EWING 2008 Clinical trial for the treatment of Localized and Disseminated Ewing sarcoma

All patient receive induction chemotherapy- six cycles of VIDE (Jurgens, 2006). Disease assessment will be performed prior to treatment and after the 2nd (latest 3rd) and 5th (latest 6th) cycle of VIDE chemotherapy.The decision regarding local therapy must be made following the fifth cycle of of induction treatment, with preference for surgical intervention with or without additional radiotherapy.Depending on the presentation at the time of diagnosis and on the histological response to induction chemotherapy, patients will be stratified into to the following risk groups: Standard Risk R1: (1) Patients with localised disease and good histological response at surgery after induction chemotherapy and (2) Patients with initial surgery or in whom surgery was not feasible and who have small tumours < 200 mL at diagnosis. High Risk localised disease R2loc*: (1) Patients with localised disease and poor histological response at surgery after induction chemotherapy and (2) Patients with initial surgery or in whom surgery was not feasible and who have large tumours > 200 mL at diagnosis.High Risk primary lung metastases R2pulm*: Patients with a Ewing sarcoma metastatic to the lungs and/or pleura, but not to any other sites, at the time of diagnosis. Very High Risk R3: Patients with metastatic disease not confined to the lungs and/or pleura, i.e. patients with bone metastases, bone marrow metastases or other metastases (e.g. lymph nodes, liver, CNS, etc) with and without additional pulmonary metastases at the time of diagnosis. Good responders (R1) will receive an additional eight cycles of chemotherapy VAC (Female) or VAI (Male). They will be randomised to receive add-on treatment with zoledronic acid, or no add-on treatment. High Risk R2 *Poor responders (R2) with localised disease (R2loc) and primary pulmonary metastases (R2pulm) will continue to be randomised as in EURO-E.W.I.N.G. 99 to receive either eight cycles of VAI chemotherapy or high dose treatment with busulfan-melphalan. Very High Risk (R3) patients receive six cycles of VIDE induction chemotherapy and are then randomised to either continue with eight cycles of VAC chemotherapy or high dose treosulfan-melphalan (TreoMel) chemotherapy followed by autologous stem cell reinfusion, followed thereafter by eight cycles of VAC chemotherapy. ##Treosulfan IV 12 g/m^2/dose IV infusion, d-5 to d-3. ##Melphalan IV 140 mg/m^2 IV infusion,. ## Busulfan IV, day -6 to d -3 adults: 0.8 mg/kg body weight (BW) children and adolescents: <9 kg= 1mg/kg BW 9 - <16 kg= 1.2 mg/kg BW 16 - 23 kg= 1.1 mg/kg BW >23 - 34 kg= 0.95 mg/kg BW >34 kg = 0.8 mg/kg BW ##Stem cell re-infusion (min. 3 x 106/kg CD 34+) ##Zoledronic acid IV at 28 day intervals beginning with cycle 6 of VAC/VAI consolidation chemotherapy for a total period of 9 months. Pts < 18 years will receive 0.05 mg/kg BW by IV infusion 30 min-1 h. Pts >= 18 years will receive a bodyweight-dependent dose: Patients >40kg receive 4 mg by IV infusion 30 min-1h Patients 20-40 kg receive 2 mg by IV infusion 30 min-1h **Basic plan of zoledronic acid** Cycles should be given at 28-D intervals for a maximum of 9 cycles beginning with cycle 6 of VAC/VAI consolidation chemotherapy (cycle 12 from start of chemotherapy). Paralell to cycles, the medication may be given at 21-d intervals. Following completion of consolidation chemotherapy, the interval must be extended to the 28-d schedule. D 1 Zoledronic acid, hydration 250 mL/m2 Ds 2-6 Oral calcium , paracetamol in case of flu-like symptoms D 7 and Prior to next cycle Controls according to institutional guidelines ***Basic plan of TreoMel** Ds -5 to -3 Treosulfan, Hydration D -2 Melphalan, Hydration D -1 Hydration D 0 Stem cell reinfusion, Hydration D +5 until recovery Hydration Recommended: G-CSF 5 microg/kg/d d5 to approx. d13 or PEG-G-CSF according to manufacturer’s guidance. Regular controls according to institutional guidelines All blood products must be irradiated and leukocyte-depleted. ***VIDE** VINCRISTINE 1.5 mg/m2/d d1 (1.5 mg/m2/cycle) (max. single dose: 2 mg) (i.v. push) IFOSFAMIDE 3.0 g/m2/d d1, d2, d3 (9 g/m2/cycle) plus MESNA* (i.v. infusion, 