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Intraoperative 5-ALA fluorescence-guided resection of high-grade glioma leads to greater extent of resection with better outcomes: a systematic review

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Abstract

Importance

High-grade gliomas (HGG) are the most aggressive and common malignant brain tumors in adults. They have a dismally fatal prognosis. Even if gross total resection of the enhancing tumor is achieved, inevitably, invading tumor cells that are indistinguishable to the un-aided eye are left behind, which eventually leads to tumor recurrence. 5-aminolevulinic acid (5-ALA) is an increasingly utilized intraoperative fluorescent imaging agent for patients with HGG. It enhances visualization of HGG tissue. Despite early promising randomized clinical trial data suggesting a survival benefit for 5-ALA-guided surgery, the growing body of literature must be analyzed to confirm efficacy on patient outcomes.

Objective

To perform a systematic review of the literature to evaluate whether there is a beneficial effect upon survival and extent of resection due to the utilization of 5-ALA in HGG surgery.

Evidence review

Literature regarding 5-ALA usage in HGG surgery was reviewed according to the PRISMA guidelines. Two databases, PubMed and SCOPUS, were searched for assorted combinations of the keywords “5-ALA,” “high-grade glioma,” “5-aminolevulinic acid,” and “resection” in July 2020 for case reports and retrospective, prospective, and randomized clinical trials assessing and analyzing 5-ALA intraoperative use in patients with HGG. Entailed studies on PubMed and SCOPUS were found for screening using a snowball search technique upon the initially searched papers. Systematic reviews and meta-analyses were excluded from our PRISMA table.

Findings

3756 previously published studies were screened, 536 of which were further evaluated, and ultimately 45 were included in our systematic review. There were no date restrictions on the screened publications. Our literature search was finalized on July 16, 2020. We found an observed increase in the overall survival (OS) and progression-free survival (PFS) of the 5-ALA group compared to the white light group, as well as an observed increase in the OS and PFS of complete resections compared to incomplete resections. Of the studies that directly compared the use of 5-ALA to white light (13 of the total analyzed 45, or 28.9%), 5-ALA lead to a better PFS and OS in 88.4 and 67.5% of patients, respectively.

When the studies that reported postoperative neurologic outcomes of surgeries using 5-ALA vs. white light were analyzed, 42.2% of subjects demonstrated 5-ALA use was associated with less post-op neurological deficits, whereas 34.5% demonstrated no difference between 5-ALA and without. 23.3% of studies showed that intraoperative 5-ALA guided surgeries lead to more post-op neurological deficits.

Conclusions and relevance

Utilization of 5-ALA was found to be associated with a greater extent of resection in HGG surgeries, as well as longer OS and PFS. Postop neurologic deficit rates were mixed and inconclusive when comparing 5-ALA groups to white light groups. 5-ALA is a useful surgical adjunct for resection of HGG when patient safety is preserved.

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Data availability

The data that support the findings of this study are openly available at https://pubmed.ncbi.nlm.nih.gov and https://www.scopus.com/home.uri.

Abbreviations

HGG:

High grade glioma

5-ALA:

δ-Aminolevulinic acid

OS:

Overall survival

PFS:

Progression-free survival

FDA:

Food and drug administration

GBM:

Glioblastoma multiforme

EMA:

European medicine’s agency

PRISMA:

Preferred reporting items for systematic reviews and meta-analyses

WHO:

World Health Organization

MD:

Mean difference

CI:

Confidence interval

iMRI:

Intraoperative magnetic resonance imaging

CEUS:

Contrast-enhanced ultrasound

ioUS:

Intraoperative ultrasound

iCT:

Intraoperative computed tomography scan

EOR:

Extent of resection

GTR:

Gross total resection

References

  1. Hadjipanayis CG, Stummer W (2019) 5-ALA and FDA approval for glioma surgery. J Neurooncol 141(3):479–486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Stummer W et al (2006) Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 7(5):392–401

    Article  CAS  PubMed  Google Scholar 

  3. Lacroix M et al (2001) A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg 95(2):190–198

    Article  CAS  PubMed  Google Scholar 

  4. Beller EM et al (2013) PRISMA for Abstracts: reporting systematic reviews in journal and conference abstracts. PLoS Med 10(4):e1001419

