title: Highly effective reduced toxicity dose-intensive pilot protocol for non-metastatic limb osteogenic sarcoma (SCOS 89).
abstract: OBJECTIVE
  Aggressive chemotherapy protocols for non-metastatic limb osteosarcoma have improved histological response without affecting prognosis. This study evaluated the toxicity and outcome of a dose-intensive, high-dose 3- to 5-drug pilot protocol, SCOS 89.
  
  
  METHODS
  The cohort included 26 patients (14 male; ages 6.5-22 years) with non-metastatic limb osteosarcoma treated at a tertiary pediatric medical center between 1989 and 2013. Preoperatively, patients received two courses of once-weekly pulses of high-dose methotrexate (12-30 g/m(2)) for 2 weeks; doxorubicin (90 mg/m(2)) with dexrazoxane, combined with cisplatin (200 mg/m(2)), was added in week 3. Following methotrexate, 760 mg/m(2) of folinic acid was administered. Postoperative chemotherapy was continued to a total of 14 courses of methotrexate, doxorubicin (up to a total dose of 360 mg/m(2)), and cisplatin (up to a total dose of 560 mg/m(2)). If toxicity occurred or <90 % tumor necrosis, ifosfamide (12 g/m(2)) plus etoposide (500 mg/m(2)) was substituted for doxorubicin, cisplatin, or methotrexate. Toxicity and death rates were calculated.
  
  
  RESULTS
  All patients underwent definitive limb salvage surgery. Six patients died of infection, recurrent disease, or secondary malignancy. Median follow-up was 100 months (range 2-290). Event-free and overall survival rates, respectively, were 88 and 96 % at 2 years, 80 and 87.6 % at 5 years, 80 and 78 % at 10 years. Eleven patients required ifosfamide/etoposide substitution. One patient had a transient decreased left ventricular ejection fraction. Two patients developed acute nephrotoxicity during therapy, but no neurotoxicity. Seven patients had hearing impairment.
  
  
  CONCLUSIONS
  The SCOS 89 yields a high event-free survival rate with reduced nephro-/neuro-/cardiotoxicity in patients with non-metastatic limb osteosarcoma.
authors.affiliation: Department of Pediatric Hematology-Oncology, Schneider Children's Medical Center of Israel, 49202, Petach Tikva, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Vered
authors.initials: V
authors.lastname: Shkalim-Zemer
authors.affiliation: Department of Pediatric Hematology-Oncology, Schneider Children's Medical Center of Israel, 49202, Petach Tikva, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Shifra
authors.initials: S
authors.lastname: Ash
authors.affiliation: Department of Pediatric Hematology-Oncology, Schneider Children's Medical Center of Israel, 49202, Petach Tikva, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Helen
authors.initials: H
authors.lastname: Toledano
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Unit of Orthopedic Oncology, Institute of Pathology, Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Kollender
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Unit of Bone and Soft Tissue Tumors, Institute of Pathology, Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Josephine
authors.initials: J
authors.lastname: Issakov
authors.affiliation: Department of Pediatric Hematology-Oncology, Schneider Children's Medical Center of Israel, 49202, Petach Tikva, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Isaac
authors.initials: I
authors.lastname: Yaniv
authors.affiliation: Department of Pediatric Hematology-Oncology, Schneider Children's Medical Center of Israel, 49202, Petach Tikva, Israel. icohen@tau.ac.il.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. icohen@tau.ac.il.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Cohen
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000601:surgery; D002648:Child; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D057915:Drug Substitution; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D005500:Follow-Up Studies; D034381:Hearing Loss / Q000139:chemically induced; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage / Q000009:adverse effects; D007674:Kidney Diseases / Q000139:chemically induced; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D012516:Osteosarcoma / Q000188:drug therapy* / Q000601:surgery; D010865:Pilot Projects; D013318:Stroke Volume / Q000187:drug effects; D015996:Survival Rate; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D005047:Etoposide; D004317:Doxorubicin; D002945:Cisplatin; D002955:Leucovorin; D007069:Ifosfamide; D008727:Methotrexate
keywords: Cisplatin; Doxorubicin; Methotrexate; Non-metastatic limb osteosarcoma; Survival