Breast cancer (BC) is the most common cancer among women worldwide. Cancer treatments are associated with numerous adverse events that reduce patients' functionality and alter their clinical and molecular profiles. Physical exercise and adherence to nutritional guidelines during treatment and survivorship have been shown to improve recovery prognosis and reduce treatment-related complications. However, the specific effects of prehabilitation, defined as "the process in the cancer continuum that occurs between diagnosis and the start of treatment," remain unknown in BC. A concurrent training program and specific nutritional guidelines during this phase could reduce treatment-related adverse events and improve recovery. Similarly, including a home-based exercise program and nutritional guidelines throughout the cancer treatment continuum could enhance the benefits achieved and improve various aspects of functionality, clinical status, and quality of life. Therefore, the main aim of this randomized controlled trial is to evaluate the impact and effects of a supervised prehabilitation program (combining high-intensity concurrent training and personalized nutritional guidelines) and a supportive care intervention (home-based exercise and personalized nutritional guidelines) on functional, neuromuscular, and cardiorespiratory capacity, quality of life, body composition, and clinical and molecular outcomes in women with BC. In addition, the sustainability of the benefits achieved in the long-term care and the evolution of the outcomes assessed throughout the continuum of cancer treatments will be analyzed.
The administration of breast cancer (BC) treatments is associated with various adverse events and acute toxicities that negatively affect molecular, functional, and clinical outcomes in patients with BC. Additionally, these adverse events may reduce treatment tolerance \[e.g., relative dose intensity (RDI)\], which has been shown to be associated with a worse prognosis in this population. Implementing a high-intensity concurrent training program and specific nutritional guidelines during this phase could reduce adverse treatment events and improve recovery. Likewise, including an unsupervised exercise program and nutritional guidelines during the rest of the cancer treatment may enhance the benefits obtained and improve different outcomes related to the patients' functionality, clinical status, quality of life, and treatment tolerance. Therefore, the aim of this study is to determine the effects of a prehabilitation program (combining high-intensity concurrent training and personalized nutritional guidelines) and a supportive care intervention (home-based exercise and personalized nutritional guidelines) on different outcomes in newly diagnosed women with BC. This prospective, two-arm parallel randomized controlled trial will be conducted in Valladolid (Castilla y León, Spain). A total of 66 newly diagnosed women with BC will be recruited through medical and diagnostic appointments. Women will be recruited immediately after diagnosis and must be scheduled to receive neoadjuvant chemotherapy or hormone therapy, surgery, or radiation therapy. After completion of baseline study assessments, participants will be randomized to an experimental group or a control group. Participants assigned to the experimental group will undergo a supervised prehabilitation program consisting of structured exercise training and personalized nutritional guidelines, followed by a home-based program during the medical treatment period. Participants in the control group will be asked to continue their usual care and will receive general recommendations for physical exercise and nutrition. Molecular (inflammation-related proteins, epinephrine and norepinephrine), functional (cardiorespiratory fitness, 30-Second Sit-to-Stand Test, Six-Minute Walk Test, handgrip strength and maximal voluntary isometric contraction), clinical (body composition, muscle thickness, and arm volume), and patient-reported (quality of life, upper-limb disability, fatigue, 24-hour nutritional record and food frequency questionnaire) outcomes will be assessed at baseline (week 0) and at various points during the scheduled cancer-associated treatments. Treatment tolerance (relative dose intensity, dose reduction, dose delay, early discontinuation of treatment, and number of patients completing the planned total dose) and treatment-related complications (seroma, infection; hematoma, wound dehiscence, persistent post-surgical pain, lymphedema, neuropathy, and thromboembolism) will be recorded throughout the continuum of treatments.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
SUPPORTIVE_CARE
Masking
NONE
Enrollment
66
Prehabilitation phase: * Exercise training: During a 2-4-week prehabilitation phase, participants will perform supervised concurrent training sessions, including a high-intensity circuit of multi-joint resistance exercises and a high-intensity interval training. * Nutrition: A dietitian will implement a 2-4-week structured plan providing 25-30 kcal/kg/day, 1.2-1.5 g protein/kg/day, at least 150 g carbohydrates/day, and ≥5 meals/day. The plan will also ensure adequate vitamins and antioxidants and include guidance on portion distribution to meet recommended intake of all food groups. Neoadjuvant or adjuvant treatment phase: * Exercise training: After treatment begins, participants will follow a home-based training plan during treatment: 3 weekly elastic-band resistance sessions + ≥150 min/week aerobic exercise. First week supervised; then remote follow-up. * Nutrition: The participants will continue the guidelines provided during the prehabilitation phase.
