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1.
Invest New Drugs ; 40(3): 622-633, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35312941

RESUMO

Chemoradiotherapy (CRT) for locally-advanced head and neck squamous cell carcinoma (LA-HSNCC) yields 5-year survival rates near 50% despite causing significant toxicity. Dichloroacetate (DCA), a pyruvate dehydrogenase kinase metabolic inhibitor, reduces tumor lactate production and has been used in cancer therapy previously. The safety of adding this agent to CRT is unknown. Our randomized, placebo-controlled, double-blind phase II study added DCA to cisplatin-based CRT in patients with LA-HNSCC. The primary endpoint was safety by adverse events (AEs). Secondary endpoints compared efficacy via 3-month end-of-treatment response, 5-year progression-free and overall survival. Translational research evaluated pharmacodynamics of serum metabolite response. 45 participants (21 DCA, 24 Placebo) were enrolled from May 2011-April 2014. Higher rates of all-grade drug related fevers (43% vs 8%, p = 0.01) and decreased platelet count (67% vs 33%, p = 0.02) were seen in DCA versus placebo. However, there were no significant differences in grade 3/4 AE rates. Treatment compliance to DCA/placebo, radiation therapy, and cisplatin showed no significant difference between groups. While end-of-treatment complete response rates were significantly higher in the DCA group compared to placebo (71.4% vs 37.5%, p = 0.0362), survival outcomes were not significantly different between groups. Treatment to baseline metabolites demonstrated a significant drop in pyruvate (0.47, p < 0.005) and lactate (0.61, p < 0.005) in the DCA group. Adding DCA to cisplatin-based CRT appears safe with no detrimental effect on survival and expected metabolite changes compared to placebo. This supports further investigation into combining metabolic agents to CRT. Trial registration number: NCT01386632, Date of Registration: July 1, 2011.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de Cabeça e Pescoço , Oxirredutases , Carcinoma de Células Escamosas de Cabeça e Pescoço , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimiorradioterapia/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Ácido Dicloroacético/administração & dosagem , Ácido Dicloroacético/efeitos adversos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/enzimologia , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Oxirredutases/antagonistas & inibidores , Oxirredutases/metabolismo , Piruvatos/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/enzimologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia
2.
Int J Radiat Oncol Biol Phys ; 55(5): 1305-10, 2003 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-12654442

RESUMO

PURPOSE: In vitro studies suggest that low-dose gemcitabine sensitizes cells to radiation therapy and that this effect persists for 48 h after drug exposure. Cisplatin is a radiation sensitizer and is also synergistic with gemcitabine in some in vitro tumor systems. Gemcitabine's radiosensitizing properties can theoretically be exploited by twice-weekly administration. This study assessed toxicity in patients with pancreatic cancer treated with radiation therapy, gemcitabine, and cisplatin. METHODS AND MATERIALS: Patients with locally advanced pancreatic or gastric cancer were eligible. Gemcitabine and cisplatin were given twice weekly for 3 weeks during radiation therapy (50.4 Gy in 28 fractions). The starting dose of gemcitabine was 5 mg/m(2) i.v. The starting dose for cisplatin was 5 mg/m(2). Chemotherapy doses escalated every 3 to 6 patients according to a standard Phase I study design. RESULTS: Twenty-four evaluable patients, all with pancreatic cancer, were treated on this protocol. Grade 3 neutropenia occurred in 2 patients, Grade 3 thrombocytopenia occurred in 2, and Grade 4 lymphopenia occurred in 1. There was no clear relationship between chemotherapy dose and hematologic toxicity. The most common Grade 3-4 nonhematologic toxic responses were vomiting (7 patients) and nausea (7 patients). Dose-limiting toxicity consisting of Grade 4 nausea and vomiting occurred in 2 of 3 patients at dose Level 6 (gemcitabine 45 mg/m(2) i.v. and cisplatin 10 mg/m(2) i.v.). Six patients were treated at dose Level 5 (gemcitabine 30 mg/m(2) i.v. and cisplatin 10 mg/m(2) i.v.) without dose-limiting toxicity. CONCLUSION: Gemcitabine 30 mg/m(2) i.v. twice weekly and cisplatin 10 mg/m(2) i.v. twice weekly may be given concurrently with radiation therapy (50.4 Gy in 28 fractions) with acceptable toxicity.


Assuntos
Adenocarcinoma/radioterapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/radioterapia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Terapia Combinada , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacologia , Diarreia/etiologia , Esquema de Medicação , Feminino , Doenças Hematológicas/etiologia , Humanos , Tábuas de Vida , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Náusea/etiologia , Pancreatectomia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Radiossensibilizantes/administração & dosagem , Radiossensibilizantes/farmacologia , Análise de Sobrevida , Resultado do Tratamento , Vômito/etiologia , Gencitabina
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