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BACKGROUND: SERENA-1 (NCT03616587) is a phase I, multi-part, open-label study of camizestrant in pre- and post-menopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Parts A and B aim to determine the safety and tolerability of camizestrant monotherapy and define doses for clinical evaluation. PATIENTS AND METHODS: Women aged ≥18 years with metastatic or recurrent ER+, HER2- breast cancer, refractory (or intolerant) to therapy, were assigned 25 mg up to 450 mg once daily (QD; escalation) or 75, 150, or 300 mg QD (expansion). Safety and tolerability, antitumor efficacy, pharmacokinetics, and impact on mutations in the estrogen receptor gene (ESR1m) circulating tumor (ct)DNA levels were assessed. RESULTS: By 9 March 2021, 108 patients received camizestrant monotherapy at 25-450 mg doses. Of these, 93 (86.1%) experienced treatment-related adverse events (TRAEs), 82.4% of which were grade 1 or 2. The most common TRAEs were visual effects (56%), (sinus) bradycardia (44%), fatigue (26%), and nausea (15%). There were no TRAEs grade 3 or higher, or treatment-related serious adverse events at doses ≤150 mg. Median tmax was achieved â¼2-4 h post-dose at all doses investigated, with an estimated half-life of 20-23 h. Efficacy was observed at all doses investigated, including in patients with prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and/or fulvestrant treatment, with and without baseline ESR1 mutations, and with visceral disease, including liver metastases. CONCLUSIONS: Camizestrant is a next-generation oral selective ER antagonist and degrader (SERD) and pure ER antagonist with a tolerable safety profile. The pharmacokinetics profile supports once-daily dosing, with evidence of pharmacodynamic and clinical efficacy in heavily pre-treated patients, regardless of ESR1m. This study established 75-, 150-, and 300-mg QD doses for phase II testing (SERENA-2, NCT04214288 and SERENA-3, NCT04588298).
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Neoplasias de la Mama , Receptor ErbB-2 , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Persona de Mediana Edad , Receptor ErbB-2/genética , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/metabolismo , Anciano , Adulto , Receptores de Estrógenos/metabolismo , Administración Oral , Receptor alfa de Estrógeno/genética , Anciano de 80 o más Años , Dosis Máxima Tolerada , Relación Dosis-Respuesta a Droga , Azetidinas , IsoquinolinasRESUMEN
Adequate drug distribution through tumors is essential for treatment to be effective. Palbociclib is a cyclin-dependent kinase 4/6 inhibitor approved for use in patients with hormone receptor positive, human epidermal growth factor receptor 2 negative metastatic breast cancer. It has unusual physicochemical properties, which may significantly influence its distribution in tumor tissue. We studied the penetration and distribution of palbociclib in vitro, including the use of multicellular three-dimensional models and mathematical modeling. MCF-7 and DLD-1 cell lines were grown as single cell suspensions (SCS) and spheroids; palbociclib uptake and efflux were studied using liquid chromatography-tandem mass spectrometry. Intracellular concentrations of palbociclib for MCF-7 SCS (C max 3.22 µM) and spheroids (C max 2.91 µM) were 32- and 29-fold higher and in DLD-1, 13- and 7-fold higher, respectively, than the media concentration (0.1 µM). Total palbociclib uptake was lower in DLD-1 cells than MCF-7 cells in both SCS and spheroids. Both uptake and efflux of palbociclib were slower in spheroids than SCS. These data were used to develop a mathematical model of palbociclib transport that quantifies key parameters determining drug penetration and distribution. The model reproduced qualitatively most features of the experimental data and distinguished between SCS and spheroids, providing additional support for hypotheses derived from the experimental data. Mathematical modeling has the potential for translating in vitro data into clinically relevant estimates of tumor drug concentrations. SIGNIFICANCE STATEMENT: This study explores palbociclib uptake and efflux in single cell suspension and spheroid models of cancer. Large intracellular concentrations of palbociclib are found after drug exposure. The data from this study may aid understanding of the intratumoural pharmacokinetics of palbociclib, which is useful in understanding how drug distributes within tumor tissue and optimizing drug efficacy. Biomathematical modelling has the potential to derive intratumoural drug concentrations from plasma pharmacokinetics in patients.
