Introduction
In recent years, the improvement of diagnostic techniques and
therapeutic strategies has led to an increase in the number of pediatric
cancer survivors (CSs). The latest data show that more than
three-quarters of children diagnosed with malignancy survive 5 years
after diagnosis, and 1 in 600 young adults are estimated to be pediatric
CSs in Western countries. In the face of improved survival, a downside
is the complications that childhood CSs might experience as a result of
the same life-saving treatments. In fact, the treatment-related
complications represent one of the main causes of morbidity, they have a
strong impact on the quality of life, and they predispose CSs to higher
mortality in adulthood [1].
Pulmonary complications in children with malignant neoplasms can be
distinguished as acute (if they occur during treatment) or as late.
Different causes related to both the neoplasm itself and the treatment
are recognized. Regarding acute complications, infections are the most
common cause of lung damage. The use of cytotoxic and immunosuppressive
drugs alters the body’s innate and adaptive physiological defense
mechanisms, and it frequently causes neutropenia, a type of
cell-mediated and humoral immunity deficiency [2].
Long-term complications are the result of lung surgery, mediastinal
radiation therapy, the immune phenomena following the transplantation of
hematopoietic cells (HCT), and chemotherapy drugs (where provided)
[3]. For these reasons, the Children’s Oncology Group (COG)
developed the COG Long-Term Follow-Up (COG-LTFU) Guidelines to identify
risk categories for patients who have undergone cancer treatment and
thus establish the stages of follow-up. Regarding respiratory
complications, follow-up is recommended for patients who have been
treated with bleomycin, busulfan, nitrosoureas, chest irradiation, or
allogenic HCT with chronic graft versus host disease, if associated with
chest X-ray abnormalities (scarring of pulmonary parenchyma or pleura)
or impairment in lung function (Forced Expiratory Volume in 1 second,
FEV1, < 80% of predicted, Forced Vital Capacity, FVC,
< 80% of predicted, Total Lung Capacity < 80% of
predicted, or Diffusing Capacity of the Lungs for Carbon Monoxide, DLCO,
< 80% of predicted).
As for the other categories of patients, no specific recommendations are
given [4]. However, more recently, cyclophosphamide has also been
reported as toxic to the lungs. This drug is widely used in the
treatment of Acute Lymphoblastic Leukemia (ALL), the most common type of
pediatric tumor [5]. Conventional spirometry is considered the main
examination method for respiratory function to evaluate the degree of
any obstructive or restrictive deficit. However, there is growing
evidence that conventional spirometry is insensitive when detecting
early damage to the small airways and assessing the distribution of
ventilation. This response has also been described in many other
pathologies, such as cystic fibrosis. In this context, there is growing
interest in gas dilution techniques, especially multiple breath-washout
(MBW), for the evaluation of peripheral airway function and to evaluate
the possible inhomogeneity of ventilation [6, 7].
The MBW technique was used for the first time more than half a century
ago but was set aside for many decades until recently. It has returned
to the fore in the field of pediatric pulmonology as an essential exam
to obtain the Lung Clearance Index (LCI). High LCI values are an
expression of ventilatory inhomogeneity reflecting damage to the small
airways. Furthermore, since tidal breathing is sufficient for the
examination, it can be performed on uncooperative children [8, 9].
Several studies have evaluated respiratory complications in childhood
CSs with conventional spirometry, but to our knowledge, there are no
studies on LCI in this cohort of patients. The aim of our study was to
evaluate this index in a cohort of patients with a history of childhood
cancer who do not belong to only the categories defined as at risk. We
also compared them to a group of healthy controls of the same age. The
findings could indicate whether this approach offers any information
beyond that obtained by conventional spirometry.
- Materials and Methods
- Study design and participants
We designed a case-control study in which child CSs were compared with
healthy controls (HCs). This study is part of a departmental project of
the University of Catania, Department of Clinical and Experimental
Medicine, with the aim of studying the long-term complications of
chemotherapy and radiotherapy in patients who have recovered from
cancers diagnosed in the pediatric age range. CSs (0–18 years old) were
recruited from the Pediatric Hemato-Oncology Unit at the Polyclinic
University Hospital of Catania, Italy. All children had a history of
pediatric cancer, undergoing chemotherapy, or radiotherapy treatment.
The eligibility criteria included an interval time of at least 1 year
from the end of the cancer treatment. The exclusion criteria included
prematurity, congenital heart disease, other chronic lung diseases, and
smoking. All these patients usually undergo one spirometry session per
year at our Pediatric Bronchopneumology Unit of the hospital. To carry
out this study, we also performed the MBW test in addition to
conventional spirometry. Frequency-matched HCs for sex and age with no
history of cancer were recruited from the general population. The study
has been approved by the local committee for clinical investigations,
and informed consent was obtained from all parents of participants.
