2013 astro refresher course: adult cns tumors · 2013 astro refresher course: adult cns tumors...
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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. MGMT promoter methylation – B. 1p19q codeletion – C. EGFR Viii mutation – D. Loss of PTEN – E. NF2 allelic loss
Gliomas: Grade vs. Survival
Tumor Type MS (mos)
Pilocytic Astrocytoma --
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
Keime-Guibert (France) et al. NEJM 356:1527-35, 2007. *Trial discontinued early due to planned interim analysis
GBM >70 yo KPS >70 n=85*
R A N D O M I Z E
Supportive Care
50.4 Gy
Control RT P-value Median OS 3.9 mo 6.7 mo 0.002
Is it worth 5 ½ weeks of RT?
Can we do the RT quicker?
“Elderly” GBM: Short vs. Std Course RT
Roa (Canada) et al. JCO 22:1583-88, 2004. *KPS = 70
GBM >60 yo n=100*
R A N D O M I Z E
60 Gy/30
40 Gy/15
60 Gy 40 Gy French Median OS 5.1 mo 5.6 mo 6.7 mo
How about chemotherapy instead?
“Elderly” HGG Trial NOA-08 Temozolomide vs. Std RT
Wick (German) et al. JCO 28:180S, 2010. *~90% were GBM. Median age 71
HGG >65 yo n=373*
R A N D O M I Z E
54-60 Gy
TMZ week on/week off
RT TMZ Median OS 9.6 mo 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
Malmstrom et al. JCO 28:180S, 2010.
HGG >60 yo n=342*
R A N D O M I Z E
60 Gy/30
TMZ d1-5q28d
34 Gy/10
60 Gy 34 Gy TMZ Median OS 6 mo 7.5 mo 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
Souhami L. et al. Int J Radiat Oncol Biol Phys. 2004;60:853-860.
Radiosurgery has not been proven to prolong survival of GBM patients.
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
Stummer W (Germany) et al. Lancet Oncology 7:392-401, 2006. 5-ALA=aminolevulinic acid; *97% GBM
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
0525: Overall Survival NOT Affected by Surgery Type
Ove
rall
Surv
ival
(%)
0
25
50
75
100
Months after Randomization0 12 24 36 48
Patients at RiskPartialTotal
354450
214286
102139
3239
75
Dead288339
Total354450
p (2-sided) = 0.09 HR (95% CI) =0.87 (0.75, 1.02)
Partial ResectionTotal Resection
Focal RT daily — 30 x 200 cGy Total dose 60 Gy
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
Concomitant TMZ/RT*
Adjuvant TMZ
Weeks 6 10 14 18 22 26 30
RT Alone
R 0
*PCP prophylaxis was required for patients receiving TMZ during the concomitant phase.
Radiation +/- Temozolomide
EORTC/NCIC PIII GBM Trial: Overall Survival
months
0 6 12 18 24 30 36 42 0
10 20 30 40 50 60 70 80 90
100
TMZ/RT
RT
Perc
enta
ge
P<0.0001
Stupp R, et al. N Engl J Med. 2005;352:987-996.
N=573
Predictive Value of MGMT
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%.
% 6-mo PFS % 2-yr survival
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 O
vera
ll Su
rviv
al (%
)
0
25
50
75
100
Months after Randomization0 12 24 36 48
Patients at RiskArm 1Arm 2
411420
257256
121123
3240
75
Dead320332
Total411420
p (1-sided) = 0.63 HR (95% CI) =1.03 (0.88, 1.20)
Arm 1Arm 2
Prog
ress
ion-
free
Surv
ival
(%)
0
25
50
75
100
Months after Randomization0 12 24 36 48
Patients at RiskArm 1Arm 2
411420
107132
5056
1918
52
Dead374379
Total411420
p (2-sided) = 0.06 HR (95% CI) =0.87 (0.75, 1.00)
Arm 1Arm 2
Overall survival Arm 1 vs Arm 2 Prog free survival Arm 1 vs Arm 2
Arm 1 = standard adjuvant. Arm 2 = dose dense
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
4 wks after RT/TMZ 3 mo after RT/TMZ
4 wks after RT/TMZ 3 mo after RT/TMZ
GBM: AVAGlio Trial • SNO: OT-03 PHASE III TRIAL OF BEVACIZUMAB ADDED TO
STANDARD RADIOTHERAPY AND TEMOZOLOMIDE FOR NEWLY-DIAGNOSED 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.
GBM Tissue
available
30 Gy + TMZ (75
mg/m2 qd x 21 d)*
R# A N D O M I Z E
30 Gy + TMZ (75
mg/m2 qd x 21 d) + Bev (10 mg/kg q
2wks)
30 Gy + TMZ (75
mg/m2 qd x 21 d) + Placebo
TMZ (200 mg/m2) d 1-5 of 28-d cycle + Placebo 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
TMZ (200 mg/m2) d 1-5 of 28-d cycle + Bev 12 cycle max
Closed 978 pts
*Analysis for MGMT methylation, molec profile
RTOG 0825: Role of Bevacizumab
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
Wolfgang et al. JCO 27:5874-5880, 2009.
* TTF defined as failure after both chemo AND RT requiring new chemotherapy
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%
NOA-04 Anaplastic Glioma Genetics
Wolfgang et al. JCO 27:5874-5880, 2009.
AO AOA AA
1p19q 77% 59% 15%
mMGMT 71% 71% 50%
IDH1 mut 71% 73% 57%
Remember Organic Chemistry?
Whole genome sequencing identifies mutation in Isocitrate Dehydrogenase 1 (IDH1)
Parsons DW, et al. Science 2008; 321: 1807-12 Sequenced 22 GBMs for 20,661 genes
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 3: XRT + BCNU 80 mg/m2 q 8 wks* Arm 2: XRT + TMZ 150 mg/m2 x 5d q 4 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)
Ove
rall
Surv
ival
(%)
0
25
50
75
100
Years after Randomization0 1 2 3 4 5 6 7 8 9 10 11 12
Ove
rall
Surv
ival
(%)
0
25
50
75
100
Years after Randomization0 1 2 3 4 5 6 7 8 9 10 11 12
Dead5853
Total7661
p= 0.39 HR=0.85 (0.58, 1.23)PCV+RTRT
/
/
/
/ / // / / / /
//
// / /
Median Survival
PCV+RT: 2.6 years
RT alone: 2.7 years
P = 0.39
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
Ove
rall
Surv
ival
(%)
0
25
50
75
100
Years after Randomization0 1 2 3 4 5 6 7 8 9 10 11 12
Dead555040
Total886644
p < 0.001
Co-del+IDH posNon co-del+IDH posNon co-del+IDH neg
OS by Treatment for IDH Mutated Cases
Median Survival
PCV+RT: 9.4 years
RT alone: 5.7 years
P = 0.006
Ove
rall
Surv
ival
(%)
0
25
50
75
100
Years after Randomization0 1 2 3 4 5 6 7 8 9 10 11 12
Dead4561
Total8076
p= 0.006 HR=0.59 (0.40, 0.86)
PCV+RTRT
Ove
rall
Surv
ival
(%)
0
25
50
75
100
Years after Randomization0 1 2 3 4 5 6 7 8 9 10 11 12
Dead2620
Total3123
p= 0.67 HR= 1.14 (0.63, 2.04)
PCV+RTRT
OS by Treatment for IDH Intact Cases
Median Survival
PCV+RT: 1.3 years
RT alone: 1.8 years
P = 0.67
RTOG 9813
TMZ BCNU P-value Grade 3+4 45% 70% P<0.01
Grade 5 2% 1% NS
TMZ combined with RT significantly
better tolerated than BCNU Chang SM, et al. Neuro-Onc 10:826, 2008
EORTC 26053/22054
RT
Observation
Observation
Adjuvant TMZ 200mg/M2 5 D/28D
Anaplastic Glioma without 1p/19q
deletions
N=680
Adjuvant TMZ 200mg/M2
5 D/28D
RT + TMZ
75mg/M2/D • RT = 5940/33fx • Adjuv. TMZ to 12 mo in
responders
• Randomized trial 4 neoadjuvant cycles intensive PCV followed by RT vs RT alone
• Central review of neuropathology
• Tissue for 1p 19q available for 70%
• Randomized trial 6 cycles postradiation standard PCV vs RT alone
• Central review of neuropathology
• Tissue for 1p 19q available for 85%
RTOG 9402 EORTC 26951
Cairncross G, et al. J Clin Oncol. 2006;24:2707-2714. van den Bent MJ, et al. J Clin Oncol. 2006;24:2715-2722.
Anaplastic Oligodendroglioma
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)
Ove
rall
Surv
ival
(%)
0
25
50
75
100
Years after Randomization0 1 2 3 4 5 6 7 8 9 10 11 12
Ove
rall
Surv
ival
(%)
0
25
50
75
100
Years after Randomization0 1 2 3 4 5 6 7 8 9 10 11 12
Dead2847
Total5967
p= 0.03 HR=0.59 (0.37, 0.95)PCV+RTRT
/ /
/// /
// // /// /
/ / /
/
/// / /
Median Survival
PCV+RT: 14.7 years RT alone: 7.3 years
(2006) Practice changing
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
LGG
Low risk:Arm 1
Age <40 and GTR
observe
High risk:
Age >40 or STR/biopsy
R
Arm 2: RT 54 Gy
Arm 3: RT + 6 cycles PCV
~111 low risk 254 high risk P60 mg/m2 CCNU 110mg/m2 VCR 1.4 mg/m2
98-02: Survival by Arm
RTOG 98-02 Intergroup Trial Low-risk LGG
*Shaw E, et al. JNS 109:835-841, 2008. 5 Yr PFS 70%* and 13%**
% A
LIVE
W/O
PR
OG
RES
SIO
N
0
25
50
75
100
YEARS FROM REGISTRATION0 1 2 3 4 5 6
All favorable prognostic factorsMixed prognostic factorsAll unfavorable prognostic factors
<4cm, oligo, <1cm imaging residual*
>4cm, astro, >1cm imaging residual**
RTOG 98-02 Intergroup Trial High-risk LGG – Progression Free Survival
RTOG 98-02 Intergroup Trial High-risk LGG - Log Rank Test
*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
RT RT + PCV P-Value
5 yr OS 63% 72% p=0.13*
5 yr PFS 46% 63% p=0.005
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
Focal RT daily — 28 x 180 cGy Total dose 50.4 Gy
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
Concomitant TMZ/RT
Adjuvant TMZ
Weeks 6 10 14 18 22 26 30
RT Alone
R 0
*Symptomatic = uncontrolled headaches or seizures, focal deficits, cognitive symptoms
E3F05 Phase III Symptomatic* or Progressive LGG: RT +/- Temozolomide
N= 540
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
• 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
Pilocytic Astrocytomas Recommendations
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
Mork, Loken Cancer 40:907-915, 1977 Rogers (Barrow Neurologic Institute) JNS 102:629-636, 2005. 96% Low grade tumors.
10 yr LC 10 yr OS GTR + RT 100% 83% GTR 50% 67% STR + RT 36% 43%
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
• 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
Adjuvant RT Observation
10 yr LC 86% 46%* 10 yr PFS 75% 37%*
Myxopapillary Ependymoma RARE CANCER NETWORK
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
Observation <50.4 Gy >50.4 Gy
5 yr PFS 50% 68%* 82%**
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. MGMT promoter methylation – B. 1p19q codeletion – C. EGFR Viii mutation – D. Loss of PTEN – E. 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%
• 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
Series % LR STR % LR STR+RT
Richmond 37 4
Weiss 60 13
Karavitaki 62 23
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/Disadvantages
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 affected ear
Complete visualization of IAC allows higher GTR rates, no hearing preservation
Surgery Complications
Post-op complications ~ 20% 1. CSF leak – 5-15% 2. Meningitis – 2-10% 3. Facial weakness – 4-15% 4. Hearing loss varies according to approach 5. Headache – 10-34% 6. Stroke 7. Brain injury
Microsurgery Results
LC=Local control; FM=Facial movement; HP=Hearing preservation C = Complications, D = Death
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 90 27 17 1.1
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
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.
Temporary enlargement (41%)
Nakamura H. et al. American Journal of Neuroradiology. 21(8):1540-6, 2000
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.
Alternating enlargement and regression (13%)
Nakamura H. et al. American Journal of Neuroradiology. 21(8):1540-6, 2000
SRS vs. Microsurgery: France
• Non Randomized prospective series using pre- and post- Rx questionnaires – Minimum follow up 3 years – GKS=97 pts; Microsurgery 110 pts
Regis et al. J Neurosurgery. 2002 Nov; 97(5):1091-100
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
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
Meijer et al, IJROBP 2003. Aug; 56(5):1390-96
Treatment Tumor Control
CN V Preservation
CN VII Preservation
Hearing Preservation
SRS 100% 92% 93% 75% FSRT 94% 98% 97% 61%
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?
Best Radiographic Response to Bevacizumab
* * * * *
Six of ten patients experienced radiographic responses; four of six remain smaller at 11-16 months
Cha
nge
from
bas
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e (%
)
* 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 5 year
recurrence rate I Removal of tumor bulk,
surrounding dura, involved bone
10%
II Removal of tumor with diathermy of involved dura
20%
III Small focus left in situ 30%
IV Macrosocopic residual disease 40%
V Simple decompression
GTR alone
Author n (GTR) Local Recurrence Mirimanoff (MGH) Stafford (Mayo) Condra (U Florida) Total:
145 465 175 785
5-year 7%
12% 7%
7-12%
10-year 20% 25% 20%
20-25%
15-year 32%
- 24%
24-32%
Mirimanoff et al, Neurosurg 62:18, 1985 Stafford et al, Mayo Clin Proc 73:936, 1998 Condra et al, IJROBP 39:427, 1997
Author Local Progression Wara (UCSF) Condra (U Florida) Mirimanoff (MGH) Stafford (Mayo)*
5-year 47% 47% 37% 39%
10-year 63% 60% 55% 61%
15-year -
70% 91%
-
20-year 75%
- - -
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
STR alone
*581 pts 1978 -1988 (116 STR) Only 10 had post-op RT
TOTAL: 37-47% 55-63% 70-91% 75%
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?
Aghi et al. Neruosurgery 64(1):56-60, January 2009
• 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
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
3D CRT or IMRT 54 Gy / 30 fxs Strata
Observation Group 1
Group 2
Group 3 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 over-expressed 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. Prolactinomas 2. ACTH-producing adenomas (somatotrophs) 3. GH-producing adenomas (somatotrophs) 4. TSH-producing adenomas (thyrotrophs) 5. 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 20-50% – 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