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Piperazinas/metabolismo , Piridinas/metabolismo , Esferoides Celulares/metabolismo , Transporte Biológico , Supervivencia Celular/efectos de los fármacos , Humanos , Células MCF-7 , Modelos Biológicos , Piperazinas/farmacología , Piridinas/farmacología , Análisis de la Célula Individual , Esferoides Celulares/efectos de los fármacosRESUMEN
The tumour vasculature and microenvironment is complex and heterogeneous, contributing to reduced delivery of cancer drugs to the tumour. We have developed an in silico model of drug transport in a tumour cord to explore the effect of different drug regimes over a 72 h period and how changes in pharmacokinetic parameters affect tumour exposure to the cytotoxic drug doxorubicin. We used the model to describe the radial and axial distribution of drug in the tumour cord as a function of changes in the transport rate across the cell membrane, blood vessel and intercellular permeability, flow rate, and the binding and unbinding ratio of drug within the cancer cells. We explored how changes in these parameters may affect cellular exposure to drug. The model demonstrates the extent to which distance from the supplying vessel influences drug levels and the effect of dosing schedule in relation to saturation of drug-binding sites. It also shows the likely impact on drug distribution of the aberrant vasculature seen within tumours. The model can be adapted for other drugs and extended to include other parameters. The analysis confirms that computational models can play a role in understanding novel cancer therapies to optimize drug administration and delivery.
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BACKGROUND: Post-treatment survival experience of early colon cancer (CC) patients is well described in the literature, which states that cure is probable for some patients. However, comparisons of treated patients' survival versus that expected from a matched general population (MGP) are limited. PATIENTS AND METHODS: A total of 32 745 patients from 25 randomized adjuvant trials conducted from 1977 to 2012 in 41 countries were pooled. Observed long-term survival of these patients was compared with expected survival matched on sex, age, country, and year, both overall and by stage (II and III), sex, treatment [surgery, 5-fluorouracil (5-FU), 5-FU + oxaliplatin], age (<70 and 70+), enrollment year (pre/post 2000), and recurrence (yes/no). Comparisons were made at randomization and repeated conditional on survival to 1, 2, 3, and 5 years. CC and MGP equivalence was tested, and observed Kaplan-Meier survival rates compared with expected MGP rates 3 years out from each landmark. Analyses were also repeated in patients without recurrence. RESULTS: Within most cohorts, long-term survival of CC patients remained statistically worse than the MGP, though conditional survival generally improved over time. Among those surviving 5 years, stage II, oxaliplatin-treated, elderly, and recurrence-free patients achieved subsequent 3-year survival rates within 5% of the MGP, with recurrence-free patients achieving equivalence. CONCLUSIONS: Conditional on survival to 5 years, long-term survival of most CC patients on clinical trials remains modestly poorer than an MGP, but achieves MGP levels in some subgroups. These findings emphasize the need for access to quality care and improved treatment and follow-up strategies.
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Neoplasias del Colon/terapia , Detección Precoz del Cáncer , Sobrevivientes , Estudios de Casos y Controles , Neoplasias del Colon/mortalidad , Neoplasias del Colon/patología , Bases de Datos Factuales , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Riesgo , Tasa de Supervivencia , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Adjuvant oxaliplatin plus capecitabine or leucovorin/5-fluorouracil (LV/5-FU) (XELOX/FOLFOX) is the standard of care for stage III colon cancer (CC); however, there is disagreement regarding oxaliplatin benefit in patients aged >70. In most analyses, the impact of medical comorbidity (MC) has not been assessed. Efficacy and safety of adjuvant XELOX/FOLFOX versus LV/5-FU were compared with respect to age and MC using pooled data from four randomized, controlled trials, selected for access to patient-level MC data and including commonly endorsed and utilized regimens. PATIENTS AND METHODS: Individual data from patients with stage III CC in NSABP C-08, XELOXA, X-ACT, and AVANT were pooled, excluding bevacizumab-treated patients. Patients were grouped by treatment, MC (low versus high), or age (<70 versus ≥70), and compared for disease-free survival (DFS), overall survival (OS), and adverse events (AEs). Multivariable Cox proportional hazards regression controlled for gender, T stage, and N stage. RESULTS: DFS benefits were shown for XELOX/FOLFOX versus LV/5-FU regardless of age or MC, although benefits were modestly attenuated for patients aged ≥70. Hazard ratios were 0.68 (P < 0.0001) and 0.77 (P < 0.014) for <70 and ≥70 age groups; 0.69 (P < 0.0001) and 0.59 (P < 0.0001) for Charlson Comorbidity Index ≤1 and >1 groups; and 0.70 (P < 0.0001) and 0.58 (P < 0.0001) for National Cancer Institute Combined Index ≤1 and >1 groups. OS was also significantly improved in all groups. Grade 3/4 serious AE rates were comparable across cohorts and MC scores and higher in patients aged ≥70. Oxaliplatin-relevant grade 3/4 AEs, including neuropathy, were comparable across ages and MC scores. CONCLUSIONS: Results further support consideration of XELOX or FOLFOX as standard treatment options for the adjuvant management of stage III CC in all age groups and in patients with comorbidities, consistent with those who were eligible for these clinical trials.