title: Multi-institutional phase I study of low-dose ultra-fractionated radiotherapy as a chemosensitizer for gemcitabine and erlotinib in patients with locally advanced or limited metastatic pancreatic cancer.
abstract: OBJECTIVE
  Gemcitabine (G) has been shown to sensitize pancreatic cancer to radiotherapy but requires lower doses of G and thus delays aggressive systemic treatment, potentially leading to distant failure. We initiated a phase I trial combining ultra-fractionated low-dose radiotherapy with full dose G and erlotinib in the treatment of patients with advanced pancreatic cancer.
  
  
  METHODS
  Patients with locally advanced or metastatic pancreatic cancer confined to the abdomen and an ECOG performance status (PS) of 0-1 who had received 0-1 prior regimens (without G or E) and no prior radiotherapy were eligible. Patients were treated in 21 day cycles with G IV days 1 & 8, E once PO QD, and twice daily RT fractions separated by at least 4h on days 1, 2, 8, and 9. Whole abdominal RT fields were used. Primary endpoint was to define dose limiting toxicity (DLT) and the maximum tolerated dose (MTD).
  
  
  RESULTS
  27 patients (median age 64 years and 15 male) were enrolled between 11/24/08 and 4/12/12. 1 patient withdrew consent prior to receiving any protocol therapy. 17 patients had a PS of 1. The majority of patients were stage IV. One DLT was noted out of 7 patients at dose level (DL) 1. Subsequently no DLTs were noted in 3 patients each enrolled at DL2-4 or 11 patients in the expansion cohort. The majority of grade 3 toxicities were hematologic with 1 grade 5 bowel perforation in dose level 1 in cycle 4. Best response in 24 evaluable patients: PR (8), stable (15), PD 1. Median survival for the entire group was 9.1 months.
  
  
  CONCLUSIONS
  This phase I study combining low-dose ultra-fractionated RT as a sensitizer to full dose G plus E was well tolerated with encouraging efficacy. This represents a novel strategy worthy of further investigation in advanced pancreatic cancer patients.
authors.affiliation: Department of Radiation Oncology, Wayne State University, Barbara Ann Karmanos Cancer Center, Detroit, USA. Electronic address: andre.konski@uphs.upenn.edu.
authors.forename: Andre
authors.initials: A
authors.lastname: Konski
authors.affiliation: Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, USA.
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Meyer
authors.affiliation: Department of Radiation Oncology, Wayne State University, Barbara Ann Karmanos Cancer Center, Detroit, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Joiner
authors.affiliation: Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hall
authors.affiliation: Department of Oncology, Wayne State University, Barbara Ann Karmanos Cancer Center, Detroit, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Philip
authors.affiliation: Department of Oncology, Wayne State University, Barbara Ann Karmanos Cancer Center, Detroit, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Shields
authors.affiliation: Department of Radiation Oncology, Wayne State University, Barbara Ann Karmanos Cancer Center, Detroit, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: McSpadden
authors.affiliation: Department of Oncology, Wayne State University, Barbara Ann Karmanos Cancer Center, Detroit, USA.
authors.forename: Minsig
authors.initials: M
authors.lastname: Choi
authors.affiliation: Clinical Trials Office, Fox Chase Cancer Center, Philadelphia, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Adaire
authors.affiliation: Clinical Trials Office, Fox Chase Cancer Center, Philadelphia, USA.
authors.forename: Gail
authors.initials: G
authors.lastname: Duncan
authors.affiliation: University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, USA.
authors.forename: Neal J
authors.initials: NJ
authors.lastname: Meropol
authors.affiliation: Reading Hospital and Medical Center, Reading, USA.
authors.forename: Terrence P
authors.initials: TP
authors.lastname: Cescon
authors.affiliation: Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Cohen
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy*; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003131:Combined Modality Therapy / Q000379:methods; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D019583:Dose Fractionation, Radiation; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy*; D011799:Quinazolines / Q000008:administration & dosage; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D011799:Quinazolines; D003841:Deoxycytidine; D000069347:Erlotinib Hydrochloride; D000093542:Gemcitabine
keywords: Pancreatic cancer; Radiation sensitization of chemotherapy; Ultra-fractionated radiotherapy