Breast cancer is the most commonly diagnosed cancer among women in the United States, with approximately 280,000 new cases each year [1]. Advances in breast cancer treatment have increased breast cancer–specific and overall survival for women with early-stage breast cancer, but side effects of therapy affect quality of life and functional status during and after cancer treatment. In particular, up to 75% of patients with breast cancer treated with chemotherapy experience treatment-related cognitive impairments commonly referred to as chemo-brain [1,2]. Although chemo-brain is often associated with chemotherapy, similar cognitive changes may also present as a result of the cancer itself or conditions resulting from cancer treatment (eg, pain and infection). These alterations in memory, concentration, and other cognitive abilities may represent long-term effects that diminish the quality of life of patients with breast cancer and increase the risks of patient morbidity and mortality [3,4].

Although the neurological mechanisms underlying chemo-brain remain unresolved, previous studies have demonstrated an association between physical activity, such as walking or cycling, and enhanced cognitive function in patients who have undergone chemotherapy treatment [5-7]. High-intensity interval training (HIIT) in particular has been shown to improve cognitive flexibility, executive function, and psychological well-being in both older adults and youths [8-11]. This exercise modality consists of brief periods of intense exercise interspersed with recovery intervals and is a safe and feasible exercise approach for patients with breast cancer undergoing chemotherapy [12-14]. However, the impact of HIIT on cognitive function in women undergoing chemotherapy for breast cancer remains unknown.

The primary aim of the Improving Cognitive Function Through High-Intensity Interval Training in Breast Cancer Patients Undergoing Chemotherapy (CLARITY) trial is to examine the impact of a 16-week HIIT exercise intervention on cognitive function assessed using the Montreal Cognitive Assessment, the National Institutes of Health (NIH) toolbox, and quantitative magnetic resonance imaging (MRI) of the brain. We hypothesize that executive function and memory scores will be higher after exercise compared with baseline and the attention control (AC) group and that participants in the HIIT intervention will have enhanced functional brain connectivity and structural white matter tracts compared with baseline and the AC group. The secondary aims are to examine the effects of HIIT on body composition; biomarkers related to metabolic dysregulation, inflammation, and cardiotoxicity; physical fitness and function; and quality of life and psychosocial outcomes in patients diagnosed with early-stage breast cancer undergoing chemotherapy. We hypothesize that participants in the HIIT intervention will have improved body composition and psychosocial health compared with baseline and the AC group.

The CLARITY trial is a 2-arm randomized controlled trial underway at the Dana-Farber Cancer Institute (NCT04724499). Outcomes are measured at baseline (week 1), midintervention (week 9), after the intervention (week 18), and at follow-up (week 34; HIIT group only; Figure 1). A total of 50 women diagnosed with breast cancer who are chemotherapy-naïve are randomized either to a 16-week clinic-based HIIT intervention or an AC group who will be provided with a 16-week flexibility intervention. After the initial 16-week intervention period, the HIIT group completes a further 16-week follow-up period of self-directed exercise. The AC group does not complete the follow-up period and is instead offered the HIIT program. Only the AC participants who choose to partake in the HIIT program complete testing at the follow-up point (week 34).

Women are eligible if they are (1) newly diagnosed with breast cancer, (2) planning to receive neoadjuvant or adjuvant chemotherapy (regardless of duration and regimen of drug), (3) aged >18 years, (4) nonsmokers (within the previous 12 months), (5) inactive (defined as <60 minutes of structured exercise per week), (6) cleared by their clinicians for exercise, and (7) English-speaking. Exclusion criteria include (1) having a second malignancy or metastases; (2) pregnancy; (3) weight loss of >10% within the past 6 months; (4) having any uncontrolled comorbidity, condition, or contraindication that may prevent participation in high-intensity exercise; (5) having a pacemaker or any implantable device not safe for MRI; (6) claustrophobia; and (7) having a history of coronary heart or artery disease, chronic or acute congestive heart failure, or history of systolic or diastolic insufficiencies.

