Adherence to and Efficacy of the Nutritional Intervention in Multimodal Prehabilitation in Colorectal and Esophageal Cancer Patients

Multimodal prehabilitation programs to improve physical fitness before surgery often include nutritional interventions. This study evaluates the efficacy of and adherence to a nutritional intervention among colorectal and esophageal cancer patients undergoing the multimodal Fit4Surgery prehabilitation program. The intervention aims to achieve an intake of ≥1.5 g of protein/kg body weight (BW) per day through dietary advice and daily nutritional supplementation (30 g whey protein). This study shows 56.3% of patients met this goal after prehabilitation. Mean daily protein intake significantly increased from 1.20 ± 0.39 g/kg BW at baseline to 1.61 ± 0.41 g/kg BW after prehabilitation (p < 0.001), with the main increase during the evening snack. BW, BMI, 5-CST, and protein intake at baseline were associated with adherence to the nutritional intervention. These outcomes suggest that dietary counseling and protein supplementation can significantly improve protein intake in different patient groups undergoing a multimodal prehabilitation program.


Introduction
The cornerstone of most oncological treatment regimens is surgery. In colorectal (CRC) and esophageal cancer (EsC) surgery, postoperative complications occur in approximately 33% and 40% of patients, respectively [1,2]. These complications are associated with a prolonged hospital stay, increased mortality rate, hospital costs, and a lower reported quality of life [1][2][3][4][5]. Even in the absence of complications, both functional and physiological capacity are known to diminish in the postoperative period, as surgery represents a major stressor [6,7].
Preoperative physical fitness has consistently been associated with postoperative outcomes after major elective surgery [8][9][10][11]. Therefore, the preoperative period is increasingly considered an opportunity to improve patients' preoperative physical status, a process termed prehabilitation. Modern prehabilitation programs encompass multiple modalities, including physical exercise, nutritional interventions, psychological support, and smoking cessation programs. Currently, multimodal prehabilitation has mainly been studied in CRC surgery, with patients showing increased preoperative physical fitness, reduced postoperative complications, and shortened length of stay [12][13][14].
Nutritional interventions within prehabilitation programs mainly focus on adequate protein, energy, and micronutrient intake. The average healthy person is estimated to require 0.83 g (g) of protein/kg body weight (BW)/day, while protein requirements for In this exploratory prospective cohort study, data were derived from patients participating in the F4S PREHAB trial, performed in the Radboudumc (Nijmegen, The Netherlands). The trial received ethical approval from METC Oost-Nederland (NL73777.091. 20). The trial has been registered in the International Clinical Trials Registry Platform (NL8699). The methods and outline of the study protocol can be found in the Appendices (Appendix A).

Study Population
Patients aged sixteen years and older, undergoing a multimodal prehabilitation program prior to elective high-impact surgery for CRC or EsC, were included.
Exclusion criteria in the F4S PREHAB trial were premorbid conditions (i.e., respiratory or cardiac disease) or impaired mobility that hampered or contraindicated exercise, cognitive disabilities, inability to read and understand the Dutch language, an American Society of Anesthesiologists (ASA) score ≥ 4 (a subjective assessment of a patient's overall health), and chronic kidney disease at a stage ≥ 3. An additional exclusion criterion in this study was missing data regarding nutritional intake at baseline or after prehabilitation.

