Effects of prehabilitation concurrent exercise on

functional capacity in colorectal cancer patients: a

systematic review and meta-analysis
Sergio Maroto-Izquierdo
European University Miguel de Cervantes
Iker J. Bautista
University of Chichester
Héctor Menéndez
European University Miguel de Cervantes
Jose Pinto-Fraga
European University Miguel de Cervantes
Vicente Simò
Hospital Universitario Rio Hortega
César Aldecoa

Hospital Universitario Rio Hortega

Research Article

Keywords: pre-surgery, resistance exercise, aerobic exercise, coadjutant therapy, oncology patients

Posted Date: March 13th, 2024

DOI: https://doi.org/10.21203/rs.3.rs-4062284/v1

License:   This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full
License

Additional Declarations: No competing interests reported.

Page 1/25
Abstract
Purpose: Preoperative fitness level is associated with surgical complications and long-term function after major
surgery in colorectal cancer (CRC) patients. Exercise-based prehabilitation may represents a feasible strategy to
improve preoperative functional and cardiometabolic outcomes. This meta-analysis aimed to examine the efficacy
of concurrent exercise (i.e., aerobic and strength exercise) during prehabilitation programs on functional capacity
assessed through the 6-minute walking test (6MWT) in comparison with standard cancer care strategies in CRC
patients scheduled for surgery.

Methods: A systematic review and meta-analysis of randomized controlled trials was performed. A search of
electronic databases [PubMed, Web of Science and EBSCO Host] was conducted to identify all publications
employing concurrent exercise in CRC patients up to April 5, 2023. 6 studies met the inclusion criteria. Random-
effects meta-analysis were used to calculate the standardized change of mean difference (SCMD) and 95% CI
between exercise intervention and control groups for 6MWT distance covered before and after prehabilitation.

Results: Concurrent training during prehabilitation led to significant positive effects on 6MWT (0.28 SCMD [0.03 to
0.54], p=0.037). Sub-group analyses showed higher SCMD (0.48 [0.00 to 0.98]) in younger (i.e., <70 years) CRC
patients compared to CRC older patients (0.10 [0.08 to 0.11]). Meta-regression models between SCMD of 6MWT and
body mass index, prehabilitation program duration, and baseline 6MWT distance covered did not show any
significant relationship. Only age variable shared 54% of variance with SCMD of 6MWT, but without statistical
significance (p = 0.076).

Conclusions: This meta-analysis provides evidence supporting the superiority of prehabilitation programs that
implement concurrent exercise compared with standard cancer care strategies to promote functional changes, which
are well-related with cardiometabolic status and lower post-operation risk in CRC patients.

INTRODUCTION
Colorectal cancer (CRC) is the third most common cancer worldwide. More than 1.9 million new cases were
diagnosed in 2022, approximately 10% of all annually diagnosed cancers. CRC is also the third most prevalent type
of cancer with an estimated number of 5 million cases in 2020, an incidence rate of 67.4 per 100,000 persons over
the most recent 5 years (2015–2020) with a rising tendency 1. Average diagnosing age is situated around 66 years,
with an incidence rate increasing rapidly with age. In addition, incidence rate is reported to be higher in men than
women (40–50% higher), especially in older people (55 to 74 years) 2. However, despite causing more than 900,000
deaths worldwide during last year and being the third most common cause of cancer death 1, over the last 20 years a
decrease in mortality index and increase in survival rate have been observed. The cause of that decline may be due
to the advanced imaging techniques and diagnoses, alongside with improvements in treatments, which include
improved surgery techniques 2, since surgery is required to treat CRC (although other treatments such as
chemotherapy, radiation therapy or immunotherapy may be necessary or appropriate depending on the cancer type
or stage).

CRC surgery is associated with a decline in functional capacity, especially in older population 3. Post-operative
complications are associated with increased hospital mortality and higher probability to remain hospitalized 4.
Complications related to CRC treatment suppose not only adverse post-operative implications but also detriments of
life quality on the long term 5. Indeed, preoperative health and fitness level are associated with surgical
complications 6,7 and long-term function after major surgery in CRC patients 3. Thus, the low physical activity level is
Page 2/25
associated with poor prognosis in patients with CRC 8. Patients can even deteriorate their functional capacity while
awaiting for surgery 9. Hence, it is important to propose health care strategies to fight against surgery-induced
adverse effects on functional capacity. Given the fact that the higher number of risk factors the higher risk of post-
operative complications, preventive strategies are needed 10. Prehabilitation may represents a feasible and efficient
strategy to improve postoperative outcomes related to modifiable risk factors 6.

The anaesthesiology department, through its perioperative consultations, should oversee promoting multimodal
prehabilitation, as advised by international scientific societies (Enhanced recovery after surgery ERAS; Grupo Español
de Rehabilitación Multimodal GERM), including physical exercise, nutrition and cognition, especially in frail patients.

