Radiotherapy in Lung Cancer: Ally or Foe of Immunotherapy?
Main Article Content
Abstract
Radiotherapy is the most common local treatment for lung cancer. The spectrum of its use ranges from the treatment of early-stage tumors in patients who are not candidates for surgery to the treatment of advanced, unresectable tumors and, very frequently, of metastatic lesions. With great interest, radiotherapy has also been currently cited as a source of neoantigens, stimulating the immune system and enhancing the effect of immunomodulatory drugs. However, the side effects of irradiation on the lung parenchyma and on the immune system can turn it into a hidden foe, impairing patients’ quality of life and survival. Pneumonitis and immunosuppression are two of the side effects of radiotherapy that best exemplify this hidden damage. Studies have shown decreased survival in patients who develop radiation pneumonitis or have a large volume of immune tissue irradiated. Irradiating less lung tissue will reduce damage to lung function and loss of immune cells. However, this alone is not sufficient for dose protection in lymphoid tissue, given the circulation of lymphoid cells in the great vessels and heart and their production in thoracic vertebral bone marrow. Identifying the optimal total dose and the most appropriate daily dose to reduce damage and boost the immune system is the target of our investigations. Although we still do not have an optimal algorithm for dose, fraction, and cost-effectiveness for radiation doses delivered to healthy tissues, we know which path to take.
Article Details
How to Cite
MATIELLO, Juliana; DALENOGARE, Maiara; BERTON, Danilo Cortesi.
Radiotherapy in Lung Cancer: Ally or Foe of Immunotherapy?.
Medical Research Archives, [S.l.], v. 11, n. 4, apr. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3748>. Date accessed: 21 nov. 2024.
doi: https://doi.org/10.18103/mra.v11i4.3748.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Sharma R. Mapping of global, regional and national incidence, mortality and mortality-to-incidence ratio of lung cancer in 2020 and 2050. Int J Clin Oncol. 2022;27(4):665-675. doi: 10.1007/s10147-021-02108-2
2. Araujo LH, Baldotto C, De Castro Jr, G, et al. Lung cancer in Brazil. J Bras Pneumol. 2018;44(1):55-64. doi: 10.1590/S1806-37562017000000135
3. Ganti AK, Klein AB, Cotarla I, Seal B, Chou E. Update of incidence, prevalence, survival, and initial treatment in patients with non-small cell lung cancer in the US. JAMA Oncol. 2021;7(12):1824-1832. doi: 10.1001/jamaoncol.2021.4932
4. Sher DJ, Koshy M, Liptay MJ, Fidler MJ. Influence of conformal radiotherapy technique on survival after chemoradiotherapy for patients with stage III non-small cell lung cancer in the National Cancer Data Base. Cancer. 2014;120(13):2060-2068. doi: 10.1002/cncr.28677
5. Harris JP, Murphy JD, Hanlon AL, Le QT, Loo BW, Jr., Diehn M. A population-based comparative effectiveness study of radiation therapy techniques in stage III non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2014;88(4):872-884. doi: 10.1016/j.ijrobp.2013.12.010
6. Chang JY. Intensity-modulated radiotherapy, not 3 dimensional conformal, is the preferred technique for treating locally advanced lung cancer. Semin Radiat Oncol. 2015;25(2):110-116. doi: 10.1016/j.semradonc.2014.11.002
7. Speirs CK, DeWees TA, Rehman S, et al. Heart dose is an independent dosimetric predictor of overall survival in locally advanced non-small cell lung cancer. J Thorac Oncol. 2017;12(2):293-301. doi: 10.1016/j.jtho.2016.09.134
8. 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(2):187-199. doi: 10.1016/S1470-2045(14)71207-0
9. Upadhyay R, Venkatesulu BP, Giridhar P, et al. Risk and impact of radiation related lymphopenia in lung cancer: A systematic review and meta-analysis. Radiother Oncol. 2021;157:225-233. doi: 10.1016/j.radonc.2021.01.034
