Can Determination of Circulating Endothelial Cells and Serum Caspase-Cleaved CK18 Predict for Response and Survival in Patients with Advanced Non–Small-Cell.

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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 Tian-Qing Chu, MD, PhD, Hao Ding, MD, PhD, David H. Garfield, MD, Ai-Qin Gu, MD, Jun Pei, MD, PhD, Wei-Dong Du, MD, Bao-Hui Han, MD, PhD Journal of Thoracic Oncology Volume 7, Issue 12, Pages 1781-1789 (December 2012) DOI: 10.1097/JTO.0b013e3182725fe0 Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Representative CEC enumeration by flow cytometry. A, Panels showing the gate used to exclude CD45− positive cells. B, Panels showing the gate used to count CECs (defined as CD45− CD146+ CD133−). CEC, circulating endothelial cell. Journal of Thoracic Oncology 2012 7, 1781-1789DOI: (10.1097/JTO.0b013e3182725fe0) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Dynamic changes of serum CK and CEC counts before and during treatment course at weeks 3 and 6. A, No significant difference observed in CKs between two groups. After endostatin therapy, serum CK levels showed gradual increase. Of the three CKs, increased ccCK18 and CK18 levels at week 6 reached significance in endostatin group (p = 0.001 and p = 0.048, respectively). Furthermore, when comparing serum CK changes between therapy courses of endostatin group and control groups, CK levels at weeks 3 and 6 were significantly increased (p = 0.003 for CK8, p = 0.008 for ccCK18, p = 0.356 for CK18 at week 3; p = 0.006 for CK8, p = 0.007 for ccCK18, p = 0.028 for CK18 at week 6, respectively). B, CECs decreased significantly after 6 weeks of endostatin therapy when compared with baseline (p = 0.000). Similarly, when compared with control group, CECs in the endostatin group showed significant decrease at week 6 (p = 0.000). CEC, circulating endothelial cell; CKs, cytokeratins; ccCK18, caspase-cleaved cytokeratins. Journal of Thoracic Oncology 2012 7, 1781-1789DOI: (10.1097/JTO.0b013e3182725fe0) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Correlation of changes of serum ccCK18 and CECs with tumor response. A, Increase of caspase-cleaved CK18 level at week 6 was significant in patients treated with endostatin achieving PR/SD when compared with PD (p = 0.04). B, Strong correlation of tumor response with CEC reduction at 6 weeks treatment with endostatin (p = 0.000). CEC, circulating endothelial cell; CKs, cytokeratins; ccCK18, caspase-cleaved cytokeratins; PR, partial remission; SD, stable disease; PD, progressive disease. Journal of Thoracic Oncology 2012 7, 1781-1789DOI: (10.1097/JTO.0b013e3182725fe0) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 Association between increase of ccCK18 and patient survival in the endostatin group. A, Best cutoff value of ccCK18 increase for prediction of survival was 19.6 ng/ml where AUC = 0.704 (95% CI = 0.559–0.849). Sensitivity and specificity of ccCK18 increase after endostatin therapy calculated using ROC analysis for survival were 70% and 61%, respectively. B and C, When cutoff value of 19.6 ng/ml was used, patients whose ccCK18 levels increased less (n = 26) presented shorter median survival (5.5 months for PFS, 14.90 months for OS). Those with significantly increased ccCK18 antigen levels (n = 28) survived 9.1 months for PFS and 22.6 months for OS. Median survival of patients with increased ccCK18 after endostatin treatment was statistically longer than those with less increase ccCK18 (p = 0.016 for PFS, p = 0.012 for OS). ccCK18, caspase-cleaved cytokeratins; ROC, receiver operating characteristic; PFS, progression-free survival; OS, overall survival; AUC, area under the curve. Journal of Thoracic Oncology 2012 7, 1781-1789DOI: (10.1097/JTO.0b013e3182725fe0) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 5 Association between CEC reduction and patient survival in the endostatin group. A, ROC analyses revealed best cutoff value for prediction of survival of 0.58/μl, where AUC = 0.759 (95% CI = 0.629–0.889). Sensitivity and specificity of CEC reduction after endostatin therapy calculated using ROC analysis for survival were 60% and 88%, respectively. B and C, When cutoff value of 0.58/μl was used, patients with CEC reduction less than 0.58/μl (n = 34) had a PFS of 5 months and OS of 10.6 months; those with CEC reduction more than 0.58/μl (n = 20) had a PFS of 9.8 months and an OS of 23.9 months. Median survival of patients with greater CEC reduction endostatin significantly longer than those with fewer reduction (p = 0.013 for PFS, p = 0.009 for OS). CEC, circulating endothelial cells; ROC, receiver operating characteristic; CI, confidence interval; AUC, area under the curve. Journal of Thoracic Oncology 2012 7, 1781-1789DOI: (10.1097/JTO.0b013e3182725fe0) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 6 Correlation of serum CK levels and CECs during therapy. In the entire group, strong correlation was observed between the increase value of serum ccCK18 levels and the reduction amount of CECs (r = −0.203, p = 0.048, Fig. 5A). However, the increase of ccCK18 and CK18 levels presented to be synchronal during therapy courses, and the correlation between them also reached significance (r = 0.260, p = 0.010, Fig. 5B). CEC, circulating endothelial cell; CKs, cytokeratins. Journal of Thoracic Oncology 2012 7, 1781-1789DOI: (10.1097/JTO.0b013e3182725fe0) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions