RESUMO
Background Purpose of this phase Ib trial was to establish the maximum tolerable dose (MTD) of capecitabine and to escalate the dosages of erlotinib and bevacizumab to determine the recommended phase II dose (RP2D) in patients with advanced/metastatic pancreatic adenocarcinoma not pretreated for metastatic disease. Methods Starting doses were capecitabine 500 mg/m2 bid orally continuously, erlotinib 100 mg orally daily, and bevacizumab 5 mg/kg intravenously q 2 weeks. Dose escalation was performed according to a 3 + 3 design for capecitabine until MTD, for erlotinib and bevacizumab until the maximum doses registered by applying a substance-related, toxicity-based scheme accompanied by pharmacokinetic analysis. Circulating tumor cells (CTCs) were determined pretherapeutically by immunohistochemical identification after enrichment with immunomagnetic separation. Results Thirty patients were evaluable at six dose levels. 900 mg/m2 bid were determined as MTD for capecitabine based on dose-limiting toxicities: cutaneous in two patients and vascular in another. The most severe (Grade (G)3/4) drug-related treatment-emergent adverse events (toxicities) belonged to the categories gastrointestinal, vascular, cutaneous, cardiovascular, metabolic/nutritional or hematological. G3 toxicities occurred in 14 (47%), G3 + G4 in a single (3%) patient. 2 out of 28 patients (7%) exerted partial response, 17 (61%) stable disease. Pharmacokinetic evaluation revealed lack of drug-drug interaction between capecitabine and erlotinib and their metabolites. Presence of CTCs was associated with shorter progression-free survival (p = 0.009). Conclusions The study met the primary objective. RP2D was capecitabine 800 mg/m2 bid continuously, erlotinib 150 mg daily, and bevacizumab 10 mg/kg q 2 weeks. The regimen could be applied safely, but demonstrated limited efficacy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Bevacizumab/administração & dosagem , Capecitabina/administração & dosagem , Estudos de Coortes , Cloridrato de Erlotinib/administração & dosagem , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Taxa de Sobrevida , Distribuição Tecidual , Resultado do TratamentoRESUMO
Recurrence and survival pattern in breast cancer (bc) patients (pts) ≥ 70 years subcategorized according to subtype and age are still an area of uncertainty. Tumor characteristics, patient demographics, therapies applied, and recurrence pattern were compared between luminal A (LA), luminal B (LB), Her2/neu overexpressing (Her+) and triple-negative (TN) bc subtypes and the age subcategories 70-74, 75-79, ≥80 years. Based on univariate Cox-regression-analyses distant-disease-free-survival (DDFS) differed significantly for bc subtypes (p = 0.0002), notably for Her+ vs. LA (p = 0.0014), TN vs. LA (p < 0.001), and TN vs. LB (p = 0.0086). Not age, but Her+ and TN represented prognostic factors for DDFS.
Assuntos
Neoplasias da Mama/diagnóstico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Terapia Combinada , Feminino , Humanos , Imuno-Histoquímica , Gradação de Tumores , Metástase Neoplásica , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do Tratamento , Carga TumoralRESUMO
Purpose BI 831266 is a potent, selective, low-molecular-weight inhibitor of Aurora kinase B. This trial aimed to determine the maximum tolerated dose (MTD) of BI 831266 in patients with advanced solid tumors (NCT00756223; EudraCT 2008-001631-36; 1257.1). Methods BI 831266 (4-130 mg) was administered over 24 h on days 1 and 15 of a 4-week schedule. A modified 3 + 3 dose-escalation design was utilized to evaluate the MTD. Safety, pharmacokinetics, pharmacodynamics, objective response rate, progression-free survival (PFS) and exploratory biomarkers were secondary endpoints. Results Twenty-five patients received BI 831266. The most frequent tumor type was colorectal cancer (48%). One patient (130 mg) experienced a dose-limiting toxicity of grade 3 febrile neutropenia. The trial was prematurely terminated (sponsor decision) without further dose-escalation. The most frequent treatment-related adverse events (AEs) were fatigue (20%), neutropenia, alopecia (16% each), anemia, dry skin, and nausea (12% each). Treatment-related grade ≥3 AEs were neutropenia (12%), anemia (8%), and febrile neutropenia (4%); 15 patients experienced serious AEs. High variability in the pharmacokinetic profiles precluded definitive pharmacokinetic conclusions. Exploratory biomarker determination revealed consistency with the mode of action as an Aurora kinase B inhibitor. One patient (4%; 32 mg) with cervical cancer demonstrated a confirmed partial response (duration 141 days, PFS 414 days). Four patients had stable disease. Conclusion The MTD of BI 831266 was not reached because of early trial termination. BI 831266 demonstrated a generally manageable safety profile and signs of antitumor activity in some patients' solid tumors.
Assuntos
Antineoplásicos/farmacologia , Aurora Quinase B/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/farmacologia , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/administração & dosagem , Proteínas Serina-Treonina Quinases/efeitos adversos , Proteínas Serina-Treonina Quinases/farmacocinéticaRESUMO
We investigated rituximab maintenance therapy in patients with diffuse large B-cell lymphoma (n=662) or follicular lymphoma grade 3b (n=21) in first complete remission. Patients were randomized to rituximab maintenance (n=338) or observation (n=345). At a median follow-up of 45 months, the event-free survival rate (the primary endpoint) at 3 years was 80.1% for rituximab maintenance versus 76.5% for observation. This difference was not statistically significant for the intent-to-treat population (likelihood ratio P=0.0670). The hazard ratio by treatment arm was 0.79 (95% confidence interval 0.57-1.08; P=0.1433). The secondary endpoint, progression-free survival was also not met for the whole statistical model (likelihood ratio P=0.3646). Of note, rituximab maintenance was superior to observation when treatment arms only were compared (hazard ratio: 0.62; 95% confidence interval 0.43-0.90; P=0.0120). Overall survival remained unchanged (92.0 versus 90.3%). In subgroup analysis male patients benefited from rituximab maintenance with regards to both event-free survival (84.1% versus 74.4%) (hazard ratio: 0.58; 95% confidence interval 0.36-0.94; P=0.0267) and progression-free survival (89.0% versus 77.6%) (hazard ratio: 0.45; 95% confidence interval 0.25-0.79; P=0.0058). Women had more grade 3/4 adverse events (P=0.0297) and infections (P=0.0341). Men with a low International Prognostic Index treated with rituximab had the best outcome. In summary, rituximab maintenance in first remission after R-CHOP-like treatment did not prolong event-free, progression-free or overall survival of patients with aggressive B-non-Hodgkin lymphoma. The significantly better outcome of men warrants further studies prior to the routine use of rituximab maintenance in men with low International Prognostic Index. This trial is registered under EUDRACT #2005-005187-90 and www.clinicaltrials.gov as #NCT00400478.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma Folicular/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Rituximab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Análise de Intenção de Tratamento , Linfoma Folicular/mortalidade , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Fatores Sexuais , Análise de Sobrevida , Resultado do TratamentoRESUMO
Before being able to develop a pharmacodynamic effect, a number of drugs have to be activated by enzymes, which are known to be potentially influenced by manifold factors, leading to a possible alteration of their activity behaviour. Based on capecitabine, we report a simple and rapid method for the estimation and comparison of the so-called 'apparent enzyme activity' (R), not only intra- (different dose levels) but also inter-schedule, to contribute to therapeutic success. Dividing the area under the curve (AUC) of the product by the AUC of the precursor generates a factor which indicates the apparent activity of the enzyme involved in the biotransformation of a compound. Our own data as well as data from the literature was used to calculate those R levels revealing that the formation of 5'-DFUR - the immediate precursor of 5-fluorouracil - was not affected by concomitant medication within the dosing range investigated. Calculated hypothetical means of R for carboxylesterase (1.49 ± 0.66) and for cytidine deaminase (1.17 ± 0.65) were obtained. Additionally, it is important to note that the method described in this report is of general use and not limited to chemotherapeutic agents, as soon as enzymes are involved in drug activation.
