Prognosis and relapse patterns in patients with non-small cell lung cancer with pathologic complete response after neoadjuvant immunochemotherapy
Highlight box
Key findings
• Patients with non-small cell lung cancer (NSCLC) having achieved pathologic complete response (pCR) have a good prognosis but still remain at risk of relapse within 18 months after surgery.
What is known and what is new?
• Patients with resectable locally advanced NSCLC who have pCR after neoadjuvant immunochemotherapy have a good prognosis.
• The majority of patients with pCR experienced recurrence within 18 months after surgery, with both intrathoracic and extrathoracic recurrences.
What is the implication, and what should change now?
• Patients who achieve pCR still need rigorous follow-up with consideration for monitoring of extrathoracic organs.
Introduction
Immunotherapy, the preferred first-line treatment for advanced non-small cell lung cancer (NSCLC), has also been shown to be effective for resectable locally advanced NSCLC (1,2). In recent years, results from several multicenter phase 3 randomized controlled trials have confirmed that the combination of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors and chemotherapy is more effective than chemotherapy alone in the preoperative setting and is associated with a higher rate of pathologic complete response (pCR) (3-8). Several clinical trials have definitively shown that neoadjuvant immunotherapy plus chemotherapy is associated with higher rates of pCR than chemotherapy alone: CheckMate 816 (3), 24.0% vs. 2.2% (P<0.001); KEYNOTE-671 (4), 18.1% vs. 4.0% (P<0.0001); AEGEAN (5), 17.2% vs. 4.3% (P<0.0001); Neotorch (6), 24.8% vs. 1.0% (P<0.0001); CheckMate 77T (7), 25.3% vs. 4.7% [odds ratio 6.64; 95% confidence interval (CI): 3.40–12.97]; and RATIONALE-315 (8), 40.7% vs. 5.7% (P<0.0001). Therefore, neoadjuvant immunochemotherapy has been recommended as the standard treatment for those patients with tumors ≥4 cm or node positive by several guidelines (9,10).
Overall survival (OS) is the reference standard for evaluating the efficacy of antitumor treatment and is a common endpoint in related clinical studies (11). However, the assessment of OS is difficult as it requires a long follow-up time. Previous studies have found that pCR is strongly associated with longer OS (12-14). Therefore, pCR is often thought to be equivalent to prolonged OS. However, previous studies have also found that the risk of relapse among patients with pCR after neoadjuvant treatment and surgery in NSCLC is 21.1–51.6% (15-17). In addition, for other solid tumor, the study showed that pCR cannot be used as a trial-level surrogate for either event-free survival (EFS) or OS (13). Some patients with pCR after neoadjuvant immunochemotherapy experience relapse, or even death, within a short period of time. There remains a lack of high-quality clinical data on whether pCR after neoadjuvant immunochemotherapy can be translated to longer OS in patients with NSCLC. Moreover, because of the relative rarity of pCR, it is unlikely that prospective studies will be able to answer this question; the rate of patients with pCR after immunotherapy was 24.0% in CheckMate 816, 18.1% in KEYNOTE-671, 17.2% in AEGEAN, 24.8% in Neotorch, 25.3% in CheckMate 77T, and 40.7% in RATIONALE-315. Therefore, at present, it appears that the only way to achieve a large sample size is to use a retrospective cohort. To address this knowledge gap, we launched a multicenter retrospective study with the goal of objectively determining long-term survival and relapse patterns among patients with NSCLC who have pCR after neoadjuvant immunochemotherapy. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2200/rc).
Methods
Study population
We analyzed the prospectively maintained databases at four high-volume medical centers in China (Peking University Cancer Hospital; Sun Yat-sen University Cancer Center; Shanghai Chest Hospital; Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College) and extracted data on consecutive patients with NSCLC who underwent neoadjuvant immunochemotherapy followed by surgery from 2018 to 2022. Inclusion criteria included: (I) pathologic diagnosis of NSCLC; (II) clinical stage IB to IIIB disease (N2); (III) receipt of at least one cycle of neoadjuvant immunochemotherapy; (IV) treatment with radical lung resection; (V) and postoperative pathologic confirmation of lack of viable tumor cells in the primary lesion and lymph nodes. Exclusion criteria included: (I) known epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations; (II) preoperative or intraoperative confirmation of distant metastasis; (III) receipt of sublobar or non-curative resection; (IV) death within 30 days of the operation; (V) and lack of a record of follow-up after surgery (Figure 1). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Peking University Cancer Hospital (E2019134), where the principal investigator is a member of the faculty. The other participating medical centers were also informed and agreed the study. Informed consent was obtained from all individual participants.

