High‐intensity exercise to improve cardiorespiratory fitness in cancer patients and survivors: A systematic review and meta‐analysis

Improving cardiorespiratory fitness (CRFit) in cancer patients is crucial to increase survivorship, promote health, and improve quality of life. High‐intensity training (HIT) has the potential to increase CRFit, perhaps better than other exercise modalities, but the extant evidence has yet to be fully explored. This systematic review and meta‐analysis aimed to evaluate the effects of HIT on CRFit in cancer patients and survivors and to identify the optimal characteristics of the interventions (eg, cancer type, intervention timing, exercise modality, intervention's duration, and the number of minutes of high‐intensity exercise in each session). The Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines were followed. A total of 31 articles (2515 participants) were included in the systematic review and 25 in the meta‐analyses. CRFit significantly improved with HIT in comparison with a control group (P < .00001, SMD = 0.44 and a 95% confidence interval from 0.25 to 0.64). The results obtained in the sub‐analysis were statistically significant except the comparison with the active group CRFit (P = .13). The results showed that higher effects could be achieved in: patients starting to exercise before treatment, interventions longer than eight weeks, programs including exclusively cardiovascular training and with a high‐intensity part of session duration of at least 20 minutes.

Improving cardiorespiratory fitness (CRFit) in cancer patients is crucial to increase survivorship, promote health, and improve quality of life. High-intensity training (HIT) has the potential to increase CRFit, perhaps better than other exercise modalities, but the extant evidence has yet to be fully explored. This systematic review and meta-analysis aimed to evaluate the effects of HIT on CRFit in cancer patients and survivors and to identify the optimal characteristics of the interventions (eg, cancer type, intervention timing, exercise modality, intervention's duration, and the number of minutes of high-intensity exercise in each session). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. A total of 31 articles (2515 participants) were included in the systematic review and 25 in the meta-analyses. CRFit significantly improved with HIT in comparison with a control group (P < .00001, SMD = 0.44 and a 95% confidence interval from 0.25 to 0.64). The results obtained in the sub-analysis were statistically significant except the comparison with the active group CRFit (P = .13). The results showed that higher effects could be achieved in: patients starting to exercise before treatment, interventions longer than eight weeks, programs including exclusively cardiovascular training and with a high-intensity part of session duration of at least 20 minutes.
stage of the cancer pathway remain unclear. 27 The consensus of exercise to cancer patients suggests; moderate-to-high intensity aerobic exercise, resistance exercise or a combination of both conduct on a frequency of 2-3 sessions per week for between 8 and 12 weeks. 27 While most cancer-related exercise interventions have been limited to low-intensity 28 and/ or moderate-intensity exercise, 29 evidence is emerging from randomized controlled trials (RTC) to suggest that health outcomes are as good if not better from higher intensity exercise protocols in adult cancer survivors. 30,31 High-intensity training (HIT) can induce greater improvements in CRFit than moderate continuous aerobic exercise in patients with heart failure 32 or stroke. 33 In cancer patients, different RTC of HIT have demonstrated improved CRFit in comparison with controls 34,35 or moderate-intensity exercise. 36 The optimal characteristics of high-intensity exercise are still unknown, and some examples of non-successful (in terms of CRFit) interventions can be read. 37,38 Therefore, an in-depth evaluation of the evidence for HIT and CRFit in cancer patients is needed. Beyond CRFit, exercise produces changes in the tumor microenvironment and lactate concentration. Thus with higher intensities, these changes could be greater and affect different health outcomes. 39 To our knowledge, two previous systematic reviews have explored the effect of high-intensity exercise on CRFit in patients with cancer. Firstly, Toohey et al 40 conducted a systematic review without meta-analysis of nine articles showing evidence of larger CRFit improvements after high-intensity exercise and suggesting that a multi-modal (combined cardiovascular and resistance exercises) program performed three times a week increases VO 2max (+21.35%). Secondly, Mugele et al conducted a review and meta-analysis 41 exploring the effects of high-intensity interval training (HIIT) on the CRFit of cancer patients and survivors, without considering resistance components and high-intensity continuous exercise. The study concluded that aerobic HIIT leads to positive outcomes compared to controls (including five studies) while the differences compared to moderate intensity are unclear (including four articles). The authors of the two reviews 40,41 concluded that the optimal characteristics of a high-intensity intervention (including duration, volume, exercise type, type of cancer, and timing) were unclear and therefore required further research.
With this in mind, the present systematic review and meta-analysis aimed to evaluate the effects of any type of HIT on CRFit in cancer patients and survivors. Furthermore, we also aimed to identify the optimal characteristics of HIT interventions by analyzing effects according to; cancer type, intervention timing (pre-treatment during treatment, and post-treatment), exercise modality (with or without resistance training), the length of the intervention (number of weeks) and the duration of the high-intensity exercise in each session (number of minutes).