    Article  PubMed  PubMed Central  Google Scholar 

  5. Stepp H et al (2007) ALA and malignant glioma: fluorescence-guided resection and photodynamic treatment. J Environ Pathol Toxicol Oncol 26(2):157–164

    Article  CAS  PubMed  Google Scholar 

  6. Kim SK et al (2014) Impact of fluorescence-guided surgery on the improvement of clinical outcomes in glioblastoma patients. Neuro-Oncol Pract 1(3):81–85

    Article  Google Scholar 

  7. Picart T et al (2017) Is fluorescence-guided surgery with 5-ala in eloquent areas for malignant gliomas a reasonable and useful technique? Neurochirurgie 63(3):189–196

    Article  CAS  PubMed  Google Scholar 

  8. Slotty PJ et al (2013) The impact of improved treatment strategies on overall survival in glioblastoma patients. Acta Neurochir 155(6):959–963

    Article  CAS  PubMed  Google Scholar 

  9. Stummer W et al (2011) 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. J Neurosurg 114(3):613–623

    Article  PubMed  Google Scholar 

  10. Díez Valle R et al (2014) Observational, retrospective study of the effectiveness of 5-aminolevulinic acid in malignant glioma surgery in Spain (The VISIONA study). Neurologia 29(3):131–138

    Article  PubMed  Google Scholar 

  11. Ng WP et al (2017) Fluorescence-guided versus conventional surgical resection of high grade glioma: a single-centre, 7-year, comparative effectiveness study. Malays J Med Sci 24(2):78–86

    PubMed  PubMed Central  Google Scholar 

  12. Eljamel MS, Goodman C, Moseley H (2008) ALA and photofrin fluorescence-guided resection and repetitive PDT in glioblastoma multiforme: a single centre phase III randomised controlled trial. Lasers Med Sci 23(4):361–367

    Article  PubMed  Google Scholar 

  13. Eyüpoglu IY et al (2016) Supra-complete surgery via dual intraoperative visualization approach (DiVA) prolongs patient survival in glioblastoma. Oncotarget 7(18):25755

    Article  PubMed  PubMed Central  Google Scholar 

  14. Hauser SB et al (2016) Combining 5-aminolevulinic acid fluorescence and intraoperative magnetic resonance imaging in glioblastoma surgery: a histology-based evaluation. Neurosurgery 78(4):475–483

    Article  PubMed  Google Scholar 

  15. Hickmann A-K, Nadji-Ohl M, Hopf NJ (2015) Feasibility of fluorescence-guided resection of recurrent gliomas using five-aminolevulinic acid: retrospective analysis of surgical and neurological outcome in 58 patients. J Neurooncol 122(1):151–160

    Article  CAS  PubMed  Google Scholar 

  16. Jacquesson T et al (2013) Surgery of high-grade gliomas guided by fluorescence: a retrospective study of 22 patients. Neurochirurgie 59(1):9–16

    Article  CAS  PubMed  Google Scholar 

  17. Aldave G et al (2013) Prognostic value of residual fluorescent tissue in glioblastoma patients after gross total resection in 5-aminolevulinic acid-guided surgery. Neurosurgery 72(6):915–920

    Article  PubMed  Google Scholar 

  18. Pichlmeier U et al (2008) Resection and survival in glioblastoma multiforme: an RTOG recursive partitioning analysis of ALA study patients. Neuro Oncol 10(6):1025–1034

    Article  PubMed  PubMed Central  Google Scholar 

  19. Stummer W et al (2000) Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients. J Neurosurg 93(6):1003–1013

    Article  CAS  PubMed  Google Scholar 

  20. Panciani PP et al (2012) Fluorescence and image guided resection in high grade glioma. Clin Neurol Neurosurg 114(1):37–41

    Article  PubMed  Google Scholar 

  21. Díez Valle R, Tejada Solis S (2015) To what extent will 5-aminolevulinic acid change the face of malignant glioma surgery? CNS Oncol 4(4):265–272

