C-reactive protein as robust laboratory value associated with prognosis in patients with stage III non-small cell lung cancer (NSCLC) treated with definitive radiochemotherapy

Abstract

To evaluate the prognostic value of biomarkers from peripheral blood obtained as routine laboratory assessment for overall survival in a cohort of stage III non-small cell lung cancer (NSCLC) patients treated with definitive radiochemotherapy at a high-volume cancer center. Seven blood biomarkers from 160 patients treated with definitive radiochemotherapy for stage III NSCLC were analyzed throughout the course treatment. Parameters were preselected using univariable and multivariable proportional hazards analysis and were assessed for internal validity using leave-one-out cross validation. Cross validated classifiers including biomarkers in addition to important clinical parameters were compared with classifiers containing the clinical parameters alone. An increased C-reactive protein (CRP) value in the final week of radiotherapy was found as a prognostic factor for overall survival, both as a continuous (HR 1.099 (1.038-1.164), p < 0.0012) as well as categorical variable splitting data at the median value of 1.2 mg/dl (HR 2.214 (1.388-3.531), p < 0.0008). In the multivariable analysis, the CRP value-maintained significance with an HR of 1.105 (1.040-1.173) and p-value of 0.0012. The cross validated classifier using CRP at the end of radiotherapy in addition to clinical parameters separated equally sized high and low risk groups more distinctly than a classifier containing the clinical parameters alone (HR = 2.786 (95% CI 1.686-4.605) vs. HR = 2.287 (95% CI 1.407-3.718)). Thus, the CRP value at the end of radiation therapy has successfully passed the crucial cross-validation test. The presented data on CRP levels suggests that inflammatory markers may become increasingly important during definitive radiochemotherapy, particularly with the growing utilization of immunotherapy as a consolidation therapy for stage III NSCLC.

Keywords: C-reactive protein (CRP); Definitive radiochemotherapy; ESPATUE trial; Laboratory values; Overall survival; Stage III non-small cell lung cancer (NSCLC).

Figure 1

Flow chart study design (definitive radiochemotherapy and documentation of laboratory parameters).

Figure 2

Kaplan–Meier survival curve, leukocyte count prior to radiotherapy dichotomized according to the median. There is a statistically significant difference between the two groups in terms of survival (log-rank test p = 0.0030, hazard ratio HR = 1.940 (95% CI 1.243—3.030), p = 0.0035, N = 157 patients with this observed parameter.

Figure 3

Kaplan–Meier survival curve, CRP in the last RTx week, dichotomized by median. There is a statistically significant difference between the two groups in terms of survival (log-rank test p = 0.0012, hazard ratio HR = 2.214 (95% CI 1.388—3.531) p = 0.0008, N = 140 patients with this observed parameter).

Figure 4

Empirical distribution function of CRP values in the serum of patients in the last week of radiotherapy, CRP unit: mg/dl.

Figure 5

(a) Leave-one-out cross-validated Kaplan–Meier survival curves for the high (red) and low (blue) risk groups according to the best 4-parameter classifier with only clinical factors; durvalumab application, ECOG 2 versus 0, ECOG 1 versus 0 and age. In the log-rank test, the X² value for a difference is X² = 11.7853 (p = 0.0006). (b) Leave-one-out cross-validated Kaplan–Meier survival curves for the high (red) and low (blue) risk groups according to the 5-parameter classifier from the 4 clinical factors; durvalumab application, ECOG 2 versus 0, ECOG 1vs 0 and age as well as the laboratory parameter CRP in the last RT week In the log-rank test, the X² value for a difference is X² = 17.4117 (p < 0.0001).