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Fatigue is prevalent in colorectal cancer (CRC) survivors, impacting their health-related quality of life (HRQoL). Inflammation-induced activation of the kynurenine pathway may play a role in cancer-related fatigue and HRQoL, but evidence is scarce. Therefore, we aimed to investigate longitudinal associations of plasma tryptophan, kynurenines, and ratios with fatigue and HRQoL in CRC survivors up to 12 months post-treatment. Repeated measurements at 6 weeks, 6 months, and 12 months post-treatment were performed in 249 stage I-III CRC survivors. Plasma tryptophan and eight kynurenines were analyzed using liquid chromatography-tandem mass spectrometry (LC/MS-MS). Fatigue and HRQoL outcomes were evaluated using validated questionnaires. Confounder-adjusted linear mixed models were conducted to analyze longitudinal associations, with false discovery rate (FDR) correction. Higher tryptophan (Trp), kynurenic acid (KA), and xanthurenic acid (XA) concentrations, as well as a higher kynurenic acid-to-quinolinic acid ratio (KA/QA), were associated with less fatigue and better functioning, while a higher kynurenine-to-tryptophan ratio (KTR) and 3-hydroxykynurenine ratio (HKr) were associated with more fatigue and worse functioning. Finally, higher KA and XA concentrations and a higher KA/QA ratio were associated with a higher overall HRQoL summary score, while a higher HKr was associated with a lower overall HRQoL summary score. In conclusion, we observed that tryptophan and several kynurenines were longitudinally associated with fatigue and HRQoL in CRC survivors up to 12 months post-treatment. Future research is needed to validate our findings and explore the potential of the kynurenine pathway as intervention target for reducing fatigue and enhancing HRQoL after CRC treatment., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: There is a growing population of survivors of colorectal cancer (CRC). Fatigue and insomnia are common symptoms after CRC, negatively influencing health-related quality of life (HRQoL). Besides increasing physical activity and decreasing sedentary behavior, the timing and patterns of physical activity and rest over the 24-h day (i.e. diurnal rest-activity rhythms) could also play a role in alleviating these symptoms and improving HRQoL. We investigated longitudinal associations of the diurnal rest-activity rhythm (RAR) with fatigue, insomnia, and HRQoL in survivors of CRC., Methods: In a prospective cohort study among survivors of stage I-III CRC, 5 repeated measurements were performed from 6 weeks up to 5 years post-treatment. Parameters of RAR, including mesor, amplitude, acrophase, circadian quotient, dichotomy index, and 24-h autocorrelation coefficient, were assessed by a custom MATLAB program using data from tri-axial accelerometers worn on the upper thigh for 7 consecutive days. Fatigue, insomnia, and HRQoL were measured by validated questionnaires. Confounder-adjusted linear mixed models were applied to analyze longitudinal associations of RAR with fatigue, insomnia, and HRQoL from 6 weeks until 5 years post-treatment. Additionally, intra-individual and inter-individual associations over time were separated., Results: Data were available from 289 survivors of CRC. All RAR parameters except for 24-h autocorrelation increased from 6 weeks to 6 months post-treatment, after which they remained relatively stable. A higher mesor, amplitude, circadian quotient, dichotomy index, and 24-h autocorrelation were statistically significantly associated with less fatigue and better HRQoL over time. A higher amplitude and circadian quotient were associated with lower insomnia. Most of these associations appeared driven by both within-person changes over time and between-person differences in RAR parameters. No significant associations were observed for acrophase., Conclusions: In the first five years after CRC treatment, adhering to a generally more active (mesor) and consistent (24-h autocorrelation) RAR, with a pronounced peak activity (amplitude) and a marked difference between daytime and nighttime activity (dichotomy index) was found to be associated with lower fatigue, lower insomnia, and a better HRQoL. Future intervention studies are needed to investigate if restoring RAR among survivors of CRC could help to alleviate symptoms of fatigue and insomnia while enhancing their HRQoL., Trial Registration: EnCoRe study NL6904 ( https://www.onderzoekmetmensen.nl/ )., (© 2024. The Author(s).)

