Lifestyle after Colorectal Cancer Diagnosis in Relation to Survival and Recurrence: A Review of the Literature

Purpose of Review This review summarizes the evidence regarding diet, physical activity, smoking, and body composition after colorectal cancer (CRC) diagnosis in relation to all-cause and CRC-specific mortality and disease recurrence and gives suggestions for future research directions. Recent Findings Overall, this review suggests that some, albeit not all, of the well-known modifiable risk factors for cancer incidence might also be associated with CRC survival. CRC prognosis appears to be worse with increased physical inactivity, smoking, or being underweight after CRC diagnosis. Emerging evidence suggests that diets associated with a positive energy balance, e.g., high consumption of sugar-sweetened beverages, may negatively impact survival in CRC survivors. In contrast, there is currently little evidence to support the recommendation to limit red and processed meat or alcohol intake after CRC diagnosis. Whether being overweight and obese after CRC diagnosis improves or worsens CRC prognosis remains controversial and may depend on the measure used to assess body fatness. Summary Further research on post-diagnosis lifestyle patterns is needed to understand the multifactorial influence on CRC prognosis. Disease recurrence and the development of comorbidities should be included as key outcomes in future studies and lifestyle should preferably be repeatedly measured.


Introduction
Diet, physical activity, smoking, alcohol, and body weight are associated with risk (incidence) of colorectal cancer (CRC) [1,2]. In contrast, far fewer studies have examined the influence of these lifestyle factors on survival after CRC diagnosis. Currently, cancer survivors are advised to follow the recommendations formulated for cancer prevention [3]. However, it is currently unclear if making lifestyle changes after diagnosis would impact disease progression and survival.
To better understand the association between lifestyle and CRC outcomes, we summarized the evidence regarding diet, physical activity, smoking, and body composition after CRC diagnosis across different groups of cancer survivors. Moreover, we also included observational studies, not included in previous reviews [23-38, 39••]. We identified three study design categories based on the selection of the included study population: (1) population-based studies including all incident CRC cases, (2) studies in the adjuvant setting limited to survivors treated with adjuvant therapy, and (3) studies in the metastatic setting limited to patients with metastatic disease (Fig. 1). We chose to focus on post-diagnosis lifestyle factors, because this is the period during which CRC survivors could be counseled to alter their behavior. Therefore, we only included studies that examined the association between lifestyle at or after CRC diagnosis and all-cause mortality, CRC-specific mortality, or cancer recurrence. Additionally, we summarized the evidence regarding changes in lifestyle, i.e., from pre-to post-diagnosis or changes made after diagnosis, among CRC survivors and survival outcomes from either observational or intervention studies. We did not include papers that examined lifestyle and CRC survival separately by molecular subtypes. These publications will be reviewed in future issue of this journal. Finally, we conclude with suggestions for future research directions.

Overview of Included Studies
We excluded all studies that did not assess lifestyle at or after CRC diagnosis (e.g., those that assessed only pre-diagnosis factors) or did not adjust for critical confounders (e.g., age, stage). Furthermore, we excluded all studies that dichotomized body mass index (BMI) when examining the association between BMI and mortality or recurrence. Dichotomized BMI is considered a crude classification of BMI by combining diverse categories of body mass and body composition. Thus, dichotomized BMI may not account for potential differential associations between sub-categories of BMI (e.g., by combining overweight and obese in one category) [15].
We included 57 relevant articles (based on 84 different observational studies) that reported on post-diagnosis diet, physical activity, smoking, or body fatness/body composition in CRC survivors in relation to all-cause mortality, CRC-specific mortality, or cancer recurrence. An overview of the number of included articles according to exposure and type of study population is shown in Fig. 2. Additionally, we included 13 relevant articles (one intervention study and 11 different observational studies) that reported on changes in lifestyle among  Fig. 1 Schematic diagram of identification of three study categories based on the characteristics of the included study population. Based on the study population, studies were categorized into (1) population-based studies including all incident colorectal cancer cases, (2) studies in the adjuvant setting limited to survivors treated with adjuvant therapy, and (3) studies in the metastatic setting limited to metastatic patients. In each study category, we identified studies with lifestyle information available at or after colorectal cancer diagnosis. Studies with lifestyle information limited to the period before colorectal cancer diagnosis, either collected prospectively before diagnosis or retrospectively after diagnosis, were not taken into account CRC survivors in relation to survival outcomes. In total, 61 articles are discussed in more detail in this review.

