Study Design and Methods for the Using Exercise to Relieve Joint Pain and Improve AI Adherence in Older Breast Cancer Survivors (REJOIN) Trial

Abstract

Background:

Aromatase Inhibitors (AIs) are recommended for survival in post-menopausal breast cancer survivors (BCS) with hormone-sensitive disease. AI Adherence is suboptimal, especially in older BCS. Joint pain is a common AI-related symptom that is associated with low AI adherence. The Using Exercise to Relieve Joint Pain in Older Breast Cancer Survivors (REJOIN) Trial will evaluate the efficacy of a self-management intervention (exercise + education) to increase knowledge/self-efficacy for symptom management, reduce joint pain and potentially increase AI adherence in older BCS planning to take AIs.

Methods:

This randomized controlled pilot trial will include sedentary BCS, 65 years and older, diagnosed with stage I-III hormone-sensitive breast cancer, who have completed primary cancer treatment and are planning to initiate AIs. We will adapt an evidence-based physical activity program for older adults that includes bi-weekly, supervised exercise sessions plus 30 minutes of education. The 16-week intervention program includes: 8-weeks of supervised sessions plus 8-weeks of self-guided home sessions with periodic phone coaching. We will conduct geriatric assessments plus measurements of exercise, joint pain, and AI adherence (baseline, 4, 6 and 12 months).

Discussion:

REJOIN is one of the first trials to exclusively target older BCS using a self-management intervention, informed by geriatric assessment and exercise physiology, to improve health outcomes in survivorship. The REJOIN trial could lay the foundation for transdisciplinary research that bridges the gap between clinical and public health perspectives in healthy aging, with the opportunity to translate clinical interventions into non-pharmacological tools for a growing, yet underserved population of older survivors.

Trial registration:

NCT03955627

1. Introduction

Currently, there are 16.9 million US adults that have been diagnosed with cancer, of whom 62% are ≥65 years^1–3. This number is expected to reach 26 million by 2040, fueled by the rising ‘silver tsunami’ of maturing baby boomers³. Breast cancer is the most commonly diagnosed invasive cancer among older women; 50% of all breast cancer survivors (BCS) are ≥65 years⁴. Many older BCS have age-related impairments, which may increase treatment side effects and negatively affect quality of life for years after primary treatment⁵. Early treatment side effects, like pain and sleep issues⁶, plus late effects, like diabetes and osteoporosis, are common for BCS⁷. Physical Activity (PA) is underutilized yet vital for mitigating treatment-related side effects⁸.

The American Cancer Society and other organizations recommend survivors achieve 150 minutes of moderate-intensity PA or 75 minutes of vigorous-intensity PA, plus ≥2 muscle-strengthening sessions per week^{9, 10}. Further, the American College of Sports Medicine (ACSM) adapted exercise guidelines for cancer survivors, based on recovery stage, from rehabilitation to long-term recovery^{11, 12}. Despite the benefits, as few as 10% of BCS achieve recommended PA^{13, 14.} Older survivors are vastly understudied¹⁵, but the benefits of PA and lifestyle research for them are paramount^{16, 17}. Still, few PA programs are designed with their needs in mind.

Predominantly, BCS are post-menopausal with hormone-receptor positive tumors, for which AIs are the recommended treatment^{18, 19}. Based on survival benefits^{20, 21}, experts first recommended continuous AI use as adjuvant hormonal therapy for 5 years after primary treatment, but there is now evidence to consider extending for up to 10 years^22–24. However, up to 50% of BCS do not complete therapy as recommended, owing partly to unmanaged symptom burden^25–27. Arthralgia, which includes joint pain and stiffness, is a known but poorly understood AI side effect affecting up to 50% of users and persists as a major reason for early AI discontinuation in BCS^{28, 29}. Despite the high prevalence of AI-related arthralgias (“arthralgia”), the etiology of this adverse effect remains unclear^{30, 31}. Treatment strategies often include analgesics which provide short-term arthralgia relief, but may have their own deleterious side effects (e.g., dizziness, stomach upset)³⁰. Increasingly, non-pharmacological approaches are needed to provide safe, long-term relief to help survivors cope with treatment side effects³².

