RESUMO
An increased dose-intensity can be achieved by either higher dose of chemotherapy per cycle (dose-escalation) or by shortening the interval between cycles (dose-dense). This multicenter randomized phase II study assessed the efficacy and safety of two different approaches: epirubicin 110 mg/m(2) combined with paclitaxel 200 mg/m(2) every 21 days and epirubicin 75 mg/m(2) combined with paclitaxel 175 mg/m(2) every 10 days, both supported with G-CSF. Patients with advanced breast cancer and without prior palliative chemotherapy were scheduled for 6 cycles. Evaluable for response were 101 patients and for toxicity 106 patients. Grade ≥ 3 toxicities occurred in 39% of patients in the dose-escalated arm and in 29% of the dose-dense arm, mainly febrile neutropenia, thrombocytopenia, neurotoxicity and (asymptomatic) cardiotoxicity. The median delivered cumulative doses for epirubicin/paclitaxel were 656/1194 and 448/1045 mg/m(2), treatment durations were 126 and 61 days, and delivered dose intensities were 36/67 and 51/120 mg/m(2)/week for the dose-escalated and dose-dense arm, respectively. Response rates were 75 and 70%, the progression-free survival 6 and 7 months, respectively. Dose-dense chemotherapy with a lower cumulative dose, a halved treatment time, but a higher dose-intensity may be as effective and safe as dose-escalated chemotherapy. The value of dose-densification over standard scheduled chemotherapy regimes yet needs to be determined.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adolescente , Adulto , Idoso , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Epirubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Metástase Linfática , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
In order to test the contention that metastasis is a selective process and that therefore metastases might show a more restricted pattern of phenotypic and genotypic characteristics than primary tumors, we compared the expression of carcinoembryonic antigen, Ca 19-9, secretory component, serotonin, and mucin production as well as flow cytometric data on DNA content and percentage of S-phase cells in 87 primary large bowel carcinomas and their lymph node metastases. In a majority of the cases primary tumors and their metastases were largely identical with regard to the examined phenotypic features. In discrepant cases, however, metastases did not invariably show a more restricted pattern than primary tumors, indicating high differentiational plasticity of primary and metastatic colorectal cancer cells. In contrast, in a number of cases genotypic discrepancies were observed. We conclude that phenotypic characteristics of colorectal cancer cells cannot be used to study the pathogenesis of lymph node metastasis. Genotypic studies, however, suggest that lymphogenic metastasis may be a selective event.
Assuntos
Neoplasias do Colo/análise , Metástase Linfática , Neoplasias Retais/análise , Antígenos de Neoplasias/análise , Antígenos Glicosídicos Associados a Tumores , Antígeno Carcinoembrionário/análise , DNA de Neoplasias/análise , Genótipo , Humanos , Mucinas/biossíntese , Fenótipo , Componente Secretório/análise , Serotonina/análiseRESUMO
Intercellular adhesion molecule 1 (ICAM-1) is involved in the recirculation of blood leukocytes and, presumably, in the infiltration of cytolytic effector leukocytes into tumors. The present report describes a down-regulated expression of vascular ICAM-1 on tumor-infiltrating endothelial cells (EC) in renal cell carcinoma. This finding was obtained by flow cytometric analysis of tumor EC compared to EC obtained from healthy tissue. Since growth of solid tumors is dependent on the formation of new blood vessels (angiogenesis), we hypothesized that angiogenic factors are responsible for the down-regulation of ICAM-1. This hypothesis was investigated in vitro using human umbilical vein- and dermis-derived EC. Using flow cytometry, we found a biphasic regulation of ICAM-1 during stimulation of cultured EC with the angiogenic agent basic fibroblast growth factor (bFGF). Although 16-24 h after activation a marked up-regulation of ICAM-1 was observed, expression was significantly decreased after 48h. The longevity of this down-regulation was at least 7 days. Northern blot analysis revealed down-regulation of the steady-state mRNA level of the gene. ICAM-2 showed similar results of intial up- and later down-regulation. Functional relevance for the changes in ICAM-1 expression was demonstrated by a corresponding biphasic regulation of EC-leukocyte adhesion after EC activation by bFGF. The described effects are specific for bFGF since other angiogenic factors (such as vascular endothelial growth factor, transforming growth factor beta, and interleukin 8) did not affect adhesion molecule expression. Subsequent experiments showed that angiogenic factors decrease the sensitivity of EC to activation with tumor necrosis factor-alpha in regard to adhesion molecule expression. The present results reveal a tumor-derived escape mechanism from cytolytic effector leukocytes by down-regulation of vascular adhesion molecules in vivo and in vitro and decreased responsiveness to proinflammatory cytokines.
Assuntos
Carcinoma de Células Renais/metabolismo , Endotélio Vascular/metabolismo , Molécula 1 de Adesão Intercelular/biossíntese , Neoplasias Renais/metabolismo , Carcinoma de Células Renais/irrigação sanguínea , Carcinoma de Células Renais/patologia , Adesão Celular , Células Cultivadas , Regulação para Baixo , Endotélio Vascular/patologia , Fator 2 de Crescimento de Fibroblastos/farmacologia , Humanos , Neoplasias Renais/irrigação sanguínea , Neoplasias Renais/patologia , Neovascularização PatológicaRESUMO
In the present study we have evaluated the prognostic significance of ploidy levels and proliferative activity in 279 cases of large bowel carcinomas which were included in a surgical prospective randomized trial. Ploidy levels and proliferative activity were determined on nuclei isolated from paraffin-embedded tissues of 279 colorectal carcinoma patients, with a mean follow-up of 51.9 months. Product limit survival analysis demonstrated a borderline significant association (P = 0.0689 by generalized Breslow; P = 0.0336 by generalized Savage) between ploidy and survival, with a 75th quantile survival of 49.8 months for patients with diploid tumors and 35.9 months for patients with aneuploid tumors. After stratification for staging, Dukes' C cases showed a statistically significant association between tumor ploidy and survival (P = 0.0224 by generalized Breslow, P = 0.0110 by generalized Savage). Product limit survival analysis for proliferative activity and survival showed a similar outcome with the strongest association in Dukes's C stage of disease (75th quantile survival of 38.9 months for low proliferative and 18.0 months for high proliferative tumors).
Assuntos
Neoplasias do Colo/genética , DNA/análise , Neoplasias Retais/genética , Aneuploidia , Divisão Celular , Neoplasias do Colo/cirurgia , Citometria de Fluxo , Humanos , Estadiamento de Neoplasias , Poliploidia , Prognóstico , Estudos Prospectivos , Distribuição Aleatória , Neoplasias Retais/cirurgia , Estudos RetrospectivosRESUMO
PURPOSE: A potential application of hematopoietic growth factors is to obtain an increased dose-intensity. This can be achieved by either higher doses of chemotherapy with standard intervals, or by standard doses with shorter intervals. The potential of these approaches has not been investigated systematically. PATIENTS AND METHODS: In a randomized, multicenter study, 49 advanced breast cancer patients were treated with granulocyte colony-stimulating factor (G-CSF) and either increasing doses of epirubicin and cyclophosphamide with fixed intervals (arm one) or progressively shorter intervals with fixed doses of epirubicin and cyclophosphamide (arm two). A cohort of at least six patients was studied at each interval/dose. A more intensified interval/dose was given if less than 50% of patients encountered a dose-intensity limiting criterium (DILC) in the first three courses. RESULTS: In arm one, epirubicin 140 mg/m2 and cyclophosphamide 800 mg/m2 every 21 days was too toxic. Subsequently, epirubicin 120 mg/m2 and cyclophosphamide 700 mg/m2 was tested with two of 10 patients encountering a DILC. All initial DILCs consisted of febrile neutropenia. In arm two, epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 could be administered safely with 14- and 12-day intervals. In the 10-day interval, eight of 12 patients completed the first three cycles without a DILC. In the 8-day interval, seven of eight patients encountered a DILC. Incomplete neutrophil recovery, and to a lesser extent stomatitis, were dose-limiting. CONCLUSION: In combination with G-CSF, epirubicin 120 mg/m2 and cyclophosphamide 700 mg/m2 every 21 days was feasible (projected dose-intensity, 40 mg/m2/wk and 233 mg/m2/wk, respectively). Epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 could be administered safely every 10 days, allowing a projected dose-intensity of 52.5 mg/m2/wk and 350 mg/m2/wk, respectively.