high grade glioma + brainstem glioma highly agressive tumours

High grade glioma + brainstem glioma

Highly agressive tumoursMedian survival ca 9 - 12 months

Curative or palliative treatments ?

Intensity of treatmentSide effectsQuality of life issues

High grade glioma + brainstem glioma

Improvement of local tumour controlUsing the advantages of modern treatment techniquesCombination withchx. / „radiosensitizers“

Aims of radiotherapy

Radio-chemotherapy / GPOH HIT GBM A - D

European Co-operation / data bank :> 400 pat.

„old“ countries: HIT-GBM-B , -C and - D prot. / data bank

Participation HIT-GBM-D protocol and Europeandata bank

Participation in European high grade gliomadata bank

Wolff / HIT GBM

High grade glioma + brainstem glioma

Age distribution / HIT data bank

Pons Cortex / white matter

3,00 6,00 9,00 12,00 15,00 18,00

age at diagnosis [years]

0

5

10

15

20

25

freq

uenc

y

Mean = 8,3653Std. Dev. = 3,27757N = 132

tumor site: pons

3 6 9 12 15 18

age at diagnosis [years]

0

2

4

6

8

10

12

14

freq

uenc

y

Mean = 11,854Std. Dev. = 3,36413N = 80

tumor site: cortex and white matter

n=132Mean : 8.3 (+/- 3.2) y.

n=80Mean : 11.8 (+/- 3.3) y.

Wolff et al., 2007, submitted

High grade glioma + brainstem glioma

Location / HIT GBM data bank (2006)Overall survival

0.00

0.25

0.50

0.75

1.00

0 2 4 6 8

y

years

Pat. Med. surv.Cortex 84 22.8 mon.Non-pons / others 92 10.6 mon.Pons 134 9.8 mon.

Overlap with resectability ?

Wolff et al., 2007, submitted

High grade glioma

Gender (cortical tumours) / HIT GBM data bank (2006)Overall survival

0.00

0.25

0.50

0.75

1.00

0 2 4 6 8

Female

Male

Pat. Med. surv.Female 39 34.6 mon.Male 45 13.7 mon.

years

Wolff et al., 2007, submitted

High grade glioma

Extent of resection / HIT GBM data bank (2006)Overall survival

0.00

0.25

0.50

0.75

1.00

0 2 4 6 8

Pat. Med. surv.Gross total 49 36.2 mon.Partial /subtotal 93 14.8 mon.None/biopsy 168 10.4 mon.

(Brain stem glioma : 118/134 - 88.1% -)

(Cortical tumours : 14/84 -16.6% -)

years

Wolff et al., 2007, submitted

High grade glioma

Spinal seeding at diagnosis

Author Pat. Rate Age group

Heidemannet al., 1997

41 4 (9.7%) children

Finlay et al.,1995

172 10 (6%) children

Packer et al.,1985

37 4 (11.8%) children

Benesch et al., 2005

187 9 (4.8%) children

High grade glioma

Hess et al., 1993 Chan et al., 2002

technique 2D conventional 3D conformal(2 cm safety margin) (0.5 – 2.5 cm

- dose escalation -)dose 60 Gy / 30 fr. 90 Gy / 45 fr.rate 58/66 23/34local 86% 91%margin 9% 9%out of field 5% 0%

Pattern of failureafter limited volume radiotherapy

High grade glioma

Pattern of failureafter limited volume radiotherapy

Distance of recurrence from primary site / time interval

46 cases of recurrences after RT tumour site 60 Gy, safety margin : 2.0 cm preop. tumour

Distance0cm <=1cm 1-2cm 2-3cm <3cm

Interval (mon.)Median 3.95 6.3 7.7 6.7 9.2

Migration of tumour cells (?) Aydin et al., 2001

High grade glioma

Conformal radiotherapy

20% less normal brain tissuewithin the

95% isodoseas compared with conventional

2 dimensional treatment planning

Grosu et al., 1998

High grade glioma

Question 1

Dose escalationusing stereotactic

approaches and modern imaging

High grade glioma

Dose escalationPatients : 34 pat with high grade glioma (33 glioblastoma, 1 anapl. Glioma)Median age : 55 yearsTechnique : 3 D conformal techniqueDose prescription :PTV 1 : (visible tumour + 0.5cm) : 90+/- 5 GyPTV 2 : (visible tumour + 1.5 cm) : 60 Gy (biol. eff. : 70Gy)PTV 3 : (visible tumour + 2.5 cm) : 44 Gy (biol. eff. : 60 Gy)

Chan et al, 2002Outcome : median survival : 11.7 months

1 and 2 year survival : 47.1% / 12.9%

High grade glioma

External fract. RT + Brachytherapy („boost“) / adults

Median survivalNo boost : 58.8 weeksn = 137

Boost : 68.8 weeksn = 133

p=0.101 (n.s.)

Selker et al., 2002

High grade glioma

RTOG 93-05 / glioblastomaPhase III : conv. RT/BCNU versus conv. RT/BCNU+stereot. Boost (15-24Gy)

Souhami et al., 2004

High grade glioma

Question 2

Target volume definition

High grade glioma

Target volume definitionPre or postoperative extent of disease

brain shiftAnatomical borders

infiltrationDefinition of safety margins

between CTV and PTV

Presently no standardsdepartmental policies

High grade glioma

Target definition 1973 / 4 year old child witha brain stem glioma / 60 Gy

Pneumoencephalographie2 lat. portals / a) 0-12 b) 12-60 Gy

2003, complete remission(endocr. deficits, no neurcog. dysf)

a

b

High grade glioma

Pre- or postoperative definition of CTV ?Technique / timing of imaging ?

10 cm 7 cm8.5 cm

MR pre-op. CT 1 day postop. MR 2 weeks post-op.

High grade glioma

Question 3Re – irradiation using

stereotactic equipment

High grade glioma

Re - irradiation in recurrent high grade gliomaRelapse of glioblastoma multiforme / 17 y. boy

Hypofractionated stereotactic radiotherapy

Before RT 4 x 5 Gy CR 1 y after RT

High grade glioma

Re - irradiation in recurrent high grade glioma / hypofr. stereot.

Author Numberof Pat.

Technique / Dose perscription Overall survival

Shepherd et al., 1997 33 Hypofract. convergence therapySingle dose 5 Gy, Eskal. 20 -> 50 Gy

11.0 mon.

Lederman et al., 2000 88 Stereot., hypofract. RTMed. 24 Gy in 4 Fract.

7 mon.

Voynov et al.,2002

10 Stereot. IMRT, med. 30 Gy(25-40 Gy), 5 Gy/Fract.

10.1 mon.

Bartsch et al., 2005

22 Stereot. RT 14 Pat. 45-54 Gy, conv. Fract. 8 Pat. 30 Gy hypofract. (6x5Gy)

7.0 mon.

Grosu et al., 2005 44 Stereot. RT, hypofract.36 PET/SPECT, 30 Gy8 CT/MRI (6 x 5 Gy)

9.0 mon.5.0 mon.

Vordermark et al.2005

19 Stereot. RT, hypofract.(4-10 Gy single dose)30 Gy (20-30 Gy)

9.3 mon.

High grade glioma

Re - irradiation in recurrent high grade glioma / conv. fract. stereot.

Author Numberof Pat.

Technique / Dose perscription

Overall Survival

Arcicasa et al., 1999

31 Conv. Fract. 2 D RTSingle dose 1.5 Gy, 34.5 Gy

13.7 mon.

Cho et al. 1999 25 Conv. fract. RT, 37.5/15 fractions

12.0 mon.

Hudes et al., 1999

20 Stereot. RT 3-3.5 Gy24.0->35 Gy dose escalationprotoc.

10.5 mon.

Combs et al., 2005b

54 GBM39 WHO III

Stereot. RT36 Gy (15-62 Gy)5 x 2.0 Gy conv. fract.

8.0 mon.12.0 mon.

Brain stem glioma

Benefit of radiotherapy (overall survival) / Dose : 54 Gy

Wagner et al., 2006

HIT data bank

Brain stem glioma

Impact of histological subtype on overall survival

HIT data bank

Wagner et al., 2006

Brain stem glioma

Expl.: Mask in a 6 year old boy withpontine glioma

Precise positioning

RT of tumour site / modern technologies

Treatment machine

Position for treatment delivery

Brain stem glioma

Prognostic factors

time between the onset of symptoms and diagnosis the presence or absence of florid neurological deficits resulting from brainstem involvement. The outcome is often better for patients with neurofibromatosis type I. A high rate of mitosis is a negative prognostic factor (15 of 18 patients deceased within 6 months). Rapid clinical progression. Multiple palsies of cranial nerves

Brain stem glioma

(No) benefit of hyperfractionation / CCSG / POG

Author Pat. Dose Survival

Freeman et al., 1988 (POG)

38 2 x 1.1 Gy, 66.0 Gy PFS / median : 6.5 mon.Overall / median : 11 mon.

