Advances in the study of local radiotherapy for driver gene-negative oligometastatic non-small cell lung cancer_West China Medical Journal

Authors：

ZHAO Jiaoya ¹ , LI Ruilin ¹ , YANG Yanping ¹ ,  ZHANG Yanjun ²

1. Graduate Affairs Department, Xi’an Medical College, Xi’an, Shaanxi 710000, P. R. China;
2. Third Department of Internal Medicine, Shaanxi Provincial Cancer Hospital, Xi’an, Shaanxi 710000, P. R. China;

Corresponding author：

ZHANG Yanjun, Email: zhyanjun.1815@yahoo.com.cn

Keywords：

Non-small cell lung cancer; oligometastasis; oligoprogression; oligorecurrence; local radiotherapy; prognosis; toxicity; population of benefit

DOI：

10.7507/1002-0179.202409015

Video：

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Advanced driver gene-negative non-small cell lung cancer is generally considered incurable, and treatment aims to prolong patient survival. Recently, however, a new definition “oligometastasis” has been proposed, which refers to the appearance of no more than 5 metastatic lesions in up to 3 different organs. The emergence of this concept has changed the traditional treatment model. Many studies have shown that standard systemic therapy combined with local therapy (radiotherapy, surgery, thermal ablation, etc.) can effectively prolong the survival time of these patients. This article reviews the clinical studies on the efficacy, toxicity, and beneficiary population of local radiotherapy combined with systemic therapy in driver gene-negative oligometastatic non-small cell lung cancer, and provides further reference for clinical decision-making.

Citation： ZHAO Jiaoya, LI Ruilin, YANG Yanping, ZHANG Yanjun. Advances in the study of local radiotherapy for driver gene-negative oligometastatic non-small cell lung cancer. West China Medical Journal, 2025, 40(4): 634-639. doi: 10.7507/1002-0179.202409015 Copy

