Increasing awareness and knowledge of lifestyle recommendations for cancer prevention in Lynch syndrome carriers

Lynch syndrome (LS) mutation carriers may reduce their cancer risk by adhering to lifestyle recommendations for cancer prevention. This study tested the effect of providing LS mutation carriers with World Cancer Research Fund-the Netherlands (WCRF-NL) health promotion materials on awareness and knowledge of and adherence to these recommendations. In this randomized controlled trial ( n = 226), the intervention group ( n = 114) received WCRF-NL health promotion materials. All LS mutation carriers were asked to fill out questionnaires at 2 weeks before (baseline, T0) and at 2 weeks (T1) and 6 months (T2) after the intervention. Linear mixed models were performed on awareness (0-7) and knowledge (0-7) of the recommendations, and on the secondary outcomes, that is adherence, distress, cancer worry, and risk perception. Compared with the control group, the intervention group became significantly more aware (overall mean difference = 1.24; 95%CI = 0.82-1.67) and obtained significantly improved knowledge of the recommendations (overall mean difference = 1.65; 95%CI = 1.27-2.03). Differences were significantly larger for T1 ( P interaction = .003 and ≤ .001, respectively) but remained significant for T2. No effect on secondary outcomes was found. In conclusion, provision of WCRF-NL health promotion materials increases awareness and knowledge of lifestyle recommendations for cancer prevention among LS mutation carriers without causing additional distress, but does not affect adherence.

intake and insufficient physical activity are associated with higher CRC risk. In addition, higher alcohol intake is associated with higher CRC risk in men, and probably also in women. Moreover, there is limited suggestive evidence for a protective effect of non-starchy vegetables and fruit. 14 Only few studies evaluated the association between dietary and other lifestyle factors and cancer risk in LS mutation carriers. 15 These studies suggested that the association of smoking and higher body fatness with CRC risk was in the same direction and generally stronger in LS mutation carriers than in the general population. 15 Other lifestyle factors have not yet or only scarcely been studied.
On the basis of the most comprehensive collection of available evidence on sporadic cancer, the World Cancer Research Fund (WCRF)/ American Institute of Cancer Research (AICR) issued 10 general recommendations on diet, physical activity, breast feeding and weight management for cancer prevention, 13 besides the recommendation to quit smoking. Little is known about the extent to which LS mutation carriers are aware of and adhere to these lifestyle recommendations.
Currently, guidelines for clinicians do not include information on these lifestyle recommendations for potential health benefits for LS mutation carriers. 16,17 Providing health promotion materials could be an easy-to implement approach to promote awareness and knowledge (ie, known determinants of adherence) in LS mutation carriers.
This may subsequently promote adherence to lifestyle recommendations, leading to potential health benefits. The aim of this randomized controlled study was to test the effect of providing LS mutation carriers with WCRF-NL health promotion materials on awareness and knowledge of the WCRF/AICR cancer prevention recommendations.
In addition, we tested the effect of providing these WCRF-NL health promotion materials on adherence to these recommendations and on levels of distress, cancer worry and cancer risk perception.

| METHODS
The medical ethical research committees of the Radboud university medical center and Maastricht University Medical Centre granted permission to perform this study.

| Participants and study procedures
LS mutation carriers were eligible for participation in this study if mutation status was confirmed by DNA testing and carriers were informed about the LS carriership at Radboud or Maastricht University Medical Center within the last 6 years, and were aged between 18 and 65 years at the time of inclusion in the study between April and September 2015. LS mutations carriers were excluded if they had insufficient command of the Dutch language to fill out Dutch questionnaires or if they were currently participating in the GeoLynch study, a prospective cohort study among LS mutation carriers, 18 to prevent interference between both studies.
After informed consent was obtained, eligible participants were randomized into an intervention or control group (Figure 1). To minimize the risk of interference between family members, randomization was performed per family in clusters.

| Intervention
The intervention group received WCRF-NL health promotion materials about lifestyle recommendations for cancer prevention.
The WCRF materials included 1 general leaflet, which provided information about cancer development, cancer prevention and the 10 WCRF/AICR cancer prevention recommendations: (1) Be as lean as possible without becoming underweight, (2) be physically active for at least 30 minutes every day, (3) limit consumption of energy-dense foods and avoid sugary drinks, (4) eat more of a variety of vegetables, fruits, whole grains and legumes such as beans, (5) limit consumption of red meats (such as beef, pork and lamb) and avoid processed meats if consumed at all, (6) limit alcoholic drinks to 2 for men and 1 for women a day, (7) limit consumption of salty foods and foods processed with salt (sodium), (8) don't rely on supplements to protect against cancer, (9) it is best for mothers to breastfeed exclusively for up to 6 months, and (10 after treatment, cancer survivors should follow the recommendations for cancer prevention.
The other leaflet provided specific information about CRC: CRC development, symptoms, risk factors, and the lifestyle recommendations that have been related to a reduced risk of CRC. A reference to the website of the WCRF was included for additional information.
The control group did not receive any information during the study period but received the same leaflets after completing the last questionnaire.

| Study outcomes
Participants filled out questionnaires at 3 time points: 2 weeks before the intervention (T0) and at 2 weeks (T1) and 6 months (T2) after the intervention, either online or on paper. These questionnaires measured the following parameters.

| Primary outcomes
Awareness of the cancer risk factors as described in the WCRF/AICR recommendations for cancer prevention (referred to as awareness of the WCRF/AICR recommendations) was measured using the question from the AICR Cancer Risk Awareness Survey "Do the following factors have a significant effect on whether or not the average person develops cancer?" with respect to the exposures: (1) overweight, (2) insufficient physical activity, (3) diets low in vegetables and fruits, (4) diets high in red meat, (5) cured/ processed meats, (6) alcohol, and (7) use of food supplements for cancer prevention. 19 Other non-cancerrelated factors were added to this list. Correct answers were rated "1," incorrect answers "0." The total awareness score ranged between 0 and 7. In addition, knowledge of the WCRF/AICR recommendations was measured using 7 multiple choice questions. In addition to the awareness questionnaire, the knowledge questions included more content-specific topics, for example "What is the minimally recommended fruit and vegetable intake per day according to the recommendations for cancer prevention?". Correct answers were rated "1," incorrect answers "0." The total knowledge score ranged between 0 and 7.

| Secondary outcomes
Adherence to the WCRF/AICR recommendations was measured using the WCRF/AICR score, which is based on the WCRF/AICR recommendations. 20 The score we used was a slightly modified version of this score and its construction is shown in Table 1. 20 For some recommendations insufficient data was available, for example, data was missing for food supplement intake, breastfeeding, or consumption of energy dense foods. The score assigned for each recommendation were the subscores for sodium and discretionary sodium. The total WCRF/AICR score ranged between 0 (no adherence) to 7 points (complete adherence).
This score was assessed using the following questionnaires: 1. Dietary behaviour was assessed using an adapted version of a 40item, validated questionnaire (FFQ) specifically developed to assess adherence to the Dutch Guidelines for a healthy diet. 21 With this questionnaire, we assessed intake of fruits (gram [g]/day [d])), vegetables (g/d), red meat (g/week [w]), processed meat (g/w), drinks that promote weight gain (sugary drinks or no sugary drinks), fiber intake (g/d), alcoholic drinks (number of drinks/d), and discretionary sodium (yes or no) during the last month. 21 2. Physical activity was assessed using the validated Short Questionnaire to Assess Health Enhancing Physical Activity (SQUASH) questionnaire which contains questions about multiple activities referring to a normal week in the past month.
Results were converted to time spent in light, moderate, and vigorous activities, which were then converted to activity scores. 22 When this total activity score was 5 or more, representing the number of activities of at least 30 minutes per week, persons were categorized as adherent to the physical activity recommendation.