Assuntos
Antineoplásicos/farmacocinética , Carboxilesterase/metabolismo , Citidina Desaminase/metabolismo , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Anticorpos Monoclonais Humanizados/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Bevacizumab , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Capecitabina , Desoxicitidina/farmacocinética , Ativação Enzimática , Cloridrato de Erlotinib , Fluoruracila/farmacocinética , Humanos , Irinotecano , Compostos Organoplatínicos/farmacocinética , Oxaliplatina , Quinazolinas/farmacocinéticaRESUMO
BACKGROUND: The attempt to act on several signalling pathways involved in tumour development simultaneously appears to be more attractive than attacking a single target structure alone. Vascular endothelial growth factor (VEGF) over-expression is frequently observed in human epidermal growth factor receptor 2 (Her2/neu) positive patients with breast cancer and over-expression of the proto-oncogene Her2/neu is associated with an up-regulation of VEGF. CASE REPORT: The case of a Her2/neu positive patient with breast cancer who refused cytotoxic chemotherapy with its potential side effects as well as mastectomy is presented. Our patient has been receiving the combined double administration of bevacizumab and trastuzumab for more than 4 years. CONCLUSIONS: This case report shows that (a) the combined double administration of bevacizumab and trastuzumab was be clinically effective. (b) The combination of bevacizumab and trastuzumab is safe and non-toxic. (c) Bevacizumab and trastuzumab can be used as a long-term application.
RESUMO
While the genome represents a static moiety, the proteome is more dynamic and can change in response to stimuli. As such, proteomics may reveal the effect of various drugs on cellular mechanisms. Protein alterations upon exogenous perturbations are vital in outlining species-to-species differences that cannot otherwise be measured quantitatively. Specifically, nicotine has been shown to be an independent risk factor for a multitude of diseases. In pancreatic research its mechanism of action remains unresolved. The pioneering work of Paulo et al. (Proteomics 2013, 13, 1499-1512) is a major step toward understanding the role of nicotine, a principal toxin in cigarette smoke, in pancreatic disease. Equally important, Paulo et al. examine the effect of nicotine on stellate cells across three species, demonstrating the importance of identifying species-specific effects in translational research.
Assuntos
Nicotina/farmacologia , Pâncreas/citologia , Pâncreas/efeitos dos fármacos , Proteínas/metabolismo , Animais , HumanosRESUMO
Sequential doxorubicin/paclitaxel (AT) followed by CMF treatment was shown to be an active neoadjuvant chemotherapy regimen in the first European Cooperative Trial in Operable Breast Cancer (ECTO I trial). The aim of the current study (ECTO II) is to assess the complete pathological response (pCR) rate following three different anthracycline and taxane-containing neoadjuvant chemotherapy regimens, with or without capecitabine (X). Patients with operable, invasive breast cancer > 2.0 cm in diameter, were randomized to ATâCMF, ATâCMX or ACâTX regimens in two parallel, randomized, open-label, phase II trials (within a single study) in patients with estrogen receptor negative (ER-) and estrogen receptor positive (ER+) diseases, respectively. Exemestane was delivered concomitantly with neoadjuvant chemotherapy in ER+ tumors. Achievement of pCR was more common in ER- than ER+ women (45.3 vs. 10.4%). Capecitabine was only associated with a higher frequency of pCR in ER+ patients receiving ATâCMX. Overall response rates (ORR) ranged from 88 to 97%, and this translated into high rates of breast-conserving surgery (67% of ER- patients and 72% of ER+ patients). All three regimens were well tolerated. Febrile neutropenia and gastrointestinal effects were the most common grade ≥ 3 adverse events. As expected, the ECTO II study showed higher pCR rates in patients with ER- disease. Substituting capecitabine