High grade glioma + brainstem glioma

Transcription

1 + brainstem glioma Highly agressive tumours Median survival ca 9-12 months Curative or palliative treatments? Intensity of treatment Side effects Quality of life issues

2 + brainstem glioma Aims of radiotherapy Improvement of local tumour control Using the advantages of modern treatment techniques Combination with chx. / radiosensitizers

3 Radio-chemotherapy / GPOH HIT GBM A - D European Co-operation / data bank :> 400 pat. Participation in European high grade glioma data bank Participation HIT-GBM-D protocol and European data bank old countries: HIT-GBM-B, -C and - D prot. / data bank Wolff / HIT GBM

4 + brainstem glioma Age distribution / HIT data bank Pons Cortex / white matter tumor site: pons tumor site: cortex and white matter 25 n=132 Mean : 8.3 (+/- 3.2) y n=80 Mean : 11.8 (+/- 3.3) y frequency frequency ,00 6,00 9,00 12,00 15,00 18,00 age at diagnosis [years] Mean = 8,3653 Std. Dev. = 3,27757 N = 132 Wolff et al., 2007, submitted age at diagnosis [years] Mean = 11,854 Std. Dev. = 3,36413 N = 80

5 + brainstem glioma Location / HIT GBM data bank (2006) Overall y survival Pat. Med. surv. Cortex mon. Non-pons / others mon. Pons mon. Overlap with resectability? Wolff et al., 2007, submitted 0 2 years 4 6 8

6 Gender (cortical tumours) / HIT GBM data bank (2006) Overall survival Pat. Med. surv. Female mon. Male mon. Female Male Wolff et al., 2007, submitted 0 2 years 4 6 8

7 Extent of resection / HIT GBM data bank (2006) Overall survival (Brain stem glioma : 118/ % -) Pat. Med. surv. Gross total mon. Partial /subtotal mon. None/biopsy mon. (Cortical tumours : 14/ % -) Wolff et al., 2007, submitted 0 2 years 4 6 8

8 Spinal seeding at diagnosis Author Pat. Rate Age group Heidemann et al., 1997 Finlay et al., 1995 Packer et al., 1985 Benesch et al., (9.7%) children (6%) children 37 4 (11.8%) children (4.8%) children

9 Pattern of failure after limited volume radiotherapy Hess et al., 1993 Chan et al., 2002 technique 2D conventional 3D conformal (2 cm safety margin) ( cm - dose escalation -) dose 60 Gy / 30 fr. 90 Gy / 45 fr. rate 58/66 23/34 local 86% 91% margin 9% 9% out of field 5% 0%

10 Pattern of failure after 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 Distance 0cm <=1cm 1-2cm 2-3cm <3cm Interval (mon.) Median Migration of tumour cells (?) Aydin et al., 2001

11 Conformal radiotherapy 20% less normal brain tissue within the 95% isodose as compared with conventional 2 dimensional treatment planning Grosu et al., 1998

12 Question 1 Dose escalation using stereotactic approaches and modern imaging

13 Patients : Dose escalation 34 pat with high grade glioma (33 glioblastoma, 1 anapl. Glioma) Median age : 55 years Technique : 3 D conformal technique Dose prescription : PTV 1 : (visible tumour + 0.5cm) : 90+/- 5 Gy PTV 2 : (visible tumour cm) : 60 Gy (biol. eff. : 70Gy) PTV 3 : (visible tumour cm) : 44 Gy (biol. eff. : 60 Gy) Outcome : median survival : 11.7 months 1 and 2 year survival : 47.1% / 12.9% Chan et al, 2002

14 External fract. RT + Brachytherapy ( boost ) / adults Median survival No boost : 58.8 weeks n = 137 Boost : 68.8 weeks n = 133 p=0.101 (n.s.) Selker et al., 2002

15 RTOG / glioblastoma Phase III : conv. RT/BCNU versus conv. RT/BCNU+stereot. Boost (15-24Gy) Souhami et al., 2004

16 Question 2 Target volume definition

17 Target volume definition Pre or postoperative extent of disease brain shift Anatomical borders infiltration Definition of safety margins between CTV and PTV Presently no standards departmental policies

18 Target definition 1973 / 4 year old child with a brain stem glioma / 60 Gy Pneumoencephalographie 2 lat. portals / a) 0-12 b) Gy 2003, complete remission (endocr. deficits, no neurcog. dysf) b a

19 Pre- or postoperative definition of CTV? Technique / timing of imaging? 10 cm 7 cm 8.5 cm MR pre-op. CT 1 day postop. MR 2 weeks post-op.

