Early Pulmonary Dysfunction in Childhood Cancer Patients

Study Overview
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Brief Summary
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This longitudinal, prospective, multicentre study is to monitor lung function prospectively in childhood cancer patients after diagnosis. The impact of cancer treatment on pulmonary dysfunction non-invasively using lung function, lung imaging and breath analysis as well as clinical symptoms using a questionnaire will be assessed at different time points.

Official Title
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Prospective Multicentre Cohort Study of Early Pulmonary Dysfunction in Childhood Cancer Patients (SWISS-Pearl Study)

Conditions
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Pulmonary Dysfunction

Intervention / Treatment
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* Diagnostic Test: Lung function measurements
* Diagnostic Test: Breath Analysis
* Diagnostic Test: Magnetic resonance imaging (MRI)
* Other: Standardized interview to assess respiratory symptoms
* Other: Data collection for assessment of clinical parameters and cumulative doses to chemotherapy, radiation, surgery and HSCT
* Other: Collection of genetic samples


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: at least one of the following cancer treatments: chest radiation treatment with any kind of chemotherapy hematopoietic stem cell transplantation (HSCT) thoracic surgery consent for Childhood Cancer Registry (ChCR) registration Exclusion Criteria: no signed informed consent Operation outside the chest area as only cancer treatment Relapsed cancer (patients who develop relapse during the study will not be excluded) In addition for MRI and lung function tests: Subjects who are respiratory insufficient and cannot perform a lung function test (less than 92% O2 saturation; under O2 therapy) Pregnant MRI measurement not possible without sedation Metal (e.g. pacemaker) in the body

