title: Neoadjuvant chemotherapy with methotrexate, cisplatin, and doxorubicin with or without ifosfamide in nonmetastatic osteosarcoma of the extremity: an Italian sarcoma group trial ISG/OS-1.
abstract: OBJECTIVE
  We compared two chemotherapy regimens that included methotrexate (MTX), cisplatin (CDP), and doxorubicin (ADM) with or without ifosfamide (IFO) in patients with nonmetastatic osteosarcoma of the extremity.
  
  
  METHODS
  Patients age ≤ 40 years randomly received regimens with the same cumulative doses of drugs (ADM 420 mg/m(2), MTX 120 g/m(2), CDP 600 mg/m(2), and IFO 30 g/m(2)) but with different durations (arm A, 44 weeks; arm B, 34 weeks). IFO was given postoperatively when pathologic response to MTX-CDP-ADM was poor (arm A) or given in the primary phase of chemotherapy with MTX-CDP-ADM (arm B). End points of the study included pathologic response to preoperative chemotherapy, toxicity, and survival. Given the feasibility of accrual, the statistical plan only permitted detection of a 15% difference in 5-year overall survival (OS).
  
  
  RESULTS
  From April 2001 to December 2006, 246 patients were enrolled. Two hundred thirty patients (94%) underwent limb salvage surgery (arm A, 92%; arm B, 96%; P = .5). Chemotherapy-induced necrosis was good in 45% of patients (48% in arm A, 42% in arm B; P = .3). Four patients died of treatment-related toxicity (arm A, n = 1; arm B, n = 3). A significantly higher incidence of hematologic toxicity was reported in arm B. With a median follow-up of 66 months (range, 1 to 104 months), 5-year OS and event-free survival (EFS) rates were not significantly different between arm A and arm B, with OS being 73% (95% CI, 65% to 81%) in arm A and 74% (95% CI, 66% to 82%) in arm B and EFS being 64% (95% CI, 56% to 73%) in arm A and 55% (95% CI, 46% to 64%) in arm B.
  
  
  CONCLUSIONS
  IFO added to MTX, CDP, and ADM from the preoperative phase does not improve the good responder rate and increases hematologic toxicity. IFO should only be considered in patients who have a poor histologic response to MTX, CDP, and ADM.
authors.affiliation: Istituto Ortopedico Rizzoli, Bologna, Italy. stefano.ferrari@ior.it
authors.forename: Stefano
authors.initials: S
authors.lastname: Ferrari
authors.forename: Pietro
authors.initials: P
authors.lastname: Ruggieri
authors.forename: Graziella
authors.initials: G
authors.lastname: Cefalo
authors.forename: Angela
authors.initials: A
authors.lastname: Tamburini
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Capanna
authors.forename: Franca
authors.initials: F
authors.lastname: Fagioli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Comandone
authors.forename: Rossella
authors.initials: R
authors.lastname: Bertulli
authors.forename: Gianni
authors.initials: G
authors.lastname: Bisogno
authors.forename: Emanuela
authors.initials: E
authors.lastname: Palmerini
authors.forename: Marco
authors.initials: M
authors.lastname: Alberghini
authors.forename: Antonina
authors.initials: A
authors.lastname: Parafioriti
authors.forename: Alessandra
authors.initials: A
authors.lastname: Linari
authors.forename: Piero
authors.initials: P
authors.lastname: Picci
authors.forename: Gaetano
authors.initials: G
authors.lastname: Bacci
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy*; D017024:Chemotherapy, Adjuvant / Q000379:methods*; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000008:administration & dosage*; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage*; D005260:Female; D005269:Femur / Q000473:pathology; D006801:Humans; D006811:Humerus / Q000473:pathology; D007069:Ifosfamide / Q000008:administration & dosage*; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage*; D012516:Osteosarcoma / Q000188:drug therapy*; D013977:Tibia / Q000473:pathology
chemical_list: D004317:Doxorubicin; D002945:Cisplatin; D007069:Ifosfamide; D008727:Methotrexate