Advertisement

Targeted therapy combined with thoracic radiotherapy for non-small cell lung cancer

  • Guler YavasEmail author
  • Cagdas Yavas
Review

Abstract

Introduction

In recent years, there has been undoubted progress in the evaluation and development of targeted agents for non-small cell lung cancer (NSCLC). At the same time, remarkable progress in radiation therapy (RT) has been developed largely due to our ability to more effectively focus and deliver radiation to the tumor target volume. Both developments brought the idea of combining the radiation with molecularly targeted agents in order to improve outcomes in NSCLC patients who have limited survival times with standard chemoradiotherapy.

Methods

We identified patients with gastric cancer treated with post-operative radiation at our institution between 2002 and 2016. Acute and late toxicities were evaluated per RTOG/EORTC Radiation Toxicity Grading Scale. Statistical analysis was performed using Chi-square tests, t tests, log-rank, and logistic regression.

Results

Cetuximab has no survival benefit, and it seems to be toxic in this patient population. Bevacizumab has severe toxicity including tracheoesophageal fistulae formation in addition to its ineffectiveness. It is difficult to have an opinion about TKIs when combined with RT since most of the studies were conducted on unselected patients. For oligometastatic/oligoprogressive NSCLC patients, it seems to be reasonable to use a combined regimen since combined regimen resulted in superior survival time; however, the patients should be followed up closely with respect to the toxicity. In patients with brain metastases, the use of concomitant RT + TKIs increased survival with acceptable toxicity levels.

Conclusions

In this review, we summarize the recent literature about the use of molecularly targeted agents with concurrent RT in NSCLC patients.

Keywords

Chemoradiotherapy EGFR inhibitors Targeted therapy Non-small cell lung cancer Radiotherapy Targeted therapy 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest

Ethical approval

This article does not contain any studies with human participants performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Siegel RL, Miller KD, Jemal A (2017) Cancer Statistics, 2017. CA Cancer J Clin 67(1):7–30Google Scholar
  2. 2.
    Koh PK, Faivre-Finn C, Blackhall FH, De Ruysscher D (2012) Targeted agents in non-small cell lung cancer (NSCLC): clinical developments and rationale for the combination with thoracic radiotherapy. Cancer Treat Rev 38(6):626–640Google Scholar
  3. 3.
    Le Chevalier T, Arriagada R, Quoix E et al (1991) Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients. J Natl Cancer Inst 83(6):417–423Google Scholar
  4. 4.
    Groen HJ, van der Leest A, Fokkema E, Timmer PR, Nossent GD, Smit WJ, Nabers J, Hoekstra HJ, Hermans J, Otter R, van Putten J, de Vries EG, Mulder NH (2004) Continuously infused carboplatin used as radiosensitizer in locally unresectable non-small-cell lung cancer: a multicenter phase III study. Ann Oncol 15(3):427–432Google Scholar
  5. 5.
    Auperin A, Le Pechoux C, Rolland E et al (2010) Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol 28(13):2181–2190Google Scholar
  6. 6.
    Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, Bogart J, Hu C, Forster K, Magliocco A, Kavadi V, Garces YI, Narayan S, Iyengar P, Robinson C, Wynn RB, Koprowski C, Meng J, Beitler J, Gaur R, Curran W Jr, Choy H (2015) 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. 16(2):187–199Google Scholar
  7. 7.
    Perez CA, Stanley K, Rubin P et al (1980) A prospective randomized study of various irradiation doses and fractionation schedules in the treatment of inoperable non-oat-cell carcinoma of the lung. Preliminary report by the Radiation Therapy Oncology Group. Cancer 45:2744–2753Google Scholar
  8. 8.
    Onishi H, Shirato H, Nagata Y, Hiraoka M, Fujino M, Gomi K,Niibe Y, Karasawa K, Hayakawa K, Takai Y, Kimura T, Takeda A,Ouchi A, Hareyama M, Kokubo M, Hara R, Itami J, Yamada K,Araki T (2007) 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 2(7 Suppl 3):S94–S100Google Scholar
  9. 9.
    Steel GG (1979) Terminology in the description of drug-radiation interactions. Int J Radiat Oncol Biol Phys 5:1145–1150Google Scholar
  10. 10.
    Bentzen SM, Harari PM, Bernier J (2007) Exploitable mechanisms for combining drugs with radiation: concepts, achievements and future directions. Nat Clin Pract Oncol 4:172–180Google Scholar
  11. 11.
    Blackhall F, Ranson M, Thatcher N (2006) Where next for gefitinib in patients with lung cancer? Lancet Oncol. 7(6):499–507Google Scholar
  12. 12.
    Morris ZS, Harari PM (2014) Interaction of radiation therapy with molecular targeted agents. J Clin Oncol 32(26):2886–2893Google Scholar
  13. 13.
    Milas L, Fan Z, Andratschke NH, Ang KK (2004) Epidermal growth factor receptor and tumor response to radiation: in vivo preclinical studies. Int J Radiat Oncol Biol Phys 58(3):966–971Google Scholar
  14. 14.
    Nyati MK, Morgan MA, Feng FY, Lawrence TS (2006) Integration of EGFR inhibitors with radiochemotherapy. Nat Rev Cancer 6(11):876–885Google Scholar
  15. 15.
    Schmidt-Ullrich RK, Mikkelsen RB, Dent P, Todd DG, Valerie K, Kavanagh BD, Contessa JN, Rorrer WK, Chen PB (1997) Radiation-induced proliferation of the human A431 squamous carcinoma cells is dependent on EGFR tyrosine phosphorylation. Oncogene. 15:1191–1197Google Scholar
  16. 16.
    Baumann M, Krause M, Dikomey E, Dittmann K, Dörr W, Kasten-Pisula U, Rodemann HP (2007) EGFR-targeted anti-cancer drugs in radiotherapy: preclinical evaluation of mechanisms. Radiother Oncol 83:238–248Google Scholar
  17. 17.
    Mendelsohn J (2000) Blockade of receptors for growth factors: an anticancer therapy-the fourth annual Joseph H Burchenal American Association of Cancer Research Clinical Research Award Lecture. Clin Cancer Res 6:747–753Google Scholar
  18. 18.
    Milas L, Mason K, Hunter N, Petersen S, Yamakawa M, Ang K, Mendelsohn J, Fan Z (2000) In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody. Clin Cancer Res 6(2):701–708Google Scholar
  19. 19.
    Huang SM, Bock JM, Harari PM (1999) Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res 59:1935–1940Google Scholar
  20. 20.
