RESUMEN
PURPOSE: On the basis of synergistic effects between green tea polyphenon E (PPE) and EGFR-tyrosine kinase inhibitor in preclinical studies, we conducted a phase Ib study of the PPE and erlotinib combination in patients with advanced premalignant lesions (APL) of the oral cavity and larynx. PATIENTS AND METHODS: Patients were treated with a fixed dose of PPE (200 mg three times a day) and dose escalation of erlotinib (50, 75, 100 mg daily) for 6 months with tissue biopsy at baseline and 6 months. Primary endpoints were safety and toxicity; secondary endpoints were evaluation of pathologic response, cancer-free survival (CFS), overall survival (OS), and biomarker modulation. RESULTS: Among 21 enrolled patients, 19 began treatment and 17 completed 6 months of treatment with PPE and erlotinib. Main characteristics of treated patients: 15 severe dysplasia or carcinoma in situ and 17 oral cavity. Only skin rash was associated with dose-limiting toxicity and MTD. Recommended doses for phase II studies are PPE 600 mg daily plus erlotinib 100 mg daily for 6 months. Pathologic responses in 17 evaluable patients: pathologic complete response (47%) and pathologic partial response (18%). The 5-year CFS and OS were 66.3% and 93%, respectively. Among tested biomarkers, only phosphorylated ERK was correlated with response to treatment. CONCLUSIONS: Treatment with PPE and erlotinib combination was well tolerated in patients with APLs of the head and neck, and showed a high rate of pathologic response with excellent CFS. This combination deserves further investigation for the chemoprevention and/or prevention of second primary tumors in early-stage head and neck cancer.
Asunto(s)
Catequina/análogos & derivados , Clorhidrato de Erlotinib/administración & dosificación , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Lesiones Precancerosas/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Catequina/administración & dosificación , Catequina/química , Clorhidrato de Erlotinib/química , Femenino , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Humanos , Estimación de Kaplan-Meier , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Té/químicaRESUMEN
Epidemiologic studies suggest that coffee intake is associated with reduced risk of oral/pharyngeal cancer. The authors examined associations of caffeinated coffee, decaffeinated coffee, and tea intake with fatal oral/pharyngeal cancer in the Cancer Prevention Study II, a prospective US cohort study begun in 1982 by the American Cancer Society. Among 968,432 men and women who were cancer free at enrollment, 868 deaths due to oral/pharyngeal cancer occurred during 26 years of follow-up. Cox proportional hazards regression was used to estimate multivariable-adjusted relative risk. Intake of >4 cups/day of caffeinated coffee was associated with a 49% lower risk of oral/pharyngeal cancer death relative to no/occasional coffee intake (relative risk = 0.51, 95% confidence interval: 0.40, 0.64) (1 cup/day = 237 ml). A dose-related decline in relative risk was observed with each single cup/day consumed (P(trend) < 0.001). The association was not modified by sex, smoking status, or alcohol use. An inverse association for >2 cups/day of decaffeinated coffee intake was suggested (relative risk = 0.61, 95% confidence interval: 0.37, 1.01). No association was found for tea drinking. In this large prospective study, caffeinated coffee intake was inversely associated with oral/pharyngeal cancer mortality. Research is needed to elucidate biologic mechanisms whereby coffee might help to protect against these often fatal cancers.