High dose chemotherapy in Ewing sarcoma Nathalie Gaspar Gustave Roussy Cancer Campus, Villejuif (France)
Principles of high-dose chemotherapy Log-linear dose/efficacy relation of alkylating agents - Increased efficacy (?) - Increased toxicity : hematologic +++ Rescue by autologous stem cell transplatation : Peripheral stem cells > bone marrow stem cells Porrata et al. BJC 2001
High dose chemotherapy in Ewing sarcoma a very long story starting in the 80ies HDC in recurrent EW HDC in newly diagnosed multimetastatic EW HCD in newly diagnosed lung metastatic EW HDC in newly diagnosed localised high-risk EW up to now
HDC in recurrent or progressive EW Small heterogenous Retrospectives studies HDC might benefit patients with Lung only EW recurrence EW Late recurrence > 2years Who achieved CR or PR before HDC EFS 20% vs 0% GASPAR et al. JCO 2015
High dose chemotherapy in Ewing sarcoma a very long story starting in the 80ies HDC in recurrent EW (?) HDC in newly diagnosed multimetastatic EW HCD in newly diagnosed lung metastatic EW HDC in newly diagnosed localised high-risk EW up to now
HDC in newly diagnosed multimetastatic EW No randomised trial Retro and prospectives studies Historical comparisons GASPAR et al. JCO 2015
HDC in newly diagnosed multimetastatic EW +/-RADIOTHERAPY CD IE Bu/Mel CSP EW93/97 CT S CT +/-RT CT S CHD +/-RT EW88 EW93/97 1.00 Oberlin, BJC 2001 Localised disease (n=141) 58 % 17 % Metastatic disease (n=28) 0.80 0.60 0.40 0.20 0.00 0 1 2 3 4 5 6 7 8 9 10 11 12 13 216 97 60 % 38 % 185 152 141 131 111 81 55 57 44 39 34 31 26 22 30 12 14 8 4 5 Localized tumors Metastatic tumors 3 Oberlin, JCO 2006
HDC in newly diagnosed multimetastatic EW No randomised trial Retro and prospectives studies Historical comparisons Various induction chemotherapies Various HDC regimens +/- Total body irradiation GASPAR et al. JCO 2015
HDC in newly diagnosed multimetastatic EW Importance of Busulfan 1.0 EWING TUMOURS EBMT 99 No relapse before MGT/SCR psu 0.8 0.6 0.4 0.2 Busulfan HDC regimen Other HDC regimens 0.0 0 2 4 6 8 10 12 14 years Busulfan n=139 5 yrs. psu = 0.54 ± 0.05 others n=120 5 yrs. psu = 0.26 ± 0.04 p<0.001
HDC in newly diagnosed multimetastatic EW No randomised trial Retro and prospectives studies Historical comparisons Two very different populations of newly diagnosed metastatic EW EW with lung metastasis only EW with metastasis other than lung only EW93/97 97 patients (1991 1999) GASPAR et al. JCO 2015
EE99-R3: multimetastatic EW TTT VIDE x6 loc 1999-2005 Med FUP 3.8 years Large prospective European non randomised trial 281 patients Med Age 15.3y Limb PT 31% ITV>200ml 65% VAIx1 R3 Bu/Mel 60% did recevied CHD - 16 PD before CHD - 24%? Status before HDC OS 34% EFS 27% Median survival time 19.2 months Ladenstein, JCO 2010
EE99-R3: multimetastatic EW CR Age HR Score Age - 14 ans - > 14 ans 1 1.7 0 1 Volume tumoral initial -<200ml - 200ml 1 1.8 0 1.5 BM VTI Métastases osseuses -0-1 -2-5 ->5 1 1.6 2.0 2.0 0 1 1.5 1.5 Métastases MO -non -oui 1 1.6 0 1 Méta pulmonaires -non -oui 1 1.5 0 1 Not really used Ladenstein, JCO 2010
