There is strong evidence that regular exercise can improve physical functioning, aerobic capacity and muscle strength, alleviate side effects of treatment and improve quality of life in cancer survivors (1,2). Therefore, exercise training is highly recommended by exercise oncology expert panels (1). However, cancer survivors often do not reach the recommended level of physical activity, and lack of time is a frequently reported reason for not being physically active (3,4). Therefore, a shorter duration of training sessions may increase adherence (5).
High-intensity interval training (HIIT) has gained attention in recent years as a time-efficient training method to overcome the barrier of lack of time (6). Furthermore HIIT may be more effective to induce physiological adaptions compared with other training methods in healthy and diseased populations (7): research suggests that in healthy athletes (8), overweight individuals (9) and cardiac patients (10–12) HIIT alone or in combination with moderate-intensity, long-duration sessions (polarized training) is superior compared with other training methods especially with regard to increase of aerobic capacity (8,9,12). This appears particularly attractive because cancer survivors demonstrate low maximal oxygen uptake (V˙O2peak) (13,14).
Two relatively well-established HIIT protocols are the 10 × 1 protocol with 10 intervals of 1 min duration at peak power output (PPO) (15) and the 4 × 4 protocol consisting of four 4 min intervals at 85% to 95% of peak heart rate (HRpeak) (16). Both protocols have already been applied in intervention studies with different patient populations. The 10 × 1 protocol was used, for example, in cardiac patients on a cycle ergometer (17) and also implemented into clinical routine care (18). The 4 × 4 protocol was applied in cardiac patients as well (10,19) and, for example, in individuals with metabolic syndrome or type 2 diabetes (20,21) on cycle ergometer, as uphill running protocol outdoors or on a treadmill. Furthermore, Devin et al. (22) incorporated a 4 × 4 HIIT protocol in a training intervention study with colorectal cancer survivors as cycle ergometer training.
Although the interest in HIIT as a training method for cancer survivors is rising, there is still a lack of research in this area (23,24) and potential safety concerns (5). Therefore, HIIT is not a recommended modality in current exercise guidelines for cancer survivors (1). In a recent meta-analysis, Mugele et al. (24) highlight the need for further investigations on the effects of different HIIT protocols on cancer-related outcomes and the feasibility and motivational impact across major cancer types. Previous (23,24) and ongoing studies (25) used heterogeneous HIIT protocols and did not investigate feasibility, safety and acute physiological and psychological responses before prescribing HIIT to cancer survivors. To extend the knowledge in this field and enable better-informed decisions on exercise prescription in future, the main objective of the present study was to investigate feasibility and safety of the 10 × 1 (15) and 4 × 4 (16) HIIT protocols as single training sessions in breast and prostate cancer survivors. Furthermore, acute physiological responses were systematically assessed, and because the enjoyment of training seems to matter for maintaining physical activity (26), acute psychological responses were also examined.
Following a repeated measures cross sectional design, participants performed a total of three tests: First, a maximal cardiopulmonary exercise test (CPET) on a cycle ergometer and then two HIIT protocols on a cycle ergometer in randomized order (block randomization). All tests were separated by at least 4 d to avoid training effects and performed at the same time of day to avoid circadian variation. The HIIT sessions were supervised by two exercise physiologists to enable data collection and keep the training intensity accurate. To evaluate feasibility, completion rate of the HIIT sessions was analyzed. To assess safety, adverse events (AE) were documented and blood pressure was measured. The acute physiological responses recorded were HR and blood lactate concentration (bLa) and the acute psychological responses recorded were RPE, enjoyment and overall feeling. The present study was approved by the ethics committee of the Medical Faculty of Heidelberg (S-347/2016) and registered at ClinicalTrials.gov (NCT02883699).
Participants were recruited through the breast and prostate cancer presentations at the National Center for Tumor Diseases (NCT) Heidelberg, medical practices and hospitals of the NCT network and self-help groups. They had to fulfill the following inclusion criteria: Diagnosed with non-metastatic (M0) breast or prostate cancer; 6 to 52 wk (in case of prostatectomy 12 to 52 wk) after the end of primary therapy (i.e., surgery and/or radio therapy and/or chemotherapy); 18 to 75 yr of age; no regular vigorous endurance or resistance training (>1 session per week) within the last 6 months (question: “Do you currently (within the last 6 months) do any structured physical exercise training? If so, what kind of training do you do? How many hours per week and of which duration? What is the intensity (rated on an RPE scale from 1 to 10?”). Exclusion criteria were: a diagnosis with additional other cancer; any comorbidities that preclude participation in exercise testing or training (acute infectious diseases, severe cardiac, respiratory, renal or neurological diseases); living >30 km away. Written informed consent was obtained from all participants prior to participation.