Diet after CRC Diagnosis
Five population-based studies and one study in the adjuvant setting provided results on diet and CRC outcomes in 10 publications [23][24][25][26][27][40][41][42][43][44] (Table 1). Three US cohorts assessed post-diagnosis diet in population-based cohorts with > 1000 CRC patients: Nurses' Health Study I (NHS) [23,44], Health Professional Follow-Up Study (HPFS) [44], and Cancer Prevention Study (CPS) II Nutrition Cohort [27,40,41]. All three cohorts consist of participants diagnosed with CRC during follow-up and have updated dietary assessment after diagnosis. Usually, questionnaires that were completed after treatment was finished were utilized in the analyses. In contrast, two non-US cohorts (the German cohort PopGen [24] and BioBank Japan [26]) recruited > 1000 CRC patients after CRC diagnosis. The study in the adjuvant setting, Cancer and Leukemia Group B (CALGB) 89,803 Diet and Lifestyle Companion study [25,42,43], was embedded in a randomized trial of adjuvant chemotherapy among~1000 patients with stage III colon cancer. Additionally, three articles, two from the CPS II Nutrition Cohort [27,40] and one report on a small randomized dietary intervention trial reported on dietary changes among CRC survivors in relation to mortality [27,40,78].
In this review, we summarized the available evidence for dietary patterns, red and processed meat, sugar-sweetened beverages, alcohol consumption, other foods and beverages, and CRC survival.

Dietary Patterns
Two observational studies, the NHS I [23] and a German cohort of CRC survivors [24], assessed post-diagnosis dietary patterns in a population-based setting [23], while CALGB 89803 [42] reported results in the adjuvant setting (Table 1). Data-driven dietary patterns were assessed within NHS I [23] and CALGB 89803 [42]. Both studies observed patterns that were given the labels a "Western" and a "Prudent" dietary pattern. The Western dietary pattern was characterized by high-and low-fat dairy, refined grains, red and processed meats, desserts, and potatoes, while the Prudent dietary pattern was characterized by high intakes of fruits, vegetables, whole grains, and poultry.
Furthermore, several a priori-defined dietary patterns were studied in the two population-based studies [23,24] (Table 1). Of the a priori-defined dietary patterns, none has been studied in more than one cohort. Some a priori-defined dietary patterns were associated with lower risk of all-cause mortality, but not all [23,24].
Only one small (n = 111) randomized dietary intervention trial among CRC survivors assessed associations with survival [78]. Throughout the 1.5 months of neoadjuvant radiotherapy patients with rectal cancer randomized to the intervention group received 6 weekly individualized nutrition counseling and education sessions using regular foods, while the control group maintained their usual diet. Overall, the main goal of the intervention was to enable every patient to achieve his or her calculated energy and protein requirements. After long-term Fig. 2 Overview of the number of included relevant articles on diet, physical activity, smoking and body mass index (BMI) or body composition at or after colorectal cancer diagnosis in relation to allcause mortality, cancer-specific mortality, or disease recurrence by type of included study population. In total, 57 articles were included: 54 articles reported on one exposure, two articles reported on both physical activity and BMI, and one article reported on all four exposures follow-up (median follow-up 6.5 (range 4.9-8.1) years), CRC-specific survival was significantly longer in the intervention group after adjustment for age and disease stage (median survival 7.3 vs. 4.9 years).

