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

Official title

Multimodal Intervention During Neoadjuvant Chemotherapy in Patients With Early-breast Cancer as a Strategy to Improve Treatment Response: DIANA Trial (Multimodal Prehabilitation: DIet, ANxiety Control Psychotherapy, Physical Activity)

Overview

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.

Interventions

• Behavioral Multimodal prehabilitation
  Multimodal prehabilitation program during NACT (4-6 months) that will combine: 1) Physical exercise: cardiovascular and strength exercises designed by specialized physiotherapists, structured in 1-hour sessions twice a week. The characteristics of the activity will be adapted to the treatment phase and the physical condition of each woman. 2) Psychological therapies: standardized mindfullness practice by a specialized psychologist. As an alternative, patients who refuse mindfullness could receiv

Primary outcome measures

• Residual Cancer Burden Index (RCB) [Time frame: From enrollment (baseline, day 1) until the end of treatment at 4-6 months (preoperative).]

Secondary outcome measures (12)

• Tumor microenvironment (Gene expression analyses) [Time frame: From enrollment (baseline, day 1) until the end of treatment at 4-6 months (postoperative).]
• Tumor staging [Time frame: At diagnosis or day 1 (clinical TNM or cTNM) and after surgery (pathological TNM or pTNM)]
• Tumor cellularity after NACT [Time frame: After the surgery (after NACT, 4-6 months from day 1)]
• Assessment of vascular density in peritumoral areas [Time frame: At enrollment (baseline, day 1) and at the end of treatment at 4-6 months (postoperative).]
• Adverse effects of neoadjuvant chemotherapy [Time frame: After the treatment (4-6 months later, presurgical).]
• Chemotherapy completion rate [Time frame: At the end of the treatment (4-6 months after day 1, preoperative)]
• Hospitalization during NACT [Time frame: At the end of the treatment (4-6 months after day 1, preoperative)]
• Post-surgical hospitalization [Time frame: From the surgery (5-7 months after day 1) until 30 days after the operation.]
• Pain control after oncological surgery [Time frame: Since the surgery is done (5-7 months from day 1) until hospital discharge.]
• Post-operative complications [Time frame: From the surgery (5-7 months from day 1) until 30 days after.]
• Weight [Time frame: Before the chemotherapy (baseline or day 1), after the treatment (4-6 months later, presurgical), and 1 year after surgery.]
• Body Mass Index [Time frame: Before the chemotherapy (baseline or day 1), after the treatment (4-6 months later, presurgical), and 1 year after surgery.]

Eligibility criteria

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).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

Spain · 1 center

• Hospital Clínic de Barcelona — Barcelona

Publications

• Angelats L, Pare L, Rubio-Perez C, Sanfeliu E, Gonzalez A, Segui E, Villacampa G, Marin-Aguilera M, Pernas S, Conte B, Albarran-Fernandez V, Martinez-Saez O, Aguirre A, Galvan P, Fernandez-Martinez A, Cobo S, Rey M, Martinez-Romero A, Walbaum B, Schettini F, Vidal M, Buckingham W, Munoz M, Adamo B, Agrawal Y, Guedan S, Pascual T, Agudo J, Grzelak M, Borcherding N, Heyn H, Vivancos A, Parker JS, Vi PMID 39765189
• Toohey K, Hunter M, McKinnon K, Casey T, Turner M, Taylor S, Paterson C. A systematic review of multimodal prehabilitation in breast cancer. Breast Cancer Res Treat. 2023 Jan;197(1):1-37. doi: 10.1007/s10549-022-06759-1. Epub 2022 Oct 21. PMID 36269525
• Denkert C, von Minckwitz G, Darb-Esfahani S, Lederer B, Heppner BI, Weber KE, Budczies J, Huober J, Klauschen F, Furlanetto J, Schmitt WD, Blohmer JU, Karn T, Pfitzner BM, Kummel S, Engels K, Schneeweiss A, Hartmann A, Noske A, Fasching PA, Jackisch C, van Mackelenbergh M, Sinn P, Schem C, Hanusch C, Untch M, Loibl S. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast ca PMID 29233559
• Valenza C, Taurelli Salimbeni B, Santoro C, Trapani D, Antonarelli G, Curigliano G. Tumor Infiltrating Lymphocytes across Breast Cancer Subtypes: Current Issues for Biomarker Assessment. Cancers (Basel). 2023 Jan 26;15(3):767. doi: 10.3390/cancers15030767. PMID 36765724
• Wiggins JM, Opoku-Acheampong AB, Baumfalk DR, Siemann DW, Behnke BJ. Exercise and the Tumor Microenvironment: Potential Therapeutic Implications. Exerc Sport Sci Rev. 2018 Jan;46(1):56-64. doi: 10.1249/JES.0000000000000137. PMID 29166299
• van Waart H, Stuiver MM, van Harten WH, Geleijn E, Kieffer JM, Buffart LM, de Maaker-Berkhof M, Boven E, Schrama J, Geenen MM, Meerum Terwogt JM, van Bochove A, Lustig V, van den Heiligenberg SM, Smorenburg CH, Hellendoorn-van Vreeswijk JA, Sonke GS, Aaronson NK. Effect of Low-Intensity Physical Activity and Moderate- to High-Intensity Physical Exercise During Adjuvant Chemotherapy on Physical Fit PMID 25918291
• Cannioto RA, Hutson A, Dighe S, McCann W, McCann SE, Zirpoli GR, Barlow W, Kelly KM, DeNysschen CA, Hershman DL, Unger JM, Moore HCF, Stewart JA, Isaacs C, Hobday TJ, Salim M, Hortobagyi GN, Gralow JR, Albain KS, Budd GT, Ambrosone CB. Physical Activity Before, During, and After Chemotherapy for High-Risk Breast Cancer: Relationships With Survival. J Natl Cancer Inst. 2021 Jan 4;113(1):54-63. doi: PMID 32239145
• Peterson LL, Ligibel JA. Physical Activity and Breast Cancer: an Opportunity to Improve Outcomes. Curr Oncol Rep. 2018 Apr 30;20(7):50. doi: 10.1007/s11912-018-0702-1. PMID 29713835

Identifiers

NCT: NCT07107594 · HCB/2023/1036

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