|Ahead of print publication
The effect of body mass index on location of recurrence and survival in early-stage colorectal cancer
Abdullah Sakin1, Nilay Sengul Samanci2, Saban Secmeler3, Serdar Arici3, Orcun Can3, Nurgul Yasar3, Caglayan Geredeli3, Cumhur Demir3, Sener Cihan3
1 Department of Medical Oncology, Yuzuncu Yil University Medical School, Van, Turkey
2 Department of Medical Oncology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey
3 Department of Medical Oncology, Okmeydani Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
Department of Medical Oncology, Yuzuncu Yil University Medical School, Van
Source of Support: None, Conflict of Interest: None
Introduction: Obesity has become one of the major public health problems in many countries. Controversial results were reported in publications on the relationship between obesity and mortality in patients diagnosed with colorectal cancer (CRC) and that receive curative treatment. In this study, we evaluated the effects of body mass index (BMI) on the location of recurrence and disease-free survival (DFS) in patients with early-stage CRC.
Materials and Methods: Patients that were followed up and treated in the Department of Medical Oncology between 1999 and 2016 were retrospectively included in the study. Patients with operated Stage I, II, and III CRC were included in the study. Patients were divided into three groups based on their BMI (kg/m2) of below 25, between 25 and 30, and above 30.
Results: A total of 950 patients, of which 527 (55.5%) were male and 423 (44.5%) were female, were included in the study. The median age of the patients was 56 years. Of the patients, 408 (42.4%) had BMI of <25, 370 (38.9%) had BMI between 25 and 30, and 172 (18.2%) had BMI of ≥30. Local recurrence rate was significantly higher in the group with BMI ≥30 compared to the other groups (P <0.01). When compared with DFS, there was a statistically significant difference between groups with BMI of <25 and ≥30 (P = 0.02) and that difference was more evidently observed in Stage III (P = 0.02). There was no statistically significant difference of overall survival in the BMI groups (P = 0.87). In multivariate analysis, the BMI ≥30 (hazard ratio [HR], 1.49, 95% confidence interval [CI], 1.02–2.17), rectal tumor (HR, 1.70, 95% CI, 1.15–2.51), Stage III (HR, 3.91, 95% CI, 1.86–8.25), number of positive lymph nodes (HR, 1.05, 95% CI, 1.03–1.07), and R1 resection (HR, 3.47, 95% CI, 1.71–7.05) were identified as independent risk factors negatively affecting DFS.
Conclusion: In this study, we observed that the high BMI increased the risk of recurrence, especially in Stage III CRC patients, and that the recurrence frequently occurred locally.
Keywords: Body mass index, colorectal cancer, obesity, survival
|How to cite this URL:|
Sakin A, Samanci NS, Secmeler S, Arici S, Can O, Yasar N, Geredeli C, Demir C, Cihan S. The effect of body mass index on location of recurrence and survival in early-stage colorectal cancer. J Can Res Ther [Epub ahead of print] [cited 2019 Oct 21]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=260133
| > Introduction|| |
Colorectal cancer (CRC) forms a significant part of cancer-related morbidity and mortality around the world. It is estimated that 135,430 new cases are diagnosed each year in the USA. CRC mortality has been gradually increasing from 2.5% to 3% per annum since 1990. CRC is the third cause in women and the second in men in cancer-related deaths.
Obesity has become one of the major public health problems in many countries. The prevalence of obesity-related comorbidities increases parallel to the increase in the prevalence of obesity. Obesity is an established risk factor for various cancers, including CRC. Epidemiological data suggest that obesity increases cancer risk and cancer-specific mortality.
Although the mechanism is not fully understood, it is expected that some changes in obesity are expected to cause an increase in cancer risk. Insulin resistance and hyperinsulinemia stimulate the release of various inflammatory cytokines from the adipose tissue. These factors promote cancer cell proliferation, survival and angiogenesis in tumor tissues. Oxygen radicals increased by obesity cause systemic inflammation contributing to cancer development. Although obesity is an established risk factor for CRC incidence and mortality, inconsistent results were reported with mortality after CRC diagnosis and curative treatment.
