Defining the surgical curative time window: identifying patients with an absence of recurrence for 5 years following surgical resection of stage I invasive non-small cell lung cancer

Introduction

Despite recent advances in the management of lung cancer, it remains the leading cause of cancer-related mortality among both men and women (1). Approximately 85% of lung cancers are classified as non-small cell lung cancer (NSCLC) (2), and nearly one-third of newly diagnosed NSCLC cases are detected at an early stage, typically undergoing curative-intent surgical resection (3,4). Although adjuvant therapy is generally not required for stage I patients due to their favorable prognosis, postoperative surveillance continues to present the standard of care. However, the conventional “one-size-fits-all” monitoring strategy is increasingly being debated. Growing clinical evidence now supports risk-adapted follow-up protocols, a shift reflected in recent updates to National Comprehensive Cancer Network (NCCN) guidelines that recommend reduced surveillance frequency for certain low-risk patient groups (5).

The concept of curability has advanced considerably through long-term observations of patients with adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and pure ground-glass opacity (pGGO) lesions; these subgroups consistently exhibit no local or distant recurrences within 10 years after resection (6). This clinical insight led to the proposal of the “surgical curative time window”, defined as a distinct postoperative state during which no recurrence is observed throughout the 5-year follow-up period (7). A more complex—and clinically meaningful—application of this concept involves invasive NSCLC. Notably, specific subgroups, particularly cT1N0 patients with a consolidation-to-tumor ratio (CTR) <0.5 and tumor size ≤2 cm, have demonstrated exceptional outcomes, achieving 5-year recurrence-free survival (RFS) rates of 97.1% (8). Although these results are promising, significant knowledge gaps persist. Current staging systems have not yet formally integrated the criterion of 5-year recurrence-free status, despite its profound implications for clinical decision-making. Furthermore, the biological heterogeneity of invasive NSCLC complicates the reliable identification of patients who may be suitable for reduced surveillance.

In this study, we systematically analyzed a large cohort of patients with completely resected stage I invasive NSCLC to identify clinicopathologic features predictive of durable cure. Our findings aim to provide an evidence base for optimizing individualized follow-up strategies, with the potential to reduce unnecessary radiation exposure, alleviate patient anxiety, and improve the allocation of healthcare resources. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-894/rc).

Methods

Patients

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Fudan University Shanghai Cancer Center (approval No. IRB2008223-9; date: 14 July 2020). Informed consent was waived in this retrospective study. The study included consecutive patients with pathologic stage I NSCLC [according to the 8th edition of the American Joint Committee on Cancer (AJCC) staging system], who underwent R0 resection between April 2008 and December 2015 and had confirmed pN0 status. Patients were excluded if they had AIS or MIA subtypes, a history of malignancy, previous neoadjuvant therapy, or incomplete clinical records.

Data collection

Patient demographics, clinicopathologic features, and follow-up information were prospectively collected. Demographic variables included age, sex, and smoking history. Clinicopathologic features consisted of tumor location, computed tomography (CT) appearance based on preoperative thin-section CT (TSCT), surgical procedure, pathological tumor size, pathological TNM stage (8th edition), histologic subtype, lymphovascular invasion (LVI), and visceral pleural invasion (VPI). Follow-up information encompassed the date of last follow-up, time to recurrence or death, and sites of initial recurrence.

Two radiologists independently evaluated GGO features on TSCT scans. Tumor size was defined as the maximum axial diameter measured on CT. The CTR was calculated as the ratio of the maximum diameter of the solid component (areas >−300 HU on TSCT) to the maximum tumor diameter (including GGO components), yielding a continuous value ranging from 0 (pGGO) to 1 (fully solid lesion). Any discrepancies between the two radiologists were resolved through consensus discussion.

