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Introduction Spinal cord injuries (SCI) have physiological, emotional, and economic consequences in the lives of affected people. Resistance training (RT) is efficient in improving several physiological factors, quality of life, and body composition. Evidence acquisition Due to the scarce literature on RT analyzed separately, the objective of this systematic review is to analyze the effects of RT with no association to other techniques, in aspects related to the quality of life and body composition of people The research for the articles was carried out in the Pubmed, Cochrane, and Web of Science databases using the terms “Spinal cord injuries” AND “Resistance Training” OR “Strength training”. Given the scarcity of evidence on the subject, no deadline was set for the study to be eligible for analysis. Evidence synthesis The research for the articles was carried out in November of 2020 and returned 349 results, of which 220 remained after the elimination of duplicates, with 145 being excluded after title analysis. Seventy-five abstracts were analyzed and 70 studies were excluded, leaving 5 complete articles for a thorough analysis with SCI. Despite the I2 being 87%, the meta-analysis revealed an overall effect of Z = 4.79 (P Conclusions After analyzing the main results, we concluded that RT is feasible, secure, and promotes significant improvements in maximum strength, local muscular endurance, power, and muscular isometric voluntary contraction in people with spinal cord injury.

Background Patients with refractory colorectal (CRC) cancer have few treatment options. This trial tests the combination of metformin and irinotecan in this setting. Methods A phase 2 single-arm trial was conducted, patients received metformin 2500 mg orally a day plus irinotecan 125 mg/m2 intravenously weekly D1 and D8 every 21 days. The primary endpoint was the disease control rate according to the Response Evaluation Criteria in Solid Tumors version 1.1 at 12 weeks. Results Between December 2015 and January 2018, 41 patients were enrolled. Seventeen patients (41%) met the primary endpoint of disease control in 12 weeks; hence, the study was deemed positive. The median progression-free survival was 3.3 months (CI 95%, 2.0–4.5 months), and the median overall survival was 8.4 months (CI 95%, 5.9–10.8 months). Both mutation RAS status and disease control at 12 weeks impacted overall survival in the multivariate model (HR 2.28, CI 95%, 1.12–4.7, p = 0.02; and HR 0.21, CI 95%, 0.08–0.5, p = 0.001, respectively). The most common adverse event was diarrhoea (29.2% grade 3). Conclusions In this trial, metformin plus irinotecan demonstrated disease control in patients with refractory CRC. Further trials with optimised diarrhoea control are needed to confirm these results.

Publicado no Journal of Global Oncology. Volume 3, Issue 1, February 2017. Com o mesmo título. Autores: Lucas Vieira dos Santos, Marco Antonio O. Lessa, João Paulo S. N. Lima, Benjamin Haaland, Gilberto de Lima Lopes.

O uso de polímeros hidrorretentores surge como uma alternativa para disponibilizar água de forma adequada na fase de implantação de povoamentos florestais, além de reter nutrientes necessários para o estabelecimento e desenvolvimento destes. No presente trabalho, objetivou-se avaliar o efeito do polímero hidrorretentor e a influência de diferentes doses de fertilização mineral no crescimento, teor e acúmulo de nutrientes do híbrido clonal de Eucalyptus urophylla x Eucalyptus grandis, na fase de implantação. O experimento foi realizado em delineamento de blocos casualizados completos, em esquema fatorial 2 x 5, sendo duas doses do polímero (0 e 1 g planta-1) e cinco combinações de fertilização mineral (N0P0K0, N0P1K0, N1P0K1, N1P1K1 e N2P2K2, correspondendo à dose de N (N0 = 0, N1 = 62 e N2 = 124 g do fertilizante por planta), P (P0 = 0, P1 = 75 e P2 = 150 g do fertilizante por planta) e K (K0 = 0, K1 = 62 e K2 = 124 g do fertilizante planta)), em três repetições com cinco plantas por parcela. As avaliações foram realizadas aos 30, 60, 120 e 150 dias pós-plantio, quando foram mensurados a altura total e o diâmetro do colo, além da análise química nutricional, aos 150 dias. A partir dos dados obtidos, observou-se que não houve interação entre o efeito do polímero e doses de fertilização mineral. Para o diâmetro do colo, o uso do polímero proporcionou maior crescimento às mudas somente nos 30 primeiros dias de avaliação, e para altura houve maior crescimento nas avaliações aos 30, 60 e 120 dias de plantio. Os tratamentos contendo fósforo (18% de P2O5) obtiveram maior incremento em diâmetro em relação aos demais nos primeiros 60 dias pós-plantio. Nas outras avaliações, a maior dose de fertilizante (N2P2K2) foi responsável pelo maior crescimento em diâmetro e altura. A maior dose de fertilização mineral promoveu maior acúmulo de NPK na parte aérea das plantas (caule, ramos e folhas). Portanto, o polímero proporcionou maior crescimento às mudas na fase inicial de desenvolvimento, e o fósforo se mostrou essencial para o crescimento em diâmetro e altura na fase de implantação do híbrido utilizado.

Human epidermal growth factor receptor 2 (HER2) dysregulation is associated with tumorigenesis in gastric/gastroesophageal junction cancer; however, the number of patients with HER2-positive disease is unclear, possibly due to differing scoring criteria/assays. Data are also lacking for early disease. We aimed to assess the HER2-positivity rate using approved testing criteria in a large, real-life multinational population. HER2-positivity was defined as an immunohistochemistry staining score of 3+, or immunohistochemistry 2+ and HER2 amplification detected by in situ hybridization. A total of 4949 patients were enrolled and results showed that 14.2% of 4920 samples with immunohistochemistry results were HER2-positive. HER2-positivity was significantly higher in males (16.1% vs. 9.6% in females), in gastroesophageal versus stomach tumors (22.1% vs. 12.9%), in biopsy versus surgical samples (18.3% vs. 13.0%), in intestinal tumor subtypes versus diffuse (21.5% vs. 4.8%) and mixed types (21.5% vs. 8.5%) (P

