Thomas Klingebiel und Ewa Koscielniak

Transcription

1 Weichteilsarkome bei Kindern und Jugendlichen Stadium IV und Rezidiv - Erfahrungen aus 30 Jahren CWS Studien - Thomas Klingebiel und Ewa Koscielniak Klinik für Kinder- und Jugendmedizin III Theodor Stern Kai 7, Frankfurt

2 Stadium IV

3 Weichteilsarkome Verteilung Histologie 11% 3% 50% 13% 23% 23% 2% 31% Age 10 - < 22 years n = % 30% Age < 10 years n = % 20% RME RMA RMS RMS-like Non-RMS

4 Weichteilsarkome EFS lokalisiert CWS 96 1,0 Event Free Survival, RMS-Like, localized, CWS96, ITT, n=831, p<0,05 0,9 0,8 0,7 Survival 100%*p 0,6 0,5 0,4 0,3 0,2 Low Risk, n=57, 5yrs: 85% 0,1 Standard Risk, n=124, 5yrs: 75% High Risk, n=650, 5yrs: 57% 0, Years

5 Weichteilsarkome OS metastasiert CWS ,0 0,9 CWS-81 - CWS-96*, RMS/EES/PNET, Stage IV n=201 deceased censored 0verall Survival (SUR) 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 5y(21±3) 0, * date of diagnosis < Aug 1998 CWS 8/2000 years

6 Weichteilsarkome OS metastasiert CWS ,0 CWS Stage IV RMS deceased censored Overall Survival (SUR) 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 Log-rank p< y (0.35) 5y (0.07) age < 10.0 yrs n=60 age >= 10.0 yrs n=67 0, years 3/2000

7 Previous Experiences CWS 86 - EFS stage I n= stage II n= stage III n= stage IV n= Koscielniak E. et al. JCO 17: (1999)

8 HD CWS 96 Treatment Schedule RT/ Surgery I 3 VA CEV I 3 VE I 3 VA CEV I 3 VE I 3 VA CEV I 3 VE OMT HD 1 HD 2 High Dose Chemotherapy (HD) OMT CEVAIE x 7 CEVAIE x 9 Cyclophosphamide + Thiotepa (HD1) (Trofosfamide + Etoposide) x 4 Melphalan + Etoposide (HD2) (Trofosfamide + Idarubicine) x 4

9 HD CWS 96 Oral Maintenance Treatment (OMT) TE TI TE TI TE TI TE TI Time [Weeks]

10 HD CWS 96 Trofosfamide (Ixoten )

11 HD CWS 96 OMT - TE Trofosfamide 2 x 75 mg/m²/d Pause cumulative 1.5 g/m² Etoposide 2 x 25 mg/m²/d Pause 500 mg/m² Day

12 HD CWS 96 OMT - TI Trofosfamide 2 x 75 mg/m²/d Pause Idarubicine 1 x 5 mg/m²/d Pause cumulative 1.5 g/m² 20 mg/m² Day

13 HD CWS 96 Dose Comparison Cyclophosphamide High Dose 4.5 g/m² Oral Maintenance Treatment Trofosfamide 12 g/m² Thiotepa 600 mg/m² Melphalan 120 mg/m² Etoposide 1.8 g/m² 2.0 g/m² Idarubicine 80 mg/m²

14 HD CWS 96 Patient Recruitment n./. Registered patients stage IV 5/95-12/ Treatment/documentation not completed 37 Available for analysis 258 According to protocol with OMT 51 According to protocol with HD 45 Klingebiel T et al. Ped Blood Cancer 50: (2008)

15 Patient Characteristics Age, Sex and Histology Parameter OMT HD Total Chi 2 [p] Age [years] < < > Sex M F Diagnosis RME (Rhabdomyosarcoma vs other) RMA RMS-like Non-RMS 2 5 7

16 Weichteilsarkome Stadium IV CWS 96 Children < 10 y n = 42 Adolescents 10 - < 22 y n = 53 7 % 19 % 10 % 40% 11% 6% 8% 38% 2% 24% 36% Parameningeal Bladder/Prostate Non Bladder Prostate Extremities Other Unknown Parameningeal Bladder/Prostate Non Bladder Prostate Extremities Other B/BM Metastases: Children 29% vs Adolescents 58%

17 Patient Characteristics Site Parameter OMT HD Total Chi 2 [p] Site PM (parameningeal) (PM vs EXT vs BP (bladder/prostate) OTH) NBP (non bladder/prostate) EXT (extremities) OTH (other) ukn (unknown) (EXT vs OTH)

18 Patient Characteristics Metastases and Size Parameter OMT HD Total Chi 2 [p] Metastases No B/BM B/BM ukn Size [cm] < > ukn B = Bone BM = Bone Marrow

