The association between lifestyle-related risk factors and survival in patients with colorectal cancer in an urban South African cohort Megan Whelan1, Heleen van Aswegen1, Ronel Roos1, June Fabian2,3, Brendan Bebington4,5 1. Department of Physiotherapy, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, South Africa. 2. Wits Donald Gordon Medical Centre, University of the Witwatersrand, Johannesburg, South Africa1; and 3. Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. 4. Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa. 5. Colorectal Unit, Wits Donald Gordon Medical Centre, Johannesburg, South Africa. Emails: meganwhelanphysio@gmail.com; helena.vanaswegen@wits.ac.za; ronel.roos@wits.ac.za; June.Fabian@mweb.co.za Abstract Background: Lifestyle-related factors have been linked with risk for colorectal cancer. Data describing the relationship between lifestyle factors of South African patients who present with colorectal cancer and their survival is sparse. Objectives: The objectives were to describe the profile of patients with colorectal cancer; to determine the association between lifestyle-related factors and survival, and to compare results of patients in the private and public sectors. Methods: A retrospective review and secondary analysis of information of patients with colorectal cancer were conducted. The independent samples t-test and Mann Whitney U test were administered to determine differences in the clinical presentation. Pearson’s Chi-Squared and Eta (η) tests were used to determine the association between survival and lifestyle-related factors. Results: Data of 441 patients were included. When compared to the public sector cohort, patients in the private sector cohort were older (p=0.0110), had earlier stages of cancer at the time of diagnosis (p<0.001), had a higher percentage of current al- cohol consumption (p<0.001) and had higher survival rates (p<0.001). Waist circumference was shown to have a large-strength effect on survival (η2=0.266). Conclusion: Emphasis should be placed on anthropometric screening and education to effect long-term behaviour change. Physiotherapists are well placed to provide screening and non-pharmacological interventions for patients with colorectal cancer. Keywords: Cancer survival; risk factors; physiotherapy. DOI: https://dx.doi.org/10.4314/ahs.v22i1.38 Cite as: Whelan M, van Aswegen H, Roos R, Fabian J, Bebington B, Neph C. The association between lifestyle-related risk factors and survival in patients with colorectal cancer in an urban South African cohort. Afri Health Sci. 2022;22(1):312-21. https://dx.doi. org/10.4314/ahs.v22i1.38 Corresponding author: Megan Whelan, Department of Physiotherapy, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, South Africa. Contact number 0714822036; Email: meganwhelanphysio@gmail.com Introduction In South Africa, colorectal cancer is the fourth most prevalent type of cancer1. According to the 2014 Nation- al Cancer Registry, the crude incidence of colorectal can- cer for men and women in South Africa is 7.34/100 000 and 5.86/100 000 respectively2. Colorectal carcinogenesis involves several complex bi- ological pathways3. Lifestyle-related risk factors include African Health Sciences, Vol 22 Issue 1, March, 2022 © 2022 Whelan M et al. Licensee African Health Sciences. This is an Open Access article distributed under the terms of the Creative commons Attribution License (https://creativecommons.org/licenses/BY/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. African Health Sciences 312 cigarette smoking, heavy alcohol consumption, nutri- tion-related practices, obesity, and lack of physical activi- ty4,5. Furthermore, research shows that physical inactivity, body mass index (BMI), and smoking may influence sur- vival after a colorectal cancer diagnosis6,7. Smoking and alcohol consumption are both associated with colorectal cancer. Tobacco carcinogens may dam- age or alter the expression of important cancer-related genes8. The carcinogens in tobacco have also been linked with the development and growth of adenomatous pol- yps, the precursor lesions for colorectal cancer9. There are several possible biological mechanisms to explain the higher mortality rates in individuals who smoke at the time of and following the diagnosis of colorectal can- cer. Smoking may result in impaired tobacco carcinogen detoxification which could promote residual tumour cell growth either by angiogenesis promotion or by chemo- therapy resistance10. Secondly, smoking may contribute to abnormal promoter methylation which results in reg- ulatory gene silencing in tumour progression11. Relating to alcohol, there are several mechanisms of alcohol-as- sociated carcinogenesis including nutritional deficienies, modulation of cellular regeneration, and the carcinogen- ic effects of acetaldehyde which is the main metabolite of ethanol12. Long term alcohol consumption induces cytochrome P-4502E1 in the liver and gastrointestinal mucosal