Background and Aim REGARD and RAINBOW were global, phase 3, randomized, double-blind trials of second-line ramucirumab for metastatic gastric or gastroesophageal junction adenocarcinoma. We describe exploratory subgroup analyses to assess the efficacy and safety of ramucirumab in REGARD and RAINBOW in young (≤45 and

Purpose In Brazil, a country with major health access disparities, resource limitations make management of pancreatic cancer (PC) challenging. This study evaluated curative-intent surgery for PC in the Brazilian public health care system. Methods We collected data for PC surgical procedures with curative intent in Brazil’s public health care system (DATASUS) and from the demographic database. Costs, lengths of stay, number of perioperative deaths, and PC deaths were analyzed for each state and then associated with population, gross domestic product (GDP) per capita, and number of procedures. Results A total of 37,142 patients died as a result of PC in Brazil between 2008 and 2012. The number of deaths (per 100,000 person-years) was highest in the south and southeast regions. Mortality from PC had a positive association with the number of procedures and GDP per capita. Between January 2008 and July 2014, 3,386 procedures were performed, the majority (51.2%) in the southeast region. Four hundred ninety-three patients died, which translates to an inpatient mortality rate of 14.6%. The northern states had the highest perioperative mortality (mean, 25%). The number of procedures per 100,000 residents was higher in the southeast and south. Overall, cost tended to increase as the number of procedures or population increased. For fixed GDP per capita and population, cost tended to increase as the number of procedures increased, whereas for a fixed number of procedures and GDP per capita, cost tended to decrease as population increased. The mean length of hospital stay was 16.9 days, which was higher than in major international centers. Conclusion This study is the first to our knowledge to evaluate regional disparities in PC care in Brazil. Perioperative mortality was high in the public health care system. Regionalized policies that improve care are needed.

Bevacizumab may improve outcomes of patients with breast cancer, but the absence of an established biomarker hampers patient selection and researchers´ ability to demonstrate a clear survival benefit. Its putative target, circulating VEGF-A, emerged as the main candidate and we sought to identify the relationship between VEGF-A levels and outcomes through systematic review. We searched electronic databases and meeting proceedings for randomized controlled trials (RCTs) comparing the addition of bevacizumab to standard chemotherapy for breast cancer. RCTs were included if outcomes were presented separately according to VEGF-A plasma levels. Random-effects model were applied to calculate the pooled hazard ratios for progression-free survival, event-free survival (EFS), comprising disease recurrence, progression or any-cause death, and overall survival (OS), with respective confidence intervals (95 % CI). High and low VEGF-A levels subgroups followed each trial definition, and results were compared using the interaction test. Heterogeneity was calculated using χ 2 test (I 2). Three trials enrolled a total of 3748 patients. 1713 patients had baseline VEGF-A levels in plasma available for assessment and were included. One trial added bevacizumab in the adjuvant setting (N = 2591) and two on first-line metastatic disease with taxane-based therapy (N = 1160) There was no interaction between VEGF-A levels and study setting (adjuvant vs. first line therapy). Bevacizumab improved PFS of patients with above median VEGF-A plasma levels (HR 0.56; 95 % CI 0.43–0.73; P

529 Background: The combination of gemcitabine-cisplatin (GC) is the current standard of care chemotherapy for metastatic/unresectable biliary tract cancer (BTC). However, the prognosis remains poor. This randomized trial aimed to evaluate the efficacy and safety of irinotecan plus cisplatin (IP) versus GC in advanced or metastatic BTC. Methods: Patients with biopsy-proven, chemo-naïve, unresectable or metastatic BTC, ECOG 0-2, measurable disease per RECIST 1.1, adequate organ function and written informed consent were stratified by ECOG (0 or 1 vs 2) and distant metastases and randomized to receive irinotecan 65 mg/m² IV D1 and D8 plus cisplatin 60 mg/m² D1 repeated every 3 weeks (IP) or gemcitabine 1000 mg/m² IV D1 and D8 plus cisplatin 25 mg/m² IV D1 and D8 repeated every 3 weeks, until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Results: Between January 2013 and April 2018, 47 pts were randomized (1:1) to receive IP (N = 24) or GC (N = 23). Overall, groups were well balanced according to prognostic factors. The ORR was 35% (complete response 5%, partial response 30%) and 31.8% in IP and GC arms, respectively. Median progression-free survival were 5.3 vs 7.8 months (HR = 1.165, 95%CI 0.628-2.161, p = 0.628) and median overall survival were 11.9 and 9.8 months (HR = 0.859, 95%CI 0.431 – 1.710, p = 0.665) for IP and GC, respectively. Adverse events were not statistically different between arms, and results were consistent with previous experiences with these regimens. No therapy-related death were reported. Conclusions: Irinotecan-cisplatin combination is active in BTC, with similar ORR, PFS and OS when compared to gemcitabine-cisplatin. Irinotecan-cisplatin were well tolerated, and adverse events were manageable. Irinotecan-cisplatin could be considered as an alternative to gemcitabine-cisplatin. Clinical trial information: NCT01859728.

Summary Background Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, prolonged survival in patients with advanced gastric cancer. Methods We did an international, randomised, double-blind, placebo-controlled, phase 3 trial between Oct 6, 2009, and Jan 26, 2012, at 119 centres in 29 countries in North America, Central and South America, Europe, Asia, Australia, and Africa. Patients aged 24–87 years with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy were randomly assigned (2:1), via a central interactive voice-response system, to receive best supportive care plus either ramucirumab 8 mg/kg or placebo, intravenously once every 2 weeks. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00917384. Findings 355 patients were assigned to receive ramucirumab (n=238) or placebo (n=117). Median overall survival was 5·2 months (IQR 2·3–9·9) in patients in the ramucirumab group and 3·8 months (1·7–7·1) in those in the placebo group (hazard ratio [HR] 0·776, 95% CI 0·603–0·998; p=0·047). The survival benefit with ramucirumab remained unchanged after multivariable adjustment for other prognostic factors (multivariable HR 0·774, 0·605–0·991; p=0·042). Rates of hypertension were higher in the ramucirumab group than in the placebo group (38 [16%] vs nine [8%]), whereas rates of other adverse events were mostly similar between groups (223 [94%] vs 101 [88%]). Five (2%) deaths in the ramucirumab group and two (2%) in the placebo group were considered to be related to study drug. Interpretation Ramucirumab is the first biological treatment given as a single drug that has survival benefits in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma progressing after first-line chemotherapy. Our findings validate VEGFR-2 signalling as an important therapeutic target in advanced gastric cancer. Funding ImClone Systems.

