Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone.
BACKGROUND
Ewing's sarcoma and primitive neuroectodermal tumor of bone are closely related, highly malignant tumors of children, adolescents, and young adults. A new drug combination, ifosfamide and etoposide, was highly effective in patients with Ewing's sarcoma or primitive neuroectodermal tumor of bone who had a relapse after standard therapy. We designed a study to test whether the addition of these drugs to a standard regimen would improve the survival of patients with newly diagnosed disease.


METHODS
Patients 30 years old or younger with Ewing's sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone were eligible. The patients were randomly assigned to receive 49 weeks of standard chemotherapy with doxorubicin, vincristine, cyclophosphamide, and dactinomycin or experimental therapy with these four drugs alternating with courses of ifosfamide and etoposide.


RESULTS
A total of 518 patients met the eligibility requirements. Of 120 patients with metastatic disease, 62 were randomly assigned to the standard-therapy group and 58 to the experimental-therapy group. There was no significant difference in five-year event-free survival between the treatment groups (P=0.81). Among the 398 patients with nonmetastatic disease, the mean (+/-SE) five-year event-free survival among the 198 patients in the experimental-therapy group was 69+/-3 percent, as compared with 54+/-4 percent among the 200 patients in the standard-therapy group (P=0.005). Overall survival was also significantly better among patients in the experimental-therapy group (72+/-3.4 percent vs. 61+/-3.6 percent in the standard-therapy group, P=0.01).


CONCLUSIONS
The addition of ifosfamide and etoposide to a standard regimen does not affect the outcome for patients with metastatic disease, but it significantly improves the outcome for patients with nonmetastatic Ewing's sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone.
Grier
Holcombe E
HE
Department of Pediatric Hematology, Dana-Farber Cancer Institute and Children's Hospital, Boston, MA 02115, USA. holcombe_grier@dfci.harvard.edu
Krailo
Mark D
MD
Tarbell
Nancy J
NJ
Link
Michael P
MP
Fryer
Christopher J H
CJ
Pritchard
Douglas J
DJ
Gebhardt
Mark C
MC
Dickman
Paul S
PS
Perlman
Elizabeth J
EJ
Meyers
Paul A
PA
Donaldson
Sarah S
SS
Moore
Sheila
S
Rausen
Aaron R
AR
Vietti
Teresa J
TJ
Miser
James S
JS
D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002648:Child; D003520:Cyclophosphamide / Q000008:administration & dosage; D003609:Dactinomycin / Q000008:administration & dosage; D018450:Disease Progression; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D018242:Neuroectodermal Tumors, Primitive / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D011379:Prognosis; D012509:Sarcoma / Q000188:drug therapy / Q000401:mortality / Q000556:secondary; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D015996:Survival Rate; D017211:Treatment Failure; D014750:Vincristine / Q000008:administration & dosage
D003609:Dactinomycin; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D007069:Ifosfamide