Comparison of the effects of high-intensity interval and moderate-intensity continuous training on inflammatory markers, cardiorespiratory fitness, and quality of life in breast cancer patients

Highlights

• •High-intensity interval training (HIIT) is a safe, feasible, and time-efficient modalities for breast cancer patients.
• •HIIT plays a better role in improving cardiorespiratory fitness and high density lipoprotein cholesterol metabolism than moderate-intensity continuous training (MICT), which decreases the risk of cardiovascular disease in breast cancer patients
• •Both HIIT and MICT can improve quality of life in breast cancer patients.
• •Further large-scale studies will help determine whether these promising results could be translated into clinical and oncological outcomes.

Abstract

Background

As the effectiveness of breast cancer treatment has improved, a growing number of long-term breast cancer survivors are seeking help for unique health problems. These patients may be at increased risk of cardiovascular disease due to the side effects of treatment. The positive impact of most types of exercise has been repeatedly reported in people with cancer, but the most effective exercise approaches for maximum beneficial adaptations remain controversial. Thus, this study aimed to compare the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on inflammatory indices, adipokines, metabolic markers, body composition, cardiorespiratory fitness, and quality of life in breast cancer patients during adjuvant endocrine therapy.

Methods

Thirty non-metastatic breast cancer patients during adjuvant endocrine therapy who had been treated with chemotherapy and/or radiotherapy were recruited from Iran and randomized to HIIT, MICT, or control groups for a supervised exercise intervention that took place 3 times a week for 12 weeks. The training intensity was determined based on the peak oxygen uptake (VO_2peak), and the volume of training was matched in HIIT and MICT based on the VO_2peak. Body composition, functional capacity, cardiorespiratory fitness, metabolic indices, sex hormones, adipokines, and inflammatory markers were assessed before and after the intervention.

Results

The VO_2peak increased by 16.8% in the HIIT group in comparison to baseline values (mean difference = 3.61 mL/kg/min). HIIT significantly improved the VO_2peak compared to control (mean difference = 3.609 mL/kg/min) and MICT (mean differences = 2.974 mL/kg/min) groups. Both HIIT (mean difference = 9.172 mg/dL) and MICT (mean difference = 7.879 mg/dL) interventions significantly increased high-density lipoprotein cholesterol levels compared to the control group. The analysis of covariance showed that physical well-being significantly improved in MICT compared to control group (mean difference = 3.268). HIIT significantly improved the social well-being compared to the control group (mean difference = 4.412). Emotional well-being subscale was significantly improved in both MICT (mean difference = 4.248) and HIIT (mean difference = 4.412) compared to the control group. Functional well-being scores significantly increased in HIIT group compared with control group (mean difference = 3.35) . Significant increase were also observed in total functional assessment of cancer therapy-General scores in both HIIT (mean difference = 14.204) and MICT groups (mean difference = 10.036) compared with control group. The serum level of suppressor of cytokine signaling 3 increased significantly (mean difference = 0.09 pg/mL) in the HIIT group compared to the baseline. There were no significant differences between groups for body weight, body mass index, fasting blood glucose, insulin resistance, sex hormone binding globulin, total cholesterol, low-density lipoprotein cholesterol, adipokines, interleukin-6, tumor necrosis factor-α, or interleukin-10.

Conclusion

HIIT can be used as a safe, feasible, and time-efficient intervention to improve cardiovascular fitness in breast cancer patients. Both HIIT and MICT modalities enhance quality of life. Further large-scale studies will help determine whether these promising results translate into improved clinical and oncological outcomes.

Graphical abstract

1. Introduction

Breast cancer is the most common type of cancer in women (25% of all cancers) and the leading cause of death in women related to cancer.¹ Anthracycline-based chemotherapy is widely used to treat breast cancer. However, it also has potential side effects, such as cardiotoxicity, decreased cardiorespiratory fitness, poor quality of life, and fat gain, which can occur both during and after treatment.^2,3 For example, cardiac-respiratory dysfunction in breast cancer patients has been observed during and after chemotherapy.³ The decline in cardiorespiratory fitness in breast cancer patients is a complex problem, and causes could include insufficient physical activity, muscle wasting, cardiotoxicity, and age.4, 5, 6, 7 Cardiorespiratory fitness is inversely associated with all-cause mortality in women. For example, Zhang et al.⁸ found in a longitudinal study that each metabolic equivalent increase of cardiorespiratory fitness was associated with a 24% lower risk (ranged 18%–30%) of all-cause mortality in women. Low cardiorespiratory fitness is associated with poorer survival in cancer patients.⁹ Cardiorespiratory fitness is directly related to quality of life in breast cancer patients.^10,11 A higher prevalence of dyslipidemia (i.e., lower levels of high-density lipoprotein cholesterol (HDL-C)) has been observed in women with breast cancer receiving adjuvant endocrine therapy, thus increasing their risk of cardiovascular disease.^12,13 It has been suggested that lifestyle modifications, including physical activity, and cholesterol-lowering medication during adjuvant endocrine therapy have a role to play in preventing breast cancer recurrence.¹⁴

Physical and psychological side effects of surgery and chemo-radiation therapy can lead to apparent deterioration in health-related quality of life in breast cancer survivors.^15,16 In addition, there are menopause-like complications that can affect the quality of life domains, including physical and psychosocial well-being, in breast cancer patients receiving hormone therapy.^16,17

Chronic inflammation contributes to the development and progression of breast cancer.¹⁸ Chronic low-grade systemic inflammation is also associated with recurrence and can reduce survival in women with breast cancer.^19,20 Inflammatory status can be a prognostic factor for breast cancer.¹⁸ Overactivation of the inflammatory network is a mechanism thought to drive persistent fatigue in breast cancer survivors,²¹ chronic inflammation may be a mechanism for the poor quality of life and impaired mobility of breast cancer patients.²² In addition, chronic inflammation is a determinant of metabolic disease.²² Preliminary evidence in populations with moderate to high levels of inflammatory markers, such as patients with cardiovascular disease, has found that regular aerobic exercise is associated with a reduction in circulating pro-inflammatory cytokines.^23,24

There is emerging evidence supporting exercise as a non-pharmacological therapy to prevent recurrence,²⁵ reduce the risk of mortality,²⁶ and improve survival rates in breast cancer patients.^11,27, 28, 29 However, the majority of breast cancer patients do not follow the physical activity recommendations.^30,31 Lack of time has been cited as one of the most common barriers to physical activity in cancer patients.^32,33 With that in mind, high-intensity interval training (HIIT) has proven to be a time-efficient alternative compared to traditional training recommendations because it promotes similar metabolic adaptations as moderate-intensity continuous training (MICT) with a lower weekly investment of time, which promotes more regular adherence to exercise.^34,35 It has also been reported that HIIT can be more enjoyable than low- or moderate-intensity aerobic exercise programs,^36,37 and that greater enjoyment may be relevant for improving exercise adherence.³⁸ There is growing evidence that HIIT protocols can produce improvements that are comparable to or even more significant than those produced by MICT in multiple health-related outcomes, including peak oxygen uptake (VO_2peak) and metabolic indices, despite significantly less time expenditure.³⁹ The beneficial effects of HIIT are not limited to the physiological adaptations but have also been shown to result in improvements in health-related quality of life⁴⁰ and systemic inflammation.⁴¹

The intensity of exercise can play a role in the effects of exercise on inflammation.⁴² Low-to-moderate-intensity exercise is generally associated with anti-inflammatory effects. In contrast, high-intensity exercise can initially elicit an acute inflammatory response due to the release of pro-inflammatory cytokines in response to tissue damage and metabolic stress.⁴³ High-intensity exercise can lead to anti-inflammatory effects over time, which could help explain its beneficial effects on inflammatory markers.⁴⁴ In addition, inflammatory processes that occur following high-intensity exercise, such as an increase in the expression of pro-inflammatory cytokines, may be crucial for the long-term adaptive responses to exercise training. In response to acute inflammation, the body increases the production of anti-inflammatory cytokines such as interleukin-10 (IL-10), which can help to reduce inflammation and promote tissue repair. In addition, HIIT has been shown to improve insulin sensitivity and glucose metabolism, which minimizes inflammation.³⁴

