Document Type : Original Article(s)

Authors

1 Clinical Oncology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt

2 Medical Oncology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt

3 Cardiothoracic Surgery Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt

10.30476/mejc.2024.103982.2161

Abstract

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors is a crucial agent in EGFR-mutated advanced lung disease. Previous studies have suggested a positive correlation between EGFR overexpression and cellular radioresistance in the treatment of non-small cell lung cancer (NSCLC). Concurrent or sequential Gefitinib with thoracic irradiation showed tolerability and possible efficacy in patients who exhibited EGFR mutation. The aim of this study was to improve treatment outcomes of local advanced NSCLC patients.
Method: A prospective study included stage III NSCLC cases divided in to 30 patients in Arm A and 20 patients B. The patients received thoracic irradiation concurrently or sequentially with Gefitinib. We used Kaplan-Meier plot and compared results using log-rank test. Percent of categorical variables were compared using Pearson’s chi-square test or Fisher’s exact test when appropriate. A P-value of less than 0.05 was considered to be statistically significant using SPSS 16.0.
Results: Pneumonitis was more observed toxicity in Arm A versus Arm B with statistical significance P = 0.039. The median progression-free survival was 10 months with a 95 % confidence interval range of 8.2-11.7 months, 8.5-11.4 months in Arm A and Arm B, respectively. The median overall survival was 18 months versus 16 months with the range at 95 % confidence interval of 12.6-23.3 months versus 13.2-18.7 months in Arm A and Arm B, respectively.
Conclusion: Gefitinib is affordable and effective with thoracic irradiation in NSCLC patients with accepted toxicity profile. 

Highlights

Amira Elwan (Google Scholar)

Keywords

Main Subjects

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination, and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.30476/mejc.2024.103982.2161

