glioblastoma

Glioblastoma immunotherapy

Glioblastoma immunotherapy

Immunotherapy has shown promising success in a variety of solid tumor types, but efficacy in glioblastoma is yet to be demonstrated. Barriers to the success of immunotherapy in glioblastoma include a heterogeneous tumor cell population, a highly immunosuppressive microenvironment, and the blood-brain barrier, to name a few. Several immunotherapeutic approaches are actively being investigated and developed to overcome these limitations 1)

Immunotherapy approaches include the use of checkpoint inhibitors, chimeric antigen receptor (CAR) T-Cell therapy, vaccine-based approaches, viral vector therapies, and cytokine-based treatment 2)

Future strategies to ameliorate the efficacy of immunotherapy and facilitate clinical translation will be provided to address the unmet medical needs of GBM 3).

With the success of immunotherapy in other aggressive cancers such as advanced melanoma and advanced non-small cell lung cancer, glioblastoma has been brought to the forefront of immunotherapy research 4).

Immunotherapy, has become a promising strategy with the ability to penetrate the blood-brain barrier since the pioneering discovery of lymphatics in the central nervous system.

The anti-tumoral contribution of Gamma delta T cells depends on their activation and differentiation into effectors. This depends on different molecules and membrane receptors, which conditions their physiology. Belghali et al. aimed to determine the phenotypic characteristics of γδT cells in glioblastoma (Glioblastoma) according to five layers of membrane receptors.

Among ten Glioblastoma cases initially enrolled, five of them who had been confirmed by pathological examination and ten healthy controls underwent phenotyping of peripheral γδT cells by flow cytometry, using the following staining: αβTCR, γδTCR, CD3, CD4, CD8, CD16, CD25, CD27, CD28, CD45, CD45RA, CD56, NKG2D, CD272(BTLA) and CD279(PD-1).

Compared to controls, the results showed no significant change in the number of γδT cells. However, they noted a decrease of double-negative (CD4- CD8- ) Tγδ cells and an increase of naive γδT cells, a lack of CD25 expression, a decrease of the expression of CD279, and a remarkable, but not significant increase in the expression of the CD27 and CD28 costimulation markers. Among γδT cell subsets, the number of Vδ2 decreased in Glioblastoma and showed no significant difference in the expression of CD16, CD56, and NKG2D. In contrast, the number of Vδ1 increased in Glioblastoma with overexpression of CD16, CD56, and NKG2D.

The results showed that γδT cells are prone to adopt a pro-inflammatory profile in the Glioblastoma’s context, which suggests that they might be a potential tool to consider in T cell-based glioblastoma immunotherapy. However, this requires additional investigation on a larger sample size 5).

A limited number of phase III trials have been completed for checkpoint inhibitor, vaccine, as well as gene therapies, and have been unable to show improvement in survival outcomes. Nevertheless, these trials have also shown these strategies to be safe and promising with further adaptations. Further large-scale studies for chimeric antigen receptors T cell therapies and viral therapies are anticipated. Many current trials are broadening the number of antigens targeted and modulating the microtumor microenvironment to abrogate early mechanisms of resistance. Future Glioblastoma treatment will also likely require synergistic effects by combination regimens 6).

As the pioneer and the main effector cells of immunotherapy, T cells play a key role in tumor immunotherapy.

For glioblastoma, immunotherapy has not been as effective 7) , the T cells in Glioblastoma microenvironment are inhibited by the highly immunosuppressive environment of Glioblastoma, (cold tumor microenvironment) posing huge challenges to T cell-based Glioblastoma immunotherapy 8) 9) 10).

As these tumors do not attract and activate immune cells, approaches based on educating immune cells on killing tumor cells, utilized in “hot” immuno-activating cancers, have not been successful in brain tumor clinical trials. In this context, the use of immune-stimulatory approaches, like therapy with oncolytic viruses (OV), is promising 11)

Xu et al. detailed the management of gliomas and previous studies assessing different immunotherapies in gliomas, despite the fact that the associated clinical trials have not been completed yet. Moreover, several drugs that have undergone clinical trials are listed as novel strategies for future application; however, these clinical trials have indicated limited efficacy in glioma. Therefore, additional studies are warranted to evaluate novel therapeutic approaches in glioma treatment 12).

Earlier forms of immune-based platforms have now given way to more current approaches, including chimeric antigen receptor T-cells, personalized neoantigen vaccines, oncolytic viruses, and checkpoint blockade 13).

Critical to mapping a path forward will be the systematic characterization of the immunobiology of glioblastoma utilizing currently available, state of the art technologies. Therapeutic approaches aimed at driving effector immune cells into the glioblastoma microenvironment as well as overcoming immunosuppressive myeloid cells, physical factors, and cytokines, as well as limiting the potentially detrimental, iatrogenic impact of dexamethasone, will likely be required for the potential of anti-tumor immune responses to be realized for glioblastoma 14).

Patients with glioblastoma (Glioblastoma) exhibit a complex state of immunodeficiency involving multiple mechanisms of local, regional, and systemic immune suppression and tolerance. These pathways are now being identified and their relative contributions explored. Delineating how these pathways are interrelated is paramount to effectively implementing immunotherapy for Glioblastoma 15).

Progress in the development of these therapies for glioblastoma has been slow due to the lack of immunogenic antigen targets that are expressed uniformly and selectively by gliomas.

Trials have revealed promising trends in overall survival and progression free survival for patients with glioblastoma, and have paved the way for ongoing randomized controlled trials 16) 17)

Some clinical trials are reaching phase III. Significant progress has been made in unraveling the molecular and genetic heterogeneity of glioblastoma multiforme and its implications to disease prognosis. There is now consensus related to the critical need to incorporate tumor heterogeneity into the design of therapeutic approaches. Recent data also indicates that an efficacious treatment strategy will need to be combinatorial and personalized to the tumor genetic signature 18).

A recurrent theme of this work is that immunotherapy is not a one-size-fits-all solution. Rather, dynamic, tumor-specific interactions within the tumor microenvironment continually shape the immunologic balance between tumor elimination and escape. High-grade gliomas are a particularly fascinating example. These aggressive, universally fatal tumors are highly resistant to radiation and chemotherapy and inevitably recur after surgical resection. Located in the immune-privileged central nervous system, high-grade gliomas also employ an array of defenses that serve as direct impediments to immune attack. Despite these challenges, vaccines have shown activity against high-grade gliomas and anecdotal, preclinical, and early clinical data bolster the notion that durable remission is possible with immunotherapy. Realizing this potential, however, will require an approach tailored to the unique aspects of glioma biology 19).

Clinical experiences with active specific immunotherapy demonstrate feasibility, safety and most importantly, but incompletely understood, prolonged long-term survival in a fraction of the patients. In relapsed patients, Van Gool et al developed an immunotherapy schedule and categorized patients into clinically defined risk profiles. He learned how to combine immunotherapy with standard multimodal treatment strategies for newly diagnosed glioblastoma multiforme patients. The developmental program allows further improvements related to newest scientific insights. Finally, he developed a mode of care within academic centers to organize cell therapy for experimental clinical trials in a large number of patients 20).

Immunostimulating oligodeoxynucleotides containing unmethylated cytosine–guanosine motifs (CpG-ODN) have shown a promising efficacy in several cancer models when injected locally. A previous phase II study of CpG-ODN in patients with Glioblastoma recurrence (Glioblastoma) has suggested some activity and has shown a limited toxicity. This multicentre single-blinded randomised phase II trial was designed to study the efficacy of a local treatment by CpG-ODN in patients with de novo glioblastomas.

Patients with a newly diagnosed glioblastoma underwent large surgical resection and CpG-ODN was randomly administrated locally around the surgical cavity. The patients were then treated according to standard of care (SOC) with radiotherapy and temozolomide. The primary objective was 2-year survival. Secondary outcomes were progression free survival (PFS), and tolerance.

Eighty-one (81) patients were randomly assigned to receive CpG-ODN plus SOC (39 patients) or SOC (42 patients). The 2-year overall survival was 31% (19%; 49%) in the CpG-ODN arm and 26% (16%; 44%) in the SOC arm. The median PFS was 9 months in the CpG-ODN arm and 8.5 months in the SOC arm. The incidence of adverse events was similar in both arms; although fever and post-operative haematoma were more frequent in the CpG-ODN arm.

Local immunotherapy with CpG-ODN injected into the surgical cavity after tumour removal and followed by SOC, although well tolerated, does not improve survival of patients with newly diagnosed Glioblastoma 21).

Epidermal growth factor receptor 3 (EGFRvIII) is present in approximately one-third of glioblastoma (Glioblastoma) patients. It is never found in normal tissues; therefore, it represents a candidate target for glioblastoma immunotherapy. PEPvIII, a peptide sequence from EGFRvIII, was designed to represent a target of glioma and is presented by MHC I/II complexes. Dendritic cells (DCs) have great potential to sensitize CD4+ T and CD8+ T cells to precisely target and eradicate Glioblastoma.

Li et al. show that PEPvIII could be loaded by DCs and presented to T lymphocytes, especially PEPvIII-specific CTLs, to precisely kill U87-EGFRvIII cells. In addition to inhibiting proliferation and inducing the apoptosis of U87-EGFRvIII cells, miR-326 also reduced the expression of TGF-β1 in the tumour environment, resulting in improved efficacy of T cell activation and killing via suppressing the SMO/Gli2 axis, which at least partially reversed the immunosuppressive environment. Furthermore, combining the EGFRvIII-DC vaccine with miR-326 was more effective in killing U87-EGFRvIII cells compared with the administration of either one alone. This finding suggested that a DC-based vaccine combined with miR-326 may induce more powerful anti-tumour immunity against Glioblastoma cells that express a relevant antigen, which provides a promising approach for Glioblastoma immunotherapy 22).

Reviews

Yuan et al. provided an overview of the basic knowledge underlying immune targeting and promising immunotherapeutic strategies including CAR T cells, oncolytic viruses, cancer vaccines, and checkpoint blockade inhibitors that have been recently investigated in glioblastoma. Current clinical trials and previous clinical trial findings are discussed, shedding light on novel strategies to overcome various limitations and challenges 23).

Rui Y, Green JJ. Overcoming delivery barriers in immunotherapy for glioblastoma. Drug Deliv Transl Res. 2021 May 30. doi: 10.1007/s13346-021-01008-2. Epub ahead of print. PMID: 34053034.

