Long term survival and failure mode analysis of locally advanced lung squamous cell carcinoma

Long term survival and failure mode analysis of locally advanced lung squamous cell carcinoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Long term survival and failure mode analysis of locally advanced lung squamous cell carcinoma Zhongfei Jia, Jingchen Huo, Jie Yang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8387530/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective This study investigated long-term survival and identified associated prognostic factors in patients with locally advanced lung squamous cell carcinoma (LSCC).. Methods In this retrospective study, 278 patients with locally advanced LSCC and complete clinical and follow-up records were enrolled. The cohort comprised patients admitted to the Fourth Hospital of Hebei Medical University from January 2012 through December 2019. All statistical analyses, including the use of the χ² test for categorical data comparisons, were performed with IBM SPSS Statistics (version 25.0).The Kaplan-Meier method was applied to calculate OS, PFS1 and PFS2; univariate analysis by Logrank method; Cox model prognosis analysis.Survival curves for OS, PFS1, and PFS2 were generated using the Kaplan-Meier method and compared with the log-rank test. Finally, a multivariate Cox proportional hazards model was applied to identify independent prognostic factors, including all variables that showed significance in the univariate analysis. Results For the entire cohort, the 1-, 3-, 5-, and 10-year overall survival rates were 86.0%, 50.6%, 40.8%, and 24.2%, respectively. The PFS1 rates in the whole group 1、3、5、and 10 years were 63.6%、28.6%、20.8%、and 8.3%, respectively. The PFS2 rates in the whole group 1、3、5、and 10 years were 91.8%、70.9%、56.5%、and 49.4%, respectively. First disease progression: 238 cases of disease progression. Among them, Primary lesion progression 108 (45.3%), mediastinal and supraclavicular lymph node metastases 34 (14.2%), distant metastases 67 (28.1%) ,mixed metastases 29 (12.1%),and oligo metastases 77 (32.3%). Second disease progression: a total of 72 cases. Local progression 24 (33.3%), liver metastasis 6 (8.3%), bone metastasis 13(18.1%), lung metastasis 5(6.9%), brain metastasis 8(11.1%), mediastinal lymph node metastasis 5 (6.9%), adrenal metastasis 3(4.1%) and mixed metastasis 8 (11.1%). Cox multivariate analysis demonstrated that overall survival (OS) was independently predicted by age, lesion location, radiation pneumonitis, first-line treatment efficacy stratification, and PFS1 (all p < 0.05). Meanwhile, PFS1 was independently influenced by radiotherapy efficacy and the actual completed radiotherapy dose (p < 0.05). For PFS2, both PFS1 stratification and first-line treatment efficacy stratification were identified as independent prognostic factors. Conclusion The prognosis of LSCC remains poor; however, an evidence-based, integrated treatment approach can prolong survival. In our study, the choice of concurrent chemoradiotherapy ±consolidation chemotherapy can obtain better objective response rate[ORR（PR+CR）]; the efficacy of first-line therapy and PFS1 are important factors for survival.First-line treatment efficacy reaching CR or PR, PFS1≥12 months, could significantly prolong the survival. Local recurrence and distant metastasis constituted the main patterns of treatment failure. This study demonstrated that initiating radiotherapy early (within 3 months of diagnosis) significantly lowered the rates of these events. locally advanced lung squamous cell carcinoma（LSCC） Chemotherapy and radiotherapy Comprehensive treatment Prognosis Failure mode Figures Figure 1 Introduction In China, lung cancer remains the most common malignancy and the leading cause of cancer-related mortality. In 2022 alone, it was responsible for an estimated 1.06 million new cases and 733,000 deaths, constituting the primary cause of cancer death in the urban population. Contrary to the declining trends observed in some Western countries, the incidence of lung cancer in China continues to rise. This persistent increase poses a substantial public health and socioeconomic burden, necessitating coordinated efforts from government, industry, and the medical community.(1). Lung squamous cell carcinoma (LSCC) is a prevalent histological subtype, constituting approximately 30% of all non-small cell lung cancer (NSCLC) cases. For early-stage and locally advanced LSCC, the standard of care is primarily surgical resection, often supplemented with adjuvant radiotherapy or chemotherapy. In the advanced (metastatic) setting, systemic chemotherapy forms the mainstay of treatment. However, a significant clinical challenge arises when LSCC is diagnosed at an advanced, unresectable stage, where surgical intervention is often no longer feasible.(2).While the role of concurrent chemoradiotherapy (cCRT) in improving survival for unresectable stage III NSCLC is well-recognized and underscores the need for multidisciplinary management (3), far less is known about its long-term outcomes in patients with lung squamous cell carcinoma (LSCC).Therefore, we evaluated patients with locally advanced, unresectable LSCC treated with chemoradiotherapy, with the goal of defining their long-term survival outcomes, prognostic determinants, and predominant modes of treatment failure.. 1. Materials and Methods 1.1 Study Population The study cohort consisted of 278 patients with locally advanced lung squamous cell carcinoma (LSCC) treated at the Fourth Hospital of Hebei Medical University between 2012 and 2019. The inclusion criteria were defined as a diagnosis of locally advanced, unresectable LSCC with subsequent treatment involving radiotherapy, chemotherapy, or chemoradiotherapy. For all included patients, a curated dataset was compiled, which encompassed baseline demographics, detailed treatment parameters (radiotherapy dose/fractionation and chemotherapy regimens), treatment sequence, patterns of failure (recurrence and metastasis sites), and toxicity profiles. This study was approved by the institutional ethics committee and complied with the Declaration of Helsinki. Informed consent was waived for this retrospective analysis. 1.2 Treatment Protocols Given that the majority of patients were treated in the pre-immunotherapy era, the therapeutic strategies evaluated were radiotherapy and chemotherapy. The study cohort comprised patients suitable for radical treatment, with all patients having an ECOG performance status of 0–2 and thus being candidates for radiotherapy. Treatments administered included radiotherapy alone or concurrent chemoradiotherapy, while patients managed with palliative care due to poor performance status were not included. Chemotherapy regimens:Induction/concurrent/sequential chemotherapy: Cisplatin/carboplatin/lobaplatin combined with vinorelbine/paclitaxel/docetaxel/etoposide, or single-agent paclitaxel/docetaxel/tegafur (S-1). Radiotherapy :Technique: 6MV X-ray intensity-modulated radiotherapy (IMRT).Target delineation: Involved-field principles were applied.Gross tumor volume (GTV): Primary lung tumor (atelectasis excluded). GTVnd: Metastatic lymph nodes. Clinical tumor volume ( CTV ) : The GTVnd with a 6mm margin, modified according to anatomical barriers.Planning tumor volume ( PTV ) : The CTV with a further 5mm margin.Prescription dose: 95% PTV received 36–75 Gy in 20–36 fractions (1.8–2.0 Gy/fraction, 5 fractions/week). Median dose: 60 Gy. 1.3 Follow-up Patient follow-up was conducted through a combination of medical record reviews, outpatient clinic visits, and telephone interviews. Regular assessments included a detailed clinical history, physical examination, and standardized imaging studies. The latter consisted of chest and abdominal computed tomography (CT), brain magnetic resonance imaging (MRI), positron emission tomography-computed tomography (PET/CT), lymph node ultrasonography, and bone scintigraphy, as clinically indicated. Disease recurrence was confirmed either radiologically (via CT or MRI) or by pathological biopsy. The follow-up period was censored on July 1, 2024. The median follow-up duration for the cohort was 36.5 months (95% confidence interval [CI]: 28.8–46.7). Five patients (1.8%) were lost to follow-up, resulting in a follow-up completion rate of 98.2%. 1.4 Statistical Approach Statistical analyses were performed using IBM SPSS Statistics (Version 25.0). Categorical variables were compared with the chi-square (χ²) test. Overall survival (OS), progression-free survival after initial treatment (PFS1), and progression-free survival after salvage therapy (PFS2) were estimated using the Kaplan-Meier method, with comparisons made by the log-rank test in univariate analyses. Variables demonstrating significance (p < 0.05) in univariate analysis were subsequently entered into a multivariate Cox proportional hazards regression model. Tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), and treatment-related toxicities were graded based on the Radiation Therapy Oncology Group (RTOG) criteria. 2. Result 2.1 Characteristics and Treatment Completion The study enrolled 278 patients with pathologically confirmed locally advanced lung squamous cell carcinoma (LSCC) from the Fourth Hospital of Hebei Medical University. All enrolled patients had complete clinical and follow-up data and were treated between January 2012 and December 2019 (Table 1).Pathological features:Moderately/well-differentiated SCC: 186 cases；Poorly differentiated SCC: 87 cases；Adenosquamous carcinoma: 5 cases；Whole group:Male: 255 cases; Female: 23 cases；Median age: 64 years (range: 29–86)；Age <65: 136 cases；Age ≥65: 142 cases；Tumor location:Central: 204 cases；Peripheral: 74 cases；TNM staging (IASLC 8th edition):IIIA: 106 cases、IIIB: 121 cases、IIIC: 51 cases；First-line treatment completion:Concurrent chemoradiotherapy (cCRT)±consolidation: 49 cases (17.6%)、Sequential chemoradiotherapy: 16 cases (5.7%)、Radiotherapy alone: 63 cases (22.6%)、Induction chemotherapy + (chemo)radiotherapy/cCRT: 150 cases (54.1%)、Chemotherapy details:Median cycles:Induction: 3 (range: 1–6)、Concurrent: 1 (range: 1–3)、Consolidation: 2 (range: 1–6)；Regimens:GP (gemcitabine + cisplatin): 56 cases、DP (docetaxel + cisplatin): 53 cases、TP (paclitaxel + cisplatin): 84 cases、EP (etoposide + cisplatin): 12 cases；Radiotherapy details:3D conformal radiotherapy (3D-CRT): 93 cases (33.4%)、Intensity-modulated radiotherapy (IMRT): 185 cases (66.6%)；Completion rate: 96.7% . 2.2 Treatment Response and Adverse Events Post-radiotherapy response:Complete response (CR): 9 cases (3.2%)、Partial response (PR): 181 cases (65.1%)、Stable disease (SD): 84 cases (30.2%)、Progressive disease (PD): 4 cases (1.4%).Radiation toxicities:Radiation pneumonitis: 84 cases (30.2%)：Grade 1: 62 cases (73.8%)、Grade 2: 18 cases (21.4%)、Grade 3: 4 cases (4.7%);Radiation esophagitis: 98 cases (35.2%)：Grade 1: 79 cases (80.6%)、Grade 2: 18 cases (18.3%)、Grade 3: 1 case (1.9%). 2.3 Disease Progression and Second-line Treatment First progression (238 cases):Lung progression: 108 cases (45.3%)、Mediastinal/supraclavicular lymph node metastasis: 34 cases (14.2%)、Distant metastasis: 67 cases (28.1%)、Mixed progression: 29 cases (12.1%)、Oligometastasis: 77 cases (32.3%).PFS1 stratification:PFS1 <12 months (98 cases):Locoregional recurrence/mediastinal nodal metastasis: 46 cases (46.9%)、Lung/distant metastasis: 46 cases (46.9%)、Mixed progression: 6 cases (6.2%)；PFS1 ≥12 months (140 cases):Locoregional recurrence/mediastinal nodal metastasis: 80 cases (57.1%)、Lung/distant metastasis: 48 cases (34.2%)、Mixed progression: 12 cases (8.5%)..PFS1 analysis: Patients with PFS1 ≥12 months had significantly reduced recurrence/metastasis compared to PFS1<12 months (p<0.001).Second-line treatment:Chemotherapy: 80 cases、Radiotherapy: 56 cases、Chemoradiotherapy: 70 cases、Surgery: 18 cases；Comprehensive therapy:Apatinib (anti-angiogenic): 2 cases、Sintilimab (PD-1 inhibitor): 2 cases、Supportive care:Bone metastasis treatment 4 cases: 2 cases；Traditional Chinese medicine: 2 cases；Treatment discontinuation: 5 cases；Targeted therapy (gefitinib/erlotinib): 2 cases. The location of the second progression and treatment status: a total of 72 cases. 24 cases (33.3%) had local progression, 6 cases (8.3%) liver metastasis, 13 (18.1%) bone metastasis, 5 (6.9%) lung metastasis, 8 (11.1%) brain metastasis, 5 (6.9%) mediastinal lymph node metastasis, 8 cases (11.1%) mixed metastasis, and 3 cases (4.1%) adrenal metastasis. After treatment, the efficacy was evaluated in 29 cases of PR, 41 cases of SD, and 2 cases of PD. 2.4 Survival and prognosis analysis Overall survival (OS) rates at 1, 3, 5, and 10 years for the entire cohort were 86.0%, 50.6%, 40.8%, and 24.2%, respectively(Fig 1). The PFS1 rates for the entire cohort at 1, 3, 5, and 10 yearswere 63.6%, 28.6%, 20.8%, and 8.3%, respectively. The PFS2 rates for the entire cohort at 1, 3, 5, and 10 years were 91.8%, 70.9%, 56.5%, and 49.4%, respectively. Univariate analysis of OS (Table2): Smoking (p=0.012), age (p=0.004), lesion location (p=0.001), chemotherapy (p=0.026), radiation pneumonitis (p=0.041), first-line treatment efficacy (p<0.001), PFS1 stratification (p<0.001) were associated with OS (p<0.05), while gender, ECOG score, family history of malignancy, pathological differentiation degree, T stage, N stage, TNM stage, and radiotherapy timing were not associated with OS. Multivariate Cox analysis (Table 3): Age (p<0.001), lesion location (p=0.002), radiation pneumonitis (p=0.048), first-line treatment efficacy stratification (p<0.001), and PFS1 stratification (p<0.001) are independent prognostic factors for overall survival (p<0.05). Among them, patients under 65 years old, peripheral lung cancer, non radiation pneumonitis, first-line treatment efficacy CR or PR, receiving chemotherapy, and PFS1 ≥ 12 months had longer OS (p0.05). Univariate analysis of PFS (Table 4): Smoking (p=0.005), alcohol consumption (p=0.002), lesion location (p=0.001), radiation pneumonitis (p=0.045), actual completed dose of radiotherapy (p=0.017), and recent efficacy (p=0.001) were associated with PFS1 (p<0.05), while gender, age, ECOG score, chemotherapy status, family history of malignancy, degree of pathological differentiation, T stage, N stage, and TNM stage were not associated with PFS1. Multivariate Cox analysis (Table 5): Radiotherapy efficacy (p=0.044) and actual completed dose of radiotherapy (p=0.020) are independent prognostic factors for PFS1 (p<0.05). Patients who received radiation therapy and had a CR or PR response, with a radiation dose of ≥ 60Gy, had a longer PFS1 (p<0.05). χ 2 test: Patients who received chemotherapy had better short-term response (CR+PR) (p<0.05), indicating a correlation between chemotherapy and treatment failure patterns. Patients who received chemotherapy had a lower incidence of distant metastasis (p<0.05). Comparison of first-line treatment options: Objective response rate ORR (CR+PR):synchronous radiochemotherapy±consolidation chemotherapy was 35 cases (71.4%),sequential radiochemotherapy was 8 cases (50%), radiotherapy alone was 23 cases (36.5%),induction chemotherapy+radiochemotherapy/synchronous radiochemotherapy was 92 cases (63.1%), and the efficacy of synchronous radiochemotherapy±consolidation chemotherapy was better (p<0.05). PFS1 stratified analysis showed that recurrence and metastasis were reduced in PFS1 ≥12 months compared to PFS1<12 months (p<0.001). Univariate analysis of PFS2 (Table 6): PFS1 stratification (p=0.001) and first-line treatment efficacy stratification (p=0.002) were associated with PFS2 (p<0.05). Gender, age, smoking, alcohol consumption, degree of pathological differentiation, tumor location, T stage, N stage, TNM stage, initial treatment plan, chemotherapy or not, actual completed dose of radiotherapy, radiotherapy technique, radiation pneumonia, radiation esophagitis are not related to PFS2. Multivariate analysis (Table 7): PFS1 stratification and first-line treatment efficacy stratification are independent prognostic factors affecting PFS2 (p<0.05). For cases with first-line treatment efficacy of CR and PR, if PFS1≥12 months, their PFS2 is longer and less likely to recur (p<0.05). χ 2 test: In cases of initial diagnosis with multiple lymph node metastases, the interval between PFS1 and PFS2 was shorter than that of single lymph node metastases (p<0.05), indicating that multiple lymph node metastases (168 cases) were more prone to recurrence and metastasis than single lymph node metastases (110 cases), but there was no statistical difference in OS. Patients with first-line treatment efficacy of CR and PR have longer intervals between PFS1 and PFS2 (p<0.05), while patients with PD and SD are more prone to disease progression (p<0.05). The interval between radiotherapy and initial diagnosis also has an impact on the efficacy of radiotherapy. The objective response rates (PR+CR) for radiotherapy and initial diagnosis intervals of less than 3 months and ≥3 months were 72.9% and 57.0%, respectively (p<0.05). 3. Discussion 3.1 Survival and prognosis analysis Lung cancer, the most prevalent malignancy worldwide, is frequently diagnosed at a locally advanced or metastatic stage. For inoperable, locally advanced non-small cell lung cancer (NSCLC), concurrent chemoradiotherapy has served as the cornerstone of treatment for three decades. Nevertheless, the 5-year overall survival rate has plateaued at approximately 30%, underscoring a critical and enduring therapeutic challenge.(4). The cohort of 278 patients with locally advanced NSCLC treated non-surgically exhibited 1-, 3-, and 5-year overall survival rates of 86.0%, 50.6%, and 40.0%, respectively, with a median overall survival of 37.8 months. Previous studies:Large-scale, comprehensive data on radical radiotherapy (RT) for locally advanced non-small cell lung cancer (LA-NSCLC) in the Chinese population remains scarce.. In this cohort of 789 patients receiving definitive radiotherapy, cCRT was administered to 42.0%, sCRT to 49.3%, and radiotherapy alone to 8.7%. The median overall survival was 31 months. The 1-, 2-, 5-, and 10-year OS rates were 83.7%, 59.5%, 28.8%, and 18.9%, while the PFS rates were 48.0%, 24.5%, 11.9%, and 5.5%, respectively. The integration of chemotherapy with radiotherapy and the total radiation dose were independent predictors of PFS, suggesting that this combination conferred a survival advantage(5). Saartje Verfaillie et al. analyzed 163 patients diagnosed with unresectable stage III NSCLC. Treatment modalities included concurrent CRT for 108 patients and sequential CRT for the remaining 55. The cohort achieved a median PFS of 13.2 months (95% CI: 10.3-16.2) and a median OS of 23.3 months (95% CI: 18.3-28.0), with 2-year and 5-year overall survival rates of 47.5% and 29.4%(6). The KINDLE study, which enrolled 1,046 patients with stage III NSCLC from Turkey, Egypt, Kuwait, and the United Arab Emirates, demonstrated superior outcomes for concurrent chemoradiotherapy (cCRT). Patients receiving cCRT achieved a median progression-free survival (mPFS) of 12.7 months (95% CI: 10.51–16.10) and a median overall survival (mOS) of 26.9 months (95% CI: 19.48–33.68), yielding a significant advantage over sequential CRT (mPFS: 9.5 months; mOS: 17.4 months), chemotherapy alone (mPFS: 6.7 months; mOS: 14.3 months), or radiotherapy alone (mPFS: 8.1 months; mOS: 12.3 months).(7).Our key outcomes are in line with the collective findings of prior research.This improvement in survival may be attributed to our intensified, multimodal treatment regimen. Beyond the standard concurrent chemoradiotherapy, the protocol incorporated either induction chemotherapy or a combination of consolidation chemotherapy with concurrent chemoradiotherapy. This approach enhanced overall treatment intensity, which likely contributed to the superior patient outcomes observed. However, the retrospective nature of this study imposes inherent limitations. Notably, there was heterogeneity in the chemotherapy regimens and the number of cycles administered. Furthermore, treatment strategies after disease progression varied considerably based on individual patient status. Consequently, our analyses provide general comparative findings rather than definitive conclusions regarding specific induction chemotherapy cycles or regimens. These specific comparisons warrant validation through prospective, randomized controlled trials. 3.2 Recent efficacy and prognosis analysis The efficacy of first-line treatment in this study is also an important prognostic factor. The 1-year, 3-year, 5-year, and 10-year overall survival rates of CR+PR and SD+PD with first-line treatment efficacy were 94.3%, 60.0%, 50.5%, 31.8%, and 75.0%, 39.2%, 28.3%, and 15.1%, respectively (P<0.001). The PFS1 rates of CR+PR and SD+PD at 1, 3, 5, and 10 years were 66.1%, 31.9%, 23.7%, 10.9%, and 56.8%, 21.3%, 17.6%, and 3.9%, respectively (p=0.039). Multivariate Cox analysis confirmed the independent prognostic value of first-line treatment efficacy for overall survival (OS). The research results showed that patients with CR+PR first-line treatment had significantly longer OS and longer PFS1 to PFS2 intervals (p<0.05) compared to SD+PD, making them less likely to relapse. SD and PD are more prone to disease progression (p<0.05). Our results indicate that the primary tumor location and the interval from diagnosis to radiotherapy (DTR) impact both OS and therapeutic outcomes. Notably, a shorter DTR was linked to significantly better responses. The objective response rate (ORR) was 72.9% for patients with a DTR of <3 months, versus 57.0% for those with a DTR of ≥3 months (p < 0.05), clearly demonstrating the efficacy advantage of earlier radiotherapy intervention..The 5- and 10-year OS rates for peripheral lung cancer were 46.2% and 36.2%, respectively, while those for central lung cancer were 35.1% and 19.4%, respectively. Peripheral lung cancer had a significantly better prognosis (p=0.001). This particular finding, however, has not been extensively reported in the existing literature (e.g., PubMed), highlighting a knowledge gap that future studies should aim to address. 3.3 Treatment mode, toxic side effects, and prognosis analysis The NCCN guidelines strongly recommend definitive chemoradiotherapy for inoperable, locally advanced NSCLC, with a stronger recommendation for the concurrent approach over the sequential regimen..Hong Mei meta-analysis of 14 RCTs (2634 patients with NSCLC) , Compared with sequential chemoradiotherapy, concurrent chemoradiotherapy (cCRT) did not improve the 1-year survival rate but significantly enhanced long-term outcomes, with higher survival rates at 2 to 5 years. cCRT also significantly reduced the risk of locoregional relapse, although it did not affect distant relapse rates, and was associated with higher overall response rates. However, these benefits were accompanied by increased toxicities, including esophagitis, nausea/vomiting, and hematological suppression(8). While concurrent chemoradiotherapy (cCRT) is broadly defined by the simultaneous delivery of chemotherapy and radiotherapy, its operational definition in clinical practice lacks uniformity. Variations exist in the specific criteria used, ranging from a strict requirement to start both modalities on the same day (typically chemotherapy cycle 1, day 1) to more flexible protocols allowing one to two cycles of chemotherapy to be administered during the radiotherapy course. Yu et al. (2020–2022) compared concurrent chemoradiotherapy (CCRT, n=80) with sequential chemoradiotherapy (SCRT, n=78) in 158 patients with NSCLC. The CCRT group demonstrated superior treatment responses, with significantly higher remission rates (90.00% vs 74.36%) and disease control rates (96.25% vs 89.74%; both P 0.05), while both progression-free survival and overall survival were significantly prolonged in the CCRT group (P < 0.05) (9). Consolidation with concurrent chemoradiotherapy (cCRT) provided significant survival benefits over radiotherapy alone in a study by Zhao et al. involving 65 stage III NSCLC patients who had received initial chemoimmunotherapy. Patients receiving cCRT (n=21) showed markedly better outcomes than those receiving RT alone (n=44) across all endpoints: PFS (HR=0.155, p=0.004), LPFS (HR=0.225, p=0.029), and DMFS (HR=0.028, p=0.006).Albeit nonsignificant, a trend toward improved OS (HR = 0.030, p = 0.069) was also observed in the cCRT group. The multivariate analysis further confirmed that cCRT (HR = 0.141, p = 0.008) was the independent factor for promoting a favorable PFS. Treatment-related adverse events were similar between groups (p > 0.05). Patients with consolidation immunotherapy exhibited a trend of improved PFS (HR = 0.398, p = 0.274) and numerically better OS (HR = 0.018, p = 0.209) compared with those without(10).Although we have entered the era of immunity, the efficacy of concurrent radiotherapy and chemotherapy can still serve as a prognostic model. Dirk De Ruysscher established a prognostic model developed to identify patients with a high risk of early mortality associated with CRT. These individuals represent potential candidates for clinical trials aimed at enhancing their survival.(11). The integration of immune checkpoint inhibitors into oncology has added further nuance to the treatment of advanced NSCLC. In a multinational survey of thoracic oncologists from 11 countries, experts reported that a median of 66% (IQR 60–75) of stage III patients receive chemoradiotherapy. Of these, roughly two-thirds undergo cCRT and one-third sCRT. Although durvalumab is reimbursed in all included health systems, its utilization is constrained in some settings by requirements such as PD-L1 ≥1% and prior cCRT(12). Treatment decision-making for stage III NSCLC remains a nuanced and heterogeneous process, even in the current era of consolidation immunotherapy after CRT.A French observational study evaluated real-world practices in stage III NSCLC using data from 414 eligible patient charts. Disease staging was 53% IIIA, 37% IIIB, and 10% IIIC, and PD-L1 testing was completed for 98% of the cohort. Of the 292 patients with unresectable disease, 190 (65%) received CRT followed by consolidation immunotherapy. Specifically, concurrent CRT was utilized in 52% of these cases, compared to 13% for sequential CRT. (13) . In contrast to the studies above, a French national multicenter cohort reported similar long-term outcomes for patients receiving sequential versus concurrent chemoradiotherapy.The radiotherapy-alone group, characterized by features such as advanced age, lower body weight, and increased COPD frequency, appeared to be the most vulnerable, underscoring that prolonged survival may be achieved through careful patient selection(14). In our study, synchronous radiochemotherapy±consolidation chemotherapy showed better short-term efficacy, but the 5- and 10-year survival rates were similar between the groups. Meanwhile, through χ2 test, The addition of chemotherapy to first-line and subsequent second-line treatment was associated with a significant extension of not only PFS1 but also the interval to PFS2..This suggests that chemotherapy plays an important role in both first-line and second-line treatments. 3.4 Analysis of Failure Modes Our study revealed that patients presenting with multi-site lymph node metastasis at initial diagnosis experienced a significantly shorter interval between the first and second disease progression (PFS1 to PFS2) compared to those with single-site involvement (p < 0.05). This finding suggests that multi-site nodal disease may be associated with a more aggressive tumor biology, conferring a higher propensity for recurrence and metastasis. Although the combined modality of radiotherapy and chemotherapy extended both OS and PFS, an analysis of failure patterns revealed a consistent trend: regardless of treatment approach (radiotherapy alone or chemoradiotherapy) or radiation dose (≥60 Gy or <60 Gy), disease progression occurred predominantly in the lungs and in mediastinal/supraclavicular lymph nodes (over 50% of cases). No statistically significant differences were observed across subgroups. It may also be related to the imbalance of our enrolled patients. However, our prior analysis established that first-line treatment response is a critical prognostic factor for recurrence, and that early radiotherapy intervention can reduce its incidence. Taken together, these findings In summary, while the overall prognosis of LSCC in this retrospective cohort—treated predominantly with radiotherapy and chemotherapy in the pre-immunotherapy era—remains poor, our findings demonstrate that a judicious multimodal regimen can nevertheless confer a meaningful survival benefit. In our study, choosing synchronous radiochemotherapy±consolidation chemotherapy as first-line treatment can achieve better objective response rate ORR (PR+CR); The efficacy of first-line treatment and PFS1 are important factors affecting patient prognosis. The efficacy of first-line treatment reaches CR or PR, PFS1≥12 months, and survival is significantly prolonged. The failure mode is mainly characterized by local recurrence and metastasis. Early radiotherapy intervention (within 3 months of initial diagnosis) is associated with a marked reduction in the incidence of local recurrence and distant metastasis, thereby potentially improving disease control outcomes. Abbreviations NSCLC:non-small cell lung cancer LSCC:lung squamous cell carcinoma cCRT:concurrent chemoradiotherapy ORR: objective response rate CR: complete response PR:partial response SD: stable disease PD:progressive disease OS:overall survival PFS1:progression-Free Survival 1 PFS2:progression-Free Survival 2 IMRT:intensity-modulated radiotherapy GTV:gross tumor volume GTVnd: metastatic lymph nodes CTV:clinical tumor volume PTV:planning tumor volume CT:computed tomography MRI,:brain magnetic resonance imaging PET/CT:positron emission tomography-computed tomography Locoregional recurrence: supraclavicular/mediastinal lymph nodes or lung progression Distant metastasis: any extracranial/extrathoracic site Mixed failure: concurrent locoregional and distant recurrence Oligometastasis: single-organ metastasis RECIST:response evaluation criteria in solid tumors RTOG):Radiation Therapy Oncology Group Declarations Ethics approval and consent to participate : This retrospective study was conducted in accordance with our Ethics Committee（The Committee of the Fourth Hospital of Hebei Medical University）， approved by our Institutional Review Board, and complied with the Declaration of Helsinki. Informed consent was waived for this retrospective analysis. C onsent for publication: Not Applicable. V ailability of data and material: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests: The authors declare that they have no competing interests. Financial Disclosure or Funding: S&TProgramofHebei,Serial Number：2026343 Author contributions: Zhongfei Jia:Statistical analysis、Manuscript preparation Jingchen Huo:Data acquisition、Data analysis Jie Yang：Concepts、Design、Definition of intellectual content、Manuscript review Acknowledgments: Sincere thanks to our hospital's treatment team for their outstanding contributions, and heartfelt gratitude to every author for their dedicated efforts. References Wu F, Wang L, Zhou C. Lung cancer in China: current and prospect. Curr Opin Oncol. 2021 Jan;33(1):40-46. doi: 10.1097/CCO.0000000000000703 Guo Q, Liu L, Chen Z, Fan Y, Zhou Y, Yuan Z, et al. 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Concurrent chemoradiotherapy versus radiotherapy alone after induction chemoimmunotherapy for stage III NSCLC patients who did not undergo surgery: a single institution retrospective study. Radiat Oncol. 2023 Jul 25;18(1):122. doi: 10.1186/s13014-023-02305-5. Vaes RDW, Cortiula F, Lyu S，et al. Chemoradiotherapy efficacy in patients with stage III non-small cell lung cancer (NSCLC): A prognostic clinical and biomarker-based model. Lung Cancer. 2025 May;203:108541. doi: 10.1016/j.lungcan.2025.108541.. Agbarya A, Shalata W, Addeo A，et al. Real-World Journey of Unresectable Stage III NSCLC Patients: Current Dilemmas for Disease Staging and Treatment. J Clin Med. 2022 Mar 21;11(6):1738. doi: 10.3390/jcm11061738. Auliac JB, Greillier L, Martin E，et al.Profiles, diagnostic process, and patterns of care of patients with stage III non-small cell lung cancer: A French national study. Respir Med Res. 2024 Jun;85:101087. doi: 10.1016/j.resmer.2024.101087. Girard N, Perol M, Simon G，et al. Treatment strategies for unresectable locally advanced non-small cell lung cancer in the real-life ESME cohort. Lung Cancer. 2021 Dec;162:119-127. doi: 10.1016/j.lungcan.2021.10.017. Tables Tables 1 to 7 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files table.doc Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8387530","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":597663550,"identity":"1294afee-9350-4deb-9657-19387836004d","order_by":0,"name":"Zhongfei Jia","email":"","orcid":"","institution":"The Fourth Hospital of Hebei Medical University and Hebei Province Tumor Hospital, Hebei Clinical Research Center for Radiation Oncology","correspondingAuthor":false,"prefix":"","firstName":"Zhongfei","middleName":"","lastName":"Jia","suffix":""},{"id":597663551,"identity":"7ab735ed-6f07-4ead-8595-f28ddbedbb0d","order_by":1,"name":"Jingchen Huo","email":"","orcid":"","institution":"The Fourth Hospital of Hebei Medical University and Hebei Province Tumor Hospital, Hebei Clinical Research Center for Radiation Oncology","correspondingAuthor":false,"prefix":"","firstName":"Jingchen","middleName":"","lastName":"Huo","suffix":""},{"id":597663552,"identity":"0b42a972-df3c-41c2-9784-34ac6f9a283a","order_by":2,"name":"Jie Yang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9klEQVRIiWNgGAWjYDCCAwhm4mMYV4KAFsYGKDPZmGQtbNJEaeE73vz8wcc9h+XN+Rc8qy6ouBNtcID54G0eBrs8XFokzxwzbJzx7LDhzhkP0m7POPMsd8MBtmRrHobkYlxaDG7kMDbzHDjMuOHGgbTbvG2HgVp4zKR5GA4kNhDQYg/SUsz7D6SF/xtRWhI3nG9IY+ZtANvChlcLyC8zZxxIT95wgyFZmufYs9yZh9mMLecYJOPUAgyxBx8+HLC23XD+TOJnnpo7uX3Hmx/eeFNhh1MLFDQD4yInAcJmBjsYv3ogqGNg4D9+gKCyUTAKRsEoGJkAADAEaTXKNHGEAAAAAElFTkSuQmCC","orcid":"","institution":"The Fourth Hospital of Hebei Medical University and Hebei Province Tumor Hospital, Hebei Clinical Research Center for Radiation Oncology","correspondingAuthor":true,"prefix":"","firstName":"Jie","middleName":"","lastName":"Yang","suffix":""}],"badges":[],"createdAt":"2025-12-17 17:06:55","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8387530/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8387530/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104170031,"identity":"3416ca47-c8ac-4478-8325-9909bd193d0a","added_by":"auto","created_at":"2026-03-08 14:42:55","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":168322,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival curves of 278 patients with locally advanced lung squamous cell carcinoma\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8387530/v1/f64dc735b10abcd901520670.png"},{"id":108572217,"identity":"229a25c9-f23c-4256-8881-44a0baed27ef","added_by":"auto","created_at":"2026-05-06 06:26:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":327420,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8387530/v1/4503b4cd-c296-46dd-8ade-159b159aeb39.pdf"},{"id":104170029,"identity":"c82020e7-e7d6-4e17-8ac8-d171fcaef83c","added_by":"auto","created_at":"2026-03-08 14:42:55","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":111616,"visible":true,"origin":"","legend":"","description":"","filename":"table.doc","url":"https://assets-eu.researchsquare.com/files/rs-8387530/v1/79f4ce3c0e6b49888ba3ec9f.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eLong term survival and failure mode analysis of locally advanced lung squamous cell carcinoma\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIn China, lung cancer remains the most common malignancy and the leading cause of cancer-related mortality. In 2022 alone, it was responsible for an estimated 1.06 million new cases and 733,000 deaths, constituting the primary cause of cancer death in the urban population. Contrary to the declining trends observed in some Western countries, the incidence of lung cancer in China continues to rise. This persistent increase poses a substantial public health and socioeconomic burden, necessitating coordinated efforts from government, industry, and the medical community.(1).\u003c/p\u003e\n\u003cp\u003eLung squamous cell carcinoma (LSCC) is a prevalent histological subtype, constituting approximately 30% of all non-small cell lung cancer (NSCLC) cases. For early-stage and locally advanced LSCC, the standard of care is primarily surgical resection, often supplemented with adjuvant radiotherapy or chemotherapy. In the advanced (metastatic) setting, systemic chemotherapy forms the mainstay of treatment. However, a significant clinical challenge arises when LSCC is diagnosed at an advanced, unresectable stage, where surgical intervention is often no longer feasible.(2).While the role of concurrent chemoradiotherapy (cCRT) in improving survival for unresectable stage III NSCLC is well-recognized and underscores the need for multidisciplinary management (3), far less is known about its long-term outcomes in patients with lung squamous cell carcinoma (LSCC).Therefore, we evaluated patients with locally advanced, unresectable LSCC treated with chemoradiotherapy, with the goal of defining their long-term survival outcomes, prognostic determinants, and predominant modes of treatment failure..\u003c/p\u003e"},{"header":"1. Materials and Methods","content":"\u003ch4\u003e1.1 Study Population\u003c/h4\u003e\n\u003cp\u003eThe study cohort consisted of 278 patients with locally advanced lung squamous cell carcinoma (LSCC) treated at the Fourth Hospital of Hebei Medical University between 2012 and 2019. The inclusion criteria were defined as a diagnosis of locally advanced, unresectable LSCC with subsequent treatment involving radiotherapy, chemotherapy, or chemoradiotherapy. For all included patients, a curated dataset was compiled, which encompassed baseline demographics, detailed treatment parameters (radiotherapy dose/fractionation and chemotherapy regimens), treatment sequence, patterns of failure (recurrence and metastasis sites), and toxicity profiles.\u003c/p\u003e\n\u003cp\u003eThis study was approved by the institutional ethics committee and complied with the Declaration of Helsinki. Informed consent was waived for this retrospective analysis.\u003c/p\u003e\n\u003ch4\u003e1.2 Treatment Protocols\u003c/h4\u003e\n\u003cp\u003eGiven that the majority of patients were treated in the pre-immunotherapy era, the therapeutic strategies evaluated were radiotherapy and chemotherapy. The study cohort comprised patients suitable for radical treatment, with all patients having an ECOG performance status of 0\u0026ndash;2 and thus being candidates for radiotherapy. Treatments administered included radiotherapy alone or concurrent chemoradiotherapy, while patients managed with palliative care due to poor performance status were not included.\u003c/p\u003e\n\u003cp\u003eChemotherapy regimens:Induction/concurrent/sequential chemotherapy: Cisplatin/carboplatin/lobaplatin combined with vinorelbine/paclitaxel/docetaxel/etoposide, or single-agent paclitaxel/docetaxel/tegafur (S-1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRadiotherapy\u003c/strong\u003e:Technique: 6MV X-ray intensity-modulated radiotherapy (IMRT).Target delineation: Involved-field principles were applied.Gross tumor volume (GTV): Primary lung tumor (atelectasis excluded).\u003cstrong\u003eGTVnd:\u003c/strong\u003e Metastatic lymph nodes. Clinical tumor volume (\u003cstrong\u003eCTV\u003c/strong\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e The GTVnd with a 6mm margin, modified according to anatomical barriers.Planning tumor volume (\u003cstrong\u003ePTV\u003c/strong\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e The CTV with a further 5mm margin.Prescription dose: 95% PTV received 36\u0026ndash;75 Gy in 20\u0026ndash;36 fractions (1.8\u0026ndash;2.0 Gy/fraction, 5 fractions/week). Median dose: 60 Gy.\u003c/p\u003e\n\u003ch4\u003e1.3 Follow-up\u003c/h4\u003e\n\u003cp\u003ePatient follow-up was conducted through a combination of medical record reviews, outpatient clinic visits, and telephone interviews. Regular assessments included a detailed clinical history, physical examination, and standardized imaging studies. The latter consisted of chest and abdominal computed tomography (CT), brain magnetic resonance imaging (MRI), positron emission tomography-computed tomography (PET/CT), lymph node ultrasonography, and bone scintigraphy, as clinically indicated. Disease recurrence was confirmed either radiologically (via CT or MRI) or by pathological biopsy. The follow-up period was censored on July 1, 2024. The median follow-up duration for the cohort was 36.5 months (95% confidence interval [CI]: 28.8\u0026ndash;46.7). Five patients (1.8%) were lost to follow-up, resulting in a follow-up completion rate of 98.2%.\u003c/p\u003e\n\u003ch4\u003e1.4\u0026nbsp;Statistical Approach\u003c/h4\u003e\n\u003cp\u003eStatistical analyses were performed using IBM SPSS Statistics (Version 25.0). Categorical variables were compared with the chi-square (\u0026chi;\u0026sup2;) test. Overall survival (OS), progression-free survival after initial treatment (PFS1), and progression-free survival after salvage therapy (PFS2) were estimated using the Kaplan-Meier method, with comparisons made by the log-rank test in univariate analyses. Variables demonstrating significance (p \u0026lt; 0.05) in univariate analysis were subsequently entered into a multivariate Cox proportional hazards regression model. Tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), and treatment-related toxicities were graded based on the Radiation Therapy Oncology Group (RTOG) criteria.\u003c/p\u003e"},{"header":"2. Result","content":"\u003cp\u003e\u003cstrong\u003e2.1 Characteristics and Treatment Completion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study enrolled 278 patients with pathologically confirmed locally advanced lung squamous cell carcinoma (LSCC) from the Fourth Hospital of Hebei Medical University. All enrolled patients had complete clinical and follow-up data and were treated between January 2012 and December 2019\u0026nbsp;(Table 1).Pathological features:Moderately/well-differentiated SCC: 186 cases；Poorly differentiated SCC: 87 cases；Adenosquamous carcinoma: 5 cases；Whole group:Male: 255 cases; Female: 23 cases；Median age: 64 years (range: 29\u0026ndash;86)；Age \u0026lt;65: 136 cases；Age \u0026ge;65: 142 cases；Tumor location:Central: 204 cases；Peripheral: 74 cases；TNM staging (IASLC 8th edition):IIIA: 106 cases、IIIB: 121 cases、IIIC: 51 cases；First-line treatment completion:Concurrent chemoradiotherapy (cCRT)\u0026plusmn;consolidation: 49 cases (17.6%)、Sequential chemoradiotherapy: 16 cases (5.7%)、Radiotherapy alone: 63 cases (22.6%)、Induction chemotherapy + (chemo)radiotherapy/cCRT: 150 cases (54.1%)、Chemotherapy details:Median cycles:Induction: 3 (range: 1\u0026ndash;6)、Concurrent: 1 (range: 1\u0026ndash;3)、Consolidation: 2 (range: 1\u0026ndash;6)；Regimens:GP (gemcitabine + cisplatin): 56 cases、DP (docetaxel + cisplatin): 53 cases、TP (paclitaxel + cisplatin): 84 cases、EP (etoposide + cisplatin): 12 cases；Radiotherapy details:3D conformal radiotherapy (3D-CRT): 93 cases (33.4%)、Intensity-modulated radiotherapy (IMRT): 185 cases (66.6%)；Completion rate: 96.7% .\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2 Treatment Response and Adverse Events\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePost-radiotherapy response:Complete response (CR): 9 cases (3.2%)、Partial response (PR): 181 cases (65.1%)、Stable disease (SD): 84 cases (30.2%)、Progressive disease (PD): 4 cases (1.4%).Radiation toxicities:Radiation pneumonitis: 84 cases (30.2%)：Grade 1: 62 cases (73.8%)、Grade 2: 18 cases (21.4%)、Grade 3: 4 cases (4.7%);Radiation esophagitis: 98 cases (35.2%)：Grade 1: 79 cases (80.6%)、Grade 2: 18 cases (18.3%)、Grade 3: 1 case (1.9%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.3 Disease Progression and Second-line Treatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFirst progression (238 cases):Lung progression: 108 cases (45.3%)、Mediastinal/supraclavicular lymph node metastasis: 34 cases (14.2%)、Distant metastasis: 67 cases (28.1%)、Mixed progression: 29 cases (12.1%)、Oligometastasis: 77 cases (32.3%).PFS1 stratification:PFS1 \u0026lt;12 months (98 cases):Locoregional recurrence/mediastinal nodal metastasis: 46 cases (46.9%)、Lung/distant metastasis: 46 cases (46.9%)、Mixed progression: 6 cases (6.2%)；PFS1 \u0026ge;12 months (140 cases):Locoregional recurrence/mediastinal nodal metastasis: 80 cases (57.1%)、Lung/distant metastasis: 48 cases (34.2%)、Mixed progression: 12 cases (8.5%)..PFS1 analysis: Patients with PFS1 \u0026ge;12 months had significantly reduced recurrence/metastasis compared to PFS1\u0026lt;12 months (p\u0026lt;0.001).Second-line treatment:Chemotherapy: 80 cases、Radiotherapy: 56 cases、Chemoradiotherapy: 70 cases、Surgery: 18 cases；Comprehensive therapy:Apatinib (anti-angiogenic): 2 cases、Sintilimab (PD-1 inhibitor): 2 cases、Supportive care:Bone metastasis treatment 4 cases: 2 cases；Traditional Chinese medicine: 2 cases；Treatment discontinuation: 5 cases；Targeted therapy (gefitinib/erlotinib): 2 cases.\u003c/p\u003e\n\u003cp\u003eThe location of the second progression and treatment status: a total of 72 cases. 24 cases (33.3%) had local progression, 6 cases (8.3%) liver metastasis, 13\u0026nbsp;(18.1%) bone metastasis, 5 (6.9%) lung metastasis, 8\u0026nbsp;(11.1%) brain metastasis, 5 (6.9%) mediastinal lymph node metastasis, 8 cases (11.1%) mixed metastasis, and 3 cases (4.1%) adrenal metastasis. After treatment, the efficacy was evaluated in 29 cases of PR, 41 cases of SD, and 2 cases of PD.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4 Survival and prognosis analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOverall survival (OS) rates at 1, 3, 5, and 10 years for the entire cohort\u0026nbsp;were 86.0%, 50.6%, 40.8%, and 24.2%, respectively(Fig 1).\u0026nbsp;The PFS1 rates for the entire cohort at 1, 3, 5, and 10 yearswere 63.6%, 28.6%, 20.8%, and 8.3%, respectively.\u0026nbsp;The PFS2\u0026nbsp;rates for the entire cohort at 1, 3, 5, and 10 years\u0026nbsp;were\u0026nbsp;91.8%, 70.9%, 56.5%, and 49.4%, respectively.\u003c/p\u003e\n\u003cp\u003eUnivariate analysis of OS (Table2): Smoking (p=0.012), age (p=0.004), lesion location (p=0.001), chemotherapy (p=0.026), radiation pneumonitis (p=0.041), first-line treatment efficacy (p\u0026lt;0.001), PFS1 stratification (p\u0026lt;0.001) were associated with OS (p\u0026lt;0.05), while gender, ECOG score, family history of malignancy, pathological differentiation degree, T stage, N stage, TNM stage, and radiotherapy timing were not associated with OS. Multivariate Cox analysis (Table 3): Age (p\u0026lt;0.001), lesion location (p=0.002), radiation pneumonitis (p=0.048), first-line treatment efficacy stratification (p\u0026lt;0.001), and PFS1 stratification (p\u0026lt;0.001) are independent prognostic factors for overall survival (p\u0026lt;0.05). Among them, patients under 65 years old, peripheral lung cancer, non radiation pneumonitis, first-line treatment efficacy CR or PR, receiving chemotherapy, and PFS1 \u0026ge; 12 months had longer OS (p\u0026lt;0.05),\u0026nbsp;Though patients receiving chemotherapy demonstrated a trend toward prolonged overall survival compared with those who did not, but there was no statistical significance (p\u0026gt;0.05).\u003c/p\u003e\n\u003cp\u003eUnivariate analysis of PFS (Table\u0026nbsp;4): Smoking (p=0.005), alcohol consumption (p=0.002), lesion location (p=0.001), radiation pneumonitis (p=0.045), actual completed dose of radiotherapy (p=0.017), and recent efficacy (p=0.001) were associated with PFS1 (p\u0026lt;0.05), while gender, age, ECOG score, chemotherapy status, family history of malignancy, degree of pathological differentiation, T stage, N stage, and TNM stage were not associated with PFS1. Multivariate Cox analysis (Table\u0026nbsp;5): Radiotherapy efficacy (p=0.044) and actual completed dose of radiotherapy (p=0.020) are independent prognostic factors for PFS1 (p\u0026lt;0.05). Patients who received radiation therapy and had a CR or PR response, with a radiation dose of \u0026ge; 60Gy, had a longer PFS1 (p\u0026lt;0.05).\u003c/p\u003e\n\u003cp\u003e\u0026chi;\u003csup\u003e2\u003c/sup\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003etest: Patients who received chemotherapy had better short-term response (CR+PR) (p\u0026lt;0.05), indicating a correlation between chemotherapy and treatment failure patterns. Patients who received chemotherapy had a lower incidence of distant metastasis (p\u0026lt;0.05). Comparison of first-line treatment options: Objective response rate ORR (CR+PR):synchronous radiochemotherapy\u0026plusmn;consolidation chemotherapy was 35 cases (71.4%),sequential radiochemotherapy was 8 cases (50%), radiotherapy alone was 23 cases (36.5%),induction chemotherapy+radiochemotherapy/synchronous radiochemotherapy was 92 cases (63.1%), and the efficacy of synchronous radiochemotherapy\u0026plusmn;consolidation chemotherapy was better (p\u0026lt;0.05). PFS1 stratified analysis showed that recurrence and metastasis were reduced in PFS1 \u0026ge;12 months compared to PFS1\u0026lt;12 months (p\u0026lt;0.001).\u003c/p\u003e\n\u003cp\u003eUnivariate analysis of PFS2 (Table 6): PFS1 stratification (p=0.001) and first-line treatment efficacy stratification (p=0.002) were associated with PFS2 (p\u0026lt;0.05). Gender, age, smoking, alcohol consumption, degree of pathological differentiation, tumor location, T stage, N stage, TNM stage, initial treatment plan, chemotherapy or not, actual completed dose of radiotherapy, radiotherapy technique, radiation pneumonia, radiation esophagitis are not related to PFS2. Multivariate analysis (Table 7): PFS1 stratification and first-line treatment efficacy stratification are independent prognostic factors affecting PFS2 (p\u0026lt;0.05). For cases with first-line treatment efficacy of CR and PR, if PFS1\u0026ge;12 months, their PFS2 is longer and less likely to recur (p\u0026lt;0.05). \u0026chi;\u003csup\u003e2\u0026nbsp;\u003c/sup\u003etest: In cases of initial diagnosis with multiple lymph node metastases, the interval between PFS1 and PFS2 was shorter than that of single lymph node metastases (p\u0026lt;0.05), indicating that multiple lymph node metastases (168 cases) were more prone to recurrence and metastasis than single lymph node metastases (110 cases), but there was no statistical difference in OS. Patients with first-line treatment efficacy of CR and PR have longer intervals between PFS1 and PFS2 (p\u0026lt;0.05), while patients with PD and SD are more prone to disease progression (p\u0026lt;0.05). The interval between radiotherapy and initial diagnosis also has an impact on the efficacy of radiotherapy. The objective response rates (PR+CR) for radiotherapy and initial diagnosis intervals of less than 3 months and \u0026ge;3 months were 72.9% and 57.0%, respectively (p\u0026lt;0.05).\u003c/p\u003e"},{"header":"3. Discussion","content":"\u003cp\u003e\u003cstrong\u003e3.1\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Survival and prognosis analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLung cancer, the most prevalent malignancy worldwide, is frequently diagnosed at a locally advanced or metastatic stage. For inoperable, locally advanced non-small cell lung cancer (NSCLC), concurrent chemoradiotherapy has served as the cornerstone of treatment for three decades. Nevertheless, the 5-year overall survival rate has plateaued at approximately 30%, underscoring a critical and enduring therapeutic challenge.(4).\u0026nbsp;The cohort of 278 patients with locally advanced NSCLC treated non-surgically exhibited 1-, 3-, and 5-year overall survival rates of 86.0%, 50.6%, and 40.0%, respectively, with a median overall survival of 37.8 months.\u0026nbsp;Previous studies:Large-scale, comprehensive data on radical radiotherapy (RT) for locally advanced non-small cell lung cancer (LA-NSCLC) in the Chinese population remains scarce.. In this cohort of 789 patients receiving definitive radiotherapy, cCRT was administered to 42.0%, sCRT to 49.3%, and radiotherapy alone to 8.7%. The median overall survival was 31 months. The 1-, 2-, 5-, and 10-year OS rates were 83.7%, 59.5%, 28.8%, and 18.9%, while the PFS rates were 48.0%, 24.5%, 11.9%, and 5.5%, respectively. The integration of chemotherapy with radiotherapy and the total radiation dose were independent predictors of PFS, suggesting that this combination conferred a survival advantage(5).\u003c/p\u003e\n\u003cp\u003eSaartje Verfaillie et al. analyzed 163 patients diagnosed with unresectable stage III NSCLC. Treatment modalities included concurrent CRT for 108 patients and sequential CRT for the remaining 55. The cohort achieved a median PFS of 13.2 months (95% CI: 10.3-16.2) and a median OS of 23.3 months (95% CI: 18.3-28.0), with 2-year and 5-year overall survival rates of 47.5% and 29.4%(6).\u003c/p\u003e\n\u003cp\u003eThe KINDLE study, which enrolled 1,046 patients with stage III NSCLC from Turkey, Egypt, Kuwait, and the United Arab Emirates, demonstrated superior outcomes for concurrent chemoradiotherapy (cCRT). Patients receiving cCRT achieved a median progression-free survival (mPFS) of 12.7 months (95% CI: 10.51\u0026ndash;16.10) and a median overall survival (mOS) of 26.9 months (95% CI: 19.48\u0026ndash;33.68), yielding a significant advantage over sequential CRT (mPFS: 9.5 months; mOS: 17.4 months), chemotherapy alone (mPFS: 6.7 months; mOS: 14.3 months), or radiotherapy alone (mPFS: 8.1 months; mOS: 12.3 months).(7).Our key outcomes are in line with the collective findings of prior research.This improvement in survival may be attributed to our intensified, multimodal treatment regimen. Beyond the standard concurrent chemoradiotherapy, the protocol incorporated either induction chemotherapy or a combination of consolidation chemotherapy with concurrent chemoradiotherapy. This approach enhanced overall treatment intensity, which likely contributed to the superior patient outcomes observed.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHowever, the retrospective nature of this study imposes inherent limitations. Notably, there was heterogeneity in the chemotherapy regimens and the number of cycles administered. Furthermore, treatment strategies after disease progression varied considerably based on individual patient status. Consequently, our analyses provide general comparative findings rather than definitive conclusions regarding specific induction chemotherapy cycles or regimens. These specific comparisons warrant validation through prospective, randomized controlled trials.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Recent efficacy and prognosis analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe efficacy of first-line treatment in this study is also an important prognostic factor. The 1-year, 3-year, 5-year, and 10-year overall survival rates of CR+PR and SD+PD with first-line treatment efficacy were 94.3%, 60.0%, 50.5%, 31.8%, and 75.0%, 39.2%, 28.3%, and 15.1%, respectively (P\u0026lt;0.001). The PFS1 rates of CR+PR and SD+PD at 1, 3, 5, and 10 years were 66.1%, 31.9%, 23.7%, 10.9%, and 56.8%, 21.3%, 17.6%, and 3.9%, respectively (p=0.039). Multivariate Cox analysis confirmed the independent prognostic value of first-line treatment efficacy for overall survival (OS). The research results showed that patients with CR+PR first-line treatment had significantly longer OS and longer PFS1 to PFS2 intervals (p\u0026lt;0.05) compared to SD+PD, making them less likely to relapse. SD and PD are more prone to disease progression (p\u0026lt;0.05). Our results indicate that the primary tumor location and the interval from diagnosis to radiotherapy (DTR) impact both OS and therapeutic outcomes. Notably, a shorter DTR was linked to significantly better responses. The objective response rate (ORR) was 72.9% for patients with a DTR of \u0026lt;3 months, versus 57.0% for those with a DTR of\u0026nbsp;\u0026ge;3 months (p \u0026lt; 0.05), clearly demonstrating the efficacy advantage of earlier radiotherapy intervention..The 5- and 10-year OS rates for peripheral lung cancer were 46.2% and 36.2%, respectively, while those for central lung cancer were 35.1% and 19.4%, respectively. Peripheral lung cancer had a significantly better prognosis (p=0.001). This particular finding, however, has not been extensively reported in the existing literature (e.g., PubMed), highlighting a knowledge gap that future studies should aim to address.