3.
Anthropometric measurements included self-reported body weight and height. These measures were used to calculate the body mass index (BMI) (kg/m 2 ).
Cancer risk perception was assessed by 2 standardized questions. 23 Participants were asked to indicate their cancer risk quantitatively (percentage from 0 to 100) and qualitatively (5 categories: very low to very high). a Lowered by matching the percentage coverage of total energy intake as assessed by the adapted short version of the DHD-FFQ (68%).
The total score of the Dutch version of the Hospital Anxiety and Depression Scale (HADS) 24 was used to measure distress. The questionnaire contained 14 items scored on a 4-point scale with total scores ranging from 0 to 42. A higher total score corresponded with a higher level of distress. A score ≥12 was appointed as a clinically increased level of distress. This questionnaire has been shown to have good reliability. 24 Cancer worry was assessed using the Cancer Worry Scale (CWS), consisting of 8 items. The reliability and validity is good among breast and colorectal cancer survivors. 25,26 The total score ranges between 8 and 32, with higher scores corresponding to more cancer worry. A cut-off score of 14 is generally accepted for differentiating normal from increased levels of cancer worry.
Satisfaction with and the use of the WCRF health promotion materials were measured at T2, using self-developed questions concerning general satisfaction, timing of the intervention, frequency of use of the WCRF health promotion materials, and reasons for non-usage. At T2, both groups were asked whether they searched for additional or other information concerning lifestyle and cancer risk during the study period.
Questions concerning medical data (on personal and family cancer history, colon surgery, time since LS diagnosis), and demographic questions (age, occupation, marital status and education) were included in the baseline questionnaire. (3) Same analysis as (2) adjusted for the covariates age, gender, level of education, and years since LS diagnosis. For the primary outcomes awareness and knowledge, the same analysis as (3) was performed with an interaction term for the covariates [age less than or greater than or equal to median of 49 years, gender, level of education (low vs middle and high) and years since LS diagnosis less than or greater than or equal to median of 3 years] and intervention to assess whether the intervention effect differed for the subgroups.

| Power calculations and statistical analyses
Additionally, analyses were performed separately for participants with vs without a personal history of cancer, completing questionnaires online vs on paper, and with baseline WCRF adherence scores <5 vs ≥5. Differences in awareness and knowledge of and adherence to the individual WCRF/AICR recommendations between the intervention and the control group were analyzed with generalized estimation equations using a logistic model, taking into account the repeated measures but not the family-clustered design (no significant cluster effect in linear mixed models analyses). We performed (1) a crude analysis for the overall intervention effect and (2) a crude analysis with time (categorical dummy variable) and an interaction term for time and intervention to assess the intervention effect at T1 and T2.
All analyses were carried out according to modified intention-to-treat (mITT) methodology. mITT allows the exclusion of some randomized subjects in a justified way (such as subjects who were deemed ineligible after randomization or certain subjects of whom all measurements were missing). 28 All reasons for exclusions after randomization are shown in Figure 1. All the analyses were performed using IBM SPSS, version 22 and P < .05 was considered statistically significant.

| RESULTS
We invited 425 LS mutation carriers and 226 agreed to participate (response rate 53%). In total, 114 carriers (from 62 families) were randomized to the intervention group and 112 carriers (from 62 families) to the control group. Reasons for exclusion after randomization are described in Figure 1, leaving a total of 218 LS mutation carriers for analysis. Patient characteristics are shown in Table 2. The percentage of higher educated persons and never smokers was higher in the intervention group compared with the control group. Other than that, characteristics were similar for the intervention and control group. A total of 35% of the study population reported a personal history of cancer.
As shown in Table 3 Awareness and knowledge did not differ by mode of completing the questionnaire (online for n = 152, on paper for n = 66) and by baseline WCRF adherence score (score <5 for n = 97; score ≥5 for n = 121) (data not shown).
The awareness and knowledge of the WCRF/AICR recommendations varied per recommendation, and was significantly higher for all recommendations in the intervention group compared with the control group at T1 (Table 4)

