Impact of the time interval to surgery after neoadjuvant immunotherapy on prognosis of patients with non-small cell lung cancer: A retrospective cohort study_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

LUO Haopeng ^1,2,3 , YANG Jiyong ¹ , ZHANG Chao ^1,2,3 ,  MA Minjie ² ,  CHEN Chang ³

1. Department of The First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou, 730000, P. R. China;
2. Department of Thoracic Surgery, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, 730000, P. R. China;
3. Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200443, P. R. China;

Corresponding?author：

MA Minjie, Email: chenxwk@163.com; CHEN Chang, Email: maminjie24@sina.com

Keywords：

Non-small cell lung cancer; neoadjuvant immunotherapy; interval between treatment and surgery; prognosis; overall survival; recurrence-free survival; major pathologic response

DOI：

10.7507/1007-4848.202603083

Video：

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Objective To investigate the impact of the interval between neoadjuvant immunotherapy and surgery on the prognosis of patients with non-small cell lung cancer (NSCLC), and to provide evidence-based guidance for the selection of surgical timing in clinical practice. Methods Clinical data of NSCLC patients who underwent surgery following neoadjuvant immunotherapy at the First Hospital of Lanzhou University from October 2020 to May 2022 were retrospectively collected. According to the interval between the last neoadjuvant immunotherapy and surgery, patients were stratified into three groups using cutoff values of 4 and 6 weeks: a ≤4 weeks group, a >4-6 weeks group, and a >6 weeks group. The Kaplan-Meier method and Cox proportional hazards model were employed to analyze overall survival (OS) and recurrence-free survival (RFS), while logistic regression was performed to identify independent predictors of major pathologic response (MPR). Results A total of 165 patients were finally enrolled, comprising 143 (86.67%) males and 22 (13.33%) females, with a median age of 65.00 years. The ≤4 weeks, >4-6 weeks, and >6 weeks groups included 33, 80, and 52 patients, respectively, with well-balanced baseline characteristics among the groups. The median follow-up duration was 28.3 months with a follow-up rate of 89.2%. The overall MPR (including pathologic complete response) rate was 55.16%; however, no significant difference in pathological response was observed among the three groups. Kaplan-Meier analysis revealed no obvious separation in OS or RFS among the three groups. Nevertheless, when regrouped using a cutoff of 65 days, the ≤65 days group demonstrated significant survival benefits (OS: P=0.032; RFS: P=0.003). Logistic regression analysis identified squamous cell carcinoma as an independent predictor of MPR (P=0.05). Cox regression analysis showed that receiving ≥3 cycles of neoadjuvant therapy (P=0.01) and postoperative adjuvant therapy (P=0.02) were independent protective factors for OS. Conclusion The interval between neoadjuvant immunotherapy and surgery of ≤4 weeks, >4-6 weeks, or >6 weeks has no significant effect on surgical safety, pathological response, or long-term prognosis in patients with NSCLC.