1.	Xia C, Dong X, Li H, et al. Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chin Med J (Engl), 2022, 135(5): 584-590.
2.	Gadgeel S, Rodríguez-Abreu D, Speranza G, et al. Updated analysis from KEYNOTE-189: pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer. J Clin Oncol, 2020, 38(14): 1505-1517.
3.	Lu S, Wang J, Yu Y, et al. Tislelizumab plus chemotherapy as first-line treatment for locally advanced or metastatic nonsquamous NSCLC (RATIONALE 304): a randomized phase 3 trial. J Thorac Oncol, 2021, 16(9): 1512-1522.
4.	Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med, 2018, 379(21): 2040-2051.
5.	Ren S, Chen J, Xu X, et al. Camrelizumab plus carboplatin and paclitaxel as first-line treatment for advanced squamous NSCLC (CameL-Sq): a phase 3 trial. J Thorac Oncol, 2022, 17(4): 544-557.
6.	Wang J, Lu S, Yu X, et al. Tislelizumab plus chemotherapy vs chemotherapy alone as first-line treatment for advanced squamous non-small-cell lung cancer: a phase 3 randomized clinical trial. JAMA Oncol, 2021, 7(5): 709-717.
7.	Yang Y, Wang Z, Fang J, et al. Efficacy and safety of sintilimab plus pemetrexed and platinum as first-line treatment for locally advanced or metastatic nonsquamous NSCLC: a randomized, double-blind, phase 3 study (Oncology pRogram by InnovENT anti-PD-1-11). J Thorac Oncol, 2020, 15(10): 1636-1646.
8.	Zhou C, Chen G, Huang Y, et al. Camrelizumab plus carboplatin and pemetrexed versus chemotherapy alone in chemotherapy-naive patients with advanced non-squamous non-small-cell lung cancer (CameL): a randomised, open-label, multicentre, phase 3 trial. Lancet Respir Med, 2021, 9(3): 305-314.
9.	Zhou C, Wu L, Fan Y, et al. Sintilimab plus platinum and gemcitabine as first-line treatment for advanced or metastatic squamous NSCLC: results from a randomized, double-blind, phase 3 trial (ORIENT-12). J Thorac Oncol, 2021, 16(9): 1501-1511.
10.	Xu Y, Li H, Fan Y. Progression patterns, treatment, and prognosis beyond resistance of responders to immunotherapy in advanced non-small cell lung cancer. Front Oncol, 2021, 11: 642883.
11.	Chai R, Yin Y, Cai X, et al. Patterns of failure in patients with advanced non-small cell lung cancer treated with immune checkpoint inhibitors. Front Oncol, 2021, 11: 724722.
12.	Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol, 1995, 13(1): 8-10.
13.	Lievens Y, Guckenberger M, Gomez D, et al. Defining oligometastatic disease from a radiation oncology perspective: an ESTRO-ASTRO consensus document. Radiother Oncol, 2020, 148: 157-166.
14.	Guckenberger M, Lievens Y, Bouma AB, et al. Characterisation and classification of oligometastatic disease: a European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus recommendation. Lancet Oncol, 2020, 21(1): e18-e28.
15.	Torok JA, Gu L, Tandberg DJ, et al. Patterns of distant metastases after surgical management of non-small-cell lung cancer. Clin Lung Cancer, 2017, 18(1): e57-e70.
16.	Nieder C, Tollåli T, Reigstad A, et al. Oligometastatic non-small cell lung cancer: a significant entity outside of specialized cancer centers?. Med Princ Pract, 2014, 23(6): 526-531.
17.	Parikh RB, Cronin AM, Kozono DE, et al. Definitive primary therapy in patients presenting with oligometastatic non-small cell lung cancer. Int J Radiat Oncol Biol Phys, 2014, 89(4): 880-887.
18.	No HJ, Raja N, Von Eyben R, et al. Characterization of metastatic non-small cell lung cancer and oligometastatic incidence in an era of changing treatment paradigms. Int J Radiat Oncol Biol Phys, 2022, 114(4): 603-610.
19.	Christ SM, Pohl K, Muehlematter UJ, et al. Imaging-based prevalence of oligometastatic disease: a single-center cross-sectional study. Int J Radiat Oncol Biol Phys, 2022, 114(4): 596-602.
20.	Hendriks LE, Derks JL, Postmus PE, et al. Single organ metastatic disease and local disease status, prognostic factors for overall survival in stage IV non-small cell lung cancer: results from a population-based study. Eur J Cancer, 2015, 51(17): 2534-2544.
21.	Iyengar P, All S, Berry MF, et al. Treatment of oligometastatic non-small cell lung cancer: an ASTRO/ESTRO clinical practice guideline. Pract Radiat Oncol, 2023, 13(5): 393-412.