10. Matiello J, Dal Pra A, Zardo L, Silva R, Berton DC. Impacts of post-radiotherapy lymphocyte count on progression-free and overall survival in patients with stage III lung cancer. Thorac Cancer. 2020;11(11):3139-3144. doi: 10.1111/1759-7714.13621
11. 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. 2022;40(12):1301-1311. doi: 10.1200/JCO.21.01308
12. Kingsley DP. An interesting case of possible abscopal effect in malignant melanoma. Br J Radiol. 1975;48(574):863-866. doi: 10.1259/0007-1285-48-574-863
13. Wersall PJ, Blomgren H, Pisa P, Lax I, Kalkner KM, Svedman C. Regression of non-irradiated metastases after extracranial stereotactic radiotherapy in metastatic renal cell carcinoma. Acta Oncol. 2006;45(4):493-497. doi: 10.1080/02841860600604611
14. Robin HI, AuBuchon J, Varanasi VR, Weinstein AB. The abscopal effect: demonstration in lymphomatous involvement of kidneys. Med Pediatr Oncol. 1981;9(5):473-476. doi: 10.1002/mpo.2950090510
15. Brandmaier A, Formenti SC. The impact of radiation therapy on innate and adaptive tumor immunity. Semin Radiat Oncol. 2020;30(2):139-144. doi: 10.1016/j.semradonc.2019.12.005
16. Hellmann MD, Nathanson T, Rizvi H, et al. Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer. Cancer Cell. 2018;33(5):843-852 e844. doi: 10.1016/j.ccell.2018.03.018
17. Lussier DM, Alspach E, Ward JP, et al. Radiation-induced neoantigens broaden the immunotherapeutic window of cancers with low mutational loads. Proc Natl Acad Sci U S A. 2021;118(24). doi: 10.1073/pnas.2102611118
18. Nakamura N, Kusunoki Y, Akiyama M. Radiosensitivity of CD4 or CD8 positive human T-lymphocytes by an in vitro colony formation assay. Radiat Res. 1990;123(2):224-227. doi: 10.2307/3577549
19. Venkatesulu B, Giridhar P, Pujari L, et al. Lymphocyte sparing normal tissue effects in the clinic (LymphoTEC): A systematic review of dose constraint considerations to mitigate radiation-related lymphopenia in the era of immunotherapy. Radiother Oncol. 2022;177:81-94. doi: 10.1016/j.radonc.2022.10.019
20. Ladbury CJ, Rusthoven CG, Camidge DR, Kavanagh BD, Nath SK. Impact of radiation dose to the host immune system on tumor control and survival for stage III non-small cell lung cancer treated with definitive radiation therapy. Int J Radiat Oncol Biol Phys. 2019;105(2):346-355. doi: 10.1016/j.ijrobp.2019.05.064
21. Tagliaferri L, Lancellotta V, Fionda B, et al. Immunotherapy and radiotherapy in melanoma: a multidisciplinary comprehensive review. Hum Vaccin Immunother. 2022;18(3):1903827. doi: 10.1080/21645515.2021.1903827
22. 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. 2017;18(7):895-903. doi: 10.1016/S1470-2045(17)30380-7
23. Cho Y, Park S, Byun HK, et al. Impact of treatment-related lymphopenia on immunotherapy for advanced non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2019;105(5):1065-1073. doi: 10.1016/j.ijrobp.2019.08.047
24. McCall NS, McGinnis HS, Janopaul-Naylor JR, et al. Impact of radiation dose to the immune cells in unresectable or stage III non-small cell lung cancer in the durvalumab era. Radiother Oncol. 2022;174:133-140. doi: 10.1016/j.radonc.2022.07.015
25. Timmerman RD, Hu C, Michalski JM, et al. Long-term results of stereotactic body radiation therapy in medically inoperable stage I non-small cell lung cancer. JAMA Oncol. 2018;4(9):1287-1288. doi: 10.1001/jamaoncol.2018.1258
26. ClinicalTrials.gov. Durvalumab vs placebo with stereotactic body radiation therapy in early stage unresected non-small cell lung cancer (NSCLC) patients/Osimertinib following SBRT in patients with early stage unresected NSCLC harboring an EGFR mutation (PACIFIC-4). Accessed February 10, 2023. http://clinicaltrials.gov/ct2/show/NCT03833154
27. SWOG. Cancer Research Network. A randomized phase III trial of induction/consolidation atezolizumab (NSC #783608) plus SBRT versus SBRT alone in high risk, early stage NSCLC (SWOG 1914). Accessed February 10, 2023. https://www.swog.org/clinical-trials/s1914 90.