Despite recent advances in treatment of head and neck cancer, survival has not been improved as expected. Bcl-2 family proteins play important role in regulating apoptosis. Recently newer molecules have been developed for inhibition of Bcl-2 related proteins. We herein aim to discuss the importance of Bcl-2 family proteins to the development of head and neck cancer and how the targeted-therapy for inhibition of Bcl-2 and related proteins, based on new drugs and recent patents, could improve the efficacy of the systemic therapy. Keywords: anticancer drugs, apoptosis, Bcl-2 family proteins, head and neck cancer, patents, targeted-therapy. INTRODUCTION Head and neck cancer is the ninth in incidence in United States, with almost 50.000 estimated new cases in 2009,[1] and more than 500.000 worldwide [2]. The most common histology is squamous cell carcinoma (SCC), which com-prises more than 90% of HNSCC. The incidence of HNSCC is higher in less developed countries [2, 3]. Smoking and alcohol intake are the major risk factors, although other factors are known, including human papillomavirus (HPV) infection and occupational exposure [4, 5]. The five-year survival rate is 82% for patients with stages I and II, 53% for patients with stage III and 28% for patients with stage IV[1]. Recent advances in the management of HNSCC had increased the survival for some subsites of HNSCC in the past few decades, however this increment in survival was lower than expected [6]. Two modalities of treatment are useful for localized HNSCC: surgery and radiotherapy. Surgery and radiation therapy lead to similar survival rates for localized disease. The treatment of locally advanced disease must be multi-modal: radiochemotherapy or surgery followed by radio-chemotherapy [7]. Chemotherapy remains the backbone of treatment for metastatic disease [4]. Nowadays we have directed our attention to new treatment modalities: induction chemotherapy and molecular targeted therapy. Induction chemotherapy has been studied in some trials, but survival improvement with this approach has not yet been shown [8]. Cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, has

e15527Background: Metformin (Met) may exert anticancer effects through activation of AMP-activated protein kinase (AMPK) and reduction of mTOR signaling. Our preclinical studies have shown synergis...

The optimal duration of first-line chemotherapy for advanced non-small cell lung cancer (NSCLC) has been a matter for debate for nearly 20 years. In order to elucidate this issue, a meta-analysis comparing the different durations of same treatments was performed.We searched for all published randomised controlled trials (RCTs) comparing different durations of first-line treatment of advanced NSCLC. The MEDLINE, EMBASE, LILACS and CENTRAL databases were searched for RCTs comparing a defined number of cycles of chemotherapy versus continuing treatment until disease progression, or a defined number of cycles versus a higher number of cycles of the same chemotherapy. Trials including biological agents were excluded.Seven trials that included 1559 patients were analysed. Treatment for more than 4 cycles was associated with a non-statistically significant decrease in the hazard of mortality relative to shorter treatment (hazard ratio (HR)=0.97; 95% confidence interval (CI)=0.84-1.11; P=.65). In those treated with third-generation chemotherapy through the whole study time, treatment for more than 4 cycles was associated with a non-statistically significant increase in mortality (HR=1.08; 95% CI=0.90-1.28; P=.28). Patients receiving more chemotherapy had significant longer progression-free survival (HR=.75; 95% CI=0.60-0.85; P0.0001) than the group with shorter duration of treatment. In an intent-to-treat analysis, there was no difference in the overall response rate between the groups (odds ratio (OR)=0.78; 95% CI=0.60-1.01; P=.96). Longer treatment was associated with more severe leucopaenia but with no significant increase in non-haematological toxicities.In patients with advanced NSCLC the use of more than 4 cycles of first-line chemotherapy with third-generation regimens significantly increases progression-free survival but not overall survival and is associated with higher incidence of adverse events. There is no evidence to support continuous chemotherapy until progression in patients with lung cancer.

Working on both sides, as an author of journals and a reviewer, I am aware of the importance of a good review. It is powerful to enhance the description of results in an article, in addition to highlighting its strengths and limitations, which are ultimately translated in improving articles of a certain journal. Many times I have felt grateful for the unknown hero – the reviewer – for the contribution made to a work I had submitted.

Hand-foot syndrome (HSF) is a distinctive adverse event relatively frequent to some chemotherapeutic agents as capecitabine, pegylated liposomal doxorubicin, sorafenib and other tyrosine-kinase inhibitors. Since the prevention of HFS would be crucial to avoid treatment interruptions and delays, many studies have been conducted with this purpose.The aim of this systematic review and meta-analysis was to analyze the clinical efficacy of prevention strategies for HFS, through a wide search of electronic databases as well as congress abstracts. The endpoints evaluated were the dichotomic data for mild (Grade 1), moderate to severe (Grades 2 to 3) and all-grade HFS. Meta-analysis was calculated through RevMan v5.1 software.Amongst 295 studies identified, only ten met the inclusion criteria. Celecoxib prevented both moderate to severe (odds ratio [OR] 0.39, 95 % confidence interval [CI] 0.20-0.73, P = 0.003) and all-grade HFS (OR 0.47, 95 % CI 0.29-0.78, P = 0.003), whereas pyridoxine and topical urea/lactic acid formulations failed to prove efficacy. There were no proven benefits in mild HFS. The use of topical antiperspirant has not been shown to improve results, according to a single trial.From all available possibilities for the prevention of HFS, celecoxib appears to be the most promising, with statistically significant results. Larger, multicentric studies are required to reinforce this finding.

Imatinib mesylate represents a revolution in the management of patients with metastatic gastrointestinal stromal tumors (GISTs). More recently, postoperative imatinib has been shown to improve both disease-free and overall survivals in patients with a high risk of recurrence. This article presents a well-documented case of a patient with painful and reversible bone edema related to imatinib.

