Simplified Exercise-based Risk Assessment in Lung Cancer (EXHALE-CO2)

EXercise-based Evaluation of Ventilatory Efficiency for enHanced Risk Assessment in Lungcancer trEatment Using End-tidal CO2: a Multicenter, Prospective Study

Physiological evaluation is part of the preoperative risk estimation in patients with lung cancer, and it aids in the choice of treatment. Ventilatory efficiency during exercise has emerged as a strong predictor of major postoperative complications, so far determined during a maximal cardiopulmonary exercise test. However, this test is limited by its availability and high cost, due to the requirement of high-technological equipment and advanced expertise. The current project aims to evaluate a simplified and accessible method for risk evaluation before decision on treatment in lung cancer. It builds on recent advances in technology and knowledge and combines a simple, low-intensity cycling test with measurement of ventilatory efficiency (end-tidal carbon dioxide pressure) with a handheld monitor. In a prospective, multi-center design the investigators will include patients evaluated for suspected lung cancer. The main objective is to establish threshold values for end-tidal carbon dioxide associated with low respectively high risk of major complications in patients undergoing surgery. In addition, the study aims to determine if end-tidal carbon dioxide can predict severe side-effects during neoadjuvant or curatively aiming systemic therapy. The project is closely linked to clinical practice, and the results can be easily implemented due to the simple and cost-efficient methodology. the suggested simplified approach would also allow access to physiological evaluation where more advanced methods are unavailable.

Study Overview

• Status: Not yet recruiting
• Conditions: Exercise; Lobectomy; Lung Cancer (Diagnosis); End-Tidal Carbon Dioxide; Neoadjuvant Chemoimmunotherapy; Surgery Complications

Detailed Description

Lung cancer remains one of the leading causes of cancer-related mortality worldwide. Surgical resection offers a potential cure in selected patients; however, the risk of serious postoperative cardiopulmonary complications is substantial. Accurate pre-treatment risk stratification is therefore critical to guide treatment decisions, optimize perioperative care, and improve outcomes. Current clinical practice includes cardiopulmonary exercise testing (CPET) to assess physiological reserve, particularly peak oxygen uptake (VO₂peak) and ventilatory efficiency (VE/VCO₂ slope). While effective, CPET is resource-intensive, requiring specialized equipment and trained personnel, limiting its availability in many healthcare settings.

This study evaluates a simplified, low-resource method for assessing ventilatory efficiency using end-tidal carbon dioxide (PetCO₂) measured during a short, low-intensity cycling test. Prior research has demonstrated that PetCO₂ reflects ventilatory efficiency and has predictive value comparable to CPET-derived measures for postoperative complications. Notably, PetCO₂ measured during low-intensity exercise appears to provide the strongest prognostic signal. Because PetCO₂ can be obtained using a portable device with a nasal cannula, this approach has the potential to enable accessible, scalable physiological risk assessment.

The primary objective is to determine whether PetCO₂ measured during a standardized low-intensity cycle ergometer test can identify patients at low versus high risk of major complications or death within 90 days following lung cancer surgery (lobectomy). Secondary objectives include: (1) comparison of predictive accuracy with established CPET-based risk stratification; (2) evaluation of PetCO₂ as a predictor of severe adverse events during systemic cancer therapy (chemotherapy and/or immunotherapy); and (3) assessment of its prognostic value for two-year overall survival independent of treatment modality.

This is a prospective, multicenter cohort study conducted across multiple hospitals in Sweden, including regional and university centers. Patients referred for evaluation of suspected lung cancer are eligible for inclusion. The study is observational; all participants undergo standard diagnostic work-up and treatment according to routine clinical practice. The investigational test does not influence clinical decision-making, as results are not disclosed to treating clinicians.

Participants who provide informed consent perform a standardized, submaximal cycle ergometer test at a fixed low workload (20 W). PetCO₂ is measured continuously using a portable capnography device with nasal cannula before exercise, after 2 minutes of seated rest, and during 5 minutes of cycling. The test is brief (approximately 5 minutes), requires no change of clothing, and can be performed by trained healthcare personnel without specialized expertise.

Clinical and physiological data, including demographics, smoking status, lung function, and PetCO₂ measurements, are recorded in a centralized electronic data capture system (REDCap). Data are entered locally at each site using standardized case report forms. For participants undergoing CPET as part of routine care, CPET data are collected separately and linked for comparative analyses. A retrospective CPET dataset (2008-2023) will be used for validation of identified PetCO₂ thresholds.