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2.	Osmani L, Askin F, Gabrielson E, et al. Current WHO guidelines and the critical role of immunohistochemical markers in the subclassification of non-small cell lung carcinoma (NSCLC): moving from targeted therapy to immunotherapy. Semin Cancer Biol, 2018, 52(Pt 1): 103-109.
3.	Forde PM, Spicer J, Lu S, et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med, 2022, 386(21): 1973-1985.
4.	Cascone T, Awad MM, Spicer JD, et al. Perioperative nivolumab in resectable lung cancer. N Engl J Med, 2024, 390(19): 1756-1769.
5.	Wakelee H, Liberman M, Kato T, et al. Perioperative pembrolizumab for early-stage non-small-cell lung cancer. N Engl J Med, 2023, 389(6): 491-503.
6.	Gao SJ, Corso CD, Wang EH, et al. Timing of surgery after neoadjuvant chemoradiation in locally advanced non-small cell lung cancer. J Thorac Oncol, 2017, 12(2): 314-322.
7.	O'Donnell JS, Hoefsmit EP, Smyth MJ, et al. The promise of neoadjuvant immunotherapy and surgery for cancer treatment. Clin Cancer Res, 2019, 25(19): 5743-5751.
8.	Liu J, O'Donnell JS, Yan J, et al. Timing of neoadjuvant immunotherapy in relation to surgery is crucial for outcome. Oncoimmunology, 2019, 8(5): e1581530.
9.	Lin SD, Tong CY, Huang DD, et al. The time-to-surgery interval and its effect on pathological response after neoadjuvant chemoimmunotherapy in non-small cell lung cancer: a retrospective cohort study. Transl Lung Cancer Res, 2024, 13(10): 2761-2772.
10.	Chen J, Deng H, He J, et al. Impact of the interval between neoadjuvant immunochemotherapy and surgery on surgical-pathological outcomes in non-small cell lung cancer. Front Oncol, 2022, 12: 909726.
11.	Yang G, Hong Y, Zhang X, et al. Impact of the interval between neoadjuvant immunotherapy and surgery on prognosis in esophageal squamous cell carcinoma (ESCC): a real-world study. Cancer Immunol Immunother, 2024, 73(10): 202.
12.	Li J, Zhou X, Liu Y, et al. Optimal time-to-surgery recommendations based on primary tumor volume regression for patients with resectable esophageal cancer after neoadjuvant chemoradiotherapy: a retrospective study. Ann Surg Oncol, 2024, 31(6): 3803-3812.
13.	Sutton TL, Schlitt A, Gardiner SK, et al. Time to surgery following neoadjuvant chemotherapy for breast cancer impacts residual cancer burden, recurrence, and survival. J Surg Oncol, 2020, 122(8): 1761-1769.
14.	van der Werf LR, Dikken JL, van der Willik EM, et al. Time interval between neoadjuvant chemoradiotherapy and surgery for oesophageal or junctional cancer: a nationwide study. Eur J Cancer, 2018, 91: 76-85.
15.	Chiu CH, Chao YK, Chang HK, et al. Interval between neoadjuvant chemoradiotherapy and surgery for esophageal squamous cell carcinoma: does delayed surgery impact outcome? Ann Surg Oncol, 2013, 20(13): 4245-4251.
16.	Tsang JS, Tong DKH, Lam KO, et al. Appropriate timing for surgery after neoadjuvant chemoradiation for esophageal cancer. Dis Esophagus, 2017, 30(9): 1-8.
17.	Nilsson K, Klevebro F, Sunde B, et al. Oncological outcomes of standard versus prolonged time to surgery after neoadjuvant chemoradiotherapy for oesophageal cancer in the multicentre, randomised, controlled NeoResⅡtrial. Ann Oncol, 2023, 34(11): 1015-1024.
18.	Haisley KR, Laird AE, Nabavizadeh N, et al. Association of intervals between neoadjuvant chemoradiation and surgical resection with pathologic complete response and survival in patients with esophageal cancer. JAMA Surg, 2016, 151(12): e1642743.
19.	Shaikh T, Ruth K, Scott WJ, et al. Increased time from neoadjuvant chemoradiation to surgery is associated with higher pathologic complete response rates in esophageal cancer. Ann Thorac Surg, 2015, 99(1): 270-276.
20.	Franko J, Voynov G, Goldman CD. Esophagectomy timing after neoadjuvant therapy for distal esophageal adenocarcinoma. Ann Thorac Surg, 2016, 101(3): 1123-1130.
21.	Deng H, Xiong S, Zhong R, et al. "Major pathologic response" in lymph nodes: a modified nodal classification for non-small cell lung cancer patients treated with neoadjuvant immunochemotherapy. Exp Hematol Oncol, 2023, 12(1): 40.
22.	Dacic S, Travis W, Redman M, et al. International Association for the Study of Lung Cancer study of reproducibility in assessment of pathologic response in resected lung cancers after neoadjuvant therapy. J Thorac Oncol, 2023, 18(10): 1290-1302.
23.	Riely GJ, Wood DE, Ettinger DS, et al. Non-small cell lung cancer, version 4. 2024, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw, 2024, 22(4): 249-274.
24.	張斌, 汪昱. 新輔助放化療后手術時機選擇對進展期直腸癌患者預后影響的研究進展. 中國癌癥雜志, 2015, 25(8): 635-640.Zhang B, Wang Y. Research progress on the influence of surgical timing after neoadjuvant chemoradiotherapy on prognosis of patients with advanced rectal cancer. Chin J Cancer, 2015, 25(8): 635-640.
25.	Kokaine L, Gardovskis A, Gardovskis J. Evaluation and predictive factors of complete response in rectal cancer after neoadjuvant chemoradiation therapy. Medicina, 2021, 57(10): 1044.
26.	Cardenal F, Palmero R. Treatment of resectable stage ⅢA non-small cell lung cancer. J Thorac Dis, 2017, 9(1): 13-15.
27.	Munoz-Guglielmetti D, Sanchez-Lorente D, Reyes R, et al. Pathological response to neoadjuvant therapy with chemotherapy vs chemoradiotherapy in stageⅢNSCLC-contribution of IASLC recommendations. World J Clin Oncol, 2021, 12(11): 1047-1063.
28.	Moloney CD, Forde PM. The role of immunotherapy in resectable non-small-cell lung cancer. Ther Adv Med Oncol, 2025, 17: 17588359251361883.
29.	Hu J, Zhang J, Wan S, et al. Neoadjuvant immunotherapy for non-small cell lung cancer: opportunities and challenges. Chin Med J Pulm Crit Care Med, 2024, 2(4): 224-239.
30.	Allouchery M, Beuvon C, Perault-Pochat MC, et al. Safety of immune checkpoint inhibitor resumption after interruption for immune-related adverse events, a narrative review. Cancers (Basel), 2022, 14(4): 955.
31.	Zhang B, Guo X, Jia R, et al. Neoadjuvant chemoimmunotherapy cycle number selection for non-small cell lung cancer and clinical outcomes: a real-world analysis. Front Oncol, 2023, 13: 1200625.
32.	白廣宇. 肺癌新輔助免疫治療后手術的預后研究和腫瘤免疫微環境差異分析. 中國醫學科學院, 2024.Bai GY. Prognosis research of surgery after neoadjuvant immunotherapy for lung cancer and differential analysis of tumor immune microenvironment. Chinese Academy of Medical Sciences, 2024.