cells, which increases reactive oxidative species generation, leading to activation of various carcinogens – similar to those in cigarette smoke12. Even low daily doses of alcohol can enhance carcinogenesis12. Smoking, but not alcohol consumption, has been associated with an increased risk of mortality following colorectal cancer diagnosis7,13. The relationship between BMI and colorectal cancer out- comes is complex14,15. Central and general obesity have been shown to have a dose-dependent relationship with risk for colorectal cancer16,17. Overweight individuals with colorectal cancer have shown better overall survival out- comes7,14,18. Evidence suggests that physical activity exerts an inde- pendent effect on risk for colorectal cancer5,19. Physical activity increases gut motility which in turn reduces fae- cal transit time20. Beyond risk, physical activity has also been linked with survival in patients with colorectal can- cer7,21,22. Results of a large-scale European prospective study showed that prediagnosis leisure time activity was associated with improved survival in patients with col- orectal cancer22. Physical activity may reduce tissue insulin and insulin-like growth factor levels as well as play a role in anti-inflammatory actions and immune modulation23. Activity-induced body changes may increase cancer treat- ment efficacy and could support counteracting cancer progression22. The objectives of this study were to describe the profile of patients with colorectal cancer; to determine the asso- ciation between lifestyle-related factors and survival; and to compare results of patients presenting with colorectal cancer at private sector hospitals to those presenting at public sector hospitals within a University teaching com- plex. To our knowledge, data describing the relationship be- tween lifestyle-related risk factors of South African pa- tients who present with colorectal cancer and their sur- vival is sparse. This information is vital to determine the need for management of modifiable risk factors in this patient population. As far as we know, this is the first study of this nature in a South African group of patients with colorectal cancer. Methods Approval to conduct this study was obtained from the University of the Witwatersrand Human Research Ethics (Medical) committee (M181075). A retrospective review and secondary analysis of information captured on Re- search Electronic Data Capture (REDCap) hosted at the University of the Witwatersrand were conducted24,25. Patient sample and database information The database includes patient information collected from the study sites based in the Academic Teaching Complex of the University of the Witwatersrand in Johannesburg. These sites included one private hospital (private univer- sity referral centre) and three public hospitals (two of which are tertiary referral centres and one is a secondary care facility)26. Inclusion criteria comprised patients 18 years or older, a confirmed histological diagnosis of pri- mary colon or rectal adenocarcinoma, diagnosed within the last 12 months, and written informed consent. The records of a convenience sample of patients enrolled be- tween 1 January 2016 and 30 June 2018, with at least six months follow-up data were included. African Health Sciences, Vol 22 Issue 1, March, 2022 313 Information was collected for the following variables: de- mographics (age, gender, and self-reported race), anthro- pometrics (weight, height, and waist circumference), life- style factors (physical activity, smoking, and alcohol use) and cancer staging. Outcome was reported as survival - disease or disease-free. Overall survival was determined from the date of recruitment to date of death or date of last contact session. Three trained data capturers entered data onto the RED- Cap system. Patients were referred by specialists and from relevant departments such as chemotherapy, radio- therapy, and from multidisciplinary meetings hosted at the various study sites. At the time of data capturing, spe- cialists were available to answer any questions and queries regarding the data. The data capturers assisted with data extraction from REDCap onto excel spreadsheets. Outcome measures The staging of cancer was measured using the American Joint Committee on Cancer (AJCC) Tumor-Node-Metas- tasis (TNM) staging model27. The AJCC tool (7th edition) categorises the malignancy from stage 0 (presence of a primary tumour) to stage IVB (distant metastases in more than one site)28. The tool demonstrates good prognostic validity28. Physical performance was measured using the Eastern Cooperative Oncology Group Scale of Performance Sta- tus (ECOG)29. The ECOG is a scale that measures pa- tients’ functional status including self-care ability and dai- ly activity. The scale was designed to measure the impact of a patient’s disease on their ability to perform various activities of daily living and was created specifically to be used in the field of cancer