Title: 4th Annual NCCTG Patient Advocate Symposium NeuroOncology
14th Annual NCCTGPatient Advocate
SymposiumNeuro-Oncology
- Paul Brown, MD
- Associate Professor of Oncology
- Department of Radiation Oncology
- Mayo Clinic
- Rochester, MN
2Intermediate Gratification in My Practice
- Direct Patient Care
- Education
- Research
Satisfaction
3BEFORE RT
1.5 YEARS AFTER RT
28 yo Middle School Teacher Unresectable Grade 2
Astrocytoma
4Bueracracy, Red-Tape, Extremely Slow Process
5WHY DO RESEARCH
- MOTIVATION
- Money
- Fame
- Cure Cancer
- Crazy?
- Initial Reason Improve Patient Care
- Sustaining Intellectual Curiosity and Larger
Impact Patient Care
6Brain 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
7Types 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
8Glioblastoma Multiforme
- Rapid progression
- Greater extent resection beneficial
- Radiation doubles survival
T1 post-contrast
FLAIR
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11High 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
12TEMOZOLOMIDE
13Rationale 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.
14Phase III Study New GBM Radiation /-
Temozolomide
Focal RT daily
573 patients accrued.
15EORTC/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
16Phase III EORTC/NCIC MGMT Status
Hegi NEJM. 200510997-1003. 1/3 tested PCR 45
methylated
170525 Protocol Schema
N800, Prospective MGMT testing
18Oligodendroglioma
- 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
19Impact of 1p 19q LOH
Ino Y, et al. Clin Cancer Res 200117839-845.
20 21Intergroup-9402
22Intergroup-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
23Kaplan-Meier estimates of overall survival by
treatment group
Cairncross, G. et al. J Clin Oncol 242707-2714
2006
24Intergroup-9402 Results
- 2/3 grade III or IV toxicity with PCV
- 46 1p 19q deletion
- 57 Oligodendrogliomas (plt0.001)
- 14 Mixed Oligoastrocytoma
25Kaplan-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
26NCCTG/RTOG N0577 Phase III 1p/19q Co-deleted
Anaplastic Oligo
27Low-Grade Gliomas
28Low 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
29Intergroup 86-72-5250.4 Gy vs 64.8 Gy
30Intergroup 86-72-52
Arm A 50.4 Gy vs Arm B 64.8 Gy
31RTOG 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
32RTOG 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.
33Phase III Study LGG Radiation /-
Temozolomide-David Schiff
Focal RT daily
34Neurocognitive ToxicityBrain Necrosis
35Etiology Neurocognitive Deficits
- Radiation
- Chemotherapy
- Surgery
- Tumor location and progression
- Medications
- Nutritional deficiency states
- Trauma
- Infections
- Vascular disease
- Intrinsic neurologic diseases
- Metabolic
- Hydrocephalus
36Neurocognitive 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.
37Neurocognitive 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.
38Neurocognitive 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.
39Brain Metastases
40Management of Brain Metastases Therapeutic
Choices
- WBRT alone
- Surgical resection /- WBRT
- Single brain metastasis
- Stereotactic radiosurgery /- WBRT
41Radiosurgery
- 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
43Rationale 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
44JRSOG 9901 Phase III Trial
- GK
-
- 1-4 Brain Mets n132
-
- GK WBRT
- No neurocognitive or QOL testing
Aoyama, H. et al. JAMA 20062952483-2491.
45Withholding WBRT significantly increases relapse
risk in the brain and at the local site
Aoyama, H. et al. JAMA 20062952483-2491.
46N0574
Radiosurgery
1-3 Brain Mets on MRI
QOL, Neurocog
Radiosurgery WBRT
47Future 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