User Tools

Site Tools


glioblastoma_outcome

Glioblastoma outcome

High grade gliomas (HGGs) have remained particularly difficult to treat with no noteworthy improvements reported in the past years. This lack of progress is partly because of the invasive nature displayed by HGGs, which are able to easily infiltrate the surrounding parenchyma, making complete surgical resection impossible. Additionally, HGGs present a significant number of genetic and epigenetic alterations with an enormous impact on heterogeneity, inter and intracellular signaling, immune system dampening, resistance to treatment and proliferation. The current therapeutic standard, first established in 2005, has a low therapeutic index and presents a large number of side effects 1).

Amongst some the most important causes for the poor outcome are the immune privileged status of the brain and the immune suppressing attributes of the tumor and its microenvironment. Initially, it was thought that the Blood Brain Barrier was the reason behind this phenomenon; however, this theory has been disproven 2) 3) 4).


Glioblastoma patients who were readmitted within 30 days had significantly shorter survival than nonreadmitted patients. Future studies that attempt to decrease readmissions and evaluate the impact of reducing readmissions on patient outcomes are needed 5).


Liang et al., demonstrated that high SII and low AGR values may serve as promising prognostic markers to identify HGG patients with poor prognosis 6).


The outcome of patients with anaplastic gliomas varies considerably depending on single molecular markers, such as mutations of the isocitrate dehydrogenase (IDH) genes, as well as molecular classifications based on epigenetic or genetic profiles.

Despite advances in treatment, the median patient survival is 12 to 15 months 7).

see Recurrent high grade glioma.

Malignant brain tumor, including the most common type glioblastoma, are histologically heterogeneous and invasive tumors known as the most devastating neoplasms with high morbidity and mortality. Despite multimodal treatment including surgery, radiotherapy, chemotherapy, and immunotherapy, the disease inevitably recurs and is fatal. This lack of curative options has motivated researchers to explore new treatment strategies and to develop new drug delivery systems (DDSs); however, the unique anatomical, physiological, and pathological features of brain tumors greatly limit the effectiveness of conventional chemotherapy 8).

The current standard of care in glioblastoma is not very effective, resulting in tumor recurrence with patients rarely surviving over 2 years. This tumor recurrence is attributed to the presence of chemo and radiation resistant glioma stem cells (GSCs).

The hallmark of glioblastoma multiforme (GBM) is its penchant for relentless progression. The median progression free survival (PFS) is 4.4 to 8.4 months in patients with newly diagnosed GBM following the current standard of care, safely obtained maximal resection at initial surgery followed by concomitant temozolomide (TMZ) and radiotherapy and adjuvant TMZ.


Glioblastoma multiforme is the most aggressive type of primary brain tumors, but there is a small percentage of patients who have a long-term survival and some exceptional cases who survive decades after surgical removal of tumor 9)

Outcome remains dismal despite advances in therapeutic interventions including chemotherapy, radiotherapy and surgical resection.

Currently, the best that can be offered is a modest 14-month overall median survival in patients undergoing maximum safe resection plus adjuvant chemoradiotherapy. 10).

Less than 10% of patients live longer than 5 years from diagnosis 11).

Prognostic factors involved in survival include age, performance status, grade, specific markers (MGMT methylation, mutation of IDH1, IDH2 or TERT, 1p19q codeletion, overexpression of EGFR, etc.) and, likely, the extent of resection. Certain adjuncts to surgery, especially cortical mapping and 5-ALA fluorescence, favor higher rates of gross total resection with apparent positive impact on survival. Recurrent tumors can be offered re-intervention, participation in clinical trials, anti-angiogenic agent or local electric field therapy, without an evident impact on survival. Molecular-targeted therapies, immunotherapy and gene therapy are promising tools currently under research 12).


Kawano et al., observed a gradual improvement in glioblastoma multiforme outcome, presumably because of improvements in therapeutic modalities for surgery, anticancer agents, and radiation, but the efficacy of CyberKnife-SRT remains unclear 13)

The best glioblastoma multiforme outcome is observed in patients with complete resection of the contrast enhancement tumor (CRET).

However, removal of the final 1%–2% of the contrast-enhancing tumor carries not only the greatest impact from an oncological point of view but also the greatest risk for neurological impairment, especially in glioblastomas adjacent to motor eloquent areas.

A larger prospective analysis that compares CyberKnife SRS and hypofractionated radiotherapy to focal external beam radiation therapy EBRT is warranted 14).

Quality of life

Outcome in elderly patients

Prognostic factors

Prognostic markers in glioblastoma multiforme is complex. In addition to previously recognized prognostic variables such as age and Karnofsky performance score, tumor size, total resection and proliferative index were identified as predictors of survival in a series of patients with glioblastoma multiforme 15).

Many reports on glioblastoma multiforme discuss the prognostic impact of anatomical features such as cysts, necrotic changes, extent of edema or subependymal spread of tumor cells.

A merely anatomical analysis of the glioblastoma growth pattern cannot reliably provide prognostic information. The occurrence of most recurrences next to the resection margin and the high percentage of growing residual tumors underline the importance of complete resections 16).

Geometry

Patients with tumours having small geometric heterogeneity and/or spherical rim widths had significantly better prognosis. These imaging biomarkers have a strong individual and combined prognostic value for GBM patients 17) 18).


Multi-channel MR image derived texture features, tumor shape, and volumetric features, and patient age were obtained for 163 GBM patients. In order to assess the impact of tumor shape features on OS prediction, two feature sets, with and without tumor shape features, were created. For the feature set with tumor shape features, the mean prediction error (MPE) was 14.6 days and its 95% confidence interval (CI) was 195.8 days. For the feature set excluding shape features, the MPE was 17.1 days and its 95% CI was observed to be 212.7 days. The coefficient of determination (R2) value obtained for the feature set with shape features was 0.92, while it was 0.90 for the feature set excluding shape features. Although marginal, inclusion of shape features improves OS prediction in GBM patients. The proposed OS prediction method using regression provides good accuracy and overcomes the limitations of GBM OS classification, like choosing data-derived or pre-decided thresholds to define the OS groups. Graphical abstract Two feature sets: with and without tumor shape features were extracted from T1-weighted contrast-enhanced, T2-weighted and FLAIR MRI. These feature sets were analyzed using the Mean Prediction Error (MPE) and its 95% Confidence Interval (CI) obtained from the Bland-Altman plot, along with the coefficient of determination (R2) value to assess the impact of tumor shape features on overall survival prediction of glioblastoma multiforme patients 19).

Neurologic status

Neurologic status is one of the major prognostic factor; however, no consensus exists on a clinical index for predicting patient outcomes.

One proposed neurologic index enables significantly identifying glioblastoma patients receiving tumor resection with poor outcomes, independent of other common prognostic factors. Using the index provides a preoperative predictor of prognosis in glioblastoma patients receiving tumor resection 20).

In glioblastoma, progression-free survival (PFS) and overall survival (OS) are strongly correlated, indicating that PFS may be an appropriate surrogate for OS. Compared with OS, PFS offers earlier assessment and higher statistical power at the time of analysis 21).

Prior studies that have reported only the readmissions back to index hospitals are likely underestimating the true 30-day readmission rate. GBM patients who were readmitted within 30 days had significantly shorter survival than nonreadmitted patients. Future studies that attempt to decrease readmissions and evaluate the impact of reducing readmissions on patient outcomes are needed 22).

Several clinical studies have reported that valproic acid could prolong survival of GBM patients. However, the results of these studies are inconsistent.

A bibliographic search was performed in the EMBASE, MEDLINE, ClinicalTrials.gov and Cochrane Central Register of the Controlled Trials databases to identify potentially relevant articles or conference abstracts that investigated the effects of VPA on the outcome of glioma patients. Five observational studies were included.

Pooled estimates of the hazard ratio (HR) and 95% confidence intervals (CI) were calculated. The meta-analysis confirmed the benefit of using VPA (HR, 0.56; 95% CI, 0.44-0.71). Sub-group analysis shows that patients treated with VPA had a hazard ratio of 0.74 with a 95% confidence interval of 0.59-0.94 vs. patients treated by other-AEDs and a hazard ratio of 0.66 with a 95% confidence interval of 0.52-0.84 vs. patients treated by administration of non-AEDs. No heterogeneity was observed in the subset analysis.

The results suggest that glioblastoma patients may experience prolonged survival due to VPA administration. Sub-analysis confirmed the benefit of VPA use compared to a non-AEDs group and an other-AEDs group. Further RCTs of this subject should be performed 23).


The surface regularity obtained from high-resolution contrast-enhanced pretreatment volumetric T1-weighted MR images is a predictor of survival in patients with glioblastoma. It may help in classifying patients for surgery 24).

References

1)
Vatu BI, Artene SA, Staicu AG, Turcu-Stiolica A, Folcuti C, Dragoi A, Cioc C, Baloi SC, Tataranu LG, Silosi C, Dricu A. Assessment of efficacy of dendritic cell therapy and viral therapy in high grade glioma clinical trials. A meta-analytic review. J Immunoassay Immunochem. 2018 Nov 30:1-11. doi: 10.1080/15321819.2018.1551804. [Epub ahead of print] PubMed PMID: 30497337.
2)
Carson, M. J.; Doose, J. M.; Melchior, B.; Schmid, C. D.; Ploix, C. C. CNS Immune Privilege: Hiding in Plain Sight. Immunol. Rev. 2006, 213, 48–65. DOI: 10.1111/j.1600- 065X.2006.00441.x.
3)
Hickey, W. F.; Hsu, B. L.; Kimura, H. T-Lymphocyte Entry into the Central Nervous System. J. Neurosci. Res. 1991, 28(2), 254–260. DOI: 10.1002/jnr.490280213.
4)
Laman, J. D.; Weller, R. O. Drainage of Cells and Soluble Antigen from the CNS to Regional Lymph Nodes. J. Neuroimmune Pharmacol. 2013, 8(4), 840–856. DOI: 10.1007/s11481-013-9470-8.
5) , 22)
Nuño M, Ly D, Ortega A, Sarmiento JM, Mukherjee D, Black KL, Patil CG. Does 30-Day Readmission Affect Long-term Outcome Among Glioblastoma Patients? Neurosurgery. 2014 Feb;74(2):196-205. doi: 10.1227/NEU.0000000000000243. PubMed PMID: 24176955.
6)
Liang R, Li J, Tang X, Liu Y. The prognostic role of preoperative systemic immune-inflammation index and albumin/globulin ratio in patients with newly diagnosed high-grade glioma. Clin Neurol Neurosurg. 2019 Jun 24;184:105397. doi: 10.1016/j.clineuro.2019.105397. [Epub ahead of print] PubMed PMID: 31306893.
7)
DeAngelis LM. Brain tumors. N Engl J Med. 2001;344(2):114–123.
8)
Chakroun RW, Zhang P, Lin R, Schiapparelli P, Quinones-Hinojosa A, Cui H. Nanotherapeutic systems for local treatment of brain tumors. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2017 May 24. doi: 10.1002/wnan.1479. [Epub ahead of print] Review. PubMed PMID: 28544801.
9)
Caruso R, Pesce A, Wierzbicki V. A very rare case report of long-term survival: A patient operated on in 1994 of glioblastoma multiforme and currently in perfect health. Int J Surg Case Rep. 2017 Feb 20;33:41-43. doi: 10.1016/j.ijscr.2017.02.025. [Epub ahead of print] PubMed PMID: 28273605.
10)
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.
11)
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 Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group. 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. 2009 May;10(5):459-66. doi: 10.1016/S1470-2045(09)70025-7. Epub 2009 Mar 9. PubMed PMID: 19269895.
12)
Delgado-López PD, Corrales-García EM. Survival in glioblastoma: a review on the impact of treatment modalities. Clin Transl Oncol. 2016 Nov;18(11):1062-1071. Review. PubMed PMID: 26960561.
13)
Kawano H, Hirano H, Yonezawa H, Yunoue S, Yatsushiro K, Ogita M, Hiraki Y, Uchida H, Habu M, Fujio S, Oyoshi T, Bakhtiar Y, Sugata S, Yamahata H, Hanaya R, Tokimura H, Arita K. Improvement in treatment results of glioblastoma over the last three decades and beneficial factors. Br J Neurosurg. 2014 Oct 14:1-7. [Epub ahead of print] PubMed PMID: 25311043.
14)
Lipani JD, Jackson PS, Soltys SG, Sato K, Adler JR. Survival following CyberKnife radiosurgery and hypofractionated radiotherapy for newly diagnosed glioblastoma multiforme. Technol Cancer Res Treat. 2008 Jun;7(3):249-55. PubMed PMID: 18473497.
15)
Donato V, Papaleo A, Castrichino A, Banelli E, Giangaspero F, Salvati M, Delfini R. Prognostic implication of clinical and pathologic features in patients with glioblastoma multiforme treated with concomitant radiation plus temozolomide. Tumori. 2007 May-Jun;93(3):248-56. PubMed PMID: 17679459.
16)
Nestler U, Lutz K, Pichlmeier U, Stummer W, Franz K, Reulen HJ, Bink A; 5-ALA Glioma Study Group. Anatomic features of glioblastoma and their potential impact on survival. Acta Neurochir (Wien). 2015 Feb;157(2):179-86. doi: 10.1007/s00701-014-2271-x. Epub 2014 Nov 14. PubMed PMID: 25391974.
17)
Pérez-Beteta J, Martínez-González A, Molina D, Amo-Salas M, Luque B, Arregui E, Calvo M, Borrás JM, López C, Claramonte M, Barcia JA, Iglesias L, Avecillas J, Albillo D, Navarro M, Villanueva JM, Paniagua JC, Martino J, Velásquez C, Asenjo B, Benavides M, Herruzo I, Delgado MD, Del Valle A, Falkov A, Schucht P, Arana E, Pérez-Romasanta L, Pérez-García VM. Glioblastoma: does the pre-treatment geometry matter? A postcontrast T1 MRI-based study. Eur Radiol. 2017 Mar;27(3):1096-1104. doi: 10.1007/s00330-016-4453-9. PubMed PMID: 27329522.
18)
Molina D, Pérez-Beteta J, Luque B, Arregui E, Calvo M, Borrás JM, López C, Martino J, Velasquez C, Asenjo B, Benavides M, Herruzo I, Martínez-González A, Pérez-Romasanta L, Arana E, Pérez-García VM. Tumour heterogeneity in glioblastoma assessed by MRI texture analysis: a potential marker of survival. Br J Radiol. 2016 Jun 20:20160242. [Epub ahead of print] PubMed PMID: 27319577.
19)
Sanghani P, Ang BT, King NKK, Ren H. Regression based overall survival prediction of glioblastoma multiforme patients using a single discovery cohort of multi-institutional multi-channel MR images. Med Biol Eng Comput. 2019 May 18. doi: 10.1007/s11517-019-01986-z. [Epub ahead of print] PubMed PMID: 31104273.
20)
Liang HK, Wang CW, Tseng HM, Huang CY, Lan KH, Chen YH, You SL, Cheng JC, Cheng AL, Kuo SH. Preoperative prognostic neurologic index for glioblastoma patients receiving tumor resection. Ann Surg Oncol. 2014 Nov;21(12):3992-8. doi:10.1245/s10434-014-3793-4. Epub 2014 May 23. PubMed PMID: 24854491.
21)
Han K, Ren M, Wick W, Abrey L, Das A, Jin J, Reardon DA. Progression-free survival as a surrogate endpoint for overall survival in glioblastoma: a literature-based meta-analysis from 91 trials. Neuro Oncol. 2013 Dec 12. [Epub ahead of print] PubMed PMID: 24335699.
23)
Yuan Y, Xiang W, Qing M, Yanhui L, Jiewen L, Yunhe M. Survival analysis for valproic acid use in adult glioblastoma multiforme: A meta-analysis of individual patient data and a systematic review. Seizure. 2014 Jul 8. pii: S1059-1311(14)00196-4. doi: 10.1016/j.seizure.2014.06.015. [Epub ahead of print] PubMed PMID: 25066904.
24)
Pérez-Beteta J, Molina-García D, Ortiz-Alhambra JA, Fernández-Romero A, Luque B, Arregui E, Calvo M, Borrás JM, Meléndez B, Rodríguez de Lope Á, Moreno de la Presa R, Iglesias Bayo L, Barcia JA, Martino J, Velásquez C, Asenjo B, Benavides M, Herruzo I, Revert A, Arana E, Pérez-García VM. Tumor Surface Regularity at MR Imaging Predicts Survival and Response to Surgery in Patients with Glioblastoma. Radiology. 2018 Jul;288(1):218-225. doi: 10.1148/radiol.2018171051. PubMed PMID: 29924716.
glioblastoma_outcome.txt · Last modified: 2019/07/20 14:26 by administrador