CTR=Maximumdiameterofsolidcomponent(HU>−300)Maximumtumordiameter(includingGGO)[1]

Lung adenocarcinomas (LUADs) were classified according to the grading system established by the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS), and the European Respiratory Society (ERS) in the international multidisciplinary classification of LUAD (9). Intermediate-grade invasive adenocarcinoma (IAC) included acinar-predominant adenocarcinoma (APA), papillary-predominant adenocarcinoma (PPA), and invasive mucinous adenocarcinoma (IMA). High-grade IAC comprised micropapillary-predominant adenocarcinoma (MPA) and solid-predominant adenocarcinoma (SPA). Pathological tumor size was defined as the maximum diameter measured along the largest dimension of the resected specimen. LVI was identified by the presence of tumor cells within lymphatic vessels, and VPI was defined by tumor cell infiltration into the visceral pleural layer. Two experienced pathologists independently reviewed all pathological findings. Any discrepancies were resolved through joint re-evaluation and consensus discussion.

Follow-up protocol

For all the enrolled patients, follow-up evaluations commenced on the date of surgery. During the first 3 years after surgery, physical examinations, chest CT scans, ultrasounds of the abdominal, cervical, and supraclavicular regions, and magnetic resonance imaging or CT scans of the brain were conducted every 6 months. From the third to the fifth year, these examinations were performed yearly and continued yearly thereafter.

Whole-body bone scans were performed at least once per year. Overall survival (OS) was defined as the time from the date of surgery to the date of death from any cause or the last follow-up. RFS was calculated from the date of surgery to the date of recurrence, death, or the last follow-up. Lung cancer-specific survival (LCSS) was defined as the time from surgery to death attributable specifically to lung cancer.

All patients were followed regularly after surgery. For RFS analysis, patients who died from non-cancer-related causes were censored, indicating that no recurrence event had been observed before death.

Recurrence was evaluated using imaging studies and/or tissue biopsy. The distinction between recurrence and a second primary lung tumor was made according to the Martini-Melamed criteria and, when feasible, supported by molecular testing. Locoregional recurrence was defined as disease reappearance at the surgical margin, within the ipsilateral lung, in regional lymph nodes, or in the ipsilateral mediastinum. Distant recurrence refers to disease occurrence in the pleura or any site outside the ipsilateral hemithorax. Patients presenting with both locoregional and distant recurrence were classified as having distant recurrence. Isolated distant recurrences were categorized by the involved organ, while cases with involvement of multiple organs were classified as multiple recurrences.

Statistical analysis

Categorical variables are summarized as frequencies with percentages, and continuous variables as medians with standard deviations. Group comparisons were conducted using Pearson’s chi-square test for categorical variables, while continuous variables were analyzed using Student’s t-test for normally distributed data or the Mann-Whitney U test (or Kruskal-Wallis test, as appropriate) for non-normally distributed data.

Univariate analysis was first performed to screen for potential prognostic factors. Variables with a P below 0.05 were subsequently entered into a multivariate Cox proportional hazards regression model (enter method) to identify independent protective factors. Based on these factors, a scoring system was constructed in which each protective variable contributed one point. The cutoff for defining the low-risk group, representing the surgical curative time window, was determined based on the condition associated with 100% RFS at 5 years.

RFS, OS, and LCSS were estimated using the Kaplan-Meier method, and survival differences between groups were compared with the log-rank test. All statistical tests were two-sided, and a P<0.05 was considered statistically significant. All analyses were performed using R software (version 4.3.1) and EmpowerStats (X&Y Solutions, Inc., Boston, MA, USA).

Results

Baseline information of patients

A total of 1,817 patients met the inclusion criteria for this study. The mean age at diagnosis was 61 years (range, 21–84 years). Of these, 906 patients (49.9%) were male, and 659 (36.3%) had a history of smoking. Lobectomy was performed in the majority of patients (86.7%). Tumor size ranged from 0.3 to 4.0 cm, with a mean diameter of 2.1 cm. Regarding histologic subtypes, APA was identified in 885 cases (48.7%), PPA in 137 (7.5%), IMA in 59 (3.3%), lepidic-predominant adenocarcinoma (LPA) in 264 (14.5%), MPA in 9 (0.5%), SPA in 102 (5.6%), squamous cell carcinoma (SQCC) in 277 (15.3%), and other subtypes in 84 (4.6%). LVI was observed in 70 patients (3.9%), VPI in 202 (11.1%), and perineural invasion (PNI) in 28 (1.5%). Detailed clinicopathological characteristics are summarized in Table 1.

