Effects of Obesity and Smoking on Survival in Non-Small Cell Lung Cancer

Background: Obesity is an emerging leading cause of morbidity and mortality in the US and the relationship between obesity, tobacco, and survival in NSCLC is unclear. Methods: Data (n = 87,631) were obtained from linkage of the 1996-2007 Florida Cancer Data System to the Agency for Health Care Administration database providing procedure and diagnoses codes. Survival time was calculated from date of diagnosis to date of death. Smoking status was categorized as never, current, and former. Obesity (yes/no) = ICD9 code BMI > 30 kg/m2, cachexia = ICD9 code “wasting syndrome”, & non-obese = non-obese & non cachectic. Cox proportional regression models used to predict survival; demographic, clinical, treatment factors, & comorbidities were included in adjusted models with smoking status and obesity as the main factors. Results: The majority of patients (pts) were either former (49%) or current (40%) smokers, & non-obese (88%). 6.8% of pts were obese & 4.8% of pts were cachectic. There were significant differences between survival curves and median survival (months) for obese vs. non-obese vs. cachectic pts. (20 vs 10 vs. 7.9; P < 0.001). Former and current smokers had shorter median survival than never smokers (10.8 & 9.2 vs. 11.9; P < 0.001). Survival rates (%) at 1-yr (60.1 vs. 45.2 vs. 37.7; P < 0.001), 5-yr (30.3 vs. 15.4 vs. 9.5; P < 0.001), 10-yr (18.1 vs. 7.6 vs. 2.7; P < 0.001) were better for obese vs. non-obese and cachectic pts respectively. Independent predictor of worse survival in the unadjusted model was former (HR 1.08; P < 0.001) and current (HR 1.20; P < 0.001) smokers compared to never. Obese and non-obese pts had better survival vs. cachexia pts. (HR 0.52; P < 0.001 and HR 0.80, p < 0.001 respectively) and obese had better survival than Non-obese pts (HR 0.65, p < 0.001). In the adjusted model, controlling for extensive variables and comorbidities, former (HR 1.11; P < 0.001) and current (HR 1.19; P < 0.001) smokers still had significantly worse survival vs. never smokers. Obese patients still had better survival (HR 0.87; P < 0.001, and HR 0.88, p < 0.001) vs. cachexia patients and non-obese respectively, survival rate was not significantly different compare nonCorresponding author.


Introduction
Tobacco, the leading cause of preventable death in the United States (US), has been linked to the development of many cancers, most notably lung cancer [1].Other risk factors for lung cancer have been explored in the literature: radon gas [2], asbestos exposure [3], high-dose beta carotene [4], low dietary consumption of fruits and vegetables [5], and obesity [6].Smoking not only increases the risk of developing lung cancer but is also associated with decreased survival after diagnosis [7].Although obesity is a major cause of morbidity and mortality in the US, the impact of obesity on lung cancer survival is unclear.Furthermore, the interrelationship between obesity, tobacco, and survival time after diagnosis for patients with non-small cell lung cancer (NSCLC) is uncertain.We examined BMI and smoking as predictors of survival in patients with NSCLC using a populationbased cancer registry in the state of Florida.

Methods
After institutional review board approval, data were obtained from linkage of the 1996-2007 Florida Cancer Data System (FCDS), a population-based cancer registry, to the Agency for Health Care Administration (AHCA) database which provides procedure and diagnoses codes, and the US census.We followed this cohort for an additional 3 years to allow for a determination of survival status through the year 2010.

Sample
Inclusion criteria were all adult patients 18 years or older diagnosed with NSCLC from 1996-2007 and residing in the state of Florida during 1996-2007 (n = 106,824).Exclusion criteria were patients with missing values on age of diagnosis, county of diagnosis, survival time, race, ethnicity, socioeconomic status (SES), smoking history, and obesity.Also, patients with carcinoma in situ were excluded.A total of 19,193 patients were excluded and 87,631 patients met full inclusion criteria.

