Acta Neurochirurgica

, 151:109 | Cite as

Editorial: on the road to multi-modal and pluri-disciplinary treatment of glioblastomas



Despite major advances in the management of malignant gliomas of which glioblastomas represent the ultimate grade of malignancy, they remain incurable. Indeed, glioblastoma patients have a median survival expectancy of only 14 months on the current standard treatment of surgical resection to the extent which is feasible, followed by adjuvant radiotherapy plus temozolomide given concomitantly with and after radiotherapy (Lefranc et al., J Clin Oncol 23:2411–2422, 2005; Expert Rev Anticancer Ther 6:719–732, 2006; Stummer et al., Neurosurgery 62:564–576, 2008). Accordingly, the present editorial discusses (1) the high cell motility and resistance to apoptosis which characterise glioblastoma growth and malignancy with respect to the failure of conventional therapy, (2) ways to overcome apoptosis resistance and the real hope offered by temozolomide, (3) targeted chemotherapeutic approaches and the disappointing results obtained in monotherapy but their potential in combination therapy, (4) anti-migratory strategies that could supplement conventional therapy notably by inhibiting a new target; the α1 subunit of the sodium pump, (5) dendritic cell therapy, (6) cancer stem cell targeting and finally (7) topical therapies and new surgical approaches for more radical resection which could be used to complement multi-modal treatments within a multi-disciplinary approach.


Multi-modal Pluri-disciplinary treatment of glioblastomas 

Malignant gliomas are associated with a dismal prognosis because glioma cells can actively migrate through the narrow extra-cellular spaces in the brain, often travelling relatively long distances, making them elusive targets for effective surgical management [13, 18]. There is therefore a need for more definitive non-invasive tumour visualisation and intra-operative monitoring to permit more radical resection. Clinical and experimental data have also demonstrated that invasive malignant glioma cells show decreased proliferation rates and a relative resistance to apoptosis (type I programmed cell death) compared to the highly cellular centre of the tumour, and this may contribute to their resistance to conventional pro-apoptotic chemotherapy and radiotherapy [13]. However, as recently indicated by both Okada and Mak [24] and ourselves [13, 16], despite resistance to apoptosis being closely linked to tumourigenesis, tumour cells can still be induced to die by non-apoptotic mechanisms such as necrosis, senescence, autophagy (type II programmed cell death) and mitotic catastrophe. Provoking autophagic cell death may therefore be used to overcome apoptosis resistance. Indeed part of temozolomide’s cytotoxic activity is exerted through pro-autophagic processes, at least in glioblastoma cells, via the formation of O6-methylguanine in DNA, which mispairs with thymine during subsequent cycles of DNA replication [10, 16]. Glioma cells thus respond to temozolomide by undergoing G2/M arrest but will ultimately die from autophagy [10, 16]. Temozolomide’s cytotoxic activity is also in part due to the induction of late apoptosis [28]. These actions of the compound are not contradictory because at a molecular level, apoptotic and autophagic response machineries share common pathways that either link or polarise cellular responses [14].

Hegi et al. [8] and Chinot et al. [2] have shown that patients who have glioblastomas containing a methylated O6-methylguanine-DNA methyltransferase (MGMT) promoter benefit from temozolomide, while those who do not are less responsive.

A prognostic factor analysis of a European Organisation for Research and Treatment of Cancer and the National Cancer Institute of Canada trial [6] revealed that in patients who had tumours resected, were assigned temozolomide and radiotherapy, had had MGMT promoter status defined indicating methylated MGMT and who had a better performance status and a mini-mental state examination score of 27 or higher, were associated with improved survival [6]. Therefore, stratifying by MGMT promoter methylation status should be mandatory in all glioblastoma trials that use alkylating chemotherapy [6].

