Imaging all the people : Associations of computed tomography-based body composition with mortality and fatigue in stage I-III colorectal cancer patients

Colorectal cancer (CRC) is the third most common cancer worldwide. Mainly due to the implementation of screening practices and improved treatment, survival rates for stage I-III CRC patients have increased for several decades. Identifying modifiable factors associated with better prognosis could contribute to further improvement of cancer outcomes such as better survival, good quality of life (QoL) and less recurrence in patients with stage I-III CRC. One potential modifiable factor might be body composition.Over the last decade, the relationship between skeletal muscle mass index (SMI, skeletal muscle cross-sectional surface area divided by height squared in meters), skeletal muscle radiodensity (SMR, which reflects the lipid content of the muscle cells), visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) at time of diagnosis, and outcomes including mortality, complications after surgery, length of hospital stay, QoL and fatigue has received much attention. At the start of this PhD project, no studies had reported on these associations in exclusively stage I-III CRC patients.Furthermore, an association between higher adherence to the World Cancer Research Fund / American Institute for Cancer Research (WCRF/AICR) lifestyle recommendations and less fatigue had been observed among stage I-III CRC patients who had been diagnosed with CRC more than 5 years ago. If better adherence to the recommendations is also associated with less fatigue experienced during or shortly after treatment, was still unknown. Additionally, the potential mediating role of inflammation in this association needed to be confirmed.The overall objectives of this thesis were 1) to increase knowledge about the association of body composition in stage I-III CRC patients with both mortality and fatigue by using CT images to quantify skeletal muscle mass, skeletal muscle radiodensity and adipose tissue, and 2) to increase knowledge about the association of adherence to the WCRF/AICR lifestyle recommendations with fatigue among stage I-III CRC and to elucidate the underlying mechanism.Body composition and mortalityIn Chapter 2 the association between low SMR and mortality was investigated among 1,681stage I-III CRC patients. The average age of the study population was 67.7 ± 10.3 years, 41% were women and 414 patients (25%) died. Thirty-nine percent of the patients had low SMR. Low SMR was significantly associated with higher overall mortality (low vs. normal: adjusted HR 1.91, 95% CI 1.53–2.38).The association of SMI, VAT and SAT with mortality among 2,016 men and among women with stage I-III CRC was investigated in Chapter 3, using restricted cubic splines analyses. The average age of the patients was 67.9 ± 10.6 years, 42% were women and 558 (28%) patients died. Among men, the association of SMI and mortality was statistically significant in a non-linear way, with lower SMI levels associated with higher mortality, but there was no association among women. SAT was non-linearly associated with mortality for both men and women, with lower SAT levels being associated with higher mortality. VAT was not significantly associated with mortality.Body composition and fatigueIn Chapter 4 we studied how SMR, SMI, VAT and SAT at diagnosis are associated with fatigue at diagnosis, at 6 and 24 months post-diagnosis in 646 stage I-III CRC patients. The association of SMI, SMR, VAT, and SAT with fatigue (yes/no) was assessed using confounder-adjusted restricted cubic spline analyses. At diagnosis, a significant non-linear association of higher levels of SAT with higher prevalence of fatigue was observed. Lower SMR was linearly associated with higher prevalence of fatigue at 6 months post-diagnosis. None of the body composition parameters were significantly associated with fatigue at 24 months.Adherence to the WCRF/AICR lifestyle recommendations and fatigueWe examined the association between adherence to the WCRF/AICR lifestyle recommendations and fatigue among 1,417 stage I-III CRC patients in Chapter 5. Within a subpopulation we investigated whether inflammation mediated this association. Adherence to the WCRF/AICR recommendations was assessed shortly after diagnosis. Six months post-diagnosis fatigue and plasma levels of inflammation markers (IL6, IL8, TNFα, and hsCRP) in non-fasting blood samples were assessed.A higher WCRF/AICR adherence score at diagnosis was associated with less fatigue six months after diagnosis. A statistically significant indirect association via inflammation was explaining 45% of the total association between lifestyle and fatigue. Thus, inflammation is probably one of the underlying mechanisms linking lifestyle to fatigue.General conclusion and recommendationsThe results presented in this thesis show that low SMR, low SAT and, among men, low SMI are associated with higher mortality risk among stage I-III CRC patients. SMI in women and VAT in men and women were not statistically significantly associated with mortality risk. Low SMR was associated with more fatigue at six months post-diagnosis and high levels of SAT were associated with more fatigue at diagnosis. Furthermore, a higher WCRF/AICR adherence score at diagnosis was associated with less fatigue six months after diagnosis among stage I-III CRC patients. This association was observed to be partly mediated by inflammation. The next step will be investigating the effect of improving pre-treatment body composition in a controlled setting (i.e. prehabilitation) on fatigue, QoL and surgical outcomes; and investigating the effect of improving body composition by healthy lifestyle changes on fatigue and other QoL components after treatment

