Acta Neurochirurgica

, Volume 153, Issue 6, pp 1211–1218 | Cite as

Cytoreductive surgery of glioblastoma as the key to successful adjuvant therapies: new arguments in an old discussion

  • Walter StummerEmail author
  • Martin J. van den Bent
  • Manfred Westphal
Clinical Article



This article discusses data from 3 randomized phase 3 trials, supporting a role for surgery in glioblastoma.


Data were reviewed by extent of resection during primary surgery from the ALA-Glioma Study (fluorescence-guided versus conventional resection), the BCNU wafer study (BCNU wafer versus placebo), and the EORTC Study 26981–22981 (radiotherapy versus chemoradiotherapy with temozolomide).


For glioblastoma patients in the ALA study, median survival was 16.7 and 11.8 months for complete versus partial resection, respectively (P < 0.0001). Survival effects were maintained after correction for differences in age and tumor location. For glioblastoma patients who received ≥90% resection in the BCNU wafer study, median survival increased for BCNU wafer versus placebo (14.5 versus 12.4 months, respectively; P = 0.02), but no survival increase was found for <90% resection (11.7 versus 10.6 months, respectively; P = 0.98). In the EORTC study, absolute median gain in survival with chemoradiotherapy versus radiotherapy was greatest for complete resections (+4.1 months; P = 0.0001), compared with partial resections (+1.8 months; P = 0.0001), or biopsies (+1.5 months; P = 0.088), suggesting surgery enhanced adjuvant treatment.


Complete resection appears to improve survival and may increase the efficacy of adjunct/adjuvant therapies. If safely achievable, complete resection should be the surgical goal for glioblastoma.


5-aminolevulinic acid BCNU wafer Glioblastoma Surgery Temozolomide 



We would like to thank Dr. Roger Stupp for insightful comments on the manuscript. We also want to thank Susan Wingeron, Michael Raffin and Donna Stefanoni from Nexus Communications, Inc. (North Wales, PA) for their editorial assistance, which was financially supported by Archimedes Pharma.

Conflicts of interest

Walter Stummer, MD, PhD, has received research funding from Medac GmbH and is a consultant with Medac GmbH. Martin J. van den Bent, MD, PhD, is a consultant for MSD and is member of the MSD speakersbureau. Manfred Westphal, MD, PhD, has received honoraria from Ark Therapeutics and Archimedes Pharma.


