RESUMO
Hypomorphic germline variants in TERT, the gene encoding the reverse transcriptase component of the human telomerase complex, occur with a frequency of 3-5% in acute myeloid leukemia. We analyzed the clinical and prognostic impact of the most common TERT A1062T variant in younger patients with acute myeloid leukemia intensively treated within two prospective multicenter trials. Four hundred and twenty patients (age 17-60 years) were analyzed for the TERT A1062T variant by direct sequencing. Fifteen patients (3.6%) carried the TERT A1062T variant. Patients with the TERT A1062T variant had a trend towards less favorable and more intermediate 2/adverse karyotypes/genotypes according to the European Leukemia Net classification. In univariate and multivariate analysis, patients with the TERT A1062T variant had a significantly inferior overall survival compared to wild-type patients (6-year overall survival 20 vs. 41%, p = 0.005). Patients with the TERT A1062T variant showed a high rate of treatment-related mortality: 5/15 (33%) died during induction therapy or in complete remission as compared to 62/405 (15%) of the wild-type patients. In patients with the TERT variant, 14/15 (93%) suffered from non-hematological/non-infectious grade 3/4 adverse events (mostly hepatic and/or mucosal) as compared to 216/405 (53%) wild-type patients (p = 0.006). In multivariate analysis, the TERT A1062T variant was an independent risk factor predicting for adverse events during induction chemotherapy. In conclusion, the TERT A1062T variant is an independent negative prognostic factor in younger patients with acute myeloid leukemia and seems to predispose those patients to treatment-related toxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide/terapia , Mutação Puntual , Polimorfismo de Nucleotídeo Único , Transplante de Células-Tronco/métodos , Telomerase/genética , Doença Aguda , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ensaios Clínicos como Assunto , Terapia Combinada , Diarreia/etiologia , Feminino , Humanos , Leucemia Mieloide/enzimologia , Leucemia Mieloide/genética , Masculino , Pessoa de Meia-Idade , Mucosite/etiologia , Estudos Multicêntricos como Assunto , Análise Multivariada , Prognóstico , Estudos Prospectivos , Transplante de Células-Tronco/efeitos adversos , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
Deregulation of the hematopoietic stem cell (HSC) compartment represents a hallmark of acute myeloid leukemia (AML). Recently, in vivo screening for genes that are involved in the regulation of HSCs has led to the discovery of Musashi-2 (MSI2) as a key regulator of HSCs and as a suppressor of NUMB. In order to analyze the prognostic importance of MSI2 and NUMB expression in AML, MSI2 and NUMB transcript levels from 454 AML patients treated in multicenter trials AML SHG 0199 (ClinicalTrials Identifier NCT00209833) and 0295, and 38 healthy volunteers were analyzed by reverse transcriptase PCR in the context of other molecular markers (NPM1, FLT3, CEBPA, IDH1/IDH2, DNMT3A, NRAS, WT1, KIT, MN1, BAALC, ERG, and WT1). In AML, patients with high MSI2 expression were more likely to be FLT3-ITD positive (P < .001), NPM1 (P < .001), and DNMT3A (P = .003) mutated. Overall survival (OS) was shorter in AML patients with high MSI2 expression (hazard ratio, 1.48; 95 % confidence interval, 1.13-1.95, P = .005). However, relapse-free survival (RFS, P = .15) and complete remission (CR, P = .39) rates were not influenced by MSI2 expression. In multivariate analysis, MSI2 expression remained an independent prognostic factor for OS (P = .03). NUMB expression had no impact on survival (OS, P = .47; RFS, P = .59) and CR rate (P = .39). MSI2 but not NUMB is associated with shorter OS in AML patients and may indicate a more aggressive form of AML.