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos Clínicos como Asunto , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/mortalidad , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Neoplasias del Colon/patología , Comorbilidad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: T-cell infiltration in estrogen receptor (ER)-negative breast tumours has been associated with longer survival. To investigate this association and the potential of tumour T-cell infiltration as a prognostic and predictive marker, we have conducted the largest study of T cells in breast cancer to date. PATIENTS AND METHODS: Four studies totalling 12 439 patients were used for this work. Cytotoxic (CD8+) and regulatory (forkhead box protein 3, FOXP3+) T cells were quantified using immunohistochemistry (IHC). IHC for CD8 was conducted using available material from all four studies (8978 samples) and for FOXP3 from three studies (5239 samples)-multiple imputation was used to resolve missing data from the remaining patients. Cox regression was used to test for associations with breast cancer-specific survival. RESULTS: In ER-negative tumours [triple-negative breast cancer and human epidermal growth factor receptor 2 (human epidermal growth factor receptor 2 (HER2) positive)], presence of CD8+ T cells within the tumour was associated with a 28% [95% confidence interval (CI) 16% to 38%] reduction in the hazard of breast cancer-specific mortality, and CD8+ T cells within the stroma with a 21% (95% CI 7% to 33%) reduction in hazard. In ER-positive HER2-positive tumours, CD8+ T cells within the tumour were associated with a 27% (95% CI 4% to 44%) reduction in hazard. In ER-negative disease, there was evidence for greater benefit from anthracyclines in the National Epirubicin Adjuvant Trial in patients with CD8+ tumours [hazard ratio (HR) = 0.54; 95% CI 0.37-0.79] versus CD8-negative tumours (HR = 0.87; 95% CI 0.55-1.38). The difference in effect between these subgroups was significant when limited to cases with complete data (P heterogeneity = 0.04) and approached significance in imputed data (P heterogeneity = 0.1). CONCLUSIONS: The presence of CD8+ T cells in breast cancer is associated with a significant reduction in the relative risk of death from disease in both the ER-negative [supplementary Figure S1, available at Annals of Oncology online] and the ER-positive HER2-positive subtypes. Tumour lymphocytic infiltration may improve risk stratification in breast cancer patients classified into these subtypes. NEAT ClinicalTrials.gov: NCT00003577.
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Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Linfocitos T CD8-positivos/patología , Linfocitos Infiltrantes de Tumor/patología , Adulto , Anciano , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Linfocitos T CD8-positivos/metabolismo , Femenino , Humanos , Recuento de Linfocitos , Linfocitos Infiltrantes de Tumor/metabolismo , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Receptores de Progesterona/metabolismo , Análisis de Supervivencia , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/mortalidadRESUMEN
The ability to predict how far a drug will penetrate into the tumour microenvironment within its pharmacokinetic (PK) lifespan would provide valuable information about therapeutic response. As the PK profile is directly related to the route and schedule of drug administration, an in silico tool that can predict the drug administration schedule that results in optimal drug delivery to tumours would streamline clinical trial design. This paper investigates the application of mathematical and computational modelling techniques to help improve our understanding of the fundamental mechanisms underlying drug delivery, and compares the performance of a simple model with more complex approaches. Three models of drug transport are developed, all based on the same drug binding model and parametrized by bespoke in vitro experiments. Their predictions, compared for a 'tumour cord' geometry, are qualitatively and quantitatively similar. We assess the effect of varying the PK profile of the supplied drug, and the binding affinity of the drug to tumour cells, on the concentration of drug reaching cells and the accumulated exposure of cells to drug at arbitrary distances from a supplying blood vessel. This is a contribution towards developing a useful drug transport modelling tool for informing strategies for the treatment of tumour cells which are 'pharmacokinetically resistant' to chemotherapeutic strategies.