  1. 1.
    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 34:45–60PubMedCrossRefGoogle Scholar
  2. 2.
    Ashby LS, Ryken TC (2006) Management of malignant glioma: steady progress with multimodal approaches. Neurosurg Focus 20:E3PubMedCrossRefGoogle Scholar
  3. 3.
    Athanassiou H, Synodinou M, Maragoudakis E, Paraskevaidis M, Verigos C, Misailidou D, Antonadou D, Saris G, Beroukas K, Karageorgis P (2005) Randomized phase II study of temozolomide and radiotherapy compared with radiotherapy alone in newly diagnosed glioblastoma multiforme. J Clin Oncol 23:2372–2377PubMedCrossRefGoogle Scholar
  4. 4.
    Barker FG 2nd, Prados MD, Chang SM, Gutin PH, Lamborn KR, Larson DA, Malec MK, McDermott MW, Sneed PK, Wara WM, Wilson CB (1996) Radiation response and survival time in patients with glioblastoma multiforme. J Neurosurg 84:442–448PubMedCrossRefGoogle Scholar
  5. 5.
    Berger MS, Deliganis AV, Dobbins J, Keles GE (1994) The effect of extent of resection on recurrence in patients with low grade cerebral hemisphere gliomas. Cancer 74:1784–1791PubMedCrossRefGoogle Scholar
  6. 6.
    Ciric I, Vick NA, Mikhael MA, Cozzens J, Eller T, Walsh A (1990) Aggressive surgery for malignant supratentorial gliomas. Clin Neurosurg 36:375–383PubMedGoogle Scholar
  7. 7.
    Collingridge DR, Piepmeier JM, Rockwell S, Knisely JP (1999) Polarographic measurements of oxygen tension in human glioma and surrounding peritumoural brain tissue. Radiother Oncol 53:127–131PubMedCrossRefGoogle Scholar
  8. 8.
    Curran WJ Jr, Scott CB, Horton J, Nelson JS, Weinstein AS, Fischbach AJ, Chang CH, Rotman M, Asbell SO, Krisch RE, Nelson F (1993) Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst 85:704–710PubMedCrossRefGoogle Scholar
  9. 9.
    Curran WJ Jr, Scott CB, Horton J, Nelson JS, Weinstein AS, Nelson DF, Fischbach AJ, Chang CH, Rotman M, Asbell SO, Powlis W (1992) Does extent of surgery influence outcome for astrocytoma with atypical or anaplastic foci (AAF)? A report from three Radiation Therapy Oncology Group (RTOG) trials. J Neurooncol 12:219–227PubMedCrossRefGoogle Scholar
  10. 10.
    Devaux BC, O'Fallon JR, Kelly PJ (1993) Resection, biopsy, and survival in malignant glial neoplasms. A retrospective study of clinical parameters, therapy, and outcome. J Neurosurg 78:767–775PubMedCrossRefGoogle Scholar
  11. 11.
    Evans SM, Judy KD, Dunphy I, Jenkins WT, Hwang WT, Nelson PT, Lustig RA, Jenkins K, Magarelli DP, Hahn SM, Collins RA, Grady MS, Koch CJ (2004) Hypoxia is important in the biology and aggression of human glial brain tumors. Clin Cancer Res 10:8177–8184PubMedCrossRefGoogle Scholar
  12. 12.
    Fleming AB, Saltzman WM (2002) Pharmacokinetics of the carmustine implant. Clin Pharmacokinet 41:403–419PubMedCrossRefGoogle Scholar
  13. 13.
    Fung LK, Ewend MG, Sills A, Sipos EP, Thompson R, Watts M, Colvin OM, Brem H, Saltzman WM (1998) Pharmacokinetics of interstitial delivery of carmustine, 4-hydroperoxycyclophosphamide, and paclitaxel from a biodegradable polymer implant in the monkey brain. Cancer Res 58:672–684PubMedGoogle Scholar
  14. 14.
    Giese A, Bjerkvig R, Berens ME, Westphal M (2003) Cost of migration: invasion of malignant gliomas and implications for treatment. J Clin Oncol 21:1624–1636PubMedCrossRefGoogle Scholar
  15. 15.
    Gottfried ON, Deogaonkar M, Way DL (2000) Postoperative cerebral edema after intracavitary implantation of Gliadel(R) wafers for treatment of malignant gliomas [abstract]. J Invest Med 48(1):79AGoogle Scholar
  16. 16.
    Hess KR (1999) Extent of resection as a prognostic variable in the treatment of gliomas. J Neurooncol 42:227–231PubMedCrossRefGoogle Scholar
  17. 17.
    Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D, Yancopoulos GD, Wiegand SJ (1999) Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284:1994–1998PubMedCrossRefGoogle Scholar
  18. 18.