Hospital Recoletas Campo Grande
Valladolid, Valladolid, Spain
RECRUITINGMiguel de Cervantes European University
Valladolid, Valladolid, Spain
RECRUITINGCardiorespiratory fitness (peak oxygen consumption): Direct method
The change in peak oxygen consumption (ml·kg-¹·min-¹) will be assessed. A Wattbike AtomX cycle ergometer (Wattbike, Nottingham, England) and a stationary gas analyzer (Cortex Metalyzer 3B, Leipzig, Germany) will be used in the study. A gradual incremental exercise protocol will be applied, starting at 50 watts with increments of 25 watts every two minutes, until voluntary exhaustion is reached or medical reasons are presented to end exercise.
Time frame: Baseline; up to 1 week before initiation of systemic therapy; up to 1 week after completion of systemic therapy; up to 1 week before initiation of radiotherapy; and up to 1 week after completion of radiotherapy.
Cardiorespiratory fitness: Indirect method (30-Second Sit-to-Stand Test)
The change in the estimated peak of oxygen consumption (ml·kg-¹·min-¹) will be assessed.
Time frame: Baseline; up to 1 week after prehabilitation; 1 week post-surgery; up to 1 week before systemic therapy; up to 1 week after systemic therapy; up to 1 week before radiotherapy; up to 1 week after radiotherapy; mid-chemotherapy (an average of 6 weeks).
Cardiorespiratory fitness: Indirect method (Six-Minute Walk Test)
The change in the estimated peak of oxygen consumption (ml·kg-¹·min-¹) will be assessed.
Time frame: Baseline; up to 1 week after prehabilitation; 1 week post-surgery; up to 1 week before systemic therapy; up to 1 week after systemic therapy; up to 1 week before radiotherapy; up to 1 week after radiotherapy; mid-chemotherapy (an average of 6 weeks).
Handgrip strength
The change in handgrip strength (in kilograms) will be assessed. The Jamar® Smart hand dynamometer (Patterson Medical Ltd., Sammons Preston, Nottinghamshire, UK) will be used to assess handgrip strength.
Time frame: Baseline; up to 1 week after prehabilitation; 1 week post-surgery, up to 1 week before systemic therapy; up to 1 week after systemic therapy; up to 1 week before radiotherapy; up to 1 week after radiotherapy; mid-chemotherapy (an average of 6 weeks)
Upper-body maximal voluntary isometric contraction: Chest press
The change in the chest press maximal voluntary isometric contraction (MVIC) (in Newton) will be assessed. MVIC will be evaluated with the Chronojump Force Sensor Kit (Chronojump Boscosystems®, Barcelona, Spain) and the open-source Chronojump software 2.30.0 for Windows. Upper-body MVIC will be assessed using the unilateral chest press exercise.
Time frame: Baseline; up to 1 week after prehabilitation; up to 1 week before systemic therapy; up to 1 week after systemic therapy; up to 1 week before radiotherapy; up to 1 week after radiotherapy; mid-chemotherapy (an average of 6 weeks)
Lower-body maximal voluntary isometric contraction: Squat
The change in the squat maximal voluntary isometric contraction (MVIC) (in Newton) will be assessed. MVIC will be evaluated with the Chronojump Force Sensor Kit (Chronojump Boscosystems®, Barcelona, Spain) and the open-source Chronojump software 2.30.0 for Windows. Lower-body MVIC will be assessed during the 90º knee-flexion squat test.
