We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

Pneumonitis with combined immune checkpoint inhibitors and chemoradiotherapy in locally advanced non-small-cell lung cancer: a systematic review and meta-analysis

    Linlin Yang‡

    Department of Radiation Oncology, Shandong Cancer Hospital & Institute, Shandong First Medical University & Shandong Academy of Medical Science, Jinan, 250117, China

    ‡Authors contributed equally

    Search for more papers by this author

    ,
    Butuo Li‡

    Department of Radiation Oncology, Shandong Cancer Hospital & Institute, Shandong First Medical University & Shandong Academy of Medical Science, Jinan, 250117, China

    ‡Authors contributed equally

    Search for more papers by this author

    ,
    Yiyue Xu

    Department of Radiation Oncology, Shandong Cancer Hospital & Institute, Shandong First Medical University & Shandong Academy of Medical Science, Jinan, 250117, China

    ,
    Bing Zou

    Department of Radiation Oncology, Shandong Cancer Hospital & Institute, Shandong First Medical University & Shandong Academy of Medical Science, Jinan, 250117, China

    ,
    Bingjie Fan

    Department of Radiation Oncology, Shandong Cancer Hospital & Institute, Shandong First Medical University & Shandong Academy of Medical Science, Jinan, 250117, China

    ,
    Chunni Wang

    Department of Radiation Oncology, Shandong Cancer Hospital & Institute, Shandong First Medical University & Shandong Academy of Medical Science, Jinan, 250117, China

    &
    Linlin Wang

    *Author for correspondence: Tel.: +86 137 9318 7739;

    E-mail Address: wanglinlinatjn@163.com

    Department of Radiation Oncology, Shandong Cancer Hospital & Institute, Shandong First Medical University & Shandong Academy of Medical Science, Jinan, 250117, China

    Published Online:https://doi.org/10.2217/fon-2022-1274

    Aims: This study systematically evaluated cases of pneumonitis following combined immune checkpoint inhibitors (ICI) and chemoradiotherapy (CRT) for locally advanced non-small-cell lung cancer (LA-NSCLC). Methods: Studies from Embase, PubMed and the Cochrane Library on patients with LA-NSCLC who received CRT and ICIs were reviewed. The primary outcomes were rates of all-grade, grade 3–5 and grade 5 pneumonitis. Results: Overall, 35 studies involving 5000 patients were enrolled. The pooled rates of all-grade, grade 3–5 and grade 5 pneumonitis were 33.0% (95% CI: 23.5–42.6), 6.1% (95% CI: 4.7–7.4) and 0.8% (95% CI: 0.3–1.2), respectively, with 7.6% of patients discontinuing ICIs because of pneumonitis. Conclusion: The incidence rates of pneumonitis following combined CRT and ICIs for LA-NSCLC were acceptable. However, the pulmonary toxicity of concurrent CRT and nivolumab plus ipilimumab should be noted.

