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Workshop on Advanced Technologies in Radiation Oncology. Minesh Mehta. Principal “Dose-Limiting Toxicity” Brain Tumors. Necrosis rates of ~5% starting at 60 Gy. 72 Gy with altered fractionation Visual damage of ~1-3% starting at >54 Gy. Endocrine damage starts at ~45 Gy. - PowerPoint PPT Presentation
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Workshop on Advanced Technologies
in Radiation Oncology
Minesh Mehta
Principal “Dose-Limiting Toxicity”Brain Tumors
Principal “Dose-Limiting Toxicity”Brain Tumors
Necrosis rates of ~5% starting at 60 Gy.
72 Gy with altered fractionation
Visual damage of ~1-3% starting at >54 Gy.
Endocrine damage starts at ~45 Gy.
Neurocognitive damage:
Depends on what you measure, when, & age
Cochlear dysfunction starts at >50 Gy
Evidence Levels
Logically, few of the toxicity data come from phase III trials with toxicity endpoints.
Most come from phase I trials, or “institutional experiences”
Numerous variables need to be teased out separately, e.g., age, volume, fractionation, comorbidities, other therapies, etc.
An example of a phase III trial: RTOG
9006: 60 vs. 72 Gy for GBM
Late Toxicities
Assigned Treatment Standard
(n=305) HFX
(n=318) Grade Grade 3 4 5 3 4 5 Neurological 3 3 0 7 2 0 Pulmonary 0 2 3 5 1 3 Hepatic 8 0 0 0 0 0 Infection 0 0 0 1 0 0 Mucous membrane 1 0 0 0 0 0 Nausea & vomiting 2 0 0 1 0 0 Ototoxicity 0 1 0 1 0 0 Other 0 1 2 0 0 0 Skin 3 0 0 1 0 0 Worst Non -Hematologic Overall
12 7 5 13 3 3
(4%) (2%) (2%) (4%) (1%) (1%)
Further Dose Escalation: Necrosis
CCG BSG Trials went upto 78 Gy (1 Gy bid) U Mich 3 D Trials went upto 90 Gy with reduced volumes
Recent RTOG 3D dose-escalation trial (9803):
PTV2 < 75 cc: escalated to 84 Gy (n = 95)PTV2 > 75 cc: escalated to 84 Gy (n = 109)Group Level n % RT Necrosis (95% CI)
Group 1 66 Gy 19 5.0% (0, 15.3%)
72 Gy 20 10.0% (0, 23.1%)
78 Gy 24 8.3% (0, 19.4%)
84 Gy 15 6.7% (0, 19.3%)
Group 2 66 Gy 29
72 Gy 18
78 Gy 32 6.2% (0, 14.6%)
84 Gy 10
An Example: Risk of Dementia with WBRT for Brain Metastases
Retrospective study of 47 patients one-year survivors treated at MSKCC 5/47 (11%) patients treated with WBRT developed severe dementia:
6 Gy x 3, 4 Gy x 35 Gy x 3, 3 Gy x 55 Gy x 3, 3 Gy x 4 6 Gy x 3, 4 Gy x 3 + adria analog3 Gy x 10 + radiosensitizer
0f 15 patients treated with <3 Gy/fx, 0 had dementia
DeAngelis LM, et.al. Neurosurgery 1989;24:798-805.
Dementia associated with high-dose fractions.
Can SRS or SRT reduce toxicities?
Few direct comparisons exist Significant dose-escalation can be achieved
In general, necrosis rates remain under 5% However, only small volumes are generally treated For long-term toxicity, benign tumors need to be studied
and these are generally not included on any clinical trials, e.g. meningioma, vestibular schwannoma, etc.
RTOG 90-05: Phase I SRS trial 156 patients with rec CNS tumors < 40 mm diameter SRS dose by size For < 20 mm tumors, dose not escalated > 24 Gy
Size Dose n Grade 3, 4, 5 CNS tox
mm Gy Acute Chronic Total %
20
18
21
24
12
18
10
0
0
0
0
6
10
0
6
10
21-30
15
18
21
24
15
15
13
12
7
0
7
33
7
20
31
8
14
20
38
41
31-40
12
15
18
21
22
18
5
0
17
5
14
28
10
14
45
An example of a phase III trial: RTOG 9305: SRS boost for GBM
60 Gy + BCNU +/- SRS boost (15-24 Gy) 186 analyzable patients 4 vs 0 G3 late neuro toxicity in SRS arm QOL comparable (Spitzer) MMSE comparable Quality-adjusted survival comparable
RTOG 9508: QOL, ToxicityTrait WBRT +RS p
KPS @ 3 mo 33% 50% .02
KPS @ 6 mo 27% 43% .03
Tumor RR @ 3 mo 62% 73% .04
Edema RR @ 3 mo* 47% 70% .0017
Actuarial LC @ 1 yr 71% 82% .01
CNS death 31% 28% ns
G3/4 late tox < 2% < 3% ns
* Significantly lower steroid dependence on RS arm
No difference in outcome by technique, Linac vs. Gamma Knife
VS Radiosurgery vs FSRTAuthor Year N LC V n VII n VIII n Noren 1998 669 95% 38% 33% 65%Flickinger 2001 190 97% 1% 3% 71%Spiegelman 2001 40 98% 8% 71%Prasad 2000 200 94% 2.5% 1.5% 40%Miller 1999 42 95% 29% 38%Miller 1999 40 100% 15% 8%Foote 2001 149 93% 12% (5%) 10% (2%)
Author Year N Dose LC V n VII n VIII n Poen 1999 33 21/3/24 hr 97% 16% 3% 77%Shirato 2000 45 36-50/20-25 92% 0% 0%Meijer 2000 37 20-25/4-5 91% 3% 0% 66%Varlotto 1996 12 54/30 100% 8% 0% 92%Shirato 1999 27 36-44/20-22 98% 0% 0%
Dose, Length & Complications
Flickinger, IJROBP
Andrews et al, Int J Rad Onc Biol Phys 50:1265-1278, 2001
Pro
babi
lity
of
Ser
vice
able
Hea
rin
g
Intensity Modulated RT
Shannon M MacDonald1, Salahuddin Ahmad2, Stefanos Kachris3, Betty J Vogds2, Melissa DeRouen3, Alicia E Gitttleman3, Keith DeWyngaert3, Maria T Vlachaki4
1 Massachusetts General Hospital 2 University of Oklahoma Health Sciences Center
3 New York University Medical Center4 Wayne State University
INTENSITY MODULATED RADIATION THERAPY VERSUS THREE DIMENSIONAL CONFORMAL RADIATION THERAPY FOR THE TREATMENT
OF HIGH GRADE GLIOMA: A DOSIMETRIC COMPARISON
STUDY DESIGN
•Dosimetric comparison of IMRT versus 3DCRT in twenty patients with high-grade glioma. •Prescribed Dose: 59.4 Gy, 33 fractions, 4-10 MV
•Dose constraints for brainstem: 55-60 Gy
•Dose constraints for optic chiasm & nerves: 50-54 Gy
•DVHs for target, brain, brainstem and optic nerves/chiasm were generated and compared
•TCP and NTCP were also calculated and compared
p=0.004
Brainstem
0
10
20
30
40
50
% > 45Gy % > 54Gy
Pe
rce
nt
Org
an
Vo
lum
e
IMRT
3DCRT
p=0.004
0
10
20
30
40
50
60
70
min PTV max PTV mean PTV min PTVcd max PTVcd mean PTVcd
Dos
e (G
y) IMRT
3DCRT
p=0.023
p=0.006p=0.01
p=0.003 p≤0.0001
Optic Chiasm
0
10
20
30
40
50
60
% > 45Gy % > 50.4Gy
Perc
ent O
rgan
Vol
ume
IMRT
3DCRT
p=0.047
p=0.047
Brain
0
10
20
30
40
50
60
% > 18Gy % > 24Gy % > 45Gy
Dos
e (G
y)
IMRT
3DCRT
p=0.06 p=0
.01
p<0.0001
p=0.059
p=0.015
p≤0.0001
COMPARISON OF TARGET AND NORMAL TISSUE DOSIMETRY:
IMRT v. 3DCRT
So, Can IMRT further reduce toxicities?
Almost no direct comparisons exist Significantly improved DVHs can be achieved
These may be meaningful for sites such as the chiasm,
pit gland, hypothalamus, hippocampus, etc. Limited data support that cochlear sparing in the
pediatric population might preserve hearing
Subventricular zone stem cell compartment Remains mitotically active in adulthood Cells have self-renewal capacity
and differentiate into neurons or glia whichcan migrate over long distances in the brainand are involved in repair processes after brain injury/toxicity
In young rats, irradiation with 2 Gy produces apoptosis in the subependymal cell layer and also in the proliferating cellsin the hippocampus
which leads to prolonged impairment of repopulative capacity
Compartmental Studies: Stem Cells
Doetsch, 1999; Hopewell, 1972; Bellinzona, 1996; Peissner, 1999; Tada, 1999
Many patients exhibit learning/memory deficits with no pathologic changes, especially when the RT field involves the temporal lobes.
Recent work has shown that hippocampus-dependent learning and memory are strongly influenced by the activity of neural stem cells and their proliferative progeny.
The hippocampal granule cell layer undergoes continuous renewal and restructuring by the addition of new neurons.
Radiation at low doses affects the highly proliferative progenitors. A single low dose to the cranium of a mature rat is sufficient to ablate hippocampal neurogenesis.
The Role of the Hippocampus
Monje ML: Radiation injury and neurogenesis. Current Opinion in Neurology. 16:129-34, 2003.
Hippocampus Avoidance Hypothesis
The hippocampus plays a significant role in RT induced dementia
Doses as low as 2 Gy cause significant toxicity to the hippocampus
Conformal avoidance of the hippocampus may help reduce neurocognitive deficits
Hippocampus Delineation by Software
Hippocampus Avoidance with IMRT
30 Gy6 Gy3 GY
Avoidance Region
IMRT with tomotherapyachieves significant dosereduction (hippocampus), while delivering 30 Gy to the rest of the brain
Can IGRT further reduce toxicities?
Even in the head, positioning is a significant issue IGRT reveals this dramatically Application of IGRT might permit more accurate dose
delivery H/N serves as a good surrogate for the brain in this
regard
Study Design
Twenty patients analyzed 10 conventional patients
Prospectively enrolled Daily measurements (6 degrees of freedom) with optically
guided patient localization system
10 IMRT patients Plans analyzed and selected analysis of impact daily set-up
variation
Mean Set-up Error (SD)
Mean Vector: 6.97 mm
Patient No.
Lateral (mm)
A-P (mm)
Cranio-caudal (mm)
Couch (deg)
Spin (deg)
Tilt (deg)
Vector (mm)
1 -4.7(2.2) 0.3(2.3) 2.8(1.9) 0.5(1.5) -3.2(1.6) 0.4(1.1) 6.2(2.0) 2 4.0(3.7) 1.5(1.8) -0.2(1.5) 1.4(1.7) 4.2(1.1) 2.0(1.5) 5.4(2.9) 3 -0.3(1.7) 0.5(3.4) 2.8(1.3) -0.7(0.7) -0.7(0.9) 2.8(1.1) 4.7(1.6) 4 -4.0(1.0) 1.7(2.4) -3.8(1.3) 1.6(0.6) 1.4(0.6) 2.0(1.2) 6.3(1.3) 5 3.5(2.1) 1.1(1.3) 3.2(1.3) 0.8(1.1) 1.4(1.8) 0.0(0.7) 5.4(1.4) 6 -3.6(2.5) 12.3(3.4) 0.5(4.7) -0.1(1.3) 2.9(1.3) -3.3(1.9) 13.8(3.3) 7 7.1(2.3) 8.0(2.0) 4.6(2.4) -1.5(0.9) 3.0(1.3) -2.4(1.4) 11.9(2.7) 8 4.2(1.9) -3.8(3.1) 0.0(1.8) 1.6(1.2) -2.8(0.9) -0.3(1.3) 6.3(2.8) 9 -0.8(2.8) 5.0(4.0) -2.8(2.5) -0.8(1.6) 1.9(1.9) -0.1(1.5) 7.4(2.9)
10 -0.1(2.0) -2.3(3.3) -1.0(2.5) 0.7(0.7) 3.9(5.3) 2.2(1.5) 4.6(2.3) group 0.8(4.4) 2.1(5.1) 0.4(3.4) 0.5(1.6) 1.4(3.2) 0.5(2.3) 6.97(3.63)
6.97 mm shift- Optic Chiasm
Paranasal Sinus – Daily Offset
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1. Ideal 3. Median
2. Best 4. Worst
Low grade astrocytoma SchwannomaAnaplastic astrocytoma CraniopharyngiomaGBM Pituitary tumorsLow grade oligo CNS germ cell tumorsAnaplastic oligo Pilocytic astrocytomaMixed gliomas GangliogliomaEpendymoma HemangioblastomaPNET HemangiopericytomaCNS lymphoma SarcomaMeningioma Choroid plexus carcinoma
CNS Tumors with a role for Radiotherapy
Roles of Radiotherapy
Post-op adjunct to: decrease local failure delay progression/relapse prolong survival, eg GBM, AA
Primary curative therapy: PNET, Germ Cell Tumors, Pilocytic astrocytoma
To halt tumor growth: Meningioma, Schwannoma
To alter endocrine functionTo palliate
Radiotherapy Improves Survival
Disease Survival(no XRT)
Survival(with XRT)
PNET < 10% 50-70%
CNS Germinoma < 5% > 90%
Craniopharyngioma 10 yr: 37% 10 yr: 77%
Vest Schwannoma 5yrPFS >90% 5yrPFS: > 90%
Glioblastoma MS: 18 wks MS: 42 wks
Radiotherapy improves Local Control
Outcome TR STR STR/RT
5-YR SURV 81% 53% 89%
10-YR SURV 69% 37% 77%
RECURRENCE 29% 73% 17%
Craniopharyngioma as a case-study: 34 literature reports
Diminished Local Failure Rates Impact Survival
Radiotherapy diminishes Local Failure
Outcome TR STR STR/RT
5-YR PROGR 5% 37% 11%
10-YR PROGR 10% 55% 23%
15-YR PROGR 32% 91%
Meningioma as a case-study: Literature reports
The Impact of Radiation Dose
Medulloblastoma as a case-study: Literature reports
Author Year <50 Gy >50 GyHarisiadis 1977 24% 48%Cumberlin 1979 17% 86%
Berry 1981 42% 78%Silverman 1982 38% 80%Kopelson 1983 50% 78%
CCG 1987 33% 58%
Decreasing posterior fossa dose increases relapses
The Impact of Radiation Dose
2 -ve Ph III trialsCCG 923: 36 (#44) vs. 23.4 (#45)
Gy CSI.3 yr isolated neuraxis failure:
2/44 vs. 11/45.SIOP II: 4 arms; 35 vs. 25 Gy CSI
+/- pre-RT chemo5 yr RFS= 75 vs. 42% for chemo
RT arms
01020
30405060
7080
CCG SIOP
3/5 yr RFS (CCG & SIOP)
24 Gy
36 Gy
Medulloblastoma as a case-study: Clinical Trials
Decreasing CSI dose increases relapses
GBM: Dose Escalation
1201008060402000
20
40
60
80
100
120
Dose (Gy)
Med
ian
Surv
ival
(W
ks)
No RT BTCG, RTOG, ECOG
UCSF/Harvard: Control
RTOG HFX
Canada TID
UCSF/Harvard: Implant1. Dose escalation matters
2. Focal boost volumes can be identified
3. RT can be focally delivered
RTOG 9803 (3D CRT)is exploring this range
RTOG 9305: GBM RS Ph III trial
203 patients with GBM60 Gy + BCNU +/- RS boost (15-24 Gy)Median f/u 44 monthsMS: 14.1 vs 13.7 months2 yr survival: 22 vs 18%3 yr survival: 16 vs 8%General QOL & cognitive function
comparable
Souhami, ASTRO 2002
RADIOSURGERY NOT PROVEN TO PROLONG SURVIVAL IN GBM
Technologies for dose-escalation
5 field Fractionated Stereotactic Radiotherapy Technique
Phase II RTOG trial: RTOG 0023
RTOG 0023: Results
Cardinale, Red J, 2006
FSRT MIGHT BENEFIT GROSS-TOTALLY RESECTED GBM
Although overall survivalwas not improved, there was a trend toward improvedsurvival with FSRT forpatients with total resection
RTOG 9508 Phase III Single Brain Mets: Survival
RT + SRS (Median survival = 6.5 mo)
RT alone (Median survival = 4.9 mo)
P=0.0470
100
80
60
40
20
00 6 12 18 24
Months
Pe
rce
nt
aliv
e
SRS = stereotactic radiosurgery.
Infiltrative Margins
A B
Mets GBM
MRSI for Treatment Planning34 pts (22 G3, 12 G4) evaluated with MRI/MRSIMRI contours:T2 for initial field; T1 for boostMRSI: Multivoxel technique: CNI (Choline/NAA
Index)Results: MRSI would change fields
T2 estimated microscopic region 50% larger than MRSI
T2 missed MRSI abnormality in 88% of pts (upto 28 mm)
T1 suggested lesser volume than MRSI T1 suggested different location than MRSI
Pirzkall A: IJROBP 2001
McKnight: J Neurosurg, 2002: 90% sensitivity & 86% biopsy specificity for CNI >2.5
Conclusions
Radiotherapy plays a major role in the management of most primary brain tumors
Local failure is still paramountFailed strategies: limited dose escalation,
neutrons, brachytherapy, Imidazoles & BUdRNewer technologies may allow an improved
therapeutic index