Red and Processed Meats
Both NHS I [23] and CPS II Nutrition Cohort [40] reported on post-diagnosis red and processed meat intake, although the NHS I paper focused on dietary patterns (Table 1). The CPS II Nutrition Cohort also provided information regarding preto post-diagnosis change in red and processed meat consumption [40] ( Table 2). These two studies did not observe an association between red and processed meat intake and both all-cause mortality and CRC-specific mortality [23,40]. Furthermore, changing meat intake from high (median or higher) before CRC diagnosis to low (below median) after diagnosis was not associated with lower mortality when compared to survivors with a consistently high intake [40].
Both studies [23,43] reported increased all-cause mortality risk for sugar-sweetened beverage consumption after CRC diagnosis, of which the association in the NHS I was statistically significant [23]. Each additional serving of sugarsweetened beverages (including fruit juices) after CRC diagnosis was associated with an 11% increased risk for all-cause mortality (HR 1.11; 95% CI 1.01-1.23) [23]. A similar relative risk was reported for CRC-specific mortality, although it was not statistically significant [23]. For colon cancer recurrence, CALGB 89803 reported a statistically significant increased recurrence risk for patients consuming ≥ 2 servings of sugar-sweetened beverages per day (HR 1.75; 95% CI 1.04-2.94) compared to those consuming < 2 servings per month (P trend = 0.04) [43].
In NHS I, moderate drinking was used as the reference group and abstaining from alcohol consumption was associated with a statistically significant increased all-cause mortality risk (HR 1.30; 1.05-1.61) compared to women consuming 5-15 g of alcohol per day [23]. Drinking > 15 g/day (approximately 1.5 drinks) was not statistically significantly associated with increased mortality risk. Similarly, abstainers had a higher mortality risk than drinkers in the Japanese cohort [26] and after combining both NHS I and HPFS cohort data [44]. However, the CPS II Nutrition cohort reported that drinking alcohol after diagnosis was not associated with allcause mortality [27]. For CRC-specific mortality, similar results were reported as for all-cause mortality ( Table 1).
The CPS II Nutrition cohort also provided information regarding pre-to post-diagnosis change in alcohol consumption ( Table 2). Participants who reported drinking before CRC diagnosis but stopped drinking alcohol after diagnosis had a statistically non-significant increased risk of all-cause and CRC-specific mortality compared to participants who continued to drink alcohol [27].

Other Foods, Beverages, and Nutrients
The intake of some foods, beverages, and nutrients were only reported in one study each (Table 1). Higher nut consumption was associated with lower risk of CRC mortality (HR/serving/ day 0.69; 95% CI 0.49-0.97) in the NHS I, while no statistically significant association was reported for all-cause mortality [23]. Furthermore, no associations were observed within the NHS I with either all-cause mortality or CRC-specific mortality for vegetables, fruits, or whole grains [23]. However, in the Japanese study, lower green leafy vegetable intake after CRC diagnosis was associated with an increased all-cause mortality risk [26].
Higher dietary glycemic load and total carbohydrate intake were statistically significant associated with an increased risk of mortality and recurrence in CALGB 89803 [45]. Higher total calcium intake was statistically significantly associated with both lower all-cause mortality and CRC-specific mortality in the CPS II Nutrition Cohort, while no significant associations were reported for vitamin D [41]. Also no significant associations were reported for intake of one-carbon nutrients (folate, vitamins B 6 and B 12 ) in NHS I [44].

Diet: Key Points
One small randomized intervention trial which provided individualized nutritional counseling and education about regular foods suggest that making dietary changes may improve cancer-specific survival. No dietary pattern or food has been studied in more than two observational cohorts, with cancer recurrence only studied in one cohort in the adjuvant setting embedded in a randomized chemotherapy trial. While alcohol consumption has been studied more frequently, these studies often used abstainers as comparison group. Abstainers are probably an inappropriate reference group, as this group may, at least in part, include people who stopped drinking because of comorbidities or cancer-related symptoms. Overall, emerging evidence shows that diet after CRC diagnosis might affect survival, but further research is needed to clarify what aspects of diet are important and which dietary changes could affect survival.

Physical Activity after CRC Diagnosis
Seven population-based studies [26,[46][47][48][49][50][51] and one study in the adjuvant setting [52] provided results on physical activity after CRC diagnosis and mortality outcomes (Table 1). Five large US cohorts assessed post-diagnosis physical activity in population-based cohorts with > 500 CRC patients: NHS I [46], HPFS [47], CPS II Nutrition Cohort [50], Women's Health Initiative [49], and National Institutes of Health-AARP Diet and Health Study [51]. All five cohorts consist of participants diagnosed with CRC during follow-up and have updated physical activity assessment after diagnosis, usually when treatment was completed. In contrast, two non-US cohorts (an Australian cohort [48] and BioBank Japan [26]) recruited > 1500 CRC patients after CRC diagnosis. All studies reported on leisure time physical activity.

