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1.
Cancer Rep (Hoboken) ; : e1578, 2022 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-35075804

RESUMO

BACKGROUND AND AIM: The objective of this retrospective, observational, noninterventional cohort study was to investigate prognostic factors of overall survival (OS) in patients with advanced non-small cell lung cancer (aNSCLC) and to develop a novel prognostic model. METHODS: A total of 4049 patients with aNSCLC diagnosed between January 2011 and February 2020 who received atezolizumab, nivolumab, or pembrolizumab as second-line monotherapy were selected from a real-world deidentified database to build the cohort. Patients could not have received first-line treatment with clinical study drug(s) nor immune checkpoint inhibitors including anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1), and anti-cytotoxic T-lymphocyte-associated protein 4 therapies. RESULTS: Patients had a median age of 69 years; 45% were female, 75% White, 70% had stage IV at initial diagnosis, and 70% had nonsquamous histology. A Cox proportional hazards model with lasso regularization was used to build a prognostic model for OS using 18 baseline demographic and clinical factors based on the real-world data cohort. The risk-increasing prognostic factors were abnormally low albumin and chloride levels, Eastern Cooperative Oncology Group performance status score ≥ 2, and abnormally high levels of alkaline phosphatase and white blood cells. The risk-decreasing prognostic factors were PD-L1 positivity, longer time from advanced diagnosis to start of first-line therapy, and higher systolic blood pressure. The performance of the model was validated using data from the OAK trial, and the c-index for the OAK trial validation cohort was 0.65 and 0.67 for the real-world data cohort. CONCLUSIONS: Based on baseline demographic and clinical factors from a real-world setting, this prognostic model was developed to discriminate the risk of death in patients with aNSCLC treated with checkpoint inhibitors as second-line monotherapy, and it performed well in the real-world data and clinical trial cohorts.

2.
Pharm Stat ; 20(2): 202-211, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32869509

RESUMO

One of the challenges in the design of confirmatory trials is to deal with uncertainties regarding the optimal target population for a novel drug. Adaptive enrichment designs (AED) which allow for a data-driven selection of one or more prespecified biomarker subpopulations at an interim analysis have been proposed in this setting but practical case studies of AEDs are still relatively rare. We present the design of an AED with a binary endpoint in the highly dynamic setting of cancer immunotherapy. The trial was initiated as a conventional trial in early triple-negative breast cancer but amended to an AED based on emerging data external to the trial suggesting that PD-L1 status could be a predictive biomarker. Operating characteristics are discussed including the concept of a minimal detectable difference, that is, the smallest observed treatment effect that would lead to a statistically significant result in at least one of the target populations at the interim or the final analysis, respectively, in the setting of AED.


Assuntos
Neoplasias , Projetos de Pesquisa , Ensaios Clínicos Adaptados como Assunto , Biomarcadores , Humanos , Imunoterapia , Neoplasias/terapia , Ensaios Clínicos Pragmáticos como Assunto
3.
Pharm Stat ; 19(1): 44-58, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31461220

RESUMO

For a trial with primary endpoint overall survival for a molecule with curative potential, statistical methods that rely on the proportional hazards assumption may underestimate the power and the time to final analysis. We show how a cure proportion model can be used to get the necessary number of events and appropriate timing via simulation. If phase 1 results for the new drug are exceptional and/or the medical need in the target population is high, a phase 3 trial might be initiated after phase 1. Building in a futility interim analysis into such a pivotal trial may mitigate the uncertainty of moving directly to phase 3. However, if cure is possible, overall survival might not be mature enough at the interim to support a futility decision. We propose to base this decision on an intermediate endpoint that is sufficiently associated with survival. Planning for such an interim can be interpreted as making a randomized phase 2 trial a part of the pivotal trial: If stopped at the interim, the trial data would be analyzed, and a decision on a subsequent phase 3 trial would be made. If the trial continues at the interim, then the phase 3 trial is already underway. To select a futility boundary, a mechanistic simulation model that connects the intermediate endpoint and survival is proposed. We illustrate how this approach was used to design a pivotal randomized trial in acute myeloid leukemia and discuss historical data that informed the simulation model and operational challenges when implementing it.


