title: Phase I trial using a time-to-event continual reassessment strategy for dose escalation of cisplatin combined with gemcitabine and radiation therapy in pancreatic cancer.
abstract: OBJECTIVE
  The primary objective of this study was to determine the maximum-tolerated dose of cisplatin that could be added to full-dose gemcitabine and radiation therapy (RT) in patients with pancreatic cancer.
  
  
  METHODS
  Nineteen patients were treated. Gemcitabine 1,000 mg/m(2) was administered over 30 minutes on days 1, 8, and 15 of a 28-day cycle. Cisplatin followed gemcitabine on days 1 and 15. The initial dose level of cisplatin was 30 mg/m(2), escalated to a targeted dose of 50 mg/m(2) using Time-to-Event Continual Reassessment Method. RT was initiated on cycle 1, day 1, in 2.4 Gy fractions to a total dose of 36 Gy. A second cycle of chemotherapy was planned following a 1-week rest.
  
  
  RESULTS
  Four of eight patients experienced acute dose limiting toxicity at the 50 mg/m(2) cisplatin dose level. Patients treated at 30 and 40 mg/m(2) cisplatin dose level tolerated therapy without dose-limiting toxicity. Median survival was 10.7 months (95% CI, 5.4 to 18.2) for all patients, and 12.9 months (95% CI, 7.4 to 21.2) for those without metastasis.
  
  
  CONCLUSIONS
  Cisplatin at doses up to 40 mg/m(2) may be safely added to full-dose gemcitabine and conformal RT. The Time-to-Event Continual Reassessment Method trial design allowed rapid completion of the study and confidence in the conclusion about the maximum tolerated dose, but accrued more patients to a dose level above the maximum tolerated dose than the typical phase I design. Local and systemic disease control and survival in this study cohort supports further investigation of gemcitabine-based RT and combination chemotherapy in this disease.
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109-0934, USA.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Muler
authors.forename: Cornelius J
authors.initials: CJ
authors.lastname: McGinn
authors.forename: Daniel
authors.initials: D
authors.lastname: Normolle
authors.forename: Theodore
authors.initials: T
authors.lastname: Lawrence
authors.forename: Diane
authors.initials: D
authors.lastname: Brown
authors.forename: Gwen
authors.initials: G
authors.lastname: Hejna
authors.forename: Mark M
authors.initials: MM
authors.lastname: Zalupski
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D023381:Endpoint Determination; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D020266:Radiotherapy, Conformal; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D002945:Cisplatin; D000093542:Gemcitabine