Assuntos
Regulação Neoplásica da Expressão Gênica , Células-Tronco Hematopoéticas/fisiologia , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/metabolismo , Proteínas de Membrana/biossíntese , Proteínas do Tecido Nervoso/biossíntese , Proteínas de Ligação a RNA/biossíntese , Adolescente , Adulto , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Nucleofosmina , Prognóstico , Taxa de Sobrevida/tendências , Adulto JovemRESUMO
PURPOSE: To study the incidence and prognostic impact of mutations in DNA methyltransferase 3A (DNMT3A) in patients with acute myeloid leukemia. PATIENTS AND METHODS: A total of 489 patients with AML were examined for mutations in DNMT3A by direct sequencing. The prognostic impact of DNMT3A mutations was evaluated in the context of other clinical prognostic markers and genetic risk factors (cytogenetic risk group; mutations in NPM1, FLT3, CEBPA, IDH1, IDH2, MLL1, NRAS, WT1, and WT1 SNPrs16754; expression levels of BAALC, ERG, EVI1, MLL5, MN1, and WT1). RESULTS: DNMT3A mutations were found in 87 (17.8%) of 489 patients with AML who were younger than 60 years of age. Patients with DNMT3A mutations were older, had higher WBC and platelet counts, more often had a normal karyotype and mutations in NPM1, FLT3, and IDH1 genes, and had higher MLL5 expression levels as compared with patients with wild-type DNMT3A. Mutations in DNMT3A independently predicted a shorter overall survival (OS; hazard ratio [HR], 1.59; 95% CI, 1.15 to 2.21; P = .005) by multivariate analysis, but were not associated with relapse-free survival (RFS) or complete remission (CR) rate when the entire patient cohort was considered. In cytogenetically normal (CN) AML, 27.2% harbored DNMT3A mutations that independently predicted shorter OS (HR = 2.46; 95% CI, 1.58 to 3.83; P < .001) and lower CR rate (OR, 0.42; 95% CI, 0.21 to 0.84; P = .015), but not RFS (P = .32). Within patients with CN-AML, DNMT3A mutations had an unfavorable effect on OS, RFS, and CR rate in NPM1/FLT3-ITD high-risk but not in low-risk patients. CONCLUSION: DNMT3A mutations are frequent in younger patients with AML and are associated with an unfavorable prognosis.
Assuntos
Biomarcadores Tumorais/genética , DNA (Citosina-5-)-Metiltransferases/genética , Leucemia Mieloide Aguda/genética , Mutação , Adolescente , Adulto , Fatores Etários , Biomarcadores Tumorais/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA , DNA Metiltransferase 3A , Análise Mutacional de DNA , Intervalo Livre de Doença , Regulação Leucêmica da Expressão Gênica , Predisposição Genética para Doença , Alemanha , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Pessoa de Meia-Idade , Nucleofosmina , Medição de Risco , Fatores de Risco , Análise de Sobrevida , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Whether it is possible to reduce the intensity of treatment in early (stage I or II) Hodgkin's lymphoma with a favorable prognosis remains unclear. We therefore conducted a multicenter, randomized trial comparing four treatment groups consisting of a combination chemotherapy regimen of two different intensities followed by involved-field radiation therapy at two different dose levels. METHODS: We randomly assigned 1370 patients with newly diagnosed early-stage Hodgkin's lymphoma with a favorable prognosis to one of four treatment groups: four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by 30 Gy of radiation therapy (group 1), four cycles of ABVD followed by 20 Gy of radiation therapy (group 2), two cycles of ABVD followed by 30 Gy of radiation therapy (group 3), or two cycles of ABVD followed by 20 Gy of radiation therapy (group 4). The primary end point was freedom from treatment failure; secondary end points included efficacy and toxicity of treatment. RESULTS: The two chemotherapy regimens did not differ significantly with respect to freedom from treatment failure (P=0.39) or overall survival (P=0.61). At 5 years, the rates of freedom from treatment failure were 93.0% (95% confidence interval [CI], 90.5 to 94.8) with the four-cycle ABVD regimen and 91.1% (95% CI, 88.3 to 93.2) with the two-cycle regimen. When the effects of 20-Gy and 30-Gy doses of radiation therapy were compared, there were also no significant differences in freedom from treatment failure (P=1.00) or overall survival (P=0.61). Adverse events and acute toxic effects of treatment were most common in the patients who received four cycles of ABVD and 30 Gy of radiation therapy (group 1). CONCLUSIONS: In patients with early-stage Hodgkin's lymphoma and a favorable prognosis, treatment with two cycles of ABVD followed by 20 Gy of involved-field radiation therapy is as effective as, and less toxic than, four cycles of ABVD followed by 30 Gy of involved-field radiation therapy. Long-term effects of these treatments have not yet been fully assessed. (Funded by the Deutsche Krebshilfe and the Swiss Federal Government; ClinicalTrials.gov number, NCT00265018.)