Time frame: Baseline; up to 1 week after prehabilitation; 1 week post-surgery; up to 1 week before systemic therapy; up to 1 week after systemic therapy; up to 1 week before radiotherapy; up to 1 week after radiotherapy; mid-chemotherapy (an average of 6 weeks).
Inflammation-related proteins
The change in the levels of inflammation-related proteins (in Normalized Protein eXpression levels, an arbitrary unit on a log2 scale) in plasma will be assessed. Venous samples will be collected. Plasma samples will be sent with dry ice to the Cobiomic laboratory of Olink ® Proteomics, Córdoba, Spain, which will analyze 1 μL of each sample using the Olink ® Target 96 Inflammation panel (Cobiomic Bioscience, S.L; https://olink.com/products/olink-target-96).
Time frame: Baseline; up to 1 week after prehabilitation; 1 week after surgery or immediately after completion of the first treatment.
Epinephrine and norepinephrine
The change in the plasma concentration of epinephrine and norepinephrine (mg/l and ng/ml) will be assessed. Venous blood samples will be collected before the cardiopulmonary exercise testing and immediately afterwards. The plasma concentrations of epinephrine and norepinephrine will be analyzed using an enzyme-linked immunosorbent assay (ELISA).
Time frame: Baseline; 1 week before initiation of the first treatment (radiotherapy, chemotherapy or hormone therapy).
Weight
The change in the weight will be assessed by kilograms (kg).
Time frame: Baseline; up to 1 week after prehabilitation; 1 week post-surgery; up to 1 week before systemic therapy; up to 1 week after systemic therapy; up to 1 week before radiotherapy; up to 1 week after radiotherapy; mid-chemotherapy (an average of 6 weeks).
Height
The change in the height will be assessed by centimeters (cm).
Time frame: Baseline; up to 1 week after prehabilitation; 1 week post-surgery; up to 1 week before systemic therapy; up to 1 week after systemic therapy; up to 1 week before radiotherapy; up to 1 week after radiotherapy; mid-chemotherapy (an average of 6 weeks).
Body composition (Bioimpedance)
The change in body composition (%) will be assessed using the NUTRILAB bioimpedance device (AKERN Srl, Florence, Italy). This non-invasive method measures the body's resistance and reactance of the body to the passage of a low-intensity electric current and enables the determination of various body parameters. Bioimpedance provides accurate data on body composition. Users will be instructed to remove all metal-containing objects and remain in a supine position on a couch during the measurements, with the legs in 45° abduction, the shoulders in 30° abduction relative to the center of the body and the hands in pronation. After cleaning the skin with alcohol, two adhesive electrodes (Biatrodes Akern Srl, Florence, Italy) will be placed on the surface of the right hand and two on the right foot. The measurement results will be given in different unit measures depending on the specific variable assessed.
Time frame: Baseline; 1 week post-surgery; up to 1 week before systemic therapy; up to 1 week after systemic therapy; up to 1 week before radiotherapy; up to 1 week after radiotherapy; mid-chemotherapy (an average of 6 weeks).
Muscle thickness: vastus lateralis
Muscle thickness (in centimeters) of the vastus lateralis will be measured using a real-time B-mode ultrasound device with a linear transducer. A water-soluble, hypoallergenic transmission gel will be applied to the probe, to serve as a conductive interface between the probe and the participant's skin. Sufficient gel will be used to prevent compression of the muscle by the probe.
Time frame: Baseline; 1 week post-surgery; up to 1 week before systemic therapy; up to 1 week after systemic therapy; up to 1 week before radiotherapy; up to 1 week after radiotherapy; mid-chemotherapy (an average of 6 weeks).
Muscle thickness: rectus femoris
Muscle thickness (in centimeters) of the rectus femoris will be measured using a real-time B-mode ultrasound device with a linear transducer. A water-soluble, hypoallergenic transmission gel will be applied to the probe, to serve as a conductive interface between the probe and the participant's skin. Sufficient gel will be used to prevent compression of the muscle by the probe.
