Can the complete pathomorphological response be predicted based on PET/CT data in patients with resectable non-small cell lung cancer after neoadjuvant chemotherapy?

Introduction. Predicting complete pathological response (pCR) after neoadjuvant chemo-immunotherapy (CIT) in resectable non-small cell lung cancer (NSCLC) is clinically important, but the diagnostic accuracy of positron emission tomography combined with computed tomography (PET/CT) for this purpose remains uncertain.

Aim. To evaluate whether PET/CT can reliably predict pCR in patients with resectable NSCLC following neoadjuvant CIT.

Materials and methods. 40 patients with resectable NSCLC stage II–IIIB were treated with neoadjuvant CIT. All patients were recruited for radical surgery for potentially resectable tumors, assessed after neoadjuvant therapy according to RECIST 1.1, PERCIST criteria. The resected tumor samples were morphologically evaluated to determine the response to neoadjuvant therapy.

Results. The best response, evaluated by the dynamics of the tumor process according to RECIST 1.1 and PERCIST criteria, in the form of complete tumor regression was achieved in 3 patients (7.5%). A partial response was achieved in 27 patients (67.5%). Stabilization of the tumor process occurred in 10 patients (25%). Thus, an objective response was achieved in 30 patients (75%) and a pCR in the examination of postoperative material was registered in 50% of cases. The obtained data on the complete clinical response of the tumor to treatment based on PET/CT results and the frequency of achieving a pCR coincided in only 10% of cases, indicating a low accuracy of PET/CT in predicting the pCR to treatment.

Conclusions. This study showed that the use of whole-body PET/CT to predict pCR in patients with resectable lung cancer after neoadjuvant CIT appears to be impractical.

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7–30. https://doi.org/10.3322/caac.21590.

2. Holt GE, Podack ER, Raez LE. Immunotherapy as a strategy for the treatment of non-small-cell lung cancer. Therapy. 2011;8(1):43–54. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC3042692/.

3. Mencoboni M, Ceppi M, Bruzzone M, Taveggia P, Cavo A, Scordamaglia F et al. Effectiveness and Safety of Immune Checkpoint Inhibitors for Patients with Advanced Non Small-Cell Lung Cancer in Real-World: Review and Meta-Analysis. Cancers. 2021;13(6):1388. https://doi.org/10.3390/cancers13061388.

4. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(17):1627–1639. https://doi.org/10.1056/NEJMoa1507643.

5. Rittmeyer A, Barles F, Waterkamp D, Park K, Ciardiello F, von Pawel J et al. Atezolizumab versus docetaxel in patients with previously treated nonsmall-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389(10066):255–265. https://doi.org/10.1016/S0140-6736(16)32517-X.

6. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372(21):2018–2028. https://doi.org/10.1056/NEJMoa1501824.

7. Jiang J, Wang Y, Gao Y, Sugimura H, Minervini F, Uchino J et al. Neoadjuvant immunotherapy or chemoimmunotherapy in non-small cell lung cancer: a systematic review and meta-analysis. Transl Lung Cancer Res. 2022;11(2):277–294. https://doi.org/10.21037/tlcr-22-75.

8. Blumenthal GM, Bunn PA, Jr Chaft JE, McCoach CE, Perez EA, Scagliotti GV et al. Current Status and Future Perspectives on Neoadjuvant Therapy in Lung Cancer. J Thorac Oncol. 2018;13(12):1818–1831. https://doi.org/10.1016/j.jtho.2018.09.017.

9. Forde PM, Chaft JE, Smith KN, Anagnostou V, Cottrell TR, Hellmann MD et al. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med. 2018;378(21):1976–1986. https://doi.org/10.1056/NEJMoa1716078.

10. Carbone D, Lee J, Kris M, Wistuba I, Kwiatkowski D, Owen D et al. Clinical/ Biomarker Data for Neoadjuvant Atezolizumab in Resectable Stage IB-IIIB NSCLC: Primary Analysis in the LCMC3 Study. J Thorac Oncol. 2021;16(3):S115–S116. https://doi.org/10.1016/j.jtho.2021.01.294.

11. Gao S, Li N, Gao S, Xue Q, Ying J, Wang S et al. Neoadjuvant PD-1 inhibitor (Sintilimab) in NSCLC. J Thorac Oncol. 2020;15(5):816–826. https://doi.org/ 10.1016/j.jtho.2020.01.017.

12. Eichhorn F, Klotz LV, Kriegsmann M, Bischoff H, Schneider MA, Muley T et al. Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Lung Cancer. 2021;153:150–157. https://doi.org/10.1016/j.lungcan.2021.01.018.

