RESUMO
BACKGROUND: To address the feasibility and outcome of moderate dose intensification with granulocyte-colony stimulating factor (G-CSF) for patients with aggressive non-Hodgkin lymphoma (NHL), the Cancer and Leukemia Group B (CALGB) conducted two studies evaluating dose-escalated cyclophosphamide and etoposide in the cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide (CHOPE) regimen. METHODS: Eligibility criteria included histologically documented, diffuse small cleaved, diffuse mixed, diffuse large cell, or immunoblastic lymphoma, Stage III--IV or bulky Stage II disease, and an ECOG performance status of 0--1. CALGB 8852, a group-wide study, accrued 227 patients: 120 patients in the pilot study to determine the maximum tolerated dose (MTD) without G-CSF and 107 in the pilot study of dose-escalated CHOPE with G-CSF. CALGB 8854, a limited-institution, Phase I study, enrolled 38 patients and determined the MTD of CHOPE with G-CSF to be used in CALGB 8852. The MTD in both studies was defined as the dose at which 50% of patients had 1) Grade 4 neutropenia or thrombocytopenia lasting 7 days or more, or 2) Grade 3--4 hemorrhage or nonhematologic toxicity (excluding alopecia, nausea, and emesis), or 3) were prevented from receiving 100% of drug on Day 22. RESULTS: The MTD of CHOPE without G-CSF was cyclophosphamide 1000 mg/m(2) on Day 1 and etoposide 100 mg/m(2) on Days 1--3 with doxorubicin 50 mg/m(2) on Day 1, vincristine 1.4 mg/m(2) (maximum, 2 mg) on Day 1, and prednisone 100 mg on Days 1--5. With the addition of G-CSF at 200 microg/m(2) on Days 5--19, the MTD was cyclophosphamide 1500 mg/m(2) and etoposide 160 mg/m(2) on Days 1-3 with standard doses of doxorubicin, vincristine, and prednisone. Increasing the dose of G-CSF from 200 microg/m(2) to 400 microg/m(2) did not allow for further dose escalation. The primary toxicity in all cohorts was neutropenia. Four toxic deaths occurred on CALGB 8852. The 5-year failure free survival (FFS) and overall survival (OS) rates for eligible patients on CALGB 8852 were 31% (95% confidence interval [95%CI], 23--39) and 48% (95%CI, 40--57), respectively. The 5-year FFS and OS rates for eligible patients on CALGB 8854 were 34% (95%CI, 17--52) and 51% (95%CI, 33--70), respectively. CONCLUSIONS: Moderate dose escalation with G-CSF is feasible. However, response and survival rates of patients who receive dose-escalated CHOPE, even with the addition of G-CSF, appear similar to the rates reported with standard-dose CHOP.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Imunoblástico de Células Grandes/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Linfoma Difuso de Grandes Células B/patologia , Linfoma Imunoblástico de Células Grandes/patologia , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/prevenção & controle , Prednisona/administração & dosagem , Resultado do Tratamento , Vincristina/administração & dosagemRESUMO
Successful treatment of advanced-stage Hodgkin's disease (HD) may critically depend on dose intensity. Because mechlorethamine, Oncovin, procarbazine, and prednisone (MOPP), and Adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) are not suitable for major dose escalation, we evaluated the activity and toxicity of combined cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOPE) in advanced HD, here used at conventional dose intensity, as a preparatory study prior to using this regimen at higher dose intensity. Ninety-two patients were treated with CHOPE (cyclophosphamide, 750 mg/m2, day 1; doxorubicin, 50 mg/m2, day 1; vincristine, 1.4 mg/m2, days 1 and 8; prednisone, 100 mg/day, days 1-5; and etoposide, 80 mg/m2, days 1, 2, and 3) every 21 days. All had advanced HD with no prior chemotherapy with 46% stage IV, 63% with B symptoms, and 57% with bulky disease (> 5 cm). Radiation and growth factor support were not permitted. Full-dose vincristine (not capped at maximum 2 mg/dose) was used in the first 33 patients. An initial cohort of 41 patients was treated with four cycles of CHOPE to evaluate safety and efficacy followed by four cycles of ABVD. A second cohort of 51 patients was treated with 6-8 cycles of CHOPE alone. Toxicity was generally acceptable and primarily hematologic, with neutrophils < 500 in 63% of cohort I and 90% of cohort II, and platelets < 25,000 in 7% of cohort I and 8% of cohort II. The long-term neurotoxicity of full-dose, high-intensity vincristine was acceptable and largely reversible. In cohort I, 92% of patients achieved a complete response (CR) or partial response (PR) with four cycles of CHOPE and 85% were in CR after four additional cycles of ABVD. In cohort II, 77% achieved a CR with 6-8 cycles of CHOPE alone. FFS was 76% in cohort I and 59% in cohort II, with a median follow-up of 8.2 and 5.7 years, respectively. CHOPE, at conventional dose intensity as used here, is an effective first-line regimen for the treatment of advanced-stage HD and may warrant evaluation using higher doses of cyclophosphamide and etoposide with granulocyte colony stimulating factor (G-CSF) support.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Esquema de Medicação , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prednisona/administração & dosagem , Resultado do Tratamento , Vincristina/administração & dosagemRESUMO
BACKGROUND: The purine nucleoside phosphorylase inhibitor peldesine is a new agent being evaluated as a T-cell inhibitor. OBJECTIVE: We attempted to determine the efficacy of peldesine (BCX-34) in a 1% dermal cream formulation as a treatment for cutaneous T-cell lymphoma (CTCL). METHODS: Ninety patients with patch and plaque phase CTCL, histologically confirmed by a referee dermatopathologist, were enrolled in a randomized, double-blind, placebo-controlled study. BCX-34 dermal cream 1% or the vehicle cream (as a placebo control) was applied twice daily to the entire skin surface for up to 24 weeks. Efficacy of the topical therapy was assessed in terms of complete or partial (> or = 50%) clearing of patches and plaques. RESULTS: Of the 89 patients able to be examined, 43 received BCX-34 and 46 received the placebo vehicle cream. One patient withdrew early and was not analyzed. The two groups were well balanced for potential prognostic factors. A total of 28% (12/43) of the patients treated with BCX-34 showed a response, but 24% (11/46) of patients who received vehicle also responded (P =.677). CONCLUSION: Although BCX-34 dermal cream 1% was not significantly better than the control as therapy for patch and plaque-phase CTCL, this appears to be the first published placebo-controlled trial evaluating treatment for CTCL. Whether the vehicle cream has more than a placebo therapeutic effect is unclear. The relatively high (24%) placebo response rate should be kept in mind in assessing other treatments for early-stage CTCL.
Assuntos
Inibidores Enzimáticos/farmacologia , Guanina/análogos & derivados , Guanina/farmacologia , Linfoma Cutâneo de Células T/tratamento farmacológico , Administração Cutânea , Adulto , Idoso , Método Duplo-Cego , Inibidores Enzimáticos/administração & dosagem , Feminino , Guanina/administração & dosagem , Humanos , Linfoma Cutâneo de Células T/patologia , Masculino , Pessoa de Meia-Idade , Placebos , Resultado do TratamentoRESUMO
Purine nucleoside phosphorylase (PNP) is one of the enzymes comprising the purine salvage pathway , and is responsible for the catalysis of the reversible phosphorolytic cleavage of purine ribonucleosides and 2'-deoxyribonucleosides. The pivotal role of PNP in T-cell proliferation has been demonstrated in patients with inherited PNP deficiency, where T-cell levels may be 1-3% of normal. This observation helped establish the critical role of PNP in T-cells and provided a rationale for developing inhibitors of PNP. Inhibitors of PNP may be useful for treating a variety of T-cell related autoimmune diseases including psoriasis, rheumatoid arthritis and Crohn s disease and T-cell cancers. In this manuscript, the x-ray crystal structure of the PNP enzyme is described. Results of a structure-based drug design program aimed at designing small-molecule inhibitors of PNP are also described. Of the many classes of compounds synthesized, studied and reviewed, only one, the 3-pyridinylmethyl-9-deazaguanine (BCX-34, 39) analog has been used in clinical trials. Both topical and oral formulations of BCX-34 were studied in psoriatic patients and the results of these clinical trials are described.