28. ClinicalTrials.gov. Efficacy and safety study of stereotactic body radiotherapy (SBRT) with or without pembrolizumab (MK-3475) in adults with unresected stage I or II non-small cell lung cancer (NSCLC) (MK-3475-867/KEYNOTE-867). Accessed February 10, 2023. https://clinicaltrials.gov/ct2/show/NCT03924869
29. Zhou ZC, Chen KY, Li N, et al. Real-world utilization of PD-1/PD-L1 inhibitors with palliative radiotherapy in patients with metastatic non-small cell lung cancer. Thorac Cancer. 2022;13(16):2291-2300. doi: 10.1111/1759-7714.14553
30. Liu L, Yuan M, Ding Z, et al. Immunotherapy with radiotherapy fails to improve prognosis of patients with stage IV non-small cell lung cancer: a retrospective cohort analysis of the THUNDER-2 study. Transl Lung Cancer Res. 2022;11(12):2507-2520. doi: 10.21037/tlcr-22-843
31. Amin S, Baine MJ, Meza JL, Lin C. The Association of the Sequence of Immunotherapy With the Survival of Unresectable Pancreatic Adenocarcinoma Patients: A Retrospective Analysis of the National Cancer Database. Front Oncol. 2020;10:1518. doi: 10.3389/fonc.2020.01518
32. Lee YH, Kim YS, Lee SN, et al. Interstitial lung change in pre-radiation therapy computed tomography is a risk factor for severe radiation pneumonitis. Cancer Res Treat. 2015;47(4):676-686. doi: 10.4143/crt.2014.180
33. Kashihara T, Nakayama Y, Ito K, et al. Usefulness of simple original interstitial lung abnormality scores for predicting radiation pneumonitis requiring steroidal treatment after definitive radiation therapy for patients with locally advanced non-small cell lung cancer. Adv Radiat Oncol. 2021;6(1):100606. doi: 10.1016/j.adro.2020.10.019
34. Arbour KC, Mezquita L, Long N, et al. Impact of Baseline Steroids on Efficacy of Programmed Cell Death-1 and Programmed Death-Ligand 1 Blockade in Patients with Non-Small-Cell Lung Cancer. J Clin Oncol. 2018;36(28):2872-2878. doi: 10.1200/JCO.2018.79.0006
2. Araujo LH, Baldotto C, De Castro Jr, G, et al. Lung cancer in Brazil. J Bras Pneumol. 2018;44(1):55-64. doi: 10.1590/S1806-37562017000000135
3. Ganti AK, Klein AB, Cotarla I, Seal B, Chou E. Update of incidence, prevalence, survival, and initial treatment in patients with non-small cell lung cancer in the US. JAMA Oncol. 2021;7(12):1824-1832. doi: 10.1001/jamaoncol.2021.4932
4. Sher DJ, Koshy M, Liptay MJ, Fidler MJ. Influence of conformal radiotherapy technique on survival after chemoradiotherapy for patients with stage III non-small cell lung cancer in the National Cancer Data Base. Cancer. 2014;120(13):2060-2068. doi: 10.1002/cncr.28677
5. Harris JP, Murphy JD, Hanlon AL, Le QT, Loo BW, Jr., Diehn M. A population-based comparative effectiveness study of radiation therapy techniques in stage III non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2014;88(4):872-884. doi: 10.1016/j.ijrobp.2013.12.010
6. Chang JY. Intensity-modulated radiotherapy, not 3 dimensional conformal, is the preferred technique for treating locally advanced lung cancer. Semin Radiat Oncol. 2015;25(2):110-116. doi: 10.1016/j.semradonc.2014.11.002