Exercise interventions have been shown to be associated with low risk of adverse events, leading to beneficial effects
on a wide range of health-related outcomes in CRC patients, including: quality of life, fatigue, sleep, depression,
aerobic fitness, functional strength and body fat and decrease in mortality 11. Thus, prehabilitation programs for
cancer patients awaiting for CRC surgery where an exercise component was included, promoted significant
improvements in physical performance and functional capacity 12,13. Traditionally, aerobic low-to-moderate intensity
activities (e.g., walking) have been proposed as a feasible and safe post-operative exercise intervention for CRC
survivors taking general recommendations of 150 min per week into account 14–18. Therefore, aerobic exercise has
been usually prescribed to improve functional capacity and physical activity levels in CRC patients either before and
after surgery 19,20

To determine the effects of systemic exercise on functional capacity, the 6-minute walking test (6MWT) is considered
as a clinically relevant measure 21–23, which has been validated for colorectal cancer patients to measure physical
function 24. In addition, the distance walked has been significantly correlated with VO2peak, being both measures
associated with lower postoperative morbidity 21. Additionally, functional walking capacity has been traditionally
considered as a modifiable risk factor associated with better postoperative recovery for patients undergoing CRC
surgery 25.Therefore, the 6MWT has been used to assess the effects of prehabilitation interventions on cardio-
metabolic health profile in CRC patients by several studies 26–32. These cardiometabolic health factors are linked to
the risk of disease recurrence and mortality in CRC survivors 33,34 and, hence, they are important targets for life-style
intervention trials in this population 8.

Aiming to increase functional walking capacity, both aerobic and resistance exercise have been recommended for
cancer patients 35. Indeed, benefits on cardiorespiratory fitness and muscle strength have been observed after 1–4
weeks of concurrent training during prehabilitation in cancer patients undergoing tumor resection 13. Thus, recent
CRC prehabilitation programs included both exercise modalities, which have shown significant gains in functional
capacity prior to surgery 26,28,29,36 and led to higher physical activity levels in CRC patients 36. Which in turn was
associated with a most successful post-operative recovery 21 and reduced lean tissue muscle mass losses induced
by surgical stress 37.

Given the proven benefits of concurrent training in CRC patients, prehabilitation programs including both aerobic and
resistance exercise training may be associated with higher gains in functional capacity and cardiometabolic health-
related factors prior to surgery than standard care. Therefore, the aim of this systematic review and meta-analysis
was to analyze the effects of concurrent exercise programs during prehabilitation on functional capacity assessed
through the 6MWT compared to traditional low-to-moderate intensity aerobic exercise traditionally prescribed along
with standard cancer care strategies in CRC patients scheduled for surgery.

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METHODS
A systematic review of the literature was performed using guidelines in the Cochrane Handbook for Systematic
Reviews of Interventions (version 6.0) and following the checklist for the Preferred Reporting Items for Systematic
reviews and Meta-Analyses 2020 (PRISMA) 38. The PRISMA statement includes 27-item checklist, an expanded
checklist that details reporting recommendations for each item, and it is designed to be used as a basis for reporting
systematic review of randomized trials. A review protocol was not registered for this review. The review protocol was
registered on the PROSPERO data base.(registration number: CRD42022307792). Human Ethics and Consent to
Participate declarations were not applicable. Not funding were obtained.

A systematic, computerized search of the literature in PubMed, Web of Science (including Web of Science and
MEDLINE results) and EBSCO Host (CINAHL with Full Text, eBook Collection (EBSCOhost), ERIC, Food Science
Source, Library, Information Science & Technology Abstracts, MEDLINE Complete, PSICODOC, SPORTDiscus with Full
Text was conducted by an independent researcher with controlled vocabulary and keywords related to, colorectal
cancer prehabilitation and concurrent exercise. Our search time frame was restricted to 14 years (January 2009 to
December 2023); 2009 was chosen because research on exercise-based prehabilitation programs for CRC patients
began that year 20. We developed our search strategy based on the lack of reviews and meta-analysis about CRC
prehabilitation and functional capacity. To do this, the search strategy used by previous reviews in the field of CRC
was used Boereboom et al., 2015; Singh et al., 2020). Thus, a PICOC systematic search strategy was developed for
PubMed using the Word Frequency Analyser tool (http://sr-accelerator.com/#/help/wordfreq) to suggest potentially
relevant search terms. The Research refiner tool (https://ielab-sysrev2.uqcloud.net/) was subsequently used to
optimize the sensitivity and specificity of the search, while the Polyglot Search Translator Tool (https://sr-
accelerator.com/#/polyglot) was used to adapt the search to another database. The search language was restricted
to English, and a filter containing Medical Subject Headings (MeSH) terms was applied. A more specific search
included the terms of "Prehabilitation", “training", "fitness", "resistance", "strength", "weight", "cancer", "colon”, "rectal",
"colorectal" and "Oncology". Thus, the following search string was: "Prehabilitation"[All Fields] AND ("training"[All
Fields] OR "fitness"[All Fields] OR "resistance"[All Fields] OR "strength"[All Fields] OR "weight"[All Fields]) AND ("cancer"
[All Fields] OR "colon"[All Fields] OR "rectal"[All Fields] OR "colorectal"[All Fields] OR "oncology"[All Fields]).

The reference list of all selected publications was verified to retrieve relevant publications that were not identified by
the computerized search. References of selected and included original articles, abstracts and available conference
proceedings were also searched, including publications, posters, abstracts or conference proceedings. To identify
relevant articles, titles and abstracts of all selected publication after the first search were analyzed looking for
prehabilitation strategies which included any exercise form for CRC patients. In the specific search, in addition to the
identified citations of the first search, titles and abstracts of all recognized publications were examined in detail. Full-
text papers were recovered if the abstract provided insufficient information to establish eligibility or if the article
abstract had passed the first eligibility review.

All articles examining any exercise intervention as prehabilitation in colorectal cancer patients were eligible for full-
text review. An article was eligible for study inclusion if it met all the following criteria:

1. The original article was a randomized controlled trial (RCT) or clinical controlled trial (CCT) published in peer-
reviewed journals.
2. The article reported CRC patients of either sex who had completed a prehabilitation protocol during at least 2
weeks with a minimum training frequency of 2 days per week.

