Multimodal prehabilitation to prevent loss of cardiorespiratory fitness in patients with locally advanced lung cancer undergoing chemoimmunotherapy: protocol for a non-randomized multicentre study

Introduction

Lung cancer ranks as the second most prevalent malignancy worldwide, with non-small cell lung cancer (NSCLC) representing the predominant subtype and serving as the leading cause of cancer-related mortality (1). Despite recent improvements in lung cancer screening and early diagnosis, as well as the development of new targeted drugs, 5-year survival rates for all stages continue among the lowest across all cancer types, currently at 25% (2). The main cause for these low numbers is a delay in cancer diagnosis, since it is estimated that one out of four cases is diagnosed at an advanced stage of the disease (stage III–IV) (3). Current guidelines for lung cancer management state that patients with locoregional advanced NSCLC—tumour size (≥ T3) and/or mediastinal lymph node infiltration (N2)—must be treated by a multidisciplinary team and encompass different anti-cancer therapies including potential lung resection surgery (LRS) associated with systemic therapy (4,5). However, recent studies in locally advanced NSCLC have pointed out to the introduction of other systemic therapies such as immunotherapy in locally disseminated disease with the aim of decreasing tumour size and or node involvement. Particularly, two studies, NADIM and Checkmate 816 (6,7) have demonstrated that NAT combining traditional platinum-based chemotherapy and immunotherapy with immune checkpoint inhibitors (ICIs) (nivolumab) resulted in improved chemotherapy completion and efficacy, increased time to recurrence and better post-operative outcomes. This new therapy combination has recently received approval by the Food and Drug Administration (FDA) (August 2022) and thus positions concurrent chemo-immunotherapy as the new treatment standard for resectable locally advanced NSCLC.

Despite improvements in disease response, several studies have pointed out that NAT can lead to various side effects on the lungs, potentially impacting patients undergoing LRS. Studies reported an increase in surgical risk for patients receiving neoadjuvant therapy (NAT) before LRS (8,9). Although the mechanisms behind this increase in surgical risk are not fully understood and may be influenced by multiple factors, a decline in pulmonary function and potentially in cardiorespiratory fitness (CRF) could be two major contributing factors (10,11). According to one prior study, platinum- and/or taxol-based chemotherapy plus gemcitabine was associated with a reduction in diffusing capacity of the lung for carbon monoxide adjusted for alveolar ventilation (DLCO/VA) of up to 20% (12). Particularly, Cerfolio et al. reported in 2009 that a reduction in DLCO/VA after NAT was the only independent factor associated with an increased risk of post-operative complications in this population, with a higher incidence of complications in those patients with a decrease greater than 8% (10). In a more recent study, those patients with a diffusion capacity of carbon monoxide (DLCO) reduction below 80% after NAT had twice the risk of post-operative complications than those whose DLCO was preserved [odds ratio (OR) 2.23, 95% confidence interval (CI): 1.12–4.29] (11). In addition to a reduction in lung function parameters, NAT can also be associated with a decrease in CRF and exercise tolerance (13-15). It is well established in the literature that peak oxygen consumption (VO₂peak) achieved during an incremental exercise test is one of the more consistent factors associated with post-operative outcomes in patients undergoing several procedures, including LRS (16-18). As such, patients who are scheduled for LRS after NAT can be at greater risk of poor post-operative outcomes than those with preserved CRF, given the well-known impact of NAT on oxygen delivery and utilisation (15).

Prehabilitation is a multimodal, multidisciplinary intervention that takes advantage of the period between a major diagnosis (i.e., cancer) and the initiation of proposed therapies (i.e., surgery) (19). The main objective of prehabilitation is to increase patients’ functional reserve to better withstand the effects associated with a stressful event such as major surgery (18). Multimodal prehabilitation has been shown to decrease post-operative complications and length of hospital stay in patients undergoing major cancer surgery (20) as well as fasten recovery of functional capacity and self-efficacy post-intervention (21,22). A key pillar of multimodal prehabilitation is exercise prescription, particularly endurance training, whose main aim is to improve functional reserve by increasing CRF (VO₂peak). Several systematic reviews and meta-analyses (23-25) have concluded that preoperative exercise training in patients undergoing LRS can reduce post-operative complications (particularly in patients undergoing open thoracotomy) as well as hospital length of stay and improve physical fitness. However, these studies did not include patients undergoing NAT before LRS. In similar surgical procedures like an esophagectomy, a multimodal prehabilitation programme consisting of a combination of supervised and non-supervised exercise training reduced deterioration of CRF and muscle mass in addition to increasing the number of patients receiving the prescribed targeted doses of NAT (26). Furthermore, according to one prior study, patients undergoing NAT who are able to maintain VO₂peak during treatment have a greater one-year survival than those who experience a reduction CRF during treatment (12).

