RESUMEN
OBJECTIVES: To determine whether early switch to oral antibiotic treatment in adults with neutropenic sepsis at low risk of complications is non-inferior to switching later. METHODS: This non-inferiority, parallel-group, randomized, open-label clinical trial enrolled UK adults hospitalized with neutropenic sepsis. Participants were randomly assigned to either switch to oral ciprofloxacin plus co-amoxiclav within 12-24 hours or to continue intravenous treatment for at least 48 hours. The primary outcome was a composite measure of treatment failure, 14 days after randomization. The non-inferiority margin was 15%. RESULTS: There were 129 participants from 16 centres and 125 were assessed for the primary outcome. Of these, 113 patients completed protocolized treatment and comprised the per-protocol population. In total, 9 (14.1%) of 64 patients in the standard care arm met the primary end point, compared with 15 (24.6%) of 61 in the early switch arm, giving a risk difference of 10.5% (1-sided 95% CI, -∞% to 22%; p 0.14). In the per-protocol population, 8 (13.3%) of the 60 patients in the standard care arm met the primary end point, compared with 9 (17%) of 53 in the intervention arm giving a risk difference of 3.7% (one-sided 95% CI, -∞% to 14.8%; p 0.59). Duration of hospital stay was shorter in the intervention arm (median 2 [inter-quartile range (IQR) 2-3] vs. 3 days [IQR 2-4]; p 0.002). DISCUSSION: Although non-inferiority of early oral switch was found in the per-protocol population, the intervention was not non-inferior in the intent-to-treat population.
Asunto(s)
Neutropenia , Sepsis , Adulto , Humanos , Antibacterianos , Ciprofloxacina/uso terapéutico , Sepsis/tratamiento farmacológico , Sepsis/inducido químicamente , Neutropenia/complicaciones , Resultado del TratamientoRESUMEN
Malignant dysphagia is the most common symptom in advanced oesogastric cancers patients. Relief of dysphagia allows quality of life improvement, nutritional replenishment and potentially improves prognosis. Chemotherapy alone is effective and should be prioritised in patients with metastatic disease a good performance status, and its impact on dysphagia should be determined before further interventions are planned. Regarding local treatments, the insertion of a covered self-expandable metallic stent is the most commonly used alternative, as it allows for the rapid relief of severe dysphagia. Although several randomised trials have highlighted the role of oesophageal brachytherapy, this technique is often not easily accessible. Contemporary trials are ongoing to better define the role of external radiation therapy. While awaiting these results, external radiation therapy can be considered as a second-best option for patients with a life-expectancy > 3 months. It is important to offer nutritional support and to integrate quality of life measures in the palliative management of dysphagia. This multidisciplinary international position paper aims to propose a decision-making process and highlight randomised trials for the management of malignant dysphagia in metastatic oesogastric cancer patients.
Asunto(s)
Antineoplásicos/uso terapéutico , Trastornos de Deglución/terapia , Deglución , Neoplasias Esofágicas/tratamiento farmacológico , Cuidados Paliativos , Braquiterapia , Consenso , Trastornos de Deglución/etiología , Trastornos de Deglución/fisiopatología , Neoplasias Esofágicas/complicaciones , Neoplasias Esofágicas/patología , Humanos , Metástasis de la Neoplasia , Apoyo Nutricional , Calidad de Vida , Recuperación de la Función , Stents Metálicos Autoexpandibles , Resultado del TratamientoRESUMEN
BACKGROUND: Neutropenic sepsis remains a common treatment complication for patients receiving systemic anti-cancer treatment. The UK National Institute for Health and Care Excellence have not recommended switching from empirical intravenous antibiotics to oral antibiotics within 48 h for patients assessed as low risk for septic complications because of uncertainty about whether this would achieve comparable outcomes to using intravenous antibiotics for longer. The UK National Institute for Health Research funded the EASI-SWITCH trial to tackle this uncertainty. METHODS: The trial is a pragmatic, randomised, non-inferiority trial that aims to establish the clinical and cost-effectiveness of early switching from intravenous to oral antibiotics in cancer patients with low-risk neutropenic sepsis. Patients ≥ 16 years, receiving systemic anti-cancer treatment (acute leukaemics/stem cell transplants excluded), with a temperature of > 38 °C, neutrophil count ≤ 1.0 × 109/L, MASCC (Multinational Association of Supportive Care in Cancer) score ≥ 21 and receiving IV piperacillin/tazobactam or meropenem for less than 24 h are eligible to participate. Patients are randomised 1:1 either (i) to switch to oral ciprofloxacin and co-amoxiclav within 12-24 h of commencing intravenous antibiotics, completing at least 5 days total antibiotics (intervention), or (ii) to continue intravenous antibiotics for at least 48 h, with ongoing antibiotics being continued at the physician's discretion (control). Patients are discharged home when their physician deems it appropriate. The primary outcome measure is a composite of treatment failures as assessed at day 14. The criteria for treatment failure include fever persistence or recurrence 72 h after starting intravenous antibiotics, escalation from protocolised antibiotics, hospital readmission related to infection/antibiotics, critical care support or death. Based on a 15% treatment failure rate in the control group and a 15% non-inferiority margin, the recruitment target is 230 patients. DISCUSSION: If the trial demonstrates non-inferiority of early switching to oral antibiotics, with potential benefits for patient quality of life and resource savings, this finding will have significant implications for the routine clinical management of those with low-risk neutropenic sepsis. TRIAL REGISTRATION: ISRCTN: 84288963. Registered on the 1 July 2015. https://doi.org/10.1186/ISRCTN84288963. EudraCT: 2015-002830-35.
Asunto(s)
Antibacterianos/administración & dosificación , Neoplasias/complicaciones , Neutropenia/tratamiento farmacológico , Sepsis/tratamiento farmacológico , Administración Intravenosa , Administración Oral , Combinación Amoxicilina-Clavulanato de Potasio , Antibacterianos/efectos adversos , Ciprofloxacina , Análisis Costo-Beneficio/economía , Esquema de Medicación , Estudios de Equivalencia como Asunto , Humanos , Meropenem , Estudios Multicéntricos como Asunto , Piperacilina , Ensayos Clínicos Pragmáticos como Asunto , Calidad de Vida , Tazobactam , Resultado del TratamientoRESUMEN
PURPOSE: Response to preoperative chemo-radiotherapy (CRT) varies. We assessed whether circulating tumor DNA (ctDNA) might be an early indicator of tumor response or progression to guide therapy adaptation in rectal cancer. EXPERIMENTAL DESIGN: A total of 243 serial plasma samples were analyzed from 47 patients with localized rectal cancer undergoing CRT. Up to three somatic variants were tracked in plasma using droplet digital PCR. RECIST and MRI tumor regression grade (mrTRG) evaluated response. Survival analyses applied Kaplan-Meier method and Cox regression. RESULTS: ctDNA detection rates were: 74% (n = 35/47) pretreatment, 21% (n = 10/47) mid CRT, 21% (n = 10/47) after completing CRT, and 13% (n = 3/23) after surgery. ctDNA status after CRT was associated with primary tumor response by mrTRG (P = 0.03). With a median follow-up of 26.4 months, metastases-free survival was shorter in patients with detectable ctDNA after completing CRT [HR 7.1; 95% confidence interval (CI), 2.4-21.5; P < 0.001], persistently detectable ctDNA pre and mid CRT (HR 3.8; 95% CI, 1.2-11.7; P = 0.02), and pre, mid, and after CRT (HR 11.5; 95% CI, 3.3-40.4; P < 0.001) compared with patients with undetectable or nonpersistent ctDNA. In patients with detectable ctDNA, a fractional abundance threshold of ≥0.07% mid CRT or ≥0.13% after completing CRT predicted for metastases with 100% sensitivity and 83.3% specificity for mid CRT and 66.7% for CRT completion. All 3 patients with detectable ctDNA post-surgery relapsed compared with none of the 20 patients with undetectable ctDNA (P = 0.001). CONCLUSIONS: ctDNA identified patients at risk of developing metastases during the neoadjuvant period and post-surgery, and could be used to tailor treatment.