Assuntos
Inibidores Enzimáticos/uso terapêutico , Guanina/análogos & derivados , Psoríase/tratamento farmacológico , Purina-Núcleosídeo Fosforilase/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Guanina/farmacologia , Guanina/uso terapêutico , Humanos , Modelos Moleculares , Psoríase/enzimologia , Purina-Núcleosídeo Fosforilase/fisiologia , Relação Estrutura-AtividadeAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Tumor Trofoblástico de Localização Placentária/tratamento farmacológico , Neoplasias Uterinas/tratamento farmacológico , Cisplatino/administração & dosagem , Ciclofosfamida/administração & dosagem , Dactinomicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Metotrexato/administração & dosagem , Gravidez , Vincristina/administração & dosagemRESUMO
The pharmacokinetic parameters of peldesine (BCX-34) were investigated after single and multiple oral doses in two groups of healthy adult volunteers. The pharmacodynamic elevation of endogenous inosine and 2'-deoxyguanosine was simultaneously monitored. The first group of 8 subjects received an intravenous dose (18 mg/m2) and five oral doses (30, 63, 108, 144, and 192 mg/m2) of drug. A second group of 12 subjects received 160 mg/m2 in four and in six divided doses orally. Serial blood samples and total urine outputs were collected during dosing and for at least 24 hours after the last dose was administered. One set of samples was analyzed using high-pressure liquid chromatography/ultraviolet (LC/UV) methods, validated for intact drug in human plasma and urine samples. Another set of samples was analyzed for the biomarkers, inosine and 2'-deoxyguanosine, using high-pressure LC with either mass spectrometry (MS) or electrochemical detection (EC) methods. The pharmacokinetic parameters of inosine and 2'-deoxyguanosine were calculated using noncompartmental methods and correlated against the pharmacokinetic parameters of BCX-34. For the single-dose study, the results exhibited linear pharmacokinetics over the dose range from 30 to 144 mg/m2. The calculated terminal half-life was 3.5 +/- 1.0 h, and the absolute bioavailability of the oral formulation was approximately 51%. Analysis of urine in the first 24 hours of collection accounted for approximately 82% of the absorbed intact drug. Evaluation of the multiple-dose pharmacokinetics indicated that steady-state blood concentrations were achieved by 24 hours when the drug was administered four or six times a day. A drug dose-related elevation of plasma 2'-deoxyguanosine was observed. This phenomenon was not seen with plasma inosine levels. However, analysis of urine samples showed an increase in inosine output with an increase in the drug dose. The calculated terminal half-life of inosine and 2'-deoxyguanosine was 15.3 +/- 1.8 h and 1.3 +/- 0.1 h, respectively.
Assuntos
Inibidores Enzimáticos/farmacocinética , Guanina/análogos & derivados , Purina-Núcleosídeo Fosforilase/antagonistas & inibidores , Administração Oral , Adulto , Área Sob a Curva , Cápsulas , Desoxiguanosina/sangue , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Guanina/sangue , Guanina/farmacocinética , Guanina/urina , Humanos , Inosina/sangue , Inosina/urina , Masculino , Pessoa de Meia-Idade , Soluções , Fatores de TempoRESUMO
OBJECTIVE: Although doxorubicin is not currently popular as a primary agent in ovarian cancer, overviews of previous studies suggest that the inclusion of doxorubicin may have improved outcome. The purpose of this phase I study was to determine the maximal dose of doxorubicin that could be added to standard doses of paclitaxel and cisplatin with G-CSF support. METHODS: Women with FIGO stage III or IV epithelial ovarian cancer were primarily treated with escalating doses of doxorubicin in combination with paclitaxel (135 mg/m2 over 24 h) and cisplatin (75 mg/m2) every 3 weeks. Doxorubicin was started at 30 mg/m2 and escalated by 10 mg/m2 per treatment level. All patients received G-CSF support. RESULTS: Eleven patients were treated at two dose levels. Dose limiting toxicity (DLT) was