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Surgery for Recurrent Glioblastoma (RESURGE)

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ClinicalTrials.gov Identifier: NCT02394626
Recruitment Status : Recruiting
First Posted : March 20, 2015
Last Update Posted : June 25, 2019
Sponsor:
Collaborator:
European Organisation for Research and Treatment of Cancer - EORTC
Information provided by (Responsible Party):
University Hospital Inselspital, Berne

Brief Summary:

Patients with glioblastoma face a grim prognosis. Despite recent advancement in neurosurgical technology and neuro-oncology glioblastomas almost invariably progress or recur after a median of 4-8 months. The strategy to repeat tumor resection at recurrence in order to minimize tumor load and thus to facilitate subsequent second-line therapy has been shown to be feasible and safe.

However, evidence for a survival benefit of surgery for recurrent glioblastoma is scarce and relies entirely on retrospective analyses. While most retrospective analyses report an apparent survival benefit, an EORTC meta-analysis on second-line therapies found no survival difference in patients with or without surgery at recurrence. With regard to the risks and costs inherent to surgery for glioblastoma, a randomized controlled trial is required.

The purpose of the study is to compare the effect of craniotomy and tumor resection followed by adjuvant second-line therapy to no surgery followed by second-line therapy on overall survival, neurological status, and quality of life. Analysis of overall survival will be used to improve sample size estimation of a subsequent phase III trial for craniotomy and tumor resection of glioblastoma recurrence in cooperation with the EORTC.


Condition or disease Intervention/treatment Phase
Glioblastoma Procedure: Surgery followed by adjuvant second-line therapy Procedure: Second-line therapy alone Phase 2

Detailed Description:

Background

Glioblastoma is a malignant, locally invasive brain tumor whose prognosis remains grim despite various intense treatment modalities. In the past, radical surgery was met with skepticism due to the aggressive infiltrative character of the tumor. However, an increasing number of retrospective studies over the last decade suggest a survival benefit for surgery. A recent post-hoc analysis of a randomized controlled trial on the use of the surgical adjunct 5-ALA reported a prolonged overall survival from 11.9 to 16.7 months (evidence level 2a) after more extensive resection. Thus, maximal safe resection has become a mainstay of treatment for newly diagnosed glioblastoma, followed by adjuvant radio-chemotherapy.

Glioblastoma almost invariably recurs after a median of 6.9 months, leaving but few options for further treatment. Recurrence of glioblastoma after surgery and concomitant adjuvant therapy represents an additional therapeutic challenge and may be treated with second-line pharmacotherapy. In addition, a second surgery may also be considered in highly selected patients.

The rationale for surgery - maximum safe resection - is to prolong survival through reduction of tumor load, and, maybe due to an increased efficacy of adjuvant treatment. However, surgery carries risks of complications, that may result in a decreased functional and survival outcome. The crucial question therefore is whether, to what extent, and at what costs in terms of neurological risks a second resection prolongs survival.

Objective

The primary objective of this randomized trial is to compare survival outcome after surgery followed by adjuvant second-line therapy to no surgery followed by second-line therapy in recurrent glioblastoma. An auxiliary objective to primary objective is to compare the survival outcomes of operated patients to control in the subgroups stratified by extent of resection: incomplete resection (non-CRET) vs complete resection (CRET).

Secondary objectives are: assessment of recruitment for all screened patients, comparison of progression-free survival between treatment arms, evaluation of crossover and comparison of patient quality of life between treatment arms.

Safety objectives are: to assess neurological deficits, local infections and morbidity associated to surgery and hospital stay after surgery and during follow-up.

Methods

All patients (≥18 years) with a radiological suspicion of first recurrence of glioblastoma are screened for this trial. Patients eligible for study participation are informed on the treatment options for recurrent glioblastoma (surgery followed by adjuvant second-line therapy, second-line therapy, or palliative therapy alone) by the center investigators. Patients randomized to the control group will receive second-line therapy according to local guidelines. Patients randomized to the interventional group will receive a craniotomy and resection of the tumor followed by adjuvant second-line therapy. Outcome will be measured at 3 months intervals.

