Study protocol: a multicentre, prospective, phase II trial of isotoxic hypofractionated concurrent chemoradiotherapy for non-small cell lung cancer

Yue-E Liu, Xiao-Ying Xue, Rui Zhang, Xue-Ji Chen, Yu-Xia Ding, Chao-Xing Liu, Yue-Liang Qin, Wei-Qian Li, Xiao-Cang Ren, Qiang Lin, Yue-E Liu, Xiao-Ying Xue, Rui Zhang, Xue-Ji Chen, Yu-Xia Ding, Chao-Xing Liu, Yue-Liang Qin, Wei-Qian Li, Xiao-Cang Ren, Qiang Lin

Abstract

Introduction: Concurrent chemoradiotherapy with conventional fractionation has been acknowledged as one of the standard treatments for locally advanced non-small cell lung cancer (NSCLC). The radiotherapy dose of 60 Gy is far from enough for local tumour control. Due to this fact, hypofractionated radiotherapy can shorten the total treatment duration, partially counteract the accelerated repopulation of tumour cells and deliver a higher biological effective dose, it has been increasingly used for NSCLC. In theory, concurrent hypofractionated chemoradiotherapy can result in an enhanced curative effect. To date, the vast majority of radiotherapy prescriptions assign a uniform radiotherapy dose to all patients. However this kind of uniform radiotherapy prescription may lead to two consequences: excess damage to normal tissues for large tumours and insufficient dose for small tumours. Our study aims to evaluate whether delivering individualised radiotherapy dose is feasible using intensity-modulated radiotherapy.

Methods and analysis: Our study of individualised radiotherapy is a multicenter phase II trial. From April 2019, a total of 30 patients from three Chinese centres, with a proven histological or cytological diagnosis of inoperable NSCLC, will be recruited. The dose of radiation will be increased until one or more of the organs at risk tolerance or the maximum dose of 69 Gy is reached. The primary end point is feasibility, with response rates, progression-free survival and overall survival as secondary end points. The concurrent chemotherapy regimen will be docetaxel plus lobaplatin.

Ethics and dissemination: The study has been approved by medical ethics committees from three research centres. The trial is conducted in accordance with the Declaration of Helsinki.The trial results will be disseminated through academic conference presentations and peer-reviewed publications.

Trial registration number: NCT03606239.

Keywords: oncology; radiotherapy; respiratory tract tumours.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

