Standard maintenance therapy versus local consolidative radiation therapy and standard maintenance therapy in 1-5 sites of oligometastatic non-small cell lung cancer: a study protocol of phase III randomised controlled trial

Anil Tibdewal, Jai Prakash Agarwal, Shashank Srinivasan, Naveen Mummudi, Vanita Noronha, Kumar Prabhash, Vijay Patil, Nilendu Purandare, Amit Janu, Sadhna Kannan, Anil Tibdewal, Jai Prakash Agarwal, Shashank Srinivasan, Naveen Mummudi, Vanita Noronha, Kumar Prabhash, Vijay Patil, Nilendu Purandare, Amit Janu, Sadhna Kannan

Abstract

Introduction: Two-phase II randomised studies have shown a significant benefit of local consolidation therapy in oligometastatic non-small cell lung cancer (NSCLC). This phase III randomised controlled trial (RCT) will evaluate the efficacy of local consolidation radiation therapy (RT) in oligometastases (OM) NSCLC after completion of initial systemic therapy.

Methods and analysis: This is a single-centre phase III RCT of OM NSCLC patients. One hundred and ninety patients will undergo 1:1 randomisation to either standard maintenance therapy (control arm) or local consolidation RT and standard maintenance therapy (experimental arm). Patients will be stratified into the number of OM sites (1-2 vs 3-5), nodal metastases (N0-N1 vs N2-N3) and presence or absence of brain metastases. Stereotactic body radiation therapy to all the oligometastatic sites and definitive RT to primary disease will be given in the experimental arm. The primary endpoint is overall survival and secondary endpoints include progression-free survival, local control of OM sites, new distant metastases free survival, objective response rate, toxicity and quality of life. Translation endpoint include circulating tumour cells and radiomics using texture analysis.

Ethics and dissemination: All patients will be provided with a written informed consent form which needs to be signed before randomisation. The study is approved by the institutional ethics committee-II (project number 3445) and registered with Clinical Trials Registry-India, dated 21 April 2020.

Trial registration number: CTRI/2020/04/024761; Pre-Results.

Keywords: chemotherapy; radiation oncology; respiratory tract tumours.

Conflict of interest statement

Competing interests: VN has received institutional research funding from Amgen, Sanofi India, Dr. Reddy’s Laboratories, Intas Pharmaceuticals and Astra Zeneca Pharma India. All research grants have been paid to the institution. KP has received research funding from Dr. Reddy’s Laboratories, Fresenius Kabi India, Alkem Laboratories, Natco Pharma, BDR Pharmaceuticals Intl. and Roche Holding AG (all research grants paid to the institution and are unrelated to this study project). The rest of the authors declare that they have no competing interest in the proposed study protocol.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Study schema. BM, Brain metastases; CT, Computed Tomography; LCRT, local consolidative radiation therapy; NSCLC, non-small cell lung cancer; PET, positron emission tomography; SMT, standard maintenance therapy.