  1. Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, 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(2):187-99. doi: 10.1016/S1470-2045(14)71207-0. PMID: 25601342; PMCID: PMC4419359.
  2. Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113-25. doi: 10.1056/NEJMoa1713137. PMID: 29151359.
  3. Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41-50. doi: 10.1056/NEJMoa1913662. PMID: 31751012.
  4. Tanaka K, Hida T, Oya Y, Oguri T, Yoshida T, Shimizu J, et al. EGFR mutation impact on definitive concurrent chemoradiation therapy for inoperable stage III adenocarcinoma. J Thorac Oncol. 2015;10(12):1720-5. doi: 10.1097/JTO.0000000000000675. PMID: 26743855.
  5. Yagishita S, Horinouchi H, Katsui Taniyama T, Nakamichi S, Kitazono S, Mizugaki H, et al. Epidermal growth factor receptor mutation is associated with longer local control after definitive chemoradiotherapy in patients with stage III nonsquamous non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2015;91(1):140-8. doi: 10.1016/j.ijrobp.2014.08.344. PMID: 25442336.
  6. Nakamura M, Kageyama SI, Niho S, Okumura M, Hojo H, Motegi A, et al. Impact of EGFR mutation and ALK translocation on recurrence pattern after definitive chemoradiotherapy for inoperable stage III non-squamous non-small-cell lung cancer. Clin Lung Cancer. 2019;20(3):e256-e264. doi: 10.1016/j.cllc.2019.02.021. PMID: 30926356.
  7. Akamatsu H, Kaira K, Murakami H, Serizawa M, Koh Y, Ono A, et al. The impact of clinical outcomes according to EGFR mutation status in patients with locally advanced lung adenocarcinoma who recieved concurrent chemoradiotherapy. Am J Clin Oncol. 2014;37(2):144-7. doi: 10.1097/COC.0b013e31826e04f9. PMID: 23211219.
  8. Akamatsu H, Murakami H, Harada H, Shimizu J, Hayashi H, Daga H, et al. Gefitinib with concurrent thoracic radiotherapy in unresectable locally advanced NSCLC with EGFR mutation; West Japan Oncology Group 6911L. J Thorac Oncol. 2021;16(10):1745-52. doi: 10.1016/j.jtho.2021.05.019. PMID: 34116229.
  9. Wang M, Kern AM, Hülsk¨otter M, Greninger P, Singh A, Pan Y, et al. EGFR-mediated chromatin condensation protects KRAS-mutant cancer cells against ionizing radiation. Cancer Res J. 2014;74(10):2825-34. doi:10.1158/0008-5472.CAN-13-3157. PMID: 24648348 PMCID: PMC4278592.
  10. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2342-50. doi: 10.1056/NEJMoa1809697. PMID: 30280658.
  11. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377(20):1919-29. doi: 10.1056/NEJMoa1709937. PMID: 28885881.
  12. Gray JE, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Three-year overall survival with durvalumab after chemoradiotherapy in stage III NSCLC-update from PACIFIC. J Thorac Oncol. 2020;15(2):288-93. doi: 10.1016/j.jtho.2019.10.002. PMID: 31622733; PMCID: PMC7244187.
  13. Faivre-Finn C, Vicente D, Kurata T, Planchard D, Paz-Ares L, Vansteenkiste JF, et al. Four-year survival with durvalumab after chemoradiotherapy in stage III NSCLC-an update from the PACIFIC trial. J Thorac Oncol. 2021;16(5):860-7. doi: 10.1016/j.jtho.2020.12.015. PMID: 33476803.
  14. Spigel DR, Faivre-Finn C, Gray JE, Vicente D, Planchard D, Paz-Ares L, et al. Five-year survival outcomes from the PACIFIC trial: Durvalumab After chemoradiotherapy in stage III non-small-cell lung cancer. J Clin Oncol. 2022;40(12):1301-11. doi: 10.1200/JCO.21.01308. Erratum in: J Clin Oncol. 2022;40(17):1965. doi: 10.1200/JCO.22.01023. PMID: 35108059; PMCID: PMC9015199.
  15. Zhou Y, Yu F, Zhao Y, Zeng Y, Yang X, Chu L, et al. A narrative review of evolving roles of radiotherapy in advanced non-small cell lung cancer: from palliative care to active player. Transl Lung Cancer Res. 2020;9(6):2479-93. doi: 10.21037/tlcr-20-1145. PMID: 33489808; PMCID: PMC7815368.
  16. Ruchalski K, Braschi-Amirfarzan M, Douek M, Sai V, Gutierrez A, Dewan R, et al. A primer on RECIST 1.1 for oncologic imaging in clinical drug trials. Radiol Imaging Cancer. 2021;3(3):e210008. doi: 10.1148/rycan.2021210008. PMID: 33988475 PMCID: PMC8183261.
