Luciano de Souza Viana

Aflibercept versus placebo in combination with docetaxel/prednisone for first-line treatment of men with metastatic castration-resistant prostate cancer (mCRPC): Results from the multinational phase III trial (VENICE).

13 Background: Docetaxel/prednisone is standard first-line chemotherapy for mCRPC. Aflibercept (known as ziv-aflibercept in the US) is a recombinant human fusion protein that binds VEGF-A, VEGF-B and Placental Growth Factor (PlGF), thereby inhibiting angiogenesis. METHODS VENICE was a double-blind, randomized phase III study with overall survival (OS) as primary endpoint. Men with mCRPC, ECOG PS 0-2, adequate organ function and no prior cytotoxic therapy were treated with docetaxel (75 mg/m² iv q3w) and oral prednisone (5mg bid) and randomized double blind 1:1 to receive aflibercept (A) 6 mg/kg or placebo (Pbo), IV every 3 weeks. Pts were stratified by ECOG PS (0-1 vs 2). For final OS analysis, 873 deaths were required to detect a hazard ratio (HR) of 0.8 with 90% power (overall 2-sided α = 0.05). RESULTS From Aug 2007 to Feb 2010, 1224 patients (median age 68 yr, PS 0-1 96%) were randomized. Baseline characteristics were well balanced between arms. Median number of cycles was 8 (A) and 9 (Pbo). Median relative dose intensity was >0.93 for A, Pbo and docetaxel. At final cut-off, median follow-up was 35.4 mos and 873 pts had died. Results for primary and key secondary endpoints with confidence intervals are in the table. Higher incidence of all grade hypertension, stomatitis, appetite disorders, diarrhea, dehydration, epistaxis, dysphonia, cough, headache and infections was observed in the aflibercept arm. CONCLUSIONS Aflibercept in combination with docetaxel/prednisone given as first line chemotherapy for mCRPC did not lead to a statistically significant improvement in OS and added toxicity. (NCT00519285 sponsored by Sanofi and Regeneron Pharmaceuticals, Inc.) Clinical trial information: NCT00519285. [Table: see text].

MiR-21 as prognostic biomarker in head and neck squamous cell carcinoma patients undergoing an organ preservation protocol

Despite progress in the treatment of head and neck squamous cell carcinoma (HNSCC) in recent decades, including new surgical techniques, radiotherapy advances and chemotherapy schedules, the prognosis for the affected patients has not improved at the same pace, and still, most HNSCC patients are diagnosed in advanced stages. To increase their survival, the development of better screening methods for early detection is required and appropriate tailored therapeutic interventions are desired. The aim of the present study was to evaluate miRNAs as prognostic biomarkers in patients undergoing organ preservation protocol for locally advanced HNSCC. For this purpose, we assessed the global miRNA expression profile of 15 HNSCC patients (‘screening set’) to identify miRNAs differentially expressed in responders and non-responders to therapy. Four miRNAs differentially expressed in HNSCC samples from the ‘screening set’ were validated in a different cohort of patients (47 samples - ‘validation set’). The results from the ‘validation set’ showed that the higher expression of one of these miRNAs, miR-21, was negatively associated with the treatment response to the organ preservation protocol (p=0.029). A multivariate analysis showed that, in a model adjusted for age, tumor site, p16 immunoexpression and tumor resectability, high expression of miR-21 remained an independent predictor of poor response to the organ preservation protocol (OR=5.69; 95%CI 1.27-25.58; p=0.023), together with clinical stage IV (OR=5.05; 95%CI 1.22-20.88; p=0.025). Furthermore, considering the entire cohort, patients with high expression of miR-21 had worse survival. A multivariate Cox regression analysis also showed miR-21 (HR=2.05; 95%CI 1.05-4.02; p=0.036) and clinical stage IV (HR=3.17; 95%CI 1.49-6.77; p=0.003) as independent prognostic factors (model adjusted for age, tumor site, tumor resectability, and sets ‘screening’ or ‘validation’). In conclusion, the results of this study suggest that the evaluation of miR-21 expression could be an important tool for treatment planning and a prognosis predictior for HNSCC patients undergoing organ preservation protocols.

Evaluation of PD-L1 Expression in Tumor Tissue of Patients with Lung Carcinoma and Correlation with Clinical and Demographic Data

Lung cancer is the leading world cause of cancer-related death, in both genders, and smoking is the main etiological factor. The discovery of immune checkpoints corroborates the hypothesis that ligands presented in tumors modulate the mechanisms of carcinogenesis and the immune activity of tumor microenvironment. Among the most studied coregulatory molecules, PD-1 (programmed cell death 1) and its ligand PD-L1 (programmed cell death 1 ligand 1) are noteworthy. The present study aims to enhance the understanding of the tumor microenvironment of lung cancer patients who underwent surgery, by means of analysis of PD-L1 expression in tumor cells and in intratumoral immune cells (IICs). It was found that PD-L1 expression was more frequent in tumor cells than in IICs. Collective analysis by Tissue Microarray Assay (TMA) for PD-L1 expression in tumor cells and IICs did not reproduce the findings for separate individual analysis of tumor tissues. Patients with past history of smoking were more likely to express PD-L1 in tumor cells than those who never smoked. Patients with past history of smoking were less likely to have PD-L1 positive IICs compared to those who had never smoked. The immunohistochemical expression of PD-L1 in tumor cells and IICs did not correlate with survival.Lung cancer is the leading world cause of cancer-related death, in both genders, and smoking is the main etiological factor. The discovery of immune checkpoints corroborates the hypothesis that ligands presented in tumors modulate the mechanisms of carcinogenesis and the immune activity of tumor microenvironment. Among the most studied coregulatory molecules, PD-1 (programmed cell death 1) and its ligand PD-L1 (programmed cell death 1 ligand 1) are noteworthy. The present study aims to enhance the understanding of the tumor microenvironment of lung cancer patients who underwent surgery, by means of analysis of PD-L1 expression in tumor cells and in intratumoral immune cells (IICs). It was found that PD-L1 expression was more frequent in tumor cells than in IICs. Collective analysis by Tissue Microarray Assay (TMA) for PD-L1 expression in tumor cells and IICs did not reproduce the findings for separate individual analysis of tumor tissues. Patients with past history of smoking were more likely to express PD-L1 in tumor cells than those who never smoked. Patients with past history of smoking were less likely to have PD-L1 positive IICs compared to those who had never smoked. The immunohistochemical expression of PD-L1 in tumor cells and IICs did not correlate with survival.

Efficacy and safety of a cisplatin and paclitaxel induction regimen followed by chemoradiotherapy for patients with locally advanced head and neck squamous cell carcinoma

The purpose of this phase II trial was to evaluate the tolerability, safety, and efficacy of a non–5‐fluorouracil (5‐FU)‐based induction chemotherapy followed by chemoradiotherapy (CRT) for patients with locally advanced head and neck squamous cell carcinoma (HNSCC).

Eticidade do uso de placebo em pesquisa clínica: proposta de algoritmos decisórios

The use of placebos in clinical research has been a matter of considerable debate in recent years, notably when the World Medical Association published, in 2002, a note of clarification for paragraph 29 of the Helsinki Declaration. Brazil is known for its strong opposition to the flexible use of placebos. Both the Federal Council of Medicine and the National Health Council have published resolutions regulating the use of placebos in Brazil, preventing their use if there is a more effective therapeutic method already in place. The present study reinforces that position and aims to describe the various uses of placebos in clinical research, as well as examining the complex decisions relating to the ethics of their use. Additionally, the authors propose a reflection on the use of placebos through decision-making algorithms based on Brazilian ethical standards.The use of placebos in clinical research has been a matter of considerable debate in recent years, notably when the World Medical Association published, in 2002, a note of clarification for paragraph 29 of the Helsinki Declaration. Brazil is known for its strong opposition to the flexible use of placebos. Both the Federal Council of Medicine and the National Health Council have published resolutions regulating the use of placebos in Brazil, preventing their use if there is a more effective therapeutic method already in place. The present study reinforces that position and aims to describe the various uses of placebos in clinical research, as well as examining the complex decisions relating to the ethics of their use. Additionally, the authors propose a reflection on the use of placebos through decision-making algorithms based on Brazilian ethical standards.Tavares Guerreiro Fregnani, Jose Humberto; Lopes Carvalho, Andre; Rocha Lima Paranhos, Flavio; de Souza Viana, Luciano; Serrano, Sergio Vicente; Carcano, Flavio; Monteiro Ferreira, Joao Fernando; Solci Zier, Sandra; Anicio Magalhaes Gontijo, Pollyana; Stefanoff, Claudio Gustavo; Condeixa Franca, Paulo Henrique; de Almeida Bendati, Maria Mercedes; Marodin, Gabriela; de Almeida Venâncio, Jorge Alves Eticidade do uso de placebo em pesquisa clinica: proposta de algoritmos decisorios Revista Bioetica, vol. 23, num. 3, 2015, pp. 456-467 Conselho Federal de Medicina Brasilia, Brasil

Is Lipidomic the Answer to the Search of a Biomarker for Organ Preservation Protocol in Head and Neck Squamous Cell Carcinoma

In the last decade organ preservation protocols based on chemoradiotherapy (CRT) has been showing the possibility of preserving function without jeopardizing survival for locally advanced head and neck squamous cell carcinoma (HNSCC). Still, only a percentage of the patients will benefit from this approach and, to date, no biomarkers are known to correctly predict these patients. More recently, modern mass spectrometry method has been used to determine metabolic profiles, and lipidomics, in particular, emerged as a new field of study in oncology and other diseases. This study aimed to analyze the lipid profile on saliva from patients undergoing to a prospective, single center, open-label, non-randomized phase II trial for organ preservation on HNSCC. The lipid analysis was performed using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF-MS). Multivariate statistical analyses based on principal component analysis and orthogonal partial least square-discriminant analysis were applied to MALDI-TOF-MS data to visualize differences between the lipid profiles and identify potential biomarkers. The results assisted on distinguishing complete responders from non-responders to the treatment protocol. In conclusion, we demonstrated that a group of lipids is differentially abundant in saliva from HNSCC patients submitted to an organ preservation protocol, being able to differentiate responders from non-responders. These results suggest the potential use of lipid biomarkers to identify patients who may benefit from this treatment. Also, we showed that saliva testing might be routinely used in clinical practice, for being a non-invasive alternative to blood testing, besides inexpensive and easy to obtain.