Staging methods
Standard staging examinations, including chest enhanced computed tomography (CT), positron emission tomography (PET)/CT, and brain enhanced magnetic resonance imaging (MRI), were completed within 30 days before treatment. If brain MRI was not possible, CT with contrast of the head was performed. For patients without a PET/CT scan, abdominal ultrasound (including liver and adrenal glands) or upper abdominal enhanced CT and whole-body bone scan were performed. Patients with suspected metastasis to the hilar or mediastinal lymph nodes on CT or PET/CT were recommended to undergo biopsy and pathologic diagnosis. Staging was performed in accordance with the eighth edition of the American Joint Committee on Cancer staging system.
Indications for and strategy of neoadjuvant treatment
For patients with cN2 disease, neoadjuvant treatment was recommended; for patients with cN1 disease and patients with N0 disease with T2 or higher, treatment decisions were made by means of a multidisciplinary team (MDT) discussion that involved medical oncologists, surgeons, radiation oncologists, and radiologists. Pemetrexed combined with platinum was the recommended chemotherapy regimen for patients with adenocarcinoma; paclitaxel combined with platinum was the most common regimen for other patients. Neoadjuvant treatment was repeated every 21 days, for a total of two to four cycles, as determined by the MDT.
Reevaluation after neoadjuvant treatment
Within 30 days before surgery, after neoadjuvant treatment, chest enhanced CT was performed to reevaluate T and N stages. If >90 days had elapsed since the initial assessment, PET/CT and brain enhanced MRI were performed to exclude distant metastasis. For patients with suspected N2 or N3 disease after neoadjuvant treatment, biopsy was performed again.
Indications for and methods of surgical resection
Patients whose disease was restaged to stage I to IIIa after neoadjuvant treatment underwent resection. For patients with ycN2 disease, the decision to undergo resection was made by the MDT. In most cases, lobectomy was performed; for some patients with central lesions, sleeve lobectomy, bilobectomy, or pneumonectomy was performed. Lymph node dissection typically involved systematic lymph node dissection, including at least 3 N1 stations and 3 N2 stations (and requiring the inclusion of station 7 lymph nodes).
Pathologic assessment
Postoperative pathologic assessment was performed in accordance with International Association for the Study of Lung Cancer standards, which entailed continuous sectioning of all lesions and calculation of the tumor bed on the basis of areas of tumor, necrosis, and fibrosis. An experienced pathologist performed the assessment at each center, with confirmation by an additional senior pathologist. pCR was defined as the lack of residual viable tumor cells in both the tumor bed and the lymph nodes after neoadjuvant treatment (ypT0N0).
Principles of postoperative treatment
The decision of whether to administer adjuvant treatment and the specific regimen to administer was made by the MDT in accordance with published treatment guidelines (including National Comprehensive Cancer Network and Chinese Society of Clinical Oncology lung cancer treatment guidelines).
Follow-up
For the first two years after surgery, blood tests, chest enhanced CT, and abdominal ultrasound (including liver and adrenal glands) were performed every 3 months, and brain enhanced MRI was performed every 6 to 12 months; 3 to 5 years after surgery, exams were performed every 6 months, and brain enhanced MRI was performed annually; after 5 years, examinations were performed annually. For patients unable to undergo MRI, head enhanced CT could be used as a substitute.
Statistical analysis
Continuous variables were analyzed using the independent sample t-test for normal distribution and Mann-Whitney U test for non-normal distribution, and data were presented as medians and quartiles. Categorical variables were analyzed using the Chi-squared test, and data are presented as counts and percentages. OS was defined as the time from surgery to death or last follow-up. Disease-free survival (DFS) was defined as the time from surgery to relapse, death, or last follow-up. OS and DFS were estimated using the Kaplan-Meier method with log-rank test. All tests were two-sided, with α=0.05. Data analysis was performed using R software for Windows (version 4.3.2, R Development Core Team, Vienna, Austria). The cutoff date of follow-up was September 30, 2023.