As described earlier, exercise has been shown to reduce treatment-related side effects and can improve health outcomes and quality of life in people diagnosed with cancer.⁴⁵ Considering the effects of the cancer itself as well as the consequences of its treatment, which may include cancer-related fatigue and other comorbidities such as cardiovascular toxicity and chronic low-grade inflammation, HIIT is still a questionable recommendation for cancer patients. Oncologists and healthcare providers generally avoid prescribing high-intensity exercise for cancer patients because they suspect that high-intensity exercise could have side effects, such as suppressing the immune system. However, there is sufficient evidence that high-intensity exercise is safe and has no adverse effects on immune function in clinical populations.^46,47 Recently, we⁴⁸ and others⁴⁹ have shown that HIIT is feasible and safe for breast cancer patients. Still, few studies have directly compared the impact of HIIT as compared to (a) no exercise controls and (b) MICT with respect to cardiorespiratory fitness, body composition, metabolic indices, sex hormones, adipokines, inflammatory markers, and quality of life in breast cancer patients.^49,50 For example, Hooshmand Moghadam et al.⁵⁰ demonstrated improvement in cardiorespiratory fitness with HIIT or MICT intervention in obese breast cancer survivors. Interestingly, they noted that HIIT provided no additional benefit compared to MICT in terms of improving aerobic power. A recent meta-analysis showed that a high-intensity portion of the session must last at least 20 min to see improvement in cardiorespiratory function from HIIT in cancer patients.⁵¹ However, the volume of exercise performed in the interventions is quite heterogeneous, ranging from very low to low volume.⁴⁹ It is challenging to define clinical training standards for breast cancer patients because of the impact of different prognoses, the length of the training, and the variety of protocols used in the studies with different lengths, recovery time, and intensities. Moreover, it has been suggested that before translating HIIT from research to practice in cancer rehabilitation, some limitations should be addressed, including a lack of generalizability and a paucity of studies comparing the MICT and HIIT programs.⁵² Therefore, future studies should determine the optimal intensity and duration of exercise programs for cancer patients by observing their effects on inflammatory markers in breast cancer patients. While determining the optimal exercise protocols for cancer patients is a priority research question in exercise oncology, the precise mechanisms involved in the anticancer effects of regular exercise are not well understood. In this research, we attempt to test the volume-matched HIIT and MICT modalities with respect to their effects on inflammatory markers, adipokines, metabolic indices, body composition, functional capacity, cardiorespiratory fitness, and quality of life in breast cancer patients during adjuvant endocrine therapy.

The primary objective was to compare the effects of HIIT and MICT on inflammatory markers after 12-week of volume-matched programming. The secondary objectives were to assess the efficacy of these interventions in improving physical function, cardiorespiratory fitness, body composition, quality of life, metabolic indices, lipid profile, sex globulin hormone binding protein, suppressor of cytokine signaling 3 (SOCS3), and adipokines (leptin and adiponectin).

2. Methods

2.1. Procedures

The present study is a single randomized controlled trial with 3 arms: HIIT, MICT, and usual care (CON). A person independent of the research team used the research randomizer computer software to assign participant codes to the 3 groups (HIIT, MICT, and CON).⁴⁹ The study was conducted after receiving ethics permission from the Shahed University Ethics Committee (IR.SHAHED.REC.1389.051). The trial has been registered in the Iranian registry of clinical trials (IRCT 20200208046418N1). Prior to participation, all participants provided written informed consent.

Eligible women were non-metastatic (Stages I, II, and III) breast cancer patients who had completed either chemotherapy and/or radiotherapy treatment at least 1 month before recruitment to the present trial, who were receiving adjuvant endocrine therapy concurrent with randomization, and who were available during the study intervention period. Participants were recruited from patients referred to oncology clinics in Imam Hossein and Naft hospitals in Tehran, Iran. After obtaining the oncologist's approval, participants were deemed eligible for the study if they met the following criteria: age ≥ 30 years; insufficient physical activity level (<150 min/week of moderate intensity or 75 min/week of vigorous intensity); hormone-responsive breast cancer; completed chemotherapy and radiotherapy within the last month; receiving adjuvant endocrine therapy; performing no strenuous exercise (e.g., running, cycling, swimming, or resistance training); and willing to participate voluntarily in this randomized controlled trial. The exclusion criteria were as follows: current smoking; evidence of metastatic breast cancer; planning to receive any additional adjuvant chemotherapy or surgery; pregnant or breastfeeding; unable to provide a baseline blood sample; cardiac conditions (e.g., myocardial infarction or coronary artery disease); liver conditions; lymphedema; uncontrolled hypertension (defined as systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 100 mmHg); high-risk or uncontrolled heart arrhythmias; clinically significant heart valve disease; decompensated heart failure or known aortic aneurysm; and any musculoskeletal abnormality that would limit exercise participation. The physical activity level of all participants was measured by an international physical activity questionnaire. Accordingly, all participants have insufficient physical activity (<600 metabolic equivalent task min/week).

A sport medicine physician also demonstrated that participation in HIIT is acceptable based on the American College of Sport Medicine guidelines using the physical activity readiness questionnaire and medical health/history. In addition, participants were examined for mobility and other physical limitations, as well as for heart and respiratory diseases, and were excluded from consideration if they met any of the above exclusion criteria. The HIIT inclusion was also checked according to hypertensive response during the cardiopulmonary exercise testing. Accordingly, 30 eligible participants who had the desire and met the conditions to participate in the study were randomly divided into 3 groups: HIIT (n = 10), MICT (n = 10), and CON (n = 10). A flowchart of study participation and group assignment is shown in Fig. 1.

Fig. 1.

Research flowchart. HIIT = high-intensity interval training; MICT = moderate-intensity continuous training.

All phases of the research, possible benefits, and potential reverse effects—including joint pain, back pain, and muscle soreness—were explained to the participants, and they were assured that their information would be kept confidential at all phases of the study.

The pre-exercise screening was carried out before performing HIIT. Participants were excluded from the exercise program on a particular day if any of the following criteria were met: diastolic blood pressure < 45 mmHg or > 95 mmHg; pulse at rest >100 beats per min; temperature >38°C; respiration frequency > 20 per min; infections requiring treatment with antibiotics; ongoing bleeding; fresh petechiae or bruises; thrombocytes < 50 × 10⁹/L; and leucocytes < 1.0 × 10⁹/L.⁵³

2.2. Randomization and blinding

The assignment sequence and group assignments were created by a research assistant and then enclosed in sequentially numbered and sealed envelopes. The contents of the envelopes were withheld from the project manager, who assigned participants to groups. Investigators and participants were unaware of group assignments until the completion of baseline assessments. Participants were randomly assigned to HIIT, MICT, or CON groups. The laboratory staff and those assessing the study outcomes were blinded to the treatment task.

2.3. Assessments

2.3.1. Medical history, anthropometry, and body composition

Demographics and medical history data were collected via an interviewer-administered questionnaire at the baseline visit (Table 1). Body composition was assessed indirectly via changes in body weight, body mass index (BMI), and skinfold measurements. Body weight was evaluated to the nearest 0.1 kg with an electronic balance and height with a fixed stadiometer (Seca 220; Seca GmbH & KG, Hamburg, Germany).Other anthropometric measurements, including waist circumference and hip circumference were taken according to the protocol of the International Society for the Advancement of Kinanthropometry.⁵⁴ The waist circumference was measured using a flexible tape, and determined to the nearest 0.1 cm at the midpoint between the lowest margin of the rip and the uppermost border of the iliac crest with ergonomic circumference measuring Seca tape 203 (Seca GmbH & KG). Regarding hip circumferences, the evaluator placed the band around the hips to the level of the major trochanter. Both circumferences were measured at the end of regular exhalation. Participants were upright, with both feet placed together and arms suspended next to the torso. The BMI was calculated as weight in kilograms divided by height in meters squared. The waist-to-hip ratio was determined by measuring waist circumference at the narrowest point between the edge of the ribs and the iliac crest and then dividing it by the hip circumference measured at the most significant prominence of the buttocks. Three points of skinfold thickness were measured using a Harpenden skinfold caliper (Chasmors Ltd., London, UK) on the non-surgical side of participants on the triceps, supra-iliac crest, and quadriceps. Body fat percentage was estimated by the Jackson-Pollack equation. All measurements were performed twice in a row by the same technician and averaged for data entry.

Table 1.

Training protocol (including walking or running).