Assuntos
Leucemia Mieloide Aguda/tratamento farmacológico , Modelos Estatísticos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Projetos de Pesquisa , Ensaios Clínicos Fase II como Assunto/métodos , Ensaios Clínicos Fase III como Assunto/métodos , Simulação por Computador , Interpretação Estatística de Dados , Desenvolvimento de Medicamentos , Determinação de Ponto Final , Humanos , Taxa de Sobrevida , Incerteza
4.
JAMA Oncol ; 5(5): e190339, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30998824

RESUMO

Importance: Confirmation of long-term comparability between subcutaneous and intravenous trastuzumab is essential. Objective: To evaluate efficacy and safety of subcutaneous trastuzumab compared with that of intravenous trastuzumab for patients with ERBB2 (HER2)-positive early breast cancer after 6 years' follow-up in the HannaH (Enhanced Treatment With Neoadjuvant Herceptin) trial. Design, Setting, and Participants: Open-label, prospective, multicenter, international, neoadjuvant-adjuvant, randomized, phase 3 noninferiority clinical trial (primary end points: pathologic complete response and serum trough concentration predose cycle 8) conducted for 596 patients with ERBB2-positive early breast cancer enrolled from October 19, 2009, to December 1, 2010. Interventions: Eligible patients received 8 cycles of chemotherapy (4 cycles of docetaxel, 75 mg/m2, followed by 4 cycles of fluorouracil, 500 mg/m2, epirubicin, 75 mg/m2, and cyclophosphamide, 500 mg/m2) with either fixed-dose subcutaneous trastuzumab, 600 mg, or intravenous trastuzumab (loading dose, 8 mg/kg; maintenance dose, 6 mg/kg) every 3 weeks in the neoadjuvant setting. Patients received an additional 10 cycles of subcutaneous trastuzumab or intravenous trastuzumab (according to their initial randomization) after surgery in the adjuvant setting to complete 1 year of anti-ERBB2 therapy. Main Outcomes and Measures: Event-free and overall survival rates were calculated using the Kaplan-Meier method. Hazard ratios were estimated by Cox proportional hazards regression. Adverse events and serious adverse events were graded per standard criteria. Results: In total, 294 women (mean [SD] age, 50.3 [11.1] years) treated with subcutaneous trastuzumab and 297 women (mean [SD] age, 49.5 [10.8] years) treated with intravenous trastuzumab were included in respective intention-to-treat populations. Six-year event-free survival rates (65% in both study groups; hazard ratio, 0.98; 95% CI, 0.74-1.29) and overall survival rates (84% in both study groups; hazard ratio, 0.94; 95% CI, 0.61-1.45) were similar between the subcutaneous and intravenous trastuzumab groups. Patients achieving a total pathologic complete response had longer event-free survival and higher 6-year overall survival rates than those with residual disease. Incidence of adverse events (290 of 297 [97.6%] vs 282 of 298 [94.6%]), grade 3 or higher adverse events (158 of 297 [53.2%] vs 160 of 298 [53.7%]), cardiac events (44 of 297 [14.8%] vs 42 of 298 [14.1%]), and serious adverse events (65 of 297 [21.9%] vs 45 of 298 [15.1%]) was comparable between the subcutaneous and intravenous trastuzumab treatment groups. Conclusions and Relevance: This final analysis of the HannaH trial further confirms the comparable efficacy and safety of subcutaneous and intravenous trastuzumab and highlights the suitability of subcutaneous trastuzumab as an alternative route of administration for patients with ERBB2-positive early breast cancer. Trial Registration: ClinicalTrials.gov identifier: NCT00950300.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2 , Trastuzumab/administração & dosagem , Adulto , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias da Mama/mortalidade , Feminino , Humanos , Injeções Subcutâneas , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Terapia Neoadjuvante , Intervalo Livre de Progressão , Taxa de Sobrevida , Trastuzumab/efeitos adversos
5.
Clin Pharmacokinet ; 56(9): 1033-1043, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28255850