Background: Fatigue is often reported by colorectal cancer survivors and largely impacts their quality of life. Inflammation has been linked to fatigue mainly in patients with breast cancer. Therefore, we investigated how inflammation is longitudinally associated with fatigue in colorectal cancer survivors, up to 2 years posttreatment., Methods: A total of 257 patients from the ongoing Energy for life after ColoRectal cancer cohort study were included in the analysis. Plasma levels of IL6, IL8, IL10, TNFα, high-sensitivity C-reactive protein (hsCRP), and fatigue were measured at 6 weeks, 6, 12, and 24 months posttreatment. Fatigue was measured through the validated Checklist Individual Strength (CIS; total, 20-140), consisting of four subscales - subjective fatigue (8-56), motivation (4-28), physical activity (3-21), and concentration (5-35), and the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 fatigue subscale (0-100). Linear mixed-models were used to assess the confounder-adjusted longitudinal associations between inflammatory markers and overall fatigue along with the subscales., Results: Mean levels of CIS fatigue decreased from 62.9 at 6 weeks to 53.0 at 24 months. In general, levels of inflammatory markers also decreased over time. No statistically significant longitudinal associations were found between IL6, IL8, IL10, TNFα, and fatigue. Higher levels of hsCRP were associated with more CIS fatigue (β per SD 3.21, 95% confidence interval (CI), 1.42-5.01) and EORTC fatigue (β 2.41, 95% CI, 0.72-4.10)., Conclusions: Increased levels of hsCRP are longitudinally associated with more posttreatment fatigue in colorectal cancer survivors., Impact: These findings suggest that low-grade inflammation may play a role in fatigue reported by colorectal cancer survivors up to 2 years posttreatment., (©2022 American Association for Cancer Research.)

Introduction: Given the growing population of colorectal cancer (CRC) survivors, identifying ways to enhance health-related quality of life (HRQoL) and alleviate complaints of fatigue and chemotherapy-induced peripheral neuropathy (CIPN) is essential., Purpose: We aimed to assess longitudinal associations of sedentary behavior (SB) and moderate to vigorous physical activity (MVPA) independently, as well as their joint association, with HRQoL, fatigue, and CIPN in CRC survivors., Methods: In a prospective cohort among stage I-stage III CRC survivors (n = 396), five repeated home visits from diagnosis up to 24 months posttreatment were executed. SB was measured using triaxial accelerometers, and MVPA, HRQoL, fatigue, and CIPN were measured by validated questionnaires. We applied confounder-adjusted linear mixed models to analyze longitudinal associations from 6 wk until 24 months posttreatment., Results: Average time in prolonged SB (accumulated in bouts of duration ≥30 min) was 5.3 ± 2.7 h·d-1, and approximately 82% of survivors were classified as sufficiently active (≥150 min·wk-1 of MVPA) at 6 wk posttreatment. Decreases in SB and increases in MVPA were independently associated with better HRQoL and less fatigue over time. No associations were found for CIPN complaints. A synergistic interaction was observed between prolonged SB and MVPA in affecting functioning scales. Relative to CRC survivors with low prolonged SB and high MVPA, survivors with high prolonged SB and low MVPA reported a stronger decrease in physical functioning and role functioning over time than expected based on the independent associations of prolonged SB and MVPA., Conclusion: Our longitudinal results show that less SB and more MVPA are beneficial for CRC survivors' HRQoL and fatigue levels. Our findings regarding interaction underscore that joint recommendations to avoid prolonged sitting and accumulate MVPA are important., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Sports Medicine.)

Colorectal cancer (CRC) survivors need evidence-based guidelines pertaining to post-treatment body composition, which could benefit health-related quality of life (HRQoL). We aimed to describe the course of several body composition measures, and to assess longitudinal associations of these measures with HRQoL, fatigue and chemotherapy-induced peripheral neuropathy (CIPN). In a prospective cohort among stage I-III CRC survivors (n = 459), five repeated home visits from diagnosis up to 24 months post-treatment were executed. Body mass index (BMI), waist circumference and fat percentage were assessed as measures of adiposity, and muscle arm circumference and handgrip strength as measures of muscle mass and function. We applied linear mixed-models to describe changes in body composition over time and to analyze overall longitudinal associations. Of included participants, 44% was overweight and 31% was obese at diagnosis. All body composition measures followed similar trends, decreasing from diagnosis to 6 weeks and then increasing up to 24 months post-treatment. In confounder-adjusted mixed models, increases in adipose tissue and muscle function were longitudinally associated with better HRQoL and less fatigue, regardless of pre-treatment body composition. With regards to improving HRQoL, decreasing fatigue and CIPN, clinical practice should also focus on restoring body tissues after CRC treatment.Trial registration: NTR7099.