Variables
Overall survival (OS) was defined as the time from diagnosis to death (information found in the FCDS database) from any cause with surviving patients censored at the date of last contact.Self-reported smoking status was categorized as never, current, and former.Obesity (yes/no) was determined by presence of an ICD9 diagnosis code for obesity indicating body mass index (BMI) of ≥30.Cachexia was determined by presence of ICD9 diagnosis code for "wasting syndrome".Non-obese patients were all non-obese and non-cachectic patients.

Statistical Analysis
Descriptive statistics of the demographic, pathological, and clinical characteristics were calculated for the overall sample as well as by smoking status and obesity status.Frequencies and percentages are shown for categorical variables and means, standard deviations, medians, first and the third quintiles for the continuous variables.The overall survival rates at 1-, 3-, 5-, and 10-years were calculated for the whole population, by smoking status, by presence of obesity status, and by smoking status x obesity status.Median overall survival was estimated and survival curves were plotted using the Kaplan-Meier methodology.Log-rank tests were used for the survival plots to compare overall survival by smoking status, and obesity status.
Cox proportional hazards regression models were used to determine the effect of potential factors on OS.Unadjusted and adjusted hazard ratios (HR), 95% confidence intervals (95% CI) and p-values were calculated from these models.We first performed univariate Cox regression to examine the association of OS with smoking, obesitystatus, and other factors such as race, ethnicity, and SES, respectively.Multivariate Cox regression models were then performed with the main predictors of smoking status and obesity.We adjusted for potential confounding variables using the sociodemographic variables in Table 1, the clinical characteristic variables in Table 2    and 31 individual Elixhauser comorbidity conditions entered as yes/no variables.We examined the models for violations of the proportional hazards assumptions, and found no violations.We also found no significant interactions between obesity status and smoking status in the adjusted models.The outcomes of patients treated at individual facilities are not independent, and therefore, we used robust standard errors to adjust for this clustering of patients in facilities.Statistical analyses were conducted using SAS software version 9.3 (SAS Institute Inc, Cary, North Carolina).

Results
The majority of patients were former (49.4%) or current (40%) smokers, and not obese (88.5%) (Table 1).6.8% of patients were obese and 4.8% of patients were cachectic.The median age at diagnosis was 70 years old with a range of 18 to 104 years old.Most patients were male (56.1%), White (91.8%) and non-Hispanic (94%) patients.
The mean age at diagnosis of current smokers was substantially younger (64.9 years) than that of former smokers (71.6 years) or never smokers (71.1 years).A higher percentage of never smokers were female (62.2%) than male (37.8%); whereas more current smokers were male (57.2%) than female (42.8%).
Table 2 shows clinical characteristics of patients.There was a high rate of comorbidities in this population, with 84.8% overall having 4 or more comorbidities.The most common comorbidities include congestive heart failure, cardiac arrhythmia, hypertension, diabetes, and depression.More current (84.7%) and former (86.1%) smokers had 4 or more comorbidities than did never smokers (79.2%); and a much higher percentage of obese patients (98.8%) and cachectic patients (98.7%) had 4 or more comorbidities than did non-obese patients (83.0%).Conversely, obese patients were more likely to be diagnosed with localized disease (31.5%) than were non-obese patients (21.9%) and cachectic patients (17.1%).Also obese patient were less likely to be diagnosed with distant disease (31.8%) compared with non-obese (41.4%) and cachectic patients (47.3%).The majority of patients who never smoked had adenocarcinoma (55.5%) compared with 44.8% of former smokers and 40.3% of current smokers (Table 2).In terms of treatments, 40.4% obese patients vs. 30.4% of non-obese patients vs 20.8% of cachectic patients had surgery (Table 2).31.4% of obese patients vs. 32.3% of non-obese patients vs. 36.2% of cachectic patients had chemotherapy.38% of obese patients had radiation vs. 43.8% of non-obese patients vs. 48% of cachectic patients.
Figure 1 shows Kaplan-Meier survival curves for the entire population, by smoking status, and by obesity status.There are significant differences in overall survival by obesity status, with patients who are obese having significantly better survival than non-obese and cachectic patients (log rank test, p < 0.001).Also, significant differences in overall survival by smoking status, with survival lowest for current smokers and highest for never smokers (log rank test, p < 0.001).Table 4 shows results from the univariate and multivariate Cox regressions.In the univariate model, compared to never smokers, former (HR 1.08; 95% CI 1.06 -1.11, P < 0.001) and current smokers (HR 1.20; 95% CI 1.16 -1.23, P < 0.001) had significantly worse survival.Obese and non-obese patients had better survival when compared with cachectic patients (HR 0.52; 95% CI 0.49 -0.54, P < 0.001 & HR 0.80; 95% CI 0.77 -0.82 respectively).Furthermore obese patients had better survival compared with non-obese patients (HR 0.65; 95% CI 0.63 -0.67).Blacks had significantly worse and patients in higher SES categories had significantly better survival in univariate models.
There were no significant interactions between smoking status and obesity in the adjusted model.