Asunto(s)
Biomarcadores de Tumor/genética , Quimioradioterapia/métodos , ADN Tumoral Circulante/sangre , Imagen por Resonancia Magnética/métodos , Mutación , Recurrencia Local de Neoplasia/patología , Neoplasias del Recto/patología , Adulto , Anciano , Biomarcadores de Tumor/sangre , ADN Tumoral Circulante/genética , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/terapia , Medicina de Precisión , Estudios Prospectivos , Neoplasias del Recto/sangre , Neoplasias del Recto/genética , Neoplasias del Recto/terapia , Factores de Riesgo , Resultado del TratamientoRESUMEN
PURPOSE: To report patient-focused outcomes as measured by quality of life (QoL) and performance status (PS) in REACH, a phase III placebo-controlled randomised study, assessing ramucirumab in advanced hepatocellular carcinoma (HCC) patients who received prior sorafenib. METHODS: Eligible patients had advanced HCC, Child-Pugh A, PS 0 or 1 and prior sorafenib. Patients received ramucirumab (8 mg/kg) or placebo (1:1) on day 1 of a 2-week cycle. QoL was assessed by FACT Hepatobiliary Symptom Index (FHSI)-8 and EuroQoL (EQ-5D) at baseline; cycles 4, 10, and 16; and end of treatment. PS was assessed at baseline, each cycle, and end of treatment. Deterioration in FHSI-8 was defined as a ≥3-point decrease from baseline and PS deterioration was defined as a change of ≥2. Both intention-to-treat and pre-specified subgroup of patients with baseline serum alpha-fetoprotein (AFP) ≥400 ng/mL were assessed. RESULTS: There were 565 patients randomised to ramucirumab and placebo. Compliance with FHSI and EQ-5D was high and similar between groups. In the ITT population, deterioration in FHSI-8, EQ-5D, and PS was similar between ramucirumab and placebo. In patients with baseline AFP ≥400 ng/mL, ramucirumab significantly reduced deterioration in FHSI-8 at the end of treatment compared with placebo (P = 0.0381), and there was a trend towards a delay in the deterioration of symptoms in FHSI-8 (HR 0.690; P = 0.054) and PS (HR 0.642; P = 0.057) in favour of ramucirumab. CONCLUSIONS: We report one of the most comprehensive data sets of QoL and symptom burden in patients undergoing systemic therapy for advanced HCC. Ramucirumab was associated with no worsening of QoL. In patients with baseline AFP ≥400 ng/mL, the significant survival benefit observed in patients treated with ramucirumab was coupled with a trend in patient-focused outcome benefits. CLINICAL TRIAL REGISTRATION: NCT01140347.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Supervivencia sin Enfermedad , Método Doble Ciego , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Niacinamida/administración & dosificación , Niacinamida/análogos & derivados , Compuestos de Fenilurea/administración & dosificación , Calidad de Vida , Sorafenib , RamucirumabRESUMEN
BACKGROUND: 35% of patients with pancreatic cancer have unresectable locally advanced disease at diagnosis. Several studies have examined systemic chemotherapy with FOLFIRINOX (leucovorin and fluorouracil plus irinotecan and oxaliplatin) in patients with locally advanced pancreatic cancer. We aimed to assess the effectiveness of FOLFIRINOX as first-line treatment in this patient population. METHODS: We systematically searched Embase, MEDLINE (OvidSP), Web of Science, Scopus, PubMed Publisher, Cochrane, and Google Scholar from July 1, 1994, to July 2, 2015, for studies of treatment-naive patients of any age who received FOLFIRINOX as first-line treatment of locally advanced pancreatic cancer. Our primary outcome was overall survival. Secondary outcomes were progression-free survival; rates of grade 3 or 4 adverse events; and the proportion of patients who underwent radiotherapy or chemoradiotherapy, surgical resection after FOLFIRINOX, and R0 resection. We evaluated survival outcomes with the Kaplan-Meier method with patient-level data. Grade 3 or 4 adverse events, and the proportion of patients who underwent subsequent radiotherapy or chemoradiotherapy or resection, were pooled in a random-effects model. FINDINGS: We included 13 studies comprising 689 patients, of whom 355 (52%) patients had locally advanced pancreatic cancer. 11 studies, comprising 315 patients with locally advanced disease, reported survival outcomes and were eligible for patient-level meta-analysis. Median overall survival from the start of FOLFIRINOX ranged from 10·0 months (95% CI 4·0-16·0) to 32·7 months (23·1-42·3) across studies with a pooled patient-level median overall survival of 24·2 months (95% CI 21·7-26·8). Median progression-free survival ranged from 3·0 months (95% CI not calculable) to 20·4 months (6·5-34·3) across studies with a patient-level median progression-free survival of 15·0 months (95% 13·8-16·2). In ten studies comprising 490 patients, 296 grade 3 or 4 adverse events were reported (60·4 events per 100 patients). No deaths were attributed to FOLFIRINOX toxicity. The proportion of patients who underwent radiotherapy or chemoradiotherapy ranged from 31% to 100% across studies. In eight studies, 154 (57%) of 271 patients received radiotherapy or chemoradiotherapy after FOLFIRINOX. The pooled proportion of patients who received any radiotherapy treatment was 63·5% (95% CI 43·3-81·6, I(2) 90%). The proportion of patients who