Results
Over the twenty-year study period from January 1994 to December 2014, 212 children were diagnosed with HL, GCT or WT at CHEO. Of these, 86 met inclusion criteria for both pulmonary toxic treatment exposure and pulmonary function testing (Figure 1).
Characteristics of included patients are presented in Table 1. The median age at diagnosis for included patients was 14.95 [12.2, 16.0] years. A significant proportion (14.0%) reported respiratory symptoms at diagnosis, and 14.0% had evidence of malignancy in the lungs. In total, 22.1% had a complication that included either an emergency department visit or inpatient admission for a respiratory cause between their date of diagnosis and 1-year post-treatment completion. During follow-up, approximately 12.8% and 17.4% reported ever smoking tobacco or marijuana respectively, and 14.0% have had an asthma diagnosis. None of the patients in the study cohort received busulfan, lomustine, or thoracic surgery, which are common causes of pulmonary dysfunction15. Carmustine was excluded from analysis because it was only used post-relapse. Reactions linked to bleomycin were documented or suspected in four patients, and were considered mild (e.g., pneumonitis, rash). Thirteen (15.1%) children relapsed following their initial treatment, after which their treatment and pulmonary function data were censored. Five (5.8%) patients died before the end of the study period and were also censored at the date of death.
Given the difference in treatment protocols, patients with a diagnosis of HL had shorter treatment duration and larger doses of pulmonary toxic chemotherapy, on average, than patients with WT or GCT. The median time from treatment start to treatment completion was 4 [3, 6] months, and follow-up (time from diagnosis to last recorded pulmonary function test) was 19 [13, 31] months. Characteristics of the study population throughout and following treatment are shown in Table 2.
Overall, from pulmonary function testing, there were a total of 404 FEV1 measurements, for an average of 4.7 per patient. There were 387 TLC and 328 DLCOadj measurements. Analysis of lung function data revealed that a greater proportion of patients with lung function below 80% predicted were female than male. Further analysis stratified by sex revealed that females showed a different trajectory and had lower lung function than males post-treatment, despite similar lung function pre-treatment (Figure 2). During treatment, females and males showed similar increases in FEV1 and TLC and decreases in DLCOadj. Although in males the lung function recovered to baseline or improved post-treatment, females continued to decline and eventually stabilized at a lower percent predicted value. This divergence in lung function persisted throughout follow-up, to 80 months post-treatment. This was consistent across all three lung function outcomes (FEV1, DLCOadj, and TLC). The breakdown of lung function outcomes during and post treatment are shown in Table 3.
Additional descriptive statistical analysis stratified by sex shows poorer lung function in females despite being exposed to fewer factors that could explain this difference. Females tended to be diagnosed at an older age and receive less radiation and pulmonary toxic chemotherapy than males (E-table 1 – Females and E-table 2 – Males).
Sensitivity analysis of children who received both radiation therapy (pooled high and low volume radiation therapy exposure) and bleomycin (n=65) showed similar lung function trajectories compared to the overall population (E-image 1).