+ brainstem glioma Highly agressive tumours Median survival ca 9-12 months Curative or palliative treatments? Intensity of treatment Side effects Quality of life issues
+ brainstem glioma Aims of radiotherapy Improvement of local tumour control Using the advantages of modern treatment techniques Combination with chx. / radiosensitizers
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
+ 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. 14 12 n=80 Mean : 11.8 (+/- 3.3) y. 20 10 frequency 15 10 frequency 8 6 4 5 2 0 3,00 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 0 3 6 9 12 15 18 age at diagnosis [years] Mean = 11,854 Std. Dev. = 3,36413 N = 80
+ brainstem glioma Location / HIT GBM data bank (2006) Overall y survival 0.00 0.25 0.50 0.75 1.00 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 0 2 years 4 6 8
Gender (cortical tumours) / HIT GBM data bank (2006) Overall survival 0.00 0.25 0.50 0.75 1.00 Pat. Med. surv. Female 39 34.6 mon. Male 45 13.7 mon. Female Male Wolff et al., 2007, submitted 0 2 years 4 6 8
Extent of resection / HIT GBM data bank (2006) Overall survival 0.00 0.25 0.50 0.75 1.00 (Brain stem glioma : 118/134-88.1% -) Pat. Med. surv. Gross total 49 36.2 mon. Partial /subtotal 93 14.8 mon. None/biopsy 168 10.4 mon. (Cortical tumours : 14/84-16.6% -) Wolff et al., 2007, submitted 0 2 years 4 6 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., 2005 41 4 (9.7%) children 172 10 (6%) children 37 4 (11.8%) children 187 9 (4.8%) children
Pattern of failure after limited volume radiotherapy 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 23/34 local 86% 91% margin 9% 9% out of field 5% 0%
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 3.95 6.3 7.7 6.7 9.2 Migration of tumour cells (?) Aydin et al., 2001
Conformal radiotherapy 20% less normal brain tissue within the 95% isodose as compared with conventional 2 dimensional treatment planning Grosu et al., 1998
Question 1 Dose escalation using stereotactic approaches and modern imaging
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 + 1.5 cm) : 60 Gy (biol. eff. : 70Gy) PTV 3 : (visible tumour + 2.5 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
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
RTOG 93-05 / glioblastoma Phase III : conv. RT/BCNU versus conv. RT/BCNU+stereot. Boost (15-24Gy) Souhami et al., 2004
Question 2 Target volume definition
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
Target definition 1973 / 4 year old child with a brain stem glioma / 60 Gy Pneumoencephalographie 2 lat. portals / a) 0-12 b) 12-60 Gy 2003, complete remission (endocr. deficits, no neurcog. dysf) b a
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.
Question 3 Re irradiation using stereotactic equipment
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
Re - irradiation in recurrent high grade glioma / hypofr. stereot. Author Number of Pat. Technique / Dose perscription Shepherd et al., 1997 33 Hypofract. convergence therapy Single dose 5 Gy, Eskal. 20 -> 50 Gy Lederman et al., 2000 88 Stereot., hypofract. RT Med. 24 Gy in 4 Fract. Voynov et al., 2002 10 Stereot. IMRT, med. 30 Gy (25-40 Gy), 5 Gy/Fract. Overall survival 11.0 mon. 7 mon. 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 Gy 8 CT/MRI (6 x 5 Gy) Vordermark et al. 2005 19 Stereot. RT, hypofract. (4-10 Gy single dose) 30 Gy (20-30 Gy) 9.0 mon. 5.0 mon. 9.3 mon.
Re - irradiation in recurrent high grade glioma / conv. fract. stereot. Author Number of Pat. Technique / Dose perscription Overall Survival Arcicasa et al., 1999 31 Conv. Fract. 2 D RT Single 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 Combs et al., 2005b 20 Stereot. RT 3-3.5 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. 10.5 mon. 8.0 mon. 12.0 mon.
Brain stem glioma Benefit of radiotherapy (overall survival) / Dose : 54 Gy HIT data bank Wagner et al., 2006
Brain stem glioma Impact of histological subtype on overall survival HIT data bank Wagner et al., 2006
Brain stem glioma Precise positioning Expl.: Mask in a 6 year old boy with pontine glioma
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 weeks No dose dependency
Brain stem glioma (No) benefit of radio-chx Author Pat. Dose + chx. Survival Mandell et al., 1999 POG Phase III 66 64 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 days Overall / median: 10 mon. Doz et al., 2002 38 54 Gy / 1.8 Gy prior+ simult. Carboplatin Wolff et al., 2002 20 54 Gy / 1.8 Gy Trophosphamide + VP16 PFS / median : n.a. Overall / median: 11 mon. PFS / median : 9.6 mon Overall / median: 8 mon.
Brain stem glioma CCSG / POG : 8 prospective trials for hyperfractionated radiotherapy with dose escalation Total number of patients : 433 Dose prescriptions : 2x1.1-1.26 Gy / 64.8-78 Gy Median survival : 6.5 11 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
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
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) 85 87 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., 1996 39 (< 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 39-59 mon. after treatment Graham et al., 1997 12 High dose chx. + BMT 6 Primary / 6 rec. disease Glial tumours 2 of 12 alive Bouffet et al., 1997 22 High dose chx. + BMT Primary / rec. disease High grade glioma 15% alive 54-65 mon. after treatment
Phase III studies Study Pat. survival Signif. CCG (1989) (WHO III+IV) EFS (5 years) 0.026 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 1 87 36% HIT GBM A (2001) (Gr. IV) med. survival RT+ Troph/VP16 22 12 mon (22% 4 y. EFS) n.s. RT / control (no chx.) 13 12 mon. (4% 4 y. EFS)
Phase III study CCG934 RT + CCNU, Vincristine, Prednisone versus RT alone Sposto et al., 1989
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
Induction Consolidation A: 07.95-04.97 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: 04.97-09.99 Radiation 54-60 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 01.99 Radiation 54-60 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
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 : 10 58 (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
Radio-chemotherapy / GPOH HIT GBM A - D HIT GBM A / overall survival (as compared to RT alone) 1.0.9.8 Cumulative Survival (Kaplan Meier).7.6.5.4.3.2 VP16/TRO n=22 4 censored.1 SEER n=13 0.0 1 censored 0 1 2 Overall Survival (Years) 3 4 5 Wolff et al., 2001
Radio-chemotherapy / GPOH HIT GBM A - D HIT 91 / high grade glioma Overall survival : sandwich versus maintenance chemotherapy 1.0 Cumulative Survival (Kaplan Meier).9.8.7.6.5.4.3.2.1 0 1 2 Overall Survival Time (Years) 3 Treatment Protocol 4 Sandwich n=15 11 alive Maintenance n=16 8 alive 5 Wolff et al., 2002
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 -10-5 0 5 10 15 20 25 30 Wolff / HIT GBM
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 54-60 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 2 8 12 60 Arm M 0 2 6 12 16 64
+ 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?