Group	Time	Intensity
HIIT (33 min)	Warm-up 5 min	50%–60% VO2peak (65%–75% HRpeak)
	4 × 4 min	90% VO2peak (95% HRpeak)
	3 × 3 min	60% VO2peak (75% HRpeak)
	Cool-down 3 min	50%–60% VO2peak (65%–75% HRpeak)
MICT (41 min)	Warm-up 5 min	50%–60% VO2peak (65%–75% HRpeak)
	Main training 33 min	60% VO2peak (75% HRpeak)
	Cool-down 3 min	50%–60% VO2peak (65%–75% HRpeak)

Abbreviations: HIIT = high-intensity interval training; HR_peak = peak heart rate; MICT = moderate-intensity continuous training; VO_2peak = peak oxygen uptake.

2.3.2. Cardiorespiratory fitness

All participants were instructed to exercise to their maximum limit before the cardiorespiratory fitness test. A standard 12-lead electrocardiogram (Norav medical, Wiesbaden, Germany) was recorded at rest and at the end of each work level and patients were stopped if anything indicated the need to terminate testing according to current guidelines. Participants were encouraged to expend maximal effort during the test. The protocol was as follows: Minute 1 at 2.0 miles per hour (mph) (3.2 km/h) at 0% grade; Minute 2 at 2.7 mph (4.3 km/h) at 0% grade; from Minute 3 to the end of testing at 3.7 mph (5.9 km/h) at 1% grade, with an increase of 1% every other minute until VO_2peak was reached.⁵⁵ Participants were encouraged to continue walking/running on the treadmill at an increasing incline until exhaustion unless indications for terminating the maximal test were observed (American College of Sport Medicine 2009). Participants cooled down at 1.5–2.0 mph at 0% grade for 2–5 min. To determine aerobic capacity, gas exchange was measured using a breath-by-breath automated exercise metabolic system (ZAN 600 USB; Oberthulba, Germany) until VO_2peak was reached. The average of the 3 highest 15-s measurements determined VO_2peak. The patient's heart rate (HR), minute ventilation (VE), oxygen uptake (VO₂), and carbon dioxide production (VCO₂) as well as the ventilator equivalents for oxygen (VE/VO₂) and carbon dioxide (VE/VCO₂) were determined during the evaluation as previously described.⁵⁵ Confirmation of maximal effort was determined by meeting 3 out of 4 of the following criteria: (a) plateau in HR and VO₂ with the increased workload, (b) respiratory exchange ratio > 1.1, (c) rating of perceived exertion (RPE) > 17, and (d) HR >90% of age-predicted maximal HR.⁵⁶ HR, blood pressure, and RPE score were determined at the end of each stage.

2.3.3. Quality of life

The Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire was used to assess the multidimensional quality of life.⁵⁷ The FACT-G is a validated survey with 27 items. The questions are divided into 4 categories: (a) physical well-being, (b) social/family well-being, (c) emotional well-being, and (d) functional well-being. The questionnaire is regularly used to measure the quality of life of cancer survivors.^58,59 All participants completed the questionnaire at baseline and after the 12-week intervention. Responses to questions from each subscale ranged from 0 (not at all) to 4 (very much), and the total FACT-G score was obtained by summing up the subscale scores.⁶⁰

2.3.4. Physical function

Physical function was assessed using the 30-s sit-to-stand test. All participants were asked to wear comfortable clothing and appropriate shoes for testing. The test was performed with a stable chair that was prevented from sliding backward. Participants were instructed to sit in the middle of the chair with their hands on opposite shoulders, crossed at the wrists.⁶¹ Participants were asked 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 30 s. The number of repetitions of full sit-to-stand motions completed in 30 s was recorded.

2.3.5. Biomarkers

Fasting (≥12 h) blood was drawn from participants within 48 h before testing, and they were also asked to avoid vasoactive drugs, caffeine, vitamin C, alcohol, and tobacco for at least ≥8 h prior to the draw.⁶² In order to ensure the measurement of chronic and not acute effects, sampling took place no earlier than 48 h after an exercise session. Blood was drawn from the antecubital vein between 7:00 a.m. and 10:00 a.m. after a 12-h fasting period (water only) and then clotted at room temperature for 31.2 min. After centrifugation (Sigma 30K; Sigma Laborzentrifugen GmbH; Osterede am Harz, Germany) at 2000g for 5 min, the serum was collected and centrifuged again at 12,000 revolution per minute (rpm) for 15 min to remove cell debris. Blood was collected by venipuncture, and serum was centrifuged, aliquoted, and stored at 80°C until analysis of selected cytokines, adiponectin, leptin, and SOCS3. The selected metabolic biomarkers, including fasting insulin, fasting blood glucose, total cholesterol (TC), HDL-C, low-density lipoprotein cholesterol (LDL-C), sex hormone binding globulin (SHBG), and 17-β-estradiol were measured after blood collection on the same day. Post-intervention blood sampling was performed 2–3 days after the last exercise session to avoid the acute effects of exercise. The selected biomarkers fasting insulin, fasting blood glucose, TC, HDL-C, and LDL-C were analyzed by standardized automated analyses for clinical samples.

TC levels were measured using an Elitech kit (Elitech Group, Paris, France); LDL-C, HDL-C, and fasting blood glucose were analyzed using a Pars Azmoon kit (Pars Azmoon, Karaj, Iran). All lipid profiles were analyzed on a Mindray BS300 chemistry autoanalyzer (Shenzhen Mindray Bio-Medical Electronics Co., Ltd., Shenzhen, China). Plasma insulin levels were measured using an enzyme-linked immunosorbent assay (ELISA) kit (Mercodia, Uppsala, Sweden). The coefficient of variation (CV) for insulin was 4.2%, and the sensitivity of the assay was 1 U/mL. Plasma glucose concentration was determined using the enzymatic (glucose oxidase-amino antipyrine) colorimetric method. The CV for glucose was 1.3%, and the sensitivity was 1 mg/dL. Insulin resistance estimated from the homeostasis model assessment of insulin resistance that was calculated using the formula: fasting insulin (µU/L) × fasting glucose (mmol/L)/22.5. In each subject, the degree of insulin resistance was calculated by HOMA formula. The serum levels of estradiol (pg/mL) were measured by the radioimmunoassay method and using the specteriaorion diagnostic kit (Spectria estradiol; Orion Diagnostica, Espoo, Finland) with intra-assay CV = 5.3% and inter-assay CV = 5.4%.

The serum concentration of leptin (μg/mL), adiponectin (pg/mL), SOCS3 (pg/mL), and SHBG (pg/ mL) was determined by an ELISA using commercial kits (Human Adiponectin, Zell Bio GmbH, Ulm, Germany) according to the manufacturer's standard protocol. The serum concentration of tumor necrosis factor-α (TNF-α) (catalog numbers: DY210-05/DY210/DY217B; R&D System Inc., Minneapolis, MN, USA), IL-6 (catalog numbers: DY206-05/DY206; R&D System Inc.), and IL-10 (catalog number: DY217B-05; R&D System Inc.) were measured using the ELISA method according to the manufacturer's instructions.

2.3.6. Outcomes

Our primary outcomes were inflammatory cytokines, including IL-6, IL-10, TNF-α, and adipokines, including leptin and adiponectin.

The secondary outcomes were training adherence, body composition (BMI, body weight, body fat, and lean body mass), anthropometry indices (waist circumference and hip circumference), physical function (sit-to-stand test), cardiorespiratory fitness (VO_2peak), and quality of life.

2.4. Exercise interventions

The patients met for training 3 times per week for 12 weeks under the supervision of a certified exercise physiologist. The patients trained at the lower intensity limit for the first 2 weeks of the training period before increasing the intensity towards the upper limit. A 3-min walk at 50%–60% VO_2peak was performed between intervals. The training session ended with a 3-min cool-down period at 50%–60% VO_2peak. This resulted in a total exercise time of 33 min for the HIIT group. To equate the training volume of the 2 groups, the following calculation was used: the average VO_2peak for all subjects before training was 1.15 L/min. The HIIT group completed four 4-min exercises at 1.03 L/min (90% of VO_2peak) and three 3-min exercises at 0.69 L/min (60% of VO_2peak). The total VO₂–time relationship for the high-intensity group was then divided by the intensity for the moderate-intensity group (22.77 L/0.69 L/min = 33 min). Finally, the warm-up and cool-down exercise time for the HIIT group (5 min + 3 min) at 0.69 L/min was added to this value. Moderate-intensity training thus consisted of 41 min of continuous training at an intensity of 60% VO_2peak, which corresponds to the same total training volume as the HIIT group.⁶³

All subjects exercised with an HR monitor during each training session. Subjects were thus able to control their corresponding exercise HR relative to VO_2peak and were encouraged by the instructor to exercise as close to the upper-intensity limit as possible (after 2 weeks for the HIIT group).⁶⁴ The speed and incline of the treadmill were continuously adjusted during the workout. The exercise intensity monitored based on maximal HR corresponds to VO_2peak. Adherence was tracked to verify that prescribed intensities were tolerable.

Exercise attendance, reasons for missed sessions, and ability to achieve the prescribed goal (intensity and distance) were recorded at each exercise session to determine adherence. HR and RPE were continuously monitored during each interval and during recovery to monitor participants’ responses to the exercise and to make adjustments as needed. All exercise sessions were supervised by an accredited exercise physiologist experienced in working with cancer survivors.

2.5. Sample size

To estimate the sample size, we relied on measures of cardiorespiratory fitness improvement from studies comparing HIIT and MICT clinical subjects. The difference in VO_2peak improvement ranged from 10% to 19% in mixed samples.⁴⁶ We selected 10 subjects per group, as an n of at least 8 would be required to provide a power of 80% to detect a 10% change in VO_2peak and to predict a large effect size (ES) of 1.34 discernible between HIIT and MICT at p < 0.05.

2.6. Statistical analysis

Statistical analysis was performed using the SPSS Version 17 (SPSS Inc., Chicago, IL, USA). The normality of the data was confirmed using the Shapiro–Wilk test, and the data are presented as mean ± SD. General comparisons between groups were performed using analysis of variance followed by Tukey's honestly significant difference test to determine specific statistically significant group differences. We compared the means of post- and pre-intervention within groups using the paired t test. An analysis of covariance was performed to determine the mean differences between groups for each variable at baseline and the end of the study. The pre-test values are considered covariates. Bonferroni tests were performed to compare means between groups. The ES was measured by partial eta squared (η_p²). Cohen⁶⁵ provided benchmarks to define small (η_p² = 0.01), medium (η_p² = 0.06), and large (η_p² = 0.14) effects. The two-tailed p < 0.05 was considered significant.

3. Results

3.1. Baseline characteristics

Table 2 presents the summary statistics of demographic and clinical factors measured at baseline among all participants by intervention group. The analysis of variance revealed no statistically significant differences between groups in age, BMI, body weight, body fat, waist circumference, hip circumference, physical function, cardiorespiratory fitness, resting HR, fasting blood sugar, insulin, lipids (TC, HDL-C, and LDL-C), SHGB, SOCS3, leptin, adiponectin, IL-6, TNF-α, IL-10, quality of life domains, or physical activity levels at baseline. There were some adverse events possibly related to participation in the trial, including reports of muscle soreness and joint pain. There were no serious adverse events reported. Exercise adherence in the HIIT group was better than in the MICT group (proportion of sessions attended is 98% vs. 92%), but there were no significant differences between groups (p = 0.396). For the HIIT group, the average HR during the session was 135 ± 15 beats per minute (bpm) during intervals (mean ± SD), while RPE = 15 ± 2 using the Borg 6–20 scale. The average HR and RPE at the end of the 3-min active recovery was 117.8 ± 15.0 bpm and 8 ± 2, respectively. The average HR for the MICT group was 102.8 ± 11.3 bpm and RPE = 11.3 ± 4.6 during the main sessions.

Table 2.

Baseline characteristics by randomization group (mean ± SD or n).

Characteristics	Total (n = 30)	CON (n = 10)	MICT (n = 10)	HIIT (n = 10)
Age (year)	45.13 ± 6.86	44.90 ± 5.02	46.29 ± 6.29	44.00 ± 9.14
Weight (kg)	70.02 ± 10.72	68.94 ± 1011.18	72.85 ± 11.07	68.08 ± 8.87
BMI (kg/m2)	27.51 ± 4.96	27.37 ± 4.88	28.10 ± 5.14	26.50 ± 3.48
Stage at diagnosis
Stage 0	0	0	0	0
Stage I	2	0	1	1
Stage II	13	5	4	4
Stage III	15	5	5	5
Breast cancer subtype
Triple negative	3	1	1	1
HER2+, ER+, and/or PR+	8	4	3	1
HER2+, ER–, and/or PR–	8	1	2	5
HER2–, ER+, and/or PR+	11	4	4	3
Treatment
Lumpectomy/axillary	6	1	2	3
Mastectomy	8	3	1	4
Chemotherapy	29	10	9	10
Radiation (yes)	30	10	10	10
Targeted (herceptin)	3	1	1	1
Hormone—tamoxifen	27	9	9	9
Hormone—letrozol	3	1	1	1
Previous frequency of activity
≤ 1 day/week	23	7	8	8
2–5 days/week	7	3	2	2
>5 days/week	0	0	0	0
Previous intensity of activity
Low	26	8	8	8
Moderate	4	2	1	1
High	0	0	0	0
Previous duration (min/day)
<30	4	1	2	1
30–60	25	9	8	7
>60	1	0	0	1

Abbreviations: BMI = body mass index; CON = control; ER = estrogen receptor; HER2 = human epidermal growth factor receptor-2; HIIT = high-intensity interval training; MICT = moderate-intensity continuous training; PR = progesterone receptor.

3.2. Primary outcomes

We observed no significant changes in inflammatory markers IL-6, TNF-α, or IL-10 (Table 3). No statistically significant effects of exercise interventions (HIIT and MICT) on leptin or adiponectin were observed (Table 3). We did observe a significant increase in SOCS3 (mean difference = 0.09 pg/mL, 95% confidence interval (95%CI): 0.01–0.17, p = 0.032) in HIIT compared to baseline (Table 3).

Table 3.

Changes in adipokines and inflammatory markers of HIIT, MICT, and control groups.

Variable	Pre-intervention (mean ± SD)	Post-intervention (mean ± SD)	p	Change		Between-group differences
				Marginal means	95% confidence interval	p	Effect size
Adiponectin (μg/mL)
CON	2.54 ± 0.51	2.33 ± 0.63	0.241	–0.20	–0.57 to 0.16	0.855	0.012
MICT	2.40 ± 0.53	2.29 ± 0.57	0.548	–0.10	–0.47 to 0.27
HIIT	2.32 ± 0.49	2.32 ± 0.30	0.994	0.01	–0.28 to 0.28
Leptin (μg/mL)
CON	66.79 ± 13.40	73.03 ± 18.62	0.156	6.23	–2.86 to 15.34	0.487	0.054
MICT	70.29 ± 18.80	68.62 ± 13.71	0.825	–1.67	–18.28 to 14.95
HIIT	68.74 ± 13.25	75.24 ± 15.29	0.057	6.49	–0.23 to 13.22
SOCS3 (pg/mL)
CON	0.95 ± 0.20	0.86 ±0.18	0.125	–0.094	–0.21 to 0.03	0.001$	0.154†
MICT	0.79 ± 0.21	0.92 ± 0.23	0.147	0.13	–0.05 to 0.31
HIIT	0.75 ± 0.30	0.84 ± 0.33	0.032⁎	0.09	0.01 to 0.17
IL-6 (pg/mL)
CON	30.19 ± 1.81	31.91 ± 6.31	0.454	1.72	–3.25 to 6.70	0.498	0.052
MICT	31.13 ± 3.45	32.30 ± 3.02	0.178	1.17	–0.64 to 2.98
HIIT	29.71 ± 1.37	29.83 ± 1.59	0.805	0.12	–1.00 to 1.26
IL-10 (pg/mL)
CON	180.59 ± 14.08	186.8 ± 17.86	0.394	6.24	–9.53 to 22.03	0.913	0.007
MICT	191.77 ± 30.58	193.7 ± 41.8	0.825	1.93	–17.34 to 21.21
HIIT	176.97 ± 10.02	185.7 ± 18.6	0.114	8.75	–2.54 to 20.05
TNF-α (pg/mL)
CON	156.1 ± 53.50	173.0 ± 62.0	0.189	16.87	–9.99 to 43.75	0.837	0.014
MICT	205.6 ± 108.6	229.9 ± 158.9	0.483	24.32	–50.86 to 99.52
HIIT	161.6 ± 41.9	166.0 ± 41.6	0.500	4.47	–9.19 to 18.86
TNF-α/IL-10
CON	0.86 ± 0.29	0.91 ± 0.28	0.517	0.04	–0.11 to 0.21	0.680	0.029
MICT	1.03 ± 0.36	1.10 ± 0.49	0.406	0.07	–0.17 to 0.26
HIIT	0.90 ± 0.18	0.89 ± 0.22	0.771	–0.01	–0.15 to 0.88

Note: The data in bold are to show those that are significant.

