Abstract
Background: Several studies have demonstrated that obesity is a risk factor for colorectal cancer (CRC), but few data are available regarding its role in multifocal disease and postoperative recurrence. The present study aimed to assess the role of obesity as a risk factor for multifocal disease and postoperative recurrence in patients with CRC. Patients and Methods: The records of 940 consecutive patients with CRC admitted to three surgical centres between January 2006 and January 2011 were retrospectively analysed. The 595 individuals whose preoperative body mass index (BMI) values were available were included in the study. Following WHO guidelines, the patients were stratified into four groups depending on their BMI values. Age at disease onset, clinical presentation, tumor invasiveness, the presence of multiple foci, and the colon cancer recurrence rate in the four groups were assessed and compared. Results: At multivariate analysis, diagnosis of familial adenomatous polyposis (FAP) and a BMI>30 were found to be independent predictors of synchronous polyps (Odd Ratio [OR]=10.7, 95% Confidence interval (CI)=2-75, p=0.005; and OR=2.2, 95% CI=1.3-3.9, p=0.003, respectively). The cancer recurrence rate in the patients with stage 2 CRC was significantly higher in the obese with respect to the non-obese (p=0.05). At multivariate analysis, BMI>30, FAP, and positivity by the Bethesda criteria were found to be independent predictors of recurrence after CRC surgery. Conclusion: Obese patients diagnosed with CRC require thorough colonic exploration prior to surgery and necessitate more frequent postoperative endoscopic examinations with respect to patients without any risk factors.
Colorectal cancer (CRC) is the second leading cause of cancer death among American adults and in Western countries (1), and a rapid increase in CRC morbidity has also been observed over recent decades, especially in rapidly developing countries such as China, characterized by significant diet and lifestyle changes (2). Several meta-analyses have consistently reported that adult obesity is specifically associated with an increased risk of colonic cancer (3-6), and metabolic syndrome has also been found to be associated with a higher risk of colorectal cancer (CRC) and mortality in both sexes (7). According to a review/meta-analysis examining the association between CRC with metabolic syndrome and its components, risk estimates were significant for each single factor (higher body mass index (BMI)/waist, dysglycemia, and higher blood pressure) (7). Although the etiology of CRC is not completely understood, several studies have demonstrated that lifestyle choices, such as smoking, higher consumption of red meat, low consumption of vegetables and fruit, low levels of physical activity, high-fat/low-fiber diets may be contributing factors (8-10). The fact that the prevalence of overweight/obesity, and with it, the risk of mortality from cancer, continues to increase in most parts of the world (including the Asia-Pacific region) is clearly indicative of the need for strategies to prevent obesity and for screening for cancer (11).
Several mechanisms have been implicated in the association between obesity and CRC onset. For one, obesity is characterized by high leptin levels. Leptin can induce preneoplastic colon is epithelial cells to orchestrate vascular endothelial growth factor (VEGF)-driven angiogenesis (12), and in males, high leptin concentrations seem to be associated with an increased risk of colonic adenoma (13). Leptin receptor polymorphisms have been associated with an increased risk for CRC and this association seems to be strengthened by cigarette smoking and family history of cancer (14). For another, while adiponectin has been reported to have anti-carcinogenic properties, its levels are lower in obese patients and its receptors seem to be intimately related to CRC progression (15).
Familial adenomatous polyposis (FAP), Lynch or hereditary non polyposis colonic cancer syndrome (HNPCC), inflammatory bowel disease (IBD), and smoking are the best-characterized risk factors for multifocal disease and CRC recurrence. FAP is by definition multifocal and the cumulative risk of pouch adenoma after restorative proctocolectomy is 20% after eight years (16). Small adenomas are common occurrences and frequently missed in patients with HNPCC syndrome (17). The National Comprehensive Cancer Network guidelines recommend more frequent (i.e. annual) post-treatment colonoscopies in these patients (18). Patients with ulcerative colitis (UC) are at higher risk of CRC. Polypoid dysplasia can be classified as within (adenoma-like dysplasia) or outside (sporadic adenoma) the most proximal endoscopic or histological extent of colitis. According to a recent study, following polypectomy, the 5-year cumulative incidence of cancer or flat dysplasia was 13% (19), and the cumulative risk of pouch dysplasia after restorative proctocolectomy for UC was approximately 3-4% (20). Finally, the findings that the association between cigarette smoking and colorectal polyp risk is modified by tobacco carcinogen-metabolizing polymorphisms (21) and that the association between smoking and adenoma recurrence is significant after a long exposure (22) provide support for a causal role of cigarette smoking in the etiology of colorectal tumors.