RESUMO

Vemurafenib is an orally administered small-molecule inhibitor of the oncogenic BRAF kinase that is indicated for the treatment of patients with unresectable or metastatic melanoma harbouring BRAF V600 mutations. Vemurafenib is absorbed rapidly after a single oral dose of 960 mg, reaching maximum drug concentration approximately 4 h after administration. Extensive accumulation occurs after multiple dosing at 960 mg twice daily. Steady state is achieved after approximately 15-21 days and exposure at steady state is relatively constant. Population pharmacokinetic analysis identified a vemurafenib half-life of ≈57 h and elimination appears to be predominantly via the hepatic route. Pharmacokinetic parameters are generally consistent regardless of age, sex or race. No dose adjustments are necessary for patients with mild or moderate hepatic or renal impairment, but the effects of severe hepatic or renal impairment on vemurafenib pharmacokinetics are uncertain. Vemurafenib appears to be a substrate and inducer of cytochrome P450 (CYP) 3A4, a moderate inhibitor of CYP1A2 and both a substrate and inhibitor of the drug efflux transporters P-glycoprotein and breast cancer resistance protein. The relationship between plasma vemurafenib concentrations and response remains to be clarified.


Assuntos
Antineoplásicos/farmacocinética , Inibidores do Citocromo P-450 CYP1A2/farmacocinética , Indutores do Citocromo P-450 CYP3A/farmacocinética , Indóis/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Sulfonamidas/farmacocinética , Animais , Antineoplásicos/uso terapêutico , Ensaios Clínicos Fase I como Assunto/estatística & dados numéricos , Inibidores do Citocromo P-450 CYP1A2/uso terapêutico , Indutores do Citocromo P-450 CYP3A/uso terapêutico , Interações Medicamentosas/fisiologia , Humanos , Indóis/uso terapêutico , Melanoma/sangue , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Sulfonamidas/uso terapêutico , Vemurafenib
6.
Eur J Cancer ; 62: 62-75, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27208905

RESUMO

BACKGROUND: In the phase III, open-label, randomised HannaH study, fixed-dose neoadjuvant-adjuvant subcutaneous trastuzumab for human epidermal growth factor receptor 2 (HER2)-positive early breast cancer was non-inferior to standard weight-based intravenous infusion in terms of serum trough concentration and pathological complete response (pCR). Evidence suggests that pCR, particularly total pCR (tpCR), is likely to predict clinical benefit. We report associations between tpCR and event-free survival (EFS) from HannaH (the largest population from a single study of patients presenting with newly diagnosed HER2-positive breast cancer treated with neoadjuvant-adjuvant trastuzumab to date) plus long-term efficacy and safety. METHODS: Eligible patients received four cycles of neoadjuvant docetaxel followed by four cycles of fluorouracil/epirubicin/cyclophosphamide administered concurrently with 3-weekly subcutaneous (600 mg fixed dose) or intravenous trastuzumab (8 mg/kg loading, 6 mg/kg maintenance doses). Post-surgery, patients received adjuvant trastuzumab as randomised to complete 1 year of standard treatment. In exploratory analyses, we used Cox regression to assess associations between tpCR and EFS. EFS rates per subgroup were estimated using the Kaplan-Meier method. FINDINGS: Three-year EFS rates were 76% for subcutaneous and 73% for intravenous trastuzumab (unstratified hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.69-1.30; intention-to-treat population). Three-year overall survival rates were 92% for subcutaneous and 90% for intravenous trastuzumab (unstratified HR 0.76, 95% CI 0.44-1.32). tpCR was associated with a reduced risk of an EFS event: subcutaneous arm HR 0.38 (95% CI 0.22-0.65); intravenous arm HR 0.32 (95% CI 0.18-0.60). Results were similar for subgroups, including oestrogen receptor status. The few additional adverse events occurring during treatment-free follow-up were balanced between arms. INTERPRETATION: Long-term efficacy supports the established non-inferiority of subcutaneous trastuzumab, and its safety profile remains consistent with the known intravenous profile. In each of HannaH's treatment arms, tpCR was associated with improved EFS, adding to evidence that tpCR is associated with clinical benefit in HER2-positive early breast cancer.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Trastuzumab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Injeções Subcutâneas , Pessoa de Meia-Idade , Terapia Neoadjuvante , Adulto Jovem
7.
Cancer Chemother Pharmacol ; 77(1): 77-88, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26645407