reached at the 40 mg/m2 dose of doxorubicin. All patients experienced grade 4 neutropenia although none required hospitalization. DLT included renal toxicity and prolonged thrombocytopenia. Despite vigorous antiemetic regimens 60% of patients experienced severe nausea and vomiting. Nine patients were assessable for response. Eight patients have had a complete clinical response (89%). Of the five patients undergoing second-look laparotomy two were negative. CONCLUSIONS: The maximum tolerated dose of doxorubicin in this three-drug regimen is 30 mg/m2 with standard doses of paclitaxel and cisplatin. Hematologic toxicity is manageable using G-CSF. Doxorubicin appears to increase the renal toxicity of cisplatin which may be exaggerated by marked nausea and vomiting. This is an active but toxic regimen and alternative sequences and strategies should be evaluated.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversosRESUMO
PURPOSE: Cisplatin, mitolactol (dibromodulcitol), and ifosfamide have been the most active single agents in squamous carcinoma of the cervix identified so far by the Gynecologic Oncology Group (GOG). Combinations of cisplatin plus ifosfamide and cisplatin plus mitolactol are prospectively compared with cisplatin alone. PATIENTS AND METHODS: Patients were randomized to receive cisplatin 50 mg/m2 or the same dose of cisplatin plus mitolactol (C + M) 180 mg/m2 orally on days 2 to 6, or cisplatin plus ifosfamide (CIFX) 5 g/m2 given as a 24-hour infusion plus mesna 6 g/m2 during and for 12 hours after the ifosfamide infusion, every 3 weeks for up to six courses. Of 454 patients entered, 438 were eligible and analyzed for response and survival. RESULTS: CIFX had a higher response rate (31.1% v 17.8%, p = .004) and longer progression-free survival (PFS) time (P = .003) compared with cisplatin alone. The median times to progression or death were 4.6 and 3.2 months, respectively. C + M showed no significant improvement in these parameters compared with cisplatin alone. Survival was associated with initial performance score (PS; 0 was more favorable; P < .001) and with age (younger was unfavorable, P = .025). There was no significant difference in overall survival between cisplatin and either of the combinations. Leukopenia, renal toxicity, peripheral neurotoxicity, and CNS toxicity were more frequent with CIFX (P < .05). CONCLUSION: CIFX improved the response rate and PFS duration in advanced cervix cancer compared with cisplatin alone, but at the cost of greater toxicity and with no improvement in survival.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológico , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Escamosas/patologia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Feminino , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/efeitos adversos , Pessoa de Meia-Idade , Mitolactol/administração & dosagem , Mitolactol/efeitos adversos , Estudos Prospectivos , Indução de Remissão , Análise de Sobrevida , Neoplasias do Colo do Útero/patologiaRESUMO
Numerous drugs and drug combinations have been evaluated, largely in phase II trials, for the treatment of carcinoma of the uterine cervix. There clearly is a need for effective chemotherapy for this disease, but the results to date have unfortunately not met that need. Cisplatin is active but overrated. Drug combinations have not shown a consistent advantage and require careful study, with the initial focus on maximizing the complete response rate in women with no or minimal prior chemotherapy and with adequate sample size to have confidence about the results. The patient populations under treatment need to be carefully defined with respect to potential prognostic factors for response and survival, so that results will be more reproducible. The few large, randomized trials completed so far have failed to show a survival benefit with combination chemotherapy; in fact, there does not appear to have been a comparison of chemotherapy with best supportive care. Systemic therapy of cervical cancer remains experimental.
