Role of Repeat Resection in Recurrent Glioblastoma

Recurrent Glioblastoma Clinical Trial

Official title:

Role of Repeat Resection in Recurrent Glioblastoma (4rGBM) Trial: a Randomized Care Trial for Patients With Recurrent GBM

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04838782
• Other study ID #: CC-210049
• Status: Recruiting
• Phase: N/A
• Start date: August 26, 2021
• Est. completion date: January 1, 2031

Study information

• Verified date: April 2024
• Source: University of Alberta
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Patients with recurrent Glioblastoma (GBM) are commonly presented to surgeons, along with the question of whether or not to re-resect the recurrence. There is no Level 1 evidence to support a role for repeat surgery in this context, but a multitude of observational research suggests that repeat surgery may improve quality survival. Unfortunately, these studies all suffer from selection bias.

The goal of this study is to provide a care trial context to help neurosurgeons manage patients presenting with recurrent GBM, with no additional risks, tests, or interventions than what they would normally encounter in routine care. Secondary goals include a test of the hypothesis that repeat resection can improve median overall survival, and that it can increase the number of days of survival outside of a hospital/nursing/palliative care facility.

Description:

Glioblastoma (GBM) is the most common malignant brain tumor (48.3% of malignant tumors).1 It has a predilection for Caucasian men with a mean age of 65.1, 2 There are approximately 13,000 new diagnoses of GBM made every year in the United States.1 Patients have an average survival of 12-15 months, with a 5-year survival rate of 6.8% despite various treatments.1 If the prognosis at the time of initial diagnosis is grim, it is even worse at the time of recurrence. Recurrence after the initial resection, which can be symptomatic or discovered on surveillance MRI imaging, occurs in nearly all patients, usually within the first year, even when the initial management is aggressive.3-6 There is no standard way to care for recurrent GBM patients and treatment may include one or more of the following: repeat surgery, radiation therapy, or second-line chemotherapy.7

Repeat surgical management carries a greater risk of wound infection and cerebrospinal fluid leak than the initial surgery, especially in patients who received radiation.8 When maximal resection was attempted at the time of the initial procedure, the second surgery is more at risk of neurological injury. Repeat surgical management often also entails a delay in the initiation of further chemotherapy, as these agents are not administered peri-operatively because of potentially deleterious effects on wound healing. Nonetheless, despite, or because of the desperate setting, patients and surgeons are often pressed to consider repeat surgery, which is performed in at least 10-30% of patients.9 Repeat surgical treatment may be more favorable with younger age (<60 years), and preoperative Karnofsky performance status (KPS) of at least 70.9 Median survival following repeat resection varies between 13-54 weeks,10, 11 but all reports suffer from the limitations of retrospective studies, the most obvious being selection bias in terms of patient age, functional status, tumor location and size.11, 12 Yet, despite favorable biases some studies report no improvement in terms of survival or quality of life.13, 14 Two recent systematic meta-analyses of case series offer conflicting conclusions about the merit of re-operation.15, 16

If the intent of repeat surgery is to improve quality and quantity of life, there is no level 1 evidence it is effective.3, 16, 17 Thus repeat surgery should be considered the experimental arm of a randomized trial designed in the best interest of the patient, being only offered as a 50% chance, always balanced by a 50% chance of being allocated non-surgical care, or a chance to escape what could turn out to be unnecessary or harmful surgery.18 For patients may be better served by being free to pursue other life priorities in the company of loved ones rather than being scheduled to endure repeat craniotomy and multiple clinical or research follow-up visits. There is sufficient community equipoise to support the conduct of such a randomized trial.19

Tria Design:

The trial is a simple, all-inclusive, prospective, multicenter, randomized care trial18 that allocates 1:1 re-operation (or not) for patients with recurrent Glioblastoma. The primary outcome is overall survival. Secondary outcomes include standard peri-operative safety outcomes and (a notion of) 'quality survival', or survival at home, measured by counting days of survival minus days in hospital/nursing home/palliative care setting. Blinding is not feasible; treatment allocation will not be masked. The trial allows for pre-randomization.22 The burden of the proof of benefit is on surgery. While some patients allocated non-surgical management may still want surgery, and some patients allocated surgery may prefer non-surgical management, we feel participating patients will be better informed by the discussion around trial participation.

