Introduction: Gefitinib, an orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces growth arrest in squamous cancer cell carcinoma of head and neck (SCCHN) cell lines mainly by blocking cells in G1 and preventing them from entering the cell cycle. Clinical studies have demonstrated the activity of gefitinib monotherapy in SCCHN. Preclinical studies have shown that the combination of radiotherapy (RT) and drugs interfering with the EGF pathway may result in radiosensitization in squamous cell carcinomas that over express EGFR. Purpose: Two different doses of gefitinib, administered along with standard radiation therapy, were tested in locally advanced inoperable head and neck cancer who have neiver received radiotherapy or chemotherapy or undergone surgery for head and neck carcinoma, with the aim of finding the maximum tolerated dose and assessing the toxicity and activity of the combination. Patients and methods: The standard “3+3” design was used for the phase I study. Radiation therapy was given according to conventional dose and schedule. Gefitinib dose escalation was stopped if more than a third of patients of a given cohort had dose limiting toxicity (DLT). Results: DLT was observed in 3 out of 4 patients treated at the dose of 500 mg and included grade 3 stomatitis in 3 patients and grade 3 liver toxicities in 1 patient. The dose level of 250 mg was recommended for the phase II study. Six confirmed objective responses were observed among 16 patients. Four patients had a complete response, which was confirmed in three cases; eight patients had a partial response, which was not confirmed in six patients. Stable disease and disease progression were observed in one and three patients, respectively. Median duration of response was 5.4 (range: 1–21) months. The observed stable disease lasted 7.4 months. The median progression free-survival was 6.7 months (95% CI: 4.5–12.1) and the median OS was 8.5 months. Conclusion: Our results do not support further trials with gefitinib and radiation therapy, according to our schedule, in this patient population. Integration of gefitinib within chemoradiotherapy regimens and combination with other biological therapies may represent the next challenge.

TESI DI DOTTORATO:Gefitinib and Radiotherapy in patients with locally advanced inoperable squamous cell carcinoma of the head and neck. CANDIDATO: C.Romano. RELATORE: S.Pepe.

PEPE, Stefano
2007

Abstract

Introduction: Gefitinib, an orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces growth arrest in squamous cancer cell carcinoma of head and neck (SCCHN) cell lines mainly by blocking cells in G1 and preventing them from entering the cell cycle. Clinical studies have demonstrated the activity of gefitinib monotherapy in SCCHN. Preclinical studies have shown that the combination of radiotherapy (RT) and drugs interfering with the EGF pathway may result in radiosensitization in squamous cell carcinomas that over express EGFR. Purpose: Two different doses of gefitinib, administered along with standard radiation therapy, were tested in locally advanced inoperable head and neck cancer who have neiver received radiotherapy or chemotherapy or undergone surgery for head and neck carcinoma, with the aim of finding the maximum tolerated dose and assessing the toxicity and activity of the combination. Patients and methods: The standard “3+3” design was used for the phase I study. Radiation therapy was given according to conventional dose and schedule. Gefitinib dose escalation was stopped if more than a third of patients of a given cohort had dose limiting toxicity (DLT). Results: DLT was observed in 3 out of 4 patients treated at the dose of 500 mg and included grade 3 stomatitis in 3 patients and grade 3 liver toxicities in 1 patient. The dose level of 250 mg was recommended for the phase II study. Six confirmed objective responses were observed among 16 patients. Four patients had a complete response, which was confirmed in three cases; eight patients had a partial response, which was not confirmed in six patients. Stable disease and disease progression were observed in one and three patients, respectively. Median duration of response was 5.4 (range: 1–21) months. The observed stable disease lasted 7.4 months. The median progression free-survival was 6.7 months (95% CI: 4.5–12.1) and the median OS was 8.5 months. Conclusion: Our results do not support further trials with gefitinib and radiation therapy, according to our schedule, in this patient population. Integration of gefitinib within chemoradiotherapy regimens and combination with other biological therapies may represent the next challenge.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11386/3882033
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