Results
Patients and preoperative treatments
We identified 675 patients who underwent neoadjuvant immunochemotherapy followed by surgery at four high-volume medical centers in China. In total, 130 patients met the inclusion criteria and were included in the study (Table 1). Median age was 62 years. Most patients had squamous cell carcinoma, which was followed by adenocarcinoma [24 (18.5%)] and other histologic types [3 (2.3%)], including one case of mucoepidermoid carcinoma, one case of large cell neuroendocrine carcinoma, and one case of poorly differentiated carcinoma). Patients with non-squamous cell carcinoma were treated with pemetrexed combined with platinum, while those with squamous cell carcinoma were treated with paclitaxel or gemcitabine combined with platinum. No grade ≥3 treatment-related adverse events were observed during neoadjuvant treatment.
Table 1
Characteristic | Overall (n=130) | Without relapse (n=119) | With relapse (n=11) | P value |
---|---|---|---|---|
Age (years) | 0.75 | |||
<60 | 49 (37.7) | 44 (37.0) | 5 (45.5) | |
≥60 | 81 (62.3) | 75 (63.0) | 6 (54.5) | |
Sex | >0.99 | |||
Female | 10 (7.7) | 10 (8.4) | 0 | |
Male | 120 (92.3) | 109 (91.6) | 11 (100.0) | |
Smoking history | >0.99 | |||
Current or former smoker | 94 (72.3) | 86 (72.3) | 8 (72.7) | |
Never smoker | 36 (27.7) | 33 (27.7) | 3 (27.3) | |
Clinical T stage | 0.66 | |||
T1 | 10 (7.7) | 10 (8.4) | 0 (0.0) | |
T2 | 61 (46.9) | 54 (45.4) | 7 (63.6) | |
T3 | 26 (20.0) | 25 (21.0) | 1 (9.1) | |
T4 | 33 (25.4) | 30 (25.2) | 3 (27.3) | |
Clinical N stage | 0.25 | |||
N0 | 19 (14.6) | 17 (14.3) | 2 (18.2) | |
N1 | 40 (30.8) | 39 (32.8) | 1 (9.1) | |
N2 | 71 (54.6) | 63 (52.9) | 8 (72.7) | |
Clinical stage | 0.80 | |||
IB | 5 (3.8) | 5 (4.2) | 0 | |
IIA | 3 (2.3) | 3 (2.5) | 0 | |
IIB | 26 (20.0) | 25 (21.0) | 1 (9.1) | |
IIIA | 66 (50.8) | 58 (48.7) | 8 (72.7) | |
IIIB | 30 (23.1) | 28 (23.5) | 2 (18.2) | |
Tumor location | 0.10 | |||
LUL | 41 (31.5) | 40 (33.6) | 1 (9.1) | |
LLL | 23 (17.7) | 20 (16.8) | 3 (27.3) | |
RUL | 29 (22.3) | 28 (23.5) | 1 (9.1) | |
RML | 11 (8.5) | 9 (7.6) | 2 (18.2) | |
RLL | 26 (20.0) | 22 (18.5) | 4 (36.4) | |
Immunotherapy drug | >0.99 | |||
PD-1 | 125 (96.2) | 114 (95.8) | 11 (100.0) | |
PD-L1 | 5 (3.8) | 5 (4.2) | 0 | |
Cycles of neoadjuvant immunochemotherapy | 0.75 | |||
2 | 47 (36.2) | 44 (37.0) | 3 (27.3) | |
≥3 | 83 (63.8) | 75 (63.0) | 8 (72.7) | |
Histologic type | >0.99 | |||
SCC | 103 (79.2) | 94 (79.0) | 9 (81.8) | |
Non-SCC | 27 (20.8) | 25 (21.0) | 2 (18.2) | |
PD-L1 expression (n=129) | 0.27 | |||
<1% | 9 (7.0) | 7 (5.9) | 2 (18.2) | |
1–49% | 10 (7.8) | 10 (8.5) | 0 | |
≥50% | 18 (14.0) | 16 (13.6) | 2 (18.2) | |
Unknown | 92 (71.3) | 85 (72.0) | 7 (63.6) | |
Molecular analysis | >0.99 | |||
No EGFR or ALK mutation | 37 (28.5) | 34 (28.6) | 3 (27.3) | |
Unknown | 93 (71.5) | 85 (71.4) | 8 (72.7) | |
Extent of resection | 0.41 | |||
Lobectomy/bilobectomy | 109 (83.8) | 100 (84.0) | 9 (81.8) | |
Sleeve lobectomy | 13 (10.0) | 11 (9.2) | 2 (18.2) | |
Pneumonectomy | 8 (6.2) | 8 (6.7) | 0 | |
Adjuvant immunotherapy | 0.92 | |||
Yes | 67 (51.5) | 62 (52.1) | 5 (45.5) | |
No | 63 (48.5) | 57 (47.9) | 6 (54.5) |
Data are n (%). ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; LLL, left lower lobe; LUL, left upper lobe; PD-1, programmed death 1; PD-L1, programmed death ligand 1; RLL, right lower lobe; RML, right middle lobe; RUL, right upper lobe; SCC, squamous cell carcinoma.
Surgery
Of the 130 included patients, more than 83% of patients underwent lobectomy or bilobectomy. Most patients [110 (84.7%)] underwent systematic lymph node dissection, which was followed by lobe-specific lymph node dissection [15 (11.5%)] and lymph node sampling [5 (3.8%)].
Postoperative complications and treatments
Eight patients (6.2%) experienced postoperative complications, including three cases of immunotherapy-related pneumonitis, one case of immunotherapy-related hepatitis, one case of deep venous thrombosis, one case of chylothorax, one case of pulmonary fungal infection, and one case of persistent air leak. A total of 67 patients received adjuvant immunotherapy after surgery, 10 of whom experienced treatment-related side effects. One patient died of immunotherapy-related pneumonitis during adjuvant treatment. Of the eight patients who experienced postoperative complications, two (one with chylothorax and one with immunotherapy-related pneumonitis) received adjuvant immunotherapy, with no further treatment-related side effects.
Long-term survival
The median follow-up time in this study was 23.3 months (range, 2.9–54.3 months); 3-year DFS was 84.6% (95% CI: 77.3–92.6%), and 3-year OS was 93.5% (95% CI: 87.9–99.7%) (Figure 2). Five patients died during the study period; one died of disease progression, one died of postoperative adjuvant immunotherapy-related pneumonitis, one died of myocardial infarction, and two died of unknown causes (did not receive adjuvant treatment).

Patterns of relapse
In total, 11 patients (8.5%) experienced relapse (Table 2); the median time from surgery to relapse was 7.6 months (range, 0.7–25.8 months). Most relapses (90.9%) occurred within 18 months of surgery. Six patients had intrathoracic relapse, and five patients had extrathoracic relapse (Figure 3). Of the patients with relapse, one died of disease progression. Treatments after relapse included chemotherapy in four cases (one with bone metastasis, one with liver metastasis, and two with multiple lymph node metastases), radiation therapy in four cases (one with brain metastasis, one with pleural metastasis, one with stump relapse, and one with lung metastasis), surgical treatment in one case (lung metastasis), and unknown treatment in one case.
Table 2
Patient No. | Histology | Clinical stage | Neoadjuvant therapy | Cycles of neoadjuvant therapy | Extend of resection | Adjuvant therapy | Cycles of adjuvant therapy | DFS (months) | Relapse site | Status | OS (months) |
---|---|---|---|---|---|---|---|---|---|---|---|
1 | SCC | IIIA | PD-1 + Chemo | 4 | Lobectomy/bilobectomy | – | – | 6.7 | Extrathoracic LN | Dead | 13.0 |
2 | SCC | IIB | PD-1 + Chemo | 2 | Sleeve lobectomy | – | – | 14.1 | Stump/intrathoracic LN | Alive | 22.2 |
3 | Non-SCC | IIIA | PD-1 + Chemo | 3 | Lobectomy/bilobectomy | – | – | 7.7 | Brain | Alive | 8.9 |
4 | SCC | IIIA | PD-1 + Chemo | 2 | Lobectomy/bilobectomy | – | – | 3.5 | Stump | Alive | 19.6 |
5 | SCC | IIIA | PD-1 + Chemo | 3 | Lobectomy/bilobectomy | PD-1 | 3 | 15.9 | Intrathoracic LN | Alive | 17.5 |
6 | SCC | IIIA | PD-1 + Chemo | 3 | Lobectomy/bilobectomy | PD-1 | 3 | 9.0 | Lung | Alive | 25.3 |
7 | SCC | IIIB | PD-1 + Chemo | 3 | Lobectomy/bilobectomy | PD-1 | 12 | 26.0 | Lung | Alive | 26.1 |
8 | Non-SCC | IIIA | PD-1 + Chemo | 3 | Lobectomy/bilobectomy | PD-1 | 7 | 9.3 | Pleura | Alive | 23.6 |
9 | Non-SCC | IIIA | PD-1 + Chemo | 4 | Lobectomy/bilobectomy | PD-1 | 4 | 4.5 | Bone/extrathoracic LN | Alive | 19.7 |
10 | SCC | IIIB | PD-1 + Chemo | 3 | Lobectomy/bilobectomy | Chemo | 2 | 4.9 | Bone | Alive | 20.9 |
11 | SCC | IIIA | PD-1 + Chemo | 2 | Sleeve lobectomy | – | – | 0.7 | Liver | Alive | 16.7 |
Chemo, chemotherapy; DFS, disease-free survival; LN, lymph node; OS, overall survival; PD-1, programmed death 1; SCC, squamous cell carcinoma.

Risk factors for relapse
Univariable analysis to identify potential risk factors for relapse showed that age, sex, smoking status, pathologic type, clinical stage, cycles of neoadjuvant treatment, immunotherapy drugs, extent of resection, lymph node dissection, and adjuvant immunotherapy were not statistically significantly associated with relapse. Because of an insufficient number of events, multivariable analysis was not performed.
Discussion
This study represents the largest cohort, to date, of patients with NSCLC who had pCR after neoadjuvant immunochemotherapy followed by surgery. We found that patients with pCR after neoadjuvant immunotherapy had a good long-term prognosis, with a 3-year OS of 93.5%. Nonetheless, 8.5% of patients experienced relapse, with a median time to relapse of 7.6 months, and 90.9% of relapses occurred within 18 months after surgery. Three-year DFS was 84.6%. No clinical or pathologic factors were associated with risk of relapse in our study.
Previous studies have shown that patients with pCR after neoadjuvant chemotherapy generally have a good prognosis (18,19). In immunotherapy era, several randomized clinical trials have shown the EFS benefit in neoadjuvant immunotherapy group (Table 3). However, few clinical studies on neoadjuvant immunotherapy have investigated outcomes among patients with pCR. CheckMate 816 (3) is the first phase 3 randomized controlled trial to support the use of neoadjuvant immunotherapy combined with chemotherapy, but data on patients with pCR in the study group and the control group have not been published. KEYNOTE-671—a representative study of the sandwich-like model—observed 2-year EFS of >80% for patients with pCR in both the pembrolizumab group and the chemotherapy group 4. The analysis of Neotorch (6) and CheckMate 77T (7) also found that patients with pCR appeared to have longer EFS than patients without pCR. Although AEGEAN (5) and RATIONALE-315 (8) observed that patients treated with immunochemotherapy had statistically significantly better EFS and rates of pCR, survival data for the patients with pCR have not yet been published. Some retrospective studies have also found that patients with pCR after neoadjuvant treatment have a good prognosis. Melek and colleagues (18) found that patients with locally advanced NSCLC who had pCR after neoadjuvant treatment had 5-year OS similar to that of patients with stage Ib disease who underwent direct surgery (72.2% vs. 70.3%). Lococo and colleagues (15) found that patients with locally advanced NSCLC who had pCR after neoadjuvant chemoradiotherapy had 5-year OS of 56.18% and 5-year DFS of 48.84%. In light of our data and current research findings, we can observe that patients with locally advanced NSCLC who achieve pCR after neoadjuvant immunochemotherapy have a significant benefit in EFS compared to those who do not achieve pCR. However, OS data is not yet mature, and whether pCR can translate into OS benefits still awaits confirmation from the results of large-scale randomized controlled studies.
Table 3
Study cohort | CheckMate 816 (3) | KEYNOTE-671 (4,20) | AEGEAN (5) | Neotorch (6) | CheckMate 77T (7) | RATIONALE-315 (8) | Our cohort |
---|---|---|---|---|---|---|---|
Compared regimens | PD-1 + Chemo vs. Chemo | PD-1 + Chemo vs. Chemo | PD-L1 + Chemo vs. Chemo | PD-1 + Chemo vs. Chemo | PD-1 + Chemo vs. Chemo | PD-1 + Chemo vs. Chemo | PD-1/PD-L1 + Chemo |
CR (%) | 0.6 vs. 1.7 | NA | 1.1 vs. 0.3 | ORR: 64.4 vs. 32.7 | 3.1 vs. 2.6 | NA | NA |
PR (%) | 53.1 vs. 35.8 | NA | 55.2 vs. 33.7 | 55.0 vs. 40.1 | NA | NA | |
SD (%) | 39.1 vs. 49.2 | NA | 33.9 vs. 50.5 | 29.2 vs. 50.5 | 31.9 vs. 46.1 | NA | NA |
PD (%) | 4.5 vs. 6.1 | 3.8 vs. 6.5 | 3.0 vs. 4.0 | NA | 3.9 vs. 5.6 | NA | NA |
EFS | mEFS (months): 31.6 vs. 20.8; HR 0.63 (97.38% CI: 0.43–0.91). 2-y EFS: 63.8% vs. 45.3% | mEFS (months): 47.2 vs. 18.3; HR 0.59 (95% CI: 0.48–0.72). 4-y EFS: 48.4% vs. 26.2% | mEFS (months): NR vs. 25.9; HR 0.68 (95% CI: 0.53–0.88). 2-y EFS: 63.3% vs. 52.4% | mEFS (months): NR vs. 15.1; HR 0.40 (95% CI: 0.28–0.57). 2-y EFS: 64.7% vs. 38.7% | mEFS (months): NR vs. 18.4; HR 0.58 (97.36% CI: 0.42–0.81). 1.5-y EFS: 70.2% vs. 50.0% | mEFS: NR vs. NR; HR 0.56 (95% CI: 0.40–0.79). 2-y EFS: 68% vs. 52% | 3-y DFS: 84.6% |
OS | mOS (months): NR vs. NR; HR 0.57 (99.67% CI: 0.30–1.07). 2-y OS: 82.7% vs. 70.6% | mOS (months): NR vs. 52.4; HR 0.72 (95% CI: 0.56–0.93). 4-y OS: 67.1% vs. 51.5% | NA | mOS (months): NR vs. 30.4; HR 0.62 (95% CI: 0.38–1.00) | NA | mOS: NR vs. NR; HR 0.62 (95% CI: 0.39–0.98). 2-y OS: 89% vs. 79% | 3-y OS: 93.5% |
CI, confidence interval; CR, complete response; EFS, event-free survival; HR, hazard ratio; mEFS, median event-free survival; mOS, median overall survival; NA, not available; NR, not reached; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PD, progressive disease; PD-1, programmed death-1; PD-L1, programmed death ligand 1; PR, partial response; SD, stable disease; y, year.
In the present study, six patients had intrathoracic relapse, and five patients had extrathoracic relapse. In previous studies, the most common site of relapse was the central nervous system (15,21,22). Similarly, Lococo and colleagues (15) found that, among patients with pCR, 71.8% of relapses (23/32) were distant metastases—in particular, brain metastases (60.9%). However, in the CheckMate 816 (23) follow-up analysis, no patients with pCR who had received neoadjuvant immunotherapy had brain metastasis. In our cohort, only one patient had brain metastasis. Taken together, these findings suggest that immunotherapy may be effective for the prevention of brain metastasis. Of note, the patterns of relapse in the era of neoadjuvant immunotherapy might differ from those in the era of neoadjuvant chemotherapy or chemoradiation therapy. Therefore, it is important to identify patients with a high risk of relapse in this new era and to implement proper treatment after surgery to reduce this risk.