2.2 Clinical and pulmonary function evaluation
A physician collected the medical history and performed a detailed
physical examination of the study participants. The medical history
included the type of cancer, date of diagnosis, type of treatment, date
of suspension of treatment, and any respiratory symptoms. Subsequently,
MBW and then the conventional spirometry were performed (always in that
order).
MBW testing was performed during relaxed and stable tidal breathing
using the Exhalyzer D (EcoMedics AG, Duernten, Switzerland) and an inert
intrinsic gas (nitrogen). All subjects underwent the test until the test
gas reached 1/40th of the initial gas concentration to
obtain the LCI value. Testing was performed in triplicate, and the mean
LCI is reported from a minimum of two (but aiming for three) technically
acceptable tests [10-12]. LCI was analyzed as both raw scales and
z-scores calculated based on published reference equations [13].
Spirometry was performed in the laboratory according to ERS/ATS
guidelines [14, 15]. The best spirometric measure of at least three
attempts was recorded for the analysis. FEV1 and FVC were expressed as a
percentage of predicted values and z-scores using the GLI equations
[16].
Statistical analysis
Statistical analyses were performed with the software Graph Pad Prism
version 8.3.0. CSs and HCs were matched by sex, age, and height.
Subjects’ characteristics are presented as the median (interquartile
range) for continuous variables or a frequency for categorical
variables. Comparisons between groups were calculated using the student
t-test or Mann-Whitney U test for continuous variables, while Fisher’s
exact test was used for categorical variables. The degree of association
was determined by applying a linear regression model and calculating the
Pearson correlation coefficient (r). P-values < 0.05 were
considered to be significant.
Results
The baseline clinical characteristics of the study subjects are
summarized in Table 1 . We enrolled 57 off-treatment CSs and 50
HCs matched for sex, age, and height. Three CSs and two HCs were also
asthmatic. Among the patients with a history of cancer, those with a
history of ALL were the most common (n = 38, 67%), followed by four
(7%) patients with a history of Acute Myeloid Leukemia (AML). 15 (26%)
patients had solid tumors (Figure 1 ). The median age at
diagnosis was 3.2 years, and the median number of years since the last
treatment was 6.2 years. Cyclophosphamide was the most frequently used
chemotherapeutic agent (Table 2 ).
Compared with HCs, CSs’ mean LCI values were 0.46 units higher (95%
confidence interval (CI): 0.06–0.85), and their z-scores were 0.003774
units higher (95% CI: 0.000160–0.007388). However, these differences
were not statistically significant. For conventional spirometry, we
observed that CSs maintained good levels of respiratory function indices
in comparison with HCs (Table 3 ).
Next, we assessed whether there was a correlation between the
respiratory function indices and the years since the last chemotherapy
session. To make the sample homogeneous, we only considered patients
with ALL as having undergone similar treatment. In these patients, we
observed that the LCI z-scores were closely related to the years that
had passed since the end of chemotherapy treatment (r = 0.35, P
< 0.05, Figure 2 ). This correlation was not shown for
conventional respiratory function indices, such as FEV1 (r = 0.16, P =
not significant (ns)) and FVC (r = 0.20, P = 0.23, Figure 3 ).
Discussion
The results of our study show that off-treatment CSs maintain good
respiratory function values during childhood according to conventional
spirometry and the LCI, which is a sensitive index of damage to the
small airways. The respiratory function values obtained in both methods
(MBW and spirometry) were comparable to those of healthy subjects. With
regard to drug-induced respiratory complications, the most frequent
clinical conditions described in CSs in the literature are
hypersensitivity pneumonia, pulmonary edema, pulmonary hypertension,
pleural effusions, pulmonary veno-occlusive disease (VOD), restrictive
diseases, and obstructive pulmonary diseases [17, 18].
Among these complications, the most frequent clinical presentation is
Drug-induced Interstitial Lung Disease (DILD) [17]. Although this
pathological condition occurs in a minority of subjects treated with
anticancer drugs, it can evolve towards severe respiratory insufficiency
and acute respiratory distress syndrome. From a histopathological
[19] and radiographic [20, 21] profile, DILD can present in
various ways, such as diffuse alveolar damage, chronic interstitial
pneumonia, eosinophilic pneumonia, hypersensitivity pneumonia, and
granulomatous pulmonary disease. The two main etiopathogenetic factors
responsible for lung damage from drugs are direct lung toxicity
mechanisms (production of reactive oxygen species, reduction of
inactivation of metabolites in the lungs, and the same drugs) and
immune-mediated mechanisms [17, 22].
Several chemotherapeutic agents have toxic effects on the lungs. These
include bleomycin, a drug used in therapy for Hodgkin lymphomas and germ
cell tumors. This drug accumulates in the lungs due to the reduced
presence of the enzyme that performs detoxification in these organs.