Assuntos
Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos Fase I como Assunto , Feminino , Humanos , Estadiamento de Neoplasias , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
PURPOSE: Intravenous dolasetron has been shown to be an effective antiemetic agent in patients receiving high-dose cisplatin-containing chemotherapy. Previous studies have suggested that 1.8 mg/kg is an optimal dose for achieving control of emesis and nausea. The objective of this study was to compare the efficacy and safety of a single intravenous (IV) dose of dolasetron with an equal divided multiple dose. METHODS: In this randomized, double-blind, parallel-group, multicenter study, the efficacy and safety of a single 1.8-mg/kg dose of dolasetron given 30 min prior to high-dose cisplatin ( > or = 80 mg/m2) chemotherapy was compared with the same total amount of dolasetron administered in three separate doses (0.6 mg/kg each) over a 12-h interval commencing 30 min prior to beginning chemotherapy and ending 11.5 h later. Antiemetic efficacy, safety, and tolerability were compared in 55 patients with various malignancies during the 24 h following the initiation of chemotherapy. The number of emetic episodes was the primary efficacy parameter. RESULTS: A single IV dose of dolasetron was generally more effective than a multiple-dose regimen in all measures of efficacy. There was a larger proportion of complete responders in the single-dose group compared with the multiple-dose group (48% vs 23%), although this difference did not reach statistical significance. Compared with the multiple-dose group, patients who received a single dose of dolasetron had a significantly (P = 0.034) longer median time to the first emetic episode (10.1 h vs > 24 h, respectively). Overall, 53% of patients had either a complete response or a major response to dolasetron, and only 40% of the total patient population received escape antiemetic medication in the 24 h after cisplatin administration. Except for headache, adverse events were similar with both regimens and were generally of mild or moderate intensity; no serious adverse events occurred. Neither dolasetron treatment regimen was associated with any clinically important events, trends in laboratory variables, or differences in safety profile. CONCLUSIONS: single-dose dolasetron was well tolerated and effectively controlled emesis and nausea in patients who received highly emetogenic, high-dose cisplatin chemotherapy. The greater antiemetic efficacy of a single prophylactic dose of dolasetron offers both convenience and potential cost savings, compared with a multiple-dose schedule of administration.
Assuntos
Antieméticos/administração & dosagem , Antineoplásicos/efeitos adversos , Cisplatino/efeitos adversos , Indóis/administração & dosagem , Quinolizinas/administração & dosagem , Antagonistas da Serotonina/administração & dosagem , Vômito/tratamento farmacológico , Idoso , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Náusea/tratamento farmacológico , Modelos de Riscos Proporcionais , Estados Unidos , Vômito/induzido quimicamenteRESUMO
PURPOSE: From December 1983 through February 1992, a prospective study designed to determine the clinical course of patients with ovarian tumors of low malignant potential (LMP) was conducted by the Gynecologic Oncology Group (GOG). MATERIALS AND METHODS: This protocol was developed to evaluate the following (1) the biologic behavior of ovarian LMP tumors, (2) the effectiveness of melphalan chemotherapy in patients with clinically detectable residual disease after surgical staging and in patients whose tumors progress or recur after surgical therapy, and (3) the response rate to cisplatin in those who failed to respond to melphalan therapy. The study group consisted of 146 assessable patients with stage I serous LMP tumors. All of these women had the affected ovary (or ovaries) removed, and a complete staging operation was performed in each case. While 123 patients had a total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO), 21 retained the uterus and one normal-appearing ovary and fallopian tube. No adjuvant chemotherapy or radiation therapy was administered to any patients in the stage I study group. RESULTS: The median follow-up time was 42.4 months (range, 1.6 to 108). Thus far, no patient with a stage I ovarian serous LMP tumor has developed recurrent disease. CONCLUSION: Stage I ovarian serous LMP tumors rarely, if ever, recur. Limited resection, after meticulous surgical exploration, is adequate therapy for women of reproductive age.
