ASTRO Spring Refresher 2014 Management of … Spring Refresher 2014 Management of Central Nervous System Malignancies Christina Tsien, MD University of Michigan Medical Center Learning

ASTRO Spring Refresher 2014 Management of Central Nervous

System Malignancies

Christina Tsien, MD University of Michigan Medical Center

Learning Objectives • Discuss the current clinical practice in the treatment

of brain metastases

• Discuss the current clinical practice in the treatment of the major adult primary CNS tumors

• Understand the prognostic and predictive variables that allow for the appropriate selection of therapeutic choices, tailored for a specific patient

Overview

• Brain Metastases

• GBM

• Anaplastic Gliomas • Low Grade Gliomas

Presented by:

Brain Metastases

• Presentation

• Role of Surgery

• Treatment

Presented by:

What is the Appropriate Clinical Trial Endpoint in Brain Metastases Trials?

• Overall Survival Issue of “competing” systemic disease

• Response Rate

Image interpretation may be complicated by RT effect. Brain response but also systemic progression, how to score?

• Progression-free survival

Challenge with multiple metastases (individual vs composite)

• Preservation of Function -Neurocognitive Function -QOL/Symptom Burden

Brain Metastases Presentation

Signs – Hemiparesis (59%) – Cognitive problems (58%) – Hemisensory loss (21%) – Papilledema (20%) – Ataxia (19%) – Apraxia (18%)

Symptoms – Headache (49%) – Altered Mental status (32%) – Focal weakness (30%) – Ataxia (21%) – Seizures (18%) – Speech problems (12%)

Posner, 1995

RPA Class: Not all Mets are Created Equal

• Class I – <65, KPS ≥ 70, – Controlled primary – No extracranial mets

• Class II-Rest • Class III-KPS <70

•Gaspar, IJROBP, 47: 1001-6, 2000. •Gaspar, IJROBP, 37: 745-51, 1997.

(7.1)

(2.3)

N = 445 Original 1200

(4.2)

Updated Graded Prognostic Assessment (GPA) by Diagnosis

Sperduto P et al, JCO;30(4):419-25, 2012

Indications for Surgery

• Establish a tissue diagnosis

• Relieve mass effect

• Therapeutic – Randomized trials support surgery for a patient

with a solitary metastasis

Patchell RA, et al. N Engl J Med. 1990;322;494-500. Noordijk EM, et al. Int J Radiat Oncol Biol Phys. 1994;29;711-717. Mintz AH, et al. Cancer. 1996;78:1470-1476.

Randomized Surgical Trials WBRT with/without Surgical Resection

Trial Year Rx N MS Fl P-value

Patchell 90 S/RT 25 40 38 wks <0.01

RT 23 15 8 wks

Noordijk 94 S/RT 32 43 34 0.04

RT 31 26 21

Mintz 96 S/RT 41 24 ~ ns

RT 43 27 ~

Intergroup 90 S/RT 25 55

Fewer local recurrences and remained functionally independent for longer

WBRT lowers all recurrences and CNS deaths, but has no impact on survival

Phase III Surgery +/-WBRT Failure Patterns and Survival

Recurrence Surgery S + WBRT p

Anywhere in CNS 32/46 (70%) 9/49 (18%) <0.001 Local 21/46 (46%) 5/49 (10%)

CNS Death 17/39 (44%) 6/43 (14%) 0.003

Median Survival 43 weeks 48 weeks 0.39

Patchell et al. JAMA 1998;280:1485-9

Surgery for 2 - 4 Metastases

• Retrospective review of 26 patients with resection of multiple mets consistent with 26 similar patients with resected single mets

• Median survival at 1, 2, and 5 years was similar – Median: 14 months vs 14 months – 1 year: 55 vs 50% – 2 years: 32 vs 30% – 5 years: 11 vs 166%

Bindal, et al. J Neurosurg. 1993;79:210.

