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Harmesh Naik, MD. · PDF file Anaplastic Oligodendroglioma A recent phase III study compared radiation therapy alone with chemotherapy plus radiation therapy. Progression-free survival

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  • Harmesh Naik, MD.

    June 22, 2011

    Marriott Series CME symposium

  • Primary brain tumors

     Discussion is limited to Primary brain

    tumors

  • Interesting facts

     Annual incidence: 14 per 100,000

    population

     Most common tumors are:

     Meningiomas 27%

     Glioblastomas 23%

  • Epidemiology

     Gender: Slightly more common in men

     Age: Bimodal distribution with tow

    peaks

     Small peal in children

     Second peak between 75-84 years

  • Risk factors

     Genetic factors: plays a minor role

     Hereditary: Less than 5%

     Increased risk in

     Tuberous sclerosis

     Neurofibromatosis

     Turcot syndrome

     Li-Fraumeni syndrome

  • Genetics

     Loss of heterozygosity (LOH): Loss of

    function of one copy of a gene where one

    copy was already inactivated

     High grade gliomas

     LOH on 9p

     LOH on 10q

     P16 deletions

     Low grade gliomas

     Fewer molecular abnormalities

  • Genetics

     Oligodendrogliomas:

     Better prognosis with

     LOH on 1p

     LOH on 19p

  • Environmental factors

     Prior brain radiation is a risk

     Not clear or not associated

     Smoking

     Alcohol use

     Cell phone use

  • Symptoms

     General: Headaches, nausea, vomiting,

    seizures, mental status changes

     Site specific: Loss of functions,

    paralysis, speech problems, visual filed

    defects, etc

  • Diagnosis:

     Radiology:

     MRI or contrast CT

     Contrast enhancing mass with edema

     About 5% are multi-focal

     Low grade gliomas can be non enhancing

     PET scan: May not be as accurate as

    MRI

  • Biopsy

     Diagnosis by biopsy is preferred.

     Stereotactic biopsy can be used for

    lesions that are difficult to reach and

    resect.

  • Pathology

     Grade I to IV

     Low grade:

     Astrocytoma

     Oligodendroglioma

     Ependymomas-high recurrence rate

     High grade:

     Glioblastoma multiforme

     Anaplastic astrocytoma

     Anaplastic Oligodendroglioma

  • Staging

     No uniform staging system

  • Prognostic factors

     Pathologic grade

     High grade - poor prognosis

     Anaplastic oligodendrogliomas and

    oligoastrocytomas -better prognosis than

    anaplastic astrocytomas.

     Age

     Older age – worse prognosis

     Genetic defects

     1p and 19q LOH- better prognosis

  • Prognosis: Median survival

    Histology Years Comment

    Anaplastic astrocytoma 3 Surgery + RT + CT

    Glioblastoma 1 Surgery + RT + CT

    Low grade astrocytoma 5-10

    Low grade oligodendroglioma 16

    Low grade glioma 5 with age >40 yrs

    Secondary brain mets 4-6 months

  • Supportive care

     Anti-consultants

     Given to those with seizures (25%)

     Traditional agents: Phenytoin,

    Carbamazepine, Phenobarbital

     Newer anti-convulsants may have lesser

    cognitive side effects (Keppra, Topamax

    etc)

     Prophylactic use: Not well proven

  • Steroids

     Reduce brain edema –reduce mass effect

     Prompt relief of symptoms

     Dexamethasone – first choice – 16 mg/day

     Taper as tolerated once definitive treatment

    is started

     Long term side effects

  • Definitive therapy

     Multi-disciplinary therapy

     Surgery

     Radiation

     Chemotherapy

     Generally non curative

  • Surgery

     Surgical removal is recommended for most

    types of brain tumors in most locations.

     Surgical removal should be as complete as

    possible within the constraints of

    preservation of neurologic function

     Further discussion by another panel

    speaker

  • Radiation

     Radiation therapy has a major role in the

    treatment of patients

     Further discussion by another panel

    speaker

  • Local chemotherapy

     Local chemotherapy with a nitrosourea

    applied to a polymer placed directly in

    the brain during surgery has been

    shown to be a safe modality and is

    under clinical evaluation

     Best discussed by a neuro-surgeon

  • Chemotherapy (Systemic)

     Limited but measurable role to play

     Sensitivity depends on histology of

    tumor

  • Role of Chemotherapy

     Low grade astrocytoma: No major role

     Oligodendroglioma: Chemo-sensitive

     Anaplastic or high grade tumors:

    Important role

  • Timing

     Adjuvant chemotherapy: for initially

    diagnosed – given after surgery –

    concurrent with radiation

     Palliative Chemotherapy: for recurrent

    or progressive cancer

  • Chemotherapy: Results

     May prolong survival in patients with

    some tumor types

     Has been reported to lengthen disease-

    free survival

     Used in patients with

     Gliomas,

     Medulloblastoma,

     Some germ cell tumors.

  • Agents - regimens

     Temozolamide: Most active and most

    commonly used agent currently

     PCV (Procarbazine, CCNU, Vinblastine)

    has been used in past

     BCNU – no longer used commonly

     Bevacizumab, Irinotecan – newer agents

  • Glioblastoma Multiforme

     Radiation therapy and concurrent

    chemotherapy (Current standard)

     Based on EORTC 26981) : A randomized

    study

    Stupp, R et al. N Engl J Med 2005; 352:987-996

  • Design

    EORTC 26981 trial

    Arm I

    RT

    Arm II

    RT + CT

  • Details of study arms

     Arm I: Radiotherapy 5

    days a week for 6 weeks.

     Arm II: Radiotherapy +

    concurrent oral

    Temozolomide daily for 6

    weeks  Adjuvant oral

    Temozolomide alone on

    days 1-5 every 28 days for

    6 courses beginning 4

    weeks after completion of

    radiotherapy.

    RT + TEM

    6 weeks

    TEM

    6 courses

  • Temozolamide (TMZ) details

    • Concomitant chemotherapy: Temozolomide 75 mg/ m2/ day, given 7 days per week, start day 1 of RT until the last day of radiotherapy, but for no longer than 49 days.

    CT-RT

    • Then 4-week break Rest

    •Then up to six cycles of adjuvant Temozolomide standard 5-day schedule every 28 days.

    The dose was 150 mg/ m2/ day, for the first cycle and was increased to 200 mg/ m2/ day, beginning with the second cycle, so long as there were no hematologic toxic effects.

    CT

    Follow up

  • Anti PCP prophylaxis

     Lymphocytopenia  with a possible increased risk of opportunistic infections.

     Temozolomide group were to receive prophylaxis against Pneumocystis carinii pneumonia

     Inhaled Pentamidine

     or

     Oral trimethoprim–sulfamethoxazole during concomitant treatment with radiotherapy plus

    temozolomide.

  • Antiemetic prophylaxis

     Recommended before the initial doses

    of concomitant Temozolomide

     Required during the adjuvant five-day

    courses of temozolomide.

  • Results

     Study demonstrated a statistically

    significant increase in median survival of 3

    months in the combination-treated group

    (12.1 months versus 14.6 months)

     The 2-year survival rate was 26.5% in the

    combination group compared with only

    10.4% in the radiation-only group.

     The treatment is relatively safe and well

    tolerated.

  • Median Survival

    12.1

    14.6

    0

    2

    4

    6

    8

    10

    12

    14

    16

    Months

    RT

    RT + CT

  • Survival in %

    10.4

    26.5

    0

    5

    10

    15

    20

    25

    30

    2 year

    RT

    RT + CT

  • Standard of care

     EORTC regimen is considered standard of care by most for high grade GBM

  • Sequential CT-RT

     Interesting concept

     NOA-04: A randomized phase III trial of sequential radio chemotherapy of anaplastic glioma with Procarbazine, Lomustine, and Vincristine or Temozolomide.

     CONCLUSIONS:  Initial radiotherapy or chemotherapy achieved comparable

    results i