title: A two-cohort phase I study of weekly oxaliplatin and gemcitabine, then oxaliplatin, gemcitabine, and erlotinib during radiotherapy for unresectable pancreatic carcinoma.
abstract: OBJECTIVE
  Gemcitabine is a potent radiosensitizer. When combined with standard radiotherapy (XRT) the gemcitabine dose must be reduced to about 10% of its conventional dose. Oxaliplatin and erlotinib also have radiosensitizing properties. Oxaliplatin and gemcitabine have demonstrated synergy in vitro. We aimed to determine the maximum tolerated dose of oxaliplatin and gemcitabine with concurrent XRT, then oxaliplatin, gemcitaibine, and erlotinib with XRT in the treatment of locally advanced and low-volume metastatic pancreatic or biliary cancer.
  
  
  METHODS
  A modified 3+3 dose-escalation design was used for testing 4 dose levels of oxaliplatin and gemcitabine given once weekly for a maximum of 6 weeks with daily XRT in fractions of 1.8 Gy to a total dose of 50.4 Gy. Dose-limiting toxicity (DLT) was defined as any grade 4 toxicity or grade 3 toxicity resulting in a treatment delay of >1 week. In addition, dose reduction in 2 of the 3 patients in a given cohort was counted as a DLT in dose escalation-deescalation rule in the modified 3+3 design.
  
  
  RESULTS
  Eighteen patients were enrolled, all with pancreatic cancer. Grade 4 transaminitis in a patient in cohort 3 resulted in cohort expansion. Cohort 4, the highest planned dose cohort, had no DLTs. The recommended phase II dose is oxaliplatin 50 mg/m(2)/wk with gemcitabine 200 mg/m(2)/wk and 50.4 Gy XRT. The most prevalent grade 3 toxicities were nausea (22%), elevated transaminases (17%), leucopenia (17%), and hyperglycemia (17%). Median progression-free survival was 7.1 months (95% confidence interval, 4.6-11.1 mo) and median overall survival was 10.8 months (95% confidence interval, 7.1-16.7 mo). The addition of erlotinib was poorly tolerated at the first planned dose level, but full study of the combination was hindered by early closure of the study.
  
  
  CONCLUSIONS
  Weekly oxaliplatin 50 mg/m/wk combined with gemcitabine 200 mg/m/wk and XRT for pancreatic cancer has acceptable toxicity and interesting activity.
authors.affiliation: Division of Hematology and Oncology, Ohio State University, Columbus, OH, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Raftery
authors.forename: Joel E
authors.initials: JE
authors.lastname: Tepper
authors.forename: Richard M
authors.initials: RM
authors.lastname: Goldberg
authors.forename: A William
authors.initials: AW
authors.lastname: Blackstock
authors.forename: Mebea
authors.initials: M
authors.lastname: Aklilu
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Bernard
authors.forename: Anastasia
authors.initials: A
authors.lastname: Ivanova
authors.forename: Janine M
authors.initials: JM
authors.lastname: Davies
authors.forename: Bert H
authors.initials: BH
authors.lastname: O'Neil
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D059248:Chemoradiotherapy; D015331:Cohort Studies; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000069347:Erlotinib Hydrochloride; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy; D011799:Quinazolines / Q000008:administration & dosage; D011879:Radiotherapy Dosage; D015996:Survival Rate; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D009944:Organoplatinum Compounds; D011799:Quinazolines; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000069347:Erlotinib Hydrochloride; D000093542:Gemcitabine