20 Question 3 Re irradiation using stereotactic equipment

21 Re - irradiation in recurrent high grade glioma Relapse of glioblastoma multiforme / 17 y. boy Hypofractionated stereotactic radiotherapy Before RT 4 x 5 Gy CR 1 y after RT

22 Re - irradiation in recurrent high grade glioma / hypofr. stereot. Author Number of Pat. Technique / Dose perscription Shepherd et al., Hypofract. convergence therapy Single dose 5 Gy, Eskal. 20 -> 50 Gy Lederman et al., Stereot., hypofract. RT Med. 24 Gy in 4 Fract. Voynov et al., Stereot. IMRT, med. 30 Gy (25-40 Gy), 5 Gy/Fract. Overall survival 11.0 mon. 7 mon mon. Bartsch et al., Stereot. RT 14 Pat Gy, conv. Fract. 8 Pat. 30 Gy hypofract. (6x5Gy) 7.0 mon. Grosu et al., Stereot. RT, hypofract. 36 PET/SPECT, 30 Gy 8 CT/MRI (6 x 5 Gy) Vordermark et al Stereot. RT, hypofract. (4-10 Gy single dose) 30 Gy (20-30 Gy) 9.0 mon. 5.0 mon. 9.3 mon.

23 Re - irradiation in recurrent high grade glioma / conv. fract. stereot. Author Number of Pat. Technique / Dose perscription Overall Survival Arcicasa et al., Conv. Fract. 2 D RT Single dose 1.5 Gy, 34.5 Gy 13.7 mon. Cho et al Conv. fract. RT, 37.5/15 fractions 12.0 mon. Hudes et al., 1999 Combs et al., 2005b 20 Stereot. RT Gy 24.0->35 Gy dose escalation protoc. 54 GBM 39 WHO III Stereot. RT 36 Gy (15-62 Gy) 5 x 2.0 Gy conv. fract mon. 8.0 mon mon.

24 Brain stem glioma Benefit of radiotherapy (overall survival) / Dose : 54 Gy HIT data bank Wagner et al., 2006

25 Brain stem glioma Impact of histological subtype on overall survival HIT data bank Wagner et al., 2006

26 Brain stem glioma Precise positioning Expl.: Mask in a 6 year old boy with pontine glioma

27 RT of tumour site / modern technologies Treatment machine Position for treatment delivery

28 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

29 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., x 1.0 Gy, Gy Overall / median : 72 weeks No dose dependency

30 Brain stem glioma (No) benefit of radio-chx Author Pat. Dose + chx. Survival Mandell et al., 1999 POG Phase III x 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., x 1.0 Gy, 72.0 Gy + simult. carboplatin PFS / median : 8 mon. Overall / median: 12 mon. Broniscer et al., Gy / 1.8 Gy + Tamoxifen PFS / median : n.a. Overall / median: 10.3 mon. Bouffet et al., Gy / 1.8 Gy + High dose chx. PFS / median : 119 days Overall / median: 10 mon. Doz et al., Gy / 1.8 Gy prior+ simult. Carboplatin Wolff et al., Gy / 1.8 Gy Trophosphamide + VP16 PFS / median : n.a. Overall / median: 11 mon. PFS / median : 9.6 mon Overall / median: 8 mon.

31 Brain stem glioma CCSG / POG : 8 prospective trials for hyperfractionated radiotherapy with dose escalation Total number of patients : 433 Dose prescriptions : 2x Gy / Gy Median survival : months 5x1.8 Gy / 54 Gy : 9 months No benefit of hfx. radiotherapy including dose escalations Present recommendation : 5 x 1.8 Gy, 54 Gy total dose

32 Radio- /chx. in childhood high grade glioma Rationale Rationale for chx. before RT Open blood brain barrier (surgery) lesser toxicity of agents, greater selection of protocols, reduction of tumour burden Rationale for chx. during RT Radiosensitization Rationale for chx. after RT Elimination of persistent tumour cells Maintenance approach to prevent early relapse

