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4th Annual NCCTG Patient Advocate Symposium NeuroOncology

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Initial Reason Improve Patient Care ... Hydrocephalus. Neurocognitive Toxicity. Retrospective trials neurocognitive decline in adults ... – PowerPoint PPT presentation

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Title: 4th Annual NCCTG Patient Advocate Symposium NeuroOncology


1
4th Annual NCCTGPatient Advocate
SymposiumNeuro-Oncology
  • Paul Brown, MD
  • Associate Professor of Oncology
  • Department of Radiation Oncology
  • Mayo Clinic
  • Rochester, MN

2
Intermediate Gratification in My Practice
  • Direct Patient Care
  • Education
  • Research

Satisfaction
3
BEFORE RT
1.5 YEARS AFTER RT
28 yo Middle School Teacher Unresectable Grade 2
Astrocytoma
4
Bueracracy, Red-Tape, Extremely Slow Process
5
WHY DO RESEARCH
  • MOTIVATION
  • Money
  • Fame
  • Cure Cancer
  • Crazy?
  • Initial Reason Improve Patient Care
  • Sustaining Intellectual Curiosity and Larger
    Impact Patient Care

6
Brain Cancers Frequency
  • Total new primary 17,500 (1.35)
  • Total deaths primary 14,000 (2.35)
  • Total metastatic tumors 300,000
  • 30 of patients with cancer develop brain
    metastases eventually

7
Types of Primary Adult Brain Tumors
  • Other
  • Primary CNS lymphomas
  • Germ cell tumors
  • Ependymomas
  • Medulloblastoma
  • Pituitary adenomas
  • Meningiomas
  • Chordomas
  • Gliomas
  • Low Grade
  • Pilocytic
  • Oligodendroglioma
  • Mixed tumors
  • Astrocytomas
  • High Grade
  • Anaplastic
  • Glioblastoma Multiforme

NCCTG Research
Worse Survival
8
Glioblastoma Multiforme
  • Rapid progression
  • Greater extent resection beneficial
  • Radiation doubles survival

T1 post-contrast
FLAIR
9
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10
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11
High Grade GliomaBackground
  • Time period 1 Yr Surv 5 Yr Surv
  • McGill Univ 1939-1958 44 7
  • Mayo Clinic 1990-1994 47 10
  • Jean Bouchard (McGill Univ. Montreal), Radiation
    therapy of tumors and diseases of the nervous
    system, Lea Febinger 1966.
  • Buckner et al. "A phase III study of radiation
    therapy plus carmustine with or without
    recombinant interferon-alpha in the treatment of
    patients with newly diagnosed high-grade glioma."
    Cancer 92(2) 420-33, 2001.
  • Values taken from curves

12
TEMOZOLOMIDE
13
Rationale for TMZ Treatment
  • Ease oral administration
  • Favorable toxicity profile
  • Metabolism not significantly influenced by
    anti-seizure medication
  • Crosses the blood-brain barrier
  • Active agent glioblastoma
  • Synergistic with XRT

Ostermann S, et al. Clin Cancer Res
2004103728-3736.
14
Phase III Study New GBM Radiation /-
Temozolomide
Focal RT daily
573 patients accrued.
15
EORTC/NCIC Phase III GBM Trial Overall Survival

100
90
80
70
Plt0.0001
60

50
40
30
TMZ/RT
20
RT
10
0
0
6
12
18
24
30
36
42
months
16
Phase III EORTC/NCIC MGMT Status
Hegi NEJM. 200510997-1003. 1/3 tested PCR 45
methylated
17
0525 Protocol Schema
N800, Prospective MGMT testing
18
Oligodendroglioma
  • Classified as low-grade or anaplastic
  • Very responsive to treatment chemotherapy and
    radiation
  • Prognosis and treatment response strongly
    correlated with 1p 19q LOH

100 response to chemotherapy with 1p 19q LOH
19
Impact of 1p 19q LOH
Ino Y, et al. Clin Cancer Res 200117839-845.
20

21
Intergroup-9402
22
Intergroup-9402 Results
  • 50 of patients with pure AO
  • 69 age lt50 years
  • 1 year benefit progression free survival

80 of patients in the radiation-only arm
received PCV at relapse
23
Kaplan-Meier estimates of overall survival by
treatment group
Cairncross, G. et al. J Clin Oncol 242707-2714
2006
24
Intergroup-9402 Results
  • 2/3 grade III or IV toxicity with PCV
  • 46 1p 19q deletion
  • 57 Oligodendrogliomas (plt0.001)
  • 14 Mixed Oligoastrocytoma

25
Kaplan-Meier estimates of overall survival by 1p
and 19q deletion
Median survival 1p,19q intact equal to Gr3 astro
Cairncross, G. et al. J Clin Oncol 242707-2714
2006
26
NCCTG/RTOG N0577 Phase III 1p/19q Co-deleted
Anaplastic Oligo
27
Low-Grade Gliomas
28
Low Grade Astrocytomas
  • Types
  • Pilocytic astrocytoma
  • Oligodendroglioma
  • Oligoastrocytoma
  • Low grade astroctyoma
  • Occur in younger patients (20-50 years)
  • Diffuse in nature
  • Slow growing
  • Typically in cerebral hemispheres
  • More likely to present with seizure
  • Responsive to radiation

29
Intergroup 86-72-5250.4 Gy vs 64.8 Gy
30
Intergroup 86-72-52
Arm A 50.4 Gy vs Arm B 64.8 Gy
31
RTOG 98-02 Intergroup Trial
Low riskArm 1 Age lt40 and GTR
observe
LGG
Arm 2 RT 54 Gy
High risk Age gt40 or STR/biopsy
R
Arm 3 RT 6 cycles PCV
112 low risk 254 high risk
32
RTOG 98-02 Intergroup Trial
  • 251 high risk patients
  • No benefit progression free or overall survival
  • Toxicity Gr 34 67 vs 9

Shaw E, et al. abstract 1500, oral presentation
ASCO 2006.
33
Phase III Study LGG Radiation /-
Temozolomide-David Schiff
Focal RT daily
34
Neurocognitive ToxicityBrain Necrosis
35
Etiology Neurocognitive Deficits
  • Radiation
  • Chemotherapy
  • Surgery
  • Tumor location and progression
  • Medications
  • Nutritional deficiency states
  • Trauma
  • Infections
  • Vascular disease
  • Intrinsic neurologic diseases
  • Metabolic
  • Hydrocephalus

36
Neurocognitive Toxicity
  • Retrospective trials neurocognitive decline in
    adults
  • Outdated, primitive technique (whole brain RT)
  • Large fraction sizes
  • Unknown denominator
  • Most important- LACK OF BASELINE TESTING

Gregor A, et al. Radiother Oncol 19964155-59.
Surma-aho O. Neurology 2001561285-1290. Curnes
JT. Am J Roentgenol 1986147119-124. Imperato
JP, et al. Ann Neurol 199028818-822. Brown PD,
et al. Neuro-oncol 20035161-167. DeAngelis LM,
et al. Neurology 198939789-796.
37
Neurocognitive Toxicity
  • NCCTG 86-72-51 corollary study
  • 20 patients (10 Arm 50.4 Gy,10 Arm 64.8 Gy)
  • Underwent extensive battery of neurocognitive
    tests at baseline (after surgery, before RT), and
    q18 months up to 5 years

Laack N, et al. Int J Radiat Biol Oncol Phys.
2003S134.
38
Neurocognitive Toxicity
  • No differences in neurocognitive function between
    the two arms or compared to baseline
  • Results consistent with other prospective trials
    tumor progression most important cause of
    deterioration

Laack N, et al. Int J Radiat Biol Oncol Phys.
2003S134.
39
Brain Metastases
40
Management of Brain Metastases Therapeutic
Choices
  • WBRT alone
  • Surgical resection /- WBRT
  • Single brain metastasis
  • Stereotactic radiosurgery /- WBRT

41
Radiosurgery
  • A focal, single-fraction radiation
  • delivery method
  • Linear accelerator
  • Gamma knife
  • Charged particles
  • Delivers a high dose of radiation to
  • a small, discrete, well-defined target,
  • with rapid dose fall-off
  • Does not use the advantages of
  • fractionation

42
Gamma Knife
  • ? Equal to surgery (more accessible lesions)
  • Less invasive than surgery

43
Rationale for Radiosurgery
  • Spherical/pseudospherical
  • Most mets lt4 cm
  • Generally noninfiltrative
  • Improved local control single lesions--better
    survival
  • Need higher doses for local control than can be
    achieved with WBRT

If surgery works, so should radiosurgery
44
JRSOG 9901 Phase III Trial
  • GK
  • 1-4 Brain Mets n132
  • GK WBRT
  • No neurocognitive or QOL testing

Aoyama, H. et al. JAMA 20062952483-2491.
45
Withholding WBRT significantly increases relapse
risk in the brain and at the local site
Aoyama, H. et al. JAMA 20062952483-2491.
46
N0574
Radiosurgery
1-3 Brain Mets on MRI
QOL, Neurocog
Radiosurgery WBRT
47
Future Directions
  • TMZ beneficial Glioblastomas
  • -? TMZ dosing ? Phase III trial
  • ? Benefit Oligodendrogliomas ? Phase III trial
  • ? Benefit Low-grade Gliomas ? Phase III trial
  • MGMT prognostic Glioblastoma ? Phase III trial
  • WBRT decreases brain failure after radiosurgery
  • -? WBRT improve survival and cognitive function ?
    Phase III trial
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