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Unmet Clinical Need in the Management of Locally Advanced Unresectable Lung Cancer: Treatment Strategies to Improve Patient Outcomes

Abstract

Stage III locally advanced non-small cell lung cancer (LA NSCLC) comprises the most heterogeneous group of patients, accounts for one-third of patients with lung cancer, and is unresectable at presentation. Multiple treatment approaches have evolved over the past few decades focusing on timing of chemoradiation (concurrent vs. sequential) and sequencing of therapy (induction vs. consolidation). Concurrent chemoradiation (CCRT) emerged as the standard of care for the majority of the patients worldwide. Despite improvements in median and overall survival (OS) using the concurrent approach, the rate of distant failure remains high. Consolidation with chemotherapy or targeted agents, adding more radiation dose, or induction chemotherapy did not improve OS. With continued research on defining optimal radiation doses and schedules and integrating novel systemic agents, immunotherapy consolidation has renewed optimism. Synergistic use of radiation and immunotherapy can prevent micrometastatic disease and reduce local failure and may have an abscopal effect in addition to survival benefits. The PACIFIC study reported an absolute progression-free survival benefit of 11.2 months with durvalumab consolidation after standard CCRT compared with placebo. The OS data with durvalumab consolidation are encouraging. Durvalumab is the only approved immunotherapy for unresectable stage III LA NSCLC. Improved survival confirms the definitive role of durvalumab as an effective adjuvant therapy after CCRT with no new safety signals. However, the potential mechanisms driving interaction between immunotherapy and chemoradiotherapy require definitive investigation. These mechanisms may help define the timing of immunotherapy initiation as neoadjuvant, adjuvant, or consolidation and maintenance therapy after progression.

Funding

AstraZeneca Pharma India Limited.

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Fig. 1

Reproduced with permission from Detterbeck F.C, Boffa D.J, Kim A.W, et al. The Eighth Edition Lung Cancer Stage Classification. CHEST. 2017; 151: 193–203 [4]

Fig. 2
Fig. 3

Modified with permission from Faien. I, Cummings. A.L, Crosetti A.M, et al. Durvalumab: an investigational anti-PD-L1 monoclonal antibody for the treatment of urothelial carcinoma. Drug Des Devel Ther. 2018; 12: 209–215 [52]

Fig. 4

References

  1. 1.

    Ferlay J, Bray F, Pisani P, Parkin DM. IARC cancer base no 5. Version 2.0. Lyon: IARC Press; 2004. GLOBOCAN 2002: Cancer incidence, mortality and prevalence worldwide.

  2. 2.

    Govindan R, Bogart J, Vokes EE. Locally advanced non-small cell lung cancer: the past, present, and future. J Thorac Oncol. 2008;3:917–28.

    Article  PubMed  Google Scholar 

  3. 3.

    Carter BW, Lichtenberger JP 3rd, Benveniste MK, et al. Revisions to the TNM staging of lung cancer: rationale, significance, and clinical application. Radiographics. 2018;38:374–91.

    Article  PubMed  Google Scholar 

  4. 4.

    Detterbeck FC, Boffa DJ, Kim AW, Tanoue LT. The eighth edition lung cancer stage classification. Chest. 2017;151:193–203.

    Article  PubMed  Google Scholar 

  5. 5.

    Lemjabbar-Alaoui H, Hassan OR, Yang YW, Buchanan P. Lung cancer: biology and treatment options. Biochim Biophys Acta. 2015;1856:189–210.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Eberhardt WE, De Ruysscher D, Weder W, et al. Locally advanced stage III non-small-cell lung cancer. Ann Oncol. 2015;26:1573–88.

    Article  CAS  Google Scholar 

  7. 7.

    Perez CA, Pajak TF, Rubin P, et al. Long-term observations of the patterns of failure in patients with unresectable non-oat cell carcinoma of the lung treated with definitive radiotherapy. Report by the Radiation Therapy Oncology Group. Cancer. 1987;59:1874–81.

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Dillman RO, Seagren SL, Propert KJ, et al. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med. 1990;323:940–5.

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Sause W, Kolesar P, Taylor S IV, et al. Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest. 2000;117:358–64.

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ. 1995;311:899–909.

  11. 11.

    Schaake-Koning C, van den Bogaert W, Dalesio O, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med. 1992;326:524–30.

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    Jeremic B, Shibamoto Y, Acimovic L, Djuric L. Randomized trial of hyperfractionated radiation therapy with or without concurrent chemotherapy for stage III non-small-cell lung cancer. J Clin Oncol. 1995;13:452–8.

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    Jeremic B, Shibamoto Y, Acimovic L, Milisavljevic S. Hyperfractionated radiation therapy with or without concurrent low-dose daily carboplatin/etoposide for stage III non-small-cell lung cancer: a randomized study. J Clin Oncol. 1996;14:1065–70.

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Aupérin A, Le Péchoux C, Pignon JP, et al. Meta-Analysis of Cisplatin/carboplatin based Concomitant Chemotherapy in non-small cell Lung Cancer (MAC3-LC) Group. Concomitant radio-chemotherapy based on platin compounds in patients with locally advanced non-small cell lung cancer (NSCLC): a meta-analysis of individual data from 1764 patients. Ann Oncol. 2006;17:473–83.

    Article  PubMed  Google Scholar 

  15. 15.

    Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol. 1999;17:2692–9.

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Fournel P, Robinet G, Thomas P, et al. Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d’Oncologie Thoracique-Groupe Francais de Pneumo-Cancerologie NPC 95-01 Study. J Clin Oncol. 2005;23:5910–7.

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Zatloukal P, Petruzelka L, Zemanova M, et al. Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study. Lung Cancer. 2004;46:87–98.

    Article  PubMed  Google Scholar 

  18. 18.

    Curran WJ Jr, Paulus R, Langer CJ, et al. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011;103:1452–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Auperin A, Le Pechoux 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.

    Article  CAS  Google Scholar 

  20. 20.

    El-Sharouni SY, Kal HB, Battermann JJ, Schramel FM. Sequential versus concurrent chemo-radiotherapy in inoperable stage III non-small cell lung cancer. Anticancer Res. 2006;26:495–505.

    CAS  PubMed  Google Scholar 

  21. 21.

    Murali AN, Radhakrishnan V, Ganesan TS, et al. Outcomes in lung cancer: 9-year experience from a tertiary cancer center in India. J Glob Oncol. 2017;3:459–68.

    Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Agarwal JP, Hotwani C, Prabhash K, et al. Optimizing treatment and analysis of prognostic factors for locally advanced nonsmall cell lung cancer in resource-limited population. Indian J Cancer. 2016;53:96–101.

    Article  CAS  PubMed  Google Scholar 

  23. 23.

    Baumann M, Herrmann T, Koch R, fset al. Final results of the randomized phase III CHARTWEL-trial (ARO 97-1) comparing hyperfractionated-accelerated versus conventionally fractionated radiotherapy in non-small cell lung cancer (NSCLC). Radiother Oncol. 2011;100:76–85.

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Mauguen A, Le Péchoux C, Saunders MI, et al. Hyperfractionated or accelerated radiotherapy in lung cancer: an individual patient data meta-analysis. J Clin Oncol. 2012;30:2788–97.

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Baker S, Dahele M, Lagerwaard FJ, Senan S. A critical review of recent developments in radiotherapy for non-small cell lung cancer. Radiat Oncol. 2016;11:115.

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Mazzarella L, Guida A, Curigliano G. Cetuximab for treating non-small cell lung cancer. Expert Opin Biol Ther. 2018;18:483–93.

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    Calikusua Z, Pelin A. Treatment of locally advanced, unresectable or medically inoperable stage III non-small-cell lung cancer; the past, present and future of chemoradiotherapy. J Oncol Sci. 2018;4:49e52.

    Google Scholar 

  29. 29.

    Gandara DR, Chansky K, Albain KS, et al. Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB non-small-cell lung cancer: phase II Southwest Oncology Group Study S9504. J Clin Oncol. 2003;21:2004–10.

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    Flentje M, Huber RM, Engel-Riedel W, et al. GILT—a randomised phase III study of oral vinorelbine and cisplatin with concomitant radiotherapy followed by either consolidation therapy with oral vinorelbine and cisplatin or best supportive care alone in stage III non-small cell lung cancer. Strahlenther Onkol. 2016;192:216–22.

    Article  PubMed  Google Scholar 

  31. 31.

    Hanna N, Neubauer M, Yiannoutsos C, et al. Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and US Oncology. J Clin Oncol. 2008;26:5755–60.

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    Kelly K, Chansky K, Gaspar LE, et al. 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. 2008;26:2450–6.

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Senan S, Brade A, Wang LH, et al. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016;34:953–62.

    Article  CAS  Google Scholar 

  34. 34.

    Chang XJ, Wang ZT, Yang L. Consolidation chemotherapy after concurrent chemoradiotherapy vs. chemoradiotherapy alone for locally advanced unresectable stage III non-small-cell lung cancer: a meta-analysis. Mol Clin Oncol. 2016;5:271–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Vokes EE, Herndon JE 2nd, Kelley MJ, al. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol. 2007;25:1698–704.

    Article  CAS  Google Scholar 

  36. 36.

    Kim S, Kim M, Choi E, et al. Induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) versus CCRT alone for unresectable stage III non-small cell lung cancer (NSCLC): randomized phase III trial. J Clin Oncol. 2007;25:7528.

    Google Scholar 

  37. 37.

    Van Houtte P. Adjuvant or induction chemotherapy for non small cell lung cancer treated with chemoradiotherapy: an individual data metaanalysis of phase II trials [Abstract]. WCLC2013 IASLC. P2:24 021.

  38. 38.

    Steuer CE, Behera M, Ernani V, et al. Comparison of concurrent use of thoracic radiation with either carboplatin-paclitaxel or cisplatin-etoposide for patients with stage III non-small-cell lung cancer: a systematic review. JAMA Oncol. 2017;3:1120–9.

    Article  PubMed  Google Scholar 

  39. 39.

    Yamamoto N, Nakagawa K, Nishimura Y, et al. Phase III study comparing second-and third-generation regimens with concurrent thoracic radiotherapy in patients with unresectable stage III non-small-cell lung cancer: West Japan Thoracic Oncology Group WJTOG0105. J Clin Oncol. 2010;28:3739–45.

    Article  PubMed  Google Scholar 

  40. 40.

    Belani CP, Choy H, Bonomi P, et al. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005;23:5883–91.

    Article  CAS  PubMed  Google Scholar 

  41. 41.

    van Reij EJ, Dahele M, van de Ven PM, et al. Changes in non-surgical management of stage III non-small cell lung cancer at a single institution between 2003 and 2010. Acta Oncol. 2014;53:316–23.

    Article  PubMed  Google Scholar 

  42. 42.

    Ahn JS, Ahn YC, Kim JH, et al. Multinational randomized phase III trial with or without consolidation chemotherapy using docetaxel and cisplatin after concurrent chemoradiation in inoperable stage III non-small-cell lung cancer: KCSG-LU05-04. J Clin Oncol. 2015;33:2660–6.

    Article  CAS  Google Scholar 

  43. 43.

    Chiramel J, Tay R, Califano R. Durvalumab after chemo-radiotherapy in stage III non-small cell lung cancer. J Thorac Dis. 2018;10:S991–4.

    Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    The National Comprehensive Cancer Network® Clinical Practice Guidelines in Oncology. https://www.nccn.org/professionals/physician_gls/default.aspx#site. Accessed 20 July 2018.

  45. 45.

    De Ruysscher D, Botterweck A, Dirx M, et al. Eligibility for concurrent chemotherapy and radiotherapy of locally advanced lung cancer patients: a prospective, population-based study. Ann Oncol. 2009;20:98–102.

