PD Dr Alessia Pica, Pr Damien Charles Weber: Paul … · Radiotherapy for intracranial meningiomas ... figures/HPF • Increased ... Holland EC, Beal K, Bilsky MH, Brennan CW, Tabar

WIR SCHAFFEN WISSEN – HEUTE FÜR MORGEN

Radiotherapy for intracranial meningiomas

SAMO Interdisciplinary Workshop on Brain Tumors and Metastases 18.-19. November 2016

PD Dr Alessia Pica, Pr Damien Charles Weber: Paul Scherrer Institut

Introduction

Type of ‘radiotherapies’and RTQA

Management of Grade 1 Meningiomas

Management of non-grade 1 Meningiomas

NRG/EORTC prospective trials

Conclusions

Plan

• Apprimately 20% of ‘brain tumors’

• Increase with age

• Twice as frequent in women than in men

• Grade WHO grade 1+++

• Importance of the

• extend of surgery

Introduction

Mitotic rate > 4 mitotic

figures/HPF

• Increased cellularity

• Small cells with high ratio nucleus

(cytoplasm

• Prominent nucleoli

• Sheet-like growth pattern

• ‘Geographic’ necrosis

3/5 features

Atypical meningioma

Simpson D J Neurol Neurosurg Psychiatry 1957;20:22-39

Introduction

HUG EB, J Neuro-Oncology 2000

Milker-Sabel S IJROBP 2005

Perry, A. Meningiomas. McLendon R, Rosenblum M, Bigner DD (ed.) Russell & Rubinstein’s Pathology

of Tumors of the Nervous System. 7th ed. Hodder Arnold (Publisher), London, England 2006, p 427-474

Introduction: the outcome of AM patients is suboptimal

Relapse-Free Survival Overall Survival

Introduction: Local Control

Weber D

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t Oncol B

iol P

hys 2

012; 8

3(3

):86

5

• Many ways to

administer RT

• EBRT with or

without IM

• Stereotactic RT

(SFRT, SRS)

• Proton therapy,

Carbon beam

therapy

Type of Radiotherapy

Weber DC Int J Radiat Oncol Biol Phys 2012; 83(3):865

Proton Therapy

Photon versus Proton Therapy

Photon Therapy Proton Therapy

Dose Distributions of the same Volume from Photon and Proton Fields

Courtesy of A. Lomax

Case Study: meningioma « en plaque »

Page 12

RTQA in RT

RTQA in RT

• Several retrospective studies have shown that RT after STR is beneficial for patients

with benign meningioma (WHO Grade 1)

Management of grade 1 Meningioma

Author Year Journal

Barbaro NM et al. 1987 Neurosurgery

Carella RJ et al. 1982 Neurosurgery

Condra KS et al. 1997 Int J Radiat Oncol Biol Phys

DeMonte F et al. 1995 Oncology

Glaholm J et al. 1990 Int J Radiat Oncol Biol Phys

Maguire PD et al. 1999 Int J Radiat Oncol Biol Phys

Maire JP et al. 1995 Int J Radiat Oncol Biol Phys

Mesic JB et al. 1989 Am J Clin Oncol

Miralbell R et al. 1992 J Neurooncol

Pourel N et al. 2001 Radiother Oncol

Taylor Jr BW et al. 1988 Int J Radiat Oncol Biol Phys

Wenkel E et al. 2000 Int J Radiat Oncol Biol Phys

• Debate over the timing of RT-whether it should be given

postoperatively or at the time of progression.


Chang EL, Radiother Oncol, 2004;71:85

• Phase III trial assessing the impact of radiation therapy on tumor

control and QoL for patients with non-gross total resection

• (Simpson 3) as documented on MRI performed 1 month

postoperatively.

• Targeted sample size of 478 patients was calculated

• and the protocol was activated in 2004.


