Impact of Verbal Cueing in Multimodal Exercise Rehabilitation: A Retrospective Study in Breast Cancer Survivors Undergoing Radiation Therapy
Phase: NA
Conditions: Breast Cancer Survivors, Range of Motion, Cortisol, Shoulder Dysfunction, Fatigue After Adjuvant Breast Cancer Treatment
Sponsor: Saveetha University

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FULL STUDY PROTOCOL, STATISTICAL 
ANALYSIS PLAN (SAP) & INFORMED 
CONSENT FORMS (ICF) 
 
 
Impact of Verbal Cueing in Multimodal Exercise 
Rehabilitation: A Retrospective Study in Breast 
Cancer Survivors Undergoing Radiation Therapy 
 
 
Ethical Approval: 064/05/2025/ISRB/PGSR/SCPT 
 
07th August 2025

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Table of Contents 
1. Personnel ....................................................................................................................... 3 
2. Introduction ................................................................................................................... 4 
2.1 Background & Aims ................................................................................................ 4 
2.2 Background Literature Review ............................................................................... 6 
3. Study Protocol ............................................................................................................... 7 
3.1 Research Design Outline ......................................................................................... 7 
3.2 Participants ............................................................................................................... 8 
3.3 Recruitment .............................................................................................................. 8 
3.4 Administration ......................................................................................................... 8 
3.5 Assessment & Outcomes Measures ...................................................................... 10 
4. Statistical Analysis Plan (SAP) .................................................................................. 12 
4.1 Primary Outcomes .................................................................................................. 12 
4.2. Secondary Outcomes ............................................................................................. 12 
4.3 Missing Data ........................................................................................................... 12 
5. Informed Consent Forms (ICF) .................................................................................. 13 
5.1 Risks to participants ............................................................................................... 13 
5.2 Privacy and Confidentiality ................................................................................... 13 
6. References ................................................................................................................... 14 

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1. Personnel 
 
 
 
Principal 
Investigator 
 
 
Investigators 
 
 
 
Dr. Tamil Ponni  
 
 
Prof. Dr. Shenbaga Sundaram Subramanian 

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2. Introduction 
 
2.1 Background & Aims 
Breast cancer is one of the most prevalent malignancies affecting women worldwide, and advances in 
treatment modalities such as surgery, chemotherapy, and radiation therapy have substantially improved 
survival rates. However, despite improved prognosis, many survivors experience persistent long-term 
physical and psychological complications following treatment. Reduced shoulder range of motion 
(ROM), cancer-related fatigue (CRF), and heightened stress levels are among the most commonly 
reported adverse outcomes. These complications are often the result of radiation-induced fibrosis, post-
surgical scarring, muscular tightness, and systemic fatigue, with elevated cortisol levels serving as a 
physiological indicator of chronic stress. Collectively, these impairments negatively affect functional 
independence, limit participation in daily activities, and reduce overall quality of life among breast 
cancer survivors. 
Exercise has emerged as a safe, effective, and non-pharmacological strategy to address many of these 
treatment-related sequelae. Multimodal exercise programs incorporating aerobic training, resistance 
exercises, flexibility training, and mind–body components have demonstrated beneficial effects on 
physical function, fatigue reduction, and stress modulation in cancer populations. Nevertheless, the 
effectiveness of these programs may vary depending on factors such as program delivery, patient 
engagement, and the quality of instruction provided during exercise sessions. Verbal cueing defined as 
structured linguistic instructions, motivational prompts, and corrective feedback delivered during 
exercise—has been shown in sports science and rehabilitation literature to enhance motor learning, 
improve biomechanical performance, increase adherence, and optimize exercise outcomes. By directing 
attention, reinforcing correct movement patterns, and promoting motivation, verbal cues may play a 
critical role in maximizing the therapeutic benefits of exercise interventions. 