Study Outline
In addition to standard preoperative care, patients underwent a personalized multimodal prehabilitation program. The length of the program depended on the available time between diagnosis and surgery. In the case of neoadjuvant chemoradiotherapy, the start of the intervention was postponed until the last treatment. This multimodal prehabilitation program contained four different modalities: a nutritional intervention, an exercise program, psychological support, and a smoking cessation program (Appendix A).
Nutritional assessment occurred at baseline and prior to surgery (after prehabilitation), collecting the following parameters: BW, height, hand grip strength, fat-free mass measured through bioelectrical impedance analysis (BIA), and a three-day food diary. A general impression of a patient's nutritional status was obtained using the Patient-Generated Subjective Global Assessment Short Form (PG-SGA SF). Additionally, all patients were referred to a registered in-hospital dietician in order to provide personalized dietary advice aiming for optimal nutritional intake (protein, energy, and micronutrients) to support achieving an anabolic state and enhancing the effect of physical training on lean body mass increment.
A daily protein intake of at least 1.5 g/kg BW was aimed for since it is fundamental for muscle health [33,34]. BW was corrected for patients with a body mass index (BMI) lower than 20 or higher than 30 to fit a BMI of 20 or 27.5, respectively [35,36]. Nutritional advice was given to aim for at least two meals per day containing 25 g of protein or more. Patients received high-quality whey protein shakes (Nutri Whey™ Isolate, FrieslandCampina, Wageningen, the Netherlands) containing 30 g of whey protein and 20 µg vitamin D. Patients were instructed to consume the protein shakes before bedtime on a daily basis, and an additional shake within one hour following supervised exercise. Patients relying on tube feeding received one sachet of PROSource NoCarb (Generic Life quality enhancing Niche Products, GLNP, Naarden, The Netherlands) daily, containing 15 g of protein. Energy requirements were calculated using the WHO formula with a 30% addition to account for physical activity. Additionally, daily multivitamin supplementation (50% of the daily recommendation) was provided to all patients to target possible vitamin deficiencies.
The exercise program was preceded by an assessment and screening using the American College of Sports Medicine (ACSM) exercise preparticipation health screening questionnaire to identify possible individuals at risk of exercise-related adverse cardiovascular events. Exercise was supervised by a first-line physiotherapist and performed two to three times a week, focusing on both resistance and high-intensity endurance training. Patients were also advised to perform 60 min of low-intensity aerobic exercise on days without supervised training.
Patients at risk for anxiety and depression were identified using the Hospital Anxiety and Depression Scale (HADS) and referred to a trained psychologist to improve coping mechanisms regarding future surgery. Furthermore, all active smokers were offered a smoking cessation program, including counseling and nicotine replacement therapy.

Study Outcomes
The primary aim of this study was to assess the adherence of patients to the nutritional intervention (daily protein intake ≥1.5 g/kg BW or ≥1.9 g/kg FFM [37]). The total protein intake was measured using three-day food records including two weekdays and one weekend day, at baseline and after prehabilitation, and expressed as g per day, g per kg BW per day, and g per kg fat-free mass (FFM) per day. Food records were structured according to meal moments. During dietary consultations at baseline and after prehabilitation, food records were reviewed by both patient and dietician to ensure an adequate description of dietary intake. A dietary history assessment was conducted in case of incomplete food records. Nutrient intake was calculated using Evry (version 2.7.4.2), a dietary calculation tool based on the Dutch Food Composition Table 7.0 (National Institute for Public Health and the Environment, Bilthoven, The Netherlands). Secondary outcomes were protein distribution throughout the day (defined as the number of patients achieving ≥25 g in at least two meals per day), daily energy intake, and daily consumption of protein and multivitamin supplements. Furthermore, characteristics associated with adherence to the nutritional intervention were evaluated.

Statistical Analyses
Baseline characteristics of the study population and data regarding protocol adherence and nutritional intake were described separately for CRC and EsC patients. To determine potential associations with adherence, baseline characteristics were also described separately for adherent and non-adherent patients. Continuous data are presented as mean ± SD or median [inter-quartile range] in normally and non-normally distributed data, respectively, and compared using independent samples t-tests or Mann-Whitney U tests. Categorical data are described as total numbers (percentages) and compared using chi-square and Fisher's exact tests. The difference in protein goal achievement between baseline and after prehabilitation was compared using McNemar's test for related samples. Changes in protein intake per meal moment between baseline and after prehabilitation were compared using the Wilcoxon signed rank test.

Baseline Characteristics of the Study Population
Between March 2021 and September 2022, 139 CRC and EsC patients were included in the F4S PREHAB trial. After the exclusion of 75 patients due to incomplete or missing data on nutritional intake at baseline or after prehabilitation, 35 CRC and 29 EsC patients were eligible for analysis (Table 1). Patients had a median age of 66 years at the time of inclusion and were predominantly male (70.3%), without significant differences between CRC and EsC patients. The PG-SGA SF score was significantly higher in EsC patients compared to CRC patients (7 [8] vs. 2 [4], p = 0.003). Ten (15.6%) patients were at high risk for malnutrition based on the PG-SGA SF score. Among EsC patients, 20 (69.0%) received either tube feeding or ONS at baseline.