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 3. The manuscript included a prehabilitation intervention based on concurrent exercise and a control or exercise-
based alternative intervention group, comparing functional capacity.
4. The prehabilitation program included strength exercise and moderate-to-high intensity aerobic exercise.
5. The main outcome considered to analysis was 6MWT.

An article was excluded if:

1. Had participants with any other cancer type or severe pathologies or included subjects with existing, or under
treatment for, musculoskeletal injuries.
2. Did not have the minimum requirements regarding the prehabilitation protocol (e.g., duration or frequency).
3. Reports focused on healthy subjects.
4. Were not written in English.

All criteria were independently applied by two reviewers (CA and SMI) to the full text of the articles that passed the
eligibility screening of titles and abstracts. One researcher (IJB) double checked the included papers from the
systematic search and modified the eligibility criteria to limit the scope of the review. Any disagreement was resolved
by discussion. Duplicate references were first removed using an online deduplicate tool for systematic reviews
(https://sr-accelerator.com/#/libraries/dedupe) and subsequent manual methods. Two authors (CA and SMI) then
independently screened titles and abstracts to determine initial eligibility using systematic review software (Rayyan).
Blinding of authors was used to reduce bias during this process. Finally, the authors reviewed the full-text to
determine eligibility for inclusion based on the eligibility criteria. Disagreements in eligibility decisions were resolved
through discussion, or with a third reviewer (IJB) when required.

Data extraction was completed independently and in duplicate by two authors (CA and SMI). The data were then
merged by one author (CA) and any discrepancies in the extracted data were resolved through discussion, or with a
third reviewer (IJB) if required. Extracted data from each full-text article included 1) study identification information;
2) study design; 3) sample size; 4) sex and ethnicity; 5) age, height and body mass; 6) exercise program
characteristics (e.g., program duration, weekly training frequency and training volume, exercises prescribed, exercise
intensity, training load management and supervision); 7) 6MWT distance covered at baseline and before surgery; 8)
means and standard deviations for relevant outcome measures (i.e., pre- and post-test 6MWT performance) and 9)
an exact p-value, r-value, t-value, or confidence intervals for an association between two outcomes or a comparison
between groups. When insufficient data were reported, authors were contacted by-email. When data were not
presented in tables or text and when authors did not provide the requested data, these were extracted from figures
using WebPlot Digitizer (Web Plot Digitizer, V.4.1. Texas, USA) when possible.

Methodological quality and risk of bias was independently assessed by two researchers (CA and SMI) using the
Cochrane risk of bias 2 (RoB2). In case of disagreement between the scores provided, a third author made the final
decision (IJB). The RoB2 assessment scale was structured into a fixed set of domains of bias, focusing on different
aspect of trial design, conduct and reporting. A total of five domains were assessed: D1) bias arising from the
randomization process, D2) bias due to deviations from intended interventions, D3) bias due to missing outcome
data, D4) bias in measurement of the outcome and D5) bias in selection of the reported results. These categories
were classified as “high risk of bias”, “low risk of bias” and “some concerns”. RoB 2 was considered in the
interpretation of the results by applying the Grading of Recommendations Assessment, Development and Evaluation
(GRADE) system. Briefly, the overall quality was rated as high and downgraded one level to moderate, low or very low
for each of the following limitations. For imprecision, the level of evidence was downgraded one level whether

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conclusion about the effect magnitude would be altered based on the lower or upper boundary of the confidence
interval. For example, if the mean effect was small, but the 95% confidence interval crossed the threshold for a trivial
effect (i.e., g < 0.2), the precision was insufficient to support a strong recommendation the confidence interval does
not exclude the possibility for the effect to be trivial. Similarly, whether the confidence interval crossed the threshold
for a large effect, while the mean effect was moderate, conclusion was considered imprecise and as such, level of
evidence was also downgraded one level. For inconsistency, level of evidence was downgraded one level if high
statistical heterogeneity was observed, and if more than 50% of studies had > 1 risk of bias item assessed to be high
risk. Finally, no indirectness rated was applied since all the studies had a similar sample (i.e., CCR patients
undergoing and intervention in the following 2-4 weeks), all of them used the same tool to asses functional capacity
and interventions were similar, including both resistance and aerobic exercise forms. In addition, no indirect
measurements were analysed.

Statistical analysis

Sample size, means, standard deviation, and 95% confident intervals of distance (meters) were extracted
independently by two authors from the included studies. Standardized of change mean differences (SCMD) were
therefore calculated (equation B) using the following equations:

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Where “r” is the average correlation coefficient between the pre and post measurements in both groups. The
correlation coefficient between pre-post measurements for both groups was computed from the standard deviation
of change score (SD diff) in each group, with the standard deviation of change score being determined as detailed by
Higgins et al. 42. If the reported outcomes could not be used to calculate SD diff, the corresponding author of each
paper was contacted to provide the data. The SCMD was considered trivial (< 0.20), small (0.20 – 0.59), moderate
(0.60 – 1.19), large (1.20 – 1.99), and very large (> 2.00) 43. Variance estimations between studies were calculated
using a random effects model (i.e., Hartung-Knapp/Sidik-Jakman adjustment [HKSJ]) with a 95% confidence interval
(CI95%). The consistency of the effects found was assessed using the heterogeneity (I2) and Tau-square tests (t2)
tests, with I2 being considered small (<25%), moderate (25 – 49%) and high (>50%). In addition, t2 and prediction
interval (PI) were included, because t2 cannot readily point to the clinical implications of the unobserved
heterogeneity. The prediction interval allows a better clinical evaluation of the results obtained because it represents
the range in which the effect size of a future study conducted on the topic will most likely be (i.e., probability of true-
positive effect). Prediction intervals and the probability of the true-positive effects calculations were performed in
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accordance with IntHout, Ioannidis and Goeman 44. Contour-enhanced funnel plot were used to assess small study
bias. P-curve analysis was included as an alternative way to assess publication bias and estimate meta-analysis
power. All statistical analyses were performed using statistical software (R version 4.1.9, metaphor and meta-
analysis package, general meta-analysis package, risk of bias figures were created using Robvis).

