Radiotherapy prolongs the survival of advanced non-small-cell lung cancer patients undergone to an immune-modulating treatment with dose-fractioned cisplatin and metronomic etoposide and bevacizumab (mPEBev)

Abstract

Radiotherapy (RT), together with a direct cytolytic effect on tumor tissue, also elicits systemic immunological events, which sometimes result in the regression of distant metastases (abscopal effect). We have shown the safety and anti-tumor activity of a novel metronomic chemotherapy (mCH) regimen with dose-fractioned cisplatin, oral etoposide and bevacizumab, a mAb against the vasculo-endothelial-growth-factor (mPEBev regimen), in metastatic non-small-cell-lung cancer (mNSCLC). This regimen, designed on the results of translational studies, showed immune-modulating effects that could trigger and empower the immunological effects associated with tumor irradiation. In order to assess this, we carried out a retrospective analysis in a subset of 69 consecutive patients who received the mPEBev regimen within the BEVA2007 trial. Forty-five of these patients, also received palliative RT of one or more metastatic sites. Statistical analysis (a Log-rank test) revealed a much longer median survival in the group of patients who received RT [mCH <i>vs</i> mCH + RT: 12.1 +/-2.5 (95%CI 3.35-8.6) <i>vs</i> 22.12 +/-4.3 (95%CI 11.9-26.087) months; <i>P</i>=0.015] with no difference in progression-free survival. In particular, their survival correlated with the mPEBev regimen ability to induce the percentage of activated dendritic cells (DCs) (CD3-CD11b+CD15-CD83+CD80+) [Fold to baseline value (FBV) ≤1 <i>vs</i> >1: 4+/-5.389 (95%CI,0- 14.56) <i>vs</i> 56+/-23.05 (95%CI,10.8-101.2) months; <i>P</i>:0.049)] and central-memory- T-cells (CD3+CD8+CD45RA-CCR7+) [FBV ≤ 1 <i>vs</i> >1: 8+/-5.96 (95%CI,0-19.68) <i>vs</i> 31+/-12.3 (95%CI,6.94-55.1) months; <i>P</i>:0.045]. These results suggest that tumor irradiation may prolong the survival of NSCLC patients undergone mPEBev regimen presumably by eliciting an immune-mediated effect and provide the rationale for further perspective clinical studies.