    Plain language summary

    Combined immune checkpoint inhibitors (ICI) and chemoradiotherapy (CRT) may cause severe pneumonitis due to overlapped pulmonary toxicity. However, the safety data on pneumonitis are limited to a small number of prospective clinical trials and retrospective studies with limited evidence. Thus we conducted a systematic review of pneumonitis in relation to the combination treatment. A total of 35 studies, involving 5000 patients, were included for the final analysis. The pooled rates of all-grade, grade 3–5 and grade 5 pneumonitis were 33.0, 6.1 and 0.8%, respectively, and 7.6% of patients stopped taking ICIs because of pneumonitis. The pneumonitis rates following combined CRT and ICIs for LA-NSCLC were acceptable, but the pulmonary toxicity of concurrent CRT and nivolumab plus ipilimumab should be noted.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. Bobbili P, Ryan K, Duh MS et al. Treatment patterns and overall survival among patients with unresectable, stage III non-small-cell lung cancer. Future Oncol. 15(29), 3381–3393 (2019).
    • 2. Chansky K, Detterbeck FC, Nicholson AG et al. The IASLC Lung Cancer Staging Project: external validation of the revision of the TNM stage groupings in the Eighth Edition of the TNM Classification of Lung Cancer. J. Thorac. Oncol. 12(7), 1109–1121 (2017).
    • 3. 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. 103(19), 1452–1460 (2011).
    • 4. 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. 16(2), 187–199 (2015).
    • 5. Spigel DR, Faivre-Finn C, Gray JE et al. Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. J. Clin. Oncol. 40(12), 1301–1311 (2022). • The PACIFIC study led to a new standard of consolidation immunotherapy 1 year after concurrent chemoradiotherapy for locally advanced non-small-cell lung cancer.
    • 6. Ko EC, Raben D, Formenti SC. The integration of radiotherapy with immunotherapy for the treatment of non-small cell lung cancer. Clin. Cancer Res. 24(23), 5792–5806 (2018).
    • 7. Theelen W, Chen D, Verma V et al. Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Respir. Med. 9(5), 467–475 (2021).
    • 8. Barker HE, Paget JT, Khan AA, Harrington KJ. The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat. Rev. Cancer 15(7), 409–425 (2015).
    • 9. Santivasi WL, Xia F. Ionizing radiation-induced DNA damage, response, and repair. Antioxid. Redox Signal. 21(2), 251–259 (2014).
    • 10. Rodríguez-Ruiz ME, Vanpouille-Box C, Melero I, Formenti SC, Demaria S. Immunological mechanisms responsible for radiation-induced abscopal effect. Trends Immunol. 39(8), 644–655 (2018).
    • 11. Kaur P, Asea A. Radiation-induced effects and the immune system in cancer. Front. Oncol. 2, 191 (2012).
    • 12. Daly ME, Monjazeb AM, Kelly K. Clinical trials integrating immunotherapy and radiation for non-small-cell lung cancer. J. Thorac. Oncol. 10(12), 1685–1693 (2015).
    • 13. Shaverdian N, Lisberg AE, Bornazyan K et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol. 18(7), 895–903 (2017).
    • 14. Shaverdian N, Beattie J, Thor M et al. Safety of thoracic radiotherapy in patients with prior immune-related adverse events from immune checkpoint inhibitors. Ann. Oncol. 31(12), 1719–1724 (2020).
    • 15. Hanania AN, Mainwaring W, Ghebre YT, Hanania NA, Ludwig M. Radiation-induced lung injury: assessment and management. Chest 156(1), 150–162 (2019).
    • 16. Weber JS, Yang JC, Atkins MB, Disis ML. Toxicities of immunotherapy for the practitioner. J. Clin. Oncol. 33(18), 2092–2099 (2015).
    • 17. Li M, Gan L, Song A, Xue J, Lu Y. Rethinking pulmonary toxicity in advanced non-small cell lung cancer in the era of combining anti-PD-1/PD-L1 therapy with thoracic radiotherapy. Biochim. Biophys. Acta Rev. Cancer 1871(2), 323–330 (2019). •• Demonstrated that for patients with locally advanced non-small-cell lung cancer treated with combined chemoradiotherapy and immune checkpoint inhibitors, treatment-related adverse pulmonary events should be of particular concern because both treatments may simultaneously induce pulmonary toxicity.
    • 18. Page MJ, Moher D, Bossuyt PM et al. PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. BMJ 372, n160 (2021). •• Provides the research methods for this study.
    • 19. Page MJ, McKenzie JE, Bossuyt PM et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372, n71 (2021). •• Provides the research methods for this study.
    • 20. Yan M, Durm GA, Mamdani H et al. Consolidation nivolumab/ipilimumab versus nivolumab following concurrent chemoradiation in patients with unresectable stage III NSCLC: a planned interim safety analysis from the BTCRC LUN 16-081 trial. J. Clin. Oncol. 38(15), 9010–9010 (2020).
    • 21. Herbst RS, Majem M, Barlesi F et al. COAST: an open-label, phase II, multidrug platform study of durvalumab alone or in combination with oleclumab or monalizumab in patients with unresectable, stage III non-small-cell lung cancer. J. Clin. Oncol. 40(29), 3383–3393 (2022).
