The RECSUR-study: Resection Versus Best Oncological Treatment for Recurrent Glioblastoma (ENCRAM 2302) (RECSUR)

The RECSUR-study: Resection Versus Best Oncological Treatment for Recurrent Glioblastoma: Study Protocol for An International Multicenter Prospective Cohort Study (ENCRAM 2302)

Previous evidence has indicated that resection for recurrent glioblastoma might benefit the prognosis of these patients in terms of overall survival. However, the demonstrated safety profile of this approach is contradictory in the literature and the specific benefits in distinct clinical and molecular patient subgroups remains ill-defined. The aim of this study, therefore, is to compare the effects of resection and best oncological treatment for recurrent glioblastoma as a whole and in clinically important subgroups.

This study is an international, multicenter, prospective observational cohort study. Recurrent glioblastoma patients will undergo tumor resection or best oncological treatment at a 1:1 ratio as decided by the tumor board. Primary endpoints are: 1) proportion of patients with NIHSS (National Institute of Health Stroke Scale) deterioration at 6 weeks after surgery and 2) overall survival. Secondary endpoints are: 1) progression-free survival (PFS), 2) NIHSS deterioration at 3 months and 6 months after surgery, 3) health-related quality of life (HRQoL) at 6 weeks, 3 months, and 6 months after surgery, and 4) frequency and severity of Serious Adverse Events (SAEs) in each arm. Estimated total duration of the study is 5 years. Patient inclusion is 4 years, follow-up is 1 year.

The study has been approved by the Medical Ethics Committee (METC Zuid-West Holland/Erasmus Medical Center; MEC-2020-0812). The results will be published in peer-reviewed academic journals and disseminated to patient organisations and media.

Study Overview

• Status: Recruiting
• Conditions: Glioblastoma; Glioblastoma Multiforme; Recurrent Glioblastoma; Glioblastoma, IDH-wildtype; Glioblastoma Multiforme, Adult; Glioblastoma Multiforme of Brain; Astrocytoma of Brain; Astrocytoma, Malignant
• Intervention / Treatment: Procedure: Re-resection; Drug: Temozolomide; Drug: Lomustine; Radiation: Re-irradiation; Procedure: Experimental therapy; Other: Best supportive care

Detailed Description

This is an international, multicenter, prospective, cohort study. Eligible patients are operated or receive best oncological treatment with a 1:1 ratio with a sequential computer-generated random number as subject ID. Intraoperative mapping techniques and/or surgical adjuncts can be used in both treatment arms to ensure the safety of the resection (to minimize the risk of postoperative deficits).

Study patients undergo tumor re-resection or receive best oncological treatment and will undergo evaluation at presentation (baseline) and during the follow-up period at 6 weeks, 3 months, and 6 months postoperatively. Motor function will be evaluated using the NIHSS (National Institute of Health Stroke Scale) and MRC (Medical Research Council) scale. Language function will be evaluated using a standard neurolinguistic test-battery consisting of the Aphasia Bedside Check (ABC), Shortened Token test, Verbal fluency, Picture description and Object naming. This neurolinguistic test-battery is the result of a consensus between the participating centers. Cognitive function will be assessed using the Montreal Cognitive Assessment (MOCA). Overall patient functioning with be assessed with the Karnofsky Performance Scale (KPS) and the ASA (American Society of Anesthesiologists) physical status classification system for comorbidities. Health-related quality of life (HRQoL) will be assessed with the EQ-5D questionnaire and the EORTC QLQ-C30 and EORTC QLQ-BN20 questionnaires. Overall survival and progression-free survival will be assessed. We expect to complete patient inclusion in 4 years. The estimated duration of the study, including follow-up, will be 5 years.