Enrollment: 1/96-6/01: 331 pts Arm 1: WBRT + SRS ( 164 pts) Arm 2: WBRT (37.5 Gy) alone ( 167 pts) Stratification: 1. Number of brain metastases (1 vs 2 - 3) 2. Extracranial mets (none vs present)

• < 2 cm 24 Gy • 2.1 – 3.0 cm 18 Gy • 3.1 – 4.0 cm 15 Gy

15 & 24% of 1 & 2-3 brain met pts randomized to RS did not receive it

RTOG 9508: Phase III Trial

RTOG Phase I 9005 Shaw E. Int J Radiat Oncol Biol Phys. 2000;47: 291-298.

Summary RTOG 95-08 WBRT +/- SRS

Andrews DW. Lancet. 2004;363:1665-72

Improved OS with WBRT+ SRS only in solitary brain metastasis

Survival Analyses WBRT & SRS WBR P-value

Overall 6.5 mos 5.7 mos 0.13

Solitary brain met 6.5 mos 4.9 mos 0.04

1-3 mets & Age < 50 9.9 mos 8.3 mos 0.04

1-3 mets & NSCLC 5.9 mos 3.9 mos 0.05

1-3 mets & RPA Class 1 11.6 mos 9.6 mos 0.05

Sperduto, ASTRO 2002

RTOG 9508: Subset Analysis

JRSROG 99-1 Phase III SRS +/- WBRT • 132 patients with 1-4 brain metastases < 3 cm

• WB (3 Gy x 10) + SRS vs. SRS alone

– SRS dose for lesions <2 cm: • 22-25 Gy vs. 15.4-17.5 Gy*

– SRS dose for lesions 2-3 cm:

• 18-20 Gy vs. 12.6-14 Gy*

• MRI every 3 months after treatment

Aoyama et al. JAMA 2006,295:2483-91

*30% dose reduction in RS dose if WBRT used

RESULTS: JROSG 99-1 SRS +/- WBRT

Local Tumor Control

Aoyama et al. JAMA 2006,295:2483-91

JROSG 99-1 MMSE

• Progressive disease is worse than WBRT

Aoyama, Int J Radiat Oncol Biol Phys, 68:1388-395, 2007

SRS + WBRT p

Median time to 3 point drop

7.6 mo 16.5 mo .05

1Y freedom from 3 point drop

59 % 76 %

2Y freedom from 3 point drop

52 % 69 %

MD Anderson Randomized Trial Schema

RANDOMIZE

SRS alone

(30 pts)

• RPA class I vs. II

• 1 or 2 vs. 3 Brain Mets

• Melanoma / Renal cell carcinoma vs. Other

STRATIFY

SRS + WBRT

(28 pts)

Mean Probability of NCF Decline

SRS 23%

SRS+WBRT 49%

Neuro-cognitive Decline 4 months post RT HVLT Immediate Recall

96% conf

Results: Freedom From Local Progression

Chang et al, Lancet 10(11):1037-44, 2009

Results: Overall Survival

Chang et al, Lancet 10(11):1037-44, 2009

Summary

• Small study with a single time point assessed

• Impact of disease progression on HVLT was not assessed

• Unexplained survival differences due to imbalanced arms

Results: Overall Survival

Kocher M et al, JCO 29(2):134-41, 2011

10.7 mths

10.9 mths

Rate of Intracranial Progression is Higher in Observation arm

Kocher M et al, JCO 29(2):134-41, 2011

Summary: HRQOL Results No difference in Global HRQOL between WBRT or Observation except at 9 mths

Soffietti R et al, JCO 31(1):65-72, 2013

Summary

• No difference in OS or maintenance of performance status between WBRT or Observation (OBS)

• Improved CNS control at both initial and distant sites with the addition of WBRT

• Adjuvant WBRT substantially reduced the risk of local recurrence following resection of a solitary met

SRS Dosing Post-Resection Cavity

PI: Paul Brown, MD Anderson Cancer Center

Stereotactic Radiosurgery +/- WBRT

• No clear winner or standard of care

• If only focal treatment provided (surgery or SRS) careful imaging follow up is required

• Outcomes may be best with focal treatment in a single lesion

• Clinical trial enrollment is needed to obtain high quality neuro-cognitive data to select therapy

Potential strategies to minimize risk of neuro-cognitive decline with WB RT

Coronal

Axial

Learning & Memory Short Term memory

• Memantine (RTOG 0614) • Hippocampal Sparing

(RTOG 0933)

RTOG 0614: PI Paul Brown, MD

Results • Memantine was well tolerated (similar SE to placebo)

• Less decline in HVLT-delayed recall (DR) at 24 wks in

the memantine arm (p=0.059, primary endpoint )

• Not statistically significant with only 149/508 pts analyzable at 24 wks resulting in 35% statistical power

• Memantine appears to delay time to cognitive decline compared to placebo

Results

Brown P et al, Neuro-Oncology 16(3), 2013

Conclusions • No statistically significant difference noted in HVLT-DR

at 24 wks between Memantine vs. placebo

• Overall, memantine is well-tolerated and delayed time to cognitive decline and reduced rates of decline in memory, executive function and processing speed

• Next NRG Trial will compare the role of WBRT and Memantine +/- hippocampal sparing RT in reducing long-term neuro-cognitive effects

Hippocampal Sparing Whole Brain IMRT

Gondi V, Int J Radiat Biol Phys 2010

RTOG 0933 (PI: Minesh/Gondi)

• Phase II study of Hippocampal Sparing WB RT

• Primary endpoint: HLVT-delayed recall at 4 mths -Target sample size: 102 patients -51 analyzable patients to detect mean relative HLVT-delayed recall decline ≤15%

Results/Conclusion • Median overall survival of 6.8 mths

• Conformal avoidance of the hippocampus during

WBRT – Is associated with memory and quality of life preservation

up to 6 months of f/u – Can be safely administered with 4.5% risk of relapse in the

hippocampal avoidance region (3 pts)

• Phase II results are promising but warrant further validation in a phase III trial Gondi V, ASTRO Plenary Session 2013

Advances in Treatment for Malignant Gliomas

• GBM

• Anaplastic oligodendroglioma/oligoastrocytomas

• Low Grade Gliomas

What is the Appropriate Clinical Trial Endpoint in Glioblastoma?

• Overall Survival – the gold standard

• Treatment response (Physician measured) – Radiographic response based on contrast enhanced MRI

• Clinical Improvement (Patient measured)

– Quality of Life – Neurocognitive function – Symptom Burden

Presented by:

Phase III trial of concomitant temozolomide and RT

Stupp et al; NEJM 2005

MGMT Status Correlates with OS Hegi et al, NEJM 2005

Long-term F/U confirms Combined Therapy Improves Survival

Mirimanoff, Lancet Oncology 10(5): 459-66, 2009

Who Benefits Most From Combined Therapy?

• MGMT Methylated Tumors

• RPA Class III/IV

• Age < 60

• Regardless of Type of Resection

Current Standard of Care-GBM

• Maximal safe surgical resection • Partial brain RT 60 Gy with concomitant and

adjuvant temozolomide

• No standard of care therapy at recurrence

Clinical Target Volume

• GTV plus area of microscopic disease

• MR FLAIR imaging (include edema if present) with margin (2.0 cm)

MR FLAIR

Standard Radiation 60 Gy

• PTV1= GTV + edema + 2 cm margin

PTV1= 46 Gy in 23 fx

• PTV2= GTV+ 2.5 cm margin

PTV2= 14 Gy in 7 fx

46 Gy

14 Gy

Target Volume Definition Based on MR/PET Imaging

T1-Weighted MR FLAIR MR Perfusion 11C MET PET

NRG Br-1 Trial Schema

Tsien C et al, Clin Cancer Res 18(1):273-9, 2012

Molecular Biomarkers in Glioma

• MGMT Promoter Methylation

• 1p19q

• IDH Mutations

• Genomic subtypes (Proneural etc)

IDH Mutations Associated Pathogenesis of Malignant Gliomas

Smeitink J, NEJM 2010

Low Frequency of IDH Mutations in Primary GBM

Yan et al, NEJM 360:765-73,2009

IDH1 Mutations Associated with Gliomas of Better Prognosis

Yan et al, NEJM 360:765-73,2009

Summary

• Novel molecular biomarkers in glioma require further validation

• Identify subgroup of patients with different outcome and approach to treatment

Promise of Anti-Angiogenic Therapy in GBM

VEGF expression on tumor cells

Imaging Changes with Bevacizumab: Pseudo-response

2235027

Baseline Cycle 1 Cycle 2

T1+C

T2

Taal et al, ASCO 2013

Cycle 3

Clinical Problem: Pseudoprogression

RTOG 0825:Phase III Trial Testing First-line Treatment with Bevacizumab

RT (30 Gy) TMZ (75 mg/m2 /d)

ARM A 30 Gy + Daily TMZ

(75 mg/m2 qd) + placebo q 2 wks

TMZ (150 - 200 mg/m2)

d 1-5 q28d X 12 C + placebo q 2 wks

ARM B 30 Gy + Daily TMZ

(75 mg/m2 qd) + Bev (10 mg/m2 q 2 wks)

TMZ (150 - 200 mg/m2) d 1-5 q28d X 12 C +

Bev (10 mg/m2 q 2 wks)

Eligible GBM KPS ≥ 70 Age ≥ 18 Tissue + MGMT & Molecular

Profile Analysis

R A N D O M I Z E

Stratify RPA Class MGMT

Status Molecular

Profile

R E G I S T E R

Molecular stratification factors

Clinical stratification factor

9 gene assay -Prognostic -?Predictive

Wefel, ASCO 2013

RTOG 0825

• Primary Endpoints: – Overall Survival – Progression Free Survival

• Secondary Endpoints

– Outcomes by Tumor Molecular Profile – Toxicity

• Tertiary Endpoints

– Patient Reported Outcomes: Symptoms and QOL – Neurocognitive Function

RTOG 0825- Did not meet pre-defined criteria for PFS

Gilbert M et al, NEJM 370(8): 699-708, 2014

RTOG 0825: No difference in OS

Gilbert M et al, NEJM 370(8): 699-708, 2014

No OS Benefit for BEV in any Subset

BEV PLACEBO

Gilbert M et al, NEJM 370(8): 699-708, 2014

Results • Over time, an increased symptom burden, a worse quality of life and a decline in neurocognitive function was more frequent in the bevacizumab arm

Wefel, ASCO 2013

Conclusions • Determination of progression in patients

receiving anti-angiogenic therapy is more difficult and may be delayed compared to the placebo arm

• There is a potential bias comparing the two arms at the later time points (comparing progressing vs non-progressing patients)

• In BEV treated patients, symptom burden and NCF may be identifying progressing patients prior to conventional imaging

Presented by:

AVAglio Study Design

n=463

n=458

Randomization N=921

Stratification • RPA class • Region

Treatment start 4–7 weeks post-surgery

RT 2Gy; 5 days/week

TMZ 75mg/m² qd

Placebo q2w

TMZ 150–200mg/m² qd days 1–5 q28d

Placebo q2w

RT 2Gy; 5 days/week

TMZ 75mg/m² qd

BEV 10mg/kg q2w

TMZ 150–200mg/m² qd days 1–5 q28d

BEV 10mg/kg q2w

BEV 15mg/kg q3w

Placebo q3w

Debulking surgery or biopsy

Concurrent phase 6 weeks

Tx break 4 weeks

Maintenance phase 6 cycles

Monotherapy phase until PD

Wick W, ASCO 2013

AVAGlio Trial: Investigator-Assessed PFS (Co-Primary Endpoint)

Stratified HR: 0.64 (95% CI: 0.55–0.74) p<0.0001 (log-rank test)