1-3 h) DOXORUBICIN 20 mg/m2/d d1, d2, d3 (60 mg/m2/cycle) (i.v. infusion, 4 h) ETOPOSIDE 150 mg/m2/d d1, d2, d3 (450 mg/m2/cycle) (i.v. infusion, 1 h) G-CSF 5 microg/kg/d d5 to approx. d13 *Recommended Mesna dosage: 1.0 g/m2/d d1 (i.v. push 1 h prior to ifosfamide) 3.0 g/m2/d d1, d2, d3 (i.v. infusion, e.g. 24 h) Cycles of VIDE should be given at 21-d intervals or on haematological recovery to WBC >= 2.0*109/L with absolute neutrophil count (ANC) >= 1.0*109/L; platelets >= 80*109/L. ##Basic plan of VIDE cycles ## D 1 Vincristine, Ifosfamide, Doxorubicin, Etoposide, Mesna bolus, Mesna, Hydration D 2 Ifosfamide, Doxorubicin, Etoposide, Mesna, Hydration D 3 Ifosfamide, Doxorubicin, Etoposide, Mesna, Hydration D 4 Hydration D 5 G-CSF until leukocyte recovery Ds 5 – 19 Regular follow-up visits as needed. FBC controls according to institutional guidelines. Ds 20-22 PRIOR TO NEXT CYCLE Controls according to institutional guidelines including FBC, urea & electrolytes, calcium, magnesium, phosphate, bicarbonate, alkaline phosphatase, bilirubin, liver enzymes GFR (calculated creatinine clearance (Ccrea) or isotopic) Fractional phosphate reabsorption (Tp/Ccrea) = Renal tubular threshold for phosphate (Tmp/GFR). Cardiac monitoring ***VAI** VINCRISTINE IV, 1.5 mg/m2/d d1 (1.5 mg/m2/cycle) (max. single dose: 2 mg) ACTINOMYCIN IV, D 0.75 mg/m2/d d1, d2 (1.5 mg/m2/cycle) (max. single dose per d: 1.5 mg) IFOSFAMIDE IV, 3.0 g/m2/d d1, d2 (6 g/m2/cycle) plus MESNA* G-CSF 5microg/kg/d in case of poor haematological recovery *Recommended Mesna dosage IV, 1.0 g/m2/d d1 (i.v. push 1 h prior to ifosfamide) IV, 3.0 g/m2/d d1, d2 Cycles of VAI should be given at 21-d intervals or on haematological recovery to WBC >= 2.0*109/L with absolute neutrophil count (ANC) >= 1.0*109/L; platelets >= 80*109/L. ## Basic plan of VAI## D 1 Vincristine, Actinomycin D, Ifosfamide, Mesna bolus, Mesna, Hydration D 2 Actinomycin D, Ifosfamide, Mesna, Hydration D 3 Hydration Ds 4-9 Controls as needed according to institutional guidelines D 5 G-CSF 5microg/kg/d in patients with history of poor haematological recovery Ds 10-19 Regular check-up visits, FBC controls according to institutional guidelines Ds 20-22 PRIOR TO NEXT CYCLE Controls according to institutional guidelines including - FBC - Urea & electrolytes, calcium, magnesium, phosphate, bicarbonate, alkaline phosphatase, bilirubin, liver enzymes - GFR (calculated creatinine clearance (Ccrea) or isotopic) - Fractional phosphate reabsorption (Tp/Ccrea) = Renal tubular threshold for phosphate (Tmp/GFR). ***VAC** VINCRISTINE IV, 1.5 mg/m2/d d1 (1.5mg/m2/cycle) (max. single dose: 2 mg) ACTINOMYCIN D IV, 0.75 mg/m2/d d1, d2 (1.5mg/m2/cycle) (max. single dose/d: 1.5 mg) CYCLOPHOSPHAMIDE IV, 1500mg/m2/d d1 (1500 mg/m2/cycle) plus MESNA* *Recommended Mesna dosage 500 mg/m2/d d1 (i.v. push 1 h prior to cyclophosphamide) 1500 mg/m2/d d1 (i.v. infusion, e.g. 24 h) Cycles of VAC should be given at 21-d intervals or on haematological recovery to WBC => 2.0*109/L with absolute neutrophil count (ANC) => 1.0*109/L; platelets => 80*109/L. ##Basic plan of VAC## D 1 Vincristine, Actinomycin D, Cyclophosphamide, Mesna bolus, Mesna, Hydration D 2 Actinomycin D D 3-9 Controls as needed according to institutional guidelines D 5 G-CSF 5microg/kg/d in patients with history of poor haematological recovery Ds 10-19 FBC controls according to institutional guidelines. Busulfan–Melphalan Patients randomised* to BuMel receive busulfan-melphalan consolidation as cycle 8. As only the IV formulation of busulfan (Busilvex TM) has obtained approval for use in high-dose treatment regimens it is recommended for use within this trial. * R2 accrual discontinued on December 1st 2015 Bu (Busulfan) Adults: 0.8 mg/kg Children and adolescents: <9 kg = 1 mg/kg 9-<16 kg = 1.2 mg/kg 16-23 kg = 1.1 mg/kg >23-34 kg= 0.95 mg/kg >34 kg = 0.8 mg/kg Melphalan (Mel) 140 mg/m² Basic plan of BuMel Day -7 Clonazepam, Hydration Day -6 to -3 Clonazepam, Busulfan, Hydration Day -2 Clonazepam, Melphalan, Hydration Day -1 Clonazepam, Hydration Day 0 Stem cell reinfusion, Hydration Day +5 until recovery Hydration Recommended: G-CSF 5 microg/kg/d d5 to approx. d13 or PEG-G-CSF according to manufacturer’s guidance.