FET-PET-Guided Management of Pseudoprogression in Glioblastoma (FET-POPPING)

June 24, 2024 updated by: Veerle Ruijters

The goal of this diagnostic randomised clinical trial is to determine, in glioblastoma patients with diagnostic uncertainty between pseudoprogression and tumor progression on follow-up MRI after chemoradiation, the added value of a direct [¹⁸F] FET-PET scan for clinical management.

The main questions it aims to answer are:

  • Does the clinical management guided by an additional FET-PET scan leads to fewer unnecessary interventions, compared with management based on MRI only?
  • Does the clinical management guided by an additional FET-PET scan leads to better health-related quality of life after 12 weeks, compared with management based on MRI only?
  • Does the clinical management guided by an additional FET-PET scan leads to reduced net healthcare costs, compared with management based on MRI only?

Researchers will compare the investigational arm, where clinical management is based on the index MRI scan and an additional FET-PET scan, with the control arm, where clinical management is based solely on the index MRI scan, to investigate the added value of the FET PET scan for clinical management.

Participants in the investigational arm will undergo the FET PET scan. All participants will complete health-related quality of life questionnaires at four different timepoints.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

During follow-up of glioblastoma patients after chemoradiation, expert teams often observe MRI abnormalities with difficulty in distinguishing between tumor growth and pseudoprogression. Although techniques such as perfusion MRI provide additional information, diagnostic uncertainty often remains, leading to incorrect or delayed diagnosis and, inappropriate treatment, such as unnecessary surgery. Despite the good discriminating power of [¹⁸F] Fluoro-ethyl-tyrosine-PET (FET-PET), this diagnostic tool is not used frequently in the Netherlands due to costs, logistics, and misconceptions about clinical benefit. In the FET POPPING study we aim to determine the added value of [¹⁸F] FET-PET for clinical management. A multicenter diagnostic randomised clinical trial will be performed, from July 2024 until December 2027. 144 adult patients with isocitrate dehydrogenase (IDH)-wildtype glioblastoma will be included, who, after the concomitant phase of chemoradiation, have increased contrast enhancement on MRI, causing doubt between tumor growth or pseudoprogression. Included patients will be randomised 1:1 in two arms. The investigational arm receives an additional [¹⁸F] FET-PET scan, and clinical management is based on the index MRI and [¹⁸F] FET-PET together. Clinical management of the control arm is based on the index MRI alone. Exact clinical management, following from the available imaging, is chosen at the discretion of a multidisciplinary board. The primary study endpoints are (a) the percentage of patients undergoing unnecessary interventions and (b) health-related quality of life after 12 weeks. Secondary endpoints include time-to-diagnosis, overall survival and cost-effectiveness. We hypothesize that the clinical management guided by an additional [¹⁸F] FET-PET scan leads to fewer unnecessary interventions, better health-related quality of life after 12 weeks and among others reduced net healthcare costs, compared with management based on MRI only.

Study Type

Interventional

Enrollment (Estimated)

