MEDICO-ECONOMIC EVALUATION OF SURGERY GUIDED BY FLUORESCENCE FOR THE OPTIMIZATION OF RESECTION OF GLIOBLASTOMAS (RESECT)

Randomized, Prospective, Multicenter Blinding Singles With Arm A and Arm B Innovative Strategy Strategy Conventional

Glioblastoma is the most frequent primary malignant brain tumor in adults (3,000 new cases per year) and is characterized by a poor prognosis (median survival 12 months). Treatment is based mainly on surgical excision as complete as possible followed by an additional radiochemotherapy. The prognosis depends mainly on the quality of resection when it is macroscopically complete. Different techniques to support the surgical resection have been developed over the past 20 years. The reference technique is currently the intraoperative neuronavigation for guiding excision by matching the intraoperative tumor boundaries with those of the preoperative MRI. Its main drawback is the loss of precision during the resection related to changes in anatomical limits of the tumor.

The per-operative fluorescence-guided surgery (FGS) is an innovative alternative technique to support the surgical resection. The 5-aminolevulinic acid (5-ALA), a molecule absorbed by the patient before surgery is captured specifically by the tumor cells and transformed into a fluorochrome revealed intraoperatively by a light source length adapted wave with a set of lenses included in the microscope. Resection is thus guided by this fluorescence whose disappearance translates complete tumor resection.

Its interest is twofold:

• Increase the percentage of complete tumor resection.
• Improve disease-free survival and overall survival. The objective of the study is to compare the FGS to the intraoperative neuronavigation for the resection of glioblastoma, on a medical and economical level through a randomized, prospective, multicenter trial.

The annual number of patients likely to benefit of this technique in France is estimated at 2200 new cases.

Study Overview

• Status: Unknown
• Conditions: Glioblastoma
• Intervention / Treatment: Drug: 5-aminolévulinique acid (5-ALA); Drug: Placebo

Detailed Description

Main Outcome Measure: Percentage of patients with surgical resection of the tumor is complete, objectified by the absence of residual tumor on MRI early postoperative (within 48 hours) by a central committee of independent reading with qualitative analysis taking a contrast replay console for diagnostic use

• Study Type: Interventional
• Enrollment (Actual): 170
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Lyon, France
    • Guyotat

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age greater than 18 years with no upper age limit
• Competent adult patient.
• Patient affiliated to the National Health Insurance.
• Patient with an intra-cerebral supra-tentorial hemispheric, newly diagnosed and previously untreated, which MRI characteristics are suggestive of a glioblastoma.
• Indication for surgical treatment by excision.
• Brain tumor location distant from critical functional areas allowing a wide resection of contrast enhancement on imaging, the a priori character completely resectable has been validated by an evaluation committee composed of three surgeons
• No-cons contain medical surgery, ASA score below 4.
• Patient eligible for further treatment by radiotherapy and concurrent chemotherapy followed by adjuvant chemotherapy according to the so called Stupp scheme (standard protocol of adjuvant chemoradiotherapy)
• Negative pregnancy test for women of childbearing age.

Exclusion Criteria:

• Contraindications to performing an MRI (pacemaker).

  • Glioblastoma known and previously treated with surgery, radiotherapy and / or chemotherapy.
  • History of cancer.
  • Anatomical Location of the tumor-cons indicating a wide excision, neurosurgeon at the discretion of medical officer participating center.
  • Location tumor in the brain stem, the middle line, the basal ganglia and the posterior cranial fossa.
  • Patient with cons-indication to the achievement of further treatment with radiotherapy and concurrent chemotherapy followed by adjuvant chemotherapy according to the scheme proposed by Stupp. (1)
  • Patients with porphyria, renal insufficiency (creatinine> 177 μmolL), liver insufficency(gamma glutamyl transpeptidase> 100 U / L, prothrombin time <60%, bilirubin> 51μmol / L).
  • Patient refused to sign an informed consent form.
  • Ongoing participation of the patient to another clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 5-aminolévulinique acid (5-ALA); 5-aminolévulinique acid :microsurgical resection guided by fluorescence (CGF) in addition to the usual techniques of neuronavigation, after oral administration of 20mg/kg of 5-ALA 3-5 hours prior to surgical incision	Drug: 5-aminolévulinique acid (5-ALA); oral administration of 20mg/kg of 5-ALA 3-5 hours before the surgical incision; Other Names: Bras A
Placebo Comparator: Placebo; Laroscorbine :microsurgical excision guided solely by neuronavigation, after oral administration of a placebo 3 to 5 hours before the surgical incision	Drug: Placebo; Oral administration of 1g of ascorbic acid LAROSCORBINE in 50ml of water 3 hours before surgery; Other Names: Bras B

