gliomas.ppt - Florida Brain Tumor Association

Management of Low Grade Management of Low Grade GliomasGliomas

Management of Low Grade Management of Low Grade GliomasGliomas

Erin M. Dunbar, MDMedical Neuro-Oncology

Co-Director, Preston A. Wells, Jr., Center for Brain Tumor Therapyat the University of Florida

352-273-9000www.neurosurgery.ufl.edu

[email protected]

Erin M. Dunbar, MDMedical Neuro-Oncology

Co-Director, Preston A. Wells, Jr., Center for Brain Tumor Therapyat the University of Florida

352-273-9000www.neurosurgery.ufl.edu

[email protected]

Low Grade Gliomas (LGGs)Low Grade Gliomas (LGGs)Low Grade Gliomas (LGGs)Low Grade Gliomas (LGGs)Primary CNS tumors composed of one or more

type of neuroglial cellsependymal cells, astrocytes, oligodendrocytes, etc

Divided into subtypesbased upon their histopathologic appearancebased on known differences in behavior

Develop anywhere, but most often in the cerebral hemispheres, optic pathways, brainstem

Vary in malignant behavior, but without anaplasia (= HGGs)

Primary CNS tumors composed of one or more type of neuroglial cellsependymal cells, astrocytes, oligodendrocytes, etc

Divided into subtypesbased upon their histopathologic appearancebased on known differences in behavior

Develop anywhere, but most often in the cerebral hemispheres, optic pathways, brainstem

Vary in malignant behavior, but without anaplasia (= HGGs)

Selections of this presentation generally reference the free, online patient resource: Up-to-date patient information:

www.uptodate.com/patients/index.html

High-grade Gliomas (HGGs) More consistent growth speed

and symptoms Typically, trimodality therapy

at diagnosis Typically, continued

treatment (until intolerance/toxicity)

Typically, more consistent and inferior outcome

High-grade Gliomas (HGGs) More consistent growth speed

and symptoms Typically, trimodality therapy

at diagnosis Typically, continued

treatment (until intolerance/toxicity)

Typically, more consistent and inferior outcome

Low Grade Gliomas More variable growth speed

and symptoms Typically, uni or bimodality

therapy at diagnosis Typically, intermittent

treatment (clinical and/or radiographic progression/recurrence)

Typically, less consistent and inferior outcome

Low Grade Gliomas More variable growth speed

and symptoms Typically, uni or bimodality

therapy at diagnosis Typically, intermittent

treatment (clinical and/or radiographic progression/recurrence)

Typically, less consistent and inferior outcome

Different detectors, equipment, management, & outcomes!

US Primary Adult Brain TumorsUS Primary Adult Brain TumorsUS Primary Adult Brain TumorsUS Primary Adult Brain Tumors

46%

1%7%7%

9%

3%

27%Gliomas

Germ Cell

Schwanoma

SellarTumorsOther

Lymphoma

Meningioma

~1,800/yr diagnosed with LGGLGGs = ~ 20% of CNS gliomas

Central Brain Tumor Registry of the US, 2005 -2006

DiagnosisDiagnosisDiagnosisDiagnosisRadiographical

Clinical

Pathologic

Radiographic DiagnosisRadiographic DiagnosisRadiographic DiagnosisRadiographic Diagnosis MRI (and CT)

Standard for imaging Typically in cerebral

hemispheres Typically, little mass-effect ~80% non-contrast

enhancing at presentationException: JPAs

Calcifications, sometimesUsually odendrogliomas

Functional imaging Emerging role for imaging Positron-emission

tomography (PET)Typically “cold” (glucose

hypo-metabolism) Thallium-201 SPECT Etc.

MRI (and CT) Standard for imaging Typically in cerebral

hemispheres Typically, little mass-effect ~80% non-contrast

enhancing at presentationException: JPAs

Calcifications, sometimesUsually odendrogliomas

Functional imaging Emerging role for imaging Positron-emission

tomography (PET)Typically “cold” (glucose

hypo-metabolism) Thallium-201 SPECT Etc.

imaging.birjournals.org

Clinical DiagnosisClinical DiagnosisClinical DiagnosisClinical Diagnosis

Symptoms from:location of the tumor

Weakness, ataxia, seizures, etc.

seizures can be as high as ~80%

result of increased intracranial pressureheadache, change in

mental status, etc.

