Counterbalancing risks and gains from extended resections in malignant glioma surgery: a supplemental analysis from the randomized 5-aminolevulinic acid glioma resection study

Clinical article

Restricted access


Accumulating data suggest more aggressive surgery in patients with malignant glioma to improve outcome. However, extended surgery may increase morbidity. The randomized Phase III 5-aminolevulinic acid (ALA) study investigated 5-ALA–induced fluorescence as a tool for improving resections. An interim analysis demonstrated more frequent complete resections with longer progression-free survival (PFS). However, marginal differences were found regarding neurological deterioration and the frequency of additional therapies. Presently, the authors focus on the latter aspects in the final study population, and attempt to determine how safety might be affected by cytoreductive surgery.


Patients with malignant gliomas were randomized for fluorescence-guided (ALA group) or conventional white light (WL) (WL group) microsurgery. The final intent-to-treat population consisted of 176 patients in the ALA and 173 in the WL group. Primary efficacy variables were contrast-enhancing tumor on early MR imaging and 6-month PFS. Among secondary outcome measures, the National Institutes of Health Stroke Scale (NIH-SS) score and the Karnofsky Performance Scale (KPS) score were used for assessing neurological function.


More frequent complete resections and improved PFS were confirmed, with higher median residual tumor volumes in the WL group (0.5 vs 0 cm3, p = 0.001). Patients in the ALA group had more frequent deterioration on the NIH-SS at 48 hours. Patients at risk were those with deficits unresponsive to steroids. No differences were found in the KPS score. Regarding outcome, a combined end point of risks and neurological deficits was attempted, which demonstrated results in patients in the ALA group to be superior to those in participants in the WL group. Interestingly, the cumulative incidence of repeat surgery was significantly reduced in ALA patients. When stratified by completeness of resection, patients with incomplete resections were quicker to deteriorate neurologically (p = 0.0036).


Extended resections performed using a tool such as 5-ALA–derived tumor fluorescence, carries the risk of temporary impairment of neurological function. However, risks are higher in patients with deficits unresponsive to steroids.

Abbreviations used in this paper: AE = adverse event; KPS = Karnofsky Performance Scale; NIH-SS = National Institutes of Health Stroke Scale; PFS = progression-free survival; SAE = serious AE; WL = white light; 5-ALA = 5-aminolevulinic acid.

Article Information

* See Appendix 2 for a complete list of study participants.

Address correspondence to: Walter Stummer, M.D., Department of Neurosurgery, University of Münster, Albert-Schweitzer Strasse 33, 48149 Münster, Germany. email:

Please include this information when citing this paper: published online April 16, 2010; DOI: 10.3171/2010.3.JNS097.

© AANS, except where prohibited by US copyright law.



  • View in gallery

    Chart showing the cumulative incidence of repeat surgery. m = month; n.a. = not applicable.

  • View in gallery

    Kaplan-Meier curves showing PFS by using a combined end point analysis adapted from Macdonald et al. Progression is defined as a > 25% increase in size of enhancing tumor or any new tumor on MR imaging studies, or neurological worsening (that is, increase in the NIH-SS score of ≥ 1 compared with the preceding visit) in case of stable or increased use of steroids.

  • View in gallery

    Time from randomization to NIH-SS deterioration (≥ 1 point) with stable/increased use of steroids—event-free survival—Kaplan-Meier estimates (death/radiological progression censored). CR = complete resection; IR = incomplete resection.


  • 1

    Albanese MAClarke WRAdams HP JrWoolson RF: Ensuring reliability of outcome measures in multicenter clinical trials of treatments for acute ischemic stroke. The program developed for the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Stroke 25:174617511994

  • 2

    Albert FKForsting MSartor KAdams HPKunze S: Early postoperative magnetic resonance imaging after resection of malignant glioma: objective evaluation of residual tumor and its influence on regrowth and prognosis. Neurosurgery 34:45611994

  • 3

    Barker FG IIPrados MDChang SMGutin PHLamborn KRLarson DA: Radiation response and survival time in patients with glioblastoma multiforme. J Neurosurg 84:4424481996

  • 4

    Chang SMParney IFMcDermott MBarker FG IISchmidt MHHuang W: Perioperative complications and neurological outcomes of first and second craniotomies among patients enrolled in the Glioma Outcome Project. J Neurosurg 98:117511812003

  • 5

    Goldstein LBBertels CDavis JN: Interrater reliability of the NIH stroke scale. Arch Neurol 46:6606621989

  • 6

    Kowalczuk AMacdonald RLAmidei CDohrmann G IIIErickson RKHekmatpanah J: Quantitative imaging study of extent of surgical resection and prognosis of malignant astrocytomas. Neurosurgery 41:102810381997

  • 7

    Lacroix MAbi-Said DFourney DRGokaslan ZLShi WDeMonte F: A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg 95:1901982001

  • 8

    Macdonald DRCascino TLSchold SC JrCairncross JG: Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:127712801990

  • 9

    Pichlmeier UBink ASchackert GStummer W: Resection and survival in glioblastoma multiforme: an RTOG recursive partitioning analysis of ALA study patients. Neuro Oncol 10:102510342008

  • 10

    Stummer WPichlmeier UMeinel TWiestler ODZanella FReulen HJ: Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 7:3924012006

  • 11

    Stummer WReulen HJMeinel TPichlmeier USchumacher WTonn JC: Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias. Neurosurgery 62:5645762008

  • 12

    Van den Bent MJStupp RMason WMirimanoff ROLacombe DGorlia T: Impact of the extent of resection on overall survival in newly-diagnosed glioblastoma afer chemo-irradiation with temozolamide: further analysis of EORTC study 26981. Eur J Cancer Suppl 3:1342005. (Abstract)

  • 13

    Wityk RJPessin MSKaplan RFCaplan LR: Serial assessment of acute stroke using the NIH Stroke Scale. Stroke 25:3623651994

  • 14

    Yung WKAlbright REOlson JFredericks RFink KPrados MD: A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 83:5885932000




All Time Past Year Past 30 Days
Abstract Views 155 155 23
Full Text Views 244 244 2
PDF Downloads 139 139 1
EPUB Downloads 0 0 0


Google Scholar