Outcome data are obtained through structured medical record review performed by trained research staff blinded to baseline PetCO₂ values. The primary endpoint is a composite of major cardiopulmonary complications within 90 days of surgery, including events such as myocardial infarction, heart failure, arrhythmia, stroke, pulmonary embolism, pneumonia, respiratory failure, acute respiratory distress syndrome, or death. Secondary endpoints include severe adverse events (grade ≥3 according to CTCAE v5) during systemic therapy and all-cause mortality within two years, the latter assessed through linkage with national mortality registries.

The planned sample size is based on the primary endpoint and aims to include approximately 105 patients undergoing lobectomy, corresponding to an estimated total cohort of approximately 1,050 participants undergoing the index test. This calculation assumes an expected complication rate of approximately 14-17%, an area under the curve (AUC) of 0.70, 80% power, and a one-sided significance level of 0.05. Recruitment is expected to occur over approximately 18 months across participating sites.

Quality assurance procedures include the use of standardized operating procedures (SOPs) for test performance, data collection, and data entry across all sites. Training materials are provided to ensure consistency in test administration. Data validation is performed within the REDCap system using predefined range checks and consistency rules. Regular monitoring of data completeness and quality is conducted centrally. Source data verification is performed through comparison with medical records during outcome adjudication. Data are pseudonymized prior to analysis to ensure patient confidentiality.

A structured data dictionary defines all variables, including measurement methods, coding schemes, and clinically relevant ranges. Standardized definitions are used for clinical endpoints (e.g., CTCAE for adverse events), ensuring harmonization across sites. Procedures for handling missing or inconsistent data include predefined rules for exclusion, imputation, or sensitivity analyses, depending on the nature and extent of missingness.

The statistical analysis plan includes evaluation of predictive performance using receiver operating characteristic (ROC) analysis, estimation of optimal PetCO₂ thresholds, and comparison with CPET-derived metrics. Multivariable regression models will be used to adjust for potential confounders. Survival analyses will be conducted using time-to-event methods. Exploratory analyses will assess subgroup effects and treatment-specific outcomes.

The study poses minimal risk to participants, as the intervention consists of a brief, low-intensity exercise test comparable to activities of daily living. The primary risks relate to handling of sensitive personal data, which are mitigated through secure data management and pseudonymization. Ethical approval has been attained, and participation is voluntary with informed consent.

If validated, this simplified test could be rapidly implemented in routine care, improving access to physiological risk assessment, reducing reliance on resource-intensive testing, and supporting more efficient and individualized treatment decision-making in lung cancer care.

• Study Type: Observational
• Enrollment (Estimated): 500

Contacts and Locations

• Study Contact: Name: Kristofer Hedman, MD, PhD; Phone Number: +46 10 1033356; Email: kristofer.hedman@liu.se
• Study Contact Backup: Name: Karolina Kristenson; Email: karolina.kristenson@regionostergotland.se

Study Locations

• Sweden
  • Jönköping, Sweden
    • Department of Pulmonology, Ryhov
    • Contact: Magnus Kentson, MD, PhD; Phone Number: + 46 10-241 00 00.; Email: magnus.kentson@rjl.se
  • Kalmar, Sweden
    • Department of Pulmonology, Kalmar County Hospital
    • Contact: Niels Hornstra, MD; Phone Number: +46 10-358 00 00; Email: Niels.Hornstra@regionkalmar.se
  • Karlskrona, Sweden
    • Department of Pulmonology, Blekinge Hospital
    • Contact: Magnus Ekström, MD, PhD; Phone Number: +46 455-73 10 00; Email: pmekstrom@gmail.com
  • Linköping, Sweden
    • Department of Pulmonology, University Hospital
    • Contact: Gabriel Högström, MD, PhD; Phone Number: +46 10 103 00 00; Email: gabriel.hogstrom@regionostergotland.se
  • Lund, Sweden
    • Department of Clinical Physiology
    • Contact: Henrik Mosén, MD, PhD; Phone Number: +46 40-33 10 00; Email: henrik.mosen@med.lu.se

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients referred for suspected lung cancer to one out of five Department of Pulmonology in Sweden will be asked to participate in study. Patients will perform a low-workload exercise test with measurement of end-tidal carbon dioxide with a handheld equipment. Patients in who further work-up dimiss lung cancer diagnosis will be excluded.