Hypothesis:

Patients with recurrent Glioblastoma, at the time they are considered for repeat resection, who undergo repeat resection for the GBM, will experience an increase in median overall survival from 6 to 9 months.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 250
• Est. completion date: January 1, 2031
• Est. primary completion date: January 1, 2030
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age = 18

• Previously histologically confirmed and surgically resected Glioblastoma

• Previous craniotomy for open tumor resection (needle biopsies alone do not count as resection)

• The attending surgeon considers re-operation may improve quality survival

Exclusion Criteria:

• Informed consent not possible

Related Conditions & MeSH terms

• Glioblastoma
• Glioblastoma - Category
• Recurrence
• Recurrent Glioblastoma

Intervention

Procedure:
• Repeat Surgical Management of Recurrent GBM
Routine of surgical operative management. Details of treatment will be left to local centers, and recorded in the case report form (CRF).

Locations

Country	Name	City	State
Canada	University of Alberta Division of Neurosurgery	Edmonton	Alberta

Sponsors (1)

Lead Sponsor	Collaborator
University of Alberta

Country where clinical trial is conducted

Canada, 

References & Publications (23)

Barbagallo GM, Jenkinson MD, Brodbelt AR. 'Recurrent' glioblastoma multiforme, when should we reoperate? Br J Neurosurg. 2008 Jun;22(3):452-5. doi: 10.1080/02688690802182256. — View Citation

Chaichana KL, Zadnik P, Weingart JD, Olivi A, Gallia GL, Blakeley J, Lim M, Brem H, Quinones-Hinojosa A. Multiple resections for patients with glioblastoma: prolonging survival. J Neurosurg. 2013 Apr;118(4):812-20. doi: 10.3171/2012.9.JNS1277. Epub 2012 Oct 19. — View Citation

Chen MW, Morsy AA, Liang S, Ng WH. Re-do Craniotomy for Recurrent Grade IV Glioblastomas: Impact and Outcomes from the National Neuroscience Institute Singapore. World Neurosurg. 2016 Mar;87:439-45. doi: 10.1016/j.wneu.2015.10.051. Epub 2015 Nov 14. — View Citation

De Bonis P, Anile C, Pompucci A, Fiorentino A, Balducci M, Chiesa S, Lauriola L, Maira G, Mangiola A. The influence of surgery on recurrence pattern of glioblastoma. Clin Neurol Neurosurg. 2013 Jan;115(1):37-43. doi: 10.1016/j.clineuro.2012.04.005. Epub 2012 Apr 24. — View Citation

Franceschi E, Omuro AM, Lassman AB, Demopoulos A, Nolan C, Abrey LE. Salvage temozolomide for prior temozolomide responders. Cancer. 2005 Dec 1;104(11):2473-6. doi: 10.1002/cncr.21564. — View Citation

Gempt J, Forschler A, Buchmann N, Pape H, Ryang YM, Krieg SM, Zimmer C, Meyer B, Ringel F. Postoperative ischemic changes following resection of newly diagnosed and recurrent gliomas and their clinical relevance. J Neurosurg. 2013 Apr;118(4):801-8. doi: 10.3171/2012.12.JNS12125. Epub 2013 Feb 1. — View Citation

Goldman DA, Hovinga K, Reiner AS, Esquenazi Y, Tabar V, Panageas KS. The relationship between repeat resection and overall survival in patients with glioblastoma: a time-dependent analysis. J Neurosurg. 2018 Nov 1;129(5):1231-1239. doi: 10.3171/2017.6.JNS17393. — View Citation

Helseth R, Helseth E, Johannesen TB, Langberg CW, Lote K, Ronning P, Scheie D, Vik A, Meling TR. Overall survival, prognostic factors, and repeated surgery in a consecutive series of 516 patients with glioblastoma multiforme. Acta Neurol Scand. 2010 Sep;122(3):159-67. doi: 10.1111/j.1600-0404.2010.01350.x. Epub 2010 Mar 18. — View Citation

Hervey-Jumper SL, Berger MS. Reoperation for recurrent high-grade glioma: a current perspective of the literature. Neurosurgery. 2014 Nov;75(5):491-9; discussion 498-9. doi: 10.1227/NEU.0000000000000486. — View Citation

Hoover JM, Nwojo M, Puffer R, Mandrekar J, Meyer FB, Parney IF. Surgical outcomes in recurrent glioma: clinical article. J Neurosurg. 2013 Jun;118(6):1224-31. doi: 10.3171/2013.2.JNS121731. Epub 2013 Mar 15. — View Citation