3 Background: REGARD and RAINBOW are two phase 3 studies which demonstrated significant survival benefits and manageable toxicity in patients with advanced gastric cancer (GC) randomized in the second-line setting to receive RAM or placebo. We examined outcomes by age (≤45, 45-70, ≥70, ≥75 years). Methods: Patients were randomized 2:1 to receive RAM 8 mg/kg + best-supportive care (BSC) or placebo (PL) + BSC (REGARD); or 1:1 RAM 8 mg/kg + paclitaxel (PTX) or PL + PTX (RAINBOW). Kaplan-Meier analysis and Cox proportional hazards regression were performed for overall survival (OS) and progression-free survival (PFS). Subpopulation treatment effect pattern plot (STEPP) assessed efficacy and the incidence of adverse events (AEs) across age subgroups. Results: Baseline characteristics were generally well balanced between arms amongst the age subgroups. Efficacy outcomes are summarized in the Table. STEPP analysis revealed no obvious patterns for differential risks in terms of efficacy and AEs (any grade or grade ≥3) according to age. Conclusions: Compared with PL, the efficacy of RAM was maintained in all age groups, with similar rates of toxicity. Despite some limitations regarding patient numbers in some age subgroups, this exploratory subgroup analysis supports the use of RAM for the treatment of GC, irrespective of age. Clinical trial information: NCT00917384 and NCT01170663. [Table: see text]

Orientadores: Andre Deeke Sasse, Carmen Silvia Passos Lima Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas Resumo: Introdução: O linfoma não-Hodgkin é o sexto grupo de neoplasias em mortalidade no mundo. Quando em estágio precoce, o linfoma não-Hodgkin pode ser curado com quimioterapia. A radioterapia tem sido utilizada para se reduzir a recorrência local, entretanto o seu impacto nos desfechos de sobrevivência é desconhecido. Vários estudos tentaram responder a esta questão, mas com resultados conflitantes. Frente a resultados controversos derivados de estudos randomizados, uma revisão sistemática da literatura faz-se necessária para determinar se a radioterapia, acrescentada ao tratamento sistêmico, traz ganhos reais para o paciente. Objetivos: Comparar os desfechos do paciente com linfoma não-Hodgkin agressivo e localizado tratado com quimioterapia seguido de radioterapia, com os da quimioterapia isoladamente. Métodos: Revisão sistemática da literatura com meta-análise. Estudos clínicos randomizados no tratamento do linfoma não-Hodgkin foram identificados, através de busca nas bases de dados Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, e LILACS. Referências de artigos encontrados, Resumos de apresentações em congressos e bases de dados de estudos em andamento também foram utilizados para localizar estudos pertinentes. Critérios de inclusão: estudos controlados randomizados que compararam radioterapia adicionada ao tratamento sistêmico com tratamento sistêmico isoladamente em pacientes com linfoma não-Hodgkin agressivo e localizado. Dois revisores extraíram independentemente os dados dos artigos utilizando formulários de extração de 10 dados. Quando possível, para cada desfecho clínico foi feita meta-análise com os dados extraídos, com o fim de calcular o efeito dos tratamentos entre os estudos. Os resultados da meta-análise são expressos como Risco Relativo (RR), e Hazard Ratio (HR), com o correspondente intervalo de confiança (IC) de 95%. Os desfechos clínicos avaliados foram sobrevida global, sobrevida livre de progressão, resposta radiológica e toxicidade. O modelo de efeito fixo foi usado para se calcular as variáveis de interesse. Resultados: De um total de 7020 estudos identificados por meio da estratégia de busca, cinco foram selecionados. Destes, um estudo foi excluído. Quatro estudos, compreendendo 1796 pacientes foram incluídos na meta-análise. A adição de radioterapia trouxe incremento na sobrevivência livre de progressão [HR 0,81; IC95% 0,67-0,98; p=0,03], sem, entretanto trazer impacto na taxa de resposta ou em sobrevivência global. As diferenças em como os dados foram reportados não permitiu que os dados de segurança fossem combinados. Conclusão: Até o presente momento, não há evidência de que a radioterapia traga ganhos em sobrevivência global em pacientes com linfoma não-Hodgkin agressivo e localizado. Investigações adicionais, com a incorporação dos agentes biológicos à quimioterapia, são necessárias Abstract: Background: Non-Hodgkin lymphoma is the sixth group of neoplasms in mortality in the world. Aggressive and localized non-Hodgkin lymphoma can be cured by chemotherapy. Radiotherapy has been used to reduce local recurrence, however its impact on survival outcomes is unknown. Several studies have attempted to answer this question, but with conflicting results. Thus, a systematic literature review is needed to determine whether radiation therapy added to systemic treatment enhances the efficacy in non-Hodgkin lymphoma treatment. Objectives: To compare outcomes of patients with aggressive and localized non- Hodgkin lymphoma treated with chemotherapy followed by radiotherapy with chemotherapy alone. Methods: This is a systematic review with meta-analysis. Randomized clinical trials were identified the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and LILACS. Inclusion criteria: randomized controlled trials that compared the addition of radiotherapy to systemic therapy versus systemic therapy alone in patients with aggressive and localized lymphoma. Two reviewers independently extracted data from articles using data extraction forms. When possible, for each clinical outcome was performed meta-analysis of the extracted data in order to calculate the effect of treatments across studies. The results of the meta-analysis are expressed as relative risk (RR) and hazard ratio (HR) with corresponding confidence interval (CI) of 95%. The main outcomes were overall 12 survival, progression-free survival, radiologic response and toxicity. The fixed-effect model was used to estimate the effect size. Results: A total of 7,020 studies identified through the search strategy, five were selected. Of these, one study was excluded. Four studies comprising 1,796 patients were included in the meta-analysis. The addition of radiotherapy increased the progression-free survival [HR 0.81, 95% CI 0.67 to 0.98, p = 0.03]. There were no differences in response rate or overall survival. The differences in how data was reported did not allow us to combine toxicity data Conclusion: To date, there is no evidence that radiotherapy will increase overall survival in patients with aggressive and localized non-Hodgkin lymphoma. Further investigations, with the incorporation of biologic agents to chemotherapy, are needed Mestrado Clínica Médica Mestre em Clínica Médica

