In this study, the relationship between adipose tissue parameters in PET / CT and survival in mCRC patients was evaluated. A significant relationship was found between SAT ratio and overall survival and progression-free survival. In addition, in the subgroup of patients who received bevacizumab therapy, higher VAT SUV mean value was better in terms of progression-free survival.
Fat tissue is divided into two regions as visceral and subcutaneous fat tissue according to its distribution. Apart from the anatomical location, these two adipose tissues differ in terms of endocrine function, lipolytic activity and molecular aspects. Proinflammatory cytokine production and inflammatory cell number are higher in visceral adipose tissue [6, 7, 20]. We measured the volume and density values in PET / CT to evaluate the prognostic effect of the differences between VAT and SAT in colorectal cancer.
Previous studies on various cancer types have found different results in the effect of VAT and SAT volume on survival. In studies conducted in patients with head and neck cancer and non-small cell lung cancer, those with high BMI have been shown to have better survival [16, 21]. In this condition, which is called the obesity paradox, VAT and SAT volumes were measured to illuminate the protective effect of obesity. While better survival was observed in patients with high VAT volume in head and neck cancer, better survival was observed in patients with high SAT volume in non-small cell lung cancer. A similar relationship between high SAT volume and better survival has been demonstrated in renal cell carcinoma and prostate cancer studies [22, 23]. In these studies, it was thought that high SAT volume can prevent cancer cachexia against lipolysis and increased energy consumption as the protective mechanism of adipose tissue.
In our study, no relationship was found between VAT and SAT volume and survival. However, the ratio obtained by dividing the volume of SAT by density showed a significant correlation with overall survival in all patients, and progression-free survival and overall survival in patients receiving bevacizumab therapy. At this ratio, higher SAT volume was associated with better survival.
Due to adipose tissue dysfunction, the secretion of proinflammatory cytokines and chemokines increases and macrophage infiltration occurs [24]. As a result of the changes, the adipose tissue microenvironment becomes suitable for cancer development and tumor growth. In this environment, with the effect of cancer cells, adipocytes lose their lipid content and differentiate into fibroblast-like cells [25]. These adipocytes associated with differentiating cancer can increase tumor progression and metastasis. Fat tissue density on CT images was used to evaluate these changes in the adipose tissue environment. In a study conducted on non-human primates, it was found that high adipose tissue density was associated with adipocytes with lower lipid content and fibrotic change [26]. In previous studies conducted with pancreatic cancer, head and neck cancer and stomach cancer, it has been shown that high fat tissue density is worse in terms of prognosis [14, 21, 27]. Unlike the results of these studies conducted on various cancer types, in our study, no significant association was found between SAT and VAT density values and survival. However, it was shown that higher SAT density at SAT ratio may be associated with better survival.
FDG uptake of adipose tissue reflects glucose metabolism and inflammatory status. Conflicting results have been found in previous studies evaluating the relationship between FDG uptake of VAT and SAT with clinical results. In studies conducted with colon cancer, pancreatic and stomach cancer, it has been shown that high FDG uptake in VAT is worse in terms of survival [14, 15, 27]. It has been suggested that high FDG intake in these studies is associated with the inflammatory response that develops due to the increase in the expression of proinflammatory cytokines and macrophage infiltration in visceral adipose tissue. Studies on head and neck cancer and lung cancer did not show a significant relationship between fat tissue FDG uptake and survival [16, 21]. Apart from these, two studies have shown that low FDG uptake in adipose tissue is worse in terms of prognosis. One of the studies was conducted in pancreatic cancer patients, and it was found that SAT FDG uptake is decreased in advanced stage and tumors with high FDG uptake [28]. As an explanation, it has been shown that inhibitors released from tumor cells reduce fatty acid uptake in adipose tissue and inhibit lipoprotein catabolism. The other study is evaluating the relationship between the presence of colorectal adenoma and adipose tissue metabolism [29]. In this study, it was shown that the probability of having a colorectal adenoma was higher in those with low FDG uptake on VAT, and it was stated that this situation was caused by insulin resistance due to obesity. Decreased glucose metabolism in insulin resistant adipocytes and the increase in this insulin resistant adipocyte mass and low FDG uptake in VAT were explained. In our study, a significant association was found between VAT SUV and progression-free survival in patients receiving bevacizumab therapy. Survival was better in patients with high VAT SUV. In previous studies have been shown that VEGF release is higher in visceral adipose tissue [30, 31]. It has also been found that increased VEGF release is associated with proinflammatory cytokines and inflammation [32, 33]. The high VAT SUV mean may be associated with increased VEGF release. This may affect the response of bevacizumab therapy.
PET / CT is one of the imaging methods used for diagnosis, staging and follow-up of treatment response of colorectal cancer. The standard uptake value (SUV) is the parameter used to evaluate the degree of FDG uptake in PET / CT. Tumor SUV value is thought to be related with tumor aggressiveness and prognosis [34]. Previous studies on colon cancer, non-small cell lung cancer and nasopharyngeal cancer have shown that tumor SUV max value is associated with prognosis and higher SUV max value is associated with poorer survival [34–36]. In our study, PFS was found to be better in patients with high tumor SUV max value in the survival analysis performed in all patients and the group receiving bevacizumab therapy. Perhaps anti-VEGF therapy may be more effective in these patients.
Our study has some limitations. The study was conducted retrospectively in patients who were followed-up in a single center. In addition, there were limitations in the comparisons due to the lack of established method for the evaluation of adipose tissue metabolism and volume measurement.