underwent surgical resection for locally advanced pancreatic cancer ranged from 0% to 43%. The proportion of patients who had R0 resection of those who underwent resection ranged from 50% to 100% across studies. In 12 studies, 91 (28%) of 325 patients underwent resection after FOLFIRINOX. The pooled proportion of patients who had resection was 25·9% (95% CI 20·2-31·9, I(2) 24%). R0 resection was reported in 60 (74%) of 81 patients. The pooled proportion of patients who had R0 resection was 78·4% (95% CI 60·2-92·2, I(2) 64%). INTERPRETATION: Patients with locally advanced pancreatic cancer treated with FOLFIRINOX had a median overall survival of 24·2 months-longer than that reported with gemcitabine (6-13 months). Future research should assess these promising results in a randomised controlled trial, and should establish which patients might benefit from radiotherapy or chemoradiotherapy or resection after FOLFIRINOX. FUNDING: None.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Quimioterapia Adyuvante , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Fluorouracilo/administración & dosificación , Humanos , Irinotecán , Leucovorina/administración & dosificación , Estadificación de Neoplasias , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Neoplasias Pancreáticas/patología , Pronóstico , Tasa de Supervivencia , GemcitabinaRESUMEN
BACKGROUND: VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis. Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 antagonist. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib. METHODS: In this randomised, placebo-controlled, double-blind, multicentre, phase 3 trial (REACH), patients were enrolled from 154 centres in 27 countries. Eligible patients were aged 18 years or older, had hepatocellular carcinoma with Barcelona Clinic Liver Cancer stage C disease or stage B disease that was refractory or not amenable to locoregional therapy, had Child-Pugh A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, had previously received sorafenib (stopped because of progression or intolerance), and had adequate haematological and biochemical parameters. Patients were randomly assigned (1:1) to receive intravenous ramucirumab (8 mg/kg) or placebo every 2 weeks, plus best supportive care, until disease progression, unacceptable toxicity, or death. Randomisation was stratified by geographic region and cause of liver disease with a stratified permuted block method. Patients, medical staff, investigators, and the funder were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01140347. FINDINGS: Between Nov 4, 2010, and April 18, 2013, 565 patients were enrolled, of whom 283 were assigned to ramucirumab and 282 were assigned to placebo. Median overall survival for the ramucirumab group was 9·2 months (95% CI 8·0-10·6) versus 7·6 months (6·0-9·3) for the placebo group (HR 0·87 [95% CI 0·72-1·05]; p=0·14). Grade 3 or greater adverse events occurring in 5% or more of patients in either treatment group were ascites (13 [5%] of 277 patients treated with ramucirumab vs 11 [4%] of 276 patients treated with placebo), hypertension (34 [12%] vs ten [4%]), asthenia (14 [5%] vs five [2%]), malignant neoplasm progression (18 [6%] vs 11 [4%]), increased aspartate aminotransferase concentration (15 [5%] vs 23 [8%]), thrombocytopenia (13 [5%] vs one [<1%]), hyperbilirubinaemia (three [1%] vs 13 [5%]), and increased blood bilirubin (five [2%] vs 14 [5%]). The most frequently reported (≥1%) treatment-emergent serious adverse event of any grade or grade 3 or more was malignant neoplasm progression. INTERPRETATION: Second-line treatment with ramucirumab did not significantly improve survival over placebo in patients with advanced hepatocellular carcinoma. No new safety signals were noted in eligible patients and the safety profile is manageable. FUNDING: Eli Lilly and Co.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Intervalos de Confianza , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Niacinamida/uso terapéutico , Selección de Paciente , Modelos de Riesgos Proporcionales , Inducción de Remisión , Sorafenib , Análisis de Supervivencia , Factores de Tiempo , Resultado del Tratamiento , RamucirumabRESUMEN
BACKGROUND: The VELOUR study demonstrated a survival benefit for FOLFIRI + aflibercept versus FOLFIRI + placebo in metastatic colorectal cancer (mCRC) patients who progressed on oxaliplatin-based chemotherapy. Continued divergence of overall survival (OS) curves in the intension to treat (ITT) population, with the survival advantage persisting beyond median survival time, suggested subpopulations might have different magnitudes of survival gain. Additionally, 10% of patients within VELOUR had recurrence during or within 6 months of completing oxaliplatin-based adjuvant therapy (adjuvant fast relapsers)--previously identified as having poorer survival outcomes. METHODS: To determine which patients received the greatest benefit from FOLFIRI-aflibercept, a post hoc multivariate analysis of the VELOUR ITT population was conducted. Prognostic factors identified were applied to the ITT population, excluding adjuvant fast relapsers, to derive OS prognostic profiles. RESULTS: The better efficacy subgroup was identified as patients within VELOUR exclusive of