Based on this preliminary evidence, enhancing or at least maintaining presurgical fitness of patients with lung cancer undergoing NAT appears to be crucial for preventing postoperative complications and improving oncologic outcomes. Considering the potential of prehabilitation (particularly endurance training) to increase CRF in various cancer populations, it is essential to determine both the feasibility and efficacy of this non-pharmacological intervention in patients with NSCLC receiving chemoimmunotherapy before LRS.

Hypothesis

This study hypothesizes that multimodal prehabilitation is an effective therapeutic strategy to mitigate the decline in CRF associated with NAT and enhance both treatment-related and surgical outcomes.

As secondary hypotheses, we propose that: (I) multimodal prehabilitation during NAT is safe (not associated with serious adverse events) and feasible (achieving a recruitment and retention rate exceeding 70%); and (II) multimodal prehabilitation will minimize treatment toxicity while enhancing tumour response and postoperative outcomes.

Objectives

The primary objective of this study is to compare the impact of prehabilitation versus standard care (no prehabilitation) on VO₂peak in patients with resectable lung cancer undergoing NAT.

Secondary objectives include:

• Determine the feasibility (recruitment, completion, and adherence rates) and safety (incidence of adverse events) of the intervention, with particular focus on the exercise component. Adverse events will be classified by severity and causality (see Table S1).
• Assess the effects of the intervention on functional capacity (1-minute sit-to-stand test), emotional well-being (Hospital Anxiety and Depression Scale), and self-reported physical activity (Yale Physical Activity Survey) post-intervention in the experimental group.
• Examine the impact of multimodal prehabilitation on treatment completion, including dose reductions, delays in treatment, or discontinuation, as well as pathological response [pathologic complete response (pCR), and major pathologic response (mPR)] and tolerability/toxicity of NAT [using the Common Terminology Criteria for Adverse Events version 5.03 (CTCAE v5.03)].
• Evaluate surgical outcomes, particularly the number and severity of postoperative complications according to the Comprehensive Complication Index (CCI) of the Clavien-Dindo classification system, and the length of hospital stay.
• Determine the intervention’s effect on postoperative functional recovery, measured with a 1-minute sit-to-stand test at discharge.

We present this article in accordance with the SPIRIT reporting checklist (27) (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-311/rc).

Methods

The study protocol has been registered at ClinicalTrials.gov (NCT05636969). The study will be conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Research Ethics Committee of Hospital Clinic of Barcelona (No. HCB/2022/1210) and informed consent will be obtained from all individual participants. All participating hospitals were informed and agreed to the study.

Design

An ambispective design will be employed in this study, as it was considered unethical to conduct a randomized controlled trial given that prehabilitation is already embedded in the clinical pathway for NSCLC patients in the recruiting centres (Hospital Clinic of Barcelona, Rouen University Hospital and University Hospital Our Lady Candelaria). The prehabilitation cohort will be formed by patients who agree to participate in the multimodal prehabilitation program; the control cohort will include those patients who decline participation in the prehabilitation program, as well as a historic cohort of those patients treated prior to the start of this study (Figure 1).

Figure 1 Flow diagram of the study phases and interventions. CPET, cardiopulmonary exercise test; LRS, lung resection surgery; NAT, neoadjuvant therapy; STS, sit-to-stand.

Study management and oversight

This study did not establish an independent coordinating center, steering committee, or endpoint adjudication committee. The overall management of the study is overseen by the principal investigator (PI), who is responsible for coordinating the work across study centres, including data collection, quality control, and issue resolution. The research team will conduct monthly online meetings to share study progress, discuss challenges, and make key decisions.

Population

Patients will be invited to participate in the study if they: (I) have a confirmed pathological diagnosis of NSCLC with a clinical indication for NAT (stage II-IIIB disease according to the AJCC 9th edition) (28) followed by surgical resection. Patients will be excluded if they: (I) are physically unable to perform either a cardiopulmonary exercise test (CPET) (29) or have a contraindication to exercise training; (II) are deemed non-surgical due to low CRF or other factors; (III) refuse to undergo either NAT or surgical resection.

