There is clear evidence that nutrition and lifestyle can modify colorectal cancer risk. However, it is not clear if those factors can affect colorectal cancer treatment, recurrence, survival and quality of life. This paper describes the background and design of the “COlorectal cancer: Longitudinal, Observational study on Nutritional and lifestyle factors that may influence colorectal tumour recurrence, survival and quality of life” – COLON – study. The main aim of this study is to assess associations of diet and other lifestyle factors, with colorectal cancer recurrence, survival and quality of life. We extensively investigate diet and lifestyle of colorectal cancer patients at diagnosis and during the following years; this design paper focusses on the initial exposures of interest: diet and dietary supplement use, body composition, nutrient status (e.g. vitamin D), and composition of the gut microbiota.

Background: Glycemic traits—such as hyperinsulinemia, hyperglycemia, and type 2 diabetes—have been associated with higher colorectal cancer risk in observational studies; however, causality of these associations is uncertain. We used Mendelian randomization (MR) to estimate the causal effects of fasting insulin, 2-hour glucose, fasting glucose, glycated hemoglobin (HbA1c), and type 2 diabetes with colorectal cancer.Methods: Genome-wide association study summary data were used to identify genetic variants associated with circulating levels of fasting insulin (n = 34), 2-hour glucose (n = 13), fasting glucose (n = 70), HbA1c (n = 221), and type 2 diabetes (n = 268). Using 2-sample MR, we examined these variants in relation to colorectal cancer risk (48 214 case patient and 64 159 control patients).Results: In inverse-variance models, higher fasting insulin levels increased colorectal cancer risk (odds ratio [OR] per 1-SD = 1.65, 95% confidence interval [CI] = 1.15 to 2.36). We found no evidence of any effect of 2-hour glucose (OR per 1-SD = 1.02, 95% CI = 0.86 to 1.21) or fasting glucose (OR per 1-SD = 1.04, 95% CI = 0.88 to 1.23) concentrations on colorectal cancer risk. Genetic liability to type 2 diabetes (OR per 1-unit increase in log odds = 1.04, 95% CI = 1.01 to 1.07) and higher HbA1c levels (OR per 1-SD = 1.09, 95% CI = 1.00 to 1.19) increased colorectal cancer risk, although these findings may have been biased by pleiotropy. Higher HbA1c concentrations increased rectal cancer risk in men (OR per 1-SD = 1.21, 95% CI = 1.05 to 1.40), but not in women.Conclusions: Our results support a causal effect of higher fasting insulin, but not glucose traits or type 2 diabetes, on increased colorectal cancer risk. This suggests that pharmacological or lifestyle interventions that lower circulating insulin levels may be beneficial in preventing colorectal tumorigenesis.

Survival from colorectal cancer is positively associated with vitamin D status. However, whether this association is causal remains unclear. Inflammatory processes may link vitamin D to colorectal cancer survival, and therefore investigating inflammatory markers as potential mediators may be a valuable next step. This review starts with an overview of inflammatory processes suggested to be involved in colorectal cancer progression and regulated by vitamin D. Next, we provide recommendations on how to study inflammatory markers in future epidemiologic studies on vitamin D and colorectal cancer survival. Mechanistic studies have shown that calcitriol—active form of vitamin D—influences inflammatory processes involved in cancer progression, including the enzyme cyclooxygenase 2, the NF-κB pathway, and the expression of the cytokines TNFα, IL1β, IL6, IL8, IL17, and TGFβ1. Based on this and taking into account methodologic issues, we recommend to include analysis of specific soluble peptides and proteins, such as cytokines, in future epidemiologic studies on this issue. Vitamin D and the markers should preferably be measured at multiple time points during disease progression or recovery and analyzed using mediation analysis. Including these markers in epidemiologic studies may help answer whether inflammation mediates a causal relationship between vitamin D and colorectal cancer survival. Cancer Epidemiol Biomarkers Prev; 24(12); 1–9. ©2015 AACR.

Purpose of Review This review summarizes the evidence regarding diet, physical activity, smoking, and body composition after colorectal cancer (CRC) diagnosis in relation to all-cause and CRC-specific mortality and disease recurrence and gives suggestions for future research directions. Recent Findings Overall, this review suggests that some, albeit not all, of the well-known modifiable risk factors for cancer incidence might also be associated with CRC survival. CRC prognosis appears to be worse with increased physical inactivity, smoking, or being underweight after CRC diagnosis. Emerging evidence suggests that diets associated with a positive energy balance, e.g., high consumption of sugar-sweetened beverages, may negatively impact survival in CRC survivors. In contrast, there is currently little evidence to support the recommendation to limit red and processed meat or alcohol intake after CRC diagnosis. Whether being overweight and obese after CRC diagnosis improves or worsens CRC prognosis remains controversial and may depend on the measure used to assess body fatness. Summary Further research on post-diagnosis lifestyle patterns is needed to understand the multifactorial influence on CRC prognosis. Disease recurrence and the development of comorbidities should be included as key outcomes in future studies and lifestyle should preferably be repeatedly measured.