Description

Inclusion Criteria:

• Lung Cancer Diagnosis
• Age of at least 18 years

Exclusion Criteria:

• Not able to perform cycle ergometer exercise
• Not able to understand spoken or written Swedish

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
Primary objective cohort - Lung cancer lobectomy; For primary objective, patients undergoing lobectomy for lung cancer will be studied.
Neoadjuvant treatment cohort; As one secondary objective, patients with lung cancer undergoing neoadjuvant treatment before surgery or other non-surgical treatment will be studied separately
Sub-lobular resection cohort; As one secondary objective, patients undergoing sublobular resection for lung cancer will be studied separately.
Non-surgical treatment cohort; As one secondary objective, patients undergoing other treatment than surgery for lung cancer will be studied.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major cardiopulmonary complications following lung cancer lobectomy	Any of the following within 90 days of surgery: Respiratory failure requiring intervention (continuous positive airway pressure, non-invasive ventilation, high flow oxygen therapy or re-intubation); Pneumonia: Patient has received antibiotics for a suspected respiratory infection and met one of the following criteria: (a) new or changed sputum, (b) new or changed lung opacities, (c) fever, (d) white blood cell count <4 × 109/L or >12 × 109/L, (e) C-reactive protein >20; Pulmonary embolus: verified with computed tomography pulmonary angiography or pulmonary scintigraphy; Atelectasis requiring bronchoscopy; Empyema; Delayed extubation (not able to extubate same day as surgery); Reoperation; chest drainage >5 days post-operatively; new chest drainage post-operatively,; oxygen treatment after post-operative day 0,; non-fatal cardiac arrest; acute myocardial infarction,; angina pectoris,; stroke,; Death by any cause	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major cardiopulmonary complications following sublobular resection for lung cancer	Any of the following within 90 days of surgery: Respiratory failure requiring intervention (continuous positive airway pressure, non-invasive ventilation, high flow oxygen therapy or re-intubation); Pneumonia: Patient has received antibiotics for a suspected respiratory infection and met one of the following criteria: (a) new or changed sputum, (b) new or changed lung opacities, (c) fever, (d) white blood cell count <4 × 109/L or >12 × 109/L, (e) C-reactive protein >20; Pulmonary embolus: verified with computed tomography pulmonary angiography or pulmonary scintigraphy; Atelectasis requiring bronchoscopy; Empyema; Delayed extubation (not able to extubate same day as surgery); Reoperation; chest drainage >5 days post-operatively; new chest drainage post-operatively,; oxygen treatment after post-operative day 0,; non-fatal cardiac arrest; acute myocardial infarction,; angina pectoris,; stroke,; Death by any cause	90 days
Two-year mortality following lung cancer surgery	Death by any cause following lung cancer surgery	2 years
Severe adverse effects in primary systemic therapy in lung cancer	In patients with lung cancer not undergoing surgery, any severe side-effect defined as grade III to V according to Common Terminoly of Adverse Events (CTAEA version 5) as any of the following: Severe or medically significant but not immedialetly life-threatening; hospitalization or prolongation of hospitalization is indicated, disabling, limiting self-care (grade III),; Life-threatening consequences: urgent intervention indicated (grade IV) or; death related to an adverse event	90 days
Severe side-effects in neoadjuvant treatment for lung cancer	In patients with lung cancer undergoing neoadjuvant treatment before surgery or non-surgival treatment, any severe side-effect defined as grade III to V according to Common Terminoly of Adverse Events (CTAEA version 5) as any of the following: Severe or medically significant but not immedialetly life-threatening; hospitalization or prolongation of hospitalization is indicated, disabling, limiting self-care (grade III),; Life-threatening consequences: urgent intervention indicated (grade IV) or; death related to an adverse event	90 days or start of primary treatment
Length of hospital stay after surgical treatment for lung cancer	Days in hospital before admission following surgical treatment for lung cancer	90 days

Collaborators and Investigators

• Sponsor: Linkoeping University
• Collaborators: Region Östergötland; Region Jönköping County; Region Skane; Region Blekinge; Region Kalmar län
• Investigators: Principal Investigator: Kristofer Hedman, MD, PhD, Department of Medical, Health and Caring Sciences, Linkoping University, Linkoping, Sweden

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: March 26, 2026
• First Submitted That Met QC Criteria: March 26, 2026
• First Posted (Actual): April 2, 2026

Study Record Updates

• Last Update Posted (Actual): April 8, 2026
• Last Update Submitted That Met QC Criteria: April 2, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Pathological Conditions, Signs and Symptoms; Behavior; Lung Neoplasms; Disease; Motor Activity
• Other Study ID Numbers: 2025-05681-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No