Prehabilitation in Modern Colorectal Cancer Surgery: A Comprehensive Review

Simple Summary Surgical resection is the primary curative treatment option for colorectal cancer. However, colorectal resections remain associated with significant postoperative morbidity and mortality. Furthermore, most rectal cancer patients and some patients with locally advanced colon cancer may need preoperative neoadjuvant therapy. It improves long-term outcomes but impairs patients’ physical fitness and thus further increases surgical risk. Prehabilitation is a novel approach, aiming to improve patients’ physical and psychological capacity to reduce postoperative morbidity and improve treatment outcomes. This study aims to comprehensively overview current knowledge on colorectal cancer surgery’s prehabilitation. Abstract Colorectal cancer remains the third most prevalent cancer worldwide, exceeding 1.9 million new cases annually. Surgery continues to be the gold standard treatment option. Unfortunately, colorectal cancer surgery carries significant postoperative morbidity and mortality. Moreover, most rectal cancer patients and some patients with locally advanced colon cancer require preoperative neoadjuvant therapy. It improves long-term outcomes but impairs patients’ physical fitness and thus further increases surgical risk. Recently, prehabilitation has gained interest as a novel strategy to reduce treatment-related morbidity for patients undergoing colorectal cancer surgery. However, the concept is still in its infancy, and the role of prehabilitation remains controversial. In this comprehensive review, we sum up present evidence on prehabilitation before colorectal cancer surgery. Available studies are very heterogenous in interventions and investigated outcomes. Nonetheless, all trials show at least some positive effects of prehabilitation on patients’ physical, nutritional, or psychological status or even reduced postoperative morbidity. Unfortunately, the optimal prehabilitation program remains undetermined; therefore, this concept cannot be widely implemented. Future studies investigating optimal prehabilitation regimens for patients undergoing surgery for colorectal cancer are necessary.


Introduction
Colorectal cancer (CRC) remains the third most prevalent cancer worldwide, exceeding 1.9 million new cases annually [1]. Surgery continues to be the gold standard treatment option. However, colorectal cancer surgery carries significant postoperative morbidity and mortality [2]. Moreover, the standard advanced rectal cancer management regimen includes neoadjuvant chemoradiotherapy (CRT) with or without neoadjuvant chemotherapy [3][4][5]. Similarly, some locally advanced colon cancer cases may also benefit from neoadjuvant chemotherapy [6]. Despite neoadjuvant cytotoxic therapy improving long-term oncological

The Present Concept of Prehabilitation in Surgical Management of Colorectal Cancer
The definition of prehabilitation is not yet standardized. Currently, it may be defined as any interventions initiated preoperatively, aiming to strengthen patients' physical, nutritional, medical, and mental condition to increase patients' capacity for resisting surgical trauma and facilitating a postoperative return to preoperative conditions [16]. There is a clear emphasis on the time-sensitive component [22]. The preoperative period provides a unique window to condition patients for the upcoming physiological and psychological stress, because most are willing to modify behavior for improved outcomes [23,24]. Today, prehabilitation remains an experimental treatment modality, and there is no general agreement on the optimal design of such programs. Available protocols may include one (unimodal) or several (multimodal) interventions to improve patients' physical fitness and capacity, optimize nutritional status, and promote psychological resilience. The real benefits of prehabilitation also remain the topic for discussion because today's evidence is very contradictory. Some studies report minimal benefits regarding the decreased length of hospital stay (LOS) [25]. At the same time, others show largerscale benefits such as improved nutritional status and physical performance as well as better quality of life (QoL) or even up to 50% lower postoperative morbidity [23,[26][27][28].