BACKGROUND The addition of neurokinin-1 receptor (NK1R) antagonists to antiemetic regimens has substantially reduced chemotherapy-induced nausea and vomiting (CINV). We sought to systematically review the overall impact of NK1R antagonists on CINV prevention. METHODS We systematically searched the MEDLINE, EMBASE, and CENTRAL databases, and meeting proceedings for randomized controlled trials (RCTs) that evaluated NK1R antagonists plus standard antiemetic therapy for CINV prevention. Complete response (CR) to therapy was defined as the absence of emesis and the absence of rescue therapy. The endpoints were defined as CR in the overall phase (during the first 120 hours of chemotherapy), CR in the acute phase (first 24 hours), and the delayed phase (24-120 hours) after chemotherapy, nausea, and toxicity. Subgroup analyses evaluated the type of NK1R antagonist used, the emetogenic potential of the chemotherapy regimen, and prolonged use of 5-HT3 (serotonin) receptor antagonists, a class of standard antiemetic agents. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Statistical tests for heterogeneity were one-sided; statistical tests for effect estimates and publication bias were two-sided. RESULTS Seventeen trials (8740 patients) were included in this analysis. NK1R antagonists increased the CR rate in the overall phase from 54% to 72% (OR = 0.51, 95% CI = 0.46 to 0.57, P < .001). CR and nausea were improved in all phases and subgroups. The expected side effects from NK1R antagonists did not statistically significantly differ from previous reports; however, this analysis suggests that the incidence of severe infection increased from 2% to 6% in the NK1R antagonist group (three RCTs with a total of 1480 patients; OR = 3.10; 95% CI = 1.69 to 5.67, P < .001). CONCLUSIONS NK1R antagonists increased CINV control in the acute, delayed, and overall phases. They are effective for both moderately and highly emetogenic chemotherapy regimens. Their use might be associated with increased infection rates; however, additional appraisal of specific data from RCTs is needed.

Background Chemotherapy is the mainstay of non-Hodgkin lymphoma (NHL) treatment. Based on expert opinion, the use of radiotherapy (RT) is currently preferred in some institutions as consolidative treatment for patients with localized disease. The lack of conclusive data coming from conflicting studies about the impact of treatment demands a systematic review, which could provide the most reliable assessment for clinical decision-making. We evaluate the addition of RT post-CT, for aggressive and localized NHL (ALNHL). Methods Randomized controlled trials (RCT) that evaluated chemotherapy alone versus chemotherapy plus RT were searched in databases. The outcomes were overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and toxicity. Risk ratio (RR) and hazard ratio (HR) with their respective 95% confidence intervals (CI) were calculated using a fized-effect model. Results Four trials (1,796 patients) met the inclusion criteria. All trials tested the use of RT after systemic therapy comprising anthracycline-based chemotherapy. This systematic review showed that RT enhances PFS after chemotherapy (hazard ratio [HR] 0.81; 95% CI 0.67-0.98; p = 0.03), with no impact on ORR and OS. Some heterogeneity between trials could limit the conclusions about OS. Toxicity data could not be pooled due to differences in reporting adverse events. Conclusions This systematic review with meta-analysis shows no improvement in survival when adding RT to systemic therapy for ALNHL. Our conclusions are limited by the available data. Further evaluations of new RT technologies and its association with biologic agents are needed.

To perform a meta-analysis addressing evaluation bias in local radiologic assessment (LRA) of lesions when compared with independent radiologic review (IRR) in randomized controlled trials (RCTs) testing chemotherapy for metastatic colorectal cancer (CRC).MEDLINE, EMBASE, ClinicalTrials.gov, the Cochrane Library, and Web sites for major medical meetings were searched for RCTs of chemotherapy for metastatic CRC that reported response evaluation by both LRA and IRR. The risk ratios (RRs) of response in the experimental (RR(exp)) and control (RR(cont)) arms were calculated (response rate in LRA divided by response rate in IRR) for each selected study. The ratio of RR of response was calculated (RR of response of LRA divided by RR of response of IRR). The random-effects model was applied. Meta-regression was used to examine the effect of study characteristics on outcomes.LRA and IRR results were concordant (13 studies; 7742 patients; ratio of RR of response = 0.97; 95% confidence interval [95% CI]: 0.90, 1.04; P = .35). However, LRA overestimated tumor response independently of therapy allocation (interaction test, P = .81) both in control (RR(cont), 1.163; 95% CI: 1.086, 1.246; P.001) and experimental (RR(exp), 1.156; 95% CI: 1.093, 1.222; P.001) therapies. Meta-regression did not show any effect of trial characteristics on effects.LRA yields higher response rates in RCTs testing chemotherapy for metastatic CRC, although there was no sign of bias toward experimental therapy. The need for IRR to control evaluation bias must be reappraised.

Bevacizumab-containing treatment is one of the approved first-line options for the management of metastatic colorectal cancer (CRC). Carcino-embryonic antigen (CEA) is a reasonable tumour marker for monitoring the efficacy of treatment. We report here a case of a 58-year-old male patient with metastatic CRC. He received first-line chemotherapy consisting of the mFOLFOX6 regimen plus bevacizumab. Initially he had an increase in CEA after which the level reduced, suggesting the occurrence of a CEA flare. The patient experienced a good response to therapy. In recent literature, CEA flare was identified as a good predictor of response to first-line chemotherapy.

