Research Papers:

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)

Pierpaolo Pastina, Valerio Nardone, Cirino Botta, Stefania Croci, Paolo Tini, Giuseppe Battaglia, Veronica Ricci, Maria Grazia Cusi, Claudia Gandolfo, Gabriella Misso, Silvia Zappavigna, Michele Caraglia, Antonio Giordano, Donatella Aldinucci, Pierfrancesco Tassone, Pierosandro Tagliaferri, Luigi Pirtoli and Pierpaolo Correale _

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Oncotarget. 2017; 8:75904-75913. https://doi.org/10.18632/oncotarget.20411

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Pierpaolo Pastina1, Valerio Nardone1, Cirino Botta2, Stefania Croci1, Paolo Tini1, Giuseppe Battaglia1, Veronica Ricci3, Maria Grazia Cusi4, Claudia Gandolfo4, Gabriella Misso5, Silvia Zappavigna5, Michele Caraglia5,6, Antonio Giordano6,7, Donatella Aldinucci8, Pierfrancesco Tassone2,6, Pierosandro Tagliaferri2, Luigi Pirtoli1 and Pierpaolo Correale1,9

1 Radiotherapy Unit, Department of Medicine, Surgery, and Neuroscience, Siena University Hospital, Siena, Italy

2 Medical Oncology Unit, AUO “Mater Domini”, “Magna Graecia” University, Catanzaro, Italy

3 Radiology Unit,Department of Medicine, Surgery, and Neuroscience, Siena University Hospital, Siena, Italy

4 Department of Medical Biotechnology, Microbiology and Virology Unit, University of Siena, Siena, Italy

5 Department of Biochemistry, Biophysics and General Pathology, University of Campania “L. Vanvitelli”, Naples, Italy

6 Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University, Philadelphia, PA, USA

7 Department of Medicine, Surgery, and Neuroscience, University of Siena and Istituto Toscano Tumori (ITT), Siena, Italy

8 Department of Experimental Oncology 2, CRO Aviano National Cancer Institute, Aviano, Italy

9 Medical Oncology Unit, Metropolitan Hospital “Bianchi-Melacrino-Morelli, Reggio Calabria, Italy

Correspondence to:

Pierpaolo Correale, email:

Michele Caraglia, email:

Keywords: immune-modulation, radiation therapy, metronomic chemotherapy, NSCLC, retrospective analysis

Received: March 21, 2017 Accepted: June 20, 2017 Published: August 24, 2017


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 vs mCH + RT: 12.1 +/-2.5 (95%CI 3.35-8.6) vs 22.12 +/-4.3 (95%CI 11.9-26.087) months; P=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 vs >1: 4+/-5.389 (95%CI,0- 14.56) vs 56+/-23.05 (95%CI,10.8-101.2) months; P:0.049)] and central-memory- T-cells (CD3+CD8+CD45RA-CCR7+) [FBV ≤ 1 vs >1: 8+/-5.96 (95%CI,0-19.68) vs 31+/-12.3 (95%CI,6.94-55.1) months; P: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.

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