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.