Reply to P.J. Leary et al.

We thank Leary et al for their thoughtful comments regarding our article. Because a growing number of survivors of childhood cancer who have received treatment that may damage the heart and/or lungs are now aging through early and middle adulthood, it is increasingly important to thoroughly describe the onset and trajectory of cardiopulmonary toxicity, the second most common cause of treatment-related mortality in aging survivors. Our data suggest that some survivors, on the continuum of progression to cardiopulmonary failure, may develop pulmonary hypertension. We hope that by documenting this next stage of cardiopulmonary failure, we have highlighted the need for additional research that identifies the etiology of pulmonary hypertension in this population and establishes directions for therapeutic intervention. We strongly agree with Leary et al that the results of our study should not be misinterpreted as an analysis of the frequency of pulmonary arterial hypertension (WHO group I pulmonary hypertension) among adult survivors of childhood cancer. As Leary et al state, the current analysis suggests that left-sided heart failure may be the etiology of the increased tricuspid regurgitant jet velocity, consistent with WHO Group II pulmonary hypertension. However, it is notable that the analysis also suggests that pulmonary hypertension was associated specifically with chest-directed radiotherapy, but not anthracycline exposure, a common cause of left-sided heart failure among adult survivors of childhood cancer. There remains the possibility that direct radiation injury to the pulmonary arterial vasculature (WHO group I, pulmonary arterial hypertension) may contribute to the etiology of the current findings. The potential for direct vascular injury from radiotherapy is well established. Additionally, direct radiation to the lung parenchyma (WHO group III) may also contribute. Our survivor population was evaluated using the Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. Thus, pulmonary function testing was not performed on all of the participants in our study, which reduces the statistical power of our analysis to determine the contribution of direct pulmonary injury. Future research should incorporate a complete assessment of pulmonary function among survivors who are at risk of treatment-associated cardiac dysfunction to further define the potential contribution of pulmonary toxicity in the observed elevations in tricuspid regurgitant jet velocity. We also agree with Leary et al that research collaboration among oncologists, cardiologists, and pulmonary vascular experts will be necessary to unravel the potentially complex etiology of elevated tricuspid regurgitant jet velocity among adult survivors of childhood cancer. Right heart catheterization augmented by exercise testing will be the next step in validating these findings, determining etiology, and most importantly, directing appropriate medical therapy. More comprehensive evaluation and continued follow-up of the St Jude Lifetime Cohort will allow us to clarify these issues and determine the impact of elevated tricuspid regurgitant velocity on subsequent morbidity and mortality.