10.6 mo

RT/TMZ/Plb (n=463) RT/TMZ/BEV (n=458)

Prob

abili

ty o

f PFS

Months N at risk RT/TMZ/Plb RT/TMZ/BEV

463 458

349 424

247 366

170 278

110 189

77 104

47 71

23 25

8 13

4 2

0 1

0 0

0 0

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

0 3 6 9 12 15 18 21 24 27 30 33 36

6.2 mo

Wick W, ASCO 2013

No Difference in OS with Addition of BEV

Chinot O et al, NEJM 370(8):709-22, 2014

“Deterioration Free Survival”: Motor Dysfunction

RT/TMZ/Plb (n=463) RT/TMZ/BEV (n=458)

Stratified HR: 0.67 (95% CI: 0.58–0.78) p<0.0001 (log-rank test)

Prop

ortio

n w

ithou

t de

finiti

ve d

eter

iora

tion

1.0

0.8

0.6

0.4

0.2

0 0 3 6 9 12 15 18 21 24 27 30 33

Months

5.0 mo

8.6 mo

N at risk RT/TMZ/Plb 463 281 184 121 77 54 34 14 5 2 0 0 RT/TMZ/BEV 458 349 279 204 125 63 45 18 8 2 1 0

N at risk RT/TMZ/Plb 463 284 176 111 76 55 34 14 5 2 0 0 0 RT/TMZ/BEV 458 328 271 189 124 61 43 17 8 2 1 0 0

Stratified HR: 0.87 (95% CI: 0.68–1.11) p=0.2747 (log-rank test)

Prop

ortio

n w

ithou

t de

finiti

ve d

eter

iora

tion

0.8

0.6

0.4

0.2

0 0 3 6 9 12 15 18 21 24 27 30 33 36

Months

31.6 mo

1.0

A. Including PD B. Excluding PD

RT/TMZ/Plb Median not reached

Wick W, ASCO 2013

Deterioration-free Survival in KPS Score

Chinot O et al, NEJM 370(8):709-22, 2014

Conclusions

• In the Avaglio trial, the addition of Bevacizumab showed an improvement in PFS but did not show an improvement in OS

• Gr 3 or higher adverse events was more frequent in

the Bevacizumab than placebo arm respectively (67% vs 51%)

• Decreased need for steroid use, baseline HRQOL and KPS were maintained longer in the bevacizumab arm

Presented by:

Summary • There is no overall survival benefit in the upfront

use of Bevacizumab in newly diagnosed GBM

• Further analysis is required to confirm a role for specific patient populations that may benefit from Bevacizumab (molecular profile, unresectable patients, etc)

Presented by:

Howard Fine, ASCO Plenary 2013

Pseudo Progression

• Reported rates in 15-30% of pts treated with combined chemo-RT

• Higher rate in patients with methylated MGMT promoter (Brandes, JCO 2008)

• Critical to recognize due to its influences on treatment choices and therefore possibly prognosis

Pseudo-Progression

• Currently, there are no reliable methods for distinguishing pseudo-progression from disease progression exist.

• Advanced MR imaging can reveal early differences in vascular properties and tumor cellularity. MR perfusion showed significant changes in rCBV were predictive of progressive disease (p<0.01) Tsien, JCO 2010

RANO Response Criteria

Criterion CR PR SD PD

T1-Gd + None ≥ 50% ↓ < 50% ↓ - < 25% ↑ ≥ 25% ↑*

T2/FLAIR Stable or ↓ Stable or ↓ Stable or ↓ ↑*

New Lesion None None None Present*

Steroids None Stable or ↓ Stable or ↓ NA**

Clinical Status Stable or ↑ Stable or ↑ Stable or ↑ ↓*

Requirement for response

All all All Any*

Wen P et al, JCO 2010

Why is the outcome poor for older patients with GBM ?

• Is biology worse than younger patients?

• Is there a higher rate of morbidity and mortality associated with conventional therapy delivered in older patients?