Background: B vitamins have been associated with the risk and progression of colorectal cancer (CRC), given their central roles in nucleotide synthesis and methylation, yet their association with quality of life in established CRC is unclear., Objectives: To investigate whether quality of life 6 months postdiagnosis is associated with: 1) circulating concentrations of B vitamins and related biomarkers 6 months postdiagnosis; 2) changes in these concentrations between diagnosis and 6 months postdiagnosis; 3) B-vitamin supplement use 6 months postdiagnosis; and 4) changes in B-vitamin supplement use between diagnosis and 6 months postdiagnosis., Methods: We included 1676 newly diagnosed stage I-III CRC patients from 3 prospective European cohorts. Circulating concentrations of 9 biomarkers related to the B vitamins folate, riboflavin, vitamin B6, and cobalamin were measured at diagnosis and 6 months postdiagnosis. Information on dietary supplement use was collected at both time points. Health-related quality of life (global quality of life, functioning scales, and fatigue) was assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 6 months postdiagnosis. Confounder-adjusted linear regression analyses were performed, adjusted for multiple testing., Results: Higher pyridoxal 5'-phosphate (PLP) was cross-sectionally associated with better physical, role, and social functioning, as well as reduced fatigue, 6 months postdiagnosis. Associations were observed for a doubling in the hydroxykynurenine ratio [3-hydroxykynurenine: (kynurenic acid + xanthurenic acid + 3-hydroxyanthranilic acid + anthranilic acid); an inverse marker of vitamin B6] and both reduced global quality of life (β = -3.62; 95% CI: -5.88, -1.36) and worse physical functioning (β = -5.01; 95% CI: -7.09, -2.94). Dose-response relations were observed for PLP and quality of life. No associations were observed for changes in biomarker concentrations between diagnosis and 6 months. Participants who stopped using B-vitamin supplements after diagnosis reported higher fatigue than nonusers., Conclusions: Higher vitamin B6 status was associated with better quality of life, yet limited associations were observed for the use of B-vitamin supplements. Vitamin B6 needs further study to clarify its role in relation to quality of life., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Purpose: Evidence from cross-sectional studies suggests that higher levels of light-intensity physical activity (LPA) are associated with better health-related quality of life (HRQoL) in colorectal cancer (CRC) survivors. However, these associations have not been investigated in longitudinal studies that provide the opportunity to analyse how within-individual changes in LPA affect HRQoL. We investigated longitudinal associations of LPA with HRQoL outcomes in CRC survivors, from 6 weeks to 2 years post-treatment., Methods: Data were used of a prospective cohort study among 325 stage I-III CRC survivors (67% men, mean age: 67 years), recruited between 2012 and 2016. Validated questionnaires were used to assess hours/week of LPA (SQUASH) and HRQoL outcomes (EORTC QLQ-C30, Checklist Individual Strength) at 6 weeks, and 6, 12 and 24 months post-treatment. We applied linear mixed regression to analyse longitudinal confounder-adjusted associations of LPA with HRQoL., Results: We observed statistically significant longitudinal associations between more LPA and better global quality of life and physical, role and social functioning, and less fatigue over time. Intra-individual analysis showed that within-person increases in LPA (per 8 h/week) were related to improved HRQoL, including better global quality of life (β = 1.67, 95% CI 0.71; 2.63; total range scale: 0-100) and less fatigue (β = - 1.22, 95% CI - 2.37; - 0.07; scale: 20-140). Stratified analyses indicated stronger associations among participants below the median of moderate-to-vigorous physical activity (MVPA) at diagnosis., Conclusion: Higher levels of LPA were longitudinally associated with better HRQoL and less fatigue in CRC survivors up to two years post-treatment. Further prospective studies using accelerometer data are necessary to inform development of interventions targeting LPA.