Intervention

All contemporaneous patients who agree to participate in this study will be assessed at baseline (T0). The following variables will be collected: (I) sociodemographic and clinical data; (II) frailty (Clinical Frailty Scale) (30); (III) CRF (CPET); (IV) health-related quality of life [The European Organization for Research and Treatment of Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) (31) and Quality of Life Questionnaire-Lung Cancer 29 (EORTC QLQ-LC29) (32)]; (V) mood (Anxiety and Depression Scale) (33); and (VI) nutritional status [Malnutrition Universal Screening Tool (MUST)] (34).

Patients who also agree to participate in the prehabilitation program will undergo the following interventions during the duration of NAT and until surgery (9–12 weeks):

• Exercise training: the exercise component will be conducted twice weekly during NAT (approximately 12 weeks) and the additional 3 to 4 weeks leading up to LRS. Exercise will be tailored based on the results of the initial CPET and will be supervised by an experienced physiotherapist. During NAT, patients will perform stationary cycling exercises at the first ventilatory threshold (VT1) for 20 to 30 minutes, with intensity gradually increased if tolerated, aiming for moderate intensity (60–70% of VO₂peak). Following NAT, patients will transition to a high-intensity interval training (HIIT) regimen involving 3 minutes pedalling at VT1 followed by 2–3 minutes at the second ventilatory threshold (VT2) for a total duration of 26–30 minutes. If a patient is unable to complete at least 8 minutes of HIIT at the targeted workload, the intensity will be reduced by 10%. Resistance training will be incorporated into each session, targeting major muscle groups (latissimus dorsi, pectoralis major, quadriceps, and hamstrings). Patients will be asked to perform 2–3 sets of 10 to 12 repetitions for each muscle group at a low-to-moderate effort level (3–4 on the modified Borg Scale) (35), resulting in a mild loss of contraction velocity. In addition to the supervised exercise training, patients will be encouraged to engage in daily walking for 30 to 45 minutes at a heart rate intensity corresponding to VT1 or rating of perceived exertion scale (RPE) of 3–4. Vital signs—including heart rate, blood pressure, and oxygen saturation—were measured immediately before, during and after each session using validated monitoring devices. To assess tolerability, each session included real-time assessments of symptoms (e.g., dizziness, chest discomfort, pain) and session-specific completion rates. Global tolerability indicators included loss to follow-up, session attendance rate (attended/planned), and relative dose intensity (RDI: completed/planned cumulative exercise volume).
• Individualized dietary intervention: patients will receive a protein-rich diet and/or protein supplementation tailored to their baseline status, as determined through the initial screening (36). The objective will be to meet energy requirements of 25–30 kcal/kg/day and protein requirements of 1.2–1.5 g/kg/day, according to current guidelines for nutritional therapy in oncology (37). All patients will receive dietary advice based on protein enrichment due to increasing physical exercise, and in cases diagnosed with malnutrition, nutritional supplementation will also be prescribed. These recommendations will be tailored to address any digestive symptoms patients may experience, such as nausea, vomiting, diarrhea, or anorexia.
• Group-based or individual psychological counselling: weekly or fortnightly sessions with a clinical psychologist will be facilitated to help manage stress and anxiety and promote behavioural change.
• Inspiratory muscle training: at the end of NAT, in the weeks leading to surgery, an inspiratory muscle training program will also be provided using a hand-held device (Powerbreathe^Ò, Powerbreathe International Ltd., Southam, Warwickshire, England UK). Patients will be asked to use the device twice daily and to complete 6 sets of 6 repetitions at 60% of the maximal inspiratory pressure previously recorded using a selected device (microRPM Respiratory Pressure Meter, CareFusion^Ò, Basingstoke, England, UK.). Loading will be increased weekly by 5% if tolerable.

Standard medical optimization, such as iron deficiency correction and smoking or alcohol cessation, will be offered to both groups as needed.

To enhance adherence to the program and patient compliance, an attendance registry will be kept, and participants will receive regular follow-up phone calls from the supervising physiotherapist in case of missing sessions.

Outcomes

Patients in the study will be assessed at three endpoints: baseline (T0), post-NAT (T1), and after surgery (T1).

The main outcome in the study will be a change in VO₂peak after NAT, measured during an incremental CPET in both cohorts (prehabilitation versus decliners). The test will be conducted according to the national and international guidelines (38). Additional variables collected from the CPET will include oxygen consumption at the anaerobic threshold (VO₂AT), ventilatory efficiency (VE/VCO₂ slope), peak load achieved (Watts), peak heart rate and oxygen pulse (VO₂/FC), oxygen uptake efficiency slope (OUES) and muscular efficiency. The test will be conducted at baseline (T0) before the beginning of NAT and repeated after NAT (T1).

Secondary variables include:

• Pulmonary function tests: standard forced spirometry [forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1)] and DLCO will be performed before and after NAT, following international guidelines (39,40).
• Feasibility: this will be evaluated based on recruitment rate, completion rate, adherence and compliance. Recruitment rate will be calculated as the ratio of consenting patients to the number of eligible patients. Completion rate will be determined by the number of patients who finish the program versus the number of patients who started the intervention. Adherence to the exercise training component will be established as a percentage of sessions attended versus the number of sessions scheduled. Finally, compliance with exercise program, including dosage reductions and modifications, will be recorded by the supervising physiotherapist.
• Treatment completion rates and response to treatment: the number of patients completing treatment in both groups will be recorded through a medical records review. Deviations from the initial protocol, including dose reductions, dose delays and treatment interruptions or withdrawals, will be documented. PCR and mPR will be assessed by the pathologist using the Residual Cancer Burden (RCB) formula available at MD Anderson’s calculator. (https://www3.mdanderson.org/app/medcalc/index.cfm?pagename=jsconvert3).
• Treatment toxicity/tolerance: symptoms and adverse events related to treatment will be documented from medical records according to CTCAE v5.03 (41).
• Adverse events: potential adverse events related to the exercise training or other components of the multimodal prehabilitation will be recorded, with severity and causality classified per the criteria established in Table S1.
• Intraoperative outcomes: including extent of resection, surgical approach (open vs. minimally invasive), duration of surgery, blood loss, time of unipulmonary ventilation, and intraoperative blood transfusion.
• Post-operative outcomes: the number and severity of postoperative complications will be recorded using the CCI based on the Clavien-Dindo Classification System (42). Days in intensive care unit (ICU), duration of mechanical ventilation, and total length of hospital stay will also be recorded from medical records.
• Use of healthcare resources 30 days postsurgery: hospital re-admissions, re-interventions, emergency room visits and mortality within 30 days postsurgery will be documented using the medical records.
• Postoperative recovery: recovery from surgery will be assessed in a subjective and objective manner. Patients will respond to the Quality of Recovery Questionnaire (QoR-15) (43) and they will also perform the one-minute sit-to-stand (STS) test as a global measure of functional recovery (44). Both will be conducted during a consultation with the thoracic surgeon approximately 2–3 weeks after hospital discharge.

Both treatment-related as well as postoperative outcomes will be retrieved from hospital electronic medical records by an independent third party not involved in the study.

Data management

All data will be entered in REDCap^Ò by the outcome assessors hosted by the Hospital Clinic (redcap.clinic.cat). Codification will be applied by assigning study numbers to study participants, with personal data stored separately. Data identifying patients in the study will be encrypted and stored on a password-secured server hosted by the Hospital Clinic of Barcelona, conforming to data protection standards. Raw datasets will be retained for five years post-trial, and anonymized data may be shared publicly upon journal requirements or reasonable request.

Data monitoring

This study will not establish a formal data monitoring committee. Instead, data and safety monitoring responsibilities will be assumed by the trial management team, led by the PI. The team will closely monitor all serious adverse events from baseline through follow-up and all recorded adverse events will be communicated to the PI within 24 hours of happening.

Statistical analyses

The primary analysis will involve assessing the effect of the intervention on the main outcome (DVO₂peak post-NAT) using an analysis of covariance (ANCOVA), controlling for potential confounders such as age, haemoglobin levels, and treatment received. Continuous secondary variables (e.g., CCI, length of hospital stay, mood) will be compared between groups using an independent t-test or the Wilcoxon rank-sum test, depending on the distribution of the variables. Categorical variables, including 30-day mortality, NAT completion rates, toxicities, hospital readmissions, and ER visits, will be analysed using a Chi-squared test. All analyses will be performed using SPSS^® v26 (IBM Corporation) for Windows^® 11.

Discussion

To our knowledge, this is the first prospective study to evaluate the impact of concurrent multimodal prehabilitation during NAT in patients with resectable NSCLC, aiming to mitigate the associated declines in CRF. NAT significantly affects patients’ physical, psychosocial, and psychological well-being, and some patients may not complete full-dose treatment due to dose reductions or delays. Given the high rate of NAT-related side effects and instances of suboptimal treatment completion, patients with resectable NSCLC might benefit from a comprehensive and personalized strategy during this period to enhance resilience and potentially improve treatment response (45).

