Neoadjuvant immunotherapy combined with stereotactic body radiation therapy for stage Ⅲ/N2 non-small cell lung cancer: Three cases reports_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

WANG Zhen ¹ , GU Haoyu ² , LUO Jing ³ , ZHU Xixu ¹ , SONG Yong ⁴ , SHEN Yi ³ ,  QIANG Yong ³

1. Department of Radiation Oncology, General Hospital of Eastern Theater Command, Nanjing, 210016, P. R. China;
2. Medical College, Nantong University, Nantong, 226006, Jiangsu, P. R. China;
3. Department of Cardiothoracic Surgery, General Hospital of Eastern Theater Command, Nanjing, 210016, P. R. China;
4. Department of Respiratory and Critical Medicine, General Hospital of Eastern Theater Command, Nanjing, 210016, P. R. China;

Corresponding author：

QIANG Yong, Email: 3947885@qq.com

Keywords：

Neoadjuvant therapy; radiation therapy; programmed cell death protein-1; non-small cell lung cancer; stereotactic body radiation therapy; case report

DOI：

10.7507/1007-4848.202210022

Video：

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We reported three cases of stageⅢ/N2 non-small cell lung cancer (NSCLC) treated with neoadjuvant immunotherapy and stereotactic body radiation therapy (SBRT) in our hospital, including 2 males and 1 female with a mean age of 65.7 years. The patients received two doses of the programmed cell death protein-1 inhibitor toripalimab after 1 week of SBRT. Thereafter, surgery was planned 4-6 weeks after the second dose. One patient achieved pathologic complete response, one achieved major pathologic response (MPR), and one did not achieve MPR with 20% residual tumor. There were few side effects of toripalimab combined with SBRT as a neoadjuvant treatment, and the treatment did not cause a delay of surgery.

Citation： WANG Zhen, GU Haoyu, LUO Jing, ZHU Xixu, SONG Yong, SHEN Yi, QIANG Yong. Neoadjuvant immunotherapy combined with stereotactic body radiation therapy for stage Ⅲ/N2 non-small cell lung cancer: Three cases reports. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2023, 30(8): 1210-1216. doi: 10.7507/1007-4848.202210022 Copy

