Multimodal Prehabilitation Program That Combines Physical Exercise, Psychological Intervention and Nutritional Support to Improve the Response to Neoadjuvant Chemoterhapy in Early Breast Cancer Patients

Not Applicable

Recruiting

• Conditions: Breast Cancer Early Stage Breast Cancer (Stage 1-3); Prehabilitation

• Registration Number: NCT07107594
• Lead Sponsor: Hospital Clinic of Barcelona

Brief Summary

The aim of this clinical trial is to evaluate whether following a multimodal prehabilitation program including physical exercise, nutritional support and psychological intervention during neoadjuvant chemotherapy in breast cancer patients could improve the pathological response to chemotherapy.

214 women with non-metastatic breast cancer with indication of chemotherapy before surgery will be eligible to participate. Patients will be randomly assigned to either the intervention group or the control group.

* Patients assigned to the intervention group (107 women) will undergo a directed multimodal prehabilitation program during the chemotherapy (4-6 months), including structured physical exercise, psychological intervention and nutritional guidance.

* Patients assigned to the control group (107 women) will undergo standard clinical management for their disease without multimodal prehabilitation.

The response to chemotherapy between the two groups will be evaluated and compared. It is expected that multimodal prehabilitation will increase the response to chemotherapy and will improve the postoperative recovery of patients and their quality of life, as well as reducing the number of complications from surgery and chemotherapy treatment. Changes in the tumor microenvironment are also expected after prehabilitation.

Detailed Description

Breast cancer (BC) is the most common neoplasm worldwide and the leading cause of death among women. Neoadjuvant chemotherapy (NACT) is currently one of the main therapeutic pillars. The pathological response after NACT has demonstrated prognostic value in BC, being also a determinant factor for posterior treatments. In recent years, research has increasingly focused on the impact of lifestyle changes on BC, such as physical exercise, diet, and psychological interventions. These actions are part of what is known as prehabilitation, defined as the set of strategies applied prior to surgery to optimize the physical and emotional condition of patients before the surgical intervention.

The individual application of these strategies in BC patients has shown improved oncological outcomes, with positive effects on quality of life and tolerance to medical treatments. Furthermore, evidence suggests that these interventions may favorably modulate the tumor microenvironment by reducing intratumoral hypoxia, enhancing antitumor immune responses, and modulating systemic pro-inflammatory states.

Despite the demonstrated benefits of prehabilitation in multiple medical and surgical fields, there is limited evidence regarding its impact on systemic treatment outcomes in BC patients. There is also a lack of solid evidence evaluating the role of multimodal prehabilitation (combining different prehabilitation strategies) in BC, as well as its effect on treatment response and tolerance.

The current study proposes the application of a multimodal prehabilitation program during the NACT window, based on structured physical exercise, psychological therapy (mindfulness or anxiety-control techniques), and nutritional counseling in BC patients, as a strategy to enhance treatment response through changes in the tumor microenvironment. Additionally, it will be assessed whether the intervention improves treatment tolerance and postoperative recovery, among others.

The study consists of a randomized, single-blind, controlled clinical trial with two parallel groups that will include 214 women diagnosed with non-metastatic breast cancer, eligible for NACT, and awaiting surgery at our center.

Participants will be randomized into two parallel groups in a 1:1 ratio (control and intervention group, including 107 women each). A basal evaluation will be performed in all patients before starting NACT, reporting their physical, nutritional and psychological status, as well as a tumor microenvironment study in the diagnostic biopsy sample. All patients will undergo 4-6 months of NACT, the control group with standard clinical management and the intervention group following the multimodal prehabilitation program. After NACT, the physical, nutritional and psychological status of all patients will be re-evaluated. Patients will undergo surgery according to their disease and the pathological response to the treatment will be assessed.

The primary outcome will be the pathological response after NACT in both groups, assessed through the Residual Cancer Burden (RCB) index. Secondary outcomes will include NACT tolerance, quality of life, psychological and nutritional status, postoperative recovery, tumor microenvironment changes and patients' physical condition.

The group of BC patients undergoing the multimodal prehabilitation program during NACT is expected to achieve better response rates (RCB 0 and I) than the control group. Furthermore, the multimodal intervention is anticipated to promote quantitative and/or qualitative changes in the tumor microenvironment, improve NACT tolerance, enhance quality of life, and optimize postoperative recovery and the patients' physical, psychological, and nutritional status.