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Despite the growing evidence supporting exercise-based rehabilitation, limited research has specifically 
examined the added value of verbal cueing in exercise programs for breast cancer survivors, particularly 
those undergoing radiation therapy. This period is often associated with heightened fatigue, increased 
stress, and progressive musculoskeletal impairments, including shoulder stiffness and reduced ROM. 
Radiation therapy, while essential for cancer control, can exacerbate joint pain, muscle tightness, and 
systemic exhaustion, thereby contributing to elevated cortisol levels that may further impair recovery and 
overall health. Although multimodal exercise interventions have shown promise in improving functional 
outcomes and regulating stress biomarkers in various clinical populations, their specific effects 
particularly when delivered with structured verbal cues remain insufficiently explored in radiation-
treated breast cancer survivors. 
The need for targeted and comprehensive rehabilitation strategies in this population is increasingly 
evident due to the rising global incidence of breast cancer and the growing number of long-term 
survivors. A high prevalence of shoulder dysfunction, upper limb impairment, postural abnormalities, 
pain, lymphedema, and reduced quality of life has been documented following multimodal cancer 
treatments. Moreover, there is limited emphasis on structured physiotherapy programs that 
simultaneously address shoulder function, cancer-related fatigue, and psychological stress, as well as a 
lack of evidence examining the combined effects of such interventions on functional, subjective, and 
physiological outcomes. Exercise-based rehabilitation and targeted physiotherapy represent cost-
effective and accessible approaches to restoring shoulder mobility, reducing fatigue, and improving 
quality of life. The use of validated and objective outcome measures, such as active shoulder ROM and 
salivary cortisol levels, further strengthens the clinical relevance and translational significance of such 
interventions. 
 

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Accordingly, the aim of the present study is to evaluate the effectiveness of a multimodal exercise 
program delivered with and without verbal cues on shoulder range of motion, cancer-related fatigue, and 
cortisol levels in breast cancer survivors undergoing radiation therapy.  
 
2.2 Background Literature Review 
Rao et al. (2025) described the anatomy and physiology of the human breast, explaining its complex 
structure and the changes it undergoes throughout life, from development in the womb to puberty, 
pregnancy, lactation, and menopause. The authors highlighted the importance of understanding breast 
components such as lobules, ducts, connective tissue, lymphatic drainage, and blood supply, as this 
knowledge is essential for accurate diagnosis, treatment planning, and effective management of breast 
diseases(1). 
 
Xiong et al. (2025) discussed the diverse and heterogeneous nature of breast cancer, focusing on the role 
of genetic changes, molecular subtypes, and biological mechanisms in disease progression. Their review 
emphasized recent advances in precision medicine, including targeted therapies and AI-assisted 
diagnostic tools, which support personalized treatment approaches and improve long-term survivorship 
outcome (2). 
 
Zhang et al. (2025) examined global breast cancer trends using GLOBOCAN 2022 data and reported that 
breast cancer is the most common cancer among women worldwide. The study highlighted major 
regional differences, with higher incidence rates in developed countries and higher mortality in 
developing regions, particularly South-Central Asia and India. These findings stress the need for better 
early detection, access to care, and comprehensive treatment strategies(3). 
 
Gupta et al. (2025) showed that structured exercise programs significantly improve the quality of life of 
breast cancer patients and survivors. Their analysis demonstrated improvements in physical, emotional, 

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and functional well-being, emphasizing the importance of including exercise-based rehabilitation as part 
of routine survivorship care(4). 
Murena et al. (2025) conducted a retrospective analysis of 67 breast cancer patients who underwent 
mastectomy followed by reconstruction and adjuvant therapy to examine scapular dyskinesis. A high 
prevalence was reported, with static dyskinesis in 64.2% and dynamic dyskinesis in 73.1% of patients, 
including notable bilateral involvement. The study found that surgical technique and rehabilitation 
exposure significantly influenced shoulder outcomes, with longer physiotherapy duration reducing the 
risk of dynamic dyskinesis and prepectoral reconstruction showing better scapular mechanics. These 
findings underscore the importance of early and sustained physiotherapy to prevent long-term shoulder 
dysfunction in breast cancer survivors(5).  
 
3. Study Protocol 
3.1 Research Design Outline  
 
The study was conducted as a completed clinical trial among breast cancer survivors undergoing 
radiation therapy at Saveetha Medical College and Hospital.  
Initially titled “Impact of Verbal Cueing in Multimodal Exercise Rehabilitation: A Retrospective 
Study in Breast Cancer Survivors Undergoing Radiation Therapy,” the trial successfully evaluated 
the effectiveness of a multimodal exercise rehabilitation program delivered with verbal cueing 
compared to the same program delivered without verbal cueing. 
Participants who were undergoing radiation therapy were allocated into two groups: one group 
received the multimodal exercise program accompanied by structured verbal cues, while the 
comparison group performed the same exercise program without verbal guidance. Upon 
completion of the intervention period, outcomes were assessed to determine the impact of verbal 
cueing on physical and physiological parameters. 
The outcome measures included shoulder range of motion, cancer-related fatigue, and 

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physiological stress levels. Shoulder range of motion was measured using a universal goniometer 
for shoulder flexion, abduction, and external rotation. Cancer-related fatigue was evaluated using 
the FACIT–Fatigue scale, and physiological stress was assessed through salivary cortisol analysis.  
Participants 
Breast cancer survivors undergoing radiation therapy from Saveetha medical college and hospital 
attended the study setting will be eligible to participate in this study. 
3.3 Recruitment 
All breast cancer survivors undergoing radiation therapy and attending the study setting were enrolled in 
the clinical trial after meeting the eligibility criteria. Participant information sheets and informed consent 
forms were provided to all eligible individuals, detailing the purpose of the study, intervention 
procedures, and inclusion and exclusion criteria. Participants who consented to participate were enrolled 
in the trial and underwent baseline assessments prior to the initiation of the intervention. 
 
