Fluorescence-guided resection of glioblastoma multiforme utilizing 5-ALA-induced porphyrins: a prospective study in 52 consecutive patients

Restricted access

Object. It has been established that 5-aminolevulinic acid (5-ALA) induces the accumulation of fluorescent porphyrins in glioblastoma multiforme (GBM), a phenomenon potentially exploitable to guide tumor resection. In this study the authors analyze the influence of fluorescence-guided resection on postoperative magnetic resonance (MR) imaging and survival in a series of patients who underwent surgery in the authors' department.

Methods. Fifty-two consecutive patients with GBM received oral doses of 5-ALA (20 mg/kg body weight) 3 hours before induction of anesthesia. Intraoperatively, tumor fluorescence was visualized using a modified operating microscope. Fluorescing tissue was removed whenever it was considered safely possible. Residual enhancement on early postoperative MR imaging was quantified and related to each patient's characteristics to determine which factors influenced resection. Survival was analyzed using the Kaplan—Meier method and multivariate analysis was performed in which the Karnofsky Performance Scale (KPS) score, residual fluorescence, patient age, and residual enhancement on MR images were considered.

Intraoperatively, two fluorescence qualities were perceived: solid fluorescence generally reflected coalescent tumor, whereas vague fluorescence mostly corresponded to infiltrative tumor. Complete resection of contrast-enhancing tumor was accomplished in 33 patients (63%). Residual intraoperative tissue fluorescence left unresected for safety reasons predicted residual enhancement on MR images in 18 of the 19 remaining patients. Age, residual solid fluorescence, and absence of contrast enhancement in MR imaging were independent explanatory factors for survival, whereas the KPS score was significant only in univariate analysis. No perioperative deaths and one case of permanent morbidity were encountered.

Conclusions. The observations in this study indicate the usefulness of 5-ALA—induced tumor fluorescence for guiding tumor resection. The completeness of resection, as determined intraoperatively from residual tissue fluorescence, was related to postoperative MR imaging findings and to survival in patients suffering from GBM.

Article Information

Address reprint requests to: Walter Stummer, M.D., Department of Neurosurgery, Klinikum Grosshadern, Ludwig-Maximilians-University, 81366 Munich, Germany. email: wstummer@nc.med.uni-muenchen.de.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Intraoperative photographs demonstrating tumor cavity viewed under conventional white light (left) and violet-blue illumination (right). Note different qualities of tumor fluorescence (necrosis, solid, vague).

  • View in gallery

    Graph showing intraoperative fluorescence spectra obtained from regions with solid and vague fluorescence. Peaks at 635 nm and 704 nm indicate protoporphyrin IX fluorescence.

  • View in gallery

    Photomicrographs showing morphological features of tissue with solid and vague fluorescence. Upper Left: Fluorescence videomicroscopy image of smear preparation obtained from biopsy sample featuring solid fluorescence. Image shows confluent red protoporphyrin fluorescence with negatively contrasted nuclei and nonfluorescing proliferated capillaries. Upper Right: Periodic acid Schiff staining of the smear in upper left. Lower Left: Fluorescence videomicroscopy image of smear preparation obtained from biopsy sample, featuring vague fluorescence associated with various large abnormal nuclei in invaded brain tissue. Note interspersed white fluorescence of lipid droplets. Lower Right: Giemsa staining of the preparation in lower left.

  • View in gallery

    Bar graphs showing dependence of fluorescence accumulation on morphological features. Left: Coalescent tumor compared with infiltrating tumor (p = 0.0136, chi-square test, 60 patients). Right: Association of fluorescence impression with tumor cellularity (p = 0.0112, chi-square test, 60 patients).

  • View in gallery

    Pie chart illustrating the relationship between the presence and quality of residual, fluorescing tissue and residual enhancement on early postoperative MR images (MR+ = residual enhancement on MR imaging; MR− = no enhancement on MR imaging; for statistics see Table 2).

