A prospective Phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas

Restricted access

OBJECT

There is evidence that 5-aminolevulinic acid (ALA) facilitates greater extent of resection and improves 6-month progression-free survival in patients with high-grade gliomas. But there remains a paucity of studies that have examined whether the intensity of ALA fluorescence correlates with tumor cellularity. Therefore, a Phase II clinical trial was undertaken to examine the correlation of intensity of ALA fluorescence with the degree of tumor cellularity.

METHODS

A single-center, prospective, single-arm, open-label Phase II clinical trial of ALA fluorescence-guided resection of high-grade gliomas (Grade III and IV) was held over a 43-month period (August 2010 to February 2014). ALA was administered at a dose of 20 mg/kg body weight. Intraoperative biopsies from resection cavities were collected. The biopsies were graded on a 4-point scale (0 to 3) based on ALA fluorescence intensity by the surgeon and independently based on tumor cellularity by a neuropathologist. The primary outcome of interest was the correlation of ALA fluorescence intensity to tumor cellularity. The secondary outcome of interest was ALA adverse events. Sensitivities, specificities, positive predictive values (PPVs), negative predictive values (NPVs), and Spearman correlation coefficients were calculated.

RESULTS

A total of 211 biopsies from 59 patients were included. Mean age was 53.3 years and 59.5% were male. The majority of biopsies were glioblastoma (GBM) (79.7%). Slightly more than half (52.5%) of all tumors were recurrent. ALA intensity of 3 correlated with presence of tumor 97.4% (PPV) of the time. However, absence of ALA fluorescence (intensity 0) correlated with the absence of tumor only 37.7% (NPV) of the time. For all tumor types, GBM, Grade III gliomas, and recurrent tumors, ALA intensity 3 correlated strongly with cellularity Grade 3; Spearman correlation coefficients (r) were 0.65, 0.66, 0.65, and 0.62, respectively. The specificity and PPV of ALA intensity 3 correlating with cellularity Grade 3 ranged from 95% to 100% and 86% to 100%, respectively. In biopsies without tumor (cellularity Grade 0), 35.4% still demonstrated ALA fluorescence. Of those biopsies, 90.9% contained abnormal brain tissue, characterized by reactive astrocytes, scattered atypical cells, or inflammation, and 8.1% had normal brain. In nonfluorescent (ALA intensity 0) biopsies, 62.3% had tumor cells present. The ALA-associated complication rate among the study cohort was 3.4%.

CONCLUSIONS

The PPV of utilizing the most robust ALA fluorescence intensity (lava-like orange) as a predictor of tumor presence is high. However, the NPV of utilizing the absence of fluorescence as an indicator of no tumor is poor. ALA intensity is a strong predictor for degree of tumor cellularity for the most fluorescent areas but less so for lower ALA intensities. Even in the absence of tumor cells, reactive changes may lead to ALA fluorescence.

ABBREVIATIONSALA = 5-aminolevulinic acid; EOR = extent of resection; GBM = glioblastoma; GTR = gross-total resection; H & E = hematoxylin and eosin; LFT = liver function test; NPV = negative predictive value; PPV = positive predictive value; WHO = World Health Organization.
Article Information

Contributor Notes

Correspondence Mitchel S. Berger, Chair Department of Neurological Surgery, University of California, San Francisco, 505 Parnassus Ave., M779, San Francisco, California 94143. email: bergerm@neurosurg.ucsf.edu.INCLUDE WHEN CITING Published online November 6, 2015; DOI: 10.3171/2015.5.JNS1577.Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

© AANS, except where prohibited by US copyright law.

Headings
References
  • 1

    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

    • Search Google Scholar
    • Export Citation
  • 2

    Arita HKinoshita MKagawa NFujimoto YKishima HHashimoto N: 11C-methionine uptake and intraoperative 5-aminolevulinic acid-induced fluorescence as separate index markers of cell density in glioma: a stereotactic image-histological analysis. Cancer 118:161916272012

    • Search Google Scholar
    • Export Citation
  • 3

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

    • Search Google Scholar
    • Export Citation
  • 4

    Chung IWEljamel S: Risk factors for developing oral 5-aminolevulinic acid-induced side effects in patients undergoing fluorescence guided resection. Photodiagn Photodyn Ther 10:3623672013

    • Search Google Scholar
    • Export Citation
  • 5

    Della Puppa ACiccarino PLombardi GRolma GCecchin DRossetto M: 5-Aminolevulinic acid fluorescence in high grade glioma surgery: surgical outcome, intraoperative findings, and fluorescence patterns. BioMed Res Int 2014:2325612014