Participants are currently being recruited through clinician referral and screening of patient lists at the Dana-Farber Cancer Institute, Boston, Massachusetts, as well as by way of advertisements in patient waiting rooms, the Partners Rally Platform, and other relevant breast cancer community newsletters and servers. Pending accrual rate, potential additions to recruitment efforts to boost enrollment include offering travel compensation for testing visits for those who live outside the city and offering exercise sessions at additional satellite locations. All participants require clinician clearance before being formally screened via phone. Phone screening comprises 2 short questionnaires to determine eligibility: the Godin Leisure Time Questionnaire [15] to assist in determining the participant’s current exercise levels and the Physical Activity Readiness Questionnaire [16] to confirm the participants’ health status and how this relates to undertaking an exercise program. Upon confirmation of eligibility and interest, participants consent via wet or electronic signature.

Approval of the trial protocol was obtained from the institutional review board at the Dana-Farber Cancer Institute (20-222).

After baseline testing, participants are randomly allocated to either the HIIT or AC group using a 1:1 ratio and a permuted blocked design with varying block sizes where investigators are blinded to this process. The study biostatistician and coinvestigator (HU) prepared the randomization list before study start-up, after which the investigators access through a web-based application to conduct randomization and subsequently verbally inform the participants of their group allocation. Testers and participants are blinded to group allocation during baseline testing. Owing to the nature of the intervention and logistical limitations, participants and study staff cannot be blinded to the intervention allocation.

Any expected and unexpected adverse events are or will be reported to the principal investigator, who then subsequently reports to the institutional review board of the Dana-Farber Cancer Institute. Serious events must be reported within 24 hours of occurrence or finding out about the event. All adverse events, both serious and nonserious, and deaths that are encountered from the initiation of the study intervention, throughout the study, and within 30 days of the last study intervention are followed to their resolution or until the principal investigator assesses them as stable or determines the event to be irreversible or the participant is lost to follow-up. The presence and resolution of adverse events are documented on the appropriate case report form and recorded in the participant’s medical record.

Data are monitored internally within the Dana-Farber Cancer Institute for timeliness of submission, completeness, and adherence to protocol requirements. Monitoring begins at the time of participant registration and will continue during protocol performance and completion. The study team collects, manages, and performs quality checks of the data. Potential audits or inspections may be conducted by the principal investigator or their designated representatives. All data are stored on a secure network drive using REDCap (Research Electronic Data Capture; Vanderbilt University), a Health Insurance Portability and Accountability Act–compliant web-based application hosted by Partners HealthCare Research Computing, Enterprise Research Infrastructure & Services, on password-protected computers. Any hard-copy data are stored in locked filing cabinets in card-access facilities. The results of this study will be presented in publication, conference, and invited speaker formats.

We will enroll 50 patients with breast cancer (n=25, 50% per group) in this study. We estimate that the dropout rate will at most be 20%. Assuming a 20% dropout, data from 40 (n=20, 50% per group) patients will be available for the analyses. With this sample size, we will be able to estimate within-group means for our outcome variables with a 95% CI of –0.47 to +0.47 SD units and mean differences between groups with a 95% CI of –0.64 to +0.64 SD units. Although the primary objective of the analysis for this pilot study is not to detect a between-group difference but to estimate the effect size for designing a subsequent confirmatory study, we also calculated a detectable effect size for the between-group comparison for reference. This sample size offers 80% power to detect a between-group difference at a .05 2-sided α level when the difference is 0.91 SD units.

