3. The effect of obesity on clinical outcomes

#### 3.1. In the adjuvant setting

As we mentioned earlier, several studies have established a link between obesity and colon cancer risk, but there is little information about the effects of obesity on clinical outcomes after diagnosis and surgical treatment. In the first publication, Dignam et al. reported a significant increased risk for recurrence and death from colon cancer in very obese patients (BMI ≥35 kg/m2 ) who receive adjuvant chemotherapy [146]. They investigated the association of BMI with the outcomes of 4288 patients with Dukes B and C colon cancer. This study cohort was from cooperative group clinical trials. They observed 2074 events in this study population and hazard ratio (HR) for risk of recurrence was 1.38 (95% confidence interval [CI] = 1.10–1.73), and HR for risk of mortality was 1.28 (95% CI = 1.04–1.57) in very obese patients compared with normal weight patients.

The Adjuvant Colon Cancer Endpoints database also compared the outcomes in patients (N = 25,291) with stage II and stage III colon cancer receiving adjuvant chemotherapy, and they showed inferior outcomes both for obese as well as underweight patients [147]. Men with class 2 and 3 obesity (BMI ≥ 35.0 kg/m2 ) had a statistically significant reduction in DFS (HR: 1.16; 95% CI = 1.01–1.33; p = .0297) compared with normal-weight patients. These worse outcomes appeared to be cancer-related.

On the other hand, Cancer and Leukemia Group B (CALGB) 89803 trial investigators did not find any significant associations between an increased risk of recurrence and mortality and BMI in patients with stage III colon cancer [148]. In this study, they observed 369 events in 1053 patients. The difference between studies should be related to statistical power. Another explanation is related to suboptimal adjuvant therapy (calculating dose according to a maximum body surface area of 2.0 m<sup>2</sup> ) in very obese patients in the study by Dignam et al.

#### 3.2. In metastatic disease

Clustering of clinical findings made up of abdominal obesity (apple-shaped body), hyperglycemia with insulin resistance, dyslipidemia (high triglyceride, low high-density lipoprotein), and hypertension is accepted as metabolic syndrome [23]. It is clear that one of the conse-

Insulin, IGFs PI3K-Akt Evading apoptosis (resisting cell death) Insulin, IGFs RAS-RAF-MAPK-Cyclin D1 Sustaining proliferative signaling IGFs Disruption of E-cadherin/catenin Activating invasion and metastasis Leptin JAK2-STAT3-MAPK Sustaining proliferative signaling

As we mentioned earlier, several studies have established a link between obesity and colon cancer risk, but there is little information about the effects of obesity on clinical outcomes after diagnosis and surgical treatment. In the first publication, Dignam et al. reported a significant increased risk for recurrence and death from colon cancer in very obese patients (BMI ≥35

The Adjuvant Colon Cancer Endpoints database also compared the outcomes in patients (N = 25,291) with stage II and stage III colon cancer receiving adjuvant chemotherapy, and they showed inferior outcomes both for obese as well as underweight patients [147]. Men with

1.16; 95% CI = 1.01–1.33; p = .0297) compared with normal-weight patients. These worse out-

On the other hand, Cancer and Leukemia Group B (CALGB) 89803 trial investigators did not find any significant associations between an increased risk of recurrence and mortality and BMI in patients with stage III colon cancer [148]. In this study, they observed 369 events in 1053 patients. The difference between studies should be related to statistical power. Another

) had a statistically significant reduction in DFS (HR:

) who receive adjuvant chemotherapy [146]. They investigated the association of BMI with the outcomes of 4288 patients with Dukes B and C colon cancer. This study cohort was from cooperative group clinical trials. They observed 2074 events in this study population and hazard ratio (HR) for risk of recurrence was 1.38 (95% confidence interval [CI] = 1.10–1.73), and HR for risk of mortality was 1.28 (95% CI = 1.04–1.57) in very obese patients compared with

quences of metabolic syndrome is the increased risk of carcinogenesis.

Growth factors Pathways Hallmarks of cancer

Leptin/VEGF PI3K-MAPK Inducing angiogenesis

Leptin, TNF-alpha, IL-6 Multiple pathways Tumor promoting inflammation

Table 4 summarizes obesity-related mechanisms of carcinogenesis.

3. The effect of obesity on clinical outcomes

Table 4. Obesity-related mechanisms of carcinogenesis.

3.1. In the adjuvant setting

86 Body-mass Index and Health

normal weight patients.

class 2 and 3 obesity (BMI ≥ 35.0 kg/m2

comes appeared to be cancer-related.

kg/m2

In advanced colorectal cancer, there are more trials than in the adjuvant setting evaluating the role of obesity on clinical outcomes. In a pooled analysis from four large, prospective studies, among 6128 patients with metastatic CRC treated with first-line bevacizumab and chemotherapy, patients with the lowest BMI (<25 kg/m2 ) experienced the lowest median OS [149]. This study is presented at the World Congress on Gastrointestinal Cancer 2015. This observation concerning the relationship between worse outcome and the lowest BMI does not mean that obesity is an advantage in patients with mCRC [150]. Probably, in patients with mCRC with a lower BMI, the effects of cancer-related cachexia may be more deleterious. These patients may have less tolerance to the treatments. According to another explanation, obesity may promote angiogenesis and bevacizumab, which is an anti-VEGF monoclonal antibody and may have a vital role in obese patients.

There are also other trials with contradictory results [151–155]. In a trial investigating the influence of BMI on outcomes in advanced CRC patients receiving chemotherapy with or without targeted therapy, BMI was shown as an independent prognostic factor for survival in patients receiving chemotherapy (CT), but not in patients receiving CT plus targeted therapy [151]. In patients receiving only CT, median OS was 19.5 months for BMI category >30 kg/m<sup>2</sup> versus 8 months for BMI category <18.5 kg/m<sup>2</sup> (p = 0.001). In patients receiving CT plus targeted therapy, median OS was 21.4 months for BMI category >30 kg/m<sup>2</sup> versus 16.6 months for BMI category <18.5 kg/m<sup>2</sup> (p = 0.8). In another trial, the authors speculate that higher circulating levels of VEGF may confer resistance to bevacizumab [152]. In our retrospective trial, we found better time to progression (TTP) in patients who have BMI < 25 kg/m<sup>2</sup> compared to patients who have BMI > 25 kg/m<sup>2</sup> ; median TTP was 11.7 months versus 6 months, respectively (p = 0.004) [153]. All patients had been treated with fluoropyrimidine-based combination CT plus bevacizumab. We think that patients with high BMI may require higher dosages. In another similar trial, the investigators compared OS across the BMI groups for CRC, and they found that the OS was shorter for patients who were underweight and overweight compared to normal in the group of patients receiving CT + targeted therapy. There was no difference in OS for CT alone [154]. In a recent multicentric study, we demonstrated that obesity serves as a prognostic factor for mCRC patients who have been treated with bevacizumab-based regimens. In particular, among Kras wild-type left-sided tumor patients with bevacizumab-based regimens, the prognosis could be worse for obese patients than that for non-obese patients [155].

#### 4. Conclusion

High BMI or obesity is an established risk factor in colorectal carcinogenesis. Adipose tissue excess, particularly abdominal obesity is linked to hyperinsulinemia, insulin resistance, hyperglycemia, and to the development of type 2 diabetes which are the components of metabolic syndrome. Chronic low-grade inflammation is a hallmark of obesity, and obesity supports many hallmarks of carcinogenesis. It is clear that one of the consequences of metabolic syndrome is the increased risk of carcinogenesis. Targeting obesity and metabolic syndrome should be beneficial in the prevention and the treatment of colorectal cancer.

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