RESUMO

PURPOSE: To characterize the population pharmacokinetics (PKs) of subcutaneous (SC) and intravenous (IV) trastuzumab in early breast cancer (EBC), assess the impact of covariates on trastuzumab PK, and evaluate fixed (nonweight-based) dosing for the SC regimen administrated via handheld syringe. METHODS: Serum trastuzumab concentrations from 595 patients with HER2-positive EBC in the HannaH study (fixed 600 mg SC trastuzumab or weight-based IV trastuzumab) were analyzed using nonlinear mixed-effects modeling. Multiple logistic regression was used to assess the exposure-response relationships between PK, efficacy [pathologic complete response (pCR)], and safety [grade ≥3 adverse events (AEs)]. RESULTS: Trastuzumab PK was described by a two-compartment model with parallel linear and nonlinear elimination and first-order SC absorption, with a bioavailability of 77 %. Estimated total clearance (CL) values were 0.18-0.22 L/day for steady-state trough/peak concentrations of 75-148 µg/mL; the estimate for central volume of distribution was 2.9 L. Body weight and alanine transaminase, while showing significant effects on PK, only explained 8% of the variability in CL. Exposure-response analyses showed no relationship between PK, pCR, and grade ≥3 AEs for either regimen. CONCLUSION: A fixed 600 mg SC dose of trastuzumab provides the desired exposure, with steady-state trough concentrations (35-123 µg/mL for the 5th-95th percentiles) above the historical target concentration of 20 µg/mL for efficacy. Fixed dosing is further supported by lack of an exposure-response relationship between PK, pCR, and grade ≥3 AEs. No dose adjustment per patient factors is required within the ranges studied.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Trastuzumab/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Disponibilidade Biológica , Feminino , Humanos , Infusões Intravenosas , Injeções Subcutâneas , Modelos Logísticos , Dinâmica não Linear , Receptor ErbB-2 , Seringas , Distribuição Tecidual , Trastuzumab/metabolismo , Trastuzumab/uso terapêutico
8.
Future Oncol ; 11(1): 61-71, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25163910

RESUMO

AIMS: Identify sensitive end points and populations for similarity studies of trastuzumab and biosimilar monoclonal antibodies. METHODS: We performed meta-analyses of trastuzumab clinical trials data: overall response rate (ORR) and progression-free survival in metastatic breast cancer (MBC), and total pathologic complete response (tpCR) and event-free survival in the neoadjuvant setting. Fitted models predicted the maximum loss in long-term efficacy for different similarity trial designs. Immunogenicity rates were investigated in different early breast cancer (EBC) study phases. RESULTS: Using the same equivalence margins for ORR (MBC) and tpCR (EBC), the predicted maximum loss in long-term efficacy with a biosimilar candidate versus the reference product is smaller for tpCR than for ORR. In EBC this predicted loss could be controlled with feasible patient numbers for a typical clinical trial. Analyses suggested that a treatment-free follow-up phase is preferable for immunogenicity characterization. CONCLUSION: Treatment of patients with neoadjuvant breast cancer represents a sensitive setting for establishing biosimilarity of efficacy and immunogenicity. tpCR is a sensitive end point in this setting to establish biosimilarity between a biosimilar candidate and its reference product.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Terapia Neoadjuvante , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos dos fármacos , Neoplasias da Mama/epidemiologia , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Feminino , Humanos , Trastuzumab
9.
Lancet Oncol ; 15(6): 640-7, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24657003

