Perspectives

Russell R. Lonser, M.D.

Chair, Surgical Neurology BranchNational Institute of Neurological Disorders and Stroke

National Institutes of Health

Surgery for Glioblastoma Multiforme: Striking a Balance

Commentary on:The Risk of Getting Worse: SurgicallyAcquired Deficits, PerioperativeComplications, and Functional OutcomesAfter Primary Resection of Glioblastomaby Gulati et al. pp. 572-579.

Raymund L. Yong and Russell R. Lonser

G lioblastoma multiforme (GBM) is the most common primarybrain tumor in adults. GBM is composed of highly prolifera-tive and infiltrative neoplastic cells that frequently invade

eloquent areas of the cerebral hemispheres (6), producing progressiveneurological deficits and symptoms of increased intracranial pressure.When possible, surgical resection of GBMs after diagnosis is used torelieve mass effect, confirm the diagnosis pathologically, and set thestage for multimodal adjunctive therapy (3, 4, 10, 14).

A long-standing point of contention among neurosurgeons is thecapacity of surgical cytoreduction to prolong a patient’s quality ofsurvival. A fine balance must be struck between the aggressiveremoval of malignant tissue and minimizing the risk of worsening orinducing new neurologic deficits that may negatively impact outcomes.Furthermore, residual microscopic disease, even in the most seem-ingly resectable lesions, invariably results in disease progression withinmonths (12), which perhaps lends support for a more conservativeapproach, particularly in elderly patients with poor functional status.

To develop an optimal balance between maximal surgical cytoreduc-tion and minimization of operative risk, the neurosurgeon must assessthe patient’s preoperative prognosis and tumor location to determinethe extent of resection (EOR) that provides maximal survival andfunctional benefit. For lesions in noneloquent areas, the answer may bean aggressive gross total removal. For lesions near or involving elo-quent or critical areas, the answer may be a subtotal resection or tissuebiopsy only because of the potential costs of surgically acquireddeficits.

To date, the best data to assess the balance between EOR and survivalbenefit come from large institutional retrospective analyses. Lacroix etal. (5) reported on the outcomes of 416 patients with newly diagnosedand recurrent GBMs. Seventy-five percent of patients had a Karnofskyperformance status of 80 or more, and 92% of the lesions were nearor involved eloquent or deep-brain structures. The authors found that

Key words� Brain neoplasms� Neurosurgery� Quality control

Abbreviations and AcronymsEOR: Extent of resectionGBM: Glioblastoma multiforme

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an EOR of 98% or more was associated with improved survival.Although overall survival benefit at this EOR or more was 4.2 months,complication rates and functional outcomes were not provided. Manyhave used this study to justify the performance of debulking surgeryonly when a greater than 98% EOR is thought to be achievable.

More recently, Sanai et al. (9) reported the outcomes of 500 newlydiagnosed GBM patients undergoing initial resection. Patients had amedian Karnofsky performance status of 80, and 69% of tumorsinvolved eloquent areas. When intraoperative functional mapping ad-juncts were used where appropriate, significant survival benefits wereobserved with an EOR of as little as 78% but increased as the EORapproached 100%, at which point median overall survival exceeded 16months (compared with 12.2 months for the entire cohort). With itsrelatively large and homogeneous patient sample, this series providessubstantive evidence that the cytoreductive threshold for a meaningfulsurvival benefit may be lower than previously thought.

However, identifying an EOR threshold is only one aspect of the gliomasurgeon’s dilemma. To develop rational operative strategies, the rela-tionship between EOR, tumor resectability, and surgical risk must alsobe carefully elucidated. A gross total resection of a tumor locatedentirely within the anterior right temporal lobe entails different risks, andhence different implications for the goal of resection, compared withone abutting the motor cortex or infiltrating the thalamus.

Emerging evidence indicates that the consequences of surgicallyacquired neurologic deficits are significant. In a series of 306 consec-utive patients with good performance status operated on for newlydiagnosed GBM, McGirt et al. (7) describe 15 patients (5%) whodeveloped a new language deficit and 19 patients (6%) who developeda new motor deficit perioperatively. Both types of deficit were associ-ated with a decreased median survival (reduced survival of 3.2 monthsand 3.8 months, respectively). These findings would suggest that, atleast in the case of tumors near or involving motor and language cortex,

Surgical Neurology Branch, National Institute of Neurological Disorders andStroke, National Institutes of Health, Bethesda, Maryland, USA

To whom correspondence should be addressed: Russell R. Lonser, M.D.[E-mail: lonserr@ninds.nih.gov]

Citation: World Neurosurg. (2011) 76, 6:528-530.DOI: 10.1016/j.wneu.2011.06.053

RLD NEUROSURGERY, DOI:10.1016/j.wneu.2011.06.053

PERSPECTIVES

patients risk losing virtually all survival gains from cytoreduction. Thus,it is imperative that these eloquent areas be identified and preservedmeticulously (8, 11, 13).

