Background: Gefitinib, an orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces growth arrest in 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 RT and drugs interfering with the EGF pathway may result in radiosensitization in squamous cell carcinomas that over express EGFR.in radiosensitization in squamous cell carcinomas that over express EGFR. Methods: Pts with histologically confirmed, newly diagnosed, locally advanced inoperable SCCHN, never pretreated with surgery, chemotherapy or RT were enrolled into a phase I-II trial of gefitinib and RT. Two doses of gefitinib were tested (250 and 500 mg/day) in the dose-escalation phase and continued for up to 12 months; RT was administered concomitantly according to standard procedures (minimum of 52.0 grays; boost to the primary tumor site up to at least 64.0 grays). The recommended dose of gefitinib for phase II was determined by the dose-limiting toxicities (DLTs) observed during its combined administration with RT and for 2 weeks thereafter (phase I). Activity was evaluated 4 weeks after the end of the combined treatment and every 8 weeks thereafter, according to RECIST criteria. Results: 12 pts (9 M, 3 F, median age 58) have been evaluated thus far. The most common primary tumor site was the hypopharynx (5 cases); TNM stage was IV A (10 pts) and IV B (2 pts); tumor grades were 1 (2 pts), 2 (6 pts) and 3 (4 pts). All pts completed the combined treatment according to the protocol. Total radiation dose was 60-74 grays. Overall best response was complete response in 3 pts, partial response in 5 pts, and unconfirmed partial response in 1 pt; 3 pts were not evaluable. Gefitinib-related grade 3 toxicities were mucositis (n = 1), liver toxicity (n = 1). RT-related grade 3 toxicities were stomatitis/mucositis (n =5), general health deterioration (n = 1). Three pts died during treatment with gefitinib alone (not considered treatment related). DLT occurred in 3 pts treated with gefitinib 500 mg (grade 3 stomatitis, 3 pts [RT-related]; grade 3 ALT increased, 1 pt [gefitinibrelated]), and therefore 250 mg was selected as the recommended gefitinib dose for phase I1. Conclusion: Accrual is continuing in the phase II trial. More mature data will be presented.
A phase I-II trial of gefitinib (IRESSA) and radiotherapy in patients with locally advanced inoperable squamous cell carcinoma of the head and neck (SCCHN)
PEPE, Stefano
2005-01-01
Abstract
Background: Gefitinib, an orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces growth arrest in 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 RT and drugs interfering with the EGF pathway may result in radiosensitization in squamous cell carcinomas that over express EGFR.in radiosensitization in squamous cell carcinomas that over express EGFR. Methods: Pts with histologically confirmed, newly diagnosed, locally advanced inoperable SCCHN, never pretreated with surgery, chemotherapy or RT were enrolled into a phase I-II trial of gefitinib and RT. Two doses of gefitinib were tested (250 and 500 mg/day) in the dose-escalation phase and continued for up to 12 months; RT was administered concomitantly according to standard procedures (minimum of 52.0 grays; boost to the primary tumor site up to at least 64.0 grays). The recommended dose of gefitinib for phase II was determined by the dose-limiting toxicities (DLTs) observed during its combined administration with RT and for 2 weeks thereafter (phase I). Activity was evaluated 4 weeks after the end of the combined treatment and every 8 weeks thereafter, according to RECIST criteria. Results: 12 pts (9 M, 3 F, median age 58) have been evaluated thus far. The most common primary tumor site was the hypopharynx (5 cases); TNM stage was IV A (10 pts) and IV B (2 pts); tumor grades were 1 (2 pts), 2 (6 pts) and 3 (4 pts). All pts completed the combined treatment according to the protocol. Total radiation dose was 60-74 grays. Overall best response was complete response in 3 pts, partial response in 5 pts, and unconfirmed partial response in 1 pt; 3 pts were not evaluable. Gefitinib-related grade 3 toxicities were mucositis (n = 1), liver toxicity (n = 1). RT-related grade 3 toxicities were stomatitis/mucositis (n =5), general health deterioration (n = 1). Three pts died during treatment with gefitinib alone (not considered treatment related). DLT occurred in 3 pts treated with gefitinib 500 mg (grade 3 stomatitis, 3 pts [RT-related]; grade 3 ALT increased, 1 pt [gefitinibrelated]), and therefore 250 mg was selected as the recommended gefitinib dose for phase I1. Conclusion: Accrual is continuing in the phase II trial. More mature data will be presented.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
