Abstract
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Introduction: Lung cancer is the leading cause of cancer-related mortality with over 2.2 million new cases and 1.7 million deaths worldwide each year. Most patients with locally advanced non-small cell lung cancer (NSCLC), 85% of lung malignancies, receive photon radiotherapy (RT) as either definitive or adjunct treatment. Despite recent advances, RT interventions are associated with a significant risk of treatment-induced toxicities including radiation-induced heart disease (RIHD), pneumonitis, and vasculitis. RT toxicity is an increasingly recognized cause of morbidity and mortality but clear guidelines and best practices for external beam RT and radiopharmaceutical therapy (RPT) have yet to be established. Over the past 2 years, several research groups have initiated major efforts to assess RT-induced inflammation with [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) and [18F] sodium-fluoride (NaF-PET) imaging. In this review, we examine the published literature related to the utility of FDG-PET and NaF-PET to assess RT-induced inflammation in patients with thoracic malignancies.
Methods: Multiple databases including but not limited to Google Scholar and PubMed were accessed to compile a comprehensive body of literature related to FDG-PET and NaF-PET imaging of RT-induced inflammation in NSCLC patients. Preliminary data comparing RT-induced inflammation in NSCLC patients treated with proton vs photon therapy was included to illustrate prior applications of FDG-PET in this context.
Results: To date, most studies have assessed RT-induced cardiovascular toxicity with FDG-PET imaging as this modality is uniquely suited for quantifying and localizing inflammatory activity before and after treatment. Prior studies with FDG-PET have demonstrated that rates of RIHD are related to RT dose and duration and that patients treated with RT for left-sided malignancies are at greater risk for cardiac damage. Another study that examined NSCLC patients treated with photon RT revealed the presence of significant vascular inflammation in the ascending aorta and aortic arch using FDG-PET/CT. Interestingly, a follow-up study that examined RT-induced vasculitis in lung cancer patients treated with proton RT vs photon RT found a statistically significant difference between the proton and photon cohorts when comparing the change in mean standardized uptake value (SUV) in the ascending aorta (AA) and arch of the aorta (AoA) before and after RT treatment. Namely, the mean SUV for the AA and AoA increased 1.9% and 1.3% for the proton cohort and 15.8% and 15.6% for the photon cohort, respectively (Figure 2).
The pathogenesis of RT-induced vasculopathy and RIHD is thought to be related, at least in part, to the generation of reactive oxygen species (ROS) that damage DNA and blood vessels and accelerate atherosclerotic plaque formation. In this domain, researchers have applied NaF-PET to assess micro-calcification in early atherosclerotic plaques and track their progression through time with high sensitivity. A pilot study with 128 subjects noted that the SUVmax of NaF uptake in the left common carotid was significantly higher in patients with increased risk of cardiovascular (one-way ANOVA p<0.01) and thromboembolic events (one-way ANOVA p<0.01), and significantly lower in patients with a greater level of physical activity (one-way ANOVA p<0.02).
Conclusions: FDG-PET/CT is ideally suited for assessing RT-induced inflammation. Further study is warranted to examine the role of NaF-PET in the assessment of vascular micro-calcification. These methodologies could be of great value for RT and RPT risk profiling. Knowledge gained from the application of these techniques in larger cohorts could inform future RT and RPT treatment planning for patients with thoracic malignancies and reduce future RT-induced cardiovascular complications.
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