RESUMO
BACKGROUND: Nonpegylated liposomal doxorubicin liposomal doxorubicin, (Myocet™; Sopherion Therapeutics, Inc Canada, and Cephalon, Europe) (NPLD; Myocet(®)) in combination with trastuzumabHerceptin(®) (Hoffmann-La Roche) has shown promising activity and cardiac safety. We conducted a randomized phase III trial of first-line NPLD plus trastuzumab and paclitaxel (Pharmachemie B.V.) (MTP) versus trastuzumab plus paclitaxel (TP) in patients with human epidermal growth factor 2 receptor (HER2)-positive metastatic breast cancer. PATIENTS AND METHODS: Patients were randomly assigned to NPLD (M, 50 mg/m(2) every 3 weeks for six cycles), trastuzumab (T, 4 mg/kg loading dose followed by 2 mg/kg weekly), and paclitaxel (P, 80 mg/m(2) weekly) or T + P at the same doses until progression or toxicity. The primary efficacy outcome was progression-free survival (PFS). RESULTS: One hundred and eighty-one patients were allocated to receive MTP, and 183 to TP. Median PFS was 16.1 and 14.5 months with MTP and TP, respectively [hazard ratio (HR) 0.84; two-sided P = 0.174]. In patients with estrogen receptor (ER)- and progesterone receptor (PR)-negative tumors, PFS was 20.7 and 14.0 months, respectively [HR 0.68; 95% confidence interval (CI) 0.47-0.99]. Median overall survival (OS) was 33.6 and 28.9 months with MTP and TP, respectively (HR 0.79; two-sided P = 0.083). In ER- and PR-negative tumors, OS was 38.2 and 27.9 months, respectively (HR 0.63; 95% CI 0.42-0.93). The frequency of adverse events was higher with MTP, but there was no significant difference in cardiac toxicity between treatment arms. CONCLUSION(S): The trial failed to demonstrate a significant clinical improvement with the addition of M to TP regimen. The clinical benefit observed in an exploratory analysis in the ER- and PR-negative population deserves consideration for further clinical trials. CLINICAL TRIAL NUMBER: NCT00294996.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/análogos & derivados , Paclitaxel/uso terapêutico , Receptor ErbB-2/metabolismo , Antibióticos Antineoplásicos/efeitos adversos , Antibióticos Antineoplásicos/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Esquema de Medicação , Feminino , Humanos , Metástase Neoplásica/tratamento farmacológico , Paclitaxel/efeitos adversos , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/uso terapêutico , Estudos Prospectivos , Trastuzumab , Resultado do TratamentoRESUMO
Bone marrow cells obtained from 166 patients with acute nonlymphocytic leukemia were cloned in vitro. The number and size of clones produced differed among patients and was unrelated to French-American-British type of leukemia, to patient age, to whether the patient was studied at the time of initial diagnosis or at relapse, or to the cytogenetic (normal or abnormal metaphases) or cell cycle characteristics of the leukemic bone marrow cells. The ability of leukemic cells to clone in vitro was associated with poor response to therapy in vivo, with the remission rate being inversely related to cloning efficiency of the leukemic cells, and with remission durations being inversely correlated with the size of the cluster/colonies formed in vitro. Only an occasional patient whose marrow cells produced clonal growth in vitro and in whom cytogenetic abnormalities were detected entered complete remission with conventional remission induction therapy. Measurement of the clonogenic potential in vitro of leukemic marrow cells together with their cytogenetic type may help to distinguish between patients who should and should not receive cytosine arabinoside/anthracycline antibiotic remission induction therapy and patients who do and do not require intensive remission consolidation chemotherapy.
