Results of a phase I trial of 12 patients with locally advanced pancreatic carcinoma combining gefitinib, paclitaxel, and 3-dimensional conformal radiation: report of toxicity and evaluation of circulating K-ras as a potential biomarker of response to therapy

Am J Clin Oncol. 2009 Apr;32(2):115-21. doi: 10.1097/COC.0b013e318180baa3.

Abstract

Objective: To evaluate the toxicity of daily gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor, with concurrent chemoradiation (CRT) in patients with locally advanced pancreatic adenocarcinoma and prospectively evaluate plasma k-ras as a potential marker of response to gefitinib and CRT.

Methods: Eleven of 12 eligible patients enrolled received a 7-day induction of gefitinib (250 mg PO) followed by daily gefitinib with concurrent CRT. Patients received 50.4 Gy/28 fractions of external beam radiation with weekly paclitaxel (40 mg/m IV) followed by maintenance on gefitinib. Plasma k-ras codon 12 mutations were detected using a two-stage restriction fragment length polymorphism-polymerase chain reaction assay on patients' plasma both before and after therapy. Mutations were confirmed by direct sequencing.

Results: Common adverse events included grade 1 skin rash (63%), grade 1 to 2 gastrointestinal symptoms including anorexia, nausea, vomiting, and diarrhea occurred in 63% of patients, grade 3 nausea occurred in 45% of patients. Three patients did not complete therapy, only one was possibly associated with study drug. K-ras mutations were detected in the pre-gefitinib plasma of 5/11 patients and in the matched tumor tissue of 3/4 patients. In patients where k-ras mutations were undetectable post-treatment, survival times were favorable.

Conclusions: Combination of daily gefitinib with concurrent CRT in this locally advanced pancreatic cancer population was reasonably tolerated. Rapid changes in serum k-ras may provide critical information as to the efficacy of a novel agent and assist in tailoring treatment for cancers of the pancreas.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / blood
  • Adenocarcinoma / pathology
  • Adenocarcinoma / therapy
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biomarkers, Tumor / blood*
  • Combined Modality Therapy
  • DNA Mutational Analysis
  • Female
  • Gefitinib
  • Humans
  • Imaging, Three-Dimensional
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Neoplasm Staging
  • Paclitaxel / administration & dosage
  • Pancreatic Neoplasms / blood
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / therapy*
  • Polymerase Chain Reaction
  • Polymorphism, Restriction Fragment Length
  • Prognosis
  • Prospective Studies
  • Proto-Oncogene Proteins / blood*
  • Proto-Oncogene Proteins p21(ras)
  • Quinazolines / administration & dosage
  • Radiotherapy, Conformal*
  • Survival Rate
  • ras Proteins / blood*

Substances

  • Biomarkers, Tumor
  • KRAS protein, human
  • Proto-Oncogene Proteins
  • Quinazolines
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins
  • Paclitaxel
  • Gefitinib