Multimetastatic EW EE99-R3 VIDE x6 C H I R VAIx1 Bu/Mel Experience Monocentrique Gustave Roussy VIDE x6 C H I R Thio HD Bu/Mel 3y-EF 11% 3y-OS 22% N=18 patients 2002-2009 To improve the CR rate before HDC Loschi, BMT 2015
Multimetastatic EW To improuve induction CT PR 15 SD 2 PD 2 ISG up-front window melphalan N=19 patients 2001-2004 Patients <40 years All Met 2y-OS 21% Cisplatinum (Luksch PBC 2017) N=8 Luksch, ECJ 2007 n=102 n=97 n=79 n=57 /65 with Lung Mets Luksch, Ann Oncol 2007 15 Gy 12 Gy <14y ISG/SSG IV N=102 patients 1999-2008 Patients <40 years All Met 5y-EFS 44% 5y-OS 52% To improuve lung mets control
Multimetastatic EW To improuve MRD control by maintenance treatment Oral metronomic cyclophosphamide Celocoxib Vinblastine PI: Valérie Laurence, France ONOING
Multimetastatic EW Ewing 2008 A HDC randomised trial in multimetastatic EW There are no data to support equivalent efficacy with treosulfan, which, although closely related to busulfan, is less radiosensitizing. PI: Utah Dirksen, Germany ONOING
High dose chemotherapy in Ewing sarcoma a very long story starting in the 80ies HDC in recurrent EW (?) HDC in newly diagnosed multimetastatic EW (?) HCD in newly diagnosed lung metastatic EW HDC in newly diagnosed localised high-risk EW up to now
HDC in newly diagnosed multimetastatic EW No randomised trial Retro and prospectives studies Historical comparisons Two very different popuations of metastatic EW at diagnosis EW with lung metastasis only EW with metastasis other than lung only EW93/97 97 patients (1991 1999) GASPAR et al. JCO 2015
EE99-R2pulm : EW lung metastasis Historical comparison: Bu/Mel vs CT+ total lung irradiation (TLI) EW93/97 1991-1997 WITH CHD Paulussen, JCO 1998 CESS81, CESS86, EICESS92 1981-1997 WithOUT CHD RT bipulm 15-18Gy n=75; 5y-EFS 36% No RT pulm Oberlin, JCO 2006 Paulussen, JCO 1998 Rational for the EE99- R2pulm randomised trial VIDE x6 Loc TTT VAIx1 R2pulm Bu/Mel VAIx7 + TLI
EURO-E.W.I.N.G 99 stratification All newly diagnosed Ewing Sarcoma up to age 50 years Surgery after VIDE Histological response Localised disease Other local treatment Initial tumour volume Initial surgery Pre-op RT Exclusive RT Metastatic disease <10% >10% <200ml >200ml Standard risk Localised High risk Pulmonary metastases Other metastases R1 R2Loc R2Pulm R3 Le Deley et al, JCO 2014 Whelan et al. ASCO 2016 Dirksen et al. ASCO2016 Ladenstein et al, JCO 2010 JCO 2018
2000-2015 Med FUP 7,8 ans Randomisation rate 55% 132 assigned to VAI & WLI rando 131 eligible for R2pulm trial 1 not eligible for R2pulm trial 120 started assigned intervention 2 received BuMel 6 early stop of Tx due to progression 4 no information EE99-R2pulm : EW lung metastasis 3327 patients assessed for eligibility 592 pulmonary met. patients 480 pts with documented eligibility criteria 265 pts included in the R2pulm trial from 144 centres, 14 countries - One pulmonary/pleural nodule of > 1 cm - or more than one nodule of > 0.5 cm - A solitary nodule of 0.5- <1 cm or multiple nodules of 0.3-0.5 cm was questionable evidence of metastatic disease, pathologic confirmation was recommended. 133 assigned to BuMel rando 130 eligible for R2pulm trial 3 not eligible for R2pulm trial 100 received assigned intervention 30 did not receive BuMel HD 1 received another HD 2 received BuMel + WLI 2735 pts other than pulmonary met. disease 112 pmets pts did not meet eligibility criteria 215 pts not included 128 because of refusal 87 for miscellaneous reasons 132 in the intention-to-treat analysis 133 in the intention-to-treat analysis Dirksen, ASCO 2016