The primary study objective is to evaluate the safety and efficacy of re-resection versus best oncological treatment (neurological morbidity and overall survival) in recurrent glioblastoma patients as expressed by NIHSS scores and survival data. Secondary study objectives are to study the overall progressive-free survival (PFS), long-term neurological morbidity (3 months and 6 months postoperatively), health-related quality of life (HRQoL), and Serious Adverse Events (SAEs) after resection versus best oncological treatment as expressed by progression on follow up MRI scans based on the RANO criteria24 for tumor progression; NIHSS scores, quality of life questionnaires (EORTC QLQ C30, EORTC QLQ BN20, EQ-5D), and registration of SAEs.

Patients will be recruited for the study from the neurosurgical or neurological outpatient clinic or through referral from general hospitals of the participating neurosurgical hospitals of the ENCRAM Research Consortium, located in Europe and the United States.

• Study Type: Observational
• Enrollment (Estimated): 464

Contacts and Locations

• Study Contact: Name: Jasper Gerritsen, MD PhD; Phone Number: 31107036130; Email: j.gerritsen@erasmusmc.nl
• Study Contact Backup: Name: Arnaud Vincent, MD PhD; Phone Number: 31107034211; Email: a.vincent@erasmusmc.nl

Study Locations

• Belgium
  • Leuven, Belgium
    • Recruiting
    • University Hospital Leuven
    • Contact: Steven De Vleeschouwer, MD PhD
• Germany
  • Heidelberg, Germany
    • Recruiting
    • University Hospital Heidelberg
    • Contact: Christine Jungk, Dr. med.
  • Munich, Germany
    • Not yet recruiting
    • Technical University Munich
    • Contact: Arthur Wagner, MD
• Netherlands
  • Zuid-Holland
    • Rotterdam, Zuid-Holland, Netherlands, 3015 CE
      • Recruiting
      • Erasmus MC
      • Contact: Jasper Gerritsen, MD; Phone Number: +31629119553; Email: j.gerritsen@erasmusmc.nl
      • Contact: Arnaud Vincent, MD PhD; Phone Number: +31639428949; Email: a.vincent@erasmusmc.nl
    • The Hague, Zuid-Holland, Netherlands, 2261 CP
      • Recruiting
      • Medical Center Haaglanden
      • Contact: Marike Broekman, MD PhD; Phone Number: +31639758253; Email: m.broekman@haaglandenmc.nl
• Switzerland
  • Bern, Switzerland
    • Not yet recruiting
    • INSELSPITAL Universitatsspital Bern
    • Contact: Philippe Schucht, MD PhD
• United States
  • California
    • San Francisco, California, United States, 94143
      • Recruiting
      • University of California, San Francisco
      • Contact: Mitchel Berger, MD PhD
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
      • Contact: Brian Nahed, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Patients with recurrent glioblastoma will be recruited from the neurosurgical or neurological outpatient clinic or through referral from general hospitals of the participating neurosurgical hospitals, located in Europe and the United States. The study is carried out by centers from the ENCRAM Consortium.

Description

Inclusion Criteria:

1. Age ≥18 years and ≤90 years
2. Tumor recurrence according to the RANO criteria of a previously diagnosed glioblastoma based on the WHO 2021 classification for glioma
3. The tumor is suitable for resection (according to neurosurgeon)
4. Written informed consent

Exclusion Criteria:

1. Tumors of the cerebellum, brainstem, or midline
2. Medical reasons precluding MRI (e.g., pacemaker)
3. Inability to give written informed consent
4. Secondary high-grade glioma due to malignant transformation from low-grade glioma
5. Clinical data unavailable for the newly diagnosed setting

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Re-resection; Resection of the recurrent tumor	Procedure: Re-resection; Resection of the recurrent tumor
Best oncological treatment; Best oncological treatment consisting of re-challenge temozolomide, re-irradiation, experimental therapy, or best supportive care	Drug: Temozolomide; Re-challenge Temozolomide chemotherapy; Drug: Lomustine; Second line chemotherapy with Lomustine; Radiation: Re-irradiation; Re-irradiation with single dose, fractionated, or hypofractionated radiation of the recurrent tumor; Procedure: Experimental therapy; Experimental phase I therapy with oncolytic virotherapy or immunotherapy (this list is not exhaustive); Other Names: Immunotherapy; Oncolytic virotherapy; Other: Best supportive care; Best supportive care, focused on alleviating symptoms