However, how to identify patients with a high risk of relapse remains a challenge. In previous studies, pneumonectomy appeared to be associated with a worse prognosis, whereas younger age, female sex, resection of >10 lymph nodes, lack of neoadjuvant radiotherapy, and receipt of postoperative adjuvant treatment were associated with a better prognosis (15,24). We were not able to identify similar prognostic factors in our cohort. Therefore, the use of novel approaches may be necessary. Variability between pathologists may be an issue in assessment of major pathologic response and pCR (25). One study found that the rate of pCR determined by a researcher might be higher than that determined by blinded independent pathologic review (26). Therefore, some patients with residual tumor lesions might be misclassified as having pCR, and these residual lesions could be the primary site of disease relapse. Additionally, a residual lesion that is not visible to the eye—in particular, minimal residual disease (MRD) that is undetectable by routine examination but that remains in the circulatory system—is considered to be a significant predictor of disease relapse. Hence, an effective way to detect nonvisible disease is needed. Abbosh and colleagues (27) proposed that assessment of circulating tumor DNA (ctDNA) could have utility in the adjuvant therapeutic setting by enabling the identification of patients with a high risk of disease recurrence on the basis of detection of postsurgical MRD. Provencio and colleagues (28) found that an undetectable ctDNA level after neoadjuvant immunotherapy in patients with NSCLC was associated with longer progression-free survival and OS. In a recent review article, Pellini and Chaudhuri (29) observed that ctDNA MRD testing for the prediction of disease recurrence after curative treatment for NSCLC had a sensitivity of 82–100% and a specificity of 70–100%. Several studies have found that detection of the level of ctDNA MRD after surgery is helpful for predicting the risk of recurrence, especially with longitudinal detection. Qiu and colleagues (30) found that the use of postsurgical ctDNA status to guide adjuvant therapy was beneficial and could predict risk of recurrence. Zhang and colleagues (31) confirmed the prognostic value of MRD testing after curative surgery in patients with NSCLC, suggesting that peaks in detectable MRD occur 12 to 18 months after surgery. Patients with no MRD detectable >18 months after surgery were considered to be potentially cured. These findings are consistent with the relapse patterns observed in our study cohort. Studies (27-31) investigating this approach suggest that molecular markers could help to identify patients with pCR who have a high risk of relapse, although results from prospective studies are needed to confirm this hypothesis.
The current guidelines for postoperative follow-up may underestimate the importance of monitoring for extrathoracic metastasis within 18 months of surgery—for instance, the National Comprehensive Cancer Network guidelines do not include any recommendations regarding screening of distant metastasis for non-symptomatic patients. However, in our study, 45% of relapses were extrathoracic, all of which occurred within 18 months of surgery. Therefore, we believe rigorous follow-up with consideration for monitoring of extrathoracic organs are needed within 18 months after surgery for patients with NSCLC who have pCR after neoadjuvant immunochemotherapy.
Our study is retrospective in nature; therefore, it cannot avoid the potential of selection bias, such as the inability to trace patients who did not have a completed resection after neoadjuvant therapy. Moreover, as this was a multicenter study, pCR assessments were conducted by local pathologists without centralized laboratory evaluation. Although we implemented the same assessment standards across centers, the subjectivity of evaluations could still negatively affect the study results. In addition, this study mainly enrolled men and patients with squamous cell carcinoma; whether the study results are applicable to women or patients with adenocarcinoma needs to be verified by subsequent studies. Last, given the good prognosis of patients with pCR, the findings of this study may require longer follow-up for validation.
Conclusions
Patients with resectable locally advanced NSCLC who have pCR after neoadjuvant immunochemotherapy followed by surgery have a good prognosis. However, some patients still experience relapse. The high risk of extrathoracic relapse in the period shortly after surgery advocates for the tailoring of surveillance strategies. Additionally, molecular testing may be helpful for guiding postoperative therapy and predicting recurrence.
Acknowledgments
None.
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2200/rc
Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2200/dss
Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2200/prf
Funding: This work was supported by
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2200/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was granted approval by the Ethics Committee of Peking University Cancer Hospital (E2019134), where the principal investigator is a member of the faculty. The other participating medical centers were also informed and agreed the study. All patients signed written informed consent forms.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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