EE99-R2pulm : EW lung metastasis Hypothesis: detection of a 15%-EFS improvement at 3 years in Bu/mel arm (EFS 55% vs. 40%, HR=0.65), 2-sided alpha=0.05; power=80% Sample size calculation: 188 events, 326 patients No advantage of Bu/Mel No survival benefit ITT analysis BuMel, 3-y EFS= 55% VAI+TLI, 3-y EFS=51% HR = 0.82 (95%CI, 0.58 1.15) p= 0.24 BuMel, 3-y OS= 68% VAI+TLI, 3-y OS=68% HR = 0.96 (95%CI, 0.65 1.40) p= 0.82 Stable results in per-protocol analysis Dirsksen, ASCO 2016
EE99-R2pulm : EW lung metastasis Cumulative incidence of secondary metastase (competing risk approach) No major heterogeneity across subgroups Dirsksen, ASCO 2016
EE99-R2pulm : EW lung metastasis Late effect analysis not done Dirsksen, ASCO 2016
High dose chemotherapy in Ewing sarcoma a very long story starting in the 80ies HDC in recurrent EW (?) HDC in newly diagnosed multimetastatic EW (?) HCD in newly diagnosed lung metastatic EW: no BU/Mel advantage HDC in newly diagnosed localised high-risk EW up to now
HDC in newly diagnosed localised high-risk EW Société Française des Cancers de l Enfant; 1993 to 1999; prospective study 37 34 of 48 (PHR) HDC added to CyDoxo is feasable and show historical improve EFS compared to EW88 without HDC Homogenous induction Chemotherapy And HDC regien Gaspar et al. GASPAR et al. JCO 2015
HDC in newly diagnosed localised high-risk EW CT S CT +/-RT CT S CHD +/-RT EW88 EW93 Oberlin, BJC 2001 Gaspar, EJC 2012 Residual tumour cells 5% Initial tumoral volume 200ml Residual tumour cells 30% Initial tumoral volume 200ml Rational for the randomised EE99-R2loc trial VIDE x6 TTT loc VAIx1 R2loc VAIx7 Bu/Mel
EURO-E.W.I.N.G 99 stratification Histological response is the main prognostic factor in patients with localised disease undergoing surgery after induction chemotherapy Disease-free survival Joint SFOP-GPOH study Le Deley et al, SIOP 2001
EURO-E.W.I.N.G 99 stratification All newly diagnosed Ewing Sarcoma up to age 50 years Surgery after VIDE Histological response Localised disease Other local treatment Initial tumour volume Initial surgery Pre-op RT Exclusive RT Metastatic disease <10% >10% <200ml >200ml Standard risk Localised High risk Pulmonary metastases Other metastases R1 R2Loc R2Pulm R3 Le Deley et al, JCO 2014 Whelan et al. ASCO 2016 Dirksen et al. ASCO2016 Ladenstein et al, JCO 2010 JCO sept 2018
EE99 and Ewing2008 R2loc trial 5% February 2000 and December 2015 Recruitment was stopped before reaching this target because of low accrual. 40% Whelan, JCO 2018
EE99 and Ewing2008 R2loc trial median age was 17.1 years (range, 11 months to 44.7 years). Whelan, JCO 2018
