Radiotherapy in IDH Mutated Glioma: Evaluation of Late Outcomes (RIGEL)

Rationale: Standard postoperative treatment of isocitrate dehydrogenase 1/2 mutated grade 2 and 3 glioma (IDHmG) consists of radiotherapy and chemotherapy. The improving prognosis of these patients leads towards more emphasis on the long-term effects of treatment. Specifically radiotherapy has been implicated in the development of delayed neurocognitive deterioration. The impact of modern radiotherapy techniques (such as intensity modulated radiotherapy, volumetric modulated radiotherapy and proton beam therapy) and chemotherapy on general toxicity, late neurocognitive outcomes and imaging changes is currently unclear.

Objectives:

• To report treatment outcomes and radiation-induced toxicity from a prospective, multicentre observational cohort of IDHmG patients treated with radiotherapy and chemotherapy,
• To integrate radiotherapeutic dose distributions, imaging changes and neuropsychological outcome in IDHmG.
• To evaluate the Dutch selection criteria for proton therapy applied to IDHmG based on the outcomes collected in this observational study.
• To assess the impact of proton and photon therapy on health-related quality of life (HRQoL) and health-related economics (HR-E) in IDHmG patients.
• To collect genetic material for future translational research into the interaction between germline DNA, prognosis and radiation-induced toxicity.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: This project is a multicentre, observational cohort of patients undergoing radiotherapy and chemotherapy for IDHmG. The protocol closely follows the local guidelines for clinical follow-up. Specific to the study are extra questionnaires and specific imaging acquired during scheduled MRI's. Routine neuropsychological investigation is standard of care in Erasmus Medical Center (Erasmus MC), but not in all participating centers. We feel the additional burden of participation in this study to be low.

Study Overview

• Status: Recruiting
• Conditions: Oligodendroglioma; Astrocytoma, Grade III; Astrocytoma, Grade II; Oligodendroglioma, Anaplastic

• Study Type: Observational
• Enrollment (Anticipated): 79

Contacts and Locations

• Study Contact: Name: Jaap Jaspers, MD; Phone Number: +31 107042982; Email: j.jaspers@erasmusmc.nl

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • Not yet recruiting
    • Amsterdam UMC
    • Contact: Frank Lagerwaard, MD, PhD; Phone Number: +31 20 4440436; Email: fj.lagerwaard@vumc.nl
  • Delft, Netherlands, 2629 JH
    • Recruiting
    • HollandPTC
    • Contact: Marco van Vulpen, Prof. MD; Phone Number: +31 88 5018800; Email: m.van.vulpen@hollandptc.nl
  • Leiden, Netherlands, 2333 ZA
    • Not yet recruiting
    • Leiden University Medical Center
    • Contact: Ida Coremans, MD, PhD; Phone Number: 071 5263525; Email: i.e.m.coremans@lumc.nl
  • Leidschendam, Netherlands, 2262BA
    • Not yet recruiting
    • Haaglanden Medical Center
    • Contact: Ruud Wiggenraad, MD, PhD; Phone Number: +31 88 979 2071; Email: r.wiggenraad@haaglandenmc.nl
  • Zuid Holland
    • Rotterdam, Zuid Holland, Netherlands, 3015 CE
      • Recruiting
      • Erasmus MC
      • Contact: Alejandra Mendez Romero, MD PhD; Phone Number: +31 (0)10 7035829; Email: a.mendezromero@erasmusmc.nl
      • Principal Investigator: Alejandra Méndez Romero, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

IDH mutated glioma patients, WHO grade 2 and 3, who undergo postoperative radiotherapy and chemotherapy as standard treatment.

Description

Inclusion Criteria:

• Histologically confirmed glioma, World Health Organisation (WHO) grade 2 or 3, IDH mutated
• Indication for standard treatment with radiotherapy and chemotherapy. For WHO grade 2 tumors 50.4 Gy relative biological equivalent (RBE) in 28 fractions. For WHO grade 3 tumors 59.4 Gy (RBE) in 33 fractions.
• Ability to comply with the protocol, including neuropsychological testing and imaging.
• Ability to understand the requirements of the study and to give written informed consent, as determined by the treating physician.
• Written informed consent.

