Medulloblastoma / high risk. Radiotherapy in high risk medulloblastoma

Transcription

1 Radiotherapy in high risk medulloblastoma PROS Meeting London October 2012 Reference Centre for Radiotherapy, Dept. for Radiation Oncology University of Leipzig Johannisallee 34, Leipzig/Germany Phone: R.-D. Kortmann Co-Workers: A. Klein; A. Lehmann, Dr.rer.nat. S. Klagges, Dr. med. K. Müller

2 2. Posterior fossa (subclinical disease high risk?) Medulloblastoma / high risk Areas at risk 1. Leptomeningeal space (subclinical disease / low risk ) 3. Tumour site (residual tumour R1-2) tumour SSD 100 cm SSD 100 cm rotation of collimator according to divergence angle of upper spinal field isocentre Spinal canal SSD : source to skin distance

3 HIT 91 / relapse free survival with respect to risk profile M0 versus M2/3 1 0, (+/- 0.06) 0, (+/- 0.09) 0,4 0,2 0 p < (+/- 0.15) no residual tumour (n=82) residual tumour (n=36) M 2/3 (n=19) 0 0,5 1 1,5 2 2,5 3 3,5 4 4,5 5 5,5 6 relapse-free survival (years) Kortmann et al., 2000

4 SFOP high risk / chx, RT 35-36Gy / 55 56Gy, maint.-chx. Event free / overall survival pat. EFS Res. tu. only % M % M % P = 0.12 n.s. Verlooy et al., 2006

5 M1 versus M 2 3

6 high risk (M1-3) St. Jude / retrospective analysis 5 year EFS M0 80.5% M1 60.6% M2/M3 41.8% Sanders et al., 2008

7 CCG 921 / phase III (immediate RT versus sandwich chx. / RT) M0, n = 86 M1, n = 31 M2+, n = 51 (M0 v M1 v M21) (P =.0006). Zeltzer et al., 1999

8 HIT 91 / overall survival with respect to immediate or delayed RT / M1 10 year EFS 10 year OS Maintenance 17 71% (±11) 70% (±12) Sandwich 16 36% (±12) 34% (±12) Timing of RT in M 1 Von Hoff et al., 2009

9 MET- HIT 2000 ab 4 M1sig-M years 2 x HIT SKK / RT hfx (2x1.0Gy) 40Gy CSA, boosts 50-68Gy, 4 x Packer Interim analysis M2/3 M 1 arm discontinued -> switch back to HIT 91 / maintenance M1

10 HIT 91 versus HIT 2000 / PFS with respect to immediate or delayed RT / M1 M1: PFS (since diagnosis) HF versus HIT 91 Interimanalysis - 09/12 HIT 91 Immediate RT (CSA 35.2 / PF : 55 Gy) Followed by 8 x CCNU, Cispl., VCR ( Packer ) HIT 2000 ab 4 M1sig-M years 2 x HIT SKK / RT hfx (2x1.0Gy) 40Gy CSA, boosts 50-68Gy, 4 x Packer

11 Is there a dose response relationship for high risk disease (M1-3)?

12 SIOP II / M2-3 / event - free survival and overall survival High risk patients (metastases versus no metastases) (Standard dose RT : 35 Gy / 55 Gy) 5 year EFS no pre RT chx : 52.8% 5 year EFS pre RT chx. : 56.3% p=n.s EFS : ca 65% No metastases / n = 87 EFS : ca 40% Pat. +/- pre RT chx. EFS data not given in publication Metastases / n = 29 All patients received maintenance chx. Bailey et al., 1995

13 SIOP III / M2-3 / event - free survival and overall survival 4 cycles chx followed by RT CSA : 5 x 1.67 Gy / 35 Gy Boost PF : 55 Gy Boost metastases Gy n = 68 pat. 3 years 5 years EFS 39.7% 34.7% OS 50.0% 43.9% Taylor et al., 2005

14 SFOP high risk / chx, RT 35-36Gy / 55 56Gy, maint.-chx. Event free / overall survival 115 pat. (3-18 years) High risk : residual tumour only / M1-3) 5 year EFS : 49.8% OS : 60% pat. EFS Res. tu. only % M % M % Verlooy et al., 2006

15 High risk MB (larger residual tumour or / M1 or M2 3 Event free survival CSA 39.6 Gy /55.8Gy, boost to metast. if M2/3 (33 / 42 pat.) M1 M2 M3 9 pat. 6 pat. 27 pat. Group pat. 3 year 5 year Average 86 87% 83% High 48 75% 70% M % Log-rank p = Gajjar et al., 2006