Symptoms from:location of the tumor

Weakness, ataxia, seizures, etc.

seizures can be as high as ~80%

result of increased intracranial pressureheadache, change in

mental status, etc.

http://content.revolutionhealth.com/contentimages/images-image_popup-ww990304.jpg

PrognosisPrognosisPrognosisPrognosis

Improving! In general, longer survival than HGGs,

regardless of treatmentHighly variable, likely impacted by:

Histologic subtypeAgeGeneral healthPerformance status (functionality, activity)Anatomical locationUnique profile of tumorPreferences & approach to treatment

Improving! In general, longer survival than HGGs,

regardless of treatmentHighly variable, likely impacted by:

Histologic subtypeAgeGeneral healthPerformance status (functionality, activity)Anatomical locationUnique profile of tumorPreferences & approach to treatment

Pathologic DiagnosisPathologic DiagnosisPathologic DiagnosisPathologic Diagnosis Degree of Malignancy

Absence of anaplasia (= defines HGGs)

Example of grading system… Cell Type of Origin

Pure vs mixedExample of subtypes….

Molecular/Genetic19/19q co-deletion by FISH

=Oligodendroglioma lineagechromosomal abnormality, short arm of

chromosome 1 (1p) & the long arm of chromosome 19 (19q)

Prognostic for improved outcome, regardless of treatment

Degree of MalignancyAbsence of anaplasia (= defines HGGs)

Example of grading system… Cell Type of Origin

Pure vs mixedExample of subtypes….

Molecular/Genetic19/19q co-deletion by FISH

=Oligodendroglioma lineagechromosomal abnormality, short arm of

chromosome 1 (1p) & the long arm of chromosome 19 (19q)

Prognostic for improved outcome, regardless of treatment

http://www.neuropathologyweb.org/chapter7/images7/7-gemisto.jpg; http://www.nature.com/modpathol/journal/v18/n9/thumbs/3800415f1th.jpg

WHO Grading System (evolves)WHO Grading System (evolves)

Low-gradeWHO Grade I i.e., Juvenile Pilocytic Astrocytoma

WHO Grade II i.e., Diffuse Astrocytoma

High-grade WHO Grade III i.e., Anaplastic Astrocytoma

WHO Grade IV i.e., Glioblastoma Multiforme

Low-gradeWHO Grade I i.e., Juvenile Pilocytic Astrocytoma

WHO Grade II i.e., Diffuse Astrocytoma

High-grade WHO Grade III i.e., Anaplastic Astrocytoma

WHO Grade IV i.e., Glioblastoma Multiforme

http://www.suck.uk.com/photos/FireBucket1.jpg

Examples of LGG SubtypesExamples of LGG SubtypesExamples of LGG SubtypesExamples of LGG Subtypes

Diffuse astrocytomasMost common LGG,

peak ~ mid-30sSurvival highly

variable, average ~ 7 yrs

Typically, slow clinical/radiographic progression initially

Usually speeds & eventually progresses to ~ HGGs

Diffuse astrocytomasMost common LGG,

peak ~ mid-30sSurvival highly

variable, average ~ 7 yrs

Typically, slow clinical/radiographic progression initially

Usually speeds & eventually progresses to ~ HGGs

http://www.nature.com/ncponc/journal/v4/n6/images/ncponc0820-f1.jpg

Subtype Examples, cont’dSubtype Examples, cont’dSubtype Examples, cont’dSubtype Examples, cont’dOligodendrogliomas

Less common, peak ~ late 30sSurvival highly variable, but ~ 10

yrsmost common in cerebral

hemispheresTypically, seizures Often, calcifications

imaging or under the microscopeTypically, better outcome than

other LGGs, regardless of therapyespecially with 1p/1q co-deletions

Typically, more responsive to chemotherapy

especially with 1p/1q co-deletions

OligodendrogliomasLess common, peak ~ late 30sSurvival highly variable, but ~ 10

yrsmost common in cerebral

hemispheresTypically, seizures Often, calcifications

imaging or under the microscopeTypically, better outcome than

other LGGs, regardless of therapyespecially with 1p/1q co-deletions

Typically, more responsive to chemotherapy

especially with 1p/1q co-deletions

http://www.neuropathologyweb.org/chapter7/images7/7-15l.jpg

Subtype Examples, Cont’dSubtype Examples, Cont’dSubtype Examples, Cont’dSubtype Examples, Cont’d  Juvenile pilocytic astrocytomas (JPAs)