RESULTS
Figure 1 shows a flow chart with the different phases of the search and selection of the studies included in the
review. The initial search of electronic databases identified 1107 titles, of which 621 were rejected for duplication
issues. A total of 5 titles/articles 9,25,26,36,45 were identified through manual search. Thus, 491 titles were identified,
but 424 of them were rejected after reading the title because they did not meet the inclusion criteria. From a total of
67 abstracts that were screened, 32 were excluded because they did not meet inclusion criteria: 18 studies were
reviews, 3 studies analyzed prehabilitation on other types of cancer, 1 study was excluded due to applying a
nutritional intervention, 1 study was a nursing standard, 1 study was not available, 1 study did not include a control
group, 3 studies were not written in English and 4 studies were out of interest. Thus, thirty-five full texts were
reviewed, but only 6 studies satisfied the inclusion criteria to be considered for this review 26,27,29,30,45,46. The main
reasons for exclusion were: lack of a comparison group (n = 8), intervention did not include resistance training (n = 4)
or did not specify the type of exercise intervention (n = 1), included diseases other than CRC and did not differentiate
results (n = 3), reanalyzed results from previous controlled trials (n = 3), did not measure functional capacity (n = 2),
did not assess functional capacity through the 6MWT (n = 4), was an intervention protocol proposal (n = 3) or there
was a lack of data (n = 1). The complete list of excluded references and the rationale for their exclusion can be found
in Supplementary File 1. The RoB2 scores of included studies is reported in Supplementary File 2. Visual inspection
of the contour-enhanced funnels plots and egger test indicated no presence of asymmetries in 6MWT.

***Insert Fig. 1 here***

The main characteristics of the studies included in the review regarding participants, interventions and results are
illustrated in Table 1. After adjusting for dropouts, the total number of participants in the studies included was 379.
Of these 379 participants, 192 (50.7%) received prehabilitation, while 187 (49.3%) received standard care and served
as controls. All studies included both male and female patients. In total 110 (29.0%) men and 82 (21.6%) women
were allocated to the prehabilitation group, while 106 (28.0%) men and 81 (21.4%) women received standard care.
There was a total of 216 men and 163 women involved in the selected studies. Demographic data were provided for
all studies. The estimated mean age of the prehabilitation group was 72.1 ± 7.7 years, and 70.4 ± 6.8 years for the
standard care group, and 70.4 ± 6.2 years considering all participants independently their allocation. BMI information
was available in 5 out of 6 of the studies 26,27,29,45,46. Mean BMI for all participants was 27.5 ± 1.4 and showed that
both prehabilitation (27.4 ± 1.9) and control (27.6 ± 1.0) groups were overweight. Mean distance covered at baseline
on the 6MWT was 404.1 ± 41.8 m for the prehab group, 358.2 ± 21.7 m for the control one, and 381.2 ± 35.3 m for all
participants independently of their allocation. All of the studies measured functional walking capacity through
6MWT. In addition, the stair climb test, the five times sit to stand test 26, the chair stands in 30 seconds test 30, the
time up and go test, handgrip strength 26, habitual and maximal gait speed and inspiratory muscle strength 30 were
also measured. However, these results were not analyzed.

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 Table 1
Main characteristics of the studies included. Abbreviatures: 6MWT, the six-minute walking test; AE, aerobic exercise;
Control: Control group; CD, cool-down; HRmax, Maximum heart rate; HRR; heart rate reserve; Prehab: prehabilitation
group; RPE, rate of perceived exertion; RT, resistance training; WU, warm-up.
Study Participants Functional Program Exercise Other Results
outcomes Intervention interventions
Supervision

Bousquet- 63 6MWT Non- Average Nutritional Both groups

Dion et al. supervised duration: 32 intervention & improved
(29) Prehab (n = home- days, 3–4 anxiety 6MWT over
37), based days/week. reduction the
program strategies preoperative
Rehab (n = Session: 30 min period
26) + a weekly AE (including 5 (Prehab: 4.9%,
session min WU) + 25 Rehab: 2.2%).
supervised min RT + 5 min However,
at hospital stretching. Prehab group
showed higher
AE intensity: 60– changes.
70% HRmax. Including a
weekly
AE activities: supervised
walking, cycling session did
or jogging. not provide
higher
RT: 8 exercises functional
targeting major enhancements
muscle groups. compared to
home-based
RT volume: 2 multimodal
sets x 8–15 prehabilitation
reps. programs.
RT was
progressed (i.e.,
increasing
intensity) when
patients were
able to complete
the program with
perceived mild
exertion (12 RPE
points or less on
the 20-point
Borg scale).