research . The ECOG score is often used to prognosticate for outcomes following can- cer treatment. The scale grades patients according to their abilities (grade 0 - patients who are fully active and have no restrictions; grade 5 - patients who have died)30. The scale is known for its intraobserver reliability and simplic- ity31. The Global Physical Activity Questionnaire (GPAQ) was used to measure physical activity. The questionnaire was designed to collect information on physical activity participation across three domains namely work activity, travel to and from work, and recreation32. The World Health Organisation (WHO) recommends that an in- dividual should achieve 150 minutes of weekly moder- ate-intensity aerobic physical activity or 75 minutes of weekly vigorous-intensity aerobic physical activity or 600 met-minutes of combined weekly moderate-and-vigor- ous-intensity physical activity33. The GPAQ scoring is based on these recommendations and is a reliable and val- id measure of changes in moderate-to-vigorous physical activity 34,35. Data was not collected for one sub-domain which resulted in incomplete overall GPAQ scores. This resulted in complete GPAQ data being available only for vigorous-intensity physical activity. Data analysis Data obtained were analysed using IBM SPSS (version 25) software36. Data describing the profiles and clinical presentations of patients with colorectal cancer were summarised using descriptive analysis and reported as frequencies (%), means and standard deviation (SD) and median and interquartile range (IQR). The normality of distribution of continuous data was measured using the Shapiro Wilk test. The independent samples t-test and Mann Whitney U test were administered to determine dif- ferences in the presentation of those presenting at private versus public sector hospitals. The Kaplan-Meier method was used to plot survival data and the log rank test was used to compare survival between the two groups. Pearson’s Chi-Squared test was used to determine the as- sociation between survival and nominal variables (smok- ing and alcohol consumption). The strength of associa- tion was measured using the Cramer’s V test: a value of 0 indicated no relationship existed, 0.05-0.10 represented a weak relationship, 0.10-0.15 represented a moderate rela- tionship, 0.15-0.25 represented a strong relationship, and >0.25 suggested a very strong relationship37. Eta (η) test was administered to determine the associationetween sur- vival and ratio variables (BMI, waist circumference, and vigorous-intensity weekly minutes). Eta-squared (η2) was used to determine the effect size. The following guide- lines were used to interpret the strength of association for η2: 0.02-0.13 represented a small effect size, 0.13-0.26 represented a medium effect size, and >0.26 represented a large effect size38. The significance of findings was set at an alpha level of ≤0.05. Missing data that couldn’t be recovered was coded and recorded as ‘missing’. Results Overall, 441 patients met the eligibility criteria for inclu- African Health Sciences, Vol 22 Issue 1, March, 2022314 sion in the study sample. Of those recruited, 152 (34.5%) were in the private sector and 289 (65.5%) were in the public sector. Table 1: Demographic profile of South African urban cohort presenting with colorectal cancer Private sector cohort (n=152) Public sector cohort (n=289) p-value Gender Male Female 77 (50.7) 75 (49.3) 147 (50.9) 142 (49.1) 0.967 Age (yrs) 60 (51-67.75) 56 (46-65) 0.011 Self-reported race Caucasian Black Mixed race Indian East Asian Other 98 (64.5) 26 (17.1) 4 (2.6) 23 (15.1) 0 (0) 1 (0.7) 41 (14.2) 212 (73.4) 25 (8.7) 9 (3.1) 2 (0.7) 0 (0) <0.001 (overall) Gender (n, %), age (median, IQR), self-reported race (n, %). IQR (interquartile range), n (number), yrs (years). The term ‘other’ refers to patients that felt that their race did not fall under any of the given options. Those with colorectal cancer in the private sector were significantly older (p=0.011) and predominantly from the Caucasian population group (p<0.001) when compared to the profile of patients with colorectal cancer from state hospitals. Cancer staging The stage of cancer for both groups is represented in Table 2. Table 2: Staging of colorectal cancer of South African urban cohort using AJCC Private sector cohort (n=152) Public sector cohort (n=289) p-value AJCC Stage 1 Stage IIa Stage IIb Stage IIc Stage IIIa Stage IIIb Stage IIIc Stage IVa Stage IVb Missing 17 (12.4) 32 (23.4) 5 (3.6) 2 (1.5) 2 (1.5) 31 (22.6) 16 (11.7) 25 (18.2) 7 (5.1) 15 11 (4.6) 25 (10.4) 8 (3.3) 7 (2.9) 1 (0.4) 29 (12) 59 (24.5) 57 (23.7) 44 (18.3) 48 <0.001 (overall) AJCC (n, %) African Health Sciences, Vol 22 Issue 1, March, 2022 Demographic profile The profile of this cohort is summarised in Table 1. 