The study's aim was to assess obesity as a risk factor for multifocal disease and post-treatment CRC recurrence in obese patients who underwent surgery for CRC.
Patients and Methods
Study design. This retrospective case–control study was carried-out in accordance with the principles of the amended Helsinki Declaration, and all potential participants were asked to give their written permission for the investigators to collect and review their hospital records. The records of 940 consecutive patients diagnosed with colorectal adenocarcinoma admitted to three surgical centers (Second Department of Surgery, Cà Foncello Regional Hospital, Treviso; Department of Surgical and Gastroenterological Sciences, University of Padova; Oncological Surgery Unit, Veneto Institute of Oncology, Padova) between January 2006 and January 2011 were retrospectively collected and analyzed. Patients' weight, height, and BMI were measured/calculated, and their healthy weight and BMI values at diagnosis were retrieved from their clinical records. Only those whose BMI values at diagnosis were available were included in the study.
Following the WHO guidelines, the patients were stratified into four groups on the basis of their BMI values before disease onset: patients whose BMI was over 30 were considered obese, those whose BMI was between 25 and 29.9 were considered overweight, those whose BMI was lower than 25 were considered normal weight, and those with BMI lower than 20.9 were considered underweight. The patients' demographic and oncological features, the presence of multifocal disease, and recurrence rate of the four groups were compared.
Surgical technique. The surgical approach was the same in all three groups. Colonic resection consisted in the complete removal of the primary cancer ensuring adequate tumor-free margins, complete anatomic lymphadenectomy (at least 12 lymph nodes) and, wherever possible, en bloc resection extending to any involved adjacent organs. Total mesorectal excision with removal of the mesorectum and all lymph nodes within an oncological package was the standard treatment for all the patients. Patients with tumors located in the middle or upper rectum underwent an anterior or low anterior resection with preservation of the anal sphincter, while patients with distal tumors underwent complete abdominoperineal resection of the rectum with a permanent colostomy. Both conventional open surgery with median laparotomy and video laparoscopic approaches were performed in all three surgical units involved in this study.
Follow-up protocol. The follow-up protocol adopted by all three participating centers was designed in accordance with the American Society of Clinical Oncology (ASCO) guidelines (23). Briefly, our protocol recommended yearly computed tomography (CT) scans, carcinoembryonic antigen (CEA) testing every three months, and an evaluation by both the surgeon and oncologist every six months for the first two years and once a year thereafter for the following five years. Colonoscopies were to be performed one and three years after surgery and, if these were negative, every five years thereafter. Patients with high-risk hereditary CRC syndromes or those with rectal cancer had yearly colonoscopy. Patients who did not come to their outpatient appointments were contacted personally or through their family physician. All patients received a minimum follow-up of six months.
Statistical analysis. Data are expressed as medians (interquartile range-IQR-) or numbers (percentage of patients). Univariate analyses were performed using the Chi-squared test for qualitative variables and Kruskall–Wallis ANOVA or Mann–Whitney U-test for quantitative variables, as appropriate. Known risk factors (FAP diagnosis, positivity by the Bethesda criteria for HNPCC diagnosis (24), Inflammatory bowel diseases (IBD) diagnosis, active smoking and BMI>30) were included in logistic regression analysis models to identify independent predictors of multifocal disease. Cox proportional hazard regression models with the same potential predictors were used to analyze CRC recurrence stratified according to stage. The threshold for statistical significance was set at p≤0.05. Statistical analysis was performed with STATISTICA 5.1 (Statsoft, Tulsa, OK, USA).