Study Timeline

• Study Start: 2025-01-14
• Study First Submitted: 2025-07-06
• Status Verified: 2025-08
• Study First Submitted QC: 2025-08-04
• Last Update Submitted: 2025-08-04
• Study First Posted: 2025-08-06
• Last Update Posted: 2025-08-06
• Primary Completion: 2028-01
• Study Completion: 2028-03-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Female
• Target Recruitment: 214

Inclusion Criteria

• Histologically confirmed diagnosis of non-metastatic breast cancer: stages cT1-T4, cN0-N3, M0, and candidates for neoadjuvant chemotherapy (NAC).
• Age ≥ 18 years.
• Signed informed consent.

Exclusion Criteria

• Contraindication or physical inability to perform moderate-to-high intensity physical exercise.
• Pregnant or breastfeeding patients.
• Presence of other active synchronous neoplasms.
• Metastatic breast cancer (stage IV).
• Patients already engaging in regular physical exercise: more than 150 minutes of moderate or intense aerobic exercise per week.
• Male breast cancer patients.
• Personal history of a previous malignancy treated with chemotherapy.
• Severe or poorly controlled psychiatric illness (including uncontrolled active substance abuse).

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Residual Cancer Burden Index (RCB)	From enrollment (baseline, day 1) until the end of treatment at 4-6 months (preoperative).	The main variable of the trial is the RCB index score, obtained from the histological specimen of the oncological surgery performed after NAC. The four levels of response of the RCB index (RCB 0, I, II and III) will be divided into a favorable profile of response (fRCB), that will include cathegories RCB 0 and I, and an unfavorable response profile (uRCB), including RCB II and III.; It is estimated that the average rate of a favorable RCB (fRCB) score, including RCB 0 and RCB I, will be approximately 40% in the control arm. Parallelly, the expected rates of unfavorable RCB (uRCB) scores, including RCB II and RCB III, are 60%. The objective is to improve the response rates by 20% in the intervention group, with 60% of fRCB scores and 40% of uRCB scores in this group.