The Using Exercise to Relieve Joint Pain and Improve AI Adherence in Older Breast Cancer Survivors (REJOIN) trial builds on previous trials seeking to address arthralgia and AI adherence through education-only^{33, 34} or exercise-only programs^{35, 36}. Programs combining education and exercise are key, but previous studies have not been tailored to older BCS^{31, 37}. This intervention will do both, building on the Chronic Disease Self-Management Model^38–40. Self-management programs that include exercise are a well-known and effective means of addressing arthritis and similar conditions in older adults^{41, 42}. By using exercise training and engaging users early (i.e., at AI initiation), there is an opportunity to proactively address arthralgia and concurrently promote exercise in older BCS, both important survivorship goals.^{38, 43–45}

1.1. Aims and Hypotheses

The purpose of this pilot study is to adapt an evidence-based exercise program (Fit & Strong!)^45,46 for older adults and test the efficacy of this self-management approach combining education- and exercise-based strategies (treatment group) compared to education only (control group) for improving arthralgia in older breast cancer survivors (≥65 years).

1: Adapt an evidence-based Physical Activity (PA) intervention based on educational needs of older cancer survivors planning to take AIs.

The steps are: a) Consult with clinicians on scientific advisors to adapt content relevant to the joint and breast cancer issues; b) Conduct interviews with older BCS who are eligible for adjuvant hormonal therapy; c) adapt educational content on AIs and arthralgia; d) Conduct an open pilot with three volunteers to pre-test suitability of adapted module with potential users. Based on user feedback, final changes will be made to the educational approach prior to implementation of intervention.

2: Test the effect of a pilot intervention on arthralgia and behavioral predictors for AI medication adherence (e.g., knowledge and self-efficacy).

Hypothesis 1:

Participants in the treatment group will have less arthralgia/joint pain than controls.

Hypothesis 2:

Participants in the treatment group will have more knowledge and better self-efficacy to use exercise to manage arthralgia than controls.

3: Test the effect of a pilot intervention on adherence to aromatase inhibitors.

Hypothesis 3:

Participants in the treatment group will have better AI adherence than controls.

2. Methods

2.1. Trial Design

The Using Exercise to Relieve Joint Pain and Improve AI Adherence in Older Breast Cancer Survivors (REJOIN) trial is a two-armed, pilot randomized controlled trial to test the efficacy of self-management program to teach exercise-and education-based methods for arthralgia management upon initiation of adjuvant hormonal therapy. The intervention will include supervised group exercise followed by a self-guided, home-based version of this program. The control group will receive enhanced standard care (i.e., information plus standard care); the treatment group will receive information plus a supervised exercise and education program (adapted version of Fit & Strong!).

All participants will complete data collection at baseline (T0), 4 months (T1), 6 months (T2) and 12 months (T3). All participants randomized to the treatment group will first receive a one-on-one consultation with an American College of Sports Medicine (ACSM)-certified exercise trainer. The primary intervention components include: 1) a bi-weekly self-management program that includes 60 minutes of supervised exercise (low-impact aerobics plus light weights) and 30 minutes of education and discussion about breast cancer survivorship (90 minutes total/session). The first 8 weeks of the program occur in a live, remote group format (via Zoom technology) led by the exercise trainer (16 supervised sessions), followed by another 8 weeks using a self-guided, home version of the program, reinforced with individualized phone coaching every other week (five calls). Owing to the remote format of the intervention, additional modules on use of Zoom technology and a separate instructional session on how to use weights safely were added. More details about the flow of the intervention delivery are available in Figure 1.

Figure 1. Diagram of Intervention.

AI = Aromatase Inhibitors; Rx = Prescription; PA = Physical Activity

The REJOIN Trial protocol was initially approved by the Institutional Review Board (IRB) at The Pennsylvania State University College of Medicine on February 25, 2020. Due to COVID-19 restrictions and required protocol modifications, the recruitment and enrollment period was delayed but resumed in May 2021. The primary funding for this study is from the American Cancer Society, with supplementary funding from the Penn State Cancer Institute and Highmark Corporation (see Funding Acknowledgements for more information).