The median postoperative follow-up time was 50 months (range, 34–126.7 months). Among all stage I NSCLC patients, the 5-year OS rate was 91.3%, the 5-year RFS rate was 85.4%, and the 5-year LCSS rate was 93.8%.

Uni- and multivariate analyses of prognostic factors

The associations between clinical features and recurrence were evaluated. Univariate analysis identified several significant protective features for RFS in stage I NSCLC patients, including younger age (P=0.03), female sex (P<0.001), smaller tumor size (P<0.001), LPA histologic type (P<0.001), absence of LVI (P<0.001), absence of VPI (P<0.001), non-smoking status (P<0.001), presence of a GGO component (P<0.001), smaller solid component size (P<0.001), and lower CTR (P<0.001). Multivariate analysis confirmed that female sex [hazard ratio (HR) =0.77; 95% confidence interval (CI): 0.59–1.00; P=0.05], tumor size ≤2 cm (HR =0.66; 95% CI: 0.51–0.85; P=0.001), LPA histologic type (HR =0.04; 95% CI: 0.01–0.31; P=0.002), presence of a GGO component (HR =0.60; 95% CI: 0.42–0.85; P=0.004), and solid component size ≤10 mm (HR =0.34; 95% CI: 0.18–0.66; P=0.001) were independent prognostic factors (Table 2).

Identification of patients within the surgical curative time window

Based on the aforementioned results, we identified five protective factors: female sex, tumor size ≤2 cm, LPA histologic type, presence of a GGO component, and solid component size ≤10 mm. Using these features, we developed a scoring system. Patients who met at least four of these criteria were classified as low-risk and considered to be within the curative time window, characterized by a 5-year RFS rate of 100%. The remaining patients were classified as elevated-risk. Accordingly, 341 patients were categorized as low-risk and 1,476 as elevated-risk. Significant differences in survival outcomes were observed between the two groups. The 5-year RFS rate was 100% in the low-risk group compared to 82.0% in the elevated-risk group (P<0.001; Figure 1A). Similarly, the 5-year OS rates were 98.8% versus 89.5% (P<0.001), and the 5-year LCSS rates were 100% versus 92.4% (P<0.001; Figure 1B,1C). The clinical characteristics of both groups are detailed in Table S1.

Figure 1 Kaplan-Meier curves for RFS (A), OS (B), and LCSS (C) between low-risk and elevated-risk patient groups, as stratified by the scoring system. LCSS, lung cancer-specific survival; OS, overall survival; RFS, recurrence-free survival.

Refined risk stratification for the elevated-risk group

Given the substantial size of the elevated-risk group, we further investigated prognostic factors to enable more precise risk stratification within this population. Univariate analysis identified several factors associated with improved RFS, including smaller tumor size (P<0.001), LPA histologic type (P=0.007), stage IA disease (P=0.003), presence of a GGO component (P<0.001), smaller solid component size (P=0.005), lower CTR (P<0.001), absence of LVI (P<0.001), and absence of VPI (P=0.01). Conversely, MPA/SPA (P=0.003) and other non-adenocarcinoma subtypes (P=0.004) were associated with poorer RFS (Table 3).

Multivariate analysis confirmed that tumor size ≤1.5 cm (HR =0.53; 95% CI: 0.38–0.74; P<0.001), LPA histologic type (HR =0.07; 95% CI: 0.01–0.56; P=0.01), absence of LVI (HR =0.61; 95% CI: 0.39–0.95; P=0.03), and CTR ≤0.75 (HR =0.51; 95% CI: 0.34–0.78; P=0.002) were independent protective factors for RFS (Table 3).

Based on these results, we developed a secondary scoring system for this cohort (Figure 2). Patients meeting at least four criteria were classified as intermediate-risk (n=153, 10.3%), while the remainder constituted the high-risk subgroup (n=1,323, 89.6%). The lower-risk group demonstrated significantly better 5-year survival outcomes: RFS was 97.3% versus 80.2% (P<0.001); OS was 97.9% versus 88.5% (P<0.001), and LCSS was 99.3% versus 91.6% (P<0.001) (Figure 2). The complete risk stratification framework is shown in Figure 3.

