title: Optimizing the administration of fixed-dose rate gemcitabine plus capecitabine using an alternating-week schedule: a dose finding and early efficacy study in advanced pancreatic and biliary carcinomas.
abstract: OBJECTIVE
  This multisite study sought to optimize the dosing, schedule, and administration of fixed-dose rate (FDR) gemcitabine plus capecitabine for advanced pancreatic and biliary tract cancers using an alternating-week dose schedule of both agents.
  
  
  METHODS
  Patients with previously untreated advanced pancreatic and biliary tract cancers with Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. For the dose-finding portion, a standard 3+3 dose-escalation schema was used, with the gemcitabine dose kept at 1000 mg/m(2) administered by FDR (10 mg/m(2)/min) on day 1 of each 14-day cycle, and capecitabine given on days 1 to 7 at doses ranging from 800 to 1500 mg/m(2) twice daily. Primary study objective was determination of maximum tolerated dose (MTD). The cohort at MTD was expanded for further efficacy assessment.
  
  
  RESULTS
  A total of 45 patients (median age 61 y; 93% pancreatic/7% biliary; 84% with metastatic disease) were enrolled. Median number of cycles received was 11.5. The MTD using this dose schedule was FDR gemcitabine 1000 mg/m(2) plus capecitabine 1000 mg/m(2) bid, due to a high incidence of late hand-foot syndrome observed at the next higher dose level. Most common nonhematologic adverse events related to treatment included nausea/vomiting (overall rate, 64%; all grade 1/2) and hand-foot syndrome (overall rate, 60%; grade 3, 22%). The incidence of grade 3/4 hematologic adverse events was 24%. Six of 41 evaluable patients (14.6%) had a partial response; 18 of 31 patients (58%) with elevated baseline CA 19-9 level had ≥50% biomarker decline during treatment. Estimated median time to tumor progression and overall survival were 5.5 and 9.8 months, respectively (5.5 and 10.1 mo in the metastatic pancreatic cancer cohort).
  
  
  CONCLUSIONS
  This dosing schedule of FDR gemcitabine plus capecitabine is active in patients with advanced pancreatobiliary cancers. Given its favorable toxicity profile and convenience, this regimen represents an appropriate front-line option for this patient population and may serve as the foundation on which new investigational agents are added in future trial design.
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. andrewko@medicine.ucsf.edu
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Ko
authors.forename: Anne M
authors.initials: AM
authors.lastname: Espinoza
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Jones
authors.forename: Alan P
authors.initials: AP
authors.lastname: Venook
authors.forename: Emily K
authors.initials: EK
authors.lastname: Bergsland
authors.forename: Robin K
authors.initials: RK
authors.lastname: Kelley
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Dito
authors.forename: Anna
authors.initials: A
authors.lastname: Ong
authors.forename: Cherry S
authors.initials: CS
authors.lastname: Hanover
authors.forename: Fergus V
authors.initials: FV
authors.lastname: Coakley
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Tempero
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001661:Biliary Tract Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D005500:Follow-Up Studies; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D015996:Survival Rate; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil; D000093542:Gemcitabine