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Antineoplásicos/farmacocinética , Modelos Biológicos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Animales , Transporte Biológico , Simulación por Computador , HumanosRESUMEN
BACKGROUND: Central venous access devices in fluoropyrimidine therapy are associated with complications; however, reliable data are lacking regarding their natural history, associated complications and infusion pump performance in patients with metastatic colorectal cancer. METHODS: We assessed device placement, use during treatment, associated clinical outcomes and infusion pump performance in the NO16966 trial. RESULTS: Device replacement was more common with FOLFOX-4 (5-fluorouracil (5-FU)+oxaliplatin) than XELOX (capecitabine+oxaliplatin) (14.1% vs 5.1%). Baseline device-associated events and post-baseline removal-/placement-related events occurred more frequently with FOLFOX-4 than XELOX (11.5% vs 2.4% and 8.5% vs 2.1%). Pump malfunctions, primarily infusion accelerations in 16% of patients, occurred within 1.6-4.3% of cycles. Fluoropyrimidine-associated grade 3/4 toxicity was increased in FOLFOX-4-treated patients experiencing a malfunction compared with those who did not (97 out of 155 vs 452 out of 825 patients), predominantly with increased grade 3/4 neutropenia (53.5% vs 39.8%). Febrile neutropenia rates were comparable between patient cohorts±malfunction. Efficacy outcomes were similar in patient cohorts±malfunction. CONCLUSIONS: Central venous access device removal or replacement was common and more frequent in patients receiving FOLFOX-4. Pump malfunctions were also common and were associated with increased rates of grade 3/4 haematological adverse events. Oral fluoropyrimidine-based regimens may be preferable to infusional 5-FU based on these findings.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Cateterismo Venoso Central/estadística & datos numéricos , Neoplasias Colorrectales/tratamiento farmacológico , Dispositivos de Acceso Vascular/estadística & datos numéricos , Capecitabina , Cateterismo Venoso Central/instrumentación , Cateterismo Venoso Central/métodos , Estudios de Cohortes , Neoplasias Colorrectales/patología , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Leucovorina/administración & dosificación , Masculino , Metástasis de la Neoplasia , Compuestos Organoplatinos/administración & dosificación , OxaloacetatosRESUMEN
BACKGROUND: Efficacy and safety of first-line axitinib/paclitaxel/carboplatin versus bevacizumab/paclitaxel/carboplatin in advanced non-squamous non-small-cell lung cancer (NSCLC) was evaluated. PATIENTS AND METHODS: Patients with stage IIIB/IV disease stratified by adjuvant therapy and gender were randomised 1 : 1 to axitinib (5 mg twice daily) or bevacizumab [15 mg/kg every 3 weeks (Q3W)], both with paclitaxel (200 mg/m(2) Q3W)/carboplatin (AUC 6 mg min/ml Q3W). RESULTS: The trial was discontinued after preliminary analysis. Median progression-free survival (primary end point) for axitinib (N = 58) and bevacizumab (N = 60), respectively, was 5.7 and 6.1 months [hazard ratio (HR) 1.09, 95% confidence interval (CI) 0.68-1.76; one-sided stratified P = 0.64]; median overall survival was 10.6 and 13.3 months (HR 1.12, 95% CI 0.74-1.69; one-sided stratified P = 0.70). Objective response rates (95% CI) were 29.3% (18.1-42.7) and 43.3% (30.6-56.8), respectively; risk ratio 0.676 (95% CI 0.41-1.11; one-sided stratified P = 0.94). The most common grade 3/4 adverse events included neutropenia (28% versus 20%), fatigue (14% versus 7%), and hypertension (14% versus 5%). Patient-reported outcomes based on the EORTC QLQ-C30 were similar between arms. CONCLUSIONS: In patients with advanced non-squamous NSCLC, axitinib/paclitaxel/carboplatin did not improve efficacy versus bevacizumab/paclitaxel/carboplatin, and was less well tolerated.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Axitinib , Bevacizumab , Carboplatino/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Imidazoles/administración & dosificación , Indazoles/administración & dosificación , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neutropenia/inducido químicamente , Paclitaxel/administración & dosificación , Modelos de Riesgos Proporcionales , Resultado del TratamientoRESUMEN
BACKGROUND: Understanding their experiences of diagnosis is integral to improving the quality of care for women living with advanced/metastatic breast cancer. METHODS: A survey, initiated in March 2011, was conducted in two stages. First, the views of 47 breast cancer-related patient groups in eight European countries were sought on standards of breast cancer care and unmet needs of patients. Findings were used to develop a patient-centric survey to capture personal experiences of advanced breast cancer to determine insights into the 'trade-off' between extending overall survival and side effects associated with its treatment. The second online survey was open to women with locally advanced or metastatic breast cancer, or their carers, and responders were recruited through local patient groups. Data were collected via anonymous local language questionnaires. RESULTS: The online stage II survey received a total of 230 responses from 17 European countries: 94% of respondents had locally advanced or metastatic breast cancer and 6% were adult carers. Although the overall experience of care was generally good/excellent (77%), gaps were still perceived in terms of treatment choice and information provision. Treatment choice for patients was felt to be lacking by 32% of responders. In addition, 68% of those who responded would have liked more information about future medical treatments and research, with 57% wishing to receive this information from their oncologist. Two-thirds (66%) of women with advanced breast cancer, or their carers, believed life-extending treatment to be important so that they can spend more time with family and friends, and 67% said that the treatment was worthwhile, despite potential associated side effects. CONCLUSION: These findings show a continuing need to provide women with advanced breast cancer with better information and emphasise the importance that these patients often place on prolonging survival.
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Neoplasias de la Mama/psicología , Evaluación de Necesidades , Satisfacción del Paciente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Recolección de Datos , Europa (Continente) , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Encuestas y Cuestionarios , Adulto JovenRESUMEN
BACKGROUND: The National Epirubicin Adjuvant Trial (NEAT) and BR9601 trials tested the benefit of epirubicin when added to cyclophosphamide, methotrexate and 5-fluorouracil (E-CMF) compared with standard CMF in adjuvant chemotherapy for women with early breast cancer. This report details longer follow-up with interesting additional time-dependent analyses. METHODS: National Epirubicin Adjuvant Trial used epirubicin (E) 3-weekly for four cycles followed by classical (c) CMF for four cycles (E-CMF) compared with cCMF for six cycles. BR9601 used E 3-weekly for four cycles followed by CMF 3-weekly for four cycles, compared with CMF 3-weekly for eight cycles. RESULTS: In all, 2391 eligible patients were randomised and with a median 7.4-year follow-up, E-CMF confirmed a significant benefit over CMF in both relapse-free survival (RFS) (78% vs 71% 5 years RFS, respectively, hazard ratio (HR)=0.75 (95% CI: 0.65-0.86), P<0.0001) and overall survival (OS) (84% vs 78% 5 years OS, respectively, HR=0.76 (95% CI: 0.65-0.89), P=0.0007). Interaction of treatment effect and prognostic factors was demonstrated for duplication of chromosome 17 centromeric enumeration (Ch17CEP) as previously reported. Poor prognostic factors at diagnosis (ER and PR negative and HER2 positive) showed time-dependent annual hazard rates for RFS and OS. In univariate analysis, these factors demonstrated more favourable HRs for RFS after 5 years. Treatment effects also suggested a differential benefit for E-CMF within the first 5 years for poor prognosis tumours. CONCLUSION: Longer follow-up has confirmed E-CMF as significantly superior to CMF for all patients. Ch17CEP duplication was the only biomarker that demonstrated significant treatment interaction. Standard poor prognostic factors at diagnosis were time-dependent, and after 5 years disease-free, poor prognosis patients demonstrated favourable HRs for survival.
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Antibióticos Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Epirrubicina/administración & dosificación , Cumplimiento de la Medicación , Anciano , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Ciclofosfamida/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Humanos , Metotrexato/administración & dosificación , Persona de Mediana EdadRESUMEN
BACKGROUND: Selecting patients with 'sufficient life expectancy' for Phase I oncology trials remains challenging. The Royal Marsden Hospital Score (RMS) previously identified high-risk patients as those with ≥ 2 of the following: albumin <35 g l(-1); LDH > upper limit of normal; >2 metastatic sites. This study developed an alternative prognostic model, and compared its performance with that of the RMS. METHODS: The primary end point was the 90-day mortality rate. The new model was developed from the same database as RMS, but it used Chi-squared Automatic Interaction Detection (CHAID). The ROC characteristics of both methods were then validated in an independent database of 324 patients enrolled in European Organization on Research and Treatment of Cancer Phase I trials of cytotoxic agents between 2000 and 2009. RESULTS: The CHAID method identified high-risk patients as those with albumin <33 g l(-1) or ≥ 33 g l(-1), but platelet counts ≥ 400.000 mm(-3). In the validation data set, the rates of correctly classified patients were 0.79 vs 0.67 for the CHAID model and RMS, respectively. The negative predictive values (NPV) were similar for the CHAID model and RMS. CONCLUSION: The CHAID model and RMS provided a similarly high level of NPV, but the CHAID model gave a better accuracy in the validation set. Both CHAID model and RMS may improve the screening process in phase I trials.