22.	Ng TL, Morgan RL, Patil T, et al. Detection of oligoprogressive disease in oncogene-addicted non-small cell lung cancer using PET/CT versus CT in patients receiving a tyrosine kinase inhibitor. Lung Cancer, 2018, 126: 112-118.
23.	Bonnette P, Puyo P, Gabriel C, et al. Surgical management of non-small cell lung cancer with synchronous brain metastases. Chest, 2001, 119(5): 1469-1475.
24.	中华医学会肿瘤学分会, 中华医学会杂志社. 中华医学会肺癌临床诊疗指南(2023 版). 中华肿瘤杂志, 2023, 45(7): 539-574.
25.	中国临床肿瘤学会指南工作委员会. 中国临床肿瘤学会(CSCO)非小细胞肺癌诊疗指南 2023. 北京: 人民卫生出版社, 2023.
26.	国家卫生健康委办公厅. 原发性肺癌诊疗指南(2022 年版). 协和医学杂志, 2022, 13(4): 549-570.
27.	Porte H, Siat J, Guibert B, et al. Resection of adrenal metastases from non-small cell lung cancer: a multicenter study. Ann Thorac Surg, 2001, 71(3): 981-985.
28.	Schanne DH, Heitmann J, Guckenberger M, et al. Evolution of treatment strategies for oligometastatic NSCLC patients - a systematic review of the literature. Cancer Treat Rev, 2019, 80: 101892.
29.	Ball D, Mai GT, Vinod S, et al. Stereotactic ablative radiotherapy versus standard radiotherapy in stage 1 non-small-cell lung cancer (TROG 09.02 CHISEL): a phase 3, open-label, randomised controlled trial. Lancet Oncol, 2019, 20(4): 494-503.
30.	Collen C, Christian N, Schallier D, et al. Phase II study of stereotactic body radiotherapy to primary tumor and metastatic locations in oligometastatic nonsmall-cell lung cancer patients. Ann Oncol, 2014, 25(10): 1954-1959.
31.	Gerber DE. Maintenance therapy for advanced lung cancer: who, what, and when?. J Clin Oncol, 2013, 31(24): 2983-2990.
32.	Chen Y, Wang Y, Yang Z, et al. Local consolidative therapy for synchronous oligometastatic non-small cell lung cancer treated with first-line pembrolizumab: a retrospective observational study. Thorac Cancer, 2022, 13(5): 732-741.
33.	Gomez DR, Blumenschein GR, Lee JJ, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol, 2016, 17(12): 1672-1682.
34.	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.
35.	Gray JE, Villegas A, Daniel D, et al. Three-year overall survival with durvalumab after chemoradiotherapy in stage III NSCLC-update from PACIFIC. J Thorac Oncol, 2020, 15(2): 288-293.
36.	Bauml JM, Mick R, Ciunci C, et al. Pembrolizumab after completion of locally ablative therapy for oligometastatic non-small cell lung cancer: a phase 2 trial. JAMA Oncol, 2019, 5(9): 1283-1290.
37.	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.
38.	Xu Q, Zhou F, Liu H, et al. Consolidative local ablative therapy improves the survival of patients with synchronous oligometastatic NSCLC harboring EGFR activating mutation treated with first-line EGFR-TKIs. J Thorac Oncol, 2018, 13(9): 1383-1392.
39.	Lehrer EJ, Singh R, Wang M, et al. Safety and survival rates associated with ablative stereotactic radiotherapy for patients with oligometastatic cancer: a systematic review and meta-analysis. JAMA Oncol, 2021, 7(1): 92-106.
40.	De Rose F, Cozzi L, Navarria P, et al. Clinical outcome of stereotactic ablative body radiotherapy for lung metastatic lesions in non-small cell lung cancer oligometastatic patients. Clin Oncol (R Coll Radiol), 2016, 28(1): 13-20.
41.	Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy for the comprehensive treatment of oligometastatic cancers: long-term results of the SABR-COMET phase II randomized trial. J Clin Oncol, 2020, 38(25): 2830-2838.
42.	Gomez DR, Tang C, Zhang J, et al. Local consolidative therapy vs. maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer: long-term results of a multi-institutional, phase II, randomized study. J Clin Oncol, 2019, 37(18): 1558-1565.
43.	Tree AC, Khoo VS, Eeles RA, et al. Stereotactic body radiotherapy for oligometastases. Lancet Oncol, 2013, 14(1): e28-e37.
44.	Kowalchuk R, Mullikin TC, Breen W, et al. Development and validation of a unifying pre-treatment decision tool for intracranial and extracranial metastasis-directed radiotherapy. Front Oncol, 2023, 13: 1095170.
45.	Allen AJ, Labella DA, Kowalchuk RO, et al. Effect of histology on stereotactic body radiotherapy for non-small cell lung cancer oligometastatic pulmonary lesions. Transl Lung Cancer Res, 2023, 12(1): 66-78.