Pneumonia induced by this drug is a serious and often fatal
complication. Pulmonary fibrosis is actually rare in children, whose
bleomycin dosages are lower than in adults. Obstructive airway diseases
and pulmonary hyperinflation are more frequently observed but are
symptomatic in only a minority of patients [23, 24].
Another drug that is believed to be toxic to the lungs is
cyclophosphamide, one of the most common alkylating agents in the
treatment of pediatric tumors. It is also frequently used in preparatory
regimens for hematopoietic cell transplantation. Cyclophosphamide is
responsible for interstitial pneumonia (early onset), which can evolve
into pulmonary fibrosis (late complication) [5]. Also, for busulfan
and nitrosoureas (carmustine and lomustine), there is a possibility of
conditions similar to those previously described [1].
Most of the follow-up studies of such patients have assessed the onset
of respiratory complications in only categories of at-risk patients
defined by the COG-LTFU guidelines (i.e., patients who have undergone
treatment with thoracic radiation therapy, thoracic surgery, HCT,
busulfan, bleomycin, and nitrosoureas) [4]. In such patients,
studies have shown a percentage of lung complications varying between
45% and 85% [25-29]. Mulder et al. identified restrictive lung
disease in patients treated with radiation only, bleomycin and
radiation, and radiation with surgery and compared them to those treated
with bleomycin only [25]. Landier et al. studied 370 childhood CSs
and applied the COG-LTFU guidelines to identify patients at risk for
pulmonary complications, of which 84% experienced lung complications
over the years [26].
A report from the St. Jude Lifetime Cohort Study on 1713 adult survivors
of childhood cancer showed that 65.2% have abnormalities in pulmonary
function among survivors exposed to pulmonary-toxic cancer treatments.
The highest prevalence occurred among those treated with lung radiation
(74.4%), followed by those treated with bleomycin (73.3%) and
thoracotomy (53.2%) [27]. In a study by Armenian et al., the
percentage of patients in the risk category for lung complications
experienced restrictive dysfunctions in 45% of cases [28]. The
Childhood Cancer Survivor Study (CCSS) published in 2016 reported a
cumulative incidence of pulmonary symptoms (chronic cough, oxygen need,
lung fibrosis, and recurrent pneumonia) of 29.6% among a population of
14,316 CSs at 45 years of age (vs. 26.5% in siblings) [29].
In our patient series, few belonged to the risk categories since few
patients had undergone treatments known to be associated with pulmonary
complications. There is an exception with cyclophosphamide, however,
which instead represents one of the main treatments of ALL and was
associated with neoplasm occurring more frequently in our case history.
In this regard, studies that have assessed respiratory complications in
patients with a history of ALL are mainly dated and thus involve
patients undergoing chemotherapy regimens with different drugs than
those used today.
In 1998, Nysom et al. studied 94 survivors of ALL and showed that
several of their participants had a subclinical, restrictive ventilatory
insufficiency or restrictive flow-volume curve patterns [30].
Previously, in a study by Miller et al. on 15 patients with a history of
ALL, 48% had lung function abnormalities [31]. Jenney et al.
demonstrated that at a median of 6 years after diagnosis among 70
survivors of childhood ALL, more than 50% had lower lung volumes and
impaired maximal exercise capacity [32].
The strength of our study is that it evaluated not only patients at risk
but all patients with a history of cancer for the first time.
Furthermore, a more sophisticated method, MBW, was used and allowed for
the study of the LCI. These data suggest that the chemotherapeutic
agents used in the treatment of tumors previously analyzed have less
toxicity than expected, at least in childhood. Furthermore, this study
allowed for validation of the MBW method in this category of patients
since it can also be carried out on preschool children who have
difficulties performing the forced expiratory maneuvers, unlike
traditional spirometry.
Also, the LCI study showed that this index increases and worsens as the
years pass after the end of the treatment. This correlation is not
evident with conventional spirometry and probably expresses a greater
sensitivity than MBW in identifying lung damage, albeit minimal, for
small airways 5-6 years after the end of treatment. In this age range,
the degeneration to pulmonary fibrosis becomes more evident.
Conclusions
Our study described the trend of LCI in a variegated cohort of
off-treatment cancer survivors and compared it with the results obtained
from HCs. The results showed that patients maintain good values of
respiratory function and good homogeneity of ventilation during
childhood. However, the LCI identifies the tendency towards pulmonary
fibrosis, which is typical of adult CSs, at an earlier time than
spirometry.
Our study also assessed not only classically defined at-risk patients
but all cancer patients, including those with previous ALL treated with
cyclophosphamide, a drug for which toxic effects of the lungs have been
were described but not included in the list of COG-LTFU guidelines.
Finally, the study allowed for the validation of MBW for the calculation
of the LCI in these patients since it can also be performed on preschool
patients who are unable to perform forced expiratory maneuvers, unlike
conventional spirometry.