Freeman et al., 1991 (POG)

57 2 x 1.17 Gy, 70.2 Gy PFS / median : 6 mon.Overall / median 10 mon.

Freeman et al., 1993 (POG)

41 2 x 1.26 Gy, 75.6 Gy PFS / median : 7 mon.Overall / median: 10 mon

Packer et al., 1987 (CCG)

16 2 x 1.2 Gy, 64.8 Gy PFS / median : 7 mon.Overall / median: 9 mon

Shrieve et al., 1992

41 2 x 1.0 Gy, 66 – 78 Gy Overall / median : 72 weeksNo dose dependency

Brain stem glioma

(No) benefit of radio-chxAuthor Pat. Dose + chx. Survival

Mandell et al., 1999 POG Phase III

6664

1x 1.8 Gy / 54 Gy (I)2 x 1.17 Gy, 70.2 Gy (II)+ simult. cisplatin (I+II)

I PFS / median : 6 mon.Overall / median: 9 mon.II PFS / median : 5 mon.Overall / median: 8 mon.

Allen et al., 1999 34 2 x 1.0 Gy, 72.0 Gy + simult. carboplatin

PFS / median : 8 mon.Overall / median: 12 mon.

Broniscer et al., 2000

29 54 Gy / 1.8 Gy + Tamoxifen PFS / median : n.a.Overall / median: 10.3 mon.

Bouffet et al., 2000

36 54 – 55 Gy / 1.8 Gy + High dose chx.

PFS / median : 119 daysOverall / median: 10 mon.

Doz et al., 2002 38 54 Gy / 1.8 Gy prior+ simult. Carboplatin

PFS / median : n.a.Overall / median: 11 mon.

Wolff et al., 2002 20 54 Gy / 1.8 Gy Trophosphamide + VP16

PFS / median : 9.6 monOverall / median: 8 mon.

Brain stem glioma

CCSG / POG : 8 prospective trials for hyperfractionatedradiotherapy with dose escalation

Total number of patients : 433Dose prescriptions : 2x1.1-1.26 Gy / 64.8-78 GyMedian survival : 6.5 – 11 months

5x1.8 Gy / 54 Gy : 9 months

No benefit of hfx. radiotherapyincluding dose escalations

Present recommendation : 5 x 1.8 Gy, 54 Gy total dose

Radio- /chx. in childhood high grade glioma

Rationale

Rationale for chx. before RTOpen blood brain barrier (surgery)lesser toxicity of agents, greater selectionof protocols, reduction of tumour burden

Rationale for chx. during RTRadiosensitization

Rationale for chx. after RTElimination of persistent tumour cellsMaintenance approach to prevent early relapse

High grade glioma

Survival in prospective series

Author Pat. Treatment Histologies Survival

Sposto et al., 1989 (CCG)

58 Phase III studyRT versus RT + CCNU/ VCR / Prednisone

High grade glioma 5 y. EFSRT alone : 18%RT + Chx. : 46%

Finlay et al., 1995 (CCG)

8587

Phase III studyRT + CCNU / VCR / Pred”8 in 1” + RT

High grade glioma 5 y. PFS : 33%, no diff.erence

Geyer et al., 1995

39(< 24 Mon.)

”8 in 1”, ” delayed RT Astrocytoma WHO Gr. IIIGlioblastoma

3 y. PFS All pat. : 36%WHO Gr. III : 44%WHO Gr. IV : 0%

Finlay et al., 1996

18 High dose chx. + BMTRec. disease

High grade glioma 16% DOC5 of 18 (28)alive 39-59 mon. after treatment

Graham et al., 1997

12 High dose chx. + BMT6 Primary / 6 rec. disease

”Glial tumours” 2 of 12 alive

Bouffet et al., 1997

22 High dose chx. + BMTPrimary / rec. disease

High grade glioma 15% alive 54-65 mon. after treatment

High grade glioma

Phase III studies

CCG (1989) (WHO III+IV) EFS (5 years) 0.026RT 30 18%RT + (CCNU,VCR,Pred.) 28 46%CCG (1995) (WHO III+IV) PFS (5 years)RT+ (CCNU,VCR,Pred.) 85 33% n.s.RT + „8 in 1“ 87 36%

HIT – GBM A (2001) (Gr. IV) med. survivalRT+ Troph/VP16 22 12 mon

(22% 4 y. EFS) n.s.RT / control (no chx.) 13 12 mon.