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Ensayos Clínicos Fase I como Asunto/métodos , Modelos Estadísticos , Neoplasias/sangre , Neoplasias/tratamiento farmacológico , Recuento de Plaquetas/métodos , Albúmina Sérica/metabolismo , Algoritmos , Árboles de Decisión , Determinación de Punto Final , Femenino , Humanos , Masculino , Selección de Paciente , Valor Predictivo de las Pruebas , Pronóstico , Reproducibilidad de los Resultados , Tasa de SupervivenciaRESUMEN
BACKGROUND: Duplication of the centromeric region of chromosome 17 (Ch17CEP) is associated with sensitivity to anthracyclines. An explanation may be chromosome instability (CIN); a frequent event in solid tumours associated with poor outcome. The predictive value of CIN seems to be drug dependent and CIN has been associated with both sensitivity and resistance to chemotherapy. METHODS: In this study, we used fluorescent in situ hybridisation for chromosomes 1, 7, 11, 17 and 18 to identify patients with high tumour CIN% in 322 patients recruited into the BR9601 clinical trial. RESULTS: High tumour CIN% was correlated to Ch17CEP (P=3.68e-7) and is associated with a reduced RFS (P=0.0011) and OS (P=0.04). Patients with high CIN had a decreased risk of death on E-CMF compared with CMF. CONCLUSION: CIN is of prognostic significance and may be of predictive value in determining anthracycline response, although further testing is required.
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Antraciclinas/uso terapéutico , Antibióticos Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Inestabilidad Cromosómica , Cromosomas Humanos Par 17 , Adulto , Anciano , Biomarcadores , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Adulto JovenRESUMEN
BACKGROUND: This multicenter randomized trial compared oral capecitabine with bolus i.v. 5-fluorouracil (5-FU)/folinic acid (FA) as adjuvant therapy for stage III colon cancer. PATIENTS AND METHODS: Patients were assigned to 24 weeks of capecitabine 1250 mg/m(2) twice daily on days 1-14 every 3 weeks or 5-FU/FA (Mayo Clinic regimen). The primary end point was disease-free survival (DFS). RESULTS: The intent-to-treat population received capecitabine (n = 1004) or 5-FU/FA (n = 983). With a median follow-up of 6.9 years, capecitabine was at least equivalent to 5-FU/FA in terms of DFS [hazard ratio (HR) = 0.88; 95% confidence interval (CI) 0.77-1.01] and overall survival (OS) (HR = 0.86; 95% CI 0.74-1.01); the 95% CI upper limits were significantly less than the predefined noninferiority margins of 1.20 (P < 0.0001) and 1.14 (P < 0.001), respectively. This pattern was maintained in all subgroups, including patients aged ≥ 70 years. Preplanned multivariate analyses showed that capecitabine had statistically significant beneficial effects on DFS (P = 0.021) and OS (P = 0.020) versus 5-FU/FA. A post hoc analysis suggested that the occurrence of hand-foot syndrome may be associated with better outcomes in capecitabine recipients. CONCLUSION: Oral capecitabine is an effective alternative to bolus 5-FU/FA as adjuvant treatment of patients with stage III colon cancer with efficacy benefits maintained at 5 years and in older patients.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores Farmacológicos/metabolismo , Neoplasias del Colon/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Fluorouracilo/análogos & derivados , Fluorouracilo/administración & dosificación , Leucovorina/administración & dosificación , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Factores de Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Biomarcadores Farmacológicos/análisis , Capecitabina , Quimioterapia Adyuvante , Neoplasias del Colon/metabolismo , Neoplasias del Colon/mortalidad , Neoplasias del Colon/patología , Desoxicitidina/administración & dosificación , Desoxicitidina/farmacocinética , Femenino , Fluorouracilo/farmacocinética , Estudios de Seguimiento , Síndrome Mano-Pie/diagnóstico , Síndrome Mano-Pie/epidemiología , Humanos , Leucovorina/farmacocinética , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Farmacocinética , Proyectos Piloto , Pronóstico , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Literature reviews of cancer trials have highlighted the need for better understanding of phase II statistical designs. Understanding the key elements associated with phase II design and knowledge of available statistical designs is necessary to enable appropriate phase II trial design. METHODS: A systematic literature review was performed to identify phase II trial designs applicable to oncology trials. The results of the review were used to create a library of currently available designs, and to develop a structured approach to phase II trial design outlining key points for consideration. RESULTS: A total of 122 papers describing new or adapted phase II trial designs were obtained. These were categorised into nine levels, reflecting the practicalities of implementation, and form a library of phase II designs. Key design elements were identified by data extraction. Along with detailed description of the key elements and the library of designs, a structured thought process was developed to form a guidance document for choice of phase II oncology trial design. CONCLUSION: The guidance offers researchers a structured and systematic approach to identifying phase II trial designs, highlighting key issues to be considered by both clinicians and statisticians and encouraging an interactive approach to more informed trial design.
