Survival outcomes of radical surgery after induction chemoimmunotherapy in clinical stage IIIA–IIIB (N2) non-small cell lung cancer

To the Editor: Neoadjuvant chemoimmunotherapy (NCIT) followed by surgery has been widely used for stage III patients with resectable tumors and limited mediastinal node (N2) involvement.[1–3] In clinical practice, patients typically undergo two to four cycles of induction chemoimmunotherapy (ICIT), after which they are re-evaluated through multidisciplinary team (MDT) discussions to assess the feasibility of surgical intervention.[4,5] Individuals who meet the surgical criteria could be scheduled for surgery. However, little is known about the impact of ICIT followed by radical surgery on stage IIIA–IIIB (N2) patients. Thus, we conducted a retrospective analysis of patients receiving ICIT followed by radical resection from two large-volume centers in China to explore the impact of ICIT on mid-/long-term survival in IIIA–IIIB (N2) NSCLC patients in the real world. This study was approved by the Institutional Review Boards of West China Hospital, Sichuan University (2024-674) and Sichuan Cancer Hospital (SCCHEC-02-2022-124). Informed consent was waived by the Ethical Committees. The detailed information on study design and analysis is presented in Supplementary Methods and Supplementary Figures 1 and 2, https://links.lww.com/CM9/C486. A total of 86 patients were included and more than half of the patients (55.81%) had stage IIIB (N2) disease, and the others had stage IIIA disease [Supplementary Table 1, https://links.lww.com/CM9/C486]. Fifty-six patients (65.12%) received two cycles of ICIT, 19 patients (22.09%) received three cycles of ICIT, and another 11 patients (12.79%) received four cycles of ICIT. Treatment effectiveness evaluation revealed that four patients (4.65%) achieved complete response (CR), the majority of patients (72.09%) achieved partial response (PR), 18 patients (20.93%) had stable disease (SD), and two patients (2.33%) experienced progressive disease (PD). The overall tumor regression rate (PR/CR) was 76.74% in the overall cohort. Tumor regression did not differ significantly between the two-cycle ICIT group and the three- or four-cycle ICIT group. Patients who received 3/4 cycles of ICIT were more likely to have delayed surgery (more than 6 weeks from the last dose of induction therapy to surgery), and the rate was as high as 63.33% (19/30), whereas 21.43% (12/56) of the patients received two cycles of ICIT. The mean postoperative hospital stay was 8.05 days in the two-cycle ICIT group and 7.47 days in the three- or four-cycle ICIT group [Supplementary Table 2, https://links.lww.com/CM9/C486]. In the postoperative pathological evaluation, 32 patients achieved pathological complete response (pCR) (37.21%), and 55 patients achieved major pathological response (MPR) (63.95%) [Supplementary Figure 3, https://links.lww.com/CM9/C486]. The number of ICIT cycles had no influence on the pathological response. The pCR rate was 37.5% in the two-cycle ICIT group and 36.67% in the three- or four-cycle ICIT group. The MPR rate was 69.64% in the two-cycle ICIT group, which was slightly greater than that in the three- or four-cycle ICIT group (53.33%) [Supplementary Table 3, https://links.lww.com/CM9/C486]. Adjuvant immunotherapy was given to 70.93% (61/86) of the patients, 83.61% (51/61) of whom received at least 12 months of adjuvant immunotherapy (median 12 [12–16] months). [Supplementary Table 3, https://links.lww.com/CM9/C486]. At the time of data cutoff, the median follow-up was 38 months from surgery. At 1 year, 2 years, and 3 years, the percentages of patients surviving without disease recurrence or death were 95.35%, 84.87%, and 74.26%, respectively, in the overall cohort. The 3-year OS rate was 91.86%. In the Cox regression univariate analysis, pathology type, pathological response, and length of adjuvant immunotherapy were found to be significantly associated with 3-year disease-free survival (DFS) in stage IIIA–IIIB (N2) NSCLC patients receiving ICIT followed by radical resection [Supplementary Table 4, https://links.lww.com/CM9/C486]. Cox multivariate regression analysis revealed that pathology type (hazard ratio [HR] = 0.24, 95% confidence interval [CI]: 0.08–0.72), pathological response (HR = 0.32, 95% CI: 0.12–0.82), and length of adjuvant immunotherapy (HR = 0.20, 95% CI: 0.06–0.68) remained significant [Supplementary Table 4, https://links.lww.com/CM9/C486]. When comparing the 3-year DFS among patients with different pathology types or durations of adjuvant immunotherapy, we found that SCC patients had better 3-year DFS than non-SCC patients (HR = 0.26, 95% CI: 0.07–0.93). The 3-year DFS of patients who achieved MPR was better than that of patients who did not (HR = 0.38, 95% CI: 0.15–0.96). Patients who received adjuvant immunotherapy for at least 12 months generally had improved 3-year DFS compared with those who received adjuvant immunotherapy for less than 12 months (HR = 0.42, 95% CI: 0.18–0.99). To further delineate the ability of residual viable tumor (RVT) in the primary tumor (PT) to predict 3-year DFS, we compared 3-year DFS between patients with different RVT-PTs with cutoffs of 0, 1%, 5%, and 10%.