The effects and toxicity profiles of consolidative and salvage thoracic radiotherapy following chemoimmunotherapy in patients with extensive-stage small cell lung cancer

Abstract

The present study assessed the efficacy and safety of thoracic radiotherapy (TRT) following first-line chemotherapy or chemoimmunotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC), focusing on the influence of different TRT timing strategies (consolidative vs. salvage) on survival rates. We retrospectively analyzed a total of 54 patients with ES-SCLC treated between January 2019 and July 2022. Patients receiving consolidative TRT (cTRT) within three months after completion of first-line treatment were compared with those receiving salvage TRT (sTRT) after disease progression. The primary endpoints were overall survival (OS), progression-free survival (PFS), locoregional-free survival (LRFS), and distant metastasis-free survival (DMFS); the secondary endpoint included safety. The cTRT group (n = 41) showed significantly longer median OS (26.6 vs. 14.8 months, P = 0.048), PFS (12.9 vs. 3.5 months, P < 0.0001), and DMFS (10.7 vs. 3.4 months, P = 0.0044) than the sTRT group (n = 13). Multivariate analysis revealed that cTRT was an independent, favorable prognostic factor. No significant differences in OS or LRFS were observed between high-dose (≥ 50 Gy) and low-dose (< 50 Gy) TRT. Hematologic and respiratory toxicities were the most frequently reported adverse events, with acceptable tolerability. In conclusion, cTRT after chemoimmunotherapy significantly improves survival outcomes for ES-SCLC patients, and low-dose TRT may be a suitable option.

Keywords

extensive-stage small cell lung cancer / thoracic radiotherapy / chemoimmunotherapy / survival rate / safety

Fundings

The present study was supported by the Young Talents Program of Jiangsu Cancer Hospital (Grant No. QL201802) and the Science and Technology Development Fund of Jiangsu Cancer Hospital (Grant No. ZL202105).

Acknowledgments

None.

References

[1] Thai AA, Solomon BJ, Sequist LV, et al. Lung cancer[J]. Lancet, 2021, 398(10299): 535-554. doi: 10.1016/S0140-6736(21)00312-3

[2] Gazdar AF, Bunn PA, Minna JD. Small-cell lung cancer: What we know, what we need to know and the path forward[J]. Nat Rev Cancer, 2017, 17(12): 725-737. doi: 10.1038/nrc.2017.87

[3] Megyesfalvi Z, Gay CM, Popper H, et al. Clinical insights into small cell lung cancer: Tumor heterogeneity, diagnosis, therapy, and future directions[J]. CA Cancer J Clin, 2023, 73(6): 620-652. doi: 10.3322/caac.21785

[4] American Cancer Society. Cancer facts & figures 2021[EB/OL]. [2024-05-19]. https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2021.html.

[5] Ganti AKP, Loo JR BW, Bassetti M, et al. Small cell lung cancer, version 2.2022, NCCN clinical practice guidelines in oncology[J]. J Natl Compr Canc Netw, 2021, 19(12): 1441-1464. doi: 10.6004/jnccn.2021.0058

[6] Farago AF, Keane FK. Current standards for clinical management of small cell lung cancer[J]. Transl Lung Cancer Res, 2018, 7(1): 69-79. doi: 10.21037/tlcr.2018.01.16

[7] Rossi A, Di Maio M, Chiodini P, et al. Carboplatin- or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: The COCIS meta-analysis of individual patient data[J]. J Clin Oncol, 2012, 30(14): 1692-1698. doi: 10.1200/JCO.2011.40.4905

[8] Wang Y, Zou S, Zhao Z, et al. New insights into small-cell lung cancer development and therapy[J]. Cell Biol Int, 2020, 44(8): 1564-1576. doi: 10.1002/cbin.11359

[9] Liu SV, Reck M, Mansfield AS, et al. Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133)[J]. J Clin Oncol, 2021, 39(6): 619-630. doi: 10.1200/JCO.20.01055

[10] Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): A randomised, controlled, open-label, phase 3 trial[J]. Lancet, 2019, 394(10212): 1929-1939. doi: 10.1016/S0140-6736(19)32222-6

[11] Cheng Y, Han L, Wu L, et al. Effect of first-line serplulimab vs placebo added to chemotherapy on survival in patients with extensive-stage small cell lung cancer: The ASTRUM-005 randomized clinical trial[J]. JAMA, 2022, 328(12): 1223-1232. doi: 10.1001/jama.2022.16464