In this study, we evaluated the effects of body mass index (BMI) on the location of recurrence and disease-free survival (DFS) in patients with early-stage CRC.
| > Materials and Methods|| |
Patients that were followed up and treated for CRC cancer at the Medical Oncology Clinic between 1999 and 2016 were retrospectively studied. The study included patients with the diagnosis of Stage I, II, and III colon or rectal adenocarcinoma. Patients with distant metastasis at the time of diagnosis, patients under the age of 18, and patients with >1 primary tumor were excluded from the study. Age, gender, height, weight, smoking and alcohol history, comorbidities, complaints at admission, radiological and pathological stages, and treatment data of the patients were obtained from their records retrospectively. Patients whose data were not available or missing were excluded from the study. A total of 950 patients who were eligible for the study and with accessible data were included in the study. The seventh edition of the tumor, node, and metastasis staging system of the American Joint Committee on Cancer/Union for International Cancer Control issued in 2010 was used for staging of patients. The BMI was calculated as weight/height (kg/m2). BMI was calculated in all patients using the postoperative first outpatient scale. Patients were divided into groups based on their BMI levels of below 25, between 25 and 30, and above 30. DFS was calculated as the time from diagnosis to local recurrence, systemic metastasis, or the date of death. Overall survival (OS) was calculated from the time of diagnosis to the date of death.
The study was performed in accordance with the Declaration of Helsinki and was approved by the Institutional Ethics Committee.
SPSS version 15.0 (SPSS Inc., Chicago, IL, USA) for Windows was used for statistical analysis. Descriptive statistics were given as mean, standard deviation, minimum and maximum for numerical variables, and as numbers and percentages for categorical variables. Numerical variable was analyzed using the Student's t-test when it met the normal distribution condition in both independent groups and by the Mann–Whitney U-test when it was unable to meet normal distribution condition. Ratios between the groups of categorical variables were analyzed by the Chi-square test. Monte Carlo simulation was used when conditions were not met. Survival analyses were performed with the Kaplan–Meier analysis. Determinants were analyzed by Cox regression analysis. Statistical significance alpha level was accepted as P < 0.05.
| > Results|| |
A total of 950 patients of which 527 (55.5%) were male and 423 (44.5%) were female, were included in the study. Of the patients, 408 (42.4%) had BMI of <25, 370 patients (38.9%) had BMI between 25 and 30, and 172 patients (18.2%) had BMI of ≥30. The mean age of the patients was 56 (range: 19–89), and there was no statistically significant difference among the groups (P = 0.3). There was a difference in gender ratios among the groups. The rate of female patients was significantly higher in the group with BMI ≥30 (P < 0.01). There were differences between the symptoms according to BMI groups (P = 0.01). Constipation was greater in those with a BMI of ≥30, and weight loss was more in the group with a BMI of <25 (P = 0.01). Diabetes and hypertension were significantly higher in the group with a BMI of ≥30 (P < 0.01). A statistically significant difference was not found among BMI groups in terms of grade, primary tumor localization, stage, pathologic tumor stage, number of lymph nodes (LN), R1 resection, and adjuvant treatment rates (P = 0.27, P = 0.21, P = 0.82, P = 0.34, P = 0.3, P = 0.84, P = 0.39, and P = 0.60, respectively). A significant difference was found in BMI groups regarding location of recurrence. Local recurrence rate was significantly higher in the group with a BMI of ≥30 compared to that of the other groups (P < 0.01) [Table 1].
|Table 1: Comparison of demographic and clinical data of patients according to body mass index groups|
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When DFS time was compared, there was a statistically significant difference between groups with a BMI of <25 and ≥30 (P = 0.02). When evaluated based on the stage, a statistically significant difference was observed between the groups with BMI <25 and ≥30 (P = 0.02), especially at Stage III. There was no statistically significant difference between the groups in terms of other stages [Figure 1].
A statistically significant difference was not found in OS in the BMI groups (P = 0.87) [Figure 2].
A statistically significant difference was not observed between DFS and OS based on gender in the BMI groups [Table 2].
|Table 2: Disease-free survival and overall survival in groups according to gender|
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DFS rates of 60, 120, and 180 months were 80.4%, 77.7%, and 77.7%, and the OS rates were 88.3%, 82.7%, and 82.7%, respectively. [Table 3] shows DFS and OS rates of 60, 120, and 180 months based on the BMI groups [Table 3].