144

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Netherlands
      • Amsterdam, Netherlands
        • Amsterdam UMC
        • Contact:
        • Principal Investigator:
          • Elsmarieke M van de Giessen, MD, PhD
      • Den Haag, Netherlands
        • Haaglanden MC
        • Contact:
        • Principal Investigator:
          • Maaike J Vos, MD, PhD
      • Enschede, Netherlands
        • Medisch Spectrum Twente
      • Groningen, Netherlands
        • Umc Groningen
      • Maastricht, Netherlands
        • Maastricht UMC
      • Nijmegen, Netherlands
        • Radboud UMC
        • Contact:
        • Principal Investigator:
          • Dylan JH Henssen, MD, PhD
        • Sub-Investigator:
          • Anne I Arens, MD, PhD
      • Rotterdam, Netherlands
        • Erasmus MC
        • Contact:
        • Principal Investigator:
          • Sophie EM Veldhuijzen van Zanten, MD, PhD
        • Sub-Investigator:
          • Marjolein Geurts, MD, PhD
      • Utrecht, Netherlands, 3508 GA
        • UMC Utrecht
        • Contact:
        • Contact:
        • Principal Investigator:
          • Nelleke Tolboom, MD, PhD
        • Principal Investigator:
          • Tom J Snijders, MD, PhD
        • Sub-Investigator:
          • Veerle J Ruijters, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Patients with a glioblastoma, IDH-wildtype, World Health Organization (WHO) grade 4, according to WHO 2021 criteria.
  • Age ≥18 years
  • New or increased enhancement within the high-dose radiation field (defined as within the 80% isodose line) on follow-up MRI
  • Follow up MRI ≥3 months after the end of the standard-of-care temozolomide-based concomitant chemoradiation (60 Gy/30 fractions or 40 Gy/15 fractions). Of note, very early increase - within 3 months of last radiation - will not be grounds for inclusion because of the high rate of pseudoprogression and slightly lower diagnostic performance of FET-PET compared to the situation of increase beyond 3 months after last radiation. Patients with such very early increase may have subsequent further increase after 3 months post-radiation, causing (further) diagnostic doubt; these may be included at that later timepoint if they meet the other inclusion criteria.
  • First moment of clinicoradiological uncertainty regarding the diagnosis (≥3 months after the end of chemoradiation): pseudoprogression or tumor recurrence. The determination of 'uncertainty' is made by the treating physician, preferably in the multidisciplinary tumor board, based on available clinical and standard-of-care MRI-data, which generally includes perfusion-MRI.
  • Previous usage of bevacizumab as a symptom treatment is allowed. However, inclusion is only allowed at the first moment of clinical doubt between pseudoprogression and tumor recurrence, not at later timepoints.

Exclusion Criteria:

  • Previous treatment for recurrence of disease
  • An enhanced lesion size of less than 1 cm on the index MRI. In the newest RANO PET criteria, it is advised to use FET-PET for increasing lesions only in cases with a minimum lesion size.
  • Life expectancy of less than 6 months, determined by the treating physician
  • Contra-indications for PET (claustrophobia, inability to lay still)
  • Women of childbearing potential without adequate contraception
  • Any other concomitant disease that may influence PET imaging or clinical outcomes of this study, this includes but is not limited to: cerebral inflammatory diseases and other cancers with brain- or leptomeningeal metastases

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: Standard of care
Experimental: Clinical management is based on the index MRI and an additional [¹⁸F] FET-PET together
Other: Clinical management based on the index MRI and an additional [¹⁸F] FET PET scan

Patients in the investigational arm will undergo the extra FET-PET scan, with use of the O-(2-

¹⁸F-fluoroethyl)-L-tyrosine (¹⁸F-FET) tracer. FET-PET scanning will be performed according to the joint European Association of Nuclear Medicine (EANM)/European Association of Neuro-Oncology (EANO)/Response Assessment in Neuro-oncology (RANO) guidelines. In most patients, a static scan (20-40 minutes post-injection) will performed. If the logistics of the research site allow for a dynamic scan (0-60 minutes post-injection), this will be performed. Interpretation will be done by an experienced nuclear medicine physician from the local center according to current European guidelines. Central review will be performed by a panel of nuclear medicine physicians from the study team. Clinical management is based on the index MRI and this additional [¹⁸F] FET PET scan.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Composite score of proportion (0-100%) of patients undergoing unnecessary interventions.
Time Frame: at six months

Determination of 'unnecessary interventions' will be done retrospectively, by the researchers and the treating physician.

An 'unnecessary intervention' is defined as:

  • Biopsy or debulking for diagnostic uncertainty and/or with pseudoprogression as the final pathological diagnosis
  • The administration of one or more cycles of (temozolomide) chemotherapy as continued treatment for presumed pseudoprogression, in cases with a final diagnosis of tumor progression
  • The administration of one or more doses of bevacizumab for presumed pseudoprogression, in cases with a final diagnosis of tumor progression
at six months
Health-related quality of life: general
Time Frame: at twelve weeks
This will be reported by the questionnaire EQ5D. The EQ5D is a generic utility questionnaire which allows for comparison of quality of life between indications, and is considered the golden standard by the Dutch National Heath Care Institute. Both the total score of the questionnaire is used as the individual scores to analyse individual patients' changes over time.
at twelve weeks
Health-related quality of life: brain tumor specific
Time Frame: at twelve weeks
This will be reported by the questionnaire European Organization for Research and Treatment of Cancer Quality of Life Brain Cancer Module (EORTC-QLQ-BN20). The EORTC-QLQ-BN20 is a brain tumor specific questionnaire and is a reliable tool to capture changes in specific health domains for this population. Both the total score of the questionnaire is used as the individual scores to analyse individual patients' changes over time.
at twelve weeks
Health-related quality of life: productivity
Time Frame: at twelve weeks

This will be reported by the questionnaire iMTA Productivity Cost Questionnaire (iPCQ). The iPCQ questionnaire measures productivity losses and is applicable to national and international studies.