Assuntos
Antineoplásicos/toxicidade , Leucemia/fisiopatologia , Medula Óssea/fisiopatologia , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Células Clonais , Avaliação Pré-Clínica de Medicamentos , Granulócitos/fisiologia , Humanos , Leucemia/tratamento farmacológico , Macrófagos/fisiologiaRESUMO
A phase Ilate/II trial of hyperfractionated (HFX) radiation therapy for non-small-cell carcinoma of the lung (NSCCL) was conducted by the Radiation Therapy Oncology Group (RTOG) between 1983 and 1987. Fractions of 1.2 Gy were administered twice daily with greater than or equal to 4 hours between fractions. Patients were randomized to receive minimum total doses of 60.0, 64.8, and 69.6 Gy. After acceptable risks of acute and late effects were found, 74.4 Gy and 79.2 Gy arms were added, and the lowest total dose arms were closed. No significant differences in the risks of acute or late effects in normal tissues were found among the 848 patients analyzed in the five arms; risks of severe or life-threatening pneumonitis were 2.6% for 60.0 to 64.8 Gy, 5.7% for 69.6 to 74.4 Gy, and 8.1% for 79.2 Gy. Among 350 patients who had the same criteria as Cancer and Leukemia Group B (CALGB) protocol 84-33 (American Joint Committee on Cancer Staging [AJCCS], 1984, stage III; Karnofsky performance status [KPS] 70 to 100; less than 6% weight loss), there was a dose response for survival: survival with 69.6 Gy (median, 13.0 months; 2 years, 29%) was significantly (P = .02) better than the lower total doses. There were no differences in survival among the three highest total-dose arms. Comparisons with results in similar patients treated with 60 Gy in 30 fractions of 2.0 Gy 5 days per week for 6 weeks suggest benefit from HFX radiation therapy with 69.6 Gy. Improvement in survival with HFX radiation therapy at 69.6 Gy total dose without increase in normal tissue effects, justifies phase III comparison with standard fractionation alone and combined with systemic chemotherapy in this common presentation of NSCCL.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/radioterapia , Adulto , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Relação Dose-Resposta à Radiação , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Lesões por Radiação/etiologia , Dosagem Radioterapêutica , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
PURPOSE: To estimate the toxicity and response rate of high-dose liposome-encapsulated doxorubicin (TLC D-99, Evacet, The Liposome Company Inc, Princeton, NJ) in patients with advanced breast cancer. PATIENTS AND METHODS: Fifty-two breast cancer patients with bidimensionally measurable metastatic disease and no prior chemotherapy for metastatic disease received a 135 mg/m2 intravenous (i.v.) bolus of TLC D-99 with 5 microg/kg of granulocyte colony-stimulating factor via subcutaneous injection every 21 days. RESULTS: The median number of treatment cycles of TLC D-99 was three (range, one to 10 cycles), and the median total cumulative dose of TLC D-99 was 405 mg/m2 (range, 135 to 1,065 mg/m2). Grade IV neutropenia, thrombocytopenia, and mucositis were experienced by 48 (92%), 46 (88%), and 10 (19%) patients, respectively. Twenty (38%) of patients experienced cardiac toxicity: four (8%) experienced a decrease of 20% or more in left ventricular ejection fraction (LVEF) to a final value > or = 50%, nine (17%) experienced a decrease of 10% or more in LVEF to a final value less than 50%, and seven (13%) developed symptomatic congestive heart failure (CHF), including one patient who died of cardiomyopathy after receiving a total dose of 1,035 mg/m2. In a stepwise logistic regression model, the significant risk factors for the development of CHF were the cumulative dose of prior adjuvant doxorubicin (P = .007) and the total cumulative dose of TLC D-99 (P = .032). The overall response rate was 46% (95% confidence interval [CI], 32% to 61%) on an intent-to-treat basis. The median duration of response was 7.4 months (95% CI, 6.1 to 19.6 months) and the median progression-free survival was 6.1 months (95% CI, 5.4 to 7.5 months). CONCLUSION: There was no added therapeutic benefit to the dose escalation of TLC D-99 in this study. A high rate of cardiotoxicity was also observed, especially among patients who had received prior adjuvant doxorubicin. This was probably attributable to the dose and schedule of TLC D-99 used in this trial, as well as the patient's lifetime cumulative doxorubicin dose. Administration of high-dose TLC D-99 at 135 mg/m2 every 3 weeks by i.v. bolus infusion does not warrant further investigation.