Prophylactic Cranial Irradiation Reduces Brain Metastases and Improves Overall Survival in High-Risk Metastatic Non-Small Cell Lung Cancer Patients: A Randomized phase 2 Study (PRoT-BM trial)

Published:February 25, 2021DOI:


      To date, studies regarding the use of prophylactic cranial irradiation (PCI) versus standard of care (SoC) for patients with non-small cell lung cancer (NSCLC) have not shown a significant effect in terms of overall survival (OS). Additionally, the effect of PCI among high-risk patients has been scarcely studied. The objective of this randomized phase 2 study was to evaluate the role of PCI in a population of patients at high risk for development of brain metastases (BM).

      Methods and Materials

      Eligible patients had histologically confirmed NSCLC without baseline BM, harboring epidermal growth factor receptor mutations, anaplastic lymphoma kinase rearrangements, or elevated carcinoembryonic antigen levels at the time of diagnosis. Participants received systemic therapy according to molecular status, those without progressive disease were then assigned to receive SoC or SoC + PCI (25 Gy in 10 fractions). The primary outcome was cumulative incidence of brain metastases (CBM). The secondary endpoints included progression-free survival and OS. Quality of life and neurocognitive function are discussed in a separate article ( NCT01603849).


      From May 2012 to December 2017, 84 patients were enrolled in the study, with 41 patients allocated to receive PCI and 43 received SoC. Patients allocated to receive PCI had a CBM at 24 months of 7% versus 38% in those allocated to the SoC arm. PCI was associated with a hazard ratio of 0.12 (95% confidence interval, 0.035-0.42) for developing BM. A benefit in OS was also observed (64.5 vs 19.8 months; hazard ratio: 0.41 (95% confidence interval, 0.22-0.78; P =∙007).