TPS485 Background: Gallbladder and biliary tract cancer (GBTC) have an aggressive behavior and gemcitabine-platinum chemotherapy emerged as the new standard of care for advanced or metastatic GBTC. Despite optimal management, prognosis is still poor. This randomized trial aims to compare irinotecan plus cisplatin versus gembitabine plus cisplatin in advanced or metastatic GBTC. Methods: Patients with biopsy-proven, chemo-naïve, unresectable or metastatic carcinoma of GBTC (gallbladder, intrahepatic biliary tract, extrahepatic biliary tract, or ampulla of Vater), ECOG 0-2, measurable disease per RECIST 1.1, adequate organ function and written informed consent are stratified by ECOG (0 or 1 vs 2) and hematogenic metastases (yes vs no) and randomized to receive Irinotecan 65mg/m² D1 and D8 q21 days plus Cisplatin 60mg/m² D1 q 21 days (IP) or Gemcitabine 1000mg/m² D1 and D8 every 21 days plus cisplatin 25mg/m² D1 and D8 every 21 days (GC), until disease progression or unacceptable toxicity, with standard hydration and antiemetics. Computed tomography for response evaluation is undertaken every 6 weeks. The primary end-point is overall response rate (ORR). Assuming p0 = 25%, p1 = 50%, alpha = 5% and beta = 20% in an optimal Simon’s two stage design, 24 patients per arm will be recruited (N1 = 9; R1 = 2; Ntot = 24; Rtot = 9). The sample size for each arm was calculated separately. Secondary end-points are progression-free survival (PFS), overall survival (OS), disease control rate (DCR), quality of life and safety. This clinical trial was activated in January 2013 and the accrual period is expected to end by December 2017. This protocol was approved by institutional review board. Clinical trial information: NCT01859728.

246 Background: In Brazil, a large country with major socioeconomic and health access disparities, resource limitations make the management of pancreatic tumors challenging. We aimed to evaluate curative-intent surgical procedures for pancreatic cancer (PC) in the public health care system. Methods: Based on Brazilian’s public health system database (DATASUS) and demographic database (IBGE), we collected data for curative-intent surgical procedures for pancreatic tumors. Information about number of procedures, costs, length of stay, number of perioperative deaths and PC deaths were analyzed for each State and Region and then correlated to State specific population, gross domestic product (GDP) per capita and number of procedures. Results: Between 2008 and 2012, 37,142 patients died due to PC in Brazil, with an increase of 6.3% in mortality annually. Mortality (per 100,000 persons-year) increases from North to South States. GPD per capita (rho=0.636, 2-tailed p

3614 Background: Delay in commencing adjuvant therapy for colorectal cancer seems to impair survival in some retrospective studies. This is a large, bi-institutional retrospective study evaluating ...

4057 Background: The REGARD trial demonstrated significant improvements in overall survival (OS), progression free survival (PFS), and disease control rates in pts receiving RAM, a human IgG1 recep...

In this issue, Molassiotis et al. report the predictors of chemotherapy-induced nausea and vomiting (CINV) in the largest prospective observational study to date. The impact of Multinational Association of Supportive Care in Cancer (MASCC) guideline compliance on CINV has been reported in a previous publication using the same data set. This well-conducted study found that female gender was not a key predictor of CINV. Three other predictors of CINV emerged and must be appraised by every physician involved in cancer care. Complete response in the first cycle of chemotherapy, as defined by the study, was a determinant factor for CINV in the following cycles. This suggests that complete response in the first cycle of chemotherapy may be a more important clinical goal. Second, factors related to the patients themselves, such as anticipatory nausea and prechemotherapy anxiety, were demonstrated for the first time in a prospective study to be important risk factors for CINV. This illustrates a possible role of behavioral and symptomatic therapy during treatment planning and before the start of chemotherapy.

e20506 Background: We have previously shown (dos Santos JNCI 2012) that NK1 receptor antagonists (NK1RA), such as aprepitant and casopitant, improve chemotherapy-induced nausea and vomiting (CINV) at the cost of increasing severe infection risk. Herein, we update our results. Methods: We searched MEDLINE, EMBASE, CENTRAL and meeting proceedings to identify randomized controlled trials (RCTs) comparing standard antiemetic therapy (dexamethasone + 5-HT3R inhibitors) versus NK1RA plus standard therapy for CINV prevention. Complete response (CR) was defined as absence of emesis and rescue therapy. The endpoints were CR post-chemotherapy in the overall phase (first 120 hours), CR in the acute phase (first 24 hours), and the delayed phase (24–120 hours), nausea, and toxicity. Subgroup analyses evaluated the type of NK1RA, the emetogenic potential of the chemotherapy, and prolonged use of 5-HT3R inhibitor. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Results: A total of 20 trials (9,935 patients) were included. NK1RA increased CR rate and nausea in all phases and subgroups. The CR in overall phase improved from 56% to 72% (OR = 0.52, 95% CI = 0.46 to 0.59, P < .00001, NNT=6). The side effects of NK1RA followed our previous report: the severe infection rate increased from 2.4% to 5.6% in the NK1RA group (four trials, 1656 patients; OR = 2.87; 95% CI = 1.58 to 5.19, P = .0005, NNH=31). Conclusions: NK1RA consistently improve CINV control in the acute, delayed, and overall phases, either for moderately or highly emetogenic chemotherapy regimens. Their use might be associated with increased infection rate, and a patient-level meta-analysis is warranted to clarify this safety issue.

e18534 Background: Superiority of irinotecan-platinum (IP) regimens over etoposide-platinum (EP) in ED-SCLC has been extensively debated, with ethnic and pharmacogenomics issues hypothesized as causes of the divergent findings. We undertook a systematic review to scrutinize the data according to geographic origin. Methods: Randomized controlled trials comparing first-line EP doublets versus IP in ED-SCLC patients were searched in major meeting proceedings and databases. The outcomes were overall survival (OS), one-year survival, two-year survival, and safety. Meta-analyses were performed using random-effects model. Subgroup analyses and meta-regression were undertaken to compare and measure the impact of geographical origin of study over the estimated effect size. Results: Seven studies (2,029 patients) were included. IP improved OS worldwide (HR = 0.83; 95% CI 0.76-0.92; P>0.001; I²=0%). However, the impact of IP on OS was different according to geographic origin, with relevant benefit for Japanese, little benefit for North American/Australian and intermediate for European patients (P for interaction = 0.029, table 1). One year survival was homogenously improved from 34% with EP to 40% with IP (P=0.006). IP improved two year survival just for Japanese and European patients but not to North American ones (Table). Toxicity was not impacted by trial origin. Conclusions: IP improved survival for both Western and Eastern patients, but seems to exist a gradient of benefit according to geographic origins, with maximal benefit for Japanese, some relevant for European ones and little, if any, for North American/Australian patients. These findings should be taken in account when considering IP or EP as first-line therapy for ED-SCLC patients worldwide. [Table: see text]