Figure 2 Kaplan-Meier estimates of RFS (A), OS (B), and LCSS (C) for patients in the intermediate-risk group compared to those in the high-risk group. LCSS, lung cancer-specific survival; OS, overall survival; RFS, recurrence-free survival.

Figure 3 Risk Stratification and the surgical curative time window in stage I NSCLC. The proposed risk-stratified framework classifies patients with invasive stage I NSCLC into low-risk (defined as meeting ≥4 favorable criteria) and elevated-risk groups. The low-risk group represents the invasive subset of the surgical curative time window population. When integrated with AIS, MIA, and pGGO cases—as established by existing criteria—these groups collectively constitute the complete surgical curative time window cohort. Patients in the elevated-risk group require alternative surveillance strategies. AIS, adenocarcinoma in situ; CTR, consolidation-to-tumor ratio; GGO, ground-glass opacity; LPA, lepidic-predominant adenocarcinoma; LVI, lymphovascular invasion; MIA, minimally invasive adenocarcinoma; NSCLC, non-small cell lung cancer; pGGO, pure ground-glass opacity; RFS, recurrence-free survival.

Discussion

Research into prognostic models for NSCLC has evolved considerably since the early 2000s (10,11), with tools like the Lung Cancer Prognostic Index (LCPI) (12) demonstrating the value of integrating molecular and clinical data for risk stratification. Subsequent efforts have largely bifurcated into refining clinical parameters or discovering novel biomarkers (13). In early-stage lung cancer, ongoing research has further elucidated prognostic factors (14-16) and yielded several practical models (17,18). A particularly important contemporary goal is the identification of patient subgroups with exceptionally favorable outcomes, such as those with AIS, MIA, or pGGO. These patients exhibit long-term survival rates nearing 100% (19), implying an extremely low risk of recurrence. However, while these pre-invasive and minimally invasive entities are well-established as benchmarks of excellent prognosis, an analogous, evidence-based framework for identifying invasive NSCLC patients with similar curative potential has remained elusive. Existing models, designed primarily for broad risk stratification across heterogeneous cohorts, have not systematically targeted this specific population, leaving a critical gap in our ability to de-escalate care for those with invasive yet indolent disease.

In response to this unmet need, our study was designed to systematically identify patients within a defined “surgical curative time window” by extending the principle of curability, well-established for AIS/MIA/pGGO, to invasive NSCLC. We developed and validated a novel clinical model based on five clinicopathological variables, establishing the first pragmatic threshold for curative potential in this population. This tool identifies a distinct subset of patients with invasive stage I disease whose outcomes approach those of their pre-invasive counterparts. By translating probabilistic prognostic estimates into actionable clinical decisions, our model provides a widely applicable methodology to guide postoperative surveillance strategies, ultimately aiming to optimize resource allocation, reduce patient anxiety, and minimize unnecessary interventions for those with a highly favorable prognosis.

This study showed that when a patient meets four of the following five conditions, no recurrence is observed during the 5-year follow-up period. These criteria include: (I) female sex; (II) tumor size ≤2 cm; (III) solid component size ≤10 mm; (IV) presence of a GGO component; and (V) LPA histologic type. These patients have an extremely low risk of recurrence and can be considered surgically cured for practical purposes. A postoperative bedside chest X-ray showing well-inflated lungs would be adequate. Given their excellent prognosis, these patients could then come for a follow-up even more than 2 or 3 years later.

Moreover, our study indicates that certain patients can be identified before surgery. Specifically, female cT1N0 patients presenting with a GGO lesion measuring ≤2 cm in total size and with a solid component ≤1 cm fall within the curative time window and are expected to achieve definitive cure following surgical resection. Therefore, during the preoperative consultation, she can be fully informed of this situation. This information can be communicated during preoperative counseling to provide reassurance and help alleviate anxiety.

Currently, numerous international guidelines recommend that patients undergo follow-up every 6 months during the first 2 or 3 years after surgery. Each visit should include a review of medical history, physical examination, and preferably a contrast-enhanced chest CT scan, supplemented with an abdominal CT or ultrasound. From the third to the fifth year after surgery, follow-up is conducted annually with the same components. Even beyond 5 years, patients are still advised to continue standard follow-up examinations. However, for patients within the curative time window or those who possess the protective factors mentioned above, the intervals between follow-up imaging may be appropriately extended. In these cases, the primary aim of follow-up shifts from monitoring recurrence to detecting second primary tumors.