Typically, occur < 25 years Typically, in cerebellar hemispheres & around 3rd ventricle Typically cystic, well-demarcated, and contrast-enhancing Typically, substantially better outcome than other LGGs

Can be cured by resection Gangliogliomas

Typically, in temporal lobe Typically, seizures History and outcome ~ JPAs

Ependymomas Typically, occur in young Typically, around 4th ventricle More variable outcome

impacted by age, extent of resection, histology Other rare LGGs

pleomorphic xanthoastrocytomas, subependymomas, desmoplastic gangliogliomas

Typically, long history Can be cured by resection

 Juvenile pilocytic astrocytomas (JPAs) Typically, occur < 25 years Typically, in cerebellar hemispheres & around 3rd ventricle Typically cystic, well-demarcated, and contrast-enhancing Typically, substantially better outcome than other LGGs

Can be cured by resection Gangliogliomas

Typically, in temporal lobe Typically, seizures History and outcome ~ JPAs

Ependymomas Typically, occur in young Typically, around 4th ventricle More variable outcome

impacted by age, extent of resection, histology Other rare LGGs

pleomorphic xanthoastrocytomas, subependymomas, desmoplastic gangliogliomas

Typically, long history Can be cured by resection

http://www.neuropathologyweb.org/chapter7/images7/7-16b.jpg http://www.pathconsultddx.com/images/S1559867506702327/gr1-sml.jpg

TreatmentTreatmentTreatmentTreatment

IndicationsMeasurements

Multidisciplinary Care Teams Tumor & Supportive Treatments

IndicationsMeasurements

Multidisciplinary Care Teams Tumor & Supportive Treatments

Indications for TreatmentIndications for TreatmentIndications for TreatmentIndications for TreatmentRadiographicClinical

Seizures, especially if progressive and/or difficult to manage medically

Increased intracranial pressure (mass-effect)Etc.

Timing i.e., at diagnosis or at progression

Highly individualizedPreferences and approach

Patient, providers“Controversial”Evolving!

RadiographicClinical

Seizures, especially if progressive and/or difficult to manage medically

Increased intracranial pressure (mass-effect)Etc.

Timing i.e., at diagnosis or at progression

Highly individualizedPreferences and approach

Patient, providers“Controversial”Evolving!

Measurements of Treatment Measurements of Treatment ResponseResponse

Measurements of Treatment Measurements of Treatment ResponseResponse

For both Radiographic and Clinical:Difficult

i.e., LGGs often non-enhancing and ill-definedi.e., prolonged natural history

“Controversial”i.e., clinical improvement without radiographic

improvementImpacts: Diagnosis, Natural History,

Response to treatmentEvolvingThe most reliable end point remains survival

For both Radiographic and Clinical:Difficult

i.e., LGGs often non-enhancing and ill-definedi.e., prolonged natural history

“Controversial”i.e., clinical improvement without radiographic

improvementImpacts: Diagnosis, Natural History,

Response to treatmentEvolvingThe most reliable end point remains survival

Neuro-Oncology Neuro-Oncology Multidisciplinary Care TeamMultidisciplinary Care Team

Neuro-Oncology Neuro-Oncology Multidisciplinary Care TeamMultidisciplinary Care Team

Therapists Trial Coordinators Psychologists,

PharmacistsPsychiatristsGenetic counselorsNutritionistsNeuro-Oncologists

Therapists Trial Coordinators Psychologists,

PharmacistsPsychiatristsGenetic counselorsNutritionistsNeuro-Oncologists

Palliative & symptom care specialists

NursesSocial workersPathologistsRadiologistsResearchersResearch Office StaffTrainees

Palliative & symptom care specialists

NursesSocial workersPathologistsRadiologistsResearchersResearch Office StaffTrainees

