Early reduction in cardiorespiratory fitness and diastolic reserve following radiation therapy for lung cancer

Abstract

Background: Contemporary radiotherapy for the treatment of lung cancer is effective in targeting tumor tissue while limiting heart exposure, yet cardiac toxicity still occurs, often becoming clinically apparent years later. Cardiorespiratory fitness (CRF) is an independent predictor of cardiovascular, cancer-related, and overall mortality and may serve as a sensitive measure of subclinical cardiac toxicity following anti-cancer treatments. Prior work has demonstrated a significant relationship between reduced CRF and impaired left-ventricular (LV) diastolic reserve in cancer survivors following thoracic radiotherapy. The purpose of this study was to assess early longitudinal changes in CRF and cardiac function in patients with lung cancer following radiotherapy.

Methods: Ten patients (69 [61-76] years, 70% female) with lung cancer without known cardiovascular disease scheduled to receive radiotherapy involving a clinically-relevant heart dose (≥ 5 Gy to > 10% of heart volume) were evaluated prior to and following treatment. Changes in CRF (peak oxygen consumption [VO_2peak], oxygen uptake efficiency slope [OUES]), cardiac function (LV ejection fraction [LVEF], rest and exercise diastolic function [diastolic functional reserve index (DFRI)]), cardiac biomarkers (N-terminal pro-brain natriuretic peptide [NT-proBNP], high-sensitivity C-reactive protein [hsCRP]), and health-related quality of life (HRQOL; Functional Assessment of Cancer Therapy-General-7 [FACT-G7]) were measured.

Results: The VO_2peak was reduced at baseline (1.245 [0.882-1.605] L·min^{- 1}; 70 [62-86] %-predicted) and significantly declined (1.095 [0.810-1.448] L·min^{- 1}, P = 0.047; 62 [56-76] %-predicted, P = 0.005) at 6.0 [3.0-6.0] months post-radiotherapy. Similarly, a significant decline in the OUES was observed (1.63 [1.27-1.88] to 1.57 [1.12-1.75], P = 0.032). Systolic cardiac function was normal at baseline and did not change following radiotherapy (LVEF; 62 [56-65]% to 66 [57-68]%, P = 0.475). The DFRI significantly declined following radiotherapy (34.9 [22.7-41.6] vs. 12.8 [3.1-35.9]). The hsCRP increased significantly from 4.4 [1.4-5.8] to 6.1 [3.7-20.7] g/L, P = 0.047 with a trend towards higher levels of NT-proBNP (65 [49-125] to 121 [88-191] pg/mL, P = 0.110). Health-related quality of life significantly decreased (FACT-G7; 21.5 [18.8-25] to 15.5 [11.5-20]; P = 0.021) post-radiotherapy.

Conclusions: Patients with lung cancer receiving radiotherapy with a clinically-significant heart dose experience reductions in CRF (VO_2peak, OUES) as early as six months following treatment with concurrent reductions in diastolic reserve (DFRI), HRQOL, and increases in cardiac biomarkers (NT-proBNP, hsCRP).

Keywords: Cardiorespiratory fitness; Diastolic reserve; Lung cancer; Radiotherapy.

Fig. 1

Pre- and post-radiotherapy box-whisker plots of significant variables Panel A: VO_2peak. Panel B: FACT-G7 questionnaire scores. Panel C: Diastolic functional reserve index (DFRI). Panel D: Change in E/e’ with stress Abbreviations: VO₂ = oxygen consumption; FACT-G7 = Functional Assessment of Cancer Therapy-General-7; DFRI = diastolic functional reserve index; E/e’= early transmitral flow [E] to early diastolic mitral annular velocity [e’] ratio