^⁎p ˂ 0.05 compared with pre-intervention.

^$p ˂ 0.05 denotes significant differences between groups

^†denotes significant effect size.

Abbreviations: CON = control; HIIT = high-intensity interval training; IL-6 = interleukin-6; IL-10 = interleukin-10; MICT = moderate-intensity continuous training; SOCS3 = suppressor of cytokine signaling 3; TNF-α = tumor necrosis factor-α.

Patients in the control group showed higher insulin levels (mean difference = 3.86 mU/L, 95%CI: 0.92–6.79, p = 0.016) and TC levels (mean difference = 17.00 mg/dL, 95%CI: 0.58–33.41, p = 0.044) in comparison to baseline. The analysis of covariance analysis showed a significant differences in the levels of HDL-C between groups (p = 0.005, ES = 0.353) (Table 4). Furthermore, the Bonferroni post hoc test showed a significant difference between HIIT (mean difference = 9.172 mg/dL, 95%CI: 2.430–15.908, p = 0.003) and MICT (mean difference = 7.879 mg/dL, 95%CI: 1.118–14.640, p = 0.014) in comparison to the control group but no difference between MICT and HIIT groups. Interestingly, pre- and post-intervention, estradiol levels were higher in the control group than both the HIIT and MICT groups, but a significant difference was only observed in the HIIT compared to control group (mean difference = 14.32 pg/mL, 95%CI: 5.77–22.86, p = 0.044). The results showed no differences in SHBG levels between the control, HIIT, and MICT groups (Table 4).

Table 4.

Changes in metabolic indices and sex hormones of HIIT, MICT, and control groups.

Variable	Pre-intervention (mean ± SD)	Post-intervention (mean ± SD)	p	Change		Between-group differences
				Marginal means	95% confidence interval	p	Effect size
Fasting blood sugar (mmol/L)
CON	5.35 ± 1.08	5.51 ± 1.30	0.588	0.18	–1.36 to 1.01	0.574	0.042
MICT	5.22 ± 0.98	5.13 ± 0.97	0.357	–0.08	–0.29 to 0.11
HIIT	4.62 ± 0.70	4.66 ± 0.56	0.769	0.04	–0.24 to 0.32
Total cholesterol (mg/dL)
CON	159.90 ± 36.78	176.90 ± 48.85	0.044⁎	17.00	0.58 to 33.41	0.275	0.094
MICT	174.00 ± 26.15	165.80 ± 32.31	0.434	–8.20	–30.83 to 14.43
HIIT	153.20 ± 27.12	166.70 ± 29.89	0.263	13.50	–12.00 to 39.00
HDL-C (mg/dL)
CON	50.00 ± 10.52	45.10 ± 10.67	0.060	–4.9	–10.06 to 0.26	0.005†	0.353‡
MICT	47.80 ± 11.04	51.40 ± 8.79	0.062	3.60	–0.21 to 7.41
HIIT	49.90 ± 11.40	54.20 ± 9.80	0.083	4.30	–0.68 to 9.28
LDL-C (mg/dL)
CON	94.70 ± 34.83	93.20 ± 31.97	0.526	–1.50	–6.65 to 3.65	0.397	0.069
MICT	86.30 ± 16.80	87.90 ± 23.41	0.771	1.60	–10.46 to 13.66
HIIT	74.80 ± 12.36	88.10 ± 22.04	0.144	13.30	–5.49 to 32.09
Insulin (mU/L)
CON	11.67± 5.86	15.53 ± 3.63	0.016*	3.86	0.92 to 6.79	0.139	0.141
MICT	15.16± 7.32	14.22 ± 6.41	0.610	–0.94	–4.96 to 3.08
HIIT	10.25 ± 4.71	12.09 ± 4.78	0.124	1.84	–0.61 to 4.29
HOMA-IR
CON	3.01 ± 1.80	3.76 ± 0.78	0.139	0.75	–0.29 to 1.78	0.096	0.165
MICT	3.72 ± 2.19	3.38 ± 1.85	0.397	–0.34	–1.20 to 0.52
HIIT	2.11 ± 0.98	2.47 ± 0.98	0.144	0.36	–0.15 to 0.88
Estradiol (pg/mL)
CON	56.41 ± 11.83	82.48 ± 13.72	0.000*	26.07	16.62 to 35.51	0.029†	0.238‡
MICT	48.58 ± 21.83	73.51 ± 12.07	0.001*	24.93	13.93 to 35.92
HIIT	54.05 ± 31.90	68.37 ± 23.66	0.004*	14.32	5.77 to 22.86
SHBG (pg/mL)
CON	9.10 ± 1.81	9.86 ± 1.96	0.184	0.75	–0.43 to 1.94	0.421	0.064
MICT	8.56 ± 3.09	8.64 ± 2.19	0.932	0.13	–0.05 to 0.31
HIIT	8.79 ± 1.90	9.38 ± 1.84	0.108	0.59	–0.15 to 1.34

Note: The data in bold are to show those that are significant.

^⁎p ˂ 0.05 compared with pre-intervention.

^†p ˂ 0.05 denotes significant differences between groups.

^‡denotes significant effect size.

Abbreviations: CON = control; HIIT = high-intensity interval training; HDL-C = high-density lipoprotein cholesterol; HOMA-IR = homeostasis model assessment of insulin resistance; LDL-C = low-density lipoprotein cholesterol; MICT = moderate-intensity continuous training; SHBG = sex hormone binding globulin.

3.3. Secondary outcomes

3.3.1. Changes in anthropometry and body composition

The age of the participants was 45.13 ± 6.86 years, with the BMI of 27.51 ± 4.96 kg/m² (Table 2). The body weight in the control group increased by about 0.46 kg post-intervention (mean difference = 0.46 kg, 95%CI: –1.29 to 2.20, p = 0.567); however, it decreased by about 0.54 kg (mean difference = –0.54 kg, 95%CI: –0.73 to 1.80, p = 0.364) and 0.08 kg (mean difference = –0.08 kg, 95%CI: –0.92 to 0.76, p = 0.835) in MICT and HIIT groups, respectively (Table 5). There is no significant difference in body weight between groups post-intervention (p = 0.613). The BMI did not change significantly in control (mean difference = –0.13 kg/m², 95%CI: –0.53 to 0.27, p = 0.483), MICT (mean difference = 0.34 kg/m², 95%CI: –1.01 to 1.70, p = 0.576), or HIIT groups (mean difference = –0.06 kg/m², 95%CI: –0.39 to 0.27, p = 0.685) when compared with pre-intervention, respectively. There is no significant difference in BMI between groups post-intervention (p = 0.497).

Table 5.

Changes in body compositions for HIIT, MICT, and control groups.

Variable	Pre-intervention (mean ± SD)	Post-intervention (mean ± SD)	p	Change		Between-group differences post-intervention
				Marginal means	95% confidence interval	p	Effect size
Body weight (kg)
CON	68.94 ± 11.18	69.40 ± 9.63	0.567	0.46	–1.29 to 2.20	0.613	0.037
MICT	72.58 ± 11.30	72.04 ± 11.39	0.364	–0.54	–0.73 to 1.80
HIIT	68.08 ± 8.87	68.00 ± 2.74	0.835	–0.08	–0.92 to 0.76
BMI (kg/m2)
CON	27.37 ± 4.88	27.24 ± 4.60	0.483	–0.13	–0.53 to 0.27	0.497	0.052
MICT	28.10 ± 5.14	28.45 ± 4.92	0.576	0.34	–1.01 to 1.70
HIIT	26.50 ± 3.48	26.44 ± 3.39	0.685	–0.06	–0.39 to 0.27
Lean body mass (kg)
CON	41.43 ± 4.21	41.23 ± 3.52	0.711	–0.20	–1.37 to 0.97	0.665	0.031
MICT	45.02 ± 6.04	44.76 ± 5.78	0.608	–0.26	–1.37 to 0.84
HIIT	44.00 ± 4.11	44.13 ± 4.11	0.764	0.12	–0.76 to 1.01
Fat mass (kg)
CON	27.50 ± 8.17	28.16 ± 7.37	0.210	0.66	–0.44 to 1.76	0.255	0.100
MICT	27.55 ± 7.90	27.27 ± 7.31	0.633	–0.27	–0.99 to 1.55
HIIT	24.07 ± 5.59	23.86 ± 6.11	0.682	–0.20	–1.27 to 0.87
Fat percent (%)
CON	39.13 ± 6.29	40.01 ± 5.66	0.122	0.88	–0.28 to 2.04	0.159	0.132
MICT	37.46 ± 6.52	37.38 ± 5.71	0.889	–0.08	–1.17 to 1.33
HIIT	34.99 ± 4.21	34.70 ± 5.20	0.631	–0.29	–1.61 to 1.03
Waist circumference (cm)
CONT	82.00 ± 10.39	81.20 ± 9.09	0.505	–0.80	–3.40 to 1.80	0.397	0.069
MICT	86.90 ± 9.51	84.70 ± 10.18	0.051	–2.20	−4.40 to −0.01
HIIT	80.10 ± 6.57	80.60 ± 7.42	0.657	0.50	–1.96 to 2.96
Hip circumference (cm)
CONT	100.20 ± 6.21	99.80 ± 6.54	0.739	0.40	–3.03 to 2.23	0.528	0.048
MICT	103.00 ± 6.94	101.90 ± 7.35	0.207	–1.10	–0.73 to 2.93
HIIT	102.90 ± 7.69	103.40 ± 6.85	0.662	0.50	–2.00 to 3.00