• Are the majority of patients simply not considered for therapy?

Scott J et al, Cancer 118:5595-600, 2012

RPA Classification of Prognostic Factors in GBM Pts ≥ 70 years of age

RT vs Best Supportive Care

Keime-Guibert et al, NEJM 356:1527-35, 2007 (France) *Trial discontinued early due to planned interim analysis

Hypofractionated vs Standard RT Course

Roa et al, JCO 22:1583-88, 2004, *KPS=70

Nordic Brain Tumor Study Grp

342 GBM pts ≥ 60 yrs of age phase III study A) 60 Gy in 30 fx RT (MS 6 mths) B) 34 Gy in 10 fx RT (7.5 mths) C) TMZ alone (8.3 mths)

Malmstrom A et al, Lancet Oncol 13(9):916-26, 2012

OS > 70 yrs OS for all pts

Health Related QOL analysis for 3 treatment groups

TMZ 60 Gy 34 Gy

Malmstrom A et al, Lancet Oncol 13(9):916-26, 2012

NOA-8 German Study 412 pts ≥ 65 yrs age GBM/AA prospective, randomized phase III multi-institutional study • A) dose dense TMZ alone (MS 8 mths) • B) 54- 60 Gy RT alone (MS 9.6 mths)

Wick W et al, Lancet Oncol 2012; 13: 707–15

OS in relation to MGMT promoter methylation status/treatment received

Wick W et al, Lancet Oncol 2012; 13: 707–15

Combined Chemo-RT

• Phase III EORTC/NCIC trial concurrent and adjuvant TMZ vs RT alone, 30% of patients were between 60-70 yrs of age – 2 yr OS benefit for chemo-RT 22% vs 6% RT arm

(Stupp R et al, Lancet Oncol 10(5):459-66,2009)

• Retrospective data chemo-RT improves median survival in favorable GBM grp in pts 65-70 and ≥ 71 yrs (Barker et al, J Neuro-onc 109:391-397,2012)

• EORTC-NCIC CTG Elderly GBM: Phase III randomized

study 40 Gy in 15 fractions alone or with concurrent and adjuvant TMZ

Summary

• In older GBM patients, combined Chemo-RT (Stupp regimen) has not been compared to a hypo-fractionated RT course with/without chemotherapy in regards to OS, HRQOL, and neuro-cognitive function

• Treatment should be recommended based on molecular predictive biomarkers and clinical factors

Anaplastic Oligodendroglioma

Molecular classification of anaplastic oligodendroglioma

• 1p/19q co-deletion is a biomarker of oligodendroglioma – Predictive and prognostic – Somatic mutations in CIC gene on 19q and FUBP1 gene

[encoding far-upstream element (FUSE) binding protein] on 1p contribute to AO pathophysiology

• CIC mutations seen in 69% of 1p19q co-deleted tumors in one study

• 1p19q often associated with IDH1 mutation and MGMT promoter methylation – Favorable overall molecular phenotype – 1p19q is the only one validated for

treatment decisions

Presented by:

Bettegowda et al, Science, 2011 Capper et al, Acta Neuropathol, 2011 Van den Bent, Clin Cancer Res, 2011 Mulholland, Int J Cancer, 2012 Yip et al, J Pathol, 2012

Anaplastic Oligodendroglioma

• 1p/19q co-deletion detected in 44% (PCV+RT) and 52% (RT)

Cairncross G. JCO 2013, 31:337

PCV+RT did not significantly increase survival compared to RT in all patients

• Median OS

– 14.7y (PCV+RT) – 7.3y (RT)

• PFS

– 8.4y (PCV+RT) – 2.9y (RT)

Cairncross G. JCO 2013, 31:337

PCV+RT improved survival in 1p/19q deleted patients only

IDH Mutational Status Identifies AO Patients that benefit from PCV Chemotherapy with RT