1. Xia C, Dong X, Li H, et al. Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chin Med J (Engl), 2022, 135(5): 584-590.
2. Gadgeel S, Rodríguez-Abreu D, Speranza G, et al. Updated analysis from KEYNOTE-189: pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer. J Clin Oncol, 2020, 38(14): 1505-1517.
3. Lu S, Wang J, Yu Y, et al. Tislelizumab plus chemotherapy as first-line treatment for locally advanced or metastatic nonsquamous NSCLC (RATIONALE 304): a randomized phase 3 trial. J Thorac Oncol, 2021, 16(9): 1512-1522.
4. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med, 2018, 379(21): 2040-2051.
5. Ren S, Chen J, Xu X, et al. Camrelizumab plus carboplatin and paclitaxel as first-line treatment for advanced squamous NSCLC (CameL-Sq): a phase 3 trial. J Thorac Oncol, 2022, 17(4): 544-557.
6. Wang J, Lu S, Yu X, et al. Tislelizumab plus chemotherapy vs chemotherapy alone as first-line treatment for advanced squamous non-small-cell lung cancer: a phase 3 randomized clinical trial. JAMA Oncol, 2021, 7(5): 709-717.
7. Yang Y, Wang Z, Fang J, et al. Efficacy and safety of sintilimab plus pemetrexed and platinum as first-line treatment for locally advanced or metastatic nonsquamous NSCLC: a randomized, double-blind, phase 3 study (Oncology pRogram by InnovENT anti-PD-1-11). J Thorac Oncol, 2020, 15(10): 1636-1646.
8. Zhou C, Chen G, Huang Y, et al. Camrelizumab plus carboplatin and pemetrexed versus chemotherapy alone in chemotherapy-naive patients with advanced non-squamous non-small-cell lung cancer (CameL): a randomised, open-label, multicentre, phase 3 trial. Lancet Respir Med, 2021, 9(3): 305-314.
9. Zhou C, Wu L, Fan Y, et al. Sintilimab plus platinum and gemcitabine as first-line treatment for advanced or metastatic squamous NSCLC: results from a randomized, double-blind, phase 3 trial (ORIENT-12). J Thorac Oncol, 2021, 16(9): 1501-1511.
10. Xu Y, Li H, Fan Y. Progression patterns, treatment, and prognosis beyond resistance of responders to immunotherapy in advanced non-small cell lung cancer. Front Oncol, 2021, 11: 642883.
11. Chai R, Yin Y, Cai X, et al. Patterns of failure in patients with advanced non-small cell lung cancer treated with immune checkpoint inhibitors. Front Oncol, 2021, 11: 724722.
12. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol, 1995, 13(1): 8-10.
13. Lievens Y, Guckenberger M, Gomez D, et al. Defining oligometastatic disease from a radiation oncology perspective: an ESTRO-ASTRO consensus document. Radiother Oncol, 2020, 148: 157-166.
14. Guckenberger M, Lievens Y, Bouma AB, et al. Characterisation and classification of oligometastatic disease: a European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus recommendation. Lancet Oncol, 2020, 21(1): e18-e28.
15. Torok JA, Gu L, Tandberg DJ, et al. Patterns of distant metastases after surgical management of non-small-cell lung cancer. Clin Lung Cancer, 2017, 18(1): e57-e70.
16. Nieder C, Tollåli T, Reigstad A, et al. Oligometastatic non-small cell lung cancer: a significant entity outside of specialized cancer centers?. Med Princ Pract, 2014, 23(6): 526-531.
17. Parikh RB, Cronin AM, Kozono DE, et al. Definitive primary therapy in patients presenting with oligometastatic non-small cell lung cancer. Int J Radiat Oncol Biol Phys, 2014, 89(4): 880-887.
18. No HJ, Raja N, Von Eyben R, et al. Characterization of metastatic non-small cell lung cancer and oligometastatic incidence in an era of changing treatment paradigms. Int J Radiat Oncol Biol Phys, 2022, 114(4): 603-610.
19. Christ SM, Pohl K, Muehlematter UJ, et al. Imaging-based prevalence of oligometastatic disease: a single-center cross-sectional study. Int J Radiat Oncol Biol Phys, 2022, 114(4): 596-602.
20. Hendriks LE, Derks JL, Postmus PE, et al. Single organ metastatic disease and local disease status, prognostic factors for overall survival in stage IV non-small cell lung cancer: results from a population-based study. Eur J Cancer, 2015, 51(17): 2534-2544.
21. Iyengar P, All S, Berry MF, et al. Treatment of oligometastatic non-small cell lung cancer: an ASTRO/ESTRO clinical practice guideline. Pract Radiat Oncol, 2023, 13(5): 393-412.