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/efeitos adversos , Neoplasias da Mama/patologia , Doxorrubicina/efeitos adversos , Portadores de Fármacos , Feminino , Humanos , Infusões Intravenosas , Injeções Subcutâneas , Lipossomos , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Volume Sistólico/efeitos dos fármacos , Trombocitopenia/induzido quimicamente , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
Sixty-seven patients with newly diagnosed acute nonlymphocytic leukemia (ANLL) who were considered to be poor candidates for treatment with cytosine arabinoside (ara-C)/anthracycline antibiotic therapy were treated with high-dose ara-C (HDara-C) remission induction therapy. Thirty-four of the 67 patients had a hematologic disorder before developing acute leukemia or had a history of exposure to marrow toxins, 23 patients were greater than 70 years old, and 10 patients had medical problems that were felt to be a contraindication to therapy with an anthracycline antibiotic. Forty-two percent of patients entered complete remission (CR), whereas 22% failed to enter remission because of persistent leukemia. Treatment was associated with substantial toxicity varying from nausea and vomiting to irreversible cerebellar toxicity. Thirty-four percent of patients died during therapy. Poor performance status, a low serum albumin, and a low platelet count were associated with death during remission induction therapy, whereas a high pretherapy leukemic cell mass and a large number of residual leukemic cells in the marrow after six days of therapy were associated with treatment failure due to persistent leukemia.
Assuntos
Citarabina/administração & dosagem , Leucemia/tratamento farmacológico , Doença Aguda , Idoso , Contagem de Células Sanguíneas , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Citarabina/efeitos adversos , Citarabina/uso terapêutico , Hematopoese/efeitos dos fármacos , Humanos , Leucemia/mortalidade , Leucemia/patologia , Prognóstico , Estatística como Assunto , Fatores de TempoRESUMO
A pilot study was conducted to determine the possible efficacy and the toxicities associated with the administration of four courses of intensive consolidation chemotherapy to patients with acute nonlymphocytic leukemia in remission. All therapy was completed within 6 months. The median duration of remission was 22 months, with 45+% of patients in remission at 3 years and few relapses to date thereafter. Sixty percent of patients experienced significant side effects after each course of therapy. The therapy appeared to be particularly efficacious for patients less than 45 years of age, since 65% are alive at 3 years and there is no projection for a median duration of remission as yet. The cytogenetic characteristics of the leukemic cells, the percentage of S phase cells, and the height of the WBC count were the most important prognostic characteristics at diagnosis.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia/tratamento farmacológico , Doença Aguda , Idoso , Feminino , Humanos , Interfase , Leucemia/patologia , Masculino , Pessoa de Meia-Idade , Pancitopenia/induzido quimicamente , Projetos Piloto , Prognóstico , Fatores de TempoRESUMO