adjuvant fast relapsers and had performance status (PS) 0 with any number of metastatic site or PS 1 with <2 metastatic site. A significant improvement in efficacy outcome was observed with aflibercept in the better efficacy subgroup. Median OS for FOLFIRI-aflibercept and FOLFIRI-placebo:16.2 and 13.1 months (adjusted Hazard Ratio [HR] = 0.73; 95% confidence interval [CI]: 0.61-0.86); median progression free survival (PFS): 7.2 and 4.8 months (adjusted HR = 0.68; 95% CI: 0.57-0.80); and objective response rate (ORR): 24% versus 11% respectively. Poorer efficacy subgroup comprised of adjuvant fast relapsers or patients with PS2 or PS1 with ≥ 2 metastatic sites. In poorer efficacy subgroup, no benefit was seen with aflibercept. Median OS for FOLFIRI-aflibercept and FOLFIRI-placebo: 10.4 and 9.6 months (adjusted HR = 0.97; 95% CI: 0.78-1.21) respectively with no improvement in PFS or ORR. CONCLUSION: This analysis suggests that within VELOUR, patients in the better efficacy subgroup may derive enhanced benefit from treatment with FOLFIRI-aflibercept. These prognostic criteria may guide practitioners toward optimal use of targeted biologicals in appropriate second-line mCRC patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/análogos & derivados , Neoplasias Colorrectales/tratamiento farmacológico , Metástasis de la Neoplasia/tratamiento farmacológico , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Camptotecina/efectos adversos , Camptotecina/uso terapéutico , Femenino , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Humanos , Leucovorina/efectos adversos , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Receptores de Factores de Crecimiento Endotelial Vascular/efectos adversos , Proteínas Recombinantes de Fusión/efectos adversos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: To evaluate the addition of cetuximab to neoadjuvant chemotherapy before chemoradiotherapy in high-risk rectal cancer. PATIENTS AND METHODS: Patients with operable magnetic resonance imaging-defined high-risk rectal cancer received four cycles of capecitabine/oxaliplatin (CAPOX) followed by capecitabine chemoradiotherapy, surgery, and adjuvant CAPOX (four cycles) or the same regimen plus weekly cetuximab (CAPOX+C). The primary end point was complete response (CR; pathologic CR or, in patients not undergoing surgery, radiologic CR) in patients with KRAS/BRAF wild-type tumors. Secondary end points were radiologic response (RR), progression-free survival (PFS), overall survival (OS), and safety in the wild-type and overall populations and a molecular biomarker analysis. RESULTS: One hundred sixty-five eligible patients were randomly assigned. Ninety (60%) of 149 assessable tumors were KRAS or BRAF wild type (CAPOX, n = 44; CAPOX+C, n = 46), and in these patients, the addition of cetuximab did not improve the primary end point of CR (9% v 11%, respectively; P = 1.0; odds ratio, 1.22) or PFS (hazard ratio [HR], 0.65; P = .363). Cetuximab significantly improved RR (CAPOX v CAPOX+C: after chemotherapy, 51% v 71%, respectively; P = .038; after chemoradiation, 75% v 93%, respectively; P = .028) and OS (HR, 0.27; P = .034). Skin toxicity and diarrhea were more frequent in the CAPOX+C arm. CONCLUSION: Cetuximab led to a significant increase in RR and OS in patients with KRAS/BRAF wild-type rectal cancer, but the primary end point of improved CR was not met.
Asunto(s)
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Quimioradioterapia Adyuvante/métodos , Terapia Neoadyuvante/métodos , Neoplasias del Recto/terapia , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Análisis de Varianza , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Capecitabina , Cetuximab , Colectomía/métodos , Terapia Combinada , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Estudios de Seguimiento , Humanos , Mucosa Intestinal/cirugía , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Cuidados Preoperatorios/métodos , Radioterapia Adyuvante , Neoplasias del Recto/mortalidad , Neoplasias del Recto/patología , Medición de Riesgo , Análisis de Supervivencia , Resultado del Tratamiento , Reino UnidoRESUMEN
Hepatocyte spheroids mimic many in vivo liver-tissue phenotypes but increase in size during extended culture which limits their application in drug testing applications. We have developed an improved hepatocyte 3D spheroid model, namely tethered spheroids, on RGD and galactose-conjugated membranes using an optimized hybrid ratio of the two bioactive ligands. Cells in the spheroid configuration maintained 3D morphology and uncompromised differentiated hepatocyte functions (urea and albumin production), while the spheroid bottom was firmly tethered to the substratum maintaining the spheroid size in multi-well plates. The oblate shape of the tethered spheroids, with an average height of 32 µm, ensured efficient nutrient, oxygen and drug access to all the cells within the spheroid structure. Cytochrome P450 induction by prototypical inducers was demonstrated in the tethered spheroids and was comparable or better than that observed with hepatocyte sandwich cultures. These data suggested that tethered 3D hepatocyte spheroids may be an excellent alternative to 2D hepatocyte culture models for drug safety applications.