The Present Concept of Prehabilitation in Surgical Management of Colorectal Cancer
The definition of prehabilitation is not yet standardized. Currently, it may be defined as any interventions initiated preoperatively, aiming to strengthen patients' physical, nutritional, medical, and mental condition to increase patients' capacity for resisting surgical trauma and facilitating a postoperative return to preoperative conditions [16]. There is a clear emphasis on the time-sensitive component [22]. The preoperative period provides a unique window to condition patients for the upcoming physiological and psychological stress, because most are willing to modify behavior for improved outcomes [23,24]. Today, prehabilitation remains an experimental treatment modality, and there is no general agreement on the optimal design of such programs. Available protocols may include one (unimodal) or several (multimodal) interventions to improve patients' physical fitness and capacity, optimize nutritional status, and promote psychological resilience. The real benefits of prehabilitation also remain the topic for discussion because today's evidence is very contradictory. Some studies report minimal benefits regarding the decreased length of hospital stay (LOS) [25]. At the same time, others show larger-scale benefits such as improved nutritional status and physical performance as well as better quality of life (QoL) or even up to 50% lower postoperative morbidity [23,[26][27][28]. The variety of interventions, differences in measured outcomes, and heterogeneity of results challenge standardization and wide adoption of this approach. The different prehabilitation programs investigated and their interventions are summarized in Table 1. • Exercise intervention: initial exercise counseling session was followed by a 13-17-week telephone-guided walking program. The program was targeted at counting steps: during the first eight weeks, the step count goal was gradually increased from the baseline and then maintained or increased over the remaining weeks.
The target was to increase the average daily step count by 3000 over the baseline by week 8.

Standard of care
Moug et al. [32]; 2020 Unimodal Start before neoadjuvant CRT; a minimum of 13 weeks duration: 5 weeks during neoadjuvant CRT followed by a minimum of 8 weeks of exercises before surgery.
• Exercise intervention: initial exercise counseling session was followed by a 13-17-week telephone-guided walking program. The program was targeted at counting steps: during the first eight weeks, the step count goal was gradually increased from the baseline and then maintained or increased over the remaining weeks.
The target was to increase the average daily step count by 3000 over the baseline by week 8. • Exercise intervention: Inspiratory muscle training performed using the handheld electronic device Power Breathe K3; functional strength workouts performing high-intensity exercises (such as chair stands and step-ups with weight belts) and endurance training (such as interval walking indoors and/or outdoors, bouts of stair climbing, and Nordic walking outdoors).

Standard of care
West et al. [44]; 2019 Unimodal Start 6 weeks before surgery.
• Exercise intervention: Tailored exercise program consisting of 40 min interval training using an electromagnetically braked cycle ergometer.

Standard of care
Li et al. [17]; 2013 Multimodal The start date was predetermined by the time remaining until surgery alone.
• Exercise intervention: Aerobic exercise sessions (30 min of walking or using an aerobic exercise machine) combined with resistance training (calisthenics and elastic band movements). • Nutrition intervention: Excess alcohol or fat intake reduction counseling; whey protein isolate provided to guarantee a daily intake of protein. Despite all studies investigating prehabilitation for CRC surgery, they were very different in interventions, timing, and measured outcomes. Table 2 provides more details on study design and measured outcomes as well as each study's quality of evidence.     Among 20 available studies on prehabilitation for CRC patients, there are 10 randomized controlled trials (RCTs) [26,27,[30][31][32][37][38][39][40]43], 9 pilot studies [16,17,29,[33][34][35][36]41,44] and 1 retrospective cohort study [42]. Table 3 summarizes the reported outcomes of selected studies. A reduction in step count was observed in both groups, with the prehabilitation group experiencing a lesser decline (non-significant). Prehabilitation increased 6 MWT scores (non-significant).

N/A
The prehabilitation group achieved high levels of satisfaction. Singh et al. [34]; 2018 Prehabilitation significantly improved muscle strength for the lower limb exercises. While leg press endurance improved, there was no significant change in chest press muscle endurance. Physical performance as measured by 6 m fast walk and 6 m backwards walk improved in the Prehabilitation group. There was no significant change in 400-meter walk time; however, there was a substantial reduction in heart rate immediately after the completion of the test.

