Randomized comparison of intensified six-drug versus standard three-drug chemotherapy for high-risk nonmetastatic rhabdomyosarcoma and other chemotherapy-sensitive childhood soft tissue sarcomas: long-term results from the International Society of Pediatric Oncology MMT95 study.
OBJECTIVE
MMT95 was the fourth of a series of International Society of Pediatric Oncology (SIOP) collaborations for children with high-risk nonmetastatic soft tissue sarcoma (STS). The principal objective was to explore survival advantage for an intensified chemotherapy strategy in a randomized trial.


METHODS
From July 1995 to June 2003, 457 previously untreated patients with incompletely resected embryonal rhabdomyosarcoma (RMS), undifferentiated sarcoma, and soft tissue primitive neuroectodermal tumor at all sites except paratesticular, vagina, and uterus, or with alveolar RMS were randomly assigned to receive either ifosfamide, vincristine, and dactinomycin (IVA) or a six-drug combination (IVA plus carboplatin, epirubicin, and etoposide) both delivered over 27 weeks. Cumulative doses were as follows: ifosfamide 54 g/m(2) (both arms), epirubicin 450 mg/m(2), etoposide 1,350 mg/m(2) (six-drug regimen). Poor responders after three courses of IVA were to be switched to the other arm. Delivery of radiotherapy was determined according to site and/or response to chemotherapy with or without surgery.


RESULTS
Overall survival (OS) for all patients was 81% (95% CI, 77% to 84%) at 3 years. No significant difference in outcome in either OS or event-free survival was noted between the two arms (3-year OS: 82% [95% CI, 76% to 86%] for IVA and 80% [95% CI, 74% to 85%] for the six-drug arm). Toxicity was significantly greater (infection, myelosuppression, and mucositis) in the six-drug arm. Overall burden of local therapy was consistent with data from previous SIOP studies and showed no difference between the two chemotherapy regimens.


CONCLUSIONS
Intensification of chemotherapy for nonmetastatic RMS and other chemotherapy-sensitive STS provides no survival advantage or reduction in the intensity of local therapy and adds toxicity.
Institut Gustave- Roussy, Villejuif, France. oberlin@igr.fr
Odile
O
Oberlin
Annie
A
Rey
José
J
Sanchez de Toledo
Hélène
H
Martelli
Meriel E M
ME
Jenney
Marcelo
M
Scopinaro
Christophe
C
Bergeron
Johannes H M
JH
Merks
Nathalie
N
Bouvet
Caroline
C
Ellershaw
Anna
A
Kelsey
David
D
Spooner
Michael C G
MC
Stevens
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002648:Child; D002675:Child, Preschool; D003609:Dactinomycin / Q000008:administration & dosage; D015251:Epirubicin / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D008297:Male; D011379:Prognosis; D012208:Rhabdomyosarcoma / Q000188:drug therapy* / Q000401:mortality; D012509:Sarcoma / Q000188:drug therapy* / Q000401:mortality; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage
D003609:Dactinomycin; D015251:Epirubicin; D014750:Vincristine; D005047:Etoposide; D016190:Carboplatin; D007069:Ifosfamide