Glioblastoma Immune Checkpoint Inhibitor Therapy

Glioblastoma Immune Checkpoint Inhibitor Therapy

Glioblastoma CAR-T cell therapy

Glioblastoma CAR-T cell therapy

1)

Zaidi SE, Moelker E, Singh K, Mohan A, Salgado MA, Essibayi MA, Hotchkiss K, Shen S, Lee W, Sampson J, Khasraw M. Novel Immunotherapeutic Approaches for the Treatment of Glioblastoma. BioDrugs. 2023 May 31. doi: 10.1007/s40259-023-00598-2. Epub ahead of print. PMID: 37256535.
2)

Sener U, Ruff MW, Campian JL. Immunotherapy in Glioblastoma: Current Approaches and Future Perspectives. Int J Mol Sci. 2022 Jun 24;23(13):7046. doi: 10.3390/ijms23137046. PMID: 35806051; PMCID: PMC9266573.
3)

Bausart M, Préat V, Malfanti A. Immunotherapy for glioblastoma: the promise of combination strategies. J Exp Clin Cancer Res. 2022 Jan 25;41(1):35. doi: 10.1186/s13046-022-02251-2. PMID: 35078492; PMCID: PMC8787896.
4)

Yu MW, Quail DF. Immunotherapy for Glioblastoma: Current Progress and Challenges. Front Immunol. 2021 May 13;12:676301. doi: 10.3389/fimmu.2021.676301. Erratum in: Front Immunol. 2021 Oct 07;12:782687. PMID: 34054867; PMCID: PMC8158294.
5)

Belghali MY, El Moumou L, Hazime R, Brahimi M, El Marrakchi M, Belaid HA, Benali SA, Khouchani M, Ba-M’hamed S, Admou B. Phenotypic characterization of human peripheral γδT-Cell subsets in glioblastoma. Microbiol Immunol. 2022 Jun 19. doi: 10.1111/1348-0421.13016. Epub ahead of print. PMID: 35718749.
6)

Zhang M, Choi J, Lim M. Advances in Immunotherapies for Gliomas. Curr Neurol Neurosci Rep. 2022 Feb 2. doi: 10.1007/s11910-022-01176-9. Epub ahead of print. PMID: 35107784.
7)

Bovenberg MS, Degeling MH, Tannous BA. Cell-based immunotherapy against gliomas: from bench to bedside. Mol Ther. 2013 Jul;21(7):1297-305. doi: 10.1038/mt.2013.80. Epub 2013 May 7. PMID: 23648695; PMCID: PMC3702108.
8)

Wang H, Zhou H, Xu J, Lu Y, Ji X, Yao Y, Chao H, Zhang J, Zhang X, Yao S, Wu Y, Wan J. Different T-cell subsets in glioblastoma multiforme and targeted immunotherapy. Cancer Lett. 2020 Oct 3:S0304-3835(20)30498-5. doi: 10.1016/j.canlet.2020.09.028. Epub ahead of print. PMID: 33022290.
9)

Lim M., Xia Y., Bettegowda C., Weller M. Current state of immunotherapy for glioblastoma. Nat. Rev. Clin. Oncol. 2018;15:422–442. doi: 10.1038/s41571-018-0003-5.
10)

Reardon D.A., Wucherpfennig K., Chiocca E.A. Immunotherapy for glioblastoma: On the sidelines or in the game? Discov. Med. 2017;24:201–208.
11)

Iorgulescu JB, Reardon DA, Chiocca EA, Wu CJ. Immunotherapy for glioblastoma: going viral. Nat Med. 2018 Aug;24(8):1094-1096. doi: 10.1038/s41591-018-0142-3. PMID: 30082860; PMCID: PMC6443579.
12)

Xu S, Tang L, Li X, Fan F, Liu Z. Immunotherapy for glioma: current management and future application. Cancer Lett. 2020 Feb 7. pii: S0304-3835(20)30056-2. doi: 10.1016/j.canlet.2020.02.002. [Epub ahead of print] PubMed PMID: 32044356.
13)

Fecci PE, Sampson JH. The current state of immunotherapy for gliomas: an eye toward the future. J Neurosurg. 2019 Sep 1;131(3):657-666. doi: 10.3171/2019.5.JNS181762. Review. PubMed PMID: 31473668.
14)

Reardon DA, Wucherpfennig K, Chiocca EA. Immunotherapy for glioblastoma: on the sidelines or in the game? Discov Med. 2017 Nov;24(133):201-208. PubMed PMID: 29278673.
15)

Jackson CM, Lim M. Immunotherapy for glioblastoma: playing chess, not checkers. Clin Cancer Res. 2018 Apr 24. pii: clincanres.0491.2018. doi: 10.1158/1078-0432.CCR-18-0491. [Epub ahead of print] PubMed PMID: 29691293.
16)

Thomas AA, Fisher JL, Ernstoff MS, Fadul CE. Vaccine-based immunotherapy for glioblastoma. CNS Oncol. 2013 Jul;2(4):331-49. doi: 10.2217/cns.13.29. PubMed PMID: 25054578.
17)

Agrawal NS, Miller R Jr, Lal R, Mahanti H, Dixon-Mah YN, DeCandio ML, Vandergrift WA 3rd, Varma AK, Patel SJ, Banik NL, Lindhorst SM, Giglio P, Das A. Current Studies of Immunotherapy on Glioblastoma. J Neurol Neurosurg. 2014 Apr 5;1(1). pii: 21000104. PubMed PMID: 25346943.
18)

Kamran N, Calinescu A, Candolfi M, Chandran M, Mineharu Y, Assad AS, Koschmann C, Nunez F, Lowenstein P, Castro M. Recent advances and future of immunotherapy for glioblastoma. Expert Opin Biol Ther. 2016 Jul 13. [Epub ahead of print] PubMed PMID: 27411023.
19)

Jackson CM, Lim M, Drake CG. Immunotherapy for Brain Cancer: Recent Progress and Future Promise. Clin Cancer Res. 2014 Apr 25. [Epub ahead of print] PubMed PMID: 24771646.
20)

Van Gool SW. Brain Tumor Immunotherapy: What have We Learned so Far? Front Oncol. 2015 Jun 17;5:98. eCollection 2015. Review. PubMed PMID: 26137448.
21)

Ursu R, Carpentier A, Metellus P, Lubrano V, Laigle-Donadey F, Capelle L, Guyotat J, Langlois O, Bauchet L, Desseaux K, Tibi A, Chinot O, Lambert J, Carpentier AF. Intracerebral injection of CpG oligonucleotide for patients with de novo glioblastoma-A phase II multicentric, randomised study. Eur J Cancer. 2017 Jan 28;73:30-37. doi: 10.1016/j.ejca.2016.12.003. [Epub ahead of print] PubMed PMID: 28142059.
22)

Li J, Wang F, Wang G, Sun Y, Cai J, Liu X, Zhang J, Lu X, Li Y, Chen M, Chen L, Jiang C. Combination epidermal growth factor receptor variant III peptide-pulsed dendritic cell vaccine with miR-326 results in enhanced killing on EGFRvIII-positive cells. Oncotarget. 2017 Feb 17. doi: 10.18632/oncotarget.15445. [Epub ahead of print] PubMed PMID: 28412740.
23)

Yuan B, Wang G, Tang X, Tong A, Zhou L. Immunotherapy of glioblastoma: recent advances and future prospects. Hum Vaccin Immunother. 2022 Mar 28:1-16. doi: 10.1080/21645515.2022.2055417. Epub ahead of print. PMID: 35344682.

Glioblastoma

Glioblastoma

J.Sales-Llopis

Neurosurgery Service, Alicante University General Hospital, Spain.

Definition

While glioblastoma was historically classified as isocitrate dehydrogenase (IDH)-wildtype and IDH-mutant groups, the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) and the World Health Organization Classification of Tumors of the Central Nervous System 2021 clearly updated the nomenclature to reflect glioblastoma to be compatible with wildtype IDH status only. Therefore, glioblastoma is now defined as “a diffuse, astrocytic glioma that is IDH-wildtype and H3-wildtype and has one or more of the following histological or genetic features: microvascular proliferation, necrosis, TERT promoter mutation, Epidermal growth factor receptor gene amplification, +7/-10 chromosome copy-number changes (CNS WHO grade 4) 1).

History

see Glioblastoma History.

Epidemiology

see Glioblastoma epidemiology.

Prior malignancies in patients harboring glioblastoma

Patients who develop Glioblastoma following a prior malignancy constitute ~8% of patients with Glioblastoma. Despite significant molecular differences these two cohorts appear to have a similar overall prognosis and clinical course. Thus, whether or not a patient harbors a malignancy prior to diagnosis of Glioblastoma should not exclude him or her from aggressive treatment or for consideration of novel investigational therapies 2).

Classification

see Glioblastoma classification.

Glioblastoma cell lines

Glioblastoma cell lines.

Glioblastoma stem-like cells

Glioblastoma stem-like cells

Glioblastoma biology

Glioblastoma biology

Pathogenesis

see Glioblastoma pathogenesis.

Pathophysiology

Glioblastoma Pathophysiology.

Molecular pathways in the development of glioblastoma

Genome-wide profiling studies have shown remarkable genomic diversity among glioblastomas.

Molecular studies have helped identify at least 3 different pathways in the development of glioblastomas.

● 1st pathway: dysregulation of growth factor signaling through amplification and mutational activation of receptor tyrosine kinase (RTK) genes. RTKs are transmembrane proteins that act as receptors for an epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) & platelet-derived growth factor (PDGF). They can also act as receptors for cytokines, hormones, and other signaling pathways

● 2nd pathway: activation of the Phosphoinositide 3 kinase (PI3K)/AKT/mTOR, which is an intracellular signaling pathway that is essential in regulating cell survival

● 3rd pathway: inactivation of the p53 and retinoblastoma (Rb) tumor suppressor pathways

Risk factors

Glioblastomas are intrinsic brain tumors thought to originate from a neuroglial stem or progenitor cells. More than 90% of glioblastomas are isocitrate dehydrogenase (IDH)-wildtype tumors. Incidence increases with age, males are more often affected. Beyond rare instances of genetic predisposition and irradiation exposure, there are no known glioblastoma risk factors.

Biomarkers

Glioblastoma biomarker.

Microcirculation patterns

Vessels with different microcirculation patterns are required for glioblastoma (Glioblastoma) growth. However, details of the microcirculation patterns in Glioblastoma remain unclear.

Mei et al. examined the microcirculation patterns of Glioblastoma and analyzed their roles in patient prognosis together with two well-known GMB prognosis factors (O6 -methylguanine DNA methyltransferase [MGMT] promoter methylation status and isocitrate dehydrogenase [IDH] mutations).

Eighty Glioblastoma clinical specimens were collected from patients diagnosed between January 2000 and December 2012. The microcirculation patterns, including endothelium-dependent vessels (EDVs), extracellular matrix-dependent vessels (ECMDVs), Glioblastoma cell-derived vessels (GDVs), and mosaic vessels (MVs), were evaluated by immunohistochemistry (IHC) and immunofluorescence (IF) staining in both Glioblastoma clinical specimens and xenograft tissues. Vascular density assessments and three-dimensional reconstruction were performed. MGMT promoter methylation status was determined by methylation-specific PCR, and IDH1/2 mutations were detected by Sanger sequencing. The relationship between the microcirculation patterns and the patient prognosis was analyzed by the Kaplan-Meier method.

