General
- If Glioblastoma or Grade 4
- No more PCV just TMZ.
Management algorithm
Steroids
- Dexamethasone is vitally important in controlling cerebral oedema associated with tumours.
- The response to steroids can be extremely rapid.
- Stummer 2011.pdf: Failure to improve with steroids suggests radical surgical resection may cause a worsening neurological deficit
Surgery
Aims
- Tissue diagnosis
- Histological
- Molecular marker assessment
- Improving pressure symptoms
- Improving efficacy of adjuvant therapy
- Delaying deterioration
- Improving survival
- Potential of delivering surgically delivered treatments
Biopsy
- Considered when the risks of resection outweigh the benefits.
- Biopsy is best utilized in cases where the initial diagnosis may influence subsequent management.
- Pros
- Minimally invasive
- Well tolerated
- Suitable for lesions at any site or of any size
- Cons
- Sampling error especially in small or heterogeneous samples
- Image- guidance is now normally used to reduce the risk of non- diagnostic biopsies
- Glantz et al., 1991
- Discrepancies in results
- Resection:
- 82% had glioblastomas
- 18% had anaplastic astrocytomas,
- Biopsy
- 49% had glioblastomas
- 51% had anaplastic astrocytomas
- Jackson et al., 2001; McGirt et al., 2003
- In patients who underwent an initial biopsy before a subsequent resection the diagnosis changes in 39– 49% of cases
- Complications due to haemorrhage.
Debulking
- Aim of surgery for glioblastomas
- Remove as much of the tumour as possible without damaging the surrounding normal brain.
- Pros
- Reducing the tumour load → reduce side effects of raised ICP
- Better tissue diagnosis
- Estimates suggest that 50% of patients are suitable for radical resection (Schucht et al., 2012).
- Whether it provides an improvement in survival has been controversial.
- The difficulty with these cohort studies is that there is an inherent resectability bias.
- Patients with good prognostic features (i.e. those that are young, with good performance status, with smaller tumours in non- eloquent areas) are more likely to have a gross total resection than older patients with poorer performance status and larger tumours in eloquent regions
- Most surgeons would now consider it unethical to randomize their patients into partial resection.
- Hart et al., 2000: The Cochrane review of the literature has highlighted the lack of quality studies in this area
- Does extent of resection matter ? Probably yes but not enough good quality data (RCT) to support it
- stummer 2008.pdf: not RCT
- Residual tumour was defined as contrast enhancement with a volume greater than 0.175 cm
- Patients without residual tumour survived longer (16.7 versus 11.8 mo) = 5 months
- This is the case still when controlled for
- Berger 2011
- 100% resection on post op imaging gets better outcome than 80%
- Proescholdt 2005
- 90% of all recurrence occur with 2cm of resection margin
- Stummer et al., 2012:
- Surgery (complete resection of contrast enhancement) + chemotherapy + radiotherapy
- Associated with a prolonged survival
- This improvement was not seen where any residual enhancing tumour remained.
- Stummer et al., 2011
- The results of three major randomized controlled studies also confirm improvement in survival with radical resection
- Lacroix et al., 2001:
- Retrospective studies
- Gross total resection (Post op MRI of > 98% tumour resection)
- Better QOL and progression- free survival
- McGirt et al., 2009
- Median survival: improved from 8 months for subtotal resection to 13 months after gross total resection
Age
Eloquent areas of brain
- Supramaximal resection in Glioblastoma
- Mier-gracia 2023:
- Better clinical outcomes favouring supramaximal resection over gross total resection—in terms of progression-free survival (hazard ratio 0.67) and overall survival (hazard ratio 0.7), specifically in glioblastoma IDH wild-type and high-grade astrocytoma
- Roh 2023:
- Resection extending into T2-FLAIR regions ("supramaximal") is associated with longer progression-free survival (PFS) and overall survival (OS).
- Multiple systematic reviews and meta-analyses show benefits of supramaximal resection compared to gross total resection (GTR), notably without a substantially higher complication rate.
- Survival increases are most pronounced when >53% of the T2-FLAIR lesion is resected.
- Studies note the largest difference between 98% and 100% removal, with extra survival benefit likely from additional T2-lesion resection.