N/A
There were significant changes in 3 measures of QoL (emotional function, financial difficulties, diarrhea), with patients also reporting having less constipation.
The exercise program did not cause any adverse events.
Heldens et al. [35]; 2016 Prehabilitation increased patient walking distance as determined by 6 MWT and functional exercise capacity (not significant) as well as both leg and arm muscle strength (significantly).

N/A
The feasibility and safety of the program were observed, with a very high attendance rate (95.7%).
Loughney et al. [36]; 2017 Significant improvements in lying down time, sleep efficiency, and duration were reported in the prehabilitation group compared to the control group.In all participants, there was a significant reduction in daily step count, EE, and MET. The apparent improvement in daily step count and overall PAL in the prehabilitation group was not statistically significant compared to the control group.

N/A N/A
Gillis et al. [37]; 2019 Prehabilitation did not significantly alter body mass compared to rehabilitation. The prehabilitation group had substantially more relative and absolute LBM and less FBM than the control group.

N/A N/A
Gillis et al. [38]; 2016 The prehabilitation group experienced a clinically meaningful improvement in 6 MWT scores. Recovery rates were similar between groups. No significant differences in self-reported outcomes were observed between the groups. No significant differences were observed between the groups in an overall 30-day complications rate and severity, emergency department visits and readmission, and median length of stay. Bousquet-Dion et al. [40]; 2018

N/A
No significant changes in 6 MWD were found between the groups; however, there was a significant correlation between physical activity, energy expenditure, and 6 MWD in the prehabilitation group.
There were no significant differences in the length of stay, emergency department visits, and complications rate between the groups.
Tweed et al. [41]; 2021 Prehabilitation improved handgrip strength and exercise capacity. No difference was observed in VO 2max and VO 2 at VAT before and after prehabilitation.

N/A
No adverse effects were reported.
Organizational feasibility was achieved. Overall acceptability of interventions was positive.
Compared to the standard care group, rehabilitation reduced complication rate, shortened the median stay, and patients had fewer unplanned readmissions.
There was no significant difference in mortality between the groups.

N/A
Arias et al. [27]; 2021 Reduced the deterioration of body composition as compared to the control group 45 days after surgery. These differences, however, were attenuated at 90 days.
Prehabilitation reduced hospital stay duration and postoperative complications.
No significant increase in complications was observed in the prehabilitation group. The intervention group showed a shorter median length of stay and better recovery, although not statistically significant.
The recruitment rate was low, at only 35%. Compliance was much higher, at 97%. The overall intervention achieved a high level of acceptability.
West et al. [44]; 2019 Prehabilitation reversed the fall in VO 2 at VAT due to NACRT.
The prehabilitation group had significantly greater ypTRG at the time of surgery, which did not result in a significant difference in the ypT-stage.

N/A
Li et al. [17]; 2013 Postoperative walking capacity improved significantly in the prehabilitation group at weeks 4 and 8. A higher share of patients recovered in the prehabilitation group compared to the standard of care at week 8.
In addition, higher levels of physical activity before and after surgery were reported in the intervention group.
Similar postoperative complication rates and length of stay were observed in both groups.
Prehabilitated patients immediately before surgery had significantly decreased anxiety and depression symptoms. No clinically or statistically significant increases in any domains of HRQOL were reported for the prehabilitation group.

