Supramarginal Resection in Glioblastoma

Overview

Gliomas are the most common malignant brain tumor. Glioblastoma, WHO grade IV astrocytoma, is the most common subtype and unfortunately also the most aggressive subtype with median survival in population based cohorts being only 10 months. Extensive surgical resections followed by postoperative fractioned radiotherapy and concomitant and adjuvant temozolomide prolong survival and is the standard treatment. The investigators think there is significant potential in individualized surgical decision-making in glioblastoma management. The idea that some patients are amendable to radical surgery, while others should be treated more conservatively, is not controversial in other fields of oncology. The current concept in all patients with glioblastoma is "maximum safe resection of the contrast enhancing tumor", but this may in selected cases be extended to simply "maximum safe resection" tailored to the patient and extent of disease at hand. Densely proliferating tumor cells have been found from at an average of 10 mm beyond the margins of contrast enhancement in high-grade gliomas. There are now several case series, using various definitions of supramarginal resection, but they have in common that they report a benefit of resection with a margin. This potential benefit also comes together with an associated neurological risk, making this approach unethical and simply not feasible in the patients with glioblastoma as a whole. Objective of this study is: To investigate if resection with a margin, that is significantly beyond the radiological contrast enhancement, improves survival in selected patients with glioblastoma.

Full Title of Study: “Supramarginal Resection in Patients With Glioblastoma: A Randomised Controlled Trial”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Double (Participant, Outcomes Assessor)
  • Study Primary Completion Date: March 2024

Interventions

  • Procedure: Supramarginal resection
    • Aim of supramarginal resection, where a margin of at least 10 mm is considered feasible prior to surgery. The resection is guided by the T2 volume (i.e. zone of edema) where removal of as much as possible of this zone (or beyond) is attempted as long as considered safe
  • Procedure: Conventional surgery
    • Aim of gross total resection (i.e. removal of contrast enhancing tumor) according to institutional practice. No limit in use of technical adjuncts in this arm.

Arms, Groups and Cohorts

  • Active Comparator: Conventional surgery
    • Aim of gross total resection (i.e. removal of contrast enhancing tumor) according to institutional practice. No limit in use of technical adjuncts in this arm.
  • Experimental: Supramarginal surgery
    • Aim of supramarginal resection, where a margin of at least 10 mm is considered feasible prior to surgery. The resection is guided by the T2 volume (i.e. zone of edema) where removal of as much as possible of this zone (or beyond) is attempted as long as considered safe

Clinical Trial Outcome Measures

Primary Measures

  • Overall survival
    • Time Frame: 36 months after the last included patient.
    • Overall survival according to intention-to-treat