| METHODS
The systematic review followed the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. 42 It was registered in the International prospective register of systematic reviews (PROSPERO) with the identification number CRD42020167203. A change from the registered protocol is that the results reported here are only based on CRFit. Given the large number of analyses and figures included in the current manuscript, it was not possible to also include the analysis of overall quality of life and its dimensions.

| Data sources and searches
Searches were conducted using scientific databases: PubMed (MEDLINE) and Web of Sciences (including KCI-Korean Journal Database, MEDLINE, Russian Science Citation Index, and SciELO Citation Index). The search terms used were "cancer", "neoplasm", HIIT, "high intensity", "VO2", "aerobic capacity", "oxygen consumption", "oxygen uptake", "cardiorespiratory fitness", "physical fitness", "aerobic fitness" separated by the operators AND and OR. The following restrictions were added (a) articles published in English or Spanish, (b) published in the last 10 years and (c) not having the word "ultrasound" in the title (due to the misunderstanding | 267 with high-intensity focused ultrasound therapy). The search started in November 2019 and ended in February 2020.
The articles were incorporated if they fulfilled the following inclusion criteria: (a) participants had any kind of cancer, (b) the intervention included a HIT component, (c) the article reported effects on VO 2peak , and (d) the design included one or more comparison group/s. RCT and non-RCT were included. The following exclusion criteria were set: (a) The article was not written in English or Spanish, (b) the article was a consensus, guideline, letter to editor, conference abstract, case report, and/or a study protocol or design, and (c) the article was focused on childhood cancer. The term high intensity is defined herein to be any exercise program whose authors have described to have any "high-intensity" component including aerobic and anaerobic high-intensity components as well as resistance. Cardiovascular training is defined as any aerobic, anaerobic exercise (or a combination of both) focused on the improvement of the cardiovascular function such as cycling or exercise on a treadmill. The article selection was undertaken by the lead author (AMLP) and revised by the second researcher (DCM). There was no disagreement in the selection process.

| Risk of bias assessment
PEDro scale was used to evaluate the risk of bias. PEDro is specific in physical therapies, commonly adopted in sport sciences 43 and is considered a valid and reliable tool to assess eligibility, allocation to groups, blinding of allocation, and comparison between groups at baseline and its outcomes. 44

| Data extraction
Following PRISMA methodology, participants, intervention, comparisons, results, and study design (PICOS) were obtained. Regarding participants, some baseline parameters were extracted, such as sample size, mean age, body mass index, physical activity level, cancer type, stage, type of treatment, and timing. Intervention characteristics included FITT principle (frequency, intensity, time, and type) together with the exercise description, intensity, progression of the exercise program, and adherence to the intervention (% attendance to the prescribed number of sessions). The activity of the comparison group(s) was also extracted. Furthermore, the outcome of the current systematic review and meta-analysis was CRFit. In this regard, VO 2peak values measured during the maximal or submaximal tests could be expressed in different units: mL/min or mL/min/kg. Regardless of the units shown, articles were included in the meta-analysis whenever it was possible. Detailed information of those articles which did not report sufficient data to be included in the meta-analyses is reported in the Supplementary data (Tables S2 and S3).
Finally, the study design was also reported since RCT and non-RCT were included. Data extraction was performed by the lead author (AMLP) and then checked by another author (DCM).