  • View in gallery

    Graph showing Kaplan—Meier survival curves. A: Overall survival (mean survival 79 ± 7 weeks). B: Survival stratified by age (< 57 years, 100 ± 12 weeks; ≥ 57 years, 58 ± 5 weeks). C: Survival stratified by KPS score (90–100, 98 ± 10 weeks; 60–80, 50 ± 3 weeks). D: Survival stratified by presence of residual enhancement on MR images (no enhancement, 103 ± 11 weeks; residual enhancement, 54 ± 5 weeks). E: Survival stratified by tumor proximity to eloquent brain regions (noneloquent, 86 ± 11 weeks; eloquent, 59 ± 3 weeks). F: Survival stratified by residual tissue fluorescence (no fluorescence, 101 ± 15 weeks; vague fluorescence, 79 ± 6 weeks; solid fluorescence, 51 ± 3 weeks).

References

1.

Albert FKForsting MSartor Ket al: Early postoperative magnetic resonance imaging after resection of malignant glioma: objective evaluation of residual tumor and its influence on regrowth and prognosis. Neurosurgery 34:45611994Albert FK Forsting M Sartor K et al: Early postoperative magnetic resonance imaging after resection of malignant glioma: objective evaluation of residual tumor and its influence on regrowth and prognosis. Neurosurgery 34:45–61 1994

2.

Ammirati MVick NLiao Yet al: Effect of the extent of surgical resection on survival and quality of life in patients with supratentorial glioblastomas and anaplastic astrocytomas. Neurosurgery 21:2012061987Ammirati M Vick N Liao Y et al: Effect of the extent of surgical resection on survival and quality of life in patients with supratentorial glioblastomas and anaplastic astrocytomas. Neurosurgery 21:201–206 1987

3.

Barker FG IIIPrados MDChang SMet al: Radiation response and survival time in patients with glioblastoma multiforme. J Neurosurg 84:4424481996Barker FG III Prados MD Chang SM et al: Radiation response and survival time in patients with glioblastoma multiforme. J Neurosurg 84:442–448 1996

4.

Coffey RJLunsford LDTaylor FH: Survival after stereotactic biopsy of malignant gliomas. Neurosurgery 22:4654731988Coffey RJ Lunsford LD Taylor FH: Survival after stereotactic biopsy of malignant gliomas. Neurosurgery 22:465–473 1988

5.

Collett D: Modelling Survival Data in Medical Research. London: Chapman & Hall1994 pp 8081Collett D: Modelling Survival Data in Medical Research. London: Chapman & Hall 1994 pp 80–81

6.

Cox DR: Regression models and life tables. J R Stat Soc (B) 34:1872201972Cox DR: Regression models and life tables. J R Stat Soc (B) 34:187–220 1972

7.

Devaux BCO'Fallon JRKelly PJ: Resection, biopsy, and survival in malignant glial neoplasms. A retrospective study of clinical parameters, therapy and outcome. J Neurosurg 78:7677751993Devaux BC O'Fallon JR Kelly PJ: Resection biopsy and survival in malignant glial neoplasms. A retrospective study of clinical parameters therapy and outcome. J Neurosurg 78:767–775 1993

8.

Duncan GGGoodman GBLudgate CMet al: The treatment of adult supratentorial high grade astrocytomas. J Neurooncol 13:63721992Duncan GG Goodman GB Ludgate CM et al: The treatment of adult supratentorial high grade astrocytomas. J Neurooncol 13:63–72 1992

9.

Earnest F IIKelly PJScheitauer BWet al: Cerebral astrocytomas: histopathologic correlation of MR and CT contrast enhancement with stereotactic biopsy. Radiology 166:8238271988Earnest F II Kelly PJ Scheitauer BW et al: Cerebral astrocytomas: histopathologic correlation of MR and CT contrast enhancement with stereotactic biopsy. Radiology 166:823–827 1988

10.