Baseline evaluations included assessment of shoulder range of motion using a universal goniometer, 
cancer-related fatigue assessment using the FACIT–Fatigue scale, and evaluation of physiological stress 
through salivary cortisol analysis. Written informed consent was obtained from all participants, and 
signed consent forms were collected and retained by the site principal investigator before the 
commencement of any study-related procedures. 
 
3.3Administration 
 
TABLE- 1(MMV protocol) 
Phase 
Activities 
1. Warm-Up 
- Marching in place  

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(5 – 10 minutes) 
- Arm swings and ankle pumps  
- Neck and shoulder rolls 
2. Aerobic exercise  
(15 – 20 minutes) 
-Walking depending on progress and tolerance or  
-Cycling 
3. Resistance Training 
(15 – 20 minutes) 
- Bodyweight (push-ups, squats, lunges) 
- Resistance bands/light weights (bicep curls, shoulder press, 
leg extensions). 
- Progression: Gradually increase reps, sets, or intensity as 
tolerated. 
4. Flexibility and Stretching 
(5 to 10 minutes) 
Static stretching: Shoulders, elbows, wrists, quadriceps, 
hamstrings, and calves. 
Hold each stretch for 15-30 seconds. 
5.Relaxation and Cool 
down  
(5 – 10 minutes)   
 
- Deep breathing, 
- Ankle pumps and 
- Neck/ Shoulder rolls 

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Assessment & Outcomes Measures 
 
3.1.1 
Primary outcomes 
 
Shoulder Range of Motion (ROM) 
 
Shoulder range of motion was evaluated as a primary functional outcome measure, with particular 
emphasis on shoulder flexion, abduction, and external (lateral) rotation of the affected upper limb. These 
movements are critical for performing overhead activities, self-care tasks, and functional reaching, and 
are commonly restricted in breast cancer survivors due to radiation-induced fibrosis, post-surgical 
scarring, pain, and muscle tightness. 
 
Active ROM was measured using a standard universal goniometer, following established anatomical 
landmarks and standardized testing positions to ensure accuracy and reproducibility. Assessments were 
conducted at baseline prior to the initiation of the exercise intervention and repeated at the end of the 
intervention period. 
 
Improvements in shoulder flexion, abduction, and external rotation following the intervention indicate 
enhanced joint mobility, improved soft-tissue extensibility, and better functional use of the upper limb. 
Goniometric assessment of shoulder ROM is widely accepted in clinical and research settings and has 
demonstrated high intrarater and interrater reliability, making it a valid and responsive tool for evaluating 
changes in shoulder function in oncological rehabilitation populations. 
 
3.1.2 Secondary outcomes 
Cancer-related fatigue was assessed using the Functional Assessment of Chronic Illness Therapy–Fatigue 
(FACIT–F) Scale, a validated, self-administered questionnaire specifically developed to evaluate fatigue 

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and its impact on daily functioning in individuals with chronic illnesses, including cancer. The FACIT–F 
consists of 13 items rated on a 5-point Likert scale ranging from 0 (“not at all”) to 4 (“very much”), with 
total scores ranging from 0 to 52. 
 
o Higher FACIT–F scores indicate lower levels of fatigue and better functional well-being. Participants 
completed the questionnaire at baseline and after completion of the intervention period. 
 
o Cancer-related fatigue is one of the most common and persistent symptoms experienced by breast 
cancer survivors undergoing radiation therapy and can markedly affect physical performance, emotional 
health, and overall quality of life. The FACIT–Fatigue Scale has demonstrated excellent reliability, 
validity, and sensitivity to change in oncology populations, making it an appropriate and responsive 
outcome measure for evaluating the effectiveness of exercise-based rehabilitation interventions.  
 
