Effects of 5-ALA dose on resection of glioblastoma
Fluorescence-guided surgery (FGS) with the use of 5-aminolevulinic acid (5-ALA) leads to more extensive resection of high-grade glioma (HGG) and longer overall survival (OS) of patients compared to conventional resection. The purpose of this study is to investigate the effect of 5-ALA dosages on residual tumor volume (RTV) and OS in patients with glioblastoma.
A retrospective cohort study for patients who participated in a phase I and II dose-escalation clinical trial on 5-ALA for resection of HGG. A total of 25 patients were found to have newly diagnosed glioblastoma on histology and enrolled in our study. Patients receiving low doses of 5-ALA (10–30 mg/kg) (n = 6) were compared to those receiving high doses (40–50 mg/kg) (n = 19). Pre- and post-operative contrast enhanced T1W MRI were evaluated with volumetric analysis.
Median RTV was 0.69 cm3 and 0.00 cm3 in the low and high dose groups respectively (p = 0.975). A gross total resection (GTR) was more likely in the high dose group, though this was not statistically significant. No significant difference was found in median OS between the high and low dose groups (p = 0.6787).
High doses of 5-ALA FGS are associated with less RTV and greater probability of GTR. 5-ALA dose was not associated with OS. Further studies with a larger patient cohort are warranted.
Keywords5-ALA 5-Aminolevulinic acid Glioblastoma Volumetric analysis
Funding for this work was received from the Memorial Medical Center Foundation, Springfield, Illinois.
Compliance with ethical standards
Conflict of interest
The authors have no personal or institutional conflicts of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
- 1.Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO, European Organisation for R, Treatment of Cancer Brain T, Radiation Oncology G, National Cancer Institute of Canada Clinical Trials G (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10: 459–466 https://doi.org/10.1016/S1470-2045(09)70025-7 CrossRefGoogle Scholar
- 4.Lacroix M, Abi-Said D, Fourney DR, Gokaslan ZL, Shi W, DeMonte F, Lang FF, McCutcheon IE, Hassenbusch SJ, Holland E, Hess K, Michael C, Miller D, Sawaya R (2001) A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg 95:190–198. https://doi.org/10.3171/jns.2001.95.2.0190 CrossRefGoogle Scholar
- 5.Sanai N, Berger MS (2008) Glioma extent of resection and its impact on patient outcome. Neurosurgery 62:753–764. https://doi.org/10.1227/01.neu.0000318159.21731.cf. (discussion 264–756) CrossRefGoogle Scholar
- 7.Stummer W, Reulen HJ, Meinel T, Pichlmeier U, Schumacher W, Tonn JC, Rohde V, Oppel F, Turowski B, Woiciechowsky C, Franz K, Pietsch T, Group AL-GS (2008) Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias. Neurosurgery 62:564–576. https://doi.org/10.1227/01.neu.0000317304.31579.17. (discussion 564–576) CrossRefGoogle Scholar
- 9.Schucht P, Knittel S, Slotboom J, Seidel K, Murek M, Jilch A, Raabe A, Beck J (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 (Wien) 156:305–312. https://doi.org/10.1007/s00701-013-1906-7. (discussion 312) CrossRefGoogle Scholar
- 11.Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ, Group AL-GS (2006) Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 7:392–401. https://doi.org/10.1016/S1470-2045(06)70665-9 CrossRefGoogle Scholar
- 12.Aldave G, Tejada S, Pay E, Marigil M, Bejarano B, Idoate MA, Diez-Valle R (2013) Prognostic value of residual fluorescent tissue in glioblastoma patients after gross total resection in 5-aminolevulinic acid-guided surgery. Neurosurgery 72:915–920. https://doi.org/10.1227/NEU.0b013e31828c3974. (discussion 920–911) CrossRefGoogle Scholar