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: VEGF and VEGF receptor-2 mediated signaling and angiogenesis may contribute to gastric cancer pathogenesis. Ramucirumab (RAM; IMC-1121B) is a fully human IgG1 monoclonal antibody targeting VEGFR-2. We conducted a placebo-controlled, double-blind, phase III international trial to evaluate the safety and efficacy of RAM in pts with metastatic gastric or GEJ adenocarcinoma progressing on 1st-line platinum- and/or fluoropyrimidine containing combination therapy. Methods: Pts were randomized 2:1 to receive RAM (8 mg/kg IV) or placebo (PL) every 2 weeks (wks) until disease progression, unacceptable toxicity, or death. Pts had disease progression within 4 months (m) after 1st-line therapy for metastatic disease or within 6 m after adjuvant therapy. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), 12-wk PFS rate, overall response rate (ORR) and safety. Results: From 10/09 to 01/12, 355 pts were randomized (RAM: 238; PL: 117). Baseline characteristics were well balanced between arms. RAM significantly reduced all-cause mortality by 22% when compared to PL (Hazard Ratio [HR] for OS = 0.776; 95% CI, 0.603-0.998; p = 0.0473). Median OS was 5.2 m for RAM and 3.8 m for PL. The OS benefit for RAM appeared consistent across subgroups and after adjustment for other prognostic factors (multivariate HR = 0.774; 95% CI, 0.605-0.991). The HR for PFS was 0.483 (95% CI, 0.376-0.620; p < 0.0001). Median PFS was 2.1 m for RAM and 1.3 m for PL. 12-wk PFS was 40% for RAM and 16% for PL. ORR was 3.4% for RAM and 2.6% for PL. Disease control rate was 49% for RAM and 23% for PL (p < 0.0001). Use of anti-cancer therapy post-study: 32% RAM; 39% PL. The most frequent grade ≥3 AEs were: hypertension (7.6% RAM; 2.6% PL), fatigue (6.4% RAM; 9.6% PL), anemia (6.4% RAM; 7.8% PL), abdominal pain (5.9% RAM; 2.6% PL), ascites (4.2% RAM; 4.3% PL), decreased appetite (3.4% RAM; 3.5% PL), bleeding (3.4% RAM; 2.6% PL), and hyponatremia (3.4% RAM; 0.9% PL). Conclusions: Ramucirumab significantly prolonged survival in pts with advanced gastric or GE junction adenocarcinoma following progression on first-line therapy with an acceptable safety profile. These results validate VEGFR-2 signaling as a therapeutic target in gastric cancer. Clinical trial: [NCT00917384][1] Citation Format: Charles S. Fuchs, Jiri Tomasek, Jae Yong Cho, Dumitru Filip, Rodolfo Passalacqua, Chancal Goswami, Howard Safran, Lucas Vieira Dos Santos, Giuseppe Aprile, David Ferry, Bohuslav Melichar, Moustapha Tehfe, Eldar Topuzov, Josep Tabernero, John Raymond Zalcberg, Ian Chau, Minori Koshiji, Yanzhi Hsu, Jonathan Schwartz, Jaffer Ajani. REGARD: A phase III, randomized, double-blind trial of ramucirumab and best supportive care (BSC) versus placebo and BSC in the treatment of metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma following disease progression on first-line p [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-67. doi:10.1158/1538-7445.AM2013-LB-67 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00917384&atom=%2Fcanres%2F73%2F8_Supplement%2FLB-67.atom

LBA5 Background: VEGF and VEGF receptor-2 mediated signaling and angiogenesis may contribute to gastric cancer pathogenesis. Ramucirumab (RAM; IMC-1121B) is a fully human IgG1 monoclonal antibody targeting VEGF-receptor 2. We conducted a placebo-controlled, double-blind, phase III international trial to evaluate the safety and efficacy of RAM in pts with metastatic gastric or GEJ adenocarcinoma progressing on first-line platinum- and/or fluoropyrimidine containing combination therapy. Methods: Pts were randomized 2:1 to receive RAM (8 mg/kg IV) plus BSC or placebo (PL) plus BSC every 2 weeks (wks) until disease progression, unacceptable toxicity, or death. Eligible patients had disease progression within 4 months (m) after 1st-line therapy for metastatic disease or within 6 m after adjuvant therapy. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), 12-wk PFS rate, overall response rate (ORR) and safety. Results: From 10/09 to 01/12, 355 pts were randomized (RAM: 238; PL: 117). Baseline characteristics were well balanced between arms. The Hazard Ratio (HR) for OS was 0.776 (95% CI, 0.603-0.998; p = 0.0473). Median OS was 5.2 m for RAM and 3.8 m for PL. The HR for PFS was 0.483 (95% CI, 0.376-0.620; p < 0.0001). Median PFS was 2.1 m for RAM and 1.3 m for PL. 12-wk PFS was 40% for RAM and 16% for PL. ORR was 3.4% for RAM and 2.6% for PL. Disease control rate was 49% for RAM and 23% for PL (p < 0.0001). Use of anti-cancer therapy post-study: 32% RAM; 39% PL. The most frequent of grade ≥ 3 adverse events (AEs) were: hypertension (7.2% RAM; 2.6% PL), anemia (6.4% RAM; 7.8% PL), abdominal pain (5.1% RAM; 2.6% PL), ascites (4.2% RAM; 4.3% PL), fatigue (4.2% RAM; 3.5% PL), decreased appetite (3.4% RAM; 3.5% PL) and hyponatremia (3.4% RAM; 0.9% PL). Conclusions: Ramucirumab conferred a statistically significant benefit in OS and PFS compared to PL in metastatic gastric or GEJ adenocarcinoma following progression on 1st-line therapy with an acceptable safety profile. Clinical trial information: NCT00917384.