Franklin CI: Does the extent of surgery make a difference in high grade malignant astrocytoma. Australas Radiol 36:44471992Franklin CI: Does the extent of surgery make a difference in high grade malignant astrocytoma. Australas Radiol 36:44–47 1992

11.

Grant WEHopper CMacRobert AJet al: Photodynamic therapy of oral cancer: photosensitisation with systemic aminolaevulinic acid. Lancet 342:1471481993Grant WE Hopper C MacRobert AJ et al: Photodynamic therapy of oral cancer: photosensitisation with systemic aminolaevulinic acid. Lancet 342:147–148 1993

12.

Hebeda KMSaarnak AEOlivo Met al: 5-Aminolevulinic acid induced endogenous porphyrin fluorescence in 9L and C6 brain tumours and in the normal rat brain. Acta Neurochir 140:5035131998Hebeda KM Saarnak AE Olivo M et al: 5-Aminolevulinic acid induced endogenous porphyrin fluorescence in 9L and C6 brain tumours and in the normal rat brain. Acta Neurochir 140:503–513 1998

13.

Kabuto MKubota TKobayashi Het al: Experimental and clinical study of glioma at surgery using fluorescent imaging by a surgical microscope after fluorescein administration. Neurol Res 19:9161997Kabuto M Kubota T Kobayashi H et al: Experimental and clinical study of glioma at surgery using fluorescent imaging by a surgical microscope after fluorescein administration. Neurol Res 19:9–16 1997

14.

Kaplan ELMeier P: Non-parametric estimation for incomplete observations. J Am Stat Assoc 53:4574811958Kaplan EL Meier P: Non-parametric estimation for incomplete observations. J Am Stat Assoc 53:457–481 1958

15.

Kelly PFDaumas-Duport CKispert DBet al: Imaging-based stereotaxic serial biopsies in untreated intracranial glial neoplasms. J Neurosurg 66:8658741987Kelly PF Daumas-Duport C Kispert DB et al: Imaging-based stereotaxic serial biopsies in untreated intracranial glial neoplasms. J Neurosurg 66:865–874 1987

16.

Kennedy JCPottier RH: Endogenous protoporphyrin IX, a clinically useful photosensitizer for photodynamic therapy. J Photochem Photobiol B 14:2752921992Kennedy JC Pottier RH: Endogenous protoporphyrin IX a clinically useful photosensitizer for photodynamic therapy. J Photochem Photobiol B 14:275–292 1992

17.

Kowalczuk AMacdonald RLAmidei Cet al: Quantitative imaging study of extent of surgical resection and prognosis of malignant astrocytomas. Neurosurgery 41:102810381997Kowalczuk A Macdonald RL Amidei C et al: Quantitative imaging study of extent of surgical resection and prognosis of malignant astrocytomas. Neurosurgery 41:1028–1038 1997

18.

Kreth FWWarnke PCScheremet Ret al: Surgical resection and radiation therapy versus biopsy and radiation therapy in the treatment of glioblastoma multiforme. J Neurosurg 78:7627661993Kreth FW Warnke PC Scheremet R et al: Surgical resection and radiation therapy versus biopsy and radiation therapy in the treatment of glioblastoma multiforme. J Neurosurg 78:762–766 1993

19.

Loh CSVernon DMacRobert AJet al: Endogenous porphyrin distribution induced by 5-aminolaevulinic acid in the tissue layers of the gastrointestinal tract. J Photochem Photobiol B 20:47541993Loh CS Vernon D MacRobert AJ et al: Endogenous porphyrin distribution induced by 5-aminolaevulinic acid in the tissue layers of the gastrointestinal tract. J Photochem Photobiol B 20:47–54 1993

20.

Miller PJHassanein RSGiri PGSet al: Univariate and multivariate statistical analysis of high-grade gliomas: the relationship of radiation dose and other prognostic factors. Int J Radiat Oncol Biol Phys 19:2752801990Miller PJ Hassanein RS Giri PGS et al: Univariate and multivariate statistical analysis of high-grade gliomas: the relationship of radiation dose and other prognostic factors. Int J Radiat Oncol Biol Phys 19:275–280 1990

21.