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Treatment mode, toxic side effects, and prognosis analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe NCCN guidelines strongly recommend definitive chemoradiotherapy for inoperable, locally advanced NSCLC, with a stronger recommendation for the concurrent approach over the sequential regimen..Hong Mei meta-analysis of 14 RCTs (2634 patients with NSCLC) , Compared with sequential chemoradiotherapy, concurrent chemoradiotherapy (cCRT) did not improve the 1-year survival rate but significantly enhanced long-term outcomes, with higher survival rates at 2 to 5 years. cCRT also significantly reduced the risk of locoregional relapse, although it did not affect distant relapse rates, and was associated with higher overall response rates. However, these benefits were accompanied by increased toxicities, including esophagitis, nausea/vomiting, and hematological suppression(8).\u003c/p\u003e\n\u003cp\u003eWhile concurrent chemoradiotherapy (cCRT) is broadly defined by the simultaneous delivery of chemotherapy and radiotherapy, its operational definition in clinical practice lacks uniformity. Variations exist in the specific criteria used, ranging from a strict requirement to start both modalities on the same day (typically chemotherapy cycle 1, day 1) to more flexible protocols allowing one to two cycles of chemotherapy to be administered during the radiotherapy course.\u003c/p\u003e\n\u003cp\u003eYu et al. (2020\u0026ndash;2022) compared concurrent chemoradiotherapy (CCRT, n=80) with sequential chemoradiotherapy (SCRT, n=78) in 158 patients with NSCLC. The CCRT group demonstrated superior treatment responses, with significantly higher remission rates (90.00% vs 74.36%) and disease control rates (96.25% vs 89.74%; both P \u0026lt; 0.05). During the 36-month follow-up period, Kaplan-Meier analysis revealed a trend toward improved overall survival with CCRT (90.00% vs 83.33%, P \u0026gt; 0.05), while both progression-free survival and overall survival were significantly prolonged in the CCRT group (P \u0026lt; 0.05)\u003csup\u003e\u0026nbsp;\u003c/sup\u003e(9).\u003c/p\u003e\n\u003cp\u003eConsolidation with concurrent chemoradiotherapy (cCRT) provided significant survival benefits over radiotherapy alone in a study by Zhao et al. involving 65 stage III NSCLC patients who had received initial chemoimmunotherapy. Patients receiving cCRT (n=21) showed markedly better outcomes than those receiving RT alone (n=44) across all endpoints: PFS (HR=0.155, p=0.004), LPFS (HR=0.225, p=0.029), and DMFS (HR=0.028, p=0.006).Albeit nonsignificant, a trend toward improved OS (HR = 0.030, p = 0.069) was also observed in the cCRT group. The multivariate analysis further confirmed that cCRT (HR = 0.141, p = 0.008) was the independent factor for promoting a favorable PFS. Treatment-related adverse events were similar between groups (p \u0026gt; 0.05). Patients with consolidation immunotherapy exhibited a trend of improved PFS (HR = 0.398, p = 0.274) and numerically better OS (HR = 0.018, p = 0.209) compared with those without(10).Although we have entered the era of immunity, the efficacy of concurrent radiotherapy and chemotherapy can still serve as a prognostic model. Dirk De Ruysscher established a prognostic model developed to identify patients with a high risk of early mortality associated with CRT. These individuals represent potential candidates for clinical trials aimed at enhancing their survival.(11).\u003c/p\u003e\n\u003cp\u003eThe integration of immune checkpoint inhibitors into oncology has added further nuance to the treatment of advanced NSCLC. In a multinational survey of thoracic oncologists from 11 countries, experts reported that a median of 66% (IQR 60\u0026ndash;75) of stage III patients receive chemoradiotherapy. Of these, roughly two-thirds undergo cCRT and one-third sCRT. Although durvalumab is reimbursed in all included health systems, its utilization is constrained in some settings by requirements such as PD-L1 \u0026ge;1% and prior cCRT(12).\u003c/p\u003e\n\u003cp\u003eTreatment decision-making for stage III NSCLC remains a nuanced and heterogeneous process, even in the current era of consolidation immunotherapy after CRT.A French observational study evaluated real-world practices in stage III NSCLC using data from 414 eligible patient charts. Disease staging was 53% IIIA, 37% IIIB, and 10% IIIC, and PD-L1 testing was completed for 98% of the cohort. Of the 292 patients with unresectable disease, 190 (65%) received CRT followed by consolidation immunotherapy. Specifically, concurrent CRT was utilized in 52% of these cases, compared to 13% for sequential CRT.\u003csup\u003e\u0026nbsp;\u003c/sup\u003e(13) .\u003c/p\u003e\n\u003cp\u003eIn contrast to the studies above, a French national multicenter cohort reported similar long-term outcomes for patients receiving sequential versus concurrent chemoradiotherapy.The radiotherapy-alone group, characterized by features such as advanced age, lower body weight, and increased COPD frequency, appeared to be the most vulnerable, underscoring that prolonged survival may be achieved through careful patient selection(14).\u003c/p\u003e\n\u003cp\u003eIn our study, synchronous radiochemotherapy\u0026plusmn;consolidation chemotherapy showed better short-term efficacy, but the 5- and 10-year survival rates were similar between the groups. Meanwhile, through \u0026chi;2 test, The addition of chemotherapy to first-line and subsequent second-line treatment was associated with a significant extension of not only PFS1 but also the interval to PFS2..This suggests that chemotherapy plays an important role in both first-line and second-line treatments.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.4 Analysis of Failure Modes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur study revealed that patients presenting with multi-site lymph node metastasis at initial diagnosis experienced a significantly shorter interval between the first and second disease progression (PFS1 to PFS2) compared to those with single-site involvement (p \u0026lt; 0.05). This finding suggests that multi-site nodal disease may be associated with a more aggressive tumor biology, conferring a higher propensity for recurrence and metastasis.\u0026nbsp;Although the combined modality of radiotherapy and chemotherapy extended both OS and PFS, an analysis of failure patterns revealed a consistent trend: regardless of treatment approach (radiotherapy alone or chemoradiotherapy) or radiation dose (\u0026ge;60 Gy or \u0026lt;60 Gy), disease progression occurred predominantly in the lungs and in mediastinal/supraclavicular lymph nodes (over 50% of cases). No statistically significant differences were observed across subgroups.\u003c/p\u003e\n\u003cp\u003eIt may also be related to the imbalance of our enrolled patients. However, our prior analysis established that first-line treatment response is a critical prognostic factor for recurrence, and that early radiotherapy intervention can reduce its incidence. Taken together, these findings\u003c/p\u003e\n\u003cp\u003eIn summary, while the overall prognosis of LSCC in this retrospective cohort\u0026mdash;treated predominantly with radiotherapy and chemotherapy in the pre-immunotherapy era\u0026mdash;remains poor, our findings demonstrate that a judicious multimodal regimen can nevertheless confer a meaningful survival benefit.\u003c/p\u003e\n\u003cp\u003eIn our study, choosing synchronous radiochemotherapy\u0026plusmn;consolidation chemotherapy as first-line treatment can achieve better objective response rate ORR (PR+CR); The efficacy of first-line treatment and PFS1 are important factors affecting patient prognosis. The efficacy of first-line treatment reaches CR or PR, PFS1\u0026ge;12 months, and survival is significantly prolonged. The failure mode is mainly characterized by local recurrence and metastasis. Early radiotherapy intervention (within 3 months of initial diagnosis) is associated with a marked reduction in the incidence of local recurrence and distant metastasis, thereby potentially improving disease control outcomes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eNSCLC:non-small cell lung cancer\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLSCC:lung squamous cell carcinoma\u003c/p\u003e\n\u003cp\u003ecCRT:concurrent chemoradiotherapy\u003c/p\u003e\n\u003cp\u003eORR:\u0026nbsp;objective response rate\u003c/p\u003e\n\u003cp\u003eCR:\u0026nbsp;complete response\u003c/p\u003e\n\u003cp\u003ePR:partial response\u003c/p\u003e\n\u003cp\u003eSD:\u0026nbsp;stable disease\u003c/p\u003e\n\u003cp\u003ePD:progressive disease\u003c/p\u003e\n\u003cp\u003eOS:overall survival\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePFS1:progression-Free Survival 1\u003c/p\u003e\n\u003cp\u003ePFS2:progression-Free Survival\u0026nbsp;2\u003c/p\u003e\n\u003cp\u003eIMRT:intensity-modulated radiotherapy\u003c/p\u003e\n\u003cp\u003eGTV:gross tumor volume\u003c/p\u003e\n\u003cp\u003eGTVnd: metastatic lymph nodes\u003c/p\u003e\n\u003cp\u003eCTV:clinical tumor volume\u003c/p\u003e\n\u003cp\u003ePTV:planning tumor volume\u003c/p\u003e\n\u003cp\u003eCT:computed tomography\u003c/p\u003e\n\u003cp\u003eMRI,:brain magnetic resonance imaging\u003c/p\u003e\n\u003cp\u003ePET/CT:positron emission tomography-computed tomography\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLocoregional recurrence: supraclavicular/mediastinal lymph nodes or lung progression\u003c/p\u003e\n\u003cp\u003eDistant metastasis: any extracranial/extrathoracic site\u003c/p\u003e\n\u003cp\u003eMixed failure: concurrent locoregional and distant