 58 patients who underwent PFT, 37 (63,8%) had normal functions.
Obstructive disorder was detected in 3 (5,2%), restrictive disorder in
16 (27,6%), and mixed type disorder in 2 (3,4%).
Of the 58 patients who underwent PFT, 45 (77,6%) received the ABVD
(adriamycin, bleomycin, vinblastine, dacarbazine) protocol, 1 (1,7%)
received the COPP (cyclophosphamide, oncovin, procarbazine,
prednisone)-ABV(adriamycin, bleomycin, vinblastine) protocol, 12
(20,7%) received the BEP(bleomycin, etoposide, cisplatin) protocol, and
acute bleomycin toxicity occurred in only 1 (1,7%) was observed in the
patient, and bleomycin treatment was discontinued due to unexplained
changes in the patient’s lung imaging that did not improve despite
treatment for metastasis and infection.
When the histopathological subtypes of all 46 HL patients who underwent
PFT were examined, there were no patients diagnosed as nodular
lymphocyte predominant and classical lymphocyte -depleted, 2 (4.3%)
patients were classical lymphocyte-rich, 20 (43,5%) patients were
classical nodular sclerosing, 17 (37%) The patient had mixed
cellularity, and 7 (15,2%) patients could not be classified. Of the 46
HL patients who underwent PFT, 32 (69,6%) had post-treatment thorax CT
scans. 11 (52,2%) had a ground glass appearance on thorax CT, 2
(10,9%) had a nodular lesion, 2 (4,3%) had an infection, 1 (2,2%) had
a ground glass appearance. There was elevation of the hemidiaphragm. Of
46 patients diagnosed with HL, PFT was normal in 28 (60.9%),
restrictive disorder in 14 (30.4%), obstructive disorder in 3 (6.5%),
and mixed in 1 (2.2%) there was a type of disorder. One of the HL
patients (2.2%) who underwent PFT was a smoker.
Considering the histolopathological subtypes of all 12 GCT patients who
underwent PFT, 1 patient (8,3%) was germinoma, 1 patient (8,3%) was
immature teratoma, 6 patients (50%) were yolk sac tumors, 4 patients
(33,4%) were mixed. It was classified as a germ cell tumor. 8 of these
patients (67%) were girls and 4 (33%) were boys. Only 1 of 12 patients
(8,3%) was a smoker. None of the patients had a post-treatment thorax
CT. Chest radiography of 11 of 12 patients diagnosed with GCT (91,7%)
was normal, and only 1 (8,3%) had interstitial fibrosis. In the PFTs
performed on the patients, 2 (16,7%) patients had a restrictive
disorder, 1 (8,3%) patient had a mixed type disorder, while 9 (75%)
patients had normal PFTs.
Of the 58 patients who underwent PFT, 21 (36,2%) had defective PFT. Of
the 21 patients with impaired PFT, 8 (38,1%) were female and 13
(61,9%) were male. Of the PFT disorder patients, 18 (85,7%) were
diagnosed with HL and 3 (14,3%) were diagnosed with GCT. Only 1 (4,8%)
patient with PFT disorder was a smoker. Among the patients with PFT
disorders, 3 (14,3%) had obstructive type disorder, 16 (76,2%) had
restrictive type disorder and 2 (9,5%) had mixed type disorder.
Of 21 patients with PFT disorders, 3 (14,3%) received the BEP protocol
and 18 (85,7%) received the ABVD protocol. In our study also we found a
similar rate with the above mentioned study(The rate of PFT disorder
detected in asymptomatic patients was 71%).
The mean height (p=0.05) and body weight (p=0.048) were lower in
patients with impaired PFT (Table 1). There was no significant
difference between the bleomycin dose and PFT impairment.
DISCUSSION
While the incidence of HL is higher in adolescents and in the male
gender,14,15 in our study, 2/3 of our patients with
impaired PFT and diagnosed with HL were under the age of 15, and the
gender ratios of these patients were equal between boys and girls.
When looked at according to HL histopathological subtypes, the NSHL
subtype of classical HL ranks first in terms of
frequency16 and in our study, it was the most common
histopathological subtype in patients who were diagnosed with HL,
received bleomycin treatment were in remission for at least 6 months and
were also found to have PFT disorder.
Protocols such as ABVD and COPP are used in the treatment of
HL17 but in our study, the chest protocol received by
all HL patients with PFT abnormalities was ABVD. COPP treatment is not
applied to HL patients Department Pediatric Oncology in Cukurova
University Faculty of Medicine.
GHT is rare in childhood with a rate of 2% under the age of 15 and it
peaks between the ages of 0-4 and during
adolescence18,19 in our study, 3 patients with
impaired PFT were diagnosed with GHT, and 1 of our patients was in the
adolescence period while the other 2 were diagnosed under 4 years.
Bleomycin is an antibiotic agent with known lung toxicity and is used as
part of the chest protocol in the treatment of HL and
GCT20. Lung fibrosis develops as a result of cell
damage due to bleomycin accumulation, and its effects are seen between 1
and 6 months after treatment6. It causes the
development of interstitial fibrosis, especially in the
lung7.
In our study, 32 of the 58 patients who received bleomycin treatment and
were in remission for at least 6 months and underwent PFT had a thorax
CT in the system, and while half of them were associated with
interstitial fibrosis, the remaining half were normal.
When the thorax CT and chest radiographs of patients with PFT disorders
were examined, the most common finding indicating interstitial fibrosis
was the ground glass appearance.