Results
Characteristics of excluded patients. Five hundred and ninety-five individuals who underwent colorectal resection and whose BMI values at diagnosis were available were included in the study. BMI values were not available in 342 cases because height was not always registered in patients' medical records. As shown in Table I, the demographic and oncological characteristics at baseline of the excluded and included patients were similar.
Patient characteristics.
Characteristics of the included patients. Seventy-five of the 595 patients were classified as obese (BMI>30), 226 were classified as overweight (BMI=25-29.9), 249 were classified as normal weight (BMI<24.9), and 45 were classified as underweight (BMI<20). No statistically significant difference was observed in the four groups in terms of age at disease onset, cancer stage, cancer localization, serum levels of CEA, cancer antigen 125 (CA125), cytokeratin 18 (CK18) and CA19.9, the Bethesda criteria for HNPCC diagnosis, FAP diagnosis, or active smoking habits. The obese patients were more frequently male, had significantly higher serum CA15.3 levels, and more frequently self-reported a history of smoking. Obese patients tended to have a higher American Society Anesthesiologists score. Some symptoms and features, such as abdominal pain, weight loss and abdominal mass, were significantly more frequent in the underweight patients. Underweight patients more frequently reported history of IBD. There was a significantly more frequent history of previous CRC and more frequent family history of CRC or HNPCC syndrome-related cancer in the underweight patients. The Signet ring cell histotype was, moreover, more frequent in the underweight patients. No statistically significant differences were found in the four groups in terms of age at disease onset. When the patients were stratified according to gender, age at disease onset was significantly lower in the underweight and obese male patients (p=0.03). Characteristics of patients included are outlined in Table II.
Multifocal disease. One hundred and sixteen (19.4%) of the patients studied had synchronous polyps and 20 (3.4%) had synchronous CRC. The obese patients had a significantly higher frequency of synchronous colon polyps (p=0.007). They also had a higher frequency, although not significantly, of synchronous CRC. At multiple logistic regression analysis, FAP diagnosis and a BMI>30 were independent predictors of synchronous polyps (OR=10.7, 95% CI=2-75, p=0.005 and OR=2.2, 95% CI=1.3-3.9, p=0.003, respectively), while IBD, at least one positive Bethesda criterion, and active smoking did not seem to be implicated in multifocal disease. The relationship between the presence of synchronous colonic lesions and obesity is outlined in Figure 1.
Characteristics of patients stratified into four groups based on body mass index (BMI.)
Colonic recurrence of CRC. The overall and disease-free survival rate of the 595 patients who underwent colonic resection for CRC did not seem to be correlated to BMI status even when the patients were stratified by stage and BMI class. Colonic recurrence in the patients with stage 2 CRC was, however, significantly higher in the obese with respect to their non-obese counterparts (p=0.05). Colonic recurrence in patients with stage 3 disease also tended to be more frequent in the obese with respect to the non-obese patients (p=0.08). At multivariate analysis, BMI>30, FAP, and positivity by Bethesda criteria were independent predictors of colonic recurrence after CRC resection. The relationship between cancer recurrence and obesity is outlined in Figure 2.
Discussion
A vast, highly authoritative twin study examining the overall contribution of inherited genes to the development of malignant diseases concluded that the environment has the principal role in causing sporadic cancer (25). Higher BMI, red meat consumption, cigarette smoking, low levels of physical activity and of vegetable/fruit consumption have all been found to be associated with a moderately increased risk of CRC (10). While several meta-analyses have consistently reported that adult obesity is associated with an increased risk of colonic cancer (3-6), few studies have examined how obesity affects multifocal disease, CRC recurrence, and survival (26). The aim of the present study was to assess the role of obesity as a risk factor for multifocal disease and to evaluate and compare postoperative cancer recurrence in obese and non-obese patients who have undergone surgery for CRC.
