title: Phase II study with the combination of gemcitabine and DTIC in patients with advanced soft tissue sarcomas.
abstract: OBJECTIVE
  Based on the promising results of a Phase I study with a combination of gemcitabine and DTIC performed in advanced soft tissue sarcoma (ASTS) patients, and due to the limited efficacy of second or third line therapies in those patients, we designed a Phase II study to determine the activity of this new regimen.
  
  
  METHODS
  Patients with ASTS, measurable disease, pretreated with chemotherapy, received gemcitabine 1,800 mg/m2 infused over 180 min followed by DTIC 500 mg/m2 (one cycle), every 2 weeks. The pharmacokinetics (PK) of gemcitabine and 2',2'-difluorodeoxyuridine (dFdU), and the accumulation of gemcitabine triphosphate (dFdCTP) by peripheral blood mononuclear cells were studied. The influence of the sequence of administration on those parameters was examined to exclude potential drug interactions.
  
  
  RESULTS
  Twenty-six patients received a total of 158 cycles (mean four cycles, range 1-18). Grade 3-4 anemia (23% of patients), granulocytopenia (46%) or thrombocytopenia (12%), and grade 3 increase in AST (18%), ALT (21%), or gamma-glutamyl-transferase (9%) were noted. Response rate in 23 patients was 4% (95% CI: 0-24%), and in 8 of 11 patients stable disease lasted > 6 months. Progression-free rate (PFR) at 3 and 6 months was, respectively, 48 and 28%, and median overall survival 37 weeks. Pooled data from the Phase I and Phase II studies showed clinical benefit in patients with leiomyosarcomas (LMS) (57%) and malignant fibrous histiocytomas (MFH) (33%). The sequence of administration did not influence PK of gemcitabine or dFdU. There was a trend (P = 0.11) toward a lower accumulation of dFdCTP when DTIC preceded gemcitabine.
  
  
  CONCLUSIONS
  Although the remission rate was low, PFR figures indicate that this regimen has activity in patients with ASTS. It should be compared with DTIC, or other gemcitabine-containing combinations, in patients with LMS or MFH, to determine whether this combination offers advantages in PFR or in overall activity.
authors.affiliation: Servicio de Oncología, Hospital Central de Asturias, 33006, Oviedo, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Losa
authors.forename: J
authors.initials: J
authors.lastname: Fra
authors.forename: A
authors.initials: A
authors.lastname: López-Pousa
authors.forename: M
authors.initials: M
authors.lastname: Sierra
authors.forename: A
authors.initials: A
authors.lastname: Goitia
authors.forename: E
authors.initials: E
authors.lastname: Uña
authors.forename: R
authors.initials: R
authors.lastname: Nadal
authors.forename: J García
authors.initials: JG
authors.lastname: Del Muro
authors.forename: M
authors.initials: M
authors.lastname: Gión
authors.forename: J
authors.initials: J
authors.lastname: Maurel
authors.forename: P
authors.initials: P
authors.lastname: Escudero
authors.forename: E
authors.initials: E
authors.lastname: Esteban
authors.forename: José M
authors.initials: JM
authors.lastname: Buesa
mesh_terms: D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D001219:Aspartate Aminotransferases / Q000097:blood; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D018450:Disease Progression; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D007262:Infusions, Intravenous; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012074:Remission Induction; D012509:Sarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077204:Temozolomide; D014057:Tomography, X-Ray Computed / Q000379:methods; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D003606:Dacarbazine; D004317:Doxorubicin; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D007069:Ifosfamide; D000077204:Temozolomide; D000093542:Gemcitabine