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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 mortality
In Chapter 2 the association between low SMR and mortality was investigated among 1,681
stage 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 fatigue
In 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 fatigue
We 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 recommendations
The 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.
|Qualification||Doctor of Philosophy|
|Award date||21 Oct 2021|
|Place of Publication||Wageningen|
|Publication status||Published - 2021|
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- 1 Finished
1/04/15 → 21/10/21