Explaining the obesity paradox - Letter

In the recent publication entitled, “Explaining the Obesity Paradox: The Association between Body Composition and Colorectal Cancer Survival (C-SCANS Study)” (1), Caan and colleagues present data of their large observational study on body composition and colorectal cancer survival. In this interesting article, the authors demonstrated that it is very likely that the “obesity paradox” (higher BMI associated with better survival) may be driven by the underlying body composition. We have two points that we hope Caan and colleagues could clarify for us about their analyses, which will help in interpreting their findings, and in comparing their results with other articles.First, we have a question about the selection of CT scans the authors included in their dataset. In the Materials and Methods section, the authors describe that for 83% of the patients, these scans were taken presurgery, which means that for 17% of the patients, the scans took place after surgery. Colorectal cancer surgery and additional systemic or local treatment may importantly affect body weight and probably body composition (2), and thus, the muscle and/or fat cross-sectional areas on postsurgery CT scans may have been affected by surgery and/or other treatment. We would like to ask the authors whether they could present additional sensitivity analyses, including only patients of whom a presurgery scan was available, to assess whether this selection of CT scans affected their results.Second, we have a question on how muscle mass was included as variable in their analyses. In defining sarcopenia, the authors created cut-off points based on the continuous variable skeletal muscle index (SMI), which is muscle mass at L3 in cm2 divided by height2 in meters. Adjusting muscle mass for height2—in other words adjusting for the fact that taller people have more muscle as a result of their larger body—is a sensible thing to do. However, in the analyses where the authors categorized muscle mass in tertiles, they did not use SMI in cm2/m2, but they used the unadjusted muscle mass at L3 in cm2. We would like to ask the authors to explain this decision, and to show whether this affected the results in Table 2 and Fig. 3B

Associations of Abdominal Skeletal Muscle Mass, Fat Mass, and Mortality among Men and Women with Stage I-III Colorectal Cancer

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Dietary intake of magnesium or calcium and chemotherapy-induced peripheral neuropathy in colorectal cancer patients

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and severe side-effect in colorectal cancer (CRC) patients. This study assessed the association between habitual dietary intake of magnesium or calcium and prevalence and severity of chronic CIPN in CRC patients receiving adjuvant chemotherapy. For this prospective cohort study, 196 CRC patients were considered. Magnesium and calcium intake was determined using a food frequency questionnaire at diagnosis, during and after chemotherapy. Chronic CIPN was assessed 12 months after diagnosis using the quality of life questionnaire CIPN20. Prevalence ratios were calculated to assess the association between magnesium or calcium intake and the prevalence of CIPN. Multivariable linear regression analysis was used to assess the association between magnesium or calcium intake and severity of CIPN. CIPN was reported by 160 (82%) patients. Magnesium intake during chemotherapy was statistically significantly associated with lower prevalence of CIPN (prevalence ratio (PR) 0.53, 95% confidence interval (CI) 0.32, 0.92). Furthermore, higher dietary intake of magnesium during (β-1.08, 95% CI -1.95, -0.22) and after chemotherapy (β-0.93, 95% CI -1.81, -0.06) was associated with less severe CIPN. No associations were found for calcium intake and the prevalence and severity of CIPN. To conclude, we observed an association between higher dietary magnesium intake and lower prevalence and severity of CIPN in CRC patients

Colorectal cancer survivors only marginally change their overall lifestyle in the first 2 years following diagnosis