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/radioterapia , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bleomicina/administração & dosagem , Bleomicina/efeitos adversos , Terapia Combinada , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Seguimentos , Doença de Hodgkin/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Dosagem Radioterapêutica , Taxa de Sobrevida , Vimblastina/administração & dosagem , Vimblastina/efeitos adversos , Adulto JovemRESUMO
Mutations in the nicotinamide adenine dinucleotide phosphate(+)-dependent isocitrate dehydrogenase gene 2 (IDH2) have recently been found in patients with acute myeloid leukemia (AML) as well as in patients with leukemic transformation of myeloproliferative neoplasms. We analyzed 272 adult patients with cytogenetically normal AML (CN-AML) for the presence of IDH2 mutations in codons R140 and R172. IDH2 mutations of amino acid 140 or 172 could be identified in 12.1% of CN-AML patients, with the majority of mutations (90%) occurring at position R140. The incidence of IDH2 mutations in AML patients with aberrant karyotypes (n = 130) was significantly lower (3.8%, P = .006). IDH2 mutations were mutually exclusive with mutations in IDH1. IDH2 mutation status alone or in combination with IDH1 mutations had no impact on response to therapy, overall survival, and relapse-free survival in patients with CN-AML. In conclusion, IDH2 mutations are frequently found in CN-AML, but in our analysis these mutations did not influence treatment outcome. This study was registered at www.clinicaltrials.gov as #NCT00209833.
Assuntos
Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Adulto , Ensaios Clínicos como Assunto , Análise Citogenética , Análise Mutacional de DNA , Humanos , Isocitrato Desidrogenase/fisiologia , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Estudos Multicêntricos como Assunto , Mutação/fisiologia , Prognóstico , Recidiva , Análise de Sobrevida , Resultado do TratamentoRESUMO
There were only a few options 3 years ago to treat metastatic renal cell carcinoma (mRCC), a disease with a very poor prognosis. With the approval of targeted therapies for mRCC since December 2005, this situation has changed dramatically. Currently, oncologists can choose between several promising options to improve the longevity and quality of their patients' lives. A widely accepted treatment scheme for targeted therapies in mRCC does not yet exist. Based on a selective literature search, drawing on studies with six targeted therapies for mRCC, and including data from the latest American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) Annual Meetings, this review introduces the available therapies, evaluates patient-specific criteria for their application and suggests an algorithm for a patient-based treatment scheme. Clinical experiences with sequential therapies are summarized and potential combination therapies discussed. In conclusion, the crucial criteria of the treatment scheme we propose are the tumor burden and the disease pace, as well as the quality of life of a patient. These define whether tumor control or tumor remission should be the primary therapeutic goal. This scheme suggests which kind of therapeutic sequence to pursue to optimize patient care in mRCC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/terapia , Neoplasias Renais/terapia , Algoritmos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma de Células Renais/patologia , Sistemas de Liberação de Medicamentos , Humanos , Neoplasias Renais/patologia , Metástase Neoplásica , Medicina de Precisão/métodos , Prognóstico , Qualidade de Vida , Indução de Remissão/métodos , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacosRESUMO
PURPOSE: We assessed the prognostic impact of IDH1 R132 mutations and a known single nucleotide polymorphism (SNP) located in the same exon of the IDH1 gene in patients with cytogenetically normal acute myeloid leukemia (CN-AML) in the context of other prognostic markers. PATIENTS AND METHODS: IDH1 exon four was directly sequenced in 275 CN-AML patients from two subsequent AML multicenter treatment trials and 120 healthy volunteers. Moreover, mutations in NPM1, FLT3, CEBPA, and WT1 were analyzed, and mRNA expression of IDH1 was quantified. RESULTS: IDH1 R132 mutations were found in 10.9% of CN-AML patients. IDH1 SNP rs11554137 was found in 12% of CN-AML patients and 11.7% of healthy volunteers. IDH1 R132 mutations had no impact on prognosis. In contrast, IDH1 SNP rs11554137 was an adverse prognostic factor for overall survival in univariate and multivariate analysis. Other significant factors were age, NPM1/FLT3 mutational status, WT1 SNP rs16754, and platelet count. The impact of IDH1 SNP rs11554137 was most pronounced in the NPM1/FLT3 high-risk patients (either NPM1 wild-type or FLT3-internal tandem duplication positive). Patients with IDH1 SNP rs11554137 had a higher expression of IDH1 mRNA than patients with two wild-type alleles. CONCLUSION: IDH1 SNP rs11554137 but not IDH1 R132 mutations are associated with an inferior outcome in CN-AML.
Assuntos
Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/genética , Mutação , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Distribuição de Qui-Quadrado , Análise Mutacional de DNA , Intervalo Livre de Doença , Éxons , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Genótipo , Alemanha , Humanos , Estimativa de Kaplan-Meier , Cariotipagem , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Nucleofosmina , Razão de Chances , Fenótipo , Modelos de Riscos Proporcionais , RNA Mensageiro/análise , Recidiva , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVES: Patients with metastatic papillary renal cell carcinoma (RCC) show special clinical behavior compared to patients with other histologic subtypes of RCC. This study aimed to assess the relevance of surgical and systemic options used in treatment of these patients prior to the recent era of targeted therapies. METHODS: Retrospectively, we assessed clinical data of 61 patients with metastatic papillary RCC who were treated at eight centers in Germany. RESULTS: Median follow-up was 20 (range 1-114) months and median age at time of diagnosis was 62 (range 24-85) years. Men were affected predominantly (50/61; 82%). Twenty-one patients (34%) showed metastases at time of diagnosis. In the remaining 40 patients, median time to development of metastases was 30.4 (range 3-143; mean 16.5) months. Sites of metastases were lung (37; 61%), bone (24; 38%), liver (20; 33%), lymph nodes (24; 38%), and local recurrence (17; 28%). Others sites of disease were brain metastases (6 patients/10%), peritoneal carcinosis (5 patients/8%), and others. A surgical approach with potentially curative intention was performed primarily in 11 patients (18%). 31 patients received an immuno- (interferon-alpha +/- interleukin-2) or immunochemotherapy as first line treatment for metastatic disease. Overall, 42/61 patients (69%) received systemic therapy. Supportive care only was performed in 12 patients (20%) because of poor performance status. Median overall survival after diagnosis of metastatic disease was longer than 48 months in patients with tumor resection (n = 11) compared to 13.0 +/- 4.3 months 95% CI 4.5-21.5 (n = 42) months in patients without surgical approach. CONCLUSIONS: Complete resection of metastases represents a valid option in management of patients with relapsing or metastatic papillary RCC.
Assuntos
Neoplasias Encefálicas/cirurgia , Carcinoma Papilar/cirurgia , Carcinoma de Células Renais/cirurgia , Neoplasias Renais/cirurgia , Neoplasias Hepáticas/cirurgia , Neoplasias Pulmonares/cirurgia , Recidiva Local de Neoplasia/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Carcinoma Papilar/secundário , Carcinoma Papilar/terapia , Carcinoma de Células Renais/secundário , Carcinoma de Células Renais/terapia , Quimioterapia Adjuvante , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Nefrectomia , Radioterapia Adjuvante , Estudos Retrospectivos , Resultado do TratamentoRESUMO
PURPOSE: We assessed the prognostic impact of a known single nucleotide polymorphism (SNP) located in the mutational hotspot of WT1 in patients with cytogenetically normal acute myeloid leukemia (CN-AML) in the context of other prognostic markers. PATIENTS AND METHODS: WT1 exons 7 and 9 from 249 CN-AML patients from multicenter treatment trials AML-SHG Hannover 0199 (Clinical Trials Identifier NCT00209833) and 0295, and 50 healthy volunteers were analyzed by direct sequencing. NPM1, FLT3, CEBPA, and MLL were assessed for mutations and WT1 expression was quantified. RESULTS: The minor allele of SNP rs16754 (WT1(AG/GG)) was found in 25.7% of CN-AML patients' blasts and germline DNA and in 36% of healthy volunteers. Patient characteristics, frequencies of mutations, or WT1 expression levels were similarly distributed between patients homozygous for the major allele compared with patients heterozygous or homozygous for the minor allele. SNP rs16754 status was an independent predictor of relapse-free survival (RFS; hazard ratio [HR], 0.49; 95% CI, 0.3 to 0.81; P = .005) and overall survival (OS; HR, 0.44; 95% CI, 0.27 to 0.74; P = .002) in multivariate analysis. The favorable effect of SNP rs16754 was stronger in NPM1/FLT3-ITD (internal tandem duplication of the FLT3 gene) high-risk patients compared with NPM1/FLT3-ITD low-risk patients. Favorable prognosis could not be identified by any other known low-risk marker in half the patients with at least one minor allele (13% of all patients). No difference for complete remission rate, RFS, or OS was found between patients with or without acquired WT1 mutations. CONCLUSION: WT1 SNP rs16754 may be a novel independent favorable-risk marker in CN-AML patients that might improve risk and treatment stratification.
Assuntos
Biomarcadores Tumorais/genética , Leucemia Mieloide Aguda/genética , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas WT1/genética , Adolescente , Adulto , Proteínas Estimuladoras de Ligação a CCAAT/genética , Feminino , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Histona-Lisina N-Metiltransferase , Humanos , Cariotipagem , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Proteína de Leucina Linfoide-Mieloide/genética , Estadiamento de Neoplasias , Proteínas Nucleares/genética , Nucleofosmina , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
We randomized 66 elderly patients with AML unfit for conventional chemotherapy to receive GCSF from d6 or from d12 after induction-chemotherapy with cytarabine/idarubicin. There was no difference in duration of neutropenia (17 days vs. 19 days, p=0.67) or rate of complications. Delayed treatment can reduce the administration of G-CSF without adverse consequences.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Humanos , Idarubicina/administração & dosagem , Idarubicina/efeitos adversos , Leucemia Mieloide Aguda/complicações , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Proteínas Recombinantes , Estudos Retrospectivos , Fatores de TempoRESUMO
Early allogeneic hematopoietic stem cell transplantation (HSCT) has been proposed as primary treatment modality for patients with chronic myeloid leukemia (CML). This concept has been challenged by transplantation mortality and improved drug therapy. In a randomized study, primary HSCT and best available drug treatment (IFN based) were compared in newly diagnosed chronic phase CML patients. Assignment to treatment strategy was by genetic randomization according to availability of a matched related donor. Evaluation followed the intention-to-treat principle. Six hundred and twenty one patients with chronic phase CML were stratified for eligibility for HSCT. Three hundred and fifty four patients (62% male; median age, 40 years; range, 11-59 years) were eligible and randomized. One hundred and thirty five patients (38%) had a matched related donor, of whom 123 (91%) received a transplant within a median of 10 months (range, 2-106 months) from diagnosis. Two hundred and nineteen patients (62%) had no related donor and received best available drug treatment. With an observation time up to 11.2 years (median, 8.9 years), survival was superior for patients with drug treatment (P = .049), superiority being most pronounced in low-risk patients (P = .032). The general recommendation of HSCT as first-line treatment option in chronic phase CML can no longer be maintained. It should be replaced by a trial with modern drug treatment first.
