The Kinetic Changes of Systemic Inflammatory Factors during Bevacizumab Treatment and Its Prognostic Role in Advanced Non-small Cell Lung Cancer Patients

Butuo Li; Shijiang Wang; Cheng Li; Meiying Guo; Yiyue Xu; Xindong Sun; Jinming Yu; Linlin Wang

doi:10.7150/jca.30478

The Kinetic Changes of Systemic Inflammatory Factors during Bevacizumab Treatment and Its Prognostic Role in Advanced Non-small Cell Lung Cancer Patients

J Cancer. 2019 Aug 28;10(21):5082-5089. doi: 10.7150/jca.30478. eCollection 2019.

Authors

Butuo Li^{1

2

3}, Shijiang Wang³, Cheng Li⁴, Meiying Guo^{3

5}, Yiyue Xu^{3

5}, Xindong Sun³, Jinming Yu^{1

2

3}, Linlin Wang³

Affiliations

¹ Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
² Department of Radiation Oncology, Tianjin Medical University, Tianjin, China.
³ Department of Radiation Oncology, Shandong Cancer Hospital and Institute Affiliated to Shandong University, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, China.
⁴ Department of Dean's Office, Shandong Cancer Hospital and Institute Affiliated to Shandong University, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, China.
⁵ Department of Radiation Oncology, School of Medicine, Shandong University, Jinan, China.

Abstract

Background: Bevacizumab combined with chemotherapy is still one of the standard options for treatment of advanced non-small cell lung cancer (NSCLC) patients without driver mutations. Serum inflammatory factors, representing the systemic immune status, are shown to have complicated relationships with tumor angiogenesis, and proved to be associated with survival of advanced NSCLC patients. However, the information from the baseline factors is relatively limited, which cannot reflect the dynamic changes of systemic immune status during bevacizumab treatment. We, thus, attempted to evaluate longitudinal kinetics of systemic inflammatory factors during treatment of bevacizumab and to explore their predictive role in treatment response and patient outcomes in advanced NSCLC. Method: Systemic inflammatory factors (neutrophil/lymphocyte (NLR), platelet/lymphocyte (PLR), neutrophil×platelet/lymphocyte (SII) and lymphocyte/monocyte (LMR)) and clinical variables were collected and analyzed from 161 advanced NSCLC patients treated with bevacizumab. Mixed effect regression models were first performed for longitudinal analysis of the changes of serum inflammatory factors during bevacizumab treatment. Then, univariate and multivariate Cox models were used for overall survival (OS) and progression free survival (PFS) analyses to determine the independent prognostic factors. Results: In the first 6 cycles of bevacizumab treatment, patients with complete response/partial response (CR/PR) had a -0.11, -0.066, -0.15, and 0.073 change every 2 cycles in transformed NLR (95%CI: -0.19--0.03, p=0.008), PLR (95%CI: -0.12--0.013, p=0.015), SII (95%CI: -0.23--0.05, p<0.001) and LMR (95%CI: 0.049-0.14, p=0.036), respectively, compared to patients with progressive disease (PD). With respect to analysis of the longitudinal changes before progression, patients experienced a significant increase in transformed NLR (Coef=0.09, 95%CI: 0.019-0.17, p=0.014), PLR (Coef=0.05, 95%CI: 0.002-0.10, p=0.04), and SII (Coef=0.091, 95%CI: 0.015-0.17, p=0.019), but a decrease in transformed LMR (Coef=-0.08, 95%CI: -0.14-0.018, p=0.012). On multivariate Cox model analyses, decrease of LMR (HR=0.62, 95% CI: 0.4-0.96, p=0.033) was shown to be the independent risk factor for PFS; and low level of baseline LMR (HR=0.4, 95% CI: 0.17-0.94, p=0.036), increase of NLR (HR=2.36, 95%CI: 1.25-4.44, p=0.008), and decrease of LMR (HR=0.42, 95%CI: 0.18-0.97, p=0.041) were the independent risk factors for death. Conclusion: The activation of systemic immune status evaluated by the kinetic changes of serum inflammatory factors was associated with good response to bevacizumab; however, the suppressive status may indicate the resistance to bevacizumab. Dynamic changes of systemic inflammatory factors also had prognostic value in predicting outcomes of advanced NSCLC patients treated with bevacizumab.

Keywords: longitudinal changes; mixed effect model; prognostic factors; survival analysis; systemic immune status.