Both the total score of the questionnaire is used as the individual scores to analyse individual patients' changes over time.
at twelve weeks
Health-related quality of life: medical consumption
Time Frame: at twelve weeks
This will be reported by the questionnaire iMTA Medical Consumption Questionnaire (iMCQ). The iMCQ questionnaire is an instrument for measuring medical consumption. Both the total score of the questionnaire is used as the individual scores to analyse individual patients' changes over time.
at twelve weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cost-effectiveness
Time Frame: at six months
Expressed in Quality Adjusted Life Years (QALY). The results of the cost utility analysis will be combined with observed and extrapolated uptake to estimate the budget impact over several relevant time horizons.
at six months
Cost-effectiveness
Time Frame: at six months
Expressed in Incremental Cost Effectiveness Ratio's (ICERs). The results of the cost utility analysis will be combined with observed and extrapolated uptake to estimate the budget impact over several relevant time horizons.
at six months
Time-to-diagnosis
Time Frame: During the study period (but expected within three months)
Defined as index MRI to eventual management, including watchful waiting
During the study period (but expected within three months)
Overall survival
Time Frame: Through study completion (expected median of less than 1.5 year)
Defined from index MRI until death (patients who are still alive at the end of the study will be censored)
Through study completion (expected median of less than 1.5 year)
Number of unnecessary treatment cycles
Time Frame: at six months
Chemotherapy
at six months
Health-related quality of life: general
Time Frame: at six weeks and six months
This will be reported by the questionnaire EQ5D. The EQ5D is a generic utility questionnaire which allows for comparison of quality of life between indications, and is considered the golden standard by the Dutch National Heath Care Institute. Both the total score of the questionnaire is used as the individual scores to analyse individual patients' changes over time.
at six weeks and six months
Health-related quality of life: brain tumor specific
Time Frame: at six weeks and six months
This will be reported by the questionnaire European Organization for Research and Treatment of Cancer Quality of Life Brain Cancer Module (EORTC-QLQ-BN20). The EORTC-QLQ-BN20 is a brain tumor specific questionnaire and is a reliable tool to capture changes in specific health domains for this population. Both the total score of the questionnaire is used as the individual scores to analyse individual patients' changes over time.
at six weeks and six months
Health-related quality of life: productivity
Time Frame: at six weeks and six months

This will be reported by the questionnaire iMTA Productivity Cost Questionnaire (iPCQ). The iPCQ questionnaire measures productivity losses and is applicable to national and international studies.

Both the total score of the questionnaire is used as the individual scores to analyse individual patients' changes over time.
at six weeks and six months
Health-related quality of life: medical consumption
Time Frame: at six weeks and six months
This will be reported by the questionnaire iMTA Medical Consumption Questionnaire (iMCQ). The iMCQ questionnaire is an instrument for measuring medical consumption. Both the total score of the questionnaire is used as the individual scores to analyse individual patients' changes over time.
at six weeks and six months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Veerle Ruijters

Collaborators

ZonMw: The Netherlands Organisation for Health Research and Development
Curium PET France

Investigators

  • Principal Investigator: Tom J Snijders, MD, PhD, UMC Utrecht
  • Principal Investigator: Nelleke Tolboom, MD, PhD, UMC Utrecht

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

August 1, 2024

Primary Completion (Estimated)

December 1, 2027

Study Completion (Estimated)

December 1, 2027

Study Registration Dates

First Submitted

June 17, 2024

First Submitted That Met QC Criteria

June 24, 2024

First Posted (Actual)

June 28, 2024

Study Record Updates

Last Update Posted (Actual)

June 28, 2024

Last Update Submitted That Met QC Criteria

June 24, 2024

Last Verified

June 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NL86008.041.24
  • 10390022210022 (Other Grant/Funding Number: ZonMw)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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