RESUMO
PURPOSE: Patients with glioblastoma (GBM) have a dismal prognosis. Although the DNA alkylating agent temozolomide (TMZ) is the mainstay of chemotherapy, therapeutic resistance rapidly develops in patients. Base excision repair inhibitor TRC102 (methoxyamine) reverses TMZ resistance in preclinical glioma models. We aimed to investigate the efficacy and safety of oral TRC102+TMZ in recurrent GBM (rGBM). PATIENTS AND METHODS: A preregistered (NCT02395692), nonrandomized, multicenter, phase 2 clinical trial (BERT) was planned and conducted through the Adult Brain Tumor Consortium (ABTC-1402). Arm 1 included patients with bevacizumab-naïve GBM at the first recurrence, with the primary endpoint of response rates. If sufficient activity was identified, a second arm was planned for the bevacizumab-refractory patients. The secondary endpoints were overall survival (OS), progression-free survival (PFS), PFS at 6 months (PFS6), and toxicity. RESULTS: Arm 1 enrolled 19 patients with a median of two treatment cycles. Objective responses were not observed; hence, arm 2 did not open. The median OS was 11.1 months [95% confidence interval (CI), 8.2-17.9]. The median PFS was 1.9 months (95% CI, 1.8-3.7). The PFS6 was 10.5% (95% CI, 1.3%-33.1%). Most toxicities were grades 1 and 2, with two grade 3 lymphopenias and one grade 4 thrombocytopenia. Two patients with PFS ≥ 17 months and OS > 32 months were deemed "extended survivors." RNA sequencing of tumor tissue, obtained at diagnosis, demonstrated significantly enriched signatures of DNA damage response (DDR), chromosomal instability (CIN70, CIN25), and cellular proliferation (PCNA25) in "extended survivors." CONCLUSIONS: These findings confirm the safety and feasibility of TRC102+TMZ in patients with rGBM. They also warrant further evaluation of combination therapy in biomarker-enriched trials enrolling GBM patients with baseline hyperactivated DDR pathways.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Recidiva Local de Neoplasia , Temozolomida , Humanos , Temozolomida/uso terapêutico , Temozolomida/administração & dosagem , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioblastoma/genética , Glioblastoma/mortalidade , Feminino , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Adulto , Idoso , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Reparo do DNA/efeitos dos fármacos , Hidroxilaminas/uso terapêutico , Hidroxilaminas/administração & dosagem , Prognóstico , Reparo por ExcisãoRESUMO
Evaluation at all levels is a fundamental function at World Health Organization (WHO). Evaluation of public health surveillance systems is essential to ensure that problems of public health importance are monitored efficiently and effectively. The WHO's Vitamin and Mineral Nutrition Information System (VMNIS) was evaluated from the perspective of public health surveillance and informatics. Steps included: engaging the stakeholders of the evaluation; describing the surveillance system; focusing the evaluation design; gathering credible evidence regarding system performance; justifying and stating conclusions and recommendations, and sharing lessons learned from the evaluation. Following this assessment, WHO has begun major efforts to upgrade and expand the VMNIS and now the database is more flexible and efficient. The database evaluation summarized in this paper provides a good example of how public health evaluation frameworks can lead to improved surveillance and enhanced information systems, thus making progress toward the ultimate goal of improving public health.
La evaluación en todos los niveles es una función fundamental en la Organización Mundial de la Salud (OMS). La evaluación de los sistemas de vigilancia epidemiológica es esencial para asegurar que los problemas de importancia para la salud pública sean monitorizados de manera eficiente y efectiva. El Sistema de Información Nutricional sobre Vitaminas y Minerales (VMNIS, por sus siglas en inglés) se evaluó desde la perspectiva de sistema de vigilancia e informática en salud pública. Los pasos incluyeron: el involucramiento de las partes interesadas en la evaluación, la descripción del sistema de vigilancia, el enfoque del diseño para la evaluación, la recopilación de pruebas fiables sobre el rendimiento del sistema, la justificación y desarrollo de conclusiones y recomendaciones, y la diseminación de las lecciones aprendidas de la evaluación. Después de este proceso, la OMS inició importantes esfuerzos para mejorar y ampliar el Sistema de Información Nutricional sobre Vitaminas y Minerales para lograr una base de datos más flexible y eficiente. Este artículo resume la evaluación de esta base de datos para documentar un buen ejemplo de cómo los marcos de evaluación en salud pública pueden llevar a mejorar la información en los sistemas de vigilancia contribuyendo de esta manera al objetivo final de mejorar la salud pública.