astro spring refresher 2014 management of … spring refresher 2014 management of central nervous...

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


No OS Benefit for BEV in any Subset

BEV PLACEBO


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



• 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



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


Wait and see Early RT Median OS 7.4 years 7.2 years

5yr OS 66% 68%


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

Overall survival not affected by early RT


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

astro spring refresher 2014 management of … spring refresher 2014 management of central nervous...

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