RESUMO
BACKGROUND: This Phase-I-study aimed to determine the recommended Phase-II-dosing-schedule of LY2334737, an oral gemcitabine prodrug, in patients with advanced/metastatic solid tumors. Pharmacokinetics, cytokeratin-18 (CK18) levels, genetic polymorphisms, and antitumor activity were additionally evaluated. METHODS: Patients received escalating doses of LY2334737 either every other day for 21 days (d) followed by 7 days-drug-free period (QoD-arm) or once daily for 7 days every other week (QD-arm). The 28 days-cycles were repeated until disease progression or unacceptable toxicity. Standard 3 + 3 dose-escalation was succeeded by a dose-confirmation phase (12 additional patients to be enrolled on the maximum tolerated dose [MTD]). RESULTS: Forty-one patients received QoD- (40-100 mg) and 32 QD-dosing (40-90 mg). On QoD, 3/9 patients experienced dose-limiting toxicities (DLTs) on the 100 mg dose (2 × G3 diarrhea, 1 × G3 transaminase increase); 1 additional DLT (G3 diarrhea) occurred during dose confirmation at 90 mg (12 patients). On QD, 1 patient each experienced DLTs on 60 mg (G3 transaminase increase) and 80 mg (G3 prolonged QTcF-interval); 2/7 patients had 3 DLTs on the 90 mg dose (diarrhea, edema, liver-failure; all G3). The MTD was established at 90 mg for the QoD-arm. Seven patients on QoD and 4 on QD achieved SD (no CR + PR). Pharmacokinetics showed a dose-proportional increase in exposure of LY2334737 and dFdC without accumulation after repeated dosing. Significant increases in CK18 levels were observed. Genetic polymorphism of the cytidine deaminase gene (rs818202) could be associated with ≥ G3 hepatotoxicity. CONCLUSIONS: Both schedules displayed linear pharmacokinetics and acceptable safety profiles. The recommended dose and schedule of LY2334737 for subsequent Phase-II-studies is 90 mg given QoD for 21 day.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxiuridina/análogos & derivados , Neoplasias/tratamento farmacológico , Pró-Fármacos/administração & dosagem , Administração Oral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacocinética , Desoxiuridina/administração & dosagem , Desoxiuridina/farmacocinética , Progressão da Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Neoplasias/metabolismo , Pró-Fármacos/farmacocinética , GencitabinaRESUMO
BACKGROUND: Preoperative chemoradiotherapy, total mesorectal excision surgery, and adjuvant chemotherapy with fluorouracil is the standard combined modality treatment for rectal cancer. With the aim of improving disease-free survival (DFS), this phase 3 study (CAO/ARO/AIO-04) integrated oxaliplatin into standard treatment. METHODS: This was a multicentre, open-label, randomised, phase 3 study in patients with histologically proven carcinoma of the rectum with clinically staged T3-4 or any node-positive disease. Between July 25, 2006, and Feb 26, 2010, patients were randomly assigned to two groups: a control group receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil (1000 mg/m(2) days 1-5 and 29-33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m(2) days 1-5 and 29; fluorouracil group); and an experimental group receiving preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil (250 mg/m(2) days 1-14 and 22-35) and oxaliplatin (50 mg/m(2) days 1, 8, 22, and 29), followed by surgery and eight cycles of adjuvant chemotherapy with oxaliplatin (100 mg/m(2) days 1 and 15), leucovorin (400 mg/m(2) days 1 and 15), and infusional fluorouracil (2400 mg/m(2) days 1-2 and 15-16; fluorouracil plus oxaliplatin group). Randomisation was done with computer-generated block-randomisation codes stratified by centre, clinical T category (cT1-4 vs cT4), and clinical N category (cN0 vs cN1-2) without masking. DFS is the primary endpoint. Secondary endpoints, including toxicity, compliance, and histopathological response are reported here. Safety and compliance analyses included patients as treated, efficacy endpoints were analysed according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, number NCT00349076. FINDINGS: Of the 1265 patients initially enrolled, 1236 were evaluable (613 in the fluorouracil plus oxaliplatin group and 623 in the fluorouracil group). Preoperative grade 3-4 toxic effects occurred in 140 (23%) of 606 patients who actually received fluorouracil and oxaliplatin during chemoradiotherapy and in 127 (20%) of 624 patients who actually received fluorouracil chemoradiotherapy. Grade 3-4 diarrhoea was more common in those who received fluorouracil and oxaliplatin during chemoradiotherapy than in those who received fluorouracil during chemoradiotherapy (73 patients [12%] vs 52 patients [8%]), as was grade 3-4 nausea or vomiting (23 [4%] vs nine [1%]). 