7. Speirs CK, DeWees TA, Rehman S, et al. Heart dose is an independent dosimetric predictor of overall survival in locally advanced non-small cell lung cancer. J Thorac Oncol. 2017;12(2):293-301. doi: 10.1016/j.jtho.2016.09.134
8. 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(2):187-199. doi: 10.1016/S1470-2045(14)71207-0
9. Upadhyay R, Venkatesulu BP, Giridhar P, et al. Risk and impact of radiation related lymphopenia in lung cancer: A systematic review and meta-analysis. Radiother Oncol. 2021;157:225-233. doi: 10.1016/j.radonc.2021.01.034
10. Matiello J, Dal Pra A, Zardo L, Silva R, Berton DC. Impacts of post-radiotherapy lymphocyte count on progression-free and overall survival in patients with stage III lung cancer. Thorac Cancer. 2020;11(11):3139-3144. doi: 10.1111/1759-7714.13621
11. 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. 2022;40(12):1301-1311. doi: 10.1200/JCO.21.01308
12. Kingsley DP. An interesting case of possible abscopal effect in malignant melanoma. Br J Radiol. 1975;48(574):863-866. doi: 10.1259/0007-1285-48-574-863
13. Wersall PJ, Blomgren H, Pisa P, Lax I, Kalkner KM, Svedman C. Regression of non-irradiated metastases after extracranial stereotactic radiotherapy in metastatic renal cell carcinoma. Acta Oncol. 2006;45(4):493-497. doi: 10.1080/02841860600604611
14. Robin HI, AuBuchon J, Varanasi VR, Weinstein AB. The abscopal effect: demonstration in lymphomatous involvement of kidneys. Med Pediatr Oncol. 1981;9(5):473-476. doi: 10.1002/mpo.2950090510
15. Brandmaier A, Formenti SC. The impact of radiation therapy on innate and adaptive tumor immunity. Semin Radiat Oncol. 2020;30(2):139-144. doi: 10.1016/j.semradonc.2019.12.005
16. Hellmann MD, Nathanson T, Rizvi H, et al. Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer. Cancer Cell. 2018;33(5):843-852 e844. doi: 10.1016/j.ccell.2018.03.018
17. Lussier DM, Alspach E, Ward JP, et al. Radiation-induced neoantigens broaden the immunotherapeutic window of cancers with low mutational loads. Proc Natl Acad Sci U S A. 2021;118(24). doi: 10.1073/pnas.2102611118
18. Nakamura N, Kusunoki Y, Akiyama M. Radiosensitivity of CD4 or CD8 positive human T-lymphocytes by an in vitro colony formation assay. Radiat Res. 1990;123(2):224-227. doi: 10.2307/3577549
19. Venkatesulu B, Giridhar P, Pujari L, et al. Lymphocyte sparing normal tissue effects in the clinic (LymphoTEC): A systematic review of dose constraint considerations to mitigate radiation-related lymphopenia in the era of immunotherapy. Radiother Oncol. 2022;177:81-94. doi: 10.1016/j.radonc.2022.10.019
20. Ladbury CJ, Rusthoven CG, Camidge DR, Kavanagh BD, Nath SK. Impact of radiation dose to the host immune system on tumor control and survival for stage III non-small cell lung cancer treated with definitive radiation therapy. Int J Radiat Oncol Biol Phys. 2019;105(2):346-355. doi: 10.1016/j.ijrobp.2019.05.064
21. Tagliaferri L, Lancellotta V, Fionda B, et al. Immunotherapy and radiotherapy in melanoma: a multidisciplinary comprehensive review. Hum Vaccin Immunother. 2022;18(3):1903827. doi: 10.1080/21645515.2021.1903827
22. 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. 2017;18(7):895-903. doi: 10.1016/S1470-2045(17)30380-7
