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

Christine C. Olsen, Tracey E. Schefter, Honglin Chen, Madeleine Kane, Stephen Leong, Martin D. McCarter, Yang Chen, Philip Mack, S. Gail Eckhardt, Greg Stiegmann, David Raben

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)115-121
Number of pages7
JournalAmerican Journal of Clinical Oncology: Cancer Clinical Trials
Volume32
Issue number2
DOIs
StatePublished - Apr 2009

Fingerprint

Paclitaxel
Biomarkers
Radiation
Therapeutics
Mutation
Pancreatic Neoplasms
Nausea
Pancreatic Carcinoma
gefitinib
Anorexia
Exanthema
Epidermal Growth Factor Receptor
Codon
Restriction Fragment Length Polymorphisms
Protein-Tyrosine Kinases
Vomiting
Diarrhea
Adenocarcinoma
Maintenance
Polymerase Chain Reaction

Keywords

  • Gefitinib
  • K-ras
  • Pancreatic adenocarcinoma
  • Radiation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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. / Olsen, Christine C.; Schefter, Tracey E.; Chen, Honglin; Kane, Madeleine; Leong, Stephen; McCarter, Martin D.; Chen, Yang; Mack, Philip; Eckhardt, S. Gail; Stiegmann, Greg; Raben, David.

In: American Journal of Clinical Oncology: Cancer Clinical Trials, Vol. 32, No. 2, 04.2009, p. 115-121.

Research output: Contribution to journalArticle

Olsen, Christine C. ; Schefter, Tracey E. ; Chen, Honglin ; Kane, Madeleine ; Leong, Stephen ; McCarter, Martin D. ; Chen, Yang ; Mack, Philip ; Eckhardt, S. Gail ; Stiegmann, Greg ; Raben, David. / 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. In: American Journal of Clinical Oncology: Cancer Clinical Trials. 2009 ; Vol. 32, No. 2. pp. 115-121.
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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.",
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AU - Schefter, Tracey E.

AU - Chen, Honglin

AU - Kane, Madeleine

AU - Leong, Stephen

AU - McCarter, Martin D.

AU - Chen, Yang

AU - Mack, Philip

AU - Eckhardt, S. Gail

AU - Stiegmann, Greg

AU - Raben, David

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N2 - 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.

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