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Supramarginal Resection in Glioblastoma

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ClinicalTrials.gov Identifier: NCT04243005
Recruitment Status : Recruiting
First Posted : January 27, 2020
Last Update Posted : July 16, 2021
Sponsor:
Collaborators:
Odense University Hospital
Sahlgrenska University Hospital, Sweden
Turku University Hospital
Karolinska University Hospital
Norwegian University of Science and Technology
University Hospital, Linkoeping
Uppsala University Hospital
University Hospital, Umeå
Skane University Hospital
Haukeland University Hospital
Ullevaal University Hospital
Rikshospitalet University Hospital
University Hospital of North Norway
Aarhus University Hospital
Rigshospitalet, Denmark
Tampere University Hospital
Helsinki University Central Hospital
Kuopio University Hospital
Oulu University Hospital
Information provided by (Responsible Party):
St. Olavs Hospital

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Glioblastoma Procedure: Supramarginal resection Procedure: Conventional surgery Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Masking Description: Participants will be masked until postoperative period. Outcome assessor will be masked until all predefined outcomes have been analysed
Primary Purpose: Treatment
Official Title: Supramarginal Resection in Patients With Glioblastoma: A Randomised Controlled Trial
Actual Study Start Date : July 1, 2020
Estimated Primary Completion Date : March 2024
Estimated Study Completion Date : March 2027

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.
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.

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
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




Primary Outcome Measures :
  1. Overall survival [ Time Frame: 36 months after the last included patient. ]
    Overall survival according to intention-to-treat


Secondary Outcome Measures :
  1. Proportion alive [ Time Frame: 24 months after randomization. ]
    Proportion alive

  2. Proportion alive [ Time Frame: 36 months after randomization. ]
    Proportion alive

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. Surgical complication [ Time Frame: 30 days ]
    surgical complication grade 3, 4 and 5, assessed using the Dindo-Clavien classification

  9. Proportion with contrast remnant [ Time Frame: Within 72 hours postoperative ]
    Resection proportion with contrast remnant

  10. Extent of resection, T2/FLAIR remnant [ Time Frame: Within 72 hours postoperative ]
    Proportion with remnant in terms of hyper intensity changes in T2/FLAIR

  11. Margin of resection [ Time Frame: Within 72 hours postoperative ]
    Cavity volume/contrast enhancement volume


Other Outcome Measures:
  1. Overall Survival; as treated [ Time Frame: 36 months after the last included patient. ]
    Accounting for cross-over or failure to achieve predefined surgical aim. "As treated" populations when no margins in supramarginal group and unintended contrast remnant in group aiming at conventional gross-total resection or even if significant supramarginal resection in this group



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

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): NCT04243005


Contacts
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Contact: Asgeir S Jakola, MD, PhD +47 72 57 30 00 legepost@gmail.com
Contact: Sasha Gulati, MD, PhD +47 72 57 30 00 sasha.gulati@ntnu.no

Locations
Show Show 19 study locations
Sponsors and Collaborators
St. Olavs Hospital
Odense University Hospital
Sahlgrenska University Hospital, Sweden
Turku University Hospital
Karolinska University Hospital
Norwegian University of Science and Technology
University Hospital, Linkoeping
Uppsala University Hospital
University Hospital, Umeå
Skane University Hospital
Haukeland University Hospital
Ullevaal University Hospital
Rikshospitalet University Hospital
University Hospital of North Norway
Aarhus University Hospital
Rigshospitalet, Denmark
Tampere University Hospital
Helsinki University Central Hospital
Kuopio University Hospital
Oulu University Hospital
Investigators
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Principal Investigator: Asgeir S Jakola, MD, PhD St.Olavs University Hospital and Sahlgrenska University Hospital
Study Director: Geir Bråthen, MD, PhD St. Olavs Hospital
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Responsible Party: St. Olavs Hospital
ClinicalTrials.gov Identifier: NCT04243005    
Other Study ID Numbers: 2019/1046
First Posted: January 27, 2020    Key Record Dates
Last Update Posted: July 16, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by St. Olavs Hospital:
Neurosurgical procedures
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