title: Phase I trial of gefitinib with concurrent radiotherapy and fixed 2-h gemcitabine infusion, in locally advanced pancreatic cancer.
abstract: OBJECTIVE
  Pancreatic cancers are resistant to radiotherapy (RT) and current chemotherapy agents. Epidermal growth factor receptor is overexpressed in pancreatic cancer, and in vitro studies have shown that epidermal growth factor receptor inhibitors can overcome radio- and chemoresistance. The aim of the study was to determine whether the addition of gefitinib to RT and gemcitabine for patients with locally advanced pancreatic carcinoma (LAPC) was feasible and safe.
  
  
  METHODS
  Eighteen patients with pathologically proven LAPC, based on major vascular invasion based on helical computed tomography (CT) and endoscopic ultrasound, were entered into the study. The targeted irradiated volume included the tumor and 2-cm margin. Prophylactic irradiation of regional nodes was not allowed. Patients with >500 cm(3) of planning tumor volume were excluded. An initial cohort of 6 patients was treated with RT (45 Gy/25 fractions/5 weeks) plus concomitant gefitinib (250 mg/day). Successive cohorts of patients received 100, 150, and 200 mg/m(2)/day of gemcitabine in a 2-h infusion over Weeks 1, 2, 3, 4, and 5 with gefitinib (250 mg/day) and RT. Gefitinib was continued after RT until progression. A pharmacodynamic study of angiogenic markers was also performed to evaluate a possible antiangiogenic effect.
  
  
  RESULTS
  There were no dose-limiting toxicities. Common toxicities were mild neutropenia, asthenia, diarrhea, cutaneous rash and nausea/vomiting. The median (95% confidence interval [CI]) progression-free survival was 3.7 (95% CI = 1.9-5.5) months, and the median overall survival was 7.5 (95% CI = 5.2-9.9) months. No significant reduction of vascular endothelial growth factor and interleukin-8 was observed after treatment.
  
  
  CONCLUSIONS
  Our results support that the combination of gefitinib, RT, and gemcitabine has an acceptable toxicity but with modest activity in LAPC.
authors.affiliation: Medical Oncology Department, Hospital Clinic, Institut dé Investigacions Biomediques Científiques Agustí Pi I Suryer (IDIBAPS), University of Barcelona, Barcelona, Catalonia, Spain. jmaurel@clinic.ub.es
authors.forename: Joan
authors.initials: J
authors.lastname: Maurel
authors.forename: Marta
authors.initials: M
authors.lastname: Martin-Richard
authors.forename: Carlos
authors.initials: C
authors.lastname: Conill
authors.forename: Marcelo
authors.initials: M
authors.lastname: Sánchez
authors.forename: Lourdes
authors.initials: L
authors.lastname: Petriz
authors.forename: Angels
authors.initials: A
authors.lastname: Ginès
authors.forename: Rosa
authors.initials: R
authors.lastname: Miquel
authors.forename: Rosa
authors.initials: R
authors.lastname: Gallego
authors.forename: Rosana
authors.initials: R
authors.lastname: Cajal
authors.forename: Carmen
authors.initials: C
authors.lastname: Ayuso
authors.forename: Salvador
authors.initials: S
authors.lastname: Navarro
authors.forename: Maribel
authors.initials: M
authors.lastname: Marmol
authors.forename: Cristina
authors.initials: C
authors.lastname: Nadal
authors.forename: Josep Maria
authors.initials: JM
authors.lastname: Augé
authors.forename: Laureano
authors.initials: L
authors.lastname: Fernández-Cruz
authors.forename: Pere
authors.initials: P
authors.lastname: Gascón
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003131:Combined Modality Therapy / Q000379:methods; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D004334:Drug Administration Schedule; D005240:Feasibility Studies; D005260:Female; D000077156:Gefitinib; D006801:Humans; D016209:Interleukin-8 / Q000097:blood; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D011879:Radiotherapy Dosage; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D000093542:Gemcitabine
chemical_list: D016209:Interleukin-8; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D003841:Deoxycytidine; D000077156:Gefitinib; D000093542:Gemcitabine