Prehabilitation Programs for Cancer Patients: a Systematic Review of Randomized-controlled Trials

Background: Prehabilitation programs focusing on exercise training as the main component are known as a promising alternative for improving patients’ outcomes before surgical treatment of different cancers. This systematic review aimed to determine the effects of prehabilitation programs compared with usual care for cancer patients. Methods/design: We searched CENTRAL, MEDLINE, and EMBASE from inception to 2020, and hand-searched clinical trial registries. We included randomized controlled trials (RCTs) in adults, survivors of any type of cancer, that compared prehabilitation programs focusing on exercise training as the major component with usual care or other active interventions. Outcome measures were health-related quality of life (HRQL), muscular strength, postoperative complications, average length of stay (ALOS), handgrip strength, and physical activity levels. Two reviewers independently selected the studies, extracted data, assessed the risk of bias and the quality of evidence using the GRADE approach. Results: 14 RCTs published between 2010-2020 met our inclusion criteria (n=1044 participants). Colorectal and lung cancers were the most common diagnoses with 5 studies (36%) each. The studies showed concerns regarding outcome measurement, selective reporting, and attrition. Four comparisons were identied: combined training vs rehabilitation/usual care; high-intensity interval training vs usual care; respiratory muscle training plus aerobic training vs usual care, and pelvic oor training vs usual care. The studies provided no clear evidence of an effect between groups. We assessed the certainty of the body of evidence as very low, downgraded due to serious study limitations and imprecision. Conclusion: It is uncertain whether prehabilitation programs compared with usual care have an effect in cancer patients. We have very little condence in the results and the true effect is likely to be substantially different from these. Further research is needed before we could draw a more certain conclusion. Systematic


Background
The National Cancer Institute in the USA de nes cancer as a chronic disease in which abnormal cells divide without control, can invade nearby tissues, and can spread to other parts of the body through the blood and lymph systems (1). GLOBOCAN reported 18.1 million new cases of cancer and 9.6 million deaths in 2018 (2). Cancer treatment might comprise surgery, chemotherapy, radiation therapy, immunotherapy, hematopoietic stem cell transplant, and hormone therapy; it all depends on the type of cancer and its stage (1).
In most cases, cancer treatments require surgery and postoperative care that lead to long periods of physical inactivity and deconditioning with loss of muscle function and a higher rate of medical complications (3). Further, inactivity-induced loss of muscle mass predominantly affects the lower body musculature, being larger during the rst days of inactivity (4-6). Exercise training interventions during and after medical treatment are associated with improvements in the quality of life (7) and decreases in fatigue and depression (7), and this is accompanied by lower tumor activity (8,9) in cancer patients.
Cancer prehabilitation represents "a process on the continuum of care that occurs between the time of cancer diagnosis and the beginning of acute treatment. It includes physical and psychological assessments that establish a baseline functional level, identi es impairments, and provides targeted interventions that improve a patient's health to reduce the incidence and the severity of current and future impairments" (10). This systematic review focuses on cancer prehabilitation programs that include exercise training as the main component before surgical treatment. Recent data from a Swedish cohort study showed that higher values of walking distance, leg strength, grip strength, gait speed, and inspiratory muscle strength are associated with fewer postoperative complications and shorter length of stay after abdominal cancer resection (11). Prehabilitation programs might also improve lean mass and muscular strength, and delay the incidence of sarcopenia (12).
However, most research in cancer patients has focused on the impact of exercise training interventions during the postoperative period (rehabilitation) (4,13). The period known as rehabilitation might be too late for people over 60 years with cancer, who are considered as a high-risk population because the physical capacity in this population is often diminished due to inactivity especially before surgery. High values of muscular strength and cardiorespiratory tness in cancer patients may make them better prepared for recovery after surgery (13). A recent systematic review conducted by Hamaker and colleagues (14) found relatively small bene ts of prehabilitation programs and therefore questioned the investments that prehabilitation interventions require from both health care providers and patients.
Findings from previous systematic reviews (14,15) have discussed the need for an appraisal of the reporting completeness of the prehabilitation programs in order to facilitate transferability of research ndings, as well as the relevance of grading the quality of the evidence. This systematic review aimed to determine the effects of prehabilitation programs compared with usual care for cancer patients.

Methods
This systematic review was conducted according to the Cochrane Handbook for Systematic Reviews of Interventions (16) and reported in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) declaration (17). The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO registration number: CRD42019125658).