Cardiopulmonary exercise test
The CPET started at 20 W and work rate increased by 10 W·min−1 until voluntary exhaustion. The participants were told to pedal at a cadence between 60 and 80 rpm and to spend maximal effort. HR and gas exchange were recorded continuously (see below for assessment procedures). HRpeak and V˙O2peak were considered the highest 20‐s average values during or immediately post exercise. Maximal respiratory exchange ratio (RERpeak) was considered the highest 20‐s average value during exercise. Blood samples for the determination of peak bLa (bLapeak) were taken at the end of exercise and in the first, third and fifth min of the recovery period. Blood pressure was monitored every 2 min. Peak power output and RPE were recorded immediately post exercise. The test was considered maximal when one of the following criteria was fulfilled: RERpeak ≥ 1.1, HRpeak ≥ 200 minus age, bLapeak ≥ 8 mmol·L−1 (27,28).
10 × 1 HIIT protocol
The 10 × 1 protocol is displayed in Figure 1A. The protocol started with a 3 min warm-up at 30 W followed by 10 intervals of 1 min duration at PPO in alternation with 1:15 min recovery periods at 30 W and finished with a 3 min cool-down at 30 W (15). Total duration was 28:15 min. Pedal rate was kept between 60 and 80 rpm. HR, bLa, RPE, and feeling scale were recorded before the start of exercise and within the last 30 s of every second interval (resulting in six measurement points). Blood pressure was taken before the start of exercise and directly after the fifth and last interval. Enjoyment was recorded within 30 min after exercise. Adverse events and early session terminations were recorded. The average values of the intervals (5 measurement points) for HR, bLa, RPE, systolic blood pressure, and work rate were used for further analyses.
4 × 4 HIIT protocol
The 4 × 4 protocol is displayed in Figure 1B. The protocol started with a 10 min warm-up at 70% HRpeak followed by four 4-min intervals at 85%–95% HRpeak, interspersed with 3 min recovery at 70% HRpeak and finished with a 3-min cool-down at 70% HRpeak. Total duration was 38:00 min. Because the 4 × 4 protocol was HR controlled, the work rate was adjusted. If HR did not decrease to 70% HRpeak during the recovery period despite work rate adjustments or a complete stop of pedaling, the session was still continued. The intended pedal rate was 90 rpm during intervals (to elevate heart rate to the target zone) and 60–80 rpm during warm-up and recovery. HR, bLa, RPE, and feeling scale were recorded before the start of exercise and within the last 30 s of each interval (resulting in five measurement points). Blood pressure was taken before the start of exercise and directly after each interval. Enjoyment was recorded within 30 min after exercise. Adverse events and early-session terminations were recorded. The average values of the intervals (four measurement points) for HR, bLa, RPE, systolic blood pressure, and work rate were used for further analyses. For work rate and bLa, the average values in the recovery periods were also calculated.
The CPET and both HIIT sessions were performed on electronically braked cycle ergometers (Ergoselect 100 or 200; Ergoline, Bitz, Germany). HR was taken from a 12-lead electrocardiogram (CardioPart 12 Blue; Amedtec, Aue, Germany) in the CPET and from a telemetric system (Polar Electro, Kempele, Finland) in the HIIT sessions. Blood pressure was taken manually. Gas exchange was measured using a breath-by-breath gas analysis system (Ergostik; Geratherm Respiratory, Bad Kissingen, Germany). To determine bLa, blood samples were collected from the hyperemized (Finalgon balm) earlobe using 10 μL end-to-end capillaries. The blood samples were analyzed by using an enzymatic–amperometric method (Super GL compact; Hitado, Möhnesee, Germany). Adverse events and early session terminations were documented on a record form.
RPE was assessed using the 6 to 20 Borg scale (29) in general and for legs and breathing. The Feeling scale (30) ranging from −5, “very bad” to +5, “very good” served to record overall feeling during the HIIT sessions, and the change from before the start to the end of exercise was calculated. Enjoyment of the exercise session was assessed using a single item 7-point scale “How much did you enjoy the training session?” with answers ranging from “1, not at all” to “7, very much” adjusted from Rogers et al. (31). In addition, participants were asked after each training session if they can imagine doing the training regularly with the answer options “yes” or “no.”