PURPOSE: To determine the efficacy and safety profile, including the risk for cardiac toxicity, of liposome-encapsulated doxorubicin (TLC D-99), fluorouracil (5-FU), and cyclophosphamide as first-line chemotherapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-one women were registered in this phase II study. All patients had measurable disease and no previous chemotherapy for MBC. Treatment consisted of TLC D-99 60 mg/m2 and cyclophosphamide 500 mg/m2 on day 1 and 5-FU 500 mg/m2 on days 1 and 8 every 3 weeks. Serial cardiac monitoring, including endomyocardial biopsies, was performed. RESULTS: The overall response rate was 73% (95% confidence interval, 57% to 86%). The median duration of response was 11.2 months, the median time to treatment failure was 8.1 months, and the median overall survival duration was 19.4 months. The median number of cycles per patient was 10. The median cumulative dose of TLC D-99 was 528 mg/m2. Ten patients required hospitalization for febrile neutropenia. Nausea/vomiting, stomatitis, and fatigue higher than grade 2 occurred in 12%, 15%, and 41% of patients, respectively. Twenty-one patients reached a cumulative doxorubicin dose greater than 500 mg/m2. Three patients (7%) were withdrawn from the study due to protocol-defined cardiac toxicity, two because of a decrease in left ventricular ejection fraction to < or = 40%, and one because her endomyocardial biopsy result was grade 1.5. One patient had congestive heart failure that was probably nonanthracycline related. CONCLUSION: This chemotherapy regimen, including TLC D-99, was highly active against MBC and associated with low cardiac toxicity despite high cumulative doses of doxorubicin.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Neoplasias da Mama/patologia , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Portadores de Fármacos , Feminino , Fluoruracila/administração & dosagem , Humanos , Lipossomos , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Volume Sistólico/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
TLC D-99 is a unique liposomal formulation of doxorubicin that consists of phosphatidyl choline/cholesterol. The objectives of the study were to evaluate safety and efficacy of two doses of TLC D-99 in the treatment of patients with AIDS-related Kaposi's Sarcoma (KS). Forty HIV-infected persons with biopsy-proven KS were randomized to receive TLC D-99 at doses of either 10 (low) or 20 (high) mg/m2 every 2 weeks. Patients assigned to the low-dose arm could be escalated to the high-dose arm if their KS progressed after 3 cycles of therapy. Median age was 35 years (range, 26-47) and median CD4 count was 13 (range, 0-440). Nineteen patients were assigned to receive the low dose, and 21 patients were assigned to the high dose. Partial response occurred in 15% (6 of 40) of the patients or in 5% (1 of 19) and 24% (5 of 21) in the low- and high-dose arms, respectively; stable disease was observed in 65% (26 of 40) or in 68% (13 of 19) and 62% (13 of 21) in the low and high doses, respectively. Neutropenia was the major toxicity and was observed in 68 and 81% of patients with the low- and high-dose arms, respectively; grade 4 neutropenia was observed in 16 and 14%, respectively. Mild alopecia was noted in only 8%. Therefore, TLC D-99 is active against AIDS-related KS, and the response is dose-dependent.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Sarcoma de Kaposi/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/imunologia , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Contagem de Linfócito CD4 , Colesterol , Intervalos de Confiança , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Portadores de Fármacos , Humanos , Lipossomos , Masculino , Pessoa de Meia-Idade , Fosfatidilcolinas , Sarcoma de Kaposi/etiologia , Neoplasias Cutâneas/etiologia , Fatores de TempoRESUMO
Clinical Stage III (N2) non-small cell carcinoma of the lung encompasses a large group of patients, frequently treated with radiation therapy alone, who are now considered to have borderline-resectable tumors. Pilot studies are proceeding which use combinations of resection, radiation therapy, and chemotherapy. To place trials of combination therapy in perspective with contemporary results of radiation therapy alone, recently completed trials of the RTOG were analyzed specifically for clinical Stages T1-3N2. A prospective randomized trial of hyperfractionated radiation therapy (HFX), conducted from 1983 through 1987, compared total doses of 60.0, 64.8, and 69.6 Gy using 1.2 Gy bid with greater than or equal to 4 hr interval. After acute and late effects were considered tolerable, 74.4 Gy and 79.2 Gy arms supplanted the two lowest dose arms. Survival was compared among the five