| Statistical analysis
Post-intervention means and standard deviations were extracted from the manuscript or supplemental data or calculated using reported data from high-intensity exercise group (HIEG) and the comparison group, which could be an inactive control group (CG) or a low-to-moderate intensity exercise group (LMEG).
All analyses were performed using the Review Manager Software (RevMan, 5.3). 45 The analysis method used was the inverse variance and random effects due to the heterogeneity of articles. 46 The standardized mean difference (SMD) was employed when there were different units of VO 2peak (mL/ min/kg or mL/min) whereas mean difference (MD) was used for the same VO 2peak values (mL/min/kg). SMD was interpreted according to the Cochrane Handbook of Systematic Reviews. 47 The results obtained were represented with a confidence interval (CI) of 95%. The I2 statistic model calculated heterogeneity, and Z test was used for the overall effect.
To analyze the effectiveness of the interventions on CRF, the following group comparisons were performed: (1) according to the comparison group, HIEG compared to CG and HIEG compared to LMEG; (2) according to the type of cancer, HIEG vs an inactive CG in breast cancer patients and high-intensity interventions vs an inactive CG in lung patients (types of cancer with five or more articles were included); (3) according to the timing of the intervention, high-intensity interventions compare to an inactive CG before chemotherapy, high-intensity interventions compared to an inactive CG during chemotherapy and high-intensity interventions compare to an inactive CG after chemotherapy; (4) according to the type of exercise intervention, different subgroups were compared, relating in all of them the CRF outcome of the HIEG compared to an inactive CG including: (a) interventions of 8 or less weeks of duration and programs longer than 8 weeks; (b) interventions including a resistance component and cardiovascular only; (c) interventions involving sessions with a high-intensity duration of <20 minutes and independently with a duration of 20 minutes or more.

| Study selection
A total of 214 total studies were identified in PubMed (98 studies) and Web of Science (116), and another three articles were recovered from a previous HIIT meta-analysis. 41 The flow diagram, in Figure 1, describes the process by which studies were included or excluded. Seventy-six studies were then excluded in the first screening and 27 in the full-text analysis. In total, 31 studies were included in the systematic review, 25 of which were incorporated in the meta-analysis. Table 1 shows the internal and external validity of the articles included in the systematic review measured by the PEDro scale. The mean score of all the studies was 6.27 (range 3-8) on a scale from 0 to 10, with 10 being the highest score. The items related to blinding criteria were not commonly met. This  is common in sport sciences since participants know at what intensity they have to exercise. Furthermore, therapists require exhaustive information of each participants need and undertake exercise training according to strict the intervention protocols.

| Participants characteristics
Participants' baseline characteristics of the studies included in the meta-analysis are shown in Table 2 and Table S1.
Information on the remaining articles can be found in the Supplementary data (Table S2). The total sample size of all included studies was 2515 participants, 1115 from the CG, 1104 in the HIEG, and 296 belonging LMEG. The mean age of the participants was 51.8 years (24-72), 51.0 in the CG, 51.6 in the HIEG, and 55.7 in the other active group. There were 22 different cancer types included in the sample. Articles involved breast cancer (n = 10), lung cancer (n = 6), colorectal cancer (n = 4), prostate cancer (n = 2), and testicular cancer (n = 1). Eight studies reported sample

| Cardiorespiratory fitness measures
The assessment of CRFit was mostly conducted using maximal or submaximal incremental test with a gas analysis to assess VO 2peak (in mL/kg / min or mL/min  38 Treadmill assessments increment the incline 2% every 2 minutes, 70 or increased velocity and incline at the same time. 30 Some interventions used field test to estimate CRFit such as the 6MWT (Six-Minute-Walking-Test) 31 and Rockport Walk Test. 68

| Overall results
Meta-analysis outcomes reported the effects of the studies reporting enough information to conduct the calculations. However, the results of those interventions that do not report enough data were reported in the Supplementary data (Table S3). The results in Figure 2 show that, in contrast to inactive CG (ie, usual care or waitlist group), the enhancement F I G U R E 2 Effects in cardiorespiratory fitness of the comparisons between high-intensity group and control group, and high-intensity group and moderate-intensity group of the VO 2peak in the HIEG was higher (P < .00001, with a SMD of 0.44 and a 95% CI from 0.25 to 0.64), which is considered a "moderate" effect. 47 In comparison with an active group (low to moderate or moderate-intensity exercise), however, the results were not different (P = .13; SMD = 0.20 with 95% CI from −0.06 to 0.47).

| High-intensity exercise for cancer types
As Figure 3 reports, the effects of HIT with respect to cancer type were evaluated by separately analyzing the results in those two cancer types with 5 or more studies, breast and lung. In breast cancer, patients and survivors achieved a significant improvement (P < .00001; MD = 3.30 mL/min/ kg and a 95% CI from 2.40 to 4.19 mL/min/kg) compared with the inactive CG. Furthermore, patients with lung cancer showed a significant improvement (P = .04; MD = 2.09 mL/ min/kg and a 95% CI from 0.13 to 4.04 mL/min/kg) compared to the inactive CG.