Calculations and statistical analyses
Given the descriptive nature of the study, the sample size estimation was based on a preceding similar study with healthy male participants (32). From the number of early HIIT session terminations, completion rates were calculated and compared between protocols. Then, the data of participants who stopped a session prematurely were excluded from further analyses. The actual work rate performed for the HIIT sessions was calculated. Under the assumption that V˙O2 equals 10 mL·min−1·W−1 + 500 mL·min−1 (33) and applying the caloric equivalent of 4.825 kcal·L−1 of oxygen (34), energy expenditure was calculated. Normality of the data was tested using the Shapiro–Wilk test. Responses to the HIIT protocols were analyzed descriptively and given as means, SD, and minimum to maximum for HR, bLa, blood pressure, and RPE. Enjoyment and feeling scale are given as median and quartiles. Differences between the HIIT protocols were analyzed using dependent samples t-tests for performed work, energy expenditure, bLa, blood pressure, and RPE and using Wilcoxon tests (nonparametric test for dependent samples) for work rate, relative work rate, HR, relative HR, enjoyment, and changes in feeling scale. Differences between sexes were analyzed using independent samples t-tests for performed work, energy expenditure, bLa, blood pressure, and RPE and Mann–Whitney U tests (nonparametric test for independent samples) for work rate, relative work rate, HR, and relative HR. An alpha level of 0.05 was applied, and data were analyzed using IBM SPSS Version 25 (IBM Corp, Armonk, NY).
A patient flowchart is given in Figure 2. Forty participants completed all tests consisting of 20 female breast cancer survivors and 20 male prostate cancer survivors. Characteristics of the study population are presented in Table 1. Due to fear of wearing the facemask V˙O2peak could not be determined in one case. Of the remaining 39 CPET 35 (90%) were considered maximal. Results of the CPET are given in Table 2.
Regarding feasibility, 38 (95%) of 40 participants were able to complete each HIIT protocol. Two early terminations occurred for each protocol: In the 10 × 1 protocol power output could not be maintained due to exhaustion in one case after the seventh and in the second case after the eighth interval. The 4 × 4 session was experienced too exhausting and terminated after the third interval in one case although HR was in the planned range. In the other case a minor AE (see below) led to early termination. In one further case incorrect values (94 W instead of 82 W during intervals) were used in the 4 × 4 protocol, and these data were excluded from analyses and comparisons of mean values.
As expected for the 4 × 4, in 25 (71%) of 35 participants work rate estimated from the CPET had to be adapted to keep the HR in the prescribed range. The average adaptation during the intervals was −14.6 ± 11.3 W (0 to −40 W) and the average adaptation during the recovery period was −21.8 ± 14.4 W (0 to −48 W, N = 25).
In terms of safety, no major AE occurred. Three minor AE occurred consisting of two times knee pain after the session (in one participant once in each protocol) and one time a drop in blood pressure and dizziness in the third recovery period (after 29 min) of the 4 × 4 that led to early termination. Mean systolic blood pressure did not differ between the HIIT protocols (P = 0.873).
Data of the two HIIT protocols are presented in Table 2. In the intervals, work rate and relative work rate were higher in the 10 × 1 (P < 0.001) whereas in the recovery periods they were higher in the 4 × 4 (P < 0.001). Work rate in the intervals ranged from 80 to 212 W for the 10 × 1 and from 50 to 152 W for the 4 × 4 (relative work rate, 100% and 44%–84% PPO). In recovery period of the 10 × 1, 30 W was performed by all participants and the range for the 4 × 4 was 7 to 104 W (relative work rate: 14%–38% and 6%–62% PPO). Performed total work and total energy expenditure were higher in the 4 × 4 than in the 10 × 1 (P < 0.001). Performed work ranged from 74 to 153 kJ in the 10 × 1 and from 61 to 274 kJ in the 4 × 4. Estimated energy expenditure ranged from 132 to 196 kcal in the 10 × 1 and from 139–312 kcal in the 4 × 4. Mean HR (P < 0.001) and bLa (P = 0.035) were also higher in the 4 × 4. Ranges of mean HR and bLa for the 10 × 1 and 4 × 4 were 88–189 and 92–170 bpm as well as 3.2 to 6.7 and 1.7 to 8.9 mmol·L−1. Time courses of HR and bLa are displayed in Figure 3. Mean systolic blood pressure ranged from 115 to 235 mm Hg in the 10 × 1, from 119 to 220 mm Hg in the 4 × 4 and from 110 to 255 mm Hg in the CPET. Mean diastolic blood pressure ranged from 70 to 98 mm Hg in the 10 × 1, from 71 to 95 mm Hg in the 4 × 4 and from 70 to 110 mm Hg in the CPET.