Our Multidisciplinary Team at the

Specialty TeamsSpecialty TeamsSpecialty TeamsSpecialty Teams

NeurosurgeryNeurosurgeryNeurosurgeryNeurosurgery

leaders in applying modern microsurgical and image guided techniques

latest microsurgical, computer assisted, and radiosurgical techniques

patented UF Radiosurgery System, has treated > 2800 patients

Novel translational & clinical research

leaders in applying modern microsurgical and image guided techniques

latest microsurgical, computer assisted, and radiosurgical techniques

patented UF Radiosurgery System, has treated > 2800 patients

Novel translational & clinical research

Additional Faculty:Albert J. Rhoton, Jr., MDJ. Richard Lister, MD, MBAKelly D. Foote, MDBrian L. Hoh, MDStephen B. Lewis, MDSteven N. Roper, MDR. Patrick Jacob, MDGregory A. Murad, MDJay Mocco, MDJobyna Whiting, MDR. Rick Bhasin, MD

William A. Friedman, MD David W. Pincus, MD, PhD

Medical Neuro-OncologyMedical Neuro-OncologyMedical Neuro-OncologyMedical Neuro-Oncologyprovides a full complement of

comprehensive adult and pediatric services

novel UF clinical researchparticipation in consortium and

industry-sponsored researchexperimental & palliative

therapies. robust tissue repositories and

clinical databases

provides a full complement of comprehensive adult and pediatric services

novel UF clinical researchparticipation in consortium and

industry-sponsored researchexperimental & palliative

therapies. robust tissue repositories and

clinical databases

Erin M. Dunbar, MD Amy A. Smith, MD

NeuroscienceNeuroscienceNeuroscienceNeuroscienceNovel individual and

collaborative investigations A full spectrum of research,

from fundamental discovery to clinical application

Evelyn F. and William L. McKnight Brain Institute: one of the world’s largest research institutions devoted to the nervous system and its disorders

Novel individual and collaborative investigations

A full spectrum of research, from fundamental discovery to clinical application

Evelyn F. and William L. McKnight Brain Institute: one of the world’s largest research institutions devoted to the nervous system and its disorders

Additional faculty: Eric Laywell, PhD Wolfgang Streit, PhD David Borchelt, PhD And many others…

Additional faculty: Eric Laywell, PhD Wolfgang Streit, PhD David Borchelt, PhD And many others…

Dennis Steindler, PhD Brent Reynolds, PhD

Neuro-PathologyNeuro-PathologyNeuro-PathologyNeuro-Pathology specializes in intra-operative

diagnoses, tissue preservation and specialized diagnostic testing

diagnoses >500 brain tumors a year and provides national consultative referral services

Provide diagnoses for the Florida Center for Brain Tumor Research, a statewide brain tumor bank and associated database

specializes in intra-operative diagnoses, tissue preservation and specialized diagnostic testing

diagnoses >500 brain tumors a year and provides national consultative referral services

Provide diagnoses for the Florida Center for Brain Tumor Research, a statewide brain tumor bank and associated database

Additional faculty: Tom A. Eskin, MD

Jing Qui, MD, PhD Anthony T. Yachnis, MD, MS

Radiation-OncologyRadiation-OncologyRadiation-OncologyRadiation-Oncologyprovides state-of-the-art

external beam radiation and brachytherapy using a team approach

The University of Florida, Jacksonville, houses the proton therapy treatment facility

Part of the UF Radiosurgery Team

UF and consortium trials

provides state-of-the-art external beam radiation and brachytherapy using a team approach

The University of Florida, Jacksonville, houses the proton therapy treatment facility

Part of the UF Radiosurgery Team

UF and consortium trials

Additional Faculty:

Nancy Mendenhall, MD

Robert Malayapa, MD

Sameer Keole, MD

Robert J. Amdur, MD William Mendenhall, MD

Neuro-RadiologyNeuro-RadiologyNeuro-RadiologyNeuro-Radiology

Provides complete adult and pediatric neuroimaging services

Provides imaging-guided biopsies

Provides consultative services

Research Collaborations

Provides complete adult and pediatric neuroimaging services

Provides imaging-guided biopsies

Provides consultative services

Research Collaborations

Additional Faculty: Jeffery Bennett, MD Fabio Rodriguez, MD Anthony A. Mancuso, MD

