RESUMO
OBJECTIVES: Cisplatin-induced ototoxicity is a common permanent consequence of curative chemoradiation for locally advanced head and neck squamous cell carcinoma (HNSCC). Predictors of ototoxicity in HNSCC were examined. MATERIALS AND METHODS: In this prospective, observational cohort study, 206 adult HNSCC patients underwent audiometric testing at baseline, during and after treatment with cisplatin-based chemoradiation. Ototoxicity was defined as ≥grade 2 audiometric change from baseline (CTCAE v4.02). Relationships between clinical and pharmacogenetic (TPMT, COMT, ACYP2, CTR1, OCT2, MATE1, ABCC2, ABCC3, and ABCG2) covariates and ototoxicity, progression-free (PFS) and overall survival (OS) were assessed by Cox regression. RESULTS: Weekly cisplatin resulted in lower ototoxicity risk while PFS and OS were similar compared to high dose cisplatin (Pâ¯=â¯0.00035; HRâ¯=â¯0.18; 95% CI, 0.07-0.46). COMT (rs9332377) carriers had higher ototoxicity risk (Pâ¯=â¯0.00556; HRâ¯=â¯1.72; 95% CI, 1.17-2.52) while MATE1 (rs2289669) A/A carriers were protected from ototoxicity (Pâ¯=â¯0.01062; HRâ¯=â¯0.46; 95% CI, 0.26-0.84). Absence of the protective MATE1 allele among those who carry the risk allele in COMT predicted increased ototoxicity risk, (Pâ¯=â¯0.00414; HRâ¯=â¯3.22; 95% CI, 1.45-7.17 and Pâ¯=â¯0.00022; HRâ¯=â¯4.89; 95% CI, 2.11-11.36). Survival outcomes did not differ between carriers of protective or risk alleles. CONCLUSIONS: Weekly cisplatin dosing, COMT and MATE1 are predictors of ototoxicity without affecting treatment efficacy. COMT and MATE1 genotyping and weekly dosing may be a potential strategy for mitigating cisplatin-induced ototoxicity in HNSCC.
Assuntos
Quimiorradioterapia/métodos , Cisplatino/efeitos adversos , Neoplasias de Cabeça e Pescoço/complicações , Ototoxicidade/etiologia , Adulto , Idoso , Feminino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 2 Associada à Farmacorresistência Múltipla , Ototoxicidade/patologia , Estudos Prospectivos , Taxa de SobrevidaRESUMO
PURPOSE: To determine the efficacy and safety of single-agent sorafenib in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) and nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: In this single-arm phase II trial, oral continuous sorafenib was administered in 28-day cycles. Patients had Assuntos
Antineoplásicos/uso terapêutico
, Benzenossulfonatos/uso terapêutico
, Carcinoma de Células Escamosas/tratamento farmacológico
, Neoplasias de Cabeça e Pescoço/tratamento farmacológico
, Neoplasias Nasofaríngeas/tratamento farmacológico
, Piridinas/uso terapêutico
, Adulto
, Idoso
, Carcinoma de Células Escamosas/mortalidade
, Carcinoma de Células Escamosas/secundário
, Progressão da Doença
, Intervalo Livre de Doença
, Feminino
, Neoplasias de Cabeça e Pescoço/mortalidade
, Neoplasias de Cabeça e Pescoço/patologia
, Humanos
, Masculino
, Pessoa de Meia-Idade
, Neoplasias Nasofaríngeas/mortalidade
, Neoplasias Nasofaríngeas/patologia
, Recidiva Local de Neoplasia
, Niacinamida/análogos & derivados
, Compostos de Fenilureia
, Inibidores de Proteínas Quinases/uso terapêutico
, Sorafenibe
, Taxa de Sobrevida
, Quinases raf/antagonistas & inibidores
RESUMO
PURPOSE: To determine the phase II dose and objective response rate of erlotinib, a selective epidermal growth factor receptor tyrosine kinase inhibitor, in combination with cisplatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC). PATIENTS AND METHODS: HNSCC patients with no prior chemotherapy and measurable disease were treated in three escalating-dose cohorts of daily continuous oral (PO) erlotinib and intermittent intravenous (IV) cisplatin given every 21 days. The recommended phase II dose (RPTD) was then evaluated in a two-stage trial with a primary end point of objective response rate. RESULTS: A total of 51 patients were enrolled. The RPTD was identified as erlotinib 100 mg PO daily and cisplatin 75 mg/m2 IV every 21 days. Forty-five patients were treated at the RPTD, of which 44 and 43 were eligible for toxicity and efficacy evaluations, respectively. The intention-to-treat response rate was 21%, with one complete and eight partial responses (95% CI, 10% to 36%), and disease stabilization was achieved in 21 patients (49%; 95% CI, 33% to 65%). Median progression-free survival was 3.3 months (95% CI, 2.7 to 4.8 months) and median overall survival was 7.9 (95% CI, 5.6 to 9.5) months. The combination was well tolerated, with minimal grade 3 or higher toxicity. Subgroup analysis suggested that patients who developed higher grade skin rashes during cycle 1 had better survival outcomes (P = .034). CONCLUSION: This schedule of erlotinib and cisplatin has a favorable toxicity profile and has antitumor activity in HNSCC comparable to standard combination chemotherapy regimens.