Secondary Measures

  • Proportion alive
    • Time Frame: 24 months after randomization.
    • Proportion alive
  • Proportion alive
    • Time Frame: 36 months after randomization.
    • Proportion alive
  • Neurological function
    • Time Frame: Early postoperative (i.e. prior to radiotherapy) to 36 months
    • Neurological assessment in Neuro-Oncology (NANO) Scale is a tool used by healthcare providers to objectively quantify the impairment caused by a tumor within the central nervous system. The NANO is composed of 9 items. For each item, a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. The individual scores from each item are summed in order to calculate a patient’s total NANO scale score. The maximum possible score is 23, with the minimum score being a 0.
  • Health-related quality of life assessed by EQ-5D 3L
    • Time Frame: Early postoperative (i.e. prior to radiotherapy) to 36 months
    • The EQ-5D-3L descriptive system comprises the following five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results into a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient’s health state.
  • Health-related quality of life assessed by EORTC QLQ C30
    • Time Frame: Early postoperative (i.e. prior to radiotherapy) to 36 months
    • The QLQ-C30 is a cancer health-related quality-of-life questionnaire that has been widely used in clinical trials and investigations using PROs for individual patient management. It includes five function domains (physical, emotional, social, role, cognitive), eight symptoms (fatigue, pain, nausea/vomiting, constipation, diarrhea, insomnia, dyspnea, and appetite loss), as well as global health/quality-of-life and financial impact. Subjects respond on a four-point scale from “not at all” to “very much” for most items. Most items use a “past week” recall period. Raw scores are linearly converted to a 0-100 scale with higher scores reflecting higher levels of function and higher levels of symptom burden.
  • Health-related quality of life assessed by BN20
    • Time Frame: Early postoperative (i.e. prior to radiotherapy) to 36 months
    • The European Organization for Research and Treatment of Cancer (EORTC) QLQ-BN20 is a quality of life assessment specific to brain neoplasms. Consists of 20 items that assess future uncertainty, visual disorder, motor dysfunction, and communication deficit. Items are presented as questions on a scale ranging from 1 = “not at all” to 4 = “very much.” Higher score means worse outcome.
  • Neurocognition
    • Time Frame: Early postoperative (i.e. prior to radiotherapy) to 36 months
    • The Mini-Mental State Examination (MMSE) or Folstein test is a 30-point questionnaire that is used extensively in clinical and research settings to measure cognitive impairment. It examines functions including registration (repeating named prompts), attention and calculation, recall, language, ability to follow simple commands and orientation. Any score of 24 or more (out of 30) indicates a normal cognition. Below this, scores can indicate severe (≤9 points), moderate (10-18 points) or mild (19-23 points) cognitive impairment.
  • Surgical complication
    • Time Frame: 30 days
    • surgical complication grade 3, 4 and 5, assessed using the Dindo-Clavien classification
  • Proportion with contrast remnant
    • Time Frame: Within 72 hours postoperative
    • Resection proportion with contrast remnant
  • Extent of resection, T2/FLAIR remnant
    • Time Frame: Within 72 hours postoperative
    • Proportion with remnant in terms of hyper intensity changes in T2/FLAIR
  • Margin of resection
    • Time Frame: Within 72 hours postoperative
    • Cavity volume/contrast enhancement volume

Participating in This Clinical Trial

Inclusion Criteria

1. A suspected diagnosis of supratentorial glioblastoma by MRI.(A) 2. Indication for surgical treatment and where supramarginal resection is considered possible according to the preoperative imaging. This consideration needs to be verified by two specialists in neurosurgery. 3. Negative work-up for other primary tumor(B) 4. Karnofsky performance status of 70 – 100. A) If randomized to supramarginal surgery, intraoperative frozen section must conclude with "high-grade glioma" to be able to proceed. Surgery in two sessions is also possible in supramarginal group if there is no intraoperative frozen section available or frozen section indicate another diagnosis, but final histopathology reveals a glioblastoma. In case of surgery in two session, there must be no more than 30 days between procedures. See flow-chart in attachment 1. B) No suspected primary tumor seen on CT chest, abdomen and pelvis. If relevant symptoms/clinical suspicion also supplement with mammography, dermatologist exam, relevant endoscopies etc. Exclusion Criteria:

1. Not willing to be randomized. 2. Informed consent not possible (e.g. language barriers, aphasia, cognitive severely impaired). 3. Contrast enhancement volume bilateral OR involving corpus callosum. 4. Contrast enhancement along the ependymal lining of ventricles (contact is however not an exclusion criteria). 5. Contrast enhancement involving several lobes. 6. History of major psychiatric disorder such as psychosis, schizophrenia and/or mood disorder (e.g. depression and bipolar disorder) in need of hospitalization 7. Unfit for participation for any other reason judged by the including physician

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 70 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • St. Olavs Hospital
  • Collaborator
    • Odense University Hospital
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Asgeir S Jakola, MD, PhD, Principal Investigator, St.Olavs University Hospital and Sahlgrenska University Hospital
    • Geir Bråthen, MD, PhD, Study Director, St. Olavs Hospital
  • Overall Contact(s)
    • Asgeir S Jakola, MD, PhD, +47 72 57 30 00, legepost@gmail.com

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