Intracranial AT RT / radiotherapy. Therapeutic dilemma / radiotherapy

Transcription

1 Therapeutic dilemma / radiotherapy Agressive tumour, poor outcome Past treatments based on MB concepts (RT CSA) MB Overall survival Mean age : 6.52 years n=36, 5 year 75% 1. Tumour occurs in the very young (< 3 years) 2. Requires intensive treatment (high doses of RT / CSA?) 3. Chemotherapy necessary (additional toxicity of RT) AT-RT Mean age : 1.32 years n=19, 5 year 26.3% Koral et al., 2008

2 Survival / radiotherapy - chemotherapy Data base Author Pat. Treatment median age Survival Cleveland Hilden et al., Chx.+ RT (n=13) : 47 mon. Hd. Chx. (+RT) (n=13) : n.a. Chx only (n=29) : n.a. Med. EFS OS 48 mon. 48 mon. 10 mon mon. n.a. Memphis Tekautz et al., Chx.+ RT (n=10) : n.a. (> 3 y.) Chx. Only (n=21) : n.a. (< 3 y.) 2 year EFS 2 year OS 90% 90% 0% 12% HIT Dannenmann- Stern et al., All pat. : 19 mon. Chx.+ RT (n=36) : 37 mon. Chx. Only (n=28) : 10 mon. Med. EFS OS 9 mon. 15 mon. 22 mon. 31 mon. 4 mon. 9 mon. Chen et al., Chx. + RT (n=19) 4.5 y. 11 mon. 17 mon.

3 Open questions 1. Should radiotherapy (XRT) be part of standard therapy in CNS-AT/RT? 2. Where should XRT be placed primary vs salvage therapy? 3. XRT and local tumour control target volume (focal RT vs CSA-RT)? dose prescription (dose-response relationship)?

4 Pattern of relapse / rationale for RT CSA All cases Primary site Primary site and leptomeningeal leptomeningeal Total relapses (46%) 9 (17%) 16 (31%) 49 (94%) Pattern of initial spread / rationale for RT CSA Burger et al., 1998 Parmar et al Rorke et al % : leptomeningeal metastases 33% : leptomeningeal metastases Dannenmann-Stern younger age/ infratent site. : 28.6% M2/3 et al (HIT) older age / supratent. site : 5.6% M2/3

5 Survival after chx / RT CSA Overall survival CSA : Gy Boost : 44-54Gy Total dose 36 Gy / 54 Gy p=0.034 Interval surgery - start of RT p= patients Median age 4.5 y. (2-19 y.) Months after end of RT Chen et al., 2006

6 AT/RT - HIT data base 65 patients (8/1988 8/2004) Follow-up: median 15 mths. (1 109 mths.) Histopathology: 61 / 65 (93.8%) centrally reviewed Data retrospectively collected

7 Patient characteristics HIT data base ( ) All patients ChX - Pat. RT/ChX - Pat. nr gender 41 m / 23 f 16 m / 12 f 25 m / 11 f location infratent. supratent infra-/supratent age at diagnosis (months) 19 (1 170) 10 (1 62) 37 (5 170) age groups 3 yrs. > 3 yrs. 44 (68.8%) 20 (31.2%) low risk (M0/M1) 54 (84.4%) 20 (71.4%) 34 (94.4%) high risk (M2/M3) 10 (16.6%) 8 (28.6%) 2 (5.6%) resection S0 S+ 17 (26.2%) 47 (73.8%) 4 (14.3%) 24 (85.7%) 13 (36.1%) 23 (63.9%)

8 Radiotherapy group (n=36) XRT as primary therapy : n = 19 low risk (M 0/1) n = 18 (95 %) high risk (M 2/3) n = 1 (5 %) all in curative intent (100 %) XRT as salvage therapy : n = 17 in local relapse (M 0/1) n = 14 (82 %) in dissemin. relapse (M 2/3) n = 3 (18 %) 14 / 17 in curative intent (82 %)

9 Radiotherapy / treatment data RT volume focal XRT n = 14 (39 %) 7 x primary RT / 7 x RT at relapse CSA - XRT n = 21 (58 %) 11 x primary RT / 10 x RT at relapse no inf. n = 1 (primary RT) RT dose prescription 33 x conventionally fract. XRT: dose to tumour : med Gy ( ) dose to CSA : med Gy ( ) 2 x hyperfractionated XRT (68 Gy, 72 Gy) 1 x radiosurgery (16 Gy)

10 Radiotherapy / acute toxicity - CTC - Haematological toxicity (CTC grade 3/4): 12 / 33 focal XRT 3 / 12 (25 %) CSA - XRT 9 / 21 (43 %) Neurological toxicitiy (CTC grade 3/4): 1 / 33 1 x SAE (brainstem bleeding at the end of focal XRT)

11 Relapse and survival radiotherapy versus chemotherapy Prim. chx.- pat. : 41 / 44 (93.2%) local (25 = 56.8%), diss. (4), comb (6), M4 (2) no inf. (3) (17 received RT as salvage treatment) Prim. RT-pat. : 10 / 19 (52.6%) local (5 = 26.3%), dissemin. (5) Long - term survival 19 / 64 Pat. (29.7%) survived more than 24 months med. 37 months (24 109) all of them had received XRT (primary / salvage)

12 Progressionfree and overall survival radiotherapy versus chemotherapy Progressionfree survival all pat.: median 9 mths. (1-109) primary chx.: median 4 mths. (1-15) primary XRT : median 22 mths. (3-44) Overall survival all pat.: median 15 mths. (1-109) primary chx: median 9 mths. (2-17) primary XRT: median 31 mths. (2-109)