Exercise Programs Used in Unimodal and Multimodal Prehabilitation
It is well known that exercise in the perioperative period is safe and has many benefits for patients' health. Exercise has been shown to improve physical fitness, enhance the quality of life, alleviate depression and anxiety symptoms, and reduce cancer-related fatigue [17,29,34]. Thus, it is unsurprising that most studies on prehabilitation in CRC patients investigated unimodal exercise-based programs [16,26,[29][30][31][32][33][34][35][36]43,44]. Today, there is no consensus on the best exercise program for CRC patients. This fact explains the heterogeneity of interventions throughout the available studies. Different interventions may include aerobic, resistance, and other training options or combinations. These different types of exercise have various benefits for human health. Even a short intervention with aerobic training (2-3 weeks) was shown to elicit improvements in physical fitness, cardiac, respiratory, and musculoskeletal function [10]. Resistance training is known to stimulate muscle hypertrophy and increase muscle mass, strength, and function. Crucially, it is effective in any age group, including frail elderly patients, who have the highest risk for postoperative complications following CRC surgery [45].
Studies included in this review showed that unimodal exercise prehabilitation consisting of aerobic and/or resistance exercises is a safe and viable option for CRC patients [29][30][31][33][34][35]40,41,43]. Additionally, it positively impacts fitness level (improved VO 2peak , 6-minute walking distance scores, functional walking capacity), leg (e.g., quadriceps), arm, and inspiratory muscle strength. Different tools and outcomes were used to objectify exercise's impact on a patient's physical condition. Five studies [16,26,29,30,41,44] measured VO 2peak and VO 2 at the ventilatory anaerobic threshold (VAT). All, except one [41], of these studies showed improved VO 2 after prehabilitation. Three studies by Moug and Loughney [31,32,36] investigated the effects of prehabilitation on daily step count and showed a positive impact on the parameter. Previous knowledge indicates that lower physical activity levels, determined by daily step count, are associated with increased rehospitalization rates and poor adherence to neoadjuvant treatment protocols [46]. Thus, prehabilitation may be considered to have the potency to improve postoperative outcomes and patients' ability to tolerate neoadjuvant treatment [40,42,46]. Another common parameter investigated in a series of studies [17,31,34,35,38,40,42] is the 6-minute walking test (6 MWT) results. All available studies except one [40] show that prehabilitation improves 6 MWT outcomes. This improvement of objective functional reserves representing parameters indicates that prehabilitation improves CRC patients' physical condition before surgical trauma and that intervention may have therapeutic benefits [26,27,42]. Moreover, seven studies [26,[32][33][34][35]41,42] presented the prehabilitation effect on different skeletal muscle functions representing parameters. Every trial showed at least a slight improvement in muscle strength and endurance after prehabilitation. Such impact is relevant because lower muscle mass is associated with impaired postoperative outcomes in cancer patients [9]. Additionally, one study [43] showed that prehabilitation also improves inspiratory muscle strength, and this improvement was linked with a minor decrease in postoperative hospital stay and improved recovery. Besides positively impacting physical capacity, exercise interventions enhanced the quality of life (reduced depression and anxiety symptoms scores) [16,17,26,27,[29][30][31][32][33][34][35][36]38,[41][42][43][44]. The exercise interventions were effective in both unimodal and multimodal prehabilitation settings.

