4th Annual NCCTG Patient Advocate Symposium NeuroOncology

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4th Annual NCCTGPatient Advocate
SymposiumNeuro-Oncology

• Paul Brown, MD
• Associate Professor of Oncology
• Department of Radiation Oncology
• Mayo Clinic
• Rochester, MN

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Intermediate Gratification in My Practice

• Direct Patient Care
• Education
• Research

Satisfaction
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BEFORE RT
1.5 YEARS AFTER RT
28 yo Middle School Teacher Unresectable Grade 2
Astrocytoma
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Bueracracy, Red-Tape, Extremely Slow Process
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WHY DO RESEARCH

• MOTIVATION
• Money
• Fame
• Cure Cancer
• Crazy?
• Initial Reason Improve Patient Care
• Sustaining Intellectual Curiosity and Larger
  Impact Patient Care

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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

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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
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Glioblastoma Multiforme

• Rapid progression
• Greater extent resection beneficial
• Radiation doubles survival

T1 post-contrast
FLAIR
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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

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TEMOZOLOMIDE
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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.
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Phase III Study New GBM Radiation /-
Temozolomide
Focal RT daily
573 patients accrued.
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EORTC/NCIC Phase III GBM Trial Overall Survival

100
90
80
70
Plt0.0001
60

50
40
30
TMZ/RT
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RT
10
0
0
6
12
18
24
30
36
42
months
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Phase III EORTC/NCIC MGMT Status
Hegi NEJM. 200510997-1003. 1/3 tested PCR 45
methylated
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0525 Protocol Schema
N800, Prospective MGMT testing
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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
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Impact of 1p 19q LOH
Ino Y, et al. Clin Cancer Res 200117839-845.
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Intergroup-9402
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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
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Kaplan-Meier estimates of overall survival by
treatment group
Cairncross, G. et al. J Clin Oncol 242707-2714
2006
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Intergroup-9402 Results

• 2/3 grade III or IV toxicity with PCV
• 46 1p 19q deletion
• 57 Oligodendrogliomas (plt0.001)
• 14 Mixed Oligoastrocytoma

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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
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NCCTG/RTOG N0577 Phase III 1p/19q Co-deleted
Anaplastic Oligo
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Low-Grade Gliomas
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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

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Intergroup 86-72-5250.4 Gy vs 64.8 Gy
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Intergroup 86-72-52
Arm A 50.4 Gy vs Arm B 64.8 Gy
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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
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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.
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Phase III Study LGG Radiation /-
Temozolomide-David Schiff
Focal RT daily
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Neurocognitive ToxicityBrain Necrosis
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Etiology Neurocognitive Deficits

• Radiation
• Chemotherapy
• Surgery
• Tumor location and progression
• Medications
• Nutritional deficiency states

• Trauma
• Infections
• Vascular disease
• Intrinsic neurologic diseases
• Metabolic
• Hydrocephalus

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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.
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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.
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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.
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Brain Metastases
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Management of Brain Metastases Therapeutic
Choices

• WBRT alone
• Surgical resection /- WBRT
• Single brain metastasis
• Stereotactic radiosurgery /- WBRT

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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

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Gamma Knife

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

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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
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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.
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Withholding WBRT significantly increases relapse
risk in the brain and at the local site
Aoyama, H. et al. JAMA 20062952483-2491.
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N0574
Radiosurgery
1-3 Brain Mets on MRI
QOL, Neurocog
Radiosurgery WBRT
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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