Daily Protein Intake at Baseline and after Prehabilitation
Daily protein intake relative to kg BW increased significantly from 1.20 ± 0.39 g/kg BW at baseline to 1.61 ± 0.41 g/kg BW after prehabilitation in the total study population (p < 0.001). Analysis in CRC and EsC patients showed a significant increase in relative daily protein intake after prehabilitation compared to baseline, from 1.09 ± 0.40 g/kg BW and 1.33 ± 0.34 g/kg BW to 1.61 ± 0.45 g/kg BW and 1.61 ± 0.39 g/kg BW, respectively, with a higher increment in protein intake per kg BW in CRC patients (p = 0.006) (Figure 1). 34 [12] 33 [8] 35 [24] 0.204

Daily Protein Intake at Baseline and after Prehabilitation
Daily protein intake relative to kg BW increased significantly from 1.20 ± 0.39 g/kg BW at baseline to 1.61 ± 0.41 g/kg BW after prehabilitation in the total study population (p < 0.001). Analysis in CRC and EsC patients showed a significant increase in relative daily protein intake after prehabilitation compared to baseline, from 1.09 ± 0.40 g/kg BW and 1.33 ± 0.34 g/kg BW to 1.61 ± 0.45 g/kg BW and 1.61 ± 0.39 g/kg BW, respectively, with a higher increment in protein intake per kg BW in CRC patients (p = 0.006) (Figure 1). At baseline, the number of patients with a mean protein intake of ≥1.5 g/kg BW per day was 12 (18.8%), which increased to 36 (56.3%) following prehabilitation (p < 0.001) ( Figure 2). Additional analyses comparing the number of patients achieving mean protein intakes of ≥1.2 and ≥0.83 g/kg BW at baseline and after prehabilitation showed increments of 30 (46.9%) to 54 (84.4%) patients and 52 (81.2%) to 63 (98.5%) patients, respectively, both statistically significant (p < 0.001). Considering the protein intake per kg FFM, a total of 46 (75.4%) patients achieved a mean protein intake of 1.9 g/kg FFM after prehabilitation, compared to 19 (31.1%) at baseline. Protein intake relative to FFM also significantly At baseline, the number of patients with a mean protein intake of ≥1.5 g/kg BW per day was 12 (18.8%), which increased to 36 (56.3%) following prehabilitation (p < 0.001) ( Figure 2). Additional analyses comparing the number of patients achieving mean protein intakes of ≥1.2 and ≥0.83 g/kg BW at baseline and after prehabilitation showed increments of 30 (46.9%) to 54 (84.4%) patients and 52 (81.2%) to 63 (98.5%) patients, respectively, both statistically significant (p < 0.001). Considering the protein intake per kg FFM, a total of 46 (75.4%) patients achieved a mean protein intake of 1.9 g/kg FFM after prehabilitation, compared to 19 (31.1%) at baseline. Protein intake relative to FFM also significantly increased from 1.70 ± 0.66 g/kg FFM to 2.27 ± 0.75 g/kg FFM for the total study population (p < 0.001) (Appendix B). The crude daily protein intake increased significantly in this study population from 93 ± 31 g/day at baseline to 124 ± 28 g/day after prehabilitation (p < 0.001). EsC patients had a significantly higher protein intake compared to CRC patients at baseline (107 ± 30 g/day vs. 82 ± 27 g/day, p < 0.001). However, there was no significant difference between the groups after prehabilitation (129 ± 30 g/day vs. 121 ± 27 g/day, p = 0.248). The total increase in protein intake was lower in EsC patients compared to CRC patients (22 ± 27 g/day vs. 39 ± 23 g/day, p = 0.009).

Daily Protein Intake at Baseline and after Prehabilitation per Meal Moment
Daily protein intake per meal moment was analyzed for 54 patients, since 10 patients received continuous tube feeding. Median protein intake was highest at dinner, both at baseline and after prehabilitation (Figure 3). Protein intake increased significantly during breakfast as well as morning, afternoon, and evening snacks, while the changes were non- The crude daily protein intake increased significantly in this study population from 93 ± 31 g/day at baseline to 124 ± 28 g/day after prehabilitation (p < 0.001). EsC patients had a significantly higher protein intake compared to CRC patients at baseline (107 ± 30 g/day vs. 82 ± 27 g/day, p < 0.001). However, there was no significant difference between the groups after prehabilitation (129 ± 30 g/day vs. 121 ± 27 g/day, p = 0.248). The total increase in protein intake was lower in EsC patients compared to CRC patients (22 ± 27 g/day vs. 39 ± 23 g/day, p = 0.009).