Search methods
We conducted a systematic search according to Chapter 4 of the Cochrane Handbook (16). A research librarian searched Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE in November 2019 (latest update in August 2020). The search strategy used in MEDLINE is available in the protocol (18). No restrictions were applied for publication date or language. In terms of additional sources, one reviewer (JM) searched the following registers for ongoing studies: WHO International Clinical Trials Registry Platform (www.who.int/ictrp/) and ClinicalTrials (https://clinicaltrials.gov/). Two reviewers (JM and ALB) independently reviewed the reference lists from key journals, identi ed articles, meta-analyses, and reviews; scrutinized all promising or potential references; and added appropriate titles to the search output.

Inclusion criteria and study eligibility
We included randomized-controlled trials (RCTs) in participants older than 13 years old, survivors of any type of cancer, de ned according to the Centers for Disease Control and Prevention (CDC), as anyone who has been diagnosed with cancer, from the time of diagnosis through the rest of life (19). We applied no restrictions regarding nationality, ethnicity, gender, duration of illness, or treatment setting. We included prehabilitation programs, in which exercise training was the major component. De nitions are provided in the protocol (18). We accepted for inclusion different training modes, such as aerobic, resistance, and exibility training, as well as yoga, Qi-gong, and Tai-Chi, and carried out in any environment or setting (20). RCTs with usual care or also named sham intervention, usual care, or wait-list controls were included.
In order to provide a more comprehensive and clinically relevant set of outcome measures, three reviewers (ALB, VD, and AE) conducted a scoping search of recent systematic reviews and mapped out the outcome measures explored among them. All team members reviewed and discussed the nal set of outcomes that were included in this systematic review. Further details are presented in the protocol (18). We included the following outcomes: Primary outcomes: Health-related quality of life (HRQoL), muscular strength, and postoperative complications Secondary outcomes: average length of stay (ALOS), handgrip strength, physical activity levels (both light and moderate).
Pairs of reviewers independently evaluated all references for eligibility. The retrieved references were exported to Rayyan (21). In case of discrepancy, we discussed this with the other reviewers and if the resolution had been di cult, we contacted the study authors for clari cation.

Data Extraction and Risk of Bias Assessment
Pairs of reviewers independently used a structured and piloted electronic form to extract information from each study, and assessed the risk of bias by using the using criteria described in the Cochrane Handbook for Systematic Reviews of Interventions (16,21). Further details are provided in the protocol (18).

Completeness of Reporting of exercise training interventions in the prehabilitation programs
We used the CERT tool (Consensus on Exercise Reporting Template) to evaluate the completeness of reporting of exercise training interventions in the prehabilitation programs (23,24). Two independent reviewers (AE and VD) applied the tool to the included studies.

Data synthesis
One reviewer (ALB) entered the extracted data in Review Manager (RevMan), and data were checked by a second reviewer (JM). We calculated risk ratio (RR) and its 95% con dence interval (CI) for binary outcomes, whereas continuous data were expressed as group post-test means and standard deviations (SDs) to calculate effect sizes. We presented effect sizes preferentially in the form of mean difference (MD) and 95% CIs, but when different scales were used to measure the same outcome, we calculated standardized mean difference (SMD) instead. If needed, we used the quantile estimation (QE) method to estimate the sample mean and standard deviation from median, minimum and maximum values, and sample size (25,26) Given heterogeneity across trials, DerSimonian-Laird random-effects models were constructed, as it incorporates an assumption that the different studies are estimating different, yet related, intervention effects (16). We used the I 2 statistic to quantify the proportion of variability attributable to between-study heterogeneity (16); I 2 values were interpreted qualitatively as low (25%-50%), moderate (50%-75%), and high (75%-100%). All studies included in the meta-analysis had comparable baseline characteristics between intervention and control groups.
Considering the high variability in the time points used to report outcome data across studies, we registered all relevant data reported in the studies, and organized them as clinically relevant follow-up periods of before surgery, after surgery or post-intervention, 4 weeks, 8-9 weeks, 12 weeks, and 24-26 weeks post-intervention.

Certainty of the evidence: GRADE approach
We followed the GRADE approach to assess the certainty (or quality) of evidence in six major outcomes (27). The GRADE approach considers the risk of bias and the body of evidence to rate the certainty of the evidence into one of four levels: High certainty: We are very con dent that the true effect lies close to that of the estimate of the effect.
Moderate certainty: We are moderately con dent in the effect estimate-the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: Our con dence in the effect estimate is limited-the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little con dence in the effect estimate-the true effect is likely to be substantially different from the estimate of effect.