Mean RPE (legs P = 0.038, breathing P = 0.003) was higher in 4 × 4. Ranges of RPE for the 10 × 1 and 4 × 4 were: 8.8–17.4 and 8.0–18.0 for legs, and 9.0 to 17.6 and 8.0 to 18.3 for breathing. RPE values in the last interval just before the end of exposure did not differ between the HIIT protocols (legs 15.2 ± 2.4 vs 14.9 ± 2.3, P = 0.341, breathing 14.9 ± 2.2 vs 14.3 ± 2.3, P = 0.136). Time courses of RPE are displayed in Figure 3. The median and quartiles of enjoyment were 6.0 (5.0;6.0) in the 10 × 1 and 6.0 (4.0;7.0) in the 4 × 4 with no significant difference between protocols (P = 0.301). The feeling scale decreased (from start to end) from +3 (+3;+4) to +1 (0;+3) within the 10 × 1 and from +4 (+3;+4) to 0 (0;+3) within the 4 × 4 and with a higher decrease in the 4 × 4 (P = 0.017). For both protocols, 30 participants (75%) stated that they could imagine doing the training regularly.
The current study investigated feasibility, safety, and for the first time, acute physiological and psychological responses to two different HIIT protocols in breast and prostate cancer survivors after completion of primary therapy. Both single training sessions, the 4 × 4 and the 10 × 1, can be considered feasible because 95% of the patients were able to finish the training sessions and no serious AE occurred. The acute physiological responses were consistent with vigorous-intensity training (35) and the psychological responses indicate that patients enjoyed the training and were mostly willing to do it regularly.
HIIT has gained more and more importance as a time-efficient and effective training method over the recent years. However, studies on HIIT in cancer patients are still scarce and there is a lack of knowledge regarding feasibility and safety in this special population (24). Our findings indicate that the two tested HIIT protocols as single training sessions are feasible for the vast majority (95%) of breast and prostate cancer survivors who are at least 6 wk after the end of primary therapy or in case of prostatectomy at least 12 wk postsurgery. In the remaining 5% of cancer survivors, a reduction in exercise intensity in the first training sessions and a continuous increase to the targeted intensity might be applicable.
Regarding safety of the HIIT protocols, no major AE occurred. The minor AE might be person-specific and not specific to the training method: knee pain appeared in one person in both HIIT protocols and circulatory problems occurred in a person who reported to have circulatory problems occasionally and also experienced them during continuous exercise. This person had no initial diagnosis of cardiovascular disease. Blood pressure values stayed well below the criteria for terminating an exercise test of >250 mm Hg systolic or >120 mm Hg diastolic blood pressure (36). In one single case during the 10 × 1, a systolic blood pressure of 250 mm Hg was reached but no blood pressure–related premature exercise cessation was necessary. In patients prone to high blood pressure, blood pressure measurements are advised but this also holds true for continuous training and not only for HIIT. In summary, the two HIIT protocols seem to be safe for the investigated population. This is in line with previous findings in other clinical populations: Investigations in cardiac patients also showed that HIIT is safe and well tolerated (18).
Previous studies investigating HIIT in cancer survivors are very heterogeneous in terms of cancer entity, treatment phases of the patients and HIIT protocols used (23,24) and did not focus on acute responses to HIIT. For example, Dolan et al. (37) compared a 6-wk continuous moderate training with aerobic interval training (four to six intervals up to 95% of V˙O2peak) in 36 postmenopausal women with breast cancer (57 ± 9 yr) who had completed therapy. Licker et al. (38) investigated in 151 patients (64 ± 10 yr) before lung cancer surgery if a short-term HIIT training (two 10-min series of 15-s sprint intervals at 80%–100% peak work rate interspersed with 15-s pauses) enhances cardiorespiratory fitness and reduces the risk of postoperative complications. Kampshoff et al. (39) investigated a 12-wk high-intensity (until week 4 12 × 30 s at 65% of the maximum short exercise capacity; from week 5 onward 6 × 30 s at 65% of the maximum short exercise capacity plus 3 × 5 min at ≥80% of HR reserve) and low- to moderate-intensity resistance and endurance exercise program in a mixed group of cancer survivors (54 ± 11 yr in high-intensity group; n = 91) 4 to 6 wk after primary therapy. These studies report that HIIT is feasible and safe, with no AE (37,39) or no serious AE (38) or a low risk of AE (23), which is consistent with the results of the present study. However, due to the limited number of studies and their high heterogeneity, this should still be interpreted cautiously (24).