    Govindan R, Bogart J, Stinchcombe T, Wang X, Hodgson L, Kratzke R, Garst J, Brotherton T, Vokes EE (2011) Randomized phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small-cell lung cancer: Cancer and Leukemia Group B trial 30407. J Clin Oncol 29(23):3120–3125Google Scholar
  21. 21.
    Blumenschein GR Jr, Paulus R, Curran WJ, Robert F, Fossella F, Werner-Wasik M, Herbst RS, Doescher PO, Choy H, Komaki R (2011) Phase II study of cetuximab in combination with chemoradiation in patients with stage IIIA/B non-small-cell lung cancer: RTOG 0324. J Clin Oncol 29:2312–2318Google Scholar
  22. 22.
    Bradley JD, Hu C, Komaki RU, Masters G, Blumenschein GR, Schild SE, Bogart JA, Forster KM, Magliocco A, Kavadi VS, Narayan S, Iyengar P, Robinson CG, Wynn RB, Koprowski CD, Olson MR, Meng J, Curran WJ Jr, Choy H (2017) Long-term results of RTOG 0617: a randomized phase 3 comparison of standard dose versus high dose conformal chemoradiation therapy +/− cetuximab for stage III NSCLC. Int J Radiat Oncol Biol Phys 99(2):S105Google Scholar
  23. 23.
    Kotsakis AR, Ramalingam SS, Tarhini AA, Heron DE, Smith R, Friedland D (2011) Multicenter phase II study of cetuximab (C) with concomitant radiotherapy (RT) followed by consolidation chemotherapy (CT) in locally advanced non-small cell lung cancer (NSCLC). J Clin Oncol 29(Suppl):abstr 7019Google Scholar
  24. 24.
    Jensen AD, Munter MW, Bischoff HG et al (2011) Combined treatment of non-small cell lung cancer NSCLC stage III with intensity-modulated RT radiotherapy and cetuximab: the NEAR trial. Cancer 117(13):2986–2994Google Scholar
  25. 25.
    Jatoi A, Schild SE, Foster N, Henning GT, Dornfeld KJ, Flynn PJ, Fitch TR, Dakhil SR, Rowland KM, Stella PJ, Soori GS, Adjei AA (2010) A phase II study of cetuximab and radiation in elderly and/or poor performance status patients with locally advanced non-small-cell lung cancer (N0422). Ann Oncol 21(10):2040–2044Google Scholar
  26. 26.
    Chen YM, Pandya J, Kelly KJK et al (2011) Pilot study (SWOG S0429) of weekly cetuximab and chest radiotherapy (RT) for poor-risk stage III non-small cell lung cancer (NSCLC). J Clin Oncol 29(Suppl):abstr 7040Google Scholar
  27. 27.
    Hughes S, Liong J, Miah A, Ahmad S, Leslie M, Harper P, Prendiville J, Shamash J, Subramaniam R, Gaya A, Spicer J, Landau D (2008) A brief report on the safety study of induction chemotherapy followed by synchronous radiotherapy and cetuximab in stage III non-small cell lung cancer (NSCLC): SCRATCH study. J Thorac Oncol 3(6):648–651Google Scholar
  28. 28.
    Dingemans A-MB, van Baardwijk G, Reymen A et al (2011) Determination of standard dose cetuximab together with concurrent individualised, isotoxic accelerated radiotherapy and cisplatin-vinorelbine for patients with stage III non-small cell lung cancer (NSCLC): a phase I study (NCT00522886). J Thorac Oncol 6(6):abstr MO02.02Google Scholar
  29. 29.
    Nguyen KS, Neal JW, Wakelee H (2014) Review of the current targeted therapies for non-small-cell lung cancer. World J Clin Oncol 5(4):576–587Google Scholar
  30. 30.
    Ready N, Jänne PA, Bogart J, Dipetrillo T, Garst J, Graziano S, Gu L, Wang X, Green MR, Vokes EE, Cancer, Leukemia Group B, Chicago, IL (2010) Chemoradiotherapy and gefitinib in stage III non-small cell lung cancer with epidermal growth factor receptor and KRAS mutation analysis: Cancer and Leukemia Group B (CALEB) 30106, a CALEB-stratified phase II trial. J Thorac Oncol 5(9):1382–1390Google Scholar
  31. 31.
    Niho S, Ohe Y, Ishikura S, Atagi S, Yokoyama A, Ichinose Y, Okamoto H, Takeda K, Shibata T, Tamura T, Saijo N, Fukuoka M (2012) Induction chemotherapy followed by gefitinib and concurrent thoracic radiotherapy for unresectable locally advanced adenocarcinoma of the lung: a multicenter feasibility study (JCOG 0402). Ann Oncol 23:2253–2258Google Scholar
  32. 32.
    Stinchcombe T, Socinski MA, Moore DT, Gettinger NS, Decker RH, Petty WJ et al (2011) Phase I/II trial of bevacizumab (B) and erlotinib (E) with induction (IND) and concurrent (CON) carboplatin (Cb)/paclitaxel (P) and 74 Gy of thoracic conformal radiotherapy (TCRT) in stage III non-small cell lung cancer (NSCLC). J Clin Oncol 29:457s (suppl 15; abstr 7016)Google Scholar
  33. 33.
    Center B, Petty WJ, Ayala D, Hinson WH, Lovato J, Capellari J, Oaks T, Miller AA, Blackstock AW (2010) A phase I study of gefitinib with concurrent dose-escalated weekly docetaxel and conformal three-dimensional thoracic radiation followed by consolidative docetaxel and maintenance gefitinib for patients with stage III non-small cell lung cancer. J Thorac Oncol 5(1):69–74Google Scholar
  34. 34.
    Rothschild S, Bucher SE, Bernier J, Aebersold DM, Zouhair A, Ries G, Lombrieser N, Lippuner T, Lütolf UM, Glanzmann C, Ciernik IF (2011) Gefitinib in combination with irradiation with or without cisplatin in patients with inoperable stage III non-small cell lung cancer: a phase I trial. Int J Radiat Oncol Biol Phys 80(1):126–132Google Scholar
  35. 35.
    Okamoto I, Takahashi T, Okamoto H, Nakagawa K, Watanabe K, Nakamatsu K, Nishimura Y, Fukuoka M, Yamamoto N (2011) Single-agent gefitinib with concurrent radiotherapy for locally advanced non-small cell lung cancer harboring mutations of the epidermal growth factor receptor. Lung Cancer 72(2):199–204Google Scholar
  36. 36.
    Levy A, Bardet E, Lacas B, Pignon JP, Adam J, Lacroix L, Artignan X, Verrelle P, Péchoux L (2017) A phase II open-label multicenter study of gefitinib in combination with irradiation followed by chemotherapy in patients with inoperable stage III non-small cell lung cancer. Oncotarget. 8(9):15924–15933Google Scholar
  37. 37.
    Kelly K, Chansky K, Gaspar LE, Albain KS, Jett J, Ung YC, Lau DHM, Crowley JJ, Gandara DR (2008) Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol 26(15):2450–2456Google Scholar
  38. 38.
    Komaki R, Allen PK, Wei X, Blumenschein GR, Tang X, Lee JJ, Welsh JW, Wistuba II, Liu DD, Hong WK (2015) Adding erlotinib to chemoradiation improves overall survival but not progression-free survival in stage III non-small cell lung cancer. Int J Radiat Oncol Biol Phys 92(2):317–324Google Scholar
  39. 39.
    Ramella S, Trodella L, Alberti A et al (2011) Multimodality treatment with radiochemotherapy and erlotinib in advanced NSCLC (MARTE trial). J Thorac Oncol 6:Abstr MO02.04Google Scholar
  40. 40.
    Martinez E, Martinez M, Viñolas N, Casas F, de la Torre A, Valcarcel F, Minguez J, Paredes A, Casas AP, Dómine M (2008) Feasibility and tolerability of the addition of erlotinib to 3D thoracic radiotherapy (RT) in patients (p) with unresectable NSCLC: a prospective randomized phase II study. J Clin Oncol 26(Supplement):7563Google Scholar
  41. 41.
    Choong NW, Mauer AM, Haraf DJ, Lester E, Hoffman PC, Kozloff M, Lin S, Dancey JE, Szeto L, Grushko T, Olopade OI, Salgia R, Vokes EE (2008) Phase I trial of erlotinib-based multimodality therapy for inoperable stage III non-small cell lung cancer. J Thorac Oncol 3(9):1003–1011Google Scholar
  42. 42.
    Wan J, Cohen V, Agulnij J, Faria S, Portelance L, Ofiara L, Sultanem K, Souhami L, Hirsh V (2009) Unexpected high lung toxicity from radiation pneumonitis in a phase I/II trial of concurrent erlotinib with limited field radiation for intermediate prognosis patients with stage III or inoperable stage IIB non– small-cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 75(3):S110Google Scholar
  43. 43.
    Lilenbaum R, Samuels M, Wang X, Kong FM, Jänne PA, Masters G, Katragadda S, Hodgson L, Bogart J, Bradley J, Vokes E (2015) A phase II study of induction chemotherapy followed by thoracic radiotherapy and erlotinib in poor risk stage III non-small cell lung cancer: results of CALGB 30605 (Alliance)/RTOG 0972 (NRG). Thorac Oncol 10:143–147Google Scholar
  44. 44.
    Carmeliet P, Jain RK (2011) Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 10:417–427Google Scholar
  45. 45.
    Spigel DR, Hainsworth JD, Yardley DA, Raefsky E, Patton J, Peacock N, Farley C, Burris HA 3rd, Greco FA (2010) Tracheoesophageal fistula formation in patients with lung cancer treated with chemoradiation and bevacizumab. J Clin Oncol 28(1):43–48Google Scholar
  46. 46.
    Wozniak AJ, Moon J, Thomas CR Jr, Kelly K, Mack PC, Gaspar LE, Raben D, Fitzgerald TJ, Pandya KJ, Gandara DR (2015) A pilot trial of cisplatin/etoposide/radiotherapy followed by consolidation docetaxel and the combination of bevacizumab (NSC-704865) in patients with inoperable locally advanced stage III non-small-cell lung cancer: SWOG S0533. Clin Lung Cancer 16(5):340–347Google Scholar
  47. 47.
    Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, de Pas T, Besse B, Solomon BJ, Blackhall F, Wu YL, Thomas M, O'Byrne KJ, Moro-Sibilot D, Camidge DR, Mok T, Hirsh V, Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD, Jänne PA (2013) Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368:2385–2394Google Scholar