Analyses will reflect the trial hypotheses that involve comparisons of HIIT and AC. Initial descriptive analyses will evaluate baseline comparability between the 2 intervention groups using the 2-sample, 2-tailed t test or 2-sample Wilcoxon test for continuous variables and the chi-square test or Fisher exact test for categorical variables. The primary analysis variables will be changed from baseline to week 16 of neuroimaging and cognitive function measures. Summary statistics (mean, SD, median, IQR, minimum, and maximum) will be used to describe the distribution of the variables. The mean and median will be reported along with the corresponding 95% CIs. Paired tests will be performed for these continuous outcomes for each group to assess whether there is a significant difference between baseline and week 16 in each group. For between-group comparison, a 2-sample t test will be performed. Analysis of covariance will also be used to assess the intervention effect on those continuous outcomes (changes from baseline to week 16), adjusting for patient baseline characteristics and other clinical covariates, including any participant who is required to switch to MIIT. Furthermore, those who are transferred to the MIIT group will be included in the HIIT group in the primary analysis based on the intention-to-treat principle. As an exploratory analysis, we will identify baseline factors of the patients who are likely to be transferred to the MIIT group. We will then exclude those who are transferred to the MIIT group and compare the HIIT and AC groups adjusting for factors that affect the transfer from HIIT to MIIT. Chi-square tests will be used for group comparison of binary outcomes (eg, the occurrence of adverse events). The magnitude of the intervention effect on binary outcomes will be summarized using odds ratio and the corresponding 95% CI. For each analysis, a 2-sided P value of <.05 will be considered statistically significant. As this is a pilot study, we will not adjust for multiple testing. Linear mixed-effects models will be used to estimate the trajectories of those repeatedly measured continuous outcomes across the intervention to assess group differences and explore the impact of potential prognostic factors (eg, body weight, age, fat mass, race, and menopausal status) on outcomes. Linear mixed-effects models will also be used for exploratory analysis of potential neuroimaging biomarkers. The primary analysis will include all completed outcome assessments (regardless of whether the woman stayed on the intervention), inviting those who drop out of the intervention to return for outcome assessments. The only missing data would be of those who drop out of the intervention and do not return for outcome assessments. Preliminary analyses will compare women who do and do not contribute to this analysis of baseline characteristics. A sensitivity analysis will include multiple imputations of all missing outcome data, including those patients who have missing assessments.

The CLARITY trial is the first randomized controlled trial to examine the impact of HIIT on cognitive function in patients with breast cancer undergoing chemotherapy. We hypothesize that undertaking HIIT will lead to improved executive function and memory scores and advance the current scientific knowledge regarding exercise and chemotherapy-induced brain function by incorporating (1) HIIT as an effective intervention that can enhance cognitive function; (2) multidimensional yet novel approaches to assess the effects of exercise on chemo-brain, such as fMRI, DTI, and the NIH toolbox; and (3) important secondary outcomes to provide a comprehensive understanding of the links between exercise and chemotherapy, including body composition, biomarkers related to metabolism, inflammation, cardiotoxicity, physical fitness and function, and quality of life and psychosocial outcomes.

Most patients with breast cancer experience cognitive decline during chemotherapy (up to 75%) [76,77], which may linger after treatment and even increase the risk of morbidity and mortality [78]. The onset of chemotherapy-induced cognitive decline has been an important clinical issue over the last few decades; however, the underlying mechanisms and potential interventions that can address cancer-related cognitive decline are still largely under investigation [3]. A promising nonpharmacological intervention is to engage in active physical movement, and a body of evidence supports the association between higher physical activity levels and improved cognitive function in patients with cancer [79]. A recent nationwide cohort study of 580 patients with breast cancer and 363 age-matched controls reported that patients who met the physical activity guidelines (ie, 150 minutes per week of moderate to vigorous physical activity) during chemotherapy showed significantly better self-reported cognitive function than those who did not meet the guidelines [80]. Nevertheless, the impact of exercise interventions on cognitive function in women receiving chemotherapy for breast cancer is not known. Previous exercise oncology trials have reported the preliminary benefits of exercise for cognitive function, but the overall quality of studies has been poor [79], warranting rigorously designed exercise clinical trials to explore the efficacy and mechanisms of exercise and cognition outcomes in patients with cancer undergoing chemotherapy treatment.