Exclusion Criteria:

• Any prior chemotherapy for IDHmG. This includes upfront postoperative chemotherapy.
• Any prior cranial radiotherapy, including but not limited to radiotherapy for IDHmG.
• Prior invasive malignancy, except non-melanoma skin cancer, completely resected cervical or prostate cancer (with current prostate specific antigen (PSA) of less than or equal to 0.1 ng/mL).
• Extensive white matter disease visible on pre-therapy imaging (Fazekas grade ≥2)
• Contra-indication for magnetic resonance (MR) imaging (i.e. metal implants, claustrophobia)
• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule in the participating hospitals
• Any other serious medical condition that could interfere with follow-up.
• Severe aphasia or language barrier interfering with assessing endpoints (i.e. completion of questionnaires or neurocognitive performance)

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Study group; Glioma, IDH mutated, grade 2 and 3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity (selected CTCAE 5.0 items)	The Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 displays Grade 1 to 5, ranging from 'mild' to 'death'. The case report form will include a predefined set of CTCAE items of expected radiotherapy related toxicities. In addition, other CTCAE toxicities grade ≥ 2 that are likely, possibly or definitely related to the radiotherapy should be recorded in the case report form (CRF), when they occur. All items will include a causality assessment: likely or definitely attributable to radiotherapy, unrelated or unlikely attributable to radiotherapy, or not assessable.	24 months
Neurocognitive testing	Neurocognitive functioning will be assessed with a standard and well established short neuropsychological test battery, developed for use in clinical trials. The following tests are included: Hopkins Verbal Learning Test (HVLT), Trail Making Test part A and B (TMT A/B), Controlled Oral Word Association (COWA), Medical Outcomes Study Cognitive Functioning Scale (MOS), Diagnostic Instrument for Mild Aphasia (DIMA)	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Next intervention free survival (NIFS)	NIFS is defined as time from first irradiation to date of initiation of further treatment after radio- and/or chemotherapy or death (any cause), whichever occurs first.	48 months
Progression Free Survival (PFS)	PFS is defined as the time from first irradiation to progressive disease, according to (any of) the Response Asessment in Neuro Oncology (RANO) criteria for progressive disease in low grade glioma.	48 months
Overall Survival (OS)	OS is defined as time from first irradiation to date of death from any cause.	48 months
Health Related Quality of Life (HRQOL)	HRQoL will be assessed with the EORTC quality of life questionnaire (QLQ-C30) supplemented by the neuro-oncological module (QLQ-BN20) and the Euro Quality of Life questionnaire (EQ5D-5L)	24 months
Health - Related Economics	For the Health Related Economics (HR-E) analyses, the EQ5D - 5L questionnaire will be used in conjunction with the Productivity Costs Questionnaire (iPCQ) and the Medical Consumption Questionnaire (iMCQ). These questionaires are optional.	24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Radiological data	If feasible, pre- and 4 months post-treatment a scan protocol will be used that, besides the standard clinical imaging, will focus on (micro-)structural and microvascular characteristics that could predict neurocognitive outcome and treatment efficacy. This feasibility is site-specific.	4 months

Collaborators and Investigators

• Sponsor: Erasmus Medical Center
• Collaborators: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); Leiden University Medical Center; HollandPTC; Medical Center Haaglanden; Delft University of Technology

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 10, 2019
• Primary Completion (ANTICIPATED): May 1, 2024
• Study Completion (ANTICIPATED): May 1, 2026

Study Registration Dates

• First Submitted: March 9, 2020
• First Submitted That Met QC Criteria: March 9, 2020
• First Posted (ACTUAL): March 11, 2020

Study Record Updates

• Last Update Posted (ACTUAL): March 25, 2020
• Last Update Submitted That Met QC Criteria: March 23, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Astrocytoma; Oligodendroglioma
• Other Study ID Numbers: NL69780.078.19; Netherlands Trial Register (REGISTRY: NL7993)

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