2015 ASTRO Refresher Course:Adult CNS Tumors

Minesh P Mehta, MD, FASTRO

University of Maryland

Disclosures 2014-15

• Consultant: Elekta, Novartis, Novocure

• Grants: Novellos, Novocure

• Stock Options: Pharmacyclics

• Board of Directors: Pharmacyclics

• Patents: WARF

• Royalties: DEMOS Publishers

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

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 mocompared 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.

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 Gyin 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 vs14.8 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.

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 yoKPS >70n=85*

RANDOMIZE

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 yon=100*

RANDOMIZE

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-08Temozolomide vs. Std RT

Wick (German) et al. JCO 28:180S, 2010.*~90% were GBM. Median age 71

HGG>65 yon=373*

RANDOMIZE

54-60 Gy

TMZ week on/week off

RT TMZ

Median OS 9.6 mo 8 mo

GBM in the Elderly: MGMT

• THE NOA-08 TRIAL, Michael Weller, et al

• mOS [HR, =1.09] and EFS [HR = 1.15] of TMZ vs RT did not differ.

• Pts with MGMT methylation had longer EFS with TMZ (8.4 vs 4.6 mo).

• 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 TMZ vs. Std RT vs. Hypofx RT

Malmstrom et al. JCO 28:180S, 2010.

HGG>60 yon=342*

RANDOMIZE

60 Gy/30

TMZ d1-5q28d

34 Gy/10

60 Gy 34 Gy TMZ

Median OS 6 mo 7.5 mo 8 mo

GBM in the Elderly: Chemo vs RT, Meta-analysis

• Yin A, et al; J Neuroncol. 2013 Nov 1. [Epub ahead of print]: A meta-analysis of temozolomide versus radiotherapy in elderly glioblastoma patients.

• Systematic lit search of studies comparing TMZ vs RT (≥65 years; 2 RCTs, 3 comparative studies): OS advantage for TMZ (HR 0.86, 95 % CI 0.74-1.00).

• Sensitivity analysis only support non-inferiority (HR 0.91, 95 % CI 0.66-1.27).

• A clear increase in G3-4 toxicities with TMZ, with similar QOL between groups.

• Methylated tumors had longer OS with TMZ (HR 0.50, cfunmethylated); TMZ was more beneficial than RT for OS for methylated tumors (HR 0.66) but the opposite was true for unmethylated tumors (HR 1.32).

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

RANDOMIZE

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

30 patients, age >65, radiographic findings suggestive of glioblastoma

23 patients with histologically confirmed glioblastoma

Randomized to biopsy/resection

13 biopsied 10 resected

Vuorinen, Acta Neurochir , 2003; 145:5

Level 1: Gross-total resection (OS)

2.8 v 5.7 mo

Focal RT daily — 30 x 200 cGyTotal 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

Weeks6 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 36 420

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-ResultsO

ve

rall

Su

rviv

al

(%)

0

25

50

75

100

Months after Randomization

0 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

Pro

gre

ss

ion

-fre

e S

urv

iva

l (%

)

0

25

50

75

100

Months after Randomization

0 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

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

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

GBM Tissue

available

30 Gy +TMZ (75

mg/m2 qd x 21 d)*

R#ANDOMIZE

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 + Placebo12 cycle max

# Stratify by: (Random 10d post start RT)Recursive partitioning analysis (RPA) class (III vs IV vs V)MGMT methylation statusMolecular profile

TMZ (200 mg/m2) d 1-5 of 28-d cycle + Bev12 cycle max

Closed 978 pts

*Analysis for MGMT methylation, molec profile

RTOG 0825: Role of Bevacizumab

Primary Outcomes by Treatment

Presented by: Mark R. Gilbert, MD

Median overall survivalPlacebo: 16.1 monthsBevacizumab: 15.7 monthsHR (bev/placebo:1.13 (95%CI:0.93,1.37))

Median progression free survivalPlacebo: 7.3 monthsBevacizumab: 10.7 monthsHR (bev/placebo:0.79 (95%CI:0.66,0.94))

Neither OS or PFS achieved pre-specified endpoints

Outcomes by MGMT Status: Both Arms Pooled

Presented by: Mark R. Gilbert, MD

Median overall survivalMethylated: 23.2 monthsUnmethylated: 14.3 monthsHR (unmeth/meth:2.10 (95%CI:1.65,2.68)

Median progression free survivalMethylated: 14.1 monthsUnmethylated: 8.2 monthsHR (unmeth/meth:1.67 (95%CI:1.36,2.05)

2014: Banner Year for Positive Trials

• GBM:

– EF-14 Optune (Novo-TTF) study

– ICT 107 vaccine study

– BELOB study (rGBM)

– Rindopepimut (rGBM) ReACT Trial

Randomized phase II study of Bevacizumabversus Bevacizumab plus Lomustine versus

Lomustine in patients with recurrent Glioblastoma

1st recurrenceGlioblastoma

follow

up

Lomustine every 6 weeks

RANDOMIZATION

Bevacizumab every 2 weeks

+

Lomustine every 6 weeks

Bevacizumab every 2 weeks

Stratification: age, PFS Taal et al, Lancet Oncol 2014

OS 9 mo, median OS, PFS 6 mo, ORR

(Between brackets: 95% confidence interval)*local diagnosis; 138 patients evaluable for response

Endpoint Lomustine Bevacizumab Bev/Lom 90 Bev/Lom all

9 mo OS 43% (29-57%) 38% (25- 51%) 59% (43-72%) 63% (49-75%)

Median OS 8 mo 8 mo 11 mo 12 mo

6 mo PFS 13% (5- 24%) 16% (7 – 27%) 41% (26-55%) 42% (29-55%)

ORR* 2:41 (5%) 18:48 (38%) 14:41 (34%) 19:49 (39%)

Open-label treatment

Randomization (1:1)

Double-blind treatment

Phase II “ReACT” Study Design

Bevacizumab refractory (Initial cohort: n=25

Expansion cohort: n=up to 73) Progression during or within two

months of bevacizumab

Bevacizumab naïve (n=70)

No prior bevacizumab or VEGF/ VEGF receptor-targeted agents Control + bevacizumab

Study vaccine + bevacizumab

Study vaccine + bevacizumab

41 41

M o n t h s

Ov

er

all S

ur

viv

al (

%)

0 5 1 0 1 5 2 0 2 5 3 0

0

2 5

5 0

7 5

1 0 0

42

Overall Survival Bevacizumab-Naïve Relapsed GBM

Median

(95% CI)

Study Vaccine + Bevacizumab (n=35) 12.0 (9.7, --)

Control + Bevacizumab (n=37) 8.8 (6.8, 11.4)

HR = 0.47 (0.25, 0.91)

p = 0.0208

Patients have not yet experienced progression of disease on study treatment

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%

RTOG 9813

Phase I

Arm 1: XRT + BCNU 200 mg/m2 + TMZ 150 mg/m2 x 5d q 8 wks15 pts enrolled: 7/10 eligible pts needed dose mods

Arm 5: XRT + TMZ 150 mg/m2 x 5d + BCNU 150 mg/m2 q 8 wks15 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

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

The World of Molecular Markers is Emerging and 1p19q Proves to be Highly

Prognostic…..but not Predictive

Cairncross G, et al. J Clin Oncol. 2006;24:2707-2714. van den Bent MJ, et al. J Clin Oncol. 2006;24:2715-2722.

Patience is a Virtue

• 18 years after the first patient was randomized

– Median follow-up for the entire cohort is 11.3 years

– Persistence has allowed tissue collection for 1p19q analysis in 90% of patients on study.

– Data are reanalyzed with longer follow-up and a greater proportion of patients with molecular characterization

2012: OS by Treatment (1p/19q co-del)

Ov

era

ll S

urv

iva

l (%

)

0

25

50

75

100

Years after Randomization

0 1 2 3 4 5 6 7 8 9 10 11 12

Ov

era

ll S

urv

iva

l (%

)

0

25

50

75

100

Years after Randomization

0 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 SurvivalPCV+RT: 14.7 yearsRT alone: 7.3 years

2006

Practice changing

If it’s not in the Mind, the Eye Cannot See: 2012: OS, Non-Co-deleted (N=137)

Ove

rall

Sur

viva

l (%

)

0

25

50

75

100

Years after Randomization

0 1 2 3 4 5 6 7 8 9 10 11 12

Ove

rall

Sur

viva

l (%

)

0

25

50

75

100

Years after Randomization

0 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

What is Not in the Mind, the Eye Cannot See: 2012: OS, Non-Co-deleted (N=137)

Ove

rall

Sur

viva

l (%

)

0

25

50

75

100

Years after Randomization

0 1 2 3 4 5 6 7 8 9 10 11 12

Ove

rall

Sur

viva

l (%

)

0

25

50

75

100

Years after Randomization

0 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

Whole genome sequencing identifies mutation in Isocitrate Dehydrogenase 1 (IDH1) as a Prognostic

Marker in GBM

Parsons DW, et al. Science 2008Sequenced 22 GBMs for 20,661 genes

OS by IDH & Co-deletion Status O

vera

ll S

urvi

val (

%)

0

25

50

75

100

Years after Randomization

0 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

Sur

viva

l (%

)

0

25

50

75

100

Years after Randomization

0 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

Su

rviv

al (

%)

0

25

50

75

100

Years after Randomization

0 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

IDH is both prognostic and predictive

Anaplastic Oligodendroglioma1p-19q Co-Deleted

Treatment with Chemotherapy AlonePCV N = 21TemozolomideN = 68

Time To ProgressionPCV 7.6 yTemozolomide3.3 y

Overall SurvivalPCV 10.5 yTemozolomide7.2 y

CAUTION: Retrospective, observational study, these are hypothesis-generating results and await further study

Lassman AB, et al. Neurooncol 2011; 13: 649-659

Coke vs Pepsi: PCV vs. TMZ?

RTOG 0131: Phase II Trial of Pre-Irradiation and

Concurrent Temozolomide in Patients with Newly

Diagnosed Anaplastic Oligodendrogliomas and

Mixed Anaplastic Oligodendrogliomas – Updated

Survival and Progression Free Survival Analysis

Michael A. Vogelbaum M.D., Ph.D.

RTOG BR-0131: Evaluable Patients

• 42 patients enrolled

– July 2002 to June 2004

– 40 eligible patients• 1 hospital withdrew from protocol

• 1 consented patient refused protocol treatment

– Of the 40 eligible patients:

• 32 completed protocol treatment and are evaluable

• 4 withdrew due to toxicity

• 4 withdrew without evidence of toxicity or progression

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 GliomasKey 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.

Historic Standard of Care• In the past many patients were observed until

sxs dictated resection.

• Modern recommendations (EORTC 22844 and 5; NCCTG 86-71-52) , are a maximum safe resection with adjuvant radiotherapy (45-54 Gy) to prolong PFS

– Some would delay RT as there is no OS benefit

– Prior chemo trials were not positive

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

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

JCO 2012: Overall Survival

©2012 by American Society of Clinical Oncology

HR = 0.72p=0.33 (Wilcoxon)p=0.13 (Log rank)

JCO 2012: Progression Free Survival

©2012 by American Society of Clinical Oncology

p=0.06 (Wilcoxon)p=0.005 (Log rank)HR=0.6

Long-term Overall Survival

RT Alone RT + PCV

Median5 year

7.8 years63.1 %

13.3 years72.3%

10 year 40.1% 60.1%

2012 to 2014: HR improved from .72 to .59

Conclusions• For patients with a. G2 glioma, <GTR, or b. > 40,

irrespective of extent of resection.

RT + PCV prolongs both PFS and OS vs. RT alone

• Median survival is increased by 5.5 years.

– Five- and 10-year OS increased by 9 and 20%

– First randomized study to demonstrate a treatment-related increase in survival in G2 glioma

• No major increase in severe acute/late toxicities, including cognition

• Treatment, gender and histology prognostic on MVA

Coke vs. Pepsi: RTOG 0424 Design and Hypothesis

R

E

G

I

S

T

E

R

Daily temozolomide (75 mg/m2/day) + RT(54 Gy/30 fractions/6 weeks) followed by temozolomide (150-200 mg/m2 )x 12 cycles

Hypothesis:

43% increase in MS from 40.5 to 57.9 months and 20% increase in 3YS from 54 to 65%; 96% power with a 0.10 1-sided.

A Phase II Study of a Temozolomide-Based Chemoradiotherapy Regimen for High

Risk Low-Grade Gliomas: Preliminary Results of RTOG 0424

Pignatti F et al. JCO 2002:20;2076-2084

EORTC Survival by Pignatti Category

RTOG 0424 OS by Risk Group

EORTC 22033-26033

LGGn=466

STRATIFY

1p Statusetc.

RANDOMIZE

50.4 Gy*

TMZ x 12

*Age> 40 years; radiologically proven progressive lesion, new or worsening neurological symptoms, intractable seizures Completed accrual 03/2010

EORTC 22033 2013 ASCO

• 477 pts, RT (240) vs TMZ (237).

• TMZ DOES NOT improve PFS in these high-risk low grade glioma patients.

• 1p deletion was confirmed to be a positive prognostic factor with either treatment

– p-value stratified by treatment, progression-free survival: p = 0.0003; HR = 0.59, 95% CI (0.45 - 0.78),

– overall survival: p = 0.002; HR = 0.49, 95% CI (0.32 -0.77).

Abstract 2007

EORTC 22033 2013 ASCO Abstract 2007

EORTC 22033 RT TMZ

N 240 237

Med PFS (mo) 47 (40, 56) 40 (35, 44)

1p intact PFS 41 (32, 55) 30 (24, 40)

1p deleted PFS 58 (41, 67) 55 (38, N)

OS NR 74

9802 RT RT/PCV

Med PFS (mo) 48 (37, 66) 125 (73, NR)

Mol Abnormalities in LGG

Type FrequencyWildtype IDH 19%

IDH mut 81%MGMT unmet 30%

MGMT met 70%p53 wt 73%

p53 mut 27%1p19q int 76%

1p19q LOH 24%

Leu, NeuroOncol, 2013

HR for Death by Mol Subtype (G2/3)

Parameter Frequency HR for Death

IDH wt 33 % 1

IDH mut/MGMT met 20 % 0.33

IDH mut/MGMT met/1p19q LOH (Triple positive)

25 % 0.18

IDH mut/MGMT met/p53+ 13% 0.88

Others* 9 %

Leu, NeuroOncol, 2013

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 AstrocytomasRecommendations

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, but not easy to achieve–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 EpendymomaRARE 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

Craniopharyngioma

• Locally extensive, benign tumor 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

• 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 50-70%

• In modern series, local recurrence after Sx and RT is < 10%

• Timing of RTcontroversial; some argue for immediate RT

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

Craniopharyngioma: RT Dose/Timing

• Used for inoperable, partial resection, or recurrent disease

• 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):611-7.1992Habrand et al. IJROBP. 44(2):255-63. May 1999Cavazzuti 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.

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

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

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)

– >95% local progression free survival > 5 years

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: 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

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%

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

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)

SRS and EBRT by Grade

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

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%)

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

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

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)1239-1245Landolt et al. J Neurosurg. 1998;88(6)1002-08Landolt 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):331-37Van den Bergh et al. IJROBP. 2007;67(3):863-69

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