Evidence supporting cancer prehabilitation, particularly during neoadjuvant or adjuvant treatment, is primarily based on single-modality exercise interventions (46). However, the factors contributing to physical functional deterioration and increased surgical risk due to NAT are multifaceted and interrelated. Therefore, multimodal interventions that integrate exercise, nutrition, psychological support, and medical optimization may yield greater benefits (47). For instance, a retrospective study in advanced NSCLC treated with immunotherapy, body composition, particularly muscle mass, has been shown to predict poorer overall survival and disease progression (48). In a recent systematic review published by our group (49), we demonstrated that prehabilitation during NAT can help maintain muscle mass and CRF, which is crucial for minimizing surgical risk and mitigating treatment-related toxicities (50). In addition, exercise has been shown not only to promote health benefits but also to exert therapeutic effects (51). Evidence from preclinical tumour models suggests that exercise can enhance the effectiveness of immunotherapy (52). Specifically, endurance training has been shown to increase the number of circulating natural killer (NK) cells (53), which is recognized as a prognostic factor in NSCLC (54).

Based on these preliminary data, and consistent with previous studies in other cancer populations (55,56), we anticipate that multimodal prehabilitation will limit or prevent the decline in cardiopulmonary reserve during NAT, helping patients withstand surgery and reducing the risk of postoperative cardiorespiratory complications. Finally, the inclusion of psychological support is widely advocated in the literature as an essential component during prehabilitation. It helps to reduce anxiety and stress related to cancer and its treatment and supports behavioural changes during this “teachable moment”, enhancing adherence to both the exercise and the nutritional interventions.

Strengths and limitations

The strengths of this study include its novelty, as it is the first prospective trial to investigate the effects of multimodal prehabilitation concurrently with NAT in patients with lung cancer. The multicentre design further enhances the study’s robustness and generalizability. Additionally, the provision of dietary and psychological support alongside exercise within a multimodal approach may optimize the response to exercise training in this patient population. Finally, the addition of chemoimmunotherapy-related outcomes, such as treatment response, offers valuable insights into the potential role of exercise training in the clinical management of NSCLC patients receiving ICIs. This could facilitate the development of larger-scale studies exploring the role of exercise as an adjuvant treatment in cancer therapy.

Limitations of this study include its non-randomized design, which may introduce confounding factors and potential patient selection bias. To address this, we will perform adjusted analyses to control for these potential confounders. Additionally, while the study is statistically powered to detect changes in VO₂peak, the relatively small sample size may limit our ability to identify significant differences in other assessed outcomes. The shorter follow-up period, which focuses on immediate postoperative results, may not fully capture the long-term benefit of prehabilitation on critical outcomes such as overall and disease-free survival.

Finally, we anticipate variability in the attendance and adherence to the intervention protocol among participants in the prehabilitation group, as some patients may struggle to handle the combined stress of exercise and systemic treatment on their physiological resilience. To mitigate this, we will adapt the training stimulus by periodizing the exercise based on patients’ self-reported recovery between sessions. Additionally, we will conduct a per-protocol analysis alongside the intention-to-treat analysis to provide a comprehensive understanding of the intervention’s impact.

Acknowledgments

We would like to extend our gratitude to all the patients and their families who will participate in this study, as well as to all the staff members and collaborators involved for their dedication and support.

Footnote

Reporting Checklist: The authors have completed the SPIRIT reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-311/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-311/prf

Funding: This work was supported by the Spanish Society of Pneumology and Thoracic Surgery (SEPAR) (No. 1483/2022) and the Catalan Society of Pneumology (SOCAP) (No. 1 Allied Health Professionals, call 2022) to R.S.G. as principal investigator.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-311/coif). R.S.G. reported that she has received payment from AstraZeneca, MSD, Pfizer related to presentations or lectures within the topic of lung cancer. N.R. reported fees from advisory boards from AbbVie, Amgen, Astra Zeneca, Bayer, Boeringher, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi and Takeda; for speaker roles from Amgen, AstraZeneca, BMS, Merck, MSD, Novartis and Sanofi and for expert testimony from Janssen and Merck. And N.R. served as Principal Investigator for an investigator-initiated trial sponsored by MSD. M.S. reports receiving fees from Boehringer for educational events. A.C.G. reports receiving payment honoraria for speaker roles or educational events from BMS, Pfizer, Takeda, AstraZeneca, MSD, Amgen, Abbot and Roche; for expert testimony from Abbot and MSD; for support for attending meetings or traveling from Pharmamar, Roche, Takeda and BMS and for participation on an advisory board from BMS. R.P.G. has received consulting fees from Pfizer. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study will be conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Research Ethics Committee of Hospital Clinic of Barcelona (No. HCB/2022/1210) and informed consent will be obtained from all individual participants. All participating hospitals were informed and agreed to the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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