Lung Cancer Survival with Current Therapies and New Targeted Treatments: A Comprehensive Update from the Srinagarind Hospital-Based Cancer Registry from (2013 to 2017)

Background: Lung cancer (LC) is a common malignancy and leading cause of cancer death worldwide and in Thailand. An update on LC survival factors after diagnosis at Srinagarind Hospital is needed. Methods: We conducted a retrospective cohort study, and the data were sourced from the Srinagarind Hospital-Based Cancer Registry. All LC cases were diagnosed between January 1, 2013, and December 31, 2017, and followed up until November 30, 2019. Cases of LC (ICD-O-3) numbered 2,149, but only those with coding C34.0-C34.9 were included. The survival rate was estimated using Kaplan-Meier, while the Log-rank test was used to estimate survival. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard regression models. Results: The 2,149 patients had a total follow-up of 269.6 person-years. Overall, 1,867 patients died during the study, for a corresponding case-fatality mortality rate of 86.0 per 100 person-years. The respective 1-, 3-, and 5-year survival rate was 31.2 % (95% CI; 29.21 to 33.15%), 12.9 % (95%CI: 11.49 to 14.45), and 10.2% (95%CI: 8.74 to 11.70). After patient diagnosis, the median survival time was 0.46 years (5.51 months) (95% CI: 0.42 to 0.50). Targeted therapy was associated with longer survival than non-targeted therapy (p-value < 0.001). After adjusting for sex, TNM stage, and histologic type, multivariable analysis of the entire cohort identified chemotherapy as an independent predictor of improved survival (adjusted HR= 0.48; 95% CI: 0.42 to 0.55; P < 0.001), and that sex, TNM stage, and histologic type were associated with survival. Conclusion: The study confirmed that sex, stage of disease, histology, and chemotherapy are associated with survival of LC. Primary prevention and screening for early detection improve survival. Further investigations into factors affecting survival of LC in Northeast Thailand should focus on targeted therapy.


Introduction
Lung cancer (LC) is a malignant tumor with the highest global morbidity and mortality of all cancers. In 2018, the number of new cases was 2,093,876 (11.6% of all cancers), while the number of deaths was 1,761,007 (18.4% of all cancers) among both sexes for all ages (Bray et al., 2017). The respective age-standardized rate (ASR) for LC in males and females is 31.5 and 14.6 per 100,000. The respective age-standardized incidence and mortality rate for both sexes is 22.5 and 18.6 per 100,000 (International Agency for Research on Cancer, 2019).
For Thais, the ASR for LC is between 20.6 and 27.1 per 100,000 in males and between 9.3 and 11.9 per 100,000 in females. In Khon Kaen province, Thailand, the ASR is improvement of LC survival are essential (Allemani et al., 2018). The first-ever population-based cancer survival data (1985)(1986)(1987)(1988)(1989)(1990)(1991)(1992) for Khon Kaen, Thailand, were published in 1995. The study revealed that the most common cancers in the province were liver (5-year relative survival rate 9.2%), cervix (60.1%), lung (15.4%), breast (48.1%), and large bowel (41.9%) (Sriamporn et al., 1995). A later study on Cancer Survival in Khon Kaen, Thailand, revealed that the 5-year survival between 1993 and 1997 was highest for localized disease, followed by regional and distant metastatic categories. Trends in the 5-year relative survival between 1993 and 1997 vs. 1985 and 1992 showed a marked increase for cancers of the rectum, breast, ovary, Hodgkin and non-Hodgkin lymphomas, and a decrease for cancers of the lip and larynx (Suwanrungruang et al., 2011). Previous studies showed the prognostic factors in non-small cell LC patients include stage of disease, performance status (León-Atance et al., 2011), weight loss, male vs. female, age, smoking status, smoking history, quality of life, marital status, diagnosed with depression, and genetic mutations (Jazieh et al., 2000;Brundage et al., 2002).
The prognostic factors and survival rate for LC have not been updated recently for the tertiary hospitals in northeastern Thailand where cancer patients are treated. The current research thus aimed to determine the factors affecting the survival of LC patients after diagnosis at Srinagarind Hospital.

