Trial Information

EUROPEAN INTERGROUP COOPERATIVE EWING'S SARCOMA STUDY [EICESS 92]

OBJECTIVES: I. Determine whether morbidity can be reduced while preserving survival by
substituting cyclophosphamide for ifosfamide in adjuvant combination chemotherapy in
standard-risk patients with Ewing's sarcoma or peripheral neuroectodermal tumor (PNET). II.
Determine whether survival is improved without unacceptable toxicity for high-risk patients
with Ewing's sarcoma or PNET by the addition of etoposide to the VAIA regimen
(vincristine/doxorubicin/ifosfamide/dactinomycin). III. Evaluate the impact of surgery and
conventional vs. hyperfractionated radiotherapy (definitive and adjuvant) on local control,
overall survival, and morbidity in these patients. IV. Relate treatment outcome with patient
characteristics, histologic subtype at diagnosis, and histologic response to neoadjuvant
treatment. V. Evaluate prospectively ifosfamide-induced nephrotoxicity and
doxorubicin-induced cardiotoxicity.

OUTLINE: Randomized study. Patients are initially stratified as STANDARD RISK (tumor volume
at diagnosis < 100 ml) and HIGH RISK (tumor volume at diagnosis at least 100 ml or, if < 100
ml, metastasis present). All patients receive 14 courses of chemotherapy, administered q 3
weeks throughout protocol treatment. Standard-risk patients receive 4 courses of NEOADJUVANT
CHEMOTHERAPY on Regimen A, while high-risk patients are randomized on Arms I and II for 4
courses of neoadjuvant chemotherapy. LOCAL THERAPY is usually initiated on week 12, after 4
courses of neoadjuvant chemotherapy, and consists of either total removal of the
tumor-bearing compartment, intracompartmental surgery (with or without adjuvant
radiotherapy), or definitive radiotherapy alone; the choice is dictated by the site, tumor
size, and patient age, among other variables. Postoperatively, all patients receive 10
courses of ADJUVANT CHEMOTHERAPY (plus adjuvant radiotherapy when given); standard-risk
patients are randomized on Arms III and IV, while high-risk patients receive the same
regimen to which they were assigned at initial randomization. When given, adjuvant
radiotherapy begins on week 19 and is administered concurrently with chemotherapy. As a
variant of this general plan, patients with < 50% regression of the soft tissue component of
their tumors at restaging after 2 courses of neoadjuvant chemotherapy (slow response) may
receive preoperative irradiation, beginning on week 7, concomitantly with the third and
fourth courses of chemotherapy. The following acronyms are used: CTX Cyclophosphamide,
NSC-26271 DACT Dactinomycin, NSC-3053 DOX Doxorubicin, NSC-123127 IFF Ifosfamide, NSC-109724
Mesna Mercaptoethane sulfonate, NSC-113891 VCR Vincristine, NSC-67574 VP-16 Etoposide,
NSC-141540 NEOADJUVANT CHEMOTHERAPY. Regimen A (Standard risk): Alternating 3-Drug
Combination Chemotherapy Regimens. VAIA: VCR/DOX/IFF alternating with VCR/DACT/IFF. Arm I
(High risk): Alternating 3-Drug Combination Chemotherapy Regimens. VAIA: VCR/DOX/IFF
alternating with VCR/DACT/IFF. Arm II (High-risk): Alternating 4-Drug Combination
Chemotherapy Regimens. EVAIA: VP-16/VCR/DOX/IFF alternating with VP-16/VCR/DACT/IFF. LOCAL
THERAPY. Surgery: Resection of entire tumor-bearing compartment, including bone and soft
tissue, when possible, is the treatment of choice. The range of possible surgical procedures
includes: radical resection (e.g., amputation), wide resection (en bloc removal of the
entire tumor-bearing compartment), marginal surgery (en bloc removal, but resection line
runs through pseudocapsule and microscopic residual disease is likely), intralesional
resection (tumor incised with contamination of surgical field), and no resection.
Radiotherapy: There are 3 settings in which radiotherapy is delivered in these patients: as
definitive treatment when definitive surgery is not feasible, as postoperative adjuvant
treatment, and preoperatively in patients with a slow response to neoadjuvant chemotherapy.
Patients who are to receive definitive and postoperative adjuvant treatment are randomized
between conventional fractionation and hyperfractionated accelerated split-course delivery;
individuals receiving preoperative irradiation are not randomized for radiotherapy schedule
but are assigned nonrandomly to receive the hyperfractionated accelerated split-course
scheme (conventional fractionation requires that DOX and DACT be eliminated from concomitant
chemotherapy, whereas these agents can be continued during the hyperfractionated schedule).
Individual institutions may elect not to randomize for the radiotherapy fractionation
scheme, i.e., to treat all patients on one schedule or the other; in such institutions, all
patients must follow the same scheme, decided upon prior to treatment of the first patient.
Use of photons with energies of 4-6 MV (including Co60) is recommended for extremity
lesions, and 6-15 MV energies are recommended for trunk lesions; electrons may be considered
for small superficial boosts, but are not adequate as a sole modality. ADJUVANT THERAPY. Arm
III (Standard risk): Alternating 3-Drug Combination Chemotherapy Regimens. VACA: VCR/DOX/CTX
alternating with VCR/DACT/CTX. Arm IV (Standard risk): Alternating 3-Drug Combination
Chemotherapy Regimens. VAIA: VCR/DOX/IFF alternating with VCR/DACT/IFF. High-risk patients
continue with 10 additional courses of VAIA or EVAIA according to original randomization.
Adjuvant Radiotherapy, when administered, begins on week 19, and is given concomitantly with
chemotherapy.

PROJECTED ACCRUAL: It is anticipated that 600 patients (200 standard-risk and 400 high-risk)
will be accrued over 4 years.