    Jeremic B, Milicic B, Grujicic D, Dagovic A, Aleksandrovic J, Nikolic N (2004) Clinical prognostic factors in patients with malignant glioma treated with combined modality approach. Am J Clin Oncol 27:195–204PubMedCrossRefGoogle Scholar
  19. 19.
    Keles GE, Anderson B, Berger MS (1999) The effect of extent of resection on time to tumor progression and survival in patients with glioblastoma multiforme of the cerebral hemisphere. Surg Neurol 52:371–379PubMedCrossRefGoogle Scholar
  20. 20.
    Keles GE, Chang EF, Lamborn KR, Tihan T, Chang CJ, Chang SM, Berger MS (2006) Volumetric extent of resection and residual contrast enhancement on initial surgery as predictors of outcome in adult patients with hemispheric anaplastic astrocytoma. J Neurosurg 105:34–40PubMedCrossRefGoogle Scholar
  21. 21.
    Knisely JP, Rockwell S (2002) Importance of hypoxia in the biology and treatment of brain tumors. Neuroimaging Clin N Am 12:525–536PubMedCrossRefGoogle Scholar
  22. 22.
    Kole M, Rock J (2002) Malignant Glioma Surgery: Complication Avoidance. Neurosurgery Quarterly 12:251–258CrossRefGoogle Scholar
  23. 23.
    Koritzinsky M, Seigneuric R, Magagnin MG, van den Beucken T, Lambin P, Wouters BG (2005) The hypoxic proteome is influenced by gene-specific changes in mRNA translation. Radiother Oncol 76:177–186PubMedCrossRefGoogle Scholar
  24. 24.
    Kowalczuk A, Macdonald RL, Amidei C, Dohrmann G 3rd, Erickson RK, Hekmatpanah J, Krauss S, Krishnasamy S, Masters G, Mullan SF, Mundt AJ, Sweeney P, Vokes EE, Weir BK, Wollman RL (1997) Quantitative imaging study of extent of surgical resection and prognosis of malignant astrocytomas. Neurosurgery 41:1028–1036PubMedCrossRefGoogle Scholar
  25. 25.
    Kreth FW, Berlis A, Spiropoulou V, Faist M, Scheremet R, Rossner R, Volk B, Ostertag CB (1999) The role of tumor resection in the treatment of glioblastoma multiforme in adults. Cancer 86:2117–2123PubMedCrossRefGoogle Scholar
  26. 26.
    Kreth FW, Warnke PC, Scheremet R, Ostertag CB (1993) Surgical resection and radiation therapy versus biopsy and radiation therapy in the treatment of glioblastoma multiforme. J Neurosurg 78:762–766PubMedCrossRefGoogle Scholar
  27. 27.
    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 95:190–198PubMedCrossRefGoogle Scholar
  28. 28.
    Lal A, Peters H, St Croix B, Haroon ZA, Dewhirst MW, Strausberg RL, Kaanders JH, van der Kogel AJ, Riggins GJ (2001) Transcriptional response to hypoxia in human tumors. J Natl Cancer Inst 93:1337–1343PubMedCrossRefGoogle Scholar
  29. 29.
    Laws ER, Parney IF, Huang W, Anderson F, Morris AM, Asher A, Lillehei KO, Bernstein M, Brem H, Sloan A, Berger MS, Chang S, Investigators GO (2003) Survival following surgery and prognostic factors for recently diagnosed malignant glioma: data from the Glioma Outcomes Project. J Neurosurg 99:467–473PubMedCrossRefGoogle Scholar
  30. 30.
    Mendez I, Jacobs P, MacDougall A, Schultz M (2001) Treatment costs for glioblastoma multiforme in Nova Scotia. Can J Neurol Sci 28:61–65PubMedGoogle Scholar
  31. 31.
    Mirimanoff R, Mason W, Van den Bent M (2007) Is long-term survival in glioblastoma possible? Updated results of the EORTC/NCIC Phase III randomized trial on radiotherapy (RT) and concomitant and adjuvant temozolomide (TMZ) versus RT alone [abstract]. Int J Radiat Oncol Biol Phys 69(3 Suppl):S2Google Scholar
  32. 32.
    Navalitloha Y, Schwartz ES, Groothuis EN, Allen CV, Levy RM, Groothuis DR (2006) Therapeutic implications of tumor interstitial fluid pressure in subcutaneous RG-2 tumors. Neuro Oncol 8:227–233PubMedCrossRefGoogle Scholar
  33. 33.
    Pichlmeier U, Bink A, Schackert G, Stummer W, ALA Glioma Study Group (2008) Resection and survival in glioblastoma multiforme: An RTOG recursive partitioning analysis of ALA study patients. Neuro Oncol 10:1025–1034PubMedCrossRefGoogle Scholar
  34. 34.
    A Report of the Medical Research Council Brain Tumour Working Party (1990) Prognostic factors for high-grade malignant glioma: development of a prognostic index. J Neurooncol 9:47–55CrossRefGoogle Scholar
