RESUMO
Nanoliposomal irinotecan with fluorouracil and folinic acid (NFF) is a standard regimen after gemcitabine-based therapy for patients with unresectable or recurrent pancreatic cancer. However, there are limited clinical data on its efficacy and safety in the real-world. We therefore initiated a retrospective and prospective observational study (NAPOLEON-2). The results of the retrospective part were reported herein. In this retrospective study, we evaluated 161 consecutive patients who received NFF as second-or-later-line regimen. The main endpoint was overall survival (OS), and the other endpoints were response rate, disease control rate, progression-free survival (PFS), dose intensity, and adverse events (AEs). The median age was 67 years (range, 38-85 years). The median OS and PFS were 8.1 and 3.4 months, respectively. The objective response and disease control rates were 5% and 52%, respectively. The median relative dose intensity was 81.6% for nanoliposomal irinotecan and 82.9% for fluorouracil. Grade 3 or 4 hematological and nonhematological AEs occurred in 47 and 42 patients, respectively. Common grade 3 or 4 AEs included neutropenia (24%), anorexia (12%), and leukocytopenia (12%). Subanalysis of patients treated with second-line and third-or-later-line demonstrated no statistical significant difference in OS (7.6 months vs. 9.1 months, respectively; hazard ratio, 0.92; 95% confidence interval, 0.64-1.35; p = 0.68). In conclusion, NFF has acceptable efficacy and safety profile even in real-world clinical settings. The prospective study is in progress to validate these findings.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Fluoruracila , Irinotecano , Leucovorina , Lipossomos , Neoplasias Pancreáticas , Humanos , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Idoso , Leucovorina/administração & dosagem , Leucovorina/uso terapêutico , Leucovorina/efeitos adversos , Irinotecano/administração & dosagem , Irinotecano/uso terapêutico , Irinotecano/efeitos adversos , Feminino , Pessoa de Meia-Idade , Masculino , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/mortalidade , Idoso de 80 Anos ou mais , Estudos Retrospectivos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Resultado do Tratamento , Estudos ProspectivosRESUMO
Discrimination of oncogenic growth signals from normal growth signals is crucial for tumor suppression. The transcription factor E2F, the main target of pRB, plays central role in cell proliferation by activating growth-promoting genes. E2F also plays an important role in tumor suppression by activating growth-suppressive genes such as pro-apoptotic genes. The regulatory mechanism of the latter genes is not known in detail, especially in response to normal and oncogenic growth signals. E2F is physiologically activated by growth stimulation through phosphorylation of pRB. In contrast, upon dysfunction of pRB, a major oncogenic change, E2F is activated out of control by pRB, generating deregulated E2F activity. We show here that the tumor suppressor TAp73 gene, which can induce apoptosis independently of p53, responds to deregulated E2F activity, but not to physiological E2F activity induced by growth stimulation in human normal fibroblasts. We identified E2F-responsive elements (ERE73s) in TAp73 promoter that can specifically sense deregulated E2F activity. Moreover, RB1-deficient cancer cell lines harbored deregulated E2F activity that activated ERE73s and the TAp73 gene, which were suppressed by re-introduction of pRB. These results underscore the important role of deregulated E2F in activation of the TAp73 gene, a component of major intrinsic tumor suppressor pathways.