Can Determination of Circulating Endothelial Cells and Serum Caspase-Cleaved CK18 Predict for Response and Survival in Patients with Advanced Non–Small-Cell Lung Cancer Receiving Endostatin and Paclitaxel–Carboplatin Chemotherapy? A Retrospective Study

Introduction: Early prediction of the efficacy of a combination of an antiangiogenic drug with cytotoxic chemotherapy is a significant challenge. In that regard, circulating endothelial cells (CECs) and cytokeratins (CKs) seem to reflect their roles in both tumor angiogenesis and tumor cell death. Methods: Patients with advanced, previously untreated non–small-cell lung cancer were randomly assigned to an endostatin treatment group (paclitaxel + carboplatin + endostatin) and a control group (paclitaxel + carboplatin + placebo). A total of 122 patients were evaluated, of whom 107 had measurements of blood CECs, CK8, caspase-cleaved CK18 (ccCK18), and uncleaved CK18 (CK18) before and at weeks 3 and 6 of treatment, respectively. Results: Higher baseline CECs in patients with a tumor response (partial remission + stable disease, p = 0.002 for the entire group; p = 0.000 for the treatment group) were observed. The number of CECs decreased significantly after endostatin treatment ( p = 0.000), whereas CK levels increased. Increased levels of ccCK18 and CK18, but not CK8, reached significance ( p = 0.001 and p = 0.048, respectively) when compared with the baseline. Tumor response showed a strong correlation with reduction of CECs ( p = 0.000) and increase of ccCK18 ( p = 0.040) after endostatin therapy. Cutoff values of changes of CECs and ccCK18 for prediction of survival were 0.58/μl and 19.6 ng/ml, respectively. Reduction of CECs and increase of ccCK18 significantly correlated with longer median survival ( p = 0.013 and p = 0.016 for progression-free survival; p = 0.009 and p = 0.012 for overall survival, respectively). Conclusions: CECs and CKs could be biomarkers for selecting patients with non–small-cell lung cancer who will benefit from treatment with endostatin in combination with paclitaxel plus carboplatin.