All 4 microcirculation patterns were observed in both Glioblastoma clinical specimens and xenograft tissues. EDVs was detected in all tissue samples, while the other three patterns were observed in a small number of tissue samples (ECMDVs in 27.5%, GDVs in 43.8%, and MVs in 52.5% tissue samples). GDV-positive patients had a median survival of 9.56 months versus 13.60 months for GDV-negative patients (P = 0.015). In MGMT promoter-methylated cohort, GDV-positive patients had a median survival of 6.76 months versus 14.23 months for GDV-negative patients (P = 0.022).

GDVs might be a negative predictor for the survival of Glioblastoma patients, even in those with MGMT promoter methylation 3).

Pathology

Glioblastoma Pathology.

Genetics

see Glioblastoma Genetics.

Growth

see Glioblastoma growth.

Radioresistance

Glioblastoma Radioresistance

Clinical Features

It generally presents with epilepsy, cognitive decline, headache, dysphasia, or progressive hemiparesis. 4).

Seizures as the presenting symptom of glioblastoma predicted longer survival in adults younger than 60 years. The IDH1 R132H mutation and p53 overexpression (>40%) were associated with seizures at presentation. Seizures showed no relationship with the tumor size or proliferation parameters 5).

Diagnosis

see Glioblastoma diagnosis.

Differential diagnosis

Glioblastoma Differential Diagnosis

Scores

SHORT score.

Treatment

see Glioblastoma treatment.

Outcome

see Glioblastoma outcome

Diet

see Ketogenic Diet in glioblastoma.

Complications

see Glioblastoma complications.

Case series

see Glioblastoma case series.

Case reports

Glioblastoma case reports.

1)

Chen J, Han P, Dahiya S. Glioblastoma: Changing concepts in the WHO CNS5 classification. Indian J Pathol Microbiol. 2022 May;65(Supplement):S24-S32. doi: 10.4103/ijpm.ijpm_1109_21. PMID: 35562131.
2)

Zacharia BE, DiStefano N, Mader MM, Chohan MO, Ogilvie S, Brennan C, Gutin P, Tabar V. Prior malignancies in patients harboring glioblastoma: an institutional case-study of 2164 patients. J Neurooncol. 2017 May 27. doi: 10.1007/s11060-017-2512-y. [Epub ahead of print] Review. PubMed PMID: 28551847.
3)

Mei X, Chen YS, Zhang QP, Chen FR, Xi SY, Long YK, Zhang J, Cai HP, Ke C, Wang J, Chen ZP. Association between glioblastoma cell-derived vessels and poor prognosis of the patients. Cancer Commun (Lond). 2020 May 2. doi: 10.1002/cac2.12026. [Epub ahead of print] PubMed PMID: 32359215.
4)

Thomas DGT,Graham DI, McKeran RO,Thomas DGT. The clinical study of gliomas. In: Brain tumours: scientific basis, clinical investigation and current therapy. In: Thomas DGT, Graham DI eds. London: Butterworths, 1980:194–230.
5)

Toledo M, Sarria-Estrada S, Quintana M, Maldonado X, Martinez-Ricarte F, Rodon J, Auger C, Aizpurua M, Salas-Puig J, Santamarina E, Martinez-Saez E. Epileptic features and survival in glioblastomas presenting with seizures. Epilepsy Res. 2016 Dec 26;130:1-6. doi: 10.1016/j.eplepsyres.2016.12.013. [Epub ahead of print] PubMed PMID: 28073027.

Glioblastoma targeted therapy

Glioblastoma targeted therapy

Latest articles

Glioblastoma chemotherapy is limited due to the blood-brain barrier (BBB), poor drug targeting, and short biological half-lives.

Resistance of high-grade tumors to treatment involves cancer stem cell features, deregulated cell division, acceleration of genomic errors, and the emergence of cellular variants that rely upon diverse signaling pathways. This heterogeneous tumor landscape limits the utility of the focal sampling provided by invasive biopsy when designing strategies for targeted therapy.

Yao et al. synthesized and characterized a biomimetic nano drug CMS/PEG-DOX-M. The CMS/PEG-DOX-M effectively and rapidly released DOX in U87 MG cells. Cell proliferation and apoptosis assays were examined by the MTT and TUNEL assays. The penetration of nano drugs through the BBB and anti-tumor efficacy were investigated in the orthotopic glioblastoma xenograft models.

They showed that CMS/PEG-DOX-M inhibited cell proliferation of U87 MG cells and effectively induced cell apoptosis of U87 MG cells. Intracranial antitumor experiments showed that free DOX hardly penetrated the BBB, but CMS/PEG-DOX-M effectively reached the orthotopic intracranial tumor through the BBB and significantly inhibited tumor growth. Immunofluorescence staining of orthotopic tumor tissue sections confirmed that nano drugs promoted apoptosis of tumor cells. This study developed a multimodal nano drug treatment system with the enhanced abilities of tumor-targeting, BBB penetration, and cancer-specific accumulation of chemotherapeutic drugs by combining chemotherapy and photothermal therapy. It can be used as a flexible and effective GBM treatment system and it may also be used for the treatment of other central nervous systems (CNS) tumors and extracranial tumors 1).

In a roadmap review paper, Parker et al. proposed and developed methods for enabling the mapping of cellular and molecular features in vivo to inform and optimize cancer treatment strategies in the brain. This approach leverages 1) the spatial and temporal advantages of in vivo imaging compared with surgical biopsy, 2) the rapid expansion of meaningful anatomical and functional MR signals, 3) widespread access to cellular and molecular information enabled by next-generation sequencing, and 4) the enhanced accuracy and computational efficiency of deep learning techniques. As multiple cellular variants may be present within volumes below the resolution of imaging, we describe a mapping process to decode micro- and even nano-scale properties from the macro-scale data by simultaneously utilizing complimentary multiparametric image signals acquired in routine clinical practice. We outline design protocols for future research efforts that marry revolutionary bio-information technologies, growing access to increased computational capability, and powerful statistical classification techniques to guide rational treatment selection 2)

Classic targets such as the p53 and retinoblastoma (RB) pathway and epidermal growth factor receptor (EGFR) gene alteration have met failed due to complex regulatory networks. There is an ever-increasing interest in immunotherapy (immune checkpoint molecule, tumor-associated macrophage, dendritic cell vaccine, CAR-T cell Therapy, tumor microenvironment, and a combination of several efficacious methods. With many targeted therapy options emerging, biomarkers guiding the prescription of a particular targeted therapy are also attractive. More pre-clinical and clinical trials are urgently needed to explore and evaluate the feasibility of targeted therapy with the corresponding biomarkers for effective personalized treatment options 3).

Comprehensive approaches are necessary to gain maximally from promising targeted therapies. Common methods used for critical evaluation of targeted therapies for glioblastoma include (1) novel methods for targeted delivery for glioblastoma chemotherapy; (2) strategies for delivery through BBB and blood-tumor barriers; (3) innovations in radiotherapy for selective destruction of tumor; (4) techniques for local destruction of tumor; (5) tumor growth inhibitors; (6) immunotherapy; and (7) cell/gene therapies. Suggestions for improvements in glioblastoma therapy include: (1) controlled targeted delivery of anticancer therapy to glioblastoma through the BBB using nanoparticles and monoclonal antibodies; (2) direct introduction of genetically modified bacteria that selectively destroy cancer cells but spare the normal brain into the remaining tumor after resection; (3) use of better animal models for preclinical testing; and (4) personalized/precision medicine approaches to therapy in clinical trials and translation into practice of neurosurgery and neurooncology. Advances in these techniques suggest optimism for the future management of glioblastoma 4)

Surgery as safely feasible followed by involved-field radiotherapy plus concomitant and maintenance temozolomide chemotherapy defines the standard of care since 2005. Except for prolonged progression-free, but not overall survival afforded by the vascular endothelial growth factor antibody, bevacizumab, no pharmacological intervention has been demonstrated to alter the course of the disease. Specifically, targeting cell signalings frequently altered in glioblastoma, such as the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), the p53 and the retinoblastoma (RB) pathways, or epidermal growth factor receptor (EGFR) gene amplification or mutation, have failed to improve outcome, likely because of redundant compensatory mechanisms, insufficient target coverage related in part to the blood brain barrier, or poor tolerability and safety. Yet, uncommon glioblastoma subsets may exhibit specific vulnerabilities amenable to targeted interventions, including, but not limited to: high tumor mutational burden, BRAF mutation, neurotrophic tyrosine receptor kinase (NTRK) or fibroblast growth factor receptor (FGFR) gene fusions, and MET gene amplification or fusions. There is increasing interest in targeting not only the tumor cells, but also the microenvironment, including blood vessels, the monocyte/macrophage/microglia compartment, or T cells. Improved clinical trial designs using pharmacodynamic endpoints in enriched patient populations will be required to develop better treatments for glioblastoma 5).

Glioblastoma immunotherapy

Glioblastoma immunotherapy

1)

Yao Z, Jiang X, Yao H, Wu Y, Zhang F, Wang C, Qi C, Zhao C, Wu Z, Qi M, Zhang J, Cao X, Wang Z, Wu F, Yao C, Liu S, Ling S, Xia H. Efficiently targeted therapy of glioblastoma xenograft via multifunctional biomimetic nanodrugs. Biomater Res. 2022 Dec 2;26(1):71. doi: 10.1186/s40824-022-00309-y. PMID: 36461108.
2)

Parker JG, Servati M, Diller EE, Cao S, Ho C, Lober R, Cohen-Gadol A. Targeting intra-tumoral heterogeneity of human brain tumors with in vivo imaging: A roadmap for imaging genomics from multiparametric MR signals. Med Phys. 2022 Nov 13. doi: 10.1002/mp.16059. Epub ahead of print. PMID: 36371678.
3)

Yang K, Wu Z, Zhang H, Zhang N, Wu W, Wang Z, Dai Z, Zhang X, Zhang L, Peng Y, Ye W, Zeng W, Liu Z, Cheng Q. Glioma targeted therapy: insight into future of molecular approaches. Mol Cancer. 2022 Feb 8;21(1):39. doi: 10.1186/s12943-022-01513-z. PMID: 35135556; PMCID: PMC8822752.
4)

Jain KK. A Critical Overview of Targeted Therapies for Glioblastoma. Front Oncol. 2018 Oct 15;8:419. doi: 10.3389/fonc.2018.00419. PMID: 30374421; PMCID: PMC6196260.
5)

Le Rhun E, Preusser M, Roth P, Reardon DA, van den Bent M, Wen P, Reifenberger G, Weller M. Molecular targeted therapy of glioblastoma. Cancer Treat Rev. 2019 Sep 11;80:101896. doi: 10.1016/j.ctrv.2019.101896. [Epub ahead of print] Review. PubMed PMID: 31541850.

Glioblastoma recurrence treatment

Glioblastoma recurrence treatment

There is no consensus as to the standard of care as no therapeutic options have produced substantial survival benefit for Glioblastoma recurrences (Glioblastomas) 1) 2).

A purely radiological diagnosis of recurrence or progression can be hampered by flaws induced by pseudoprogression, pseudoresponse, or radionecrosis

There is sufficient uncertainty and equipoise regarding the question of reoperation for patients with Glioblastoma recurrence to support the need for a randomized controlled trial 3).