315 The cancer staging data are distributed in a bimodal man- ner. The majority of patients in the private cohort pre- sented with Stage IIa and Stage IIIb colorectal cancer according to the AJCC whereas the greatest percentage of patients in the public cohort presented with Stage IIIc and Stage IVa colorectal cancer. The difference between the two groups was significant (p<0.001). Lifestyle profile The ECOG scores (physical performance), modified GPAQ scores (physical activity), anthropometric mea- sures, smoking, and alcohol consumption of both co- horts are summarized in Table 3. Table 3: Anthropometric and lifestyle profiles of the study cohort Private sector cohort (n=152 ) Public sector cohort (n=289 ) p-value Anthropometric data Weight (kg) Height (m) Waist circumference (cm) BMI (kg/m2) 65 (56.4-79) 1.67 (1.59- 1.73) 89.5 (83-99) 24 (21-28) 67.9 (56- 80.63) 1.65 (1.58- 1.73) 92 (85-102) 25 (21-29) 0.364 0.567 0.108 0.212 Alcohol consumption Current alcohol consumer Previous alcohol consumer Never consumed alcohol Missing 86 (57) 19 (12.6) 46 (30.5) 1 83 (28.7) 84 (29.1) 122 (42.2) 0 <0.001 (overall) Smoking Current smoker Previous smoker Never smoked 16 (10.5) 52 (34.2) 84 (55.3) 45 (15.6) 65 (22.5) 179 (61.9) 0.021 (overall) ECOG score Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Missing 36 (30.5) 47 (39.8) 23 (19.5) 9 (7.6) 3 (2.5) 34 73 (35.3) 84 (40.6) 31 (15) 18 (8.7) 1 (0.5) 82 0.341 (overall) GPAQ score Vigorous-intensity physical activity weekly minutes Vigorous-intensity minutes achieved Yes No Missing (n) 67.5 (193.6) 22 (19) 94 (81) 36 92.38 (387.9) 26 (12.5) 182 (87.5) 81 0.191 0.116 Anthropometric data (median, IQR), alcohol consumption (n, %), smoking (n, %), ECOG score (n, %), GPAQ score vigorous-intensity physical activity weekly minutes (mean, SD), vigorous-intensity minutes achieved (n, %). SD (standard deviation), kg (kilogram), m (meters), m2 (meters squared), cm (centimetres). There was no significant difference in anthropometric profiles between the two groups. There was a significant difference in smoking (p=0.021) and alcohol consump- tion (p<0.001) between the private and public sector co- horts. The largest percentage of patients in the private and public cohorts had never smoked whereas more than half of the private cohort were current alcohol consum- ers. Survival Table 4 summarises the survival rates and Figure 1 shows the Kaplan-Meier survival plot. Association between lifestyle factors and survival: For the combined cohort, there were weak, non-signif- icant, inverse associations between survival and smok- ing (x2=2.34, Cramer’s V=0.052, p=0.886) and between survival and alcohol consumption (x2=9.58, Cramer’s V=0.086, p=0.386). African Health Sciences, Vol 22 Issue 1, March, 2022316 African Health Sciences, Vol 22 Issue 1, March, 2022 Figure 1: Differences in survival between the private and public sector cohorts There was a non-significant, weak positive association between the frequency of achievement of vigorous-in- tensity weekly minutes and survival (x2=2.542, Cramer’s V=0.090, p=0.468). There was a small-strength effect of the number of weekly vigorous-intensity minutes achieved on survival in patients with colorectal cancer (η=0.222, η2=0.049). There was a medium-strength effect of BMI on survival (η=0.325, η2=0.106) and a large-strength effect of waist circumference on survival (η=0.0.516, η2=0.266). Discussion To our knowledge, this is the first paper describing clin- ical profiles, lifestyle-related risk factors, and survival of an urban South African cohort with colorectal cancer. In this cohort, patients in the public sector were younger and mostly Black-African, whereas those in the private cohort were older and more frequently Caucasian. In concor- dance with our findings, previous epidemiological studies have shown Black individuals develop colorectal cancer earlier than Caucasian individuals39. Although there may be genetic and cultural factors, the differences in cancer incidence may be linked to socioeconomic status40. The AJCC scores presented in the results showed a signif- icant difference in cancer staging between those present- ing in the private and public sectors. A potential explana- tion for this might be patient-related or linked to barriers to accessing appropriate care. Healthcare in South Africa is comprised of public and private sectors with vast dif- ferences separating the two. The public healthcare system serves approximately 80 percent of the South African population; with limited capacity to manage complicat- ed conditions like colorectal cancer, which often requires highly specialised services in multiple disciplines41. The difference in cancer staging may in turn also explain the significant difference in survival between the two cohorts. Authors of an American study who analysed data collect- ed from 1981 to 2013 showed younger age and the Afri- can race were significant risk factors for advanced staging of colorectal cancer42. 