13 Progressionfree and overall survival / XRT patients Überlebensfunktion Progressionfree survival Überlebensfunktion Overall survival 1,0 1,0,9,9,8,8 Cumulative survival Kum. Überleben,7,6,5,4,3,2,1 0, Überlebensfunktion Survival function Zensiert Cumulative survival Kum. Überleben,7,6,5,4,3,2,1 0, Überlebensfunktion Survival function Zensiert PFS: time from 1.RT until 1. relapse/death (y) OS: time from 1.RT until death (years)

14 Survival / timing of RT 1,0 PFS EFS: : prim.rt RT vs. vssalv.rt RT 1,0 Overall OS : prim. survival: RT vs prim.rt salv. RT vs salv.rt,9,9,8,8 Cumulative survival Kum. Überleben,7,6,5,4,3,2,1 0,0 0 n= 13 n= prim.rt vs salv.rt salv.rt salv.rt-zensiert prim-rt prim-rt-zensiert 10 Cumulative survival Kum. Überleben,7,6,5,4,3,2,1 0,0 0 2 n= 13 n= prim.rt vs. salv.rt salv.rt salv.rt-zensiert prim-rt prim-rt-zensiert 10 PFS: time from 1.RT until 1. relapse/death (y) 2-year-PFS in prim.rt: 53 % +/- 12 % 2-year-PFS in salv.rt: 58 % +/- 14 % Logrank-Test: p= OS: time from 1.RT until death (years) 2-year-OS in prim.rt: 55 % +/- 12 % 2-year-OS in salv.rt: 52 % +/- 14 % Logrank-Test: p=

15 Survival / treatment volume of RT PFS EFS (local disease): loc.rt vs CSI 1,0,9,8 OS OS (local (local disease): loc. loc.rt vs. CSI 1,0,9,8 Cumulative survival Kum. Überleben,7,6,5,4,3,2,1 0,0 0 2 n= 16 n= 14 n= 14 radiation field CSI CSI-zensiert loc.rt loktu-zensiert Cumulative survival Kum. Überleben,7,6,5,4,3,2,1 n= 16 0, radiation field CSI CSI-zensiert loc.rt loc.rt-zensiert 10 PFS: time from 1.RT until 1. relapse/death (y) 2-year-PFS in local RT: 59 % +/- 14 % 2-year-PFS in CSI RT: 46 % +/- 13 % Logrank-Test: p= OS: time from 1.RT until death (years) 2-year-OS in local RT: 54 % +/- 14 % 2-year-OS in CSI RT: 46 % +/- 14 % Logrank-Test: p=

16 Conclusions 1. Primary XRT improved local tumour control better median OS and PFS than primary chx. alone XRT should be part of treatment concept 2. PFS and OS between primary / salvage XRT no significant difference 3. PFS and OS between local / craniospinal XRT no significant difference However : bias in tumour site, age and risk profile Radiotherapy should be part of treatment / open questions optimal sequence optimal treatment volume dose prescription (local / CSA)

17 RT guidelines EUROPEAN RHABDOID REGISTRY / CNS tumours Localized disease supratentorial or infratentorial (M0 according to Chang), age 18 months RT to the extended tumor region according to CT planning. Total dose and fractionation 5 x 1.8 Gy per week, 54.0 Gy PTV acc. to ICRU 50/62. The target volume should include the postoperative or postchemotherapeutic tumor region including potential residual tumor as indicated by CT or T1-T2 MRI following contrast application. A safety margin of 1 cm (= CTV) should be used. Anatomical borders with initial tumor contact need to be included in the planning target volume. The definition of the PTV needs to regard the precision of the technique used. Usually an additional safety margin of 5 mm to 1 cm has to be included.

18 RT guidelines EUROPEAN RHABDOID REGISTRY / CNS tumours Patients with metastatic disease (M1 to M3), age > 18 month to 3 years RT CSA 5 x 1.6 Gy total dose 24.0 Gy. The primary tumour site (not PF in PF tumour sites) total dose of 54.6 Gy, 5 x 1.8 Gy. Boost to spinal deposits Circumscribed solid spinal lesions should be boosted up to 49.2 Gy cumulative dose (for spinal lesions extension according to prior to chemotherapy), 5 x 1.8 Gy. Safety margins in longitudinal extension 1 cm. In diffuse spinal spread up to 35.2 Gy. Boost to intracranial deposits. boosted up to 49.2 Gy cumulative dose, 5 x 1.8 Gy. For children older than 3 years (M1 to M3) RT CSA 5 x 1.6 Gy total dose 35.2 Gy. Boost tumor region 55.0 Gy, 5 x 1.8Gy. Boost to metast deposits : 49.2Gy If tumor persists in a control MRI following 45.0 Gy a boost of the residual disease up to 59.4 Gy can be applied.

19 RT guidelines EUROPEAN RHABDOID REGISTRY / CNS tumours Timing of radiotherapy: Children below the age of 18 months should only be irradiated under exceptional circumstances. We propose a timepoint for RT following immediately after the 4th element of chemotherapy in children 18 months and older. In case of primary metastasized disease RT may be delayed until the end of intensive chemotherapy (following element 9). Other special circumstances may apply such as progressive disease, when RT may be performed at any time (after discussion with the trial coordinator). For infants and children below 18 months radiotherapy may be delayed until age permits or following element 9..