Therefore, our current research focuses on identifying this specific patient subgroup. By confirming that they have achieved curative outcomes through surgery, we can help alleviate their psychological burden and reduce the frequency of unnecessary hospital visits. Although the prognostic impact of reduced follow-up in this population remains incompletely understood—as existing studies mainly focus on general cohorts and often overlook long-term outcomes of patients lost to follow-up—initial tumor characteristics and treatment response can offer valuable insight into their long-term prognosis. Furthermore, previous research indicates that although intensive follow-up can detect recurrences earlier, it does not lead to improved survival compared with less-frequent regimens (20). Therefore, streamlining follow-up for selected patients may alleviate anxiety without compromising survival. Future studies should prioritize large-scale investigations into the long-term outcomes of patients who discontinue follow-up and develop more tailored surveillance strategies to obtain more comprehensive clinical evidence.

In the first stage, we identified key factors—including female sex, tumor size ≤2 cm, solid component ≤10 mm, LPA histologic type, and GGO component—that exhibited the highest odds ratios and population attributable risks, in order to establish broad risk categories suitable for initial triage. During the second stage, we focused on distinguishing between intermediate-risk and high-risk patients within the elevated-risk group. This more granular analysis incorporated additional factors—such as CTR and absence of LVI—which, though not significant in the primary model, improved predictive accuracy within this specific subgroup. The difference in key predictive factors between stages reflects the need for finer discrimination when stratifying elevated-risk patients.

In addition to patients with no recurrence during the 5-year follow-up, we also identified an intermediate-risk group (n=153), which exhibited a 5-year RFS rate of 97.3%. While some of these patients likely fall within the surgical curative time window, we cannot yet accurately identify all such individuals. For these patients, an appropriately extended follow-up strategy would be sufficient.

Furthermore, we have identified a subgroup within stage I NSCLC characterized by a less favorable prognosis (5-year RFS rate: 80.2%). This subgroup comprises patients who do not meet any of the following criteria: (I) female sex; (II) tumor size ≤2 cm; (III) LPA histologic type; (IV) presence of a GGO component; or (V) solid component size ≤10 mm. It is noteworthy that even among these high-risk patients, more than three-quarters will remain recurrence-free. Therefore, it remains reasonable to maintain a site-specific follow-up strategy for patients falling outside the surgical curative time window. Previous studies have developed prediction models based on clinicopathologic features to anticipate recurrence at specific sites in completely resected NSCLC patients (21-23). Accordingly, we recommend continuing a site-specific surveillance approach while appropriately extending the follow-up interval for this population.

Among the five criteria defining the surgical curative time window, LPA is characterized as a solitary adenocarcinoma exhibiting predominant lepidic growth with invasive foci greater than 0.5 cm (24). In addition, even tumors with predominant lepidic growth are classified as LPA if they demonstrate tumor necrosis, lymphovascular invasion, or VPI (9). Radiologically, LPA typically presents as a mixture of ground-glass and solid opacities on CT, corresponding to the invasive component of the lesion. It is well established that LPA is associated with an excellent prognosis (25). Favorable outcomes are also observed in patients whose tumors are not lepidic-predominant but still contain a lepidic component. The presence of any lepidic component identifies a subgroup of LUAD with notably superior survival (26). This is particularly relevant as early-stage LUAD frequently harbors a lepidic growth pattern (9,27,28). Supporting this, one study reported a 5-year OS rate of 95.2% in LUAD patients with a lepidic component, compared to 75.2% in those without (T1b: 94.9% vs. 83.5%, P<0.001; T1c: 93.8% vs. 72.8%, P<0.001; T2a: 93.0% vs. 57.6%, P<0.00) (26).