Changes in Physical Activity
The Australian cohort [48] and NHS I [46] also provided results on changes in physical activity and mortality outcomes in CRC patients (Table 2). An increase of physical activity > 2 h/week between 5 and 12 months post-diagnosis was statistically significantly associated with lower all-cause (HR 0.69; 95% CI 0.50-0.94) and CRC-specific mortality (HR 0.64; 95% CI 0.44-0.93) among Australian CRC survivors [48]. A pre-to postdiagnosis increase in physical activity showed a statistically significant lower all-cause and CRC-specific mortality risk in the NHS I [46], but no association was reported among Australian CRC survivors [48] ( Table 2). The first randomized controlled trial designed primarily to assess the impact of physical activity on survival among colon cancer survivors is ongoing [83]. As of April 2017, the trial has enrolled 536 of its planned 972 participants [84] and only 1 year feasibility results have been published so far [85].

Sedentary Behavior
Three of the population-based studies, CPS II Nutrition Cohort [50], National Institutes of Health-AARP Diet and Health [51], and HPFS [53] also reported on post-diagnosis sedentary behavior and all-cause as well as CRC-specific mortality (Table 1). CPS II reported on leisure time spent sitting [50], whereas the other two studies assessed TV viewing [51,53]. All three studies [50,51,53] reported no statistically significant associations between sedentary behavior and allcause mortality. With regard to CRC-specific mortality, only one study, the CPS II Nutrition Cohort showed a statistically significant positive association between sedentary behavior and CRC-specific mortality (≥ 6 h vs. < 3 h/day sitting time: HR 1.62; 95% CI 1.07-2.44) [50].

Physical Activity: Key Points
Evidence from prospective observational studies has consistently suggested that higher physical activity after CRC diagnosis is associated with a lower risk of CRC-specific and allcause mortality, but whether physical activity is causally related to CRC mortality remains unclear. A randomized controlled trial is currently ongoing to address whether aerobic physical activity after complement of adjuvant therapy improves survival. Based on a few studies, there is some evidence suggesting that excessive sedentary behavior after CRC diagnosis might be associated with increased CRC-specific mortality, but findings are less consistent than for leisure time physical activity.

Smoking
For all-cause mortality, eight out of nine population-based studies [26,28,29,31,[54][55][56][57] reported increased all-cause mortality risk for smoking, of which six [26,28,29,54,55,57] were statistically significant. Furthermore, the study in the adjuvant setting also reported a statistically significant increased all-cause mortality risk for smoking [61]. For CRC-specific mortality, five population-based studies [14,29,30,57,58] reported increased CRC-specific mortality risk for smoking, of which three [14,29,30] were statistically significant (Table 1). However, one study that reported results separately for men and women reported a statistically nonsignificant positive association among women for postdiagnosis smoking, while among men, a statistically nonsignificant inverse association was reported [56]. Furthermore, one study in the adjuvant setting also reported a statistically significant increased CRC-specific mortality risk for smoking [59].
For colon cancer recurrence, one study embedded in the trial N0147 [61] reported a statistically significant increased cancer recurrence risk for smoking, while CALGB 89803 [60] reported no association with smoking among stage III colon cancer patients treated with adjuvant chemotherapy.

Smoking Cessation
Four population-based studies provided results on smoking cessation and mortality outcomes in CRC patients ( Table 2). People who continued smoking after CRC diagnosis had a more than threefold increased risk of all-cause mortality (HR 3.46; 95% CI 1.69-7.10) compared to people who quit smoking after diagnosis [28]. Pre-to post-diagnosis smoking cessation was not statistically significantly associated with all-cause or CRC-specific mortality risk [29,58,79], although one of these studies reported lower mortality risk for those who quit smoking compared to those who continued to smoke [29].

Smoking: Key Points
Overall, evidence from observational studies has consistently suggested that smoking after CRC diagnosis increases the risk of CRC-specific and all-cause mortality. It seems plausible that smoking cessation would improve survival outcomes in CRC survivors, although direct evidence is limited.

Body Fatness and Body Composition after CRC Diagnosis
This review first focusses on studies that assessed BMI at or after CRC diagnosis. Next, we discuss weight changes and lastly, we describe the results of studies which quantified visceral adipose tissue or skeletal muscle mass from CT images.