  17. Chung AE, Shoenbill K, Mitchell SA, Dueck AC, Schrag D, Bruner DW, et al. Patient free text reporting of symptomatic adverse events in cancer clinical research using the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). J Am Med Inform Assoc. 2019;26(4):276-85. doi: 10.1093/jamia/ocy169. PMID: 30840079 PMCID: PMC6402312.
  18. Fu Z, Yang X, Wang W, Deng L, Zhang T, Bi N, et al. Radiotherapy combined with gefitinib for patients with locally advanced non-small cell lung cancer who are unfit for surgery or concurrent chemoradiotherapy: a phase II clinical trial. Radiat Oncol. 2020;15(1):155. doi: 10.1186/s13014-020-01596-2. PMID: 32563259; PMCID: PMC7305585.
  19. Zheng L, Wang Y, Xu Z, Yang Q, Zhu G, Liao XY, et al. Concurrent EGFR-TKI and thoracic radiotherapy as first-line treatment for stage IV non-small cell lung cancer harboring EGFR active mutations. Oncologist. 2019;24(8):1031-e612. doi: 10.1634/theoncologist.2019-0285. PMID: 31040256; PMCID: PMC6693693.
  20. Chen F, Niu J, Wang M, Zhu H, Guo Z. Re-evaluating the risk factors for radiation pneumonitis in the era of immunotherapy. J Transl Med. 2023;21(1):368. doi: 10.1186/s12967-023-04212-5. PMID: 37287014; PMCID: PMC10246421.
  21. Haslett K, Koh P, Hudson A, Ryder WD, Falk S, Mullan D, et al. Phase I trial of the MEK inhibitor selumetinib in combination with thoracic radiotherapy in non-small cell lung cancer. Clin Transl Radiat Oncol. 2021;28:24-31. doi: 10.1016/j.ctro.2021.02.008. PMID: 33748440; PMCID: PMC7970011.
  22. Shimizu J, Akamatsu H, Murakami H, Harada H, Hayashi H, Daga H, et al. A single-arm phase II study of gefitinib with concurrent thoracic radiotherapy in unresectable locally-advanced non-small cell lung cancer patients with EGFR mutation (West Japan Oncology Group 6911L) Ann Oncol J. 2020;31(S4):S803. doi:10.1016/j.annonc.2020.08.109.
  23. Hsu F, Sit D, Pastuch A, Dingler A, Atwal P. Lung cancer epidermal growth factor receptor mutations and radiotherapy response: A multicentre clinical study. Clin Transl Radiat Oncol. 2021;30:15-8. doi: 10.1016/j.ctro.2021.06.006. PMID: 34278010; PMCID: PMC8267427.
  24. Martínez E, Martínez M, Rico M, Hernández B, Casas F, Viñolas N, et al. Feasibility, tolerability, and efficacy of the concurrent addition of erlotinib to thoracic radiotherapy in locally advanced unresectable non-small-cell lung cancer: a Phase II trial. Onco Targets Ther. 2016;9:1057-66. doi: 10.2147/OTT.S89755. PMID: 27042098; PMCID: PMC4780183.
  25. Zhou F, Qin Y, Liu X, Huang J, Wu B, Zhang Z, et al. Survival benefit of thoracic radiotherapy plus EGFR-TKIs in patients with non-oligometastatic advanced non-small-cell lung cancer: a single-center retrospective study. Ther Adv Med Oncol. 2023;15:17588359231161411. doi: 10.1177/17588359231161411. PMID: 36970112; PMCID: PMC10031612.
  26. Rajeev-Kumar G, Pitroda SP. Synergizing radiotherapy and immunotherapy: Current challenges and strategies for optimization. Neoplasia. 2023;36:100867. doi: 10.1016/j.neo.2022.100867. PMID: 36563632; PMCID: PMC9798173.
  27. Hsieh K, Dickstein DR, Runnels J, Lehrer EJ, Rosenzweig K, Hirsch FR, et al. Radiotherapy and immunotherapy in lung cancer. Biomedicines. 2023;11(6):1642. doi: 10.3390/biomedicines11061642. PMID: 37371737; PMCID: PMC10295589.
  28. von Reibnitz D, Chaft JE, Wu AJ, Samstein R, Hellmann MD, Plodkowski AJ, et al. Safety of combining thoracic radiation therapy with concurrent versus sequential immune checkpoint inhibition. Adv Radiat Oncol. 2018;3(3):391-8. doi: 10.1016/j.adro.2018.05.001. PMID: 30202807; PMCID: PMC6128092.
  29. Bozorgmehr F, Chung I, Christopoulos P, Krisam J, Schneider MA, Brückner L, et al. Thoracic radiotherapy plus Durvalumab in elderly and/or frail NSCLC stage III patients unfit for chemotherapy - employing optimized (hypofractionated) radiotherapy to foster durvalumab efficacy: study protocol of the TRADE-hypo trial. BMC Cancer. 2020;20(1):806. doi: 10.1186/s12885-020-07264-8. Erratum in: BMC Cancer. 2023;23(1):740. doi: 10.1186/s12885-023-11270-x. PMID: 32842974; PMCID: PMC7447611.