Resistance to apoptosis results from changes at the genomic, transcriptional and post-transcriptional level of proteins, protein kinases and their transcriptional factor effectors. The PTEN/ PI3-K/Akt /mTOR/NF-κB and the Ras/Raf/MEK/ERK signalling cascades play critical roles in the regulation of gene expression and prevention of apoptosis [13, 14, 16]. Components of these pathways are mutated or aberrantly expressed in human cancer, notably glioblastomas. Monoclonal antibodies and low molecular weight kinase inhibitors of these pathways are the most common classes of agents in targeted cancer treatment. Most clinical trials of these agents as monotherapies have failed to demonstrate survival benefit [32] and responses seem to be related to co-expression of epidermal growth factor receptor (EGFR) deletion mutant variant III and tumour-suppressor protein PTEN; markers that could potentially be used as predictive factors for such therapies [22]. To date, the most positive results with targeted therapy remain the high response rates with bevacizumab and irinotecan in a phase II trial for recurrent malignant gliomas [25]. The monoclonal antibody bevacizumab targets vascular endothelial growth factor (VEGF), the paracrine stimulator of angiogenesis [11, 25]. An update on survival from this trial in recurrent malignant gliomas was presented at the ASCO annual meeting in May 2008 [37]. The overall response rate for both grade III and IV was 59% (grade III, 61% and grade IV, 57%). The 6 months period free survival and overall survival for grade III were 59% and 79% and for grade IV 43% and 74%, respectively. For grade III and IV patients, the 2 year overall survival rates were 33% and 15%, respectively [37]. Therefore, the combination of bevacizumab and irinotecan provides a clinically meaningful treatment option for patients with recurrent malignant gliomas. However, combination of anti-angiogenic drugs with more potent cytotoxics will probably be necessary. Additionally, it is imperative that clinical trials which hitherto have focused largely on the intrinsic response of glioma cells to new targeted therapies, move to novel designs which are biomarker-guided to ensure better efficacy.

Another way to potentially overcome apoptosis resistance is to decrease the migration of malignant glioma cells in the brain, which should then restore a certain level of sensitivity to pro-apoptotic drugs. We have recently verified this concept in vivo on combining temozolomide with two distinct anti-migratory strategies for the treatment of athymic mice bearing a human model of glioblastoma in their brains [15, 20]. Drivers of glioma invasion include autocrine/paracrine signals. Malignant gliomas have been shown to release glutamate, which kills surrounding brain cells, creating room for tumour expansion [21]. Moreover, glioma cells are “self-propelled” and are able to adjust their shape and volume rapidly as they invade the brain parenchyma. Essential to this process is the activity of chloride channels, anion transport mechanisms [27] and aquaporins [7]. The sodium pump is another ion transporter which in addition to exchanging cations is also directly involved in the migration of cancer cells in general and of glioma cells in particular [17, 23, 33]. Accordingly, we have been the first to propose the sodium pump and more specifically its α1 subunit, which is highly expressed in glioma cells compared to normal brain tissues, as a new target in the context of malignant glioma treatment. By inhibiting sodium pump activity, it has been possible to markedly impair both glioblastoma cell proliferation and migration (through a disorganisation of the actin cytoskeleton), with marked features of autophagy as the terminal outcome [17]. A new compound targeting the α1 subunit of the sodium pump will enter Phase I clinical trials in the summer of 2008 [17].

The discovery of dendritic cells, the most potent antigen presenting cells to initiate specific immune responses and the possibility of producing them ex vivo have given rise to new protocols of active immunotherapy against gliomas [9]. Phase I clinical trials [3] have shown that vaccination using patients’ peripheral dendritic cells pulsed with tumour lysates, cell fusions, RNA and/or peptides can elicit anti-tumour immune responses against central nervous system neoplasms. Although the currently available clinical data are too limited to arrive at any firm conclusions concerning its effectiveness, the advantages of dendritic cell-based immunotherapy and its documented safety and feasibility are stimulating further development and testing.

Cancer stem cells are thought to be crucial for tumourigenesis [31]. Gilbertson and Rich [5] recently reviewed data showing that the stem cells of glioblastomas are found in intimate contact with aberrant tumour vasculature. These cancer stem cells can secrete diffusible factors such as VEGF, which recruit aberrant tumour vasculature to the niche. In turn, tumour vasculature and other glioma cells secrete factors that maintain aberrant cancer stem cell self-renewal. The targeting of such stem cells could thus present another therapeutic option.