- Techniques
- 5-Aminolevulinic Acid (5-ALA) Fluorescence-Guided Surgery
- Lobectomy
- For tumors located in non-dominant (usually right) hemisphere or specific lobes (frontal, temporal, occipital), an entire lobe may be removed—beyond the visible tumor and margin—to reduce residual disease and improve survival.
- Dual Intraoperative Visualization Approach (DiVA)
- Combines two visualization modalities—commonly 5-ALA fluorescence and standard neuronavigation—to maximize accuracy and completeness of resection.
- Awake Craniotomy for Tumors Near Eloquent Cortex
- Conducting surgery with the patient awake for real-time functional testing, enabling maximal resection right up to the borders of eloquent areas, preserving neurological function while enhancing extent of resection.
- Subpial Resection & Selective Cortical Mapping
- Utilizes cortical stimulation and subpial surgical techniques to safely extend resection margins beyond imaging abnormalities, up to the limit of subcortical functional boundaries.
- Functionally Guided Resection ("FLAIRectomy")
- Removes contrast-enhancing (T1CE) as well as non-enhancing (T2/FLAIR) MRI abnormality, up to the borders of eloquent structures, guided by intraoperative mapping and functional monitoring.
- Extent of Resection Criteria (RANO Resect Group)
- Utilizes standardized volumetric criteria (i.e., complete removal of CE tumor plus removal of non-CE tissue with ≤5 cm³ residual non-CE tissue) for classifying and guiding supramaximal resection.
- Used only for high grade
- Safety
- complication rates are not significantly higher for supramaximal resection than for GTR, provided neurological function is carefully preserved.
- Onco-functional balance
Predicting resection
- GBM resectability score Marcus et al 2020
- Previously reported grading system for adults with supratentorial glioblastoma. All features are assessed using the pre-operative contrast-enhanced T1-weighted MRI.
- 0-1 Low complexity; 2-3 Moderate complexity; 4-5 High complexity
Pre-operative MRI feature | Score |
Periventricular or deep location | ㅤ |
≥10 mm from ventricle | 0 |
<10 mm from ventricle | 1 |
Corpus callosum or bilateral location | ㅤ |
No corpus callosum involvement | 0 |
Corpus callosum involvement or bilateral location | 1 |
Eloquent location | ㅤ |
Not eloquent location | 0 |
Eloquent location (motor or sensory cortex, language cortex, insula or basal ganglia) | 1 |
Largest diameter of tumour | ㅤ |
<40 mm | 0 |
≥40 mm | 1 |
Associated oedema | ㅤ |
<10 mm from contrast-enhancing tumour | 0 |
≥10 mm from contrast-enhancing tumour | 1 |
TOTAL | 0–5 |
Difficulty with GTR
- Poor margin between normal brain and tumour
- Tools have been developed to improve this resection rate.
- Image- guidance for planning craniotomies
- But unpredictable brain shift limits its use in identifying the tumour limits.
- Intraoperative ultrasound
- Is a useful method, but user dependent.
- Assessment of the tumour border with biopsies, preresection shows a high specificity and sensitivity of 95%, but this deteriorates during resection (sensitivity 87% and specificity 42%) (Rygh et al., 2008).
- Intraoperative MRI
- Provides the most accurate method, but is very expensive and does add time to tumour resections.
- Cohort studies suggest that maximal resection using intraoperative MRI improves survival (Mehdorn et al., 2011).
- Intraoperative fluorescence
- 5- aminolevulinic acid fluorescence guidance (5- ALA)
- 2 months difference
- Na-Fi with yellow 560nm filter when 5ALA not available
- Transcranial magnetic stimulation
- Magnetic Pulse supresses brain function
- Intraoperative neurophysiology
- Asleep
- Only check for MEP
- Awake
- Language
- MEP
- Can lead to deficits
- McGirt 2009:
- For GBM. surgical morbidities (motor or language deficits ) may also affect survival despite similar extent of resection and adjuvant therapy.
- Median and 2-year survival in patients who acquired a new perioperative motor deficit, a new perioperative language deficit, or did not acquire a new operative-induced neurological deficit.