for fluorouracil (± methotrexate) in anthracycline/taxane-containing regimens appeared to be beneficial only in ER+ tumors. Translational studies investigating interactions between therapeutic agents and tumor biology are warranted to refine patient selection and improve the results of neoadjuvant chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Terapia Neoadjuvante , Receptores de Estrogênio/metabolismo , Adulto , Idoso , Androstadienos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Capecitabina , Ciclofosfamida/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Doxorrubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Humanos , Leucopenia/induzido quimicamente , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasia Residual , Neutropenia/induzido quimicamente , Paclitaxel/administração & dosagem , Resultado do TratamentoRESUMO
Pemetrexed/cyclophosphamide was evaluated as first-line treatment for patients with locally advanced/metastatic breast cancer. In this randomized phase II study (NCT00190671), therapy consisted of either 600 mg/m(2) (P600) or 1,800 mg/m(2) (P1800) pemetrexed, followed by 600 mg/m(2) cyclophosphamide, every 21 days; 103 females (42 P600; 61 P1800) were enrolled. P600 was discontinued, as response rate (19.1%) was lower than targeted. In the P1800 arm, 20 patients had partial response (32.8%; 95% CI: 21.0-44.6) and 26 (42.6%) had stable disease. Median progression-free survival was 6.3 months (range: 0.3-31.1). P1800 plus cyclophosphamide 600 represents a regimen of reasonable efficacy and acceptable tolerability.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/farmacocinética , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Glutamatos/administração & dosagem , Glutamatos/efeitos adversos , Glutamatos/farmacocinética , Guanina/administração & dosagem , Guanina/efeitos adversos , Guanina/análogos & derivados , Guanina/farmacocinética , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Pemetrexede , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
An adjuvant chemotherapeutic standard has not been identified in triple negative breast cancer (TNBC) yet. One hundred and forty-one adjuvant treated TNBC patients had a median follow-up of 71 months. Larger tumor size (p = .005) and positive lymph-node status (p = .033) were associated with a significant shorter overall survival. Sixty-one percent of patients received anthracycline-containing chemotherapy, 28.4% a non-anthracycline-containing regimen, and 10.6% an anthracycline/taxane-containing regimen. Overall survival, disease-free survival, local recurrence-free survival and distant disease-free survival did not differ between the chemotherapeutic groups. Non-anthracycline-containing regimen appeared to be an effective treatment in TNBC.
Assuntos
Neoplasias da Mama/mortalidade , Receptor ErbB-2/análise , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Adulto , Idoso , Antraciclinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/química , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , PrognósticoRESUMO
Treatment of metastasized colorectal cancer (mCRC) patients with anti-epidermal growth factor receptor (EGFR)-directed monoclonal antibodies is driven by the results of the KRAS mutational status (wild type [WT]/mutated [MUT]). To find out as to what extent the treatment selection based on the KRAS status had impact on overall costs, a retrospective analysis was performed. Of 73 mCRC patients 31.5% were MUT carriers. Costs of EGFR inhibitor treatment for WT patients were significantly higher compared to those for patients with MUT (p = 0.005). Higher treatment costs in WT carriers reflect a significantly higher number of treatment cycles (p = 0.012) in this cohort of patients. Savings of drug costs minus the costs for the determination of KRAS status accounted for EUR 779.42 (SD ±336.28) per patient per cycle. The routine use of KRAS screening is a cost-effective strategy. Costs of unnecessary monoclonal EGFR inhibitor treatment can be saved in MUT patients.
Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/economia , Detecção Precoce de Câncer/economia , Receptores ErbB/antagonistas & inibidores , Genes ras , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/economia , Anticorpos Monoclonais/uso terapêutico , Estudos de Coortes , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Análise Custo-Benefício/métodos , Detecção Precoce de Câncer/métodos , Receptores ErbB/economia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Valor Preditivo dos Testes , Inibidores de Proteínas Quinases/economia , Proteínas Proto-Oncogênicas/economia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Estudos Retrospectivos , Proteínas ras/economia , Proteínas ras/genéticaRESUMO
BACKGROUND: Immunomagnetic EpCAM based methods are used to enrich circulating tumor cells (CTCs) in metastatic breast cancer (mBC) patients. EpCAM negative CTCs may be missed. We addressed the question of the reliability of an EpCAM dependent assay to enrich CTCs. METHODS: To elucidate this issue, our study has been designed to assess two different CTC enrichment technologies (i) in EpCAM positive (+) and EpCAM negative cell lines and (ii) in mBC patients in dependency on their respective EpCAM expression. These two technologies encompass one anti-EpCAM immunomagnetic enrichment technology, MACS HEA MicroBeads(®) (MACS), and one EpCAM independent density centrifugation method, OncoQuick(®) plus (OQ+). Furthermore, the coherence between EpCAM expression in the primary tumor tissue of mBC patients and the CTC detection rates in the corresponding patients is analyzed. RESULTS: (i) MACS recovered significantly more EpCAM (+) than EpCAM (-) tumor cells (p < 0.001) in spiked blood samples. With OQ+ no significantly different recovery rates between EpCAM (+) and EpCAM (-) tumor cells (p = 0.796) were detected. (ii) In mBC patients MACS yielded a significantly higher (p = 0.024) detection rate of EpCAM (+) CTCs. No statistically significant difference (p = 0.070) was found concerning the EpCAM status-based detection rate of CTCs by OQ+. (iii) CTC detection rates are independent of the primary tumors' EpCAM expression. CONCLUSIONS: EpCAM (-) CTCs can not be detected by immunomagnetic EpCAM dependent enrichment methods. EpCAM independent enrichment technologies seem to be superior to detect the entire CTC population. Evaluation of CTCs as prognostic marker should compromise EpCAM (+) and (-) subpopulations.
Assuntos
Antígenos de Neoplasias/metabolismo , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Carcinoma/diagnóstico , Carcinoma/patologia , Moléculas de Adesão Celular/metabolismo , Células Neoplásicas Circulantes/patologia , Adulto , Idoso , Antígenos de Neoplasias/sangue , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Carcinoma/metabolismo , Estudos de Casos e Controles , Moléculas de Adesão Celular/sangue , Linhagem Celular Tumoral , Separação Celular/métodos , Molécula de Adesão da Célula Epitelial , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Células Neoplásicas Circulantes/metabolismo , Prognóstico , Sensibilidade e EspecificidadeRESUMO
Aim: We report results of a first-in-human study of pasotuxizumab, a PSMA bispecific T-cell engager (BiTE®) immune therapy mediating T-cell killing of tumor cells in patients with advanced castration-resistant prostate cancer. Patients & methods: We assessed once-daily subcutaneous (SC) pasotuxizumab. All SC patients developed antidrug antibodies; therefore, continuous intravenous (cIV) infusion was assessed. Results: A total of 47 patients received pasotuxizumab (SC: n = 31, 0.5-172 µg/d; cIV: n = 16, 5-80 µg/d). The SC maximum tolerated dose was 172.0 µg/d. A sponsor change stopped the cIV cohort early; maximum tolerated dose was not determined. PSA responders occurred (>50% PSA decline: SC, n = 9; cIV, n = 3), including two long-term responders. Conclusion: Data support pasotuxizumab safety in advanced castration-resistant prostate cancer and represent evidence of BiTE monotherapy efficacy in solid tumors. Clinical trial registration: NCT01723475 (ClinicalTrials.gov).
Assuntos
Anticorpos Biespecíficos , Antineoplásicos Imunológicos , Neoplasias de Próstata Resistentes à Castração , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/farmacocinética , Anticorpos Biespecíficos/uso terapêutico , Antígenos de Superfície/imunologia , Antineoplásicos Imunológicos/imunologia , Antineoplásicos Imunológicos/farmacocinética , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/sangue , Complexo CD3/imunologia , Glutamato Carboxipeptidase II/imunologia , Imunoterapia , Infusões Intravenosas , Injeções Subcutâneas , Dose Máxima Tolerável , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/imunologia , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/terapia , Resultado do TratamentoRESUMO
BACKGROUND: The aim of this retrospective study was to analyse the MGMT (0(6)-methylguanine-DNA methyltransferase) promoter methylation status in long-term surviving (≥ 3 years) patients with glioblastoma multiforme (GBM). METHODS: The methylation status of the MGMT promoter was determined by bisulfite modification of the DNA and subsequent methylation-specific polymerase-chain-reaction (MSP). DNA was extracted from routinely formalin-fixed and paraffin-embedded tumour tissue samples. RESULTS: MSP yielded interpretable results in only 14 of 33 (42%) long-term surviving patients with GBM. A methylated band was seen in 3 of 14, methylated as well as unmethylated bands in 8 of 14 and an only unmethylated band in 3 of 14 patients, thus, yielding MGMT promoter methylation in 11 of 14 patients. The two groups of patients with methylated and unmethylated MGMT promoter status were too small to draw any firm statistical conclusions. CONCLUSIONS: Long-term surviving patients with GBM have very frequently intratumoural MGMT promoter methylation. This phenomenon discriminates long-term survivors from a non-selected group of patients with GBM. The standardization of the MSP for the determination of the MGMT promoter methylation status seems to be necessary in order to make this methodology a more reliable one.