Control of glioblastomas by topical therapy applied to the resection cavity during surgery may reduce the rate of local failure and increase the time required for localised tumour progression. These agents function inside tumour cells with microscopic and sub-microscopic precision. The only FDA-approved drug delivery system consists of carmustine (BCNU)-impregnated polymers in the form of wafers (GliadelR) [38]. These wafers are implanted into the tumour cavity during surgery and slowly release the active drug. In a Phase III trial, median survival in a BCNU wafer-treated glioblastoma group was longer (13.5 months) than in a placebo wafer-treated glioblastoma group (11.4 months). However, the comparison of the survival curves by the Kaplan–Meier method showed that the difference was not statistically significant (stratified log-rank statistics). The significance of the treatment was observed only after additional analysis [38]. Furthermore, this result was similar to the benefit derived from systemic adjuvant nitrosoureas [34]. However, to date no studies have directly compared the efficacy of systemic versus topical chemotherapy in glioblastoma. One promising surgical technique for the delivery of drugs directly into the brain parenchyma involves a convection-enhanced delivery system (CED) [30]. CED uses positive pressure infusion to generate a pressure gradient that optimises the distribution of macromolecules within the tumour and the surrounding tissue. Target tissue anatomy and catheter position are critical parameters in optimising drug delivery [30]. Using this surgical technique, a recombinant toxin (TP-38) targeting EGFR was administered to 20 patients with recurrent malignant brain tumours [29]. CED delivered intra-cerebral TP-38 was well tolerated and produced some durable radiographic responses at doses of ≤100 ng/ml [29]. However, the potential efficacy of drugs delivered by this technique may be severely constrained by ineffective infusion in many patients.

In conclusion, more fundamental information on the nature of these cancers in terms of molecular biology is being addressed through the auspices of a European project, resulting in the creation of a malignant glioma database and tissue bank and through ongoing research activities being undertaken by specified groups [1, 4].

However, at present it remains unclear how best to integrate new discoveries in glioma molecular biology into clinical practice [12]. Recent studies have supported the concept that malignant gliomas might to be seen as an orchestration of cross-talk between cancer cells, their micro-environment, the vasculature and cancer stem cells.

Furthermore, the oncogenetic process in such tumours is driven by several signalling pathways that are differentially activated or silenced with both parallel and converging complex interactions. Therefore, it is difficult to identify prevalent targets that act as key promoters of oncogenesis that can be successfully addressed by novel agents [26]. A better strategy may be to identify common molecular abnormalities that are targets of more universally applicable therapies. Thus, novel successes in the fight against certain devastating cancers might be achieved by the combination of pro-autophagic drugs such as temozolomide with mTOR, class I PI3-K or Akt inhibitors or with endoplasmic reticulum stress inhibitors or anti-migratory drugs as adjuvant chemotherapies [14, 19]. It is probable that the improved treatment of these invasive brain tumours will depend on the blending of cocktails of targeted agents that are tailored for individual patients.

Finally, it is to be further hoped that novel therapies derived from better cellular and molecular understanding of glial tumourigenesis and of the interaction between these cancers and their micro-environment, and advances in non-invasive diagnosis including the visualisation of tumour tissue by fluorescent methods [35] and intra-operative monitoring permitting more radical tumour resection and adjuvant treatment, will significantly improve the clinical outcome of these devastating lesions.



We apologise to those authors whose work could not be cited owing to space limitations.