One of the limitations of our study is that thorax CT is more valuable
than chest radiography in the diagnosis of interstitial fibrosis and not
all of our patients with defective PFTs had thorax CT in the system.
None of our patients diagnosed with GCT had a thorax CT in the system.
On the other hand, since having a thorax CT scan would create a
radiation load for our patients who had primary oncological disease and
received multiple CT and RT, chest radiography, which has a much lower
radiation load compared to CT, was taken for our patients. On the other
hand, it is difficult to evaluate interstitial fibrosis in chest
radiographs, and changes in chest radiographs may vary depending on the
evaluating physician.
In a study conducted in adults8,9, lung fibrosis was
observed in 10% of patients who received bleomycin over 400
units/m2, whereas in our study, the highest bleomycin
dose taken by our patients with PFT disorders was 160
units/m2. Although some of our patients received
bleomycin at a dose of 80 units/m2 lung fibrosis
findings were detected on chest radiographs. Although some of our
patients received doses higher than 80 units/m2 it was
observed that there was no effect on thorax CT and chest radiography.
Since our patients did not receive doses as high as 400
units/m2 of bleomycin a significant relationship
between lung fibrosis and cumulative dose of bleomycin may not have been
detected.
PFT is performed on children over the age of 5 who can comply, and the
age limit reduced the number of patients participating in our study.
When interpreting the PFTs performed in our study, they were categorized
into 4 types: normal, obstructive disorder, restrictive disorder and
mixed type disorder. Disorders in PFT were detected in 36% of 58
patients who underwent PFT. In a study21, it was found
that 18% of PFT disorders were of restrictive type. In our study,
restrictive disorders were found in 27,6% of the patients who underwent
PFT. Obstructive disorder was not reported in the same study but in our
study obstructive disorder was found in 5,2% and mixed type disorder
was found in 3,4%.
When restrictive, obstructive, and mixed type disorders were examined,
no significant relationship was found regarding whether or not receiving
RT, cumulative dose of bleomycin, smoking, and chronic respiratory
symptoms. This may be due to the small number of patients in our study.
In our study, significantly lower FEV1, FVC, FEV1/FVC, PEF,
MEF25-75 values were found in patients with PFT
disorders who received RT to the mediastinum, 6 months and received
bleomycin treatment. Another limitation of our study was that DLCO could
not be evaluated in PFT. Because low DLCO is considered limit the most
sensitive and first sign of PFT disorder that may develop in the future.
In our study, patients diagnosed with GHT who received bleomycin and
were in remission for at least 6 months were found to have PFT
abnormalities in the absence of clinical and radiological changes, which
may be a precursor to bleomycin-induced pulmonary damage in the future.
Two of the patients who received bleomycin treatment, were in remission
for at least 6 months, and underwent PFT were smoking. No statistically
significant difference was detected between bleomycin and cigarettes.
This may be because the number of smokers was low and because our
patients were young, not enough time had passed for the effects of
smoking to be seen.
The point emphasized by Record E. et al. in their
study22 was that patients without clinical symptoms
constituted 2/3 of the study participants and had PFT disorders. In our
study, the rate of patients who received bleomycin treatment, were in
remission for at least 6 months, and were found to have impaired PFT but
were asymptomatic was 71%. The common point between our study and this
study was that both rates were very close to each other.
In a study conducted by Conte P. et al.23, it was
stated that drug-induced interstitial lung disease occurs as a result of
the use of drugs that cause inflammation and interstitial fibrosis. In
our study, only 1 patient developed interstitial lung disease due to
acute bleomycin toxicity. Bleomycin treatment was discontinued and
prednol was started. This was a similar feature of our study to this
study. Our patient was in remission for at least 6 months and PFT was
performed and chest radiography was taken. The PFT and chest radiography
of our patient, who was in remission, were normal and the patient had no
chronic respiratory symptoms. PFT was normal was the aspect of our study
that was incompatible with this study.
In a study by Dei-Adomakoh YA et al.24, they mentioned
bleomycin-induced pneumonia in a young Ghanaian male patient with HL. In
our study, respiratory symptoms developed in one of our patients while
receiving the ABVD protocol, and after the findings of lung metastasis
were excluded, bleomycin-induced lung injury was considered and the
bleomycin treatment given to our patient was discontinued and prednol
treatment was started. Our patient continued her regular follow-up, and
in this study, both a chest x-ray and PFT were performed. PFT was
normal. Our patient was lucky in terms of survival. In the study
mentioned about, even if the patients went into remission, the risk of
toxicity-related lung pathologies increased with each relapse due to
bleomycin treatment.
In a study conducted by Uzel I et al.25,
bleomycin-induced pneumonia was detected in a patient diagnosed with
testicular cancer, developing 2 years after completing the BEP protocol.
In our study, PFT disorder and lung pathology were also detected in our
patients who completed chemotherapy and were in remission for years.
Conclusion
Clinical findings should be evaluated with PFT and chest radiography in
the regular follow-up of patients who received bleomycin treatment after
the diagnosis of HL and GHT and evaluation with PFT should be performed
in the annual follow-up of those with abnormalities. Detection of
bleomycin-induced lung toxicity in later ages in patients who have
received bleomycin treatment shows how important it is to follow-up the
patients.
Conflict of interest statement: There is no conflict of interest.
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Table 1. Relationship between PFT disorder and height and body weight