Asunto(s)
Evaluación Preclínica de Medicamentos/métodos , Hepatocitos/citología , Modelos Biológicos , Esferoides Celulares/fisiología , Animales , Células Cultivadas , Colágeno/metabolismo , Hepatocitos/fisiología , Humanos , Masculino , Ratas , Ratas Wistar , Esferoides Celulares/citologíaRESUMEN
BACKGROUND: Patients with poor-risk rectal cancer defined by MRI can be at high risk of disease recurrence despite standard chemoradiotherapy and optimum surgery. We aimed to assess the safety and long-term efficacy of neoadjuvant chemotherapy with capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision, a treatment strategy developed to enhance the outcome of this population. METHODS: Between November, 2001, and August, 2005, we enrolled eligible patients with poor-risk rectal cancer defined by high-resolution MRI and without metastatic disease. The protocol was amended in January, 2004, following clinically significant cardiotoxic events (nine events in eight of 77 patients), to exclude patients with a recent history of clinically significant cardiac problems. Patients received 12 weeks of neoadjuvant capecitabine and oxaliplatin (oxaliplatin 130 mg/m2 on day 1 with capecitabine 1000 mg/m2 twice daily for 14 days every 3 weeks) followed by chemoradiotherapy (54 Gy over 6 weeks) with capecitabine (825 mg/m2 twice daily), total mesorectal excision, and 12 weeks of postoperative adjuvant capecitabine (1250 mg/m2 twice daily for 14 days every 3 weeks). The primary endpoint was pathological complete response rate. We followed up patients for a median of 55 months (IQR 47-67). Efficacy analyses were undertaken for the intention-to-treat population, unless otherwise specified. This study is registered with ClinicalTrials.gov, number NCT00220051. FINDINGS: 105 eligible patients were enrolled. Radiological response rates after neoadjuvant chemotherapy and chemoradiotherapy were 74% (78/105) and 89% (93/105), respectively. 97 patients underwent surgery, of whom 95 underwent total mesorectal excision, of whom 93 had microscopically clear resection margins and 21 had pathological complete response (21/105 [20%]). 3-year progression-free and overall survival were 68% (95% CI 59-77) and 83% (76-91), respectively. 3-year relapse-free survival for patients who had complete resection was 74% (65-83). Following the protocol amendment for cardiovascular safety, only one further thromboembolic event was reported (fatal pulmonary embolism). INTERPRETATION: Intensification of systemic therapy with neoadjuvant combination chemotherapy before standard treatment is feasible in poor-risk potentially operable rectal cancer, with acceptable safety and promising long-term outcomes. Future development of this multidisciplinary treatment strategy in randomised trials is warranted. FUNDING: UK National Health Service, Sanofi-Aventis.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Terapia Neoadyuvante/métodos , Recurrencia Local de Neoplasia/prevención & control , Neoplasias del Recto/terapia , Anciano , Capecitabina , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Esquema de Medicación , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Neoplasias del Recto/patología , Análisis de SupervivenciaRESUMEN
PURPOSE: The purpose of this study was to assess the longitudinal impact of stoma formation on the health-related quality of life of rectal cancer patients treated with adjuvant chemotherapy. METHODS: Health-related quality of life data was prospectively collected in a randomized trial designed to compare 24 weeks of bolus 5-fluorouracil/leucovorin with 12 weeks of continuous 5-fluorouracil in patients with resected Dukes B and C colorectal cancer. Health-related quality of life data was collected at baseline, during adjuvant treatment, and at one and three years after completion of chemotherapy. RESULTS: Between 1993 and 2003, 186 rectal cancer patients were enrolled. One hundred thirty-nine patients had anterior resection, of whom 46 had a temporary defunctioning colostomy. Forty-seven patients had abdominoperineal resection with formation of a permanent colostomy. There was no significant difference in global health-related quality of life between patients with and patients without a stoma at any time point. However, during adjuvant treatment, role (P = 0.04) and social (P = 0.005) functioning were significantly worse in stoma patients than in nonstoma patients. Moreover, the impairment in social functioning persisted at one (P = 0.03) and three years (P = 0.04) after adjuvant chemotherapy. CONCLUSION: Our results demonstrate important adverse effects of either temporary or permanent stoma formation on subsequent health-related quality of life in patients with rectal cancer.
Asunto(s)
Adenocarcinoma/cirugía , Colostomía , Calidad de Vida , Neoplasias del Recto/cirugía , Adenocarcinoma/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia Adyuvante , Femenino , Fluorouracilo/administración & dosificación , Humanos , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Periodo Posoperatorio , Neoplasias del Recto/tratamiento farmacológicoRESUMEN
Mucosa associated lymphoid tissue (MALT) lymphoma of the lung is a rare disease with an indolent clinical behaviour. This single centre retrospective analysis evaluates the treatment strategies and clinical outcome for these patients. A total number of ten patients (7 male/3 female) were identified between January 1997 and October 2005 and their records analysed. At diagnosis the patients presented with unspecific symptoms (cough, shortness of breath and lower respiratory chest infection) which were further evaluated. Six patients had stage IAE disease, two patients stage IIAE and in two patients disease was stage IV. The initial treatment consisted of surgery alone (3 patients), chemotherapy +/- rituximab (5/1 patients), single agent rituximab (1 patient) and wait & watch strategy (1 patient). After a median follow-up time of 3.4 years the overall survival was 90% at 3 years. In conclusion, our data suggest that most of the patients with MALT of the lung had localized disease which generally responded well to systemic or local therapy and resulted in favourable long-term outcome underlining the indolent course of this disease.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pulmonares/terapia , Linfoma de Células B de la Zona Marginal/terapia , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales de Origen Murino , Clorambucilo/administración & dosificación , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/cirugía , Linfoma de Células B de la Zona Marginal/tratamiento farmacológico , Linfoma de Células B de la Zona Marginal/cirugía , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Rituximab , Resultado del Tratamiento , Vidarabina/administración & dosificación , Vidarabina/análogos & derivadosRESUMEN
Folate intake is inversely related to risk of developing colorectal neoplasia. Associations between risk of colorectal neoplasia and polymorphisms in genes coding for enzymes involved in folate metabolism have also been reported, suggesting a relationship between genotype and development of colorectal neoplasia. To further investigate the effects of folate metabolism genotypes on colorectal neoplasia, we genotyped 546 patients participating in a randomized controlled trial of folate supplementation for the prevention of colorectal adenoma recurrence. A significantly reduced risk of recurrence was observed in patients heterozygous for the MTRR A66G polymorphism [relative risk (RR), 0.64; 95% confidence interval (95% CI), 0.46-0.90] or heterozygous for the MTHFR A1298C polymorphism (RR, 0.71; 95% CI, 0.52-0.97). Furthermore, a significant reduction in recurrence risk was seen in MTRR A66G heterozygotes who received folate supplements but not in those who did not receive folate. Patients heterozygous for the MTHFR C677T polymorphism had a nonsignificant risk reduction (RR, 0.92; 95% CI, 0.69-1.23), as did patients with one or two variant alleles for the MTR A2756G polymorphism (RR, 0.82; 95% CI, 0.60-1.12). No influence on recurrence risk was observed for the TSER, TSER 3R G>C, and TS 1494del6 variants. These findings provide additional support for the hypothesis that germ line variants in folate metabolism genes influence the development of colorectal adenomas.
Asunto(s)
Adenoma/etiología , Neoplasias Colorrectales/etiología , Ácido Fólico/metabolismo , Recurrencia Local de Neoplasia/etiología , Polimorfismo Genético , Adenoma/genética , Adenoma/metabolismo , Adulto , Anciano , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Femenino , Ferredoxina-NADP Reductasa/genética , Genotipo , Humanos , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Persona de Mediana Edad , RiesgoRESUMEN
PURPOSE: To evaluate neoadjuvant capecitabine/oxaliplatin before chemoradiotherapy (CRT) and total mesorectal excision (TME) in newly diagnosed patients with magnetic resonance imaging (MRI) -defined poor-risk rectal cancer. PATIENTS AND METHODS: MRI criteria for poor-risk rectal cancer were tumors within 1 mm of mesorectal fascia (ie, circumferential resection margin threatened), T3 tumors at or below levators, tumors extending > or = 5 mm into perirectal fat, T4 tumors, and T1-4N2 tumors. Patients received 12 weeks of neoadjuvant capecitabine/oxaliplatin followed by concomitant capecitabine and radiotherapy. TME was planned 6 weeks after CRT. Postoperatively, patients received another 12 weeks of capecitabine. RESULTS: Between November 2001 and August 2004, 77 eligible patients were recruited. After neoadjuvant capecitabine/oxaliplatin, the radiologic response rate was 88%. In addition, 86% of patients had symptomatic responses in a median of 32 days (ie, just over one cycle of capecitabine/oxaliplatin). After CRT, the tumor response rate was increased to 97%. Three patients remained inoperable. Sixty-seven patients proceeded to TME, and all but one patient had R0 resection. Pathologic complete response was observed in 16 patients (24%; 95% CI, 14% to 36%), and in an additional 32 patients (48%), only microscopic tumor foci were found on surgical specimens. Four deaths occurred during neoadjuvant capecitabine/oxaliplatin therapy as a result of pulmonary embolism, ischemic heart disease, sudden death with history of chest pain, and neutropenic colitis. CONCLUSION: Capecitabine/oxaliplatin before synchronous CRT and TME results in substantial tumor regression, rapid symptomatic response, and achievement of R0 resection.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Neoadyuvante/métodos , Neoplasias del Recto/terapia , Adulto , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Capecitabina , Quimioterapia Adyuvante/efectos adversos , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/análogos & derivados , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/efectos adversos , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Oxaliplatino , Radioterapia Adyuvante/efectos adversos , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/patología , Neoplasias del Recto/radioterapia , Neoplasias del Recto/cirugía , Medición de Riesgo , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Longitudinal quality of life (QOL) assessment is infrequently made in adjuvant therapy for colorectal cancer (CRC). This analysis aims to assess QOL and quality adjusted survival (QAS) in patients receiving adjuvant 5-FU for stage II and III CRC. We performed a multicentre study in which 801 patients were randomised to 6 months of bolus 5-FU/leucovorin (LV n = 404) or 12 weeks of protracted venous infusion (PVI) 5-FU (n = 397). There were significant differences in the deterioration of QOL scores at week 2 with bolus 5-FU/LV compared to PVI 5-FU (P < 0.001), coinciding with toxicity peak during the first cycle. Following week 12, global QOL recovered to baseline when PVI 5-FU was stopped but this was delayed with bolus 5-FU/LV until completion at week 24. QOL scores significantly improved in both arms during follow-up (P < 0.001) and reached a plateau by year 1 without incremental improvement between years 2 and 5. There was a trend towards better QAS with PVI 5-FU. Twelve weeks of adjuvant PVI 5-FU was associated with significantly better QOL during treatment and faster time to recovery compared to 6 months of bolus 5-FU/LV.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Calidad de Vida , Adulto , Anciano , Quimioterapia Adyuvante , Femenino , Fluorouracilo/administración & dosificación , Estado de Salud , Humanos , Infusiones Intravenosas , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Análisis de SupervivenciaRESUMEN
PURPOSE: This analysis aims to evaluate routine carcino-embryonic antigen (CEA) and computed tomography (CT) of thorax, abdomen, and pelvis as part of protocol-specified follow-up policy for colorectal cancer (CRC). PATIENTS AND METHODS: Patients with resected stage II and III CRC were randomly assigned to bolus fluorouracil/leucovorin or protracted venous infusion fluorouracil. Following completion of chemotherapy, patients were seen in clinic at regular intervals for 5 years. CEA was measured at each clinic visit, and CT of thorax, abdomen, and pelvis was performed at 12 and 24 months after commencement of chemotherapy. RESULTS: Between 1993 and 1999, 530 patients were recruited. The median follow-up was 5.6 years. Disease relapses were observed in 154 patients. Relapses were detected by symptoms (n = 65), CEA (n = 45), CT (n = 49), and others (n = 9). Fourteen patients, whose relapses were detected by CT, had a concomitant elevation of CEA and were included in both groups. The CT-detected group had a better survival compared with the symptomatic group from the time of relapse (P =.0046). Thirty-three patients (21%) proceeded to potentially curative surgery for relapse and enjoyed a better survival than those who did not (P <.00001). For patients who underwent hepatic or pulmonary metastatic resection, 13 (26.5%) were in the CT group, eight (17.8%) in the CEA group, and only two (3.1%) in the symptomatic group (CT v symptomatic, P <.001; CEA v symptomatic, P =.015). CONCLUSION: Surveillance CT and CEA are valuable components of postoperative follow-up in stage II and III colorectal cancer.
Asunto(s)
Antígeno Carcinoembrionario/análisis , Neoplasias Colorrectales/diagnóstico , Tomografía Computarizada por Rayos X , Adulto , Anciano , Biomarcadores de Tumor/análisis , Quimioterapia Adyuvante , Neoplasias Colorrectales/tratamiento farmacológico , Femenino , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Humanos , Infusiones Intraarteriales , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Tasa de SupervivenciaRESUMEN
Colorectal cancer is the second most common cause of cancer-related mortality in Europe and North America. Studies conducted in the last two decades have established the role of adjuvant therapy in stage III colon cancer. However, there is currently no international consensus with the role of adjuvant treatment in stage II disease. The introduction of irinotecan, oxaliplatin, oral fluoropyrimidines and raltitrexed has broadened the treatment options available for patients with advanced colorectal cancer. The integration of these drugs with the new molecular targeted therapies such as epidermal growth factor receptor, cyclooxygenase, angiogenesis and matrix metalloproteinase inhibition will form the basis of clinical research in the next few years and may, in the future, impact on the survival of patients with colorectal cancer. This review will focus on the place of chemotherapy in colorectal cancer, but not its role in combination with radiotherapy in rectal cancer.