    • Search Google Scholar
    • Export Citation
  • 6

    Della Puppa ADe Pellegrin Sd’Avella EGioffrè GRossetto MGerardi A: 5-aminolevulinic acid (5-ALA) fluorescence guided surgery of high-grade gliomas in eloquent areas assisted by functional mapping. Our experience and review of the literature. Acta Neurochir (Wien) 155:9659722013

    • Search Google Scholar
    • Export Citation
  • 7

    Dietze ABerg K: ALA-induced porphyrin formation and fluorescence in synovitis tissue In-vitro and in vivo studies. Photodiagn Photodyn Ther 2:2993072005

    • Search Google Scholar
    • Export Citation
  • 8

    Díez Valle RTejada Solis SIdoate Gastearena MAGarcía de Eulate RDomínguez Echávarri PAristu Mendiroz J: Surgery guided by 5-aminolevulinic fluorescence in glioblastoma: volumetric analysis of extent of resection in single-center experience. J Neurooncol 102:1051132011

    • Search Google Scholar
    • Export Citation
  • 9

    Hefti Mvon Campe GMoschopulos MSiegner ALooser HLandolt H: 5-aminolevulinic acid induced protoporphyrin IX fluorescence in high-grade glioma surgery: a one-year experience at a single institution. Swiss Med Wkly 138:1801852008

    • Search Google Scholar
    • Export Citation
  • 10

    Ji MOrringer DAFreudiger CWRamkissoon SLiu XLau D: Rapid, label-free detection of brain tumors with stimulated Raman scattering microscopy. Sci Transl Med 5:201ra1192013

    • Search Google Scholar
    • Export Citation
  • 11

    Kamp MAGrosser PFelsberg JSlotty PJSteiger HJReifenberger G: 5-aminolevulinic acid (5-ALA)-induced fluorescence in intracerebral metastases: a retrospective study. Acta Neurochir (Wien) 154:2232282012

    • Search Google Scholar
    • Export Citation
  • 12

    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

    • Search Google Scholar
    • Export Citation
  • 13

    Lindner DTrantakis CRenner CArnold SSchmitgen ASchneider J: Application of intraoperative 3D ultrasound during navigated tumor resection. Minim Invasive Neurosurg 49:1972022006

    • Search Google Scholar
    • Export Citation
  • 14

    Marko NFWeil RJSchroeder JLLang FFSuki DSawaya RE: Extent of resection of glioblastoma revisited: personalized survival modeling facilitates more accurate survival prediction and supports a maximum-safe-resection approach to surgery. J Clin Oncol 32:7747822014

    • Search Google Scholar
    • Export Citation
  • 15

    Nimsky CGanslandt OBuchfelder MFahlbusch R: Intraoperative visualization for resection of gliomas: the role of functional neuronavigation and intraoperative 1.5 T MRI. Neurol Res 28:4824872006

    • Search Google Scholar
    • Export Citation
  • 16

    Orringer DLau DKhatri SZamora-Berridi GJZhang KWu C: Extent of resection in patients with glioblastoma: limiting factors, perception of resectability, and effect on survival. J Neurosurg 117:8518592012

    • Search Google Scholar
    • Export Citation
  • 17

    Panciani PPFontanella MGarbossa DAgnoletti ADucati ALanotte M: 5-aminolevulinic acid and neuronavigation in high-grade glioma surgery: results of a combined approach. Neurocirugia (Astur) 23:23282012

    • Search Google Scholar
    • Export Citation
  • 18

    Piccirillo SGDietz SMadhu BGriffiths JPrice SJCollins VP: Fluorescence-guided surgical sampling of glioblastoma identifies phenotypically distinct tumour-initiating cell populations in the tumour mass and margin. Br J Cancer 107:4624682012

    • Search Google Scholar
    • Export Citation
  • 19

    Regula JMacRobert AJGorchein ABuonaccorsi GAThorpe SMSpencer GM: Photosensitisation and photodynamic therapy of oesophageal, duodenal, and colorectal tumours using 5 aminolaevulinic acid induced protoporphyrin IX-a pilot study. Gut 36:67751995

    • Search Google Scholar
    • Export Citation
  • 20

    Roberts DWValdés PAHarris BTFontaine KMHartov AFan X: Coregistered fluorescence-enhanced tumor resection of malignant glioma: relationships between δ-aminolevulinic acid-induced protoporphyrin IX fluorescence, magnetic resonance imaging enhancement, and neuropathological parameters. Clinical article. J Neurosurg 114:5956032011

    • Search Google Scholar
    • Export Citation
  • 21

    Sanai NPolley MYMcDermott MWParsa ATBerger MS: An extent of resection threshold for newly diagnosed glio-blastomas. J Neurosurg 115:382011

