low grade glioma controversies in management

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LOW GRADE GLIOMAS: MANAGEMENT

CONTROVERSIES

DR PRAVEEN K TRIPATHI

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OVERVIEW

Gliomas are the most common primary brain neoplasms in adults.

The term low-grade glioma (LGG) refers to tumors classified by the World Health Organization (WHO) as grades I and II, including oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas.

While the 2007 WHO classification of gliomas was based on histological subtype (astrocytic, oligodendrocytic, and oligoastrocytic), the 2016 classification groups together astrocytic and oligodendroglial tumours and further defines specific entities based on IDH mutation and 1p/19q codeletion status

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OVERVIEWLGGs have a better prognosis than their anaplastic

counterparts; the 10-year overall survival rate for patients with WHO grade II astrocytomas is 35%.

LGGs have the potential to dedifferentiate into high-grade tumors, and approximately 50% to 75% of WHO grade II gliomas transform within 6 to 7 years of diagnosis.

LGGs are primarily reported in the frontal lobes (44%), followed by the temporal (28%) and parietal (14%) domains.

Interestingly, LGGs originating in the cerebellar region are associated with a better prognosis than those originating supratentorially.

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OVERVIEWThe mean age at diagnosis is 39.4 yearsFactors associated with longer survival time are

Younger age, Caucasian race, Tumor histology, and Extent of resection.

The most common histologic subtype of LGG is astrocytoma (69.3%), followed by oligodendroglioma (21.1%) and mixed glioma (9.6%).

Factors associated with an increased risk of glioma Exposure to highdose radiation, Increasing age, and Hereditary disorders such as li-fraumeni syndrome and neurofibromatosis type 1

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Clinical Presentation

Epilepsy(65%-95%)Headache(40%)Normal neurological examinationFocal neurological deficitsPapilloedemaNeuro-endocrine disturbanceThe most common initial clinical presentation of patients with

LGGs is seizures, followed by headaches. Symptoms from tumor mass effect are comparatively less

common, probably owing to a slow growth rate (on average, 4.1 mm/yr)

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MANAGEMENT-CONTROVERSIES

The treatment of low-grade gliomas remains one of the most uncertain and controversial areas of modern neurosurgery.

WHY CONTROVERSIESThe controversy largely stems from the lack of well-

designed clinical trials with adequate follow-up to account for the relatively long progression-free survival and overall survival of patients with LGG.

No evidence of class I or II exists regarding the optimal management of these patients

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WHAT CONTROVERSIES

1. Standard antiepileptic drug regimen for seizure control.2. What neuroradiological features should guide management?3. Which prognostic factors can help discriminate between favourable and

unfavourable patients with LGG?4. Based on molecular characterization of tumours are there subgroups of

patients that benefit from more aggressive treatment modalities?5. Should observation or surgery?6. At what time should it be interveined? What surgery7. What is the impact of extent of resection on PFS and OS in patients with

LGG?8. What is the role of RT in the management of patients with LGG?9. What is the role of chemotherapy in the management of LGG?10. What protcol in follow up?11. How should patients with recurrence be managed? 29-Mar-17

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Standard antiepileptic drug regimen

There is no standard antiepileptic drug regimen for seizure control in patients with tumors; however, levetiracetam is preferentially used because of its favorable pharmacologic properties and relatively benign side-effect profile.

Yuan Y, Yunhe M, Xiang W, et al. P450 enzyme-inducing and non enzymeinducing antiepileptic drugs for seizure prophylaxis after glioma resection surgery: A meta-analysis. Seizure. 2014;23:616–621.

There is no level I evidence that levetiracetam is more effective than phenytoin for seizure control.

Unlike phenytoin, levetiracetam does not induce hepatic cytochrome P450 enzymes; therefore, levetiracetam has a lower risk of potential adverse interactions with adjuvant chemotherapy treatments.

Starting dosages for levetiracetam range from 1000 to 4000 mg/day; dosages as high as 5000 mg/day are also well tolerated by patients with intractable seizures 29-Mar-17

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Diagnostic Neuroimaging for LGG

Magnetic resonance imaging (MRI) of LGGs demonstrates lesions that are isointense/hypointense on T1-weighted images, are homogeneously hyperintense on T2-weighted images, and do not enhance with contrast administration .

Calcifications can be detected in about 20% of lesions and appear as distinct hyperintense foci on T1-weighted images and hypointense foci on T2-weighted images.

Vasogenic edema and necrosis are not typical of LGGs, owing to their slow growth rate.

MR spectroscopy, have been used to differentiate glioma grades and even to detect key LGG metabolic mutations, such as those of the isocitrate dehydrogenase 1 (IDH1) gene

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A 32-year-old woman presenting with partial motor seizures. (A and E) The MRI revealsa right frontal mass which is hypointense on T1-weighted images, (B and F) Does not enhance following administration of contrast, (C and G) The lesion expands the cortex locally and has a sharp border with minimal surrounding vasogenic edema as seen on T2, (D and H) FLAIR images

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Diagnostic Neuroimaging for LGGBoth fluorodeoxyglucose-PET (FDG-PET) and fluorothymidine-

PET (FLT-PET) have been used to evaluate LGG metabolism and proliferation.

A prospective study of 60 patients with cerebral gliomas evaluated the ability of FDG-PET to differentiate LGGs from HGGs. The investigators reported a PPV of 97.3% and an NPV of 70.2%.

Watanabe M, Tanaka R, Takeda N. Magnetic resonance imaging and histopathology of cerebral gliomas. Neuroradiology. 1992;34:463–469.

Similarly, diffusion tensor imaging (DTI) is under investigation to differentiate low-grade and high-grade histologic appearances.

DTI analysis of 79 gliomas also demonstrated a correlation with the tumor grade and was able to differentiate LGGs from HGGs with a sensitivity of 92% to 94% and a specificity of 53% to 54%.

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Diffusion tensor imaging and tractography can often help to identify location of fiber tracts in relation to tumors and to demonstrate whether these white matter bundles are displaced or invaded by infiltrating tumor cells

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Diffusion tensor imaging (DTI) and tractography can provide an elegant visualization of the white matter tracts and their relationship with infiltrating tumors. In this example, the right corticospinal tract (motor fibers from the foot area) is displaced medially rather than being invaded by the tumor. The DTI and tractography can often help to maximize surgical resection while preserving neurological function

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fMRI is an activation-based method that identifies all regions of the brain that demonstrate activity related to a particular task, regardless of whether those areas are essential or supplementary.

Consequently, areas that appear negative for language when cortical stimulation is used may still demonstrate fMRI activation, producing false-positive results.

Decreased specificity may also be expected because fMRI is a perfusion-based method and does not directly detect neuronal activity.

Magnetoencephalography (MEG) is also increasingly used for preoperative functional mapping. MEG imaging reconstructs the spatiotemporal dynamics of brain sources from magnetoencephalographic data.

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Functional MRI -the left hand motor area can be effectively localized in relation to the right posterior frontal tumor involving the motor strip

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Prognostic Factors, Patient Outcome, andSurvival

University of California at San Francisco (UCSF) conducted a retrospective study of 256 patients and proposed a scoring system to estimate patient overall survival (OS) and progression-free survival (PFS).

This scoring system assigns a 1-point value for the following factors:

Tumor location within eloquent cortices, Karnofsky performance scale score 80 or less, Age more than 50 years, and Maximal tumor diameter more than 4 cm.

Higher scores portend a worse prognosis. Patients with a UCSF score of 0 to 1 had a 97% 5-year survival rate,

and patients with a score of 3 to 4 had a 5-year survival rate of 56%29-Mar-17

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Prognostic factors for survival in adult patients with cerebral low-grade glioma.Pignatti F, van den Bent M, Curran D etal 2002

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Radiation Therapy Oncology Group, and the North Center Cancer Treatment Group (RTOG/NCCTG) further defined prognostic factors for WHO grade II gliomas.

PFS and OS were negatively affected by the following factors: Impaired baseline neurologic status, Shorter time since first symptoms (<30 weeks), Astrocytic histology, and Maximal tumor diameter greater than 5 cm.

Early radiation therapy was correlated with improved PFS but had no impact on OS.

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LGG: Molecular Markers

Specific genetic markers helpful in dividing gliomas into subgroups with respect to prognosis and response to chemotherapy

TP53 mutations: Common in diffuse astrocytomas and aremutually exclusive from 1p/19q co-deletions.

1p/19q Deletions: 50-70% LG Oligodendroglial tumors Loss of 1p or both 1p/19q may predict chemosensitivity and predicts

prolonged survival in LGO and LGOAThere are patients that are deleted that do less well than most and there are

some intact patients that do much better than most.IDH 1 mutations: 60-90% of LGG. Associated with improved survival.May help diagnostically differentiate: gliosis vs tumor or (in comb w BRAF)

pilocytic tumors vs grade II astrocytomaWe still do not know confidently if IDH 1 mutations should be used to direct

treatment or, if so, how.29-Mar-17

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LGG: Treatment

Symptom ManagementObservation SurgeryRadiation TherapyChemotherapy

How to interveneTo intervene or notWhen to interveneSurgery ; Radical Vs PartialRadiotherapy: Timing,Low Vs High DoseRole of Chemotherapy

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LGG: Symptom Management

•Seizures: Medications such as levitiracetam, lacosamide, topirimate, lamotrigine, and others such as phenytoin, carbamazepine, etc

•Edema: Steroids, usually dexamethasone; however long term use has potential for side effects (skin changes, weight gain, muscle weakness, bone thinning, increased risk of infection, etc)

•Obstructive Hydrocephalus: may require surgery and perhaps placement of a “shunt” to bypass the blockage and lower the pressure

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“Watchful waiting” WHYCharacteristic imaging features with long history.Increased life span by surgery never proven.Increasingly patients are diagnosed neurologically intact. Postpones surgical morbidity and mortality if any.Alternate treatment strategy are availableStereotactic biopsy and radiotherapyTechnical reasons

Distinction between tumor-brain difficult and early radical surgery seldom serves purpose.

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“Watchful waiting” - WHY NOT Grading gliomas based on imaging characteristics alone underestimated the degree

of malignancy in 1/3 cases Tissue diagnosis should be attained whenever deemed safe and possible

Scott JN, Brasher PM, SevickRu, Rewcastle NB, Forsyth PA. How often are nonenhancingsupratentoralgliomas malignant? A popultion study. Neurology 2002:s9:947-9.

Recent studies have showed that contrast enhancement may occur in upto 40% of low grade gliomas.

Scott CB, Scarantino C, Urtasun R, Movsas B, Jones CU, Simpson JR, eta. validation and predictive power of Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classes ror malignant glioma patients: A report using RTOG 90-06. Int J RadiatOncolBiol Phys 1998;40:51-5.

The expectant management of patients with LGGs can bring on other risks, such as, Malignant degeneration Subsequent tumorgrowth, and Irreversible neurological deficit.

How ever despite these theoretical risks, several retrospective series revealed that the timing of surgical intervention did not affect the rates of malignant transformation, overall survival, or QOL.

Reijneveld JC, Sitskoorn MM, Klein M, Nuyen J, Taphoorn Mj. Cognitive status and quality of life in patients with suspected versus proven low grade gliomas, Neorology 2001;56:618-23

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SurgeryThe role of immediate surgical resection versus delayed resection is

controversial and data are limited to observational studies. Unless contraindicated, immediate surgical resection is an option

over observation to improve OS.Although no randomized controlled trials (RCTs) have evaluated the

extent of surgery on outcomes in LGG, numerous observational studies suggest that greater extent of resection (EOR) improves OS and seizure control.

Maximizing tumour resection while keeping the surgically induced deficit at an acceptable level is recommended over simple debulking.

Surgery alone is not curative in patients with LGG and additional therapy with RT and/or chemotherapy will likely be required at some point in their disease trajectory.

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The pros and cons of resection of gliomas

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Surgery – WHEN

RATIONALE FOR EARLY SURGERYDefinitive diagnosisPossibility of gross total resection with potential for cureControl of seizuresNeurological improvementControl of ICPLonger disease free interval Enhanced ability of immune cells to wipe out tumorGreater kill by post op RT

DISAGREEMENT WITH EARLY SURGERY Longer disease free interval is lead time bias Immunological activity against low grade glioma is controversialPost op radiotherapy does not kill all cells

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Surgery –WHAT

Stereotactic Biopsy Operative strategies for patients with LGGs include open surgical

resection and stereotactic biopsy. The choice depends in part on the patient's clinical status, the

anatomic location of the tumor, and the surgeon's preference. Immediate stereotactic biopsy is increasingly uncommon, it remains

a reliable first step for cases in which the diagnosis is uncertain. A recent Norwegian study had shown the significant difference of

survival in those centers with a preference for resection than those selecting a biopsy and watchful waiting and with no significant difference in health related quality of lifeJakola AS, Myrmel KS, Kloster R, Torp SH, Lindal S, Unsgard G, Solheim O (2012)

Comparison of a strategy favoring early surgical resection vs a strategy favoring watchful waiting in low-grade gliomas. JAMA 308:1881–1888

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Surgery –WHAT

Microsurgical ResectionIn patients with accessible LGGs who have symptoms of local

mass effect, increased intracranial pressure, and intractable seizures, the role of microsurgical resection is well established.

Resection serves several purposes in these circumstances, including alleviation of mass effect, cytoreduction, and diagnosis.

Cytoreduction can also reduce cerebral edema and potentially improve radiosensitivity and chemosensitivity of the tumor.

The degree of tumor removal afforded by open surgical resection also offers the advantage of providing more tissue for histologic analysis.

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Surgery –WHAT

EXTENT OF RESECTIONTill date no class 1 evidence to support radical resection.There are lot of retrospective data to suggest benefit in survival and

in quality of life.Two prospective studies have shown benefit of extensive surgery in

overall survival on univariate analysis.On multivariate analysis these showed minimal benefits. Recent studies looking specifically at oligodendroglioma show that

extent of resection does improve PFS and overall survival but did not influence time to malignant transformation.

Snyder LA, Wolf AB, Oppenlander ME, Bina R, Wilson JR, Ashby L, Brachman D, Coons SW, Spetzler RF, Sanai N (2013) The impact of extent of resection on malignant transformation of pure oligodendrogliomas. J Neurosurg. doi:10.3171/2013.10. JNS13368 29-Mar-17

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Surgery –WHAT

EXTENT OF RESECTIONHardesty and Sanai reviewed every major peer-reviewed clinical

publication on the role of EOR in glioma outcome between the years 1990 to 2012.

Eleven LGG articles were examined for quality of evidence, expected EOR, and survival benefit.

Three studies using volumetric analysis to determine EOR in LGG pts (n=462, range 90-216) demonstrated a benefit to increasing EOR in univariate and/or multivariate analysis.

Five-year OS was improved in all studiesHardesty DA, Sanai N. The value of glioma extent of resection in the modern neurosurgical era. Front Neurol 2012 Oct 18;3:140

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Surgery –WHAT

Contemporary neurosurgical methods Contemporary neurosurgical methods, including ultrasonography,

functional mapping, frameless navigational resection devices, and intraoperative imaging techniques, enable the neurosurgeon to achieve more extensive resections with less morbidity.

Intraoperative ultrasonography provides real-time intraoperative data and is helpful in detecting the tumor, delineating its margins, and differentiating tumor from peritumoral edema, cyst, necrosis, and adjacent normal brain tissue.

Intraoperative MRI may also allow for greater extent of resection, particularly when tumor-infiltrated tissue cannot be grossly distinguished from normal.

Claus EB, Horlacher A, Hsu L, et al. Survival rates in patients with low-grade glioma after intraoperative magnetic resonance image guidance. Cancer. 2005;103:1227–1233. 29-Mar-17

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Surgery –WHATContemporary neurosurgical methods Stimulation mapping techniques are essential to minimize morbidity

and to achieve radical resections of tumors located in or around cortical and subcortical, functionally eloquent sites.

Intraoperative mapping techniques can effectively identify tissue with motor, language, and sensory functionality.

Sanai N, Berger MS. Intraoperative stimulation techniques for functional pathway preservation and glioma resection. Neurosurg Focus. 2010;28

Awake language mapping is also essential owing to variability in the localization of language pathways and should be considered when a glioma is located in the dominant hemisphere near the frontal operculum, temporal lobe, or angular gyrus.

Caution should be observed during resection owing to the possibility that functional brain tissue resides within the tumor itself. 29-Mar-17

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Surgery –WHAT

Functional Mapping and Cortical Stimulation

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A 43-year-old man presenting with word finding difficulties. He underwent an awake craniotomy for aggressive resection of the tumor involving Wernicke’s area with language and motor cortex mapping. Note the multicompartmental endopial resection of the tumor with preservation of the cortical veins overlying the tumor

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Defer Treatment Treat

Suspicion: ? Higher gradeProgressing LGEnhancementMass effectSymptomatic> age 40Surgery not indicated or

significant residual and Rx necessary

Post op: When Should We Treat?

After large or GTRMinimal diseaseNo enhancementSeizures controlledFew or no SeizuresYounger age

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Radiation Therapy

Became a cornerstone of therapy many yrs agoOligodendrogliomas, Astroctomas, Mixed OA all respond Proton beam thought to decrease risk to normal brain however

efficacy has not been compared to standard external beam with margins. Risk is under treating the margins

Stereotactic: Not usually indicated. Focused to small area, but these tumors are infiltrative and “spread out”

RT may not always be best initial choice: Chemotherapy may be the 1stchoice for some pts, particularly with Oligodendrogliomaor Mixed OA whose tumors show 1p/19q deletions–deferring treatment with RT

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Why/why not Radiation?

Why radiation therapy?Improves time to tumor progressionSeveral studies show improved survival in patients with progressing or

aggressive tumorsNo systemic side effectsDefined treatment timeWhy not radiation therapy?No clear evidence of improved survival with immediate post op RT vs

delayed RTDelayed radiation induced neurotoxicityRT vs no RT

Perform worse on cognitive tests Have lower Karnofskyscore Not accounted for by histology, location, extent of removal, progression

• Surm-aho et al, 200129-Mar-17

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RT of benefit–Gannett et al, 1994–Wallneret al, 1988–Morket al, 1985

RT of no benefit–Shaw et al, 1992–Bullard et al, 1997–Nijjaret al, 1993

RT of benefit in some, but not allMorket al, 1985: not in pts with GTRCelli et al, 1994: not in pts with

indolent tumors;

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In the Mayo Clinic study, Shaw et al compared the outcome of 126 patients with supratentorial astrocytoma or mixed oligo-astrocytoma treated with surgery alone or surgery plus either low-dose (53 Gy) or high-dose (53 Gy) RT.

The 5-year OS was 32% with surgery alone, 47% with low-dose RT, and 68% with high-dose RT, suggesting that surgery without postoperative RT was inadequate treatment and high-dose RT was better than lower dose.

Shaw EG, Daumas-Duport C, Scheithauer BW, et al: Radiation therapy in the management of low-grade supratentorial astrocytomas. J Neurosurg 70:853-61, 1989

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Immediate vs delayed PORT

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Evidence

Phase III adult low grade glioma trials (EORTC 22844 and 22845): Risk Factors identified & Validated

Age>40 yearsSize>6cmCrossing MidlinePure Astrocytoma histologyNeurological deficit before Surgery

Low Risk Patient: </= 2 factors (Median Survival- 7.7 years)High Risk: 3 or more factors (Median Survival- 3.2 years)

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EORTC 22845 (Karim et al, 2002 & Van den Bent et al, 2005)

Randomised phase III trialRT Dose (54Gy/30#)Immediate RT vs RT at Progression

Results: Improved median progression free survival(5.3 yrs vs 3.4 yrs)Better seizure control ratesNo difference in Median survival (7.4yrs vs 7.2 yrs) No difference in rate of malignant transformation.

Pitfall: No in-depth quality of life adjusted analysis.

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RTOG (Radiation Therapy Oncology Group) 9802 (phase II portion of protocol)

Risk Factors predictive of a poorer PFS Astrocytoma histology Residual tumor of >/=1 cm on Postop MR Pre-operative tumor diameter of >/=4 cm

Patients with:All three unfavourable factors- PFS at 5years 13%None of the three factors- PFS at 5years 70%

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Delayed Radiation Encephalopathy

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So, on the basis of discussed data

Observation seems to be a reasonable strategy for the most favorable subset i.e.

<1 cm residual tumorPreoperative tumor diameter <4 cmOligodendroglioma histologyYounger patients Following a gross total resection (GTR).

Mature result of this trial is pending !!!!

Radiation Therapy-Standard approach

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Radiation Therapy-Standard approach

2] Dose of RT? EvidenceEORTC 22844 (Karim et al. 1996) – phase III:Postoperative RT 45 Gy vs. 59.4 Gy

5-year OS 58% with 45 Gy 59% with 59.4 Gy.

INT/NCCTG (Shaw et al. 2002) – phase III:Postoperative RT 50.4 Gy vs. 64.8 Gy

5-year OS 73% with 50.4 Gy 68% with 64.8 Gy.

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Based on these Phase III trials and Extrapolation of data of in-field recurrences in high grade gliomas

It will be prudent to limit the Postoperative RT Dose to 54 Gy.

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Why/Why Not Chemotherapy?

Why Chemotherapy?Spares the normal tissue of the brain the delayed effect of RTSome low grade glioma sare quite large meaning larger radiation

ports resulting in larger areas of normal brain exposed to RTSome low grade gliomas; particularly ones with 1p/19q deletions are

particularly sensitiveWhy not Chemotherapy?Responses disappointing in some low grade gliomas; particularly

those without 1p or 1p/19q deletionsProlonged treatment Systemic (body) toxicityQuality of life over time

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RT Alone or RT + Chemotherapy?

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Evidence

INT/RTOG 9802 trial (ASCO abstract 2008): phase III

Low-risk (<40 year + GTR) observed until symptoms

High-risk (>40 year or STR or biopsy) patients randomized to RT alone vs. RT --> PCV ×6 cycles q8 weeks

5 year OS was 72 vs. 63% (p = 0.33) 5-year PFS was 63 vs. 46%(p = 0.06) in favour of chemotherapy

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RT Alone or RT + Chemotherapy?

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Largest reported retrospective analysis of 149 patients

Temozolomide at Progression (1p/19q LOH was present in 42%)

53% - Objective response (15% - Partial response and 38% minor response) 37% - Stable disease10% - progressive disease.

Kaloshi G, Benuaich-Amiel A, Diakite F, et al: Temozolomide for low grade gliomas: predictive impact of 1p/19q loss on response and outcome. Neurology 2007; 68:1831-1836

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Phase II Trial of Temozolomide in Patients With Progressive Low-Grade Glioma(Jennifer A. Quinn et al)Objective response rate - 61% (24% CR and 37% PR)Stable disease - 35%

IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas.(C. Houillier et al) Neurology October 26, 2010 vol. 75 no. 17 1560-1566

1p-19q codeletion, MGMT promoter methylation, and IDH mutation (p = 0.01) were correlated with a higher rate of response to temozolomide

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EORTC 22033-26033/CE5 phase III randomized trial for low grade glioma: Phase III EORTC 22033-26033/NCIC CE5 intergroup trial compares 50.4 Gy radiotherapy with up-front temozolomide in previously untreated low-grade glioma (Open to accrual)

Conclusion:

Low-grade gliomas respond to temozolomide

Loss of chromosome 1p/19q predicts both a durable chemosensitivity and a favorable outcome

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If Chemotherapy added to RT- Which Chemotherapy?

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Concerns about toxicity profile of PCV

Nitrosoureas (In PCV) – Notorious for secondary malignancy

Procarbazine - Infertility

Availability of lesser toxic and effective substitute as Temozolomide

Oral administration- Convenient dosing of Temozolomide

Makes Temozolomide more preferable an option with respect to PCV chemotherapy

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Disease Progression after PORT?

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Options IncludeResurgery (If resectable)Chemotherapy (Unresectable disease)Reirradiation with SRS/FSRT (Small recurrences)Newer agents under trial (Blocking mTOR with an

investigational agent ridaforolimus ).

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Chemotherapy

Many/most low grade Oligodendrogliomas respond to chemotherapy; sometimes dramatically and for prolonged periods

Clinical improvement, decreased szeven in patients without obvious improvement on MRI

PCV (procarbazine, CCNU, vincristine)TemozolomideLength of treatment? Clearer with PCV than TMZ but PCV more

toxic1p/19q loss predicts response-in almost all ptsPts with 1p/19q intact LGO, LGOA, LGA less likely to respond to

chemotherapy; may be better served by RT if/when they need treatment

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Chemotherapy

Chemotherapy Risks/ToxicityMyelosuppression: acute, chronic, delayedOther organ toxicitiesQuality of lifeToxicity of PCV significant and dose limitingTemozolomide

significantly less toxic Length of treatment & response rate need to be defined

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Temozolomide

Classification = alkylating agentRapid conversion at physiologic pH to MTIC (, CSF

concentration is 30% of serumMTIC cytotoxicity due to methylation of DNA at the O6

position of guanineAntitumor activity is schedule dependentCytotoxicity influenced by levels of MGMTLevels not infuenced by cytochrome p450Renal and hepatic clearance minor

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Temolozomide Toxicites

DLT is myelosuppression, nadir 21-28 days, recovery within 14 days of nadir

Immunosuppression (lymphopenia)Nausea and vomitingInfertility and mutagenesis

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Chemotherapy

Oligodendroglioma1p/19q deleted 6 cycles of Temozolomide29-Mar-17

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Targeted Therapy

Glioma cells express receptors for several different growth factors

PDGF, VEGF, EGFTargeted therapies aim to inhibit these growth factor

receptors and their tyrosine kinasebased intracellular signaling pathways

Agents bind to cell surface receptors and either compete w/ or block the normal substrates from binding or bind directly to the growth factor

In tumors dependent on such pathways for growth, the use of these agents can potentially result in tumor cell death

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Therapeutic strategy for LGG stratified by EOR, histological subtype, and molecular status

29-Mar-17Nitta et al: Neurol Med Chir (Tokyo) 53:447–454, 2013

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Conclusion Innovations within the diagnostic, therapeutic, and molecular domains are

intertwining and helping to understand and treat LGGs more effectively.Prognostic factors derived from genetic analysis and clinical

characteristics allow us to stratify patients into proper treatment groups to maximize therapeutic benefit.

Maximizing the extent of resection can delay recurrence and improve the time to transformation.

However, this approach must be balanced with preservation of neurologic function, which can be improved by using intraoperative mapping.

Chemotherapy combined with radiation therapy may prolong PFS and OS. LGGs are not homogeneous and small genetic changes can significantly

affect outcomes. Future clinical trials that classify patients according to novel prognostic

factors will probably aid in creating patient-specific treatment plans with better outcomes. 29-Mar-17

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Thank You

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low grade glioma controversies in management

Health & Medicine