Fleming CA, O’Connell EP, Kavanagh RG, et al. Body composition, inflammation, and 5-year outcomes in colon cancer. JAMA Netw Open. 2021;4(8):e2115274.
To evaluate the association between body composition and related inflammatory biomarkers with 5-year survival in patients with nonmetastatic colon cancer
A prospective, multicenter, translational cohort study using a retrospective placebo comparison group
All participants included in the study were diagnosed with nonmetastatic colon cancer without underlying chronic inflammatory conditions. These patients were not treated with anti-inflammatory medications.
All participants underwent elective resection for colon cancer with curative intent.
The study included a total of 28 patients with the characteristics below:
- Median age: 67 (28–72) years
- Men: 22 (78.6%)
- Women: 6 (21.4%)
- Skeletal muscle area (SMA)
- 24 (85.7%) within reference range
- 4 (14.3%) below reference range
- Visceral-to-total fat ratio
- 21 (75.0%) above reference range
- 7 (25.0%) within reference range
- Anterior resection: 14 (50.0%)
- Right hemicolectomy: 13 (46.4%)
- Total colectomy: 1 (3.6%)
- T1: 2 (7.1%)
- T2: 5 (17.9%)
- T3: 15 (53.6%)
- T4: 6 (21.4%)
- Positive: 12 (42.8%)
- Negative: 16 (57.2%)
Investigators applied extensive exclusion criteria. This included evidence of underlying liver disease, evidence of underlying kidney disease as determined by creatinine levels, blood dyscrasia involving the neutrophils and thrombocytes, metastasis, morbid obesity, and active inflammatory disease.
Study Parameters Assessed
After initial diagnosis, all patients were staged, and metastasis was ruled out using standard imaging guidelines. Patients were followed with active surveillance for 5 years, which included measurement of carcinoembryonic antigen (CEA), colonoscopy, and imaging studies.
Blood samples were collected from patients preoperatively.
White blood cell count and albumin levels were analyzed. Acute phase protein and cytokine levels were measured and included interleukin 1b (IL-1b), IL-2, IL-10, C-reactive protein (CRP), tumor necrosis factor (TNF)-alpha, and vascular endothelial growth factor (VEGF).
CT studies measured total fat area and subcutaneous fat area. Calculations for visceral-to-total fat ratio and subcutaneous-to-total fat ratio were made.
CT studies were also used to measure skeletal muscle area (SMA).
The association of body composition profiles with 5-year cancer recurrence and disease-specific mortality were analyzed using Mantel Cox log-rank test, and Kaplan-Meier curves were produced.
When specific composition profiles were significantly associated with poor clinical and cancer outcomes, comparison of mean inflammatory mediator expression levels was performed using the Mann-Whitney U test.
Primary Outcome Measures
Associations of body composition profiles with 5-year cancer recurrence and disease-specific mortality
Overall low skeletal muscle area (SMA) and high visceral-to-total fat ratio were significantly associated with less favorable clinical and cancer outcomes.
Low SMA was associated with a more than 2-fold increase in recurrence of colon cancer in the 5-year postsurgical period (low SMA: hazard ratio [HR], 2.30 [95% CI, 1.41–2.89]; P=0.04).
High visceral-to-total fat ratio was significantly associated with developing a cancer recurrence within the first 5 years after surgery (high visceral-to-total fat ratio: HR, 5.78 [95% CI, 3.66–7.95]; P=0.02).
Low SMA (OR, 2.13 [95% CI, 1.85–5.36]; P=0.004) and high visceral-to-total fat ratio (OR, 3.20 [95% CI, 1.85–10.84]; P=0.01) were significantly associated with developing a 30-day infective complication.
High visceral-to-total fat ratio was the only body composition profile significantly associated with cancer-related mortality within the first 5 years after surgery (HR, 5.92 [95% CI, 4.04–8.00]; P=0.02). There was no significant association between low SMA and 5-year disease-specific mortality.
Patients with low SMA who developed cancer recurrence, compared with those who did not, had significantly higher levels of CRP, VEGF, and CD14 expression.
Patients with high visceral-to-total fat ratio who developed recurrence, compared with those who did not, had higher levels of IL-6 (mean [SD], 5.26 [7.05] ng/mL vs 2.76 [3.11] ng/mL; P=0.03) and TNFα (mean [SD], 5.74 [4.53] ng/mL vs 4.50 [1.99] ng/mL; P=0.03).
