Molecular and Clinical Responses in a Pilot Study of Gefitinib With Paclitaxel and Radiation in Locally Advanced Head-and-Neck Cancer

Head and Neck Surgery Branch, National Institute of Deafness and Communication Disorders, National Institutes of Health, Bethesda, MD, USA.
International journal of radiation oncology, biology, physics (Impact Factor: 4.26). 10/2009; 77(2):447-54. DOI: 10.1016/j.ijrobp.2009.05.037
Source: PubMed


Epidermal growth factor receptor (EGFR) overexpression in head-and-neck squamous cell carcinoma (HNSCC) stimulates tumor cell proliferation, inhibits apoptosis, and increases chemotherapy and radiation resistance. We examined the toxicity, safety and the effects on EGFR signaling in tumor biopsy samples from patients with locally advanced HNSCC treated with the EGFR signaling inhibitor gefitinib (GEF) combined with weekly intravenous paclitaxel (PAC) and radiation therapy (RT).
This was a pilot Phase I dose-escalation study. Eligibility included Stage III to IVB HNSCC, age >or=18 years, no prior RT or chemotherapy, adequate organ function, and informed consent. Endpoints included determination of maximum tolerated dose (MTD) and analysis of treatment effect on EGFR signaling, tumor cell proliferation, and apoptosis in biopsy samples.
Ten patients were treated. The MTD of this combination was GEF 250 mg/d with PAC 36 mg/m(2) intravenously weekly x 6 with concurrent RT. Grade 3/4 toxicities included prolonged (>8 weeks) stomatitis (7 patients), infection (2 patients), and interstitial pneumonitis (1 patient). There were five complete responses (CR) and two partial responses (PR). Of 7 patients undergoing serial biopsies, only 1 patient demonstrated a reduction in phosphorylated EGFR, decreased downstream signaling, and reduced cellular proliferation after initiating GEF.
Inhibition of EGFR by GEF was observed in only one of seven tumors studied. The addition of GEF to PAC and RT did not appear to improve the response of locally advanced HNSCC compared with our prior experience with PAC and RT alone. This treatment appeared to delay recovery from stomatitis.

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    • "2010 I Glioma 55.8 Gy þ gefitinib Trial stopped early due to haemorrhage; later thought to be unrelated to gefitinib Gefitinib [23] 2010 I HNSCC IR þ paclitaxel þ gefitinib Toxicity limits clinical acceptability; no improvement in CRR Gefitinib [24] "
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    • "Head and neck squamous cell carcinomas (HNSCCs) have been the subject for clinical or preclinical studies of several targeted agents against a few commonly activated or inactivated pathways, including epidermal growth factor receptor (EGFR; cetuximab, gefitinib, and erlotinib) [1] [2] [3] [4] [5], proteasome-dependent nuclear factor κB (NF-κB) activation (bortezomib) [6] [7], signal transducer and transcription factor 3 (STAT3; decoy oligonucleotide) [8], and disrupted tumor suppressor TP53 (TP53 adenovirus) [9]. These agents have demonstrated significant target-specific and preclinical activity but modest clinical activity at achievable concentrations as monotherapy or in combination with conventional therapies [1] [2] [3] [4] [5] [6] [7] [8] [9]. "
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