Secondary Outcome Measures

Name	Time	Method
Tumor microenvironment (Gene expression analyses)	From enrollment (baseline, day 1) until the end of treatment at 4-6 months (postoperative).	Formalin fixed-paraffin embedded tumor tissue blocks will be analyzed by hematoxylin and eosin staining, to check tumor surface area. Samples with ≥20% of tumor cells will be selected for RNA extraction. The High Pure FFPET RNA Isolation Kit (Roche) will purify RNA from FFPE tumor samples. A minimum of ∼100 ng of total RNA will be used to measure the expression of 185 breast cancer-related and immune-related genes including the genes of PAM50 and HER2DX and 7 housekeeping genes using the nCounter platform (Nanostring Technologies, Seattle, USA). The gene expression for each sample will be independently normalized to the geometric mean of housekeeping genes. The 14-gene immunoglobulin (IGG) signature (i.e., CD27, CD79A, HLA-C, IGJ, IGKC, IGL, IGLV3-25, IL2RG, CXCL8, LAX1, NTN3, PIM2, POU2AF1 and TNFRSF17) will be calculated.
Body Mass Index	Before the chemotherapy (baseline or day 1), after the treatment (4-6 months later, presurgical), and 1 month after surgery.	Body mass index (BMI) will be measured before and after chemotherapy (kg/m2)
Tumor staging	At diagnosis or day 1 (clinical TNM or cTNM) and after surgery (pathological TNM or pTNM)	Registered according to the TNM system by the. American Joint Committee on Cancer (AJCC) 8th edition
Adverse effects of neoadjuvant chemotherapy	After the treatment (4-6 months later, presurgical).	They will be recorded by the research team and classified according to the CTCAE (Common Terminology Criteria for Adverse Events) version 5.0. Data will be collected at the end of NAC in both groups.
Tumor cellularity after NACT	After the surgery (after NACT, 4-6 months from day 1)	Reported as the percentage (%) of neoplastic cells in the surgical specimen.
Post-surgical hospitalization	From the surgery (5-7 months after day 1) until 30 days after the operation.	Length of hospitalization after oncological surgery: Measured in days.
Weight	Before the chemotherapy (baseline or day 1), after the treatment (4-6 months later, presurgical), and 1 month after surgery.	Weight in kilograms will be registered before and after NACT
Assessment of vascular density in peritumoral areas	At enrollment (baseline, day 1) and at the end of treatment at 4-6 months (postoperative).	The assessment will involve evaluating microvascular density through immunohistochemical staining for CD31 on tumor or tumor bed sections. This evaluation follows a two-step process: 1. Hotspot Area Selection: Identification of hotspot areas under a light microscope at 4x magnification.; 2. Manual Counting: Manual counting of all vascular lumens in the selected field at 20x magnification.; This method ensures precise quantification of vascular density in both the peritumoral and tumor bed regions.
Chemotherapy completion rate	At the end of the treatment (4-6 months after day 1, preoperative)	The proportion of patients who received the full course of chemotherapy with the corresponding dose. This will be evaluated before surgery in both groups.
Pain control after oncological surgery	Since the surgery is done (5-7 months from day 1) until hospital discharge.	Pain will be assessed using the Visual Analogue Scale (VAS) during the hospital stay. The scale ranges from 0 to 10, with higher scores indicating greater pain severity.
Hospitalization during NACT	At the end of the treatment (4-6 months after day 1, preoperative)	Need for hospitalization during neoadjuvant chemotherapy: the number of hospital admissions prior to surgery will be recorded as an absolute count.
Anxiety and Depression levels	Before the chemotherapy (baseline or day 1), after the treatment (4-6 months later, presurgical), and 1 month after surgery.	Assessed using the Hospital Anxiety and Depression Scale (HADS), which score ranges from 0 to 21 points. Higher scores indicate more severe symptoms of anxiety or depression: 0-7: Normal or no significant anxiety/depression, 8-10: Mild anxiety/depression, 11-15: Moderate anxiety/depression, 16-21: Severe anxiety/depression.
Strength	Before the chemotherapy (baseline or day 1) and after the treatment (4-6 months later, presurgical).	Assessed through the hand grip strength test, using a hand-held dynamometer (measured in kilograms).
Post-operative complications	From the surgery (5-7 months from day 1) until 30 days after.	These will be classified based on timing as immediate postoperative complications (during the procedure or within 24 hours), early complications (up to 7 days post-surgery), and late postoperative complications (from 7 to 30 days post-surgery). Severity will be recorded using the Clavien-Dindo scale.; Emergency visits and readmissions will also be reported: The absolute number, reasons, and length of hospital stay will be recorded up to 30 days post-surgery.
Physical activity level	Before the chemotherapy (baseline or day 1) and after the treatment (4-6 months later, presurgical).	The international questionnaire of Physical Activity (IPAQ) will be used to register the level of physical activity of the subjects. Minimum score: 0 MET-min/week. Maximum score: no formal upper limit (normally 20,000 MET-min/week). According to the punctuation, the level of physical activity can be classified into low (\< 600 MET-min/week), moderate (≥ 600 and \< 3,000 MET-min/week) or high (≥ 3,000 MET-min/week).
Estimated maximal oxygen uptake (VO2 max)	Before the chemotherapy (baseline or day 1) and after the treatment (4-6 months later, presurgical).	To evaluate the general physical status of patients (as an estimate of VO₂), the 30-Second Sit-to-Stand Test will be performed and recorded as an absolute number.
Patient-perceived quality of life	Before the chemotherapy (baseline or day 1), after the treatment (4-6 months later, presurgical), and 1 month after surgery.	Measured using the EORTC QLQ-30 questionnaire (0-100 points: higher scores on functional scales and the global health status scale indicate better functioning and quality of life, while higher scores on symptom scales indicate a higher level of symptoms).
Mindfulness status	Before the chemotherapy (baseline or day 1), after the treatment (4-6 months later, presurgical), and 1 month after surgery.	Assessed through the Five Facet Mindfulness Questionnaire (FFMQ). Score 39 - 195 points. A higher score indicates a greater level of mindfulness.
Change in oxygen consumption (VO2) from baseline to post-neoadjuvant therapy	Before the chemotherapy (baseline or day 1) and after the treatment (4-6 months later, presurgical).	Through a Cardiopulmonary Exercise Testing (CPET), the oxygen consumption will be measured in all patients (ml/kg/min) before and after finishing neoadjuvant chemotherapy.
Prehabilitation program adherence	After the prehabilitation program (4-6 months from day 1, presurgical).	Measured by the number of sessions attended relative to the scheduled sessions.
Nutritional status	Before the chemotherapy (baseline or day 1), after the treatment (4-6 months later, presurgical), and 1 month after surgery.	Complete blood analysis: Including liver and renal profile, blood count, ionogram, albumin, prealbumin, glucose, interleukin-6 and IGF-1.
Adherence to mediterranean diet	Before the chemotherapy (baseline or day 1), after the treatment (4-6 months later, presurgical), and 1 month after surgery.	Validated Questionnaire of Mediterranean Diet Adherence (MEDAS-14). Scoring: 0-14 points. Higher scores mean higher adherence to Mediterranean diet, being a score equal or superior to 9 considered a good adherence to such diet.

Trial Locations

Locations (1)

Hospital Clínic de Barcelona; 🇪🇸 Barcelona, Spain