title: Weekly paclitaxel, gemcitabine, and external irradiation followed by randomized farnesyl transferase inhibitor R115777 for locally advanced pancreatic cancer.
abstract: OBJECTIVE
  The Radiation Therapy Oncology Group (RTOG) multi-institutional Phase II study 98-12, evaluating paclitaxel and concurrent radiation (RT) for locally advanced pancreatic cancer, demonstrated a median survival of 11.3 months and a 1-year survival of 43%. The purpose of the randomized Phase II study by RTOG 0020 was to evaluate the addition of weekly low- dose gemcitabine with concurrent paclitaxel/RT and to evaluate the efficacy and safety of the farnesyl transferase inhibitor R115777 following chemoradiation.
  
  
  METHODS
  Patients with unresectable, nonmetastatic adenocarcinoma of the pancreas were eligible. Patients in Arm 1 received gemcitabine, 75 mg/m(2)/week, and paclitaxel, 40 mg/m(2)/week, for 6 weeks, with 50.4 Gy radiation (CXRT). Patients in Arm 2 received an identical chemoradiation regimen but then received maintenance R115777, 300 mg twice a day for 21 days every 28 days (CXRT+R115777), until disease progression or unacceptable toxicity.
  
  
  RESULTS
  One hundred ninety-five patients were entered into this study, and 184 were analyzable. Grade 4 nonhematologic toxicities occurred in less than 5% of CXRT patients. The most common grade 3/4 toxicity from R115777 was myelosuppression; however, grade 3/4 hepatic, metabolic, musculoskeletal, and neurologic toxicities were also reported. The median survival time was 11.5 months and 8.9 months for the CXRT and CXRT+R115777 arms, respectively.
  
  
  CONCLUSIONS
  The CXRT arm achieved a median survival of almost 1-year, supporting chemoradiation as an important therapeutic modality for locally advanced pancreatic cancer. Maintenance R115777 is not effective and is associated with a broad range of toxicities. These findings provide clinical evidence that inhibition of farnesylation affects many metabolic pathways, underscoring the challenge of developing an effective K-ras inhibitor.
authors.affiliation: The Cancer Center, University of Virginia Health System West, University of Virginia, Charlottesville, VA, USA.
authors.forename: Tyvin A
authors.initials: TA
authors.lastname: Rich
authors.forename: Kathryn
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authors.lastname: Winter
authors.forename: Howard
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authors.lastname: Safran
authors.forename: John P
authors.initials: JP
authors.lastname: Hoffman
authors.forename: Beth
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authors.lastname: Erickson
authors.forename: Pramila R
authors.initials: PR
authors.lastname: Anne
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Myerson
authors.forename: Vivian Jm
authors.initials: VJ
authors.lastname: Cline-Burkhardt
authors.forename: Kimberly
authors.initials: K
authors.lastname: Perez
authors.forename: Christopher
authors.initials: C
authors.lastname: Willett