References

    1. Bray F, Ferlay J, Soerjomataram I, et al. . Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394–424. 10.3322/caac.21492
    1. Aupérin A, Le Péchoux C, Rolland E, et al. . Meta-Analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol 2010;28:2181–90. 10.1200/JCO.2009.26.2543
    1. Bradley JD, Paulus R, Komaki R, et al. . Standard-Dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 2015;16:187–99. 10.1016/S1470-2045(14)71207-0
    1. Martel MK, Ten Haken RK, Hazuka MB, et al. . Estimation of tumor control probability model parameters from 3-D dose distributions of non-small cell lung cancer patients. Lung Cancer 1999;24:31–7. 10.1016/S0169-5002(99)00019-7
    1. Onishi H, Shirato H, Nagata Y, et al. . Hypofractionated stereotactic radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer: updated results of 257 patients in a Japanese multi-institutional study. J Thorac Oncol 2007;2:S94–100. 10.1097/JTO.0b013e318074de34
    1. Bradley JD, Moughan J, Graham MV, et al. . A phase I/II radiation dose escalation study with concurrent chemotherapy for patients with inoperable stages I to III non-small-cell lung cancer: phase I results of RTOG 0117. Int J Radiat Oncol Biol Phys 2010;77:367–72. 10.1016/j.ijrobp.2009.04.029
    1. Bayman N, Blackhall F, McCloskey P, et al. . How can we optimise concurrent chemoradiotherapy for inoperable stage III non-small cell lung cancer? Lung Cancer 2014;83:117–25. 10.1016/j.lungcan.2013.11.017
    1. Partridge M, Ramos M, Sardaro A, et al. . Dose escalation for non-small cell lung cancer: analysis and modelling of published literature. Radiother Oncol 2011;99:6–11. 10.1016/j.radonc.2011.02.014
    1. Ohri N, Dicker AP, Lawrence YR. Can drugs enhance hypofractionated radiotherapy? a novel method of modeling radiosensitization using in vitro data. Int J Radiat Oncol Biol Phys 2012;83:385–93. 10.1016/j.ijrobp.2011.06.1990
    1. Lin Q, Liu Y-E, Ren X-C, et al. . Dose escalation of accelerated hypofractionated three-dimensional conformal radiotherapy (at 3 Gy/fraction) with concurrent vinorelbine and carboplatin chemotherapy in unresectable stage III non-small-cell lung cancer: a phase I trial. Radiat Oncol 2013;8:201. 10.1186/1748-717X-8-201
    1. Ren X-C, Wang Q-Y, Zhang R, et al. . Accelerated hypofractionated three-dimensional conformal radiation therapy (3 Gy/fraction) combined with concurrent chemotherapy for patients with unresectable stage III non-small cell lung cancer: preliminary results of an early terminated phase II trial. BMC Cancer 2016;16:288. 10.1186/s12885-016-2314-1
    1. Haslett K, Franks K, Hanna GG, et al. . Protocol for the isotoxic intensity modulated radiotherapy (IMRT) in stage III non-small cell lung cancer (NSCLC): a feasibility study. BMJ Open 2016;6:e010457. 10.1136/bmjopen-2015-010457
    1. Landau DB, Hughes L, Baker A, et al. . IDEAL-CRT: a phase 1/2 trial of isotoxic dose-escalated radiation therapy and concurrent chemotherapy in patients with stage II/III non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2016;95:1367–77. 10.1016/j.ijrobp.2016.03.031
    1. Fleming C, Cagney DN, O'Keeffe S, et al. . Normal tissue considerations and dose-volume constraints in the moderately hypofractionated treatment of non-small cell lung cancer. Radiother Oncol 2016;119:423–31. 10.1016/j.radonc.2016.03.013
    1. Thirion P, Holmberg O, Collins CD, et al. . Escalated dose for non-small-cell lung cancer with accelerated hypofractionated three-dimensional conformal radiation therapy. Radiother Oncol 2004;71:163–6. 10.1016/j.radonc.2003.09.006
    1. Maguire J, Khan I, McMenemin R, et al. . SOCCAR: a randomised phase II trial comparing sequential versus concurrent chemotherapy and radical hypofractionated radiotherapy in patients with inoperable stage III non-small cell lung cancer and good performance status. Eur J Cancer 2014;50:2939–49. 10.1016/j.ejca.2014.07.009
    1. Walraven I, van den Heuvel M, van Diessen J, et al. . Long-Term follow-up of patients with locally advanced non-small cell lung cancer receiving concurrent hypofractionated chemoradiotherapy with or without cetuximab. Radiother Oncol 2016;118:442–6. 10.1016/j.radonc.2016.02.011
    1. Westover KD, Loo BW, Gerber DE, et al. . Precision Hypofractionated radiation therapy in poor performing patients with non-small cell lung cancer: phase 1 dose escalation trial. Int J Radiat Oncol Biol Phys 2015;93:72–81. 10.1016/j.ijrobp.2015.05.004
    1. Rami-Porta R, Travis WD, Asamura H, et al. . Ajcc cancer staging manual. 8th edn Springer International Publishing, 2017: 431–56.
    1. Cho KH, Ahn SJ, Pyo HR, et al. . A phase II study of synchronous three-dimensional conformal boost to the gross tumor volume for patients with unresectable stage III non-small-cell lung cancer: results of Korean radiation Oncology Group 0301 study. Int J Radiat Oncol Biol Phys 2009;74:1397–404. 10.1016/j.ijrobp.2008.10.020
    1. Zhu GY, Xia TY, Wang LH, et al. . Consensus and controversies on delineation of radiotherapy target volume for patients with non-small cell lung cancer. Chines Journal of Radiation Oncology 2008;17:432–6. (in Chinese).
    1. Available: [Accessed 12 Dec 2018].
    1. Lee JJ, Han J-Y, Lee DH, et al. . A phase II trial of docetaxel plus capecitabine in patients with previously treated non-small cell lung cancer. Jpn J Clin Oncol 2006;36:761–7. 10.1093/jjco/hyl106
    1. Lai C-L, Tsai C-M, Chiu C-H, et al. . Phase II randomized trial of tri-weekly versus days 1 and 8 Weekly docetaxel as a second-line treatment of advanced non-small cell lung cancer. Jpn J Clin Oncol 2005;35:700–6. 10.1093/jjco/hyi191
    1. Qin SK, Cheng Y, Chen ZD, et al. . Dose escalation trial of lobapatin combined with paclitaxel in patients with advanced non-small cell lung cancers as the first-line therapy. Chinese Clinical Oncology 2018;23:97–100. (in Chinese).
    1. Qin SK, Cheng Y, Li J, et al. . A randomized, controlled, muticenter phase III study to compared efficacy and safety of lobaplatin plus paclitaxel versus carboplatin plus paclitaxel as the first-line therapy in Chinese patients with advanced non-small cell lung cancer. Chinese Clinical Oncology 2018;23:193–9. (in Chinese).
    1. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989;10:1–10. 10.1016/0197-2456(89)90015-9
    1. Saunders M, Dische S, Barrett A, et al. . Continuous, hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: mature data from the randomised multicentre trial. Radiotherapy and Oncology 1999;52:137–48. 10.1016/S0167-8140(99)00087-0
    1. Saunders MI, Rojas A, Lyn BE, et al. . Experience with dose escalation using CHARTWEL (continuous hyperfractionated accelerated radiotherapy weekend less) in non-small-cell lung cancer. Br J Cancer 1998;78:1323–8. 10.1038/bjc.1998.678
    1. van Baardwijk A, Bosmans G, Bentzen SM, et al. . Radiation dose prescription for non-small-cell lung cancer according to normal tissue dose constraints: an in silico clinical trial. Int J Radiat Oncol Biol Phys 2008;71:1103–10. 10.1016/j.ijrobp.2007.11.028
    1. van Baardwijk A, Bosmans G, Boersma L, et al. . Individualized radical radiotherapy of non-small-cell lung cancer based on normal tissue dose constraints: a feasibility study. Int J Radiat Oncol Biol Phys 2008;71:1394–401. 10.1016/j.ijrobp.2007.11.070
    1. van Baardwijk A, Wanders S, Boersma L, et al. . Mature results of an individualized radiation dose prescription study based on normal tissue constraints in stages I to III non-small-cell lung cancer. J Clin Oncol 2010;28:1380–6. 10.1200/JCO.2009.24.7221
    1. National comprehensive cancer network. Available: [Accessed 3 Mar 2019].
    1. Cannon DM, Mehta MP, Adkison JB, et al. . Dose-Limiting toxicity after hypofractionated dose-escalated radiotherapy in non-small-cell lung cancer. J Clin Oncol 2013;31:4343–8. 10.1200/JCO.2013.51.5353
    1. Osti MF, Agolli L, Valeriani M, et al. . Image guided Hypofractionated 3-dimensional radiation therapy in patients with inoperable advanced stage non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2013;85:e157–63. 10.1016/j.ijrobp.2012.10.012

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit