RT + - ASTRO

2013 ASTRO Refresher Course:
Adult CNS Tumors
Minesh P Mehta, MD, FASTRO
University of Maryland
Learning Objectives
• Discuss the incidence, prevalence, mortality, morbidity,
and clinical impact of the major malignant and benign
adult primary CNS tumors
• Recognize the substantial heterogeneity that exists
within these tumor types and understand the prognostic
and predictive variables allowing for appropriate
selection of therapeutic choices, tailored for a specific
patient
• Explain the major levels of evidence for therapeutic
decision-making
• Appreciate the role of various therapies, especially
surgery radiotherapy and chemotherapy in managing
these tumors
ARS Q: Pre-test
• Which one of the following is accepted as a PREDICTIVE
biomarker in neuro-oncology?
–
–
–
–
–
A.
B.
C.
D.
E.
MGMT promoter methylation
1p19q codeletion
EGFR Viii mutation
Loss of PTEN
NF2 allelic loss
Gliomas: Grade vs. Survival
Tumor Type
Pilocytic Astrocytoma
MS (mos)
--
Low-grade oligodendroglioma
~120
Low-grade astrocytoma
~60
Anaplastic oligodendroglioma
~60
Anaplastic astrocytoma
~36
Glioblastoma
<12
Glioblastoma Characteristics
• Rapid progression
• Enhancing tumor
• Surrounding edema
– Contains tumor
–GTR almost impossible
–Median Survival 12-14 mo
–SOC: ChemoRT
T1 post-contrast
T2
External Beam Radiotherapy for GBM
• Current standard is 60 Gy/2 Gy/fx on GTV + 2 - 3
cm margin
• 3D: conformal, multiple fields
• Pooling of 6 randomized trials (RT vs no RT)
improved survival
• Mean survival time 3 - 6 months without RT; 9 12 months with RT*
*Walker MD, et al. N Engl J Med. 1980;303:1323-1329.
Radiotherapy: Randomized Trials
Author
N
Schema
Results
Andersen 1978
108
RT vs best supportive
care
Post-op RT signif improves OS
Walker 1978
303
BCNU vs RT vs BCNU
+RT, vs best supportive
care
RT significantly longer MS than
BCNU or best supportive care
Walker 1980
467
Semustine vs RT vs
semustine + RT vs
BCNU +RT
RT significantly longer survival
than semustine alone
Kristiansen 1981
118 RT vs RT + bleomycin vs
supportive care
MS with RT alone 10.2 mo
compared to 5.2 mo supportive
care
Andersen AP. Acta Radiol Oncol Radiat Phys Biol. 1978;17:475-484. Walker MD, J Neurosurg. 1978;49:333-343.
Walker MD, NEJM 1980;303:1323-1329. Kristiansen K, Cancer. 1981;47:649-652.
What about elderly patients?
Do they benefit from radiotherapy?
Elderly GBM: RT vs. BSC
GBM
>70 yo
KPS >70
n=85*
Median OS
R
A
N
D
O
M
I
Z
E
Control
3.9 mo
Keime-Guibert (France) et al. NEJM 356:1527-35, 2007.
*Trial discontinued early due to planned interim analysis
Supportive Care
50.4 Gy
RT
6.7 mo
P-value
0.002
Is it worth 5 ½ weeks of RT?
Can we do the RT quicker?
“Elderly” GBM: Short vs. Std Course RT
GBM
>60 yo
n=100*
Median OS
Roa (Canada) et al. JCO 22:1583-88, 2004.
*KPS = 70
R
A
N
D
O
M
I
Z
E
60 Gy/30
40 Gy/15
60 Gy
40 Gy
French
5.1 mo
5.6 mo
6.7 mo
How about chemotherapy
instead?
“Elderly” HGG Trial NOA-08
Temozolomide vs. Std RT
HGG
>65 yo
n=373*
R
A
N
D
O
M
I
Z
E
Median OS
Wick (German) et al. JCO 28:180S, 2010.
*~90% were GBM. Median age 71
54-60 Gy
TMZ week on/week off
RT
9.6 mo
TMZ
8 mo
GBM in the Elderly
• SNO: MGMT PROMOTER METHYLATION PREDICTS BENEFIT
FROM TEMOZOLOMIDE VERSUS RADIOTHERAPY IN
MALIGNANT ASTROCYTOMAS IN THE ELDERLY: THE NOA-08
TRIAL, Michael Weller, et al
• Tested the hypothesis that dose-dense TMZ is not inferior to RT
in pts with newly diagnosed AA or GBM, aged 66+. Patients (n =
412; 39 AA, 373 GBM) were randomized to RT or TMZ (1 week
on, 1 week off). Primary endpoint was OS.
• mOS [HR, =1.09] and EFS [HR = 1.15] of TMZ vs RT did not differ.
Non-inferiority of TMZ vs RT was significant (p = 0.033). Pts with
MGMT methylation had longer EFS with TMZ (8.4 vs 4.6 mo),
whereas pts without methylation had longer EFS with RT (4.6 vs
3.3 mo). This effect persisted for OS.
• Combined TMZ-RT remains unaddressed
“Elderly” GBM Trial
TMZ vs. Standard Course RT vs. Hypofrac RT
HGG
>60 yo
n=342*
Median OS
Malmstrom et al. JCO 28:180S, 2010.
R
A
N
D
O
M
I
Z
E
60 Gy
6 mo
60 Gy/30
34 Gy/10
TMZ d1-5q28d
34 Gy
7.5 mo
TMZ
8 mo
GBM RT Dose
•
•
•
•
•
MRC: OS 9 mo 45 Gy vs. 12 mo 60 Gy
RTOG 7401: No benefit 70 vs. 60 Gy (600+ patients)
RTOG 9006: No benefit 72 (1.2 BID) vs. 60 Gy (700+ patients)
U Mich: No benefit 90 Gy (90% failed in-field)
Multiple negative Phase III (e.g. brachy)
• 60 Gy is standard
• However dose escalation with temozolomide has not been
investigated
GBM Target Volume Delineation
• SNO: RT-09: TO COMPARE THE TREATMENT OUTCOMES OF TWO
DIFFERENT TARGET VOLUME DELINEATION GUIDELINES (RTOG VS
MD ANDERSON) IN GLIOBLASTOMA MULTIFORME PATIENTS: A
PROSPECTIVE RANDOMIZED STUDY, Narendra Kumar, et al
• METHODS: 50 GBM pts were randomized to target volume
delineation per RTOG guidelines in Arm A and per MD Anderson
guidelines in Arm B. All patients received a total RT dose of 60 Gy
in 30 fractions over 6 weeks.
• RESULTS: The planning target boost volume was significantly
smaller in Arm B (436 vs 246 cc, p= 0.001). Mean overall survival
was significantly better in Arm B (18.4 mo, 95% CI 14.76-22.04 vs
14.8 mo, 95% CI 11.25-18.41; p= 0.021). Median overall survival in
Arm A was 13 months (95% CI 10.25-15.78), and not reached in
Arm B. QOL Questionnaire BN20 and C-30 scores showed
significantly better quality of life in Arm B (p =0.005).
Radiosurgery: RTOG 9305
• 203 patients with GBM
• 60 Gy + BCNU +/- RS boost (15 - 24 Gy)
• Median follow up: 61 months
• MS: 13.5 vs 13.6 months
• General QOL & cognitive function comparable
Radiosurgery has not been proven to prolong
survival of GBM patients.
Souhami L. et al. Int J Radiat Oncol Biol Phys. 2004;60:853-860.
Extent of Resection
 Need Tissue confirmation
 Controversy benefit greater extent of
resection high-grade gliomas
– Conflicting retrospective studies
– Small prospective Finnish study
– Significant concerns regarding selection bias
The role of maximal resection controversial
Vuorinen V et al. Acta Neurochir 145:5-10, 2003
Survival benefit, trend benefit time to deterioration, p=0.057.
Impact of Resection on Survival
HGG*
n=322
R
A
N
D
O
M
I
Z
E
Resection w/ 5-ALA
Resection w/ White Light
5-ALA
Standard
P-value
GTR
65%
36%
<0.001
6 mo PFS
41%
21%
<0.001
Median OS
15.2 mo
13.5 mo
0.1
Stummer W (Germany) et al. Lancet Oncology 7:392-401, 2006.
5-ALA=aminolevulinic acid; *97% GBM
0525: Overall Survival NOT Affected by Surgery Type
100
Overall Survival (%)
75
Dead Total
Partial Resection 288 354
Total Resection
339 450
p (2-sided) = 0.09
HR (95% CI) =0.87 (0.75, 1.02)
50
25
0
0
Patients at Risk
Partial
354
Total
450
12
24
36
Months after Randomization
214
102
32
286
139
39
48
7
5
Radiation +/- Temozolomide
Concomitant
TMZ/RT*
R
0
Adjuvant TMZ
6
10
14
18
22
26
30
RT Alone
Temozolomide 75 mg/m2 po qd for 6 weeks,
then 150-200 mg/m2 po qd day 1-5 q 28 days for 6 cycles
Focal RT daily — 30 x 200 cGy
Total dose 60 Gy
*PCP prophylaxis was required for patients receiving TMZ during the concomitant phase.
Weeks
EORTC/NCIC PIII GBM Trial: Overall Survival
Percentage
100
90
80
70
P<0.0001
60
50
40
30
20
10
0
TMZ/RT
N=573
0
6
RT
12
Stupp R, et al. N Engl J Med. 2005;352:987-996.
18
24
months
30
36
42
Predictive Value of MGMT
% 6-mo PFS
% 2-yr survival
MGMT
RT
+TMZ
RT +TMZ
Overall
36
54
10
26
Unmethylated
35
40
2
14
Methylated
48
69
23
46
GBM patients with methylated MGMT from EORTC
trial 2-year survival 14 vs 46%.
Hegi ME, et al. N Engl J Med. 2005;352:997-1003.
Temozolomide Intensification: RTOG 0525
Gilbert, et al. abstract #2006, oral presentation ASCO 2011.
NOTE: All had resection (NO biopsy only)
All eligible
1120
All randomized
833
RTOG 0525-Results
Overall Survival (%)
75
100
Dead Total
Arm 1 320 411
Arm 2 332 420
p (1-sided) = 0.63
HR (95% CI) =1.03 (0.88, 1.20)
Progression-free Survival (%)
100
Prog free survival Arm 1 vs Arm 2
Overall survival Arm 1 vs Arm 2
50
25
50
25
0
0
0
Patients at Risk
Arm 1
411
Arm 2
420
75
Dead Total
Arm 1 374 411
Arm 2 379 420
p (2-sided) = 0.06
HR (95% CI) =0.87 (0.75, 1.00)
12
24
36
Months after Randomization
257
121
32
256
123
40
Arm 1 = standard adjuvant. Arm 2 = dose dense
48
7
5
0
Patients at Risk
Arm 1
411
Arm 2
420
12
24
36
Months after Randomization
107
50
19
132
56
18
48
5
2
Confirmed MGMT as a Prognostic Marker
Confirmed MGMT is NOT a Predictive Marker
MGMT methylated patients
Composite Biomarker Set Results in 0525
Pseudo-Progression
• Imaging progression shortly after RT + TMZ
– Unknown if “true disease progression”
– Should one continue adjuvant TMZ or declare
progression and switch to different chemo
• Very Common
– 1/3 to 1/2 of patients
– 1/2 stabilize/improve with further TMZ
Taal W., et al. abstract #2009, oral presentation ASCO 2007.
Pre-RT and TMZ
4 wks after RT/TMZ
Pre-RT and TMZ
4 wks after RT/TMZ
3 mo after RT/TMZ
4 wks after RT/TMZ
3 mo after RT/TMZ
4 wks after RT/TMZ
GBM: AVAGlio Trial
• SNO: OT-03 PHASE III TRIAL OF BEVACIZUMAB ADDED TO
STANDARD RADIOTHERAPY AND TEMOZOLOMIDE FOR NEWLYDIAGNOSED GLIOBLASTOMA: MATURE PROGRESSION-FREE
SURVIVAL AND PRELIMINARY OVERALL SURVIVAL RESULTS IN
AVAGLIO, Olivier Chinot, et al
• Randomized, double-blinded, placebo-controlled,
multinational trial, pts ≥18 yrs with newly diagnosed,
supratentorial GBM of RT/TMZ + biweekly bevacizumab or
placebo.
• 921 pts enrolled (2009-11). Study met co-primary
endpoint of improved mPFS (4.4 mo improvement; 10.6
vs. 6.2 mo, p<0.0001); OS did not reach statistical
significance.
RTOG 0825: Role of Bevacizumab
Closed 978 pts
GBM
Tissue
available
30 Gy +
TMZ (75
mg/m2 qd
x 21 d)*
*Analysis for MGMT
methylation, molec profile
R#
A
N
D
O
M
I
Z
E
30 Gy +
TMZ (75
mg/m2 qd x 21
d) + Placebo
30 Gy +
TMZ (75
mg/m2 qd x
21 d) + Bev
(10 mg/kg q
2wks)
TMZ (200 mg/m2) d 15 of 28-d cycle +
Placebo
12 cycle max
TMZ (200 mg/m2) d 15 of 28-d cycle + Bev
12 cycle max
# Stratify by: (Random 10d post start RT)
Recursive partitioning analysis (RPA) class (III vs IV vs V)
MGMT methylation status
Molecular profile
Anaplastic Astrocytoma
•Incidence:
• 2,000 diagnosed annually in US
- Median age 5th decade
•Median Survival:
• 2 - 3 years
•Histology:
• Increased astrocytic cellularity
• Cellular atypia and mitosis, no necrosis
Anaplastic Astrocytoma
• Notes:
• Tissue sampling a major issue
• Progression to glioblastoma frequent
• Significant difficulties with pathological
identification
- In contrast to GBM,
~30% “AA patients” misdiagnosed
• Genetics
• Less than 5% 1p19q co-deleted…
• MGMT methylation ~ GBM
• IDH mutation frequent
Stupp et al., Onc Hem 63:72-80, 2007.
Wick et al. JCO 27:5874-5880, 2009. RT 60 Gy/30
•318 patients – 1/2 Astrocytoma, 1/3 oligoastrocytoma, 1/8 oligodendroglioma
80% power to detect 50%improvement TTF w/ chemo one sided level 0.05
NOA-04 Phase III Results
PCV/TMZ
RT
Median TTF*
43.8 mo
42.7 mo
Median PFS
31.9 mo
30.6 mo
4 year OS
64.6%
72.6%
Wolfgang et al. JCO 27:5874-5880, 2009.
* TTF defined as failure after both chemo AND RT requiring new chemotherapy
NOA-04 Anaplastic Glioma Genetics
AO
AOA
AA
1p19q
77%
59%
15%
mMGMT
71%
71%
50%
IDH1 mut
71%
73%
57%
Wolfgang et al. JCO 27:5874-5880, 2009.
Remember Organic Chemistry?
Whole genome sequencing identifies mutation
in Isocitrate Dehydrogenase 1 (IDH1)
Sequenced 22 GBMs for 20,661 genes
Parsons DW, et al. Science 2008; 321: 1807-12
NOA-04 Conclusions
• PCV more toxic than TMZ
• TTF similar between chemotherapy and RT
and similar between TMZ + PCV
• IDH1 and mMGMT predict better prognosis
independent of treatment
Wolfgang et al. JCO 27:5874-5880, 2009.
RTOG 9813
Phase I
Arm 1: XRT + BCNU 200 mg/m2 + TMZ 150 mg/m2 x 5d q 8 wks
15 pts enrolled: 7/10 eligible pts needed dose mods
Arm 5: XRT + TMZ 150 mg/m2 x 5d + BCNU 150 mg/m2 q 8 wks
15 pts enrolled. Combination produces unacceptable toxicity
Phase III n=480
Arm 2: XRT + TMZ 150 mg/m2 x 5d q 4 wks
Arm 3: XRT + BCNU 80 mg/m2 q 8 wks*
Closed early: 201 patients enrolled
Chang SM, et al. Neuro-Onc 10:826, 2008. *CCNU allowed
OS by Treatment (Non-Co-deleted (N=137)
100
Overall Survival (%)
/
Median Survival
75
/
PCV+RT: 2.6 years
RT alone: 2.7 years
P = 0.39
/
/
50
/
25
/
/
// / / / /
/
0
0
Dead Total
/ /
/
58
76
p=
0.39
PCV+RT
RT
53
61
HR=0.85 (0.58, 1.23)
1 2 3 4 5 6 7 8 9 10 11 12
Years after Randomization
Some patients with non-co-deleted AO/AOA live longer after PCV+RT than RT alone; 10-year:
PCV+RT 25% vs. RT 10%, p<0.05
OS by IDH Status & Co-deletion Status
100
Dead
Co-del+IDH pos
55
Non co-del+IDH pos 50
Non co-del+IDH neg 40
p < 0.001
Overall Survival (%)
75
Total
88
66
44
50
25
0
0
1
2
3 4 5 6 7 8 9
Years after Randomization
10 11 12
OS by Treatment for IDH Mutated Cases
100
Overall Survival (%)
Median Survival
PCV+RT: 9.4 years
75
RT alone: 5.7 years
P = 0.006
50
25
0
0
Dead Total
80
p= 0.006
PCV+RT 45
RT
61
76
HR=0.59 (0.40, 0.86)
1 2 3 4 5 6 7 8 9 10 11 12
Years after Randomization
OS by Treatment for IDH Intact Cases
Overall Survival (%)
100
Dead Total
26
31
20
23
75
PCV+RT
RT
p= 0.67
HR= 1.14 (0.63, 2.04)
50
Median Survival
PCV+RT: 1.3 years
RT alone: 1.8 years
P = 0.67
25
0
0
1
2
3 4 5 6 7 8 9 10 11 12
Years after Randomization
RTOG 9813
Grade 3+4
Grade 5
TMZ
BCNU
P-value
45%
2%
70%
1%
P<0.01
NS
TMZ combined with RT significantly
better tolerated than BCNU
Chang SM, et al. Neuro-Onc 10:826, 2008
EORTC 26053/22054
RT
Anaplastic Glioma
without 1p/19q
deletions
N=680
• RT = 5940/33fx
• Adjuv. TMZ to 12 mo in
responders
Observation
Adjuvant TMZ
200mg/M2
5 D/28D
Observation
RT
+ TMZ
75mg/M2/D
Adjuvant TMZ
200mg/M2
5 D/28D
Anaplastic Oligodendroglioma
RTOG 9402
EORTC 26951
• Randomized trial 4
neoadjuvant cycles
intensive PCV
followed by RT vs RT
alone
• Randomized trial 6
cycles postradiation
standard PCV vs RT
alone
• Central review of
neuropathology
• Central review of
neuropathology
• Tissue for 1p 19q
available for 70%
• Tissue for 1p 19q
available for 85%
Cairncross G, et al. J Clin Oncol. 2006;24:2707-2714.
van den Bent MJ, et al. J Clin Oncol. 2006;24:2715-2722.
9402: Initial OS
RTOG 94-02
EORTC 26951
Overall Survival in Both Arms: 1p19q
Cairncross G, et al. J Clin Oncol. 2006;24:2707-2714.
van den Bent MJ, et al. J Clin Oncol. 2006;24:2715-2722.
2012: OS by Treatment (1p/19q co-del)
Overall Survival (%)
100
/ /
75
(2006)
Practice changing
/
Median Survival
PCV+RT: 14.7 years
RT alone: 7.3 years
50
//
/
/
/
/
//
////
/
/
//
/
/ /
25
0
0
Dead Total
59
p= 0.03
PCV+RT 28
RT
47
67
HR=0.59 (0.37, 0.95)
1 2 3 4 5 6 7 8 9 10 11 12
Years after Randomization
RTOG BR-0131: Temozolomide
• Survival Analysis (2012)
– 2 patients who received only pre-RT TMZ (CR or
NED) have remained progression-free for over 7
years
– 3-year PFS and 6-year OS (Codeleted patients)
Trial
3-year PFS
6-year OS
BR-0131
77%
82%
9402 – RT Only
49%
60%
9402 – PCV/RT
68%
67%
Note: Not a protocol-defined analysis
Low-Grade Gliomas
Key Features
• 1,900 low-grade gliomas annually
• Mean age: 37 years
• Heterogenous population - wide range of median
survival times
– Diffuse astrocytomas
5 years
– Oligoastrocytomas
7.5 years
– Oligodendrogliomas
10 years
Shaw EG, et al. J Neuro Oncology 1997;31:273-278.
EORTC “Believers” Trial 22844
45 Gy vs 59.4 Gy
45 Gy 59.4 Gy P-value
5-yr PFS
47%
50%
0.94
5-yr OS
58%
59%
0.73
Intergroup 86-72-51: Overall Survival
*Arm A: 50.4 Gy
vs Arm B: 64.8 Gy
EORTC “Non-Believers” Trial 22845
Immediate vs Delayed
Control
RT
P-value
5-yr PFS
35%
55% <0.0001
5-yr OS
66%
68%
0.87
MS
3.3 y
5.3 y
+
Seizure @ 1Y
41%
25%
0.03
Van den Bent, et al. Lancet. 2005.Updated results 7.8 median F/U
RTOG 98-02 Intergroup Trial
Low risk:Arm 1
LGG
Age <40 and
GTR
High risk:
~111 low risk
254
high risk
P60 mg/m2
CCNU
110mg/m2 VCR 1.4
mg/m2
Age >40 or
STR/biopsy
R
observe
Arm 2: RT
54 Gy
Arm 3: RT + 6
cycles PCV
98-02: Survival by Arm
RTOG 98-02 Intergroup Trial
Low-risk LGG
% ALIVE W/O PROGRESSION
100
<4cm, oligo, <1cm imaging residual*
75
50
25
>4cm, astro, >1cm imaging residual**
All favorable prognostic factors
Mixed prognostic factors
All unfavorable prognostic factors
0
0
1
2
3
4
YEARS FROM REGISTRATION
*Shaw E, et al. JNS 109:835-841, 2008.
5
5 Yr PFS 70%* and 13%**
6
RTOG 98-02 Intergroup Trial
High-risk LGG – Progression Free Survival
RTOG 98-02 Intergroup Trial
High-risk LGG - Log Rank Test
RT
RT + PCV
P-Value
5 yr OS
63%
72%
p=0.13*
5 yr PFS
46%
63%
p=0.005
*Wilcoxan P-value OS = 0.33, PFS = 0.06
Shaw E, et al. abstract #2006, oral presentation ASCO 2008.
Ad hoc-Inclusion of only 2 year survivors-improved PFS + OS
EORTC 22033-26033
LGG
n=466
S
T
R
A
T
I
F
Y
1p Status
etc.
R
A
N
D
O
M
I
Z
E
50.4 Gy*
TMZ x 12
*Age> 40 years; radiologically proven progressive lesion, new or worsening neurological
symptoms, intractable seizures
Completed accrual 03/2010
E3F05 Phase III Symptomatic* or
Progressive LGG: RT +/- Temozolomide
Concomitant
TMZ/RT
R
N= 540
0
Adjuvant TMZ
6
10
14
18
22
26
30
Weeks
RT Alone
Temozolomide 75 mg/m2 po qd for 6 weeks,
then 150-200 mg/m2 po qd day 1-5 q 28 days for 12 cycles
Focal RT daily — 28 x 180 cGy
Total dose 50.4 Gy
*Symptomatic = uncontrolled headaches or seizures, focal deficits, cognitive symptoms
Pilocytic Astrocytoma
• WHO grade I tumors
• Well circumscribed,
enhancing cerebellar
lesions typically in kids
– Few adult studies
• Surgical resection alone
10 yr OS >80%
– Most important intervention
Pilocytic Astrocytomas
Recommendations
• Observation after GTR or STR
• Radiation (50.4 Gy) recommended after biopsy
or recurrence after STR
– Especially if symptomatic
• Malignant transformation rare event
– As many reports of malignant transformation after radiation
as after surgery alone
Brown et al., IJROBP 58 (4):1153-1160, 2004
Intracranial Ependymoma
• 5% brain tumors; image entire CNS axis
• Historical standard post-op RT
• BNI: 45 post fossa image defined resection
• 71% GTR; 29% STR
GTR + RT
GTR
STR + RT
10 yr LC
100%
50%
36%
10 yr OS
83%
67%
43%
Mork, Loken Cancer 40:907-915, 1977
Rogers (Barrow Neurologic Institute) JNS 102:629-636, 2005. 96% Low grade tumors.
Intraspinal Ependymoma
• 63% intramedullary spine tumors
• Image entire CNS axis
• En bloc resection (not piecemeal) curative
– Up to 95% DFS Grade II
Hanbali (MDAH) 51:1162-1174, 2002
Myxopapillary Ependymoma – MDAH
Adjuvant RT Observation
10 yr LC
86%
46%*
10 yr PFS
75%
37%*
• Authors recommend post-op RT for all patients due to
irregular shape, nerve root involvement
Akyurek J Neuro-Onc 80:177-183, 2006. Median RT dose 50.4 Gy; *P<0.05
Myxopapillary Ependymoma
RARE CANCER NETWORK
5 yr PFS
Observation
<50.4 Gy
>50.4 Gy
50%
68%*
82%**
Pica, Miller, et al. IJROBP 74:1114–1120, 2009. Median RT dose 50.4 Gy
* P=0.4 compared to surgery alone **P=0.05 compared to surgery alone
Schild et al, IJROBP 53(3): 787, 2002. Mayo also found benefit >50 Gy
Spinal Cord Astrocytoma - Mayo Clinic
• 200-300 intramedullary spinal cord
astrocytomas annually
• 136 patients treated Mayo, 1962-2005
• No role of adjuvant RT for pilocytic
• RT for all infiltrative astrocytomas
– Grade 2 – 50.4 Gy local field
– Grade 3 – 55.8 Gy local field
– Grade 4 – 59.4 Gy local field
Minehan, Brown, Scheitauer IJROBP 73(3):727-33, 2009
ARS Q: Post-test
• Which one of the following is accepted as a PREDICTIVE
biomarker in neuro-oncology?
–
–
–
–
–
A.
B.
C.
D.
E.
MGMT promoter methylation
1p19q codeletion
EGFR Viii mutation
Loss of PTEN
NF2 allelic loss
Craniopharyngioma
• Locally extensive, benign tumor arising from remnant of
Rathke’s pouch, with cystic and solid portions
• 1-3% of all intracranial tumors; 10% of peds
• Biomodal distribution
– Childhood 5-14 years, Adult 55-65 years
• Male = Female
• No known risk factors
• Histologic types:
– Adamantinomatous
– Squamous papillary
– Mixed
Treatment: Surgery
• GTR most likely for
–
–
–
–
<3cm
Pre or intrachiasmatic lesions
Solid component
No hypothalamic extension
• Retrochiasmatic tumors have higher mortality
with sx
• Trans-sphenoid approach gives higher GTR
• 10 yr LC with GTR=90%, STR=30%
Treatment: Surgery + RT
• Recurrence after STR about 50%
Series
% LR STR
% LR STR+RT
Richmond
37
4
Weiss
60
13
Karavitaki
62
23
• In modern series, local recurrence after Sx and RT is < 10%
• Timing of radiation is controversial, but some argue immediate
radiation increases local control
Richmond et al. Neurosurgery. 6(5):513-17. 1980; Weiss et al. IJROBP. 17(6):1313-21
Karavitaki et al. Clin Endocrinol. 62(4):397-409. Apr 2005; Mark et al. Radiology. 197(1):195-8. Oct 1995
Treatment: Radiation
• Used for inoperable, partial resection, or
recurrent disease
• 3DC, FSRT, SRS, intracavitary brachytherapy
• 54 Gy/1.8 Gy per fraction.
– >55 Gy increase optic neuropathy
– <54 Gy lower control rates (44 vs 16% recurrence)*
– 78% 20 yr OS for those treated for primary disease
vs 25% for recurrence
*Regine et al. IJROBP. 24(4):611-7.1992
Habrand et al. IJROBP. 44(2):255-63. May 1999
Cavazzuti et al. J Neurosurg. 59(3):409-17. 1983
Vestibular Schwannoma
• Tumor of the vestibular nerve sheath
– Acoustic neuroma is a misnomer
• Symptomatic incidence is ~1/100,000
– 0.2% of MRIs with VS
– Represent 80-90% of CPA tumors
– Rising incidence
• Almost always unilateral and benign
– Bilateral is a pathognomonic feature of NF2
• Variable growth rate
– Avg 1.9 mm/year
– 40% will show no growth or even spontaneous shrinkage
on serial images.
Biology
• Biallelic inactivating mutations of tumor
suppressor gene NF2 on 22q12 seen in
sporadic and NF2-associated VS
• NF2 encodes for merlin, a protein involved in
cell proliferation
• Merlin downstream pathways may be targets
for future therapies
Observation
•
•
•
•
5% will spontaneously shrink
Some tumors grow only 1-2 mm / year
Serial audiometry and MRI every 1-2 years
May be reasonable in some pts:
– Elderly pts with slow-growing tumors confirmed on serial
scans
– Pts with a lesion in the dominant or sole side of hearing
where an intervention would render hearing loss
• Risks:
– Hearing loss despite minimal growth
– 75% of tumors grow within 1 year
Surgery
• 50% of patients are treated surgically
– Steep learning curve (20-60 cases)
• Mortality ~ 2%
• Cure rates > 95%
• Preservation of facial nerve and hearing is goal
– Influenced significantly by tumor size and approach
• Facial nerve function is electrically monitored during
surgery.
Three Surgical Approaches
Approach
Indications
Advantages/Disadvantag
es
Retrosigmoid/suboccipital Any size with attempted
hearing preservation
Lower risk of facial injury.
Increased HA,leaks,
cerebellar injury
Middle Fossa
<2cm, involve lateral IAC,
hearing preservation
High hearing
preservation, increased
risk to facial nerve and
temporal lobe
Translabyrinthine
Nonserviceable hearing in Complete visualization of
affected ear
IAC allows higher GTR
rates, no hearing
preservation
Surgery Complications
Post-op complications ~ 20%
1.
2.
3.
4.
5.
6.
7.
CSF leak – 5-15%
Meningitis – 2-10%
Facial weakness – 4-15%
Hearing loss varies according to approach
Headache – 10-34%
Stroke
Brain injury
Microsurgery Results
YR
#
LC %
FM %
HP %
C%
D%
OJEMANN
1993
410
97
96
36
10.5
0.5
HOUSE
1982
216
99.5
83
40
10.6
0.4
HARDY
1989
100
97
82
16
18
3
TOS
1988
300
87
10.5
2
EBERSOLD
1992
256
97
92
49
28
0.7
SCRIPPS
1994
11
91
91
18
9
0
SAMII
1997
1000
98
15
20
1.1
AVERAGE
2293
2293
98
27
17
1.1
90
LC=Local control; FM=Facial movement; HP=Hearing preservation C = Complications, D = Death
Radiosurgery
– Viable option for patients with tumors <3cm or
for growing tumors in medically inoperable
patients
– 12.5 to 13 Gy
•
•
Typically prescribe to 50% IDL with GKS
TV is macroscopic volume seen on MRI
– 5 year PFS correlated with tumor size (1.5%
decrease per 1 cm3)
Noren et al.
•
•
•
•
Largest single physician experience
669 pts from 1969 to 1997
Long-term growth control of 95%
Facial numbness/weakness ↓ over time
– (32% to 2%)
• Hearing preservation 65-70%
Noren G et al. Stereotactic & Functional Neurosurgery. 70 Suppl 1:65-73, 1998
Oct
Temporary enlargement (41%)
Serial contrast-enhanced axial T1-weighted images (450/17/5) in a 51-year-old man. Note that
the tumor shows temporary enlargement with transient loss of contrast enhancement 3 months
after treatment.
Nakamura H. et al. American Journal of Neuroradiology. 21(8):1540-6, 2000
Alternating enlargement and regression (13%)
Serial contrast-enhanced axial T1-weighted images in a 64-year-old woman show enlargement of the cystic
component and transient loss of contrast enhancement in the solid component at 3 months; regression of the
cystic component, slight enlargement and recovery of contrast enhancement of the solid component, and
slight regression of the overall tumor at 18 months; further enlargement of the solid component, no change in
the cystic component, and regression of the overall tumor at 24 months; and remarkable regression of the
tumor at 50 months.
Nakamura H. et al. American Journal of Neuroradiology. 21(8):1540-6, 2000
SRS vs. Microsurgery: France
• Non Randomized prospective series using preand post- Rx questionnaires
– Minimum follow up 3 years
– GKS=97 pts; Microsurgery 110 pts
Rx
CN VII
disturbance
CN V
Disturbance
Hearing
Preserved
Functional
disturbance
Hosp
stay
Work
missed
Surgery
37%
29%
37.5%
39%
23
130
GK
0%
4%
70%
9%
3
7
Regis et al. J Neurosurgery. 2002 Nov; 97(5):1091-100
FSRT vs. SRS: Amsterdam
• 129 pts from ‘92-’99; mean f/u 33 mo
• Pseudorandomization
– Dentate patients received 20 or 25Gy/5fx
– Edentulous pts received SRS 10 or 12.5 Gy
Treatment
Tumor
Control
CN V
Preservation
CN VII
Preservation
Hearing
Preservation
SRS
FSRT
100%
94%
92%
98%
93%
97%
75%
61%
Meijer et al, IJROBP 2003. Aug; 56(5):1390-96
FSRT vs. SRS: TJ Experience
• Retrospective review
• N=69 GK and 56 FSRT patients
• 12Gy GK vs. 50Gy/25fx
Treatment
Tumor Control
CN V
Preservation
CN VII
Preservation
Hearing
Preservation
SRS
98%
95%
98%
33%
FSRT
97%
93%
98%
81%
Andrews, IJROBP. 2001 Aug 1;50(5):1265-78
Management of the NF2 Patient
• Image entire cranial spinal axis
• More aggressive course
• Worse functional outcome
– *81% LC with SRS, but only 48% hearing
preservation rate at 5 years
– Recommend limiting treatment to large
symptomatic tumors
*Mathieu et al. Neurosurgery 2007. 60(3):p460-468
Is Bevacizumab a Game Changer?
Change from baseline (%)
Best Radiographic Response to
Bevacizumab
Six of ten patients experienced
radiographic responses; four of six
remain smaller at 11-16 months
* * *
* *
*
Plotkin et al. NEJM. 261-4, 358-67 July 23, 2009
Hearing Response
• VEGF expressed in 100% of patients in study
• Median best response was 26% reduction
• 4 of 7 with hearing response (3 were not
evaluable)
Plotkin et al. NEJM. 261-4, 358-67 July 23, 2009
Meningioma
• Second commonest primary brain tumor
– ~30% of all primary intracranial tumors
• Incidence is about 6/100K
• Incidence increases with age
• May be higher based on autopsy series (up to
2%)
• 90% benign
2007 WHO Grading
Grade I
(benign)
80-90%
Any major variant other than clear cell, chordoid, papillary, or rhabdoid
Grade II
(Atypical)
5-20%
Frequent mitoses (>4 per hpf)
OR
3+ of the following: sheeting architecture, hypercellularity, prominent
nucleoli, small cells with high nuclear:cytoplasm, foci of spontaneous necrosis
OR
Chordoid, clear cell, or brain invasion
Grade III
(Anaplastic or
Malignant)
1-2%
Excessive mitotic index (>20 per 10 hpf)
OR
Frank anaplasia resembling:sarcoma, carcinoma, or melanoma
OR
Papillary or rhabdoid
Observation
• Retrospective review of 1,434 patients from
1989-2004
• 603 had asymptomatic lesions
• Size, growth over time, appearance of symptoms
• 58% of the asymptomatic lesions were observed
– Progression noted in 37%, but symptomatic
progression in only 16%
Yano S et al, J Neurosurg. 105(4)538-43, 2006
Surgery
• Gross total resection if medically operable
• GTR generally thought to give 90% RFS, but
depends on Simpson Grade
• Recommended for younger patients with
surgically accessible lesions
• IN GENERAL, convexity lesions are managed with
surgery, while base of skull lesions and optic
nerve sheath meningiomas are generally not
Simpson Grade
Grade
I
III
Removal of tumor bulk,
surrounding dura, involved
bone
Removal of tumor with
diathermy of involved dura
Small focus left in situ
IV
Macrosocopic residual disease
V
Simple decompression
II
5 year
recurrence rate
10%
20%
30%
40%
GTR alone
Author
n (GTR)
Mirimanoff (MGH)
Stafford (Mayo)
Condra (U Florida)
Total:
Mirimanoff et al, Neurosurg 62:18, 1985
Stafford et al, Mayo Clin Proc 73:936, 1998
Condra et al, IJROBP 39:427, 1997
145
465
175
785
Local Recurrence
5-year
7%
12%
7%
7-12%
10-year
20%
25%
20%
20-25%
15-year
32%
24%
24-32%
STR alone
Author
Wara (UCSF)
Condra (U Florida)
Mirimanoff (MGH)
Stafford (Mayo)*
TOTAL:
Local Progression
5-year
47%
47%
37%
39%
10-year
63%
60%
55%
61%
15-year
70%
91%
-
20-year
75%
-
37-47%
55-63%
70-91%
75%
*581 pts 1978 -1988 (116 STR)
Only 10 had post-op RT
Wara et al, Am J Roentgenol Ther Nucl Med 123:453, 1975
Stafford et al, Mayo Clin Proc 73:936, 1998
Condra et al, IJROBP 39:427, 1997
Mirimanoff et al, J Neurosurg 1985; 62: 18-24
5 yr PFS after EBRT
Rogers L. Radiation Therapy for Intracranial Meningiomas. 2010
Radiation
• Indications
– Subtotal resection
– Unresectable tumor
– High grade
– Recurrent
Radiation
• Grade 1
– 50.4 to 54 Gy at 1.8 to 2 Gy fractions (1-2 cm
margin)
• Grade 2
– 54 to 59.4 Gy at 1.8 to 2 Gy fractions (2-3 cm
margin)
• Grade 3
– 59.4 to 60 Gy at 1.8 to 2 Gy fractions (2-3 cm
margin)
What About Higher Grades?
• RR of 108 atypical
meningiomas after
GTR from ‘93 to
‘04
• 28% recurred after
GTR; 8 pts had
adjuvant RT and
none of these 8
had a recurrence
Aghi et al. Neruosurgery 64(1):56-60, January
2009
Radiosurgery
• Excellent outcomes with SRS for patients with
– Tumors <35 mm
– <15cc volume (<7.5 cc even better)
• No randomized data comparing SRS with
surgery, but for small lesions, the results
appear to be similar
Pollock, Stafford et al. IJROBP 2003; 55: 1000 - 1005
Kondziolka et al. Neurosurgery 1998; 43: 405 - 414
SRS and EBRT by Grade
Adapted from Chan, Rogers, Anderson, Khuntia: Chapter 26 Benign Brain Tumors. Clinical Radiation Oncology. In
Press 2011.
RTOG - 0539 Schema
Group 1 (Low Risk):
New Grade 1, GTR or STR
Group 2 (Interm Risk):
Recurrent Grade 1, GTR or STR
New Grade 2, GTR
Group 3 (High Risk):
Any Grade 3
Recurrent Grade 2
New Grade 2, STR
N=165
Group 1
Strata
Group 2
Group 3
Observation
3D CRT or IMRT 54 Gy / 30 fxs
IMRT 60 Gy / 30 fxs
Pituitary Adenomas
• Represent between 10-15% of all CNS
neoplasms
• Females>males (especially microadenomas)
• Usually between ages 45-55
• Benign, invasive, or carcinoma
– Majority are benign (greater than 60%)
– Invasive adenomas make up 35%
– True carcinomas are rare (<0.2%)
Genetic Associations
• MEN 1—loss of function of this tumor suppressor genes
can cause tumors in parathyroid, pancreatic islets, or
pituitary gland
• Gs-alpha—an activating mutation of the alpha subunit of
the guanine nucleotide stimulatory protein found in 40%
of somatotroph adenomas
• PTTG—pituitary tumor transforming gene is overexpressed in most pituitary adenomas
• FGF receptor-4—A truncated for of the receptor for
fibroblast growth factor-4 identified in pituitary adenoma
Anatomy
•
•
•
•
•
•
•
Midline structure in the sella turcica in
the body of the sphenoid
Posterior lobe arises as an invagination
from the floor of the third ventricle
Tumors of the posterior lobe are
virtually unknown
Anterior and intermediate lobes arise
from Rathke’s pouch
Anterior pituitary gland secretes: CRH,
TRH, GH-RH, GH-RIH (somatostatin),
FSH-RH, LH-RH, PRH, PIH
The normal gland weighs 0.6 grams
15 mm AP by 12 mm sup-inf
Size/Secretory Function
• 70% Secretory
– Prolactinomas the most common
• 30% Non-secretory (non functioning)
• Microadenomas are <10mm
– Majority are microadenomas
• Macro adenomas >10 mm
• Giant adenoma > 40 mm
Functional Endocrine Definition
1.
2.
3.
4.
5.
Prolactinomas
ACTH-producing adenomas (somatotrophs)
GH-producing adenomas (somatotrophs)
TSH-producing adenomas (thyrotrophs)
Non functioning adenomas (usually
gonadotrophs)
Listed in order of frequency
Pathology
•
•
•
•
GH and prolactin are derived from subtypes of
acidophilic cells, whereas ACTH, TSH, LH, and FSH
are secreted by different basophilic cells).
Chromophobic are non-secreting however PRL may
be increased due to compression.
Ki-67 elevated
WHO uses IHC and secretory pattern
(somatotroph, lactotroph, gonadotroph,
corticotroph, thryotroph, plurihormonal, null-cell)
Prolactinomas
• >250 μg/L common (Normal <15 μg/L)
– Symptoms not correlated with level
• Microadenomas are found in 11% of autopsies
with prolactinomas making up 44%
Klibanski, A. NEJM. 262;13, April 1, 2010
Surgery
•
•
•
•
Allows prompt decompression of mass effect
Histology
Rapid normalization of hormone levels
Long term control of 80-90% of
microadenoma and 25-50% with
macroadenomas
Medical Management
• Bromocriptine and cabergoline (a dopamine agonist)
for prolactin secreting tumors
– Can reduce secretion and size in 80%
– Can stop after 2 years of normal hormones levels and close f/u
• Somatostatin analogs (SSAs: octreotide, lanreotide)
for growth hormone secreting
– 50-60% success rate in those not responding to surgery
– Pegvisomant (IGF inhibitor) costs $150,000/year
• For ACTH secreting, mitotane, ketoconazole,
metapyrone
– Usually less effective than local therapies.
Indications for XRT
•
•
•
•
Incomplete resection
Recurrent tumors
Inoperable patients
Refractory secretory tumors
Radiation Therapy
• Cavernous sinus invasion is probably not
amenable to surgery and is better treated
with radiation.
• EBRT controls hypersecretion in about 80% of
patients with acromegaly, 50-80% of those
with Cushing’s disease, and about 1/3 of
those with hyperprolactinemia
• But this can take several years
SRS
• Reverses endocrinopathies faster and more
predictably than EBRT
• Need to hold drug therapy before and during SRS
especially for prolactinomas*
• Doses range between 12-28 Gy based on size and
location. Doses >15 Gy increase LC for secreting
tumors (try to achieve 20 Gy if can be done safely)
– Secretory tumors 24-28 Gy marginal dose
– Non-secretary 14-16 Gy
*Landolt et all. J Neurosurgery. 2000;93,14-18
*Pouratian et al. Neurosurgery. 2006;59(2):255-266
Prolactinomas
• Medical therapy normalizes and shrink tumors in 90% of cases
– Returns in 90% once discontinued
• Resection for salvage effective in 75-90% of microadenomas
and 20-50% of macroadenomas
• 45Gy/1.8Gy per fx normalizes prolactin levels in 50% but can
take years
• SRS controls tumors in 90% but hormonal control in only 2050%
– Hold dopamine agonist for 2 months
Acromegaly
• Resection often curative
• Somatostatin analogs used for second-line therapy
• Radiation can yield 80% normalization of growth hormone with
time (delayed)
• SRS yields LC in excess of 95%
• Time to normalization is 1.4 years with SRS versus 7.1 years with
EBRT
• Concurrent octreotide with SRS delays hormonal normalization
and should be discontinued 1-2 months prior
Jenkins et al. J Clin Endocrinol Metab 2006;91(4)1239-1245
Landolt et al. J Neurosurg. 1998;88(6)1002-08
Landolt et al. J Clin Endocrinol Metab. 2000;85(3):1287-89
Non Functioning Adenomas
• Most are macroadenoma
• Usually present with vision changes so usually
surgery is advocated (80-90% LC)
• Immediate postop RT yields LC >90% versus LR
after STR of 33% at 15 years
• SRS yields LC>90% with less than 25% new
endocrinopathies
Gittoes et al. Clin Endocrinol. 1998;48(3):331-37
Van den Bergh et al. IJROBP. 2007;67(3):863-69
Thank You