Weekly paclitaxel, gemcitabine, and external irradiation followed by randomized farnesyl transferase inhibitor R115777 for locally advanced pancreatic cancer

Abstract

Tyvin A Rich,1 Kathryn Winter,2 Howard Safran,3 John P Hoffman,4 Beth Erickson,5 Pramila R Anne,6 Robert J Myerson,7 Vivian JM Cline-Burkhardt,8 Kimberly Perez,3 Christopher Willett91The Cancer Center, University of Virginia Health System West, University of Virginia, Charlottesville, VA, USA; 2RTOG Statistical Center, Philadelphia, PA, USA; 3Brown University, Providence, RI, USA; 4Foxchase Cancer Center, Philadelphia, PA, USA; 5Medical College of Wisconsin, Milwaukee, WI, USA; 6Thomas Jefferson University, Philadelphia, PA, USA; 7Washington University, St Louis, MO, USA; 8Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA; 9Duke University, Durham, NC, USAPurpose: 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.Patients and methods: Patients with unresectable, nonmetastatic adenocarcinoma of the pancreas were eligible. Patients in Arm 1 received gemcitabine, 75 mg/m2/week, and paclitaxel, 40 mg/m2/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.Keywords: pancreas cancer, paclitaxel, gemcitabine, irradiation