| Timing of the intervention
We also compared three different time periods (Figure 4; before, during, and after the treatments) according to the medical therapy (chemotherapy, radiotherapy, hormonotherapy, immunotherapy, and/or surgery). There was a statistically significant improvement in each of the three phases. The largest effects were observed for interventions that occurred before treatment (P = .01; SMD = 0.76 with 95% CI from 0.15 to 1.38). The P-value for during and after treatment was .005 and .03, respectively, with a SMD slightly lower during the chemotherapy (SMD = 0.35, 95% CI from 0.11 to 0.60) compared to after chemotherapy (SMD = 0.45 and 95% CI from 0.03 to 0.87).

| Exercise prescription
High-intensity protocols with or without resistance training component showed a significant improvement in VO 2peak ( Figure 5). Based on the SMD, the only cardiovascular training interventions had more of an effect on CRFit (P = .001; SMD = 0.63 with 95% CI from 0.25 to 1.69) than combined cardiovascular-resistance programs (P < .0001; SMD = 0.32 with 95% CI from 0.17 to 0.48). In this regard, the only cardiovascular training programs achieved a moderate effect according to the SMD, while those programs including resistance training showed a small effect. Moreover, regarding the duration of the exercise programs ( Figure 6), interventions of 8 weeks or less had a significantly smaller effect on VO 2peak (P = .02; SMD = 0.32 with 95% CI from 0.06 to 0.58), compared to the moderate effect reported for programs lasting longer than 8 weeks (P < .00001;