    • Search Google Scholar
    • Export Citation
  • 22

    Schucht PBeck JAbu-Isa JAndereggen LMurek MSeidel K: Gross total resection rates in contemporary glioblastoma surgery: results of an institutional protocol combining 5-aminolevulinic acid intraoperative fluorescence imaging and brain mapping. Neurosurgery 71:9279362012

    • Search Google Scholar
    • Export Citation
  • 23

    Shinoda JYano HYoshimura SOkumura AKaku YIwama T: Fluorescence-guided resection of glioblastoma multiforme by using high-dose fluorescein sodium. Technical note. J Neurosurg 99:5976032003

    • Search Google Scholar
    • Export Citation
  • 24

    Simpson JRHorton JScott CCurran WJRubin PFischbach J: Influence of location and extent of surgical resection on survival of patients with glioblastoma multiforme: results of three consecutive Radiation Therapy Oncology Group (RTOG) clinical trials. Int J Radiat Oncol Biol Phys 26:2392441993

    • Search Google Scholar
    • Export Citation
  • 25

    Stummer WNovotny AStepp HGoetz CBise KReulen HJ: Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients. J Neurosurg 93:100310132000

    • Search Google Scholar
    • Export Citation
  • 26

    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

    • Search Google Scholar
    • Export Citation
  • 27

    Stummer WStocker SNovotny AHeimann ASauer OKempski O: In vitro and in vivo porphyrin accumulation by C6 glioma cells after exposure to 5-aminolevulinic acid. J Photochem Photobiol B 45:1601691998

    • Search Google Scholar
    • Export Citation
  • 28

    Stummer WStocker SWagner SStepp HFritsch CGoetz C: Intraoperative detection of malignant gliomas by 5-aminolevulinic acid-induced porphyrin fluorescence. Neurosurgery 42:5185261998

    • Search Google Scholar
    • Export Citation
  • 29

    Stummer WTonn JCGoetz CUllrich WStepp HBink A: 5-Aminolevulinic acid-derived tumor fluorescence: the diagnostic accuracy of visible fluorescence qualities as corroborated by spectrometry and histology and postoperative imaging. Neurosurgery 74:3103202014

    • Search Google Scholar
    • Export Citation
  • 30

    Utsuki SOka HSato SShimizu SSuzuki STanizaki Y: Histological examination of false positive tissue resection using 5-aminolevulinic acid-induced fluorescence guidance. Neurol Med Chir (Tokyo) 47:2102142007

    • Search Google Scholar
    • Export Citation
  • 31

    Valdés PAKim ABrantsch MNiu CMoses ZBTosteson TD: δ-aminolevulinic acid-induced protoporphyrin IX concentration correlates with histopathologic markers of malignancy in human gliomas: the need for quantitative fluorescence-guided resection to identify regions of increasing malignancy. Neuro Oncol 13:8468562011

    • Search Google Scholar
    • Export Citation
  • 32

    Valdés PALeblond FKim AHarris BTWilson BCFan X: Quantitative fluorescence in intracranial tumor: implications for ALA-induced PpIX as an intraoperative biomarker. J Neurosurg 115:11172011

    • Search Google Scholar
    • Export Citation
  • 33

    Vecht CJAvezaat CJvan Putten WLEijkenboom WMStefanko SZ: The influence of the extent of surgery on the neurological function and survival in malignant glioma. A retrospective analysis in 243 patients. J Neurol Neurosurg Psychiatry 53:4664711990

    • Search Google Scholar
    • Export Citation
  • 34

    Widhalm GMinchev GWoehrer APreusser MKiesel BFurtner J: Strong 5-aminolevulinic acid-induced fluorescence is a novel intraoperative marker for representative tissue samples in stereotactic brain tumor biopsies. Neurosurg Rev 35:3813912012

    • Search Google Scholar
    • Export Citation
  • 35

    Willems PWTaphoorn MJBurger HBerkelbach van der Sprenkel JWTulleken CA: Effectiveness of neuronavigation in resecting solitary intracerebral contrast-enhancing tumors: a randomized controlled trial. J Neurosurg 104:3603682006

    • Search Google Scholar
    • Export Citation
  • 36

    Wirtz CRAlbert FKSchwaderer MHeuer CStaubert ATronnier VM: The benefit of neuronavigation for neurosurgery analyzed by its impact on glioblastoma surgery. Neurol Res 22:3543602000

    • Search Google Scholar
    • Export Citation
  • 37

    Zhao SWu JWang CLiu HDong XShi C: Intraoperative fluorescence-guided resection of high-grade malignant gliomas using 5-aminolevulinic acid-induced porphyrins: a systematic review and meta-analysis of prospective studies. PLoS One 8:e636822013

    • Search Google Scholar
    • Export Citation
TrendMD
Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 661 532 25
PDF Downloads 389 296 22
EPUB Downloads 0 0 0
PubMed
Google Scholar