title: Phase I escalation of gemcitabine combined with protracted oral etoposide in gynecologic malignancies: A Gynecologic Oncology Group study.
abstract: OBJECTIVE
  Although improvements have been made in the management of patients with advanced ovarian cancer, long-term survivors are still uncommon. Gemcitabine and prolonged oral etoposide have shown reproducible single-agent activity in patients with platinum/paclitaxel-resistant ovarian cancer. This, combined with preclinical synergism, prompted the Gynecologic Oncology Group to determine the maximum tolerated dose (MTD) of this combination.
  
  
  METHODS
  Eligible patients had recurrent epithelial ovarian cancer, primary papillary peritoneal, or fallopian tube carcinoma. All had received prior platinum/paclitaxel-based chemotherapy and had adequate hepatic, renal and bone marrow function. Oral etoposide was administered at 50 mg/m2 for ten days, with three proposed dose levels for gemcitabine on days 1 and 8: 400, 550 and 700 mg/m2. Cycles were to be repeated every 28 days. Three patients were to enter at each dose level.
  
  
  RESULTS
  Patients were enrolled only to dose level 1 as this dose exceeded MTD. Of six patients initially enrolled, one was removed after three days with fever, ascites and decreased albumin believed not to be treatment related. Five patients were evaluable for toxicity and response. One of the first three patients developed dose limiting toxicity (DLT) manifested as grade 4 neutropenia. A second DLT (neutropenic fever and thrombocytopenia associated with bleeding) occurred among the next three patients: therefore, MTD was reached at dose level 1. Grade 4 toxicities included episodes of neutropenia (4) and thrombocytopenia (3). No objective response was observed.
  
  
  CONCLUSIONS
  Oral etoposide and gemcitabine at this dose and schedule was associated with substantial toxicity in this population. Patients who are previously treated with platinum/paclitaxel-based chemotherapy may be at particular risk for toxicity.
authors.affiliation: Division of Medical Oncology, University of Southern California/Norrris Comprehensive Cancer Center, Los Angeles 90089, USA. aagarcia@hsc.usc.edu
authors.forename: Agustin A
authors.initials: AA
authors.lastname: Garcia
authors.forename: Michael A
authors.initials: MA
authors.lastname: Bookman
authors.forename: Lorna
authors.initials: L
authors.lastname: Rodriguez-Rodriguez
authors.forename: David G
authors.initials: DG
authors.lastname: Mutch
authors.forename: Katherine Y
authors.initials: KY
authors.lastname: Look
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D003841:Deoxycytidine / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives*; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D005833:Genital Neoplasms, Female / Q000188:drug therapy*; D006801:Humans; D008875:Middle Aged; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D005047:Etoposide; D000093542:Gemcitabine