User Tools

Site Tools


glioblastoma_multiforme_treatment

Glioblastoma multiforme treatment

Not good candidates for surgery

Extensive dominant lobe glioblastoma

Butterfly glioblastoma.

Glioblastoma in elderly patients

Karnofsky performance score < 70

Multicentric glioblastoma.


Since 2005, state-of-the-art therapy in glioblastoma multiforme consists of maximal safe resection followed by combined radiotherapy and chemotherapy with temozolomide, according to Stupp regimen 1) , particularly in patients that demonstrate MGMT promoter methylation. At recurrence there is no consensus as to the standard of care as no therapeutic options have produced substantial survival benefit 2).

The last major advance in glioblastoma multiforme treatment was the introduction of temozolomide in 1999.

Although overall survival (OS) is the standard for determining GBM treatment efficacy, using OS as an endpoint when studying new therapeutic strategies can be problematic because of potential influence of therapies prior to or subsequently following the therapy being studied. For example, it is difficult to definitively conclude that bevacizumab has no efficacy in GBM when a large percentage of patients in the placebo arms in both III trials studying efficacy of bevacizumab (i.e. AVAglio and RTOG 0825) eventually crossed over and received bevacizumab (31% in AVAglio) 3) and 48% in RTOG-0825 4). If bevacizumab increased OS when given at any time during treatment, we may expect both treatment arms to have similar median OS since most patients eventually were treated with bevacizumab, disguising any therapeutic effects of the drug. Together, these results suggest OS may not be a suitable endpoint when studying new therapeutics or when there is a high chance of cross over in the control arm 5).

To overcome the limitations associated with using OS as the primary endpoint in studies involving new therapeutics, progression free survival (PFS) and objective response rate (ORR) should be considered important end points 6).

Surgery

Radiochemotherapy

The recommended treatment for O6-methylguanine-DNA methyltransferase (MGMT) promoter unmethylated glioblastoma (GBM) is radiation therapy with concurrent/adjuvant temozolomide (TMZ). However, it is well known that the clinical benefit from TMZ is lower in these patients.

Waiting time after surgery and overall time data do not indicate a relevant time factor in the treatment of glioblastoma multiforme in a large contemporary single-centre cohort. Although a study was limited by its retrospective nature, its results indicate that short delays of postoperative radiochemotherapy, e.g. for screening of a patient for a clinical trial, may be uncritical 7).

Glioblastoma multiforme antiangiogenic therapy

Future Direction

GBM is one of the most active areas of research. Significant efforts are being made to look beyond basic morphology.

The retrospective analysis of the AVAglio trial reported 4.3 months incremental survival in the proneural glioblastoma subgroup 8).

Hence, patient selection and personalization of treatment should be done with more appropriateness in future. However, the complexity of performing these molecular assays in the lab appears to be labor and cost intensive and may limit routine use. In this context, a simplified model incorporating MGMT methylation, human telomerase (TERT) methylation, and IDH mutation may be formulated to dictate the optimum treatment. Treatment personalization may further be refined with the incorporation of these molecular factors along with patient factors like age, performance status, etc., (molecular-clinical profiling). A Large number of newer drugs and virus based therapy are being evaluated in different phase III and phase II trials as well.

The subventricular zone (SVZ) forms the lining the lateral ventricles and represents the origin of neural and some cancer stem cells. Gupta et al. reported on dose volume parameters of SVZ in 40 patients of adult GBM. Dose to the ipsilateral SVZ dose was found to be an independent predictor of survival in multivariate analysis in this study. Although a novel finding, this requires further validation in a prospective study 9).


Citalopram with standard RT and Temozolomide TMZ

RT alone versus RT and TMZ for elderly

CCNU/TMZ combination therapy versus standard TMZ (MGMT-methylated cases)

Standard RT plus concomitant and adjuvant OSAG 101 (Theraloc°) plusTMZ versus standard RT plus concomitant and adjuvant TMZ

Rindopepimut/GM-CSF with adjuvantTMZ in EGFvall-positive GBM CDX110-04

DCVax-L, autologous dendritic cells pulsed with tumor Iysate antigen 020221

Adjuvant TMZ with or without Interferon-alpha NCT 01765088

Adjuvant RT and temozolomide with or without Velipari b NCT 02152982

CCNU - Lomustine; TMZ -Temozolomide; MGMT - O‘-methylguanine—DNA methyltransferase; GBM - Glioblastoma multiforme; RT - Radiotherapy,-

GM-CSF -Granulocyte-monocyte colony stimulating factor,- EGFRvIII - Epidermal growth factor receptor variant III.

Immunotherapy

1)
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. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. PubMed PMID: 15758009.
2)
Weller M, Cloughesy T, Perry JR, Wick W. Standards of care for treatment of recurrent glioblastoma–are we there yet? Neuro Oncol. 2013 Jan;15(1):4-27. doi: 10.1093/neuonc/nos273. Epub 2012 Nov 7. Review. PubMed PMID: 23136223; PubMed Central PMCID: PMC3534423.
3)
Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):709-22. doi: 10.1056/NEJMoa1308345. PubMed PMID: 24552318.
4)
Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):699-708. doi: 10.1056/NEJMoa1308573. PubMed PMID: 24552317; PubMed Central PMCID: PMC4201043.
5)
Ellingson BM, Wen PY, Cloughesy TF. Modified Criteria for Radiographic Response Assessment in Glioblastoma Clinical Trials. Neurotherapeutics. 2017 Apr;14(2):307-320. doi: 10.1007/s13311-016-0507-6. Review. PubMed PMID: 28108885; PubMed Central PMCID: PMC5398984.
6)
Lamborn KR, Yung WK, Chang SM, Wen PY, Cloughesy TF, DeAngelis LM, Robins HI, Lieberman FS, Fine HA, Fink KL, Junck L, Abrey L, Gilbert MR, Mehta M, Kuhn JG, Aldape KD, Hibberts J, Peterson PM, Prados MD; North American Brain Tumor Consortium. Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro Oncol. 2008 Apr;10(2):162-70. doi: 10.1215/15228517-2007-062. Epub 2008 Mar 4. PubMed PMID: 18356283; PubMed Central PMCID: PMC2613818.
7)
Seidlitz A, Siepmann T, Löck S, Juratli T, Baumann M, Krause M. Impact of waiting time after surgery and overall time of postoperative radiochemotherapy on treatment outcome in glioblastoma multiforme. Radiat Oncol. 2015 Aug 16;10(1):172. PubMed PMID: 26276734.
8)
Sandmann T, Bourgon R, Garcia J, Li C, Cloughesy T, Chinot OL, et al. Patients with proneural glioblastoma may derive overall survival benefit from the addition of bevacizumab to first line radiotherapy and temozolomide: Retrospective analysis of the AV Aglio trial. J Clin Oncol. 2015:pii–JCO.2015.61.5005. Epub ahead of print.
9)
Mallick S, Gandhi AK, Rath GK. Therapeutic approach beyond conventional temozolomide for newly diagnosed glioblastoma: Review of the present evidence and future direction. Indian J Med Paediatr Oncol. 2015 Oct-Dec;36(4):229-37. doi: 10.4103/0971-5851.171543. Review. PubMed PMID: 26811592; PubMed Central PMCID: PMC4711221.
glioblastoma_multiforme_treatment.txt · Last modified: 2018/09/20 08:41 by administrador