Nutritional and Psychological Interventions Used in Multimodal Prehabilitation
Malnutrition is the most common comorbidity in cancer patients [47], affecting 30% to 60% of patients with CRC [48]. This is mainly due to systemic inflammation caused by cancer cells. Cancer expansion triggers the release of proinflammatory cytokines such as IL-1, IL-6, and TNF-α, which in turn increase lipolysis, muscle breakdown, and insulin resistance. All these effects lead to muscle wasting with or without loss of adipose tissue [49]. The oncological patients frequently have impaired physical status and decreased quality of life, preventing adherence to therapy, reducing efficacy and tolerability, and worsening the prognosis. Cancer cachexia remains a decisive, independent prognostic factor for poor treatment outcomes [50,51]. Timely nutritional intervention can improve prognosis as well as decrease rates of morbidity and mortality among cancer patients [52]. Thus, dietary interventions appear to be a good part of multimodal prehabilitation programs in CRC management [17,27,37,[39][40][41][42].
Currently, eight studies [17,27,[37][38][39][40][41][42] investigated the effect of different nutritional interventions. They included personalized dietary counseling, whey protein supplementation, or a complete diet by providing daily meals. All but one [39] trial found at least some beneficial effect of nutritional support resulting in increased muscle mass and reduced fat mass. These studies indicate that multimodal prehabilitation, which includes nutritional support, could be superior to unimodal prehabilitation in terms of functional status improvement. However, randomized trials are necessary to confirm this hypothesis.
In addition to all the physiological challenges affecting CRC patients, psychological and emotional distress cannot be forgotten. The prevalence of depression among cancer survivors can be as high as 49% [53]. Even for patients with no history of psychological disorders, the extreme burden of cancer diagnosis increases the risk of mental disorders, which can harm patients' adherence to treatment, postoperative recovery, and quality of life [54]. Personal risk factors for depression include such demographic factors as gender, age, and socioeconomic factors -unemployment and lack of social support [55][56][57]. A biological explanation for increased psychological stress in cancer patients includes a hyperactive hypothalamic-pituitary-adrenal axis, glutamate excitotoxicity, and inflammation [58]. Because psychological stress is a modifiable risk factor for poor CRC treatment outcomes, there is a rationale to address it via specific prehabilitation.
Four studies in CRC patients included psychological support as a part of multimodal prehabilitation [17,27,37,40]. All of them incorporated breathing and relaxation exercises as anxiety-reducing techniques. However, only one trial [17] measured psychological well-being as an outcome. This trial determined that prehabilitation reduced symptoms of anxiety and depression before surgery. However, it had no impact on any domain of healthrelated quality of life (HRQOL). It is challenging to evaluate the effect of psychological prehabilitation because current studies lack appropriate outcomes.

Considerations for the Wider Use of Prehabilitation Programs in Colorectal Cancer Surgery Patients and Existing Gaps in Prehabilitation Research
This review provided an overview of available evidence of prehabilitation use in the management of CRC. Current trials are very heterogeneous in design, used interventions, and evaluated outcomes. Nonetheless, all trials show at least some positive effects of prehabilitation on patients' physical, nutritional, or psychological status or even reduced postoperative morbidity [16,17,26,27,[29][30][31][32][33][34][35]38,[42][43][44]. The differences in available trials preclude the broad implementation of prehabilitation in CRC management despite a sufficient amount of evidence encouraging the use. Physicians seeking to implement prehabilitation in CRC management will have a number of questions, with some having no answer because of the gaps in present knowledge. The best modality of prehabilitation remains unknown. Both unimodal and multimodal prehabilitation programs can be used for CRC management [59], with comparable effects on clinical outcomes, fitness, and quality of life. Considering that CRC patients suffer physical, nutritional, and psychological burdens [60], it appears that multimodal prehabilitation may be superior [61]. The downside of multimodal prehabilitation mainly lies in the additional resources (both financial and human) needed for adequate care. Ongoing clinical trials investigating multimodal prehabilitation in CRC patients will shed more light on this topic [61].

Question 2: Is Supervised Prehabilitation Superior to the Home-Based Programs?
Prehabilitation is usually implemented either supervised by a medical professional in a health care facility or, after introductory training, in-home setting. Each modality carries its respective advantages and disadvantages. Supervised prehabilitation allows for the monitoring of adherence and swift implementation of any necessary changes. Supervised exercises in patients with chronic low back pain [62], intermittent claudication [63], or after anterior cruciate ligament reconstruction [64] were shown to improve the outcomes. However, the supervised prehabilitations protocols carries significant logistical challenges for patients and healthcare providers. During the COVID-19 pandemic, a new way to provide supervised prehabilitation appeared. This can be achieved via tele-prehabilitation, where patients are supervised utilizing video conferencing applications. This eliminates the logistical challenges of supervised prehabilitation while maintaining all the advantages. Current studies indicate that patients prefer home-based prehabilitation; thus, a higher level of adherence could be achieved [27]. Prehabilitation in a home setting with or without telemonitoring may seem the most effective and rational approach for most patients with CRC. On the other hand, there is a great discussion regarding this topic in the current literature. Most scepsis and criticism for the home-based approach are given for unclear safety and efficacy of this approach. Additionally, the rates of non-compliance and attrition for facility-based prehabilitation may be overestimated [65][66][67][68]. Thus, there is a place for studies that would directly compare home-based vs. supervised prehabilitation for CRC cancer patients.