Weber DC, Curr Opinion Neurol 2010;23:563-79

•Survey BSNS


Seite 18

Adjuvant RT RT @ salvage

Simpson < 3 No Yes

Simpson >3, Young/male Maybe Yes

Simpson > 3, no FU possible Maybe NA

Simpson >3, Elderly/female No Yes

Simpson >3, ‘atypical’ histology but nevertheless grade 1

Maybe NA

Marcus HJ British J Neurosurg;2008:22(4):520-8

Potential therapeutic strategy

Management of non-grade 1 Meningioma

Weber DC, Curr Opinion Neurol 2010;23:563-79

•Dose escalation in newly diagnosed

grade II/III meningioma




Adjuvant Radiotherapy for Atypical and

Malignant Meningiomas: A Systematic Review

Kaur G, Sayegh ET, Larson A, Bloch O, Madden M, Sun MZ, Barani IJ, James CD, Parsa AT. Adjuvant radiotherapy for

atypical and malignant meningiomas: a systematic review. Neuro-Oncology 2014;16(5):628-636. DOI: 10.1093/neuronc/nou025

Atypical Meningioma Synopsis


% of Simpson grade 1 resected AMs with radiographic recurrence after resection

with and without post-op RT

Aghi MK, Carter BS, Cosgrove GR, Ojemann RG, Amin-Hanjani S, Martuza RL, Curry WT, Barker FG. Long-term recurrence

rates of atypical meningiomas after GTR with or without postoperative adjuvant radiation. Neurosurgery 2009;64(1):56-60

Massachusetts General Hospital

108 atypical meningioma patients

Each with Simpson Gr1 resection

48 men, 60 women, mean age 55

Mean serial imaging f/u 39 month

8 patients received post-op FSRT

Mean 60.2Gy, 1.5-1.8 Gy/fraction

PTV=resection bed + 1cm (mean)

Mean isodose 88%

Only RT morbidity was an enhancing

abnormality in the resection cavity of

1 pt 1y after GTR, required resection,

and was necrosis w/o tumor.

Time (yrs)

! "#"$%&"

No RT (n=100)

RT (n=8)

100%

75%

50%

25%

0%

0.0 2.5 5.0 7.5 10.0

* Determined from graph


% of gross totally resected AMs with radiologic (MRI) recurrence after resection

with and without post-op RT

Komotar RJ, Iorgulescu JB, Raper DMS, Holland EC, Beal K, Bilsky MH, Brennan CW, Tabar V, Sherman JH, Yamada Y, Gutin

PH. The role of radiotherapy following gross-total resection of atypical meningiomas. Journal of Neurosurgery 2012.

* Determined from graph

Memorial Sloan Kettering

45 G2 meningioma patients, 1992-2011

Each with gross total resection

20 men, 25 women, mean age 56

Mean f/u 44.1 months

13 pts received post-op CRT / IMRT

Mean 59.4 Gy, 1.8-2.0 Gy / fraction

PTV = resection bed + 0.5-1.0 cm

Med time to recur 19 mo w/o RT

1 pt recurred after RT at 52.5 mo

“All patients tolerated treatment well.” Time (yrs)

% R

ecu

rren

ce

100

80

60

40

20

0

0 2 4 6 8 10

20%*

65%*

p = .085

GTR alone (n=32) GTR + RT (n=13)

“Recurrences resulted in shortened OS & additional treatment burden. Our results

contribute to a growing number of series in support of routine post-op RT.”


“Impact of adjuvant radiosurgery/IMRT on atypical meningioma recurrence following aggressive microsurgical

resection” Barrow Neurological Institute

228 atypical mening pts, 1992-2011

Re-graded per current WHO criteria

“Aggressive microsurgical resection”

GTR (Simpson I or II) 58%, STR 42%

97 men (43%), 131 women (57%)

Mean age at 1st surg 62 (range 2-94) yr

Mean post-op clin & imaging f/u 52 mo

32 patients received post-op SRS

SRS after GTR in 31%, STR 69%

19 GK, median 14 Gy x 1

13 CK, 14-16 Gy in 1, 21-27 Gy in 3, 25 in 5

39 patients received post-op IMRT

IMRT after GTR 49%, STR 51%

Median 54 Gy, 1.8-2.0 Gy / fraction

PTV = not reported

Med time to recur 20.2 mo

“No SRS related complications”

IMRT: “1 cranial wound breakdown”

Hardesty DA, Wolf AB, Brachman DG, McBride HL, Youssef E, Nakaji P, Porter RW, Smith KA, Spetzler RF, Sanai N. The impact of adjuvant radiosurgery on atypical

meningioma recurrence following aggressive microsurgical resection. Journal of Neurosurgery February 2013. DOI 10.3171/2012.12.JNS12414

