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Management of Low GradeManagement of Low Grade
GliomasGliomas
Erin M. Dunbar, MD
Medical Neuro-Oncology
Co-Director, Prest...
Low Grade Gliomas (LGGs)Low Grade Gliomas (LGGs)
Primary CNS tumors composed of one or more
type of neuroglial cells
epe...
High-grade Gliomas (HGGs)
 More consistent growth speed
and symptoms
 Typically, trimodality therapy
at diagnosis
 Typi...
US Primary Adult Brain TumorsUS Primary Adult Brain Tumors
46%
1%7%
7%
9%
3%
27%
Gliomas
Germ Cell
Schwanoma
Sellar
Tumors...
DiagnosisDiagnosis
Radiographical
Clinical
Pathologic
Radiographic DiagnosisRadiographic Diagnosis
 MRI (and CT)
 Standard for imaging
 Typically in cerebral
hemispheres
 T...
Clinical DiagnosisClinical Diagnosis
Symptoms from:
location of the tumor
Weakness, ataxia,
seizures, etc.
seizures can...
PrognosisPrognosis
Improving!
In general, longer survival than HGGs,
regardless of treatment
Highly variable, likely im...
Pathologic DiagnosisPathologic Diagnosis
 Degree of Malignancy
Absence of anaplasia (= defines HGGs)
Example of grading...
WHO Grading System (evolves)WHO Grading System (evolves)
Low-grade
WHO Grade I i.e., Juvenile Pilocytic Astrocytoma
WHO ...
Examples of LGG SubtypesExamples of LGG Subtypes
Diffuse astrocytomas
Most common LGG,
peak ~ mid-30s
Survival highly
v...
Subtype Examples, cont’dSubtype Examples, cont’d
Oligodendrogliomas
Less common, peak ~ late 30s
Survival highly variab...
Subtype Examples, Cont’dSubtype Examples, Cont’d
 Juvenile pilocytic astrocytomas (JPAs)
 Typically, occur < 25 years
 ...
TreatmentTreatment
Indications
Measurements
Multidisciplinary Care Teams
Tumor & Supportive Treatments
Indications for TreatmentIndications for Treatment
Radiographic
Clinical
Seizures, especially if progressive and/or dif...
Measurements of TreatmentMeasurements of Treatment
ResponseResponse
For both Radiographic and Clinical:
Difficult
i.e., ...
Neuro-OncologyNeuro-Oncology
Multidisciplinary Care TeamMultidisciplinary Care Team
Therapists
Trial Coordinators
Psych...
Our Multidisciplinary Team at the
Specialty TeamsSpecialty Teams
NeurosurgeryNeurosurgery
leaders in applying modern
microsurgical and image guided
techniques
latest microsurgical, comp...
Medical Neuro-OncologyMedical Neuro-Oncology
provides a full complement of
comprehensive adult and
pediatric services
no...
NeuroscienceNeuroscience
Novel individual and
collaborative investigations
A full spectrum of research,
from fundamental...
Neuro-PathologyNeuro-Pathology
 specializes in intra-operative
diagnoses, tissue preservation
and specialized diagnostic
...
Radiation-OncologyRadiation-Oncology
provides state-of-the-art
external beam radiation and
brachytherapy using a team
app...
Neuro-RadiologyNeuro-Radiology
Provides complete adult
and pediatric
neuroimaging services
Provides imaging-guided
biops...
Many Other SpecialistsMany Other Specialists
Neuro-
Rehabilitation
Neurology
Neuro-Intensive
care
Neuro-Anesthesia
Ps...
Multidisciplinary CareMultidisciplinary Care
Patent navigator for patients & referrals
Coordinated clinic visits
Coordi...
Clinical ResearchClinical Research
Basic & Translational ResearchBasic & Translational Research
Basic & TranslationalBasic & Translational
ResearchResearch
Numerous novel UF investigator,
consortium, industry, governm...
Tumor & SupportiveTumor & Supportive
TreatmentTreatment
Goals:
Prolong overall survival
Prolong progression-free surviva...
Tumor Treatment OptionsTumor Treatment Options
Optimal strategy remains unknown
timing, order, and combinations
Maximal...
Maximal Safe ResectionMaximal Safe Resection
Diagnosis & molecular characterization
Debulk tumor and mass-effect
Alter sym...
Surgery Cont’dSurgery Cont’d
Timing
Immediately, if a large mass or extensive symptoms
Delayed, if small mass or minima...