For HIIT, either a vigorous or a near-maximal exercise intensity is expected. Given the intensity classification of the American College of Sports Medicine (35), HR responses in the current study indicate that the upper part of the vigorous-intensity zone of 77%–95% HRpeak was met in the 10 × 1 and the 4 × 4. Although this classification was developed for healthy individuals, percentages of HRpeak were shown to be also suitable for breast cancer survivors (40). Furthermore, bLa >4 mmol·L−1 is expected in a high-intensity training (8) therefore the BLa levels recorded during both 10 × 1 and 4 × 4 HIIT sessions also indicate that the participants exercised at a vigorous intensity. Interestingly, average RPE in the 10 × 1 was slightly below the vigorous-intensity zone of RPE 14–17 (35) and average RPE in the 4 × 4 met the lower part of the zone. As shown in Figure 3, RPE met the lower part of the vigorous-intensity zone at the end of each protocol. Taken together it can be stated that the 10 × 1 and the 4 × 4 revealed physiologic responses within the upper part of the vigorous-intensity zone. A slightly lower intensity was subjectively perceived by the patients which might positively affect long-term training adherence.
When comparing the two HIIT protocols, average HR, bLa and RPE were significantly higher in the intervals of the 4 × 4 which indicates increased physical strain. Furthermore, performed work was about 55% higher and estimated energy expenditure was about 40% higher in the 4 × 4. Considering that in the 4 × 4 the total duration under strain is 16 min compared to 10 min in the 10 × 1, this is plausible. It is striking that despite these differences similar subjective training responses were found. RPE at the end of the protocols (Fig. 3) was not significantly different. Furthermore, patients enjoyed both protocols, which appears important for maintenance of training programs (26). Although the participants’ overall feeling decreased from start to end of the sessions they still felt “fairly good” at the end of the sessions and there were no differences between protocols. Furthermore, 75% of the patients could imagine doing either HIIT protocol on a regular basis. The results are promising with regards to the maintenance of both HIIT protocols in cancer survivors. If a higher training stimulus is intended, the 4 × 4 should be preferred. However, the 10 × 1 has a shorter duration and might be preferred in patients with limited time.
The practicability of the two HIIT protocols depends on the type of cycle ergometer. If the ergometer can be programmed, the 10 × 1 protocol is very easy to carry out. If not, to switch between loads can take nearly the whole minute. Timing is also prone to errors because the resting periods are 15 s longer than the intervals. In the 4 × 4 protocol, switching manually is easy due to the long duration of the intervals. Because the work rate needs to be adapted in the 4 × 4 to remain within the targeted HR range, programming does not work well. Altogether, we recommend programmable cycle ergometers for the 10 × 1 whereas for the 4 × 4 a manually adjustable cycle ergometer is more useful.
The present investigation has strengths and limitations. To the best of our knowledge this is the first study systematically investigating different HIIT protocols as single training sessions in terms of feasibility, safety and acute physiological and psychological responses in cancer survivors. Patients with the most common cancer types worldwide (41) were investigated. For these patients, convincing evidence for positive effects of exercise on health outcomes exists and the next step is to find the appropriate dose of training – where HIIT might play an important role. Limitations of the study include different measurement time points for the protocols. Due to the different nature of the protocols, measurements were carried out after less time under strain in the 10 × 1 which complicates comparison and interpretation of the results. However, for practical reasons, no more measurement time points were set. As we investigated single training sessions of the two different HIIT protocols no conclusions can be drawn about the safety of these two protocols if they are applied on a regular basis with several sessions per week. In athletes there are hints that three sessions of HIIT per week compared to one session had no beneficial effects but may lead to overtraining (8). Based on these findings future studies should investigate the optimal frequency for HIIT in cancer survivors.
The present study systematically investigated the 10 × 1 and the 4 × 4 HIIT protocol in terms of feasibility, safety and acute exercise responses in breast and prostate cancer survivors 6 to 52 wk after the end of primary therapy. The 10 × 1 and the 4 × 4 HIIT as single sessions were safe and in the vast majority (95%) of the population feasible. Of the two protocols, the 4 × 4 might be favored because of a higher-energy expenditure, cardio-circulatory and metabolic strain and, therefore, a higher training stimulus. However, the 10 × 1 has a shorter duration and might be preferred if time is limited. Patients enjoyed both protocols and the majority could imagine performing the HIIT training on a regular basis. These findings help to extend knowledge on HIIT in exercise oncology and identify feasible and safe protocols for future training studies.
The authors thank the Dietmar Hopp Foundation for funding the study. Furthermore, the authors thank the German Cancer Research Center (DKFZ) for the study assessment support.
The authors declare no conflicts of interest. The results of the present study do not constitute endorsement by ACSM. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation.
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