Key points

Introduction

The hallmark of glioblastoma multiforme (GBM) is its penchant for relentless progression. The median progression-free survival (PFS) is 4.4 to 8.4 months in patients with newly diagnosed GBM following the current standard of care, safely obtained maximal resection at initial surgery followed by concomitant temozolomide (TMZ) and radiotherapy and adjuvant TMZ. In the highly favorable patient population typically garnered for clinical trials research, some patients have seen significantly improved median overall survival (mOS) to 20.5 months. However, not all patients are eligible for clinical trial involvement, let alone surgery with a goal of complete resection. Indeed, it has been estimated that less than half of patients presenting with GBM receive an operation for resection owing to inoperability of the tumor or the poor surgical candidacy of the patient.

The situation is even more dire for patients with recurrent GBM as rates of reoperation range from 3% to 30%. Some evidence supports reoperation in select individuals with accessible focal tumors, younger age, and higher performance status (PS) in which a complete or near complete resection of the enhancing tumor can be achieved. Nevertheless, there is also significant data indicating no benefit of reoperation, particularly when controlling for these prognostic variables and others. Despite evidence-based guidelines and review articles focused on the role of reoperation for recurrent or progressive disease, repeat surgery remains controversial. Several well-written reviews have been published in the last several years, but none focused on patients predominantly treated in the modern neuro-oncology era or inclusive of the relative surge in studies published over the last 3 to 4 years on this topic. Further evaluation and literature review is, therefore, warranted; herein the authors seek to identify the current available contemporary evidence, report on its conclusions, and reconcile the data when possible.

Introduction

The hallmark of glioblastoma multiforme (GBM) is its penchant for relentless progression. The median progression-free survival (PFS) is 4.4 to 8.4 months in patients with newly diagnosed GBM following the current standard of care, safely obtained maximal resection at initial surgery followed by concomitant temozolomide (TMZ) and radiotherapy and adjuvant TMZ. In the highly favorable patient population typically garnered for clinical trials research, some patients have seen significantly improved median overall survival (mOS) to 20.5 months. However, not all patients are eligible for clinical trial involvement, let alone surgery with a goal of complete resection. Indeed, it has been estimated that less than half of patients presenting with GBM receive an operation for resection owing to inoperability of the tumor or the poor surgical candidacy of the patient.

The situation is even more dire for patients with recurrent GBM as rates of reoperation range from 3% to 30%. Some evidence supports reoperation in select individuals with accessible focal tumors, younger age, and higher performance status (PS) in which a complete or near complete resection of the enhancing tumor can be achieved. Nevertheless, there is also significant data indicating no benefit of reoperation, particularly when controlling for these prognostic variables and others. Despite evidence-based guidelines and review articles focused on the role of reoperation for recurrent or progressive disease, repeat surgery remains controversial. Several well-written reviews have been published in the last several years, but none focused on patients predominantly treated in the modern neuro-oncology era or inclusive of the relative surge in studies published over the last 3 to 4 years on this topic. Further evaluation and literature review is, therefore, warranted; herein the authors seek to identify the current available contemporary evidence, report on its conclusions, and reconcile the data when possible.

Methods

The authors sought to determine the role of reoperation in extending survival for patients with progressive or recurrent GBM in the modern neuro-oncology era. The modern neuro-oncology era was defined as the era since wide recognition and adoption of radiotherapy plus concomitant and adjuvant TMZ and includes studies published since 2005 and excludes studies whereby recruitment of patients precedes 1995. A comprehensive literature review was undertaken using Medline, Embase, Cochrane Library, and Web of Science. These databases were queried for English-language articles published since 2005 based on the following search strategies (accessed August 26, 2016):

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  PubMed

  
  
  
  
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    (“glioblastoma multiforme” OR GBM OR “Glioblastoma”[Mesh]) AND (recurrence OR “Recurrence”[Mesh] OR “Neoplasm Recurrence, Local”[Mesh]) AND (reoperation OR resection OR “repeat operation” OR “Reoperation”[Mesh] OR “Second-Look Surgery”[Mesh])

  
  
  
  
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  Embase

  
  
  
  
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    ‘glioblastoma multiforme’/exp OR ‘glioblastoma multiforme’ OR gbm OR glioblastoma OR ‘glioblastoma’/exp AND (‘recurrence’/exp OR recurrence OR ‘cancer recurrence’/exp OR ‘recurrent disease’/exp) AND (‘reoperation’/exp OR reoperation OR ‘repeat resection’ OR (resection AND repeat) OR ‘repeat operation’) AND [adult]/lim AND [English]/lim AND [2005–2016]/py

  
  
  
  
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  Cochrane

  
  
  
  
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    (‘glioblastoma multiforme’ or GBM or glioblastoma) and (recurrence) and (reoperation or ‘repeat resection’ or ‘re-resection’ or (resection and repeat) or ‘repeat operation’)