Additional Faculty: Jeffery Bennett, MD Fabio Rodriguez, MD Anthony A. Mancuso, MD

Ronald G. Quisling, MD

Many Other SpecialistsMany Other SpecialistsMany Other SpecialistsMany Other Specialists

Neuro-Rehabilitation

NeurologyNeuro-Intensive

careNeuro-AnesthesiaPsychology and

Psychiatry

Neuro-Rehabilitation

NeurologyNeuro-Intensive

careNeuro-AnesthesiaPsychology and

Psychiatry

Pain managementPsychology &

PsychiatryGenetic ScreeningPalliative ServicesHyperbaric Oxygen

Therapy

Pain managementPsychology &

PsychiatryGenetic ScreeningPalliative ServicesHyperbaric Oxygen

Therapy

Multidisciplinary CareMultidisciplinary CareMultidisciplinary CareMultidisciplinary CarePatent navigator for patients & referralsCoordinated clinic visitsCoordinated hospital careTumor boardsEducation and support services

Education & Support GroupEducation room in Clinic and on Wards

Transportation between care

Patent navigator for patients & referralsCoordinated clinic visitsCoordinated hospital careTumor boardsEducation and support services

Education & Support GroupEducation room in Clinic and on Wards

Transportation between care

Clinical ResearchClinical ResearchBasic & Translational Basic & Translational

ResearchResearch

Clinical ResearchClinical ResearchBasic & Translational Basic & Translational

ResearchResearch

Basic & Translational Basic & Translational ResearchResearch

Basic & Translational Basic & Translational ResearchResearch

Numerous novel UF investigator, consortium, industry, government sponsored trials & experiments

Please visit www.neurosurgery.ufl.edu

Numerous novel UF investigator, consortium, industry, government sponsored trials & experiments

Please visit www.neurosurgery.ufl.edu

Tumor & Supportive Tumor & Supportive TreatmentTreatment

Tumor & Supportive Tumor & Supportive TreatmentTreatment

Goals:Prolong overall survivalProlong progression-free survival Promote quality of life (QOL)

Improve, maintain, slow the declinePromote neurologic function

Improve, maintain, slow the declineMinimize treatment-related effects

Prevent, minimize, delay the onset, improve

Goals:Prolong overall survivalProlong progression-free survival Promote quality of life (QOL)

Improve, maintain, slow the declinePromote neurologic function

Improve, maintain, slow the declineMinimize treatment-related effects

Prevent, minimize, delay the onset, improve

Tumor Treatment OptionsTumor Treatment OptionsTumor Treatment OptionsTumor Treatment OptionsOptimal strategy remains unknown

timing, order, and combinationsMaximal safe resection

Pre-Operative:Imaging that identifies areas of function

Peri-Operative:MRI-guided surgeryPatient wake and being tested

RadiationExternal beamFractionated

ChemotherapyVarious timing, types, combos

Optimal strategy remains unknowntiming, order, and combinations

Maximal safe resectionPre-Operative:

Imaging that identifies areas of functionPeri-Operative:

MRI-guided surgeryPatient wake and being tested

RadiationExternal beamFractionated

ChemotherapyVarious timing, types, combos

Maximal Safe ResectionMaximal Safe ResectionMaximal Safe ResectionMaximal Safe Resection

Diagnosis & molecular characterizationDebulk tumor and mass-effect

Alter symptoms+/- add local therapy

Diagnosis & molecular characterizationDebulk tumor and mass-effect

Alter symptoms+/- add local therapy

Surgery Cont’dSurgery Cont’dSurgery Cont’dSurgery Cont’dTiming

Immediately, if a large mass or extensive symptomsDelayed, if small mass or minimal symptoms

Careful clinical & radiographic surveillance beginsSubsequent resection, if concern for progressive mass or

symptomsespecially if medically refractory or concern for HGG

Extent of resectionMaximal safe resection when feasible, especially if

symptomatic or presumed diagnosis is unclearbecause of infiltrative nature, gross total resection is often

not possibleBiopsy when resection not feasible, if minimal symptoms, if

presumed to be LGGNo prospective randomized trials

numerous (inherently biased) retrospective reviews report improved outcome with earlier and

more maximal resection

Timing Immediately, if a large mass or extensive symptomsDelayed, if small mass or minimal symptoms

Careful clinical & radiographic surveillance beginsSubsequent resection, if concern for progressive mass or

symptomsespecially if medically refractory or concern for HGG

Extent of resectionMaximal safe resection when feasible, especially if

symptomatic or presumed diagnosis is unclearbecause of infiltrative nature, gross total resection is often

not possibleBiopsy when resection not feasible, if minimal symptoms, if

presumed to be LGGNo prospective randomized trials

numerous (inherently biased) retrospective reviews report improved outcome with earlier and

more maximal resection

Tumor Resection: Pre-OperativeTumor Resection: Pre-OperativeTumor Resection: Pre-OperativeTumor Resection: Pre-Operative

Tumor Resection: Intra-OperativeTumor Resection: Intra-OperativeTumor Resection: Intra-OperativeTumor Resection: Intra-Operative

Radiation (RT)Radiation (RT)Radiation (RT)Radiation (RT)

Ionizing radiationDNA damage

Preferential damage to rapidly dividing cells

Ionizing radiationDNA damage

Preferential damage to rapidly dividing cells

Fractionated, External BeamFractionated, External BeamFractionated, External BeamFractionated, External Beam

Radiation (RT), Cont’dRadiation (RT), Cont’dRadiation (RT), Cont’dRadiation (RT), Cont’d Timing

Immediate, if significant mass or symptomsespecially if only biopsy or presence of “high-risk” features

= astrocytic, significant disease-related neurological symptoms recurrent or progression, age ≥40, size >6 cm, tumor crossing midline, high cell activity

Delayed, if minimal mass or symptomsincluding after resection

Subsequent RT, rarely performedi.e., unless recurrence/progression is in new location

ExtentTypically conforming to within 1-2.5 cm of abnormalityTypically ~54 Gy, external beam, fractionated, in six weeks

Timing Immediate, if significant mass or symptoms

especially if only biopsy or presence of “high-risk” features= astrocytic, significant disease-related neurological

symptoms recurrent or progression, age ≥40, size >6 cm, tumor crossing midline, high cell activity

Delayed, if minimal mass or symptomsincluding after resection

Subsequent RT, rarely performedi.e., unless recurrence/progression is in new location

ExtentTypically conforming to within 1-2.5 cm of abnormalityTypically ~54 Gy, external beam, fractionated, in six weeks

RT, cont’dRT, cont’dRT, cont’dRT, cont’dControversy remains over the relative effects

of recurrence/progression vs. the treatment Randomized, prospective trials:Timing of RT

EORTC 22845 randomized patients (after biopsy or sub-total resection) to receive either immediate RT or no therapy until progression.

At a median follow-up of almost eight years, immediate postoperative RT significantly prolonged the progression-free survival (median 5.4 versus 3.7 years, without postoperative RT), but did not affect overall survival (7.4 versus 7.2 years).

Better seizure control was observed among patients receiving postoperative RT.

Dose and schedule of RT  EORTC 22844 & a North American Multi-center trial both failed to show

a survival benefit from escalation of the dose of RT. Other fractionation techniques (hyper-fractionated and fractionated

stereotactic radiotherapy) have not shown benefit.

Controversy remains over the relative effects of recurrence/progression vs. the treatment

Randomized, prospective trials:Timing of RT

EORTC 22845 randomized patients (after biopsy or sub-total resection) to receive either immediate RT or no therapy until progression.

At a median follow-up of almost eight years, immediate postoperative RT significantly prolonged the progression-free survival (median 5.4 versus 3.7 years, without postoperative RT), but did not affect overall survival (7.4 versus 7.2 years).

Better seizure control was observed among patients receiving postoperative RT.

Dose and schedule of RT  EORTC 22844 & a North American Multi-center trial both failed to show

a survival benefit from escalation of the dose of RT. Other fractionation techniques (hyper-fractionated and fractionated

stereotactic radiotherapy) have not shown benefit.

ChemotherapyChemotherapyChemotherapyChemotherapy

Must cross the blood brain barrierOften augments effects of radiation

Various actions

Must cross the blood brain barrierOften augments effects of radiation

Various actions

Examples of ChemotherapyExamples of ChemotherapyExamples of ChemotherapyExamples of Chemotherapy

Cytostatic chemo-therapy

Cytotoxic

Cytotoxic ChemotherapyCytotoxic ChemotherapyCytotoxic ChemotherapyCytotoxic Chemotherapy

Typically, causes DNA lesions

Example:Temozolomide (Temodar)

Minimizes the repair of damaged DNA

Via “silencing” the DNA repair protein MGMT

Typically, causes DNA lesions

Example:Temozolomide (Temodar)

Minimizes the repair of damaged DNA

Via “silencing” the DNA repair protein MGMT

Malcolm, JM, et al, Am J Cancer, 02

Cytostatic ChemotherapyCytostatic ChemotherapyExamples include Biologic, Small molecules, “Targeted” agentsExamples include Biologic, Small molecules, “Targeted” agents

Cytostatic ChemotherapyCytostatic ChemotherapyExamples include Biologic, Small molecules, “Targeted” agentsExamples include Biologic, Small molecules, “Targeted” agents

Typically, more targeted action (treatment) to the “target” cell; Less targeted action (damage) to “bystander” cells.

Example: Vascular-endothelial growth factor receptor (VEGF-R) inhibition (Bevacizumab (Avastin))

Alters edema & imaging-featuresNormalizes the vasculatureHopefully facilitates chemotherapy

into the tumor & inhibits tumor

Typically, more targeted action (treatment) to the “target” cell; Less targeted action (damage) to “bystander” cells.

Example: Vascular-endothelial growth factor receptor (VEGF-R) inhibition (Bevacizumab (Avastin))

Alters edema & imaging-featuresNormalizes the vasculatureHopefully facilitates chemotherapy

into the tumor & inhibits tumor

Vregenbergh, J, JCO, 2007; Clinical Ce Res, Feb 2007

Chemotherapy, cont’dChemotherapy, cont’dChemotherapy, cont’dChemotherapy, cont’d Timing

Typically, reserved for recurrenceHowever, despite a lack of strong evidence, increasing trends

for:Increasing now with oligodendrogliomas, especially with

1p/19q co-deletionIncreasingly used because of emergence of presumably

“more tolerable or safe chemos”—really?Often used for symptoms, especially medically refractory

seizures Regimens

Numerous, not often compared prospectivelyTypically, temozolomide-based > PCV > clinical trials

Controversies include:measurement of response, optimal timing, long-term

toxicities, alteration of LGG natural history, etc.

TimingTypically, reserved for recurrenceHowever, despite a lack of strong evidence, increasing trends

for:Increasing now with oligodendrogliomas, especially with

1p/19q co-deletionIncreasingly used because of emergence of presumably

“more tolerable or safe chemos”—really?Often used for symptoms, especially medically refractory

seizures Regimens

Numerous, not often compared prospectivelyTypically, temozolomide-based > PCV > clinical trials

Controversies include:measurement of response, optimal timing, long-term

toxicities, alteration of LGG natural history, etc.

Chemotherapy, cont’dChemotherapy, cont’dChemotherapy, cont’dChemotherapy, cont’d Clinical Trials

Difficulty to interpret trials that include diverse histologies One example, RTOG 9802, prospectively randomized trial failed

to show improved outcome with routine post-operative chemo patients with favorable prognosis (<40yo, gross total

resection) randomized to observationpatients with unfavorable prognosis (those age ≥40 years or

whose surgery was a subtotal resection or biopsy only) randomized to to postoperative RT (54 Gy in 30 fractions) plus six cycles of PCV chemotherapy or the same dose of RT without chemotherapy

Progression free survival was slightly improved, but at the expense of moderate treatment-toxicities

Examples of retrospective or small prospective trials of chemotherapy for ~ 25-45%Usually temozolomide and partial responses

Clinical TrialsDifficulty to interpret trials that include diverse histologies

One example, RTOG 9802, prospectively randomized trial failed to show improved outcome with routine post-operative chemo patients with favorable prognosis (<40yo, gross total

resection) randomized to observationpatients with unfavorable prognosis (those age ≥40 years or

whose surgery was a subtotal resection or biopsy only) randomized to to postoperative RT (54 Gy in 30 fractions) plus six cycles of PCV chemotherapy or the same dose of RT without chemotherapy

Progression free survival was slightly improved, but at the expense of moderate treatment-toxicities

Examples of retrospective or small prospective trials of chemotherapy for ~ 25-45%Usually temozolomide and partial responses

Treatment at Treatment at Recurrence/ProgressionRecurrence/Progression

Treatment at Treatment at Recurrence/ProgressionRecurrence/Progression

Controversy over true tumor progression vs. pseudo-progression (aka: treatment effect, radiation-necrosis)

Single or multimodality combinations of re-resection, radiation, and chemotherapy are all used

Highly individualizedGoals & preferences, age, overall health, etc.!

Controversy over true tumor progression vs. pseudo-progression (aka: treatment effect, radiation-necrosis)

Single or multimodality combinations of re-resection, radiation, and chemotherapy are all used

Highly individualizedGoals & preferences, age, overall health, etc.!

Supportive TreatmentSupportive TreatmentSupportive TreatmentSupportive Treatment

-Extraordinarily Important!-Cerebral Edema-Seizures-Iatrogenic side-effects (from treatment)

-Neurologic deficits of all types-Myelo-suppression, infection-Fatigue-Neuro-cognitive-organ-toxicity-”radiation-necrosis”-etc.

-Extraordinarily Important!-Cerebral Edema-Seizures-Iatrogenic side-effects (from treatment)

-Neurologic deficits of all types-Myelo-suppression, infection-Fatigue-Neuro-cognitive-organ-toxicity-”radiation-necrosis”-etc.

Our FutureOur FutureOur FutureOur Future

Future Improvements Needed!Future Improvements Needed!Future Improvements Needed!Future Improvements Needed! Areas of remaining controversy include: Important of extent of resection Timing of RT +/- chemo

Upfront or at recurrence/progression An aggressive treatment approach including immediate surgical

intervention versus a delayed intervention in patients with limited disease and symptoms

Relative contribution of the toxicities of the tumor recurrence vs. the treatment

Role of chemotherapy-only approaches Are newer chemos really safer and more effective?

Importance of treating different LGG subtypes differently Molecular/genetic profile, etc.

QOL, neurological performance status Patient & caregiver, resource utilization

Areas of remaining controversy include: Important of extent of resection Timing of RT +/- chemo

Upfront or at recurrence/progression An aggressive treatment approach including immediate surgical

intervention versus a delayed intervention in patients with limited disease and symptoms

Relative contribution of the toxicities of the tumor recurrence vs. the treatment

Role of chemotherapy-only approaches Are newer chemos really safer and more effective?

Importance of treating different LGG subtypes differently Molecular/genetic profile, etc.

QOL, neurological performance status Patient & caregiver, resource utilization

Many being addressed in trials now!

Information, Support, & TrialsInformation, Support, & TrialsInformation, Support, & TrialsInformation, Support, & Trials Information

www.uptodate.com/patients www.plwc.org www.cancer.gov

Support www.fbta.org www.braintumor.org www.abta.org

Trials www.neurosurgery.ufl.edu www.cancer.gov www.clinicaltrials.gov Brain Tumor Center websites

MANY MORE!

Information www.uptodate.com/patients www.plwc.org www.cancer.gov

Support www.fbta.org www.braintumor.org www.abta.org

Trials www.neurosurgery.ufl.edu www.cancer.gov www.clinicaltrials.gov Brain Tumor Center websites

MANY MORE!

FutureFutureFutureFutureYour ideas & partnership is needed

Unanswered questions and unmet needsCollaboration in care, research, education, &

advocacyI warmly welcome you to contact

me regarding:Multidisciplinary careSupport group & educational eventsWebsite & Hope Heals Run FCBTR tissue donation Etc.

Your ideas & partnership is neededUnanswered questions and unmet needsCollaboration in care, research, education, &

advocacyI warmly welcome you to contact

me regarding:Multidisciplinary careSupport group & educational eventsWebsite & Hope Heals Run FCBTR tissue donation Etc.

We’ll see you atWe’ll see you atWe’ll see you atWe’ll see you at

Fall 2009------------------------------------------------------------------

The EndThe EndThe EndThe EndThank youThank you

352-273-9000

www.neurosurgery.ufl.edu

[email protected]