Tumor Resection: Pre-OperativeTumor Resection: Pre-Operative
Tumor Resection: Intra-OperativeTumor Resection: Intra-Operative
Radiation (RT)Radiation (RT)
Ionizing radiation
DNA damage
Preferential damage to rapidly dividing
cells
Fractionated, External BeamFractionated, External Beam
Radiation (RT), Cont’dRadiation (RT), Cont’d
 Timing
Immediate, if significant mass or symptoms
especially if only biop...
RT, cont’dRT, cont’d
Controversy remains over the relative effects
of recurrence/progression vs. the treatment
Randomize...
ChemotherapyChemotherapy
Must cross the blood brain barrier
Often augments effects of radiation
Various actions
Examples of ChemotherapyExamples of Chemotherapy
Cytostatic
chemo-
therapy
Cytotoxic
Cytotoxic ChemotherapyCytotoxic Chemotherapy
Typically, causes DNA
lesions
Example:Temozolomide
(Temodar)
Minimizes the...
Cytostatic ChemotherapyCytostatic Chemotherapy
Examples include Biologic, Small molecules, “Targeted” agentsExamples inclu...
Chemotherapy, cont’dChemotherapy, cont’d
 Timing
Typically, reserved for recurrence
However, despite a lack of strong e...
Chemotherapy, cont’dChemotherapy, cont’d
 Clinical Trials
Difficulty to interpret trials that include diverse histologie...
Treatment atTreatment at
Recurrence/ProgressionRecurrence/Progression
Controversy over true tumor progression vs.
pseudo-...
Supportive TreatmentSupportive Treatment
-Extraordinarily Important!
-Cerebral Edema
-Seizures
-Iatrogenic side-effects (f...
Our FutureOur Future
Future Improvements Needed!Future Improvements Needed!
 Areas of remaining controversy include:
 Important of extent of ...
Information, Support, &Information, Support, &
TrialsTrials Information
 www.uptodate.com/patients
 www.plwc.org
 www....
FutureFuture
Your ideas & partnership is needed
Unanswered questions and unmet needs
Collaboration in care, research, e...
We’ll see you atWe’ll see you at
Fall 2009
The EndThe End
Thank you
352-273-9000
www.neurosurgery.ufl.edu
edunbar@neurosurgery.ufl.edu
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gliomas.ppt - Florida Brain Tumor Association

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gliomas.ppt - Florida Brain Tumor Association

  1. 1. Management of Low GradeManagement of Low Grade GliomasGliomas Erin M. Dunbar, MD Medical Neuro-Oncology Co-Director, Preston A. Wells, Jr., Center for Brain Tumor Therapy at the University of Florida 352-273-9000 www.neurosurgery.ufl.edu edunbar@neurosurgery.ufl.edu
  2. 2. Low Grade Gliomas (LGGs)Low Grade Gliomas (LGGs) Primary CNS tumors composed of one or more type of neuroglial cells ependymal cells, astrocytes, oligodendrocytes, etc Divided into subtypes based upon their histopathologic appearance based 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
  3. 3. 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 Different detectors, equipment, management, & outcomes!
  4. 4. US Primary Adult Brain TumorsUS Primary Adult Brain Tumors 46% 1%7% 7% 9% 3% 27% Gliomas Germ Cell Schwanoma Sellar Tumors Other Lymphoma Meningioma ~1,800/yr diagnosed with LGG LGGs = ~ 20% of CNS gliomas Central Brain Tumor Registry of the US, 2005 -2006
  5. 5. DiagnosisDiagnosis Radiographical Clinical Pathologic
  6. 6. Radiographic DiagnosisRadiographic Diagnosis  MRI (and CT)  Standard for imaging  Typically in cerebral hemispheres  Typically, little mass-effect  ~80% non-contrast enhancing at presentation Exception: JPAs  Calcifications, sometimes Usually odendrogliomas  Functional imaging  Emerging role for imaging  Positron-emission tomography (PET) Typically “cold” (glucose hypo-metabolism)  Thallium-201 SPECT  Etc. imaging.birjournals.org
  7. 7. Clinical DiagnosisClinical Diagnosis Symptoms from: location of the tumor Weakness, ataxia, seizures, etc. seizures can be as high as ~80% result of increased intracranial pressure headache, change in mental status, etc. http://content.revolutionhealth.com/contentimages/images-image_popup-ww990304.jpg
  8. 8. PrognosisPrognosis Improving! In general, longer survival than HGGs, regardless of treatment Highly variable, likely impacted by: Histologic subtype Age General health Performance status (functionality, activity) Anatomical location Unique profile of tumor Preferences & approach to treatment
  9. 9. Pathologic DiagnosisPathologic Diagnosis  Degree of Malignancy Absence of anaplasia (= defines HGGs) Example of grading system…  Cell Type of Origin Pure vs mixed Example of subtypes….  Molecular/Genetic 19/19q co-deletion by FISH =Oligodendroglioma lineage chromosomal 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
  10. 10. WHO Grading System (evolves)WHO Grading System (evolves) Low-grade WHO 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
  11. 11. Examples of LGG SubtypesExamples of LGG Subtypes Diffuse astrocytomas Most common LGG, peak ~ mid-30s Survival 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
  12. 12. Subtype Examples, cont’dSubtype Examples, cont’d Oligodendrogliomas Less common, peak ~ late 30s Survival highly variable, but ~ 10 yrs most common in cerebral hemispheres Typically, seizures Often, calcifications imaging or under the microscope Typically, better outcome than other LGGs, regardless of therapy especially 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
  13. 13. Subtype 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 http://www.neuropathologyweb.org/chapter7/images7/7-16b.jpg http://www.pathconsultddx.com/images/S1559867506702327/gr1-sml.jpg
  14. 14. TreatmentTreatment Indications Measurements Multidisciplinary Care Teams Tumor & Supportive Treatments
  15. 15. Indications for TreatmentIndications for Treatment Radiographic Clinical 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 individualized Preferences and approach Patient, providers “Controversial” Evolving!
  16. 16. Measurements of TreatmentMeasurements of Treatment ResponseResponse For both Radiographic and Clinical: Difficult i.e., LGGs often non-enhancing and ill-defined i.e., prolonged natural history “Controversial” i.e., clinical improvement without radiographic improvement Impacts: Diagnosis, Natural History, Response to treatment Evolving The most reliable end point remains survival
  17. 17. Neuro-OncologyNeuro-Oncology Multidisciplinary Care TeamMultidisciplinary Care Team Therapists Trial Coordinators Psychologists, Pharmacists Psychiatrists Genetic counselors Nutritionists Neuro-Oncologists Palliative & symptom care specialists Nurses Social workers Pathologists Radiologists Researchers Research Office Staff Trainees
  18. 18. Our Multidisciplinary Team at the
  19. 19. Specialty TeamsSpecialty Teams
  20. 20. NeurosurgeryNeurosurgery 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., MD J. Richard Lister, MD, MBA Kelly D. Foote, MD Brian L. Hoh, MD Stephen B. Lewis, MD Steven N. Roper, MD R. Patrick Jacob, MD Gregory A. Murad, MD Jay Mocco, MD Jobyna Whiting, MD R. Rick Bhasin, MD William A. Friedman, MD David W. Pincus, MD, PhD
  21. 21. Medical Neuro-OncologyMedical Neuro-Oncology provides a full complement of comprehensive adult and pediatric services novel UF clinical research participation in consortium and industry-sponsored research experimental & palliative therapies. robust tissue repositories and clinical databases Erin M. Dunbar, MD Amy A. Smith, MD
  22. 22. NeuroscienceNeuroscience 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… Dennis Steindler, PhD Brent Reynolds, PhD
  23. 23. Neuro-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 Additional faculty: Tom A. Eskin, MD Jing Qui, MD, PhD Anthony T. Yachnis, MD, MS
  24. 24. Radiation-OncologyRadiation-Oncology 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
  25. 25. Neuro-RadiologyNeuro-Radiology 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 Ronald G. Quisling, MD
  26. 26. Many Other SpecialistsMany Other Specialists Neuro- Rehabilitation Neurology Neuro-Intensive care Neuro-Anesthesia Psychology and Psychiatry Pain management Psychology & Psychiatry Genetic Screening Palliative Services Hyperbaric Oxygen Therapy
  27. 27. Multidisciplinary CareMultidisciplinary Care Patent navigator for patients & referrals Coordinated clinic visits Coordinated hospital care Tumor boards Education and support services Education & Support Group Education room in Clinic and on Wards Transportation between care
  28. 28. Clinical ResearchClinical Research Basic & Translational ResearchBasic & Translational Research
  29. 29. Basic & TranslationalBasic & Translational ResearchResearch Numerous novel UF investigator, consortium, industry, government sponsored trials & experiments Please visit www.neurosurgery.ufl.edu
  30. 30. Tumor & SupportiveTumor & Supportive TreatmentTreatment Goals: Prolong overall survival Prolong progression-free survival Promote quality of life (QOL) Improve, maintain, slow the decline Promote neurologic function Improve, maintain, slow the decline Minimize treatment-related effects Prevent, minimize, delay the onset, improve
  31. 31. Tumor Treatment OptionsTumor Treatment Options Optimal strategy remains unknown timing, order, and combinations Maximal safe resection Pre-Operative: Imaging that identifies areas of function Peri-Operative: MRI-guided surgery Patient wake and being tested Radiation External beam Fractionated Chemotherapy Various timing, types, combos
  32. 32. Maximal Safe ResectionMaximal Safe Resection Diagnosis & molecular characterization Debulk tumor and mass-effect Alter symptoms +/- add local therapy
  33. 33. Surgery Cont’dSurgery Cont’d Timing Immediately, if a large mass or extensive symptoms Delayed, if small mass or minimal symptoms Careful clinical & radiographic surveillance begins Subsequent resection, if concern for progressive mass or symptoms especially if medically refractory or concern for HGG Extent of resection Maximal safe resection when feasible, especially if symptomatic or presumed diagnosis is unclear because of infiltrative nature, gross total resection is often not possible Biopsy when resection not feasible, if minimal symptoms, if presumed to be LGG No prospective randomized trials numerous (inherently biased) retrospective reviews report improved outcome with earlier and more maximal resection
  34. 34. Tumor Resection: Pre-OperativeTumor Resection: Pre-Operative
  35. 35. Tumor Resection: Intra-OperativeTumor Resection: Intra-Operative
  36. 36. Radiation (RT)Radiation (RT) Ionizing radiation DNA damage Preferential damage to rapidly dividing cells
  37. 37. Fractionated, External BeamFractionated, External Beam
  38. 38. Radiation (RT), Cont’dRadiation (RT), Cont’d  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 symptoms including after resection Subsequent RT, rarely performed i.e., unless recurrence/progression is in new location  Extent Typically conforming to within 1-2.5 cm of abnormality Typically ~54 Gy, external beam, fractionated, in six weeks
  39. 39. RT, cont’dRT, cont’d 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.
  40. 40. ChemotherapyChemotherapy Must cross the blood brain barrier Often augments effects of radiation Various actions
  41. 41. Examples of ChemotherapyExamples of Chemotherapy Cytostatic chemo- therapy Cytotoxic
  42. 42. Cytotoxic ChemotherapyCytotoxic Chemotherapy 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
  43. 43. Cytostatic ChemotherapyCytostatic Chemotherapy Examples 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-features Normalizes the vasculature Hopefully facilitates chemotherapy into the tumor & inhibits tumor Vregenbergh, J, JCO, 2007; Clinical Ce Res, Feb 2007
  44. 44. Chemotherapy, cont’dChemotherapy, cont’d  Timing Typically, reserved for recurrence However, despite a lack of strong evidence, increasing trends for: Increasing now with oligodendrogliomas, especially with 1p/19q co-deletion Increasingly 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 prospectively Typically, temozolomide-based > PCV > clinical trials  Controversies include: measurement of response, optimal timing, long-term toxicities, alteration of LGG natural history, etc.
  45. 45. Chemotherapy, 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 observation patients 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
  46. 46. Treatment atTreatment 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 individualized Goals & preferences, age, overall health, etc.!
  47. 47. Supportive 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.
  48. 48. Our FutureOur Future
  49. 49. 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 Many being addressed in trials now!
  50. 50. Information, Support, &Information, Support, & TrialsTrials 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!
  51. 51. FutureFuture Your ideas & partnership is needed Unanswered questions and unmet needs Collaboration in care, research, education, & advocacy I warmly welcome you to contact me regarding: Multidisciplinary care Support group & educational events Website & Hope Heals Run  FCBTR tissue donation  Etc.
  52. 52. We’ll see you atWe’ll see you at Fall 2009
  53. 53. The EndThe End Thank you 352-273-9000 www.neurosurgery.ufl.edu edunbar@neurosurgery.ufl.edu

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