  
  
  
  
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  Web of Science

  
  
  
  
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    (“glioblastoma multiforme” OR GBM) AND (recurrence) AND (reoperation OR “repeat resection” OR “re-resection” OR (resection AND repeat) OR “repeat operation”) NOT (elderly OR geriatric OR 65 + OR “over 65”)

  
  

After first-stage record screen, bibliographic review of the remaining full-text articles was conducted. Studies were evaluated for design, inclusion and exclusion criteria, number of patients, mOS, mOS following reoperation for recurrent GBM (rOS), PFS from initial surgery (PFS1), PFS following reoperation for recurrent GBM (PFS2), quality of life and/or performance status, indications for reoperation, inclusion and exclusion criteria, and for prognostic factors deemed important to survival.

Results

Two hundred twenty-five records were identified via PubMed, Embase, Cochrane Library, and Web of Science database review ( Fig. 1 ). The first author conducted a first-stage screening of the initial 225 records. One hundred sixty-nine records were excluded for the following reasons: duplicative results (n = 56), full-text article in language other than English (n = 11), other neoplasm (n = 27), chemotherapy or radiotherapy only (n = 15), case report or case series consisting of surgical series less than 20 patients (n = 20), or review article only (n = 40). A total of 56 full-text records then underwent second-stage review. Further exclusions were made for being mixed histology analyses (World Health Organization III and IV) (n = 6), surgery for newly diagnosed GBM (n = 3), clinical trials primarily evaluating brachytherapy, convection-enhanced delivery, or immunotherapy (n = 18). Only primary studies including reoperation for recurrent GBM published in full English text were retained for further evaluation. Reference review of this group yielded an additional 4 studies for final inclusion. A total of 33 articles were evaluated ( Table 1 ).

The article review process following database searches of PubMed, Embase, Cochrane Library, and Web of Science. ^a World Health Organization (WHO) I to III, WHO glioma grades I to III, ^b CED, convection-enhanced delivery.

Most studies were retrospective in nature (n = 27). However, 6 studies were either conducted prospectively or were derived from prospectively collected databases/post hoc analysis of clinical trial data ( Table 2 ). There were no randomized controlled trials. Most of the data supported a role for reoperation in the treatment of recurrent or progressive GBM (n = 20). Ten studies either saw no evidence for a benefit of reoperation or suggested alternative treatment strategies (eg, multimodality treatment or stereotactic radiosurgery with or without TMZ). Sixteen articles considered the extent of resection (EOR) as a factor in survival. In total, 2717 patients who underwent a reoperation for progressive or recurrent GBM are accounted for in the authors’ analysis. Two hundred fifty-eight patients had a second reoperation and 78 patients had 3 or more reoperations. Twelve studies reported on adjuvant therapies following resection. About half of the investigators reported on perioperative complications ( Table 3 ) and their indications for reoperation ( Table 4 ). Inclusion criteria for involvement in each study were explicitly given in all studies reviewed. The reported mOS from each study was averaged for all patients from initial diagnosis and from reoperation/recurrence and noted to be 19.1 (21 studies) and 9.9 (19 studies) months, respectively ( Table 5 ). The approximate mean complication rate is 18.9%.

Table 2

Study author, year, and design for original articles addressing reoperation and extent of resection

Design	Study/Year	Benefit of Surgery at Recurrence	EOR Benefit at Recurrence
Prospective study or prospectively collected data	Archavalis et al, 2014	Yes	—
	Michaelson et al, 2013	Yes	No
	Suchorska et al, 2016	Yes	Yes
	Yong et al, 2014	Yes	Yes
	Clarke et al, 2011	No	—
	Gorlia et al, 2012	No	—
Retrospective studies	Bekar et al, 2012	Yes	—
	Boiardi et al, 2008	Yes	Yes
	Bloch et al, 2012	Yes	Yes
	Chen et al, 2016	Yes	No
	Chaichana et al, 2013	Yes	—
	De Bonis et al, 2013	Yes	No
	Helseth et al, 2010	Yes	—
	Hong et al, 2013	Yes	No
	Mandl et al, 2008	Yes	—
	McGirt et al, 2009	Yes	Yes
	McNamara et al, 2014	Yes	No
	Oppenlander et al, 2014	Yes	Yes
	Quick et al, 2014	Yes	Yes
	Ringel et al, 2016	Yes	Yes
	Scorsetti et al, 2015	Yes	—
	Woernle et al, 2015	Yes	—
	Filippini et al, 2008	No	—
	Franceschi et al, 2015	No	—
	Kim et al, 2015	No	No
	Ma et al, 2009	No	Yes
	Ortega et al, 2016	No	Yes
	Skeie et al, 2012	No	—
	Sughrue et al, 2015	No	—
	Tully et al, 2016	No	—
	Park et al, 2010	—	—
	Park et al, 2013	—	—
	Woodworth et al, 2013	—	—

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