Search results
The search resulted in a total of 2917 records. We did not identify any relevant trial registry records. After 315 duplicates were removed, 2602 records remained to be screened. We excluded 2542 records on title and abstract screening. We assessed 61 full-text articles for eligibility and excluded 47 full-text articles. Fourteen studies met the inclusion criteria for this systematic review (see Fig. 1). Additional le 1 presents the list of excluded studies.

Characteristics of the included studies
All RCTs used a parallel two-arm design except for Laurienzo et al (28). The studies included 1044 participants (mean age 71 years, ranging from 46 to 84 years). Publication year varied between 2010 to 2020. Colorectal and lung cancers were the most common diagnoses with 5 studies (36%) each, followed by prostate carcinomas (4 studies, 29%). Most of the studies compared prehabilitation programs against usual care (8 studies, 57%) (28-35), whereas three studies (21%) (36-38) evaluated the comparison with rehabilitation (i.e., a combination of aerobic and resistance training after surgery). Table 1 presents further details on the included studies.
On average, the prehabilitation programs were implemented for 3 weeks (SD 2 weeks, ranging from 1 to 8 weeks), each session had a mean duration of 38 minutes (SD 24 minutes). The mean frequency was 3 sessions per week (SD 1 session).

Completeness of reporting of the exercise training interventions in the prehabilitation programs
The 14 included studies reported 20 exercise training interventions. Completeness of reporting ranged from 5-90% among the CERT items (Fig. 2). 15 out of the 19 CERT items were reported in at least 10 or more interventions. The most reported items were: the setting in which exercise is performed (item 12) with 90%, whether exercises are supervised or unsupervised (item 4) with 85%, the type of exercise equipment (item 1) together with the description of the exercise intervention (item 13) with 80% each, and whether the exercises are generics or tailored (item 14a) with 75%. Apart from the least reported items (item 8, item 11, and item 15) with 5%, 20%, and 10% respectively, the reporting of the remaining items varied between 45% and 70%. Exercise interventions in participants with colorectal cancer had the highest level of reporting relative to those in lung cancers. Combined training was the exercise mode that    (34) ICC (37) TMM (31) 1-week post-intervention: one study (33) 4 weeks post-intervention: ve studies (30,31,(35)(36)(37) 8 weeks post-intervention: one study (38) 9 weeks post-intervention: one study (29) 12 weeks post-intervention: two studies (29,34) 26 weeks post-intervention: one study (41) Average length of stay Administrative data Before surgery: one study (35) 4 weeks post-intervention: three studies (31,35,37) 9 weeks post-intervention: one study (39) 12 weeks post-intervention: one study (34) 26 weeks post-intervention: one study In order to provide a comprehensive overview of the body of evidence in the eld of prehabilitation programs, we mapped out other outcome measures reported in the included studies that were not considered in the current systematic review (Additional le 4).

Effects of prehabilitation programs
We present the effects of interventions per comparison (combined training vs rehabilitation/usual care, HIIT vs usual care, respiratory muscle training plus aerobic training vs usual care, pelvic oor training vs usual care), followed by primary and secondary outcomes. In cases where data could not be pooled, we report the results narratively. Additional le 6 presents the effect estimates reported in the primary studies sorter by comparison and outcome measure. In most cases, a meta-analysis was deemed as inappropriate due to the different follow-up periods, the use of measurement tools that impeded any standardization of the effect estimates, and clinical heterogeneity. These reasons restrict the potential of any overall estimate to be informative. At this point, we underline that readers must interpret effect estimates with caution owing to the very low level of certainty of the evidence (Tables 3-6).  (31,34,35), and one compared with rehabilitation through pelvic oor training (41). Results are summarized below and in Table 3.
Health-related quality of life (HRQoL) Four studies reported data before surgery, which corresponds to our post-intervention estimate (34,37,38,41). Two studies (n = 152 participants with colorectal cancer) (37, 38) provided data for the metaanalysis, which showed evidence of no difference in effect between groups in the physical component Therefore, it is uncertain whether combined training improves HRQoL in the long term because the quality of this evidence is very low (Table 3).

Muscular strength
Two studies found lack of evidence of an effect between groups in elbow strength in participants with lung and prostate cancer before and immediately after the surgery (34,41). Similar ndings were reported at 12-and 26-weeks post-intervention in participants with prostate cancer (41). It is uncertain whether combined training improves muscular strength because the quality of this evidence is very low (Table 3).