    Article  PubMed  PubMed Central  Google Scholar 

  22. Della Puppa A et al (2014) 5-Aminolevulinic acid fluorescence in high grade glioma surgery: surgical outcome, intraoperative findings, and fluorescence patterns. Biomed Res Int 2014:232561

    PubMed  Google Scholar 

  23. Della Puppa A et al (2013) 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 155(6):965–972

    Article  PubMed  Google Scholar 

  24. Díez Valle R et al (2011) Surgery guided by 5-aminolevulinic fluorescence in glioblastoma: volumetric analysis of extent of resection in single-center experience. J Neurooncol 102(1):105–113

    Article  PubMed  Google Scholar 

  25. Idoate MA et al (2011) Pathological characterization of the glioblastoma border as shown during surgery using 5-aminolevulinic acid-induced fluorescence. Neuropathology 31(6):575–582

    Article  PubMed  Google Scholar 

  26. Hefti M et al (2008) 5-Aminolaevulinic acid-induced protoporphyrin IX fluorescence in high-grade glioma surgery. Swiss Med Wkly 138(11–12):180–185

    CAS  PubMed  Google Scholar 

  27. Schucht P et al (2012) 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(5):927–935

    Article  PubMed  Google Scholar 

  28. Teixidor P et al (2016) Safety and efficacy of 5-aminolevulinic acid for high grade glioma in usual clinical practice: a prospective cohort study. PLoS ONE 11(2):e0149244

    Article  PubMed  PubMed Central  Google Scholar 

  29. Eriksson M et al (2019) Improved treatment of glioblastoma—changes in survival over two decades at a single regional centre. Acta Oncol 58(3):334–341

    Article  PubMed  Google Scholar 

  30. Nabavi A et al (2009) Five-aminolevulinic acid for fluorescence-guided resection of recurrent malignant gliomas: a phase ii study. Neurosurgery 65(6):1070–1076

    Article  PubMed  Google Scholar 

  31. Chan DTM, Yi-Pin Sonia H, Poon WS (2018) 5-Aminolevulinic acid fluorescence guided resection of malignant glioma: Hong Kong experience. Asian J Surg 41(5):467–472

    Article  PubMed  Google Scholar 

  32. Cordova JS et al (2016) Semi-automated volumetric and morphological assessment of glioblastoma resection with fluorescence-guided surgery. Mol Imaging Biol 18(3):454–462

    Article  PubMed  PubMed Central  Google Scholar 

  33. Cortnum S, Laursen RJ (2012) Fluorescence-guided resection of gliomas. Dan Med J 59(8):A4460

    PubMed  Google Scholar 

  34. Pastor J et al (2013) Role of intraoperative neurophysiological monitoring during fluorescence-guided resection surgery. Acta Neurochir 155(12):2201–2213

    Article  PubMed  Google Scholar 

  35. Feigl GC et al (2010) Resection of malignant brain tumors in eloquent cortical areas: A new multimodal approach combining 5-aminolevulinic acid and intraoperative monitoring. J Neurosurg 113(2):352–357

    Article  PubMed  Google Scholar 

  36. Piquer J et al (2014) Fluorescence-guided surgery and biopsy in gliomas with an exoscope system. BioMed Res Int 2014:207974

    Article  PubMed  PubMed Central  Google Scholar 

  37. Stummer W et al (2008) Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias. Neurosurgery 62(3):564–576

    Article  PubMed  Google Scholar 

  38. Tykocki T et al (2012) Fluorescence-guided resection of primary and recurrent malignant gliomas with 5-aminolevulinic acid. Preliminary results. Neurol Neurochir Pol 46(1):47–51

    Article  CAS  PubMed  Google Scholar 

  39. Barbagallo GMV et al (2016) Portable intraoperative computed tomography scan in image-guided surgery for brain high-grade gliomas: analysis of technical feasibility and impact on extent of tumor resection. Oper Neurosurg 12(1):19–30

    Article  Google Scholar 

  40. Coburger J et al (2015) Surgery for glioblastoma: impact of the combined use of 5-aminolevulinic acid and intraoperative MRI on extent of resection and survival. PLoS ONE 10(6):e0131872