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Hematopoese/efeitos dos fármacos , Adulto , Idoso , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Neoplasias da Mama/patologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Esquema de Medicação , Epirubicina/administração & dosagem , Epirubicina/efeitos adversos , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
PURPOSE: To investigate the effects of medroxyprogesterone acetate (MPA) on appetite, weight, and quality of life (QL) in patients with advanced-stage, incurable, non-hormone-sensitive cancer. PATIENTS AND METHODS: Two hundred six eligible patients were randomized between double-blind MPA 500 mg twice daily or placebo. Appetite (0 to 10 numerical rating scale), weight, and QL (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC-QLQ-C30]) were assessed before the start of treatment (t = 0), and 6 weeks (t = 6) and 12 weeks (t = 12) thereafter. RESULTS: One hundred thirty-four patients (68 MPA and 66 placebo) were assessable at t = 6 and 99 patients (53 MPA and 46 placebo) at t = 12. A beneficial effect of MPA on appetite was observed after both 6 weeks (P = .008) and 12 weeks (P = .01) of treatment. After 12 weeks, a mean weight gain of 0.6 +/- 4.4 kg was seen in the MPA, versus an ongoing mean weight loss of 1.4 +/- 4.6 kg in the placebo group. This difference of 2.0 kg was statistically significant (P = .04). During the study, several areas of QL deteriorated in the total group of patients. With the exception of an improvement in appetite and possible also a reduction in nausea and vomiting, no measurable beneficial effects of MPA on QL could be demonstrated. The side effects profile of MPA was favorable: only a trend toward an increase in (usually mild) peripheral edema was observed. CONCLUSION: In weight-losing, advanced-stage non-hormone-sensitive cancer patients, MPA exhibits a mild side effects profile, has a beneficial effect on appetite, and may prevent further weight loss. However, general QL in the present study was not measurably influenced by MPA treatment.
Assuntos
Apetite/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Acetato de Medroxiprogesterona/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/fisiopatologia , Congêneres da Progesterona/farmacologia , Qualidade de Vida , Análise de Variância , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Neoplasias do Sistema Digestório/tratamento farmacológico , Neoplasias do Sistema Digestório/fisiopatologia , Método Duplo-Cego , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/fisiopatologia , Masculino , Acetato de Medroxiprogesterona/efeitos adversos , Estadiamento de Neoplasias , Neoplasias/patologia , Congêneres da Progesterona/efeitos adversos , Resultado do TratamentoRESUMO
A 26-year-old female patient with acute myeloid leukaemia was hospitalized for the second cycle of remission induction chemotherapy. While neutropenic she developed progressive pulmonary infiltrate, with Micrococcus spp. cultured from two consecutive bronchoalveolar lavage fluids, resulting in respiratory insufficiency. The patient died after an unsuccessful cardiopulmonary resuscitation. This report of micrococcal pneumonia emphasizes that the pathogenicity of this skin commensal is not limited to infections in tissues surrounding prosthetic devices or indwelling intravenous catheters. Especially in immunocompromised patients, Micrococcus spp. from bronchoalveolar lavage fluids cannot be lightly dismissed as non-pathogenic when pneumonia is considered.
Assuntos
Infecções por Bactérias Gram-Positivas/complicações , Leucemia Mieloide Aguda/complicações , Micrococcus , Pneumonia/complicações , Adulto , Líquido da Lavagem Broncoalveolar/microbiologia , Feminino , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Hospedeiro Imunocomprometido , Leucemia Mieloide Aguda/imunologia , Micrococcus/isolamento & purificação , Infecções Oportunistas/complicações , Infecções Oportunistas/microbiologia , Pneumonia/microbiologiaRESUMO
As anemia is frequently the main problem in myelodysplastic syndromes (MDS), we studied the efficacy of human erythropoietin (rhEpo) in stimulating the erythroid lineage in 14 patients, starting with 40 U/kg three times a week and doubling the dose every 6 weeks until a response was observed. The highest doses administered were 80 (n = 1), 160 (n = 4), 320 (n = 8) and 640 U/kg (n = 1). One patient (refractory anemia with an excess of blasts, RAEB) showed an increase of hemoglobin, white blood cells and platelets with 80 U/kg rhEpo. However, this patient developed acute leukemia while on therapy. Two other patients (RAEB and RAEB in transformation) also transformed to acute leukemia. In the other 11 patients no response was observed. There was no correlation between in vitro culture data and in vivo responsiveness. The treatment was well tolerated and no nonhematological side effects were observed. From this study we conclude that rhEpo, even when given at high doses, has a low response rate in patients with MDS. Further investigation is needed in order to clarify whether rhEpo increases the potential risk of transformation to acute leukemia.
Assuntos
Eritropoetina/administração & dosagem , Síndromes Mielodisplásicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia Refratária/sangue , Anemia Refratária/tratamento farmacológico , Anemia Refratária com Excesso de Blastos/sangue , Anemia Refratária com Excesso de Blastos/tratamento farmacológico , Anemia Sideroblástica/sangue , Anemia Sideroblástica/tratamento farmacológico , Plaquetas/efeitos dos fármacos , Medula Óssea/efeitos dos fármacos , Avaliação de Medicamentos , Eritrócitos/efeitos dos fármacos , Eritropoetina/efeitos adversos , Eritropoetina/sangue , Feminino , Hemoglobinas/metabolismo , Humanos , Leucócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/sangueRESUMO
Although promising results with radioimmunotherapy and radioimmunodiagnosis in haematological diseases, have been reported, they are less encouraging results in solid tumours. Experimental mathematical models suggest that optimization of antibody-based therapy and diagnosis is possible and that further research towards improvement is warranted. In this review, the major problems of radioimmunotherapy and diagnosis are discussed. Particular items adressed include tumour uptake of antibodies and antibody-fragments, the target/non-target ratio, immunogenicity and the selection of radionuclides.
Assuntos
Neoplasias/diagnóstico por imagem , Neoplasias/radioterapia , Radioimunodetecção , Radioimunoterapia , Anticorpos Monoclonais/uso terapêutico , Humanos , Radioimunodetecção/efeitos adversos , Radioimunodetecção/métodos , Radioimunoterapia/efeitos adversos , Radioimunoterapia/métodos , RadioisótoposRESUMO
Intravenous (i.v.) granisetron was made available to patients who had received the drug during their first course of chemotherapy and requested granisetron prophylaxis at subsequent cycles. Initially at each further cycle patients received 40 micrograms/kg in each further cycle; this was later simplified to 3 mg. 574 patients were treated with 40 micrograms/kg over 1966 cycles of emetogenic chemotherapy in study 1. 335 patients (81 of whom transferred from study 1) received 3 mg over 785 cycles in study 2. With either regimen about 60% of all patients gained complete protection of symptoms over the 24-h postchemotherapy for up to 8 cycles. Complete response was maintained at around 70% in the subgroup of patients treated with moderately emetogenic regimens. Efficacy decreased over 5 cycles of cisplatin (greater than or equal to 50 mg/m2) from approximately 59% at the first additional cycle to around 37% at the fifth. This could, in part, be explained by a reversal in the proportions of males (low risk) to females (high risk) during the study. Withdrawal was largely due to completion of chemotherapy courses; approximately 15% of patients discontinued treatment for reasons possibly related to poor emetic control and 10% for unspecified reasons. Granisetron was well tolerated and no new toxicity developed following repeated exposure. In conclusion, granisetron maintained its efficacy over repeated cycles in most patients, although some fall-off occurred with high-dose cisplatin. 40 micrograms/kg and 3 mg were equally effective.
Assuntos
Antieméticos/administração & dosagem , Antineoplásicos/efeitos adversos , Indazóis/administração & dosagem , Náusea/prevenção & controle , Vômito/prevenção & controle , Adulto , Idoso , Antieméticos/efeitos adversos , Esquema de Medicação , Feminino , Granisetron , Humanos , Indazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Antagonistas da Serotonina , Fatores Sexuais , Vômito/induzido quimicamenteRESUMO
Pre-treatment quality of life (QOL) has been found to be an independent prognostic factor for survival in cancer patients, in particular in patients with advanced cancer. Sociodemographic factors such as marital and socioeconomic status have also been recognised as prognostic factors. We studied the influence of QOL and mood (measured with the European Organization for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-C30) and the Head and Neck Cancer Questionnaire (EORTC QLQ-H&N35), and with the Center for Epidemiologic Studies-Depression Scale (CES-D)) as measured before treatment, the use of cigarettes and alcohol and sociodemographic factors (age, gender, marital status, income and occupation) on recurrence and survival in 208 patients with head and neck cancer prior to treatment with surgery and/or radiotherapy, using Kaplan-Meier and Cox regression analyses. Cognitive functioning and, to a lesser degree, marital status were independent predictors of recurrence and survival, along with medical factors (stage and radicality). Patients with less than optimal cognitive functioning and unmarried patients had a relative risk (RR) of recurrence of 1.72 (95% confidence interval (95% CI) 1.01-2.93) and 1.85 (95% CI 1.06-3.33), respectively, and a RR of dying of 1.90 (95% CI 1.10-3.26) and 1.82 (95% CI 1.03-3.23), respectively. Performance status, physical functioning, mood and global QOL and smoking and drinking did not predict for recurrence and survival. The influence of cognitive functioning might be related to the use of alcohol. Marital status may influence prognosis through mechanisms of health behaviour and/or social support mechanisms.
Assuntos
Neoplasias de Cabeça e Pescoço/radioterapia , Neoplasias de Cabeça e Pescoço/cirurgia , Qualidade de Vida , Consumo de Bebidas Alcoólicas/efeitos adversos , Feminino , Humanos , Masculino , Análise Multivariada , Recidiva Local de Neoplasia/etiologia , Prognóstico , Estudos Prospectivos , Fatores de Risco , Fumar/efeitos adversos , Fatores Socioeconômicos , Análise de SobrevidaRESUMO
The aim of this study was to investigate whether N-(phosphonacetyl)-L-aspartic acid (PALA) can enhance the activity of low-dose methotrexate (LD-MTX) modulated infusional 5-fluorouracil (5-FU) in patients with advanced colorectal cancer. 198 patients were randomised either to (i) 5-FU 60 mg/kg as a continuous infusion over 48 h, to be given weekly four times and thereafter every 2 weeks, with methotrexate 40 mg/m(2) administered just before 5-FU (control regimen) or to (ii) PALA 250 mg/m(2) as a 15 min infusion administered 24 h before 5-FU and methotrexate which was given as described in the control regimen. The response rate was 13% in the patients randomised to the control arm and 7% in the patients randomised to the experimental arm. If stabilisation of the disease was also considered as a positive response, these figures become 54 and 46%, respectively. All these differences did not reach statistical significance. The median durations of progression-free survival (PFS) in the two treatment groups were not significantly different. The median duration of survival was 13.1 months in the control arm and 11.9 months in the experimental arm (P=0.31). No benefit was obtained by adding PALA to LD-MTX+infusional FU. Taking into account data from US trials, the modulating effect of PALA, although 'promising' in phase II, could not be substantiated in randomised studies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ácido Aspártico/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Ácido Fosfonoacéticos/análogos & derivados , Adulto , Idoso , Ácido Aspártico/administração & dosagem , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Ácido Fosfonoacéticos/administração & dosagem , Análise de Sobrevida , Resultado do TratamentoRESUMO
The aim of this prospective study was to assess the efficacy, clinical benefit and safety of CPT-11 (irinotecan) in patients with stringently-defined 5-fluorouracil-resistant metastatic colorectal cancer (CRC). 107 patients with documented progression of metastatic CRC during 5-FU were treated with CPT-11 350 mg/m2 once every 3 weeks in a multicentre phase II study. Tumour response and toxicity were assessed using WHO criteria. Changes in performance status (PS), weight and pain were also measured. The WHO response rate was 13/95 (13.7%, 95% CI 7.5% to 22.3%) eligible patients with a median duration of response of 8.5 months (37 weeks, range: 18-53+). There was also a high rate of disease stabilisation (44.2%) with a median duration of 4.8 months. The probability of being free of progression at 4 months was 50%. Median survival from first administration of CPT-11 was 10.4 months or 45 weeks (range: 3-66+ weeks). There was weight stabilisation or gain in 81% (73/90) of patients, a favourable outcome in PS in 91% (82/90) (improvement of WHO PS 2 or stabilisation of PS 0-1), and pain relief in 54% (26/48). There were no toxic deaths. Neutropenia was short-lasting and non-cumulative. Diarrhoea grade > or = 3 occurred in 7% of cycles and 28/107 (26%) of patients. CPT-11 350 mg/m2 once every 3 weeks has an encouraging degree of activity in progressive metastatic CRC truly resistant to 5-FU with a relatively high rate of tumour growth control translated into clinical benefit. The toxicity profile of CPT-11 is becoming better understood and has been considerably improved.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/uso terapêutico , Adulto , Idoso , Camptotecina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Doenças Hematológicas/induzido quimicamente , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida , Resultado do TratamentoRESUMO
In a multicenter phase III trial, 267 patients with nonbulky metastatic colorectal cancer who had failed first-line 5-fluorouracil (5-FU) therapy were randomized to receive second-line treatment with either the new topoisomerase agent, irinotecan (Rhône-Poulenc Rorer, Antony, France), or a high-dose infusional 5-FU regimen. Patients treated with irinotecan survived significantly longer than those treated with infusional 5-FU. The 1-year survival rate was 45% for patients receiving irinotecan compared with 32% for patients receiving 5-FU. There also was a significant difference in median progression-free survival (4.2 months v 2.9 months; P = .03) favoring irinotecan. Irinotecan administered at a dose of 350 mg/m2 every 3 weeks was associated with manageable toxicities (the main toxicities were neutropenia and diarrhea). The incidence of these adverse events and of vomiting was higher with irinotecan than with the comparator regimens of infusional 5-FU. However, the incidence of grade 3-4 asthenia was the same in the two treatment arms and mucositis and cutaneous adverse events were more common with 5-FU. Overall, mean global quality of life scores were similar in the two arms of the study throughout the period of treatment and follow-up, demonstrating that the more effective disease control achieved by irinotecan at least maintains quality of life. Indeed, deterioration in quality of life (defined as >50% decrease from baseline score) occurred significantly later in irinotecan-treated patients. In light of these data, irinotecan should be considered the reference treatment for patients with 5-FU-refractory advanced colorectal cancer.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/uso terapêutico , Inibidores da Topoisomerase I , Camptotecina/uso terapêutico , Neoplasias Colorretais/patologia , Feminino , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Metástase Neoplásica , Qualidade de Vida , Análise de Sobrevida , Falha de TratamentoRESUMO
BACKGROUND: Multiple endocrine neoplasia type 2A (MEN 2A) is a hereditary syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism. Familial MTC (FMTC) is characterized by MTC only. Both MEN 2A and FMTC are caused by germline mutations of the RET proto-oncogene. PURPOSE: To assess genotype/phenotype correlations, large families have to be examined periodically over a long period using an extensive screening program. PATIENTS AND METHODS: Since 1973, we screened a large family with hereditary C cell carcinoma for MTC, pheochromocytoma, and parathyroid disease by clinical tests and imaging methods. A germline codon Cys618 to Ser mutation in the RET proto-oncogene was recently identified in this family. The disease phenotype associated with this mutation was compared with that of Cys634 mutations in some other large MEN 2A families. RESULTS: The distinct course of disease in the family described here is similar to that in other FMTC families and MEN 2A families with a Cys618 mutation of the RET gene, but clearly different from that in families with a Cys634 mutation. The frequency of pheochromocytomas and parathyroid disease is clearly lower, whereas cure rates and life expectancy are higher. However, in families with a Cys618 mutation, pheochromocytoma and parathyroid disease do occur. CONCLUSION: In FMTC families with cysteine codon mutations of the RET proto-oncogene, screening for other endocrinopathies is mandatory, since these may not be MTC-only families. Therefore, we suggest that MEN 2A families should not be subclassified into MEN 2A and FMTC, but rather according to their specific mutation in the RET protein (i.e., for this family MEN 2A RET C618S).
