Association Between Chronic Pulmonary Conditions and Neurocognitive Function in Long-Term Survivors of Childhood Hodgkin Lymphoma
Authors: Cheung Yin Ting , Sabin Noah D. , Mulrooney Daniel A. , Ness Kirsten K. , Krasin Matthew J , Brinkman Tara M. , Banerjee Pia , Srivastava Deokumar , Robison Leslie L. , Hudson Melissa M. , Krull Kevin R. 
Published: October 2019

Abstract
Introduction: Literature suggests that long-term survivors of childhood Hodgkin lymphoma (HL) may be at risk for neurocognitive impairment. This study compared neurocognitive function in long-term survivors of HL to community controls and examined associations with pulmonary and cardiovascular morbidity.
Methods: 158 HL survivors treated with thoracic radiation (RT) (mean[SD] age 37.7 [7.8] years, 23.4 [8.1] years post-diagnosis) and 164 age- and sex-matched community controls completed neurocognitive testing. Neurocognitive scores were converted into age-adjusted Z-scores (μ=0, σ=1.0) using national normative data and groups were compared across all measures, adjusting for false discovery rate. Systematic grading of pulmonary (obstructive, restrictive and/or diffusion deficits based on pulmonary function tests) and cardiovascular (structural, functional defects and/or arrhythmias based on electrocardiogram and echocardiogram) conditions was conducted using the Common Terminology Criteria for Adverse Events (CTCAE) v 4.03. Presence of pulmonary and cardiovascular conditions was analyzed as predictors of neurocognitive function using generalized linear modeling (GLM) and adjusting for age at evaluation. Cumulative doses of pulmonary- or cardio-toxic drugs (anthracycline and bleomycin), thoracic RT (≥30Gy vs <30Gy) and smoking history were abstracted from medical records. Analyses were stratified by the presence/absence of pulmonary conditions to examine the contribution of smoking on neurocognitive function.
Results: Survivors performed poorer than controls on short-term (mean[SD] Z-scores: -0.24 [1.0] vs 0.13 [1.0]; P=0.008) and long-term memory (-0.29 [1.1] vs 0.05 [1.1]; P=0.02), sustained attention (-0.60 [3.1] vs 0.24 [0.8]; P =0.005) and perseveration (-0.71 [3.2] vs 0.03 [0.9]; P=0.02), as well as fine-motor (-0.35 [1.0] vs 0.04 [0.8]; P=0.002), visual (0.24 [1.0] vs 0.69 [0.9]; P=0.002) and visual-motor (0.14 [1.0] vs 0.39 [1.0]; P=0.05) processing speed. Thirty-two percent of survivors had grade 2 or higher (moderate, severe/disabling, life-threatening) pulmonary conditions and 22% had grade 2 or higher cardiac conditions. Survivors treated with ≥30Gy thoracic RT were at greater risk of developing pulmonary conditions (51% vs 27%; P=0.01) and demonstrated worse visual (-0.06 [0.9] vs 0.40 [1.0]; P=0.009) and visual-motor (-0.12 [0.9] vs 0.28 [1.0]; P=0.02) processing speed, as compared to survivors treated with <30Gy. Bleomycin (P>0.10) and anthracyline (P>0.09) doses were not associated with neurocognitive function. Survivors with pulmonary conditions performed poorer than survivors without pulmonary/cardiovascular conditions, on sustained attention (-1.47 [3.5] vs -0.09 [2.2]; P=0.009), and visual (-0.28 [1.0] vs 0.46 [1.0]; P=0.003) and visual-motor (-0.23 [0.8] vs 0.30 [1.0]; P=0.005) processing speed. The presence of cardiovascular conditions was not associated with neurocognitive outcomes (Table 1).
Current smokers (n=36) performed worse than non-current smokers (n=121) on measures of short-term (-0.71 [1.1] vs -0.11 [1.0]; P=0.004) and long-term (-1.01 [1.1] vs -0.07 [1.1]; P<0.0001) memory, sustained attention (-2.65 [5.0] vs 0.01 [2.0]; P<0.0001), abstract reasoning (-0.16 [0.9] vs 0.37 [0.7]; P=0.001), and visual (-0.06 [0.7] vs 0.33 [1.0]; P=0.03) and visual-motor (-0.23 [0.8] vs 0.26 [1.0]; P=0.02) processing speed. Stratified analysis showed that in survivors without pulmonary conditions, current smokers were more impaired than non-current smokers on measures of short-term (-0.84 [1.1] vs -0.16 [1.0]; P=0.02) and long-term (-1.27 [0.9] vs -0.11 [1.1]; P=0.0005) memory, sustained attention (-2.25 [4.6] vs 0.29 [1.0]; P<0.0001) and visual-motor processing speed (-0.25 [0.9] vs 0.39 [1.0]; P=0.03), whereas in survivors with pulmonary problems, smoking did not significantly contribute to worse neurocognitive outcomes.
Conclusions: Roughly two decades after treatment, long-term survivors of HL demonstrate poorer neurocognitive performance compared to age- and sex-matched community controls. Chronic pulmonary conditions and current smoking status were associated with worse neurocognitive performance. Future studies should evaluate the contribution of pulmonary insufficiency to neurocognitive outcomes. Survivors of HL should be educated about the potential neurocognitive effects of smoking.

Disclosures
No relevant conflicts of interest to declare.