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Study Participants Functional Program Exercise Other Results
outcomes Intervention interventions
Supervision

Carli et al. 110 6MWT Non- Duration: 28 Nutritional & Both groups
(49) supervised days. 4 improved
Prehab (n = home- days/week. Psychological walking
55), Control based strategies capacity over
(n = 55) program Supervised the
session: 30 min preoperative
+ a weekly moderate AE period,
session (including a 5 however
supervised min WU) on a greater
at hospital. recumbent improvements
stepper + 25 min were found in
RT using elastic Prehab group
bands + 5 (Prehab:6.4%;
minutes of Control: 3.9%)
stretching.
Home based
program: walk
daily for a total
of 30 minutes at
moderate
intensity + RT
(elastic band
routine 3 times
per week)

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Study Participants Functional Program Exercise Other Results
outcomes Intervention interventions
Supervision

Gillis et al. 77 6MWT Non- Average Nutritional The 6MWT

(31) supervised duration: 24.5 intervention & distance was
Prehab (n = home- days, 3 anxiety significantly
38), based days/week, reduction improved in
program strategies CRC patients
Rehab (n = Session: 5 min waiting for
39) WU + 20 min AE surgery (6.0%);
+ 20 min RT + 5 while those in
min CD. Rehab group
declined their
AE intensity: functional
prescribed based walking
on the rate of capacity
perceived (-3.9%) during
exertion (Borg the
scale) from the prehabilitation
6MWT, starting period.
at 40% HRR. AE
activities:
Walking, jogging,
swimming, or
cycling.
RT: 8 exercises
targeting major
muscle groups,
8–12 RM.

Exercise
intensity
progressions
occurred when
participants
reported mild
exertion (Borg
12) during AE
and/or when
participants
completed 15
repetitions of a
given RT
exercise.

Karlsson et 21 6MWT; Supervised Average No Trimodal

al. (32) habitual home- duration: 17 program
Prehab (n = and based days, 2–3 comprising
10), maximal program days/week, homebased
gait moderate AE
Control (n = speed; Session: 60 min. and RT
11) Block I: improved their
lower Inspiratory functional
extremity muscle training, walking
strength Block II: RT, capacity.
(chair Block III: AE. (Prehab: 1.9%,
stands in Control: 1.0%).
30s); and AE: Bouts of Prehab
Inspiratory stair climbing, participants
muscle Nordic walking improved also
strength. outdoors, and lower limb
interval walking strength
indoors and/or (Prehab:
outdoors. 34.3%;
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Study Participants Functional Program Exercise Other Results
outcomes Intervention interventions
Supervision
Intervals (RPE of Control:
7–8 on Borg CR- 12.2%); gait
10). The speed
duration of AE (Prehab:
sessions, 13.7%;
number and Control: 5.6%);
length of AE and
intervals were inspiratory
progressively muscle
increased. strength
(Prehab:
RT volume: 3 24.7%;
sets x 10 reps. Control: 1.5%).
However,
RT intensity: RPE maximal gait
of 7–8 on Borg speed did not
CR-10. seem to
change after
RT exercises: intervention
functional (prehab: -2.0%;
exercises (chair control: 5.8%)
stands and step-
up with weight
belts).
RT progression:
the chair-stand
test was
performed
before each
session to
establish load
and volume,
which were
increased
whether RPE
was lower than 7
on Borg CR-10.
During
unsupervised
days,
participants
were instructed
to follow the
general
recommendation
of 150 min/week
of moderate
intensity AE,
combined with
unloaded
functional RT
exercises 2–3
times/week.

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Study Participants Functional Program Exercise Other Results
outcomes Intervention interventions
Supervision

Li et al. (27) 87 6MWT Non- Average Nutritional Short period

supervised duration: 33 intervention & of concurrent
Prehab (n = home- days anxiety exercise
42), based reduction prehabilitation
program AE: 3 days/week, strategies program
Control (n = 30 min at 50% supposed
45) HRmax. improvements
on functional
AE activities: walking
walking or using capacity only
an aerobic in Prehab
machine. group (9.9%).

RT: 3 days/week,
calisthenics and
elastic band
movements
performed to
volitional
fatigue.

Northgraves 21 6MWT; Supervised Average No Both groups

et al. (28) by duration: 22 improved
Prehab (n = Time Up researchers days, 3 walking
10), Control and Go at days/week. capacity over
(n = 11) test; laboratory. the
Session: 60 min. preoperative
Five WU (5 min on period.
Times Sit cycle ergometry However,
To Stand at 40–50% Prehab group
test; Stair HRR) + RT circuit showed higher
Climb 2 + AE + RT improvements
Test, and circuit 1 + CD (5- (Prehab:
handgrip min walking and 17.3%;
strength. stretching). Control: 1.9%).
Concurrent
AE: Up to 25 min exercise did
of cyclergometry not improve
at 40–60% HRR any of the
and/or RPE of other
11–13 on the measures
Borg scale. As except for
tolerated, handgrip
duration of strength
cycling was (5.1%).
increased by 2–
5 min per
session up to a
maximum
duration of 25
min

RT volume: 3–4
sets for both
circuit 1 and 2.
RT exercises:
Circuit 1: Split
squat, rear foot
elevated squat,
bilateral and
unilateral gluteal
Page 13/25
 Study Participants Functional Program Exercise Other Results
outcomes Intervention interventions
Supervision
bridge, cook hip
lift, shoulders
elevated bilateral
and unilateral
gluteal bridge,
kettlebell swings,
dumbbell push
press, high
kneeling band
anti-rotation,
band resisted
side shuffles,
suitcase carry,
and slam ball
throws. Circuit 2:
Sit to stand,
band resisted sit
to stand, side
lying leg hip
abduction, X-
band walks, foot
raised thoracic
extension,
shoulder band
pull apart, band
resisted external
rotation, and
band seated row.

RT Progressions:
each 2–3
sessions based
on participant’s
exercise
technique and
participant-
reported
difficulty.

Prehabilitation interventions ranged from 2 to 6 weeks with a frequency ranged from 2 to 4 sessions per week, being
3 sessions per week the most common paradigm. Every study included both resistance and aerobic training, but not
all of them provided details about the intervention. Aerobic and resistance training were performed within the same
session in 5 of the studies 26,27,29,30,45 and its duration ranged from 50 29 to 60 min 26,27,30. Only one study did not
specify prescribing aerobic and resistance training within the same session 46. Training sessions usually took place
at patients residence 25,27,29,30,45, including a hospital session once a week 27,45. Only one study performed a
supervised exercise program by researchers at the laboratory 26. Training sessions were totally unsupervised in 2
studies 25,29, unsupervised but including a supervised session once a week in 1 study 27,45 or totally supervised in 2
studies 26,30. Most studies performed moderate intensity aerobic exercise for 20-30min 25–27,29,45 which included
exercises such as walking/jogging 25–27,29,45, cycling 27,29, swimming 29, using a recumbent stepper 45, or using an
aerobic exercise device 25, except for one which used high intensity interval aerobic training using exercises such as
brisk walking 30. Resistance training ranged from 2–4 sets, and 8–15 reps 26,27,29,30. Exercises targeted major
muscle groups 27,29 functional strength exercises 30 weightbearing and elastic band exercises 25,45 and a variety of
exercises using body weight, resistance bands, kettlebells, dumbbells and balls 26 were used.

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All exercise interventions were individualized and 4 of them progressed when needed 26,27,29,30. Resistance training
was progressed when patients could complete the routine with mild exertion 27, could complete 15 repetitions at a
given intensity 29, when using chair stand test at each session they reported an exertion lower than 7 on Borg CR-10
scale 30, and when based on participant’s ability to demonstrate correct exercise technique 26. Aerobic training was
progressed when the patient could complete the routine at a mild exertion 29, or based on the participants self-
reported difficulty every two to three sessions 26, or by increasing duration 26,30 or the number and length of training
intervals 30. While awaiting for surgery, the control group participants only received standard care through enhanced
recovery after surgery pathways 25,27,29, were required to maintain their usual physical activity level 26 or to follow the
ACSM and WHO general recommendation of 150 minutes/week of moderate physical activity 30. In addition, it
should be noted that 4 of the studies included both nutritional and psychological interventions as part of the
prehabilitation 25,27,29,45. In addition, one study included breathing exercises as part of the exercise intervention 30.

Regarding the meta-analysis on the effects of concurrent exercise compared to traditional care strategies on
distance covered in the 6MWT, results showed statistically significant differences (t-value = 2.83, p = 0.037) by 0.28
SCMD [0.03, 0.54] in favour of the intervention group (i.e., implementation of aerobic and strength exercise during
prehabilitation). The prediction interval and heterogeneity are illustrated in Fig. 2 and GRADE quality evidence is
provide in Supplementary File 3. The prediction interval revealed that concurrent exercise during prehabilitation
interventions have a probability of a true-positive effect of 0.85 in a future setting. Counter-enhanced funnel plot as
well as p-curve analysis showed no evidence of publication bias (Supplementary File 4 and 5, respectively). Visual
inspection of counter-enhanced funnels plots for distance in the 6MWT showed no large asymmetries (see
Supplementary File 4). In addition, P-curve analysis was used as an alternative way to assess publication bias. P-
curves assumes that publication bias is not primarily generated because researchers do not publish non-significant
results, but because they “play” around with their data (p-hacking). Thus, it allows to evaluate the power of the meta-
analysis results. Supplementary File 5 shows the p-curve (in blue), Right-Skewness test and Flatness test for 6MWT,
when including all distances. Right-Skewness test analyses if the p-curve resulting from 6MWT distances mean
differences is significantly right-skewed, which indicate that there is a “true” effect behind the data (Supplementary
File 6). The flatness test analyses if the p-curve is flat, which could indicate that the power is insufficient, or that there
is no “true” effect behind the data.

***Insert Fig. 2 here***

Meta-regression models showed that body mass index, age, intervention duration (sessions) and 6MWT distance
covered at baseline were not significantly associated with improvements in 6MWT distance effect size (see Table 2).
However, there is a positive trend towards age in the effect size of distance (Fig. 3).

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 Table 2
Meta-regression models between SCMD of 6MWT distance covered and body mass index (BMI), age,
prehabilitation program duration, and baseline 6MWT distance covered in all studies evaluated (k = 6).
Meta-regression models k Coefficients SE CI95% p-value R2 (%)

