RESUMO
Advanced hepatocellular carcinoma (aHCC) is a complex disease beset by underlying liver dysfunction and high molecular heterogeneity. Sorafenib, introduced in 2007, is considered the standard systemic therapy for aHCC, yet only a minority of patients show objective evidence of a response radiologically, and median overall survival is still under 1 year. Other targeted drugs for the treatment of aHCC have failed to reach their primary endpoints of improved/non-inferior overall survival in comparison with sorafenib in recent phase 3 trials. Toxicity was a significant problem, raising the question as to whether outcomes in aHCC trials are being hindered by high levels of adverse events (AEs), particularly in populations with underlying cirrhosis. This is true of six recently failed phase 3 studies involving sunitinib, erlotinib, linifanib, brivanib (two trials), and everolimus, as well as ongoing phase 2 and 3 trials of other drugs that work through similar molecular pathways. This article reviews these drugs' toxicities, with a focus on AEs as a reason for their failure in phase 3 trials of patients with aHCC. We also review completed and ongoing phase 3 studies of combination therapies with sorafenib, as well as toxicities of many of the targeted agents in aHCC, including geographic/ethnic differences, measures of toxicity, and strategies to improve management.
Assuntos
Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Terapia de Alvo Molecular/efeitos adversos , Ensaios Clínicos como Assunto , HumanosRESUMO
Mass spectrometric profiling approaches such as MALDI-TOF and SELDI-TOF are increasingly being used in disease marker discovery, particularly in the lower molecular weight proteome. However, little consideration has been given to the issue of sample size in experimental design. The aim of this study was to develop a protocol for the use of sample size calculations in proteomic profiling studies using MS. These sample size calculations can be based on a simple linear mixed model which allows the inclusion of estimates of biological and technical variation inherent in the experiment. The use of a pilot experiment to estimate these components of variance is investigated and is shown to work well when compared with larger studies. Examination of data from a number of studies using different sample types and different chromatographic surfaces shows the need for sample- and preparation-specific sample size calculations.
Assuntos
Análise Serial de Proteínas/métodos , Proteoma/análise , Projetos de Pesquisa , Análise de Variância , Proteínas Sanguíneas/análise , Humanos , Espectrometria de Massas , Plasma/química , Tamanho da AmostraRESUMO
PURPOSE AND EXPERIMENTAL DESIGN: The human Ras association domain family 1A gene (RASSF1A) is a newly isolated tumor suppressor gene. In this study, we analyzed the methylation status of the promoter region of RASSF1A using bisulfite sequencing and PCR-RFLP in four liver cancer cell lines (Hep3B, HepG(2), SK-HEP-1, and Huh-7) and a cohort of 43 hepatitis B virus-associated hepatocellular carcinoma (HCC) tissues and their corresponding nontumor tissue specimens. RESULTS: The methylation of the CpG islands in the RASSF1A promoter was not detected in 4 samples of normal liver tissue or 10 samples of peripheral blood mononuclear cells from normal subjects. However, the CpG islands were completely methylated, and transcription of the RASSF1A was silenced in the four cell lines. Treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine reactivated the expression of RASSF1A in the Hep3B and HepG2 cells. In 41 of 43 (95%) HCC specimens studied, the promoter region of RASSF1A was intensively methylated at its CpG sites. Although heterogeneous methylation was also detected in 16 of the 23 (70%) corresponding nontumorous tissues analyzed, the level of methylation was significantly lower than in the corresponding tumor tissues. CONCLUSIONS: HCC has the highest incidence of promoter methylation of RASSF1A among all malignancies yet reported suggesting that hypermethylation of the CpG island promoter of RASSF1A may play an important pathological role in this tumor.
Assuntos
Carcinoma Hepatocelular/genética , Ilhas de CpG , Metilação de DNA , Vírus da Hepatite B/metabolismo , Neoplasias Hepáticas/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Linhagem Celular , Linhagem Celular Tumoral , Estudos de Coortes , Feminino , Genes Supressores de Tumor , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição , Regiões Promotoras Genéticas , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sulfitos/farmacologiaRESUMO
In the Asia-Pacific region and elsewhere, almost 85% of patients with hepatocellular carcinoma (HCC) are inoperable at diagnosis and have a dismal prognosis. Tamoxifen (TMX) is believed to inhibit HCC positive for estrogen receptor (ER), but most HCCs are ER negative. Results of previous phase 3 trials in inoperable HCC have been conflicting and inconclusive. At higher doses, however, TMX inhibits HCC through ER-independent mechanisms. A multicenter randomized controlled trial was performed to assess the role of high-dose TMX versus placebo (P) in the treatment of patients with inoperable HCC with respect to survival and quality of life (QoL). A total of 329 patients from 10 centers in 9 countries in the Asia-Pacific region enrolled in a double-blind randomized controlled trial of TMX 120 mg/d (TMX120) against P as a control arm with an intermediate dosage of TMX 60 mg/d (TMX60) to assess possible dose response. An independent data monitoring committee reviewed all aspects of the trial. QoL was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire. Three-month survival rates for the P, TMX60, and TMX120 groups were 44%, 41%, and 35%, respectively, with a statistically significant trend difference in survival across the 3 treatment regimens (P =.011). There was a significantly higher risk of death in the TMX120 group compared with the P group (hazard ratio, 1.39; 95% confidence interval, 1.07-1.81). Adverse drug reactions were reported in 3% (9 patients), and 8 patients were lost to follow-up. In conclusion, TMX does not prolong survival in patients with inoperable HCC and has an increasingly negative impact with increasing dose. No appreciable advantage to QoL with TMX was observed.
Assuntos
Antineoplásicos Hormonais/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Tamoxifeno/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/efeitos adversos , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/psicologia , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/psicologia , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Qualidade de Vida , Tamoxifeno/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: This study prospectively examines the prognostic role of p53 oncoprotein (p53), Ki67-antigen (Ki67), tumor angiogenesis (MVD), epidermal growth factor receptor (EGFR), and HER2 receptor protein (HER2) expression in Chinese with undifferentiated nasopharyngeal carcinoma (NPC). METHODS: Seventy-eight Chinese were recruited from October 1995 to July 1997 at the Prince of Wales Hospital, Hong Kong. Pretreatment immunohistochemical preparations of the primary tumor were made, and clinical data were collected prospectively until October 30, 2000. The markers were correlated with overall survival (OS), disease-free survival (DFS), time to progression (TTP), and UICC stage. RESULTS: On univariate analysis, EGFR expression correlated with poorer OS (p =.0001), DFS (p =.01), shorter TTP (p =.0001), and advanced T stage (p =.036). Strong EGFR expression, when compared with weak or moderate, was associated with poorer OS (p =.04) and shorter TTP in a subgroup of patients with UICC stage III-IV disease. HER2 expression was associated with advanced UICC stage (p =.006). The presence of p53 expression correlated with poorer DFS (p =.01) and a trend toward shorter TTP (p =.06). No correlation was found with Ki67-antigen or MVD. On multivariate analysis, only EGFR expression was significantly linked to shorter OS and TTP. CONCLUSIONS: EGFR expression in undifferentiated NPC is associated with a poor clinical outcome. A prognostic role of p53 and HER2 expression is suggestive but not consistently defined in this study. The relatively high prevalence of positive staining for EGFR supports the use of molecular targeted therapy in this disease.