      Among a selected population at high risk for developing BM, PCI significantly decreased CBM in addition to increasing progression-free survival and OS. To our knowledge, this is the first study to evaluate PCI in epidermal growth factor receptor mutations, anaplastic lymphoma kinase rearrangements, or elevated carcinoembryonic antigen levels in patients with NSCLC, showing a significant improvement in CBM. This relevant information should be of particular importance in the context of patients without access to third-generation targeted agents. Further studies are warranted to ascertain this effect.
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        • Miranda-Filho A.
        • Pineros M.
        • Bray F.
        The descriptive epidemiology of lung cancer and tobacco control: A global overview 2018.
        Salud publica de Mexico. 2019; 61: 219-229
        • Gerson R.
        • Zatarain-Barron Z.L.
        • Blanco C.
        • Arrieta O.
        Access to lung cancer therapy in the Mexican population: opportunities for reducing inequity within the health system.
        Salud Publica Mex. 2019; 61: 352-358
        • Barron-Barron F.
        • Guzman-De Alba E.
        • Alatorre-Alexander J.
        • et al.
        National Clinical Practice Guidelines for the management of non-small cell lung cancer in early, locally advanced and metastatic stages. Extended version.
        Salud Publica Mex. 2019; 61: 359-414
        • Goldberg S.B.
        • Contessa J.N.
        • Omay S.B.
        • Chiang V.
        Lung cancer brain metastases.
        Cancer J. 2015; 21: 398-403
        • Hendriks L.E.L.
        • Subramaniam D.S.
        • Dingemans A.C.
        Editorial: Central nervous system metastases in lung cancer patients: From prevention to diagnosis and treatment.
        Front Oncol. 2018; 8: 511
        • Cacho-Diaz B.
        • Spinola-Marono H.
        • Gonzalez-Aguilar A.
        • Arrieta O.
        Factors associated with long-term survival in central nervous system metastases.
        J Neurooncol. 2018; 140: 159-164
        • Preusser M.
        • Winkler F.
        • Valiente M.
        • et al.
        Recent advances in the biology and treatment of brain metastases of non-small cell lung cancer: Summary of a multidisciplinary roundtable discussion.
        ESMO Open. 2018; 3e000262
        • Witlox W.J.A.
        • Ramaekers B.L.T.
        • Zindler J.D.
        • et al.
        The prevention of brain metastases in non-small cell lung cancer by prophylactic cranial irradiation.
        Front Oncol. 2018; 8: 241
        • Sperduto P.W.
        • Yang T.J.
        • Beal K.
        • et al.
        Estimating survival in patients with lung cancer and brain metastases: An update of the graded prognostic assessment for lung cancer using molecular markers (Lung-molGPA).
        JAMA Oncol. 2017; 3: 827-831
        • Picardi C.
        • Caparroti F.
        • Di Maio M.
        • Kassak F.
        • Banna G.L.
        • Addeo A.
        Prophylactic cranial irradiation in extensive disease small cell lung cancer: An endless debate.
        Crit Rev Oncol Hematol. 2019; 143: 95-101
        • Wen P.
        • Wang T.F.
        • Li M.
        • Yu Y.
        • Zhou Y.L.
        • Wu C.L.
        Meta-analysis of prophylactic cranial irradiation or not in treatment of extensive-stage small-cell lung cancer: The dilemma remains.
        Cancer Radiother. 2020; 24: 44-52
        • Yin X.
        • Yan D.
        • Qiu M.
        • Huang L.
        • Yan S.X.
        Prophylactic cranial irradiation in small cell lung cancer: A systematic review and meta-analysis.
        BMC Cancer. 2019; 19: 95
        • Bajard A.
        • Westeel V.
        • Dubiez A.
        • et al.
        Multivariate analysis of factors predictive of brain metastases in localised non-small cell lung carcinoma.
        Lung Cancer. 2004; 45: 317-323
        • Arrieta O.
        • Saavedra-Perez D.
        • Kuri R.
        • et al.
        Brain metastasis development and poor survival associated with carcinoembryonic antigen (CEA) level in advanced non-small cell lung cancer: A prospective analysis.
        BMC Cancer. 2009; 9: 119
        • Cacho-Diaz B.
        • Spinola-Marono H.
        • Mendoza-Olivas L.G.
        • Monroy-Sosa A.
        • Reyes-Soto G.
        • Arrieta O.
        Association of neurologic manifestations and CEA levels with the diagnosis of brain metastases in lung cancer patients.
        Clin Transl Oncol. 2019; 21: 1538-1542
        • Arrieta O.
        • Pineda B.
        • Muniz-Hernandez S.
        • et al.
        Molecular detection and prognostic value of epithelial markers mRNA expression in peripheral blood of advanced non-small cell lung cancer patients.
        Cancer Biomark. 2014; 14: 215-223
        • Arrieta O.
        • Villarreal-Garza C.
        • Martinez-Barrera L.
        • et al.
        Usefulness of serum carcinoembryonic antigen (CEA) in evaluating response to chemotherapy in patients with advanced non small-cell lung cancer: a prospective cohort study.
        BMC Cancer. 2013; 13: 254
        • Tan L.
        • Wu Y.
        • Ma X.
        • et al.
        A comprehensive meta-analysis of association between EGFR mutation status and brain metastases in NSCLC.
        Pathol Oncol Res. 2019; 25: 791-799
        • Rangachari D.
        • Yamaguchi N.
        • VanderLaan P.A.
