title: Phase II study of sequential gemcitabine followed by docetaxel for recurrent Ewing sarcoma, osteosarcoma, or unresectable or locally recurrent chondrosarcoma: results of Sarcoma Alliance for Research Through Collaboration Study 003.
abstract: BACKGROUND
  Gemcitabine and docetaxel have a broad spectrum of clinical activity in patients with carcinoma. The Sarcoma Alliance for Research Through Collaboration conducted a phase II trial of gemcitabine in combination with docetaxel in children and adults with recurrent Ewing sarcoma (EWS), osteosarcoma (OS), or unresectable or recurrent chondrosarcoma. The primary objective was to determine the objective response rate using response evaluation criteria in solid tumors (RECIST).
  
  
  METHODS
  Gemcitabine (675 mg/m2 i.v. over 90 minutes on days 1 and 8) was administered in combination with docetaxel (75 mg/m2 i.v. over 1 hour on day 8) every 21 days. All patients received filgrastim or pegfilgrastim. A Bayesian formulation was used to determine the probability of achieving the target response rate for each subtype-0.35 for EWS and OS or 0.20 for chondrosarcoma. If the probability of achieving the target response rate was <0.05, the combination was considered inactive. Toxicity was graded according to common terminology criteria for adverse events (CTCAE), version 3.0.
  
  
  RESULTS
  Fifty-three eligible patients were enrolled in the three subtype groups-OS (n = 14), EWS (n = 14), and chondrosarcoma (n = 25). Toxicities included neutropenia, thrombocytopenia, fatigue, dyspnea, bronchospasm, edema, neuropathy, and liver function abnormalities. Dose modification for toxicity was required for eight patients during cycle 1 and 16 patients in subsequent cycles. Seven patients withdrew from therapy as a result of toxicity. No complete responses were observed. Partial responses were observed in OS (n = 1), EWS (n = 2), and chondrosarcoma (n = 2) patients.
  
  
  CONCLUSIONS
  Gemcitabine in combination with docetaxel was associated with a probability of reaching the target 35% response rate of <5% in OS patients and 5.6% in EWS patients; the probability of reaching a 20% response rate in chondrosarcoma patients was 14%.
  
  
  CONCLUSIONS
  The Bayesian formulation permitted estimation of the probability of achieving the target response rate for each subtype after each response evaluation. By allowing multiple looks at the data, this design stopped the trial after considering the probability of achieving the target response rate and accrual rate. Because this design did not specify a rule for declaring the treatment as "active", a direct comparison with a standard two-stage phase II design is not appropriate. The decision to close the EWS and chondrosarcoma subtype arms was based, in part, on slow accrual and was supported by the low probability of achieving the target response rate. The rate of enrollment, rather than the statistical design, had a significant effect on the trial duration.
authors.affiliation: The Children's Hospital of Philadelphia, Division of Oncology, 3501 Civic Center Boulevard, CTRB- 4016, Philadelphia, Pennsylvania, USA. foxe@email.chop.edu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fox
authors.forename: Shreyaskumar
authors.initials: S
authors.lastname: Patel
authors.forename: J Kyle
authors.initials: JK
authors.lastname: Wathen
authors.forename: Scott
authors.initials: S
authors.lastname: Schuetze
authors.forename: Sant
authors.initials: S
authors.lastname: Chawla
authors.forename: David
authors.initials: D
authors.lastname: Harmon
authors.forename: Denise
authors.initials: D
authors.lastname: Reinke
authors.forename: Rashmi
authors.initials: R
authors.lastname: Chugh
authors.forename: Robert S
authors.initials: RS
authors.lastname: Benjamin
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Helman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001859:Bone Neoplasms / Q000188:drug therapy*; D002813:Chondrosarcoma / Q000188:drug therapy*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000077143:Docetaxel; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D012516:Osteosarcoma / Q000188:drug therapy*; D012512:Sarcoma, Ewing / Q000188:drug therapy*; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000093542:Gemcitabine
chemical_list: D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; D000093542:Gemcitabine