Lu VM, Jue TR, McDonald KL, Rovin RA. The Survival Effect of Repeat Surgery at Glioblastoma Recurrence and its Trend: A Systematic Review and Meta-Analysis. World Neurosurg. 2018 Jul;115:453-459.e3. doi: 10.1016/j.wneu.2018.04.016. Epub 2018 Apr 11. — View Citation

Mandl ES, Dirven CM, Buis DR, Postma TJ, Vandertop WP. Repeated surgery for glioblastoma multiforme: only in combination with other salvage therapy. Surg Neurol. 2008 May;69(5):506-9; discussion 509. doi: 10.1016/j.surneu.2007.03.043. Epub 2008 Feb 8. — View Citation

Ostrom QT, Cioffi G, Gittleman H, Patil N, Waite K, Kruchko C, Barnholtz-Sloan JS. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2012-2016. Neuro Oncol. 2019 Nov 1;21(Suppl 5):v1-v100. doi: 10.1093/neuonc/noz150. — View Citation

Patel M, Au K, Davis FG, Easaw JC, Mehta V, Broad R, Chow MMC, Hockley A, Kaderali Z, Magro E, Nataraj A, Scholtes F, Chagnon M, Gevry G, Raymond J, Darsaut TE. Clinical Uncertainty and Equipoise in the Management of Recurrent Glioblastoma. Am J Clin Oncol. 2021 Jun 1;44(6):258-263. doi: 10.1097/COC.0000000000000812. — View Citation

Raymond J, Darsaut TE, Altman DG. Pragmatic trials can be designed as optimal medical care: principles and methods of care trials. J Clin Epidemiol. 2014 Oct;67(10):1150-6. doi: 10.1016/j.jclinepi.2014.04.010. Epub 2014 Jul 16. — View Citation

Raymond J, Darsaut TE, Roy DJ. Recruitment in Clinical Trials: The Use of Zelen's Prerandomization in Recent Neurovascular Studies. World Neurosurg. 2017 Feb;98:403-410. doi: 10.1016/j.wneu.2016.11.052. Epub 2016 Nov 19. — View Citation

Schucht P. RESURGE: Surgery for recurrent Glioblastoma., https://clinicaltrials.gov/ct2/show/NCT02394626 (2020).

Schwartz D, Lellouch J. Explanatory and pragmatic attitudes in therapeutical trials. J Chronic Dis. 1967 Aug;20(8):637-48. doi: 10.1016/0021-9681(67)90041-0. No abstract available. — View Citation

Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. doi: 10.1056/NEJMoa043330. — View Citation

Thakkar JP, Dolecek TA, Horbinski C, Ostrom QT, Lightner DD, Barnholtz-Sloan JS, Villano JL. Epidemiologic and molecular prognostic review of glioblastoma. Cancer Epidemiol Biomarkers Prev. 2014 Oct;23(10):1985-96. doi: 10.1158/1055-9965.EPI-14-0275. Epub 2014 Jul 22. — View Citation

Weller M, Cloughesy T, Perry JR, Wick W. Standards of care for treatment of recurrent glioblastoma--are we there yet? Neuro Oncol. 2013 Jan;15(1):4-27. doi: 10.1093/neuonc/nos273. Epub 2012 Nov 7. — View Citation

Yahia-Cherif, M., De Witte, O., Mélot, C., & Lefranc, F. (2019). P14.56 Recurrent Glioblastomas: Should we operate a second and even a third time. Neuro-Oncology, 21(Suppl 3), iii80.

Zhao YH, Wang ZF, Pan ZY, Peus D, Delgado-Fernandez J, Pallud J, Li ZQ. A Meta-Analysis of Survival Outcomes Following Reoperation in Recurrent Glioblastoma: Time to Consider the Timing of Reoperation. Front Neurol. 2019 Mar 26;10:286. doi: 10.3389/fneur.2019.00286. eCollection 2019. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Length of Overall Survival	The primary outcome is time to death from any cause, starting from the time of inclusion.	Follow-up for 5 Years or until death
Secondary	Total length of hospitalization / palliative care / nursing home		Follow-up for 5 Years or until death
Secondary	Discharge to a location other than home		Follow-up for 5 Years or until death
Secondary	Total number of days spent outside a hospital or nursing care facility.		Follow-up for 5 Years or until death
Secondary	Incidence of peri-operative non-neurological complications (wound infection, CSF leaks)		Follow-up for 5 Years or until death
Secondary	Incidence of new significant neurological deficits after surgery (defined as new or substantially worsened aphasia, or new weakness (MRC power < 3 in one or more limbs).		Follow-up for 5 Years or until death