    Article  PubMed  Google Scholar 

  46. 46.

    Hoang T, Dahlberg SE, Schiller JH, et al. Randomized phase III study of thoracic radiation in combination with paclitaxel and carboplatin with or without thalidomide in patients with stage III non-small-cell lung cancer: the ECOG 3598 study. J Clin Oncol. 2012;30:616–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Tiwana MS, Lee HN, Saini S, et al. Outcomes of patients with unresected stage III and stage IV non-small cell lung cancer: a single institution experience. Lung India. 2013;30:187–92.

    Article  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Heo CK, Bahk YY, Cho EW. Tumor-associated autoantibodies as diagnostic and prognostic biomarkers. BMB Rep. 2012;45:677–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Kamta J, Chaar M, Ande A, Altomare DA, Ait-Oudhia S. Advancing cancer therapy with present and emerging immuno-oncology approaches. Front Oncol. 2017;7:64.

    Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Clinical trial data. https://clinicaltrials.gov/ct2/show/NCT02343952?cond=pembrolizumab&draw=2&rank=7. Accessed 13 July 2018.

  51. 51.

    FDA press announcement February 16, 2018. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm597217.htm. Accessed 13 July 2018.

  52. 52.

    Faiena I, Cummings AL, Crosetti AM, Pantuck AJ, Chamie K, Drakaki A. Durvalumab: an investigational anti-PD-L1 monoclonal antibody for the treatment of urothelial carcinoma. Drug Des Dev Ther. 2018;12:209–15.

    Article  CAS  Google Scholar 

  53. 53.

    Berman AT, Simone CB 2nd. Immunotherapy in locally-advanced non-small cell lung cancer: releasing the brakes on consolidation? Transl Lung Cancer Res. 2016;5:138–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Stewart R, Morrow M, Hammond SA, et al. Identification and characterization of MEDI4736, an antagonistic anti-PD-L1 monoclonal antibody. Cancer Immunol Res. 2015;3:1052–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Antonia S, Goldberg SB, Balmanoukian A, et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol. 2016;17:299–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377:1919–29.

    Article  CAS  PubMed  Google Scholar 

  57. 57.

    Hui R, Ozguroğlu M, Daniel D, et al. Patient-reported outcomes with durvalumab after chemoradiation in locally advanced unresectable NSCLC: data from PACIFIC. In: Presented at the IASLC 18th world conference on lung cancer; October 15–18, 2017, Yokohama. Abstract PL 02.02.

  58. 58.

    Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2342–2350.

  59. 59.

    AstraZeneca Pharmaceuticals LP. Imfinzi receives positive EU CHMP opinion for locally-advanced, unresectable non-small cell lung cancer [press release]. https://www.astrazeneca.com/media-centre/press-releases/2018/imfinzi-receives-positive-eu-chmp-opinion-for-locally-advanced-unresectable-non-small-cell-lung-cancer-27072018.html. Published 27 July 2018. Accessed 24 Sept 2018.

  60. 60.

    Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer. Lancet. 2009;374:379–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Funding

The preparation of this article and funding of the journal’s article processing charges were supported by AstraZeneca Pharma India Limited. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.

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The authors thank AstraZeneca Pharma India Ltd and Chinmayee Joshi from Sciformix Technologies Private Limited, Mumbai for providing medical writing assistance in the development of this manuscript.

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All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

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Senthil Rajappa, Sanjiv Sharma, and Krishna Prasad declare that they have no conflict of interest.

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This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

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Rajappa, S., Sharma, S. & Prasad, K. Unmet Clinical Need in the Management of Locally Advanced Unresectable Lung Cancer: Treatment Strategies to Improve Patient Outcomes. Adv Ther 36, 563–578 (2019). https://doi.org/10.1007/s12325-019-0876-4

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Keywords

  • Durvalumab
  • Immunotherapy
  • Stage III LA NSCLC
  • Survival benefit
  • Unresectable