SCMD of 6MWT and BMI 6 Int: -0.82 2.24 -7.96 to 6.32 0.738 0%

Slope: 0.04 0.08 -0.29 to 0.51 0.644

SCMD of 6MWT and age 6 Int: 1.93 0.81 -0.33 to 4.19 0.076 54%

Slope: -0.02 0.01 -0.05 to 0.01 0.111

SCMD of 6MWT and program duration 6 Int: -0.07 0.49 -1.43 to 1.29 0.891 0%

Slope: 0.01 0.02 -0.03 to 0.06 0.499

SCMD of 6MWT and baseline 6MWT 6 Int: -0.38 1.26 -3.86 to 3.13 0.785 0%

Slope: 0.002 0.003 -0.007 to 0.01 0.631

***Insert Table 2 and Fig. 3 here***

DISCUSSION
Given the high prevalence of CRC worldwide, and the high relevance of cardiometabolic health on the risk of
recurrence and mortality in CRC survivors, prehabilitation strategies are sought and proposed throughout the
scientific literature. Exercise-based prehabilitation interventions have proven to induce significant gains in functional
capacity which are related with cardiometabolic health and associated with a low risk of adverse events and post-
surgery morbidity 39. Therefore, this study aimed to compare the efficacy of concurrent exercise (i.e., aerobic and
strength exercise) during prehabilitation on functional capacity assessed through the 6MWT in comparison with
standard cancer care strategies in CRC patients scheduled for surgery. Thus, this is the first systematic review that
analyzes the effect of concurrent exercise prehabilitation intervention on functional capacity in CRC patients prior to
surgery. In addition, the statistical approach employed, allows comparing the efficacy of concurrent exercise eliciting
adaptations in the 6MWT and to establish some meta-regression models among age, body mass index, baseline
walking ability and program duration. The search performed yielded 6 studies that met the inclusion criteria 26,27,29–
31,45. Although from studies with some concern or high risk of bias, meta-analysis results revealed significant small
effects (SCMD = 0.28 [0.03 to 0.54]) towards higher improvements after concurrent exercise interventions in
comparison with traditional/standard cancer care strategies, such as ERAS. In addition, subgroup analysis and meta-
regression models showed that age, and likely age-related variables, seems to be a key factor in prehabilitation
effectiveness on functional capacity, since younger (i.e., < 70 years) CRC patients showed larger effects compared to
their older counterparts (SCMD 0.48 [0.00 to 0.98] vs. 0.10 [0.08 to 0.11]).

Surgical complications, which are linked to increased hospital mortality and higher likelihood of remaining
hospitalized 4 are associated with preoperative physical status 6,7. Therefore, strategies such as prehabilitation are
implemented in order to improve physical capacity, since physical activity level before or after cancer diagnosis has
been associated with lower risk of cancer-specific and all-cause mortality 11. Thus, prehabilitation programs usually
include an exercise component 27–29,31,45,47,48. Particularly in CCR patients this is especially important, since surgical
stress induces an increase in metabolic demand throughout the perioperative period, which is clinically manifested
with a marked increase in oxygen consumption and cardiac output aimed at maintaining the systemic delivery of
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nutrients and oxygen-rich blood and mobilization of energy reserves to maintain energy processes, repair tissues and
synthesize proteins involved in the immune response 49. Thus, an adequate preoperative physiological reserve is
necessary to cope with surgically-induced detrimental responses, especially to manage the increase in oxygen
consumption during the operation 49. Those patients with a low preoperative cardiorespiratory status are not able to
perform and adequated management of metabolic demands enhancements generated by surgery, which in turn
makes them more susceptible to perioperative complications. However, it is well-known that regular exercise
improves the cardiometabolic status. Consequently, it is necessary to implement functional capacity assessments in
order to analyze the effectiveness of prehabilitation interventions and to predict surgical outcomes. All studies
included in this systematic review and meta-analysis used the 6MWT to assess functional capacity, since it has been
found to be a valid test to measure physical capacity in cancer patients 24, and it is well-correlated with VO2peak. So,
the larger walking distance covered by patients waiting for surgery the better postoperative recovery and the lower
morbidity rate 21.

Regarding the results of this systematic review and meta-analysis, significant improvements after exercise-based
prehabilitation program on functional capacity were observed in those studies including CRC patients younger than
70 years compared to CRC patients older than 70 years (Fig. 2, < 70 years: SCMD 0.48 [0.00 to 0.98]; >70 years:
SCMD 0.10 [0.08 to 0.11]).). Interestingly, although significant differences were found in CRC patients older than 70
years, SCMD revealed a trivial effect on this variable. To our knowledge, no study has previously analyzed the
association between age and training-induced effects after exercise-based prehabilitation in CRC patients. However,
the tendency showed towards greater improvements in younger patients (i.e., < 70 years) compared to the older ones
(Fig. 3). This finding might be explained due to the association between age and age-related comorbidities that may
limit older patients to exercise either by walking, pedaling or strengthening, as well as frailty and sarcopenia. Indeed,
it is widely known that frailty is prevalent in about 45% of over 65-years cancer patients. Moreover, frailty is also
associated with sarcopenia and perceived fatigue 50, which is prevalent in CRC patients having elective surgery and
is a predictive factor for mortality 51. Thus, older patients at higher risk of frailty and sarcopenia, may be also the
ones at higher risk of postoperative complications since trivial effects have been shown after exercise-based
prehabilitation and they are also the ones with the lower functional capacity. However, a worse baseline physical
status has not been associated with higher improvements on functional capacity after prehabilitation. Although
previous studies had found greater benefits in CRC patients with lower baseline functional capacity (i.e., less total
distance covered in the pre-test), those studies were performed with patients younger than 70 years 25,29. Therefore,
baseline physical status might be a predictive factor for improvements in 6MWT in younger patients but not in
patients older than 70 years. In addition, the detrimental effect of aging on body composition could also explain the
observed relationship between exercise-induced effects and age. Despite the fact that a previous review reported that
exercise post-diagnosis in CRC survivors had the strongest association with a mortality index reduction in those
patients with BMI < 25 11, our results showed no significant association between BMI and walking ability
improvements, although a slight tendency toward greater adaptations was observed in those with higher BMI. This
might be explained because cancer patients with a higher BMI generally have a greater amount of muscle mass, and
thereafter, the best prognosis 52. However, these results should be considered with caution, since the vast majority of
included studies did not report data regarding lean tissue mass, fat mass percentage or fat mass distribution 53.
Hence, further research is needed to implement not only effective interventions (e.g., exercise mode and intensity,
longer intervention duration, higher frequency) for older CCR patients (i.e., > 70 years) but also more precise
measurements.

