AEWS0331: European Ewing Tumor Working Initiative of National Groups Ewing Tumour Studies 1999 (EURO-E.W.I.N.G.99)
There are several pathways for treatment in this study. All patients will start therapy with four courses of chemotherapy with VIDE (Vincristine, Ifosfamide, Dactinomycin, and Etoposide). After courses 3 and/or 4, a stem cell collection will be done. The patient[Right Quote]s stem cells will be collected using a procedure called apheresis. Stem cells can often be collected through the patient[Right Quote]s central line. If this is not possible, a catheter will be placed into another large vein in the patient[Right Quote]s chest or groin. During apheresis, one side of the catheter will collect circulating blood into a machine that filters out the stem cells. The filtered blood will be returned to the patient[Right Quote]s body through the other side of the catheter. Each apheresis procedure takes about 4 to 6 hours. The procedure may need to be done several times to collect enough stem cells for the transplant. Patients will then have two more courses of therapy with VIDE. If patient receives the high-dose treatment, the stored stem cells will be returned (infused) into their body through a catheter, like a transfusion, after the high-dose chemotherapy is completed.
Some patients may have surgery for local tumor control after the six courses of VIDE. The decision to have surgery will be made by the doctors at the local hospital where the treatment is being given.
In the special case of patients with tumor in the center of their body and who need early radiation therapy (this will be determined by the treating doctors after four courses of VIDE) patients will receive the fifth and sixth course of VIDE and then will receive radiation therapy, and perhaps, surgery. Then they will receive 7 courses of therapy with VAI (Vincristine, Adriamycin, and Ifosfamide) and whole lung radiation therapy. This is considered standard therapy.
Patients who do not need early radiation therapy after six course of VIDE will continue with one course of therapy with VAI (Vincristine, Adriamycin, and Ifosfamide). Then patients will be randomized to receive either seven more courses of VAI and whole lung radiation therapy (standard treatment) or Busulfan-Melphalan, stem cell transplant, and possibly whole lung radiation therapy (experimental treatment).
With Amendment #4, AEWS0331 was amended to revise the goal to perform a separate R2pulm analysis rather than the initially planned pooled analysis of R2loc and R2pulm. An analysis of EURO-E.W.I.N.G. 99 accrual in 2002 demonstrated lower than anticipated accrual to the R2 randomization because of the higher than predicted rate of good responding patients with localized tumors (i.e. only 50% of the anticipated number of R2loc eligible patients have been observed in the first 2 years of the study). Since EUROE.
W.I.N.G. 99 was initially designed to combine both localized tumors with poor response to Induction therapy (R2loc) with isolated pulmonary metastatic patients (R2pulm), the ability to answer the R2 randomized question was in jeopardy. To improve accrual to the R2 randomization, COG agreed to participate in EURO-E.W.I.N.G. 99, opening the study to COG institutions in July 2003. With the addition of COG R2pulm patients, a separate analysis of R2loc and R2pulm patients became feasible. In June 2007, the EURO-E.W.I.N.G. 99 study committee and its Data Safety and Monitoring Committee agreed to
perform separate analyses of R2loc and R2pulm. This is supported with documentation from the EuroEWING99 coordinating center and from the study[Right Quote]s Data Safety and Monitoring Committee.
Additionally, the radiation therapy guidelines have been extensively revised to reflect current radiation therapy standards to explicitly permit IMRT.
Treatment must begin within 30 days of definitive diagnostic biopsy. Diagnostic studies excluding metastatic disease outside of the lungs must be completed at most 2 weeks prior to the initiation of therapy. Baseline physiologic tests (biochemistry, echocardiogram, etc.) must be completed at most 10 days prior to the initiation of therapy. Patients must be less than 50 years old at time of study enrollment. For patients < 3 years of age call the COG Study Chair; infants and small children are eligible for this study, however, the treating physicians and family must be prepared to deliver adequate local control as required in this study. This will often involve surgery or radiation therapy resulting in disability or disfigurement. If there is doubt about whether adequate primary tumor treatment can be delivered without unacceptable morbidity, do not enter the patient on study. Patients with isolated pulmonary or pleural metastases at the initial diagnosis of Ewing sarcoma. As a rule, one pulmonary/pleural nodule of > 1 cm, or more than one nodule of > 0.5 cm are considered evidence of pulmonary/pleural metastases, as long as there is no other clear medical explanation for these lesions. In case of doubt, biopsies should be considered. Solitary nodules of 0.5 x 1.0 cm or multiple nodules of 0.3 x0.5 cm are questionable evidence of metastatic disease, and biopsy proof is recommended. One solitary nodule of < 0.5 cm or several nodules of < 0.3 cm are not regarded as clear evidence of lung disease. In such cases, individual decisions regarding biopsy have to be considered. Pleural effusions in patients with chest wall tumors are not regarded as proof for lung/pleural metastases, but are considered to represent loco-regional disease. The site(s), size, and number of involved sites should be documented. The use of a venous access device is strongly suggested. No previous chemotherapy. Adequate renal function defined as: Radioisotope GFR = 60ml/min/1.73m([SQUARED] OR confirmation of normal renal function for age by institutional preferred method; Adequate cardiac function defined as: Shortening fraction of = 29% by echocardiogram, or Ejection fraction of = 40% by radionuclide angiogram. Spanish speaking subjects will be eligible to participate in this study.