16 high risk / INT Mailand (n = 28 patients) Int. chx. followed by hyperfractionated accelerated RT / HART CSA : 2 x 1.3 Gy, 39 Gy (> 10 y.) 31.2 (<10y) Boost PF : 60 Gy (> 10 y.) 59.7 (< 10 y) Boost metast. 2 x 1.5 Gy, 9 Gy 5-year EFS : 70% PFS : 72% OS : 73% Gandola et al., 2009

17 HIT 2000 / PFS for RT-Duration <= 50 days vs. > 50 days, n=61 patients with 68,0 Gy, only M2/3; n = 22 events Interimanalysis - 09/12 HIT 2000 ab 4 M1sig-M years 2 x HIT SKK / RT hfx (2x1.0Gy) 40Gy CSA, boosts 50-68Gy, 4 x Packer

18 HIT 2000 / PFS for RT- dose <= 66 Gy vs. > 66 Gy n=92 patients, only M2/3; n = 35 events Interimanalysis - 09/12 HIT 2000 ab 4 M1sig-M years 2 x HIT SKK / RT hfx (2x1.0Gy) 40Gy CSA, boosts 50-68Gy, 4 x Packer

19 HIT 2000 (protocol) versus HIT 91 (non-protocol) only M2/3 / PFS Interimanalysis - 09/12

20 high risk (M2-3) Outcome in prospective series / dose prescription (all protocols contained chemotherapy) Author/study Pat. dose outcome Prados et al., 1996 M1-3: 15 24/54 Gy /boosts 5 year PFS 21% CCG Evans et al., 1996 M2 : 15 M3 : 8 35/55 Gy / boosts 5 year EFS : 20% 57% CCG Zeltzer et al., 1999 M2/3 : 49 35/55 Gy / boosts 5 year PFS : 40% PNET II Bailey et al., /55 Gy/boosts ca 40% PNET III Taylor et al., /55 Gy /boosts 5 year EFS : 34.7% HIT 91 Kortmann et al., /55 Gy / boosts 3 year EFS : 30% SFOP Verlooy et al., /55-56Gy / boosts 5 year EFS : 43.1% INT Milano Gandola et al, /60 Gy hfx acc Boosts 9 Gy (9 pat. M1) 5 year PFS : 72% HIT 2000 (interim analysis) 90 40/68Gy / Boosts 50-68Gy 4 year EFS : 65% Gajjar et al., /55.8Gy / Boosts (9 pat. M1) 66% POG 9031, 2000 Abstract /55.8Gy Boosts 3 year EFS M2: 67%, M3: 66%

21 Radiochemotherapy for high risk disease (M1-3)?

22 high risk (M1-3) carboplatin during CSA (COG Phase I/II Study) OS and PFS / central review / regimen A CSA : 36 Gy / PF 55.8 Gy Boost : Gy Jakacki et al., 2012

23 high risk (M1-3) carboplatin during CSA (COG Phase I/II Study) OS and PFS / central review / regimen A and B CSA : 36 Gy / PF 55.8 Gy Boost : Gy Jakacki et al., 2012

24 high risk (M1-3) carboplatin during CSA (COG Phase I/II Study) OS / central review / M stage CSA : 36 Gy / PF 55.8 Gy Boost : Gy Jakacki et al., 2012

25 high risk (M1-3) carboplatin during CSA (COG Phase I/II Study) PFS and OS / central review / anaplasia CSA : 36 Gy / PF 55.8 Gy Boost : Gy Jakacki et al., 2012

26 Stratification Biological Markers (M1-3)?

27 Biological markers high risk (M + versus M 0)

28 WNT / overall survival / M + versus M 0 97% : classic subtype 9% M + (n = 6 -?-, details not mentioned) M + only children Total : 68 pat. moderate RT concept in WNT M +? Kool, et al., 2012

29 Conclusions M 1 PFS / OS better than M 2 /3 - timing (immediate RT?) M 2/3 Dose response relationship - HART (Italy) : excellent outcome (however : only few patients) - HIT POG 9031 / St. Jude experience Overall treatment time (?) Open question : timing (immediate RT, chx. protocol?) role of acceleration (HART)? M 1-3 Role of concurrent radio-chemotherapy (COG protocol)? Role of biological markers? - stratification of treatment survival benefit 20-30%? (WNT : moderate RT concept?)

30 Thank you very much for your attention Leipzig Sponsored by the Deutsche Kinderkrebsstiftung Reference Centre for Radiotherapy, Dept. for Radiation Oncology University of Leipzig Johannisallee 34, Leipzig/Germany Phone: R.-D. Kortmann / Co-Workers: A. Klein; A. Lehmann, Dr.rer.nat. S. Klagges, Dr. med. K. Müller