    • 22. Liveringhouse C, Lam NB, Rosenberg SA et al. Prospective phase I/II study of radiation and chemotherapy with ipilimumab followed by nivolumab for patients with stage III unresectable NSCLC. Int. J. Radiat. Oncol. Biol. Phys. 111(3), S3–S4 (2021).
    • 23. Garassino MC, Mazieres J, Reck M et al. Durvalumab after sequential chemoradiotherapy in stage III, unresectable NSCLC: the phase 2 PACIFIC-6 trial. J. Thorac. Oncol. 17(12), 1415–1427 (2022).
    • 24. Christoph DC, Girard N, Smit HJM et al. Pacific-R real-world study: treatment duration and interim analysis of progression-free survival in unresectable stage III NSCLC patients treated with durvalumab after chemoradiotherapy. Oncol. Res. Treat. 44(Suppl. 2), 53 (2021).
    • 25. Bruni A, Scotti V, Borghetti P et al. A real-world, multicenter, observational retrospective study of durvalumab after concomitant or sequential chemoradiation for unresectable stage III non-small cell lung cancer. Front. Oncol. 11, 744956 (2021).
    • 26. Wass R, Hochmair M, Kaiser B et al. Durvalumab after sequential high dose chemoradiotherapy versus standard of care (SoC) for stage III NSCLC: a bi-centric trospective comparison focusing on pulmonary toxicity. Cancers (Basel) 14(13), 3226 (2022).
    • 27. Zhou Q, Chen M, Jiang O et al. Sugemalimab versus placebo after concurrent or sequential chemoradiotherapy in patients with locally advanced, unresectable, stage III non-small-cell lung cancer in China (GEMSTONE-301): interim results of a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 23(2), 209–219 (2022).
    • 28. Hwang WL, Pike LRG, Royce TJ, Mahal BA, Loeffler JS. Safety of combining radiotherapy with immune-checkpoint inhibition. Nat. Rev. Clin. Oncol. 15(8), 477–494 (2018).
    • 29. Deng L, Liang H, Burnette B et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J. Clin. Invest. 124(2), 687–695 (2014).
    • 30. Sanmamed MF, Chen L. A paradigm shift in cancer immunotherapy: from enhancement to normalization. Cell 175(2), 313–326 (2018).
    • 31. Kuang Y, Pierce CM, Chang HC et al. Chemoradiation-induced pneumonitis in patients with unresectable stage III non-small cell lung cancer: a systematic literature review and meta-analysis. Lung Cancer 174, 174–185 (2022).
    • 32. Park K, Vansteenkiste J, Lee KH et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with locally-advanced unresectable non-small-cell lung cancer: a KSMO-ESMO initiative endorsed by CSCO, ISMPO, JSMO, MOS, SSO and TOS. Ann. Oncol. 31(2), 191–201 (2020).
    • 33. Daly ME, Singh N, Ismaila N et al. Management of stage III non-small-cell lung cancer: ASCO Guideline. J. Clin. Oncol. 40(12), 1356–1384 (2022).
    • 34. Walraven I, Damhuis RA, Ten Berge MG et al. Treatment variation of sequential versus concurrent chemoradiotherapy in stage III non-small cell lung cancer patients in The Netherlands and Belgium. Clin. Oncol. 29(11), e177–e185 (2017).
    • 35. Hung A, Lee KM, Lynch JA et al. Chemoradiation treatment patterns among United States Veteran Health Administration patients with unresectable stage III non-small cell lung cancer. BMC Cancer 21(1), 824 (2021).
    • 36. Spencer A, Williams J, Samuel R, Boon IS, Clarke K, Jain P. Concurrent versus sequential chemoradiotherapy for unresectable locally advanced stage III non-small cell lung cancer: retrospective analysis in a single United Kingdom cancer centre. Cancer Treat. Res. Commun. 29, 100460 (2021).
    • 37. Conibear J. Rationale for concurrent chemoradiotherapy for patients with stage III non-small-cell lung cancer. Br. J. Cancer 123(Suppl. 1), 10–17 (2020).
    • 38. Weinmann SC, Pisetsky DS. Mechanisms of immune-related adverse events during the treatment of cancer with immune checkpoint inhibitors. Rheumatology 58(Suppl. 7), vii59–vii67 (2019).
    • 39. Durm GA, Mamdani H, Althouse SK et al. Consolidation nivolumab plus ipilimumab or nivolumab alone following concurrent chemoradiation for patients with unresectable stage III non-small cell lung cancer: BTCRC LUN 16-081. Journal of Clinical Oncology. 40(Suppl. 16), 8509 (2022).
    • 40. Xiao Y, Yu S, Zhu B et al. RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance. J. Exp. Med. 211(5), 943–959 (2014).
    • 41. Muraro E, Romanò R, Fanetti G et al. Tissue and circulating PD-L2: moving from health and immune-mediated diseases to head and neck oncology. Crit. Rev. Oncol. Hematol. 175, 103707 (2022).
    • 42. Mayoux M, Roller A, Pulko V et al. Dendritic cells dictate responses to PD-L1 blockade cancer immunotherapy. Sci. Transl. Med. 12(534), eaav7431 (2020).
    • 43. Takeuchi M, Doi T, Obayashi K et al. Soluble PD-L1 with PD-1-binding capacity exists in the plasma of patients with non-small cell lung cancer. Immunol. Lett. 196, 155–160 (2018).