Body Mass Index
Eleven population-based studies [16,26,32,33,48,49,[62][63][64][65][66], two studies from adjuvant chemotherapy trials [67,68], and one study among metastatic patients [34] assessed the association of BMI at or after CRC diagnosis and CRC outcomes (Table 1). Furthermore, 21 additional studies in the adjuvant setting were included in a pooled analyses of patients enrolled in trials of adjuvant chemotherapy [69]. Moreover, an additional article with pooled analyses in the metastatic setting included data of 25 treatment trials [70].
For overweight (defined as BMI 25.0-24.9 kg/m 2 ), all population-based studies [16,26,32,33,48,49,62,[64][65][66] reported lower all-cause mortality risk compared to normal weight individuals, of which three were statistically significant [48,49,62]. However, studies in the adjuvant setting of a chemotherapy trial reported that overweight individuals had a similar all-cause mortality risk as normal weight individuals (Table 1). For metastatic patients participating in treatment trials, all-cause mortality risk was lowest at BMI 28 kg/m 2 [70], while overweight was associated with an increased all-cause mortality risk among a general population of patients diagnosed with metastatic disease (HR 1.23; 95% CI 1.03-1.46) [34]. Generally, similar results were reported for CRC-specific mortality and cancer recurrence (Table 1).
For obesity (BMI ≥ 30 kg/m 2 ), none of the populationbased studies [16,26,32,33,48,49,62,[64][65][66] reported statistically significant associations with all-cause mortality. Nevertheless, the only study (Kaiser Permanente Northern California cohort) that reported on a separate group with class II or III obesity (BMI ≥ 35 kg/m 2 ) reported a statistically significant increased all-cause mortality risk [32]. Within the adjuvant setting pooled analyses showed a modest increased all-cause mortality risk (HR 1.10; 95% CI 1.04-1.17) compared with normal weight [69]. Within the metastatic setting, both publications showed that obese individuals had a somewhat similar, or lower, all-cause mortality risk as normal weight individuals [34,70]. Generally, similar results were reported for CRC-specific mortality and cancer recurrence (Table 1).

Changes in Weight
Four studies [48,[80][81][82] reported on weight changes ( Table 2). Two studies were population-based studies, a cohort from the Kaiser Permanente Northern California population [80] and an Australian cohort [48], and two studies were in the adjuvant setting, CALGB 89803 [81] and a cohort from the British Columbia Cancer Agency [82].
Large post-diagnosis weight loss (> 5 kg or ≥ 10%) was associated with a threefold increased all-cause and CRC mortality risk compared with stable weight in both populationbased studies [48,80]. Modest weight loss (2-4.9 kg or 5-9.9%) was also associated with increased all-cause and CRC mortality risk [48,80], although only statistically significant in the Kaiser Permanente Northern California cohort [80]. In fact, the association between weight loss and mortality was present regardless of at-diagnosis BMI [80]. Large weight loss during adjuvant chemotherapy was associated with increased all-cause mortality and recurrence risk in a cohort from the British Columbia Cancer Agency [82], but not in CALGB 89803 [81].
Post-diagnosis weight gain was not associated with increased all-cause or CRC-specific mortality risk [48,80,81] or colon cancer recurrence [81,82]. Furthermore, pre-to postdiagnosis weight loss or weight gain of >5 kg were both associated with a statistically significant 60% higher all-cause risk compared to stable weight [48].

Visceral Adipose Tissue
Three population-based studies [35,39,71], two studies in the adjuvant setting [72,73], and one study among metastatic patients [74] reported on post-diagnosis visceral adipose tissue and all-cause mortality ( Table 1). Most of these studies were small (n = 62 to 339), except for the population-based cohort from the Kaiser Permanente Northern California population (n~3200) [39••].
For all-cause mortality, all population-based studies [35, 39••, 71] reported statistically non-significant associations with visceral adipose tissue (Table 1). Both studies among patients treated with chemotherapy [72,73] reported an increased all-cause mortality risk with high visceral adipose tissue, of which one was statistically significant [72]. The study among metastatic CRC patients [74] reported a statistically significant increased all-cause mortality risk for high visceral adipose tissue among patients treated with chemotherapy plus the angiogenesis inhibitor bevacizumab, but not among patients treated with chemotherapy only.
One study among metastatic patients reported on loss of muscle mass during chemotherapy [36]. This study showed that ≥ 9% loss of muscle mass during chemotherapy was associated with a more than fourfold increased all-cause mortality risk (HR 4.47; 95% CI 2.21-9.05) [36].