Time frame: Baseline; 1 week post-surgery; up to 1 week before systemic therapy; up to 1 week after systemic therapy; up to 1 week before radiotherapy; up to 1 week after radiotherapy; mid-chemotherapy (an average of 6 weeks).
Arm volume
The change in total arm volume of both the affected and unaffected side (in mililiters) will be assessed using circumferential measurements taken on the affected and unaffected arms using a standard 1 cm tape measure (Orliman, Valencia, Spain) in direct contact with the skin and in the supine position with the shoulders abducted at 45° and the forearms supinated. Circumference measurements will start at the metacarpophalangeal joints and will be taken at 10 cm intervals (at 10, 20, 30, 40, and 50 cm) up the arm to the base of the axilla. Circumference measurements will be collected and converted into volume using the truncated cone (frustum) formula.
Time frame: Baseline; 1 week post-surgery; up to 1 week before systemic therapy; up to 1 week after systemic therapy; up to 1 week before radiotherapy; up to 1 week after radiotherapy; mid-chemotherapy (an average of 6 weeks).
Health-related quality of life
The change in the score of quality of life will be assessed using The EORTC Core Quality of Life questionnaire (EORTC QLQ-C30). This tool consists of 30 items, scored with a Likert scale, which are distributed in five functional subscales, three symptom subscales, six additional individual items, and a two-item global subscale.
Time frame: Baseline; 1 week post-surgery; up to 1 week before systemic therapy; up to 1 week after systemic therapy; up to 1 week before radiotherapy; up to 1 week after radiotherapy; mid-chemotherapy (an average of 6 weeks).
Upper-limb disability
The change in the score of upper-limb functionality will be assessed using the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire, consisting of 30 items and 2 optional modules aimed at evaluating this variable.
Time frame: Baseline; 1 week post-surgery; up to 1 week before systemic therapy; up to 1 week after systemic therapy; up to 1 week before radiotherapy; up to 1 week after radiotherapy; mid-chemotherapy (an average of 6 weeks).
Self-reported pain
The change in the score of pain of the affected arm will be assessed through a Numeric Rating Scale (NRS), numbered from 0 "no pain at all" to 10 "worst pain imaginable".
Time frame: Baseline; 1 week post-surgery; up to 1 week before systemic therapy; up to 1 week after systemic therapy; up to 1 week before radiotherapy; up to 1 week after radiotherapy; mid-chemotherapy (an average of 6 weeks).
Fatigue
The change in the score of fatigue of the affected arm will be assessed through the Functional Assessment of Cancer Therapy Fatigue Scale (FACT-F) questionnaire, consisting of 40 items.
Time frame: Baseline; 1 week post-surgery; up to 1 week before systemic therapy; up to 1 week after systemic therapy; up to 1 week before radiotherapy; up to 1 week after radiotherapy; mid-chemotherapy (an average of 6 weeks).
Fatigue
The change in the score of fatigue of the affected arm will be assessed through the Piper Fatigue Scale-Revised (S-PFS-R), which consists of 22, 11-point (0-10) numeric rating scales that assess fatigue by patient self-report.
Time frame: Baseline; 1 week post-surgery; up to 1 week before systemic therapy; up to 1 week after systemic therapy; up to 1 week before radiotherapy; up to 1 week after radiotherapy; mid-chemotherapy (an average of 6 weeks).
Dietary intake
The change in the dietary intake will be assessed with a Food Frequency Questionnaire (FFQ). This tool measures how often foods and food groups are consumed over a specific period, enabling the estimation of typical dietary patterns.
Time frame: Baseline; up to 1 week after prehabilitation; up to 1 week before systemic therapy; up to 1 week after systemic therapy; up to 1 week before radiotherapy; up to 1 week after radiotherapy; mid-chemotherapy (an average of 6 weeks).
Treatment-related complications
The following oncologic treatments complications will be assessed for occurrence: Seroma, infection, hematoma, wound dehiscence, persistent postoperative pain, lymphoedema, neuropathy, and thromboembolism.
Time frame: Through study completion, an average of 1 year.
