INTRODUCTION
The incidence of colorectal cancer, the fourth and second leading causes of death in men (15.4%) and women (12.1%), respectively,
1 has been gradually increasing in Korea since 2000. Additionally, the prevalence of diabetes mellitus (DM) has increased rapidly in the last three decades in Korea and is forecasted to increase from 8.6% in 2007 to 10.8% in 2015.
2 As the prevalence of DM has increased, the risk of colon cancer, pancreatic cancer, bladder cancer, breast cancer, and others has been increasing as well.
3,4 Contrast-enhanced abdomino-pelvic CT and PET-CT are used in preoperative local staging evaluations and in diagnosing metastasis. A PET-CT scan is performed after injecting a non-metabolizable glucose sugar analogue, such as
18[F]-Fluorodeoxyglucose (FDG),
1 that remains in cells as an intermediate product. The degree of
18[F]-FDG accumulation in cells with active metabolism is referred to as the standardized uptake value.
5 Although FDG uptake in the bowel is often influenced by the amount of intracellular mucus, cell size, peristaltic movement, white blood cell count, and others,
6 maximal standardized uptake values (SUV
max) are elevated by an increase in the FDG accumulation in cancer cells with active metabolism. When blood glucose levels are high, elevated glucose levels can prevent FDG uptake in malignant tumor cells due to a competitive reaction. This may lead to decreased SUV
max values, as FDG uptake is relatively lowered in malignant neoplasms.
7,8 However, previous studies on the association between blood glucose levels and SUV
max in PET-CT have mainly been focused on patients without DM. This study aimed to investigate the effect of DM in patients with colorectal cancer on SUV
max, as well as the difference in SUV
max based on the degree of blood glucose control.
METHODS
1. Subjects
This study included 397 patients diagnosed with colorectal cancer through histopathological examination in the SMG-SNU Boramae Medical Center from January 2006 to December 2012 who also underwent FDG PET-CT scans. Data were collected from patients through reviewing clinical and radiologic records and pathologic examination and included age, sex, BMI, presence of DM, blood glucose levels, glycated hemoglobin (HbA1c) levels, postoperative lesion sizes, histological findings and stages, and others. We excluded patients with severe infections and inflammatory diseases that could affect test results, those with tumors in other organs, and those with unknown SUVmax values due to lack of FDG PET-CT scan data. In addition, we also excluded DM patients without confirmed blood glucose examinations and those without HbA1c levels collected in the two months prior to the PET scan. Colorectal cancer was diagnosed based on pathologic results and Tumour, Node, Metastases staging was based on the results of contrast-enhanced abdomino-pelvic CT, PET scan, colonoscopy, and pathologic results. This study received approval from the Institutional Review Board of the SMG-SNU Boramae Medical Center.
2. PET-CT Scan
Patients underwent FDG PET-CT scan after 8-hours of fasting. Blood glucose levels were measured prior to scanning, and patients without and with DM having levels <120 mg/dL and <180 mg/dL, respectively, received PET-CT. Patients drank sufficient water before the exam and then received 5.18 MBq of 18[F]-FDG per kg of body weight intravenously. PET scan images were obtained after 60 min using a GEMINI TF-64 scanner (Phillips Medical System, Cleveland, OH, USA). CT scanning was conducted from the basal skull to the femoral region, and attenuation correction was performed in CT images. After CT scanning, PET scans were conducted for 2.5 min per frame according to standard protocols. Sixty minutes have passed after intravenous injection of FDG, the image taking was performed. If the focal FDG uptake was seen in the captured image, and then further delayed images were taken after 4 hours later. Two nuclear medicine specialists evaluated uptake regions and SUVmax by interpreting PET scan images. SUVmax, the maximum amount of FDG accumulation in tumors depending on the dose of 18[F]-FDG injected with FDG-PET activity, was calculated using the percentage of the average rate of whole body uptake and the uptake rate for lesions.
3. Pathological Findings
Surgical resection was performed in 397 patients diagnosed with colorectal cancer and confirmed with endoscopic biopsy. Tumor size and the degree of infiltration were measured through pathologic examination after resection. The diameter of lesions was measured as lesion size after formalin fixation. The location of lesions was categorized into the proximal portion from the cecum to the transverse colon, the distal portion from the splenic flexure to the sigmoid colon, and the rectum area below the sigmoid colon. Anastomosis was defined in patients with a history of intestinal surgery. Lesions were classified into polypoid, ulceroinfiltrative, and ulcerofungating based on gross type, and neoplasms were generally categorized into well differentiated, moderately differentiated, and poorly differentiated carcinoma. In addition, lymph node metastasis, perineural infiltration, lymphatic invasion, and vascular invasion were examined in surgically resected tissues.
4. FDG-PET Findings according to the Level of Blood Glucose Control
We examined differences in patients with DM and colorectal cancer to identify the effects of HbA1c levels on SUVmax by dividing them into two groups, well-controlled and poorly controlled. By reviewing HbA1c levels measured in the two months prior to the PET scan, SUVmax values could be compared between patients with DM and HbA1c levels <8% and those with HbA1c levels ≥8%.
5. Statistical Analysis
Statistical analyses were performed using the SPSS version 20.0 for Windows (SPSS Inc., Chicago, IL, USA). P-values of less than 0.05 were considered statistically significant. T-tests and one-way ANOVAs were used to analyze continuous variables, and X2-tests or Fisher's exact tests were performed to analyze categorical variables. Linear regression was conducted to examine the association between SUVmax and colorectal cancer-related factors. Multiple linear regression was performed on factors demonstrating P-values of less than 0.25 in a simple linear regression analysis.