RESUMO

BACKGROUND: In our randomised, controlled, phase 3 trial NeOAdjuvant Herceptin (NOAH) trial in women with HER2-positive locally advanced or inflammatory breast cancer, neoadjuvant trastuzumab significantly improved pathological complete response rate and event-free survival. We report updated results from our primary analysis to establish the long-term benefit of trastuzumab-containing neoadjuvant therapy. METHODS: We did this multicentre, open-label, randomised trial in women with HER2-positive locally advanced or inflammatory breast cancer. Participants were randomly assigned (1:1), by computer program with a minimisation technique, to receive neoadjuvant chemotherapy alone or with 1 year of trastuzumab (concurrently with neoadjuvant chemotherapy and continued after surgery). A parallel group with HER2-negative disease was included and received neoadjuvant chemotherapy alone. Our primary endpoint was event-free survival. Analysis was by intention to treat. This study is registered at www.controlled-trials.com, ISRCTN86043495. FINDINGS: Between June 20, 2002, and Dec 12, 2005, we enrolled 235 patients with HER2-positive disease, of whom 118 received chemotherapy alone and 117 received chemotherapy plus trastuzumab. 99 additional patients with HER2-negative disease were included in the parallel cohort. After a median follow-up of 5.4 years (IQR 3.1-6.8) the event-free-survival benefit from the addition of trastuzumab to chemotherapy was maintained in patients with HER2-positive disease. 5 year event-free survival was 58% (95% CI 48-66) in patients in the trastuzumab group and 43% (34-52) in those in the chemotherapy group; the unadjusted hazard ratio (HR) for event-free survival between the two randomised HER2-positive treatment groups was 0.64 (95% CI 0.44-0.93; two-sided log-rank p=0.016). Event-free survival was strongly associated with pathological complete remission in patients given trastuzumab. Of the 68 patients with a pathological complete response (45 with trastuzumab and 23 with chemotherapy alone), the HR for event-free survival between those with and without trastuzumab was 0.29 (95% CI 0.11-0.78). During follow-up only four cardiovascular adverse events were regarded by the investigator to be drug-related (grade 2 lymphostasis and grade 2 lymphoedema, each in one patient in the trastuzumab group, and grade 2 thrombosis and grade 2 deep vein thrombosis, each in one patient in the chemotherapy-alone group). INTERPRETATION: These results show a sustained benefit in event-free survival from trastuzumab-containing neoadjuvant therapy followed by adjuvant trastuzumab in patients with locally advanced or inflammatory breast cancer, and provide new insight into the association between pathological complete remission and long-term outcomes in HER2-positive disease.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Terapia Neoadjuvante , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Seguimentos , Genes erbB-2 , Humanos , Neoplasias Inflamatórias Mamárias/tratamento farmacológico , Neoplasias Inflamatórias Mamárias/mortalidade , Neoplasias Inflamatórias Mamárias/patologia , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Trastuzumab , Resultado do Tratamento
10.
Cancer Chemother Pharmacol ; 72(5): 1079-87, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24057039

RESUMO

PURPOSE: To demonstrate pharmacokinetic (PK) comparability for a single dose of 600 mg subcutaneous (SC) trastuzumab, administered via a novel single-use injection device (SID) or handheld syringe in 119 randomized healthy male subjects. METHODS: The co-primary PK endpoints area under the time-concentration curve from the start of dosing to day 22 (AUC(0-21 days)) and maximum observed trastuzumab serum concentration (C(max)) were dose-normalized and body-weight-adjusted, and compared using geometric mean ratios (GMRs). SID performance, injection site pain, adverse events, and antidrug antibodies (ADAs) were assessed. RESULTS: GMRs and 90 % confidence intervals (CIs) were 1.01 (0.96-1.07) for AUC(0-21 days) and 1.02 (0.96-1.10) for C(max), which fell within the prespecified bioequivalence range (0.80-1.25). No SID quality issues or failures occurred. Adverse events were mostly mild, with no deaths, adverse event-related withdrawals, or life-threatening, cardiac, or serious events reported. The ADA rate was low, and no neutralizing antibodies were detected. CONCLUSIONS: Trastuzumab SC via SID demonstrated comparable PK and safety to handheld syringe administration. SID performance was very satisfactory.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/sangue , Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Moléculas de Adesão Celular/química , Moléculas de Adesão Celular/metabolismo , Equipamentos Descartáveis , Sistemas de Liberação de Medicamentos/efeitos adversos , Sistemas de Liberação de Medicamentos/instrumentação , Hipersensibilidade a Drogas/sangue , Hipersensibilidade a Drogas/imunologia , Hipersensibilidade a Drogas/prevenção & controle , Excipientes , Meia-Vida , Humanos , Hialuronoglucosaminidase/química , Hialuronoglucosaminidase/metabolismo , Injeções Subcutâneas , Masculino , Teste de Materiais , Nova Zelândia , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Autoadministração/instrumentação , Seringas , Trastuzumab , Adulto Jovem
11.
Lancet ; 382(9897): 1021-8, 2013 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-23871490

RESUMO

BACKGROUND: Trastuzumab has established efficacy against breast cancer with overexpression or amplification of the HER2 oncogene. The standard of care is 1 year of adjuvant trastuzumab, but the optimum duration of treatment is unknown. We compared 2 years of treatment with trastuzumab with 1 year of treatment, and updated the comparison of 1 year of trastuzumab versus observation at a median follow-up of 8 years, for patients enrolled in the HERceptin Adjuvant (HERA) trial. METHODS: The HERA trial is an international, multicentre, randomised, open-label, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant chemotherapy, adjuvant chemotherapy, or both in 5102 patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival. The comparison of 2 years versus 1 year of trastuzumab treatment involved a landmark analysis of 3105 patients who were disease-free 12 months after randomisation to one of the trastuzumab groups, and was planned after observing at least 725 disease-free survival events. The updated intention-to-treat comparison of 1 year trastuzumab treatment versus observation alone in 3399 patients at a median follow-up of 8 years (range 0-10) is also reported. This study is registered with ClinicalTrials.gov, number NCT00045032. FINDINGS: We recorded 367 events of disease-free survival in 1552 patients in the 1 year group and 367 events in 1553 patients in the 2 year group (hazard ratio [HR] 0·99, 95% CI 0·85-1·14, p=0·86). Grade 3-4 adverse events and decreases in left ventricular ejection fraction during treatment were reported more frequently in the 2 year treatment group than in the 1 year group (342 [20·4%] vs 275 [16·3%] grade 3-4 adverse events, and 120 [7·2%] vs 69 [4·1%] decreases in left ventricular ejection fraction, respectively). HRs for a comparison of 1 year of trastuzumab treatment versus observation were 0·76 (95% CI 0·67-0·86, p<0·0001) for disease-free survival and 0·76 (0·65-0·88, p=0·0005) for overall survival, despite crossover of 884 (52%) patients from the observation group to trastuzumab therapy. INTERPRETATION: 2 years of adjuvant trastuzumab is not more effective than is 1 year of treatment for patients with HER2-positive early breast cancer. 1 year of treatment provides a significant disease-free and overall survival benefit compared with observation and remains the standard of care. FUNDING: F Hoffmann-La Roche (Roche).