From a pathological perspective, although non-lepidic growth patterns may also present as GGO on CT imaging (29), LUAD with a GGO component remains associated with a higher survival rate compared to purely solid lesions. This observation is largely consistent with our findings, as the criteria described above—female sex, tumor size ≤2 cm, and CTR ≤0.5—collectively define a subgroup with notably favorable outcomes. The JCOG0201 trial has previously established that tumors exhibiting GGO components are generally associated with a more favorable prognosis (30,31).

In our cohort, the incidence of second primary lung cancer (SPLC) was 2.7%, which is lower than rates reported in previous literature. Although SPLC demonstrates distinct biological features—such as differences in driver mutation profiles—and necessitates specific management approaches (including bilateral screening), its relatively low prevalence in our study population precluded separate statistical analysis. For patients presenting with multifocal nodules, we recommend adopting individualized surveillance strategies, which may include more frequent imaging follow-up. Future studies should seek to clarify the mechanisms influencing SPLC risk and refine optimal nodule management protocols.

The current study has several limitations. First, it focused specifically on stage I invasive NSCLC, and the majority of patients (86.7%) in our center underwent lobectomy during the study period. Given the evolution of surgical techniques toward more limited resections, the influences of these advances on the prognostic performance of our model require further validation using updated and larger multi-institutional datasets. Second, as this was a single-center study conducted in a Chinese population, validations in larger and more diverse cohorts are necessary to evaluate the reliability and generalizability of the scoring system across populations with varying genetic backgrounds, environmental exposures, and smoking histories. Third, as established in the literature, pre-invasive and minimally invasive lesions—such as AIS, MIA, and pure GGO—have long served as benchmarks of excellent prognosis in NSCLC, typically representing early curative windows. These subtypes are associated not only with high 5-year RFS but also sustained durability beyond 10 years. Our model extends this favorable prognostic pattern to a select subgroup of invasive NSCLC, identifying patients whose 5-year recurrence risk mirrors that of these indolent subtypes. In fact, no recurrences were observed in our low-risk group within 5 years, providing a compelling rationale to anticipate similar long-term outcomes. Nevertheless, we recognize that longer-term follow-up extending to 10 years or more remains essential to confirm durability and better characterize late recurrence patterns. Further studies with extended observation are warranted to validate these findings. Fourth, while our model effectively distinguishes between low- and elevated-risk NSCLC patients using routinely available clinical variables, its ability to precisely define a “curative time window” within the elevated-risk subgroup remains limited. Future iterations that incorporate genetic profiling may enhance individualized risk stratification and improve the timing assessment for curative intervention in this population. Fifth, it should also be noted that smokers represented a minority of the study population (36.3%), which consisted predominantly of non-smokers (63.7%). Although smoking status was associated with RFS, the relatively small number of smokers limits further subgroup analysis and may affect the generalizability of the model to populations with higher smoking prevalence. In addition, interobserver variability among pathologists may introduce bias into pathological classification. Finally, although qualitative feedback suggested potential psychological benefits from reduced surveillance intensity, the absence of a formal psychometric evaluation represents a significant limitation. Future longitudinal studies should incorporate validated instruments such as the Hospital Anxiety and Depression Scale (32) to quantitatively assess psychological distress and its relationship to clinical outcomes in this setting.

Conclusions

We established a five-factor criterion (female sex, tumor size ≤2 cm, solid component ≤10 mm, GGO component, LPA histology) to define surgical curative time window in stage I invasive NSCLC. Patients meeting four or more criteria achieve a durable cure comparable to that of pre-invasive disease. This evidence supports extending follow-up intervals for this low-risk population, shifting surveillance focus from recurrence monitoring to detection of new primaries while reducing patient burden and healthcare utilization.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-894/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-894/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-894/prf

Funding: The study was supported by National Key R&D Program of China (No. 2022YFA1103900), National Natural Science Foundation of China (No. 82430099), the Clinical Research Special Project of Shanghai Municipal Health Commission (No. 202440070), and the Medical Research Special Project for Shanghai Science and Technology Innovation Action Plan (No. 24Y12800400).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-894/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 and its subsequent amendments. The study was approved by the Institutional Review Board of Fudan University Shanghai Cancer Center (approval No. IRB2008223-9; date: 14 July 2020). Informed consent was waived in this retrospective study.

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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