title: A phase I radiation dose-escalation study to determine the maximal dose of radiotherapy in combination with weekly gemcitabine in patients with locally advanced pancreatic adenocarcinoma.
abstract: BACKGROUND
  The primary objective of this study was to determine the maximum tolerated dose (MTD) of escalating doses of radiotherapy (RT) concomitantly with a fixed dose of gemcitabine (300 mg/m2/week) within the same overall treatment time.
  
  
  METHODS
  Thirteen patients were included. Gemcitabine 300 mg/m2/week was administered prior to RT. The initial dose of RT was 45 Gy in 1.8 Gy fractions, escalated by adding 5 fractions of 1.8 Gy (one/week) to a dose of 54 Gy with a total duration kept at 5 weeks. All patients received a dynamic MRI to assess the pancreatic respiratory related movements. Toxicity was scored using the RTOG-EORTC toxicity criteria.
  
  
  RESULTS
  Three of six patients experienced an acute dose limiting toxicity (DLT) at the 54 Gy dose level. For these patients a grade III gastro-intestinal toxicity (GI) was noted. Patients treated at the 45 Gy dose level tolerated therapy without DLT. The 54 Gy dose level was designated as the MTD and was deemed not suitable for further investigation. Between both dose levels, there was a significant difference in percentage weight loss (p = 0.006) and also in cumulative GI toxicity (p = 0.027). There was no grade 3 toxicity in the 45 Gy cohort versus 4 grade 3 toxicity events in the 54 Gy cohort. The mean dose to the duodenum was significantly higher in the 54 Gy cohort (38.45 Gy vs. 51.82 Gy; p = 0.001).
  
  
  CONCLUSIONS
  Accelerated dose escalation to a total dose of 54 Gy with 300 mg/m2/week gemcitabine was not feasible. GI toxicity was the DLT. Retrospectively, the dose escalation of 9 Gy by accelerated radiotherapy might have been to large. A dose of 45 Gy is recommended. Considering the good patient outcomes, there might be a role for the investigation of a fixed dose of gemcitabine and concurrent RT with small fractions (1.8 Gy/day) in borderline resectable or unresectable non-metastatic locally advanced pancreatic cancer.
authors.affiliation: Department of Radiotherapy, University Hospitals Leuven, Leuven, Belgium. tom.budiharto@uz.kuleuven.ac.be
authors.forename: Tom
authors.initials: T
authors.lastname: Budiharto
authors.forename: Karin
authors.initials: K
authors.lastname: Haustermans
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.forename: Werner
authors.initials: W
authors.lastname: Van Steenbergen
authors.forename: Baki
authors.initials: B
authors.lastname: Topal
authors.forename: Raymond
authors.initials: R
authors.lastname: Aerts
authors.forename: Nadine
authors.initials: N
authors.lastname: Ectors
authors.forename: Didier
authors.initials: D
authors.lastname: Bielen
authors.forename: Dirk
authors.initials: D
authors.lastname: Vanbeckevoort
authors.forename: Laurence
authors.initials: L
authors.lastname: Goethals
authors.forename: Chris
authors.initials: C
authors.lastname: Verslype
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000532:radiotherapy*; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000627:therapeutic use; D015331:Cohort Studies; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D011878:Radiotherapy / Q000379:methods*; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000093542:Gemcitabine