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/metabolismo , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Quimioterapia Adjuvante , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Seguimentos , Humanos , Adesão à Medicação , Pessoa de Meia-Idade , Trastuzumab , Resultado do Tratamento
12.
Lancet Oncol ; 13(9): 869-78, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22884505

RESUMO

BACKGROUND: A subcutaneous formulation of trastuzumab has been developed, offering potential improvements in patient convenience and resource use compared with the standard intravenous infusion of the drug. We compared the pharmacokinetic profile, efficacy, and safety of the subcutaneous and intravenous formulations in patients with HER2-positive early breast cancer. METHODS: The HannaH study was a phase 3, randomised, international, open-label, trial in the (neo)adjuvant setting. Patients with HER2-positive, operable, locally advanced or inflammatory breast cancer were randomly assigned to eight cycles of neoadjuvant chemotherapy administered concurrently with trastuzumab every 3 weeks either intravenously (8 mg/kg loading dose, 6 mg/kg maintenance dose) or subcutaneously (fixed dose of 600 mg); 1:1 ratio. Chemotherapy consisted of four cycles of docetaxel (75 mg/m(2)) followed by four cycles of fluorouracil (500 mg/m(2)), epirubicin (75 mg/m(2)), and cyclophosphamide (500 mg/m(2)), every 3 weeks. After surgery, patients continued trastuzumab to complete 1 year of treatment. Coprimary endpoints were serum trough concentration (C(trough)) at pre-dose cycle 8 before surgery (non-inferiority margin for the ratio between groups of 0·80) and pathological complete response (pCR; non-inferiority margin for the difference between groups of -12·5%), analysed in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT00950300. FINDINGS: 299 patients were randomly assigned to receive intravenous trastuzumab and 297 to receive subcutaneous trastuzumab. The geometric mean presurgery C(trough) was 51·8 µg/mL (coefficient of variation 52·5%) in the intravenous group and 69·0 µg/mL (55·8%) in the subcutaneous group. The geometric mean ratio of C(trough) subcutaneous to C(trough) intravenous was 1·33 (90% CI 1·24-1·44). 107 (40·7%) of 263 patients in the intravenous group and 118 (45·4%) of 260 in the subcutaneous group achieved a pCR. The difference between groups in pCR was 4·7% (95% CI -4·0 to 13·4). Thus subcutaneous trastuzumab was non-inferior to intravenous trastuzumab for both coprimary endpoints. The incidence of grade 3-5 adverse events was similar between groups. The most common of these adverse events were neutropenia (99 [33·2%] of 298 patients in the intravenous group vs 86 [29·0%] of 297 in the subcutaneous group), leucopenia (17 [5·7%] vs 12 [4·0%]), and febrile neutropenia (10 [3·4%] vs 17 [5·7%]). However, more patients had serious adverse events in the subcutaneous group (62 [21%] of 297 patients) than in the intravenous group (37 [12%] of 298); the difference was mainly attributable to infections and infestations (24 [8·1%] in the subcutaneous group vs 13 [4·4%] in the intravenous group). Four adverse events led to death (one in the intravenous group and three in the subcutaneous group), all of which occurred during the neoadjuvant phase. Of these, two--both in the subcutaneous group--were deemed to be treatment related. INTERPRETATION: Subcutaneous trastuzumab, administered over about 5 min, has a pharmacokinetic profile and efficacy non-inferior to standard intravenous administration, with a similar safety profile to intravenous trastuzumab, and therefore offers a valid treatment alternative. FUNDING: F Hoffmann-La Roche.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Adenocarcinoma/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/química , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Epirubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Infusões Intravenosas , Infusões Subcutâneas , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Gradação de Tumores , Estadiamento de Neoplasias , Receptor ErbB-2/análise , Trastuzumab , Adulto Jovem
13.
N Biotechnol ; 27(6): 822-8, 2010 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-20178865

