Exploration of High-Intensity Interval Training for Breast Cancer Survivors: Taking a Home-based Approach Toward New Normal

Background To review the methods and outcomes of high-intensity interval training (HIIT) interventions for breast cancer survivors, and to explore the feasibility of prescribing exercise for breast cancer survivors. Methods A systematic search of electronic databases was conducted for studies published up to May 31, 2020. Eligibility criteria included randomized controlled trials of HIIT intervention in breast cancer survivors. Studies were grouped by whether the intervention was conducted during or after breast cancer treatment, and intervention methods and outcomes were reviewed within each group. Results Twenty-six studies were identied, and 13 satised the inclusion criteria. Intervention was conducted during treatment in 8 studies, and after treatment in 5. Intervention duration ranged from 3 to 16 weeks, with 2 or 3 sessions per week, for a total of 9 to 36 sessions. All interventions were supervised; 12 were lab-based, and 1 was community-based. One of most promising outcomes was improvement of cardiorespiratory tness by HIIT. This found that most studies on HIIT for breast cancer investigated lab-based, supervised interventions. HIIT is a time-ecient for increasing cardiovascular function in but further


Abstract Background
To review the methods and outcomes of high-intensity interval training (HIIT) interventions for breast cancer survivors, and to explore the feasibility of prescribing exercise for breast cancer survivors.

Methods
A systematic search of electronic databases was conducted for studies published up to May 31, 2020. Eligibility criteria included randomized controlled trials of HIIT intervention in breast cancer survivors. Studies were grouped by whether the intervention was conducted during or after breast cancer treatment, and intervention methods and outcomes were reviewed within each group.

Results
Twenty-six studies were identi ed, and 13 satis ed the inclusion criteria. Intervention was conducted during treatment in 8 studies, and after treatment in 5. Intervention duration ranged from 3 to 16 weeks, with 2 or 3 sessions per week, for a total of 9 to 36 sessions. All interventions were supervised; 12 were lab-based, and 1 was community-based. One of most promising outcomes was improvement of cardiorespiratory tness by HIIT.

Conclusion
This review found that most studies on HIIT for breast cancer survivors investigated lab-based, supervised interventions. HIIT is a time-e cient method for increasing cardiovascular function in breast cancer survivors, but further research is necessary to determine its effects on other outcomes.

Implications For Cancer Survivors
HIIT is an effective exercise method for increasing physical tness in breast cancer survivors, but there is currently no evidence of bene t from home-based HIIT. Con rmatory studies on the effects of home-based exercise programs might be required to promote the dissemination and implementation of HIIT.

Background
The strong association between physical activity and all-cause mortality risk in breast cancer survivors [1] has led experts to recommend that breast cancer survivors engage in physical activity and exercise [2] and prompted researchers to investigate exercise interventions for this population. Combination of aerobic training and resistance training is considered particularly effective [2].
High-intensity interval training (HIIT) interventions have recently been proposed as a promising method for quickly improving tness. HIIT consists of repeated sets of short bursts of high-intensity exercise followed by a rest interval, and has been shown improve tness in both athletes and the general population [3,4]. In recent years, research on the suitability of HIIT for cancer survivors has emerged as well. Systematic reviews and metaanalyses of HIIT for cardiorespiratory tness in cancer survivors have already shown HIIT to have some degree of effectiveness [5,6]. Research on HIIT for breast cancer survivors was rst published around 2016, but no review article focusing exclusively on breast cancer survivors has been published to date. Therefore, this review of HIIT interventions in breast cancer survivors was conducted with a focus on intervention methods and timing. The speci c characteristics of interest were (1) timing (during or after treatment), (2) supervision (supervised or unsupervised), and (3) setting (lab-based, community-based, or home-based). In addition, in light of concerns that sheltering in place during the novel coronavirus (SARS-CoV-2) pandemic of 2020 will lead to inadequate physical activity and consequently increased risk of cardiovascular disease worldwide [7], this review will also explore the current landscape and future possibilities of home-based, unsupervised exercise interventions.

Methods
The PRISMA checklist was used for this review [8] All studies with keywords related to HIIT interventions for breast cancer survivors were included.