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Our analysis did not find a significant association between prehabilitation program duration and gains achieved.
However, this might be due to the short and similar length of time between interventions (2–4 weeks). A previous
meta-analysis about exercise interventions in CRC patients found no significant effects on cardiovascular fitness
after interventions lasting < 12 weeks, but it did on those lasting 12 weeks or longer, which leads to think that the
longer prehabilitation interventions the greater changes 39. However, prehabilitation duration is usually determined by
time until surgery, limiting prehabilitation to a very short time frame, but sufficient to improve preoperative walking
capacity 36. Nonetheless, it has been reported that prolonged treatment delay does not lead to lower overall or
cancer-free survival in patients with primary CRC who underwent curative surgical treatment, which in turn supports
the idea of adapting waiting times to implement effective preoperative programs 54. However, the lack of a positive
correlation between a longer prehabilitation program and greater effects on functional capacity found in this study
implies the need to modify other variables of the exercise program, such as intensity, selection of exercises or weekly
training frequency. Regarding exercise selection, it has been proven that resistance training is the unique training
mode that has the ability to improve not only functional capacity but also muscle mass and fat percentage and fat
distribution in cancer patients undergoing neoadjuvant and adjuvant therapy 55. Hence, and given the fact that
concurrent training is recommended during cancer care 35, its inclusion, in combination with aerobic exercise, seems
to be essential in prehabilitation programs of CCR patients 26,28,29,31,56–61.

Consequently, the most important variable to manipulate during exercise prescription in cancer patients is intensity.
Due to the lack of information regarding exercise intensity in the included studies, it has not been possible to
establish a comparison between changes achieved in the 6MWT after exercise-based prehabilitation intervention and
exercise intensity. However, previous research has established that moderate-to-vigorous intensity exercise
interventions resulted in fitness level improvements in: VO2peak 62, muscle strength and endurance 62, functional
capacity (including 6MWT) 63, as well as measures of immune and cognitive function, depression and anxiety.
Although more research is needed, especially regarding resistance training, to determine the percentage of 1-RM or
movement velocity (i.e., specific intensity), number of repetitions, total number of exercises or the optimal weekly
training volume for a precise exercise prescription program both in prehabilitation and co-adjuvant treatment of
cancer patients. However, increasing exercise intensity requires supervision by qualified health care providers. In fact,
supervised exercise yielded superior benefits compared to unsupervised programs, and implies a significant decrease
in adverse events prevalence.

The findings of this systematic review and meta-analysis need to be considered with some limitations. One of the
main limitations is the small number of studies (k = 6) that met the eligibility criteria, and thereafter, that could be
included in the meta-regression models (being an inferior number than that recommended by the Cochrane
guidelines 42 to perform meta-regression models). In addition, there were few studies throughout scientific literature
analyzing the effects of concurrent training during prehabilitation in CRC patients. Furthermore, interventions were
heterogeneous, since some were described as multimodal prehabilitation while others only involved an exercise
component. Despite all included studies in this review prescribed aerobic and resistance training, adherence and
compliance or standard care practices varied between studies. Moreover, the exercise intervention was not reported
in detail in all of them. Which in turn supposes that results may have been altered by many other factors, such as
exercise intensity or load management strategies. Future research should further investigate the effects of different
exercise intensities during prehabilitation in CRC patients. In addition, since age, BMI or baseline walking capacity
might influence exercise adaptations, it is warren to analyze the relationship between patient biometric and clinical
characteristics and performance achieved during prehabilitation, in order to fully understand the effects of
concurrent exercise during the preoperative period and to deliver effective and individualized interventions.

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In conclusion, although moderate intensity aerobic activities are the most popular mode of exercise during
prehabilitation in cancer patients, the results of this systematic review and meta-analysis indicate that its
combination with resistance exercise (i.e., concurrent exercise) is associated with greater improvements in functional
capacity, assessed through the 6MWT, in CRC patients. Therefore, implementing concurrent exercise 3–4 times a
week for 2–4 weeks before surgery is recommended to increase walking capacity in CRC patients, which is positively
correlated with the cardiometabolic status and with a lower risk of post-operative complications. In addition,
subgroup analysis has demonstrated that younger patients (i.e., < 70 years) showed greater changes in walking
ability compared to their older counterparts. Meta-regression models showed that training-induced effects are no
dependent on baseline 6MWT distance covered, duration of intervention or BMI. Thus, to fully understand the effects
of concurrent exercise during the preoperative period, future research should involve individualized programs based
on patients biometric and clinical characteristics.

Declarations
Acknowledgments

This research received no external funding.

Conflicts of interest

The authors declare no conflict of interest. The results of the study are presented clearly, honestly, and without
fabrication, falsification, or inappropriate data manipulation.

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Figures

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Figure 1

Flow chart illustrating the different phases of the search and selection of the studies included in the review (PRISMA
2020).

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Figure 2

Forest plot with meta-analysis of SMCD showing comparison of concurrent exercises prehabilitation versus standard
cancer care on functional capacity (assessed through the 6MWT) in younger (<70 years) and older (>70 years) CRC
patients.

Figure 3
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Meta-regressions models of distance covered at baseline, program duration (i.e., number of sessions before surgery),
body mass index (BMI), and age with SMCD of 6MWT distance (vertical axis).

Supplementary Files
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