33 Survival in prospective series Author Pat. Treatment Histologies Survival Sposto et al., 1989 (CCG) 58 Phase III study RT versus RT + CCNU/ VCR / Prednisone High grade glioma 5 y. EFS RT alone : 18% RT + Chx. : 46% Finlay et al., 1995 (CCG) Phase III study RT + CCNU / VCR / Pred 8 in 1 + RT High grade glioma 5 y. PFS : 33%, no diff.erence Geyer et al., 1995 Finlay et al., (< 24 Mon.) 8 in 1, delayed RT Astrocytoma WHO Gr. III Glioblastoma 18 High dose chx. + BMT Rec. disease High grade glioma 3 y. PFS All pat. : 36% WHO Gr. III : 44% WHO Gr. IV : 0% 16% DOC 5 of 18 (28)alive mon. after treatment Graham et al., High dose chx. + BMT 6 Primary / 6 rec. disease Glial tumours 2 of 12 alive Bouffet et al., High dose chx. + BMT Primary / rec. disease High grade glioma 15% alive mon. after treatment

34 Phase III studies Study Pat. survival Signif. CCG (1989) (WHO III+IV) EFS (5 years) RT 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 % HIT GBM A (2001) (Gr. IV) med. survival RT+ Troph/VP mon (22% 4 y. EFS) n.s. RT / control (no chx.) mon. (4% 4 y. EFS)

35 Phase III study CCG934 RT + CCNU, Vincristine, Prednisone versus RT alone Sposto et al., 1989

36 Pre-irradiation ICE in high grade astrocytoma A phase II study / survival at 5 years Cave : High contribution of WHO III tumours Overall survival : 67% Disease-free survival : 56% n = AA : GBM : 25 pat. 20 pat 5 pat Lopez-Aguilar et al., 2003 months

37 Induction Consolidation A: Radiation 54 Gy total fractions: 1,8 Gy 6 weeks T + E continue for 1 year T + E T + E T + E T + E T + E B: Radiation Gy total fractions: 1,8 Gy 6-7 weeks P E P E I continue as long as progression-free Interferon-γ individual max. tolerated dose s.c. daily C C C C C C C C: ab Radiation Gy total fractions: 1,8 Gy 6-7 weeks P E V V V V V P E I MR Repeat until maximal response P P E v E I MR MR S u r g e r y MR NUC Progression: oral Topotecan 0 Induct. of Differ. MR NUC C=cyclophosphamide, E=etoposide, I=ifosfamide, P=cisplatin, V=vinristine, T=trofosfamide

38 Radio-chemotherapy / GPOH HIT GBM A - D Acute toxicity of radio-chx. 359 pat., 187 pat. documentation complete (RT) Tumour sites : supratent : 91 post. fossa : 7 brainstem : 79 spinal : (31%) : interruption of RT 19/58 (33%) : due to toxicity and tumour related 6/187 (3%) : discontinuation, all tumour related Haemat. Tox.(gr. III/IV) : 72/109 Fischer et al., 2004

39 Radio-chemotherapy / GPOH HIT GBM A - D HIT GBM A / overall survival (as compared to RT alone) Cumulative Survival (Kaplan Meier) VP16/TRO n=22 4 censored.1 SEER n= censored Overall Survival (Years) Wolff et al., 2001

40 Radio-chemotherapy / GPOH HIT GBM A - D HIT 91 / high grade glioma Overall survival : sandwich versus maintenance chemotherapy 1.0 Cumulative Survival (Kaplan Meier) Overall Survival Time (Years) 3 Treatment Protocol 4 Sandwich n=15 11 alive Maintenance n=16 8 alive 5 Wolff et al., 2002

41 Radio-chemotherapy / GPOH HIT GBM A - D Before radiochx. HIT-GBM D / background progressive non progressive After radiochx. HIT-GBM-B n HIT-GBM-A Wolff / HIT GBM

42 Radio-chemotherapy / GPOH HIT GBM A - D Non-Pons Pons OP R A N D O M I S A T I O N HIT-GBM D / design of protocol Arm S Arm M M T X M T X Induction Radiotherapy Gy P E V MRT V V V P E I V OP? MRT Consolidation CCNU VCR Pred every 6 wks max. 8 x MRT Arm S week Arm M

43 + brainstem glioma Future strategies - Modern treatment techniques (3D / stereotactic techniques) - Radio- / chemotherapy (data banks!!!) sequence of treatment / chx. protocols - Local dose escalations (?) (stereotactic techniques) - Overcome radioresistance radiosensitizers - Novel approaches antiangiogenesis, cell differentiation recurrent disease : re irradiation?