IDH Mutated and 1P/19Q Co-Deleted IDH Mutated and 1P/19Q Non Co-Deleted

Cairncross J G et al. JCO 2014;32:783-790

van den Bent M. JCO 2013, 31:344

• Improved OS in RT/PCV arm: 42 vs 30 mo (p=0.018)

•Improved PFS in RT/PCV arm: 24 vs 13 mo (p=0.003)

•Only 30% pts in the RT/PCV arm received 6 cycles (median 3 cycles delivered)

RT/PCV improved survival in all pts

van den Bent M. JCO 2013, 31:344

van den Bent M. JCO 2013, 31:344

• 1p/19q co-deletion seen in 25% of pts (n=80) with tissue available for analysis

Median Overall Survival RT/PCV RT

Co-deleted Not reached 112 mo

Non co-deleted 25 mo 21 mo

Median PFS RT/PCV RT

Co-deleted 157 mo 50 mo

Non co-deleted 15 mo 9 mo

Improved OS benefit of RT/PCV appears greater for pts with 1p/19q deletion

van den Bent M. JCO 2013, 31:344

van den Bent M. JCO 2013, 31:344

IDH and MGMT methylation prognostic for improved overall survival

Other approaches for newly diagnosed AO • Retrospective data: 1013 patients diagnosed from

1981-2007 – Before 1990 – RT alone – After 1990 50% chemo – 2005-2007 38% chemo alone in 1p19q co-deleted patients

• TMZ 87% and PCV 2% trend starting in 2000 – Overall TTP outcome:

• RT + chemo: 7.2 years • Chemo alone: 3.9 years

– PCV appeared better than TMZ • RT alone: 2.5 years

• Question 1: Is Stupp/EORTC regimen as good for AO with 1p19q co-del as RT/PCV?

• Question 2: what is the best course for non-deleted AO?

Presented by:

Panageus et al, NeuroOncol 2012 Lassman et al , 2011

Ongoing clinical studies for AOA and AO • Concurrent and/or Adjuvant Temozolomide for 1p19q non-

deleted tumors (CATNON) – 4 treatment arms:

• RT alone • RT concurrent TMZ • RT adjuvant TMZ • Stupp regimen

• CODEL

– For patients with 1p19q co-deletion – Randomized to:

• RT + PCV • RT + concomitant and adjuvant TMZ • TMZ alone (exploratory)

Conclusions

Low Grade Gliomas

• 2,000-3000 cases diagnosed yearly in the US

• Heterogeneous group of neoplasms usually occur in younger patients

• WHO Gr 2 astrocytomas, oligodendroglioma and oligoastroctyomas

Unfavorable Prognostic Factors in LGG

• Age ≥ 40

• Largest diameter ≥ 6 cm

• Tumor crossing midline

• Astrocytoma dominant histology

• Neurologic deficit

Pignatti F JCO 2002, 20:2076

Role of Resection for Low Grade Gliomas

• Provides more accurate diagnosis

• Improves neurological status and quality of life

• Gross total resection extends survival

Presented by:

A. Pts with larger pre-op volume have significantly shorter PFS B. Pts with complete resection of FLAIR abnormality have significantly longer OS C. Even small residual volumes adversely affect survival D. Patients with a greater percentage of tumor resection have significantly longer

OS Smith JS JCO 2008, 26(8):1338

p<0.001

p<0.001

p=0.001

p=0.001

Extent of Resection Improves Survival in Low Grade Gliomas

EORTC 22845- “Non-Believer’s Trial”

Karim et al, IJROBP 36: 549, 1996

Wait and see Early RT Median PFS 3.4 years 5.3 years 5yr PFS 35% 55%

van den Bent MJ Lancet 2005, 366:985

Early RT improves PFS

van den Bent MJ Lancet 2005, 366:985

Wait and see Early RT Median OS 7.4 years 7.2 years

5yr OS 66% 68%

van den Bent MJ Lancet 2005, 366:985

Same OS and PFS results when only WHO grade II tumors analyzed

Overall survival not affected by early RT

van den Bent MJ Lancet 2005, 366:985

45 Gy 59.4 Gy 5yr PFS 47% 50% 5 yr OS 58% 59%

No difference in PFS or OS with higher RT doses Karim IJROBP 1996, 36:549

EORTC 22844- “Believer’s Trial” A Randomized Trial on Dose-Response in RT

Of Low Grade Cerebral Glioma

• 203 patients 14% GTR, 35% STR, 51% biopsy

• Randomized:

– 50.4 Gy in 1.8 Gy/fx – 64.8 Gy in 1.8 Gy/fx

• (50.4 Gy + 2cm to preop tumor volume; 14.4 Gy +1cm boost)

• Median f/u 6.4 years

Shaw E JCO 2002, 20:2267

NCCTG/RTOG/ECOG Randomized Study of Low vs High Dose RT in Low Grade Glioma

• 5 yr OS was similar – 72% in the 50.4 Gy arm – 64% in the 64.8 Gy arm (p = 0.48)

Shaw E JCO 2002, 20:2267

No survival benefit with higher RT doses

Shaw E JCO 2002, 20:2267

• 5 yr actuarial incidence of radionecrosis

2% in the 50.4 Gy arm 10% in the 64.8 Gy arm

Low Grade Gliomas: RTOG 98-02

93%

66%

48%

50%

• Significantly lower OS in high risk group

• PFS is ~50% at 5 yrs, regardless of GTR estimate or age Shaw EG. J Neurosurgery 2008, 109(5):835-41

OS and PFS in Low and High Risk Low Grade Glioma Pts

PFS p=0.005 OS p=0.13

• PFS but not OS was improved with RT + PCV • Significantly higher incidence of grade 3 and 4 hematologic toxicity

with RT + PCV (66% vs 11%)

• )

Shaw EG. JCO 2012, 25:3065

Improvement in PFS but not overall Survival

RTOG 98-02 NCI Press Release

• With median f/u of 12 yrs, there was a significant improvement in OS for patients receiving RT+ PCV (13.3 yrs) vs RT alone (7.8 yrs)

• New standard of care for treatment of LGG

• Molecular subset analyses is still on-going

ECOG/Intergroup Phase III trial E3F05 of RT ± TMZ

EORTC 22033-26033: Study Schema

EORTC ROG and BTG, NCI-CTG, TROG, MRC-CTU

Stratification: 1p mutation, contrast on MRI, age and PS, institute, contrast enhancement MRI, age: <40 vs ≥ 40 yrs, WHO PS 0 /1 versus 2

Registration

Radiotherapy (standard arm): 50.4 Gy (28 x 1.8 Gy)

conformal techniques

Random Genetic testing

TMZ (experimental arm): 75 mg/m2 daily x 21 days,

q 28 days until progression or for max. 12 cycles

Initial results do not show a difference in PFS in TMZ arm compared to RT 1p deletion was confirmed to be a positive prognostic factor in both groups

Results • Initial results do not show a difference in PFS in

TMZ arm compared to RT but follow-up is short

• 1p deletion was confirmed to be a positive prognostic factor in both groups

• Further molecular analyses are on-going to determine which subgroup may benefit from TMZ alone

Conclusions • Recent press release suggest a new standard

of care for low grade glioma patients requiring radiation treatment; these patients may now be considered for adjuvant chemotherapy (PCV vs TMZ)

EORTC-NCIC 26021

– Postop MRI at 4-5 months confirming subtotal resection – <4 mitoses/10 HPF and MIB labeling index <4% – RS 12-15 Gy to tumor margin – EBRT 54 Gy in 30 fractions to tumor + 1.5-2.0 cm margin – Targeted sample size 478 patients

• Endpoints: Progression-Free Survival Also: Quality of Life, Survival, Incidence of Salvage Surgery,

Incidence of Acute and Long-term Neurotoxicity

Phase III Study of Adjuvant Radiotherapy or RS vs Observation Only in Patients with

Newly Diagnosed, Incompletely Resected, WHO Grade I Non-Orbital Meningioma