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Time from diagnosis to death from any cause	Up to 5 years postoperatively
Neurological morbidity at 6 weeks	NIHSS deterioration of 1 point or more at 6 weeks after surgery	6 weeks postoperatively

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neurological morbidity at 3 months	NIHSS deterioration of 1 point or more at 3 months after surgery	3 months postoperatively
Neurological morbidity at 6 months	NIHSS deterioration of 1 point or more at 6 months after surgery	6 months postoperatively
Progression-free survival	Time from diagnosis to disease progression (occurrence of a new tumor lesions with a volume greater than 0.175 cm3, or an increase in residual tumor volume of more than 25%) or death, whichever comes first	Up to 5 years postoperatively
Residual tumor volume	Residual tumor volume of the contrast-enhancing and non-contrast enhancing part, as assessed by a neuroradiologist on postoperative MRI scan (T1 with contrast and FLAIR sequences) using manual or semi-automatic volumetric analyses (Brainlab Elements iPlan CMF Segmentation, Brainlab AG, Munich, Germany; or similar software)	Within 72 hours postoperatively
Quality of life at 6 weeks (EORTC QLQ C30)	Quality of life as assessed by the EORTC QLQ C30 questionnaire	6 weeks postoperatively
Quality of life at 6 weeks (EORTC QLQ BN20)	Quality of life as assessed by the EORTC QLQ BN20 questionnaire	6 weeks postoperatively
Quality of life at 6 weeks (EQ-5D)	Quality of life as assessed by the EQ-5D questionnaire	6 weeks postoperatively
Quality of life at 3 months (EORTC QLQ C30)	Quality of life as assessed by the EORTC QLQ C30 questionnaire	3 months postoperatively
Quality of life at 3 months (EORTC QLQ BN20)	Quality of life as assessed by the EORTC QLQ BN20 questionnaire	3 months postoperatively
Quality of life at 3 months (EQ-5D)	Quality of life as assessed by the EQ-5D questionnaire	3 months postoperatively
Quality of life at 6 months (EORTC QLQ C30)	Quality of life as assessed by the EORTC QLQ C30 questionnaire	6 months postoperatively
Quality of life at 6 months (EORTC QLQ BN20)	Quality of life as assessed by the EORTC QLQ BN20 questionnaire	6 months postoperatively
Quality of life at 6 months (EQ-5D)	Quality of life as assessed by the EQ-5D questionnaire	6 months postoperatively
Serious Adverse Events	Serious Adverse Events within 6 weeks postoperatively	6 weeks postoperatively

Collaborators and Investigators

• Sponsor: Jasper Gerritsen
• Collaborators: Massachusetts General Hospital; Universitaire Ziekenhuizen KU Leuven; University of California, San Francisco; University Hospital Heidelberg; Technical University of Munich; Haaglanden Medical Centre; Insel Gruppe AG, University Hospital Bern
• Investigators: Principal Investigator: Jasper Gerritsen, MD PhD, Erasmus Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2023
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2028

Study Registration Dates

• First Submitted: February 21, 2024
• First Submitted That Met QC Criteria: February 21, 2024
• First Posted (Actual): February 28, 2024

Study Record Updates

• Last Update Posted (Actual): February 28, 2024
• Last Update Submitted That Met QC Criteria: February 21, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Safety; Quality of life; Radiotherapy; Chemotherapy; Glioblastoma; Resection; Overall survival; Progression-free survival; Neurological morbidity; Re-resection; Serious Adverse Events
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Disease Attributes; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Recurrence; Astrocytoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Temozolomide; Lomustine
• Other Study ID Numbers: MEC-2020-0812-5

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