516 (85%) of the 606 patients who received fluorouracil and oxaliplatin-based chemoradiotherapy had the full dose of chemotherapy, and 571 (94%) had the full dose of radiotherapy; as did 495 (79%) and 601 (96%) of 624 patients who received fluorouracil-based chemoradiotherapy, respectively. A pathological complete response was achieved in 103 (17%) of 591 patients who underwent surgery in the fluorouracil and oxaliplatin group and in 81 (13%) of 606 patients who underwent surgery in the fluorouracil group (odds ratio 1·40, 95% CI 1·02-1·92; p=0·038). In the fluorouracil and oxaliplatin group, 352 (81%) of 435 patients who began adjuvant chemotherapy completed all cycles (with or without dose reduction), as did 386 (83%) of 463 patients in the fluorouracil group. INTERPRETATION: Inclusion of oxaliplatin into modified fluorouracil-based combined modality treatment was feasible and led to more patients achieving a pathological complete response than did standard treatment. Longer follow-up is needed to assess DFS. FUNDING: German Cancer Aid (Deutsche Krebshilfe).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia , Neoplasias Retais/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Dosagem RadioterapêuticaRESUMO
BACKGROUND: Recombinant human epoetin alfa, HX575, is the first biosimilar erythropoiesis-stimulating agent (ESA) with European marketing authorisation. The primary objective of this double-blind, randomised, multicentre study was to assess the efficacy and safety of HX575 in treating chemotherapy-associated symptomatic anaemia in patients with solid tumours. PATIENTS AND METHODS: The patients (n = 114) were treated with HX575 or active control (epoetin alfa) at 150 IU/kg body weight 3 times weekly for 12 weeks, increased to 300 IU/kg body weight 3 times weekly if the haemoglobin/reticulocyte increase was insufficient after 4 or 8 weeks. RESULTS: With HX575, haemoglobin increased by > or =20 g/l in 62% (37/60 patients). The confidence interval (48.2%, 73.9%) was entirely above the pre-defined 30% threshold. Both groups showed similar results for safety profiles and secondary efficacy parameters. Transfusion requirements were 32% (19/60) (HX575) and 38% (13/34) (epoetin alfa). CONCLUSIONS: In treating chemotherapy-associated symptomatic anaemia in patients with solid tumours, the biosimilar ESA, HX575, is efficacious with a safety profile as expected for the therapeutic area.
Assuntos
Anemia/induzido quimicamente , Anemia/prevenção & controle , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Eritropoetina/administração & dosagem , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Epoetina alfa , Feminino , Alemanha , Hematínicos/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Proteínas Recombinantes , Método Simples-Cego , Resultado do TratamentoRESUMO
OBJECTIVE: The transcription factor E2F1 serves as a major regulator of the cell-cycle by controlling G1-S phase transition. However, apart from its proliferative function high levels of deregulated E2F1 are capable of inducing apoptosis depending on the cellular context. In particular the tumor suppressor p53 and its homologue p73 are implicated in this proapoptotic function. METHODS: Here, we investigated the mechanistic basis for E2F1-mediated apoptosis in vascular smooth muscle cells (VSMCs) which have previously been shown to be E2F1-responsive. RESULTS: Interestingly, E2F1-expression in these cells induced clear signs of apoptosis in the absence of any proliferative activity. Although cell-cycle regulated genes such as CCNE1 and CDC25A were activated, BrdU-staining revealed no S-phase entry. Instead, a rapid loss of cell viability by induction of apoptosis was observed. Using a transactivation-defective E2F1-mutant, we show that apoptosis induction is independent of the transactivation function and therefore independent of ARF and p73. However, this mutant retains its ability to stabilize and phosphorylate p53, suggesting that p53 is sufficient for the effect of E2F1. CONCLUSION: VSMCs therefore represent a cellular system in which the transactivation-independent, proapoptotic activity of E2F1 is the primary cellular function. Ectopic expression of E2F1 might therefore be a suitable therapy to prevent VSMC hyperproliferation.
Assuntos
Apoptose , Proteínas de Ligação a DNA , Músculo Liso Vascular/patologia , Fatores de Transcrição/farmacologia , Adenoviridae/genética , Proteínas de Ciclo Celular/genética , Células Cultivadas , Fragmentação do DNA , Fatores de Transcrição E2F , Fator de Transcrição E2F1 , Citometria de Fluxo , Expressão Gênica , Vetores Genéticos/administração & dosagem , Humanos , Músculo Liso Vascular/metabolismo , Fosforilação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
INTRODUCTION: The aim of this study was to describe a large consecutive cohort of non-small cell lung cancer (NSCLC) patients treated in daily routine within the last 25 years. An extensive list of general baseline characteristics (comorbidities, laboratory values, symptoms, performance state), NSCLC related factors (stage, histology), treatment related parameters (approach, applied therapies) and outcome (PFS, RFS, OS, perspective of decades) were analyzed in detail. PATIENTS AND METHODS: Medical files of 2293 consecutive NSCLC patients diagnosed between 1989 and 2009 at the Medical University of Innsbruck and affiliated hospitals were retrospectively analyzed. Patients were documented within our institution's comprehensive lung cancer project "Twenty-Year Retrospective of Lung Cancer (TYROL study)". RESULTS: Mean age at diagnosis was 64.1 years and 1611 patients (70.3%) were male. Most patients were diagnosed in stage IV (37.9%). The most frequent comorbidities present at diagnosis were cardiovascular disease (62.1%) and COPD (62.0%). The most common symptoms at diagnosis were coughing (54.7%) and dyspnea (45.3%). Of all 2293 patients 1981 (86.4%) received adequate antineoplastic treatment. In total 874 patients were radically operated, 119 received radiotherapy/radio-chemotherapy and the majority of patients (n=1278) were treated in palliative intent. A 2nd, 3rd, 4th and 5th-line palliative therapy was administered to 612, 278, 102, and 36 patients. Median OS, RFS and PFS were 16.4 months, 86.4 months and 5.1 months, respectively. A multitude of factors was associated with all three outcome variables. Of note, outcome has improved stepwise in the recent decade based on increased response rates leading to prolonged OS. CONCLUSION: This work incorporates most clinical aspects relevant in the treatment of NSCLC and beyond. Therefore, this comprehensive analysis provides a definite benchmark for prognostication and epidemiology of NSCLC in a Western European society.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Neoplasias Pulmonares/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/terapia , Terapia Combinada , Comorbidade , Feminino , Humanos , Estudos Longitudinais , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Sistema de Registros , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: To determine whether irinotecan plus oxaliplatin (mIROX) is superior to irinotecan plus infusional 5-fluorouracil, leucovorin (FUFIRI) as first-line therapy of patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: A phase III, randomised, open-label multicentre study compared standard treatment with FUFIRI (irinotecan 80 mg/m(2), 5-fluorouracil 2000 mg/m(2), folinic acid 500 mg/m(2) weekly times 6) to mIROX using an identical schedule of irinotecan plus oxaliplatin 85 mg/m(2) applied on days 1, 15 and 29 of a 7-week cycle. The primary end-point was progression-free survival (PFS). RESULTS: A total of 479 eligible patients were randomly assigned. Progression-free survival was 7.2 months in the mIROX arm and 8.2 months in the FUFIRI arm [hazard ratio=1.14; 95% confidence interval (CI) 0.94-1.37; P=0.178]. Comparable results were also obtained for overall survival time with 19 months in the mIROX-arm and 22 months in the FUFIRI-arm (hazard ratio=1.08, P=0.276). Both regimens induced an identical objective response rate (ORR) of 41%, but disease control rate (ORR plus stable disease) was significantly greater in the FUFIRI group (81% versus 68%, P=0.001). Most frequent grades 1-4 side-effects of mIROX and FUFIRI treatment were nausea (80% versus 73%) and delayed diarrhoea (79% versus 68%). Grades 3-4 toxicities were generally below 10%, except for diarrhoea which was more frequent in the mIROX-arm compared to the FUFIRI-arm (19% versus 30%, P=0.006) CONCLUSION: mIROX failed to show superior activity compared to high-dose 5-FU/folinic acid plus irinotecan. Due to better tolerability the combination of high-dose 5-FU/folinic acid and irinotecan remains a standard of care in first-line treatment of metastatic colorectal cancer.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias Retais/tratamento farmacológico , Adenocarcinoma/patologia , Adulto , Idoso , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias do Colo/patologia , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Infusões Intravenosas , Irinotecano , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Neoplasias Retais/patologia , Adulto JovemRESUMO
The lactococcal phage P008 was investigated for its growth characteristics under certain environmental conditions. Phage growth was characterized by the latency period, the average burst size (determined in one-step growth experiments) and by the percentage of adsorption to the host cells after 1, 5, 10 and 15 min (determined in modified one-step growth experiments). The incubation conditions studied were temperatures from 20 to 40 degrees C and pH values of 4.8 and 6.4. The growth medium was ultrafiltration permeate of skim milk, which forms the water phase of milk. Both, the temperature and the pH influenced the growth parameters: Increased temperature as well as low pH led to a faster latency along with a higher average burst size. The percentage of adsorption was at maximum when the standard conditions of 30 degrees C and pH 6.4 were applied. Below pH 5, adsorption was reduced to below 10%. A decrease of temperature slightly reduced phage multiplication. Data were incorporated into a model to simulate phage multiplication under certain conditions, taking the percentage adsorption into account. The cell destruction of the host culture was calculated accordingly. The simulation (extrapolation) was validated by experimental growth curves of phages and phage-infected host cultures.