Assuntos
Cistadenocarcinoma Seroso/patologia , Neoplasias Ovarianas/patologia , Adulto , Idoso , Cisplatino/uso terapêutico , Terapia Combinada , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/cirurgia , Feminino , Seguimentos , Humanos , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Estudos Prospectivos , Estados UnidosRESUMO
A phase III clinical trial was designed to determine if more intensive induction and consolidation therapy for acute myeloblastic leukemia increases the remission rate and prolongs survival. A minor objective was to determine if the use of non-cross resistant drugs was more effective than the same drugs used for induction. Patients with untreated leukemia between the ages of 15 and 50 were given daunorubicin 45 mg/m2 for the first 3 days of a 10-day continuous infusion of cytosine arabinoside, initially at a dose of 2000 mg/m2 but reduced to 100 mg/m2 because of toxicity. Those under 36 achieving a complete remission and with an histocompatible donor were assigned to a transplant arm. The rest were randomized to receive one of three consolidation arms: A, cytosine arabinoside, 200 mg/m2 daily for 7 days and daunorubicin 45 mg/m2 daily for 3 days for three courses; B, one course as in Arm A followed by amsacrine, 120 mg/m2 daily for 5 days followed by a 5-day continuous infusion of azacytidine, 150 mg/m2/day; C, thioguanine and cytosine arabinoside, 100 mg/m2 every 12 h and daunorubicin 10 mg/m2 daily for 5 days for three courses followed by four maintenance courses of cytosine arabinoside, 100 mg/m2 daily for 5 days and daunorubicin, 45 mg/m2 for 2 days every 13 weeks. From 1981 to 1986, 398 eligible patients were enrolled and 219 achieved a complete remission. The initial induction dose of cytosine arabinoside was reduced after five of 29 patients exhibited fatal gastrointestinal toxicity. Only 11 patients were assigned to the transplant arm. There were no significant differences in the consolidation arms. The 5 year disease-free survivals were 38, 31 and 27% in arms A, B, and C respectively. Intensive consolidation therapy with the same or different drugs used in induction was as effective as lower dose consolidation followed by maintenance therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Adolescente , Adulto , Amsacrina/administração & dosagem , Azacitidina/administração & dosagem , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Daunorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Indução de Remissão , Tioguanina/administração & dosagemRESUMO
The pharmacokinetics of cytarabine (ara-C) were determined in 265 patients with acute myeloid leukemia (AML) receiving ara-C (200 mg/m2 per day for 7 days as a continuous infusion) and daunorubicin during induction therapy. The mean (standard deviation) ara-C concentration at steady-state (Css) and systemic clearance (Cl) were 0.30 (0.13) microM and 134 (71) l/h per m2 respectively. Males had a significantly faster ara-C Cl (139 vs 131 l/h per m2, P = 0.025) than females. Significant correlations were noted between ara-C Cl and the pretreatment, peripheral white blood cell count (P = 0.005) and pretreatment blast count (P = 0.020). No significant differences in ara-C Css or Cl were noted in patients achieving complete remission compared with those failing therapy (P = 0.315, P = 0.344, respectively). No significant correlations were observed between ara-C pharmacokinetic parameters and several indices of patient toxicity. Our findings indicate that variability in ara-C disposition in plasma at this dosage level does not correlate with remission status or toxicity in patients with AML receiving initial induction therapy with ara-C and daunorubicin.
Assuntos
Citarabina/farmacocinética , Leucemia Mieloide/sangue , Doença Aguda , Adolescente , Adulto , Idoso , Citarabina/uso terapêutico , Feminino , Humanos , Leucemia Mieloide/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
A phase III clinical trial was developed to test whether the addition of etoposide to a high-dose cytosine arabinoside regimen would improve the remission rate, duration of remission, and survival in relapsed and refractory patients with acute myelogenous leukemia. One hundred and thirty-one patients stratified by age, performance status, percentage of marrow blasts, platelet count, bilirubin and presence or absence of clinical infection, refractory or relapsed (+/- 9 months) were randomized to receive high-dose cytosine arabinoside, 3 g/m2 every 12 h for 6 days with or without three doses of etoposide, 100 mg/m2 days 7-9. Of 67 patients randomized to cytosine arabinoside alone, 31% obtained a complete remission with a median remission duration of 11.9 months. Of 66 patients randomized to the combination regimen, 38% obtained a complete remission with a median duration of 25 months. None of these differences were statistically significant. Significantly (p = 0.036) longer survival was seen in patients on the combination regimen under the age of 50. There was no difference in overall survival. Six and 8%, respectively, of patients were free of disease at 5 years. The addition of etoposide to a high-dose cytosine arabinoside regimen had at best a marginal effect at the expense of some increase in toxicity.