Based on parameters like localization and tumor volume, patient’s Karnofsky Performance Score, time from initial diagnosis, and availability of alternative salvage therapies, reoperation can be considered as a treatment option to extend the overall survival and quality of life of the patient.

The achieved extent of resection of the relapsed tumor—especially with the intention of having a safe, complete resection of the enhancing tumor—most likely plays a crucial role in the ultimate outcome and prognosis of the patient, regardless of other modes of treatment. Validated scores to predict the prognosis after reoperation of a patient with a Glioblastoma recurrence can help to select suitable candidates for surgery. Safety issues and complication avoidance are pivotal to maximally preserving the patient’s quality of life. Besides a possible direct oncological effect, resampling of the recurrent tumor with detailed pathological and molecular analysis might have an impact on the development, testing, and validation of new salvage therapies 4).

Options

Options include repeat surgical resection, repeat fractionated radiation, radiosurgery.

Bevacizumab (BEV) plus daily temozolomide (TMZ) as a salvage therapy has been recommended for recurrent glioma.

In a study, Hundsberger et al investigated which treatments are currently being used for recurrent Glioblastoma within a single nation (Switzerland) and how clinicians are deciding to use them 5)

The authors surveyed Swiss hospitals with comprehensive multidisciplinary neuro-oncology practices (neurosurgery, radiation therapy, medical neuro-oncology, and a dedicated neuro-oncology tumor board) about treatment recommendations for recurrent Glioblastoma. They identified relevant clinical decision-making criteria, called diagnostic nodes or “dodes,” and compared treatment recommendations using a decision-tree format.

Eight hospitals participated. The most common treatment options for recurrent Glioblastoma were combination repeat surgical resection with temozolomide or bevacizumab, monotherapy temozolomide or bevacizumab, and best supportive care. Alternative therapies, including radiotherapy, were less common. Despite widespread disagreement between centers in clinical decision-making, the decision-tree analysis found agreement (>63%) between most centers for only 4 specific clinical scenarios. Patients without an appropriate performance status were usually managed with the best supportive care. Patients with rapid recurrence, nonresectable tumors, unmethylated O(6)-methylguanine DNA methyltransferase (MGMT) promoter, and high-performance status were usually managed with bevacizumab. Patients with late recurrence, nonresectable tumors, overt clinical symptoms, methylated MGMT promoter, multifocal disease, and high-performance status were usually managed with repeat temozolomide therapy. Patients with late recurrence, nonresectable tumors, no clinical symptoms, methylated MGMT promoter, tumor multifocality, and high-performance status were usually managed with temozolomide. The findings of this study underscore the lack of effective first- and second-line treatments for Glioblastoma, and the interhospital variability in practice patterns is not surprising. It seems likely that similar heterogeneity would also be noted in a study of American neuro-oncology centers. It is interesting to note that despite the availability of an increasing number of molecular markers for Glioblastoma stratification, MGMT promoter methylation appears to be the only biological marker widely used across multiple centers in this study. It remains to be seen when and how broadly other markers such as the epidermal growth factor receptor variant III or isocitrate dehydrogenase mutations will be adopted for clinical decision-making. The authors are to be congratulated for identifying core clinical decision-making criteria that may be useful in future studies of recurrent Glioblastoma. This decision tree is an excellent reference for clinical trial development, and several active clinical trials already target the dudes identified in this study. Subsequent studies may help to determine whether similar decision trees exist in American neuro-oncologic centers now or will exist in the future 6).

Figure. A through F, clinical decision-making tree for Glioblastoma recurrence multiforme (Glioblastoma) based on clinical scenarios that achieved a majority recommendation (ie, at least 5 of 8 Swiss hospitals). BEV, bevacizumab; BSC, best supportive care; rGlioblastoma, Glioblastoma recurrence multiforme; TMZ, temozolomide. Modified with kind permission from Springer Science+Business Media: Journal of Neuro-Oncology, Patterns of care in Glioblastoma recurrence in Switzerland: a multicenter national approach based on diagnostic nodes (published online ahead of print October 12. 2015), Hundsberger T, Hottinger AF, Roelcke U, et al [doi: 10.1007/s11060-015-1957-0. Available at: http://link.springer.com/article/10.1007%2Fs11060-015-1957-0 ].

Resection

see Glioblastoma recurrence resection.

Fractionated Stereotactic Radiotherapy

see Fractionated Stereotactic Radiotherapy for Glioblastoma recurrence.

Temozolomide

Temozolomide rechallenge is a treatment option for MGMT promoter-methylated Glioblastoma recurrence. Alternative strategies need to be considered for patients with progressive glioblastoma without MGMT promoter methylation 7).

Bevacizumab

see Bevacizumab for Glioblastoma recurrence.

Intraarterial chemotherapy

Intrarterial chemotherapy is a viable methodology in recurrent Glioblastoma patients to prolong survival at the risk of procedure-related complications and in newly diagnosed patients with the benefit of decreased complications 8).

Low-dose fractionated radiotherapy LD-FRT and chemotherapy for recurrent/progressive Glioblastoma have a good toxicity profile and clinical outcomes, even though further investigation of this novel palliative treatment approach is warranted 9).

Second surgery plus carmustine wafers followed by intravenous fotemustine

Second surgery plus carmustine wafers followed by intravenous fotemustine in twenty-four patients were analyzed. The median age was 53.6; all patients had KPS between 90 and 100; 19 patients (79%) performed a gross total resection > 98% and 5 (21%) a gross total resection > 90%. The median progression-free survival from second surgery was 6 months (95% CI 3.9-8.05) and the median OS was 14 months (95% CI 11.1-16.8 months). Toxicity was predominantly haematological: 5 patients (21%) experienced grade 3-4 thrombocytopenia and 3 patients (12%) grade 3-4 leukopenia.

This multimodal strategy may be feasible in patients with Glioblastoma recurrence, in particular, for patients in good clinical conditions 10).

Immunotherapy

The HSPPC-96 vaccine is safe and warrants further study of efficacy for the treatment of recurrent Glioblastoma. Significant pretreatment lymphopenia may impact the outcomes of immunotherapy and deserves additional investigation 11).

Laser induced interstitial thermotherapy

see Laser interstitial thermotherapy.

Galldiks et al monitored the metabolic effects of stereotaxy-guided LITT in a patient with a recurrent Glioblastoma using amino acid positron emission tomography (PET). Serial 11C-methyl-L-methionine positron emission tomography (MET-PET) and contrast-enhanced computed tomography (CT) were performed using a hybrid PET/CT system in a patient with recurrent Glioblastoma before and after LITT. To monitor the biologic activity of the effects of stereotaxy-guided LITT, a threshold-based volume of interest analysis of the metabolically active tumor volume (MET uptake index of ≥ 1.3) was performed. A continuous decline in metabolically active tumor volume after LITT could be observed. MET-PET seems to be useful for monitoring the short-term therapeutic effects of LITT, especially when patients have been pretreated with a multistep therapeutic regimen. MET-PET seems to be an appropriate tool to monitor and guide experimental LITT regimens and should be studied in a larger patient group to confirm its clinical value 12).

CP-673451

CP-673451 for glioblastoma recurrence.

Lomustine

Adjuvant lomustine to other chemotherapy may provide no obvious benefits for the glioblastoma recurrence treatment 13).

Outcome

A more favorable prognosis following surgery for recurrence or progression is associated with younger age, smaller tumor volume (~50%), motor speech-middle cerebral artery scoring and preoperative Karnofsky performance score (KPS) >80% 14) 15).

Reviews

Optimal treatment for recurrent High-grade glioma continues to evolve. Currently, however, there is no consensus in the literature on the role of reoperation in the management of these patients.

An analysis, of reoperation in patients with World Health Organization grade III or IV recurrent gliomas, focusing on how reoperation affects outcome, perioperative complications, and quality of life. An extensive literature review was performed through the use of the PubMed and Ovid Medline databases for January 1980 through August 2013. A total 31 studies were included in the final analysis. Of the 31 studies with significant data from single or multiple institutions, 29 demonstrated a survival benefit or improved functional status after reoperation for recurrent high-grade glioma. Indications for reoperation included new focal neurological deficits, tumor mass effect, signs of elevated intracranial pressure, headaches, increased seizure frequency, and radiographic evidence of tumor progression. Age was not a contraindication to reoperation. Time interval of at least 6 months between operations and favorable performance status (Karnofsky Performance Status score ≥70) were important predictors of benefit from reoperation. Extent of resection at reoperation improved survival, even in patients with subtotal resection at initial operation. Careful patient selection such as avoiding those individuals with poor performance status and bevacizumab within 4 weeks of surgery is important. Although limited to retrospective analysis and patient selection bias, mounting evidence suggests a survival benefit in patients receiving a reoperation at the time of high-grade glioma recurrence 16).

Case series

2018

Twenty patients with recurrent glioma were treated with BEV (5-10 mg/kg, i.v. every 2 weeks) plus daily TMZ (daily, 50 mg/m2). The treatment response was evaluated via the RANO criteria. HRQL were measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire core 30 (QLQ-C30) and Brain Module (QLQ-BN20).

Twenty patients received a total of 85 cycles of BEV with a median number of 4 cycles (range: 2-10). No patients showed complete response (CR) to treatment. Twelve patients had partial response (PR), stable disease (SD) in 5 patients with, and 3 patients showed progressive disease (PD). In the functioning domains of QLQ-C30, physical functioning, cognitive functioning and emotional functioning significantly improved after the second cycle of BEV compared to baseline, with the mean score of 45.0 vs. 64.0 (p = 0.020), 55.8 vs. 71.7 (p = 0.020) and 48.3 vs. 67.5 (p = 0.015), respectively. In the symptom scales, the scores of pain and nausea/vomiting significantly decreased compared to baseline from the mean score of 39.1 to 20.0 (p = 0.020) and 29.2 to 16.7 (p = 0.049), respectively. Score of global health status also increased from 47.5 to 63.3 (p = 0.001). As determined with the QLQ-BN20, motor dysfunction (43.3 vs. 25.0, p = 0.021), weakness of legs (36.7 vs. 18.3, p = 0.049), headache (38.3 vs. 20.0, p = 0.040), and drowsiness (50.0 vs. 30.0, p = 0.026) after the second cycle of BEV also significantly improved compared to baseline.

BEV plus daily TMZ as a salvage therapy improved HRQL in patients with recurrent glioma 17).

2016

Quick-Weller et al. performed tumour resections in seven patients with rGlioblastoma, combining 5-ALA (20 mg/kg bodyweight) with iMRI (0.15 T). Radiologically complete resections were intended in all seven patients.

They assessed intraoperative fluorescence findings and compared these with intraoperative imaging. All patients had early postoperative MRI (3 T) to verify final iMRI scans and received adjuvant treatment according to interdisciplinary tumour board decision.

