Lung cancer recurrence after neoadjuvant immunotherapy

J Thorac Cardiovasc Surg. 2025 Sep;170(3):852-863.e6. doi: 10.1016/j.jtcvs.2025.04.028. Epub 2025 May 4.

Abstract

Objectives: To investigate recurrence risk and patterns following neoadjuvant immunotherapy (Neo-IO) for resectable lung cancer, with a focus on identifying optimal cutoffs of residual viable tumor percentage (%RVT) of the primary tumor as a prognostic indicator.

Methods: We conducted a retrospective analysis of patients with resectable non-small cell lung cancer who received Neo-IO with or without chemotherapy followed by lung resection, using data from our prospectively maintained clinical database. The %RVT of the primary tumor in the surgical specimen was quantified (0%-100%) according to pan-tumor immune-related pathologic response criteria. The optimal %RVT cutoffs, as a continuous covariate for recurrence-free survival (RFS), were determined using the Rhier function in the rolr R package.

Results: A total of 94 patients treated between October 2017 and April 2024 met the study's inclusion criterion, with a median follow-up of 16.3 months. Seventy-nine patients received Neo-IO combined with chemotherapy, and 15 patients received Neo-IO only. A pathologic complete response (pCR) was observed in 21 patients (22.3%), and a major pathologic response (MPR) was noted in 41 (43.6%). The median %RVT was 20.0% (range, 0%-100%). The estimated optimal %RVT cutoffs were 5% and 40%. Patients with ≥40% RVT demonstrated worse RFS compared to those with 5% to 40% RVT (P = .006) and those with <5% RVT (P = .001). Multivariable analyses identified %RVT as an independent risk factor for RFS (hazard ratio, 3.96; 95% confidence interval, 1.30-12.01; P = .015). Only 3 patients with pCR (12.5%) developed recurrence; all were distant recurrences. The mediastinal lymph node (LN) recurrence rate increased progressively with advancing ypN stage (ypN0, 3.8%; ypN1, 15.0%; ypN2, 25.0%; P = .007).

Conclusions: Primary tumor %RVT in the surgical specimen is an independent risk factor for lung cancer recurrence following Neo-IO and resection, with optimal cutoffs identified at 5% and 40%. The likelihood of mediastinal LN recurrence increases progressively with advancing ypN stage. Given the high rate of mediastinal LN recurrence in ypN2 patients, planned postoperative radiotherapy may be considered.

Keywords: chemoimmunotherapy; lung cancer; neoadjuvant immunotherapy; recurrence; residual viable tumor.

MeSH terms

  • Aged
  • Carcinoma, Non-Small-Cell Lung* / mortality
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • Carcinoma, Non-Small-Cell Lung* / therapy
  • Female
  • Humans
  • Immunotherapy* / adverse effects
  • Lung Neoplasms* / mortality
  • Lung Neoplasms* / pathology
  • Lung Neoplasms* / therapy
  • Male
  • Middle Aged
  • Neoadjuvant Therapy* / adverse effects
  • Neoplasm Recurrence, Local* / epidemiology
  • Neoplasm, Residual
  • Pneumonectomy / adverse effects
  • Retrospective Studies
  • Risk Assessment
  • Risk Factors
  • Treatment Outcome