(4% 4 y. EFS)

Study Pat. survival Signif.

High grade glioma

Phase III study CCG934 RT + CCNU, Vincristine, Prednisone versus RT alone

Sposto et al., 1989

High grade glioma

Pre-irradiation ICE in high grade astrocytomaA phase II study / survival at 5 years

Lopez-Aguilar et al., 2003

n = 25 pat.AA : 20 patGBM : 5 pat

Overall survival : 67%

Disease-free survival : 56%

months

Cave : High contribution of WHO III tumours

T + E

Radiation 54 Gy total

fractions: 1,8 Gy6 weeks

T + E T + E T + E T + E T + E

Induction Consolidation

continue for 1 yearA:07.95

-04.97

B:04.97

-09.99

C:ab 01.99

Radiation 54-60 Gy total

fractions: 1,8 Gy6-7 weeks

Radiation 54-60 Gy total

fractions: 1,8 Gy6-7 weeks

PE

PEI

continue as long as progression-free

C C C C C C C

Interferon-γ individual max. tolerated dose s.c. daily

V V V V V

PE

PEI

0Repeat until maximal

response

v

Surgery

MR MRInduct. of

Differ.NUC NUC

Progression: oral Topotecan

MRMR

MRPE

PEI

C=cyclophosphamide, E=etoposide, I=ifosfamide, P=cisplatin, V=vinristine, T=trofosfamide

Radio-chemotherapy / GPOH HIT GBM A - D

Acute toxicity of radio-chx.

359 pat., 187 pat. documentation complete (RT)Tumour sites : supratent : 91post. fossa : 7 brainstem : 79 spinal : 10

58 (31%) : interruption of RT19/58 (33%) : due to toxicity and tumour related

6/187 (3%) : discontinuation, all tumour relatedHaemat. Tox.(gr. III/IV) : 72/109

Fischer et al., 2004

Radio-chemotherapy / GPOH HIT GBM A - D

HIT GBM A / overall survival (as compared to RT alone)

Overall Survival (Years)

543210

Cum

ulat

ive

Sur

viva

l (K

apla

n M

eier

)

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

VP16/TRO n=22

4 censored

SEER n=13

1 censored

Wolff et al., 2001

Radio-chemotherapy / GPOH HIT GBM A - D

O ve ra ll S u rv iva l T im e (Y e a rs )

54321

Cum

ulat

ive

Sur

viva

l (K

apla

n M

eier

)

1 .0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0

M a in te n a n c e n = 1 6

8 a live

S a n d w ic h n = 1 51 1 a live

T rea tm en t P ro to co l

HIT 91 / high grade gliomaOverall survival : „ sandwich“ versus maintenance chemotherapy

Wolff et al., 2002

Radio-chemotherapy / GPOH HIT GBM A - D

Before radiochx. HIT-GBM D / background

-10 -5 0 5 10 15 20 25 30

HIT-GBM-B

HIT-GBM-An

progressive non progressive

After radiochx.

Wolff / HIT GBM

Radio-chemotherapy / GPOH HIT GBM A - D

HIT-GBM D / design of protocol

Pons

Non-Pons

OP

Arm S

RANDOMISATION

Arm MMTX

MTX

Radiotherapy54-60 Gy

PEV V V V

PEIV

CCNUVCRPred

every 6 wksmax. 8 x

Arm SArm M

0 6 16 6422

128 12 60week

MRT

OP?

Induction Consolidation

MRT MRT

High grade glioma + brainstem glioma

Future strategies- Modern treatment techniques (3D / stereotactic techniques)

- Novel approachesantiangiogenesis, cell differentiationrecurrent disease : re –irradiation ?

- Radio- / chemotherapy (data banks !!!)sequence of treatment / chx. protocols

- Overcome radioresistanceradiosensitizers

- Local dose escalations (?) (stereotactic techniques)