Recruitment rate and reason for non-inclusion will be monitored.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: RESURGE - Randomized Controlled Comparative Phase II Trial on Surgery for Glioblastoma Recurrence
Study Start Date : May 2015
Estimated Primary Completion Date : October 2020
Estimated Study Completion Date : October 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Surgery followed by adjuvant second-line therapy
Surgery followed by adjuvant second-line therapy
Procedure: Surgery followed by adjuvant second-line therapy

Surgery:

Surgery must take place between day 1 and 14 after study inclusion and within 21 days from the MRI on which recurrence was diagnosed. The modalities of surgery and the choice of pre- and intra-operative technical adjuncts is at the treating neurosurgery discretion. Surgery must take place between day 1 and 14 after study inclusion and within 21 days from the MRI on which recurrence was diagnosed. The modalities of surgery and the choice of pre- and intra-operative technical adjuncts is at the treating neurosurgery discretion. However, some form of intra-operative resection control (iMRI or intra-operative fluorescence) and function control (electrophysiology) should be available to the surgeon and used when warranted.

Adjuvant second-line therapy:

Patients will be seen after surgery by the treating neurooncologist. Modalities of adjuvant second-line therapy are individually defined according to local guidelines and are not stipulated by study protocol.


Active Comparator: Second-line therapy alone
Second-line therapy alone
Procedure: Second-line therapy alone
Patients randomized to the non-surgical cohort receive second-line therapy according to local guidelines. Modalities thereof are not stipulated by study protocol.




Primary Outcome Measures :
  1. Overall survival from the date of inclusion [ Time Frame: From the date of inclusion until death/end of study, assessed up to 5.7 years ]

Secondary Outcome Measures :
  1. Recruitment rate for all screened patients [ Time Frame: Screening and inclusion ]
  2. Progression-free survival [ Time Frame: From the date of inclusion until the date of objective progression or the date of patient's death, whichever occurs first, assessed up to 5.7 years ]
  3. Morbidity of surgery [ Time Frame: Every 3 months up to 2 years or until death, assessed up to 5.7 years ]
  4. Total number of days spent at home after recurrence [ Time Frame: From the date of inclusion until death/end of study, assessed up to 5.7 years ]
  5. Total number of days spent outside home after recurrence [ Time Frame: From the date of inclusion until death/end of study, assessed up to 5.7 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Written informed consent
  • ≥18 years of age
  • Prior resection of glioblastoma confirmed by histology
  • Glioblastoma pretreated with standard radiotherapy without or with temozolomide
  • First progression according to RANO criteria
  • First progression not within 3 months after completion of radiation therapy
  • Complete removal of contrast-enhancing lesion considered feasible without significant risk of permanent speech or motor function according to MRI as confirmed by study eligibility committee after screening and prior to recruitment
  • No encroachment of the M1 or A1 segments of the medial and anterior cerebral artery on MRI
  • No contrast enhancement in presumed speech and primary motor areas on MRI
  • No midline shift on MRI
  • No contrast enhancing ventricular spread, multifocal recurrence, meningeosis carcinomatosa or infiltration of the contra-lateral hemisphere on MRI
  • No contra-indication for surgery
  • Good functional status (KPS ≥ 70)

Exclusion Criteria


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02394626


Contacts
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Contact: Andrea Mathis +41 31 632 95 64 andrea.mathis@insel.ch
Contact: Nicole Söll +41 31 63 2 31 6 Nicole.Soell@insel.ch