317 Evidence suggests that moderate-intensity exercise may have a biological effect in reducing colorectal cancer risk43. Patients undergoing cancer treatments may find non-vigorous intensity exercise more tolerable than vig- orous-intensity exercise. Examples of moderate-intensity physical activity include brisk walking and dancing where- as running and aerobics are classified as vigorous-inten- sity physical activity33. Due to missing data, we only had access to the vigorous-intensity weekly exercise achieved by the patients in this cohort. Research to date has shown that vigorous-intensity exercise is not associated with im- proved survival outcomes21,22. Our findings support this, as we found only a small-strength effect of the vigor- ous-intensity weekly minutes achieved on survival. Un- fortunately without data for moderate-intensity exercise, conclusions are difficult to make on patients’ physical ac- tivity profiles. Our results showed that BMI and waist circumference had moderate-and-large-strength effects respectively on survival. These findings support research which suggests that patients with increased BMI have better survival outcomes7,14,18. Patients with advanced-stage colorectal cancer experience weight loss, sarcopenia, and cachexia which may have a greater impct on patients who have a low BMI14. Therefore, being overweight may be protec- tive in patients with advanced colorectal cancer14. Screen- ing for ideal waist circumference and BMI may be essen- tial in managing patients undergoing various treatments for colorectal cancer. Waist circumference is a simple, in- expensive measure used to determine central adiposity in men and women44. However, waist circumference cut-off points for determining colorectal cancer risk and survival are yet to be established in sub-Saharan Africa. Physiotherapists can provide non-pharmacologic inter- ventions to assist patients with their physical health needs during cancer treatments and pre-and-post-operatively45. As rehabilitation specialists, they are well trained to man- age modifiable risk factors such as physical inactivity and can offer education on health behaviours like smoking, alcohol consumption, and basic nutritional practices46. Furthermore, physiotherapists have the resources and clinical reasoning to screen and refer patients to other healthcare providers as needed45. The data presented in this paper highlight the need for anthropometric screen- ing and lifestyle education in this cohort presenting with colorectal cancer. Management of modifiable risk factors could influence colorectal cancer incidence and outcomes in South Africa. Future research is required to determine the incidence of sarcopenia in South African patients with colorectal can- cer and to determine its association with survival. This will assist us to re-define and streamline the role of phys- iotherapists in the management of these patients. Limitations to the study Certain variables were considered for inclusion into the REDCap database after the start of data collection. This resulted in missing data for variables such as the ECOG score. Missing data was a limitation in calculating GPAQ scores. The between-group differences demonstrated in the re- sults of this study should be interpreted with caution due to the large difference in sample size between the two groups. This cohort only represents a sample of the South Afri- can urban population of patients with colorectal cancer. Patients living in rural areas may present with a different profile. This could be due to several factors including ac- cess to healthcare which may affect the staging of cancer on the first presentation as well as the comorbidities diag- nosed. Another limitation is that the cohort in this study is not a population-based sample. Conclusion In this urban South African cohort, lifestyle factors known to be associated with colorectal cancer risk were found. Patients in the private sector cohort were older, had earlier stages of cancer staging, and had a higher per- centage of current alcohol consumption when compared to the public cohort. There were significantly higher sur- vival rates in the private sector cohort in comparison to the public sector cohort. Waist circumference and BMI were shown to have large-and-medium-strength positive effects respectively on survival. Emphasis should be placed on screening for anthropo- metric data and education on maintaining an ideal waist circumference and BMI should be prioritised. As es- tablished healthcare professionals, physiotherapists are African Health Sciences, Vol 22 Issue 1, March, 2022318 well-positioned to provide such screening and education to effect long-term lifestyle behaviour change and im- prove outcomes. Acknowledgments This research arises from the Colorectal Cancer South Africa (CRCSA) longitudinal cohort study, funded by the Medical Research Council of South Africa, through the Wits/SAMRC Common Epithelial Cancer Research Centre (CECRC) Grant. The South African Society of Physiotherapy Research Foundation contributed to the funding of this study. 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