Assuntos
Carcinoma Medular/genética , Cisteína/genética , Proteínas de Drosophila , Mutação em Linhagem Germinativa , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias das Glândulas Suprarrenais/genética , Adulto , Idoso , Carcinoma Medular/patologia , Sondas de DNA , Feminino , Genótipo , Humanos , Hiperparatireoidismo/genética , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 2a/genética , Linhagem , Fenótipo , Feocromocitoma/genética , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-ret , Neoplasias da Glândula Tireoide/patologiaRESUMO
We developed a rapid and convenient immunocytochemical method for simultaneous detection of antigen expression and S-phase cells by means of anti-bromodeoxyuridine (BrdUrd) antibodies. Immunocytochemical detection of BrdUrd after in vivo administration in mice was compared with autoradiography using [3H]-BrdUrd. Both the sensitivity and specificity of the technique were high. For the dual peroxidase staining technique, DAB color modification by cobalt ions was used. We showed that antigen localization was not affected by the BrdUrd staining protocol. The technique we describe here can be performed on frozen or paraffin-embedded tissue and on cytocentrifuge preparations for analysis of the cytokinetics of phenotypically defined cells in heterogeneous populations.
Assuntos
Anticorpos Monoclonais , Antígenos/análise , Bromodesoxiuridina/metabolismo , DNA/biossíntese , Mucosa Intestinal/metabolismo , Animais , Autorradiografia , Bromodesoxiuridina/imunologia , Histocitoquímica , Técnicas Imunoenzimáticas , Interfase , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Camundongos , Camundongos Endogâmicos BALB CRESUMO
We investigated the influence of various fixatives on monoclonal anti-BrdUrd antibody binding of BrdUrd-substituted DNA in tissue sections of routinely processed mouse small intestine after in vivo administration of BrdUrd. For denaturing fixatives such as ethanol or Carnoy's fluid, a standard denaturation protocol showed specific crypt cell labeling. With cross-linking agents such as formalin and glutaraldehyde, a remarkable increase in staining intensity was obtained after tissue digestion with pepsin before acid denaturation. The optimal pepsin concentration was determined for maximal immunoreactivity combined with acceptable morphology.
Assuntos
Anticorpos Monoclonais , Bromodesoxiuridina/análise , Fixadores , Técnicas Imunoenzimáticas , Animais , Bromodesoxiuridina/imunologia , Reagentes de Ligações Cruzadas , DNA/análise , Formaldeído , Secções Congeladas , Glutaral , Intestino Delgado/análise , Camundongos , Camundongos Endogâmicos BALB C , Pepsina A , Desnaturação ProteicaRESUMO
UNLABELLED: Rhenium-186-1,1-hydroxyethylidene diphosphonate (186Re-HEDP) has been used for the palliative treatment of metastatic bone pain. A Phase 1 dosage escalation study was performed using 186Re-HEDP in patients with metastatic breast cancer. METHODS: Twelve patients with metastatic breast cancer were studied. Each patient had at least four bone metastases and adequate hematological function. Groups of three consecutive patients were treated with dosages starting at 1295 MBq (35 mCi) and increasing to 2960 MBq (80 mCi) (escalated in increments of 555 MBq). RESULTS: A transient increase in pain ("flare" reaction) was observed in six patients. Two patients who received 2960 MBq 186Re-HEDP showed Grades 3 (platelets 25-50 x 10(9)/l) and 4 (platelets < 25 x 10(9)/l) platelet toxicity, which was defined as unacceptable. Prior to treatment, alkaline phosphatase levels were elevated in seven cases. These patients showed a transient decline in alkaline phosphatase levels during the first 4 wk. CONCLUSION: The maximum tolerated administered activity of 186Re-HEDP in patients with metastatic breast cancer is 2405 MBq (65 mCi). Thrombocytopenia proved to be the dose-limiting toxicity, which could not be predicted adequately by the administered activity. Changes of alkaline phosphatase levels suggest anti-tumor effects of 186Re-HEDP.
Assuntos
Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Ácido Etidrônico/uso terapêutico , Cuidados Paliativos , Radioisótopos/uso terapêutico , Rênio/uso terapêutico , Fosfatase Alcalina/sangue , Antígeno Carcinoembrionário/sangue , Relação Dose-Resposta à Radiação , Ácido Etidrônico/administração & dosagem , Ácido Etidrônico/efeitos adversos , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Radioisótopos/administração & dosagem , Radioisótopos/efeitos adversos , Rênio/administração & dosagem , Rênio/efeitos adversos , Trombocitopenia/etiologiaRESUMO
UNLABELLED: A potential limitation of rhenium-186-1,1-hydroxyethylidene diphosphonate (186Re-HEDP) therapy in patients with painful bone metastases is thrombocytopenia. Given the palliative character of this therapy, it is essential to be able to predict the degree of thrombocytopenia before therapy. METHODS: Thus far, 39 prostatic cancer patients with multiple painful bone metastases were treated. Twenty-one patients underwent the therapy twice, resulting in 60 therapies. From the pre-therapy 99mTc-HDP scintigram, the bone scan index (BSI) was determined as an index of the extent of bone involvement. RESULTS: The administered activity ranged from 1104 to 3479 MBq 186Re-HEDP. The platelet count was lowest 4 wk following therapy. From this value and the pretreatment level, the percentage decrease in the platelet count was determined (47% +/- 19%, range 14%-89%). The BSI ranged from 8 to 93. Regression analysis showed a functional relation (R = 0.78; p < 0.001) of the percentage of platelet decrease with BSI and administered activity normalized to standard body surface area. CONCLUSION: Using this relation, it is possible to predict thrombocytopenia by pretreatment bone scintigraphy and to adjust the dosage to each patient to avoid unacceptable toxicity.
Assuntos
Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/secundário , Radioisótopos/efeitos adversos , Rênio/efeitos adversos , Trombocitopenia/etiologia , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta à Radiação , Ácido Etidrônico/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas/efeitos da radiação , Neoplasias da Próstata/patologia , Radioisótopos/uso terapêutico , Rênio/uso terapêuticoRESUMO
UNLABELLED: Rhenium-186-etidronate has been developed for pain relief of bone metastases and has previously been studied with regard to toxicity, pharmacokinetics and dosimetry. Its palliating effect on bone pain has not been studied extensively. To justify further efficacy investigations, patients participating in two toxicity studies were studied using a strict pain assessment methodology. METHODS: Forty-three patients entered the study, 37 of whom were evaluable for pain assessment. Administered dosages ranged from 1295 MBq (35 mCi) to 3515 MBq (95 mCi) 186Re-etidronate. Pain relief was assessed using a handwritten diary containing questions reflecting the multidimensional character of chronic pain. The diary was marked twice daily for a maximum of 10 wk (2 wk prior to and 6/8 wk after the injection). A response was determined using a specific decision rule, in which pain intensity, medication index and daily activities were core determinants. RESULTS: A response was reached in 54% (20 of 37) of the patients and varied from 33% (n = 6) in the "35-mCi" group to 78% (n = 7) in the "50/65-mCi" group to 70% (n = 7) in the "80/95-mCi" group. CONCLUSION: Pain assessment using the multidimensional pain model showed that 186Re-etidronate is an effective agent in the treatment of metastatic bone pain in prostate cancer and warrants further placebo-controlled studies.