Cancer Registries and Case Ascertainment Khon Kean Cancer Registry, KKCR
The Khon Kaen Cancer Registry (KKCR) was established in 1984 at the Faculty of Medicine and Srinagarind Hospital, Khon Kaen University, Khon Kaen, Thailand. It comprises both hospital and population-based registrations. The KKCR contains data on 1.7 million patients comprising all cancer sites as per the International Agency for Research on Cancer (IARC) guidelines (Esteban et al., 1995).

Case definitions
The database was retrieved for all patients with LC tumors treated at Srinagarind Hospital, Faculty of Medicine, Khon Kaen University between January 1, 2013, and December 31, 2017. 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 (World Health Organization, 2013).

Statistical methods Descriptive epidemiology of study patients
The characteristics of the patients were summarized using descriptive statistics. Means and standard deviations, medians, and their ranges (minima and maxima) were used for continuous variables, and frequency counts and percentages were used for categorical variables.

Survival analyses
Survival analyses excluded cases if their basis of diagnosis was Death Certificate Only (DCO) or unknown, if they did not contain any follow-up information, or had an unknown vital status. Survival was determined by calculating the follow-up time from diagnosis to each patient's last known vital status. The status was obtained by linking records between the Mortality Registry of Thailand (National Health Office, 2017) and the National Statistical Office (National Statistical Office Thailand, 2017, updated to December 31, 2016. The observed survival (OS) analysis was estimated using the Kaplan-Meier survival curve, and the logrank test was used for between-group comparisons. Multivariable analysis was performed using Cox proportional hazards regression (Kleinbaum and Klein, 2005). 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
This project was reviewed and approved by the Human Research and Ethics Committee of Khon Kaen University (HE631214).

Descriptive epidemiology and Data quality
Between 2013 and 2017, 2,149 cases of LC were recorded in the Srinagarind Hospital-Based Cancer Registry database. Male LC patients outnumbered female LC patients. The age at diagnosis trended to be late middleaged (mean, 62.4 years; standard deviation, 11.3; median, 63.0 years; Min: Max; 20: 91). Most were "married" (n=2,041; 95.1%). As for the year of diagnosis, the most numerous was in 2014 (n=497; 23.1%), while the least was in 2017 (n=364; 16.9%).
The basis of diagnosis was endoscopic and radiologic evidence vs. morphological verification (n=1,534; 71.4%) (i.e., based on either cytological or histological examination of tissue from the primary site, %MV). Based on the subtype of cancer, the highest was in the upper lobe (n=818; 38.1%), while the lowest was overlapping lesions of the lung (n=35; 1.6%). The most common histological grading was adenocarcinoma (n=930; 43.3%), while the highest was "unknown grading" (n=1,815; 84.5%).
Based on the type of cancer, the respective median overall survival (OS) and 3-year OS rates for patients with small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) was 0.58 year (95%CI: 0.39 -0.76) and 11.6% (95%CI: 4.26 to 23.06) vs. 0.60 years (95%CI: 0.53 to 0.66) and 15.1% (95%CI: 13.21 to 17.19). As for SCLC, the respective 1-year OS rate for patients treated with chemotherapy vs. non-chemotherapy was not significantly different. Meanwhile, NSCLC patients treated with chemotherapy over non-chemotherapy were associated with longer survival (    (Figure 1).

Survival and multivariable Cox regression analyses
After adjusting for sex, TNM stage, and histologic type, multivariable analysis of the entire cohort identified chemotherapy as an independent predictor of improved survival (adjusted HR= 0.48; 95% CI: 0.42 to 0.55; P < 0.001), and that sex, TNM stage, and histologic type were associated with survival (Table 3).

Discussion
The current study investigated the factors affecting the survival of LC patients after diagnosis at Srinagarind Hospital between 2013 and 2017. We describe these issues in detail for each topic.

Survival factors of LC patients Sex
In Khon Kaen, Thailand, over the last 20 years, the trend incidence for LC has increased for both sexes. (Santong et al., 2018) Male/female is the one factor that may influence survival. Previous studies have reported that for most cancers being female provides a survival benefit over being male (Micheli et al., 2009;Cook et al., 2011), although females have a higher risk of death from bladder cancer (Zaitsu et al., 2015).
The current statistical work-up shows that male/female is a significant risk factor for LC patient survival. After adjusting all the variables in the model, the mortality risk of being female was 0.78-fold compared to male patients (adjusted HR=0.78, 95%CI: 0.68 to 0.89). The result is consistent with previous studies in the USA, confirming a female survival benefit over male for LC irrespective of histologic type. [30] Since then, other studies on male vs. female difference vis-à-vis LC survival have confirmed the trend (Sagerup et al., 2011;Li et al., 2019).
A similar survival benefit trend accrued to females after adjusting for years since cessation and smoking dose. The hazard ratio (HR) for LC mortality-comparing the association with smoking in women to that in men was 0.90 (adjusted HR=0.90, 95%CI: 0.80 to 0.90) for current smokers and 0.9 (adjusted HR=0.90, 95%CI: 0.90 to 1.00) for former smokers (Freedman et al., 2008).

TNM stage
The current study shows that the 'stage of disease' is a significant risk factor for LC patient survival. After adjusting for all variables in the model, 'stage of disease' confirmed a significant risk factor of patient survival. Stage IV was associated with an 8.32-fold mortality risk compared to stages I and II (adjusted HR=8.32; 95%CI: 5.36 to 12.90), and stage III had a 6.35-fold mortality risk compared to stages I and II (adjusted HR=6.35; 95%CI: 4.05 to 9.95).

Histologic type
The current study showed that histology type was not a significant risk factor for LC survival. Compared to squamous cell carcinoma, the respective associated mortality risk for adenocarcinoma, small cell carcinoma, large cell carcinoma was 0.78-fold (adjusted HR=0.78; 95% CI: 0.63 to 0.96), 0.79-fold (adjusted HR=0.79; 95% CI: 0.50 to 1.22), and 1.01-fold (adjusted HR=1.01; 95% CI: 0.80 to 1.27). Compared to squamous cell carcinoma, the respective associated.

Chemotherapy
The current study showed that chemotherapy afforded a significant advantaged vis-à-vis LC survival. After adjusting for all variables in the model, patients undergoing chemotherapy had improved survival. Chemotherapy was associated with a 0.48-fold mortality risk compared to non-chemotherapy (adjusted HR=0.48; 95%CI: 0.42 to 0.55). Our finding is consistent with prior studies. Chemotherapy alone was associated with a 0.55-fold mortality risk compared to no-treatment (adjusted HR=0.55; 95%CI: 0.54 to 0.56) (Lou et al., 2018). For advanced non-small cell lung cancer, chemotherapy alone was associated with a 0.38-fold mortality risk compared to no-treatment (adjusted HR=0.38; 95%CI: 0.37 to 0.39) and chemotherapy and surgery a 0.22-fold mortality risk compared to no-treatment (adjusted HR=0.22; 95%CI: 0.20 to 0.24) (David et al., 2016 ).

Advantages and Disadvantages of the study
To our knowledge, the current study is the most up-todate examination of LC survival factors post-diagnosis between 2013 and 2017, according to the Srinagarind Hospital-Based Cancer Registry. Based on available data, targeted therapy significantly improved OS in LC patients of all ages, all cells types (NSCLC and SCLC), but further confirmatory research using extensive prospective clinical trials is needed. Novel targeted systemic therapies and the appropriate selection of LC patient treatments based on tumor molecular phenotypes and histologies should also be reviewed. The limitations of our study are the relatively small number of patients receiving targeted therapy.
In conclusion, the study confirmed that sex, stage of disease, histology, and chemotherapy are related to the survival of lung cancer patients. Primary prevention and screening for early detection are thus needed to improve survival. Factors affecting lung cancer survival in northeastern Thailand should focus on targeted therapy in any further investigations.

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