Median patient age was 63 years. Median KPS score was 90, and median tumour volume was 8.2 cm(3). In six of seven patients (85%), 5-ALA induced fluorescence of tumour-tissue was detected intraoperatively. All tumours were good to visualise with iMRI and contrast media. One patient received additional resection of residual contrast enhancing tissue on intraoperative imaging, which did not show fluorescence. Radiologically complete resections according to early postoperative MRI were achieved in all patients. Median survival since second surgery was 7.6 months and overall survival since diagnosis was 27.8 months.

5-ALA and iMRI are important surgical tools to maximise tumour resection also in rGlioblastoma. However, not all rGlioblastomas exhibit fluorescence after 5-ALA administration. They propose the combined use of 5-ALA and iMRI in the surgery of rGlioblastoma 18).

Old publications

In some case series reoperation extends survival by an additional 36 weeks in patients with glioblastoma, and 88 weeks in anaplastic astrocytoma 19) 20) (duration of high-quality survival was 10 weeks and 83 weeks, respectively, and was lower with pre-op Karnofsky score < 70). In addition to Karnofsky performance score, significant prognosticators for response to repeat surgery include: age and time from the first operation to reoperation (shorter times → worse prognosis) 21). Morbidity is higher with reoperation (5–18%); the infection rate is ≈ 3x that for first operation, wound dehiscence is more likely

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Balducci M, Diletto B, Chiesa S, D’Agostino GR, Gambacorta MA, Ferro M, Colosimo C, Maira G, Anile C, Valentini V. Low-dose fractionated radiotherapy and concomitant chemotherapy for recurrent or progressive glioblastoma : Final report of a pilot study. Strahlenther Onkol. 2014 Jan 17. [Epub ahead of print] PubMed PMID: 24429479.
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Lombardi G, Della Puppa A, Zustovich F, Pambuku A, Farina P, Fiduccia P, Roma A, Zagonel V. The combination of carmustine wafers and fotemustine in recurrent glioblastoma patients: a monoinstitutional experience. Biomed Res Int. 2014;2014:678191. doi: 10.1155/2014/678191. Epub 2014 Apr 9. PubMed PMID: 24812626.
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Bloch O, Crane CA, Fuks Y, Kaur R, Aghi MK, Berger MS, Butowski NA, Chang SM, Clarke JL, McDermott MW, Prados MD, Sloan AE, Bruce JN, Parsa AT. Heat-shock protein peptide complex-96 vaccination for Glioblastoma recurrence: a phase II, single-arm trial. Neuro Oncol. 2013 Dec 12. [Epub ahead of print] PubMed PMID: 24335700.
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Galldiks N, von Tempelhoff W, Kahraman D, Kracht LW, Vollmar S, Fink GR, Schroeter M, Goldbrunner R, Schmidt M, Maarouf M. 11C-methionine positron emission tomographic imaging of biologic activity of a Glioblastoma recurrence treated with stereotaxy-guided laser-induced interstitial thermotherapy. Mol Imaging. 2012 Jul-Aug;11(4):265-71. PubMed PMID: 22954142.
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Fu X, Shi D, Feng Y. The Efficacy and Safety of Adjuvant Lomustine to Chemotherapy for Recurrent Glioblastoma: A Meta-analysis of Randomized Controlled Studies. Clin Neuropharmacol. 2022 Nov-Dec 01;45(6):162-167. doi: 10.1097/WNF.0000000000000525. PMID: 36383914.
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Barbagallo GM, Jenkinson MD, Brodbelt AR. ‘Recurrent’ glioblastoma multiforme, when should we reoperate? Br J Neurosurg. 2008 Jun;22(3):452-5. doi: 10.1080/02688690802182256. Review. PubMed PMID: 18568742.
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Hervey-Jumper SL, Berger MS. Reoperation for recurrent high-grade glioma: a current perspective of the literature. Neurosurgery. 2014 Nov;75(5):491-9; discussion 498-9. doi: 10.1227/NEU.0000000000000486. PubMed PMID: 24991712.
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Liu Y, Feng F, Ji P, Liu B, Ge S, Yang C, Lou M, Liu J, Li B, Gao G, Qu Y, Wang L. Improvement of health related quality of life in patients with recurrent glioma treated with bevacizumab plus daily temozolomide as the salvage therapy. Clin Neurol Neurosurg. 2018 Mar 27;169:64-70. doi: 10.1016/j.clineuro.2018.03.026. [Epub ahead of print] PubMed PMID: 29631109.
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Ammirati M, Galicich JH, Arbit E, et al. Reoperation in the Treatment of Recurrent Intracranial Malignant Gliomas. Neurosurgery. 1987; 21:607–614
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Brem H, Piantadosi S, Burger PC, et al. Placebo- Controlled Trial of Safety and Efficacy of Intraoperative Controlled Delivery by Biodegradable Polymers of Chemotherapy for Recurrent Gliomas. Lancet. 1995; 345:1008–1012

Glioblastoma Pseudoprogression Differential diagnosis

Glioblastoma Pseudoprogression Differential diagnosis

The suspicious lesion may represent post-treatment radiation effects (PTRE) such as pseudoprogression, radiation necrosis or Glioblastoma recurrence 1).

A study aimed to investigate whether perioperative markers could distinguish and predict PsP from TeP in de novo isocitrate dehydrogenase (IDH) wild-type GBM patients. Methods: New or progressive gadolinium-enhancing lesions that emerged within 12 weeks after CCRT were defined as early progression. Lesions that remained stable or spontaneously regressed were classified as PsP, otherwise persistently enlarged as TeP. Clinical, radiological, and molecular information were collected for further analysis. Patients in the early progression subgroup were divided into derivation and validation sets (7:3, according to operation date). Results: Among 234 consecutive cases enrolled in this retrospective study, the incidences of PsP, TeP, and neither patterns of progression (nP) were 26.1% (61/234), 37.6% (88/234), and 36.3% (85/234), respectively. In the early progression subgroup, univariate analysis demonstrated female (OR: 2.161, P = 0.026), gross total removal (GTR) of the tumor (OR: 6.571, P < 001), located in the frontal lobe (OR: 2.561, P = 0.008), non-subventricular zone (SVZ) infringement (OR: 10.937, P < 0.001), and methylated O-6-methylguanine-DNA methyltransferase (MGMT) promoter (mMGMTp) (OR: 9.737, P < 0.001) were correlated with PsP, while GTR, non-SVZ infringement, and mMGMTp were further validated in multivariate analysis. Integrating quantitative MGMTp methylation levels from pyrosequencing, GTR, and non-SVZ infringement showed the best discriminative ability in the random forest model for derivation and validation set (AUC: 0.937, 0.911, respectively). Furthermore, a nomogram could effectively evaluate the importance of those markers in developing PsP (C-index: 0.916) and had a well-fitted calibration curve. Conclusion: Integrating those clinical, radiological, and molecular features provided a novel and robust method to distinguish PsP from TeP, which was crucial for subsequent clinical decision making, clinical trial enrollment, and prognostic assessment. By in-depth interrogation of perioperative markers, clinicians could distinguish PsP from TeP independent from advanced imaging 2).

Conventional structural MRI is insufficient for distinguishing pseudoprogression from true progressive disease, and advanced imaging is needed to obtain higher levels of diagnostic certainty. Perfusion MRI is the most widely used imaging technique to diagnose pseudoprogression and has high reported diagnostic accuracy. Diagnostic performance of MR spectroscopy (MRS) appears to be somewhat higher, but MRS is less suitable for the routine and universal application in brain tumor follow-up. The combination of MRS and diffusion-weighted imaging and/or perfusion MRI seems to be particularly powerful, with diagnostic accuracy reaching up to or even greater than 90%. While diagnostic performance can be high with appropriate implementation and interpretation, even a combination of techniques, however, does not provide 100% accuracy. It should also be noted that most studies to date are small, heterogeneous, and retrospective in nature. Future improvements in diagnostic accuracy can be expected with harmonization of acquisition and postprocessing, quantitative MRI and computer-aided diagnostic technology, and meticulous evaluation with clinical and pathological data 3).

The key features pseudoprogression will demonstrate include:

Magnetic resonance perfusion imaging: reduced cerebral blood volume (viable tumor will usually have increased rCBV)

Proton magnetic resonance spectroscopic imaging

low choline

ratio Cho/NAA ratio ≤1.4

increased lactate peak

increased lipid peak

the trace may also be generally flat (hypometabolic)

Apparent diffusion coefficient

tumors that respond to treatment and result in pseudoprogression will have elevated ADC values due to cell death ADC mean values ≥1300 x 10-6 mm2/s 8

Moassefi et al. reported the development of a deep learning model that distinguishes PsP from TP in GBM patients treated per the Stupp protocol. Further refinement and external validation are required prior to widespread adoption in clinical practice 4).

Incorporating all available MRI sequences into a sequence input for a CNN-LSTM model improved diagnostic performance for discriminating between pseudoprogression and true tumor progression 5).

Glioblastoma progression

see Glioblastoma progression.

1)

Parvez K, Parvez A, Zadeh G. The diagnosis and treatment of pseudoprogression, radiation necrosis and brain tumor recurrence. Int J Mol Sci. 2014 Jul 3;15(7):11832-46. doi: 10.3390/ijms150711832. PMID: 24995696; PMCID: PMC4139817.
2)

Li M, Ren X, Dong G, Wang J, Jiang H, Yang C, Zhao X, Zhu Q, Cui Y, Yu K, Lin S. Distinguishing Pseudoprogression From True Early Progression in Isocitrate Dehydrogenase Wild-Type Glioblastoma by Interrogating Clinical, Radiological, and Molecular Features. Front Oncol. 2021 Apr 20;11:627325. doi: 10.3389/fonc.2021.627325. Erratum in: Front Oncol. 2021 May 19;11:700599. PMID: 33959496; PMCID: PMC8093388.
3)

Thust SC, van den Bent MJ, Smits M. Pseudoprogression of brain tumors. J Magn Reson Imaging. 2018 May 7;48(3):571–89. doi: 10.1002/jmri.26171. Epub ahead of print. PMID: 29734497; PMCID: PMC6175399.
4)

Moassefi M, Faghani S, Conte GM, Kowalchuk RO, Vahdati S, Crompton DJ, Perez-Vega C, Cabreja RAD, Vora SA, Quiñones-Hinojosa A, Parney IF, Trifiletti DM, Erickson BJ. A deep learning model for discriminating true progression from pseudoprogression in glioblastoma patients. J Neurooncol. 2022 Jul 19. doi: 10.1007/s11060-022-04080-x. Epub ahead of print. PMID: 35852738.
5)

Lee J, Wang N, Turk S, Mohammed S, Lobo R, Kim J, Liao E, Camelo-Piragua S, Kim M, Junck L, Bapuraj J, Srinivasan A, Rao A. Discriminating pseudoprogression and true progression in diffuse infiltrating glioma using multi-parametric MRI data through deep learning. Sci Rep. 2020 Nov 23;10(1):20331. doi: 10.1038/s41598-020-77389-0. PMID: 33230285; PMCID: PMC7683728.