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 22 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Diagnostic Test: Lung function measurements|All lung function tests are non-invasive and last about 60 minutes per child: Multiple Breath Washout: The nitrogen multiple-breath-washout test (N2MBW) measures ventilation inhomogeneity of the lung that occurs when smaller airways are damaged. Spirometry/Bodyplethysmography/DLCO: Spirometry measures dynamic air flows to quantify airway obstruction of large airways and pulmonary restriction. Plethysmography assesses static lung volumes. Diffusing capacity of the lung for carbon monoxide (DLCO) evaluates diffusion deficits.|
|Diagnostic Test: Breath Analysis|Patients will exhale into a secondary electrospray-ionization-mass spectrometry (SESI-MS) breath analysis platform. SESI-MS allows real-time breath-printing by detection of both volatile and non-volatile trace components.|
|Diagnostic Test: Magnetic resonance imaging (MRI)|Functional MRI scan assessing regional fractional lung ventilation and relative perfusion, followed by a morphological MRI scan. This technique allows simultaneous assessment of all affected lung components, the airways, alveoli and pulmonary vasculature.|
|Other: Standardized interview to assess respiratory symptoms|Short questions on current airway symptoms, recent colds, exercise-related respiratory symptoms, and passive smoking exposure will be assessed. The interview takes about 10 minutes.|
|Other: Data collection for assessment of clinical parameters and cumulative doses to chemotherapy, radiation, surgery and HSCT|Assessment of clinical parameters and cumulative doses to chemotherapy, radiation, surgery and hematopoietic stem cell transplantation (HSCT). Data on cumulative doses of pulmotoxic chemotherapy (carmustine, lomustine, busulfan, bleomycin, methotrexate and cyclophosphamide, fludarabine, ifosfamide, melphalan and thiotepa) and radiation therapy at the region of the chest from patient's hospital charts will be collected. Information on chest wall and lung surgery will be retrieved from the surgical reports. Information about conditioning regimens including cumulative chemotherapy doses and total body irradiation of patients undergoing HSCT will be collected. Further information on the health state of the patient and interventions (e.g. development of pneumonia, antibiotic treatment) will be collected from the hospital charts.|
|Other: Collection of genetic samples|Germline DNA is collected (e.g. through saliva or buccal cell sampling) for later analysis on genetic risk factors for pulmonary complications.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Forced expiratory volume in 1 second (FEV1) | Dynamic lung function parameter: Forced expiratory volume in 1 second (FEV1) | At Baseline (start of therapy), at month 3 (during intensive treatment), at month 6-18 (end of intensive treatment), 12 months after end of intensive treatment,24 months after end of intensive treatment | 
| Change in ratio of FEV1/forced vital capacity (FVC) for airway obstruction | Dynamic lung function parameter: ratio of FEV1/forced vital capacity (FVC) for airway obstruction | At Baseline (start of therapy), at month 3 (during intensive treatment), at month 6-18 (end of intensive treatment), 12 months after end of intensive treatment,24 months after end of intensive treatment | 
| Change in total lung capacity (TLC) | Static lung function parameter: total lung capacity (TLC) to assess lung restriction | At Baseline (start of therapy), at month 3 (during intensive treatment), at month 6-18 (end of intensive treatment), 12 months after end of intensive treatment,24 months after end of intensive treatment | 
| Change in residual volume (RV)/TLC | Static lung function parameter: residual volume (RV)/TLC to assess hyperinflation | At Baseline (start of therapy), at month 3 (during intensive treatment), at month 6-18 (end of intensive treatment), 12 months after end of intensive treatment,24 months after end of intensive treatment | 
| Change in lung clearance index (LCI) | Global ventilation inhomogeneity assessed by lung clearance index (LCI) | At Baseline (start of therapy), at month 3 (during intensive treatment), at month 6-18 (end of intensive treatment), 12 months after end of intensive treatment,24 months after end of intensive treatment | 
| Change in Alveolar-capillary membrane diffusion | Alveolar-capillary membrane diffusion | At Baseline (start of therapy), at month 3 (during intensive treatment), at month 6-18 (end of intensive treatment), 12 months after end of intensive treatment,24 months after end of intensive treatment | 
| Change in percentage portion of the lung volume with impaired ventilation or perfusion | Functional MRI: the primary outcome of functional lung imaging is the percentage portion of the lung volume with impaired ventilation or perfusion. | Before start of therapy, 12 months after end of intensive treatment,24 months after end of intensive treatment | 
| Change in lung morphology assessed by MRI | Change in lung morphology assessed by MRI (description of structural changes: ground glass changes, thickened septal lines, interstitial infiltrates, diffuse alveolar infiltrates, haemorrhage, focal consolidation, fibrosis, pulmonary hypertension, pleural effusion, nodular changes, vasculitis (wall thickening) and thrombosis will be assessed) | Before start of therapy, 12 months after end of intensive treatment,24 months after end of intensive treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 4-hydroxy-2-nonenal in exhaled breath | Breath analysis: 4-hydroxy-2-nonenal is regarded as a surrogate marker for oxidative stress in the human body. | At Baseline (start of therapy), at month 3 (during intensive treatment), at month 6-18 (end of intensive treatment), 12 months after end of intensive treatment,24 months after end of intensive treatment | 
| Change in volatile organic compounds (VOCs) in exhaled breath | Untargeted explorative approach to assess volatile organic compounds (VOCs) in exhaled breath | At Baseline (start of therapy), at month 3 (during intensive treatment), at month 6-18 (end of intensive treatment), 12 months after end of intensive treatment,24 months after end of intensive treatment | 
| Assessment of genetic variants through saliva or buccal cell sampling (collection of germline DNA) | Genetic variants associated with susceptibility to cancer therapy or related to lung development. Assessed in the Germline DNA Biobank Switzerland for childhood cancer and blood disorders (BISKIDS, as part of the Paediatric Biobank for Research in Haematology and Oncology [BaHOP], ethics approval PB_2017-00533 to assess genetic determinants of pulmonary toxicity. | At Baseline (start of therapy) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Childhood cancer, Lung function, Lung imaging, Breath analysis, Exome-wide association studies (EWAS), Genome-wide association studies (GWAS), Pulmotoxic treatment