13. Bott MJ, Yang SC, Park BJ, Adusumilli PS, Rusch VW, Isbell JM et al. Initial results of pulmonary resection after neoadjuvant nivolumab in patients with resectable non-small cell lung cancer. J Thorac Cardiovasc Surg. 2019;158(1):269–276. https://doi.org/10.1016/j.jtcvs.2018.11.124.

14. Cascone T, William WN, Jr Weissferdt A, Leung CH, Lin HY, Pataer A et al. Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable nonsmall cell lung cancer: the phase 2 randomized NEOSTAR trial. Nat Med. 2021;27(3):504–514. https://doi.org/10.1038/s41591-020-01224-2.

15. Shu CA, Gainor JF, Awad MM, Chiuzan C, Grigg CM, Pabani A et al. Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial. Lancet. Oncol. 2020;21(6):786–795. https://doi.org/10.1016/S14702045(20)30140-6.

16. Shen D, Wang J, Wu J, Chen S, Li J, Liu J et al. Neoadjuvant pembrolizumab with chemotherapy for the treatment of stage IIB-IIIB resectable lung squamous cell carcinoma. J Thorac Dis. 2021;13(3):1760–1768. https://doi.org/10.21037/jtd-21-103.

17. Wang J, Li J, Cai L, Chen S, Jiang Y. The safety and efficacy of neoadjuvant programmed death 1 inhibitor therapy with surgical resection in stage IIIA non-small cell lung cancer. Ann Transl Med. 2021;9(6):486. https://doi.org/ 10.21037/atm-21-670.

18. Duan H, Wang T, Luo Z, Tong L, Dong X, Zhang Y et al. Neoadjuvant programmed cell death protein 1 inhibitors combined with chemotherapy in resectable non-small cell lung cancer: an open-label, multicenter, single-arm study. Transl Lung Cancer Res. 2021;10(2):1020–1028. https://doi.org/10.21037/tlcr-21-130.

19. Tfayli A, Al Assaad M, Fakhri G, Akel R, Atwi H, Ghanem H et al. Neoadjuvant chemotherapy and Avelumab in early stage resectable nonsmall cell lung cancer. Cancer Med. 2020;9(22):8406–8411. https://doi.org/10.1002/cam4.3456.

20. Forde PM, Spicer J, Lu S, Provencio M, Mitsudomi T, Awad MM et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med. 2022;386(21):1973–1985. https://doi.org/10.1056/NEJMoa2202170.

21. Rothschild SI, Zippelius A, Eboulet EI, Savic Prince S, Betticher D, Bettini A et al. Durvalumab in Addition to Neoadjuvant Chemotherapy in Patients With Stage IIIA(N2) Non-Small-Cell Lung Cancer-A Multicenter Single-Arm Phase II Trial. J Clin Oncol. 2021;39(26):2872–2880. https://doi.org/10.1200/JCO.21.00276.

22. Ren S, Xu A, Lin Y, Camidge DR, Di Maio M, Califano R et al. A narrative review of primary research endpoints of neoadjuvant therapy for lung cancer: past, present and future. Transl Lung Cancer Res. 2021;10(7):3264–3275. https://doi.org/10.21037/tlcr-21-259.

23. Wu Y, Verma V, Gay CM, Chen Y, Liang F, Lin Q et al. Neoadjuvant immunotherapy for advanced, resectable non-small cell lung cancer: A systematic review and meta-analysis. Cancer. 2023;129(13):1969–1985. https://doi.org/10.1002/cncr.34755.

24. Xu Y, Ma D, Qin Y, Li S, Li J, Jiang Y et al. Is response evaluation criteria in solid tumors (RECIST) effective in patient selection for radical resection after neoadjuvant immunotherapy with advanced NSCLC? Thorac Cancer. 2023;14(17):1635–1639. https://doi.org/10.1111/1759-7714.14909.

25. Tazdait M, Mezquita L, Lahmar J, Ferrara R, Bidault F, Ammari S et al. Patterns of responses in metastatic NSCLC during PD-1 or PDL-1 inhibitor therapy: Comparison of RECIST 1.1, irRECIST and iRECIST criteria. Eur J Cancer. 2018;88:38–47. https://doi.org/10.1016/j.ejca.2017.10.017.

26. Лавникова ГА. Гистологический метод количественной оценки терапевтического повреждения опухоли. М.: Методические рекомендации; 1979. 13 с.