This study showed an association between visceral fat and poorer outcomes, which is not surprising. There is an accumulation of literature showing that visceral fat is a risk factor for cardiovascular diseases, type 2 diabetes, breast cancer, and other chronic conditions.1 This study also demonstrated the relationship between visceral fat and measurable inflammatory mediators in the blood. In other studies, increased visceral fat has been associated with the increased release of free fatty acids into portal circulation, which results in insulin resistance and other metabolic syndromes.2 Conversely, subcutaneous fat correlated with increased levels of IL-2 and IL-10, cytokines thought to possess predominantly anti-inflammatory effects.
The World Cancer Research Fund International lists 10 established obesity-related cancers, including postmenopausal breast, endometrial, ovarian, advanced prostate, colorectal, renal, pancreatic, liver, and gallbladder cancers and esophageal adenocarcinoma.3 Clearly, obesity needs to be addressed as 1 of the strategies in approaching these obesity-related cancers. However, we must be mindful of how body fat is being assessed in our evaluation and assessment of individuals.
Body mass index (BMI), though recommended as an index of obesity and disease risk, has its limitations. It is nonspecific, with only the weight and height used to calculate BMI. There is no differentiation of muscle mass or any delineation of visceral versus subcutaneous fat.4 Therefore, BMI cannot predict the risks associated specifically with elevated levels of visceral fat.
This phenomenon is referred to as the ‘obesity paradox’ and is well-recognized in the cardiometabolic literature but less so in oncology.
The common perception is that excess adiposity, approximated by BMI, is associated with reduced cancer survival. However, several studies have demonstrated that overweight and early obese states are associated with improved survival. This phenomenon is referred to as the “obesity paradox” and is well-recognized in the cardiometabolic literature but less so in oncology.3 This suggests that BMI is not a reliable form of measurement or prognostic tool due to its inability to evaluate fat deposition, particularly subcutaneous vs visceral fat.3
Waist-to-hip ratio (WHR) may be a better tool to consider when evaluating patients who may be at increased risk for colon cancer recurrence or morbidity related to colon cancer. WHR was found to be a better anthropometric measurement compared to measuring waist circumference alone or BMI, for assessing excess levels of visceral fat.5
Increased levels of subcutaneous fat and low skeletal muscle area (SMA) were associated with increased levels of inflammatory mediators (ie, IL-6, CRP, VEGF), which are known to promote cancer cell survival and metastatic transformation.
Researchers have questioned whether targeted anti-inflammatory therapies that work to inhibit IL-6 and other inflammatory mediators have a role in modulating the inflammatory association of body composition with cancer outcomes. Perioperative use of taurolidine, a taurine derivative, significantly diminished circulating IL-6 levels for the first 7 days following surgical resection in nonmetastatic colon cancer.6 Taurolidine has been shown to inhibit pro-inflammatory cytokines, specifically TNF-alpha and IL-6.7 Whether taurolidine affects outcomes was not part of that study’s design.
Given the apparent role that high systemic inflammation plays in poorer outcomes for cancers, an anti-inflammatory dietary approach should be considered. A 2006 study observed an inverse association between fruit and vegetable intake and CRP.8 Diets high in dietary fiber and rich in fruits and vegetables are associated with lower CRP levels, while consumption of a Western diet, high in fat, sugar, sodium, and refined grains, has been correlated with elevated CRP levels.9 A 2004 study found that adhering to a Mediterranean diet (rich in olive oil, fish, nuts, seeds, fruits, and vegetables) lowered CRP levels by an average of 20 percent.10
Sleep hygiene and exercise can also be included as part of a strategy to address concerns of higher systemic inflammation. CRP, IL-6, and fibrinogen have been linked to sleep, with higher levels of these markers associated with poorer sleep.11 More active individuals involved in regular exercise have lower concentrations of IL‑6 and CRP.12
The study reviewed here found unfavorable outcomes in nonmetastatic colon cancer associated with body composition and increased expression of proinflammatory pathways. These are important points that should be acknowledged and addressed in the clinical setting. However, it is important to note that this was a small cohort study involving only 28 patients. In addition, men comprised 78.6% of the study participants, compared to women at 21.4%.