Subjects/ patients
A total of 86 women were recruited from the Breast Surgery department, at Riga East University Hospital, Latvia (Figure 1). Potential participants were identified individually through a medical oncologist’s referral and health according to the inclusion criteria in this study.
The following eligibility criteria were applied: a) age between 35 and 65, b) with a first diagnosis of stage II-III, c) assigned for neoadjuvant chemotherapy, d) BMI (>18; ≤ 30). Patients were excluded if: they had the presence of musculoskeletal, neurological, cardiovascular, endocrine, and respiratory conditions that contraindicate submaximal aerobic loads.
The patients received NACT according to the European Society for Medical Oncology and the National Comprehensive Cancer Network guidelines applying (Doxorubicin, Cyclophosphamide – Docetaxel and/ or Doxorubicin, Cyclophosphamide - Paclitaxel regime and/or Trastuzumab/ Pertuzumab “Phesgo”. The study was performed in accordance with the Declaration of Helsinki. It was approved by the Ethics Committee of the Latvian Academy of Sport Education (Nr. 1/2021/28/05) and the Scientific Department of Rīga East University Hospital (reg. nr. ZD/08-06/01-21/179).
Study Timeline
Included patients attended a standardized 1.5-h testing procedure 1-2 weeks before the first NACT session. This study was part of the CANCER BEAT project. After the testing procedure, patients were randomized with 1:1 allocation to the training group (TG) and control group (CG). After 6 months, completion of NACT, and ~1 week before scheduled surgery the 1.5-h testing procedure was repeated. The testing included assessments of incremental exercise test (IET), time to exhaustion (TTE), and functional performance. The data were collected between January 2022 and December 2023, at the Latvian Academy of Sport Education Health Care and Sports Science Research Laboratory.
Testing
Incremental exercise test
Patients underwent scheduling with a cardiologist before undergoing an incremental exercise test (IET) according to the University of Northern Colorado Cancer Rehabilitation Institute (UNCCRI) Treadmill protocol (16). The UNCCRI Treadmill Protocol consists of twenty-one 1-minute stages, with increments in speed and/or grade at each stage.
A treadmill (LifeSpan TR2000i) was used while obtaining V̇O2peak, and ventilatory parameters (ventilation, VE; respiratory exchange ratio, RER) were measured directly with a Vyaire Vyntus CPX (Germany). Heart rate was measured continuously throughout each test with a heart rate monitor (Polar H10). In addition to assessing VO2peak and HRpeak, conducting an IET is recommended to optimize patient safety and assess exercise tolerance (17) before initiating a training program.
All patients were familiarized with the treadmill testing protocol and walking on the treadmill. Patients were instructed to maximize their effort, additionally, patients could terminate the test at any time. Participants were instructed to avoid using the handrails; however, if necessary, they were directed to hold throughout the protocol. Testing was ended either upon the participant’s sign of reaching maximal effort or upon exhaustion. The mean of the three highest oxygen uptake measurements over 30 seconds was used to determine V̇O2peak, VE, and RER were calculated from the same period. HRpeak was determined from the highest measured heart rate. Objective criteria for exhaustion were: 1) peak heart rate of > 95% to the age-predicted maximal; 2) the value on the modified Rating Of Perceived Exertion (RPE 17/19); 3) maximal respiratory exchange ratio (RER) > 1.05; 4) a plateau in oxygen uptake measurements with increasing treadmill workload) (18), (19). Time to exhaustion, treadmill speed, and inclination were recorded at the end of the test.
The 5-repetition sit-to-stand and 30s sit-to-stand test
Both tests were performed in one setting with a stable chair that was prevented from sliding backward. Starting from a seated position with crossed arms. Participants were instructed to sit in the middle of the chair with their hands on opposite shoulders, crossed at the wrists (20).Participants were instructed to keep their feet flat on the floor and to keep their backs straight, with arms against the chest. On “ready, go”, the participants were asked to rise to a full standing position and then sit back down, repeating this standing-sitting action as many times as possible in the 30s. The fastest time taken to stand five times from a chair for 5 repetitions and the number of repetitions of full sit-to-stand motions completed in the 30s were recorded (17).
6 min walk test
6MWT is one of the most well-known and widely used instruments for addressing functional exercise capacity among healthcare professionals. 6MWT measures the distance walked over a flat, hard surface at a self-paced speed through 6 minutes and has been validated in a cancer population (21). Orange cones were used to mark each end of the 20-meter walking course, and verbal instructions of the Start of the test, time left, and encouragement to perform their best were given. The Polar H10 sensor to monitor the HR was used during the test, and walking distance and HRpeak reached during the test were recorded.