Inclusion criteria
Inclusion criteria were studies published in English and Japanese (only those with full text available) that included HIIT in the intervention and were conducted in breast cancer survivors. HIIT was de ned as exercise consisting of multiple repetitions of short bursts (≤4 min) of high-intensity (≥90% of maximal oxygen uptake [VO 2 max], peak oxygen uptake [VO 2 peak] or maximum heart rate [HRmax], or rating of perceived exertion [RPE] ≥ 18) aerobic exercise (e.g., running or cycling) alternated with low-intensity exercise or passive rest. Studies of interventions that combined HIIT with resistance training or aerobic training were also included in the review. When multiple datasets were available from the same research group or follow-up data were available for the same cohort of participants, the earliest published dataset was used.

Study selection and data extraction
Irrelevant articles were excluded from the review by screening the titles and abstracts displayed in the search results. Next, methods of intervention (exercise duration/frequency, exercise intensity, mode of exercise, HIIT intervals, and intervention setting) and outcomes (cardiorespiratory tness, muscle strength, indicators of cardiotoxicity/cardiovascular function, health-related quality of life [HRQOL], fatigue, related biomarkers, adverse events, and compliance) were determined by reviewing the full text. The full text was reviewed by two of the authors (KT and EO). These outcomes were selected to investigate the effects of HIIT on physical function as the primary outcome of interest, as well as the effects of HIIT on areas of clinical concern for breast cancer survivors (HRQOL, fatigue, and cardiotoxicity/cardiovascular function) and safety of and compliance with HIIT among breast cancer survivors.

Search outcome
A total of 93 search results were obtained from the four databases, but 26 were duplicates and were therefore excluded. After screening, 9 studies were excluded from the review based on their title and abstract, and 2 more studies were excluded because they were follow-up studies of the same cohort. After the full text of the remaining studies was carefully reviewed, an additional 2 studies were excluded for not meeting the exercise intensity criteria described in the Methods section. Finally, a total of 13 studies satis ed the inclusion criteria (Fig. 1).
Tables 1 and 2 summarize the studies included in the review. Table 1 lists interventions conducted during breast cancer treatment, and Table 2 lists interventions conducted after initial cancer treatment. Each table lists the authors, sample size, a summary of the HIIT program, outcomes, whether the intervention was supervised or unsupervised, and the intervention setting (lab-based, community-based, or home-based) for each study. Summaries of the HIIT programs include the duration of training, frequency, mode of exercise, intensity, and intervals.

Exercise supervision
No studies of unsupervised HIIT have been conducted to date, and thus all the studies in this review investigated supervised interventions. Three of the 13 studies did not specify who supervised the intervention. In those that did specify, the supervisor was an exercise trainer [9][10][11][12], an exercise physiologist [13][14][15][16][17][18], or an oncology nurse [13][14][15][16]. In Mijwel et al., the intervention was supervised by an exercise physiologist or oncology nurse. In Schulz et al., the intervention was supervised by a professional, but no further details were provided [19]. twice weekly for 6 weeks [19]. For HIIT, participants performed 3 sets consisting of 3 min of exercise on a cycle ergometer at an intensity of 85% to 100% VO 2 max followed by 1 min of active rest. For resistance training, they performed 8 to 12 repetitions of resistance training exercises for major muscle groups at 60% to 80% 1RM.

Lab-based HIIT or community-based HIIT
In the group of studies involving interventions after initial breast cancer treatment, Alizadeh AM et al. incrementally increasing exercise intensity over the intervention period in 3 weekly sessions for 6 weeks. The intervention started with 4 to 6 sets of 4-min running at 65% VO 2 max at 3-min intervals (50% VO 2 peak), but the intensity was increased to 90% VO 2 peak at the 13th session in Week 5, and ultimately to 4 to 6 sets of 2-min running at 95% VO 2 peak at 2-min intervals (< 60% VO 2 peak) in the nal week (Week 6) [22].