RESUMO

Undoubtedly, biotechnology has a tremendous impact on our daily lives. As a result of this and in parallel to the advancement of knowledge in this field of applied research, consumer awareness of the potential benefits and risks of this technology has steadily increased, leading to a thorough investigation of the public perception of biotechnology in the past years. Indeed, it has become clear that it is in the general interest of science and especially of applied research to inform the public of its advances. A promising next step is to strengthen biotechnology communication in scholastic institutions. In this paper, we investigate the perception of biotechnology in a specific target group, namely high-school students in the 16-20-year-old age range. We conducted a questionnaire-based survey on a total of 1410 students in six European countries to investigate students' perception, concern, scientific knowledge, and awareness. Our data revealed some unexpected patterns of acceptance and concern about biotechnology. Knowledge analysis indicated that pupils lack specific knowledge about biotechnological applications and their interest in biotechnology appeared to be linked to knowledge. Analysis of specific questions about teaching practices at schools suggests that a better targeted choice in media as vehicles for information together with selected speakers could be instrumental in increasing students' interest in science and more specifically in biotechnology.


Assuntos
Conscientização , Biotecnologia/educação , Instituições Acadêmicas , Estudos Transversais , Meio Ambiente , Europa (Continente) , Feminino , Alimentos Geneticamente Modificados , Humanos , Masculino , Opinião Pública , Ciência/educação , Estudantes , Inquéritos e Questionários , Trabalho
14.
Math Biosci ; 222(1): 27-35, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19715705

RESUMO

Compound processes are proposed as models for the acquisition of hydatid cysts in sheep, caused by the parasite Echinococcus granulosus. The hypothesis of a clumped infection process against single ingestions is tested and it is shown that the clump-based approach provides a more accurate description of the two data sets investigated. Models with simple and mixed Poisson incidence processes and different clump size distributions are compared. A mixed Poisson incidence process with a zero-truncated negative binomial distribution for the clump sizes is shown to give an adequate description, suggesting that the acquisition of hydatid cysts in the sheep population is heterogeneous, and that the clump sizes are aggregated. The estimates of the parameters derived from the data take plausible values. The average infection rate and the clump size distribution are comparable in both data sets. Goodness-of-fit measures indicate that the model fits the data reasonably well.


Assuntos
Equinococose/veterinária , Echinococcus granulosus/crescimento & desenvolvimento , Modelos Biológicos , Doenças dos Ovinos/parasitologia , Fatores Etários , Animais , Simulação por Computador , Equinococose/epidemiologia , Equinococose/parasitologia , Equinococose/transmissão , Distribuição de Poisson , Prevalência , Ovinos , Doenças dos Ovinos/epidemiologia , Doenças dos Ovinos/transmissão
15.
Vet Parasitol ; 154(3-4): 242-9, 2008 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-18495343

RESUMO

The intermediate host of Fasciola hepatica is Lymnaea truncatula in Switzerland. The snail and the free-living stages of the parasite require a moderate climate and moisture for survival, reproduction, and transmission. In Switzerland, these conditions are present in many regions, resulting in a mean prevalence of bovine fasciolosis from 8.4 to 21.4%. An interactive map was created in order to demonstrate the relative risk of transmission by modelling the environmental conditions that promote the survival and reproduction of the larval stages of the parasite and the parasite's intermediate host. The map is based on temperature and rainfall data, soil conditions including ground water and forest cover in Switzerland. Extensive information on the free-living stages of F. hepatica and the intermediate host L. truncatula and how the development of these are affected by these environmental factors was used to create the interactive risk map.


Assuntos
Fasciola hepatica/fisiologia , Lymnaea/parasitologia , Animais , Demografia , Fasciolíase/epidemiologia , Mapas como Assunto , Modelos Biológicos , Fatores de Risco , Suíça/epidemiologia , Interface Usuário-Computador
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