Salivary Cortisol Level 
 
Physiological stress response was evaluated through the measurement of salivary cortisol levels, a non-
invasive biomarker that reflects hypothalamic–pituitary–adrenal (HPA) axis activity. Saliva samples 
were collected under standardized conditions to minimize the effects of diurnal variation in cortisol 
secretion. 
Samples were obtained at consistent times of the day at baseline and after completion of the intervention 
period to ensure comparability of results. 
Elevated salivary cortisol levels are commonly associated with chronic stress, fatigue, and altered 
neuroendocrine regulation in breast cancer survivors undergoing radiation therapy. A reduction or 
normalization of cortisol levels following the intervention indicates improved stress regulation, enhanced 
autonomic balance, and better physiological adaptation to treatment-related stress. 
[Time Frame: Baseline and post-intervention] 

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4. Statistical Analysis Plan (SAP) 
The statistical analysis will be performed using IBM SPSS Statistics version 27. The study was 
conducted on breast cancer survivors aged 35 - 45 years undergoing or recently completing 
radiation therapy. The primary objective of the study was to compare the effects of two 
intervention protocols between Group A (MMV – Multimodal Exercise with Verbal Cues) and 
Group B (MMWV – Multimodal Exercise without Verbal Cues) on shoulder joint range of motion, 
fatigue, and salivary cortisol levels. 
4.1 Primary Outcome 
The primary outcome measures included shoulder range of motion, specifically shoulder 
flexion, shoulder abduction, and external rotation, measured using a goniometer. 
4.2 Secondary outcome  
The secondary outcome measures were fatigue, assessed using the Functional Assessment of 
Chronic Illness Therapy–Fatigue (FACT-F) scale, and salivary cortisol levels, measured in 
ng/mL. 
A total of 36 participants were included in the study and were equally allocated into two groups, 
with 18 participants in Group A and 18 participants in Group B. Descriptive statistics were 
expressed as mean ± standard deviation (SD). Inferential statistical analysis will include tests of 
normality, homogeneity of variance, paired sample t-tests for within-group comparisons, and 
independent sample t-tests for between-group comparisons. The level of statistical significance was 
set at p < 0.05. 
4.3 Missing Data 
For breast cancer survivors who did not attend the scheduled assessment sessions, mean imputation 
of the corresponding outcome scores from their respective intervention group was applied to 

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manage missing data.  
 
Informed Consent Forms (ICF) 
Written informed consent was obtained directly from all breast cancer survivors participating in the study 
using the approved consent forms provided with the study protocol. 
 
4.4 Rights and Risks to participants 
Rights 
Participants had the right to withdraw from the study at any time without providing any explanation. 
They were free to decline or refrain from answering any questions related to the study procedures. 
Participants also had the right to seek clarification and ask questions regarding the assessments or 
intervention procedures at any stage of the study, either before commencement or during the course of 
assessments and interventions. Participation in the study was entirely voluntary and did not involve 
any remuneration or reimbursement. 
Risks 
Researcher does not anticipate any risk from this research study. 
4.5 Privacy and Confidentiality 
 
All breast cancer survivors enrolled in the study were de-identified and assigned a unique 
identification (ID) number at the time of enrollment, which was recorded by the study 
administration personnel at the study site. All personal and clinical data were handled 
confidentially and used solely for research purposes. Any assessment records and biological 
samples collected for analysis were securely stored and were not shared outside the research team, 
in accordance with the ethical guidelines and policies of the study institution. 

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References 
1. Rao A. Anatomy and Physiology of the Breast. InAtlas of Diagnosis and Management of Breast 
Disease 2025 May 23 (pp. 1-9). CRC Press. 
2. Xiong X, Zheng LW, Ding Y, Chen YF, Cai YW, Wang LP, Huang L, Liu CC, Shao ZM, Yu KD. 
Breast cancer: pathogenesis and treatments. Signal transduction and targeted therapy. 2025 Feb 
19;10(1):49. PMID: 39966355 
3. Zhang Y, Ji Y, Liu S, Li J, Wu J, Jin Q, Liu X, Duan H, Feng Z, Liu Y, Zhang Y. Global burden of 
female breast cancer: new estimates in 2022, temporal trend and future projections up to 2050 
based on the latest release from GLOBOCAN. Journal of the National Cancer Center. 2025 Feb 
13;5(3):287. PMID: 40693239 
4. Gupta B, Gupta K, Narula K, Sharma P, Mittal A. The Effect of Exercise on Quality of Life 
among Patients and Survivors of Breast Cancer: A Systematic Review and Meta-Analysis. Asian 
Pacific Journal of Cancer Prevention: APJCP. 2025;26(3):715. PMID: 40156386 
5. Murena L, Santovito F, de Grazia A, Libretti G, Galeazzi G, Sidoti GB, Renzi N, Trobec 
B, Buoite Stella A, Ramella V, Papa G. Scapular dyskinesis after breast reconstruction 
surgery for breast cancer: a retrospective clinical analysis on 67 patients. 
Musculoskeletal 
surgery. 
2025 
May 
8:1-8. 
PMID: 4034201

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