| DISCUSSION
This systematic review and meta-analysis aimed to evaluate the effects of HIT on the CRFit of cancer patients and survivors. In addition, the study also aimed to identify the most effective high-intensity dose to achieve the greatest improvement in CRFit outcomes. Data showed that HIT significantly improves VO 2peak compared to an inactive control group, but there was difference in effect compared to moderate-intensity exercise. Regarding the most effective characteristics of exercise programs (Figure 8), HIT showed significant improvements in all phases of cancer treatment. The largest effect was seen in those interventions conducted before cancer treatment. A small effect was observed in interventions delivered during treatment, and a moderate effect in interventions after treatment. HIT interventions that were longer in duration than eight weeks were of at least 20 minutes, and included cardiovascular training component, were most effective in promoting improvements in CRFit. The largest VO 2peak improvement was reported in studies that focused on cardiovascular exercise modes, including cycling or running.
The assessment of CRFit is valuable in almost all health areas given the evidence based between low levels of VO 2peak and high risk of cardiovascular disease or mortality, 73 in addition to the association with mortality rates attributable to cancer. 74 Specifically, the American Heart Association showed that low CRFit level (<5 METs) in adults is linked F I G U R E 4 Effects of high-intensity exercise in cardiorespiratory fitness according to the treatment timing to high risk for mortality, while higher CRFit levels (>8 to 10 METs) considerably reduce the risks. 75 Three of the included articles involved patients with baseline VO 2peak < 5 METs, 49,50,65 which suggests a high risk of mortality. In this regard, the highest SMD among all studies was observed in one of these three studies. 65 Therefore, the current meta-analysis demonstrates that high-intensity exercise can improve CRFit in cancer patients particularly when patients have low baseline levels which thereby produces the greatest public health benefit. This affirmation is highly relevant regarding that the association between physical activity and mortality is even larger among people with lower CRFit levels than those in the higher values as it proved a study with 498 135 biobank participants. 76 A previous review by Mugele et al 41 found that HIT did not achieve higher benefits in CRFit than moderate-intensity training, which is confirmed here with a larger sample. However, exercising at high intensities provides a higher glycolytic metabolism, 77 inducing a decrease of intratumoral lactate concentration. 78 This physiological process is highly important due to exercise lactate reverts intratumoral lactate gradient inhibiting the production after exercise and decreasing its tumoral concentration according to the Warburg effect. 79 Consequently, inside the microenvironment, blood flow and 0 2 increases, as well as the blood perfusion, leading to a reduction in the hypoxia. 79 Moreover, HIT moderate the overexpression of reactive oxygen species limiting the tumor growth and inflammation. 80 This meta-analysis showed that breast and lung cancer patients could benefit from HIT. This finding was also observed in previous literature reviews, including all types of intensity interventions in breast 20,81 and lung cancers. 82 Our results show, however, that the timing of the HIT according to the different phases of cancer treatments may be an important variable to consider. To our knowledge, this has not been investigated by previous reviews, with these results showing that the largest effects on CRFit are produced before the initiation of cancer treatment. This enhancement in prehabilitation is crucial as it could potentially improve the response to chemotherapy and prognosis 83 positively influence future cancer complication by infertility the tumoral microenvironment, 84 and reduce inflammation by decreasing potential overweight or obesity. 85 During treatment, improvements in CRFit have a smaller effect, which may be in part due to the negative effects of the treatment itself 8,86 (eg, the cardiotoxicity and heart damage) caused by cancer-treating drugs. 13
After therapy, the aim is to increase CRFit, where possible beyond baseline and to avoid its decline even several years after 87 and to avoid the development of cardiovascular risk factors. 88 However, not all cancer treatments are so likely to decline CRFit, but exercise may still play an important role due to it stimulates the upregulation of immune cells pathways (specially natural killers) associated with a reduction in tumor growth and better cancer prognosis and response to immunotherapy. 89 To our knowledge, this is the first meta-analysis to evaluate the effects of HIT on CRFit that includes resistance training. Our results showed that HIT including resistance training achieved smaller improvements in CRFit. It is important to note that resistance training based interventions as they enhance muscle function and send signs to positively modify the mentioned cancer microenvironment. 84 Furthermore, other benefits of resistance training include the avoidance of sarcopenia, 90,91 preventing the loss of muscle mass and muscle functionality caused by chemotherapy 92,93 ; the reduction of myomatosis and chronic inflammation 94 ; the decrease in free oxidative radicals and oxidative stress 95 ; or the reduction of cardiovascular disease mortality 96 and all-cause of deaths. 97 However, the difference could be explained because of cardiovascular training interventions having higher adherence rates than interventions with resistance components. Future research may need to focus on strategies to enhance adherence in interventions with resistance components which might result in more substantial benefits.
High-intensity training interventions lasting more than eight weeks had a stronger effect in comparison with shorter programs that achieved small effects. In this regard, Toohey et al suggested that high-intensity programs must last at least four weeks in cancer survivors. 40 The number of studies included in this meta-analysis that involved programs of four or fewer weeks was not enough to reach the same conclusion. Regarding HIT components, the concrete high-intensity session duration (including movement and rest) was studied, and results revealed that sessions with a high-intensity part of 20 minutes or more could lead to slightly better results than shorter ones.
The current systematic review and meta-analysis has limitations. Firstly, the included articles had to be written in English or Spanish and indexed in PubMed or Web of Sciences (which includes all journals indexed in the Journal of Citation Reports), so eligible studies may have been omitted. Secondly, the information reported in some of the articles was not enough to be included in the meta-analysis or the subgroup analyses. Thirdly, the number of studies did not allow to compute a meta-analysis in other cancer types and to make subgroups for each cancer type. Finally, it must be noted that the HIT optimal program characteristics were obtained including both cancer patients and survivors mixed in the meta-analyses, which could influence the results.

| Perspective
Given that CRFit is associated with cancer patients' survivorship, health, and quality of life, the identification of the most beneficial physical exercise intervention is of great interest. This meta-analysis, in contrast to the previous reviews, 40,41 went further by offering details about the specific characteristics of exercise programs to achieve the larger CRFit improvements. The present recommendations (ie, training before cancer treatment with programs of more than 8 weeks and with a HIT part of at least 20 minutes), based on the existing scientific evidence, can also help healthcare and physical exercise professionals to prescribe adequate high-intensity exercises for cancer patients. Future studies may focus on the evaluation of the exercise dose-response depending on the type of cancer and the treatment received, as well as to better explore the differences between HIT and moderate-intensity exercise.

| CONCLUSIONS
High-intensity training leads to positive effects on CRFit in cancer patients and survivors. The Research showed that high-intensity exercise had greater effects in patients initiating exercise before treatment. Although high-intensity exercise had positive but smaller effects during and after treatment, HIT exercise programs should last more than 8 weeks and include at least 20 minutes of high-intensity activity. Although the results showed that the CRFit effects of adding resistance training to HIT might be limited, it is still recommended for the many other health benefits. Further research is needed to provide additional conclusions about the optimal characteristics of high-intensity exercise programs in each specific cancer type.