RESUMO
Molecular profiling provides the insight that specific genetic alterations can be detected across a wide range of different histologically characterised tumour types. Thus, the basic concept of basket trials (BTs) to target those genetic alterations with the same anti-tumour agents independent of the underlying tumour type was tumour agnostic. BTs can be divided into tumour gnostic, tumour semi-gnostic, and tumour agnostic trials which cover BTs of the conventional and the complex multiple-parallel type. At the beginning of the use of BTs, the expectation that they would function agnostically was dominating. This period was followed by an avalanche of experiments, analyses, and commentaries that underlined the importance of the microenvironment of tumours and thereby the impact of tissue also on molecularly targeted therapies. Intra-tumour heterogeneity with the phenomena of both intrinsic resistant cancer cell subclones and treatment-emergent acquired mutations that result in drug resistance as well as the co-occurrence of multiple potentially actionable molecular alterations within a tumour necessitate combinatorial treatment. However, this setting has only scarcely been addressed by BTs so far. Each of the various subtypes of BTs has contributed to meet the main goal of drug development, the approval of the agents tested. The position of BTs within the drug approval process and their potential impact on the off-label use of targeted agents are referred to as well. This review highlights the achievements reached with BTs along with failures. Selected issues of controversy are critically discussed, and potential solutions are addressed.
Assuntos
Antineoplásicos/administração & dosagem , Ensaios Clínicos como Assunto/métodos , Desenvolvimento de Medicamentos/métodos , Neoplasias/tratamento farmacológico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Medicina de PrecisãoRESUMO
A phase I and pharmacokinetic study was carried out with the new ruthenium complex indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019, FFC14A). Seven patients with various types of solid tumours refractory to standard therapy were treated with escalating doses of KP1019 (25-600 mg) twice weekly for 3 weeks. No dose-limiting toxicity occurred. Ruthenium plasma concentration-time profiles after the first dose and under multiple-dose conditions were analysed using a compartmental approach. The pharmacokinetic disposition was characterised by a small volume of distribution, low clearance and long half-life. Only a small fraction of ruthenium was excreted renally. The area under the curve values increased proportionally with dose indicating linear pharmacokinetics.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Indazóis/administração & dosagem , Indazóis/farmacocinética , Neoplasias/tratamento farmacológico , Compostos de Rutênio/administração & dosagem , Compostos de Rutênio/farmacocinética , Adulto , Idoso , Algoritmos , Antineoplásicos/efeitos adversos , Área Sob a Curva , Feminino , Humanos , Indazóis/efeitos adversos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Compostos Organometálicos , Compostos de Rutênio/efeitos adversosRESUMO
PURPOSE: This phase 1b study investigated the maximum tolerated dose (MTD; primary objective), safety, pharmacokinetics, and antitumor activity (secondary objectives) of eribulin combined with carboplatin in patients with solid tumors and, in particular, non-small cell lung cancer (NSCLC). METHODS: Two dose-escalation schemes were evaluated with carboplatin, at an area under the curve (AUC) of either 5 or 6 mg/mL·min. Eribulin, dose-escalated from 0.7 to 1.4 mg/m2 was administered 1 h before (Schedule A) or after (Schedule B) carboplatin as a 2-5-min bolus infusion on days 1 and 8 of a 21-day cycle. Following tolerability assessment, patients with NSCLC were recruited in an expansion cohort. RESULTS: The MTDs were eribulin 1.4 and 1.1 mg/m2 with carboplatin AUC 5 and AUC 6, respectively. The latter combination was used to treat NSCLC patients in the expansion cohort. Pharmacokinetics of eribulin and carboplatin were generally unaffected by administration sequence (i.e., administration of carboplatin did not significantly affect eribulin Cmax and AUC0-t and the converse was also observed). In the NSCLC cohort, the objective response rate was 27%. Median overall and progression-free survival durations were 12.1 and 4.2 months, respectively. No unexpected safety findings were observed. CONCLUSIONS: The combination of eribulin and carboplatin demonstrated antitumor activity; however, recent therapeutic advances may be more promising approaches for first-line treatment of NSCLC. Clinical trial registration NCT00268905.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Sob a Curva , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos de Coortes , Feminino , Seguimentos , Furanos/administração & dosagem , Humanos , Cetonas/administração & dosagem , Neoplasias Pulmonares/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia , Prognóstico , Taxa de Sobrevida , Distribuição TecidualRESUMO
BACKGROUND: Cell cycle progression is regulated by cyclin dependent kinases (cdk) and cdk inhibitors. Recent immunohistological studies suggested that dysregulation of cyclin A, cyclin D, cyclin E, p16(ink4), p21(waf1/cip1), and p27(kip1) are of prognostic value in patients with breast cancer. Our study represents the first comprehensive immunohistochemical cell cycle marker analysis for cdc25A, cyclin A, cyclin D, cyclin E, p16(ink4), p21(waf1/cip1), p27(kip1), and pRb in tumor tissue and adjacent benign breast tissue from 69 primarily untreated breast cancer patients. METHODS: Immunhistochemistry using primary monoclonal antibodies to detect cdc 25A, cyclin A, cyclin D, cyclin E, p16(ink4), p21(waf1/cip1), p27(kip1), and pRb has been performed. RESULTS: Sixty-nine patients with untreated, invasive breast cancer (n = 69) were divided into a low/ intermediate and a high risk group according to the St. Gallen 2005 consensus conference. High risk patients (n = 22) had a significantly (p = 0.003) shorter mean and median survival (282.85 weeks; 383.0 weeks, respectively) than low/intermediate risk patients (375.41 weeks; not reached yet, respectively). A subgroup of high risk breast cancer patients characterized in addition by overexpression of cdc25A, cyclin A, cyclin E, p16(ink4a), and p27(kip1) experienced a shortened mean survival of 222.03, 235.71, 257.25, 239.18, and 261.94 weeks, respectively. Regarding benign breast tissue adjacent to breast cancer tissue, 59.4% of the patients investigated overexpressed cdc25A, 23.2% overexpressed pRb, and 63.2% exerted dysregulation of p27(kip1) while they proved to be negative for immunohistochemical staining regarding all other markers tested. CONCLUSION: The immunohistological analyses of cdc25A, cyclin A, cyclin E, p16(ink4a), and p27(kip1) have the potential for further refining the risk assessment in patients with untreated breast cancer who belong to the high risk category defined according to the St. Gallen 2005 consensus conference. These cell cycle markers define a subgroup of high risk patients with even higher risk of metastazation and shortened survival. For confirmation a prospective study using standardized laboratory procedures in a larger population is needed.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Proteínas de Ciclo Celular/análise , Ciclo Celular , Proliferação de Células , Adulto , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Ciclina A/análise , Ciclina D , Ciclina E/análise , Inibidor p16 de Quinase Dependente de Ciclina/análise , Inibidor de Quinase Dependente de Ciclina p21/análise , Inibidor de Quinase Dependente de Ciclina p27 , Ciclinas/análise , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular/análise , Estimativa de Kaplan-Meier , Invasividade Neoplásica , Modelos de Riscos Proporcionais , Proteína do Retinoblastoma/análise , Estudos Retrospectivos , Medição de Risco , Resultado do Tratamento , Fosfatases cdc25/análiseRESUMO
PURPOSE: Data are lacking on the pharmacokinetics of oxaliplatin in patients with severe hepatic dysfunction. The aim of this study was to determine the pharmacokinetic parameters of platinum after administration of oxaliplatin in cancer patients with severe hepatic impairment due to extended metastases into the liver. PATIENTS AND METHODS: Two female breast cancer patients and one male colon cancer patient were treated with oxaliplatin monotherapy at 130 mg/m(2) given as a 3-h intravenous infusion. The patients exhibited bilirubin concentrations of 9.6, 22.5 and 41.1 mg/dl indicating severe hepatic dysfunction. Serial blood samples were collected immediately before treatment, and at fixed intervals up to 27 h after start of therapy. Platinum concentrations in plasma, ultrafilterable plasma, and whole blood were determined using a validated flameless atomic absorption spectrometry (FAAS) method. Pharmacokinetic data analysis was performed assuming a two-compartment model. Individual pharmacokinetic parameters were compared with a reference population with normal hepatic function. RESULTS: The area under the curve (AUC from 0 to infinity) as well as the elimination half-life of platinum in ultrafilterable plasma were substantially increased and clearance accordingly decreased in the three patients with severe hepatic dysfunction. In plasma and whole blood, the deviations from the reference population were less pronounced. However, partial AUC from 0 up to 2 h after end of infusion reflecting better the exposure with cytotoxic platinum species was not different or only slightly altered. Moreover, no acute oxaliplatin-associated neurotoxicity was observed. CONCLUSIONS: The comparable platinum exposure early after administration in conjunction with the lack of acute toxicity do not support a dose reduction of oxaliplatin in patients with markedly elevated bilirubin concentrations. However, a larger number of patients must be examined before valid dose recommendations can be derived.
Assuntos
Antineoplásicos/farmacocinética , Neoplasias Hepáticas/tratamento farmacológico , Fígado/fisiopatologia , Compostos Organoplatínicos/farmacocinética , Idoso , Antineoplásicos/efeitos adversos , Área Sob a Curva , Bilirrubina/sangue , Neoplasias da Mama/patologia , Neoplasias do Colo/patologia , Feminino , Meia-Vida , Humanos , Infusões Intravenosas , Testes de Função Hepática , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Compostos Organoplatínicos/efeitos adversos , Oxaliplatina , Espectrofotometria AtômicaRESUMO
AIMS: Indisulam and carboplatin have shown synergistic activity in preclinical studies. In a dose escalation study of the combination, a treatment delay was frequently required in a 3-weekly regimen to allow recovery from myelosuppression from previous cycles. A 4-weekly regimen was better tolerated, but had a decreased dose-intensity which may compromise efficacy. The aims of this study were (i) to develop a pharmacokinetic-pharmacodynamic (PK-PD) model to describe the myelosuppressive effect of the combination, and (ii) to use this model to select a dosing regimen for Phase II evaluation. METHODS: Sixteen patients were treated at four different dose levels of indisulam (1-h infusion on day 1) and carboplatin (30-min infusion on day 2). Pharmacokinetic data were analysed with nonlinear mixed effects modelling. A semiphysiological model describing chemotherapy-induced myelosuppression characterized the relationship between the pharmacokinetics and the haematological toxicity of indisulam and carboplatin. A simulation study was performed to evaluate the tolerability and dose-intensity for 3-weekly and 4-weekly treatment regimens. RESULTS: The PK-PD model described the pharmacokinetics and the myelosuppressive effect of indisulam and carboplatin. The risk of a treatment delay at cycle 2 due to myelosuppression was unacceptably high (34-65%) in a 3-weekly regimen for various dose levels (350-600 mg m(-2) indisulam in combination with carboplatin to achieve an AUC of 4-6 mg min(-1) ml(-1)). This risk was acceptable for a 4-weekly regimen (9-24%), which is in line with the clinical study results. CONCLUSIONS: This PK-PD study supports the selection of indisulam 500 mg m(-2) and a dose of carboplatin to achieve an AUC of 6 mg min(-1) ml(-1) in a 4-weekly regimen as the recommended dose for future studies.