Postoperative complications
Pooled data from two studies (136 participants with colorectal and lung cancer) (  intervention (MD -0.59, 95%CI -8.10 to 6.92). Based on this evidence, it is uncertain whether combined training improves light physical activity levels because the quality of this evidence is very low (Table 3).
Therefore, it is uncertain whether combined training improves moderate physical activity levels because the quality of this evidence is very low ( Table 3). *The risk in the intervention group (and its 95% con dence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI:  1 . Downgraded by two levels due to no blinding of personnel and outcome measurement (detection bias), and attrition bias. 2 . Downgraded by one level due to small sample size and wide con dence intervals (imprecision) 3 . Downgraded by two levels due to no blinding of personnel (performance bias), and selective outcome reporting (reporting bias). 4 . Downgraded by one level due to small sample size (imprecision). 5 . Downgraded by one level due to wide con dence intervals (imprecision).
Comparison 2: high-intensity interval training (HIIT) vs usual care Dunne et al. 2016 (29) reported outcome data for this comparison (34 participants with colorectal cancer). We found lack of evidence of an effect between groups in HRQoL and postoperative complications. It is uncertain whether HIIT improves HRQoL or reduces the incidence of postoperative complications because the quality of this evidence is very low (Table 4).  2 . Downgraded by two levels due to small sample size and wide con dence intervals (imprecision). Two studies reported data for this comparison in 161 participants with lung cancer (30,33). Results are summarized below and in Table 5.
Health-related quality of life (HRQoL) Lai et al. (30) found evidence of no difference in effect between groups in HRQoL at 4 weeks postintervention (MD 1.1, 95% CI -1.9 to 4.2). It is uncertain whether respiratory muscle training plus aerobic training improves HRQoL because the quality of this evidence is very low ( Table 5).

Postoperative complications
Lai et al. (30) found evidence of no difference in effect between groups in the incidence of postoperative complications within 30 days after surgery (RR 0.35, 95% CI 0.14 to 0.90). Pehlivan et al. (33) reported similar ndings (RR 0.2, 95% CI 0.02 to 1.6). The studies did not report the tool used to measure outcome data. It is uncertain whether respiratory muscle training plus aerobic training reduces the incidence of postoperative complications because the quality of this evidence is very low ( Table 5).

Average length of stay (ALOS)
Pehlivan et al. (33) reported evidence of no difference in effect between groups in ALOS at one week after surgery (MD -4.2 days, 95%CI -5.7 to -2.7). It is uncertain whether respiratory muscle training plus aerobic training reduces ALOS because the quality of this evidence is very low ( Table 5). *The risk in the intervention group (and its 95% con dence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Con dence interval; HRQoL: Health-related quality of life; MD: Mean Difference; RR: Risk ratio ** EORTC QLQ-C30: higher scores indicate better functioning (scaled from 0 to 100) *** Administrative data: higher number of days indicate worse outcome 1 . Downgraded by one level due to no blinding of personnel (performance bias) 2 . Downgraded by two levels due to small sample size and wide con dence intervals (imprecision). 3 . Downgraded by one level due to allocation concealment, no blinding of personnel (performance bias) Three studies provided outcome data for HRQoL in participants with prostate cancer (28,32,40). None of the studies reported evidence of an effect in this outcome between groups across the follow-up periods. Centemero et al. (40) and Laurienzo et al. (28) found evidence of no effect in HRQoL at 4 weeks postintervention. Ocampo-Trujillo et al. (32) observed similar ndings at 8 weeks post-intervention. Finally, Centemero et al. (40) and Laurienzo et al. (28) con rmed these ndings up to 24 weeks post-intervention. It is uncertain whether pelvic oor training improves HRQoL because the quality of this evidence is very low (Table 6). Data from 8 studies suggested that prehabilitation programs of combined training compared to rehabilitation or usual care confer little to no effect on HRQoL, muscular strength, postoperative complications, ALOS, handgrip strength, or physical activity levels. One small study (29) evaluated the effects of HIIT into a prehabilitation program but found no evidence of an effect in HRQoL or postoperative complications. This lack of evidence of an effect in those outcomes was also observed for prehabilitation programs of respiratory muscle training plus aerobic training. Finally, three studies provided evidence of no difference between prehabilitation programs of pelvic oor training and usual care in HRQoL.