    Article  PubMed  PubMed Central  Google Scholar 

  41. Eyüpoglu IY et al (2012) Improving the extent of malignant glioma resection by dual intraoperative visualization approach. PLoS ONE 7(9):e44885

    Article  PubMed  PubMed Central  Google Scholar 

  42. Nickel K et al (2018) The patients’ view: impact of the extent of resection, intraoperative imaging, and awake surgery on health-related quality of life in high-grade glioma patients—results of a multicenter cross-sectional study. Neurosurg Rev 41(1):207–219

    Article  PubMed  Google Scholar 

  43. Tsugu A et al (2011) Impact of the combination of 5-aminolevulinic acid-induced fluorescence with intraoperative magnetic resonance imaging-guided surgery for glioma. World Neurosurgery 76(1):120–127

    Article  PubMed  Google Scholar 

  44. Roder C et al (2014) Maximizing the extent of resection and survival benefit of patients in glioblastoma surgery: high-field iMRI versus conventional and 5-ALA-assisted surgery. Eur J Surg Oncol 40(3):297–304

    Article  CAS  PubMed  Google Scholar 

  45. Schatlo B et al (2015) Outcomes after combined use of intraoperative MRI and 5-aminolevulinic acid in high-grade glioma surgery. Neuro Oncol 17(12):1560–1567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Yamada S et al (2015) Role of neurochemical navigation with 5-aminolevulinic acid during intraoperative MRI-guided resection of intracranial malignant gliomas. Clin Neurol Neurosurg 130:134–139

    Article  PubMed  Google Scholar 

  47. Della Pepa GM et al (2020) 5-Aminolevulinic acid and contrast-enhanced ultrasound: the combination of the two techniques to optimize the extent of resection in glioblastoma surgery. Neurosurgery 86(6):E529–E540

    Article  PubMed  Google Scholar 

  48. Neidert MC et al (2016) The influence of intraoperative resection control modalities on survival following gross total resection of glioblastoma. Neurosurg Rev 39(3):401–409

    Article  PubMed  Google Scholar 

  49. Colapaoli L et al (2006) A case of anaphylactic shock possibly caused by intravesical hexvix. Acta Anaesthesiol Scand 50(9):1165–1167

    Article  CAS  PubMed  Google Scholar 

  50. Kreth FW et al (2013) Gross total but not incomplete resection of glioblastoma prolongs survival in the era of radiochemotherapy. Ann Oncol 24(12):3117–3123

    Article  PubMed  Google Scholar 

  51. Nader S et al (2011) An extent of resection threshold for newly diagnosed glioblastomas. J Neurosurg 115(1):3–8

    Article  Google Scholar 

  52. Schucht P et al (2014) 5-ALA complete resections go beyond MR contrast enhancement: shift corrected volumetric analysis of the extent of resection in surgery for glioblastoma. Acta Neurochir 156(2):305–312

    Article  PubMed  Google Scholar 

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Funding

This systematic review received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Neurological Surgery, Miller School of Medicine, University of Miami, 1475 NW 12th Ave, Miami, FL, 33136, USA

    Tiffany A. Eatz, Daniel G. Eichberg, Victor M. Lu, Long Di, Ricardo J. Komotar & Michael E. Ivan

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  1. Tiffany A. Eatz
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  2. Daniel G. Eichberg
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  3. Victor M. Lu
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  4. Long Di
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  5. Ricardo J. Komotar
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  6. Michael E. Ivan
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Contributions

All authors contributed to the study conception and design. Material, preparation, data collection, and analysis were performed by TE, DE, and VML. The first draft of the manuscript was written by TE; DGE and MEI commented/edited and VML executed statistical/data analysis. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Michael E. Ivan.

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Conflicts of interest

The following authors have no financial disclosures or personal conflicts of interest: TAE, DE, VL, LD, RJK, MEI.

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Ethical approval was not applicable for this study as only publicly accessible data was utilized.

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Eatz, T.A., Eichberg, D.G., Lu, V.M. et al. Intraoperative 5-ALA fluorescence-guided resection of high-grade glioma leads to greater extent of resection with better outcomes: a systematic review. J Neurooncol 156, 233–256 (2022). https://doi.org/10.1007/s11060-021-03901-9

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