|Table 3: Disease-free survival and overall survival rates of 60, 120, and 180 months according to body mass index groups (%)|
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In univariate analysis conducted in terms of developing recurrence, BMI ≥30 (hazard ratio [HR] =1.53, 95% confidence interval [CI] =1.05–2.22, P = 0.02), Grade 3 (HR = 2.18, 95% CI = 1.11–4.28, P = 0.02), Stage III (HR = 3.17, 95% CI = 1.55–6.47, P < 0.01), number of involved LN (HR = 1.01, 95% CI = 1.00–1.02, P = 0.03), number of positive LN (HR = 1.05, 95% CI = 1.03,-1.06, P < 0.01), R1 resection (HR = 4.08, 95% CI = 2.08–7.97, P < 0.01), and adjuvant treatment intake (HR = 0.21, 95% CI = 0.14–0.31, P < 0.01) were determined as factors affecting DFS. In multivariate analysis, the BMI ≥30 (HR = 1.49, 95% CI = 1.02–2.17, P = 0.03), rectal tumor (HR = 1.70, 95% CI = 1.15–2.51, P = 0.01), Stage III (HR = 3.91, 95% CI = 1.86–8.25, P < 0.01), number of positive LN (HR = 1.05, 95% CI = 1.03,-1.07, P < 0.01), and R1 resection (HR = 3.47, 95% CI = 1.71–7.05, P < 0.01) were identified as independent risk factors negatively affecting DFS. Adjuvant treatment intake (HR = 0.17, 95% CI = 1.11-0.25, P < 0.01) was found to be an independent risk factor positively affecting DFS [Table 4].
|Table 4: Factors affecting disease-free survival according to univariate and multivariate analysis in colorectal cancer patients|
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| > Discussion|| |
In this study, we investigated the relationship between BMI and DFS in operated nonmetastatic CRC patients, and the location of recurrence in patients who developed recurrence as per BMI. DFS was observed to be significantly shorter in the group with a BMI of >30, and recurrence developed, especially locally in this group.
The prevalence of obesity has dramatically increased over the past decades and is expected to rise further in the future. Obesity is known to be associated with many cancers. Esophageal, thyroid, and colon cancers in men and endometrium and biliary cancer in women are known to be related with obesity. The BMI classification is a set of simple determinants designed to assess the risks of diseases such as Type 2 diabetes and cardiovascular disease. Body fat percentage and body fat distribution differ among populations, and this leads to the use of different cutoff points in different countries. Despite the improvements in diagnosis and treatment, colon cancer continues to be a global health issue and remains to be one of the major causes of cancer-related morbidity and mortality worldwide., Epidemiological and large prospective studies have identified overweightedness and obesity as risk factors for the development of CRC.,, Two large prospective studies showed that obesity (BMI ≥30) increases the risk of developing colon cancer by approximately 1.5-fold compared to the normal weight (BMI = 18.5–24.9 kg/m2)., A recent study shows that there is a 6% increase in the risk of colon cancer incidence with a 5 kg weight gain in adults.
The effect of BMI on the prognosis of patients with CRC is unclear. The results of this study that investigate the effect of obesity on recurrence and survival following diagnosis and treatment of colon cancer are contradictory., In a study with 4,288 patients with Dukes B and C colon cancers, obese patients (BMI ≥30) were more likely to be women than normal weight patients (18.5–24 kg/m2), and are less likely to admit due to bowel obstruction. Neither the total LN status nor the number of positive LN were associated with BMI. In another study, the Stage I patient rate was lower in overweight (24.0–26.9 kg/m2) and normal weight (18.5–23.9 kg/m2) patients than obese patients (≥27 kg/m2). The number of Stage III patients was lower in the obese patient group. In this study, a significant relationship was not found between emergency surgery rate and BMI category. Hypertension and diabetes ratios were found to be significantly correlated with BMI. In this study, the incidence of right colon cancer was found to be increased with a lower BMI. In another study with 525 patients, 89 relapses and 131 deaths occurred during 48.8 months of follow-up. High BMI (BMI ≥23 kg/m2) was found to be associated with young age, presence of diabetes, alcohol consumption, distal colon localization, amount of LN removed, and pathological stage.
In this study, 201 (21.2%) relapses and 141 (14.8%) deaths were observed during an average of 7.6 years of follow-up. While our study found no difference in age among the groups, the rate of females was significantly higher in obese patients. Diabetes and hypertension were significantly higher in the obese group. A significant difference was not established among BMI groups in terms of grade, primary tumor localization, and stage. A difference was not found among the groups in terms of alcohol consumption, and smoking rate was significantly higher in the normal weight group.
In a study by Shibakita et al. conducted on 356 patients, lower BMI (BMI <21 kg/m2) was found to be associated with more advanced tumor stage compared to the normal BMI group (BMI 21–24 kg/m2) (P < 0.05). In the group with a high BMI (BMI ≥24 kg/m2), the mean number of LN dissected in patients was significantly lower than the normal BMI group (P < 0.05). In another study on Stage II and III colon cancer patients, obesity (BMI, ≥30 kg/m2) was associated with an increased number of LN involvement when compared with normal weight patients. In this study, there was no significant difference between the number of positive LN and the number of LN removed in BMI groups. In a study conducted by Sinicrope et al., a difference was not found in the local recurrence rates when compared with obese (BMI ≥30 kg/m2) patients and normal weight patients (BMI 20–24.9 kg/m2) and they suggested that obesity does not adversely affect adequacy of surgical resection. In this study, a difference was not established in the number of LN removed, number of LN involved, and surgical margin positivity in obese patients compared to the other group. Even if adequate surgery is performed in obese patients, local reccurrence is most commonly and more frequently observed in these patients.
In a study conducted by Liu et al., a relationship was not found between DFS and OS in patients with high BMI (BMI ≥23 kg/m2) compared with patients with normal BMI (>23). Even in male and female subgroups, PFS and OS were similar. However, in a multicenter retrospective study conducted by Meyerhardt et al. with Stage II and III colon cancer patients, obese patients (BMI ≥30 kg/m2) and normal weight patients (21.1–24.9 kg/m2) were compared, and they found a statistically insignificant 11% increase in both recurrent disease and mortality in obese patients. In their later studies, a statistically significant difference was not observed in recurrence and mortality between obese (BMI ≥30 kg/m2) and normal weight (BMI 21–25 kg/m2) patients, and there was no difference in survival between genders in the groups.
Chin et al. found in their study that patients with lower BMI (<18.5 kg/m2) had lower PFS and OS compared to the other patients. However, there was no difference in DFS and OS in patients with normal BMI (18.5–23.9 kg/m2), overweight patients (24.0–26.9 kg/m2), and obese patients (≥27 kg/m2). Dignam et al. reported that BMI >35 kg/m2 was associated with an increased risk of relapse and death, and it is also suggested that relapse, second primary tumor, and mortality were higher in obese patients (BMI ≥35 kg/m2) compared to the patients with normal BMI (18.5–24 kg/m2). Obese patients had a 27% increase in recurrence and mortality compared to normal overweight patients. However, the rate of noncancer mortality was reported as high in the group with very high BMI. In addition, the risk of mortality was found to be high in low-weight patients (BMI <18.5 kg/m2). There was no difference between the genders in the groups. Similarly, in a study by Sinicrope et al., patients were classified as low weight (BMI, <20 kg/m2), normal weight (BMI, 20–24.9 kg/m2), class 1 obesity (BMI 25–29.9 kg/m2), class 2 obesity (BMI, 30–34.9 kg/m2), and class 3 obesity (BMI, ≥35 kg/m2). Class 2–3 obesity groups were found to have poorer PFS and OS rates when compared to the normal weight group. Moreover, patients in this group also had a worse PFS in multivariate analysis. Morbidly obese men (BMI ≥35 kg/m2) had an increased risk of death by 35%, whereas morbidly obese women had an insignificant 11% risk of death compared with normal weight patients. In another study, patients were classified as obese (BMI >24.0 kg/m2), middle BMI group (BMI, 21–24.0 kg/m2), and low BMI group (BMI <21.0 kg/m2). The 5-year DFS rates of high and low BMI groups were significantly lower than those of the intermediate BMI group.
Tartter et al. concluded that body weight is an important prognostic factor in patients with colon cancer. However, BMI appears to be a stronger prognostic factor in females than males. In a highly variable analysis, the adverse prognostic effect of BMI was observed in males, but not in females. In obese males (BMI ≥35.0 kg/m2), there was a statistically significant decrease in DFS compared to normal weight male.
This study found that obese patients had an early recurrence compared to the other patient groups, and this difference was observed, especially in Stage III patients. BMI ≥30 appear to increase the risk of relapse by 1.49 times in this study. When checked the groups in terms of gender, the results of previous studies are inconsistent. Some studies suggested that the survival of obese male patients is low,, while another study found that women had lower survival. However, other studies did not find any difference between the genders.,, In this study, a statistically significant difference was not found between the genders in DFS and OS groups. OS and DFS were low in other studies in slim patients.
On the other hand, this study had some limitations. It was designed as a retrospective study and the OS rate for CRC could not be calculated since some of the patients may have died from noncancer causes because of the long follow-up period. This may be the reason as to why BMI had no effect on OS.
In conclusion, we observed that the high BMI in this study increased the risk of recurrence, especially in Stage III colon cancer patients, and that the recurrence frequently occurred locally. The interventions aiming to change the BMI of obese patients following a diagnosis of colon cancer may have the potential to improve the outcome. A wide range of prospective studies are needed to evaluate the possible benefits of weight loss in obese CRC patients.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]