  35. 35.
    Quigley MR, Maroon JC (1991) The relationship between survival and the extent of the resection in patients with supratentorial malignant gliomas. Neurosurgery 29:385–388PubMedCrossRefGoogle Scholar
  36. 36.
    Scott CB, Nelson JS, Farnan NC, Curran WJ Jr, Murray KJ, Fischbach AJ, Gaspar LE, Nelson DF (1995) Central pathology review in clinical trials for patients with malignant glioma. A Report of Radiation Therapy Oncology Group 83–02. Cancer 76:307–313PubMedCrossRefGoogle Scholar
  37. 37.
    Simpson JR, Horton J, Scott C, Curran WJ, Rubin P, Fischbach J, Isaacson S, Rotman M, Asbell SO, Nelson JS, Weinstein AS (1993) 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 26:239–244PubMedCrossRefGoogle Scholar
  38. 38.
    Steltzer KJ, Sauvé KI, Spence AM, Griffin TW, Berger MS (1997) Corpus callosum involvement as a prognostic factor for patients with high-grade astrocytoma. Int J Radiat Oncol Biol Phys 38:27–30PubMedCrossRefGoogle Scholar
  39. 39.
    Stummer W, Novotny A, Stepp H, Goetz C, Bise K, Reulen HJ (2000) Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients. J Neurosurg 93:1003–1013PubMedCrossRefGoogle Scholar
  40. 40.
    Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ, ALA-Glioma Study Group (2006) Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 7:392–401PubMedCrossRefGoogle Scholar
  41. 41.
    Stummer W, Reulen HJ, Meinel T, Pichlmeier U, Schumacher W, Tonn JC, Rohde V, Oppel F, Turowski B, Woiciechowsky C, Franz K, Pietsch T, ALA-Glioma Study Group (2008) Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias. Neurosurgery 62:564–576PubMedCrossRefGoogle Scholar
  42. 42.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996PubMedCrossRefGoogle Scholar
  43. 43.
    van den Bent MJ, Stupp R, Mason W, Mirimanoff RO, Lacombe D, Gorlia T (2005) Impact of extent of resection on overall survival in newly-diagnosed glioblastoma after chemo-irradiation with temozolomide: further analysis of EORTC study 26981 (abstract). Eur J Cancer (Suppl 2):134Google Scholar
  44. 44.
    Vecht CJ, Avezaat CJ, van Putten WL, Eijkenboom WM, Stefanko SZ (1990) 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 53:466–471PubMedCrossRefGoogle Scholar
  45. 45.
    Vuorinen V, Hinkka S, Färkkilä M, Jääskeläinen J (2003) Debulking or biopsy of malignant glioma in elderly people - a randomised study. Acta Neurochir (Wien) 145:5–10CrossRefGoogle Scholar
  46. 46.
    Westphal M, Hilt DC, Bortey E, Delavault P, Olivares R, Warnke PC, Whittle IR, Jääskeläinen J, Ram Z (2003) A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol 5:79–88PubMedGoogle Scholar
  47. 47.
    Westphal M, Ram Z, Riddle V, Hilt D, Bortey E, Executive Committee of the Gliadel Study Group (2006) Gliadel wafer in initial surgery for malignant glioma: long-term follow-up of a multicenter controlled trial. Acta Neurochir (Wien) 148:269–275CrossRefGoogle Scholar
  48. 48.
    Whittle IR (2002) Surgery for gliomas. Curr Opin Neurol 15:663–669PubMedCrossRefGoogle Scholar
  49. 49.
    Winger MJ, Macdonald DR, Cairncross JG (1989) Supratentorial anaplastic gliomas in adults. The prognostic importance of extent of resection and prior low-grade glioma. J Neurosurg 71:487–493PubMedCrossRefGoogle Scholar
  50. 50.
    Zagzag D, Zhong H, Scalzitti JM, Laughner E, Simons JW, Semenza GL (2000) Expression of hypoxia-inducible factor 1 alpha in brain tumors: association with angiogenesis, invasion, and progression. Cancer 88:2606–2618PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Walter Stummer
    • 1
    Email author
  • Martin J. van den Bent
    • 2
  • Manfred Westphal
    • 3
  1. 1.Department of NeurosurgeryUniversity of MünsterMünsterGermany
  2. 2.Neuro-Oncology Unit, Daniel den Hoed Cancer CenterErasmus University HospitalRotterdamThe Netherlands
  3. 3.Department of NeurosurgeryUniversitätsklinikum EppendorfHamburgGermany

Personalised recommendations