References

    1. Solomon BJ, Mok T, Kim D-W, et al. . First-Line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014;371:2167–77. 10.1056/NEJMoa1408440
    1. Soria J-C, Ohe Y, Vansteenkiste J, et al. . Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018;378:113–25. 10.1056/NEJMoa1713137
    1. Rosell R, Carcereny E, Gervais R, et al. . Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239–46. 10.1016/S1470-2045(11)70393-X
    1. Patil VM, Noronha V, Joshi A, et al. . Phase III study of gefitinib or pemetrexed with carboplatin in EGFR-mutated advanced lung adenocarcinoma. ESMO Open 2017;2:e000168–8. 10.1136/esmoopen-2017-000168
    1. Reck M, Rodríguez-Abreu D, Robinson AG, et al. . Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016;375:1823–33. 10.1056/NEJMoa1606774
    1. Mok TSK, Wu Y-L, Kudaba I, et al. . Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 2019;393:1819–30. 10.1016/S0140-6736(18)32409-7
    1. Ashworth AB, Senan S, Palma DA, et al. . An individual patient data metaanalysis of outcomes and prognostic factors after treatment of oligometastatic non-small-cell lung cancer. Clin Lung Cancer 2014;15:346–55. 10.1016/j.cllc.2014.04.003
    1. Van den Begin R, Engels B, Collen C, et al. . The METABANK score: a clinical tool to predict survival after stereotactic radiotherapy for oligometastatic disease. Radiother Oncol 2019;133:113–9. 10.1016/j.radonc.2019.01.001
    1. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol 1995;13:8–10. 10.1200/JCO.1995.13.1.8
    1. Weichselbaum RR, Hellman S. Oligometastases revisited. Nat Rev Clin Oncol 2011;8:378–82. 10.1038/nrclinonc.2011.44
    1. Gomez DR, Tang C, Zhang J, et al. . Local consolidative therapy vs. maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer: long-term results of a multi-institutional, phase II, randomized study. J Clin Oncol 2019;37:1558–65. 10.1200/JCO.19.00201
    1. Dingemans A-MC, Hendriks LEL, Berghmans T, et al. . Definition of synchronous oligometastatic non-small cell lung cancer-a consensus report. J Thorac Oncol 2019;14:2109–19. 10.1016/j.jtho.2019.07.025
    1. Lievens Y, Guckenberger M, Gomez D, et al. . Defining oligometastatic disease from a radiation oncology perspective: an ESTRO-ASTRO consensus document. Radiother Oncol 2020;148:157–66. 10.1016/j.radonc.2020.04.003
    1. Rusthoven KE, Hammerman SF, Kavanagh BD, et al. . Is there a role for consolidative stereotactic body radiation therapy following first-line systemic therapy for metastatic lung cancer? A patterns-of-failure analysis. Acta Oncol 2009;48:578–83. 10.1080/02841860802662722
    1. Patel SH, Rimner A, Foster A, et al. . Patterns of initial and intracranial failure in metastatic EGFR-mutant non-small cell lung cancer treated with erlotinib. Lung Cancer 2017;108:109–14. 10.1016/j.lungcan.2017.03.010
    1. Al-Halabi H, Sayegh K, Digamurthy SR, et al. . Pattern of failure analysis in metastatic EGFR-mutant lung cancer treated with tyrosine kinase inhibitors to identify candidates for consolidation stereotactic body radiation therapy. J Thorac Oncol 2015;10:1601–7. 10.1097/JTO.0000000000000648
    1. Parikh RB, Cronin AM, Kozono DE, et al. . Definitive primary therapy in patients presenting with oligometastatic non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2014;89:880–7. 10.1016/j.ijrobp.2014.04.007
    1. Xu Q, Wang Y, Liu H, et al. . Treatment outcome for patients with primary NSCLC and synchronous solitary metastasis. Clin Transl Oncol 2013;15:802–9. 10.1007/s12094-013-1008-2
    1. Gomez DR, Blumenschein GR, Lee JJ, et al. . Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol 2016;17:1672–82. 10.1016/S1470-2045(16)30532-0
    1. Iyengar P, Wardak Z, Gerber DE. Consolidative radiotherapy for limited metastatic non-small-cell lung cancer: a phase 2 randomized clinical trial. JAMA Oncol 2018;4:1–4.
    1. Elamin YY, Gomez DR, Antonoff MB, et al. . Local consolidation therapy (lct) after first line tyrosine kinase inhibitor (TKI) for patients with EGFR mutant metastatic non-small-cell lung cancer (NSCLC). Clin Lung Cancer 2019;20:43–7. 10.1016/j.cllc.2018.09.015
    1. Wang X, Zeng M. First-Line tyrosine kinase inhibitor with or without aggressive upfront local radiation therapy in patients with EGFRm oligometastatic non-small cell lung cancer: interim results of a randomized phase III, open-label clinical trial (SINDAS) (NCT02893332). JCO 2020;38:9508. 10.1200/JCO.2020.38.15_suppl.9508
    1. Mak RH, Doran E, Muzikansky A, et al. . Outcomes after combined modality therapy for EGFR-mutant and wild-type locally advanced NSCLC. Oncologist 2011;16:886–95. 10.1634/theoncologist.2011-0040
    1. Cox BW, Spratt DE, Lovelock M, et al. . International spine radiosurgery Consortium consensus guidelines for target volume definition in spinal stereotactic radiosurgery. Int J Radiat Oncol Biol Phys 2012;83:e597–605. 10.1016/j.ijrobp.2012.03.009
    1. Dou TH, Coroller TP, van Griethuysen JJM, et al. . Peritumoral radiomics features predict distant metastasis in locally advanced NSCLC. PLoS One 2018;13:e0206108–15. 10.1371/journal.pone.0206108
    1. Aerts HJWL, Velazquez ER, Leijenaar RTH, et al. . Decoding tumour phenotype by noninvasive imaging using a quantitative radiomics approach. Nat Commun 2014;5:4006. 10.1038/ncomms5006
    1. Alix-Panabières C, Pantel K. Clinical applications of circulating tumor cells and circulating tumor DNA as liquid biopsy. Cancer Discov 2016;6:479–91. 10.1158/-15-1483
    1. Lindsay CR, Faugeroux V, Michiels S, et al. . A prospective examination of circulating tumor cell profiles in non-small-cell lung cancer molecular subgroups. Ann Oncol 2017;28:1523–31. 10.1093/annonc/mdx156
    1. Sutera P, Clump DA, Kalash R, et al. . Initial results of a multicenter phase 2 trial of stereotactic ablative radiation therapy for oligometastatic cancer. Int J Radiat Oncol Biol Phys 2019;103:116–22. 10.1016/j.ijrobp.2018.08.027
    1. Petty WJ, Urbanic JJ, Ahmed T, et al. . Long-Term outcomes of a phase 2 trial of chemotherapy with consolidative radiation therapy for oligometastatic non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2018;102:527–35. 10.1016/j.ijrobp.2018.06.400
    1. Palma DA, Olson R, Harrow S, et al. . Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial. Lancet 2019;393:2051–8. 10.1016/S0140-6736(18)32487-5
    1. De Ruysscher D, Wanders R, Hendriks LE, et al. . Progression-Free survival and overall survival beyond 5 years of NSCLC patients with synchronous Oligometastases treated in a prospective phase II trial (NCT 01282450). J Thorac Oncol 2018;13:1958–61. 10.1016/j.jtho.2018.07.098
    1. Collen C, Christian N, Schallier D, et al. . Phase II study of stereotactic body radiotherapy to primary tumor and metastatic locations in oligometastatic nonsmall-cell lung cancer patients. Ann Oncol 2014;25:1954–9. 10.1093/annonc/mdu370
    1. Arrieta O, Barrón F, Maldonado F, et al. . Radical consolidative treatment provides a clinical benefit and long-term survival in patients with synchronous oligometastatic non-small cell lung cancer: a phase II study. Lung Cancer 2019;130:67–75. 10.1016/j.lungcan.2019.02.006

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi