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2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland

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Page 1: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

2013 ASTRO Refresher Course: Adult CNS Tumors

Minesh P Mehta, MD, FASTRO University of Maryland

Page 2: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 3: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 4: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 5: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

Glioblastoma Characteristics

• Rapid progression

• Enhancing tumor

• Surrounding edema

– Contains tumor

–GTR almost impossible

–Median Survival 12-14 mo

–SOC: ChemoRT

T1 post-contrast T2

Page 6: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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.

Page 7: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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.

Page 8: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

What about elderly patients?

Do they benefit from radiotherapy?

Page 9: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 10: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

Is it worth 5 ½ weeks of RT?

Can we do the RT quicker?

Page 11: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

“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

Page 12: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

How about chemotherapy instead?

Page 13: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

“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

Page 14: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 15: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

“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

Page 16: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 17: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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).

Page 18: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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.

Page 19: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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.

Page 20: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 21: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 22: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 23: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 24: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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.

Page 25: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 26: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 27: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

Confirmed MGMT as a Prognostic Marker

Page 28: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

Confirmed MGMT is NOT a Predictive Marker

MGMT methylated patients

Page 29: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

Composite Biomarker Set Results in 0525

Page 30: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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.

Page 31: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

Pre-RT and TMZ 4 wks after RT/TMZ

Page 32: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

Pre-RT and TMZ 4 wks after RT/TMZ

Page 33: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

4 wks after RT/TMZ 3 mo after RT/TMZ

Page 34: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

4 wks after RT/TMZ 3 mo after RT/TMZ

Page 35: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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.

Page 36: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 37: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 38: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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.

Page 39: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 40: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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%

Page 41: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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%

Page 42: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

Remember Organic Chemistry?

Page 43: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 44: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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.

Page 45: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 46: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 47: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 48: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 49: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 50: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 51: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 52: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

• 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

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9402: Initial OS

RTOG 94-02 EORTC 26951

Page 54: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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.

Page 55: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 56: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 57: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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.

Page 58: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 59: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

Intergroup 86-72-51: Overall Survival

*Arm A: 50.4 Gy vs Arm B: 64.8 Gy

Page 60: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

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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

Page 62: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

98-02: Survival by Arm

Page 63: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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**

Page 64: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

RTOG 98-02 Intergroup Trial High-risk LGG – Progression Free Survival

Page 65: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 66: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 67: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 68: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 69: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

• 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

Page 70: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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%

Page 71: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 72: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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%*

Page 73: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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%**

Page 74: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 75: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 76: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 77: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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%

Page 78: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 79: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 80: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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.

Page 81: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 82: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 83: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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.

Page 84: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 85: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 86: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 87: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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)

Page 88: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 89: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 90: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 91: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 92: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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%

Page 93: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 94: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 95: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

Is Bevacizumab a Game Changer?

Page 96: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

elin

e (%

)

* Plotkin et al. NEJM. 261-4, 358-67 July 23, 2009

Page 97: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 98: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 99: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 100: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 101: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 102: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 103: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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

Page 104: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

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%

Page 105: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

5 yr PFS after EBRT

Rogers L. Radiation Therapy for Intracranial Meningiomas. 2010

Page 106: 2013 ASTRO Refresher Course: Adult CNS Tumors · 2013 ASTRO Refresher Course: Adult CNS Tumors Minesh P Mehta, MD, FASTRO University of Maryland . ... and clinical impact of the major

Radiation

• Indications – Subtotal resection – Unresectable tumor – High grade – Recurrent

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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)

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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

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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

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SRS and EBRT by Grade

Adapted from Chan, Rogers, Anderson, Khuntia: Chapter 26 Benign Brain Tumors. Clinical Radiation Oncology. In Press 2011.

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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

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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%)

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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

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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

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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

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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

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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)

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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

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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

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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.

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Indications for XRT

• Incomplete resection • Recurrent tumors • Inoperable patients • Refractory secretory tumors

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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

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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

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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

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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

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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

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Thank You