Surgery for Recurrent Glioblastoma
Surgery for Recurrent Glioblastoma
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.
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.
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