2.2. Eligibility Criteria

All participants will be screened and enrolled using the eligibility and exclusion criteria listed in Table 1.

Table 1.

Eligibility Criteria

Inclusion criteria:
-- For interviews to inform adaptation process (Aim 1):
• Female breast cancer survivor, aged ≥ 65 years
• Experience taking AIs for adjuvant hormonal therapy
-- For the pretest (Aim 1) and main trial (Aims 2 and 3) criteria are:
• Female, aged ≥ 65 years at the start of study
• Planning to initiate AIs, or are <12 weeks from initiating
• Diagnosed stages I-III breast cancer
• ER+ tumor (at least 5% of cells)
• Completed surgery, radiation and/or chemotherapy
• Independent ambulator (verified by treating clinician/staff)
• Physician approval to start an exercise program
• Currently sedentary (<60 min. of physical activity per week)
• Able to complete surveys and forms/ understand English
• Agree to random assignment to treatment or control group
• Can commit to 8 weeks, bi-weekly classes offered by Zoom video
• Must have internet access or data plan to support video streamlining
• Minimum cognitive impairment (verified by cognitive screening questions administered by phone)
Exclusion criteria:
-- For interviews (Aim 1): the BCS have no experience taking AIs (did not need hormonal therapy or chose not to initiate the therapy).
-- For the pretest (Aim 1) and main trial (Aims 2 and 3) exclusion criteria are:
• Already taking AIs (may participate if 12 weeks or less after initiating)
• Presence of metastatic cancer or concurrent malignancy requiring treatment
• Recent history (past 6 months) of stroke/ MI, atrial fibrillation or class 3, 4 heart failure
• Recent joint surgery or conditions limiting physical activity.

2.3. Recruitment and Screening Methods

Recruitment for Aim 1 – Adaptation process: Interviews and Pretest

Participants will be recruited through the breast oncology team at the Penn State Cancer Institute (PSCI) and the Penn State Community Sciences and Health Outcomes Core to recruit 3 older breast cancer survivors from the community for one-on-one interviews to review the proposed content for the REJOIN participant workbook and identify any changes needed based on readability, clarity, cultural considerations and ease of use. The feedback will be synthesized and compared to feedback received from clinicians on the grant’s scientific advisory committee about any content changes needed to ensure appropriateness of advice for older BCS.

This same process will be used to recruit participants in the pretest activity for the trial. Participants in the pretest will be expected to meet similar eligibility criteria as those in Aims 2 and 3.

Recruitment for Aims 2 and 3

Participants will be recruited at the Penn State Cancer Institute, and at affiliated clinics of Penn State Health (https://www.pennstatehealth.org). For AIMs 2 and 3, research staff will monitor breast oncology schedules and review the electronic medical record (EMR) to confirm potentially eligible participants. Research staff will secure permission from the treating physician prior to approaching the patient. Once this is obtained, staff will then contact the patient to ensure eligibility for enrollment once their primary treatment is completed.

Additionally, the clinicians will be asked to refer patients to staff before completion of primary cancer treatment. Staff will then review the EMR to confirm that they are potentially eligible and contact the patient to ensure eligibility for enrollment once their primary treatment is completed. This timing is critical to achieve the aims of the study, as joint pain can occur soon after initiating AI medication in the post-treatment phase. The breast team clinicians have agreed to assist with identifying breast cancer patients and providing information about the study, who will then be approached by research staff after review of medical records and with permission from their attending physician. Once the oncologist or referring physician provides approval that the patient is cleared to participate in the study, research staff will be able to contact the patient directly, using appropriate scripts. Additionally, an IRB-compliant recruitment flyer will be used to advertise the study in clinics and provide an overview of the eligibility requirements, general information, and contact information. A telephone and zoom-based recruitment script will be provided to study staff to maintain consistency. The study will also be listed on StudyFinder (www.studyfinder.psu.edu), a web-based recruitment tool for Penn State researchers, managed and sponsored by Penn State Clinical Translational Science Institute.

2.4. Intervention

2.4.1. Theoretical Framework and Conceptual Model

This intervention will build on Lorig’s work with the Chronic Disease Self-Management Model^38–40. Self-management principles stem from Social Cognitive Theory⁴⁶, which posits that sufficient knowledge about one’s health is first required to obtain necessary skills, set goals, make plans and negotiate barriers to achieve them. In the agentic perspective, these steps enhance perceived behavioral capability to do a behavior and may increase the likelihood of doing that behavior and of repeating it in the future^{26,47, 48} (Figure 2). Social support can also be important for engagement and maintenance of healthy behaviors, which REJOIN will also assess. Self-management programs that include physical activity are a well-known and effective means of addressing arthritis and similar conditions in older adults^{41, 42}. By using exercise training principles, including gradually bringing participants along in exercise, and engaging users early (i.e., at AI initiation), there is an opportunity to proactively address arthralgia and concurrently promote physical activity in older survivors. These approaches address the call to put older patients’ preferences and abilities first, shifting their role from participant to partner on the team⁴⁹ in managing their health needs and survivorship care⁵⁰. This underscores an opportunity to help older survivors learn about side effects of treatment and the unique benefits/ways of using exercise to manage symptoms and promote QOL in recovery^{38, 43–45}.

Figure 2. Conceptual Model for REJOIN (derived from Social Cognitive Theory).

REJOIN = The Using Exercise to Rel ieve Join t Pain and Improve AI Adherence in Older Breast Cancer Survivors (REJOIN) trial

AI = Aromatase Inhibitors

2.4.2. Adaptation of Curriculum for Older BCS for Primary Intervention

For Aim 1, the process will include a series of iterative steps to adapt the intervention in preparation for conducting a randomized pilot trial with older BCS. The team used the National Cancer Institute’s Research-Tested Interventions Programs (RTIPS) resource to identify Fit & Strong! as a viable program option, given its specific evidence for use with older adults, its effectiveness in addressing osteoarthritis (a similar condition to arthralgia) and its combination of resistance training, aerobic exercise and educational sessions intended to promote self-management skills^51–53.

Adaptation Procedures.

RTIPS also provides guidelines for systematic adaptation of evidence-based health promotion programs to address unique needs of special populations^{54, 55}. Our process will follow three steps:

1. First, the research team will work with a team of scientific and clinical experts in exercise oncology, breast oncology, geriatric oncology, rheumatology and primary care advisors, mainly from Penn State College of Medicine, to identify content areas that may need to be adapted to fit the needs of older BCS.

2. Second, the team will recruit 3 older BCS to review and mark up the proposed intervention materials and participate in one-on-one, in-depth phone interviews to assess readability, clarity and cultural appropriateness. The plan is to record and transcribe the interviews verbatim and use them for thematic content analysis.

3. Third, the revised versions of the material will undergo a final test through an “open pilot” or preliminary study to pre-test the appropriateness of this adapted intervention with older BCS⁵⁶. In this method, 3 new participants that would be eligible to participate in the main intervention will be invited to pre-test exercise and educational modules and provide feedback through a final set of semi-structured interviews. As part of the interview, participants will be asked to rate their satisfaction with the final set of materials and session on a scale of 1 to 10. It was determined that a revised intervention would be considered acceptable if it received a mean satisfaction rating of 7 or higher for participants. Based on these assessments, required modifications would be made and the intervention would move forward in pilot testing.

2.4.3. Primary Intervention Arm

The active, primary intervention for REJOIN includes two main components (supervised sessions and a self-guided, at-home session) delivered over a 16-week period.

1. Initial visit and supervised sessions. At the initial clinical visit, all participants will receive printed information (i.e., written material based on American Cancer Society (ACS) web content on Hormone Therapy for Breast Cancer) at the baseline visit. In addition to information about hormonal treatment, the treatment group will receive a one-on-one exercise consultation with an ACSM-certified exercise trainer, followed by a modified version of the Fit & Strong! program, which includes bi-weekly supervised group exercise (60 minutes) and educational sessions (30 minutes) supported by a detailed participant manual.

   The supervised exercise sessions include light weights or resistance bands plus low-impact aerobic exercise (provided by study), in which movements will be explained, demonstrated and modified based on the needs of participants. Participants will be keeping weekly exercise logs to track their progress and to bring questions to the exercise trainers. Educational materials will provide information about the purpose of AI medications (e.g., to reduce cancer recurrence) in layperson language and basic information about potential treatment side effects. As part of in-person sessions, participants will develop a personalized plan to continue exercise at home. Participants can do an activity of their choice (e.g., walking) and use resistance bands which will be provided for the at-home program which will begin after 8 weeks, and will include bi-monthly phone calls to assess progress and reinforce the program. Educational sessions will be modified to reflect relevant content and advice for older survivors beginning AIs. Assessments will be taken at T0, T1, T2 and at follow up on T3.

2. Self-guided, at home exercise. During the self-guided, home portion of the exercise program, treatment group participants will execute their personalized exercise plan, use their participant manual and be provided with exercise weights and resistance bands. All participants in the treatment group will be encouraged to identify a workout partner or “buddy” (a friend or family member of their choice) as social support to encourage maintenance of activity.

   During the at-home portion of the intervention, participants will also receive phone calls from their exercise trainer. The ACSM-certified exercise trainer will call each treatment group participant on five occasions to facilitate exercise maintenance using specific strategies (such as recommending individual exercise modifications based on preferences and symptom burden) to help participants move through this part of their cancer journey⁵⁷. The first two calls will be made weekly, followed by three calls made approximately two weeks apart. The trainer will ask about progress with the exercise program, including strength training, as well as any adverse events. Trainers will review progress, identify and troubleshoot any barriers the participants are experiencing and provide encouragement to continue. A phone script will be provided to trainers to promote consistency with trial goals.

2.4.3.1. Enhanced Standard Care Arm

Participants in the enhanced standard care arm will receive printed information (i.e., written material based on American Cancer Society web content on Hormone Therapy for Breast Cancer) at the baseline visit, in addition to standard care recommended by their treating physician. They will also participate in assessment visits at T1, T2 and T3, similar to participants in the treatment group.

2.5. Measures

Once BCS are confirmed as eligible, participants will provide consent, and schedule a baseline visit (T0) during which they will provide research staff with a variety of clinical measures, including a grip strength assessment and geriatric assessment (including a cognitive function assessment and a Timed Up and Go test). All participants will also receive an Actigraph®GT3X+ accelerometer on an elasticized waist band along with instructions for wear (i.e., wear for 7 days and return by mail on the 8^th day) for an objective assessment of physical activity. One day of wear will require at least 10 hours of accelerometer wear time. Cutpoints for light, moderate and vigorous intensity activity will correspond with recommended levels for older adults⁵⁸. At the clinical visits, participants will be provided with additional written surveys to complete on their own and return to research staff using pre-paid envelopes within two weeks.

The same set of measures (described in the Table 2) will be repeated at T1, T2 and T3.

Table 2.

Measures (Aims 2 &3)