19 Patient Characteristics TN-Status Parameter OMT HD Total Chi 2 [p] T T T TX N N N NX

20 Outcome Status Parameter OMT HD Total p Status Alive DOD Follow up [months] Median 45.5 ( ) 70.3 ( ) 57.4 ( ) 5 yrs OAS EFS

21 Overall Survival Total Group - Age n=96 Survival p <10 years n= p=0.01 >10 years n= Years

22 Overall Survival Total Group - Sex n= Klingebiel T et al. Ped Blood Cancer 50: (2008) Survival p Female n= p=0.03 male n= Years

23 Overall Survival Total Group - Metastases 1.0 n= Survival p No B/BM n= p= B/BM n= Years

24 Overall Survival Total Group 1.0 Maintenance vs High Dose n= Survival p Maintenance n=51, 5yrs OS p=0.03 High Dose n=45, 5yrs OS Years

25 Overall Survival Rhabdomyosarcoma only 1.0 Maintenance vs High Dose n= Survival p Maintenance n=40, 5yrs OS p=0.001 High Dose n=34, 5yrs OS Years

26 Overall Survival High Dose - Metastases n= Survival p No B/BM n= p=0.06 B/BM n= Years

27 Overall Survival OMT - Metastases 1.0 n= No B/BM n=31 Survival p p< B/BM n= Years

28 Overall Survival No B/BM Involvement 1.0 Maintenance vs High Dose n= Maintenance n=31, 5yrs OS 0.73 Survival p , p=0.04 High Dose n=20, 5yrs OS Years

29 Overall Survival B/BM Involvement 1,0 Maintenance vs High Dose n=43 0,9 0,8 Survival p 0,7 0,6 0,5 0,4 0,3 0,2 Maintenance, n=19, 5yrs OS ,1 p=0.75 High Dose n=24, 5yrs OS , Years

30 Cox Regression Total Group Identified Risk Factors (for Overall Survival) Risk Factor Risk Ratio (95% CI) p-value B/BM Sex Histology No 1 (-) Yes 1.97 ( ) male 1 (-) female 0.38 ( ) RMA/S 1 (-) RME 0.24 ( ) RMS-like 0.29 ( ) NRSTS 0.78 ( )

31 Cox Regression Rhabdomyosarcoma only Identified Risk Factors Risk Factor Risk Ratio (95% CI) p-value B/BM Given Therapy Nodal Status No 1 (-) Yes 2.6 ( ) OMT 1 (-) HDT 2.42 ( ) N0 1 (-) N ( ) NX 3.52 ( )

32 HD CWS 96 Conclusions - Univariate OMT superior for patients With Rhabdomyosarcoma only (p=0.001) W/O Bone/BM involvement (p=0.04) Total Group (p=0.03) Risk Factors Age > 10 years (p=0.01) Bone/Bone Marrow involvement (p=0.0005) Male sex (p=0.03)

33 HD CWS 96 Conclusions - Multivariate Total Group (n=96) Sex, Bone/BM involvement and Histology related to risk Rhabdomyosarcoma only (n=74) Male sex, Bone/BM involvement and High Dose Therapy related to higher risk

34 Weichteilsarkome St IV CWS Lungen Metastasen N=29 patients <21 years with RME with isolated lung metastases in 4 consec CWS trial median age 6 years, the median follow-up 9 years N=28 with primary tumor located in an unfavorable site and 22 of the primaries were >5 cm Lung metastases in remission after induction chemotherapy in 22 N=19 no local treatment of metastases Lung radiation in 9 individuals Dantonello T et al. Ped Blood Cancer 56: (2011)

35 Weichteilsarkome St IV CWS Lungen Metastasen Dantonello T et al. Ped Blood Cancer 56: (2011)

36 Weichteilsarkome St IV Literatur SIOP Study MMT-98 Nov N=146 N=45 SRG (< 10 yrs, no B/BM) N=101 HR McDowell H et al. Eur J Cancer 46: (2010)

37 Weichteilsarkome St IV Literatur McDowell H et al. Eur J Cancer 46: (2010)

38 Weichteilsarkome St IV Literatur Pooled data obtained from 788 patients treated in nine studies performed by European and American cooperative groups Clinical factors, including age, histology, site of primary, and site(s) and number of sites of metastatic disease, were correlated with eventfree survival (EFS) and overall survival (OS). Oberlin O et al. JCO 26: (2008)

39 Weichteilsarkome St IV Literatur Oberlin O et al. JCO 26: (2008)

40 Weichteilsarkome St IV Literatur Oberlin O et al. JCO 26: (2008)

41 Hochdosistherapie

42 Definition of Risk Groups Experimental Approaches

43 Hochdosistherapie Prinzipien HDC with autologous stem cell rescue Chemotherapy dose intensification Allogeneic stem cell transplantation High dose chemotherapy and immuntherapy (graft vs. tumor)

44 Hochdosistherapie Prinzipien

45 Hochdosistherapie Ergebnisse EBMT Overall Survival (SUR) EBMT - Solid tumour working party - RMS SUR all RMS n=464* - by age complete censored 1,0 0,9 Log-Rank p< ,8 age < 10.0 yrs n=236 0,7 age >=10.0 yrs n=212 0,6 0,5 5y(0.42) 0,4 0,3 0,2 0,1 5y(0.21) 0, * 16 pts. no valid survival dat years 3/2000 Data from Koscielniak E.