Length of hospitalization
The total number of days of hospitalization will be recorded.
Time frame: Through study completion, an average of 1 year.
Physical activity levels
The levels of physical activity will be recorded using the International Physical Activity Questionnaire - Long Form (score).
Time frame: Baseline and up to 4 weeks.
Cardiorespiratory fitness (peak ventilation)
The change in peak ventilation (L·min-¹) will be assessed. A Wattbike AtomX cycle ergometer (Wattbike, Nottingham, England) and a stationary gas analyzer (Cortex Metalyzer 3B, Leipzig, Germany) will be used in the study. A gradual incremental exercise protocol will be applied, starting at 50 watts with increments of 25 watts every two minutes, until voluntary exhaustion is reached or medical reasons are presented to end exercise.
Time frame: Baseline; up to 1 week before initiation of systemic therapy; up to 1 week after completion of systemic therapy; up to 1 week before initiation of radiotherapy; and up to 1 week after completion of radiotherapy.
Cardiorespiratory fitness (mean and peak heart rate)
The change in mean and peak heart rate (beats·min-¹) will be assessed. A Wattbike AtomX cycle ergometer (Wattbike, Nottingham, England) and a stationary gas analyzer (Cortex Metalyzer 3B, Leipzig, Germany) will be used in the study. A gradual incremental exercise protocol will be applied, starting at 50 watts with increments of 25 watts every two minutes, until voluntary exhaustion is reached or medical reasons are presented to end exercise.
Time frame: Baseline; up to 1 week before initiation of systemic therapy; up to 1 week after completion of systemic therapy; up to 1 week before initiation of radiotherapy; and up to 1 week after completion of radiotherapy.
Cardiorespiratory fitness (peak respiratory quotient)
The change in peak respiratory quotient (unitless) will be assessed. A Wattbike AtomX cycle ergometer (Wattbike, Nottingham, England) and a stationary gas analyzer (Cortex Metalyzer 3B, Leipzig, Germany) will be used in the study. A gradual incremental exercise protocol will be applied, starting at 50 watts with increments of 25 watts every two minutes, until voluntary exhaustion is reached or medical reasons are presented to end exercise.
Time frame: Baseline; up to 1 week before initiation of systemic therapy; up to 1 week after completion of systemic therapy; up to 1 week before initiation of radiotherapy; and up to 1 week after completion of radiotherapy.
Physical function (30-Second Sit-to-Stand Test)
The change in the number of repetitions will be assessed.
Time frame: Baseline; up to 1 week after prehabilitation; 1 week post-surgery; up to 1 week before systemic therapy; up to 1 week after systemic therapy; up to 1 week before radiotherapy; up to 1 week after radiotherapy; mid-chemotherapy (an average of 6 weeks).
Physical function (Six-Minute Walk Test)
The change in the number of meters walked will be assessed.
Time frame: Baseline; up to 1 week after prehabilitation; 1 week post-surgery; up to 1 week before systemic therapy; up to 1 week after systemic therapy; up to 1 week before radiotherapy; up to 1 week after radiotherapy; mid-chemotherapy (an average of 6 weeks).
Treatment tolerance (relative dose intensity)
The ratio of delivered to prescribed therapy dose will be recorded, and relative dose intensity (RDI) will be calculated as (delivered dose/standard dose) × 100.
Time frame: Through study completion, an average of 1 year.
Treatment tolerance (dose reduction)
Dose reduction will be calculated as the percentage difference between the planned dose and the administered dose in subsequent cycles.
Time frame: Through study completion, an average of 1 year.
Treatment tolerance (dose delay)
The number of patients experiencing at least one delay and the total number of delayed cycles will be recorded
Time frame: Through study completion, an average of 1 year.
Treatment tolerance (early treatment discontinuation)
The proportion of patients who discontinue treatment prematurely will be recorded.
Time frame: Through study completion, an average of 1 year.
Treatment tolerance (completion of planned total dose)
The number of patients who complete the full planned chemotherapy regimen without early treatment discontinuation will be recorded
Time frame: Through study completion, an average of 1 year.
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