Outcomes
Studies were also grouped by outcomes (cardiorespiratory tness, muscle strength, indicators of cardiotoxicity/cardiovascular function, HRQOL, fatigue, related biomarkers, adverse events, and compliance). Six studies evaluated cardiorespiratory tness, all using VO 2 peak. Three studies evaluated muscle strength, 2 using 1RM and 1 using maximum isometric contraction. One study evaluated cardiovascular function, and used endothelial function in terms of brachial artery ow mediated dilation (baFMD) and carotid intima-media thickness (cIMT) as an indicator. One study evaluated HRQOL, and used the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) [13]. Two studies evaluated fatigue, one using the 22-item Piper Fatigue Scale (PFS) [13] and 1 using the Multidimensional Fatigue Inventory (MFI) [20].
Twelve studies evaluated HIIT compliance. The compliance rates in each study were as follows. Lee  consuming, that gym memberships and exercise classes are expensive, and that access to exercise facilities may depend on where they live. In fact, the top responses in a survey that asked breast cancer survivors about barriers to exercising were lack of time and lack of access to facilities [23]. Therefore, home-based HIIT programs for breast cancer survivors will be necessary to overcome these barriers. In the following sections, individual aspects of the reviewed studies are discussed.

Exercise supervision
In all past studies of interventions during breast cancer treatment, the intervention was supervised by an exercise professionals or oncology nurse. In all past studies of interventions after breast cancer treatment, the intervention was also supervised by an exercise professionals. Since the rst study of HIIT intervention after breast cancer treatment was conducted in 2016 [22], and thus only its feasibility and e cacy such as cardiorespiratory tness have been investigated to date. A study comparing supervised and unsupervised HIIT interventions in healthy adults [24] showed that supervised interventions produced greater improvements in cardiorespiratory tness, but unsupervised interventions still produced signi cant improvements. Another study of unsupervised HIIT in which participants exercised alone also showed improvements in cardiorespiratory tness [25].

Lab-based HIIT or community-based HIIT
All past studies of interventions during breast cancer treatment were lab-based. Possible reasons for this include that the purpose of these studies was to evaluate safety or feasibility, and that exercise intensity was exactly de ned to validate the e cacy of HIIT. Nearly all past studies of interventions after breast cancer treatment were also lab-based. Similarly, possible reasons for this include that the purpose of these studies was to evaluate feasibility, and that exercise intensity was precisely de ned to validate the e cacy of HIIT. Only 1 study was community-based. Unlike in the lab-based studies, the intervention in this study required no exercise equipment and allowed one supervisor to instruct a large number of participants at once [20]. In recent years, an increasing number of studies on HIIT for the general population have investigated home-based HIIT interventions [24,26].
Their results suggest that such interventions are effective for maintaining and improving cardiorespiratory tness. Home-based HIIT for breast cancer survivors has only ever been investigated in 1 study protocol [27]. In that study, participants performed bodyweight HIIT exercises at home, and their exercise was monitored with a wearable device [27]. Recent review paper has shown that home-based exercise is an effective method for promoting exercise in cancer survivors [28]. Future studies will need to determine how to assist people in engaging in these kinds of home-based exercise programs.

Exercise training protocols
The following subsections discuss about frequency and period, type of exercise, intensity, and exercise and recovery intervals in the studies reviewed.

Frequency and intervention period
The period of HIIT interventions during breast cancer chemotherapy ranged from 6 [19] to 16 weeks [13][14][15][16]. The 16-week intervention was a combined intervention with resistance training or aerobic training. The longest HIITonly interventions were 8 weeks [9][10][11]. The frequency of sessions during the intervention period was 3 times per week in 3 studies and twice per week in 5 studies. The smallest total number of sessions was 12, and the largest was 36.
The period of HIIT interventions for survivors in studies reviewed in this article ranged from 3 to 12 weeks. The frequency of sessions during the intervention period was 3 times per week in all 5 studies. The smallest total number of sessions was 9, and the largest was 36. In a study investigating the frequency and period of interval training programs, Edward Fox found that a 7-week HIIT program conducted 2 days per week produced comparable improvement in VO 2 max to a 7-or 13-week HIIT program conducted 4 days per week [29]. The study also found that training 2 days a week produced comparable improvement in cardiorespiratory tness to training 4 days a week, and other studies reviewed in the present article also showed that a frequency of 2 to 3 times per week improves cardiorespiratory tness [29]. Based on this evidence, a frequency of 2 to 3 times per week can be considered appropriate for HIIT interventions for breast cancer survivors. A study of a 3-week intervention [20] showed no signi cant improvement in cardiorespiratory tness, but a study of a 6-week intervention [22] showed signi cant. Therefore, it can be concluded that an intervention period of at least 6 weeks is necessary for HIIT to be effective.