Abbreviations: BMI = body mass index; CON = control; HIIT = high-intensity interval training; MICT = moderate-intensity continuous training.

The fat mass did not change in control (mean difference = 0.66 kg, 95%CI: –0.44 to 1.76, p = 0.210), MICT (mean difference = –0.27 kg, 95%CI: –0.99 to 1.55, p = 0.633), and HIIT (mean difference = –0.20 kg, 95%CI: –1.27 to 0.87, p = 0.682) groups, respectively. There is no significant difference in fat mass between groups post-intervention (p = 0.255). According to these findings, neither HIIT nor MICT interventions produced substantial changes in body composition (Table 5).

We observed no significant changes in waist circumferences in control (mean difference = –0.80 cm, 95%CI: –3.40 to 1.80, p = 0.505), MICT (mean difference = –2.20 cm, 95%CI: to –0.01, p = 0.051), and HIIT (mean difference = 0.50 cm, 95%CI: –1.96 to 2.96, p = 0.657) groups after intervention. There is no significant difference in waist circumferences between groups post-intervention (p = 0.397).

We observed no significant changes in hip circumferences in control (mean difference = 0.40 cm, 95%CI: –3.03 to 2.23, p = 0.739), MICT (mean difference = –1.10 cm, 95% CI: –0.73 to 2.93, p = 0.207), and HIIT (mean difference = 0.50 cm, 95%CI: –2.00 to 3.00, p = 0.662) groups after intervention. There is no significant difference in hip circumferences between groups post-intervention (p = 0.528) (Table 5).

3.3.2. Functional capacity (sit-to-stand test)

The results from sit-to-stand test showed a significant improvement in functional capacity in both HIIT group (mean difference= 4.10 times, 95%CI: 0.73–7.49, p = 0.005) and MICT group (mean difference =  4.00 times, 95%CI:  0.35–7.46, p = 0.035) after intervention, respectively. However, there are no significant differences between groups (p = 0.266) (Table 6).

Table 6.

Changes in functional capacity and cardiorespiratory fitness of HIIT, MICT, and control groups.

Variable	Pre-intervention (mean ± SD)	Post-intervention (mean ± SD)	p	Change		Between-group differences post-intervention
				Marginal means	95% confidence interval	p	Effect size
Functional capacity (sit-to-stand test)
CON	15.80 ± 5.24	16.10 ± 3.21	0.820	0.30	–2.60 to 3.20	0.266	0.097
MICT	13.40 ± 3.80	17.40 ± 6.93	0.035*	4.00	0.35 to 7.64
HIIT	14.00 ± 3.05	18.10 ± 4.40	0.005*	4.10	0.73 to 7.49
Cardiorespiratory fitness (VO2peak) (mL/kg/min)
CON	16.60 ± 2.38	16.72 ± 1.96	0.901	0.12	–2.00 to 2.24	0.001†	0.272‡
MICT	16.62 ± 3.00	17.37 ± 3.95	0.329	0.75	–0.89 to 2.39
HIIT	17.04 ± 2.99	20.65 ± 3.87	0.023⁎	3.61	–1.39 to 5.82
VCO2 (L/min)
CON	1.30 ± 0.29	1.33 ± 0.24	0.703	0.20	–0.18 to 0.13	0.843	0.014
MICT	1.25 ± 0.30	1.36 ± 0.32	0.209	0.11	–0.30 to 0.08
HIIT	1.31 ± 0.34	1.43 ± 0.23	0.103	0.11	–0.06 to 0.02
HR (beats/min)
CON	135.50 ± 21.98	144.20 ± 27.20	0.915	–1.00	–19.66 to 21.66	0.086	0.022
MICT	135.50 ± 21.9	144.20 ± 27.20	0.350	8.70	–28.70 to 11.30
HIIT	153.60 ± 19.38	152.60 ± 17.23	0.740	–1.00	–5.63 to 7.63
VE (L/min)
CON	45.70 ± 11.34	44.80 ± 6.39	0.686	–1.10	–4.85 to 7.05	0.501	0.056
MICT	43.20 ± 11.25	44.90 ± 7.59	0.650	1.70	–9.89 to 2.49
HIIT	43.40 ± 11.25	48.80 ± 7.79	0.071	5.20	–10.94 to 0.54
VE/VO2
CON	40.03 ± 8.70	35.63 ± 3.76	0.184	–4.44	–2.51 to 11.31	0.451	0.064
MICT	43.20 ± 11.25	44.90 ± 7.25	0.397	2.35	–7.66 to 2.99
HIIT	37.65 ± 4.43	34.99 ± 5.29	0.240	–2.66	–2.14 to 7.46
VE/VCO2
CON	33.55 ± 4.23	32.48 ± 2.55	0.182	–1.07	–0.60 to 1.25	0.739	0.025
MICT	35.19 ± 8.71	37.54 ± 5.04	0.397	–0.87	–1.34 to 3.08
HIIT	32.27 ± 1.81	32.76 ± 1.76	0.242	0.49	–1.37 to 0.39
VO2/HR
CON	0.0091 ± 0.0023	0.0085 ± 0.0019	0.350	0.0005	–0.0005 to 0.0006	0.837	0.015
MICT	0.0093 ± 0.0011	0.0084 ± 0.0012	0.199	0.0007	–0.0004 to 0.0021
HIIT	0.0081 ± 0.0012	0.0091 ± 0.0012	0.120	0.0005	–0.0011 to 0.0013

Note: The data in bold are to show those that are significant.

^⁎p ˂ 0.05 compared with pre-intervention.

^†p ˂ 0.05 denotes significant differences between groups.

^‡denotes significant effect size.

Abbreviations: CON = control; HIIT = high-intensity interval training; HR = heart rate; MICT = moderate-intensity continuous training; VCO₂ = carbon dioxide production; VE = ventilator equivalent; VE/VCO₂ = ventilator equivalent for carbon dioxide; VE/VO₂ = ventilator equivalent for oxygen; VO_2peak = peak oxygen uptake.

3.3.3. Cardiorespiratory fitness

The baseline values for peak VO₂, VE, VE/VCO₂, VE/VO₂, or VO₂/HR did not differ between groups (p > 0.05). Relative VO_2peak increased by 16.8% in the HIIT group in comparison to baseline values (mean difference = 3.61 mL/kg/min, 95%CI: –1.39 to 5.82, p = 0.023) (Table 6). The HIIT group saw a significant increase in VO_2peak compared to other groups. The Bonferroni post hoc test showed a significant difference between HIIT and CON group (mean difference = 3.609 mL/kg/min, 95%CI: 0.440–6.771, p = 0.001). MICT appeared to have no significant effects on VO_2peak, and we observed that HIIT was superior to MICT in terms of improving VO_2peak (mean difference = 2.974 mL/kg/min, 95%CI: −0.188 to 6.135, p = 0.005). There were no significant changes in the HR, VE, or VCO₂, as well as for VE/VO₂ or VE/VCO₂ with either HIIT or MICT interventions (p > 0.05) (Table 6).