[12] Nesbit EG, Leal TA, Kruser TJ. What is the role of radiotherapy for extensive-stage small cell lung cancer in the immunotherapy era?[J]. Transl Lung Cancer Res, 2019, 8(S2): S153-S162. doi: 10.21037/tlcr.2019.05.01

[13] Li H, Zhao Y, Ma T, et al. Radiotherapy for extensive-stage small-cell lung cancer in the immunotherapy era[J]. Front Immunol, 2023, 14: 1132482. doi: 10.3389/fimmu.2023.1132482

[14] Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice[J]. J Clin Invest, 2014, 124(2): 687-695. doi: 10.1172/JCI67313

[15] Dovedi SJ, Cheadle EJ, Popple AL, et al. Fractionated radiation therapy stimulates antitumor immunity mediated by both resident and infiltrating polyclonal T-cell populations when combined with PD-1 blockade[J]. Clin Cancer Res, 2017, 23(18): 5514-5526. doi: 10.1158/1078-0432.CCR-16-1673

[16] Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage Ⅲ non-small-cell lung cancer[J]. N Engl J Med, 2017, 377(20): 1919-1929. doi: 10.1056/NEJMoa1709937

[17] Kang K, Wu Y, Yao Z, et al. Tackling the current dilemma of immunotherapy in extensive-stage small cell lung cancer: A promising strategy of combining with radiotherapy[J]. Cancer Lett, 2023, 565: 216239. doi: 10.1016/j.canlet.2023.216239

[18] Jeremic B, Shibamoto Y, Nikolic N, et al. Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer: A randomized study[J]. J Clin Oncol, 1999, 17(7): 2092-2099. doi: 10.1200/JCO.1999.17.7.2092

[19] Slotman BJ, van Tinteren H, Praag JO, et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: A phase 3 randomised controlled trial[J]. Lancet, 2015, 385(9962): 36-42. doi: 10.1016/S0140-6736(14)61085-0

[20] Slotman BJ, Faivre-Finn C, van Tinteren H, et al. Which patients with ES-SCLC are most likely to benefit from more aggressive radiotherapy: A secondary analysis of the phase Ⅲ CREST trial[J]. Lung Cancer, 2017, 108: 150-153. doi: 10.1016/j.lungcan.2017.03.007

[21] Xu L, Zhao L, Simone II CB, et al. Receipt of thoracic radiation therapy and radiotherapy dose are correlated with outcomes in a retrospective study of three hundred and six patients with extensive stage small-cell lung cancer[J]. Radiother Oncol, 2017, 125(2): 331-337. doi: 10.1016/j.radonc.2017.10.005

[22] Han J, Fu C, Li B. Clinical outcomes of extensive-stage small cell lung cancer patients treated with thoracic radiotherapy at different times and fractionations[J]. Radiat Oncol, 2021, 16(1): 47. doi: 10.1186/s13014-021-01773-x

[23] Liu C, Zeng L, Deng C, et al. Hypofractionated radiotherapy with immunochemotherapy for extensive-stage small-cell lung cancer[J]. Front Immunol, 2023, 14: 1175960. doi: 10.3389/fimmu.2023.1175960

[24] Kuncman Ł, Fijuth J, Tworek D, et al. Radiotherapy(R) integration(I) strategy for small(S)-cell lung cancer in extensive(E) stage(RISE) with up to 10 metastases—a study protocol of a randomized phase Ⅱ trial[J]. BMC Cancer, 2025, 25(1): 142. doi: 10.1186/s12885-025-13552-y

[25] Welsh JW, Heymach JV, Chen D, et al. Phase Ⅰ trial of pembrolizumab and radiation therapy after induction chemotherapy for extensive-stage small cell lung cancer[J]. J Thorac Oncol, 2020, 15(2): 266-273. doi: 10.1016/j.jtho.2019.10.001

[26] Diamond BH, Verma N, Shukla UC, et al. Consolidative thoracic radiation therapy after first-line chemotherapy and immunotherapy in extensive-stage small cell lung cancer: A multi-institutional case series[J]. Adv Radiat Oncol, 2022, 7(2): 100883. doi: 10.1016/j.adro.2021.100883

[27] Li B, Jiang C, Pang L, et al. Toxicity profile of combining PD-1/PD-L1 inhibitors and thoracic radiotherapy in non-small cell lung cancer: A systematic review[J]. Front Immunol, 2021, 12: 627197. doi: 10.3389/fimmu.2021.627197