Asunto(s)
Ensayos Clínicos Fase II como Asunto/métodos , Guías como Asunto , Neoplasias/terapia , Proyectos de Investigación , Algoritmos , Ensayos Clínicos Fase II como Asunto/estadística & datos numéricos , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricosRESUMEN
BACKGROUND: To compare the effects of oral capecitabine-containing chemotherapy regimens with i.v. 5-fluorouracil (5-FU)-containing chemotherapy regimens on overall survival in patients with gastrointestinal cancers. METHODS: A meta-analysis, based on individual patient data from six randomised non-inferiority trials, was carried out at the request of regulatory authorities to compare the effects of single-agent capecitabine or capecitabine-containing chemotherapy versus matched 5-FU-based regimens in terms of overall survival in patients with stage III colon, metastatic colorectal or advanced gastric cancer. RESULTS: Data from a total of 6171 patients with stage III colon cancer (n = 1987), metastatic colorectal cancer (n = 3868) or advanced gastric cancer (n = 316) were included. A total of 3097 patients were treated with capecitabine-containing chemotherapy and 3074 patients with 5-FU-containing chemotherapy. The unadjusted hazard ratio for overall survival for capecitabine-containing chemotherapy versus 5-FU-containing chemotherapy was 0.94 (95% confidence interval 0.89-1.00; P = 0.0489). CONCLUSIONS: Oral capecitabine is at least equivalent to i.v. 5-FU in terms of overall survival in patients with gastrointestinal cancers. Capecitabine and 5-FU can be used interchangeably in these patient populations.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Fluorouracilo/análogos & derivados , Fluorouracilo/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Capecitabina , Neoplasias Colorrectales/mortalidad , Desoxicitidina/uso terapéutico , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Análisis Multivariante , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias Gástricas/mortalidad , Resultado del TratamientoRESUMEN
Although metastatic breast cancer remains essentially incurable, many patients previously treated with an anthracycline, taxane, and capecitabine are relatively fit and keen to receive further therapy. Several drugs are used in this setting, but with little evidence of clinically relevant benefit, and none have previously shown improved survival. Eribulin (Halaven®) is a nontaxane tubulin-binding agent with a novel mode of action, and was recently approved by the European Medicines Agency and US Food and Drug Agency as a single agent for patients with heavily pretreated metastatic breast cancer. This review provides an overview of the discovery, and preclinical and clinical development of eribulin, culminating in the recently published EMBRACE metastatic breast cancer study.