3.3.4. Changes in quality of life

We observed that participants in the HIIT group significantly improved their physical well-being (mean difference = 1.40, 95%CI: 0.43–2.36, p = 0.010), social well-being (mean difference = 2.30, 95%CI: 0.90–3.69, p = 0.005), emotional well-being (mean difference = 2.50, 95%CI: 1.32–3.68, p = 0.001), and functional well-being subscales (mean difference = 2.60, 95%CI: 0.48–4.71, p = 0.021) and total FACT-G scores (mean difference = 8.80, 95%CI: 5.88–11.71, p = 0.000) in comparison to baseline (Table 7). The MICT also significantly improved their physical well-being (mean difference = 3.20, 95%CI: 0.70–5.69, p = 0.018), social well-being subscales (mean difference = 2.00, 95%CI: 0.09–3.90, p = 0.042), and total FACT-G scores (mean difference = 7.00, 95%CI: 1.44–13.95, p = 0.021) in comparison to baseline (Table 7). According to the analysis of covariance, the physical well-being subscale score showed significant differences between groups (p = 0.043; ES = 0.214). In addition, the Bonferroni post hoc test showed a significant increase in the physical well-being subscale scores in MICT compared to the control group (mean difference = 3.268, 95%CI: 0.129–6.400, p = 0.026). Participants in the HIIT group showed a non-significant increase in physical well-being compared to the control group (mean difference = 3.927, 95%CI: –0.343 to 8.197, p = 0.076). HIIT improved social well-being compared to the control group (mean difference = 4.412, 95%CI: 0.259–8.565, p = 0.035). Emotional well-being subscale scores showed significant differences between groups (p = 0.017; ES = 0.268) (Table 7). In addition, pairwise Bonferroni post hoc test showed a significant increase in emotional well-being subscale scores in MICT (mean difference = 4.248, 95%CI: 0.105–8.392, p = 0.023) and HIIT (mean difference = 4.412, 95%CI: 0.259–8.565, p = 0.016) compared to the control group. Functional well-being showed a significant differences between groups (p = 0.015; ES = 0.209). Pairwise Bonferroni post hoc test showed a significant increase in functional well-being subscale scores in HIIT compared with control group (mean difference = 3.35, 95%CI: –0.12 to 6.57, p = 0.014). We also observed significant differences in total FACT-G scores between the 3 groups (p = 0.001; ES = 0.429) (Table 7). The Bonferroni post hoc test showed a significant increase in total FACT-G scores in HIIT (mean difference = 14.204, 95%CI: 5.642–22.406, p = 0.001) and MICT groups (mean difference = 10.036, 95%CI: 1.580–18.492, p = 0.001) compared to the control group.

Table 7.

Changes in quality of life domains of HIIT, MICT, and control groups.

Variable	Pre-intervention (mean ± SD)	Post-intervention (mean ± SD)	p	Change		Between-group differences post-intervention
				Marginal means	95% confidence interval	p	Effect size
Physical well-being (score)
CON	9.10 ± 6.80	8.80 ± 4.51	0.803	–0.30	–2.93 to 2.33	0.043*	0.214†
MICT	8.30 ± 3.09	11.50 ± 4.76	0.018‡	3.20	0.70 to 5.69
HIIT	8.80 ± 3.85	10.20 ± 3.76	0.010‡	1.40	0.43 to 2.36
Social well-being (score)
CON	16.90 ± 6.96	15.90 ± 6.93	0.594	–1.00	–5.08 to 3.08	0.026*	0.189†
MICT	16.40 ± 4.22	18.40 ± 5.01	0.042‡	2.00	0.09 to 3.90
HIIT	19.50 ± 4.47	21.80 ± 3.82	0.005‡	2.30	0.90 to 3.69
Emotional well-being (score)
CON	9.40 ± 5.12	7.10 ± 3.17	0.193	–2.30	–5.99 to 1.39	0.017*	0.268†
MICT	9.50 ± 5.48	11.40 ± 5.96	0.272	1.90	–1.77 to 5.57
HIIT	8.60 ± 4.42	11.10 ± 3.51	0.001‡	2.50	1.32 to 3.68
Functional well-being (score)
CON	20.50 ± 5.96	19.80 ± 4.49	0.684	–0.70	–5.99 to 3.071	0.015*	0.209†
MICT	18.70 ± 2.98	20.90 ± 3.72	0.062	2.20	0.13 to 4.53
HIIT	20.60 ± 5.54	23.20 ± 4.78	0.021‡	2.60	0.48 to 4.71
Total FACT-G (score)
CON	55.90 ± 13.36	51.60 ± 9.40	0.303	–4.30	–13.19 to 4.59	0.001*	0.429†
MICT	52.50 ± 7.56	60.20 ± 9.65	0.021‡	7.00	1.44 to 13.95
HIIT	57.50 ± 6.68	66.30 ± 4.73	0.000‡	8.80	5.88 to 11.71

Note: The data in bold are to show those that are significant.

^⁎p ˂ 0.05 denotes significant differences between groups.

^†denotes significant effect size.

^‡p ˂ 0.05 compared with pre-intervention.

Abbreviations: CON = control; FACT-G = functional assessment of cancer therapy-General; HIIT = high-intensity interval training; MICT = moderate-intensity continuous training.

4. Discussion

This study aimed to compare the effects of HIIT and MICT on inflammatory markers, adipokines, metabolic indices, body composition, cardiorespiratory fitness, and quality of life in breast cancer patients. Cardiorespiratory fitness increased more in response to HIIT than to MICT. We also observed an increase in HDL-C in the HIIT group as compared to the MICT or control groups. There were no significant changes in body composition, metabolic indices, TC, LDL-C, adipokines, or inflammatory markers in the HIIT and MICT groups. Quality of life improved in the HIIT and MICT groups as compared to the control group.

Our results re-emphasize that HIIT is feasible for breast cancer patients due to patients’ high adherence and compliance. The greater enjoyment associated with HIIT may be relevant for improving exercise adherence.³⁸ It appears to be a safe modality for breast cancer patients, as participants did not report any significant adverse effects during or after exercise sessions.

We observed no significant changes in body weight, fat mass, lean body mass, or BMI as a result of the HIIT or MICT interventions. However, body weight and fat mass showed a non-significant increase in the control group. According to current guidelines, patients are advised to avoid weight gain after treatment to improve breast cancer outcomes.⁶⁶ The weight changes seen in our participants were similar to those in other studies, which resulted in little or no weight loss.^67,68 Previous studies have shown that exercise alone does not lead to weight loss, but it can be essential to avoid weight gain.^69,70 Currently, Sultana et al.,⁷¹ in a systematic review and meta-analysis, demonstrated that HIIT is inefficient for modulating total body fat mass or fat percentage in comparison to a non-exercise control and MICT. As shown by studies examining the simultaneous effects of diet and exercise on weight loss in postmenopausal women, exercise alone had no significant effect on weight loss or BMI reduction.^25,72 This would indicate that, in order to see body weight or fat reduction, a nutritional intervention should be considered concurrently with exercise. Other studies have shown that exercise can reduce body fat and increase lean muscle mass in cancer patients.^73,74 The majority of these trials used dual-energy X-ray absorptiometry scanning to assess fat mass, which has been demonstrated to be more accurate in determining body composition than the sum of skinfold method used in our study. Therefore, it remains difficult to determine the true impact of exercise on body composition.

Cardiorespiratory fitness is associated with mortality in breast cancer patients. In this context, Peel et al.² observed that women with moderate and high cardiorespiratory fitness had a 33% and 55% lower risk of dying from breast cancer, respectively. Cancer treatments, such as chemotherapy or radiotherapy, can cause unfavorable changes in aerobic and functional capacity in breast cancer patients.⁷⁵ The main finding of the present study was that HIIT improved cardiorespiratory fitness compared to the control and MICT groups. Consistent with our results, Toohey et al.⁴⁹ showed that low-volume, high-intensity exercise is a promising and effective exercise program for the cancer population that shows significant improvements in cardiorespiratory fitness. Recently, Hooshmand Moghadam et al.⁵⁰ demonstrated improved cardiorespiratory fitness with HIIT or MICT intervention in obese breast cancer survivors. They also noted that HIIT provided no additional benefit compared to MICT in terms of improving aerobic power. The evidence has shown that low VO_2peak (<18 mL/kg/min) is associated with an increased risk of heart failure in breast cancer patients.⁷⁶ This level of VO_2peak indicates functional disability because it corresponds to the level of fitness required for the simple activities of daily living.⁷⁷ Breast cancer patients have lower aerobic fitness levels than their peers, which may increase the risk of breast cancer mortality and chronic health conditions, including cardiovascular disease.⁷⁸ Our study is the first to demonstrate more significant improvements in cardiorespiratory fitness with volume-matched HIIT compared with MICT in breast cancer patients during adjuvant endocrine therapy. Given the known inverse association between cardiorespiratory fitness and breast cancer risk and all-cause mortality, this finding is important for breast cancer surveillance.⁷⁹ For example, there is evidence that a 3.5 mL/kg/min increase in VO_2peak is associated with an 11% reduction in all-cause mortality and an 18% reduction in cardiovascular disease-specific mortality, respectively.⁸⁰ Therefore, our trial provides further evidence that high-intensity interval exercise can be beneficial for improving cardiorespiratory fitness for breast cancer survivors.