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of complete tumor resection between the 2 arms	Evidenced of complete resection (absence of residual tumor on early postoperative MRI (within 48 hours)) will be assessed by a central independent committee with qualitative analysis of contrast enhancement replay on a console for diagnostic use.	48 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of complete tumor resection between the 2 arms	Evidenced of complete resection (absence of residual tumor on early postoperative MRI (within 48 hours)) will be assessed by the neurosurgeon who conducted the surgery and the neuro-radiologist who conducted the RMI with qualitative analysis of contrast enhancement replay during the initial clinical analysis	less than 48 hours after surgery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnostic value of the two intraoperative techniques	Evaluate the sensitivity, specificity, positive predictive value and negative by correlating the results of pathological analysis of resection edge with intraoperative findings of the surgeon at the end of resection.	60 months
Quantification of residual tumor (contrast enhancement) on MRI post-opératre early (before 48 hours)	It will be performed by three study investigators (Dr. Pallud, Department of Neurosurgery, Centre Hospitalier Sainte-Anne, Paris; Dr. Guyotat, D department of Neurosurgery, Hospices Civils de Lyon, Lyon, Dr. Metellus, neurosurgery department, Assistance Publique - Hôpitaux de Marseille) and read separately. The volume analysis will be done by segmentation using the OsiriX software on postoperative MRI and MRI pre-operative	before 48 hours
Progression Free survival rate at 6 months	Progression is defined by the appearance of a new tumor lesion which minimum volume will be set to 0.175 cm3, by the increase of the residual tumor volume of 25% or more, or by the need to increase corticosteroid therapy. The period of progression free survival is defined as the time from the date of tumor resection and date of diagnosis of tumor progression or the date last news or date of endpoint. Progression Free survival rate at 6 months will be analyzed according to surgical approach used, according to the completeness or incompleteness of resection and by centers	6 months
Overall survival at 24 months	It will be estimated from the number of patients who died of whatever cause. The overall survival time is defined as the time between the date of tumor resection and date of death from any cause or date of last news or the date of endpoint. The overall survival at 24 months will be analyzed according to surgical approach used, according to the completeness or incompleteness of resection and by centers.	24 months
Overall survival at 60 months	It will be estimated from the number of patients who died of whatever cause. The overall survival time is defined as the time between the date of tumor resection and date of death from any cause or date of last news or the date of endpoint. The overall survival at 60 months will be analyzed according to surgical approach used, according to the completeness or incompleteness of resection and by centers.	60 months
Quality of life	Evaluation of quality of life every 3 months using the EORTC questionnaire QLQ-C30 with the specific brain tumors module BN20.	every 3 months
Evaluation of early and late morbidity	Evaluation of early morbidity in 8 days and late morbidity at 3 months (neurological deficit, surgical site infection, secondary epilepsy, Karnofsky score, performance status WHO).	in 8 days and late morbidity at 3 months
Comparison of surgical procedure duration between the 2 arms		60 months
Medico-economic evaluation of the 2 procedure	Comparison of the differential cost effectiveness ratio between the 2 strategies	60 months

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Investigators: Study Director: Jacques GUYOTAT, MD, Hospices Civils de Lyon

Study record dates

Study Major Dates

• Study Start: February 1, 2013
• Primary Completion (Actual): March 1, 2013
• Study Completion (Anticipated): August 1, 2019

Study Registration Dates

• First Submitted: February 21, 2013
• First Submitted That Met QC Criteria: March 12, 2013
• First Posted (Estimate): March 14, 2013

Study Record Updates

• Last Update Posted (Estimate): October 5, 2016
• Last Update Submitted That Met QC Criteria: October 4, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: Glioblastoma; fluorescence; resection; 5ALA
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma
• Other Study ID Numbers: 2011-697