Discussion
Lung cancer was the most commonly diagnosed cancer as well as the leading cause of cancer death in males in 2008 globally [1].Among females it was the fourth most commonly diagnosed cancer and the second leading cause of cancer death [1].In the US, there will be an estimated 228,000 new cases of lung cancer and 159,500 deaths in 2013 [8].Cigarette smoking has been positively correlated with lung cancer (both small-cell and nonsmall cell) in North America and Europe [3] and has been shown to increase mortality from lung cancer when compared with never-smoking patients [7] [9].The results of our study confirm this relationship: never smokers had better survival compared with former and current smokers.The relationship between obesity and NSCLC is not as obvious as that of smoking.While studies show that obesity is a strong risk factor for many cancers including colon, breast, endometrial, stomach, pancreas, gallbladder, and liver cancer [6] [10] [11], there is evidence that obesity may be protective against lung cancer risk [12]- [21].There are studies, however, that show null [22]- [24], mixed [25] or opposite [26] results for the protective effect of obesity.A meta-analysis by Yang et al. found that excess body weight was inversely associated with incidence of NSCLC [27].This study, however, was criticized for large heterogeneity of results, lack offormal evaluation of study quality, and confounding by smoking [28].
The association of increased BMI and NSCLC survival is not as well defined in the literature as the data on BMI and risk of developing NSCLC.Calle et al. conducted a prospective cohort analysis of different cancer types including lung cancer patients and concluded that increased body weight was associated with increased death rates for all cancers combined and for cancers at multiple specific sites [6].In this study there was a significant inverse association between BMI and death from lung cancer in the total populations with greater effect at larger BMI categories.However, these investigators did not separately analyze NSCLC and small-cell lung cancer.[6].When subgroup analyses were performed on patients who were never smokers, the inverse association was present, but not statistically significant.The lack of significance might be due to the relatively small sample size in that analysis (n = 156 males, n = 476 females).In another study Attaran et al. performed a propensity-matched analysis showing for the first time that following resection for lung cancer, survival was significantly higher in patients with a BMI ≥ 30 compared with those with BMI < 30 [29].
To the best of our knowledge, this is the largest study that has demonstrated a positive association between BMI and survival in NSCLC.There are several explanations as to how obesity is associated with survival benefit, including genetic, endocrine, and nutritional components.Brennen et al. recently reported that one allele of the fat mass and obesity-associated (FTO) gene, which has been linked with increased BMI, was associated with a decreased risk of lung cancer [30].The mechanism for this protective effect, however, is not clear [30].
Adipose tissue is considered an active and functional endocrine organ that may play a central role in explaining why obesity is protective in NSCLC.Abdul-Ghafar et al. demonstrated that expression of Adiponectin Receptor 1 (adipo R1) is indicative of a favorable prognosis in NSCLC [11].Adiponectin may have a protective role in carcinogenesis as it has anti-angiogenic [31], anti-proliferative [32], proapoptotic effects, and also arrests cell growth [33] [34].
Females have lower incidence and higher survival rates in NSCLC when compared with males across all races [35].It seems reasonable to hypothesize that females might have improved outcomes because of a protective effect from hormones such as estrogen.In fact, a recent retrospective analysis conducted by Katcoff et al. showed that the combination of estrogen plus progesterone plus the use of long term hormone therapy were associated with significant improvements in women with NSCLC [36].Like women, obese individuals have higher levels of estrogens which might play a role in increased survival in NSCLC.
Consumption of phytochemicals and antioxidant-rich foods, such as fruit and vegetables, has a known protective effect on lung cancer risk [37]; accordingly, this protection may also be afforded to those with a diagnosis of NSCLC.It could therefore be hypothesized that obese individuals have higher intake of fruits and vegetables (or other unknown protective compounds) as a result of increased overall food intake and portion sizes thereby receiving more protective nutrients than those with a smaller total dietary intake.
Nutritional reserve may provide some explanation as to why obesity is protective in NSCLC survival.Cachexia which is commonly seen in NSCLC may not be as devastating in obese individuals because there is an ample energy supply in adipose tissue and supporting musculature of obese individuals.This may not provide an adequate explanation, however, given that increased body weight was associated with increased death rates for all cancers combined and for cancers at multiple specific sites [6].
In our study obese patients had 31.5% localized presentations compared with 21.9% in non-obese and 17.1% of cachectic patients.31.8% of obese patients had distant disease vs. 41.4% of non-obese patients and 47.3% of cachectic patients which would give this cohort of obese patients a survival advantage.Furthermore 40.3% of obese patients received surgery vs. 30.4% of non-obese and 20.8% of cachectic patients.Given that surgery is a curative modality this could increase the survival of the obese patients compared to non-obese patients.However, our multivariate regression analyses included variables for both stage at diagnoses and treatment; therefore, our adjusted results controlled for these confounders.Therefore, additional non-measured clinical or treatment factors, e.g., quality of the surgery, would need to be at work for these type of factors to play a role in survival.Interestingly, the fact that obese patients present with more limited disease and less distant disease than nonobese and cachectic patients may represent a distinct less aggressive biologic entity.
We acknowledge some potential limitations in our study.Most notable was the usage of ICD-9 coding to identify the obesity status of patients.The inability to utilize actual height and weight data could have caused variability in the three categories: obese, non-obese, cachexia.However, this is a limitation of using a population-based cancer registry that is difficult to overcome.
On the other hand, our study presented a number of advantages.First, it included a large sample size (n = 87,631) which is important in providing adequate power to detect significant differences even when performing subgroup analysis by smoking status and obesity (Figure 1).Second, the broad time span from 1996-2007 plus 3 years of follow up time allowed adequate years to perform survival analysis (Figure 1).Third, we were able to control for many clinical and demographic factors, and comorbidities, thus minimizing many potential confounding variables.Fourth, we were able to include a "cachexia" arm with a significant number of patients (n = 4,175) which eliminated possible confounder of this subgroup on the non-obese population survival statistics.Last, we included only NSCLC patients whereas many previous studies combined both small-cell lung cancer and NSCLC which are different disease entities.

Conclusion
Obese individuals with NSCLC survived longer than non-obese and cachectic patients.As expected, current or former smokers had worse survival compared to never smokers.Obesity may have a protective effect and provide a survival advantage.Further investigation to determine the mechanism of this benefit, i.e., hormonal, metabolic, nutrition-related, is warranted.Alternately obesity may merely be an indicator of less advanced and/or less aggressive disease.

Table 1 .
, Demographic characteristics of lung cancer stratified by smoking status and obesity status (column %).