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gliomas.ppt - Florida Brain Tumor Association gliomas.ppt - Florida Brain Tumor Association Presentation Transcript

  • Management of Low Grade Gliomas 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 [email_address]
  • 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/ patient s/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
    • 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 Tumors
    • ~1,800/yr diagnosed with LGG
    • LGGs = ~ 20% of CNS gliomas
    Central Brain Tumor Registry of the US, 2005 -2006
  • Diagnosis Radiographical Clinical Pathologic
  • Radiographic 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
  • Clinical 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
  • Prognosis
    • 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
  • Pathologic 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
  • 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
  • Examples 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
  • Subtype 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
  • Subtype Examples, Cont’d
    •   Juvenile pilocytic astrocytomas (JPAs)
      • Typically, occur < 25 years
      • Typically, in cerebellar hemispheres & around 3 rd 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 4 th 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
  • Treatment Indications Measurements Multidisciplinary Care Teams Tumor & Supportive Treatments
  • Indications 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!
  • Measurements of Treatment Response
    • 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
  • Neuro-Oncology Multidisciplinary 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
  • Our Multidisciplinary Team at the
  • Specialty Teams
  • Neurosurgery
    • 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
  • Medical 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
  • Neuroscience
    • 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
  • Neuro-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
  • Radiation-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
  • Neuro-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
  • Many Other Specialists
    • Neuro-Rehabilitation
    • Neurology
    • Neuro-Intensive care
    • Neuro-Anesthesia
    • Psychology and Psychiatry
    • Pain management
    • Psychology & Psychiatry
    • Genetic Screening
    • Palliative Services
    • Hyperbaric Oxygen Therapy
  • Multidisciplinary 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
  • Clinical Research Basic & Translational Research
  • Basic & Translational Research
    • Numerous novel UF investigator, consortium, industry, government sponsored trials & experiments
    • Please visit www.neurosurgery.ufl.edu
  • Tumor & Supportive Treatment
    • 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
  • Tumor 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
  • Maximal Safe Resection Diagnosis & molecular characterization Debulk tumor and mass-effect Alter symptoms +/- add local therapy
  • Surgery 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
  • Tumor Resection: Pre-Operative
  • Tumor Resection: Intra-Operative
  • Radiation (RT) Ionizing radiation DNA damage Preferential damage to rapidly dividing cells
  • Fractionated, External Beam
  • Radiation (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
  • RT, 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.
  • Chemotherapy Must cross the blood brain barrier Often augments effects of radiation Various actions
  • Examples of Chemotherapy Cytostatic chemo-therapy Cytotoxic
  • Cytotoxic 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
  • Cytostatic Chemotherapy Examples 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
  • Chemotherapy, 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.
  • Chemotherapy, 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
  • Treatment at Recurrence/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.!
  • Supportive 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.
  • Our Future
  • 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!
  • Information, 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!
  • Future
    • 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.
  • We’ll see you at Fall 2009 ------------------------------------------------------------------
  • The End Thank you 352-273-9000 www.neurosurgery.ufl.edu [email_address]