Cell Death, Inflammation, Tumor Burden, and Proliferation Blood Biomarkers Predict Lung Cancer Radiotherapy Response and Correlate With Tumor Volume and Proliferation Imaging

In this study we evaluated, to our knowledge, the largest blood biomarker panel ever reported. Baseline interleukin-1b and neutrophil count and early-treatment cytokeratin-19 antigen predicted lung cancer radiotherapy response. Baseline angioprotein-1 and hepatocyte growth factor (HGF) significantly correlated with the gross tumor volume. Changes in vascular cell adhesion molecule 1 (VCAM-1) correlated with proliferation imaging, highlighting for the first time a potential role of blood biomarkers as imaging surrogates. Introduction: There is an unmet need to develop noninvasive biomarkers to stratify patients in drug-radiotherapy trials. In this pilot study we investigated lung cancer radiotherapy response and toxicity blood biomarkers and correlated findings with tumor volume and proliferation imaging. Patients and Methods: Blood samples were collected before and during (day 21) radiotherapy. Twenty-six cell-death, hypoxia, angiogenesis, inflammation, proliferation, invasion, and tumor-burden biomarkers were evaluated. Clinical and laboratory data were collected. Univariate analysis was performed on small-cell and non–small-cell lung cancer (NSCLC) whereas multivariate analysis focused on NSCLC. Results: Blood samples from 78 patients were analyzed. Sixty-one (78.2%) harbored NSCLC, 48 (61.5%) received sequential chemoradiotherapy. Of tested baseline biomarkers, undetectable interleukin (IL)-1b (hazard ratio [HR], 4.02; 95% confidence interval [CI], 2.04-7.93; P <.001) was the only significant survival covariate. Of routinely collected laboratory tests, high baseline neutrophil count was a significant survival covariate (HR, 1.07; 95% CI, 1.02-1.11; P =.017). Baseline IL-1b and neutrophil count were prognostic for survival in a multivariate model. The addition of day-21 cytokeratin-19 antigen modestly improved this model's survival prediction (concordance probability, 0.75-0.78). Chemotherapy (P <.001) and baseline keratinocyte growth factor (P =.019) predicted acute esophagitis, but only chemotherapy remained significant after Bonferroni correction. Baseline angioprotein-1 and hepatocyte growth factor showed a direct correlation with tumor volume whereas changes in vascular cell adhesion molecule 1 showed significant correlations with 18F-fluorothymidine (FLT) positron emission tomography (PET). Conclusion: Select biomarkers are prognostic after radiotherapy in this lung cancer series. The correlation between circulating biomarkers and 18F-FLT PET is shown, to our knowledge for the first time, highlighting their potential role as imaging surrogates.