| DISCUSSION AND CONCLUSIONS
This is the first study among LS mutation carriers reporting on the effect of health promotion materials for cancer prevention. We Data are reported as the mean AE SD or n (%).
a Missing for n = 48 in intervention group and n = 9 in control group.   showed that provision of WCRF-NL health promotion materials resulted in increased awareness and knowledge of the lifestyle recommendations for cancer prevention. Although effects remained up to 6 months, they were significantly smaller compared to effects found at 2 weeks after information provision. The provision of information on lifestyle recommendations for cancer prevention did not cause additional distress, cancer worry or a change in risk perception. No effects on adherence to the lifestyle recommendations were found.
Our study population had a relatively high awareness of cancer risk factors at baseline, as compared to the general population. 19,29,30 For example, 72% of our study population was aware of overweight as a cancer risk factor, while this was reported for only 52% of the general population in the US. 19 However, awareness varied by risk factor, with lowest awareness observed for use of food supplements (29%). Specific knowledge of the WCRF/AICR recommendations at baseline (e.g., the recommended intake of processed meat intake per day) was substantially lower than awareness of cancer risk factors, ranging from 10% for processed meat intake and use of food supplements to 64% for physical activity. This is in line with findings from a representative population sample in the UK, in which 79% knew that eating too much meat increased risk but only 47% and 28% knew the advised amount of red meat and processed meat, respectively. 31 We found that the provision of health promotion materials for cancer prevention improved the awareness and knowledge of all WCRF/ AICR recommendations. These improvements remained statistically significant up to 6 months after intervention, although they were statistically significantly smaller than 2 weeks after intervention.
Improvements on knowledge were larger for LS mutation carriers with versus without a personal history of cancer, which may be explained by a greater interest in factors that may reduce their (secondary) cancer risk. As expected, awareness and knowledge of the control group remained relatively stable, except for improvements in awareness concerning red meat intake and knowledge concerning body weight. This may be due to media attention with respect to an IARC publication on red meat and cancer risk which occurred after T0, and to searching for additional information on this topic after T0.
The provision of general WCRF-NL health promotion materials did not improve adherence to the WCRF/AICR recommendations for cancer prevention, as could be expected from previous studies on behaviour changes after provision of other health promotion materials. 32 We observed a large variation in adherence to the different WCRF/AICR recommendations, with hardly any participants adhering to the recommendation for fruit and vegetable intake but more than 80% of participants adhering to the recommendation for sugary drinks. Adherence to the WCRF/AICR recommendations has also been studied among colorectal cancer survivors, who had slightly lower adherence rates compared to our study population. 33 Especially, our study population had higher adherence rates to the red and processed meat recommendations and the recommendation about salt intake. These differences suggest the selection of more health conscious participants in our study, as the study among colorectal cancer survivors was not specifically focused on lifestyle behaviours. 33  However, our results show that promotion of awareness and knowledge was not sufficient to achieve health behaviour change.
These results are in line with other studies, and suggest that a more comprehensive intervention is needed to achieve health behaviour change. 37 Furthermore, our finding that awareness and knowledge of WCRF/AICR recommendations significantly improved from baseline to directly after the provision of health promotion materials, and subsequently decreased at follow-up is in line with scientific literature on lifestyle intervention effects over time. 37 This suggests that offering a more comprehensive lifestyle intervention shortly after provision of health promotion materials may bridge the gap between awareness/ knowledge and adherence to recommendations.
To achieve an optimal intervention effect and to promote participation and adherence, a lifestyle intervention offered to LS mutation carriers should meet the needs of this particular patient population.
Although we found that patient satisfaction and frequency of use of the provided WCRF-NL materials were high, almost half of the parti- From the field of health behaviour change, several proven effective behaviour change techniques exist, which may promote adherence. 39 Behaviour change techniques that have shown to be associated with intervention effectiveness include: "social support", "goal setting", action planning", "instruction on how to perform the behaviour", "self-monitoring of behaviour", and "self-monitoring of outcomes of behaviour". 40 Lifestyle interventions that have shown to be effective in promoting adherence are typically more complex and intensive than the minimal intervention we have applied in our study, and make use of a larger amount of behaviour change techniques. 37 carriers that were randomized were more likely to be older, female, and to have had a previous diagnosis of cancer compared to nonresponders. Therefore, this may not be a representative sample of LS mutation carriers. Drop-out was higher in the control group than in the intervention group. However, data were missing at random and by using a mixed models analysis unbiased effect estimates were obtained. 41 The effects of the intervention on adherence and cancer worry at T1 may have been underestimated; the questionnaires referred to health behaviours and cancer worry in the last month, which also included the period of 2 weeks prior to the intervention.
Timing of T1 at 2 weeks after the intervention was chosen best suitable for the primary outcome awareness, for which measurement shortly after the intervention was essential. Reliability of the question-