Daily Protein Intake at Baseline and after Prehabilitation per Meal Moment
Daily protein intake per meal moment was analyzed for 54 patients, since 10 patients received continuous tube feeding. Median protein intake was highest at dinner, both at baseline and after prehabilitation (Figure 3). Protein intake increased significantly during breakfast as well as morning, afternoon, and evening snacks, while the changes were non-significant for lunch and dinner. The largest increase in protein intake was during the evening snack (4.1 [7.5]

Characteristics Associated with Nutritional Adherence
There were no significant differences between adherence and non-adherence to the primary nutritional goal regarding age and sex. Patients who had a daily protein intake of ≥1.5 g/kg BW had a significantly lower BMI compared to patients who had not (25 [5] vs. 28 [4], p < 0.001). Patients who were adherent also had a faster 5-CST time in seconds (8 [3] vs. 9 [5], p = 0.017) and higher protein intake at baseline in g/kg BW/day (1.36 ± 0.39 vs. 0.99 ± 0.27, p < 0.001) compared to patients who were non-adherent (Appendix C).

Discussion
This study shows that 56% of patients with CRC and EsC met the primary criterion of ≥1.5 g protein/kg BW per day after prehabilitation. The total protein intake increased from 1.2 g/kg BW per day to more than 1.6 g/kg BW per day in this study population, without significant difference between CRC and EsC patients. Additionally, adherence to A mean protein intake of ≥25 g in ≥2 meals per day was achieved by 43 (79.6%) patients, which was a significant increase when compared to 20 (37.0%) patients at baseline (p < 0.001). After prehabilitation, median protein intake was ≥25 g for dinner and the evening snack.

Characteristics Associated with Nutritional Adherence
There were no significant differences between adherence and non-adherence to the primary nutritional goal regarding age and sex. Patients who had a daily protein intake of ≥1.5 g/kg BW had a significantly lower BMI compared to patients who had not (25 [5] vs.  28 [4], p < 0.001). Patients who were adherent also had a faster 5-CST time in seconds (8 [3] vs. 9 [5], p = 0.017) and higher protein intake at baseline in g/kg BW/day (1.36 ± 0.39 vs. 0.99 ± 0.27, p < 0.001) compared to patients who were non-adherent (Appendix C).