- To reduced deficits use Intraoperative mapping of function using cortical and subcortical mapping
- De Witt Hamer et al., 2012: can half the incidence of postoperative neurological deficits.
ㅤ | Median survival (mo) | 2-year survival (%) |
New perioperative motor deficit | 9.0 | 8 |
New perioperative language deficit | 9.6 | 0 |
No new perioperative deficit | 12.8 | 23 |
Evidence
- Pichlmeier et al., 2008
- An RPA analysis
- Survival benefit was greatest in patients with
- More severe baseline disease based on age
- Performance status
- Neurology
- Mental status
- Data from randomised trials supporting the role for surgery in high-grade glioma
- *Patients who underwent complete resection had a longer progression-free survival (7.5 vs. 3.3; P = 0.003).
Study | Year | Number of Patients | Tumor Types, Grade (n) | Study Groups (n) | Median Progression-Free Survival (months) | P Value | Median Overall Survival (months) | P Value |
Vuorinen et al. | 2003 | 30 | IV (19) III (4) Other (7) | Open resection (10) vs. stereotactic biopsy (13) | ㅤ | ㅤ | 5.7 vs. 2.8 | 0.035 |
Stummer et al. | 2006 | 270 | IV (260) III (9) | Fluorescence-guided resection (161) vs. conventional white-light microsurgery (161) | 5.1 vs. 3.6 | 0.0003 | 15.2 vs. 13.5 | 0.1 |
Senft et al. | 2011 | 49 | IV (46) III (2) Other (1) | Intraoperative magnetic resonance imaging (24) vs. conventional treatment (25) | 7.5 vs. 5.1 | 0.083* | ㅤ | ㅤ |
Chemotherapy for HGG
PCV
- Was the standard adjuvant chemotherapeutic regime in use before the advent of temozolomide.
- Provided a small survival benefit;
- A 5% increase in 2- year survival rates (Stewart, 2002).
- Regiment
- Given in six weekly cycles
- A 10- day oral course of procarbazine
- A single oral dose of CCNU (lomustine)
- A single intravenous infusion of vincristine
Temozolomide
- Has provided some improvement in survival.
- Dosage
- Given orally over five days every 28- day cycle.
- Side effects
- Leucopenia
- Thrombocytopenia
Local chemotherapy (Gliadel wafers: BCNU loaded wafers)
- Local delivery of high concentration chemotherapeutic agent bypassing the BBB
- Approved for treatment of newly diagnosed and recurrent high- grade glioma (WHO grades III and IV).
- GWs are biodegradable polymers containing 3.85% carmustine.
- These polymers are implanted into the resection cavity following surgery for tumour resection, releasing 7.7 mg of drug for roughly 5 days.
- Widespread use has been limited
- The safety and efficacy of GW has been an issue of debate, with some published reports illustrating excellent patient tolerance and improved survival, while others have found no improvement in survival by adding carmustine wafers to standard therapies (Xing et al., 2015).
- Concern regarding wound healing
- Preclude enrolment in subsequent clinical trials.
- Evidence
- Brem et al., 1995:
- A placebo- controlled study in patients at progression (who had reoperations) showed a significant improvement in median survival (31 weeks vs. 23 weeks) and six- month survival (44% dead at 6 months vs. 64%) compared to placebo
- McGirt et al., 2009b
- A retrospective review on BCNU wafer implantation in combination with temozolomide and radiotherapy in newly diagnosed GBM revealed a median survival of 20.7 months with a 2- year median survival of 36%
- Stummer et al., 2012
- It is clear that more extensive resection (>90%) is required to obtain benefit
- Controversial
- Efficacy
- Side effects
- CNS and wound infection rates as high as 28% (Engelhard, 2000; McGovern et al., 2003).
Other therapies
Targeted molecular therapies
Drugs that target the oncogenic pathways in gliomas either by interacting with receptors or affecting a downstream target.
- Drugs blocking the (been disappointing)
- EGFR
- PDGFR
- Phosphatidylinositol 3- kinase (PI3K)
- SRC-related pathways
Molecular targeting:
- Modifies DNA function in glioma cells: Mibefradil, Temozolomide (Temodar), Gliadel
- Targets tubulin (blocks mitosis): ANG 1005
- Inhibits EGFR: Afatinib
- Deactivates NF-kB/activates p53: CBLO137 (Curaxins)
- Monotherapy will have little effect and trials combining these are now underway as summarized by Wick et al. (2011).
- The reason for this poor response is thought to be the fact that multiple receptor tyrosine kinases are activated in the development of a glioma, so blocking one receptor has little effect on the overall pathway (Stommel et al., 2007).
- Combinations of targeted therapies are likely to be the way forward.
Antiangiogenic therapies
- Blocking the VEGF pathway involved in tumour angiogenesis.
- Anti-angiogenic therapy:
- Targets VEGF: Avastin (bevacizumab), Altiratinib, Panobinostat
- Targets TAEC: Trebananib
- Targets tumor associated vasculature: SapC-DOPS, VB-111
- Disrupts protein kinase: Enzastaurin
- Inhibits PDGFR: Crenolanib, AZD2171, Tandutinib (MLNS18, CTS3518)
- Inhibits Aurora-A: TC-A2317
- Vredenburgh et al., 2007:
- A small, non- randomized phase 2 study of bevacizumab at recurrence showed a high response rate (PFS at 6 months 46%; OS at 6 months 77%) ).
- This trial paved the way for an FDA approval.
- But the non- randomized nature of the study and non- standard endpoints has made the European Medicines Agency (EMEA) reject its use in Europe.
- One of the problems with studies using antiangiogenic agents is the marked decrease in enhancement due to closure of the blood- brain barrier (pseudoresponse) does not predict the response to these agents, and subsequent progression can occur with no apparent contrast enhancement (Norden et al., 2008).
- Two large, phase III studies— the European AVAGlio study (Chinot et al., 2014) and the North American RTOG 0825 study (Gilbert et al., 2014) have both failed to show any survival advantage from adding bevacizumab to standard treatment.
- The studies found differing findings on quality of life— RTOG 0825 found patients deteriorated on bevacizumab treatment whereas the AVAGlio study showed stable quality of life until tumour progression (Taphoorn et al., 2015).
Kinase inhibitor (triggers cell apoptosis):
- Inhibits PI3K and mTOR: GDC-0084
Gene therapy
- Genes triggering cytotoxicity: TOCA511 + TOC AFC
miRNA inhibition
- Targets miRNA: TargoMiR
GBM stem cell inhibition:
- Targets GBM stem cells: ICT-107 (DC cells)
Immunotherapy
- The brain is often considered an immune- privileged organ due to its
- Lack of lymphatics
- A blood- brain barrier blocking the passage of cytokines and cells into the brain
- Low baseline expression of major histocompatibility complex proteins (MHC)
- High levels of immunoregulatory cells that decrease baseline function.
- These assumptions have been refuted in recent years.
- Brain tumours further evade and suppress the immune response by
- Very low expression of MHC proteins,
- Reduction of monocyte phagocytic function and antigen presentation,
- Reduced T- cell activation,
- Expressing markers that promote immune cell apoptosis.
- Immunotherapy
- Would seem an ideal treatment to deal with invasive cells that are distributed within normal brain.
- An exciting method of targeting individual tumour cells without injuring normal tissue and is independent of whether the cell is in cycle (as is the problem with cytotoxic therapies).
- 3 methods for overcoming tumour- induced immunosuppression:
- Based on activating the immune system by these potent immunoregulators.
- The difficulty has been delivery across the BBB
- Attempts have been made with injection and infusion of cytokines or gene therapy to promote cytokine expression.
- Certain early phase studies have shown that this is safe but with variable efficacy and these methods might provide a useful adjunct to other therapies.
- Including serotherapy
- Eg:
- Antibody targeting EGFR: Depatux-M, Asunercept
- Antibody targeting PDGFR: MEDI-575, MEDI-3617
- Whereby monoclonal antibodies are directed to tumour-specific antigens to deliver toxins or radioactive substances to selectively kill cells.
- Targets such as tenascin or the mutated EGFR- Viii form that is found in gliomas have been used, but results of early phase studies have been disappointing.
- Adoptive immunotherapy
- Attempts have largely aimed to augment the tumour response by using IL2 to stimulate harvested lymphocytes to produce lymphokineactivated killing cells.
- The results of early studies have shown a small benefit, but are limited by toxicity from IL- 2 induced cerebral oedema.
- Eg
- Peptide vaccine: Rindopepimut, SurVaxM
- Autologous vaccine: ICT-107 (DC cells), Prophage (HSPPC-96), Gliovac, IMA950, DCVax-L
- Priming the immune response by vaccination against tumour- specific antigens.
- Difficulty
- The poor antigen presentation ability within the brain.
- Interest has recently focused on dendritic cells which, when stimulated by an antigen, can activate T lymphocytes to proliferate and destroy these cells.
- Approaches have involved taking autologous dendritic cells from either blood or bone marrow, stimulating them with antigens, and then delivering them back to the patient as a subdermal injection.
- The antigens used have either been common ones found within tumour or individualized from the patient’s tumour.
- Early phase studies have shown promise and minimal toxicity, thus allowing some of these methods to enter phase III studies (Hdeib and Sloan, 2015).
Cytokine therapy
Passive immunotherapies
Active immunotherapies
Virus
- Oncolytic parvovirus: ParvOryx
Nano-therapy
- Enhanced Doxorubicin tumor delivery: Nanocell
Radiotherapy
- Multiple studies from the 1970s showed a survival benefit (Walker et al., 1978).
- Attempts to improve on the initial benefits by increasing the dosage of radiation have failed.
- Unfortunately, the therapeutic window for radiotherapy to the brain is narrow and there is an increasing incidence of radiation necrosis with increasing radiation dose.
- Part of the reason for this is the inability of conventional imaging to identify infiltrating tumour.
- As a result, radiotherapy planning outlines the obvious tumour as the gross tumour volume (GTV).
- A 3 cm margin is applied around the tumour that will contain normal brain.
- A 2.5 cm margin is then applied to form the clinical target volume (CTV).
- A 0.5 cm margin is added to account for set up errors and patient movement to form the planning target volume (PTV).
- To reduce the risk of radiation necrosis the dose is therefore limited.
- There are two radiotherapy regimes normally used in HGG.
- Radical radiotherapy
- 60 Gray dose over 30 daily fractions
- Short course or palliative radiotherapy
- 30 Gray over two weeks in 6 fractions.
- There is less planning required for palliative radiotherapy so patients can start treatment very quickly and it is well tolerated.
- It is useful where patients are acutely deteriorating.
Combination
- Stupp protocol
- Strupp protocol for high grade GBMs
- Radiotherapy
- Total 60 Gy
- 2 Gy per daily fraction (Monday to Friday) over 6 weeks
- Radiation necrosis
- Enhancing mass lesion 6-12 months after DXT
- Low FDG uptake on PET
- Low rCBV
- High ADC
- Pseudo progression
- Therapy induced necrosis
- Usually within 12wks of temozolomide
- More common with MGMT methylation
- Associated with longer OS
- 22% of patients in the study reported by Stupp et al. (2009) did not receive adjuvant chemotherapy phase due to presumed tumour progression.
- Pseudo response
- Decrease in enhancement/oedema
- Increase in T2/FLAlR signal
- Associated with anti-angiogenesis therapy
- No survival increase
- Temozolomide
- During radiotherapy: 75 mg per square metre of body-surface area per day, 7 days per week
- Post-radiotherapy (adjuvant): six cycles consisting of 150-200 mg per square metre for 5 days during each 28-day cycle
- Evidence
- Stupp et al., 2005 and Stupp 2009
Features | RT + TMZ | RT only | Diff |
Median survival | 14.6 months | 12.1 months | 2 months |
2- year survival | 26.5% | 10.4% | |
5- year survival | 9.8% | 1.9% |
Managing HGG in older people
- With an increasingly aged population, gliomas in older people are becoming more of a common problem.
- Features
- More aggressive phenotype
- Frailty with co-morbidities
- Respond poorly to treatments
- Excluded from clinical trials
- As a result, patients >60 are less likely to receive the most radical treatment (Brodbelt et al., 2015)
- Radical surgery for these tumours appears to be a useful treatment with improved outcome (Ewelt et al., 2011)
- Two large studies have shown that in elderly patients who have MGMT methylated glioblastomas there is better survival with temozolomide alone than with radiotherapy (Malmström et al., 2012; Wick et al., 2012).
- Kalra 2020
- Moderately hypofractionated RT (3 weeks) with concurrent and adjuvant TMZ conferred the best overall survival probability (81%), with SUCRA (ranking score) of nearly 100%.
- This regimen was superior to all other compared treatment arms, including longer RT courses, RT alone, TMZ alone, and BSC.
- Best supportive care was ranked as the least effective.
Treatment at tumour progression
- Despite the best management, virtually all patients with HGG will develop recurrence of tumour at some point.
- Response Assessment in Neuro-Oncology (RANO) response criteria
- Is an updated version of the McDonald criteria,
- An objective radiological and clinical assessment of treatment response and tumor recurrence for malignant gliomas
- Abbreviations: FLAIR, fluid-attenuated inversion recovery; T1W, T1-weighted; T2W, T2-weighted.
- ᵃCompared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions.
- ᵇSum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement obtained either at baseline (if no decrease) or best response.
Response Type | The Criteria (All the criteria must be fulfilled to establish a response except for disease progression) |
Complete response | No new lesion in MRI images No enhancing disease in T1W post-gadolinium MRI images (must be sustained for at least 4 weeks) Stable or improved disease in T2W/FLAIR MRI images Patient must be off corticosteroids (or on physiological replacement doses) Patient is clinically stable or improved |
Partial response | No new lesion in MRI images ≥ 50% reduction of enhancing disease in T1W post-gadolinium MRI imagesᵃ (must be sustained for at least 4 weeks) Stable or improved disease in T2W/FLAIR MRI images Patient must be on the same or lower dose of corticosteroids Patient is clinically stable or improved |
Stable disease | No new lesion in MRI images < 50% reduction and < 25% increase of enhancing disease in T1W post-gadolinium MRI imagesᵃ/ᵇ (must be sustained for at least 4 weeks) Stable or improved disease in T2W/FLAIR MRI images Patient must be on the same or lower dose of corticosteroids Patient is clinically stable or improved |
Disease progression | New lesion in MRI images ≥ 25% increase in the enhancing disease in T1W post-gadolinium MRI imagesᵇ Significant increase in disease in T2W/FLAIR MRI images Patient is on stable or increasing doses of corticosteroids Patient is clinically deteriorating |
- Salvage therapies
- Surgery:
- Reoperation
- Is associated with higher morbidity and mortality than for the original operation.
- An option in patients with a long progression- free survival who have tumour that is maximally resectable.
- Insertion of carmustine wafers at this stage has been shown to improve survival (Brem et al., 1995).
- Radiotherapy:
- Re- irradiation with
- Precise fractionated radiotherapy being the most optimal technique.
- Radiosurgery
- On average, time to secondary progression is in the range of several months.
- Cytotoxic chemotherapy:
- Conventional chemotherapy regimens also improve time to secondary progression,
- Cons
- Efficacy is only modest
- Treatment related toxicities like myelosuppression occur very frequently (Niyazi et al., 2011).
- Recent phase III trials have failed to show that temozolomide has a survival advantage over PCV regimes (Brada et al., 2010).
- Recent data suggests that MGMT methylation is a prognostic biomarker for dose- intense temozolomide rechallenge (Weller et al., 2015).
- At present there is little data to support routine use of targeted therapies.
- These should therefore be considered only as part of a clinical trial.
- Nieder 2000: Survival after treatment of GBM recurrence (5-10 months)
- Abbreviations: BCNU, bis chloroethyl nitrosourea
Reference | Treatment | No. of Patients | Survival (Weeks) |
Brem et al., 1995 | Resection | 112 | 23 |
ㅤ | Resection plus BCNU polymer | 110 | 31 |
Subach et al., 1999 | Resection | 45 | 50 |
ㅤ | Resection plus BCNU polymer | 17 | 14 |
Muehling et al., 1999 | Resection | 35 | 29 |
Barker et al., 1998 | Resection | 46 | 36 |
Ammirati et al., 1987 | Resection | 55 | 36 |
Sipos and Afra, 1997 | Resection | 60 | 19 |
Harsh et al., 1987 | Resection | 39 | 36 |
Total | ㅤ | 519 | 30 |
Outcomes
- Five- and ten-year survival rates for diffuse gliomas grades 2-4
- Oligodendroglioma: 80,50
- Astrocytoma: 50,25,5
- Glioblastoma 5%
Diffuse glioma (WHO grade) | 5-year relative survival rate (%) | 10-year relative survival rate (%) |
Oligodendroglioma (2) | 79.5 | 62.8 |
Anaplastic oligodendroglioma (3) | 52.2 | 39.3 |
Astrocytoma (2) | 47.4 | 37.0 |
Anaplastic astrocytoma (3) | 27.3 | 19.0 |
Glioblastoma (4) | 5.0 | 2.6 |
- Without any treatment
- Median survival = <6 months
- With treatment
- Median survival= 18 months
- Poor prognostic factors
- Increasing age
- Poor initial neurology
- Poor general condition as evidenced by Karnofsky Performance score (KPS)
- Absence of MGMT methylation. (difference of 7 months)
- Patients who undergo surgery and chemoradiotherapy have shown better long- term benefits.
- Death is usually due to
- Cerebral oedema
- Raised ICP
- Extent of resection
- Relation between extent of resection and survival in glioblastoma multiforme patients
- Stummer 2008.pdf:
- Residual tumor was defined as contrast enhancement with a volume greater than 0.175 cm
- Patients without residual tumour survived longer (16.7 versus 11.8 mo) = 5 months
Reference | Extent of Resection | No. of Patients | Median Survival (Weeks) |
<98% | 219 | 40 | |
ㅤ | >98% | 197 | 52 |
Biopsy | 84 | 21 | |
ㅤ | Resection | 329 | 45 |
Biopsy | 13 | 33 | |
ㅤ | Partial | 57 | 57 |
ㅤ | Total | 35 | 80 |
- MGMT methylation status (Strupp 2009) (7 months)
- The MGMT status was found to be the single most important predictive factor for a favourable outcome.
- MGMT methylated
- Median survival: 19.3 months
- MGMT non methylated
- Median survival: 12.0 months
- Nieder 2000: Survival after treatment of GBM recurrence (5-10 months)
- Abbreviations: BCNU, bis chloroethyl nitrosourea
Reference | Treatment | No. of Patients | Survival (Weeks) |
Brem et al., 1995 | Resection | 112 | 23 |
ㅤ | Resection plus BCNU polymer | 110 | 31 |
Subach et al., 1999 | Resection | 45 | 50 |
ㅤ | Resection plus BCNU polymer | 17 | 14 |
Muehling et al., 1999 | Resection | 35 | 29 |
Barker et al., 1998 | Resection | 46 | 36 |
Ammirati et al., 1987 | Resection | 55 | 36 |
Sipos and Afra, 1997 | Resection | 60 | 19 |
Harsh et al., 1987 | Resection | 39 | 36 |
Total | ㅤ | 519 | 30 |
- 5- aminolevulinic acid fluorescence guidance (5- ALA)
- 2 months difference
Experimental treatments
Dietary therapy
- The role of diet in managing neurological disease is well established.
- Ketogenic diets to control medically refractory epilepsy have been used for many years.
- As gliomas preferentially metabolize glucose and do not metabolize ketone bodies well, inducing a state of ketosis using high fat, low carbohydrate diets.
- Preclinical studies have shown the antitumor, proapoptotic, and antiangiogenic effects of interrupting these glycolytic pathways in cancer cell lines including gliomas.
- It is clear that ketogenic diets will not be tolerable for most patients, so a modified Atkin’s diet has been suggested.
- Studies of varying quality have so far failed to show clear efficacy.
Tumour treating fields
- Preclinical studies showed that using a low intensity and intermediate frequency electrical field can disrupt mitosis without causing heating or depolarizing neurons.
- A recently reported phase III study shows there is a significant survival advantage when used during the adjuvant phase of chemotherapy (Stupp et al., 2015).
- There is now a move that this should be considered as standard of care (Mehta et al., 2017), although the costs may prohibit routine use at present.
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