Phase I trial of gefitinib with concurrent radiotherapy and fixed 2-h gemcitabine infusion, in locally advanced pancreatic cancer.
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.
Maurel
Joan
J
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
Martin-Richard
Marta
M
Conill
Carlos
C
Sánchez
Marcelo
M
Petriz
Lourdes
L
Ginès
Angels
A
Miquel
Rosa
R
Gallego
Rosa
R
Cajal
Rosana
R
Ayuso
Carmen
C
Navarro
Salvador
S
Marmol
Maribel
M
Nadal
Cristina
C
Augé
Josep Maria
JM
Fernández-Cruz
Laureano
L
Gascón
Pere
P
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
D016209:Interleukin-8; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D003841:Deoxycytidine; D000077156:Gefitinib; D000093542:Gemcitabine