Discussion
This study shows that 56% of patients with CRC and EsC met the primary criterion of ≥1.5 g protein/kg BW per day after prehabilitation. The total protein intake increased from 1.2 g/kg BW per day to more than 1.6 g/kg BW per day in this study population, without significant difference between CRC and EsC patients. Additionally, adherence to daily consumption of nutritional supplements was more than 90%. With a mean increment of 31 g of protein intake, supplementation seems essential in nutritional interventions as part of multimodal prehabilitation programs.
Protein intake per meal moment significantly increased during breakfast as well as morning, afternoon, and evening snacks. The distribution of protein intake across meal times was found to be skewed towards the end of the day. The largest increase in protein intake was observed during the evening snack, which corresponds to the protocol recommendation to consume daily protein shakes before bedtime. Consuming a high amount of protein during the evening can stimulate overnight muscle protein synthesis [38]. Although protein intake during breakfast increased significantly, it remained relatively low and could be improved through providing additional nutritional advice to achieve a high-protein breakfast. Protein supplementation at breakfast might be an effective way to increase protein intake during prehabilitation. Protein intake during lunch did not change significantly, but mean intake nearly reached the threshold of ≥25 g protein. Nutritional advice encouraging a small increase in protein during lunch could help reach the threshold of ≥25 g protein. Reaching a third or even fourth peak in protein intake would further stimulate MPS and remove the skewness of the protein intake distribution [39,40]. Our study found that nearly 80% of patients reached ≥2 mean peaks of ≥25 g protein per day. A previous study in preoperative patients prescribed six protein-rich dishes per day and reported ≥2 peaks of ≥20 g protein per day in merely one-third of patients [41]. This finding further emphasizes that protein supplementation can be helpful in attaining a high-protein diet in addition to dietary changes alone.
This study found several baseline characteristics that were associated with a lowered adherence to the primary goal of this nutritional intervention. A higher median BW and median BMI were seen in patients that did not achieve the protein goal. As protein goals were not adjusted to actual body composition, they may be more difficult to attain when BW increases. A technique to eliminate heightened protein goals in patients with a high BW due to fat mass instead of lean body mass is through using FFM measurements. The protein goal based on FFM is ≥1.9 g/kg FFM per day and is a more accurate way to determine protein requirements [42]. Results show 75% of patients achieved the protein goal based on FFM, which is higher than the 56% when protein requirements are based on BW. It is recommended that future trials use FFM to estimate protein requirements when measurements on FFM are available.
Patients that did not adhere to the daily protein goal showed a lower protein intake at baseline, both absolute and relative. This indicates that nutritional support may be even more important for patients with a lower protein intake at baseline. Intensive dietary counseling focusing on extra protein intake during breakfast and lunch may be helpful. Furthermore, patients with a reduced food intake may benefit from an additional serving of protein supplementation. Non-adherent patients also needed more time to complete the 5-CST at baseline. This suggests physical capacity at baseline may impact protocol adherence and possibly correlates with a prolonged protein deficit. Since protein intake is essential to retain and gain muscle strength, insufficient intake may lead to reduced muscle strength and physical performance [43].
To evaluate and compare nutritional adherence in patients with a compromised nutritional status, this study included both CRC and EsC patients undergoing elective surgery. EsC patients are often nutritionally compromised due to physical restrictions such as dysphagia and adverse effects caused by neoadjuvant treatment. However, these patients had higher protein intake at baseline. This could be the result of the majority of EsC patients (69%) receiving either tube feeding or ONS prior to prehabilitation. Furthermore, EsC patients already receive extensive dietary counseling before neoadjuvant treatment as part of standard preoperative care in the Netherlands. The higher protein intake at baseline in EsC patients supports the relevance of the early involvement of a registered dietician in the dietary management of those patients.
While some earlier prehabilitation studies did report adherence to the intake of nutritional supplementation, they did not address the total dietary intake before and after prehabilitation [44,45]. This study is one of the first to describe the assessment of adherence to a nutritional intervention in detail using validated methods. Furthermore, the results of this study show that a nutritional intervention as part of multimodal prehabilitation is feasible in different groups of patients. However, this study has some limitations. Firstly, the sample size of this study is relatively small, which limited statistical options to identify predictors regarding adherence. Secondly, selection bias might have been introduced in this study via the exclusion of patients based on missing data on food intake. It is plausible that patients who recorded their food intake at both timepoints also had higher overall motivation regarding the nutritional intervention as part of multimodal prehabilitation.
In conclusion, the nutritional intervention as part of multimodal prehabilitation increased protein intake significantly in both CRC and EsC patients during prehabilitation. This shows that dietary counseling and providing protein supplementation are effective methods to increase protein intake in cancer patients during prehabilitation. Further dietary counseling should be given to reach additional protein peaks during breakfast and lunch. Future research, preferably estimating protein requirements using FFM, should include larger study populations to identify predictors of protocol adherence more accurately. Qualitative research on the wishes and needs of patients regarding dietary advice and supplementation can help gain more understanding of how to optimize adherence to nutritional interventions.

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Examples of aerobic exercise machines on which HIIT may be performed are: bicycle, rower, treadmill, and cross-trainer. • Workload should be adjusted by 5-10% when patient is not able to complete the high intensity intervals.
-Resistance training: • Training targeting all major muscle groups composes six exercises (leg press, chest press, abdominal crunch, low row, lat pulldown, and step up) and consists of two series of 10 repetitions.

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The strength exercises are performed according to two seconds of concentric strength and 2 s of eccentric strength. The weight of the exercises will be adjusted to the muscle strength (indirect 1RM) measured at baseline using the Brzycki formula (1RM = weight/(1.0278-0.0278 • number of repetitions)) [48]. Exercises start at 65% of the calculated 1RM with a weekly increase of 5%, resulting in 80% of baseline 1RM in the fourth exercise week. • Weight should be adjusted by 5-10% according to a patients' ability to perform 10 repetitions in the second series. Planned surgical treatment can be accompanied by anxiety and depression. These components could have a potential influence on motivation regarding prehabilitation and postoperative outcomes. Therefore, patients at risk will be identified using the Hospital Anxiety and Depression Scale (HADS).
Patients at risk will be referred to a trained psychologist to optimize psychological wellbeing and learn about coping mechanisms regarding the surgical treatment. Additional sessions will be planned in the preoperative period when necessary.

Appendix A.2.5. Smoking Cessation Program
All patients who are active smokers during the baseline assessment will be offered a smoking cessation program including counseling and nicotine replacement therapy prior to surgery. With a substantial number of patients being smokers at the time of (cancer) diagnosis, the goal is to achieve a smoking cessation rate of 80%. Table A1. Number of participants achieving a goal intake of 1.9 g of protein/kg FFM. Presented for the total population (n = 61), CRC patients (n = 33), and EsC patients (n = 28).