Moore GEPeyton WTFrench LAet al: The clinical use of fluorescein in neurosurgery. The localization of brain tumors. J Neurosurg 5:3923981948Moore GE Peyton WT French LA et al: The clinical use of fluorescein in neurosurgery. The localization of brain tumors. J Neurosurg 5:392–398 1948

22.

Murray KJ: Improved surgical resection of human brain tumors. Part I. A preliminary study. Surg Neurol 17:3163191982Murray KJ: Improved surgical resection of human brain tumors. Part I. A preliminary study. Surg Neurol 17:316–319 1982

23.

Nazaaro JMNeuwelt EA: The role of surgery in the management of supratentorial intermediate and high-grade astrocytomas in adults. J Neurosurg 73:3313441990Nazaaro JM Neuwelt EA: The role of surgery in the management of supratentorial intermediate and high-grade astrocytomas in adults. J Neurosurg 73:331–344 1990

24.

Nitta TSato K: Prognostic implications of the extent of surgical resection in patients with intracranial malignant gliomas. Cancer 75:272727311995Nitta T Sato K: Prognostic implications of the extent of surgical resection in patients with intracranial malignant gliomas. Cancer 75:2727–2731 1995

25.

Poon WSSchomacker KTDeutsch TFet al: Laser-induced fluorescence: experimental intraoperative delineation of tumor resection margins. J Neurosurg 76:6796861992Poon WS Schomacker KT Deutsch TF et al: Laser-induced fluorescence: experimental intraoperative delineation of tumor resection margins. J Neurosurg 76:679–686 1992

26.

Quigley MRMaroon JC: The relationship between survival and the extent of the resection in patients with supratentorial malignant gliomas. Neurosurgery 29:3853891991Quigley MR Maroon JC: The relationship between survival and the extent of the resection in patients with supratentorial malignant gliomas. Neurosurgery 29:385–389 1991

27.

Regula JMacRobert AJGorchein Aet al: Photosensitisation and photodynamic therapy of oesophageal, duodenal and colorectal tumours using 5 aminolaevulinic acid induced protoporphyrin IX—a pilot study. Gut 36:67751995Regula J MacRobert AJ Gorchein A et al: Photosensitisation and photodynamic therapy of oesophageal duodenal and colorectal tumours using 5 aminolaevulinic acid induced protoporphyrin IX—a pilot study. Gut 36:67–75 1995

28.

Rostomily RCSpence AMDuong Det al: Multimodality management of recurrent adult malignant gliomas: results of a phase II multiagent chemotherapy study and analysis of cytoreductive surgery. Neurosurgery 35:3783881994Rostomily RC Spence AM Duong D et al: Multimodality management of recurrent adult malignant gliomas: results of a phase II multiagent chemotherapy study and analysis of cytoreductive surgery. Neurosurgery 35:378–388 1994

29.

Shrieve DCAlexander E IIIBlack PMet al: Treatment of patients with primary glioblastoma multiforme with standard postoperative radiotherapy and radiosurgical boost: prognostic factors and long-term outcome. J Neurosurg 90:72771999Shrieve DC Alexander E III Black PM et al: Treatment of patients with primary glioblastoma multiforme with standard postoperative radiotherapy and radiosurgical boost: prognostic factors and long-term outcome. J Neurosurg 90:72–77 1999

30.

Simpson JRHorton JScott Cet al: 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 26:2392441993Simpson JR Horton J Scott C et al: 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 26:239–244 1993

31.

Sneed PKPrados MDMcDermott MWet al: Large effect of age on the survival of patients with glioblastoma treated with radiotherapy and brachytherapy boost. Neurosurgery 36:8989041995Sneed PK Prados MD McDermott MW et al: Large effect of age on the survival of patients with glioblastoma treated with radiotherapy and brachytherapy boost. Neurosurgery 36:898–904 1995

32.

