title: Phase II clinical investigation of gemcitabine in advanced soft tissue sarcomas and window evaluation of dose rate on gemcitabine triphosphate accumulation.
abstract: OBJECTIVE
  To evaluate the efficacy, toxicity, and optimal dose rate of gemcitabine in adult patients with advanced soft tissue sarcomas (STS) by comparing levels of gemcitabine triphosphate (GTP) in peripheral-blood mononuclear cells (PBMCs) of patients receiving two different dose rates.
  
  
  METHODS
  Fifty-six assessable patients with STS (17 gastrointestinal [GI] leiomyosarcomas and 39 other histologies) were treated on a two-arm phase II study. Gemcitabine was given at 1 g/m2 as a 30-minute infusion weekly for up to 7 weeks followed by 1 week of rest and reassessment of tumor. Subsequent cycles were given at 1 g/m2 weekly for 3 weeks followed by 1 week of rest. Nine patients underwent cellular pharmacologic studies at two different dose rates (1 g/m2 over a standard 30-minute infusion on week 1 and over pharmacologically based infusion of 150 minutes on week 2) to evaluate GTP levels in PBMCs.
  
  
  RESULTS
  Seven partial responses were noted among 39 patients, for an overall response rate of 18% (95% confidence interval, 7% to 29%). Median duration of response was 3.5 months (range, 2 to 13 months). Four of 10 patients with non-GI leiomyosarcomas achieved a partial response. No objective responses were noted in 17 patients with GI leiomyosarcomas. One patient had a mixed response. Median time to progression for all patients (both arms) was 3 months; median survival was 13.9 months. Treatment was generally well tolerated. Comparison of cellular pharmacology demonstrated a significant 1.4-fold increase in the concentration of GTP with the 150-minute infusion.
  
  
  CONCLUSIONS
  Given the limited therapeutic armamentarium for STS, the activity of gemcitabine is encouraging. Its potential for combination therapy in the salvage setting should be studied with pharmacologically guided fixed dose-rate infusion.
authors.affiliation: Department of Sarcoma Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. spatel@mdanderson.org
authors.forename: S R
authors.initials: SR
authors.lastname: Patel
authors.forename: V
authors.initials: V
authors.lastname: Gandhi
authors.forename: J
authors.initials: J
authors.lastname: Jenkins
authors.forename: N
authors.initials: N
authors.lastname: Papadopolous
authors.forename: M A
authors.initials: MA
authors.lastname: Burgess
authors.forename: C
authors.initials: C
authors.lastname: Plager
authors.forename: W
authors.initials: W
authors.lastname: Plunkett
authors.forename: R S
authors.initials: RS
authors.lastname: Benjamin
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D003841:Deoxycytidine / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D007262:Infusions, Intravenous; D007890:Leiomyosarcoma / Q000097:blood / Q000188:drug therapy*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010710:Phosphates / Q000097:blood; D012509:Sarcoma / Q000097:blood / Q000188:drug therapy; D012983:Soft Tissue Neoplasms / Q000097:blood / Q000188:drug therapy; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D010710:Phosphates; D003841:Deoxycytidine; D000093542:Gemcitabine