Type of exercise
The mode of training was exercise on a cycle ergometer in all studies of interventions during cancer treatment.
These studies likely selected a cycle ergometer because they decided to use VO 2 max as an indicator of exercise intensity during training in order to evaluate safety and feasibility of HIIT during breast cancer treatment, and a cycle ergometer allows for quanti cation of work. The mode of training in studies in cancer survivors was a treadmill in 3 studies [17,18,22], cycling in 1 study [21], and outdoor walking in 1 study [20]. Almost all past studies of HIIT in subjects other than breast cancer survivors used equipment that allows for quanti cation of work (e.g., a cycle ergometer or treadmill) because VO 2 max was set as the indicator of exercise intensity. Exercise intensity is the most important factor in HIIT, and thus it is ideal to be able to quantify work. However, this requires exercise equipment, which makes such programs unfeasible for widespread implementation. Interestingly, Schmitt et al. used an outdoor walking intervention that utilized bodyweight in their study [20], but did not observe any improvement in cardiorespiratory tness. This indicates that walking-based HIIT may not be intense enough to improve cardiorespiratory tness.

Intensity
In all of the studies of interventions during treatment, the relative exercise intensity set at the start of the intervention was maintained until the end of the intervention, which would have resulted in the absolute intensity increasing over the duration of training. It is best to use a physiological index to calculate exercise intensity during HIIT, but Mijwel et al. used a rating of perceived exertion of 16 to 18 in their study. Past studies of home-based HIIT interventions that used the "talk test" (intensity should be great enough that talking is di cult) [25] or a modi ed Borg scale score of 6 to 8 ("very hard") [30] as an indicator of exercise intensity showed signi cant improvement in the primary endpoint of cardiorespiratory tness. Therefore, even though Mijwel et al. may have used a slightly lower or unclear exercise intensity for HIIT compared with other studies, that intensity may have been su cient to increase VO 2 max.
In studies of interventions in survivors, the relative exercise intensity set at the start of the intervention was maintained until the end of the intervention in 4 of 5 studies, and the relative exercise intensity was increased incrementally from the start of the intervention in 1 study. Northey et al. (21) had participants pedal at maximum intensity for 30 s, which was likely the most intense burst of exercise out of all 5 studies (and also including interventions during cancer treatment).

Interval and recovery durations
In studies of interventions during treatment, the exercise and recovery intervals differed greatly depending on the HIIT exercise intensity. In the HIIT programs investigated in these studies, the exercise interval ranged from 1 to 3 min, the recovery interval from 1 to 2 min, the number of sets from 3 to 10, and the total exercise duration from 11 to 19 min.
In the HIIT programs used in studies of cancer survivors, the exercise interval ranged from 30 s to 4 min, the recovery interval from 2 to 3 min, number of sets from 4 to 8, and total exercise duration from 10 to 39 min. HIIT is currently attracting global interest, and there is ongoing debate about its methodology. As such, the optimal exercise interval, recovery interval, and number of sets have not yet been established, and studies on HIIT should consider these aspects alongside exercise intensity and feasibility. High intensity is most important to maximize the effects of HIIT. Northey et al., whose intervention used the most intense bursts of exercise of any study included in this review, had participants perform 4 sets consisting of 30 s of maximum-intensity pedaling followed by 2 min of rest. This method is similar to ones used for the healthy general population and athletes [31]. This indicates that exercise and recovery intervals in HIIT for breast cancer survivors can be investigated using methods similar to HIIT for the healthy general population. It will be necessary to develop a program with the most e cient exercise and recovery intervals optimized for breast cancer survivors on the basis of ndings from studies on HIIT conducted to date.