Temozolomide resistance in glioblastoma

Temozolomide resistance in glioblastoma

Temozolomide resistance is considered to be one of the major reasons responsible for glioblastoma treatment failure.

TMZ is currently the only mono-chemotherapeutic agent for newly-diagnosed high-grade glioma patients and acquired resistance inevitably occurs in the majority of such patients, further limiting treatment options. Therefore, there is an urgent need to better understand the underlying mechanisms involved in TMZ resistance, a critical step to developing effective, targeted treatments. An emerging body of evidence suggests the intimate involvement of a novel class of nucleic acid, microRNA (miRNA), in tumorigenesis and disease progression for a number of human malignancies, including primary brain tumours. miRNA are short, single-stranded, non-coding RNA (∼22 nucleotides) that function as post-transcriptional regulators of gene expression 1).

Mechanism

At least 50% of TMZ treated patients do not respond to TMZ. This is due primarily to the over-expression of O6-methylguanine methyltransferase (MGMT) and/or lack of a DNA repair pathway in GBM cells. Multiple GBM cell lines are known to contain TMZ resistant cells and several acquired TMZ resistant GBM cell lines have been developed for use in experiments designed to define the mechanism of TMZ resistance and the testing of potential therapeutics. However, the characteristics of intrinsic and adaptive TMZ resistant GBM cells have not been systemically compared 2)

Many other molecular mechanisms have come to light in recent years. Key emerging mechanisms include the involvement of other DNA repair systems, aberrant signaling pathways, autophagy, epigenetic modifications, microRNAs, and extracellular vesicle production 3).

To date, aberrations in O6-methylguanine-DNA methyltransferase are the clear factor that determines drug susceptibility. Alterations of the other DNA damage repair genes such as DNA mismatch repair genes are also known to affect the drug effect. Together these genes have roles in the innate resistance, but are not sufficient for explaining the mechanism leading to acquired resistance. Recent identification of specific cellular subsets with features of stem-like cells may have role in this process. The glioma stem-like cells are known for its superior ability in withstanding the drug-induced cytotoxicity, and giving the chance to repopulate the tumor. The mechanism is complicated to administrate cellular protection, such as the enhancing ability against reactive oxygen species and altering energy metabolism, the important steps to survive 4).

Rabé et al. performed a longitudinal study, using a combination of mathematical models, RNA sequencing, single cell analyses, functional and drug assays in a human glioma cell line (U251). After an initial response characterized by cell death induction, cells entered a transient state defined by slow growth, a distinct morphology and a shift of metabolism. Specific genes expression associated to this population revealed chromatin remodeling. Indeed, the histone deacetylase inhibitor trichostatin (TSA), specifically eliminated this population and thus prevented the appearance of fast growing TMZ-resistant cells. In conclusion, they identified in glioblastoma a population with tolerant-like features, which could constitute a therapeutic target 5)

Ferroptosis, which is a new type of cell death discovered in recent years, has been reported to play an important role in tumor drug resistance. A study reviews the relationship between ferroptosis and glioma TMZ resistance, and highlights the role of ferroptosis in glioma TMZ resistance. Finally, the investigators discussed the future orientation for ferroptosis in glioma TMZ resistance, in order to promote the clinical use of ferroptosis induction in glioma treatment 6).

CUL4B has been shown to be upregulated and promotes progression and chemoresistance in several cancer types. However, its regulatory effect and mechanisms on TMZ resistance have not been elucidated. The aim of this study was to decipher the role and mechanism of CUL4B in TMZ resistance. Western blot and public datasets analysis showed that CUL4B was upregulated in glioma specimens. CUL4B elevation positively correlated with advanced pathological stage, tumor recurrence, malignant molecular subtype and poor survival in glioma patients receiving TMZ treatment. CUL4B expression was correlated with TMZ resistance in GBM cell lines. Knocking down CUL4B restored TMZ sensitivity, while upregulation of CUL4B promoted TMZ resistance in GBM cells. By employing senescence β-galactosidase staining, quantitative reverse transcription PCR and Chromatin immunoprecipitation experiments, we found that CUL4B coordinated histone deacetylase (HDAC) to co-occupy the CDKN1A promoter and epigenetically silenced CDKN1A transcription, leading to attenuation of TMZ-induced senescence and rendering the GBM cells TMZ resistance. Collectively, our findings identify a novel mechanism by which GBM cells develop resistance to TMZ and suggest that CUL4B inhibition may be beneficial for overcoming resistance 7).

CXCL12/CXCR4 has been demonstrated to be involved in cell proliferation, cell migration, cell invasion, angiogenesis, and radioresistance in glioblastoma (GBM). However, its role in TMZ resistance in GBM is unknown. Wang et al. aimed to evaluate the role of CXCL12/CXCR4 in mediating the TMZ resistance to GBM cells and explore the underlying mechanisms. They found that the CXCL12/CXCR4 axis enhanced TMZ resistance in GBM cells. Further study showed that CXCL12/CXCR4 conferred TMZ resistance and promoted the migration and invasion of GBM cells by up-regulating FOXM1. This resistance was partially reversed by suppressing CXCL12/CXCR4 and FOXM1 silencing. This study revealed the vital role of CXCL12/CXCR4 in mediating the resistance of GBM cells to TMZ, and suggested that targeting CXCL12/CXCR4 axis may attenuate the resistance to TMZ in GBM 8).

The YTHDF2 expression in TMZ-resistant tissues and cells was detected. Kaplan-Meier analysis was employed to evaluate the prognostic value of YTHDF2 in GBM. Effect of YTHDF2 in TMZ resistance in GBM was explored via corresponding experiments. RNA sequence, FISH in conjugation with fluorescent immunostaining, RNA immunoprecipitation, dual-luciferase reporter gene and immunofluorescence were applied to investigate the mechanism of YTHDF2 that boosted TMZ resistance in GBM.

YTHDF2 was up-regulated in TMZ-resistant tissues and cells, and patients with high expression of YTHDF2 showed lower survival rate than the patients with low expression of YTHDF2. The elevated YTHDF2 expression boosted TMZ resistance in GBM cells, and the decreased YTHDF2 expression enhanced TMZ sensitivity in TMZ-resistant GBM cells. Mechanically, YTHDF2 bound to the N6-methyladenosine (m6A) sites in the 3’UTR of EPHB3 and TNFAIP3 to decrease the mRNA stability. YTHDF2 activated the PI3K/Akt and NF-κB signals through inhibiting expression of EPHB3 and TNFAIP3, and the inhibition of the two pathways attenuated YTHDF2-mediated TMZ resistance.

YTHDF2 enhanced TMZ resistance in GBM by activation of the PI3K/Akt and NF-κB signalling pathways via inhibition of EPHB3 and TNFAIP3 9).

1) 
Low SY, Ho YK, Too HP, Yap CT, Ng WH. MicroRNA as potential modulators in chemoresistant high-grade gliomas. J Clin Neurosci. 2013 Oct 6. pii: S0967-5868(13)00518-3. doi: 10.1016/j.jocn.2013.07.033. [Epub ahead of print] PubMed PMID: 24411131.
2) 
Lee SY. Temozolomide resistance in glioblastoma multiforme. Genes Dis. 2016 May 11;3(3):198-210. doi: 10.1016/j.gendis.2016.04.007. PMID: 30258889; PMCID: PMC6150109.
3) 
Singh N, Miner A, Hennis L, Mittal S. Mechanisms of temozolomide resistance in glioblastoma – a comprehensive review. Cancer Drug Resist. 2021;4(1):17-43. doi: 10.20517/cdr.2020.79. Epub 2021 Mar 19. PMID: 34337348; PMCID: PMC8319838.
4) 
Chien CH, Hsueh WT, Chuang JY, Chang KY. Dissecting the mechanism of temozolomide resistance and its association with the regulatory roles of intracellular reactive oxygen species in glioblastoma. J Biomed Sci. 2021 Mar 8;28(1):18. doi: 10.1186/s12929-021-00717-7. PMID: 33685470; PMCID: PMC7938520.
5) 
Rabé M, Dumont S, Álvarez-Arenas A, Janati H, Belmonte-Beitia J, Calvo GF, Thibault-Carpentier C, Séry Q, Chauvin C, Joalland N, Briand F, Blandin S, Scotet E, Pecqueur C, Clairambault J, Oliver L, Perez-Garcia V, Nadaradjane A, Cartron PF, Gratas C, Vallette FM. Identification of a transient state during the acquisition of temozolomide resistance in glioblastoma. Cell Death Dis. 2020 Jan 6;11(1):19. doi: 10.1038/s41419-019-2200-2. PMID: 31907355; PMCID: PMC6944699.
6) 
Hu Z, Mi Y, Qian H, Guo N, Yan A, Zhang Y, Gao X. A Potential Mechanism of Temozolomide Resistance in Glioma-Ferroptosis. Front Oncol. 2020 Jun 23;10:897. doi: 10.3389/fonc.2020.00897. PMID: 32656078; PMCID: PMC7324762.
7) 
Ye X, Liu X, Gao M, Gong L, Tian F, Shen Y, Hu H, Sun G, Zou Y, Gong Y. CUL4B Promotes Temozolomide Resistance in Gliomas by Epigenetically Repressing CDNK1A Transcription. Front Oncol. 2021 Apr 2;11:638802. doi: 10.3389/fonc.2021.638802. PMID: 33869025; PMCID: PMC8050354.
8) 
Wang S, Chen C, Li J, Xu X, Chen W, Li F. The CXCL12/CXCR4 axis confers temozolomide resistance to human glioblastoma cells via up-regulation of FOXM1. J Neurol Sci. 2020 Apr 14;414:116837. doi: 10.1016/j.jns.2020.116837. [Epub ahead of print] PubMed PMID: 32334273.
9) 
Chen Y, Wang YL, Qiu K, Cao YQ, Zhang FJ, Zhao HB, Liu XZ. YTHDF2 promotes temozolomide resistance in glioblastoma by activation of the Akt and NF-κB signalling pathways via inhibiting EPHB3 and TNFAIP3. Clin Transl Immunology. 2022 May 9;11(5):e1393. doi: 10.1002/cti2.1393. PMID: 35582627; PMCID: PMC9082891.

Glioblastoma treatment

Glioblastoma treatment

As the biological challenges and genetic basis of glioblastoma have become more understood, new therapeutic strategies may lead to more durable clinical responses and long-term remissions 1)

Due to the lack of consensus, there exists variability amongst surgeons and centers regarding glioblastoma treatment decisions. Though, objective data about the extent of this heterogeneity is still lacking. Gerritsen et al. aimed to evaluate and analyze the similarities and differences in neurosurgical practice patterns.

The survey was distributed to members of the neurosurgical societies of the Netherlands (NVVN), Europe (EANS), the United Kingdom (SBNS), and the United States (CNS) between January and March 2021 with questions about the selection of surgical modality and decision making in glioblastoma patients.

Survey respondents (224 neurosurgeons) were from 41 countries. Overall, the most notable differences observed were the presence and timing of a multidisciplinary tumor board; the importance and role of various perioperative factors in the decision-making process, and the preferred treatment in various glioblastoma cases case variants. Tumor boards were more common at academic centers. The intended extent of resection for glioblastoma resections in eloquent areas was limited more often in European neurosurgeons. They found a strong relationship between the surgeon’s theoretical survey answers and their actual approach in presented patient cases. In general, the factors which were found to be theoretically the most important in surgical decision-making were confirmed to influence the respondents’ decisions to the greatest extent in practice as well.

This survey illustrates the theoretical and practical heterogeneity among surgeons and centers in their decision-making and treatment selection for glioblastoma patients. These data invite further evaluations to identify key variables that can be optimized and may therefore benefit from consensus 2).

The gold standard for High-Grade Glioma treatment recommends beginning chemoradiation within 6 weeks after. glioblastoma surgery.

The standard of care management for newly diagnosed glioblastoma multiforme (GBM) includes surgery, radiation, temozolomide (TMZ) chemotherapy, and tumor treating fields 3).

From 2005 chemotherapy with temozolomide, according to Stupp protocol 4) , particularly in patients that demonstrate MGMT promoter methylation.

Conflicting reports have emerged regarding the importance of the time interval between these 2 treatments and there is no clear association between duration from surgery to initiation of chemoradiation on overall survival (OS). 5).

Treatment consists of maximal safe resection, radiotherapy, and chemotherapy. Trials of patients with newly diagnosed grade III glioma have shown survival benefit from adding chemotherapy to radiotherapy compared with initial treatment using radiotherapy alone. Both temozolomide and the combination of procarbazine, lomustine, and vincristine provide survival benefit. In contrast, trials that compare single modality treatment of chemotherapy alone with radiotherapy alone did not observe survival differences. Currently, for patients with grade III gliomas who require postsurgical treatment, the preferred treatment consists of a combination of radiotherapy and chemotherapy 6).

After treatment, all patients have to undergo brain magnetic resonance imaging procedure quarterly or half-yearly for 5 years and then on an annual basis. In patients with recurrent tumor, wherever possible re-resection or re-irradiation or chemotherapy can be considered along with supportive and palliative care. High-grade malignant glioma should be managed in a multidisciplinary center

CATNON trial

see CATNON trial.

Postoperative management

The criteria used to assess extent of resection (EOR) have an impact on findings of association between EOR and survival. Current assessment of EOR mainly relies on pre and postoperative contrast-enhanced T1 weighted images (CE-T1WI).

This method is subject to several inherent limitations, including failure to evaluate nonenhancing components of glioma.

To solve this problem, fluid attenuated inversion recovery (FLAIR) imaging is added in the RANO criteria 7).

From the introduction of the first standard of care (SOC) established in 2005 in patients with a new diagnosis of GBM, a great number of trials have been conducted to improve the actual SOC, but the real turning point has never been achieved or is yet to come. Surgical gross total resection, with at least one more reoperation, radiation therapy plus concomitant and adjuvant temozolomide chemotherapy currently remains the current SOC for patients with GBM 8).

Antiepileptic medications may increase radiosensitivity, and therefore improve clinical outcomes, specifically in glioblastoma multiforme patients 9).

The recommended treatment for MGMT promoter unmethylated glioblastoma (GBM) is radiation therapy with concurrent/adjuvant temozolomide (TMZ).

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) 10) and 48% in RTOG-0825 11). 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 12).

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 13).

Surgery

see Glioblastoma surgery.

Glioblastoma Maximal Safe Resection

Glioblastoma Maximal Safe Resection

Glioblastoma Radiochemotherapy

Glioblastoma radiochemotherapy.

Glioblastoma chemotherapy

see Glioblastoma chemotherapy

Glioblastoma multiforme antiangiogenic therapy

see Glioblastoma multiforme antiangiogenic therapy.

Molecular targeted therapy of glioblastoma

see Molecular targeted therapy of glioblastoma.

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 14).

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 15).

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

see Glioblastoma immunotherapy.

ALK inhibitor for Glioblastoma

ALK inhibitor for Glioblastoma.

Alternating electric field therapy for Glioblastoma

Alternating electric field therapy for Glioblastoma

Not good candidates for surgery

Extensive dominant lobe glioblastoma

Butterfly glioblastoma.

Glioblastoma in elderly patients

Karnofsky performance score < 70

Multicentric glioblastoma.

Recurrent glioblastoma treatment

see Recurrent glioblastoma treatment.

Hyperbaric oxygen therapy for Glioblastoma

Hyperbaric oxygen therapy for Glioblastoma.

Palliative care

Palliative care for Glioblastoma.

References

1)

Binder ZA, O’Rourke DM. Glioblastoma: The Current State of Biology and Therapeutic Strategies. Cancer Res. 2022 Mar 1;82(5):769-772. doi: 10.1158/0008-5472.CAN-21-3534. PMID: 35247893.
2)

Gerritsen JKW, Broekman MLD, De Vleeschouwer S, Schucht P, Jungk C, Krieg SM, Nahed BV, Berger MS, Vincent AJPE. Decision making and surgical modality selection in glioblastoma patients: an international multicenter survey. J Neurooncol. 2022 Jan 24. doi: 10.1007/s11060-021-03894-5. Epub ahead of print. PMID: 35067847.
3)

Stupp R, Taillibert S, Kanner A et al (2017) Effect of tumortreating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA 318:2306–2316
4)

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.
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Osborn VW, Lee A, Garay E, Safdieh J, Schreiber D. Impact of Timing of Adjuvant Chemoradiation for Glioblastoma in a Large Hospital Database. Neurosurgery. 2018 Nov 1;83(5):915-921. doi: 10.1093/neuros/nyx497. PubMed PMID: 29092047.
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van den Bent MJ, Smits M, Kros JM, Chang SM. Diffuse Infiltrating Oligodendroglioma and Astrocytoma. J Clin Oncol. 2017 Jul 20;35(21):2394-2401. doi: 10.1200/JCO.2017.72.6737. Epub 2017 Jun 22. Review. PubMed PMID: 28640702.
7)

Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, et al: Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28:1963–1972, 2010
8)

Montemurro N. Glioblastoma Multiforme and Genetic Mutations: The Issue Is Not Over Yet. An Overview of the Current Literature. J Neurol Surg A Cent Eur Neurosurg. 2019 Sep 24. doi: 10.1055/s-0039-1688911. [Epub ahead of print] PubMed PMID: 31550738.
9)

Julie DAR, Ahmed Z, Karceski SC, Pannullo SC, Schwartz TH, Parashar B, Wernicke AG. An overview of anti-epileptic therapy management of patients with malignant tumors of the brain undergoing radiation therapy. Seizure. 2019 Jun 12;70:30-37. doi: 10.1016/j.seizure.2019.06.019. [Epub ahead of print] Review. PubMed PMID: 31247400.
10)

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.
11)

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.
12)

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.
13)

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.
14)

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.
15)

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.

Inoperable glioblastoma

Inoperable glioblastoma

For patients harboring inoperable GBM, due to the anatomical location of the tumor or poor general condition of the patient, the life expectancy is even worse. The challenge of managing GBM is therefore to improve the local control, especially for non-surgical patients.

Considering the treatment duration and its side effects identification of patients with survival benefit from treatment is essential to guarantee the best achievable quality of life.

The aim of a study by Löber-Handwerker et al. from Göttingen was to evaluate the survival benefit from radio-chemotherapy and to identify clinical, molecular, and imaging parameters associated with better outcomes in patients with biopsied GBMs. Consecutive patients with inoperable GBM who underwent tumor biopsy at the department from 2005 to 2019 were retrospectively analyzed. All patients had histologically confirmed GBM and were followed up until death. The overall survival (OS) was calculated from the date of diagnosis to the date of death. Clinical, radiological, and molecular predictors of OS were evaluated. A total of 95 patients with biopsied primary GBM were enrolled in the study. The mean age was 64.3 ± 13.2 years; 56.8% (54/95) were male, and 43.2% (41/95) were female. Median OS in the entire cohort was 5.5 months. After stratification for adjuvant treatment, a higher median OS was found in the group with adjuvant treatment (7 months, range 2-88) compared to the group without treatment (1 month, range 1-5) log-rank test, p < 0.0001. Patients with inoperable GBM undergoing biopsy indeed experience a very limited OS. Adjuvant treatment is associated with significantly longer OS compared to patients not receiving treatment and should be considered, especially in younger patients with the good clinical condition at presentation 1).

Adult brainstem gliomas are characterized into subtypes depending on clinicopathologic and radiographic characteristics. Among them, brainstem glioblastoma is the most malignant and has the poorest prognosis, with surgical resection for this condition posing a great challenge and risk. Postoperative synchronous radiotherapy and temozolomide (TMZ) chemotherapy, or “Stupp protocol”, is the standard of care for glioblastomas. However, antiangiogenic therapy, which is widely used for different cancers, is now an alternative treatment for malignant tumors. Angiogenesis is one of the pathological features of glioblastoma and is involved in tumor progression and metastases. Besides, previous studies suggested a better response to antiangiogenic therapy in some solid tumors with TP53 mutation than TP53 wide-type. Apatinib is a novel, oral, small-molecule tyrosine kinase inhibitor that mainly targets vascular endothelial growth factor receptor-2 (VEGFR-2) to inhibit angiogenesis. In addition, apatinib can cross the blood-brain barrier and improve encephaledema. A report by Zhu et al. describes the use of concurrent apatinib and dose-dense TMZ in a clinically inoperable patient who had a refractory brainstem glioblastoma with a TP53 germline mutation. He obtained an ongoing progression-free survival (PFS) of nearly 16.0 months after resistance to TMZ maintenance. Due to the patient’s circumstances, apatinib and TMZ was considered an effective and safe treatment method 2)

Interstitial photodynamic therapy (iPDT) is a minimally invasive treatment relying on the interaction of light, a photosensitizer and oxygen. In the case of brain tumors, iPDT consists of introducing one or several optical fibers in the tumor area, without large craniotomy, to illuminate the photosensitized tumor cells. It induces necrosis and/or apoptosis of the tumor cells, and it can destruct the tumor vasculature and produces an acute inflammatory response that attracts leukocytes. Interstitial PDT has already been applied in the treatment of brain tumors with very promising results. However, no standardized procedure has emerged from previous studies. Leroy et al. proposed a standardized and reproducible workflow for the clinical application of iPDT to GBM. This workflow, which involves intraoperative imaging, a dedicated treatment planning system (TPS), and robotic assistance for the implantation of stereotactic optical fibers, represents a key step in the deployment of iPDT for glioblastoma treatment. This end-to-end procedure has been validated on a phantom in real operating room conditions. The thorough description of a fully integrated iPDT workflow is an essential step forward to a clinical trial to evaluate iPDT in the treatment of GBM. 3).

Muir et al. retrospectively reviewed patients with newly diagnosed, unresectable GBM who underwent LITT. Progression-free survival (PFS) was the primary endpoint measured in our study, defined as time from LITT to disease progression. Results Twenty patients were identified with newly diagnosed, inoperable GBM lesions who underwent LITT. The overall median PFS was 4 months (95% CI = 2 – N/A, upper limit not reached). The median progression-free survival (PFS) for patients with less than 1 cm 3 residual tumor (gross total ablation, GTA) was 7 months (95% CI = 6 – N/A, upper limit not reached), compared to 2 months (95% CI = 1 – upper limit not reached) for patients with a lower GTA (p = .0019). The median overall survival was 11 months (95% CI = 6 – upper limit not reached). Preoperative Karnofsky performance score (KPS) less than or equal to 80 and deep-seated tumor location were significantly associated with decreased PFS (HR, .18, p = .03; HR, .08, p = .03, respectively). At the end of 1 month, only 4 patients (20%) experienced persistent motor deficits. LITT is a safe and effective treatment for patients with unresectable, untreated GBM with rates of survival and local recurrence compared to patients with surgically accessible lesions treated with conventional resection. Careful patient selection is needed to determine if GTA is attainable. 4).

1)

Löber-Handwerker R, Döring K, Bock C, Rohde V, Malinova V. Defining the impact of adjuvant treatment on the prognosis of patients with inoperable glioblastoma undergoing biopsy only: does the survival benefit outweigh the treatment effort? Neurosurg Rev. 2022 Feb 23. doi: 10.1007/s10143-022-01754-y. Epub ahead of print. PMID: 35194724.
2)

Zhu Y, Zhao L, Xu Y, Zhan W, Sun X, Xu X. Combining apatinib and temozolomide for brainstem glioblastoma: a case report and review of literature. Ann Palliat Med. 2022 Jan;11(1):394-400. doi: 10.21037/apm-22-22. PMID: 35144430.
3)

Leroy HA, Baert G, Guerin L, Delhem N, Mordon S, Reyns N, Vignion-Dewalle AS. Interstitial Photodynamic Therapy for Glioblastomas: A Standardized Procedure for Clinical Use. Cancers (Basel). 2021 Nov 17;13(22):5754. doi: 10.3390/cancers13225754. PMID: 34830908; PMCID: PMC8616201.
4)

Muir M, Patel R, Traylor JI, de Almeida Bastos DC, Kamiya C, Li J, Rao G, Prabhu SS. Laser interstitial thermal therapy for newly diagnosed glioblastoma. Lasers Med Sci. 2021 Oct 23. doi: 10.1007/s10103-021-03435-6. Epub ahead of print. PMID: 34687390.

Programmed death ligand 1 in glioblastoma

Programmed death ligand 1 in glioblastoma

Reports of programmed death ligand 1 (PD-L1) expression in glioblastoma are highly variable (ranging from 6% to 88%) and its role as a prognostic marker has yielded conflicting results.

Data points to a putative role for PD-L1 expression in glioblastoma biology, which correlates to poor patient overall survival, as well as with a general systemic inflammatory status and immunosuppression 1).

A 5% PD-L1 expression cut-off identified a subset of glioblastoma that is associated with a worse clinical outcome. This association remained significant within the newly defined IDH wildtype classification. These findings could have implications for patient stratification in future clinical trials of PD-1/PD-L1 blockade 2).

For patients receiving Dendritic cell vaccine adjuvant therapy, better outcomes are predicted in patients with younger age, with TILs or PBMCs with lower PD-1+/CD8+ ratio, with gross tumor resection, and receiving CCRT 3).

In a retrospective cohort of 115 consecutive patients with GBM, PD-L1 expression was determined using immunohistochemistry (IHC). Membranous and fibrillary PD-L1 staining of any intensity in > 5% neoplastic cells and tumour infiltrating immune cells (TIIs) was considered positive staining. In addition, isocitrate dehydrogenase 1 (IDH-1) (R132H) expression and cluster of differentiation 3 (CD3)-positive T-cell infiltration were investigated using IHC. O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation assay and fluorescence in situ hybridization (FISH) for the assessment of 1p/19q deletion were performed. Expression of PD-L1 in tumour cells and TIIs was found in 37 (32.2%) and 6 (5.2%) patients, respectively. Kaplan-Meier analysis indicated that PD-L1 expression in tumour cells was significantly associated with poor overall survival (OS) (P = 0.017), though multivariate Cox analysis did not confirm this association (hazard ratio 1.204; P = 0.615). PD-L1 expression in TIIs did not correlate with the patient prognosis (P = 0.545). In addition, MGMT methylation and IDH-1 (R132H) expression were associated with a better prognosis (P < 0.001 and P = 0.024, respectively). The expression of PD-L1 was associated with CD3-positive T-cell infiltration (P < 0.001), and IDH-1 wild type status (P = 0.008). A deeper insight into PD-L1 expression could help to ensure the success of future immunotherapy in GBM. Our study suggested that PD-L1 target therapy might be beneficial for PD-L1-expressing GBM patients with a poor prognosis 4).

Immunotherapies for glioblastoma multiforme including PD1/PD-L1 inhibition are currently tested in ongoing clinical trials. The purpose of a study was to investigate the molecular background of PD-L1 expression in glioblastoma multiforme and to find associated pathway activation and genetic alterations. Heiland et al., show that PD-L1 is up-regulated in IDH1/2 wildtype glioblastoma multiforme compared to lower-grade gliomas. In addition, a strong association of PD-L1 with the mesenchymal expression subgroup was observed. Consistent with that, NF1 mutation and corresponding activation of the MAPK pathway was strongly connected to PD-L1 expression. The findings may explain different response to PD-L1 inhibition of patients in ongoing trials and may help to select patients that may profit of immunotherapy in the future 5).

1)

Noronha C, Ribeiro AS, Taipa R, Leitão D, Schmitt F, Reis J, Faria C, Paredes J. PD-L1 tumor expression is associated with poor prognosis and systemic immunosuppression in glioblastoma. J Neurooncol. 2022 Jan 23. doi: 10.1007/s11060-021-03907-3. Epub ahead of print. PMID: 35066764.
2)

Pratt D, Dominah G, Lobel G, Obungu A, Lynes J, Sanchez V, Adamstein N, Wang X, Edwards NA, Wu T, Maric D, Giles AJ, Gilbert MR, Quezado M, Nduom EK. Programmed Death Ligand 1 Is a Negative Prognostic Marker in Recurrent Isocitrate Dehydrogenase-Wildtype Glioblastoma. Neurosurgery. 2018 Jul 12. doi: 10.1093/neuros/nyy268. [Epub ahead of print] PubMed PMID: 30011045.
3)

Jan CI, Tsai WC, Harn HJ, Shyu WC, Liu MC, Lu HM, Chiu SC, Cho DY. Predictors of Response to Autologous Dendritic Cell Therapy in Glioblastoma Multiforme. Front Immunol. 2018 May 29;9:727. doi: 10.3389/fimmu.2018.00727. eCollection 2018. PubMed PMID: 29910795; PubMed Central PMCID: PMC5992384.
4)

Lee KS, Lee K, Yun S, Moon S, Park Y, Han JH, Kim CY, Lee HS, Choe G. Prognostic relevance of programmed cell death ligand 1 expression in glioblastoma. J Neurooncol. 2018 Feb;136(3):453-461. doi: 10.1007/s11060-017-2675-6. Epub 2017 Nov 16. PubMed PMID: 29147863.
5)

Heiland DH, Haaker G, Delev D, Mercas B, Masalha W, Heynckes S, Gäbelein A, Pfeifer D, Carro MS, Weyerbrock A, Prinz M, Schnell O. Comprehensive analysis of PD-L1 expression in glioblastoma multiforme. Oncotarget. 2017 Feb 2. doi: 10.18632/oncotarget.15031. [Epub ahead of print] PubMed PMID: 28178682.

Glioblastoma Differential Diagnosis

Glioblastoma Differential Diagnosis

Tumors are classically distinguished based on biopsy of the tumor itself, as well as a radiological interpretation using diverse MRI modalities.

As its historical name glioblastoma multiforme implies, glioblastoma is a histologically diverse, World Health Organization grade IV astrocytic neoplasm. In spite of its simple definition of presence of vascular proliferation and/or necrosis in a diffuse astrocytoma, the wide variety of cytohistomorphologic appearances overlap with many other neoplastic or non-neoplastic lesions 1).

General imaging differential considerations include:

Intracranial metastases

may look identical

both may appear multifocal

metastases usually are centered on grey-white matter junction and spare the overlying cortex rCBV in the ‘edema‘ will be reduced

Primary central nervous system lymphoma should be considered especially in patients with AIDS, as in this setting central necrosis is more common otherwise usually homogeneously enhancing

Cerebral abscess central restricted diffusion is helpful, however, if GBM is hemorrhagic then the assessment may be difficult presence of smooth and complete SWI low-intensity rim presence of dual rim sign

Anaplastic astrocytoma should not have central necrosis consider histology sampling bias

Tumefactive demyelination lesion can appear similar often has an open ring pattern of enhancement usually younger patients

Subacute cerebral infarction history is essential in suggesting the diagnosis should not have elevated choline should not have elevated rCBV

Cerebral toxoplasmosis especially in patients with AIDS

In a study, Samani et al. of the overarching goal are to demonstrate that primary glioblastomas and secondary (brain metastases) malignancies can be differentiated based on the microstructure of the peritumoral region. This is achieved by exploiting the extracellular water differences between vasogenic edema and infiltrative tissue and training a convolutional neural network (CNN) on the Diffusion Tensor Imaging (DTI)-derived free water volume fraction. They obtained 85% accuracy in discriminating extracellular water differences between local patches in the peritumoral area of 66 glioblastomas and 40 metastatic patients in a cross-validation setting. On an independent test cohort consisting of 20 glioblastomas and 10 metastases, we got 93% accuracy in discriminating metastases from glioblastomas using majority voting on patches. This level of accuracy surpasses CNNs trained on other conventional DTI-based measures such as fractional anisotropy (FA) and mean diffusivity (MD), which have been used in other studies. Additionally, the CNN captures the peritumoral heterogeneity better than conventional texture features, including Gabor filter and radiomic features. The results demonstrate that the extracellular water content of the peritumoral tissue, as captured by the free water volume fraction, is best able to characterize the differences between infiltrative and vasogenic peritumoral regions, paving the way for its use in classifying and benchmarking peritumoral tissue with varying degrees of infiltration 2).

1)

Gokden M. If it is Not a Glioblastoma, Then What is it? A Differential Diagnostic Review. Adv Anat Pathol. 2017 Nov;24(6):379-391. doi: 10.1097/PAP.0000000000000170. PMID: 28885262.
2)

Samani ZR, Parker D, Wolf R, Hodges W, Brem S, Verma R. Distinct tumor signatures using deep learning-based characterization of the peritumoral microenvironment in glioblastomas and brain metastases. Sci Rep. 2021 Jul 14;11(1):14469. doi: 10.1038/s41598-021-93804-6. PMID: 34262079.