Overall completeness and applicability
The knowledge base of this systematic review applies mostly to participants aged 60 to 70, with colorectal, prostate, and lung cancer. Data about sex and ethnic characteristics were scarce across studies. Besides, the studies failed to provide information about key aspects of the prehabilitation programs implementation, such as rules for starting level and program progression. This represents a barrier to the applicability of our ndings to a particular context.
To date, the 14 studies included in this systematic review are not su cient to fully address our main objective. However, we believe that the 8 studies that compared combined training to rehabilitation or usual care offer a consistent evidence base of the lack of effect for this comparison. Conversely, few unpowered studies provide no clear evidence for the remaining comparisons. Hence, it is likely that new well-conducted studies would substantially change our ndings.

Certainty of the evidence
The included studies evaluated different modes of prehabilitation programs, where combined training (i.e., aerobic and resistance training) was the main comparison. We found incomplete information for characteristics of the participants, implementation of the prehabilitation programs, and weak reporting of outcome data in some studies.
Very low-quality evidence formed all the comparisons in this systematic review. Our certainty in the evidence was downgraded due to limitations in the risk of bias assessment, including lack of both allocation concealment and blinding of participants and providers, and uncertainty regarding selective reporting. The lack of blinding of both participants and providers can lead to an overestimation of the effect estimate (42,43) Blinding participants in exercise training trials is not easy (44), and it is likely that participants who are aware of their intervention may differ from blinded participants in how they report outcomes or on their performance in the study (45). These aspects gain relevance in the context of this systematic review due to the large number of self-reported outcomes across studies.
Furthermore, most of the studies had low numbers of participants, wide con dence intervals, and high heterogeneity in the effects across them. Undertaking a sensitivity analysis to explore these limitations was not appropriate due to the low number of studies, which could bias any effect estimate.
Potential biases in the review process The strengths of this systematic review were the prioritization process undertaken to de ne clinically relevant outcome measures, the use of systematic methods to assess both the completeness of reporting of the exercise training interventions within the prehabilitation programs, and the certainty or quality of the evidence. The integration of these processes enhances the use of this study in evidence-informed decision-making scenarios. Regarding the limitations in the review process, we believe that the comparisons in this review may be biased due to the incomplete reporting of intervention-related domains across the studies. We contacted the authors for further details, but the response rate was low. In order to tackle this limitation, we searched clinical trial registries to detect unpublished trials.
Agreements and disagreements with other reviews Several systematic reviews have addressed the effects of prehabilitation programs for cancer patients in different outcome measures (46-58). The methods used in those reviews varied considerably, and so did their ndings. Our ndings of very low-quality evidence about the effects of prehabilitation programs for HRQoL align with those reported by seven systematic reviews published recently (47, 49, 54-56, 59, 60 The discrepancies between our ndings and those of other systematic reviews are explained by several factors, such as differences in both baseline characteristics of the participants and program implementation. Besides, the lack of an assessment of the quality of the evidence has an impact on the review ndings, and the use of different approaches to conducting this assessment in uences authors' judgments about the body of evidence (63) Of note, the restriction of exercise training as the main component of the prehabilitation programs in our review did not explain the discrepancies with other systematic reviews, since our ndings are similar to those reported by reviews that included prehabilitation programs of both exercise training plus dietary counseling (61, 62, 64).

Implications for practice and further research
Findings from this systematic review highlight the need for further well-conducted RCTs to better inform recommendations pertaining to prehabilitation programs for cancer patients. The scope of our ndings to provide insight in a decision-making context is constrained because the quality of the evidence about the bene ts and harms of prehabilitation programs is very low. There is a lack of safety data, and the use of heterogeneous tools for outcome measurement poses additional limitations to this body of evidence. In order to strengthen the quality of the evidence, further studies may bene t from addressing the gaps identi ed in our assessment of the reporting level of the prehabilitation programs, and should adhere to reporting checklists, such as CONSORT and CERT.

Conclusion
We are uncertain of the bene ts and harms of prehabilitation programs compared with usual care for cancer patients. Further well-conducted randomized controlled trials are still required to test the role of exercise training as the main component of prehabilitation programs to improve patients' outcomes. We assessed the certainty of the body of evidence as very low, downgraded due to serious study limitations, imprecision and indirectness. We have very little con dence in the results and the true effect is likely to be substantially different from these. Further research is needed before we could draw a more certain conclusion.