Body Fatness and Body Composition: Key Points
Body fatness was studied most often by assessment of body mass index, while only few studies assessed other measures of body composition. Altogether, the results of studies across the three study categories (population-based, adjuvant, and metastatic setting) suggest a J-or L-shaped association between BMI and all-cause mortality or CRC-specific mortality risk. The risk of death was highest among patients who were underweight, while lowest risk was seen in patients with a BMI between 25 and < 30 kg/m 2 . If obesity confers an additional mortality risk compared to normal weight or overweight patients remains uncertain. Nevertheless, the most recent meta-analysis of post-diagnosis BMI concluded that obesity was statistically significantly associated with a modest 8% increased all-cause mortality risk (HR 1.08; 95% CI 1.03-1.13) compared to normal weight, while no association was found between obesity and CRC-specific mortality [17••]. Weight loss in the first 2 years after diagnosis was consistently associated with increased mortality risk and this association was independent of BMI at CRC diagnosis. Currently, there are no intentional weight loss trials among CRC survivors that assessed mortality risk [86••] and no study that assessed the effect of weight loss after treatment was successfully completed. That being overweight, and in some studies even obese states, seem to be associated with improved survival compared to normal weight is called the "obesity paradox." The obesity paradox could be explained by several methodological issues, including the crudeness of BMI as a measure of body fatness, especially in a cancer patient population where loss of weight and lean body mass is a strong adverse factor [87].
Other measures used to study the association between body composition and CRC outcomes were visceral adipose tissue and muscle mass quantified from CT images; studies with other measures, such as waist circumference, are currently lacking. There is only limited evidence that visceral adiposity increased mortality risk. Across study categories, studies had mixed results. Only in the adjuvant setting, two small studies consistently showed increased all-cause mortality risk with higher visceral adipose tissue. Even though quantification of adipose tissue from CT scans is regarded as a more precise measure of adiposity than BMI, the usefulness of single-slice analysis might be limited [88]. On the other hand, evidence consistently shows that low muscle mass is associated with reduced survival, although each study used other cut points to define low muscle mass. The notion that the association between overweight and lower mortality is due solely to methodologic biases is refuted by results from the only large population-based study among non-metastatic CRC patients with available data for both BMI and body composition [39••]. Within the overweight BMI range between 25 and < 30 kg/m 2 , body composition appeared to explain why a BMI higher than normal is associated with the lowest mortality. The majority (78%) of patients in the overweight group had adequate muscle mass, while less than half (43%) of the patients with a normal BMI had adequate muscle mass. Furthermore, the obesity paradox could also be explained by clinical issues [87], such as metabolic health. One study at Kaiser Permanente investigated the combination of obesity and metabolic health and concluded that mortality risk was statistically significantly increased in obese patients with the metabolic syndrome, but not in metabolically healthy obese patients, compared with metabolically healthy non-obese patients [89].