Purpose: A healthy lifestyle after colorectal cancer (CRC) diagnosis may improve prognosis. Data related to lifestyle change in CRC survivors are inconsistent and potential interrelated changes are unknown. Methods: We assessed dietary intake, physical activity, body mass index (BMI), waist circumference, and smoking among 1072 patients diagnosed with stages I–III CRC at diagnosis, 6 months and 2 years post-diagnosis. An overall lifestyle score was constructed based on the 2018 World Cancer Research Fund/American Institute of Cancer Research recommendations (range 0–7). We used linear mixed models to analyze changes in lifestyle over time. Results: Participants had a mean (± SD) age of 65 ± 9 years and 43% had stage III disease. In the 2 years following CRC diagnosis, largest changes were noted for sugary drinks (− 45 g/day) and red and processed meat intake (− 62 g/week). BMI (+ 0.4 kg/m2), waist circumference (+ 2 cm), and dietary fiber intake (− 1 g/day) changed slightly. CRC survivors did not statistically significant change their mean intake of fruits and vegetables, alcohol, or ultra-processed foods nor did they change their physical activity or smoking behavior. Half of participants made simultaneous changes that resulted in improved concordance with one component as well as deteriorated concordance with another component of the lifestyle score. Overall lifestyle score changed from a mean 3.4 ± 0.9 at diagnosis to 3.5 ± 0.9 2 years post-diagnosis. Conclusions: CRC survivors hardly improve their overall lifestyle after diagnosis. Implications for Cancer Survivors: Given the importance of a healthy lifestyle, strategies to effectively support behavior changes in CRC survivors need to be identified.</p

Are Ergothioneine Levels in Blood Associated with Chronic Peripheral Neuropathy in Colorectal Cancer Patients Who Underwent Chemotherapy?

Objective: Chronic Chemotherapy-Induced Peripheral Neuropathy (CIPN) is highly prevalent among colorectal cancer (CRC) patients. Ergothioneine (ET)–a dietary antioxidant -protected against CIPN in experimental models, but human studies are lacking. We explored whether whole blood ET levels were associated with chronic peripheral neuropathy among CRC patients who had completed chemotherapy. Methods: At diagnosis, median ET-concentration in whole blood of 159 CRC patients was 10.2 μg/ml (7.2–15.8). Patients completed questionnaires on peripheral neuropathy 6 months after completion of chemotherapy. We calculated prevalence ratios (PR) to assess associations of ET-concentrations and prevalence of peripheral neuropathy and used linear regression to assess associations with severity of peripheral neuropathy. Results: Prevalence of total and sensory peripheral neuropathy were both 81%. Higher ET-concentrations tended to be associated with lower prevalence of total and sensory peripheral neuropathy, but not statistically significant (highest versus lowest tertile of ET: PR = 0.93(0.78, 1.11) for total neuropathy, and PR = 0.84(0.70, 1.02) for sensory neuropathy). ET-concentrations were not associated with severity of neuropathy. Conclusion: Statistically significant associations were not observed, possibly because of limited sample size. Although data may putatively suggest higher levels of ET to be associated with a lower prevalence of neuropathy, analyses should be repeated in larger populations with larger variability in ET-concentrations.</p

Low radiographic muscle density is associated with lower overall and disease-free survival in early-stage colorectal cancer patients

Background: In cancer patients with a poor prognosis, low skeletal muscle radiographic density is associated with higher mortality. Whether this association also holds for early-stage cancer is not very clear. We aimed to study the association between skeletal muscle density and overall mortality among early-stage (stage I–III) colorectal cancer (CRC) patients. Furthermore, we investigated the association between skeletal muscle density and both CRC-specific mortality and disease-free survival in a subset of the study population. Methods: Skeletal muscle density was assessed in 1681 early-stage CRC patients, diagnosed between 2006 and 2015, using pre-operative computed tomography images. Adjusted Cox proportional hazard models were used to evaluate the association between muscle density and overall mortality, CRC-specific mortality and disease-free survival. Results: The median follow-up time was 48 months (range 0–119 months). Low muscle density was detected in 39% of CRC patients. Low muscle density was significantly associated with higher mortality (low vs. normal: adjusted HR 1.91, 95% CI 1.53–2.38). After stratification for comorbidities, the association was highest in patients with ≥ 2 comorbidities (HR 2.11, 95% CI 1.55–2.87). Furthermore, low skeletal muscle density was significantly associated with poorer disease-free survival (HR 1.68, 95% CI 1.14–2.47), but not with CRC-specific mortality (HR 1.68, 95% CI 0.89–3.17) in a subset of the study population. Conclusion: In early-stage CRC patients, low muscle density was significantly associated with higher overall mortality, and worse disease-free survival.</p

Are Ergothioneine Levels in Blood Associated with Chronic Peripheral Neuropathy in Colorectal Cancer Patients Who Underwent Chemotherapy?

