The Beneficial Value of PET/CT in the Follow-up of Stage III Non-small Cell Lung Cancer Patients

Study Overview
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Brief Summary
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The primary objective of this study is to compare the 3-year overall survival of stage III NSCLC patients during follow-up surveillance with 18F-Fluorodeoxyglucose Positron Emission Tomography/ Computerized Tomography (18F FDG PET/CT) versus follow-up with conventional CT surveillance. Participants will receive usual care until 3 years of follow-up (control group) with additional whole-body 18F FDG PET/CT scans during follow-up visits at 6 months, 12 months, 18 months, 24 months, and 36 months of follow-up in the intervention group. Other tasks include: filling in quality of life (QOL) questionnaires at every time point; participating in an interview evaluating the addition of the 18F FDG PET/CT scans (optional); collecting blood at the follow-up time points for our secondary endpoint (optional). Researchers will compare the usual care control group with the intervention group to see if the additional 18F FDG PET/CT scans are (cost)-effective.

Detailed Description
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Stage III non-small cell lung cancer (NSCLC) patients are at high risk of developing recurrences (50-78%) during follow-up. With more effective treatments available for patients with oligometastatic disease, early detection of tumor recurrence can prolong survival and health-related quality of life and thereby lower the disease burden. With the use of 18F FDG PET/CT during follow-up, recurrences may be detected earlier at an oligometastatic state when curative-intent treatment is still possible. Primary objective: - The primary objective of this study is to compare the 3-year overall survival of stage III NSCLC patients during follow-up surveillance with 18F FDG PET/CT versus follow-up with conventional CT surveillance. The secondary objectives of this study are: To compare the 2-year overall survival of stage III NSCLC patients during follow-up surveillance with 18F FDG PET/CT versus follow-up with conventional CT-based surveillance (interim analysis); To compare the number of detected (symptomatic and asymptomatic) recurrences of stage III NSCLC patients during follow-up surveillance with 18F FDG PET/CT versus follow-up with conventional CT-based surveillance; To compare the event-free survival of stage III NSCLC patients during follow-up surveillance with 18F FDG PET/CT versus follow-up with conventional CT-based surveillance; To determine the cost-effectiveness of 18F FDG PET/CT versus conventional CT-based surveillance during follow-up of stage III NSCLC patients; To compare the effect of 18F FDG PET/CT versus conventional CT-based surveillance on health-related quality of life during follow-up of stage III NSCLC patients; To assess the beneficial value of ctDNA in the detection of recurrences during follow-up in stage III NSCLC patients; To identify patients' experiences with the additional 18F FDG PET/CT scans in the follow-up of stage III NSCLC patients. To assess differences in type of treatment following recurrence during follow-up in stage III NSCLC patients. Primary analyses will be performed on an intention-to-treat basis as well as per protocol. Kaplan-Meier curves with stratified log-rank 2-sided tests will be used to compare the survival between groups. In case of empty strata, strata will be collapsed. The clinical relevance of the difference will be primarily expressed in terms of 3-year survival of the intervention versus the control group.

Official Title
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The Beneficial Value of 18F FDG PET/CT in the Follow-up of Stage III Non-small Cell Lung Cancer Patients: the NVALT31-PET Study

Conditions
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Stage III Non-small Cell Lung Cancer

Intervention / Treatment
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* Diagnostic Test: 18F FDG PET/CT
* Diagnostic Test: CT scan


Participation Criteria
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Eligibility Criteria
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Eligible for this study are patients with stage III NSCLC (8th edition TNM Classification) who (are about to) start(ed) follow-up care (which may include adjuvant treatment) at a participating hospital. Patients may already be included during their curative intent treatment. Patients enter a screening period that runs until their randomization. Inclusion Criteria: To be eligible to participate in this study, a subject must meet all of the following criteria at the timing of randomization: Cytological or histologically proven stage III non-small cell lung cancer before start of curative intent treatment Treated with curative intent and started follow-up care All adjuvant treatments are permitted as co-intervention during follow-up care Age 18 years or older ECOG Performance Status classification 0-2 at moment of inclusion Written and signed informed consent by the patient or patient's representative (with the understanding that consent may be withdrawn by the patient or patient's representative at any time without consequences to future medical care) Exclusion Criteria: A potential subject who meets any of the following criteria will be excluded from participation in this study: Life expectancy shorter than 6 months at the end of curative intent treatment Evidence of recurrence after end of curative intent treatment and before randomization (4 months follow-up) Any condition that, in the opinion of the investigator, would interfere with evaluation of the intervention or interpretation of HRQOL or other study results.

