gliomas.ppt - florida brain tumor association
Post on 19-Dec-2014
3.646 Views
Preview:
DESCRIPTION
TRANSCRIPT
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
edunbar@neurosurgery.ufl.edu
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
edunbar@neurosurgery.ufl.edu
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
edunbar@neurosurgery.ufl.edu
top related