EWING 2008

EWING 2008 is a joint protocol of European and North American Ewing sarcoma
study groups. The protocol is aimed at optimising treatment and treatment
results of patients with Ewing sarcomas.The EWING 2008 protocol is open to all
patients diagnosed with Ewing sarcomas, localised or metastatic, who are
considered eligible for neoadjuvant chemotherapy. All patients registered will
receive induction chemotherapy consisting of six cycles of vincristine,
ifosfamide, doxorubicin and etoposide (VIDE). The decision regarding local
therapy must be made following the fifth cycle of induction treatment, with a
preference for surgical intervention with or without additional radiotherapy.
Preoperative radiotherapy may be considered to improve the operability of
otherwise inoperable lesions. In patients with localised disease or with
pulmonary metastases, local treatment should be performed following the 6th
cycle of VIDE chemotherapy, and should be a complete tumour resection, whenever
feasible. Post-operative radiotherapy is determined by the completeness of
surgery and the histological response to chemotherapy.

Standard Risk R1
Good responders (R1) (< 10% viable tumour cells) with localised disease are
allocated to the standard risk arm and will receive a further eight cycles of
chemotherapy composed of vincristine, actinomycin D, and cyclophosphamide (VAC)
(females) or ifosfamide instead of cyclophosphamide (VAI) (males). They will
be randomised to receive add-on treatment with either fenretinide, zoledronic
acid, fenretinide plus zoledronic acid, or no add-on treatment. The fenritinide
arm is still closed since the drug is not available and the formulation is
still unknown. Therefore an amendment for this part of the study will be
handed in later.

High Risk R2 (closed per december 2015)
Poor responders (R2) with localised disease 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 busulfanmelphalan (R2loc). Patients with primary
pulmonary metastases are also allocated to 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 (R2pulm).

Very High Risk R3
Patients with disseminated disease, i.e. dissemination to bone and/or other
sites and possibly additional pulmonary dissemination (R3), receive six cycles
of VIDE induction chemotherapy. Patients are then randomised to either continue
with eight cycles of vincristine, actinomycin D and cyclophosphamide (VAC)
chemotherapy or high dose treosulfan-melphalan (TreoMel)chemotherapy followed
by autologous stem cell reinfusion followed thereafter by eight cycles of VAC
chemotherapy. Local therapy in R3 patients is following VIDE induction,
whenever feasible prior to high dose therapy (HDT). When long periods of
immobilisation following surgery are anticipated, e.g pelvic reconstruction,
surgery following HDT may be advisable. Depending on clinical response to
induction chemotherapy radiotherapy prior to HDT and surgery may be an
option to be considered in such patients. Any delay between VIDE and HDT for
reasons of e.g. local treatment must be bridged with VAC cycles. The total
number of VAC cycles is not to exceed eight cycles.

Add-on study:
Pharmacogenetics
Genetic polymorfisms of metabolic enzymes active in cytostatic drugs are
related in part with outcome of anti-tumour treatment. This study aims to
correlate such data for Ewing tumours. On the long run this study might enable
taylored therapy for Ewing tumour patient increasing efficacy and reducing
toxicity.

Amendment:

Randomisations are halted.. Studie is only a registry of patients receiving
conventional therapy

Primary objectives:
Standard Risk R1: in a randomised trial, to examine whether add-on treatment
with fenretinide or zoledronic acid, or zoledronic acid plus fenretinide in
addition to induction and maintenance chemotherapy improves event-free survival
in patients with localised Ewing sarcoma and good histological response or with
initial tumour volume <200ml compared to no add on treatment. The fernretinide
part of this study will be submitted for assessment at a later stage.
High Risk R2: in a randomised trial, to examine whether high dose chemotherapy
using busulfan-melphalan with autologous stem cell reinfusion, compared with
standard chemotherapy, improves event-free survival in patients with localised
Ewing sarcoma and unfavourable histological response or tumour volume>200ml
(R2loc). In patients with pulmonary metastases high dose busulfan-melphalan
chemotherapy with autologous stem cell reinfusion is randomised versus standard
chemotherapy plus whole lung irradiation (R2pulm).
Very High Risk R3: in a randomised trial, to examine whether the addition of
high dose chemotherapy using treosulfanmelphalan followed by autologous stem
cell reinfusion to eight cycles of standard adjuvant chemotherapy, compared to
eight cycles of standard adjuvant hemotherapy alone, improves eventfree
survival in patients with primary disseminated disease.
Secondary objectives:
Overall survival
R1: To investigate whether add-on fenretinide, zoledronic acid or zoledronic
acid plus fenretinide improves overall survival compared to no add on treatment.
R2: To investigate whether high dose chemotherapy with busulfan-melphalan
improves overall survival.