RESUMEN
BACKGROUND: Erlotinib and pemetrexed are approved single agents for second-line treatment of non-small-cell lung cancer (NSCLC) and, in combination, have shown synergistic antitumor activity in NSCLC cell lines. We investigated the safety, pharmacokinetics and preliminary efficacy of combined erlotinib-pemetrexed in patients with refractory advanced NSCLC. PATIENTS AND METHODS: A nonrandomized, open-label, phase IB study was performed in patients with advanced NSCLC whose disease had progressed on or following first-line chemotherapy with a platinum-containing regimen or for whom the erlotinib-pemetrexed combination was considered appropriate. Patients received i.v. pemetrexed 500-700 mg/m² every 3 weeks and oral erlotinib 100-150 mg/day. RESULTS: Twenty patients were recruited. The most common adverse events (AEs) were rash, diarrhea and fatigue. Serious AEs occurred in eight patients (three treatment related) and there were eight deaths (none treatment related). Dose-limiting toxic effects were not experienced up to erlotinib 150 mg/day plus pemetrexed 600 mg/m². Concurrent administration did not affect pharmacokinetic parameters. Two patients achieved partial responses and nine had stable disease. CONCLUSIONS: Erlotinib-pemetrexed combination is well tolerated at doses equal to the licensed single-agent doses (150 mg/day and 500 mg/m², respectively). The good tolerability profile and promising efficacy indicate that this combination warrants further investigation for patients with advanced NSCLC.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Grandes/tratamiento farmacológico , Carcinoma Neuroendocrino/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/secundario , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/secundario , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/secundario , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/secundario , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/secundario , Progresión de la Enfermedad , Receptores ErbB/genética , Clorhidrato de Erlotinib , Femenino , Glutamatos/administración & dosificación , Guanina/administración & dosificación , Guanina/análogos & derivados , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Mutación/genética , Estadificación de Neoplasias , Pemetrexed , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas p21(ras) , Quinazolinas/administración & dosificación , Tasa de Supervivencia , Factores de Tiempo , Distribución Tisular , Resultado del Tratamiento , Proteínas ras/genéticaRESUMEN
Inadequate drug delivery to tumours is now recognised as a key factor that limits the efficacy of anticancer drugs. Extravasation and penetration of therapeutic agents through avascular tissue are critically important processes if sufficient drug is to be delivered to be therapeutic. The purpose of this study is to develop an in silico model that will simulate the transport of the clinically used cytotoxic drug doxorubicin across multicell layers (MCLs) in vitro. Three cell lines were employed: DLD1 (human colon carcinoma), MCF7 (human breast carcinoma) and NCI/ADR-Res (doxorubicin resistant and P-glycoprotein [Pgp] overexpressing ovarian cell line). Cells were cultured on transwell culture inserts to various thicknesses and doxorubicin at various concentrations (100 or 50 microM) was added to the top chamber. The concentration of drug appearing in the bottom chamber was determined as a function of time by HPLC-MS/MS. The rate of drug penetration was inversely proportional to the thickness of the MCL. The rate and extent of doxorubicin penetration was no different in the presence of NCI/ADR-Res cells expressing Pgp compared to MCF7 cells. A mathematical model based upon the premise that the transport of doxorubicin across cell membrane bilayers occurs by a passive "flip-flop" mechanism of the drug between two membrane leaflets was constructed. The mathematical model treats the transwell apparatus as a series of compartments and the MCL is treated as a series of cell layers, separated by small intercellular spaces. This model demonstrates good agreement between predicted and actual drug penetration in vitro and may be applied to the prediction of drug transport in vivo, potentially becoming a useful tool in the study of optimal chemotherapy regimes.
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Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/farmacocinética , Modelos Biológicos , Neoplasias/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Antibióticos Antineoplásicos/administración & dosificación , Transporte Biológico , Membrana Celular/metabolismo , Cromatografía Líquida de Alta Presión/métodos , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Resistencia a Antineoplásicos , Femenino , Humanos , Proteínas de Neoplasias/metabolismo , Células Tumorales CultivadasRESUMEN
The combination of oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX-4) is still a reference regimen in advanced colorectal cancer; however, the addition of new biologic compounds represents a significant way forward. Bortezomib is an inhibitor of proteasome, a multicatalytic enzyme complex that degrades several intracellular proteins. In this study, escalating doses of Bortezomib were administered along with the standard FOLFOX-4 doses, in order to evaluate the dose-limiting toxicity (DLT), toxicity profile and activity of the combination. Patients with advanced colorectal cancer, unpretreated for metastatic disease, were enroled in the study. Bortezomib starting dose was 1.3mg/m(2), which was to be escalated in the subsequent steps according to the toxicities observed after first cycle. Exploratory pharmacogenetics research was conducted by analysing the association between clinical outcomes and polymorphisms in candidate genes for response to each of the used drugs. Correlation between tumour marker changes and response was also investigated. One mg/m(2) (DL-1) was defined as being the maximum tolerated dose since only 1 DLT was observed in 6 patients. The main toxicities were haematologic, neuropathy, diarrhoea and fatigue. Amongst 13 evaluable patients, five had a partial response, five had a stable disease and three patients progressed. Two patients are long-term survivors after a combined chemosurgical approach. Further trials of the current combination may be justified.