22. Ng TL, Morgan RL, Patil T, et al. Detection of oligoprogressive disease in oncogene-addicted non-small cell lung cancer using PET/CT versus CT in patients receiving a tyrosine kinase inhibitor. Lung Cancer, 2018, 126: 112-118.
23. Bonnette P, Puyo P, Gabriel C, et al. Surgical management of non-small cell lung cancer with synchronous brain metastases. Chest, 2001, 119(5): 1469-1475.
24. 中华医学会肿瘤学分会, 中华医学会杂志社. 中华医学会肺癌临床诊疗指南(2023 版). 中华肿瘤杂志, 2023, 45(7): 539-574.
25. 中国临床肿瘤学会指南工作委员会. 中国临床肿瘤学会(CSCO)非小细胞肺癌诊疗指南 2023. 北京: 人民卫生出版社, 2023.
26. 国家卫生健康委办公厅. 原发性肺癌诊疗指南(2022 年版). 协和医学杂志, 2022, 13(4): 549-570.
27. Porte H, Siat J, Guibert B, et al. Resection of adrenal metastases from non-small cell lung cancer: a multicenter study. Ann Thorac Surg, 2001, 71(3): 981-985.
28. Schanne DH, Heitmann J, Guckenberger M, et al. Evolution of treatment strategies for oligometastatic NSCLC patients - a systematic review of the literature. Cancer Treat Rev, 2019, 80: 101892.
29. Ball D, Mai GT, Vinod S, et al. Stereotactic ablative radiotherapy versus standard radiotherapy in stage 1 non-small-cell lung cancer (TROG 09.02 CHISEL): a phase 3, open-label, randomised controlled trial. Lancet Oncol, 2019, 20(4): 494-503.
30. Collen C, Christian N, Schallier D, et al. Phase II study of stereotactic body radiotherapy to primary tumor and metastatic locations in oligometastatic nonsmall-cell lung cancer patients. Ann Oncol, 2014, 25(10): 1954-1959.
31. Gerber DE. Maintenance therapy for advanced lung cancer: who, what, and when?. J Clin Oncol, 2013, 31(24): 2983-2990.
32. Chen Y, Wang Y, Yang Z, et al. Local consolidative therapy for synchronous oligometastatic non-small cell lung cancer treated with first-line pembrolizumab: a retrospective observational study. Thorac Cancer, 2022, 13(5): 732-741.
33. Gomez DR, Blumenschein GR, Lee JJ, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol, 2016, 17(12): 1672-1682.
34. 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.
35. Gray JE, Villegas A, Daniel D, et al. Three-year overall survival with durvalumab after chemoradiotherapy in stage III NSCLC-update from PACIFIC. J Thorac Oncol, 2020, 15(2): 288-293.
36. Bauml JM, Mick R, Ciunci C, et al. Pembrolizumab after completion of locally ablative therapy for oligometastatic non-small cell lung cancer: a phase 2 trial. JAMA Oncol, 2019, 5(9): 1283-1290.
37. 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.
38. Xu Q, Zhou F, Liu H, et al. Consolidative local ablative therapy improves the survival of patients with synchronous oligometastatic NSCLC harboring EGFR activating mutation treated with first-line EGFR-TKIs. J Thorac Oncol, 2018, 13(9): 1383-1392.
39. Lehrer EJ, Singh R, Wang M, et al. Safety and survival rates associated with ablative stereotactic radiotherapy for patients with oligometastatic cancer: a systematic review and meta-analysis. JAMA Oncol, 2021, 7(1): 92-106.
40. De Rose F, Cozzi L, Navarria P, et al. Clinical outcome of stereotactic ablative body radiotherapy for lung metastatic lesions in non-small cell lung cancer oligometastatic patients. Clin Oncol (R Coll Radiol), 2016, 28(1): 13-20.
41. Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy for the comprehensive treatment of oligometastatic cancers: long-term results of the SABR-COMET phase II randomized trial. J Clin Oncol, 2020, 38(25): 2830-2838.
42. Gomez DR, Tang C, Zhang J, et al. Local consolidative therapy vs. maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer: long-term results of a multi-institutional, phase II, randomized study. J Clin Oncol, 2019, 37(18): 1558-1565.
43. Tree AC, Khoo VS, Eeles RA, et al. Stereotactic body radiotherapy for oligometastases. Lancet Oncol, 2013, 14(1): e28-e37.
44. Kowalchuk R, Mullikin TC, Breen W, et al. Development and validation of a unifying pre-treatment decision tool for intracranial and extracranial metastasis-directed radiotherapy. Front Oncol, 2023, 13: 1095170.
45. Allen AJ, Labella DA, Kowalchuk RO, et al. Effect of histology on stereotactic body radiotherapy for non-small cell lung cancer oligometastatic pulmonary lesions. Transl Lung Cancer Res, 2023, 12(1): 66-78.

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Advances in the study of local radiotherapy for driver gene-negative oligometastatic non-small cell lung cancer

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