TULIO EDUARDO FLESCH PFIFFER

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Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina - Médico

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  • article 37 Citação(ões) na Scopus
    Phase II trial of metformin and paclitaxel for patients with gemcitabine-refractory advanced adenocarcinoma of the pancreas
    (2015) BRAGHIROLI, Maria Ignez; FERRARI, Anezka C. R. de Celis; PFIFFER, Tulio Eduardo; ALEX, Alexandra Kichfy; NEBULONI, Daniela; CARNEIRO, Allyne S.; CAPARELLI, Fernanda; SENNA, Luiz; LOBO, Juliana; HOFF, Paulo Marcelo; RIECHELMANN, Rachel P.
    Background: In patients with adenocarcinoma of the pancreas, there are no standard second-line regimens. Many pre-clinical studies have shown that metformin alone or when combined with paclitaxel has antitumour effects on this tumour. We have tested here the combination of paclitaxel and metformin for patients with gemcitabine-refractory pancreatic cancer. Methods: An uncontrolled phase II trial was carried out based on a two-stage Simon's design, with metformin and paclitaxel for patients with locally advanced or metastatic pancreatic cancer whose disease had progressed during first line treatment with a gemcitabine-based regimen. The primary endpoint was the disease control rate at eight weeks as per response evaluation criteria in solid tumours (RECIST) 1.1. Patients received paclitaxel 80 mg/m(2) weekly for three weeks every 28 days and metformin 850 mg p.o. t.i.d. continuously until progression or intolerance state was reached. Results: Twenty patients were enrolled from July 2011 to January 2014: N = 6 (31.6%) achieved the primary endpoint, with all presenting stable disease. Median overall survival (OS) was 128 days (range 17-697) and the median progression free survival (PFS) was 44 days (range 14-210). Eight patients (40%) presented treatment-related G3-4 toxicities with the most common one being diarrhoea. Conclusions: Despite the encouraging pre-clinical evidence of the antitumour activity of metformin in adenocarcinoma of the pancreas, the primary endpoint of the disease control rate was not met. Besides, the treatment combination was poorly tolerated and could not be studied further. This study highlights the importance of performing clinical trials to reassure preclinical or observational data.
  • article 668 Citação(ões) na Scopus
    Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial
    (2015) ZHU, Andrew X.; PARK, Joon Oh; RYOO, Baek-Yeol; YEN, Chia-Jui; POON, Ronnie; PASTORELLI, Davide; BLANC, Jean-Frederic; CHUNG, Hyun Cheol; BARON, Ari D.; PFIFFER, Tulio Eduardo Flesch; OKUSAKA, Takuji; KUBACKOVA, Katerina; TROJAN, Jorg; SASTRE, Javier; CHAU, Ian; CHANG, Shao-Chun; ABADA, Paolo B.; YANG, Ling; SCHWARTZ, Jonathan D.; KUDO, Masatoshi
    Background VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis. Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 antagonist. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib. Methods In this randomised, placebo-controlled, double-blind, multicentre, phase 3 trial (REACH), patients were enrolled from 154 centres in 27 countries. Eligible patients were aged 18 years or older, had hepatocellular carcinoma with Barcelona Clinic Liver Cancer stage C disease or stage B disease that was refractory or not amenable to locoregional therapy, had Child-Pugh A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, had previously received sorafenib (stopped because of progression or intolerance), and had adequate haematological and biochemical parameters. Patients were randomly assigned (1:1) to receive intravenous ramucirumab (8 mg/kg) or placebo every 2 weeks, plus best supportive care, until disease progression, unacceptable toxicity, or death. Randomisation was stratified by geographic region and cause of liver disease with a stratified permuted block method. Patients, medical staff, investigators, and the funder were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01140347. Findings Between Nov 4, 2010, and April 18, 2013, 565 patients were enrolled, of whom 283 were assigned to ramucirumab and 282 were assigned to placebo. Median overall survival for the ramucirumab group was 9.2 months (95% CI 8.0-10.6) versus 7.6 months (6.0-9.3) for the placebo group (HR 0.87 [95% CI 0.72-1.05]; p=0.14). Grade 3 or greater adverse events occurring in 5% or more of patients in either treatment group were ascites (13 [5%] of 277 patients treated with ramucirumab vs 11 [4%] of 276 patients treated with placebo), hypertension (34 [12%] vs ten [4%]), asthenia (14 [5%] vs five [2%]), malignant neoplasm progression (18 [6%] vs 11 [4%]), increased aspartate aminotransferase concentration (15 [5%] vs 23 [8%]), thrombocytopenia (13 [5%] vs one [<1%]), hyperbilirubinaemia (three [1%] vs 13 [5%]), and increased blood bilirubin (five [2%] vs 14 [5%]). The most frequently reported (>= 1%) treatment-emergent serious adverse event of any grade or grade 3 or more was malignant neoplasm progression. Interpretation Second-line treatment with ramucirumab did not significantly improve survival over placebo in patients with advanced hepatocellular carcinoma. No new safety signals were noted in eligible patients and the safety profile is manageable.
  • article 10 Citação(ões) na Scopus
    Expression of ERCC1, Bcl-2, Lin28a, and Ki-67 as biomarkers of response to first-line platinum-based chemotherapy in patients with high-grade extrapulmonary neuroendocrine carcinomas or small cell lung cancer
    (2017) REGO, Juliana Florinda de M; MEDEIROS, Raphael Salles Scortegagna de; BRAGHIROLI, Maria Ignez; GALVAO, Breno; BEZERRA NETO, Joao Evangelista; MUNHOZ, Rodrigo Ramella; GUERRA, Juliana; NONOGAKI, Suely; KIMURA, Lidia; PFIFFER, Tulio Eduardo; CASTRO JR., Gilberto de; HOFF, Paulo Marcelo; FILHO, Duilio Rocha; COSTA, Frederico Perego; RIECHELMANN, Rachel P.
    Background: Small cell lung cancer (SCLC) and high-grade extrapulmonary neuroendocrine carcinomas (EPNEC) share similar histopathological features and treatment, but outcomes may differ. We evaluated in our study the expression of biomarkers associated with response rate (RR) to chemotherapy and overall survival (OS) for these entities. Materials and Methods: This is a multicentre retrospective analysis of advanced EPNEC and SCLC patients treated with platinum-based chemotherapy. Paraffin-embedded tumour samples were reviewed by a single pathologist and tested for immunohistochemistry (IHC) expression of Ki-67, ERCC1, Bcl-2, and Lin28a. All images were evaluated by the same radiologist and RR was determined by RECIST 1.1. Results: From July, 2006 to July, 2014, 142 patients were identified, being 82 (57.7%) SCLC and 60 (42.3%) EPNEC. Clinical characteristics and median Ki-67 (SCLC: 60%; EPNEC: 50%; p = 0.86) were similar between the groups. RR was higher for SCLC patients (86.8% versus 44.6%; p<0.001), but median OS was similar (10.3 months in SCLC and 11.1 months in EPNEC; HR 0.69, p = 0.07). Bcl-2 expression was higher in SCLC patients (46.3% versus 28.3%, p = 0.03) and was associated with worse prognosis in EPNEC (median OS 8.0 months versus 14.7 months; HR 0.47, p = 0.02). Conclusion: EPNEC patients presented inferior RR to platinum-based chemotherapy than SCLC but tended to live longer. Neither ERCC1, Lin28, or Ki-67 were prognostic or predictive for RR in EPNEC or SCLC. High Bcl-2 expression was associated with poor prognosis in EPNEC patients.