Outcomes Cardiorespiratory tness
Of the 3 studies of interventions during treatment that evaluated cardiorespiratory tness, 1 found that the HIIT intervention signi cantly increased cardiorespiratory tness, and 2 found no difference. However, the 2 studies that found no difference did nd that cardiorespiratory tness decreased signi cantly at the end of the study in the control group, indicating that HIIT does prevent the reduction in cardiorespiratory tness by cancer treatment.
Of the 3 studies of interventions for cancer survivors that evaluated cardiorespiratory tness, 2 found that the HIIT intervention signi cantly increased cardiorespiratory tness, and 1 found no difference. The 2 studies that found improvement in cardiorespiratory tness used equipment that allows for quanti cation of exercise intensity, namely, a cycle ergometer or treadmill. The reason why the remaining study found no change in cardiorespiratory tness may be that the intervention was interval speed walking, which has relatively low intensity. Also, the fact that the control group underwent a moderate-intensity training intervention likely had an effect as well. These ndings suggest that HIIT has the effectiveness for improving cardiorespiratory tness in breast cancer survivors. One study found that lower body muscle strength in breast cancer survivors is lower than or comparable to that in the general population [32], and HIIT has been shown to increase lower body muscle mass in healthy young men [33]. Although further evidence is necessary, HIIT shows promise for increasing muscle strength in breast cancer survivors, a population with reduced muscle strength de cit.

E cacy of HIIT in cancer survivors
Past studies of HIIT interventions during and after breast cancer treatment conducted with common outcomes such as cardiorespiratory tness, HRQOL, fatigue, and related biomarkers. The effects of HIIT on cardiorespiratory tness were con rmed and comparable between interventions conducted during treatment (signi cant increase in 1 study, amelioration of treatment-related reduction in 2 studies) and after treatment (signi cant increase in 2 studies, no change in 1 study). HIIT compliance rates and incidence of adverse events also showed similar trends between interventions conducted during and after treatment, thus demonstrating the promising e cacy of HIIT.
However, few studies examined muscle strength and mass or changes in cardiotoxicity or cardiovascular function after HIIT intervention in survivors. Therefore, further research on these outcomes is necessary.
Possibilities for home-based HIIT A wide variety of basic and applied research has investigated HIIT in the general population. Given that HIIT is already known to improve cardiorespiratory tness, more recent studies have investigated the feasibility of HIIT programs without specialized equipment or supervision. Blackwell et al. compared the effects of unsupervised bodyweight HIIT (home HIIT) and supervised HIIT using a treadmill (lab HIIT) on VO 2 max. They found that both lab HIIT (pre 26.50 ± 6.31, post 31.00 ± 6.69 mL/kg/min, p < 0.001) and home HIIT (pre 27.77 ± 4.75, post 29.98 ± 6.09 mL/kg/min, p < 0.05) signi cantly improved VO 2 max, but lab HIIT produced a signi cantly greater increase than home HIIT (p < 0.05) [24]. In contrast, Menz et al. found that home HIIT (pre 49.5 ± 6.6, post 54.4 ± 5.3 mL/kg/min, p < 0.001) produced comparable improvement in VO 2 max to lab HIIT(pre 47.8 ± 5.6, post 54.1 ± 5.6 mL/kg/min, p < 0.001) [36]. A systematic review of bodyweight HIIT methodology has also been conducted [37].
The ndings of these studies suggest that bodyweight HIIT is bene cial for increasing cardiorespiratory tness, and a home-based bodyweight HIIT program should be developed for breast cancer survivors.

Conclusions
The majority of studies on HIIT for breast cancer survivors used lab-based, supervised interventions. HIIT is a timee cient method for increasing cardiorespiratory tness in breast cancer survivors, but further research is necessary to determine its effects on other outcomes such as HRQOL, fatigue, muscle function, and cardiovascular function because few studies have evaluated those outcomes. Due to the lack of evidence of bene t from home-based HIIT for breast cancer survivors, additional studies should be conducted to con rm the effects of such programs.

Declarations
-Ethics approval and consent to participate Not applicable -Consent for publication Not applicable