[6] Patients with RVT-PT = 0, ≤1%, ≤5%, and ≤10% were associated with higher 3-year DFS than those with RVT-PT >0 (HR = 0.40, 95% CI: 0.17–0.92), >1% (HR = 0.33, 95% CI: 0.14–0.77), >5% (HR = 0.27, 95% CI: 0.11–0.65), and >10% (HR = 0.36, 95% CI: 0.14–0.90), respectively. A total of 39.13% of patients (9/23) with positive lymph nodes (LNs) had RVT-PT ≤10%, and 77.78% (49/63) of patients with negative LNs had RVT-PT≤10%. In addition, we compared 3-year DFS between patients with and without LN involvement and reported that patients with positive LNs were associated with worse 3-year DFS than patients without positive LNs (HR = 3.46, 95% CI: 1.29–9.33) [Figure 1].Figure 1: Three-year DFS of (A) SCC vs. non-SCC; (B) MPR vs. non-MPR; (C) pCR vs. non-pCR; (D) adjuvant immunotherapy of no less than 12 months vs. less than 12 months; (E) RVT-PT = 0 vs. RVT-PT >0; (F) RVT-PT ≤1% vs. RVT-PT >1%; (G) RVT-PT ≤5% vs. RVT-PT >5%; (H) RVT-PT ≤10% vs. RVT-PT >10%; and (I) pN+ vs. pN–. DFS: Disease-free survival; MPR: Major pathological response; pCR: Pathological complete response; PN–: Pathology node negative; PN+: Pathology node positive; PT: Primary tumor; RVT: Residual viable tumor; SCC: Squamous cell carcinoma.Postoperative relapse occurred more frequently at the second and third years. Among the 22 patients who experienced disease relapse or died within 3 years, distant site metastasis was the main pattern of disease relapse [Supplementary Figure 4 and Supplementary Table 5, https://links.lww.com/CM9/C486]. There was a difference in the pattern of disease recurrence or progression between patients with different pathological responses. For patients with MPR, the intracranial cavity was the main site of metastasis (33.33%), followed by local region disease relapse (22.22%). For patients without MPR, local relapse accounted for 41.67% of disease relapses, followed by adrenal gland disease (16.17%) and liver metastasis (16.67%). For patients with MPR who experienced disease relapse within 3 years, only four patients received postoperative adjuvant therapy, and three patients received at least 12 months of immunotherapy [Supplementary Figure 5, https://links.lww.com/CM9/C486]. The duration of postoperative immune maintenance therapy remains unclear on the basis of current studies. Our data revealed that postoperative immune maintenance therapy for more than 12 months was a protective factor for 3-year DFS in the whole cohort. In particular, the majority of cases of disease recurrence occurred 12 months after surgery. This result suggested that postoperative adjuvant therapy or immune maintenance therapy should not be canceled and might be a beneficial treatment option for mid-/long-term survival. The major limitation of this study is its retrospective nature, which may have led to undiscovered patient selection bias and data distortion. We were not able to obtain detailed information on genetic testing, especially programmed cell death protein 1 status, which has been reported to be associated with pathological response and long-term survival. In addition, locally advanced NSCLC patients seldom receive surgery, even after induction therapy; thus, another limitation is that the number of patients from each center was relatively small, and IIIA–IIIB (N2) patients composed a group with rather high heterogeneity. Therefore, we could not reduce or even eliminate heterogeneity among the included patients. Furthermore, longer follow-up periods were unavailable because of the relatively short period for patients following ICIT in our centers. In summary, our findings demonstrate that in stage IIIA–IIIB (N2) NSCLC patients, the treatment strategy of ICIT followed by radical surgery resulted in a favorable 3-year DFS. Squamous cell carcinoma and the MPR were correlated with better DFS. A duration of adjuvant immunotherapy of at least 12 months may improve patients’ mid- or long-term DFS. Funding This study was supporte by a grant (Gyyx24008) from the 1-3-5 Project of the Center for High Altitude Medicine, West China Hospital, Sichuan University. Conflicts of interest None.