High Visceral Fat Index Associated With Worse Survival Outcomes in Early-Stage Lung Cancer

Joseph Barbi, PhD

The method used to calculate how obesity is measured may impact whether it should be considered as a risk factor for non–small cell lung cancer (NSCLC), according to data from a study published in the Journal of Thoracic Oncology.¹ In contrast to high body mass index (BMI), a high visceral fat index (VFI) has been found to be negatively associated with survival in this population.

An elevated VFI was linked with worse overall survival (OS; HR, 1.84; 95% CI, 1.21-2.81) and recurrence-free survival (RFS; HR, 1.82; 95% CI, 1.06-3.11) in patients with early-stage disease who were undergoing resection. Multivariable modeling confirmed these results indicating that a high VFI is associated with a worse RFS (HR, 1.79; 95% CI, 1.04-3.08) in this population.

Visceral obesity was also found to be associated with changes in the tumor immune microenvironment in patients with late-stage disease. Moreover, obesity exacerbated disease progression, altered gene expression in the tumor immune microenvironment, and attenuated anti-cancer immune responses in mice.

"These findings clarify the truly negative relationship that exists between central obesity and lung cancer outcomes, and they present a viable alternative to the use of BMI in retrospective studies of obesity rooted in biology with clear relevance to cancer outcomes," first author Joseph Barbi, PhD, an assistant professor of oncology and assistant member in the Department of Immunology of Roswell Park, said in a press release.²

Thus far, 13 cancer types have been linked with excess body weight, and obesity rates continue to rise within the United States.^3,4 Although the association between measures of obesity and cancer incidence and outcome is well understood in other tumors like breast, esophageal, and colon cancer, this correlation is more complicated in lung cancer.

Unlike what has been reported in other cancers, obesity has been associated with reduced incidence of lung cancer. For example, 1 study in which investigators examined the National Institutes of Health—American Association of Retired Persons demonstrated that a high BMI was inversely linked with risk for the disease.⁵ Controlling for smoking was found to increase the link between this obesity measure and incidence. Other studies have indicated that BMI was linked with better long-term outcomes in this disease.

To gain some clarity on the association between survival with adiposity and NSCLC, investigators set out to measure central obesity in a cohort of patients with stage I NSCLC who were undergoing lobectomy and examine its association with outcomes.

The survival analyses in the trial included data on patients with pathologic stage I and II NSCLC who were undergoing a pulmonary lobectomy at the Roswell Park Comprehensive Cancer Center between October 2008 and December 2015. Investigators included relevant information

from the institutional thoracic surgery database, as well as the medical record. Overall, they examined tumor stage, tumor grade, histology, OS, and RFS data. All confounders were treated as categorical variables, with the exception of age.

VFI was first evaluated as a continuous variable in these studies. In model generation, the following covariates were utilized: age, sex, grade, race, histology, diffusion capacity for carbon monoxide (DLCO), American Society of Anesthesiology (ASA) score, and smoking status.

Investigators conducted univariate analyses to examine the link between individual variables and OS and RFS. Only variables linked with OS and RFS on these analyses were included in the model generation by multivariable analyses. Moreover, because of the link between VFI and age and sex, interaction variables were included in model generation. Both univariate and multivariable analyses were utilized to compare the OS and RFS in these patients.

A total of 554 patients with stage I and II disease were selected for the analysis; investigators were able to collect reliable fat area measurements from 513 of these patients, with 97.3% at L3, 0.9% at L2, and 1.8% at L1. A total of 159 patients with advanced-stage disease who had molecular testing and reliable fat area measurements were included, with 91.8% at L3, 6.3% at L2, and 1.9% at L1.

Inter-observer correlation of VFI measurements were noted to be good (n = 53; R² = 0.95). Moreover, the correlation of measurements between L2 and L3 levels (n=29; R² = 0.92; slope = 1.05), as well as L1 and L3 levels (n=28; R² = 0.85; slope = 1.05) were also determined to be good. Notably, L2 and L1 measures were used when L3 measurements were not available. Computed tomography scans were successfully utilized to identify patients with predominant visceral or subcutaneous adipose tissue distribution.

Additional data revealed that VFI was not linked with BMI (Pearson correlation coefficient = -.006; P = .9), although it was linked with sex and age. The mean VFI was higher in males than it was in females, at 0.56 vs 0.37, respectively (P < .01). Moreover, VFI was noted to elevate with increasing age (Pearson’s correlation coefficient = .32; P < .01).

Data from univariate analyses indicated that there was a significant link between sex, ASA score, tumor grade, histology, age, DLCO, and VFI with OS. RFS was also linked with sex, tumor grade, tumor stage, ASA score, and VFI. Multivariable analysis led to a final OS model that retained age, sex, DLCO, ASA score, VFI, tumor grade, and the interaction term between VFI and age. A final RFS model was also produced that retained only tumor grade, tumor stage, and VFI as predictive variables.

Forty-one of the 513 patients had an unknown cause of death, leading investigators to examine disease-specific survival (DSS) in 472 patients. VFI tertile was found to be linked with DSS (HR, 2.1; P = .025), but VFI was not statistically significant as a continuous variable (P = .1). Moreover, VFI tertile was associated with worse DSS (HR = 2.25; 95% CI, 1.16-4.37; P = .016).

"Our study provides much needed clarity to the relationship between adiposity and survival [for patients with NSCLC], providing firm scientific justification for the targeting of obesity's pro-tumor effects, which include decidedly adverse effects on the antitumor immune response," Sai Yendamuri, MD, chair of the Department of Thoracic Surgery, professor of oncology, attending surgeon of the Department of Thoracic Surgery, and director of the Thoracic Surgery Laboratory at Roswell Park, stated in the press release.

References

1. Barbi J, Patnaik SK, Pabla S, et al. Visceral obesity promotes lung cancer progression – towards resolution of the obesity paradox in lung cancer. J Thor Oncol. 2021;16(8):1333-1348. doi:10.1016/j.jtho.2021.04.020
2. Research suggests BMI may not be best obesity indicator to assess risk for lung cancer. News release. International Association for the Study of Lung Cancer. June 2, 2021. Accessed July 28, 2021. https://bit.ly/3zM5CTI
3. Lauby-Secretan B, Scoccianti C, Loomis D, et al. Body fatness and cancer—viewpoint of the IARC Working Group. N Engl J Med. 2016;375(8):794-798. doi:10.1056/NEJMsr1606602
4. Ogden CL, Fakhouri TH, Carroll MD, et al. Prevalence of obesity among adults, by household income and education — United States, 2011–2014. MMWR Morb Mortal Wkly Rep. 2017;66(50):1369-1373. doi:10.15585/mmwr.mm6650a1External.
5. Smith L, Brinton LA, Spitz MR, et al. Body mass index and risk of lung cancer among never, former, and current smokers. J Natl Cancer Inst. 2012;104(10):778-789. doi:10.1093/jnci/djs179