The lifestyle recommendations of the World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) are primarily intended for cancer prevention. In the absence of specific recommendations for cancer survivors, we investigated adherence of colorectal cancer (CRC) survivors to the WCRF/AICR lifestyle recommendations and associations with health-related quality of life (HRQoL). The cross-sectional part of the Energy for life after ColoRectal cancer (EnCoRe) study was conducted in 155 CRC survivors (stage I-III), 2-10 years post diagnosis. Dietary intake, physical activity and general body fatness were measured by 7-d food diaries, by questionnaires and accelerometers and BMI, respectively. Adherence to each of the ten WCRF/AICR recommendations was scored as 0 (no/low adherence), 0·5 (moderate adherence) or 1 point (complete adherence), and summed into an overall adherence score (range: 0-10). HRQoL, disability and distress were assessed by validated questionnaires. Associations of the overall WCRF/AICR adherence score with HRQoL outcomes were analysed by confounder-adjusted linear regression. The mean adherence score was 5·1 (sd 1·4, range: 1·5-8·5). In confounder-adjusted models, a higher adherence score was significantly associated with the HRQoL dimension better physical functioning (β per 1 point difference in score: 2·6; 95 % CI 0·2, 5·1) and with less fatigue (β: -3·3; 95 % CI -6·4, -0·1). In conclusion, higher adherence of CRC survivors to WCRF/AICR lifestyle recommendations for cancer prevention was associated with better physical functioning and with less fatigue. This study adds to the limited knowledge on adherence to lifestyle behaviours in CRC survivors and relationships with quality of life. Prospective studies are needed to investigate longitudinal associations.

Purpose: Increased visceral adiposity (visceral obesity) and muscle wasting (sarcopenia) at colorectal cancer (CRC) diagnosis, quantified by computed tomography (CT) image analysis, have been unfavorably associated with short-term clinical outcomes and survival, but associations with long-term health-related quality of life (HRQoL) have not been investigated. We studied associations of visceral adiposity, muscle fat infiltration, muscle mass, and sarcopenia at CRC diagnosis with HRQoL 2-10 years post-diagnosis., Methods: A cross-sectional study was conducted in 104 stage I‒III CRC survivors, diagnosed at Maastricht University Medical Center+, the Netherlands (2002-2010). Diagnostic CT images at the level of the third lumbar vertebra were analyzed to retrospectively determine visceral adipose tissue area (cm 2 ); intermuscular adipose tissue area (cm 2 ) and mean muscle attenuation (Hounsfield units) as measures of muscle fat infiltration; and skeletal muscle index (SMI, cm 2 /m 2 ) as measure of muscle mass and for determining sarcopenia., Results: Participants showed a large variation in body composition parameters at CRC diagnosis with a mean visceral adipose tissue area of 136.1 cm 2 (standard deviation: 93.4) and SMI of 47.8 cm 2 /m 2 (7.2); 47% was classified as being viscerally obese, and 32% as sarcopenic. In multivariable linear regression models, associations of the body composition parameters with long-term global quality of life, physical, role and social functioning, disability, fatigue, and distress were not significant, and observed mean differences were below predefined minimal important differences., Conclusions: Although visceral obesity and sarcopenia are relatively common at CRC diagnosis, we found no significant associations of these parameters with long-term HRQoL in stage I-III CRC survivors.

Purpose: Previous research indicates that sedentary behavior is unfavorably associated with health-related quality of life (HRQoL) of colorectal cancer (CRC) survivors. Using isotemporal substitution modeling, we studied how substituting sedentary behavior with standing or physical activity was associated with HRQoL in CRC survivors, 2-10 years post-diagnosis., Methods: A cross-sectional study was conducted in stage I-III CRC survivors (n = 145) diagnosed at Maastricht University Medical Center+, the Netherlands (2002-2010). Sedentary, standing, and physical activity time were measured by the thigh-mounted MOX activity monitor. HRQoL outcomes comprised global quality of life, physical, role, and social functioning, and disability (scales: 0-100), fatigue (20-140), and depression and anxiety (0-21). Isotemporal substitution modeling was applied to analyze associations with HRQoL of substituting sedentary time with equal time in standing or physical activity., Results: On average, participants spent 10.2 h/day sedentary (SD, 1.7), 3.4 h/day standing (1.3), and 1.7 h/day in physical activity (0.8). In confounder-adjusted isotemporal models, substituting sedentary time with standing or with physical activity was associated with significantly better physical functioning (regression coefficient [β], i.e., difference in outcome score per 1 h/day of sedentary time substituted with standing or physical activity, 3.1; 95% confidence interval [CI] 0.5, 5.7; and 5.6; 0.7, 10.6, respectively). Substituting sedentary time with standing was also associated with significantly lower disability (β, -3.0; 95% CI -4.9, -1.1) and fatigue (-4.0; -7.6, -0.3)., Conclusions: Our results suggest that substituting sedentary behavior with standing or physical activity may be beneficially associated with certain HRQoL outcomes in CRC survivors. Prospective studies are warranted to confirm whether actual substitution of sedentary behavior with these activities may improve HRQoL in CRC survivors.