Objective: Chronic Chemotherapy-Induced Peripheral Neuropathy (CIPN) is highly prevalent among colorectal cancer (CRC) patients. Ergothioneine (ET)–a dietary antioxidant -protected against CIPN in experimental models, but human studies are lacking. We explored whether whole blood ET levels were associated with chronic peripheral neuropathy among CRC patients who had completed chemotherapy. Methods: At diagnosis, median ET-concentration in whole blood of 159 CRC patients was 10.2 μg/ml (7.2–15.8). Patients completed questionnaires on peripheral neuropathy 6 months after completion of chemotherapy. We calculated prevalence ratios (PR) to assess associations of ET-concentrations and prevalence of peripheral neuropathy and used linear regression to assess associations with severity of peripheral neuropathy. Results: Prevalence of total and sensory peripheral neuropathy were both 81%. Higher ET-concentrations tended to be associated with lower prevalence of total and sensory peripheral neuropathy, but not statistically significant (highest versus lowest tertile of ET: PR = 0.93(0.78, 1.11) for total neuropathy, and PR = 0.84(0.70, 1.02) for sensory neuropathy). ET-concentrations were not associated with severity of neuropathy. Conclusion: Statistically significant associations were not observed, possibly because of limited sample size. Although data may putatively suggest higher levels of ET to be associated with a lower prevalence of neuropathy, analyses should be repeated in larger populations with larger variability in ET-concentrations.</p

Vitamin D, magnesium, calcium, and their interaction in relation to colorectal cancer recurrence and all-cause mortality

Background: 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. Objectives: 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. Methods: 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. Results: 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 (HRQ3 vs. Q1: 0.55; 95% CI: 0.32, 0.95 and HRQ4 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. Conclusions: 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. </p

The association between circulating levels of vitamin D and inflammatory markers in the first 2 years after colorectal cancer diagnosis

Background: Calcitriol, the active form of vitamin D, may inhibit colorectal cancer (CRC) progression, which has been mechanistically linked to an attenuation of a pro-inflammatory state. The present study investigated the associations between circulating 25 hydroxy vitamin D3 (25(OH)D3) levels and inflammatory markers (IL10, IL8, IL6, TNFα and hsCRP) in the 2 years following CRC diagnosis. Methods: Circulating 25(OH)D3 levels and inflammatory markers were assessed at diagnosis, after 6, 12 and 24 months from 798 patients with sporadic CRC participating in two prospective cohort studies. Associations between 25(OH)D3 levels and individual inflammatory markers as well as a summary inflammatory z-score were assessed at each time point by multiple linear regression analyses. To assess the association between 25(OH)D3 and inflammatory markers over the course of 2 years, linear mixed model regression analyses were conducted. Results: Higher 25(OH)D3 levels were associated with lower IL6 levels at diagnosis, at 6 months after diagnosis and over the course of 2 years (β −0.06, 95% CI −0.08 to −0.04). In addition, 25(OH)D3 levels were inversely associated with the summary inflammatory z-score at diagnosis and over the course of 2 years (β −0.17, 95% CI −0.25 to −0.08). In addition, a significant inverse association between 25(OH)D3 levels and IL10 was found over the course of 2 years. Intra-individual analyses showed an inverse association between 25(OH)D3 and IL10, IL6 and TNFα. No statistically significant associations between 25(OH)D3 and IL8 and hsCRP levels were observed. Conclusions: Serum 25(OH)D3 levels were inversely associated with the summary inflammatory z-score and in particular with IL6 in the years following CRC diagnosis. This is of potential clinical relevance as IL6 has an important role in chronic inflammation and is also suggested to stimulate cancer progression. Further observational studies should investigate whether a possible 25(OH)D3-associated reduction of inflammatory mediators influences treatment efficacy and CRC recurrence