recurrence\u003c/p\u003e\n\u003cp\u003eOligometastasis: single-organ metastasis\u003c/p\u003e\n\u003cp\u003eRECIST:response evaluation criteria in solid tumors\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRTOG):Radiation Therapy Oncology Group \u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003eThis retrospective study was conducted in accordance with our Ethics Committee（The Committee of the Fourth Hospital of Hebei Medical University），\u0026nbsp;approved by our Institutional Review Board,\u0026nbsp;and complied with the Declaration of Helsinki. Informed consent was waived for this retrospective analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eC\u003c/strong\u003e\u003cstrong\u003eonsent for publication:\u0026nbsp;\u003c/strong\u003eNot Applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eV\u003c/strong\u003e\u003cstrong\u003eailability of data and material:\u003c/strong\u003e The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial Disclosure or Funding:\u003c/strong\u003eS\u0026amp;TProgramofHebei,Serial Number：2026343\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZhongfei Jia:Statistical analysis、Manuscript preparation\u003c/p\u003e\n\u003cp\u003eJingchen Huo:Data acquisition、Data analysis\u003c/p\u003e\n\u003cp\u003eJie Yang：Concepts、Design、Definition of intellectual content、Manuscript review\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003eSincere thanks to our hospital\u0026apos;s treatment team for their outstanding contributions, and heartfelt gratitude to every author for their dedicated efforts.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWu F, Wang L, Zhou C. Lung cancer in China: current and prospect. Curr Opin Oncol. 2021 Jan;33(1):40-46. doi: 10.1097/CCO.0000000000000703\u003c/li\u003e\n\u003cli\u003eGuo Q, Liu L, Chen Z, Fan Y, Zhou Y, Yuan Z, et al. Current treatments for non-small cell lung cancer. Front Oncol. (2022) 12:945102. doi: 10.3389/fonc.2022.945102.\u003c/li\u003e\n\u003cli\u003eBobbili P, Ryan K, DerSarkissian M，et al. Predictors of chemoradiotherapy versus single modality therapy and overall survival among patients with unresectable, stage III non-small cell lung cancer. PLoS One. 2020 Mar 18;15(3):e0230444. doi: 10.1371/journal.pone.0230444.\u003c/li\u003e\n\u003cli\u003eBradley, Jeffrey D ,Chen,et al.Long-Term Results of NRG Oncology RTOG 0617: Standard- Versus High-Dose Chemoradiotherapy With or Without Cetuximab for Unresectable Stage III Non-Small-Cell Lung Cancer[J].Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 38(7):706-714[2025-07-05].DOI:10.1200/JCO.19.01162.\u003c/li\u003e\n\u003cli\u003eZhu H, Xu Y, Gao H，et al. Long-term outcome of definitive radiotherapy for locally advanced non-small cell lung cancer: A real-world single-center study in the pre-durvalumab era. Cancer Med. 2024 Aug;13(15):e70051. doi: 10.1002/cam4.70051. \u003c/li\u003e\n\u003cli\u003eVerfaillie S, Lambrecht M, Berkovic P，et al. Treatment of unresectable stage III NSCLC: Real world cohort study and literature review. Cancer Treat Res Commun. 2023;36:100727. doi: 10.1016/j.ctarc.2023.100727. \u003c/li\u003e\n\u003cli\u003eSaid NS, Degu A. Assessment of survival outcomes among lung cancer patients at the National and Referral Hospital in Kenya. Cancer Med. 2023 Apr;12(8):9194-9201. doi: 10.1002/cam4.5658.\u003c/li\u003e\n\u003cli\u003eXiao W, Hong M. Concurrent vs sequential chemoradiotherapy for patients with advanced non-small-cell lung cancer: A meta-analysis of randomized controlled trials. Medicine (Baltimore). 2021 Mar 19;100(11):e21455. doi: 10.1097/MD.0000000000021455.\u003c/li\u003e\n\u003cli\u003eXu J, Ji Q, Deng J，et al. Concurrent vs. sequential chemoradiotherapy: a survival boost for lung cancer patients. Biomed Eng Online. 2025 May 16;24(1):60. doi: 10.1186/s12938-025-01390-9.\u003c/li\u003e\n\u003cli\u003eGuan S, Ren K, Zhang X，et al. Concurrent chemoradiotherapy versus radiotherapy alone after induction chemoimmunotherapy for stage III NSCLC patients who did not undergo surgery: a single institution retrospective study. Radiat Oncol. 2023 Jul 25;18(1):122. doi: 10.1186/s13014-023-02305-5.\u003c/li\u003e\n\u003cli\u003eVaes RDW, Cortiula F, Lyu S，et al. Chemoradiotherapy efficacy in patients with stage III non-small cell lung cancer (NSCLC): A prognostic clinical and biomarker-based model. Lung Cancer. 2025 May;203:108541. doi: 10.1016/j.lungcan.2025.108541..\u003c/li\u003e\n\u003cli\u003eAgbarya A, Shalata W, Addeo A，et al. Real-World Journey of Unresectable Stage III NSCLC Patients: Current Dilemmas for Disease Staging and Treatment. J Clin Med. 2022 Mar 21;11(6):1738. doi: 10.3390/jcm11061738.\u003c/li\u003e\n\u003cli\u003eAuliac JB, Greillier L, Martin E，et al.Profiles, diagnostic process, and patterns of care of patients with stage III non-small cell lung cancer: A French national study. Respir Med Res. 2024 Jun;85:101087. doi: 10.1016/j.resmer.2024.101087.\u003c/li\u003e\n\u003cli\u003eGirard N, Perol M, Simon G，et al. Treatment strategies for unresectable locally advanced non-small cell lung cancer in the real-life ESME cohort. Lung Cancer. 2021 Dec;162:119-127. doi: 10.1016/j.lungcan.2021.10.017. \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 7 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"locally advanced lung squamous cell carcinoma（LSCC）, Chemotherapy and radiotherapy, Comprehensive treatment, Prognosis,Failure mode","lastPublishedDoi":"10.21203/rs.3.rs-8387530/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8387530/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e This study investigated long-term survival and identified associated prognostic factors in patients with locally advanced lung squamous cell carcinoma (LSCC)..\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e \u0026nbsp;In this retrospective study, 278 patients with locally advanced LSCC and complete clinical and follow-up records were enrolled. The cohort comprised patients admitted to the Fourth Hospital of Hebei Medical University from January 2012 through December 2019. All statistical analyses, including the use of the χ² test for categorical data comparisons, were performed with IBM SPSS Statistics (version 25.0).The Kaplan-Meier method was applied to calculate OS, PFS1 and PFS2; univariate analysis by Logrank method; Cox model prognosis analysis.Survival curves for OS, PFS1, and PFS2 were generated using the Kaplan-Meier method and compared with the log-rank test. Finally, a multivariate Cox proportional hazards model was applied to identify independent prognostic factors, including all variables that showed significance in the univariate analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e For the entire cohort, the 1-, 3-, 5-, and 10-year overall survival rates were 86.0%, 50.6%, 40.8%, and 24.2%, respectively. The PFS1 rates in the whole group 1、3、5、and 10 years were 63.6%、28.6%、20.8%、and 8.3%, respectively. The PFS2 rates in the whole group 1、3、5、and 10 years were 91.8%、70.9%、56.5%、and 49.4%, respectively. First disease progression: 238 cases of disease progression. Among them, Primary lesion progression 108 (45.3%), mediastinal and supraclavicular lymph node metastases 34 (14.2%), distant metastases 67 (28.1%) ,mixed metastases 29 (12.1%),and oligo metastases 77 (32.3%). Second disease progression: a total of 72 cases. Local progression 24 (33.3%), liver metastasis 6 (8.3%), bone metastasis 13(18.1%), lung metastasis 5(6.9%), brain metastasis 8(11.1%), mediastinal lymph node metastasis 5 (6.9%), adrenal metastasis 3(4.1%) and mixed metastasis 8 (11.1%). Cox multivariate analysis demonstrated that overall survival (OS) was independently predicted by age, lesion location, radiation pneumonitis, first-line treatment efficacy stratification, and PFS1 (all p \u0026lt; 0.05). Meanwhile, PFS1 was independently influenced by radiotherapy efficacy and the actual completed radiotherapy dose (p \u0026lt; 0.05). For PFS2, both PFS1 stratification and first-line treatment efficacy stratification were identified as independent prognostic factors.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e The prognosis of LSCC remains poor; however, an evidence-based, integrated treatment approach can prolong survival. In our study, the choice of concurrent chemoradiotherapy ±consolidation chemotherapy can obtain better objective response rate[ORR（PR+CR）]; the efficacy of first-line therapy and PFS1 are important factors for survival.First-line treatment efficacy reaching CR or PR, PFS1≥12 months, could significantly prolong the survival. Local recurrence and distant metastasis constituted the main patterns of treatment failure. This study demonstrated that initiating radiotherapy early (within 3 months of diagnosis) significantly lowered the rates of these events.\u003c/p\u003e","manuscriptTitle":"Long term survival and failure mode analysis of locally advanced lung squamous cell carcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-08 14:42:49","doi":"10.21203/rs.3.rs-8387530/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"93718658-cd55-416e-bcfc-a41c982ed2fd","owner":[],"postedDate":"March 8th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Rejected","date":"2026-05-06T06:08:35+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-06T06:24:09+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-08 14:42:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8387530","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8387530","identity":"rs-8387530","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}