Time (yrs)

STR+IMRT

STR+SRS

STR alone

GTR alone

Kaplan Meier Analysis

Significant:

GTR at 1st Surg (v STR)

Not Signif:

SRS pGTR or STR (v No RT)

IMRT pGTR or STR (v No RT)

SRS v IMRT

GTR + SRS PFS 100% (n=10)

GTR + IMRT PFS 100% (n=19)

% P

rog

ressio

n-F

ree S

urv

ival


SEER database study of the effect of EBRT on survival with non-benign meningioma SEER database query

657 patients 1988-2007

244 received adjuvant RT

Patients with Gr III were 41.9% more

likely to receive RT after GTR and

36.7% more likely after STR

Controlling for grade, resection

extent, tumor size, anatomic locale,

race, age, gender, & yr of diagnosis,

adjuvant RT did not impact overall

or disease-specific survival benefit

“Our data underscore the need for

randomized prospective clinical trials

to assess the usefulness of adjuvant

EBRT and to more precisely define the

subset of patients who may benefit.”

Overall Survival

Non-Benign Meningioma (WHO Grades II & III)

Stessin AM, Schwartz A, Judanin G, Pannullo SC, Boockvar JA, Schwartz TH, Steig PE, Wernicke AG. Does adjuvant external-beam radiotherapy

improve outcomes for nonbenign meningiomas? A Surveillence, Epidemiology, and End Results (SEER)-based analysis. Journal of Neurosurgery 2012.

Survival Time (months)

Perc

ent

Overa

ll S

urv

ival

p=.0556

RT

No RT

0 50 100 150 200 250

Minority of Centers Recommend RT after

GTR of an Atypical Meningioma

Simon M, Bostrom J, Kock P, Schromm J. Interinstitutional variance of post-operative

radiotherapy and follow-up for meningiomas in Germany: Impact of changes of the WHO

classification. J Neurol Neurosurg Psychiatry 2006;77:767-773

German Study (Simon et al):

9 of 56 (16%) centers recommend RT following GTR

Marcus HJ British J Neurosurg;2008:22(4):520-8


RTOG 1310 Phase III

EORTC 1308 ROAM Phase III

Meningioma graded by 2007 WHO Grading

Extent of resection scored by neuro-surgeon (Simpson grade)

confirmed by post-operative MRI. *GTR = Simpson grade I-III

Central pathology and central neuro-radiology review

Surgery GTR* WHO Grade II

Stratify: Female vs Male

New vs. Recurrent NRG 1310

Simpson Grade I vs II-III

Convexity vs Non-Convexity1

MiB1 <10% vs >10%2

IMRT: 59.4 Gy (1.8 Gy x 33)

RANDOM

I

Z

E RT

Observation

1Convexity will be defined as > 1 cm from dural sinus

2 Based upon Erik Sulman and Ken Aldape


Patients N (Grade 2) 35 (33)

Mean Age 48.4 yo

Initial diagnosis 54.3%

Median GTV (range) 24.5 cc (0-441.3)

Dose (range) 62 Gy(RBE) (54-68)

68% 81%

Failure pattern N=9 (%)

In field 6 (67%)

Marginal 1 (11%)

In field and marginal 2 (22%)

Toxicity N (%)

Grade 3 CTCAE 3 (9%)

Page 31

Conclusions

• Several retrospective studies have shown that RT after

STR is beneficial for patients with WHO 1 grade

meningioma

• Debate over the timing of RT-whether it should be

given postoperatively or at the time of progression

(WHO grade 1 meningioma )

• Modification of the WHO classification

• Suboptimal outcome of grade 2-3 meningioma

patients

Conclusions

•Dose-response of non-benign meningiomas

• FSRT, SRS, Protons, Carbons

• Failure pattern: IN FIELD

•Results of phase II (RTOG-EORTC) trials awaited for

Q2-3 2017

•On going phase III trial for Simpson 1-3 Grade 2

meningiomas

Documents

PD Dr Alessia Pica, Pr Damien Charles Weber: Paul … · Radiotherapy for intracranial meningiomas ... figures/HPF • Increased ... Holland EC, Beal K, Bilsky MH, Brennan CW, Tabar