There are potential biological mechanisms to explain the benefits of exercise for chemotherapy-induced cognitive function. Exercise induces the expression of neurotrophic and neuroprotective markers, including brain-derived neurotrophic factor [81] and vascular endothelial growth factor [82], which contribute to “neurogenesis” in certain brain areas (eg, the hippocampus), leading to an enhancement of memory space and consolidation [83]. This mechanism is particularly plausible given that the hippocampus can be degenerated by toxic chemotherapy agents [84,85], whereas exercise has shown to not only improve hippocampus-dependent cognitive capacities but also increase the volume of the hippocampus [86-89]. Furthermore, neurological degeneration is significantly influenced by inflammatory markers [90], and exercise training can create a systemic anti-inflammatory environment to fight against and restore chemotherapy-induced cognitive decline [91-93].

Prior work has suggested that HIIT has significant potential to address chemotherapy-induced cognitive decline. For example, HIIT significantly improved cognitive responsiveness when compared with continuous moderate aerobic exercise in healthy young adults [94]. HIIT resulted in shorter reaction times and better response accuracy than continuous moderate-intensity exercise, suggesting that HIIT-induced neural adaptations redistribute neural resources to efficiently accomplish goal-directed behavior during cognitively demanding tasks. The observed decrease in P3 amplitude from fMRI following HIIT along with enhanced behavioral outcomes may indicate the implementation of greater efficiency in neuroelectric function. In addition, HIIT has successfully improved cognitive performance in patients with multiple sclerosis with reduced cognitive performance [95] and cancer-related fatigue in patients with breast cancer [14]. Furthermore, HIIT has shown superior effects on cognitive function (ie, verbal memory and executive functions) when compared with continuous moderate-intensity exercise in older adults [8] and individuals with Parkinson disease [96]. Therefore, HIIT may have the unique capacity to improve cognitive function in patients undergoing breast cancer chemotherapy.

Of importance, HIIT is a clinically proven, safe, and cost-effective intervention [97,98]. A recent study investigating HIIT in patients with heart failure with reduced ejection fraction revealed that the number of adverse events was not statistically different between the HIIT and moderate-intensity exercise group [99]. Furthermore, lower volumes of HIIT compared with moderate continuous-intensity exercise elicit better cardiovascular and physical fitness outcomes such as VO_2max; therefore, it is a time-efficient exercise option that promotes greater gains in cardiovascular outcomes [98]. During chemotherapy, the optimal type, timing, and intensity of exercise interventions are unclear. As such, the exercise protocols examined during chemotherapy in previous breast cancer studies are varied, with many using aerobic interventions with common exercise prescriptions, including 3 to 5 times per week of 30-75 minutes of moderate-intensity (40%-70% predicted maximum HR) continuous exercise rather than the on-off interval strategy of HIIT [100]. Given the potential barrier of compliance to regular exercise participation during chemotherapy in patients with breast cancer, HIIT is an intriguing option for increasing cardiovascular benefits with shorter exercise duration, which serves as an efficient alternative to traditional endurance-based exercise training [12].

The strengths of our study include the randomized controlled design, comprehensive set of cognitive and biomarker measures, and the inclusion of delayed exercise for the AC group to enhance the retention rate. We also acknowledge that our study has several weaknesses. There is potential recruitment bias, such as participants in our study who are already interested in exercise and, therefore, relatively more fit than other patients with breast cancer undergoing chemotherapy who are not keen to participate in such exercise studies. In addition, the clinic-based setting of our intervention may not be reproducible in other intervention settings, such as home-, remote-, or community-based exercise programs. Upon publication of positive findings of this pilot study, future studies would be beneficial to understand effective dissemination strategies within the standard of care and the best timing of implementation of HIIT for patients with breast cancer undergoing chemotherapy to prevent chemotherapy-induced cognitive decline.

The CLARITY trial is a first-of-its-kind study that incorporates a novel approach using a high-intensity exercise intervention (ie, HIIT), comprehensive cognitive measures (ie, quantitative fMRI and the NIH toolbox), and important secondary outcomes (ie, biomarkers, physical fitness and function, and psychosocial health). This study is anticipated to contribute to the current evidence on the role of HIIT in managing cognitive function and various patient-reported outcomes in patients with breast cancer undergoing chemotherapy and will establish the pilot efficacy to inform future larger phase-II and phase-III trials to confirm the findings.