46 Hochdosistherapie Ergebnisse Literatur Author Year No pts Eligibility Condit. Benefit Horowitz Loc.adv. TBI+VAC No Sato Localized Yes Lucidarme Refractory Thiotepa Yes (Resp) Hara Refractory TT/Bu/Mel Yes Ozkayanak High risk Carbo/Mel/ Eto+-Cyc Boulad High risk Me/Vp16 No Waterhouse Stage IV TT/Carbo No Carli Stage IV different Slight Yes

47 Hochdosistherapie Ergebnisse Literatur 389 pts with metastatic or recurrent RMS in 22 articles Conclusion: No significant advantage to undergoing HDC with HSCR for patients with relapsed or metastatic RMS COG & RMS Group has abandoned HDC for RMS Weigel et al. JCO 23: (2001)

48 Hochdosistherapie Allogene SZT Relapse - large lytic lesion in the right parietal bone with extradural space occupying component 24 months after HSCT complete normalisation Koscielniak E et al. JCO 23: (2005)

49 Haploidentische SZT Konditionierung Fludarabine mg/m 2 : 200 later: 150 Thiotepa (10 mg/kg) Melphalan (140 mg/m 2 )* OKT-3 MMF +10 tk_ Infusion of stem cells

50 Haploidentische SZT Patienten Number 14 [May, 28 th, 2010] Age [Years] 17.5 ( ) Follow Up [months] 10 (2-42) Diagnosis Remission at transplant STS (RMA n=13; SS n=1) CR1 >CR2 PR Pre-Treatment Chemo Add autologous SCT 14 2 tk_

51 Haploidentische SZT Ergebnisse Remission prior to SCT N CR N (%) Outcome Rel TRM N (%) N (%) Non TRM N (%) PR 6 6 (100%) CR 8 5 (63%) 1 (12%) 1 (12%) 1 (12%) Total 14 5 (36%) 7 (50%) 1 (7%) 1 (7%) tk_

52 Haploidentische SZT Ergebnisse pos pos Remission Non Remission Time [Months] Time [Months] pos: 3 years: 0.25; n=14; events n=9 tk_ Remission pos: 3 years: 0.47; n=8; ev. n=3 Non rem. pos: 3 years: 0.00; n=6; ev. n=6

53 Rezidive

54 Weichteilsarkome Rezidiv Survival (SUR) after first relapse depending on the time to relapse (TTR) N=234 from CWS-81, CWS-86, CWS-91, and CWS-96 met selection criteria Mattke AC et al. Pediatr Blood Cancer 52: (2009)

55 Weichteilsarkome Rezidiv Time Point % SUR (4yrs) SUR (local) SUR (embryonal) SUR (alveolar) Early <6 Mo Intermediate (6-12 Mo) Late (>12 Mo) Mattke AC et al. Pediatr Blood Cancer 52: (2009)

56 Weichteilsarkome Rezidiv Mattke AC et al. Pediatr Blood Cancer 52: (2009)

57 Weichteilsarkome Rezidiv N=1164 patients with nonmetastatic RMS achieved CR CWS-81, CWS-86, CWS-91, and CWS-96 between 1980 and 2002 (median followup, 5 years) N=337 locoregional, metastatic, or combined relapses Dantonello T et al. JCO 26: (2008)

58 Weichteilsarkome Rezidiv Dantonello T et al. JCO 26: (2008)

59 Weichteilsarkome Rezidiv Dantonello T et al. JCO 26: (2008)

60 Weichteilsarkome Rezidiv Dantonello T et al. JCO 26: (2008)

61 Weichteilsarkome Rezidiv Dantonello T et al. JCO 26: (2008)

62 Danksagung Alle CWS-Kliniken Alle Mitarbeiter der CWS- Studienzentrale Deutsche Krebshilfe Deutsche Kinderkrebsstiftung

63 Klinik für Kinder- und Jugendmedizin III - Frankfurt

64 Treatment 1 Age, Sex and Histology Parameter OAS EFS Age [years] < > Sex M Diagnosis RME + RMA F other OMT vs HD

65 Treatment Site Parameter OAS EFS Site PM EXT OTH

66 Treatment Metastases and Size Parameter OAS EFS Metastases No B/BM B/BM Size [cm] < >

67 Treatment TN-Status Parameter OAS EFS T T T N N N