Physical Activity
CHAMPS Questionnaire59	Frequency and time spent in strenuous, moderate, and mild PA over past 7 days
Exercise Logs	Daily frequency, duration and intensity of PA recorded in personal diaries provided to participants. Participants may also record comments about “how they felt” that day.
Actigraph Accelerometer (GT3X+)	Participants will wear for 7 consecutive days (except when bathing or swimming) after assessments
AI-induced Arthralgia
Brief Pain Inventory (Modified for Joint Pain)60	Degree to which overall pain interferes with activities (0–10 point scale) over past 7 days
Western Ontario McMasters University Osteoarthritis Index (WOMAC)61	Self-reported pain (5 items), stiffness (2 items) in lower extremities
Quick DASH62	11-items for pain or limitations in upper extremities
Grip Strength63	Average value (kilograms force) of three squeezes of handgrip dynamometer (staff administered)
Behavioral Predictors
Exercise Self-Efficacy Scale64	Confidence in ability to do exercise
Social Support for Exercise Scale65	Support for exercise received from family, friends, others
Knowledge about Breast Cancer Treatment and Survivorship (Toronto Informational Needs Questionnaire -- Breast Cancer [TINQ])66	Knowledge of breast cancer treatment and side effects, benefits of treatment for cancer control, importance of healthy lifestyle in survivorship
Morisky-Green Medication Adherence 67	4-item medication adherence assessment
Cancer-Specific Geriatric Assessment68–70
Timed “Up and Go” (mobility and balance)71	Simple mobility assessment. Patient asked to: Stand up, walk 3 meters, turn around, sit down. Expected time is 12 seconds or less.
Orientation Memory Concentration Test 72	6-item cognitive assessment (≥ 11 points indicates gross impairment)
OARS Functional Assessment73	7-items on IADLs (daily living) (Included in Cancer and Aging Research Group [CARG] questionnaire)
Medical Outcomes Survey74	10 items on Physical Function, 3 on Social Activities/Engagement (Included in CARG Questionnaire)
General Health (OARS)73	Checklist of 12 co-morbidities (other than cancer) (Included in CARG Questionnaire)
Depression75	5-items, Geriatric Depression Scale
Medication Inventory	Patient reports up to 15 medications or supplements they are currently taking (over the counter or prescribed). May be assisted by staff or family, if needed, to complete list. (Included in CARG Questionnaire)
Falls	“How many times have you fallen in last 6 months?” (Included in CARG Questionnaire)
Current Self-Rated Health76	Single item, “How would you rate your health right now?” 8-point scale, “Normal” to “Severely Disabled” (Included in CARG Questionnaire)
Blood draw for inflammatory biomarkers (IL-6, TNFα, C-reactive protein [CRP])77, 78	All participants will provide a blood draw (2 tsp) at their clinical visits. All will be instructed to fast for 8 hours beforehand.
Physical Measurements
Height, Weight,& BMI	Calculate norms and averages for the study participants

2.6. Primary and Secondary Outcomes

There will be three primary endpoints for this study that correspond with our hypotheses. These are: changes in joint pain (Aromatase Inhibitor-induced Arthralgia); changes in behavioral predictors (knowledge about breast cancer and self-efficacy) to use exercise to manage arthralgia and; AI medication adherence, defined as 80% medication adherence ratio, consistent with current American Society of Clinical Oncology guidelines. Those that have achieved 80% medical possession ratio (MPR) according to medical records will be viewed as adherent for this study. The assessment will also include self-reported medication adherence, using the Morisky-Green medication adherence scale (see Table 2).

To contextualize the primary outcomes for our population of older BCS, the study will also incorporate several secondary outcomes, including self-reported physical activity, cancer-specific geriatric assessment and a blood draw as part of the trial to understand the clinical and biological mechanisms of arthralgia in older breast cancer survivors. The geriatric assessment will include a battery of validated measures most relevant to older cancer survivors, including functional assessment, cognitive assessment, medication history and self-reported health which provide important data to interpret main effects in the context of geriatric experiences. The fasting blood draw will take place at each of four assessment visits and collect about two teaspoons of blood. Plasma concentrations of three inflammatory biomarkers (IL-6, TNFα, C-reactive protein [CRP]) will be measured at 4 time points (T0, T1, T2 and T3). These biomarkers have known associations with physical dysfunction in older adults^{77, 78} and will be informative in future analysis and targeting of onset of AI-related symptoms.

2.7. Randomization

Following completion of baseline assessments, n=76 participants will be randomized 1:1 to a treatment group and enhanced standard care group (n=38 each) using computer-generated algorithms in REDCAP, with stratification based on age groups (65–75, >75 years) and non-cancer co-morbidities (<2 v. ≥2 co-morbidities). The staff member setting up the REDCAP randomization will not the be PI and staff will use a concealed allocation process.

2.8. Covariates

In addition to our secondary outcomes, age, race/ethnicity, co-morbidities, BMI, education, marital status, cancer treatment modalities and tumor stage will be examined as potential confounders and controlled as needed.

2.9. Sample Size

Based on effect sizes of similar trials (e.g., an 0.9-point group difference for joint pain severity⁷⁹) and an expected attrition rate of 25% in this pilot trial, we determined that a sample size of 76 participants (38 in each group) would be sufficient to detect a small standardized effect size of 0.33 standard deviation units between groups, based on 80% power and alpha = 0.10. We chose a larger alpha to establish statistical significance because this is a pilot study, which may be refined/retested in the future in a fully-power trial.

2.10. Statistical Analysis

There will be three primary endpoints for this study that correspond with our hypotheses. These are: changes in joint pain (arthralgia); changes in behavioral predictors (knowledge and exercise self-efficacy) to use exercise to manage arthralgia and AI Adherence. To test these hypotheses, we will use means and standard deviations (SDs) to estimate the magnitude of the effects for joint pain, knowledge and exercise self-efficacy, and we will apply a blocked analysis of variance (ANOVA) using blocks with four strata levels to assess statistically significant overall differences between groups. We will also use the MPR ratio based on self-reported adherence (AI adherence=80% MPR) and examine predictors of AI adherence using linear regression. We will assess covariates including age, race/ethnicity, co-morbidities, BMI, education, marital status, treatment modalities, tumor stage, and self-rated health as potential confounders and control for them as needed. We will confirm adherence via clinical prescription refill records. It is anticipated that treatment group participants will adhere to ≥70% of planned sessions to be compliant with the program protocol.

3. Discussion

In this trial, we will evaluate whether a self-management intervention that combines exercise-based and educational strategies can improve AI-related joint pain and AI medication adherence in older BCS that have recently initiated adjuvant hormonal therapy. Increasing, physical activity is an important and well-recognized strategy for improving many health outcomes in BCS⁷⁹ and has been demonstrated to be specifically beneficial for relieving arthralgia⁸⁰. However, previous exercise protocols did not use a self-management intervention and were not studied in the context of geriatric assessment with BCS. Geriatric assessment will provide a valuable way to adapt future programs and identify BCS that would benefit most from exercise interventions. Geriatric assessment can also be repeated over time to continue to adjust for the needs of the survivor. In a complementary fashion, we hope that the blood draws can help generate preliminary data on the relationship between systemic inflammation and onset of arthralgia occurring during adjuvant hormonal therapy. This will inform design of future behavioral intervention studies by identifying those at highest risk for AI-related arthralgia and support targeted use of exercise as an anti-inflammatory intervention.

Additionally, most other programs did not assess the impact of improvements in arthralgia on AI adherence, which REJOIN will do. One of the unique features of REJOIN is the plan to provide supervised exercise sessions first and then offer an at-home exercise program to allow participants to practice their skills and assess their ability to maintain the program with limited coaching. This should provide valuable insight on the necessary amount and timing of contact with the intervention team for future study. Hughes et al. observed positive results in the original Fit and Strong! trial, with a retention rate of 68% and overall participation of 75% for 24, bi-weekly exercise/educational sessions with adults with a mean age of 73 years⁵², without adverse events. Adapting to the abilities and interests of the participants increased exercise self-efficacy and participation among older adults in this and similar studies^51–53.

There are limitations to our approach. It is uncertain that the adaptation process will correctly identify every necessary change or that REJOIN intervention will improve arthralgia or AI Adherence for every BCS. However, this will be the first step in an important process. The core strength of this proposal is its contribution for older BCS to maintain recommended survivorship care safely and comfortably. We believe our approach to start with geriatric assessment, integrate individual consultations with ACSM-certified exercise trainers and other activities known to be safe and effective with older adults, will empower BCS with the tools they need for long-term recovery. Further, using Zoom technology for exercise instruction may be cutting edge, as use of technology has been accelerated by COVID-19^{81, 82} and may be even more sustainable as payors increasingly support telemedicine for clinical and supportive care⁸³.

At the conclusion of this study, the expectation is to have demonstrated the preliminary efficacy of the REJOIN intervention to reduce joint pain (arthralgia), increased knowledge and self-efficacy, and potentially improve AI Adherence for older BCS. Further, we will provide evidence about the advantages of using geriatric assessment to contextualize results in an exercise study exclusively focused on geriatric survivors. Findings from this study will be used to calculate sample sizes for a larger efficacy trial and refine the approach for that study. Additional research is needed to further classify the etiology of arthralgia and integrate these findings into future refinements of an exercise protocol for older BCS.