Question 3: How to Make Sure Patients Comply with Prehabilitation?
Poor compliance remains one of the significant obstacles in current prehabilitation regimens and results in worse-than-expected outcomes [69]. Therefore, finding ways to increase compliance remains the most important. Direct supervision by healthcare professionals could boost patients' motivation and readiness to adhere to the prehabilitation regimen [70]. Although, as highlighted before, hospital-based prehabilitation has some significant logistical challenges. These challenges could be overcome by a hybrid approach or switching to tele-prehabilitation. In addition, psychological support could be implemented as it may improve motivation for adherence [71]. In our review, only four studies included some psychological prehabilitation [17,27,37,40]. Further research in this field is necessary to delineate ways to ensure maximal adherence.

Question 4: When Should the Prehabilitation Be Started?
As the time window between diagnosis and surgery in CRC patients is relatively short, the prehabilitation in patients undergoing only surgery should begin without delay. For patients receiving neoadjuvant treatment, several options are available. One possibility would be the window between the end of neoadjuvant therapy and surgery, which should ideally last 3-5 weeks [72]. Many studies in this review, however, utilized prehabilitation in conjunction with neoadjuvant CRT, where the feasibility of prehabilitation has already been established [31]. Prehabilitation has been proven to alleviate some negative impacts of neoadjuvant therapy, including declining physical fitness, increased depression and anxiety rates, and reduced HRQOL [10]. Therefore, prehabilitation should be started without delay to minimize the significant declines in function from NACRT and improve surgical outcomes.

Question 5: What Benefits Could Prehabilitation Bring to CRC Patients?
Current evidence on prehabilitation's impact on postoperative outcomes is controversial. Five studies investigating prehabilitation's impact on postoperative morbidity showed a positive effect [11,26,27,30,42]. Similarly, only 2 of 6 studies that investigated prehabilitation's impact on the length of hospital stay showed a positive effect [17,27,38,40,42,43]. Additionally, 1 study demonstrated that prehabilitation promoted neoadjuvant therapyinduced tumor regression [30], but these findings were not confirmed in another study [44]. Taken together, it is likely that prehabilitation has a positive effect on clinical outcomes in CRC patients. Still, currently, there is a lack of studies designed to confirm this.

Limitations of the Current Knowledge
There are many limitations in the present comprehensive review and current knowledge on prehabilitation for CRC surgery. First, this study is a comprehensive, but not a systematic review. Second, the analysis is limited by significant heterogeneity of available studies in terms of patients and oncologic treatment pathways (upfront surgery vs. surgery after neoadjuvant treatment), different interventions (unimodal exercise prehabilitation vs. multimodal prehabilitation), and measured outcomes. Such limitation rises from the lack of prehabilitation standardization and consequently the nature of the current literature on this topic. Third, there is only limited data from large-scale randomized studies. Therefore, current knowledge on prehabilitation for CRC has to be addressed with caution, and further studies are needed to elucidate remaining unclarities which were highlighted through this review.

Conclusions
Prehabilitation is a new approach to improve patients' physical, and nutritional status and psychological well-being before surgery. This comprehensive review summarized the currently available data on the prehabilitation in the management of CRC. Even though the majority of studies were not homogenous in their design and interventions, the majority showed at least some benefits: improved physical performance and nutritional status, reduced length of hospital stay and postoperative complication rate, as well as improved quality of life. However, more research on optimal prehabilitation techniques is needed to establish the best prehabilitation strategy for managing colorectal cancer patients.