Outcomes of Treatment, Survival Rates, and Factors related to Survival of Stage III Lung Cancer Patients Treated at Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Thailand

Background: Lung cancer (LC) is the leading cause of death worldwide. Stage III lung cancer (Stage III-LC) is characterized by local metastasis. The treatments for LC differ at each stage, while for stage IIIA and IIIB treatment various approaches have been tried with uncertain results. We determined the survival time of Stage III-LC patient and compared survival among multiple factors. Methods: Data were collected from the Srinagarind Hospital-Based Cancer Registry (2014 - 2019). 324 patients from Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Thailand, were followed up until December 31, 2021. The survival rate was estimated using Kaplan-Meier and the Log-rank test. In addition, hazard ratios (HR) and the 95% CI were estimated using Cox regression. Results: Of the 324 Stage III-LC patients, the total follow-up time was 447.3 person-years, and 288 cases died during the study, for a mortality rate of 64.4 per 100 person-years (95% CI: 57.40-72.27). The respective 1-, 3-, and 5-year survival rate was 44.1% (95% CI: 38.67-49.45), 16.2 (95% CI: 12.34-20.51), and 9.3 (95% CI: 6.14-13.31). The median survival time was 0.84 years (10.1 months) (95% CI: 0.73-1.00). After adjusting for sex and stage of disease, sequential chemoradiotherapy (SC) represented the most independent predictor of the risk of death (adjusted HR= 1.58; 95% CI: 1.41-2.18). Females had a mortality risk of 0.74-fold compared to males (adjusted HR = 0.74, 95% CI: 0.57-0.95). Stage of disease and stages IIIB and III (unknown and undefined) had a respective 1.33-fold (adjusted HR = 1.33, 95% CI: 1.00-1.84) and 1.48-fold (adjusted HR = 1.48, 95% CI: 1.09-2.00) risk of death compared to stage IIIA. Conclusion: Sex, stage of disease, and SC were related to stage III-LC survival, so physicians should emphasize combination therapy. Further research should focus on combination therapy and survival among Stage III-LC patients.

Introduction the highest incidence rate for both sexes. The number of new cases of LC was 7.6 %, the second highest after liver and bile duct cancer among males. While the fifth most common cancer contributed 5.7% among females, followed by breast cancer, liver and bile duct cancer, thyroid cancer, and colon and rectal cancer (KKU Cancer Unit, Srinagarind Hospital., 2020).
However, the previous study at Srinagarind Hospital, Khon Kaen, Thailand, revealed that the respective overall median survival time of patients with stage I-IV was 39.72, 21.84, 11.26, and 6.24 months. However, the later stages (stage III-IV) of lung cancer had the worst survival rates because most patients with LC have an advanced stage of cancer at diagnosis (Punjaruk et al., 2015). This is because Stage III-LC (including stages IIIA and IIIB) has completely different staging between stage IIIA and stage IIIB. Additionally, metastasis and treatment are distinct for stage IIIA and IIIB of the disease. Therefore, the current study aimed to determine the survival rate of Stage III-LC patients at Srinagarind Hospital and to compare survival between various factors after diagnosis. The findings of this study may help policymakers and physicians at Srinagarind Hospital, a tertiary health care center, to design a more appropriate treatment plan for Stage III-LC patients. In addition, the study findings may also shed more light on lung cancer and advance clinical practice and treatment.

Cancer Registries and Case Ascertainment Khon Kean Cancer Registry, KKCR
The Khon Kaen Cancer Registry (KKCR) was founded in 1984 at Srinagarind Hospital, Faculty of Medicine, Khon Kaen University in northeastern Thailand. It includes hospital-and population-based registrations. The KKCR comprises 1.7 million people from Khon Kaen province. For cancer registration, the KKCR adheres to the standards and guidelines of the International Agency for Research on Cancer (IARC) for all types and sites of cancer (Esteban et al., 1995).

Case definitions
All Stage III-LC patients treated at Srinagarind Hospital were retrieved from the Srinagarind Hospitalbased cancer registry (SHCR) database. Clinical staging was tracked from the medical records by following the TNM classification for Stage III-LC (Goldstraw et al., 2016). Diagnoses were obtained using the International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3). LC is an ICD-O-3 diagnosis and only includes coding C34.0-C34.9 between January 1, 2014, and December 31, 2019 (World Health Organization, 2013).
Stage III-LC treatment can include various combinations of chemotherapy followed by radiation therapy (Sequential Chemoradiotherapy, SC). In addition, stage III-LC patients may receive radiation therapy or chemotherapy alone.

Statistical methods
Descriptive epidemiology of study patients Patient characteristics were summarised using descriptive statistics. For continuous variables, means and standard deviations (SD), medians, and their ranges (minimum and maximum) were utilised; for categorical variables, frequency counts and percentages were used.

Survival analyses
A total of 324 cases with Stage III-LC were diagnosed at the SHCR with the ICD-O-3 codes C33.9 and C34.0-C34.9 (The International Classification of Diseases for Oncology (ICD-O-3).
The patients were followed up until December 31, 2021, to ascertain their vital status. The status was obtained by linking records from (1) the Mortality Registry of Thailand (National Health Office, 2017) and (2) the National Statistical Office (National Statistical Office Thailand). The vital status of each patient (alive, dead) included the date last seen and the cause of death.
The survival rate was estimated using the Kaplan-Meier method, and the survival rate, median survival time, and 95% confidence intervals (CIs) were reported. The Log-rank test was used to compare survival curves. Multivariable analysis was performed using Cox proportional hazards regression, after which Hazard ratios (HRs) were reported with their 95% CIs and p-values from the partial likelihood ratio test (Kleinbaum et al., 2012).
All test statistics were two-sided, and a p-value of < 0.05 was considered statistically significant.

Data processing
Data were recorded using the CanReg 5 software provided by the International Association of Cancer Registries (IARC) (IARC, 2019). The verification was performed with necessary corrections, including logic, range, and internal consistency, which were checked using statistical software. All analyses were performed using Stata release 10.0 (StataCorp LLC, College Station, TX, USA) (Stata Corp., 2007).

Ethical considerations
The Human Research and Ethics Committee of Khon Kaen University reviewed and approved this project (HE641492).

Descriptive epidemiology
A total of 324 Stage III-LC cases recorded between 2014 and 2019 were retrieved from the SHCR database. The database contained cases of lung cancer at Stage IIIA (n=69, 21.3%), Stage IIIB (n=103, 31.8%), and Stage III (unknown or undefined) (n=152, 46.9%). Of the 324 cases of Stage III-LC, the majority were males (n=223, 68.8%), and the mean age at diagnosis was 62.6 years (standard deviation = 10.1 years). Histology of the primary was the most common basis for the diagnosis of Stage III-LC (n=264, 81.5%), followed by cytology (n=30, 9.1%) and endoscopic biopsy (n=27, 8.2%).

Survival rate of Stage III-LC after diagnosis Mortality rate and Median survival time
The 331 Stage III-LC patients had a total follow-up of 447.3 person-years. In total, 288 patients died during the study, corresponding to a mortality rate (case fatality) of 64.4 per 100 person-years (95%CI: 57.4 -72.3). The     (Table 3).

Discussion
The current study compared the survival rate of patients diagnosed with Stage III-LC at Srinagarind Hospital between 2014 and 2019 based on several factors, as follows.

Overall Survival of Stage III-LC patients
This retrospective cohort study was conducted on patients with Stage III-LC. The SHCR was the source of the data. The mean age at diagnosis was 62.9 years (SD = 10.1 years) among the 324 cases in the study. Males outnumbered females by a ratio of 2.20 to 1.
Generally, patients diagnosed with stage IIIA had better survival than stage IIIB and Stage III (unspecified).
In contrast, the current study revealed that the survival of patients diagnosed with stage IIIA was poorer than those diagnosed with Stage IIIB and Stage III (unspecified). The reason may be that the number of patients in Stage IIIA was less than Stage IIIB and Unspec. (IIIA n=69, 21.3%) vs. Stage IIIB and Stage III (unspecified) (n=255, 78.7%) . Currently, the best treatment for Stage III-LC is multimodal, including chemotherapy and radiotherapy. In addition, the best treatment is chemoradiotherapy, followed by sequential chemoradiation and radiation or chemotherapy alone. Radiation or chemotherapy alone can be the appropriate treatment for Stage III-LC patients who are often weak and ailing, so do not tolerate a multimodal approach. In the current study, the small number of concurrent chemoradiation (5, 5.0%) and sequential chemoradiation (54, 16.7%) was due to the poor survival of Stage III-LC patients in this area (Table 1).

Survival factors of Stage III-LC patients Sex
The current study revealed a significant association between sex and survival rate (p-value = 0.018). After adjusting for all variables in the model, it was discovered that the female mortality risk is 0.74-fold compared to the male risk (adjusted HR = 0.74, 95%CI: 0.57-0.95). Thus, females survive longer than males. Our findings are consistent with prior research. For all stages of LC patients diagnosed at Srinagarind Hospital, it was discovered that sex influenced patient survival (p-value < 0.05). After adjusting for all variables in the model, females had a mortality risk of 0.78-fold compared to males (adjusted HR = 0.78, 95%CI: 0.68-0.89) . Consistent with a Japanese study, the association between sex and survival rate was statistically significant (p-value < 0.001). Male mortality risk was 1.19-fold times that of the female mortality risk (adjusted HR = 1.19, 95% CI: 1.16-1.21) (Kinoshita et al., 2017). In addition, a Swedish study reported that sex was strongly associated with the survival rate (p-value < 0.001). The female mortality risk was 0.73-fold compared to that of males (adjusted HR = 0.73, 95% CI: 0.67-0.79) (Sachs et al., 2021).

Stage of disease
The current study revealed a significant relationship between the stage of disease and survival rate (p-value < 0.001). After adjusting for all variables in the model, stage IIIB and III LC patients (unknown and undefined) were associated with a 1.33-and 1.48-fold mortality risk (adjusted HR = 1.33, 95% CI: 1.00-1.84 vs. 1.48, 95% CI: 1.09-2.00) compared to stage IIIA. Consistent with a study conducted in Ubon Ratchathani, Thailand, the survival rates of patients in the metastasis stage of the disease were significantly different (p < 0.001). After adjusting for all variables in the model, stage IIIB and IV LC patients had an increased risk of mortality compared with stage IIIA (adjusted HR = 2.00, 95% CI: 1.23-3.31) and stage IV as 3.20 (adjusted HR = 3.20, 95% CI: 1.96-5.17) (Srisam-ang et al., 2005). In addition, a study at Srinagarind Hospital revealed an association between the TNM stage and patient survival (p < 0.001). After adjusting for sex, histologic type, and chemotherapy, stage III and IV LC patients had an increased mortality risk than those with stage I and II (adjusted HR = 6.35, 95% CI: 4.05-9.95) and stage IV as 8.32 (adjusted HR = 8.32, 95% CI: 5.36-12.90), respectively .
In the current study, the TNM staging system for LC (seventh edition) was adapted from the eighth edition (Lababede et al., 2018); however, the clinical staging was used to determine the stage of the disease. As a result of imprecise clinical staging that can impact survival (Navani et al., 2019), patients with stage IIIB and III LC who have "unknown and undefined" conditions may have a poorer survival rate.

Sequential Chemoradiotherapy (SC)
In the present study, SC was statistically associated with the Stage III-LC survival rate (p-value < 0.029). After adjusting for sex and stage of disease, we found that those without SC had a 1.58-fold higher risk of mortality than those with SC (adjusted HR = 1.58, 95% CI: 1.41-2.18). Compared to patients treated with SC as a reference group (n=54), those treated with radiation alone (n=16) and chemotherapy alone (n=102) had a 1.40 (adjusted HR=1.14; 95%CI:0.76-2.56) and 1.15 (adjusted HR=1.15; 95%CI: 0.79-1.65)-fold increased risk of mortality (Data not shown). Consistent with prior research, SC was associated with a 0.51-fold increase in mortality risk compared to no SC (adjusted HR = 0.51, 95%CI: 0.28-0.91) (Sakin et al., 2021). Our findings are comparable to those of David et al., (2016) who reported that chemotherapy alone for LC was associated with a 0.40-fold mortality risk compared to no-treatment (adjusted HR=0.40; 95%CI: 0.39 -0.42). Additionally, Urvay et al. reported that sequential chemoradiotherapy (n=26) vs. concurrent chemoradiotherapy (n=122) were factors affecting survival. The combination therapy was significantly associated with a higher rate of Stage III-LC survival (p-value = 0.025) (Urvay et al., 2016). After adjusting for all variables in the model, concurrent chemoradiotherapy for Stage III-LC was associated with a 0.50-fold increased mortality risk compared to sequential chemoradiotherapy (adjusted HR = 0.50, 95% CI: 0.30-0.90). Specifically, stage III-LC was treated by chemoradiotherapy, the standard for Stage II-LC, while concurrent chemoradiotherapy was limited. Sequential chemotherapy is, therefore, flexible for the treatment because most of the analyzed data come from existing medical records. The combination of treatments has superior survival than no treatment.
Furthermore, vis-à-vis the current study, performance status is another factor affecting Stage III-LC. However, we cannot provide an analysis due to a lack of data from the cancer registry.

Advantages and Disadvantages of the study Advantages
According to the SHCR, the current study is the most recent examination of Stage III-LC post-diagnosis survival factors between 2014 and 2019. In this study, Stage III-LC was treated with chemoradiation and radiation therapy.

Disadvantages
Our study has certain limitations, such as incomplete pathological data, as some patients were diagnosed without pathological confirmation because most patients delay seeing a doctor and are diagnosed at a late stage.
In conclusion, the current study demonstrated that sex, disease stage, and SC are associated with Stage III-LC patient survival. Therefore, further research into the factors affecting LC survival in northeastern Thailand should centre on combination therapy.

Author Contribution Statement
NR was the principal investigator and provided project management supervision. SK and CS provided advice about the study design and statistical analyses. WM was involved in exploratory analysis and data quality. AP was a physician and operated on patients with apparent LC and assisted in the final diagnoses of the cases.