1.	Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: Proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol, 2007, 2(8): 706-714.
2.	Gilligan D, Nicolson M, Smith I, et al. Preoperative chemotherapy in patients with resectable non-small cell lung cancer: Results of the MRC LU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review. Lancet, 2007, 369(9577): 1929-1937.
3.	Singh S, Gupta R, Singh TP, et al. A comparative study of concurrent chemo-radiotherapy with or without neoadjuvant chemotherapy in treatment of locally advanced non-small cell lung cancer. Gulf J Oncolog. 2021, 1(37): 62-69.
4.	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.
5.	Trommer M, Adams A, Celik E, et al. Oncologic outcome and immune responses of radiotherapy with anti-PD-1 treatment for brain metastases regarding timing and benefiting subgroups. Cancers (Basel), 2022, 14(5): 1240.
6.	Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med, 2018, 378(21): 1976-1986.
7.	Provencio M, Nadal E, Insa A, et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): An open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol, 2020, 21(11): 1413-1422.
8.	Timmerman RD, Hu C, Michalski JM, et al. Long-term results of stereotactic body radiation therapy in medically inoperable stageⅠnon-small cell lung cancer. JAMA Oncol, 2018, 4(9): 1287-1288.
9.	Vanpouille-Box C, Alard A, Aryankalayil MJ, et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun, 2017, 8: 15618.
10.	Maas KW, Biere SS, Scheepers JJ, et al. Minimally invasive intrathoracic anastomosis after Ivor Lewis esophagectomy for cancer: A review of transoral or transthoracic use of staplers. Surg Endosc, 2012, 26(7): 1795-1802.
11.	Wang P, Yin T, Zhao K, et al. Efficacy of single-site radiotherapy plus PD-1 inhibitors vs. PD-1 inhibitors for oligometastatic non-small cell lung cancer. J Cancer Res Clin Oncol, 2022, 148(5): 1253-1261.
12.	Palma DA, Nguyen TK, Louie AV, et al. Measuring the integration of stereotactic ablative radiotherapy plus surgery for early-stage non-small cell lung cancer: A phase 2 clinical trial. JAMA Oncol, 2019, 5(5): 681-688.
13.	Kwiatkowski DJ, Rusch VW, Chaft JE, et al. Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): Interim analysis and biomarker data from a multicenter study (LCMC3). J Clin Oncol, 2019: 37.
14.	Bartella I, Fransen LFC, Gutschow CA, et al. Technique of open and minimally invasive intrathoracic reconstruction following esophagectomy—An expert consensus based on a modified Delphi process. Dis Esophagus, 2021, 34(11): doaa127.
15.	Demaria S, Golden EB, Formenti SC. Role of local radiation therapy in cancer immunotherapy. JAMA Oncol, 2015, 1(9): 1325-1332.
16.	McLaughlin M, Patin EC, Pedersen M, et al. Inflammatory microenvironment remodelling by tumour cells after radiotherapy. Nat Rev Cancer, 2020, 20(4): 203-217.
17.	Chen ZY, Duan XT, Qiao SM, et al. Radiotherapy combined with PD-1/PD-L1 inhibitors in NSCLC brain metastases treatment: The mechanisms, advances, opportunities, and challenges. Cancer Med, 2023, 12(2): 995-1006.
18.	Joseph K, Walker J, Raziee H, et al. PD-1 blockade with concurrent radiotherapy for locally advanced inoperable cutaneous squamous cell carcinoma. J Cutan Med Surg, 2022, 26(3): 243-248.
19.	Altorki NK, McGraw TE, Borczuk AC, et al. Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: A single-centre, randomised phase 2 trial. Lancet Oncol, 2021, 22(6): 824-835.
20.	Fuertes MB, Kacha AK, Kline J, et al. Host typeⅠIFN signals are required for antitumor CD8⁺ T cell responses through CD8α⁺ dendritic cells. J Exp Med, 2011, 208(10): 2005-2016.
21.	Jin JY, Hu C, Xiao Y, et al. Higher radiation dose to immune system is correlated with poorer survival in patients with stageⅢnon-small cell lung cancer: A secondary study of a phase 3 cooperative group trial (NRG Oncology RTOG 0617). Int J Radiat Oncol, 2017, 99(2S): S151-S152.
22.	Ladbury CJ, Rusthoven CG, Camidge DR, et al. Impact of radiation dose to the host immune system on tumor control and survival for stageⅢnon-small cell lung cancer treated with definitive radiation therapy. Int J Radiat Oncol Biol Phys, 2019, 105(2): 346-355.
23.	Marciscano AE, Ghasemzadeh A, Nirschl TR, et al. Elective nodal irradiation attenuates the combinatorial efficacy of stereotactic radiation therapy and immunotherapy. Clin Cancer Res, 2018, 24(20): 5058-5071.
24.	Welsh J, Menon H, Chen D, et al. Pembrolizumab with or without radiation therapy for metastatic non-small cell lung cancer: A randomized phaseⅠ/Ⅱtrial. J Immunother Cancer, 2020, 8(2): e001001.
25.	Theelen WSME, Peulen HMU, Lalezari F, et al. Effect of pembrolizumab after stereotactic body radiotherapy vs. pembrolizumab alone on tumor response in patients with advanced non-small cell lung cancer: Results of the PEMBRO-RT phase 2 randomized clinical trial. JAMA Oncol, 2019, 5(9): 1276-1282.
26.	Lim JU, Kim SH, Kang HS, et al. Predictive role of prior radiotherapy and immunotherapy-related adverse effects in advanced NSCLC patients receiving Anti-PD-1/L1 therapy. J Clin Med, 2021, 10(16): 3719.

1. Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: Proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol, 2007, 2(8): 706-714.
2. Gilligan D, Nicolson M, Smith I, et al. Preoperative chemotherapy in patients with resectable non-small cell lung cancer: Results of the MRC LU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review. Lancet, 2007, 369(9577): 1929-1937.
3. Singh S, Gupta R, Singh TP, et al. A comparative study of concurrent chemo-radiotherapy with or without neoadjuvant chemotherapy in treatment of locally advanced non-small cell lung cancer. Gulf J Oncolog. 2021, 1(37): 62-69.
4. 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.
5. Trommer M, Adams A, Celik E, et al. Oncologic outcome and immune responses of radiotherapy with anti-PD-1 treatment for brain metastases regarding timing and benefiting subgroups. Cancers (Basel), 2022, 14(5): 1240.
6. Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med, 2018, 378(21): 1976-1986.
7. Provencio M, Nadal E, Insa A, et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): An open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol, 2020, 21(11): 1413-1422.
8. Timmerman RD, Hu C, Michalski JM, et al. Long-term results of stereotactic body radiation therapy in medically inoperable stageⅠnon-small cell lung cancer. JAMA Oncol, 2018, 4(9): 1287-1288.
9. Vanpouille-Box C, Alard A, Aryankalayil MJ, et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun, 2017, 8: 15618.
10. Maas KW, Biere SS, Scheepers JJ, et al. Minimally invasive intrathoracic anastomosis after Ivor Lewis esophagectomy for cancer: A review of transoral or transthoracic use of staplers. Surg Endosc, 2012, 26(7): 1795-1802.
11. Wang P, Yin T, Zhao K, et al. Efficacy of single-site radiotherapy plus PD-1 inhibitors vs. PD-1 inhibitors for oligometastatic non-small cell lung cancer. J Cancer Res Clin Oncol, 2022, 148(5): 1253-1261.
12. Palma DA, Nguyen TK, Louie AV, et al. Measuring the integration of stereotactic ablative radiotherapy plus surgery for early-stage non-small cell lung cancer: A phase 2 clinical trial. JAMA Oncol, 2019, 5(5): 681-688.
13. Kwiatkowski DJ, Rusch VW, Chaft JE, et al. Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): Interim analysis and biomarker data from a multicenter study (LCMC3). J Clin Oncol, 2019: 37.
14. Bartella I, Fransen LFC, Gutschow CA, et al. Technique of open and minimally invasive intrathoracic reconstruction following esophagectomy—An expert consensus based on a modified Delphi process. Dis Esophagus, 2021, 34(11): doaa127.
15. Demaria S, Golden EB, Formenti SC. Role of local radiation therapy in cancer immunotherapy. JAMA Oncol, 2015, 1(9): 1325-1332.
16. McLaughlin M, Patin EC, Pedersen M, et al. Inflammatory microenvironment remodelling by tumour cells after radiotherapy. Nat Rev Cancer, 2020, 20(4): 203-217.
17. Chen ZY, Duan XT, Qiao SM, et al. Radiotherapy combined with PD-1/PD-L1 inhibitors in NSCLC brain metastases treatment: The mechanisms, advances, opportunities, and challenges. Cancer Med, 2023, 12(2): 995-1006.
18. Joseph K, Walker J, Raziee H, et al. PD-1 blockade with concurrent radiotherapy for locally advanced inoperable cutaneous squamous cell carcinoma. J Cutan Med Surg, 2022, 26(3): 243-248.
19. Altorki NK, McGraw TE, Borczuk AC, et al. Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: A single-centre, randomised phase 2 trial. Lancet Oncol, 2021, 22(6): 824-835.
20. Fuertes MB, Kacha AK, Kline J, et al. Host typeⅠIFN signals are required for antitumor CD8⁺ T cell responses through CD8α⁺ dendritic cells. J Exp Med, 2011, 208(10): 2005-2016.
21. Jin JY, Hu C, Xiao Y, et al. Higher radiation dose to immune system is correlated with poorer survival in patients with stageⅢnon-small cell lung cancer: A secondary study of a phase 3 cooperative group trial (NRG Oncology RTOG 0617). Int J Radiat Oncol, 2017, 99(2S): S151-S152.
22. Ladbury CJ, Rusthoven CG, Camidge DR, et al. Impact of radiation dose to the host immune system on tumor control and survival for stageⅢnon-small cell lung cancer treated with definitive radiation therapy. Int J Radiat Oncol Biol Phys, 2019, 105(2): 346-355.
23. Marciscano AE, Ghasemzadeh A, Nirschl TR, et al. Elective nodal irradiation attenuates the combinatorial efficacy of stereotactic radiation therapy and immunotherapy. Clin Cancer Res, 2018, 24(20): 5058-5071.
24. Welsh J, Menon H, Chen D, et al. Pembrolizumab with or without radiation therapy for metastatic non-small cell lung cancer: A randomized phaseⅠ/Ⅱtrial. J Immunother Cancer, 2020, 8(2): e001001.
25. Theelen WSME, Peulen HMU, Lalezari F, et al. Effect of pembrolizumab after stereotactic body radiotherapy vs. pembrolizumab alone on tumor response in patients with advanced non-small cell lung cancer: Results of the PEMBRO-RT phase 2 randomized clinical trial. JAMA Oncol, 2019, 5(9): 1276-1282.
26. Lim JU, Kim SH, Kang HS, et al. Predictive role of prior radiotherapy and immunotherapy-related adverse effects in advanced NSCLC patients receiving Anti-PD-1/L1 therapy. J Clin Med, 2021, 10(16): 3719.

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Neoadjuvant immunotherapy combined with stereotactic body radiation therapy for stage Ⅲ/N2 non-small cell lung cancer: Three cases reports

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