  1. 1.
    Bauchet L, Rigau V, Mathieu-Daudé H, Figarella-Branger D, Hugues D, Palusseau L, Bauchet F, Fabbro M, Campello C, Capelle L, Durand A, Trétarre B, Frappaz D, Henin D, Menei P, Honnorat J, Segnarbieux F (2007) French brain tumour data bank: methodology and first results on 10,000 cases. J Neuro-Oncol 84:189–199CrossRefGoogle Scholar
  2. 2.
    Chinot OL, Barrié M, Fuentes S, Eudes N, Lancelot S, Metellus P, Muracciole X, Braguer D, Ouafik L, Martin PM, Dufour H, Figarella-Branger D (2007) Correlation between O6-methylguanine-DNA methyltransferase and survival in inoperable newly diagnosed glioblastoma patients treated with neoadjuvant temozolomide. J Clin Oncol 25:1470–1475PubMedCrossRefGoogle Scholar
  3. 3.
    de Vleeschouwer S, Rapp M, Sorg RV, Steiger HJ, Stummer W, van Gool S, Sabel M (2006) Dendritic cell vaccination in patients with malignant gliomas: current status and future directions. Neurosurgery 59:988–999PubMedGoogle Scholar
  4. 4.
    Figarella-Branger D, Colin C, Chinot O, Nanni I, Baeza N, Fina F, Tong S, Eudes N, Quilichini B, Romain S, Metellus P, Fuentes S, Barrié M, Boucard C, Fraslon C, Bonavita MJ, Martin PM, Ouafik L (2006) AP-HM tumour tissue bank: molecular signature of gliomas. Med Sci (Paris) 22(Spec No 1):54–59Google Scholar
  5. 5.
    Gilberson RJ, Rich JN (2007) Making a tumour’s bed: glioblastoma stem cells and the vascular niche. Nat Rev Cancer 7:733–736CrossRefGoogle Scholar
  6. 6.
    Gorlia T, van den Bent MJ, Hegi ME, Mirimanoff RO, Weller M, Cairncross JG, Eisenhauer E, Belanger K, Brandes AA, Allgeier A, Lacombe D, Stupp R (2008) Gorlia nomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3. Lancet Oncol 9:29–38PubMedCrossRefGoogle Scholar
  7. 7.
    Hayashi Y, Edwards NA, Proescholdt MA, Oldfield EH, Merrill MJ (2007) Regulation and function of aquaporin-1 in glioma cells. Neoplasia 9:777–787PubMedCrossRefGoogle Scholar
  8. 8.
    Hegi ME, Diserens AC, Godard S, Dietrich PY, Regli L, Ostermann S, Otten P, Van Melle G, de Tribolet N, Stupp R (2004) Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res 10:1871–1874PubMedCrossRefGoogle Scholar
  9. 9.
    Jouanneau E, Poujol D, Caux C, Belin MF, Blay JY, Puisieux I, Club de Neuro-Oncologie de la Société Française de Neurochirurgie (2006) Dendritic cells and gliomas: a hope in immunotherapy? Neurochirurgie 52:555–570PubMedCrossRefGoogle Scholar
  10. 10.
    Kanzawa T, Germano IM, Komata T, Ito H, Kondo Y, Kondo S (2004) Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. Cell Death Differ 11:448–457PubMedCrossRefGoogle Scholar
  11. 11.
    Lamszus K, Heese O, Westphal M (2004) Angiogenesis-related growth factors in brain tumours. Cancer Treat Res 117:169–190PubMedGoogle Scholar
  12. 12.
    Lassman AB, Holland EC (2007) Incorporating molecular tools into clinical trials and treatment for gliomas? Curr Opin Neurol 20:708–711PubMedGoogle Scholar
  13. 13.
    Lefranc F, Brotchi J, Kiss R (2005) Possible future issues in the treatment of glioblastomas: special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis. J Clin Oncol 23:2411–2422PubMedCrossRefGoogle Scholar
  14. 14.
    Lefranc F, Facchini V, Kiss R (2007) Pro-autophagic drugs: a novel means to combat apoptosis-resistant cancers. The Oncologist 12:1395–1403PubMedCrossRefGoogle Scholar
  15. 15.
    Lefranc F, James S, Camby I, Gaussin JF, Darro F, Brotchi J, Gabius HJ, Kiss R (2005) Combined cimetidine and temozolomide, compared with temozolomide alone: significant increases in survival in nude mice bearing U373 human glioblastoma multiform orthotopic xenografts. J Neurosurg 102:706–714PubMedGoogle Scholar
  16. 16.
    Lefranc F, Kiss R (2006) Autophagy, the Trojan horse to combat glioblastomas. Neurosurg Focus 20:E7PubMedCrossRefGoogle Scholar
  17. 17.
    Lefranc F, Mijatovic T, Kondo Y, Sauvage S, Roland I, Krstic D, Vasic V, Gailly P, Kondo S, Blanco G, Kiss R (2008) Targeting the α1 subunit of the sodium pump (the Na+/K+-ATPase) to combat glioblastoma cells. Neurosurgery 62:211–221PubMedGoogle Scholar
  18. 18.
    Lefranc F, Sadeghi N, Camby I, Metens T, Dewitte O, Kiss R (2006) Present and potential future issues in glioblastoma treatment. Expert Rev Anticancer Ther 6:719–732PubMedCrossRefGoogle Scholar
  19. 19.
    Le Mercier M, Lefranc F, Mijatovic T Debeir O, Haibe-Kains B, Bontempi G, Decaestecker C, Kiss R, Mathieu V (2008) Evidence of galectin-1 involvement in glioma chemoresistance. Tox Appl Pharm 229:172–183CrossRefGoogle Scholar
  20. 20.
    Le Mercier M, Mathieu V, Haibe-Kains B, Bontempi G, Mijatovic T, Decaestecker C, Kiss R, Lefranc F (2008) Knocking down galectin-1 in human Hs683 glioblastoma cells impairs both angiogenesis through ORP150 depletion and endoplasmic reticulum stress responses. J Neuropathol Exp Neurol 67:456–469PubMedGoogle Scholar
  21. 21.
    Lyons SA, Chung WJ, Weaver AK, Oqunrinu T, Sontheimer H (2007) Autocrine glutamate signaling promotes glioma cell invasion. Cancer Res 67:9463–9471PubMedCrossRefGoogle Scholar
  22. 22.
    Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ, Lu KV, Yoshimoto K, Huang JH, Chute DJ, Riggs BL, Horvath S, Liau LM, Cavenee WK, Rao PN, Beroukhim R, Peck TC, Lee JC, Sellers WR, Stokoe D, Prados M, Cloughesy TF, Sawyers CL, Mischel PS (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353:2012–2024PubMedCrossRefGoogle Scholar
  23. 23.
    Mijatovic T, Van Quaquebeke E, Delest B, Debeir O, Darro F, Kiss R (2007) Cardiotonic steroids on the road to anti-cancer therapy. Biochim Biophys Acta 1776:32–57PubMedGoogle Scholar
  24. 24.
    Okada H, Mak TW (2004) Pathways of apoptotic and non-apoptotic death in tumour cells. Nature Rev Cancer 4:592–603CrossRefGoogle Scholar
  25. 25.
    Omuro AM, Delattre JY (2007) Editorial: what is new in the treatment of gliomas? Curr Opin Neurol 20:704–707PubMedGoogle Scholar
  26. 26.
    Omuro AM, Faivre S, Raymond E (2007) Lessons learned in the development of targeted therapy for malignant gliomas. Mol Cancer Ther 6:1909–1919PubMedCrossRefGoogle Scholar
  27. 27.
    Ransom CB, O’Neal JT, Sontheimer H (2001) Volume-activated chloride currents contribute to the resting conductance and invasive migration of human glioma cells. J Neurosci 21:7674–7683PubMedGoogle Scholar
  28. 28.
    Roos WP, Batista LF, Naumann SC, Wick W, Weller M, Menck CF, Kaina B (2007) Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine. Oncogene 26:186–197PubMedCrossRefGoogle Scholar
  29. 29.
    Sampson JH, Akabani G, Archer GE, Berger MS, Coleman RE, Friedman AH, Friedman HS, Greer K, Herndon Ii JE, Kunwar S, McLendon RE, Paolino A, Petry NA, Provenzale JM, Reardon DA, Wong TZ, Zalutsky MR, Pastan I, Bigner DD (2008) Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumours. Neuro Oncol 10:320–329PubMedCrossRefGoogle Scholar
  30. 30.
    Sampson JH, Brady ML, Petry NA, Croteau D, Friedman AH, Friedman HS, Wong T, Bigner DD, Pastan I, Puri RK, Pedain C (2007) Intracerebral infusate distribution by convection-enhanced delivery in humans with malignant gliomas: descriptive effects of target anatomy and catheter positioning. Neurosurgery 60(2 Suppl 1):ONS89–ONS98PubMedGoogle Scholar
  31. 31.
    Sanai N, Alvarez-Buylla A, Berger M (2005) Neural stem cells and the origin of gliomas. N Engl J Med 353:811–822PubMedCrossRefGoogle Scholar
  32. 32.
    Sathornsumetee S, Readon DA, Desjardins A, Quinn JA, Vredenburgh JJ, Rich JN (2007) Molecularly targeted therapy for malignant glioma. Cancer 110:13–24PubMedCrossRefGoogle Scholar
  33. 33.
    Senner V, Schmidtpeter S, Braune S, Püttmann S, Thanos S, Bartsch U, Schachner M, Paulus W (2003) AMOG/beta2 and glioma invasion: does loss of AMOG make tumour cells run amok? Neuropathol Appl Neurobiol 29:370–377PubMedCrossRefGoogle Scholar
  34. 34.
    Stewart LA (2002) Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359:1011–1018PubMedCrossRefGoogle Scholar
  35. 35.
    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
  36. 36.
    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 (2005) European Organisation for Research and Treatment of Cancer Brain Tumour and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group: radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996 (Mar 10)PubMedCrossRefGoogle Scholar
  37. 37.
    Wagner SA, Desjardins A, Reardon DA, Marcello J, Herndon JE II, Quinn JA, Rich JN, Sathornsumetee S, Friedman HS, Vredenburgh JJ (2008) Update on survival from the original phase II trial of bevacizumab and irinotecan in recurrent malignant gliomas. J Clin Oncol 26:(May 20 suppl; abstr 2021)Google Scholar
  38. 38.
    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 5:79–88PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Department of Neurosurgery Erasme University Hospital, Laboratory of Toxicology, Institute of PharmacyFree University of Brussels (U.L.B.)BrusselsBelgium

Personalised recommendations