e15192 Background: The standard curative management of muscle invasive bladder carcinoma (MIBC) has been the combination of neoadjuvant chemotherapy and radical cystectomy, neo-adjuvant chemotherap...

e20513 Background: The positive impact of neoadjuvant chemotherapy on disease free survival (DFS) for patients with osteosarcoma is well established. At the same time, the extend of histological tu...

e18507 Background: The current mainstay of NHL treatment is chemotherapy (CT). We sought to evaluate the addition of consolidative radiotherapy (RT) for aggressive and localized disease. Methods: W...

pared to best supportive care alone. 2 Trials fully published presented no gain in OS (hazard ratio [HR], 0.98; 95% CI, 0.90 to 1.07) while those presented in abstract format stated relevant gain in OS (HR, 0.79; 95% CI 0.69 to 0.91). The difference among these two groups (fully and partially published trials) cannot be overlooked (interaction P .01). Nevertheless, the main source of concern in this meta-analysis is the assumption that different therapeutic approaches were similar and could be polled. Seven trials continued all drugs used in first-line therapy, three maintained a single drug already used in first-line therapy (maintenance therapies) and three switched to a new single drug before progression (sequential therapy) in the longer therapy arms. Even though there was no relevant statistical heterogeneity, pooling all these types of trials caused an inconsistency beyond numbers. Is the use of docetaxel or pemetrexed after four cycles of platinum-based chemotherapy similar to maintaining a platinum-doublet up to six cycles? Can continuing vinorelbine after platinum doublet be considered equal to docetaxel after platinum doublets? Are six or more courses of platinum doublets better than four cycles? It is hardly believable that such specifics question could be answered by a single broad meta-analysis. Ideally, a systematic review must point to a specific direction, and this was not the case with the Soon et al metaanalysis. An appropriated answer to the optimal duration of first-line chemotherapy must be better defined. The meta-analysis presented by Soon et al 1 did not perform a straightforward comparison of duration of first-line therapy alone, it is confounded by major differences in treatment. The OS benefit identified (HR, 0.92; 95% CI 0.86 to 0.99) when all types of trials were combined merits a deeper discussion. We could speculate that not all therapeutic approaches (maintenance and sequential) contribute equally to this result. In fact, the inclusion of one large sequential trial 3 seemed to be capital for achieving this survival gain as the robust analysis pointed out. These consideration were all taken into account in other systematic review recently published. 4 This review had more restricts inclusion criteria: trials comparing early introduction of a different drug (sequential trials) were excluded to avoid confounding bias. These narrow inclusion criteria of the meta-analysis diminished the number of included trials and patients but provided an interesting clinical uniformity among trials. Prolonged use of third-generation doublets increased progressionfree survival (HR, 0.75; 95% CI, 0.65 to 0.85) but not OS (HR, 1.08; 95% CI 0.90 to 1.28). The conclusion was that three to four cycles of platinum-based doublets would provide similar benefit of longer platinum-doublets therapies with less toxicity.

8105 Background: Superiority of irinotecan/cisplatin over etoposide/cisplatin in ED-SCLC has been a matter of debate with contradictory findings in randomized trials. Methods: PUBMED, EMBASE, CENTRAL databases, ClinicalTrials.gov, ASCO, IASLC, ESMO Meeting sites were searched. Eligible studies were randomized trials comparing first-line IP versus EP in ED-SCLC patients. The primary outcome measure was overall survival (OS); secondary endpoints of interest were progression-free survival (PFS), response rate (RR), and toxicity. Two reviewers independently assessed eligibility, quality, and time-to-event (TTE) outcomes. Hazard ratios (HR) were derived from reported TTE outcomes or extracted using Parmar methods with 95% confidence intervals (CI). Odds Ratio (OR) was used to compare dichotomous data. A fixed effect model was used for meta-analysis. Results: Six studies were identified. Four of them had sufficient data to be included (four for OS and three for PFS). The data coming from 1,365 patients showed a HR for OS favoring IP, with significant heterogeneity (I2=50%). Sensitivity analysis identified one trial with exclusively Japanese population (144 patients). The exclusion of this trial in the meta-analysis resulted in a HR for OS of 0.86 (95% CI=0.76 - 0.97, p=0.01) still favoring IP, with no heterogeneity (I2=3%). For PFS, there was also significant heterogeneity between trials. After excluding the Japanese trial the HR for PFS was of 0.96 (95% CI=0.85 - 1.09, p=0.54) with acceptable heterogeneity. The ITT RRs were 60% for IP and 49% for EP (p No significant financial relationships to disclose.

e11500 Background: Anti-HER2 therapy has brought major gains to therapy of advanced breast cancer (ABC), however it is still not know if there are difference in efficacy between trastuzumab and lapatinib. We execute a systematic review and meta-analysis in order to measure the impact of anti-HER2 therapy on ABC outcome and to assess if any particular drug is more effective in this scenario. Methods: Randomized controlled trials comparing first-line antineoplastic drug plus minus antiHER2 therapy (either trastuzumab or lapatinib) in ABC patients were searched in major meeting proceedings and databases. The outcomes were overall survival (OS), progression-free survival (PFS), tumor response and safety. Meta-analyses were performed using random-effects model and outcomes measured by hazard ratio (HR) and pertinent 95% confidence intervals were calculated. Subgroup analyses and meta-regression were undertaken to compare and measure the impact of anti-HER2 drug used over the estimated effect size. Results: eight trials (1848 patients) were included, two trials used lapatinib whereas six used trastuzumab. In two trials, anti-HER2 therapy was combined to hormone therapy. All trials, except the one by Slamon, demanded tumors to be ISH+ or IHC 3+. The methodological quality of included trials was moderate to good. Either trastuzumab or lapatinib improved overall survival (HR 0.79; 95% CI 0.69-0.91; P=0.0008; I2=0%) with no difference bet drugs (test for difference P=0.75). PFS was also increased with antiHER2 addition with similar activity of trastuzumab and lapatinib (HR = 0.58; 95% CI 0.51-0.66; P