  48. 48.
    Dai Y, Wei Q, Schwager C, Moustafa M, Zhou C, Lipson KE, Weichert W, J1 D, Abdollahi A (2015) Synergistic effects of crizotinib and radiotherapy in experimental EML4-ALK fusion positive lung cancer. Radiother Oncol 114(2):173–181Google Scholar
  49. 49.
    Nasser H (2015) Current standards and clinical trials in systemic therapy for stage III lung cancer: what is new? ASCO Educational BookGoogle Scholar
  50. 50.
    Zeng J, Baik C, Bhatia S, Mayr N, Rengan R (2014) Combination of stereotactic ablative body radiation with targeted therapies. Lancet Oncol 15:e426–e433Google Scholar
  51. 51.
    Couñago F, Rodríguez A, Calvo P, Luna J, Monroy JL, Taboada B, Díaz V, Rodríguez de Dios N (2017) Targeted therapy combined with radiotherapy in non-small-cell lung cancer: a review of the Oncologic Group for the Study of Lung Cancer (Spanish Radiation Oncology Society). Clin Transl Oncol 19(1):31–43Google Scholar
  52. 52.
    García-Campelo R, Bernabé R, Cobo M, Corral J, Coves J, Dómine M, Nadal E, Rodriguez-Abreu D, Viñolas N, Massuti B (2015) SEOM clinical guidelines for the treatment of non-small cell lung cancer (NSCLC) 2015. Clin Transl Oncol. 17:1020–1029Google Scholar
  53. 53.
    Iyengar P, Kavanagh BD, Wardak Z, Smith I, Ahn C, Gerber DE, Dowell J, Hughes R, Abdulrahman R, Camidge DR, Gaspar LE, Doebele RC, Bunn PA, Choy H, Timmerman R (2014) Phase II trial of stereotactic body radiation therapy combined with erlotinib for patients with limited but progressive metastatic non-small-cell lung cancer. J Clin Oncol 32:3824–3830Google Scholar
  54. 54.
    Gan GN, Weickhardt AJ, Scheier B, Doebele RC, Gaspar LE, Kavanagh BD (2014) Stereotactic radiation therapy can safely and durably control sites of extra-central nervous system oligoprogressive disease in anaplastic lymphoma kinase-positive lung cancer patients receiving crizotinib. Int J Radiat Oncol Biol Phys 88:892–898Google Scholar
  55. 55.
    Yu HA, Sima CS, Huang J, Solomon SB, Rimner A, Paik P, Pietanza MC, Azzoli CG, Rizvi NA, Krug LM, Miller VA, Kris MG, Riely GJ (2013) Local therapy with continued EGFR tyrosine kinase inhibitor therapy as a treatment strategy in EGFR-mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors. J Thor Oncol 8:346–351Google Scholar
  56. 56.
    Weickhardt AJ, Scheier B, Burke JM, Gan G, Lu X, Bunn PA et al (2012) Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J Thorac Oncol 7:1807–1814Google Scholar
  57. 57.
    Besse B, Adjei A, Baas P, Meldgaard P, Nicolson M, Paz-Ares L, Reck M, Smit EF, Syrigos K, Stahel R, Felip E, Peters S, Stahel R, Felip E, Peters S, Kerr K, Besse B, Vansteenkiste J, Eberhardt W, Edelman M, Mok T, O'Byrne K, Novello S, Bubendorf L, Marchetti A, Baas P, Reck M, Syrigos K, Paz-Ares L, Smit EF, Meldgaard P, Adjei A, Nicolson M, Crino L, van Schil P, Senan S, Faivre-Finn C, Rocco G, Veronesi G, Douillard JY, Lim E, Dooms C, Weder W, de Ruysscher D, le Pechoux C, de Leyn P, Westeel V, Panel Members (2014) 2nd ESMO Consensus Conference on Lung Cancer: non-small-cell lung cancer first-line/second and furtherlines in advanced disease. Ann Oncol 25:1475–1484Google Scholar
  58. 58.
    Luo S, Chen L, Chen X, Xie X (2015) Evaluation on efficacy and safety of tyrosine kinase inhibitors plus radiotherapy in NSCLC patients with brain metastases. Oncotarget. 6(18):16725–16734Google Scholar
  59. 59.
    Khuntia D, Brown P, Li J, Mehta MP (2006) Whole-brain radiotherapy in the management of brain metastasis. J Clin Oncol 24:1295–1304Google Scholar
  60. 60.
    Eichler AF, Loeffler JS (2007) Multidisciplinary management of brain metas-tases. Oncologist 12:884–898Google Scholar
  61. 61.
    Zhang J, Yu J, Sun X, Meng X (2014) Epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of central nerve system metastases from NSCLC. Cancer Lett 351:6–12Google Scholar
  62. 62.
    Jiang T, Min W, Li Y, Yue Z, Wu C, Zhou C (2016) Radiotherapy plus EGFR TKIs in non-small cell lung cancer patients with brain metastases: an update meta-analysis. Cancer Med 5(6):1055–1065Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Radiation Oncology, Faculty of MedicineSelcuk UniversityKonyaTurkey

Personalised recommendations