Higher concentrations of 25-hydroxyvitamin D₃ [25(OH)D₃] at diagnosis are associated with a lower mortality risk in colorectal cancer (CRC) patients. However, magnesium and calcium are important in vitamin D metabolism. We aimed to investigate 25(OH)D₃, magnesium, or calcium and their interaction among patients with CRC in relation to recurrence and all-cause mortality. The study population included 1169 newly diagnosed stage I–III CRC patients from 2 prospective cohorts. Associations between 25(OH)D₃ concentrations, magnesium or calcium intake through diet and/or supplements at diagnosis, and recurrence and all-cause mortality were evaluated using multivariable Cox proportional hazard models. The interaction between 25(OH)D₃ and magnesium or calcium was assessed by investigating 1) joint compared with separate effects, using a single reference category; and 2) the effect estimates of 1 factor across strata of another. Serum 25(OH)D₃, calcium, and magnesium, alone and their interactions, were not associated with recurrence. Serum 25(OH)D₃ concentrations seemed to be associated with all-cause mortality. An inverse association between magnesium intake (HR_{Q3 vs. Q1}: 0.55; 95% CI: 0.32, 0.95 and HR_{Q4 vs. Q1}: 0.65; 95% CI: 0.35, 1.21), but not calcium intake, and all-cause mortality was observed. When investigating the interaction between 25(OH)D₃ and magnesium, we observed the lowest risk of all-cause mortality in patients with sufficient vitamin D concentrations (≥50 nmol/L) and a high magnesium intake (median split) (HR: 0.53; 95% CI: 0.31, 0.89) compared with patients who were vitamin D deficient (<50 nmol/L) and had a low magnesium intake. No interactions between calcium and vitamin D in relation to all-cause mortality were observed. Our findings suggest that the presence of an adequate status of 25(OH)D₃ in combination with an adequate magnesium intake is essential in lowering the risk of mortality in CRC patients, yet the underlying mechanism should be studied. In addition, diet and lifestyle intervention studies are needed to confirm our findings. The COLON study was registered at clinicaltrials.gov as NCT03191110. The EnCoRe study was registered at trialregister.nl as NTR7099.

An unhealthy lifestyle is associated with the risk of colorectal cancer (CRC), but it is unclear whether overall lifestyle after a CRC diagnosis is associated with risks of recurrence and mortality. To examine associations between postdiagnosis lifestyle and changes in lifestyle after a CRC diagnosis with risks of CRC recurrence and all-cause mortality. The study population included 1425 newly diagnosed, stage I–III CRC patients from 2 prospective cohort studies enrolled between 2010 and 2016. Lifestyle, including BMI, physical activity, diet, and alcohol intake, was assessed at diagnosis and at 6 months postdiagnosis. We assigned lifestyle scores based on concordance with 2 sets of cancer prevention guidelines—from the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) and the American Cancer Society (ACS)—and national disease prevention guidelines. Higher scores indicate healthier lifestyles. We computed adjusted HRs and 95% CIs using Cox regression. We observed 164 recurrences during a 2.8-year median follow-up and 171 deaths during a 4.4-year median follow-up. No associations were observed for CRC recurrence. A lifestyle more consistent with the ACS recommendations was associated with a lower all-cause mortality risk (HR per +1 SD, 0.85; 95% CI: 0.73–0.995). The same tendency was observed for higher WCRF/AICR (HR, 0.92; 95% CI: 0.78–1.08) and national (HR, 0.90; 95% CI: 0.77–1.05) lifestyle scores, although these associations were statistically nonsignificant. Generally, no statistically significant associations were observed for BMI, physical activity, diet, or alcohol. Improving one's lifestyle after diagnosis (+1 SD) was associated with a lower all-cause mortality risk for the ACS (HR, 0.80; 95% CI: 0.67–0.96) and national (HR, 0.84; 95% CI: 0.70–0.999) scores, yet was statistically nonsignificant for the WCRF/AICR score (HR, 0.94; 95% CI: 0.78–1.13). A healthy lifestyle after CRC diagnosis and improvements therein were not associated with the risk of CRC recurrence, but were associated with a decreased all-cause mortality risk.