Development, External Validation and Further Improvement of a Prediction Model for Survival of Non-small Cell Lung Cancer Patients Treated with (Chemo) Radiotherapy

Abstract

Radiotherapy, combined with chemotherapy, is treatment of choice for a large group of non-small cell lung cancer (NSCLC) patients. However, clinical TNM stage is highly inaccurate for survival prediction of non-surgical patients and alternatives are currently lacking. The objectives of this study were: 1) to develop and validate a prognostic model for survival of NSCLC patients, treated with (chemo) radiotherapy, using clinical factors and 2) to investigate the added prognostic value of blood biomarkers, related to hypoxia, acidosis, and inflammation. Clinical data from 403 inoperable NSCLC patients, stage I-IIIB, treated radically with (chemo) radiation were collected. Blood samples were available for 82 patients. Blood biomarkers, including Osteopontin (OPN), Carbonic Anhydrase 9 (CA9), Interleukin-6 (IL6), Interleukin-8 (IL8), Carcino-embryonic Antigen (CEA), and Cytokeratin Fragment 21.1 (CYFRA), were measured. Two-norm Support Vector Machines were used to build the models. Performance of the models was expressed as the AUC (Area Under the Curve) of the Receiver Operating Characteristic (ROC) and assessed using leave-one-out (LOO) cross-validation. The prognostic model, using clinical factors only, was validated externally using two data sets from Ghent and Leuven. In addition, a risk score was calculated and a nomogram, a graphical representation of the risk score, was made for practical use. The model, based on 403 patients and using clinical factors, consisted of gender, WHO performance status, forced expiratory volume, number of positive lymph node stations, and gross tumor volume. The LOO AUC was 0.75 (95% CI 0.70-0.82), while application of the model to the external data sets yielded an AUC of 0.75 and 0.76, respectively. By splitting the MAASTRO cohort into 3 subgroups, based on the risk score, a high, medium, and low risk group could be identified. The 2-year survival was 66% (95% CI 54%-78%) for the low risk group, 29% (95% CI 21%-37%) for the medium risk group, and 14% (95% CI 5%-23%) for the high risk group. If blood biomarkers were available, based on 82 patients, the prognostic model consisted of three additional biomarkers factors: OPN, IL8, and CEA. The LOO AUC was 0.83 (95% CI 0.76-0.94), which is significantly better than the prognostic model using only clinical factors and based on the same 82 patients (AUC 0.71, 95% CI 0.60-0.87, p < 0.001). The model, using clinical factors, successfully estimates 2-year survival of NSCLC patients and the performance, assessed internally as well as in two independent data sets, is good. Combining blood biomarkers with clinical factors yielded a significantly better performance than using clinical factors only.