The present study did not observe any significant improvement in levels of fasting blood glucose, TC, LDL-C or insulin, and insulin resistance from HIIT or MICT protocols. Consistent with our results, Fairey et al.⁸¹ found in a randomized study that insulin levels in both groups tended to increase over the 15-week study period, with no significant change in insulin levels in either group. Ligibel et al.⁸² also found a non-significant decrease in insulin and insulin resistance and no change in fasting blood glucose from a combined resistance or aerobic exercise training intervention in breast cancer survivors. Fasting glucose, insulin, and insulin resistance were not altered by a 15-week exercise program in breast cancer survivors.⁸¹ They concluded that the exercise intervention showed no significant changes in body composition or attributed the lack of significant changes in metabolic indices to this. In this context, Kang et al.⁶⁰ in a systematic review and meta-analysis, found that insulin levels were significantly more affected in studies where intervention participants experienced weight loss. Therefore, the effect of exercise on some biochemical parameters may be related to weight changes.

There is no improvement in SHBG in HIIT or MICT groups. In this regard, McTiernan et al.⁸³ observed a significant decrease in serum estrogens in athletes compared to controls, but only in women who have lost more than 2% body fat. van Gemert et al.⁷² found in a study with the goal of 5–6 kg weight loss through exercise or diet that both the exercise and diet groups met the intervention goal, and that estradiol and SHBG improved in 2 arms. In the present study, we did not observe any significant changes in SHGB by exercise intervention. Body fat loss, more than a decrease in body weight, can induce changes in sex hormones and SHBG. Campbell et al.⁸⁴ observed that dietary weight loss could reduce serum estrogens in postmenopausal women. In addition, they showed that exercise intervention with no effect on body weight does not lower serum levels of sex hormones and increase the SHBG in postmenopausal women.⁸⁴ These results confirm that body fat loss is associated with changes in sex hormones levels and suggest that exercise inducing body fat loss may effectively induce beneficial changes in these hormones as well. We found no significant differences in body weight or fat from the exercise interventions alone. Therefore, it seems that weight loss is essential to seeing changes in sex hormones in women with breast cancer.

We observed no significant changes in leptin or adiponectin after 12 weeks of HIIT or MICT interventions. As mentioned, we found no significant reduction in central obesity as measured by waist circumference in HIIT or MICT groups. We know that central obesity is associated with elevated levels of leptin, insulin resistance, and markers of chronic inflammation.⁸⁵ Both leptin and adiponectin are hormones secreted by adipose tissue that may play a role in energy storage and utilization. Evidence suggests that serum levels of leptin are closely correlated with body fat percentage,⁸⁶ a notion supported by several authors who reported an inverse association between serum levels of leptin and reduced body fat mass.^87,88 Similarly, Swisher et al.⁶⁸ observed that 12 weeks of MICT did not affect serum cytokines and adipokines. They indicated that serum levels of leptin and adiponectin and their ratio were significantly correlated with BMI. Previous research has supported moderate correlations between body fat reduction and circulating leptin levels after hypocaloric diets in obese breast cancer survivors.⁸⁹ Although our study showed no significant change in serum levels of adipokines between groups, it provided evidence that circulating adipokines, such as leptin or adiponectin, may be associated with changes in body fat or BMI in breast cancer patients.

HIIT and MICT showed no effect on serum levels of inflammatory markers. In agreement with our findings, Rogers et al.⁹⁰ and Jones et al.⁹¹ also failed to achieve significant changes in inflammatory cytokines in exercise programs for breast cancer survivors. Endocrine therapy may modify or mediate the effect of exercise on markers of inflammation as well as other cancer biomarkers. Evidence has shown that tamoxifen and aromatase inhibitors affect inflammatory and metabolic biomarkers, likely through interaction with sex steroid pathways.⁹² In this study, we observed non-significant increases in IL-6, IL-10, or TNF-α in HIIT or MICT groups, which may be due to the acute effects of the last session of exercise.⁹³ The blood samples were collected 48 h after the last exercise session. Therefore, the acute effects of exercise may play a role in these changes. While we expected to see a reduction in inflammatory markers following HIIT, no significant improvement was detected. Exercise-induced changes in serum inflammatory cytokines have been shown to depend, at least in part, on changes in visceral adiposity tissue.⁴⁷ In a previous study,⁴⁸ we observed that HIIT decreased IL-6 and TNF-α levels, which are significant markers of low-grade systemic inflammation, in breast cancer patients undergoing hormone therapy; however, we also observed significant changes in body weight and fat percentage in that study. Other studies have reported results similar to those of the present study. For example, Gómez et al.⁹⁴ showed no changes in IL-6 or TNF-α after 8 weeks of training intervention. Ligibel et al.⁹⁵ found no significant differences in adiponectin levels in obese breast cancer survivors even after 16 weeks of strength or endurance training. It is unclear why exercise-induced changes in IL-6 or TNF-α levels were not evident in the present study or other studies; however, it may be explained by fat loss. Previous research suggests that approximately 25% of circulating levels of IL-6 is derived from adipose tissue.⁹⁶ Therefore, it is possible that the exercise-induced fat loss experienced in our study was insufficient to observe a significant decrease in circulating IL-6 and TNF-α levels.

Understandably, a cancer diagnosis can negatively impact a person's quality of life,⁹⁷ and a reduction in quality of life can have a profound impact on the recovery of cancer survivors.⁹⁸ We have observed that HIIT improved several aspects of quality of life, including physical, social, emotional, and functional well-being as well as total FACT-G scores, compared to baseline. MICT also significantly improved physical and social well-being as well as total FACT-G scores compared to baseline. Overall, these improvements were more significant in patients who engaged in HIIT or MICT than in the control group. It has been shown that exercise can improve quality of life, which can reduce symptoms of fatigue in breast cancer patients.⁹⁹ Most physical activity guidelines for cancer survivors generally focus on low- to moderate-intensity exercise; however, more significant improvements in quality of life may result from more vigorous exercise. We observed that HIIT and moderate-intensity continuous modalities improved quality of life in breast cancer patients. Therefore, exercise intervention—independent of volume and intensity—can be recommended for improving the quality of life of cancer patients.³⁶

5. Strengths and limitations

The strengths of this study include the use of both HIIT and MICT protocols, which afforded direct comparisons between exercise training intensity and inflammatory and metabolic markers as well as fitness, body composition markers, and quality of life in breast cancer patients. Further strengths include the inclusion of sedentary women participants, strong HIIT and MICT compliance rates, and volume-matched exercise protocols prescribed according to the basal level of VO_2peak. Furthermore, valid and objective measures were used to evaluate inflammatory markers, VO_2peak, and quality of life. Nevertheless, this study was limited by the relatively small number of participants in each group. However, the sample size was evaluated, and some of our data reached statistical significance. Additionally, the sum of skinfold thickness was utilized to measure body composition, which is not as precise an approach as dual-energy X-ray absorptiometry or hydrostatic weighing (both of which are gold standards in the assessment of body composition). Furthermore, we did not have any diet recommendations.

6. Conclusion

This study underscores that HIIT is safe, feasible, and can produce clinically relevant changes for breast cancer patients. The HIIT protocol improved cardiorespiratory fitness compared to MICT. Both HIIT and MICT improved quality of life. HIIT can be prescribed as a shorter and more effective exercise modality to improve cardiorespiratory fitness, physical function, and quality of life in breast cancer survivors. Although we did not observe any significant improvement in markers of inflammation from HIIT, these results indicate that, contrary to popular belief, this training method has no adverse effects on inflammatory cytokines or adipokines.