Assuntos
Citarabina/administração & dosagem , Etoposídeo/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/efeitos adversos , Etoposídeo/efeitos adversos , Humanos , Análise de SobrevidaRESUMO
BACKGROUND: About 65 percent of previously untreated adults with primary acute myeloid leukemia (AML) enter complete remission when treated with cytarabine and an anthracycline. However, such responses are rarely durable when conventional postremission therapy is administered. Uncontrolled trials have suggested that intensive postremission therapy may prolong these complete remissions. METHODS: We treated 1088 adults with newly diagnosed AML with three days of daunorubicin and seven days of cytarabine and randomly assigned patients who had a complete remission to receive four courses of cytarabine at one of three doses: 100 mg per square meter of body-surface area per day for five days by continuous infusion, 400 mg per square meter per day for five days by continuous infusion, or 3 g per square meter in a 3-hour infusion every 12 hours (twice daily) on days 1, 3, and 5. All patients then received four courses of monthly maintenance treatment. RESULTS: Of the 693 patients who had a complete remission, 596 were randomly assigned to receive postremission cytarabine. After a median follow-up of 52 months, the disease-free survival rates in the three treatment groups were significantly different (P = 0.003). Relative to the 100-mg group, the hazard ratios were 0.67 for the 3-g group (95 percent confidence interval, 0.53 to 0.86) and 0.75 for the 400-mg group (95 percent confidence interval, 0.60 to 0.94). The probability of remaining in continuous complete remission after four years for patients 60 years of age or younger was 24 percent in the 100-mg group, 29 percent in the 400-mg group, and 44 percent in the 3-g group (P = 0.002). In contrast, for patients older than 60, the probability of remaining disease-free after four years was 16 percent or less in each of the three postremission cytarabine groups. CONCLUSIONS: These data support the concept of a dose-response effect for cytarabine in patients with AML who are 60 years of age or younger. The results with the high-dose schedule in this age group are comparable to those reported in similar patients who have undergone allogeneic bone marrow transplantation during a first remission.
Assuntos
Citarabina/uso terapêutico , Leucemia Mieloide/tratamento farmacológico , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Daunorrubicina/uso terapêutico , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Humanos , Infusões Intravenosas , Leucemia Mieloide/mortalidade , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Taxa de SobrevidaRESUMO
One hundred and ninety-two evaluable patients were treated on a multicenter protocol for adult acute lymphoid leukemia to determine in a prospective randomized fashion if late intensification chemotherapy beginning after about six months of treatment would improve remission duration and survival. The complete remission rate was 60%. The median remission duration from beginning of maintenance was 18.7 versus 25.9 months (P = 0.36) for standard maintenance therapy and late intensification, respectively, and the median survival from randomization was 25.8 versus 28.5 months (P = 0.94) respectively. There was a suggestion that the late intensification strategy was helpful with respect to remission duration, and this trend was sustained in long-term follow-up. However, relapse proved to be common during the earlier phases of treatment; thus, insufficient numbers of patients were available at the randomization point to conclusively address the possible value of late intensification. Intensive therapy earlier in the course of treatment should be evaluated, including transplantation in selected patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Terapia Combinada , Irradiação Craniana , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Esquema de Medicação , Feminino , Seguimentos , Humanos , Tábuas de Vida , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/radioterapia , Prednisona/administração & dosagem , Prognóstico , Estudos Prospectivos , Indução de Remissão , Terapia de Salvação , Análise de Sobrevida , Resultado do Tratamento , Estados Unidos/epidemiologia , Vincristina/administração & dosagemRESUMO
This review provides a perspective on primary chemotherapeutic approaches in epithelial ovarian cancer. Chemotherapy is not recommended in grade 1 or 2 stage I-a or b. In other early-stage cases, postoperative melphalan or intraperitoneal radioactive phosphorus remain standard of care, even though these treatments have not been shown in a randomized fashion to be superior to no further treatment. The role of platinum-based chemotherapy in the same subgroup is currently under study. Despite the introduction of cisplatin, leading to significantly improved response rates, responses have usually been brief in stage III and IV cases with only a modest impact on overall survival and little improvement in long-term survival. Systemic intensification with cisplatin has been difficult secondary to more toxicity and with no consistent improvement in survival. Intraperitoneal chemotherapy is being evaluated as a component of initial management. Recently a new drug, Taxol, has been introduced; although it has not been a cure-all, Taxol will presumably become part of the primary chemotherapy of ovarian cancer in the 1990s. Issues of optimal dosing and combinations with Taxol are being addressed. The combination of Taxol and cisplatin appears promising.