1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2024, 74(3): 229-263.
2. Osmani L, Askin F, Gabrielson E, et al. Current WHO guidelines and the critical role of immunohistochemical markers in the subclassification of non-small cell lung carcinoma (NSCLC): moving from targeted therapy to immunotherapy. Semin Cancer Biol, 2018, 52(Pt 1): 103-109.
3. Forde PM, Spicer J, Lu S, et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med, 2022, 386(21): 1973-1985.
4. Cascone T, Awad MM, Spicer JD, et al. Perioperative nivolumab in resectable lung cancer. N Engl J Med, 2024, 390(19): 1756-1769.
5. Wakelee H, Liberman M, Kato T, et al. Perioperative pembrolizumab for early-stage non-small-cell lung cancer. N Engl J Med, 2023, 389(6): 491-503.
6. Gao SJ, Corso CD, Wang EH, et al. Timing of surgery after neoadjuvant chemoradiation in locally advanced non-small cell lung cancer. J Thorac Oncol, 2017, 12(2): 314-322.
7. O'Donnell JS, Hoefsmit EP, Smyth MJ, et al. The promise of neoadjuvant immunotherapy and surgery for cancer treatment. Clin Cancer Res, 2019, 25(19): 5743-5751.
8. Liu J, O'Donnell JS, Yan J, et al. Timing of neoadjuvant immunotherapy in relation to surgery is crucial for outcome. Oncoimmunology, 2019, 8(5): e1581530.
9. Lin SD, Tong CY, Huang DD, et al. The time-to-surgery interval and its effect on pathological response after neoadjuvant chemoimmunotherapy in non-small cell lung cancer: a retrospective cohort study. Transl Lung Cancer Res, 2024, 13(10): 2761-2772.
10. Chen J, Deng H, He J, et al. Impact of the interval between neoadjuvant immunochemotherapy and surgery on surgical-pathological outcomes in non-small cell lung cancer. Front Oncol, 2022, 12: 909726.
11. Yang G, Hong Y, Zhang X, et al. Impact of the interval between neoadjuvant immunotherapy and surgery on prognosis in esophageal squamous cell carcinoma (ESCC): a real-world study. Cancer Immunol Immunother, 2024, 73(10): 202.
12. Li J, Zhou X, Liu Y, et al. Optimal time-to-surgery recommendations based on primary tumor volume regression for patients with resectable esophageal cancer after neoadjuvant chemoradiotherapy: a retrospective study. Ann Surg Oncol, 2024, 31(6): 3803-3812.
13. Sutton TL, Schlitt A, Gardiner SK, et al. Time to surgery following neoadjuvant chemotherapy for breast cancer impacts residual cancer burden, recurrence, and survival. J Surg Oncol, 2020, 122(8): 1761-1769.
14. van der Werf LR, Dikken JL, van der Willik EM, et al. Time interval between neoadjuvant chemoradiotherapy and surgery for oesophageal or junctional cancer: a nationwide study. Eur J Cancer, 2018, 91: 76-85.
15. Chiu CH, Chao YK, Chang HK, et al. Interval between neoadjuvant chemoradiotherapy and surgery for esophageal squamous cell carcinoma: does delayed surgery impact outcome? Ann Surg Oncol, 2013, 20(13): 4245-4251.
16. Tsang JS, Tong DKH, Lam KO, et al. Appropriate timing for surgery after neoadjuvant chemoradiation for esophageal cancer. Dis Esophagus, 2017, 30(9): 1-8.
17. Nilsson K, Klevebro F, Sunde B, et al. Oncological outcomes of standard versus prolonged time to surgery after neoadjuvant chemoradiotherapy for oesophageal cancer in the multicentre, randomised, controlled NeoResⅡtrial. Ann Oncol, 2023, 34(11): 1015-1024.