Stummer WGötz CHassan Aet al: Kinetics of photofrin II in perifocal brain edema. Neurosurgery 33:107510811993Stummer W Götz C Hassan A et al: Kinetics of photofrin II in perifocal brain edema. Neurosurgery 33:1075–1081 1993

33.

Stummer WStepp HMöller Get al: Technical principles for protoporphyrin-IX-fluorescence guided microsurgical resection of malignant glioma tissue. Acta Neurochir 140:99510001998Stummer W Stepp H Möller G et al: Technical principles for protoporphyrin-IX-fluorescence guided microsurgical resection of malignant glioma tissue. Acta Neurochir 140:995–1000 1998

34.

Stummer WStocker SNovotny Aet al: In vitro and in vivo porphyrin accumulation by C6 glioma cells after exposure to 5-aminolevulinic acid. J Photochem Photobiol B 45:1601691998Stummer W Stocker S Novotny A et al: In vitro and in vivo porphyrin accumulation by C6 glioma cells after exposure to 5-aminolevulinic acid. J Photochem Photobiol B 45:160–169 1998

35.

Stummer WStocker SWagner Set al: Intraoperative detection of malignant gliomas by 5-aminolaevulinic acid-induced porphyrin fluorescence. Neurosurgery 42:5185261998Stummer W Stocker S Wagner S et al: Intraoperative detection of malignant gliomas by 5-aminolaevulinic acid-induced porphyrin fluorescence. Neurosurgery 42:518–526 1998

36.

Vecht CJAvezaat CJJvan Putten WLJet al: 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 53:4664711990Vecht CJ Avezaat CJJ van Putten WLJ et al: 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 53:466–471 1990

37.

Webber JKessel DFromm D: Side effects and photosensitization of human tissues after aminolevulinic acid. J Surg Res 68:31371997Webber J Kessel D Fromm D: Side effects and photosensitization of human tissues after aminolevulinic acid. J Surg Res 68:31–37 1997

38.

Winger MJMacdonald DRCairncross JG: Supratentorial anaplastic gliomas in adults. The prognostic importance of extent of resection and prior low-grade glioma. J Neurosurg 71:4874931989Winger MJ Macdonald DR Cairncross JG: Supratentorial anaplastic gliomas in adults. The prognostic importance of extent of resection and prior low-grade glioma. J Neurosurg 71:487–493 1989

39.

Wisoff JHBoyett JMBerger MSet al: Current neurosurgical management and the impact of the extent of resection in the treatment of malignant gliomas of childhood: a report of the Children's Cancer Group Trial No. CCG-945. J Neurosurg 89:52591998Wisoff JH Boyett JM Berger MS et al: Current neurosurgical management and the impact of the extent of resection in the treatment of malignant gliomas of childhood: a report of the Children's Cancer Group Trial No. CCG-945. J Neurosurg 89:52–59 1998

40.

Wood JRGreen SBShapiro WR: The prognostic importance of tumor size in malignant gliomas: a computed tomographic scan study by the Brain Tumor Cooperative Group. J Clin Oncol 6:3383431988Wood JR Green SB Shapiro WR: The prognostic importance of tumor size in malignant gliomas: a computed tomographic scan study by the Brain Tumor Cooperative Group. J Clin Oncol 6:338–343 1988

41.

Yoshida JKajita YWakabayashi Tet al: Long-term follow-up results of 175 patients with malignant glioma: importance of radical tumour resection and postoperative adjuvant therapy with interferon, ACNU and radiation. Acta Neurochir 127:55591994Yoshida J Kajita Y Wakabayashi T et al: Long-term follow-up results of 175 patients with malignant glioma: importance of radical tumour resection and postoperative adjuvant therapy with interferon ACNU and radiation. Acta Neurochir 127:55–59 1994

TrendMD

Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 86 86 40
Full Text Views 403 403 76
PDF Downloads 139 139 12
EPUB Downloads 0 0 0

PubMed

Google Scholar