Variables	Overall Mortality		1-Year Mortality		2-Year Mortality		5-Year Mortality
	HR	P-Value	HR	P-Value	HR	P-Value	HR	P-Value
	(95.0%CI for HR)		(95.0%CI for HR)		(95.0%CI for HR)		(95.0%CI for HR)
Age	1.006	0.126	1.012	0.027	1.01	0.037	1.007	0.114
	(0.998-1.015)		(1.001-1.022)		(1.001-1.019)		(0.998-1.015)
Gender	1.071	0.57	1.369	0.061	1.24	0.12	1.084	0.511
	(0.846-1.356)		(0.986-1.902)		(0.946-1.625)		(0.852-1.378)
SVC Syndrome	1.352	0.108	1.291	0.273	1.306	0.192	1.337	0.128
	(0.936-1.953)		(0.818-2.040)		(0.874-1.949)		(0.920-1.942)
Metastases Statues	1.767	<.001	1.615	<.001	1.709	<.001	1.745	<.001
	(1.464-2.132)		(1.278-2.042)		(1.393-2.095)		(1.443-2.112)
Histology Category	1.269	0.023	1.429	0.004	1.429	0.001	1.286	0.018
	(1.033-1.558)		(1.117-1.827)		(1.152-1.774)		(1.045-1.583)

Sex and SVC syndrome showed no significant associations with mortality at any interval (p>0.05). In contrast, metastatic status was the strongest predictor of mortality: patients with metastasis had a significantly higher risk of death compared with non-metastatic patients (HR=1.767, 95% CI: 1.464–2.132, p<0.001). This effect remained significant for 1-year (HR=1.615, p<0.001), 2-year (HR=1.709, p<0.001), and 5-year mortality (HR=1.745, p<0.001). Furthermore, histological type emerged as an independent predictor of survival, with SCLC patients experiencing a significantly higher risk of death than NSCLC patients. This association was significant for overall mortality (HR=1.269, 95% CI: 1.033–1.558, p=0.023), 1-year (HR=1.429, 95% CI: 1.117–1.827, p=0.004), 2-year (HR=1.429, p=0.001), and 5-year mortality (HR=1.286, p=0.018).

In this 24-year historical cohort study of 957 lung cancer patients referred to Shahid Rajaee Radiotherapy Center in northern Iran, two major findings emerged. First, among NSCLC cases, the predominant histopathological subtypes were squamous cell carcinoma (SCC) and adenocarcinoma, with notable sex-related differences in distribution. Second, survival analyses showed that patients with NSCLC had a significantly longer median overall survival (OS) than those with SCLC. Moreover, the presence of metastasis particularly brain metastasis was identified as the strongest predictor of reduced survival. These findings are broadly consistent with national and international studies [19, 20].

Because the study population was drawn from a radiotherapy referral center serving mainly the northern provinces of Iran, the cohort represents a selected subset of patients with access to specialized oncologic care. This referral-based composition introduces some selection bias and limits generalizability to the broader Iranian population, underscoring the need for multicenter validation.

Annual case distribution demonstrated considerable variation across the 24-year period, influenced largely by documentation practices and calendar discrepancies rather than true epidemiologic fluctuations. The sharp decline in 2024 resulted from mismatches between Persian and Gregorian calendars, which excluded cases diagnosed early in 2025. These trends likely reflect referral dynamics and archival limitations.

The long study period also overlapped with major transitions in diagnostic and therapeutic practice in Iran. Access to advanced imaging modalities (CT, PET-CT, MRI) expanded substantially after 2010, and modern systemic therapies including EGFR-TKIs, ALK inhibitors, and immune checkpoint inhibitors became increasingly available from the mid-2000s onward [21-23]. These advancements, together with evolving referral pathways, likely contributed to temporal differences in diagnostic accuracy and survival outcomes.

In this study, the mean age at diagnosis was 62.5 ± 11.6 years, slightly higher than that reported in several Iranian studies. Salehi et al. (2020) reported a mean age of 60.57 ± 12.31 years [24], NRITLD-based analysis indicated 58.95 years [25], and Ketabchi et al. (2025) reported 61.17 ± 14.37 years [26]. Together, these suggest that age at diagnosis in northern Iran generally falls within the sixth decade of life.

Men in our cohort were diagnosed at a significantly older age than women (63.11 ± 11.45 vs. 59.88 ± 12.0; p<0.001), aligning with Salehi et al. [24]. However, evidence indicates that the burden of lung cancer among women in Iran is rapidly rising. Shokri Varniab et al. (2022) reported a marked increase in age-standardized mortality from 11.8 to 12.9 per 100,000 population between 1990 and 2019 attributed in part to increasing tobacco and waterpipe use among women [21].

Within our cohort, most NSCLC cases consisted of SCC and adenocarcinoma. Comparable patterns have been reported in other single-center and regional studies in Iran, although some centers have observed a relative increase in adenocarcinoma while SCC remains dominant elsewhere. For instance, Salimi et al. (2024) reported similar distributions, linking regional variations to smoking prevalence, environmental exposures, and diagnostic practices [19, 24, 26]. The high proportion of SCC in our study likely reflects the high prevalence of smoking among men in the region and late-stage diagnosis [27, 28]. Mousavi et al. (2025) further identified older age, male sex, opioid use, cumulative smoking, and non-gaseous household fuels as key risk factors for lung cancer in Iran [29].

Kaplan–Meier and Log-Rank analyses demonstrated significantly longer survival for NSCLC compared with SCLC (median OS: 29 vs. 13 months, p<0.01). This finding aligns with global evidence highlighting the aggressive biology of SCLC and its typically poor prognosis [30]. Recent systematic reviews and clinical datasets further emphasize that therapeutic advances particularly targeted therapies and immunotherapy have primarily benefited NSCLC patients [31].

In our study, overall survival rate was 39.9%, with 1-, 2-, and 5-year survival rates of 60.8%, 48.5%, and 41.4%, respectively. These values are noticeably higher than those reported in previous Iranian and international studies. For example, Mousavi et al. (2025) reported 1- and 5-year survival rates of only 18.7% and 1.6% in a smaller sample of 132 patients, while Molinier et al. (2020), analyzing more than 6,000 NSCLC patients, found 5-year survival rates below 15% [29, 32]. However, sensitivity analysis demonstrated that unverified survival status in one-third of cases could substantially reduce these estimates, suggesting that the observed rates may overestimate true survival despite robust verification efforts.

Although the high proportion of metastatic presentations is expected in a radiotherapy referral center, metastatic status remained the strongest predictor of mortality (HR=1.767, 95% CI: 1.464–2.132, p<0.001). Brain metastasis, in particular, showed the poorest outcomes. Wang et al. (2025) demonstrated that NSCLC patients harboring EGFR mutations have a heightened risk of brain metastases [33]. Oncogenic driver mutations, especially EGFR, are common in NSCLC and substantially influence outcomes [34, 35]. Wang et al. (2024) further emphasized the heavy prognostic burden of brain metastasis, noting that while interventions such as surgical resection, stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT), and tailored systemic therapies (including immunotherapy) can extend survival, associated mortality remains high [36].

Associations with other metastatic sites (e.g., bone, liver) were less consistent likely due to small sample sizes. Contralateral lung metastasis predicted overall mortality, mediastinal involvement predicted 2-year mortality, and vertebral and adrenal metastases were associated with early mortality. While time-specific, these remain clinically relevant.

Given that brain metastasis was the strongest adverse prognostic factor, strengthening early diagnostic capacity for intracranial disease and improving access to advanced therapies should be prioritized in Iran. Studies such as Paisana et al. (2025) demonstrate that immunotherapy can substantially improve outcomes in patients with brain metastases [37]. Evidence from resource-limited settings also underscores the importance of molecular profiling and targeted therapies in improving NSCLC survival [38, 39]. Putzu et al. highlighted the need to optimize the duration of immunotherapy to balance efficacy, toxicity, and cost in long-term survivors [40]. Similarly, Salari et al. (2024) showed that early treatment of brain-only metastasis in NSCLC patients significantly improved survival [41]. Finally, Hao et al. (2023) stressed the necessity of robust registries capturing metastasis timing and molecular features to enhance prognostic modeling and treatment strategies [42].

In Cox regression, our finding that age strongly influenced early mortality (1-year and 2-year), but not late mortality (5-year or overall), is clinically plausible. Older patients are more likely to experience early competing risks or have a higher burden of comorbidities, whereas among long-term survivors, disease-specific factors such as stage, metastasis, and histological subtype may play a more decisive prognostic role.

Histological type emerged as an independent predictor of survival, with SCLC patients facing a significantly higher risk of death than NSCLC patients (overall HR=1.269, 95% CI: 1.033–1.558, p=0.023), consistent with the aggressive nature of SCLC [8]. Age was significantly associated with mortality at 1 and 2 years but not at longer follow-up, suggesting that its effect is most pronounced in the short term, whereas stage, metastasis, and treatment type exert greater influence in the long term [26].

Sex was not significantly associated with survival, although NSCLC was more prevalent among females. This finding is consistent with Khazaei et al. (2017) [7]. Other Iranian studies have likewise shown that the prognostic impact of sex diminishes after adjusting for confounders [43]. Conversely, Seifi et al. (2023) reported female sex as a favorable prognostic factor [30, 44]. Spiegelman et al. (1989) suggested that women may derive greater benefit from chemotherapy [45], while lower smoking prevalence among women could also contribute [46]. Biological, hormonal, and metabolic differences are additional likely explanations [30].

Tumor grade was significantly associated with short-term mortality but not overall survival, suggesting its effect diminishes relative to metastatic burden over time. SVC syndrome was not significantly associated with mortality, likely reflecting insufficient power due to small sample size.

Strengths of the Study

The major strengths of this study include its large cohort spanning 24 years and 957 patients, which allowed robust estimation of long-term survival patterns. Cross-verification of mortality through civil registry records, alongside active follow-up, strengthened data reliability. Incorporating histopathological profiling and time-to-event analysis provided valuable insight into lung cancer characteristics in northern Iran. Additionally, the application of scenario-based sensitivity analysis enhanced the transparency and robustness of survival estimates despite missing data.

Limitations of the Study

This study has several limitations. Its retrospective design resulted in missing or incomplete data for key prognostic variables, including TNM staging, complete tumor grading, treatment details, performance status, smoking history, and molecular profiling (EGFR, ALK, PD-L1), which restricted multivariable adjustment. Metastasis timing was inconsistently documented, preventing classification according to TNM M-categories and limiting assessment of disease progression dynamics.

As a single-center study from a radiotherapy referral hospital, generalizability may be limited. The long study period also introduced temporal heterogeneity due to major changes in diagnostic imaging and therapeutic options over two decades. Additionally, survival status could not be verified in one-third of patients, which despite sensitivity analyses may still have resulted in overestimation of overall survival.

Recommendations for Future Research

Future studies should employ multicenter, prospective designs to improve data completeness and representativeness. Systematic documentation of TNM stage, treatment modalities, performance status, comorbidities, and smoking exposure is essential. Establishing infrastructure for molecular and genomic data collection will enable more accurate prognostication and personalized therapy. Analyses stratified by diagnostic and treatment eras are recommended to account for rapid technological evolution. Further research should also evaluate outcomes in relation to modern systemic therapies, particularly targeted treatments and immunotherapy, and explore region-level determinants such as environmental exposures and referral patterns.

In conclusion, this 24-year retrospective cohort of 957 lung cancer patients offers a comprehensive long-term view of disease characteristics and survival patterns in a major radiotherapy referral center in northern Iran. The cohort was distinguished by a relatively older diagnostic age compared with similar Iranian studies, suggesting potential regional, environmental, or referral-related influences on disease presentation. NSCLC predominantly squamous cell carcinoma and adenocarcinoma represented the vast majority of cases and was associated with substantially better survival than SCLC. Metastatic status, particularly brain involvement, consistently emerged as the strongest determinant of mortality, underscoring the need for earlier detection of metastatic spread and improved access to advanced therapeutic strategies.

Although the observed overall survival exceeded that reported in many national and international cohorts, scenario-based sensitivity analysis demonstrated that missing vital-status data could meaningfully shift survival estimates, indicating that the true survival rate is likely lower than the primary estimate. This highlights the importance of data completeness when evaluating long­term outcomes in retrospective settings.

Taken together, these findings emphasize the critical role of timely diagnosis, expanded molecular profiling, and equitable access to contemporary systemic therapies particularly targeted agents and immunotherapies in improving patient outcomes. Future prospective, multicenter studies integrating detailed staging, treatment data, molecular biomarkers, and environmental exposures are essential to refine prognostic models and strengthen evidence-based lung cancer management in Iran and comparable regions.

Funding statement

This research was financially supported by the Vice-Chancellor for Research and Technology, Student Research and Technology Committee, Babol University of Medical Sciences, Babol, Iran.

Clinical trial registration

Not applicable.

Conflict of Interest Statement

The authors declare that they have no conflicts of

interest related to this study.

Data Availability Statement

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

This study did not use any custom code. All analyses were performed using SPSS version 27 and Microsoft Excel.

Author Contributions

Dr. Danial Fazelat-Panah contributed to the conceptualization, funding acquisition, investigation, methodology development, project administration, supervision, drafting of the original manuscript, and critical revision and editing of the final version. Mr. Seyed Reza Najafi, as the corresponding author, was responsible for data curation, investigation, drafting of the original manuscript, and critical review and editing of the paper. Dr. Hoda Shirafkan contributed to the study methodology and performed the statistical analyses. Fahime Khoshparast, Shabnam Ashofteh, Sogand Beheshti, and Ghazaleh Tahernezhad contributed to data collection and curation.

Ethics approval statement

This study was approved by the Ethics Committee of Babol University of Medical Sciences (Approval Code: IR.MUBABOL.HRI.REC.1403.343). All patient data were obtained in accordance with institutional guidelines and remained confidential throughout the study.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

The authors would like to sincerely thank Babol University of Medical Sciences, the Student Research and Technology Committee, and Shahid Rajaee Radiotherapy Center in Babolsar for their valuable support. We are also deeply grateful to all professors, colleagues, and staff members who contributed their time and expertise to this study. Declaration on generative AI and AI-assisted technologies in the writing process: The authors declare that no generative artificial intelligence or AI-assisted technologies were used in the writing, data analysis, interpretation, or preparation of this manuscript. Only the official iThenticate platform was used to check the manuscript for potential plagiarism.

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