18. Haisley KR, Laird AE, Nabavizadeh N, et al. Association of intervals between neoadjuvant chemoradiation and surgical resection with pathologic complete response and survival in patients with esophageal cancer. JAMA Surg, 2016, 151(12): e1642743.
19. Shaikh T, Ruth K, Scott WJ, et al. Increased time from neoadjuvant chemoradiation to surgery is associated with higher pathologic complete response rates in esophageal cancer. Ann Thorac Surg, 2015, 99(1): 270-276.
20. Franko J, Voynov G, Goldman CD. Esophagectomy timing after neoadjuvant therapy for distal esophageal adenocarcinoma. Ann Thorac Surg, 2016, 101(3): 1123-1130.
21. Deng H, Xiong S, Zhong R, et al. "Major pathologic response" in lymph nodes: a modified nodal classification for non-small cell lung cancer patients treated with neoadjuvant immunochemotherapy. Exp Hematol Oncol, 2023, 12(1): 40.
22. Dacic S, Travis W, Redman M, et al. International Association for the Study of Lung Cancer study of reproducibility in assessment of pathologic response in resected lung cancers after neoadjuvant therapy. J Thorac Oncol, 2023, 18(10): 1290-1302.
23. Riely GJ, Wood DE, Ettinger DS, et al. Non-small cell lung cancer, version 4. 2024, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw, 2024, 22(4): 249-274.
24. 張斌, 汪昱. 新輔助放化療后手術時機選擇對進展期直腸癌患者預后影響的研究進展. 中國癌癥雜志, 2015, 25(8): 635-640.Zhang B, Wang Y. Research progress on the influence of surgical timing after neoadjuvant chemoradiotherapy on prognosis of patients with advanced rectal cancer. Chin J Cancer, 2015, 25(8): 635-640.
25. Kokaine L, Gardovskis A, Gardovskis J. Evaluation and predictive factors of complete response in rectal cancer after neoadjuvant chemoradiation therapy. Medicina, 2021, 57(10): 1044.
26. Cardenal F, Palmero R. Treatment of resectable stage ⅢA non-small cell lung cancer. J Thorac Dis, 2017, 9(1): 13-15.
27. Munoz-Guglielmetti D, Sanchez-Lorente D, Reyes R, et al. Pathological response to neoadjuvant therapy with chemotherapy vs chemoradiotherapy in stageⅢNSCLC-contribution of IASLC recommendations. World J Clin Oncol, 2021, 12(11): 1047-1063.
28. Moloney CD, Forde PM. The role of immunotherapy in resectable non-small-cell lung cancer. Ther Adv Med Oncol, 2025, 17: 17588359251361883.
29. Hu J, Zhang J, Wan S, et al. Neoadjuvant immunotherapy for non-small cell lung cancer: opportunities and challenges. Chin Med J Pulm Crit Care Med, 2024, 2(4): 224-239.
30. Allouchery M, Beuvon C, Perault-Pochat MC, et al. Safety of immune checkpoint inhibitor resumption after interruption for immune-related adverse events, a narrative review. Cancers (Basel), 2022, 14(4): 955.
31. Zhang B, Guo X, Jia R, et al. Neoadjuvant chemoimmunotherapy cycle number selection for non-small cell lung cancer and clinical outcomes: a real-world analysis. Front Oncol, 2023, 13: 1200625.
32. 白廣宇. 肺癌新輔助免疫治療后手術的預后研究和腫瘤免疫微環境差異分析. 中國醫學科學院, 2024.Bai GY. Prognosis research of surgery after neoadjuvant immunotherapy for lung cancer and differential analysis of tumor immune microenvironment. Chinese Academy of Medical Sciences, 2024.

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Latest ArticlesImpact of the time interval to surgery after neoadjuvant immunotherapy on prognosis of patients with non-small cell lung cancer: A retrospective cohort study

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