Locations
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Austria
Universitätsklinikum Innsbruck Recruiting
Innsbruck, Austria
Contact: Christian Freyschlag, MD       christian.freyschlag@tirol-kliniken.at   
Contact: Johannes Kerschbaumer, MD       Johannes.kerschbaumer@tirol-kliniken.at   
Germany
Helios Klinikum Erfurt Recruiting
Erfurt, Germany, 99089
Contact: Rüdiger Gerlach, MD       ruediger.gerlach@helios-gesundheit.de   
Department of Neurosurgery, Universitätsklinikum Frankfurt Recruiting
Frankfurt, Germany, 60590
Contact: Forster Marie-Thérèse, MD         
Dep. of Neurosurgery, Universitätsklinikum Freiburg Recruiting
Freiburg, Germany, 79106
Contact: Schnell Oliver, MD         
Universitätsklinikum Gießen und Marburg Recruiting
Giessen, Germany, 35392
Contact: Marco Stein, MD       Marco.Stein@neuro.med.uni-giessen.de   
Department of Neurosurgery, Universitätsklinikum Köln Recruiting
Köln, Germany, 50937
Contact: Boris Krischek, MD         
Universitätsmedizin der Johannes Gutenberg-Universität Mainz Recruiting
Mainz, Germany
Contact: Naureen Keric, MD         
Universitätsklinikum Münster Recruiting
Münster, Germany, 48149
Contact: Benjamin Brokinkel       benjamin.brokinkel@ukmuenster.de   
Greece
Department of Neurosurgery, Hospital of Larissa & General Hospital of Larissa Recruiting
Larissa, Greece, 412 21
Contact: Kostas Fountas, MD         
Department of Neurosurgery, AHEPA University Hospital Recruiting
Thessaloníki, Greece, 546 21
Contact: Nicolas Foroglou, MD         
Italy
Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta Recruiting
Milano, Italy, 20133
Contact: Francesco Di Meco       fdimeco@istituto-besta.it   
Contact: Cecilia Casali       cecilia.casali@istituto-besta.it   
Portugal
Department of Neurosurgery, Centro Hospitalar Universitário Lisboa Norte - Hospital de Santa Maria Recruiting
Lisboa, Portugal, 1649-035
Contact: Alexandre Rainha Campos, MD         
Romania
Department of Neurosurgery, Spitalul Clinic De Urgență "Bagdasar-Arseni" Recruiting
Bucharest, Romania, 041915
Contact: George Petrescu, MD         
Switzerland
Kantonsspital Aarau Recruiting
Aarau, Switzerland, 5001
Contact: Serge Marbacher, MD    +41 62 838 66 2    serge.marbacher@ksa.ch   
Universitätsspital Basel Recruiting
Basel, Switzerland, 4031
Contact: Dominik Cordier       dominik.cordier@usb.ch   
Dep. of Neurosurgery, Bern University Hospital Recruiting
Bern, Switzerland, 3010
Principal Investigator: Philippe Schucht         
Dep. of Neurosurger, Hôpitaux Universitaires de Genève Recruiting
Geneva, Switzerland, 1205
Principal Investigator: Torstein Mehling         
Dep. of Neurosurgery, Centre hospitalier universitaire vaudois Recruiting
Lausanne, Switzerland, 1011
Principal Investigator: Andreas Hottinger         
Ospedale Regionale di Lugano Recruiting
Lugano, Switzerland, 6900
Contact: Michael Reinert, MD       michael.reinert@eoc.ch   
Kantonsspital Luzern Recruiting
Luzern, Switzerland, 6000
Contact: Karl Kothbauer       karl.kothbauer@luks.ch   
Department of Neurosurgery, Kantonsspital St. Gallen Recruiting
Saint Gallen, Switzerland, 9007
Contact: Evangelos Kogias, MD         
Dep. of Neurosurgery, University Hospital of Zurich Recruiting
Zurich, Switzerland, 8091
Principal Investigator: Luca Regli         
Sponsors and Collaborators
University Hospital Inselspital, Berne
European Organisation for Research and Treatment of Cancer - EORTC
Investigators
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Principal Investigator: Philippe Schucht, Prof. Dr. med. Dep. of Neurosurgery, Inselspital Bern

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Responsible Party: University Hospital Inselspital, Berne
ClinicalTrials.gov Identifier: NCT02394626     History of Changes
Other Study ID Numbers: 368/14
First Posted: March 20, 2015    Key Record Dates
Last Update Posted: June 25, 2019
Last Verified: June 2019
Keywords provided by University Hospital Inselspital, Berne:
Recurrent glioblastoma
Surgery
Complete resection of enhancing tumor
Survival
Quality of life
Additional relevant MeSH terms:
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Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue