title: A phase I/II study of sequential, dose-escalated, high dose ifosfamide plus doxorubicin with peripheral blood stem cell support for the treatment of patients with advanced soft tissue sarcomas.
abstract: BACKGROUND
  This Phase I/II study investigates increasingly high doses of ifosfamide combined with full dose doxorubicin chemotherapy supported with peripheral blood stem cells (PBSC) and granulocyte-colony stimulating factor (G-CSF) in patients with metastatic soft tissue sarcoma (STS).
  
  
  METHODS
  Patients with histologically proven metastatic or advanced adult STS without prior treatment received doxorubicin, 75 mg/m2, on Day 1 followed by 4-day continuous infusion of ifosfamide at 5 consecutive dose levels starting with 8 g/m2 and escalating to 16 g/m2 in increments of 2 g/m2. Three patients per dose level and a maximum of 5 treatment cycles per level at 3-week intervals were planned. Each cycle was followed by G-CSF and retransfusion of PBSC. PBSC separation was performed prior to chemotherapy by steady state mobilization with G-CSF.
  
  
  RESULTS
  Eighteen patients (median age, 45 years, range, 25-57 years) were included, with 4, 3, 4, 4, and 3 patients assigned to Levels 1-5, respectively. Metastatic sites included the lungs in 12 patients (67%), lymph nodes in 8 patients (44%), and the liver in 5 patients (28%). Nine patients (50%) achieved objective responses with 4 complete responses (22%) and 5 partial responses (28%). Lung metastases and a histology of synovial sarcoma or malignant fibrous histiocytoma were favorable features for response to therapy. The median survival for all patients was 13+ months (range, 3-19+ months). Hematotoxicity was manageable and treatment could be administered at a median interval of 24 days. One case of World Health Organization Grade 3 neurotoxicity occurred. Nephrotoxicity was dose-limiting, with 1 patient in Level 4 (WHO Grade 2) and 2 patients in Level 5 (WHO Grade 3).
  
  
  CONCLUSIONS
  Multiple cycles of dose-intensive therapy with doxorubicin and high dose ifosfamide can be administered safely with PBSC support. Nephrotoxicity is dose-limiting for ifosfamide at total doses of 16 g/m2. Multiple cycles of high dose chemotherapy at short treatment intervals using ifosfamide at a dose of 14 g/m2 should be investigated further in a neoadjuvant setting in patients with STS.
authors.affiliation: Department of Hematology/Oncology/Immunology, Eberhard-Karls-University Medical Center II, Tübingen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Bokemeyer
authors.forename: A
authors.initials: A
authors.lastname: Franzke
authors.forename: J T
authors.initials: JT
authors.lastname: Hartmann
authors.forename: C
authors.initials: C
authors.lastname: Schöber
authors.forename: L
authors.initials: L
authors.lastname: Arseniev
authors.forename: B
authors.initials: B
authors.lastname: Metzner
authors.forename: H
authors.initials: H
authors.lastname: Link
authors.forename: L
authors.initials: L
authors.lastname: Kanz
authors.forename: H J
authors.initials: HJ
authors.lastname: Schmoll
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage / Q000009:adverse effects; D008113:Liver Neoplasms / Q000556:secondary* / Q000628:therapy*; D008175:Lung Neoplasms / Q000556:secondary* / Q000628:therapy*; D008207:Lymphatic Metastasis; D008875:Middle Aged; D012509:Sarcoma / Q000556:secondary* / Q000628:therapy*
chemical_list: D016179:Granulocyte Colony-Stimulating Factor; D004317:Doxorubicin; D007069:Ifosfamide