total dose arms, and with 60 Gy in 30 fractions in 6 weeks (standard fractionation-STD) from earlier RTOG studies. Of 516 HFX patients analyzed, 296 (57.3%) with Performance Status (PS) 70-100 and less than 5% weight loss (favorable) had a significantly (p = .001) better survival than those with PS 50-69 or weight loss greater than 5%. Patients with RTOG Stage III (361, 70.0%) experienced better survival (p = .027) than RTOG Stage IV M0. The 69.6 Gy total dose arm was significantly (p = .031) better in favorable RTOG Stage III patients than all other total dose arms: the 1-year survival rate was 58% and the 3-year rate was 20%. The 69.6 Gy HFX results were significantly (p = .002) better than results with STD fractionation in comparable patients from earlier RTOG trials (1-year survival = 30%, 3-year survival = 7%). A prospective, randomized Phase III comparison of STD with 60 Gy versus HFX with 69.6 Gy is underway. These results provide benchmarks for studies of surgical resection combined with chemotherapy and/or radiation therapy until results of prospective comparisons with concurrent controls are available.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/radioterapia , Adenocarcinoma/epidemiologia , Adenocarcinoma/mortalidade , Adenocarcinoma/radioterapia , Idoso , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/radioterapia , Feminino , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Dosagem Radioterapêutica , Taxa de SobrevidaRESUMO
The ability of leukemic cells to phosphorylate cytosine arabinoside (araC) and retain the triphosphate form of the drug (araCTP) is strongly predictive of remission duration for patients with acute nonlymphocytic leukemia who are treated with araC-based maintenance therapy. An increase in the intensity of therapy improves the overall median duration of remission, the increased intensity of therapy being especially beneficial for patients whose leukemic cells do not retain araCTP. This alteration in therapy reduces the prognostic significance of leukemic cell araCTP retention. Further, it seems that the use of high-dose araC as intensive consolidation therapy and the administration of conventional-dose araC by continuous infusion make it possible to further reduce or even abrogate the adverse prognostic significance of low leukemic cell retention of araCTP.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/administração & dosagem , Leucemia/tratamento farmacológico , Doença Aguda , Arabinofuranosilcitosina Trifosfato/biossíntese , Medula Óssea/metabolismo , Citarabina/metabolismo , Citarabina/uso terapêutico , Doxorrubicina/administração & dosagem , Humanos , Leucemia/metabolismo , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Fosforilação , PrognósticoRESUMO
Plasma adriamycin and adriamycinol levels were measured in 45 patients with acute nonlymphocytic leukemia 3 h after the drug was administered. A wide range of levels as found. Plasma levels increased after the administration of each of the three daily doses of the drug. High plasma levels were associated with both death during remission induction therapy and, for patients who entered remission, long remissions.
Assuntos
Doxorrubicina/análogos & derivados , Doxorrubicina/sangue , Leucemia/sangue , Doença Aguda , Adolescente , Adulto , Idoso , Relação Dose-Resposta a Droga , Doxorrubicina/uso terapêutico , Humanos , Leucemia/tratamento farmacológico , Pessoa de Meia-IdadeRESUMO
In this study, 34 patients with advanced breast cancer were treated with brequinar sodium: 75% of the patients were postmenopausal, and 94% had received chemotherapy previously; 50% had previously received an anthracycline-containing regimen. Brequinar was administered intravenously at a median weekly dose of 1,200 mg/m2. The toxicity was moderate, with 17 patients (50%) experiencing grade 3 or 4 toxicity. There were 33 patients evaluable for response: 4 patients (12%; 95% confidence interval, 3.4-28.2%) achieved partial responses, 10 patients (30%) were stable, and 19 patients (58%) had progressive disease. We conclude that, at this dose and schedule, brequinar has only modest activity in patients with advanced breast cancer.