Intervention
The TG was instructed to undergo 2-3 training sessions per week on non-consecutive days for all chemotherapy duration (~24 weeks). A healthcare professional gave the following instructions on how to conduct HIIT sessions. The aim was to initiate training before the first neoadjuvant chemotherapy session. Each patient allocated to the TG received heart rate (HR) monitors (Polar H10) and was instructed to download the Polar Flow app, to properly follow targeted HR during each training session. A healthcare specialist specializing in exercise physiology provided the necessary support on how to conduct training and control exercise intensity. In addition, the healthcare professionals provided instructions on how to use the app and transfer and save the date. After a completed training patients shared screenshots illustrating the sessions’ data with the research team. While patients were free to choose the time for training sessions, they were recommended to perform the training during the part of the day when they felt more energy. Importantly, they were advised to contact emergency medical services immediately if they encountered or suspected any adverse events during the training session. However, none of the participants experienced any adverse events.
1. Each session started with a 6-minute warm-up period at a self-selected speed (if using treadmill ≥ 2% inclination), using moderate intensity. Talking in complete sentences should still be possible (talking speed) aiming to target a rate of RPE of 13 (~ 65-70% HR max) during this stage.
2. Following the warm-up, patients commenced the 4×4-min intervals at an intensity (speed and/or incline) that elicits heavy breathing within 2 min of each interval. It was emphasized that it should be difficult to speak more than 2 to 3 words in a row, corresponding to an RPE of 16 (~ 85%-95% of HRmax).
3. The 4-minute intervals were separated by 3 min of active recovery with low to moderate intensity periods at 55-70% of HRpeak. Each session had a duration of 34 minutes in total. Furthermore, participants were asked to follow two subjective exertion key aspects during the session: (1) at the end of each 4-min interval, feeling able to continue one more minute, and (2) after the fourth intensive interval followed by an active 3 min recovery period, feeling possible to perform the fifth interval. Depending on the patients’ VO2peak levels, and self-reports on the severity of treatment side effects during intervention walking or running was recommended during the HIIT sessions. In general, patients were encouraged to continue training with targeted intensity throughout the NACT period. If the NACT-related side effects (e.g., fatigue, pain, nausea) were too severe to maintain the defined intensity, the patients were advised to reduce the intensity to 75%-80% of HRpeak until could resume the initial training mode.
The CG continued the standard of care treatment during NACT. The CG was instructed to continue their daily routine without any specific exercise training.
Assessment of exercise adherence
Previous studies of cancer patients suggest that ≥80% intervention adherence be considered as high and range from 58–77% as feasible (22), (23). However, studies in BC patients during NACT have reported adherence rates below 80% (24), (25). In the present study, the adherence threshold was set at ≥60% and it was evaluated twice per research period. First, at the midpoint of NACT (~ 3 months), at least 19 training sessions (60% of 32) had to be completed, and the second time after completion of NACT when in total 39 sessions (60% of 64) had to be completed. Those participants not reaching the intervention adherence threshold at the midpoint of NACT were instructed to keep up with the amount of planned intervention during the second half of NACT. Participants not reaching the intervention adherence threshold at the end of NACT were excluded from further data analysis.
Sample size calculation
To estimate the sample size, we relied on measures of cardiorespiratory fitness improvement from studies comparing HIIT and CG in cancer patients (14), (15), The sample size was estimated using standard hypothesis parameters of clinical trials (a=0.05; power=90%) assuming that the intervention group will demonstrate 20% better performance in VO2peak (26).
Statistical analysis
Statistical analyses were performed using IBM SPSS (version 25), and figures were made using Graph Pad Prism software (version 8). Baseline participant characteristics were summarized using descriptive statistics. Outcome data were presented as mean (SD). For group comparisons of baseline participant characteristics, the independent sample t-tests were used. To compare the means of pre and post-intervention within groups the paired t-test was used, with significance set at P < 0.05 A repeated measures ANCOVA model was conducted with the intervention group and time (baseline/post-intervention) as factors. The effect size (ES) was quantified using partial eta squared (n2p). The established benchmarks for categorizing effects were defined as small (n2p = 0.01), medium ((n2p = 0.06), and large (n2p = 0.14). A two-tailed significance level of p < 0.05 was considered statistically significant.