In their article, Gulati et al. contribute to our understanding of theimpact of morbidity on outcomes in their series of 144 consecutive

Figure 1. Conceptual framework for the relationship between risk and benefitfor cytoreductive glioblastoma surgery according to tumor resectability andpreoperative prognosis. Black curves indicate expected average months ofsurvival gained from tumor cytoreduction if the EOR threshold is assumed tobe approximately 80%. Red curves indicate expected average months of

patients undergoing initial resection of a GBM. Similar to previous

WORLD NEUROSURGERY 76 [6]: 528-530, DECEMBER 2011

studies, patients were of good functional status preoperatively.Although intraoperative electrophysiological techniques were notused, functional neuronavigation with the use of functional mag-netic resonance imaging and white matter tractography was used inlesions involving eloquent cortex. Surgically acquired cognitive,motor, language, coordination, and visual deficits occurred at an

survival lost as the result of general perioperative complications and surgicallyacquired neurological deficits. Shaded area indicates the range of EOR withinwhich a net survival benefit exists. Arrows indicate EOR at which benefit ismaximal for each scenario. Question marks indicate scenarios in whichprojected net benefit may not be clinically meaningful.

overall rate of 15.3%. Rates of language and motor deficits were

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4.9% and 5.6%, which are comparable with other studies. Similar toMcGirt et al. and others (1, 2), the current study finds that patientswith surgically acquired neurological deficits were at significantlyincreased odds of experiencing worsened functional outcome.

Gulati et al. go on to examine the functional impact of generalperioperative complications, which occurred at an overall rate of19.4%, and find that these also predicted poorer outcomes, al-though at the lower odds ratio of 4.1. The most common of thesewere new-onset seizures, urinary tract infections, and surgical-sitehematomas. Interestingly, both perioperative complications andacquired neurological deficits were associated with a decreasedlikelihood of receiving adjunctive radiotherapy and chemotherapy,both of which were independently predictive of improved 12-monthrates of survival. This finding suggests that the ramifications of theadverse effects of surgical treatment may extend well beyondproximate physiologic sequelae. Rather, patients may be cast intoprognostic categories postoperatively that dictate the course of allsubsequent treatment.

Perhaps most interestingly, Gulati et al. find that the rates ofperioperative complications and acquired neurological deficits wereconstant, irrespective of extent of resection. They use this to voicea warranted word of caution against the role of subtotal resectionsin GBM, because in their series only gross total resections wereassociated with improved survival. However, it is important torecognize that the similar rates of surgically acquired neurologicaldeficits in the subtotal, near total, and gross total resection catego-ries also imply that tumors in these groups differed in their averageinherent resectability.

Unfortunately, in few published studies on the extent of resection in

glioma did the authors rigorously control for tumor resectability.

D, Sawaya R: A multivariate analysis of 416 patientswith glioblastoma multiforme: prognosis, extent of

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11. Signorelli F, Ruggeri F,Chirchiglia D, Lavano A, V

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They may describe tumors by location or depth, or categorize themas eloquent or noneloquent in a binary fashion. None, to ourknowledge, has attempted to adjust for resectability as a continuousvariable derived from functional volumetric data, which is whatideally would be required to define with precision the “therapeuticwindow” of surgical cytoreduction in any given patient. In addition,more detailed data on resectability would allow valid comparisons tobe made across different studies, which would in turn aid inimproving the validity of systematic reviews and the developmentof practice guidelines. A 98% threshold of resection for a survivalbenefit identified in a series with a large number of noneloquenttumors, for example, cannot be taken at face value to be corrobo-rative of the same threshold identified in a series with a largenumber of eloquent or deep tumors.

Synthesizing what is currently known about resection thresholds(78%-100%), maximum survival benefit from surgery (approxi-mately 4 months), and the rate of surgical complications and theirpotential impact on survival (perhaps a reduction of as much asthree to four months), one might envision the existence of acomplex relationship between EOR and net survival benefit thatvaries according to preoperative prognosis and degree of involve-ment of critical brain areas (Figure 1). In this paradigm, although theEOR threshold remains identical at 80% in every scenario, subtlechanges in the expected magnitude of survival gains (maximum ofthe black curve) and the level of general perioperative risk (minimumof the red curve) can dramatically alter the area of the therapeuticwindow. The challenge for future studies will be to expose thenature of these risk-benefit relationships unambiguously so thatneurosurgeons have available an evidence-based therapeutic blue-

print that can readily be applied to diverse individual patients.

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