Purpose: Emerging evidence suggests that light physical activity (LPA), besides moderate-to-vigorous physical activity (MVPA), may beneficially influence physical functioning of colorectal cancer survivors, but its relation with other health-related outcomes is unknown. We applied a biopsychosocial approach to investigate independent associations between self-reported LPA, MVPA, and multiple health-related quality of life (HRQoL) outcomes in 2- to 10-yr postdiagnosis colorectal cancer survivors., Methods: Stage I-III colorectal cancer survivors diagnosed between 2002 and 2010 at Maastricht University Medical Center+, the Netherlands, were included in a cross-sectional study (n = 151). Time spent in LPA and MVPA (h·wk⁻¹), and HRQoL outcome scores (0-100 points) were assessed by validated questionnaires., Results: Median time spent in LPA and MVPA was 10.0 (interquartile range, 2.0-22.0) and 8.7 h·wk⁻¹ (4.5-15.0), respectively. In multivariable linear regression models, both LPA and MVPA were significantly and independently associated with higher physical functioning (mean difference [MD] between highest and lowest quartile, 10.2; 95% confidence interval [CI], 0.2-20.3; and 14.5; 5.1-23.9, respectively; both P-trend < 0.05). In addition, LPA was significantly associated with higher role functioning (MD, 19.5; 95% CI, 6.9-32.1; P-trend < 0.01) and lower disability (MD, -9.9; 95% CI, -17.8 to -1.9; P-trend = 0.02), independent from MVPA. Subgroup analyses showed that beneficial associations between LPA and HRQoL were mainly observed in women and participants with multiple comorbidities., Conclusions: Self-reported LPA, besides MVPA, was beneficially associated with multiple HRQoL outcomes in colorectal cancer survivors, especially in women and survivors with multiple comorbidities. Prospective studies are warranted to establish whether LPA is a suitable target for personalized lifestyle interventions to improve the HRQoL of colorectal cancer survivors.

Background: Well-designed studies on lifestyle and health-related quality of life (HRQoL) in colorectal cancer survivors based on a biopsychosocial instead of a traditional biomedical approach are warranted. We report on the applicability of the International Classification of Functioning, Disability, and Health (ICF) as useful biopsychosocial framework to improve research on how lifestyle influences colorectal cancer survivors' HRQoL, using the Energy for life after ColoRectal cancer (EnCoRe) study as an example., Methods: The ICF was used to develop a conceptual model for studying lifestyle and colorectal cancer survivors' HRQoL, by identifying relevant factors from literature and mapping them within the ICF. Subsequently, this model was used for selection of measurement instruments and biomarkers. By linking meaningful concepts within selected measures to the ICF, we could assess the ICF coverage of our developed conceptual model., Results: Within selected measures, 450 meaningful concepts were identified, of which 88% were linked to the ICF. The linking process resulted in 132 distinctive ICF categories assigned (38% within "Body Functions," 2% within "Body Structures," 46% within "Activities and Participation," and 14% within "Environmental Factors")., Conclusions: The selected EnCoRe study measures broadly cover ICF domains relevant to colorectal cancer survivors, stressing the relevance of using a biopsychosocial approach for studying this population's HRQoL., Impact: The developed conceptual model will guide data analyses and interpretation, and facilitate early transfer of results for development, evaluation, and implementation of personalized multidisciplinary lifestyle interventions. We recommend the ICF as an invaluable framework for improving the quality and scope of HRQoL studies., (©2014 American Association for Cancer Research.)