Toxicity /Safety: To evaluate short term toxicity and long term toxicity in all
risk groups.

Add-on study:
Pharmacogenetics
This study aims to correlate pharmaocogenetic data for Ewing tumours. On the
long run this study might enable taylored therapy for Ewing tumour patient
increasing efficacy and reducing toxicity.

Amendment:

Randomisations are halted.. Studie is only a registry of patients receiving
conventional therapy

Registration: * 45 days after diagnostic biopsy.

Reference pathology: * 60 days after diagnostic biopsy.

Radiol. response evaluation: After VIDE 2 (earliest) or 3 (latest), After VIDE
5 (earliest) or 6 (latest), Prior to high dose chemotherapy, Prior to add-on in
R1, i.e. after cycle 11 of chemotherapy, e.g. 6 VIDE + 5 VAI/VAC.
Stem cell harvest: After 3-4 cycles of VIDE.

Surgery for primary tumour: After 6 cycles of VIDE, In R3 patients prior to or
after HDT.

Randomisation:
R1 and R2: After 6 cycles of VIDE when histology is available.
R1 and R2: Latest after 6 cycles of VIDE when surgery is not indicated.
R3: Latest after 6 cycles of VIDE.

Surgery for metastases: After 2 cycles of consolidation treatment or after high
dose treatment.

Definitive radiotherapy: After 6 cycles of VIDE parallel to consolidation
chemotherapy, In R3 patients prior to or after HDT.
Pre-operative radiotherapy:
Prior to surgery. Post-operative radiotherapy: Concurrently with consolidation
chemotherapy. In patients receiving HDT, 8-10 weeks after HDT.

Quality of Life assessment: After VIDE 1 (earliest) or 2(latest), After VIDE 6
(prior to local treatment), After completion of protocol treatment, After 2
years follow-up.

Add on study:
Pharmacogenetic study;
On 10 ml periferal blood SNP analysisi will be done and will be correlated with
response and outcoma data.

Immunological study:
NK- and T-cells will be generated on 2 occasions (prior to start of
chemotherapy and after finishing treatment). Activity against Ewing cells, will
be studied using Ewing cells obtained at the diagnostic biopsy done to confirm
the diagnosis of Ewing tumors.

Amendment:

Randomisations are halted.. Studie is only a registry of patients receiving
conventional therapy

R1 patients.
Standard chemotherapy will be given. After local therapy 10 infusion with
zoledronic acid will be given.

R2 patients:
The standard seven courses of consolidation therapy are exchanged with high
dose chemotherapy and autologous stemcell rescue.

R3 patients
Additional high dose chemotherapy with autologous stem cell rescue.

Add-on study:
no interventions

Patients will be treated according to normal standard currently used in Ewing
sarcoma. In respect to this study the following changes should be mentioned

R1 patients.
Standard chemotherapy will be given. After local therapy 10 infusion with
zoledronic acid will be given at standard moments of check-up at the physicians
office / hospital. In total this will be add a 5 to 10 hours to the total
standard treatment. The medication will be given over an already existing
permanent intravenous device, so pain and discomfort will be minimal. Side
effects will be low frequent and will be monitored. Benefit can be improvement
of survival.
R2 patients: (closed per December 2015)
The standard seven courses of consolidation therapy are exchanged with high
dose chemotherapy and autologous stemcell rescue. Total hospitalization in
respect to numbers of days of admission will be equal. The side effects of the
high dose therapy can be more prononced, however, this can outweigh the side
effects during the prolonged period of the seven intensive chemotherapy
courses that would have been administered. Benefit can be an improved survival.
R3 patients
Additional high dose chemotherapy with autologous stem cell rescue. Risks are
related to the well known side effects of intensive chemotherapy. Benefit can
be an improved survival in these patients with otherwise a very poor outcome.

Add-on
Pharmacogenetic study:
10 ml blood sampling at the moment of regular blood sampling

Amendment:

Randomisations are halted.. Studie is only a registry of patients receiving
conventional therapy