title: A phase I/II trial of intensity modulated radiation (IMRT) dose escalation with concurrent fixed-dose rate gemcitabine (FDR-G) in patients with unresectable pancreatic cancer.
abstract: OBJECTIVE
  Local failure in unresectable pancreatic cancer may contribute to death. We hypothesized that intensification of local therapy would improve local control and survival. The objectives were to determine the maximum tolerated radiation dose delivered by intensity modulated radiation with fixed-dose rate gemcitabine (FDR-G), freedom from local progression (FFLP), and overall survival (OS).
  
  
  METHODS
  Eligibility included pathologic confirmation of adenocarcinoma, radiographically unresectable, performance status of 0-2, absolute neutrophil count of ≥ 1,500/mm(3), platelets ≥ 100,000/mm(3), creatinine <2 mg/dL, bilirubin <3 mg/dL, and alanine aminotransferase/aspartate aminotransferase ≤ 2.5 × upper limit of normal. FDR-G (1000 mg/m(2)/100 min intravenously) was given on days -22 and -15, 1, 8, 22, and 29. Intensity modulated radiation started on day 1. Dose levels were escalated from 50-60 Gy in 25 fractions. Dose-limiting toxicity was defined as gastrointestinal toxicity grade (G) ≥ 3, neutropenic fever, or deterioration in performance status to ≥ 3 between day 1 and 126. Dose level was assigned using TITE-CRM (Time-to-Event Continual Reassessment Method) with the target dose-limiting toxicity (DLT) rate set to 0.25.
  
  
  RESULTS
  Fifty patients were accrued. DLTs were observed in 11 patients: G3/4 anorexia, nausea, vomiting, and/or dehydration (7); duodenal bleed (3); duodenal perforation (1). The recommended dose is 55 Gy, producing a probability of DLT of 0.24. The 2-year FFLP is 59% (95% confidence interval [CI]: 32-79). Median and 2-year overall survival are 14.8 months (95% CI: 12.6-22.2) and 30% (95% CI 17-45). Twelve patients underwent resection (10 R0, 2 R1) and survived a median of 32 months.
  
  
  CONCLUSIONS
  High-dose radiation therapy with concurrent FDR-G can be delivered safely. The encouraging efficacy data suggest that outcome may be improved in unresectable patients through intensification of local therapy.
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, USA. edgar.ben-josef@uphs.upenn.edu
authors.forename: Edgar
authors.initials: E
authors.lastname: Ben-Josef
authors.forename: Mathew
authors.initials: M
authors.lastname: Schipper
authors.forename: Isaac R
authors.initials: IR
authors.lastname: Francis
authors.forename: Scott
authors.initials: S
authors.lastname: Hadley
authors.forename: Randall
authors.initials: R
authors.lastname: Ten-Haken
authors.forename: Theodore
authors.initials: T
authors.lastname: Lawrence
authors.forename: Daniel
authors.initials: D
authors.lastname: Normolle
authors.forename: Diane M
authors.initials: DM
authors.lastname: Simeone
authors.forename: Christopher
authors.initials: C
authors.lastname: Sonnenday
authors.forename: Ross
authors.initials: R
authors.lastname: Abrams
authors.forename: William
authors.initials: W
authors.lastname: Leslie
authors.forename: Gazala
authors.initials: G
authors.lastname: Khan
authors.forename: Mark M
authors.initials: MM
authors.lastname: Zalupski
mesh_terms: D000230:Adenocarcinoma / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D000368:Aged; D000369:Aged, 80 and over; D002423:Cause of Death; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D018450:Disease Progression; D019583:Dose Fractionation, Radiation; D005260:Female; D041981:Gastrointestinal Tract / Q000528:radiation effects; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009503:Neutropenia / Q000209:etiology; D058958:Organs at Risk / Q000528:radiation effects; D010190:Pancreatic Neoplasms / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000009:adverse effects; D050397:Radiotherapy, Intensity-Modulated / Q000009:adverse effects / Q000379:methods*; D013921:Thrombocytopenia / Q000139:chemically induced; D013997:Time Factors; D000093542:Gemcitabine
chemical_list: D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; D000093542:Gemcitabine