Abstract A78: EGF+61 A>G polymorphism is not associated with lung cancer risk in Brazilian population

Lung cancer is a malignancy with high incidence and mortality, being in Brazil the second most common cancer in men and the fourth in women. Epidermal growth factor (EGF) and its receptor (EGFR) play a central role in lung carcinogenesis, once EGF/EGFR interaction activates several intracellular pathways that control cellular growth, proliferation, differentiation, migration, and apoptosis. The association has been described between a single nucleotide polymorphism (SNP) in EGF promoter region (EGF+61 A>G – rs4444903) and cancer susceptibility to distinct tumors, including melanoma, gliomas, gastric cancer, hepatocellular carcinoma, and others. In lung cancer, the results are still scarce and unclear, with different reports showing discrepant results. Therefore, the aim of this study is to evaluate the risk of lung cancer development associated with the EGF+61 A>G SNP in a Brazilian population. For that, 437 lung cancer patients and 1104 controls were included in this study. Following DNA isolation from both tumor (FFPE) and controls (blood), the EGF+61 A>G genotype was assessed by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP), and TaqMan Genotyping Assay, respectively. Statistical analysis included chi-square and Mann-Whitney tests, and logistic regression model to estimate Odds Ratios. As expected, uni- and multivariate analyses showed that tobacco consumption (p G polymorphism is not a risk factor for lung cancer in the Brazilian population. Citation Format: Ana Carolina Laus, Flavia Escremim de Paula, Marcos Alves de Lima, Carolina Dias Carlos, Izabela Natalia Faria Gomes, Pedro Rafael Martins de Marchi, Luciano de Souza Viana, Rui Manuel Vieira Reis. EGF+61 A>G polymorphism is not associated with lung cancer risk in Brazilian population [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; Sao Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A78.

Tumor volume as a prognostic factor in patients (pts) with locoregionally advanced head and neck squamous cell carcinoma (LAHNSCC) treated with induction chemotherapy (IC).

e17507Background: Tumor volume and the ratio of volumetric change have been demonstrated to have a prognostic role in head and neck cancers during definitive treatment in LAHNSCC. The aim of this s...

Efficacy and safety of a cisplatin and paclitaxel induction regimen followed by chemoradiotherapy for patients with locally advanced head and neck squamous cell carcinoma: Cisplatin and Paclitaxel Induction Chemotherapy for Locally Advanced HNSCC

The purpose of this phase II trial was to evaluate the tolerability, safety, and efficacy of a non–5‐fluorouracil (5‐FU)‐based induction chemotherapy followed by chemoradiotherapy (CRT) for patients with locally advanced head and neck squamous cell carcinoma (HNSCC).

Ética del uso del placebo en la investigación clínica: propuesta de algoritmos para la toma de decisiones

The use of placebos in clinical research has been a matter of considerable debate in recent years, notably when the World Medical Association published, in 2002, a note of clarification for paragraph 29 of the Helsinki Declaration. Brazil is known for its strong opposition to the flexible use of placebos. Both the Federal Council of Medicine and the National Health Council have published resolutions regulating the use of placebos in Brazil, preventing their use if there is a more effective therapeutic method already in place. The present study reinforces that position and aims to describe the various uses of placebos in clinical research, as well as examining the complex decisions relating to the ethics of their use. Additionally, the authors propose a reflection on the use of placebos through decision-making algorithms based on Brazilian ethical standards.The use of placebos in clinical research has been a matter of considerable debate in recent years, notably when the World Medical Association published, in 2002, a note of clarification for paragraph 29 of the Helsinki Declaration. Brazil is known for its strong opposition to the flexible use of placebos. Both the Federal Council of Medicine and the National Health Council have published resolutions regulating the use of placebos in Brazil, preventing their use if there is a more effective therapeutic method already in place. The present study reinforces that position and aims to describe the various uses of placebos in clinical research, as well as examining the complex decisions relating to the ethics of their use. Additionally, the authors propose a reflection on the use of placebos through decision-making algorithms based on Brazilian ethical standards.Tavares Guerreiro Fregnani, Jose Humberto; Lopes Carvalho, Andre; Rocha Lima Paranhos, Flavio; de Souza Viana, Luciano; Serrano, Sergio Vicente; Carcano, Flavio; Monteiro Ferreira, Joao Fernando; Solci Zier, Sandra; Anicio Magalhaes Gontijo, Pollyana; Stefanoff, Claudio Gustavo; Condeixa Franca, Paulo Henrique; de Almeida Bendati, Maria Mercedes; Marodin, Gabriela; de Almeida Venâncio, Jorge Alves Eticidade do uso de placebo em pesquisa clinica: proposta de algoritmos decisorios Revista Bioetica, vol. 23, num. 3, 2015, pp. 456-467 Conselho Federal de Medicina Brasilia, Brasil