Ages Eligible for Study
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Minimum Age: 18 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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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a multicenter randomized controlled clinical trial with a superiority design. At approximately 4 months after the end of curative intent treatment patients will be randomized 1:1 to either the intervention (18F FDG PET/CT) or the control group (usual care, CT-based follow-up). Randomization will be done stratifying for histology and treatment. After the start of the study all patients will have regular follow-up visits at 6, 12, 18, 24 months and 36 months after the end of curative intent treatment, as is stated in the Dutch guidelines. In the intervention group these visits will be complemented by a 18F FDG PET/CT scan, while in the control group the visits will only contain a CT scan. For patients in the intervention group who give consent for participation in the collection of blood, blood will be drawn around the scan. At all time points patients will be asked to fill in the HRQOL and cost-effectiveness questionnaires.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention group<br>The intervention group (n = 345) consists of usual care until 3 years of follow-up (see comparator) with additional whole-body 18F FDG PET/CT scans (from the skull to, at least, the midfemoral region) during follow-up visits at 6 months, 12 months, 18 months, 24 months, and 36 months of follow-up. After the 36-month follow-up period, patients will receive follow-up usual care (i.e. CT-scans). The scanning protocol of Boellaard et al (2015) is the basis of all center-specific protocols and therefore will be followed approximately (PET low dose CT 60 minutes post injection with scan trajectory from skull to (at least the) thighs followed by a CT scan). | Diagnostic Test: 18F FDG PET/CT<br>* Additional 18F FDG PET/CT scans during follow-up visits at 6, 12, 18, 24 and 36 months of follow-up.<br>* Other names: Whole body PET/CT scan;Diagnostic Test: CT scan<br>* CT of the thoracic region during follow-up visits at 6, 12, 18, 24 and 36 months of follow-up.<br>|
| Active Comparator: Control group (care as usual)<br>The control group (n = 345) consists of regular follow-up visits with physical check-ups and CT-scans at least every 6 months for the first 2 years and then at least yearly CT-scans until 3 years of follow-up. In case of suspected recurrence/metastasis or inconclusive results of a CT-scan (eg, after radiotherapy), 18F FDG PET/CT should be considered. The standard protocol for a diagnostic CT of the thoracic region during IV contrast administration according to the lung tumor protocol will be followed | Diagnostic Test: CT scan<br>* CT of the thoracic region during follow-up visits at 6, 12, 18, 24 and 36 months of follow-up.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival (OS) will be defined as time from end of curative intent treatment until death or loss to follow-up or end of study defined as 3 years after end of curative treatment. | 3 years after end of curative intent treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of detected symptomatic and asymptomatic recurrences | As seen on a scan and/or confirmed by biopsy | Up to 3 years after end of curative intent treatment | 
| Event-free survival (EFS) | Event-free survival will be defined as time from end of curative intent treatment until a recurrence (disease progression or relapse) or death or loss to follow-up, whichever comes first. | 3 years after end of curative intent treatment | 
| Quality-adjusted life-years ((QALY's) for the cost-effectiveness analysis (CEA)) | The European Quality of Life Five Dimension Five Level (EQ-5D-5L) will be used to measure quality-adjusted life-years. The scores will be transformed into health utilities using the Dutch tariff. QALY's will be estimated using the area under the curve method. | Up to 3 years after end of curative intent treatment | 
| Hospital and medical resource use (for the CEA) | Hospital resource use will be taken from the hospital records, and will include all diagnostic testing, treatment information, hospital visits, telephone and email consultations, and medication use. Other medical resource use as measured using an adapted version of the iMTA Medical Consumption Questionnaire (iMCQ) will provide information on visits to the GP or use of paramedical care. The prices associated with resource use will be derived from the Dutch guideline for costing, and tariffs and prices published by the Dutch Health authority. Total costs will be calculated by multiplying resource use by integral cost prices. | Up to 3 years after end of curative intent treatment | 
| Productivity losses (for the CEA) | The iMTA Productivity Costs Questionnaire (iPCQ) will provide information on productivity losses. Productivity losses will be values by the friction cost method. | Up to 3 years after end of curative intent treatment | 
| Health-related quality of life (HRQOL) | As measured by the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) and lung module (EORTC-QLQ-LC13). The main HRQOL endpoints are physical functioning and the QLQ-C30 summary score. The QLQ-C30 summary score is calculated as the mean of the combined domains of the QLQ-C30 scale scores (excluding financial impact and a two-item global quality of life scale. All scale score are linearly transformed to 0-100, following EORTC guidelines. Effects on HRQOL will be investigated including all patients with at least one completed follow-up HRQOL questionnaire. | Up to 3 years after end of curative intent treatment collected around the follow-up scans. | 
| Patients' evaluation of the 18F FDG PET/CT scans | Semi-structured interviews with a selection of patients in the intervention group (optional) | Up to 3 years after end of curative intent treatment collected around the follow-up scans. | 
| Blood samples | Blood will be collected of intervention group patients in centers participating in the blood sample collection. For this, three cell-stabilizing tubes will be collected concurrently with the 18F FDG PET/CT scan, when the IV is inserted or at a planned blood test. The tubes will subsequently be sent to the sponsor within 24 hours, where the cell-stabilizing tubes will be centrifuged at room temperature for 10 min at 1600 g. Cell-free plasma will be stored in 5 mL aliquots at -80 °C until DNA isolation. Cell-free DNA will be isolated from 1 ml plasma for mutation analysis. | Up to 3 years after end of curative intent treatment collected around the follow-up scans. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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18F FDG PET/CT scans, Follow-up care