Conclusions and Future Directions
In conclusion, this review suggests that some, albeit not all, modifiable risk factors for cancer incidence might also be associated with mortality risk after CRC diagnosis. CRC prognosis appears to be worse with increased physical inactivity, smoking, or being underweight after CRC diagnosis. Emerging evidence suggests that diets associated with a positive energy balance, e.g., high consumption of sugarsweetened beverages, may negatively impact survival in CRC survivors. Nonetheless, data relating post-diagnosis diet to CRC prognosis are scarce; with less than three observational studies that have examined associations for each dietary pattern or individual food after CRC diagnosis. In contrast, high red and processed meat or alcohol intake, established risk factors for incident CRC, do not appear to be associated with mortality after CRC diagnosis. Whether overweight and obesity after CRC diagnosis might confer an additional mortality risk compared to normal weight is still controversial and might depend on how body fatness is assessed and whether muscle mass was accounted for.
Since the first review on lifestyle factors in CRC survivors in 2010 [90], many new studies in this evolving area of research were published and summarized in subsequent reviews and meta-analyses. This is the first paper to comprehensively review post-diagnosis diet, physical activity, smoking, and body composition together in one review. Our findings were generally consistent with previous work, regarding diet [4••], physical activity [7-10, 11••], smoking [13••], and underweight [16, 17••, 19], although we included new publications. Overweight, assessed by BMI, was consistently associated with lowest mortality risk, although discussion remains about the causal claims regarding the effects of BMI on postdiagnosis mortality for CRC survivors. The only large population-based study among non-metastatic CRC patients concluded that body composition, i.e., muscle mass, appeared to explain why a BMI higher than normal is associated with the lowest mortality risk [39••]. Moreover, low muscle mass was consistently associated with increased mortality risk. Besides observational data, there were no reported randomized controlled trials in smoking or alcohol cessation/reduction, while physical activity and/or dietary/excess weight interventions only reported on short-term outcomes [86••]. Only one small randomized trial assessed long-term follow-up among CRC survivors, finding significantly improved cancerspecific survival after dietary counseling [78].
As people do not have isolated behaviors, a multidimensional lifestyle approach would be most informative for exploring mortality risk and cancer recurrence, as well as for translating these findings into meaningful strategies to improve disease prognosis. Some randomized controlled trials with both dietary and physical activity components have included CRC survivors, but they usually did not test the impact of comprehensive lifestyle interventions on risk of cancer recurrence or survival [86••]. Furthermore, only one observational study evaluated the association of post-diagnosis comprehensive lifestyle patterns and CRC outcomes [91]. That study concluded that adherence to the WCRF recommendations on diet, physical activity, and body fatness was not statistically significantly associated with mortality [91]. However, lifestyle was assessed on average 9 years after diagnosis and survivors were therefore at low risk to die from CRC during subsequent follow-up. Further research on post-diagnosis lifestyle patterns is needed to understand the multifactorial nature of risk of mortality and cancer recurrence and, furthermore, to avoid overemphasis of single lifestyle factors.
The existing studies have several limitations. Few observational studies have reported on the association between post-diagnostic lifestyle and CRC outcomes adjusting for pre-diagnostic lifestyle; thus, it is unknown whether the observed associations between postdiagnostic lifestyle and survival are independent of prediagnosis lifestyle. Furthermore, only few studies assessed changes in lifestyle over time in relation to CRC outcomes, with weight change and smoking cessation studied most often. Large prospective cohort studies, such as NHS I, HPFS, the COLON study [92], and others [93,94], provide further opportunities to examine postdiagnosis lifestyle changes in relation to CRC prognosis during different phases of the cancer trajectory.
Studies evaluating lifestyle factors and CRC outcomes mainly focused on mortality, while cancer recurrence and comorbidities are other important outcomes. Disease recurrence was usually reported by studies in the adjuvant setting, but is not commonly reported by population-based studies. Furthermore, definitions of recurrence were inconsistent between studies. Using the standard definitions proposed by Punt et al. [95] may add to the crosscomparability of future studies. In addition, few studies among CRC survivors studied incidence and progression of comorbidities, although some studies included cardiovascular-mortality as an endpoint. Only one study assessed the incidence of comorbidities after CRC diagnosis [96]. This study observed that BMI and sedentary behavior at 5 months post-diagnosis were associated with the development of comorbid cardiovascular disease in the first 3 years after CRC diagnosis.
More research is needed on the mechanisms underlying the impact of lifestyle after CRC diagnosis on prognosis. A lifestyle contributing to a positive energy balance and hyperinsulinemia has been suggested to be implicated in the prognosis of CRC [5,97]. For instance, determinants of hyperinsulinemia, such as physical inactivity, excessive sedentary behavior, and several aspects of diet, are associated with increased mortality risk. The dietary factors included in this review that might be linked to insulinrelated pathways, a Western dietary pattern [23,42], sugar-sweetened beverages [23,43], low coffee consumption [25], and higher dietary glycemic load [45] all showed increased mortality risk. Also, a highinsulinogenic diet [98] has been associated with increased mortality risk. However, these studies were almost all conducted in the same cohort embedded in a trial of adjuvant chemotherapy (CALGB 89803) [25,42,43,45].
Overall, evidence is emerging that modifiable lifestyle factors after CRC diagnosis, such as physical activity, smoking, body composition, and diet could impact survival. Although, not all modifiable risk factors for cancer presentation seem relevant for cancer survivors. With increasing CRC survivorship, however, CRC recurrence should be studied as a key outcome within populationbased studies of CRC survivors. Additionally, studies are needed to evaluate the development and progression of comorbidities after CRC diagnosis. Studying lifestyle patterns over time, by including multiple lifestyle factors simultaneously at different time points during the cancer trajectory, would lead to a greater understanding of the multifactorial influence on CRC prognosis. Additional data from prospective observational studies and randomized controlled trials are urgently needed and, ultimately, will allow for lifestyle recommendations that are specifically tailored to cancer survivors.

Conflict of Interest
Moniek van Zutphen has received research support through a grant from the Dutch Cancer Society. Ellen Kampman declares that she has no conflict of interest. Edward L. Giovannucci declares that he has no conflict of interest. Fränzel J.B. van Duijnhoven declares that she has no conflict of interest.
Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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