23. Cho Y, Park S, Byun HK, et al. Impact of treatment-related lymphopenia on immunotherapy for advanced non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2019;105(5):1065-1073. doi: 10.1016/j.ijrobp.2019.08.047
24. McCall NS, McGinnis HS, Janopaul-Naylor JR, et al. Impact of radiation dose to the immune cells in unresectable or stage III non-small cell lung cancer in the durvalumab era. Radiother Oncol. 2022;174:133-140. doi: 10.1016/j.radonc.2022.07.015
25. Timmerman RD, Hu C, Michalski JM, et al. Long-term results of stereotactic body radiation therapy in medically inoperable stage I non-small cell lung cancer. JAMA Oncol. 2018;4(9):1287-1288. doi: 10.1001/jamaoncol.2018.1258
26. ClinicalTrials.gov. Durvalumab vs placebo with stereotactic body radiation therapy in early stage unresected non-small cell lung cancer (NSCLC) patients/Osimertinib following SBRT in patients with early stage unresected NSCLC harboring an EGFR mutation (PACIFIC-4). Accessed February 10, 2023. http://clinicaltrials.gov/ct2/show/NCT03833154
27. SWOG. Cancer Research Network. A randomized phase III trial of induction/consolidation atezolizumab (NSC #783608) plus SBRT versus SBRT alone in high risk, early stage NSCLC (SWOG 1914). Accessed February 10, 2023. https://www.swog.org/clinical-trials/s1914 90.
28. ClinicalTrials.gov. Efficacy and safety study of stereotactic body radiotherapy (SBRT) with or without pembrolizumab (MK-3475) in adults with unresected stage I or II non-small cell lung cancer (NSCLC) (MK-3475-867/KEYNOTE-867). Accessed February 10, 2023. https://clinicaltrials.gov/ct2/show/NCT03924869
29. Zhou ZC, Chen KY, Li N, et al. Real-world utilization of PD-1/PD-L1 inhibitors with palliative radiotherapy in patients with metastatic non-small cell lung cancer. Thorac Cancer. 2022;13(16):2291-2300. doi: 10.1111/1759-7714.14553
30. Liu L, Yuan M, Ding Z, et al. Immunotherapy with radiotherapy fails to improve prognosis of patients with stage IV non-small cell lung cancer: a retrospective cohort analysis of the THUNDER-2 study. Transl Lung Cancer Res. 2022;11(12):2507-2520. doi: 10.21037/tlcr-22-843
31. Amin S, Baine MJ, Meza JL, Lin C. The Association of the Sequence of Immunotherapy With the Survival of Unresectable Pancreatic Adenocarcinoma Patients: A Retrospective Analysis of the National Cancer Database. Front Oncol. 2020;10:1518. doi: 10.3389/fonc.2020.01518
32. Lee YH, Kim YS, Lee SN, et al. Interstitial lung change in pre-radiation therapy computed tomography is a risk factor for severe radiation pneumonitis. Cancer Res Treat. 2015;47(4):676-686. doi: 10.4143/crt.2014.180
33. Kashihara T, Nakayama Y, Ito K, et al. Usefulness of simple original interstitial lung abnormality scores for predicting radiation pneumonitis requiring steroidal treatment after definitive radiation therapy for patients with locally advanced non-small cell lung cancer. Adv Radiat Oncol. 2021;6(1):100606. doi: 10.1016/j.adro.2020.10.019
34. Arbour KC, Mezquita L, Long N, et al. Impact of Baseline Steroids on Efficacy of Programmed Cell Death-1 and Programmed Death-Ligand 1 Blockade in Patients with Non-Small-Cell Lung Cancer. J Clin Oncol. 2018;36(28):2872-2878. doi: 10.1200/JCO.2018.79.0006