Assuntos
Antineoplásicos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Metástase NeoplásicaRESUMO
The ability of an in vitro clonogenic drug sensitivity assay to predict the outcome of therapy for acute nonlymphocytic leukaemia was evaluated using marrow cells obtained from previously untreated or first relapsed patients treated with either cytosine arabinoside/anthracycline antibiotic or high dose cytosine arabinoside remission induction therapy. While the per cent of leukaemic cells killed in vitro was correlated with the outcome of therapy, this drug sensitivity assay provided little or no clinically useful information.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaio de Unidades Formadoras de Colônias , Leucemia/tratamento farmacológico , Ensaio Tumoral de Célula-Tronco , Doença Aguda , Medula Óssea/patologia , Sobrevivência Celular/efeitos dos fármacos , Citarabina/farmacologia , Daunorrubicina/farmacologia , Doxorrubicina/farmacologia , Humanos , Leucemia/patologia , Tioguanina/farmacologiaRESUMO
OBJECTIVE: To ascertain the efficacy and tolerability of non-pegylated liposomal doxorubicin (Myocet) and epirubicin combined with cyclophosphamide in the first-line treatment of patients with metastatic breast cancer. METHODS: One hundred and sixty anthracycline-naïve metastatic breast cancer patients were randomised to receive Myocet (M; 75 mg/m(2)) or epirubicin (E; 75 mg/m(2)) in combination with cyclophosphamide (C; 600 mg/m(2)), every 3 weeks for up to eight cycles. OUTCOME MEASURES: Response (overall response = complete + partial response rates), time to disease progression, overall survival and cardiac function (left ventricular ejection fraction). RESULTS: Overall response rates were 46% and 39% for MC and EC treatment, respectively (P=0.42). MC was superior to EC with respect to median time to treatment failure (5.7 versus 4.4 months; P=0.01) and median time to disease progression (7.7 versus 5.6 months; P=0.02). Median survival times were 18.3 and 16.0 months for MC and EC, respectively (P=0.504). Unsurprisingly, given an equimolar comparison, neutropenia and stomatitis/mucositis were significantly more common in patients who received MC. However, there was less injection site toxicity with MC. Both treatments showed a low incidence of cardiotoxicity. CONCLUSION: Myocet appears to be an acceptable alternative to epirubicin as a first-line treatment for patients with metastatic breast cancer because it combines the dose-effect reliability of doxorubicin with the level of safety provided by epirubicin.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Ciclofosfamida/administração & dosagem , Progressão da Doença , Doxorrubicina/administração & dosagem , Epirubicina/administração & dosagem , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Lipossomos , Pessoa de Meia-Idade , Metástase Neoplásica , Análise de Sobrevida , Resultado do Tratamento , Disfunção Ventricular Esquerda/induzido quimicamenteRESUMO
Levels of plasma daunorubicin, daunorubicinol and aglycone metabolites were measured in 47 patients 3 h after daunorubicin was administered daily for three days as part of a cytosine arabinoside/daunorubicin remission induction regimen. High-pressure liquid chromatography with fluorescence detection was used for separation and quantitation of the drug and its metabolites. A wide range of plasma levels were observed regardless of the outcome of therapy. Patients who had high levels of the drug, or daunorubicinol on day 1 of therapy tended to have high levels on days 2 and 3 of the regimen. Three hours after the third daily dose of daunorubicin was administered, patients who would not enter remission had significantly higher levels of aglycone metabolites in plasma than did patients who entered remission. These data indicate that resistance to chemotherapeutic effects of daunorubicin may be connected with metabolism of the drug, especially with enhanced metabolism to aglycones.
Assuntos
Daunorrubicina/sangue , Leucemia/tratamento farmacológico , Doença Aguda , Biotransformação , Daunorrubicina/administração & dosagem , Daunorrubicina/análogos & derivados , Daunorrubicina/uso terapêutico , Humanos , Injeções Intravenosas , Cinética , Leucemia/metabolismo , Naftacenos/sangueRESUMO
Since 1973, the Radiation Therapy Oncology Group (RTOG) has staged and stratified patients in non-small cell lung cancer (NSCLC) protocols according to the RTOG staging system. In 1985, the American Joint Committee on Cancer (AJCC) revised its lung cancer staging system, with the principle differences from the RTOG system being the staging of involvement of the chest wall and of contralateral mediastinal and hilar lymph nodes. To determine if the AJCC system discriminated outcome differently than the RTOG system in a nonoperative series, all 850 evaluable patients treated with hyperfractionated radiation therapy (RT) on the RTOG protocol 83-11 were restaged by the AJCC system. There was 67% agreement in patient distribution between the following comparable stages in each system: RTOG Stage II/AJCC Stage II; RTOG Stage III/AJCC Stage IIIA; and RTOG Stage IV/AJCC Stage IIIB. Both systems successfully predicted for survival (P less than 0.001), although the RTOG staging was more discriminating (relative risk ratios, 1.59 versus 1.38). Among the 507 favorable patients (those with less than or equal to 5% weight loss and Karnofsky performance status [KPS] of 70 to 100), the RTOG staging was also more predictive (P = 0.004 versus P = 0.01). When RTOG Stage III (462 patients) was divided into those without contralateral mediastinal or hilar adenopathy (AJCC Stage II/IIIA) and those with (AJCC Stage IIIB), a significant survival (P = 0.0001) was noted with 2-year survival rates of 26% versus 4%, respectively. When AJCC Stage IIIA (348 patients) was divided into the patients without chest wall invasion (RTOG Stage II/III) and those with (RTOG Stage IV), a difference in 2-year survival of 22% versus 10% was observed (P = 0.002). Although both staging systems independently predict for survival, a fusion of both staging systems is the most discriminating of outcome. Future nonoperative studies in locally advanced NSCLC should stratify for contralateral nodal involvement (per AJCC staging) and chest wall invasion (per RTOG staging).
Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/radioterapia , Estadiamento de Neoplasias/métodos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Invasividade Neoplásica , Dosagem Radioterapêutica , Fatores de Risco , Análise de Sobrevida , Tórax/patologiaRESUMO
The bone marrows of patients with acute non-lymphocytic leukemia being treated with 'high dose' cytosine arabinoside remission induction therapy were sampled prior to the initiation of chemotherapy, after 6 days of therapy and again 7 days after the conclusion of therapy. These studies demonstrated that the marrows of patients who would enter remission (CR patients) contained less leukemic cells prior to therapy than patients who would fail to enter remission because of persistent leukemia (resistant disease, or RD patients). A comparison of the day 6 and 7-day post-therapy marrows with the pretherapy marrow demonstrated that while the % reduction in leukemic cells was greater for CR patients than for RD patients, the absolute reduction in leukemic cell mass was the same for both groups. While there was no relationship between the percentage of cells in S phase and the pretherapy leukemic cell mass, the greater the pretherapy leukemic cell mass the greater the likelihood that the leukemic cells would be resistant to the metabolic effects of cytosine arabinoside in vitro.
Assuntos
Medula Óssea/patologia , Citarabina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Idoso , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Citarabina/farmacologia , DNA de Neoplasias/biossíntese , Humanos , Interfase , Leucemia Mieloide Aguda/patologia , Pessoa de Meia-Idade , Prognóstico , Fatores de TempoRESUMO
Patients with acute myeloid leukaemia who fail to show substantial bone marrow cytoreduction by day 6 of induction therapy enter complete remission (CR) less frequently than patients with good bone marrow leukaemic cytoreduction. The objective of the current study was to determine whether an increase in the intensity of therapy on days 8, 9 and 10 ('augmentation' of remission induction therapy) for patients with poor bone marrow cytoreduction detected in the day 6 bone marrow could improve the complete remission rate without increasing the number of toxic deaths. Patients from six centres were entered and treated with standard dose ara-C for 7 or 10 d and an anthracycline for the first 3 d. Patients aged less than 60 years and with greater than 30% bone marrow biopsy cellularity or greater than 10% abnormal cells on the aspirate obtained 6 d after the start of therapy were augmented with cytosine arabinoside 3 g/m2 every 12 h on days 8, 9 and 10. Therapy was augmented in 116 of the 252 patients less than 60 years. There was a highly statistically significant difference between augmented and nonaugmented patients (P less than 0.001) for the per cent biopsy cellularity and per cent abnormal cells in the day 6 marrow. The CR rate for augmented patients was 69% and for nonaugmented patients 60% suggesting that augmentation therapy abrogated the prognostic significance of more extensive residual leukaemia in the day 6 bone marrow. The results suggest that augmentation of remission induction for patients with poor bone marrow cytoreduction detected 6 d after initiation of therapy, may salvage patients who are destined to fail remission induction because of resistant disease without producing excessive toxicity.