EE99 and Ewing2008 R2loc trial Hypothesis: detection of a 15%-EFS improvement at 3 years in Bu/mel arm (3-y EFS 70% vs. 55%, HR=0.60), 2-sided alpha=0.05; power=80% The initial target sample size was 328 patients (124 events) Advantage of Bu/Mel 69.0% (95% CI, 60.2-76.6%) 60.7% (95% CI, 51.1-69.6%) 56.7% (95% CI, 47.6-65.4%) 47.1% (95% CI, 37.7-56.8%). Stable results in per-protocol analysis EFS HR, 0.64 (95% CI, 0.43 to 0.95; P =.026) Whelan, JCO 2018
EE99 and Ewing2008 R2loc trial Benefit due to the prevetion of the metastasis Cumulative incidence of metastases (competing risk approach) Translates into better OS 78.0% (95% CI, 69.6-84.5%) 64.5% (95% CI, 54.4-73.5%) VAI Bu/Mel HR = 0.59 (95%CI, 0.38-0.92) p= 0.02 OS 72.2% (95% CI, 63.3-79.6%) 55.6% (95% CI, 45.8-65.1%) HR, 0.63 (95% CI, 0.41 to 0.95; P =.028) Whelan, JCO 2018
EE99 and Ewing2008 R2loc trial Patients with an intermediate poor response may benefit more than those with a very poor response (10% to 29% v 30% viable cells; interaction test, P =.06), as well as younger patients ( 25 v >25 years of age; P =.12). Whelan, JCO 2018
EE99 and Ewing2008 R2loc trial Acute toxicity one course of BU/Mel vs 7 cours of VAI The effect of BuMel on the risk of severe acute toxicity did not differ between patients older than 25 years and younger patients Radiosensitizeing effect of Busulfan when primary tumour itrrdiation involved - Large digestive tract - Spinal cord Whelan, JCO 2018
Euro-EWING 2012 Random1: quelle backbone de CT? VIDE vs VDC-IE Random2: renforcement du TE? +/- acide zoledronique PI: Bernadette Brenan, UK
High dose chemotherapy in Ewing sarcoma a very long story starting in the 80ies HDC in recurrent EW (?) HDC in newly diagnosed multimetastatic EW (?) HCD in newly diagnosed lung metastatic EW: no BU/Mel advantage HDC in newly diagnosed localised high-risk EW: BU/Mel advantage up to now
HDC in Ewing sarcoma In newly diagnosed high-risk localised EW FIRST Proof concept of HDC efficacy in a randomised trial HDC does prevent metastasis and increase survival In newly diagnosed lung metastatic EW : HDC no better than conventional CT + TLI In newly diagnosed multimetastatic and reccurent EW : no clear proof of concept, only historical data
Thanks to all te actors of the Ewing community in Europe and across the world
COG studies : EW loc, VDC-IE INT-0154 N=478 patients, 1995-1998 Randomisation rate? AEWS0031 N=568 patients, 2001-2005 Randomisation rate? Standard Compressed Granowetter, JCO 2009 Wormer, JCO 2012
AEWS0031 : EW loc, VDC-IE Compressed > standard mean hospital days per cycle identical in both arms (around 5 days) 5y-EFS 73% vs 65% (P=0.048) HR 0.74 (95% CI, 0.54 to 0.99) 5y-OS 83% vs 77% (P=0.056) HR 0.69 (95% CI, 0.47 to 1.0) No prospective evaluation of the hisological response = no direct possible comparison to the EE99 results Wormer, JCO 2012
HDC in newly diagnosed multimetastatic EW INT-0091 N=60 patients 1988-1994 Bone EW only; All mets Standard VDC-IE Week 13 Bi-Pulm RT 15 Gy If lung metastasis AEWS02P1 N=35 patients 2004-2008 Patients <50 years BM/bone Met VAC VDC VAC IE VDC IE VAC HD IE VDC VAC HD D1C-D21C14 Vinblastine 1 mg/m2/dose IV push 3x/week Celecoxib 250 mg/m2/bid 1y-OS 35% (19 51%) Lung toxicities grade>2 7/21 pts irradiated (2 died) 3y-EFS 28% Without CHD