Clinical trial NCT02394626: Surgery for Recurrent Glioblastoma
Official title: RESURGE - Randomized Controlled Comparative Phase II Trial on Surgery for Glioblastoma Recurrence
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Glioblastoma
Keywords: Recurrent glioblastoma
Surgery
Complete resection of enhancing tumor
Survival
Quality of life
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
Collaborators: name: European Organisation for Research and Treatment of Cancer - EORTC
First posted: 2015-03-20
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Overall survival from the date of inclusion
timeFrame: From the date of inclusion until death/end of study, assessed up to 5.7 years
Secondary outcomes:
measure: Recruitment rate for all screened patients
timeFrame: Screening and inclusion
measure: Progression-free survival
timeFrame: 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
measure: Morbidity of surgery
timeFrame: Every 3 months up to 2 years or until death, assessed up to 5.7 years
measure: Total number of days spent at home after recurrence
timeFrame: From the date of inclusion until death/end of study, assessed up to 5.7 years
measure: Total number of days spent outside home after recurrence
timeFrame: From the date of inclusion until death/end of study, assessed up to 5.7 years
Other outcomes:
Locations:
city: Innsbruck
country: Austria
facility: Universitätsklinikum Innsbruck
city: Erfurt
country: Germany
facility: Helios Klinikum Erfurt
city: Frankfurt
country: Germany
facility: Department of Neurosurgery, Universitätsklinikum Frankfurt
city: Freiburg
country: Germany
facility: Dep. of Neurosurgery, Universitätsklinikum Freiburg
city: Giessen
country: Germany
facility: Universitätsklinikum Gießen und Marburg
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg-Universität Mainz
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Larissa
country: Greece
facility: Department of Neurosurgery, Hospital of Larissa & General Hospital of Larissa
city: Thessaloníki
country: Greece
facility: Department of Neurosurgery, AHEPA University Hospital
city: Milano
country: Italy
facility: Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta
city: Amsterdam
country: Netherlands
facility: Department of Neurosurgery, Amsterdam University Medical Center
city: Nijmegen
country: Netherlands
facility: Department of Neurosurgery, Radboud University Medical Center, Nijmegen
city: The Hague
country: Netherlands
facility: Department of Neurosurgery, Haaglanden Medical Center, The Hague
city: Lisboa
country: Portugal
facility: Department of Neurosurgery, Centro Hospitalar Universitário Lisboa Norte - Hospital de Santa Maria
city: Bucharest
country: Romania
facility: Department of Neurosurgery, Spitalul Clinic De Urgență "Bagdasar-Arseni"
city: Barcelona
country: Spain
facility: Department of Neurosurgery, L'Hospitalet de Llobregat, Barcelona
city: Madrid
country: Spain
facility: Department of Neurosurgery, Puerta de Hierro University Hospital, Madrid
city: Aarau
country: Switzerland
facility: Kantonsspital Aarau
city: Basel
country: Switzerland
facility: Universitätsspital Basel
city: Bern
country: Switzerland
facility: Dep. of Neurosurgery, Bern University Hospital
city: Geneva
country: Switzerland
facility: Dep. of Neurosurger, Hôpitaux Universitaires de Genève
city: Lausanne
country: Switzerland
facility: Dep. of Neurosurgery, Centre hospitalier universitaire vaudois
city: Lugano
country: Switzerland
facility: Ospedale Regionale di Lugano
city: Luzern
country: Switzerland
facility: Kantonsspital Luzern
city: Saint Gallen
country: Switzerland
facility: Department of Neurosurgery, Kantonsspital St. Gallen
city: Zurich
country: Switzerland
facility: Dep. of Neurosurgery, University Hospital of Zurich
Study officials:
affiliation: Dep. of Neurosurgery, Inselspital Bern
name: Philippe Schucht, Prof. Dr. med.
role: PRINCIPAL_INVESTIGATOR
References: