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Fleming CA, O’Connell EP, Kavanagh RG, et al. Body composition, inflammation, and 5-year outcomes in colorectal cancer.JAMA network opened. 2021; 4 (8): E2115274.
Study objective
Evaluation of the connection between the body composition and related inflammatory biomarkers with the 5-year survival in patients with non-metastasized colon cancer
Draft
A prospective, multicenter, translational cohort study with a retrospective placebo comparison group
Participant
All study participants were diagnosed with non-metastatic colon cancer without underlying chronic inflammation. These patients were not treated with anti-inflammatory medications.
All participants undergo an elective resection due to colon cancer with curative intentions.
The study included a total of 28 patients with the following characteristics:
- Durchschnittsalter: 67 (28–72) Jahre
- Männer: 22 (78,6 %)
- Frauen: 6 (21,4 %)
- Skelettmuskelbereich (SMA)
- 24 (85,7 %) im Referenzbereich
- 4 (14,3 %) unter dem Referenzbereich
- Verhältnis von viszeralem zu Gesamtfett
- 21 (75,0 %) über dem Referenzbereich
- 7 (25,0 %) im Referenzbereich
surgery
- Vordere Resektion: 14 (50,0 %)
- Hemikolektomie rechts: 13 (46,4 %)
- Totale Kolektomie: 1 (3,6 %)
Primary tumor
- T1: 2 (7,1 %)
- T2: 5 (17,9 %)
- T3: 15 (53,6 %)
- T4: 6 (21,4 %)
Node status
- Positiv: 12 (42,8 %)
- Negativ: 16 (57,2 %)
The investigators applied extensive exclusion criteria. These included evidence of underlying liver disease, evidence of underlying renal disease as determined by creatinine levels, blood dyscrasia involving neutrophils and platelets, metastases, morbid obesity, and active inflammatory disease.
Study parameters assessed
After the initial diagnosis, all patients were staged, and metastasis was excluded using standard image guidelines. The patients were actively monitored for 5 years, which included the measurement of the carcinoembryonal antigen (CEA), colonoscopy and imaging examinations.
Blood samples were taken from the patients preoperatively.
White blood cell counts 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 measure the entire fat area and the subcutaneous fat area. Calculations for the ratio of visceral to total fat and from subcutaneous to total fat were carried out.
CT studies were also used to measure the skeletal muscle area (SMA).
The association of body composition profiles with 5-year cancer recurrences and illness-specific mortality was analyzed with the Mantel Cox-Log-Rank test and Kaplan-Meier curves were created.
When specific compositional profiles were significantly associated with poor clinical and cancer outcomes, a comparison of mean inflammatory mediator expression levels was performed using the Mann-WhitneyUTest.
Primary outcome measures
Associations of body composition profiles with 5-year cancer recurrence and disease-specific mortality
Important knowledge
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 colon cancer recurrence in the 5-year postoperative period (low SMA: hazard ratio [HR]2.30 [95% CI, 1.41–2.89];P= 0.04).
A high ratio of visceral to total fat was significantly associated with the development of a cancer recurrence within the first 5 years after the operation (high ratio from visceral to total fat: 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 a high visceral to total fat ratio (OR, 3.20 [95% CI, 1.85–10.84];P= 0.01) were significantly associated with the development of a 30-day infectious complication.
A high ratio of visceral to total fat was the only body compilation profile that was significantly associated with cancer -related mortality within the first 5 years after the operation (HR, 5.92 [95% CI, 4.04–8.00];P= 0.02). There was no significant connection between low SMA and illness-specific 5-year mortality.
Patients with low SMA who developed cancer recurrence had significantly higher levels of CRP, VEGF and CD14 expression compared to those who did not.
Patients with a high visceral-to-total fat ratio who developed a recurrent, had higher IL-6 levels compared to those who did not do this (mean [SD] 26.5 [7.05] ng/ml compared to 2.76 [3.11] ng/ml;P= 0.03) and TNFα (mean [SD] 5.74 [4.53] Ng/ml compared to 4.50 [1.99] ng/ml;P= 0.03).
Practice implications
This study showed a connection between visceral fat and worse results, which is not surprising. There is a lot of literature that shows that visceral fat is a risk factor for cardiovascular diseases, type 2 diabetes, breast cancer and other chronic diseases.1This study also showed the relationship between visceral fat and measurable inflammatory mediators in the blood. In other studies, increased visceral fat was associated with the increased release of free fatty acids into the portal vein cycle, which leads to insulin resistance and other metabolic syndromes.2Conversely, correlated subcutaneous fat with increased mirrors of IL-2 and IL-10, cytokines, which are believed to have mostly anti-inflammatory effects.
The World Cancer Research Fund International lists 10 established obesity-related cancers, including postmenopausal breast, endometrial, ovarian, advanced prostate, colorectal, kidney, pancreatic, liver and gallbladder cancers, and esophageal adenocarcinoma.3Obesity clearly needs to be addressed as one of the strategies to treat these obesity-related cancers. However, we must be careful about how body fat is valued in our assessment and evaluation of people.
Although body mass index (BMI) is recommended as an index of obesity and disease risk, it has its limitations. It is non-specific as only weight and height are used to calculate BMI. There is no differentiation of muscle mass or demarcation between visceral and subcutaneous fat.4Therefore, BMI cannot predict the risks specifically associated with increased visceral fat levels.
This phenomenon is referred to as "obesity paradox" and is well known in cardiometabolic literature, but less in oncology.
The general perception is that excessive obesity, as approximated by BMI, is associated with reduced cancer survival. However, several studies have shown that overweight and early obesity are associated with improved survival. This phenomenon is referred to as the “obesity paradox” and is well known in the cardiometabolic literature but less so in oncology.3This indicates that the BMI is not a reliable shape of the measurement or forecast because it is unable to evaluate the fat deposit, especially 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 of colorectal cancer recurrence or colorectal cancer-related morbidity. WHR has been found to be a better anthropometric measurement compared to measuring waist circumference or BMI alone to assess excessive amounts of visceral fat.5
Increased mirrors of subcutaneous fat and in the lower skeletal muscle area (SMA) were associated with increased mirrors of inflammatory mediators (e.g. IL-6, CRP, VEGF), which is known that they promote the survival of cancer cells and metastasis.
Researchers have questioned whether targeted anti-inflammatory therapies that inhibit IL-6 and other inflammatory mediators play a role in modulation of the inflammatory association of body composition with cancer consequences. The perioperative application of taurolidine, a taured division, significantly reduced the circulating IL-6 levels in the first 7 days after the surgical resection in non-metastasized colon cancer.6Taurolidine has been shown to inhibit pro-inflammatory cytokines, particularly TNF-alpha and IL-6.7Whether taurolidine influences the results was not part of the study design.
In view of the obvious role, which plays high systemic inflammation in the case of poorer results in cancer, an anti -inflammatory nutritional approach should be considered. A study from 2006 observed a reverse connection between the absorption of fruit and vegetables and CRP.8Diets with high fiber content and rich in fruit and vegetables are associated with lower CRP levels, while consuming a western diet that is rich in fat, sugar, sodium and sophisticated cereals, correlated with increased CRP levels.9A 2004 study found that following a Mediterranean diet (rich in olive oil, fish, nuts, seeds, fruits and vegetables) reduced CRP levels by an average of 20 percent.10
Sleep hygiene and exercise can also be part of a strategy to address concerns about higher systemic inflammation. CRP, IL-6 and fibrinogen have been linked to sleep, with higher levels of these markers associated with poorer sleep.11More active people who exercise regularly have lower levels of IL-6 and CRP.12
The study reviewed here found unfavorable outcomes in non-metastatic colorectal cancer related to body composition and increased expression of pro-inflammatory signaling 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. Additionally, men made up 78.6% of study participants, compared to women at 21.4%.