Discussion
This study is one of the first to explore the early trajectory of
pediatric lung function following pulmonary toxic therapy using
objective pulmonary function testing. Overall, we observed that children
treated for childhood cancers with pulmonary toxic therapies experience
three key phases in pulmonary function change, (1) a transient change in
pulmonary function throughout treatment “immediate effect”, (2) a
sharp drop in pulmonary function immediately following treatment
completion “short term effect”, and (3) slow recovery in pulmonary
function starting months after the end of treatment “long term
effect”.
We suspect that the increase of FEV1 and TLC in the
immediate period resulted from a combination of cancer location and
resolution of an acute illness. Mediastinal masses, which are commonly
found in HL, can decrease pulmonary function and present with
respiratory symptoms at diagnosis16. Patients
presenting with respiratory symptoms have been seen to have an average
decrease in FEV1 of up to 28%, compared to asymptomatic
patients16. Thus, tumour shrinkage with treatment may
have played a role in the initial rise of lung function. Additionally,
certain lung function tests like spirometry are effort-dependent and
thus values may increase as patients experience improved health towards
the end of their treatments, despite our inclusion of only acceptable
and reproducible PFTs.
In the short term, we suspect that chest wall or more likely lung
inflammation as in radiation pneumonitis may play a role in the acute
but short-term drop in pulmonary function outcomes in the first few
months post-treatment. Radiation pneumonitis is a well-documented side
effect of treatment, often occurring within the first two to four months
post-radiation17, and has been previously shown to
cause decreases in both FEV1 and
DLCO18. Acute drops in pulmonary function can also be
seen with bleomycin-induced pneumonitis, which occurs in up to 46% of
patients, and can decrease both TLC and DLCO19,20though only a portion of our study population received this treatment.
In the long term, our results show that most children recover pulmonary
function within a year following pulmonary toxic treatment. While this
may be an observation secondary to overall improved health, energy and
ability to provide a maximal effort during pulmonary function testing,
interestingly, we found a difference in the degree of lung function
recovery between males and females. Furthermore, DLCO is an
effort-independent measure and also did not recover as quickly or fully
in females as in males. Key factors such as age at diagnosis, treatment
exposure did not explain the divergence in lung function over time. This
suggests that sex may influence lung function following exposure to
pulmonary toxic therapies resulting from cancer treatment. The adult
literature suggests that women may be at greater risk of lung injury as
a result of receiving similar radiation treatment protocols despite
having smaller average lung volumes21. Another
consideration is the hormonal effect of puberty on lung function.
Previous reports have shown that lung function measured by
plethysmography and single breath gas transfer (TLC and DLCO
respectively) in healthy children rise discontinuously during puberty
for males and correlate with an increase in thoracic volume, but this
increase is not seen in females22. This sex difference
has also been demonstrated during puberty when measuring
FEV123. This natural difference in
lung growth may contribute to the difference in lung function recovery
from pulmonary toxic treatment during this important phase of
development. Additionally, females have been shown to experience
disproportionate negative effects of cancer treatments on their lung
function and mortality compared to their male
counterparts2. Similar sex-related differences in
pulmonary function and poorer health outcomes among females after
puberty have been shown in other lung diseases including asthma and
cystic fibrosis24–26.
The high rate of respiratory complications which included
respiratory-related ED visits or admissions indicates that complications
often happen early (Table 1). Additionally, although it is known that
years following treatment, CCS suffer disproportionally from pulmonary
issues such as restrictive, or obstructive disease, and diffusion
defects compared to the general population27–29, our
results also suggest there may also be a difference between male and
female lung function trajectories that begins very early following
treatment completion.
Despite smoking and marijuana use being reported in patient medical
records at various time points during follow-up, because these habits
are not routinely asked for in children, it was not possible to know
whether this exposure was present at the time of onset of lung function
changes. Nevertheless, we found smoking rates similar to the rest of
Ontario’s pediatric population, with previous studies reporting that
16% of Ontario 7th to 12th graders
had smoked in the last year and 19% had used
marijuana30. The prevalence of asthma in our cohort
was below the provincial prevalence in youth, which can be up to 28% in
males 10-14 years, and suggests that treating clinicians may
under-recognize the prevalence of asthma among oncology
patients31.
In our sensitivity analysis that compared lung function trajectory in
patients who received radiation therapy in conjunction with bleomycin
(n=65), we found it did not differ significantly from the full cohort.
Nevertheless, due to the limited sample size, and because radiation is a
known potentiator of the pulmonary toxic effects of bleomycin
therapy32–34 that correlates with greater rates of
interstitial pneumonitis, fibrosis, and mortality, patients who receive
this combined treatment should be carefully monitored through pulmonary
function testing at regular intervals even in the absence of clinical
symptoms. Despite the observational design, one important strength of
our study lies in that all children had lung function testing at the end
of their treatment, regardless of symptoms. This thus reduces the
potential risk of bias caused by a disproportionately higher number of
PFTs being performed in children with respiratory dysfunction.
One potential limitation of this study was our lack of a control group.
However, as we used percent predicted lung function measures as our
outcome, these are inherently referenced against a control population
and are adjusted for height, age, and sex, thereby negating the need for
a control group as in other longitudinal studies. Given our small sample
size and single center design, we were limited in our ability to explore
individual patient lung function trajectories and thus only powered to
explore the overall trajectory of lung function in our cohort. The small
sample size further limited our ability to explore a larger number of
clinical predictors (e.g. age, treatment dosage, comorbidities) that
could affect lung function trajectory beyond the effect of sex and the
combination of bleomycin with radiation.
Our study sheds light on important factors to consider in follow-up of
childhood cancer survivors, especially in females who may be more
vulnerable to the pulmonary toxic effects of cancer treatment. This
exploratory analysis of lung function trajectory in CCS provides several
hypotheses upon which to design a future study looking at a longer
period of follow up, or a prospective multicentre study to increase
sample size, and better understand the onset and contributing factors
that influence lung function outcomes in this vulnerable population.