- 13.Cozzens JW, Lokaitis BC, Moore BE, Amin DV, Espinosa JA, MacGregor M, Michael AP, Jones BA (2017) A phase 1 dose-escalation study of oral 5-aminolevulinic acid in adult patients undergoing resection of a newly diagnosed or recurrent high-grade glioma. Neurosurgery 81:46–55. https://doi.org/10.1093/neuros/nyw182 CrossRefGoogle Scholar
- 14.Vogelbaum MA, Jost S, Aghi MK, Heimberger AB, Sampson JH, Wen PY, Macdonald DR, Van den Bent MJ, Chang SM (2012) Application of novel response/progression measures for surgically delivered therapies for gliomas: Response Assessment in Neuro-Oncology (RANO) working group. Neurosurgery 70:234–243. https://doi.org/10.1227/NEU.0b013e318223f5a7. (discussion 243–234) CrossRefGoogle Scholar
- 16.GmbH M (2008) Gliolan® user manualGoogle Scholar
- 17.Albert FK, Forsting M, Sartor K, Adams HP, Kunze S (1994) Early postoperative magnetic resonance imaging after resection of malignant glioma: objective evaluation of residual tumor and its influence on regrowth and prognosis. Neurosurgery 34:45–60. (discussion 60–41) Google Scholar
- 20.Coburger J, Engelke J, Scheuerle A, Thal DR, Hlavac M, Wirtz CR, Konig R (2014) Tumor detection with 5-aminolevulinic acid fluorescence and Gd-DTPA-enhanced intraoperative MRI at the border of contrast-enhancing lesions: a prospective study based on histopathological assessment. Neurosurg Focus 36:E3. https://doi.org/10.3171/2013.11.FOCUS13463 CrossRefGoogle Scholar
- 21.Jaber M, Wolfer J, Ewelt C, Holling M, Hasselblatt M, Niederstadt T, Zoubi T, Weckesser M, Stummer W (2016) The value of 5-aminolevulinic acid in low-grade gliomas and high-grade gliomas lacking glioblastoma imaging features: an analysis based on fluorescence, magnetic resonance imaging, 18F-fluoroethyl tyrosine positron emission tomography, and tumor molecular factors. Neurosurgery 78:401–411. https://doi.org/10.1227/NEU.0000000000001020 CrossRefGoogle Scholar
- 22.Roessler K, Becherer A, Donat M, Cejna M, Zachenhofer I (2012) Intraoperative tissue fluorescence using 5-aminolevolinic acid (5-ALA) is more sensitive than contrast MRI or amino acid positron emission tomography ((18)F-FET PET) in glioblastoma surgery. Neurol Res 34:314–317. https://doi.org/10.1179/1743132811Y.0000000078 CrossRefGoogle Scholar
- 24.McGirt MJ, Chaichana KL, Gathinji M, Attenello FJ, Than K, Olivi A, Weingart JD, Brem H, Quinones-Hinojosa AR (2009) Independent association of extent of resection with survival in patients with malignant brain astrocytoma. J Neurosurg 110:156–162. https://doi.org/10.3171/2008.4.17536 CrossRefGoogle Scholar
- 25.Brown TJ, Brennan MC, Li M, Church EW, Brandmeir NJ, Rakszawski KL, Patel AS, Rizk EB, Suki D, Sawaya R, Glantz M (2016) Association of the extent of resection with survival in glioblastoma: a systematic review and meta-analysis. JAMA Oncol 2:1460–1469. https://doi.org/10.1001/jamaoncol.2016.1373 CrossRefGoogle Scholar
- 27.Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003. https://doi.org/10.1056/NEJMoa043331 CrossRefGoogle Scholar
- 28.Molenaar RJ, Verbaan D, Lamba S, Zanon C, Jeuken JW, Boots-Sprenger SH, Wesseling P, Hulsebos TJ, Troost D, van Tilborg AA, Leenstra S, Vandertop WP, Bardelli A, van Noorden CJ, Bleeker FE (2014) The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than either IDH1 or MGMT alone. Neuro Oncol 16:1263–1273. https://doi.org/10.1093/neuonc/nou005 CrossRefGoogle Scholar