Assuntos
Antineoplásicos/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Transplante Homólogo/métodos , Adolescente , Adulto , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Risco , Resultado do TratamentoRESUMO
BACKGROUND: Breast cancer with extensive axillary-lymph-node involvement has a poor prognosis after conventional treatment. In trials with historical controls, high-dose chemotherapy produced improved outcomes. We compared an intensive double-cycle high-dose chemotherapy regimen with an accelerated conventionally dosed regimen in high-risk breast cancer in a multicentre trial. METHODS: Patients with at least nine positive nodes were randomly assigned either two courses of accelerated (2-week intervals, with filgrastim support), conventionally dosed epirubicin and cyclophosphamide followed by two courses of high-dose chemotherapy (epirubicin, cyclophosphamide, and thiotepa supported by peripheral-blood progenitors) or four identical cycles of epirubicin and cyclophosphamide followed by three cycles of accelerated cyclophosphamide, methotrexate, and fluorouracil. The primary endpoint was event-free survival. Analyses were done both by intention to treat and per protocol. FINDINGS: 403 patients were enrolled; 201 were assigned high-dose chemotherapy and 202 conventional treatment. The mean number of positive nodes was 17.6, and median follow-up was 48.6 months. 4-year event-free survival (intention-to-treat analysis) was 60% (95% CI 53-67) in the high-dose chemotherapy group and 44% (37-52) in the control group (p=0.00069). The corresponding overall survival was 75% (69-82) versus 70% (64-77; p=0.02). There were no treatment-related deaths. INTERPRETATION: Our finding of significant improvements in both event-free and overall survival for high-dose chemotherapy compared with a dose-dense conventional regimen contrasts with the results of other studies. The discrepancy might be due partly to design differences (tandem, brief induction) between our regimen and those studied in other trials. This approach merits further study.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama , Intervalo Livre de Doença , Transplante de Células-Tronco de Sangue Periférico/métodos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Quimioterapia Adjuvante , Terapia Combinada , Estudos Cross-Over , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: A technique of hyperthermic isolated lung perfusion (ILP) chemotherapy was developed. METHODS: Since April 1999, four patients with unilateral (n=2) or bilateral (n=2) sarcoma metastasis confined to a lobe (n=2) or entire lung (n=2) entered into a pilot study of hyperthermic (41 degrees C) ILP with high doses of cisplatin (70 mg/m(2)). Eligibility included drug resistant metastasis and at least four previous surgical metastectomies. The ILP of the lung segments was carried out following metastectomy, for 20-40 min at a rate of 0.3-0.5 l/min, a mean perfusion pressure lower than the own mean pulmonary artery pressure, and an inflow temperature of 41 degrees C or higher. Before and following ILP, the isolated lung segments were flushed with normothermic saline (1 l). Flow was continuously maintained by a centrifugal pump. RESULTS: All patients successfully completed 31.7+/-9 min perfusion time at 41.4+/-0.3 degrees C, and this time-point corresponded to the maximal platinum lung-uptake (93.8 ng/mg tissue). The total vascular isolation was confirmed by continuously low systemic cisplatin plasma levels. There was no systemic drug-related toxicity but all patients experienced transient pulmonary toxicity as non-cardiogenic edema of the treated lung segments. With a median follow-up of 12 months, three patients are alive and disease-free and one died from cerebral metastasis without autopsy evidence of local recurrence 13 months following ILP. CONCLUSION: Hyperthermic perfusion chemotherapy can be done safely and effectively. It represents a new treatment modality and deserves further investigations for patients with advanced, drug resistant or surgically refractory, lung sarcoma metastasis. However, further studies are needed to limit the ILP-induced pulmonary toxicity.
Assuntos
Antineoplásicos/administração & dosagem , Quimioterapia do Câncer por Perfusão Regional/métodos , Cisplatino/administração & dosagem , Hipertermia Induzida , Neoplasias Pulmonares/terapia , Sarcoma/terapia , Adulto , Estudos de Viabilidade , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Masculino , Sarcoma/tratamento farmacológico , Sarcoma/secundárioRESUMO
BACKGROUND: High-dose chemotherapy followed by transplantation of autologous haemopoietic stem cells (BEAM-HSCT) is frequently used to treat patients with relapsed Hodgkin's disease. We aimed to compare this treatment with conventional aggressive chemotherapy without stem-cell transplantation (Dexa-BEAM). METHODS: 161 patients between 16 and 60 years of age with relapsed Hodgkin's disease were randomly assigned two cycles of Dexa-BEAM (dexamethasone and carmustine, etoposide, cytarabine, and melphalan) and either two further courses of Dexa-BEAM or high-dose BEAM and transplantation of haemopoietic stem cells. Only patients with chemosensitive disease (complete or partial remission after two courses of Dexa-BEAM) proceeded to further treatment. The primary endpoint was freedom from treatment failure for patients with chemosensitive disease. Analysis was per protocol. FINDINGS: 17 patients were excluded from the study after randomisation (ten given Dexa-BEAM and seven given BEAM-HSCT). Median follow-up was 39 months (IQR 3-78). Freedom from treatment failure at 3 years was significantly better for patients given BEAM-HSCT (55%) than for those on Dexa-BEAM (34%; difference -21%, 95% CI -39.87 to -2.13; p=0.019). Overall survival of patients given either treatment did not differ significantly. INTERPRETATION: High-dose BEAM and transplantation of haemopoietic stem cells improves freedom from treatment failure in patients with chemosensitive first relapse of Hodgkin's disease irrespective of length of initial remission.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carmustina/administração & dosagem , Citarabina/administração & dosagem , Dexametasona/administração & dosagem , Etoposídeo/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin/terapia , Melfalan/administração & dosagem , Terapia de Salvação/métodos , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carmustina/efeitos adversos , Carmustina/uso terapêutico , Causas de Morte , Citarabina/efeitos adversos , Citarabina/uso terapêutico , Dexametasona/efeitos adversos , Dexametasona/uso terapêutico , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Feminino , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/mortalidade , Humanos , Masculino , Melfalan/efeitos adversos , Melfalan/uso terapêutico , Pessoa de Meia-Idade , RecidivaRESUMO
PURPOSE: To investigate whether treatment results in intermediate-stage Hodgkin's lymphoma can be improved by rapid application of non-cross-resistant drugs, the 10-drug regimen cyclophosphamide, vincristine, procarbazine, and prednisone (COPP), doxorubicin, bleomycin, and vinblastine (ABV), and ifosfamide, methotrexate, etoposide, and prednisone (IMEP), repeated every 6 weeks, was compared with conventional alternating COPP/doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) administered every 8 weeks. PATIENTS AND METHODS: From January 1988 to January 1993, 996 patients in stage I or II Hodgkin's lymphoma with at least one risk factor (massive mediastinal tumor, massive spleen involvement, extranodal disease, elevated ESR, or more than two lymph node areas involved) and all patients in stage IIIA Hodgkin's lymphoma were randomized to receive two cycles of COPP/ABVD or COPP/ABV/IMEP followed by extended-field radiotherapy. RESULTS: Both regimens produced similar rates for treatment responses (complete remission, 93% v 94%), freedom from treatment failure (80% v 79%), and overall survival (88% for both regimens) at a median follow-up time of 7 years. Most serious toxicities during chemotherapy were similar in both regimens. However, World Health Organization grade 3 and 4 leukocytopenia occurred significantly more frequently in the COPP/ABV/IMEP arm (53% v 44% of patients; P =.010). There were no differences in the number of serious infections and toxic deaths during therapy. The number of second malignancies was also the same in both arms (22 each). CONCLUSION: Alternating COPP/ABVD and rapid alternating COPP/ABV/IMEP in combination with extended-field radiotherapy are equally effective in intermediate-stage Hodgkin's lymphoma and produce excellent long-term treatment results.