    • 44. Jalali S, Price-Troska T, Paludo J et al. Soluble PD-1 ligands regulate T-cell function in Waldenstrom macroglobulinemia. Blood Adv. 2(15), 1985–1997 (2018).
    • 45. 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. Journal of clinical oncology 34(9), 953–62 (2016).
    • 46. Eichkorn T, Bozorgmehr F, Regnery S et al. Consolidation Immunotherapy After Platinum-Based Chemoradiotherapy in Patients With Unresectable Stage III Non-Small Cell Lung Cancer-Cross-Sectional Study of Eligibility and Administration Rates. Frontiers in oncology 10, 586449 (2020).
    • 47. Jabbour SK, Lee KH, Frost N et al. Pembrolizumab Plus Concurrent Chemoradiation Therapy in Patients With Unresectable, Locally Advanced, Stage III Non-Small Cell Lung Cancer: The Phase 2 KEYNOTE-799 Nonrandomized Trial. JAMA Oncol. 7(9), 1–9 (2021).
    • 48. Ryckman JM, Baine M, Carmicheal J et al. Correlation of dosimetric factors with the development of symptomatic radiation pneumonitis in stereotactic body radiotherapy. Radiation oncology. 15(1), 33 ( 2020).
    • 49. Pan WY, Bian C, Zou GL et al. Combing NLR, V20 and mean lung dose to predict radiation induced lung injury in patients with lung cancer treated with intensity modulated radiation therapy and chemotherapy. Oncotarget. 8(46), 81387–93 (2017).
    • 50. Chun SG, Hu C, Choy H et al. Impact of intensity-modulated radiation therapy technique for locally advanced non-small-cell lung cancer: a secondary analysis of the NRG Oncology RTOG 0617 randomized clinical trial. J. Clin. Oncol. 35(1), 56–62 (2017).
    • 51. Wurstbauer K, Kazil M, Meinschad M et al. Locally advanced NSCLC: a plea for sparing the ipsilateral normal lung-prospective, clinical trial with DART-bid (dose-differentiated accelerated radiation therapy, 1.8 Gy twice daily) by VMAT. Radiat. Oncol. 17(1), 120 (2022).
    • 52. Baumann BC, Mitra N, Harton JG et al. Comparative effectiveness of proton vs photon therapy as part of concurrent chemoradiotherapy for locally advanced cancer. JAMA Oncol. 6(2), 237–246 (2020).
    • 53. Bradley J, Bae K, Choi N et al. A phase II comparative study of gross tumor volume definition with or without PET/CT fusion in dosimetric planning for non-small-cell lung cancer (NSCLC): primary analysis of Radiation Therapy Oncology Group (RTOG) 0515. International journal of radiation oncology, biology, physics 82(1), 435–41.e1 (2012).
    • 54. Zou L, Chu L, Xia F et al. Is clinical target volume necessary? – a failure pattern analysis in patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiotherapy using intensity-modulated radiotherapy technique. Transl. Lung Cancer Res. 9(5), 1986–1995 (2020).
    • 55. Xia F, Zhou L, Yang X et al. Is a clinical target volume (CTV) necessary for locally advanced non-small cell lung cancer treated with intensity-modulated radiotherapy? – a dosimetric evaluation of three different treatment plans. J. Thorac. Dis. 9(12), 5194–5202 (2017).
    • 56. Xue J, Du S, Lu Y, Dicker A, Lu B. Abstract 3671: anti-PD-1 treatment may potentiate the radiation-induced lung injury. Cancer Res. 77(Suppl. 13), 3671 (2017).
    • 57. van der Woude LL, Gorris MAJ, Wortel IMN et al. Tumor microenvironment shows an immunological abscopal effect in patients with NSCLC treated with pembrolizumab-radiotherapy combination. J. Immunother. Cancer 10(10), e005248 (2022). • Provides the direction for further research in the future.
    • 58. Xue J, Li X, Lu Y et al. Gene-modified mesenchymal stem cells protect against radiation-induced lung injury. Mol. Ther. 21(2), 456–465 (2013).
    • 59. Kim KH, Pyo H, Lee H et al. Association of T cell senescence with radiation pneumonitis in patients with non-small cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 115(2), 464–475 (2022).
    • 60. Kim KH, Pyo H, Lee H et al. Dynamics of circulating immune cells during chemoradiotherapy in patients with non-small cell lung cancer support earlier administration of anti-PD-1/PD-L1 therapy. Int. J. Radiat. Oncol. Biol. Phys. 113(2), 415–425 (2022).
    • 61. Sierra-Rodero B, Cruz-Bermúdez A, Nadal E et al. Clinical and molecular parameters associated to pneumonitis development in non-small-cell lung cancer patients receiving chemoimmunotherapy from NADIM trial. J. Immunother. Cancer 9(8), e002804 (2021).
    • 62. Hawkins PG, Boonstra PS, Hobson ST et al. Radiation-induced lung toxicity in non-small-cell lung cancer: understanding the interactions of clinical factors and cytokines with the dose-toxicity relationship. Radiother. Oncol. 125(1), 66–72 (2017).
    • 63. Kainthola A, Haritwal T, Tiwari M et al. Immunological aspect of radiation-induced pneumonitis, current treatment strategies, and future prospects. Front. Immunol. 8, 506 (2017).
    • 64. Brahmer JR, Lacchetti C, Schneider BJ et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. Journal of clinical oncology 36(17), 1714–68 (2018).