The incidence of obese patients with CRC in the population studied was slightly higher than 9.4%, which is the incidence of obesity in the general population of adults over 18 living in the Veneto region in 2009 (27). The incidence of obese patients with CRC over the age of 45 years, which was between 11.9% and 40%, was likewise similar to the incidence of obesity in the general regional population.
One study carried-out at the Chicago University Hospital detected synchronous polyps in 29.8% of patients with CRC (28), and another performed at the Aristotle University in Greece found them in 23.5% (29). While 19.4% of our entire CRC population had synchronous polyps, over 30% of the obese patients did. The obese patients had, in fact, a significantly higher frequency of synchronous polyps, as well as a higher frequency (but not significantly) of synchronous CRC. According to multivariate analysis, FAP diagnosis and a BMI>30 were the only independent predictors of the presence of synchronous adenomatous polyps.
Obesity is associated with multiple disease foci.
A recent systematic review concluded that obesity and overweight are significant risk factors for colorectal adenomas (30), and according to a large Korean study, even in the absence of a metabolically unhealthy state, excess body weight is positively associated with an increased presence of colorectal adenomas (31). According to large, authoritative Dutch study, a BMI over 25 increased the risk of colorectal adenomas in male adults with HNPCC diagnosis (32), but little information is available concerning synchronous adenomas in the presence of CRC and obesity.
The recurrence rate of colonic cancer in our patients with stage 2 CRC was significantly higher in the obese compared to the non-obese patients. While in patients with stage 3 disease, the recurrence rate might have been affected by postoperative chemotherapy, this was not the case in the obese patients with stage 2 disease who did not undergo any adjuvant therapy. This consideration might explain why recurrence only tended to be more frequent in the obese patients with stage 3 colon cancer compared to the non-obese ones, with a marginal statistically significant difference.
At multivariate analysis, FAP and positivity by Bethesda criteria were found to be independent predictors of CRC recurrence after CRC resection, while a BMI over 30 was a weak independent predictor. Literature data seem to confirm these findings. In fact, according to the investigators of a large study carried out at the Howard University of Washington, obesity was associated with an increased risk of adenoma recurrence (33), and a recent meta-analysis concluded that there may be an association between high BMI and body fat at the time of diagnosis, with a high CRC-specific recurrence rate (26).
These data suggest that obesity has an independent role in the multifocality of carcinogenesis pathways that could be ascribed to the hormonal effect of leptin (13). According to a recent Irish study, in fact, the metabolic syndrome and plasma leptin were found to be associated with a more aggressive CRC phenotype in male patients (34). Obesity is then another factor that should be taken into consideration when the surgical procedure is being planned: a thorough evaluation of the entire colon is necessary in the obese patient because the surgical procedure may need to be more extensive than that dictated by the primary cancer (28). Prospective studies are, moreover, warranted to establish the most appropriate postoperative surveillance timetable: follow-up appointments may be less frequent than those adopted in the case of patients with HNPCC, but more frequent than those for patients without any risk factors. These considerations are particularly important in view of the fact that the ASCO guidelines do not consider obese patients to be at particular risk (23).
Colonic recurrence in stage II is influenced by BMI >30.
In conclusion, our study findings suggest that obesity plays an independent role in the multifocality of carcinogenesis. In practical terms, this means that obese patients diagnosed with CRC require thorough colonic exploration prior to surgery and necessitate more frequent postoperative endoscopic examinations with respect to patients without any risk factors. Further large-scale studies are, of course, warranted.
Acknowledgements
The Authors are extremely grateful to Ms Linda Inverso for her kind help in the final editing of the manuscript.
This study was partially funded by Current Research Funds from the Italian Ministry of Health to Carlo Castoro.
Footnotes
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↵* These Authors contributed equally to this study.
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Conflicts of Interest
None.
- Received May 29, 2014.
- Revision received July 11, 2014.
- Accepted July 14, 2014.
- Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