DISCUSSION
FDG uptake is elevated in malignant tumor tissues, as these tissues use energy mainly from glucose metabolic processes for survival. When blood glucose levels are high, elevated glucose levels can prevent FDG uptake in malignant tumor tissues due to a competitive reaction. This process is known to lower both the resolution of PET-CT scans and diagnostic sensitivity.
7 Only a few studies have investigated changes in FDG uptake in tumors of patients with DM and chronically elevated glucose levels.
9 The current study is the first to compare the differences in tumor SUV
max values during PET-CT according to the presence of DM in patients with colorectal cancer. No significant difference was found in SUV
max values between patients with and without DM. Only tumor size was identified as a factor that could influence SUV
max.
These results were comparable to those of a previous study that compared SUV
max values between patients with and without DM with esophageal cancer. Haley et al.
10 compared pre-treatment SUV
max values in 18 esophageal cancer patients with DM and 45 esophageal cancer patients without DM. There was no significant difference between tumor SUV
max in patients with and without DM (10.1±5.9 vs. 8.7±5.6 [
P=0.44]). When Gorenberge et al.
11 compared SUV
max between 40 lung cancer patients with DM and 145 lung cancer patients without DM, no significant difference in SUV
max was shown between patients with and without DM (5.86±3.97 vs. 6.47±5.48). Collectively, these results indicate that DM has an insignificant effect on the SUV
max values of PET-CT scans.
In the current study we used HbA1c levels to compare SUV
max according to the degree of blood glucose controlled in patients with DM. When patients with well-controlled glucose levels (HbA1c<8%) and poorly controlled glucose levels (HbA1c≥8%) were compared, no significant difference was found in SUV
max between the groups. Gorenberge et al.
11 reported no difference in SUV
max in patients with DM when comparing groups with different fasting blood sugar levels (≥126 mg/dL vs. <126 mg/dL). Moreover, a study of 219 subjects with cervical cancer compared 16 patients with DM and hyperglycemia, 12 patients with DM and normal glucose levels, and 191 patients without DM. SUV
max values were 12.83±11.47, 13.86±7.90, and 13.34±7.78 in each group, respectively, showing no difference.
12 These results imply that chronic hyperglycemia also has an insignificant influence on the SUV
max values of PET-CT scans.
There are several reasons why the presence of DM in patients with colorectal cancer would not result in differences in tumor SUVmax values, one being elevated tumor FDG uptake.
First, as part of the mechanism of increased glucose metabolism in cancer cells, a number of glucose transporter (GLUT1-GLUT7) genes are involved in the uptake of glucose to the plasma membrane. Of these GLUTs, an increase in the expression of GLUT1 and GLUT3 within tumors has been previously reported.
13,14 Because increased expression of GLUTs in tumors is sufficient to offset tumor uptake of FDG caused by increased glucose levels through competition, no differences were found in SUV
max values according to DM and blood glucose regulation.
Second, invasive cancer associated with ulceration is characterized by molecular biological instability and a large number of inflammatory cells.
15 Most of the subjects in our study had ulcerative-type lesions of colorectal cancer (88.8% in patients with DM, 87.7% in patients without DM). The lack of differences in SUV
max between these groups may be related to increased FDG uptake attributable to the large number of inflammatory cells that had a greater effect than the competitive inhibition of FDG uptake within tumors with elevated glucose levels.
The results of previous studies have suggested that OHAs can influence intestinal absorption of FDG in patients with DM. In particular, metformin has been shown to stimulate adenosine monophosphate-activated protein kinase in cells and to increase FDG uptake by mobilizing GLUT4 from the microsomal membrane to the plasma membrane.
16,17 Gontier et al.
18 performed PET scanning in 32 patients with DM receiving OHA therapy with metformin and insulin, 23 undergoing OHA therapy without metformin and insulin, and 95 patients without DM. As a result, a significant increase was observed in intestinal FDG uptake in patients undergoing OHA therapy with metformin and insulin as compared to the other groups. Moreover, a comparative study on 77 patients with DM and 77 healthy individuals reported that a significant increase in intestinal FDG uptake was observed in patients with DM receiving metformin.
19 In the current study, no differences in SUV
max were found among patients receiving OHA (71.2%), insulin (12.5%), combined insulin-OHA therapy (3.8%), or follow-up (12.5%). However, different OHAs including metformin, sulfonylureas, meglitinides, and alpha-glucosidase were administered to patients, and only three patients underwent combined therapy with insulin. For these reasons, large-scale studies are needed to further investigate the effects of OHAs on SUV
max.
The current study displayed a few limitations. First, blood glucose levels and PET scan periods may have varied in subjects due to the retrospective nature of the study. However, the impact of different blood collection times is thought to be minimal in the comparison of SUV
max by DM, as PET-CT scans were performed in patients during their hospital stay and at a glucose level <180 mg/dL. Second, there was no difference in SUV
max according to the types of OHAs used by patients in this study. However, the scope of this study was limited to analyze only the results based on the presence of DM. Third, a PET scan is usually done about an hour after the injection of
18[F]-FDG. The difference in FDG uptake may have been partially caused by inconsistent periods between PET-CT scans. This may not have been problematic, however, considering the outcomes of recent studies that have demonstrated that the SUV does not reach maximum until 130-500 min after injection of
18[F]-FDG in animal tests
20 and that
18[F]-FDG uptake is known to persist for 2-3 hours.
21,22
In conclusion, there was no difference in SUVmax values dependent on the presence of DM when performing 18[F]-FDG PET-CT scans in patients with colorectal cancer. Additionally, no association was found between glucose levels and SUVmax. Therefore, the results of the current study demonstrated that DM did not influence FDG uptake values in colorectal cancer patients.