        • et al.
        Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers.
        Lung Cancer. 2015; 88: 108-111
        • Sun A.
        • Hu C.
        • Wong S.J.
        • et al.
        Prophylactic cranial irradiation vs observation in patients with locally advanced non-small cell lung cancer: A long-term update of the NRG Oncology/RTOG 0214 phase 3 randomized clinical trial.
        JAMA Oncol. 2019; 5: 847-855
        • De Ruysscher D.
        • Dingemans A.C.
        • Praag J.
        • et al.
        Prophylactic cranial irradiation versus observation in radically treated stage III non-small-cell lung cancer: A randomized phase III NVALT-11/DLCRG-02 study.
        J Clin Oncol. 2018; 36: 2366-2377
        • Snider 3rd, J.W.
        • Gondi V.
        • Brown P.D.
        • Tome W.
        • Mehta M.P.
        Prophylactic cranial irradiation: Recent outcomes and innovations.
        CNS Oncol. 2014; 3: 219-230
        • Park H.S.
        • Decker R.H.
        • Wilson L.D.
        • Yu J.B.
        Prophylactic cranial irradiation for patients with locally advanced non-small-cell lung cancer at high risk for brain metastases.
        Clin Lung Cancer. 2015; 16: 292-297
        • Gore E.M.
        • Bae K.
        • Wong S.J.
        • et al.
        Phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced non-small-cell lung cancer: Primary analysis of radiation therapy oncology group study RTOG 0214.
        J Clin Oncol. 2011; 29: 272-278
        • Lagerwaard F.J.
        • Levendag P.C.
        • Nowak P.J.
        • Eijkenboom W.M.
        • Hanssens P.E.
        • Schmitz P.I.
        Identification of prognostic factors in patients with brain metastases: A review of 1292 patients.
        Int J Radiat Oncol Biol Phys. 1999; 43: 795-803
        • Owen S.
        • Souhami L.
        The management of brain metastases in non-small cell lung cancer.
        Front Oncol. 2014; 4: 248
        • Ramotar M.
        • Barnes S.
        • Morales F.
        • et al.
        Neurological death is common in patients with EGFR mutant non-small cell lung cancer diagnosed with brain metastases.
        Adv Radiat Oncol. 2020; 5: 350-357
        • Cox J.D.
        • Stanley K.
        • Petrovich Z.
        • Paig C.
        • Yesner R.
        Cranial irradiation in cancer of the lung of all cell types.
        JAMA. 1981; 245: 469-472
        • Umsawasdi T.
        • Valdivieso M.
        • Chen T.T.
        • et al.
        Role of elective brain irradiation during combined chemoradiotherapy for limited disease non-small cell lung cancer.
        J Neurooncol. 1984; 2: 253-259
        • Russell A.H.
        • Pajak T.E.
        • Selim H.M.
        • et al.
        Prophylactic cranial irradiation for lung cancer patients at high risk for development of cerebral metastasis: Results of a prospective randomized trial conducted by the Radiation Therapy Oncology Group.
        Int J Radiat Oncol Biol Phys. 1991; 21: 637-643
        • Pottgen C.
        • Eberhardt W.
        • Grannass A.
        • et al.
        Prophylactic cranial irradiation in operable stage IIIA non small-cell lung cancer treated with neoadjuvant chemoradiotherapy: Results from a German multicenter randomized trial.
        J Clin Oncol. 2007; 25: 4987-4992
        • Arrieta O.
        • Villarreal-Garza C.
        • Zamora J.
        • et al.
        Long-term survival in patients with non-small cell lung cancer and synchronous brain metastasis treated with whole-brain radiotherapy and thoracic chemoradiation.
        Radiat Oncol. 2011; 6: 166
        • Martin C.
        • Cardona A.F.
        • Zatarain-Barron Z.L.
        • et al.
        Real-world treatment patterns, survival, and prediction of CNS progression in ALK-positive non-small-cell lung cancer patients treated with first-line crizotinib in Latin America oncology oractices.
        Oncology. 2018; 94: 297-305
        • Lee S.M.
        • Lewanski C.R.
        • Counsell N.
        • et al.
        Randomized trial of erlotinib plus whole-brain radiotherapy for NSCLC patients with multiple brain metastases.
        J Natl Cancer Inst. 2014; 106dju151
        • Charvel S.
        • Cobo-Armijo F.
        • Hernandez-Avila M.
        • et al.
        Needs in coverage and care for lung cancer in Mexico.
        Salud Publica Mex. 2019; 61: 339-346
        • Wu Y.L.
        • Ahn M.J.
        • Garassino M.C.
        • et al.
        CNS efficacy of osimertinib in patients with T790M-positive advanced non-small-cell lung cancer: Data from a randomized phase III trial (AURA3).
        J Clin Oncol. 2018; 36: 2702-2709
        • Gourd E.
        Alectinib shows CNS efficacy in ALK-positive NSCLC.
        Lancet Oncol. 2018; 19: e520
        • Wu Y.L.
        • Tsuboi M.
        • He J.
        • et al.
        Osimertinib in resected EGFR-mutated non-small-cell lung cancer.
        N Engl J Med. 2020; 383: 1711-1723
        • Antonia S.J.
        • Villegas A.
        • Daniel D.
        • et al.
        Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.
        N Engl J Med. 2018; 379: 2342-2350
        • Button K.S.
        • Ioannidis J.P.
        • Mokrysz C.
        • et al.
        Power failure: Why small sample size undermines the reliability of neuroscience.
        Nat Rev Neurosci. 2013; 14: 365-376


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