RESUMO
PURPOSE: In adult women, most malignant ovarian tumors are epithelial in origin. The use of intra-operative frozen section to distinguish between benign and malignant histology is reliable in guiding operative decision-making to determine the extent of surgical staging required. Pediatric and adolescent patients with ovarian masses have a much different spectrum of pathology with most tumors arising from germ cell precursors. This review was undertaken to assess the concordance between the intra-operative frozen section and the final diagnosis as an aid to guide extent of surgical staging in a group of pediatric and adolescent patients with malignant ovarian germ cell tumors. METHODS: Records of patients aged 0 to 20 years with malignant ovarian germ cell tumors enrolled on Children's Oncology Group study AGCT0132 were reviewed. Pathology reports from patients who had both intra-operative frozen section diagnosis and final paraffin section diagnosis were compared using descriptive statistics. By inclusion criteria for the study, all patients had a final diagnosis of malignancy with required yolk sac tumor, choriocarcinoma or embryonal carcinoma histology. Available central review of pathology final paraffin section slides were compared with final institution pathology reports. RESULTS: Of 131 eligible patients with ovarian germ cell tumors, 60 (45.8%) had both intra-operative frozen section and final paraffin section diagnoses available. Intra-operative frozen section diagnoses were classified as: incorrect diagnosis of benign tumor (13.3%), confirmation of malignancy (61.7%), immature teratoma (16.7%), germ cell tumor not otherwise specified (5%) and no diagnosis provided (3.3%). Intra-operative frozen section was incorrect in 23 of 60 (38.3%) patients evaluated. Central pathology review was concordant with the final institution pathology diagnosis in 76.3% of patients. Central pathology review identified additional germ cell tumor components in 23.7% of patients. CONCLUSIONS: In pediatric and adolescent patients with a confirmed final diagnosis of ovarian germ cell malignancy, intra-operative frozen section diagnosis is not reliable to inform the extent of surgical staging required. Central review by an expert germ cell tumor pathologist provides important additional information to guide therapy.
Assuntos
Neoplasias Embrionárias de Células Germinativas , Neoplasias Ovarianas , Adolescente , Adulto , Criança , Feminino , Secções Congeladas , Humanos , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Neoplasias Embrionárias de Células Germinativas/cirurgia , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Parafina , Estudos Retrospectivos , Neoplasias TesticularesRESUMO
BACKGROUND: Four international study groups undertook a large study in resectable osteosarcoma, which included two randomised controlled trials, to determine the effect on survival of changing post-operative chemotherapy based on histological response. PATIENTS AND METHODS: Patients with resectable osteosarcoma aged ≤40 years were treated with the MAP regimen, comprising pre-operatively of two 5-week cycles of cisplatin 120 mg/m(2), doxorubicin 75 mg/m(2), methotrexate 12 g/m(2) × 2 (MAP) and post-operatively two further cycles of MAP and two cycles of just MA. Patients were randomised after surgery. Those with ≥10% viable tumour in the resected specimen received MAP or MAP with ifosfamide and etoposide. Those with <10% viable tumour were allocated to MAP or MAP followed by pegylated interferon. Longitudinal evaluation of quality of life was undertaken. RESULTS: Recruitment was completed to the largest osteosarcoma study to date in 75 months. Commencing March 2005, 2260 patients were registered from 326 centres across 17 countries. About 1334 of 2260 registered patients (59%) were randomised. Pre-operative chemotherapy was completed according to protocol in 94%. Grade 3-4 neutropenia affected 83% of cycles and 59% were complicated by infection. There were three (0.13%) deaths related to pre-operative chemotherapy. At definitive surgery, 50% of patients had at least 90% necrosis in the resected specimen. CONCLUSIONS: New models of collaboration are required to successfully conduct trials to improve outcomes of patients with rare cancers; EURAMOS-1 demonstrates achievability. Considerable regulatory, financial and operational challenges must be overcome to develop similar studies in the future. The trial is registered as NCT00134030 and ISRCTN 67613327.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Adolescente , Neoplasias Ósseas/cirurgia , Criança , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Terapia Combinada , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/efeitos adversos , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Terapia Neoadjuvante , Osteossarcoma/cirurgia , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Qualidade de Vida , Projetos de Pesquisa , Adulto JovemRESUMO
The introduction of multi-agent chemotherapy dramatically improved the outcome for patients with osteosarcoma. However, we appear to have reached a plateau in outcome with a long-term event-free survival of 60-70%. Therefore, detection of further improvements will likely require larger numbers of patients. This goal is best achieved via randomized clinical trials (RCTs) requiring large-scale cooperation and collaboration. With this background, four multinational groups agreed on the merits of collaboration: Children's Oncology Group (COG), Cooperative Osteosarcoma Study Group (COSS), European Osteosarcoma Intergroup (EOI) and Scandinavian Sarcoma Group (SSG); they designed a study to determine whether altering postoperative therapy based on histological response improved the outcome. The study design includes a backbone of 10 weeks of preoperative therapy using MAP (methotrexate, Adriamycin and cisplatin). Following surgery, patients are stratified according to histological response. Patients classified as "good responders" (>or=90% necrosis) are randomized to continue MAP or to receive MAP followed by maintenance pegylated interferon, while "poor responders" (<90% necrosis) are randomized to either continue MAP or to receive MAPIE (MAP+ifosfamide, etoposide). The design includes the registration of 1,400 patients over 4 years as well as the evaluation of quality of life using two different instruments. The group has established an efficient infrastructure to ensure successful implementation of the trial. This has included the EURAMOS Intergroup Safety Desk, which has established an international system for SAE, SAR and SUSAR reporting to the relevant competent authorities and ethics committees for each participating country. The group has also developed trial site monitoring and data center audits with funding from the European Science Foundation (ESF). The ESF has also funded three training courses to familiarize institutional staff with the requirements of multinational GCP trials. We have established a successful collaboration, and as of February 2008, 901 patients have been enrolled (COG 448; COSS 226; EOI 181; SSG 46) from 249 institutions in 16 different countries. As expected, 80% of the patients are <18 years of age, and accrual into the Quality of Life sub-study is proceeding as planned with 90% of the subjects agreeing to participate. International awareness is increasing and procedures for applicant countries wishing to join the collaboration have been implemented. Details about EURAMOS can be found at www.euramos.org. International trials in rare diseases are practicable with appropriate funding, planning and support. Although the implementation of such trials is difficult and time consuming, it is a worthwhile effort to rapidly complete RCTs and identify interventions that will improve the outcome of all osteosarcoma patients.EURAMOS-1 is the fastest accruing osteosarcoma trial and is already the largest osteosarcoma study conducted.
Assuntos
Neoplasias Ósseas/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Neoplasias Ósseas/mortalidade , Comportamento Cooperativo , Humanos , Cooperação Internacional , Osteossarcoma/mortalidade , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: [corrected] Lobradimil is a synthetic bradykinin analog that rapidly and transiently increases the permeability of the blood-brain barrier (BBB). The combination of lobradimil and carboplatin was studied in pediatric patients with primary brain tumors in a phase II trial, the primary endpoints of which were to estimate the response rate and time to disease progression. PATIENTS AND METHODS: Patients were stratified by histology into five cohorts: brainstem glioma, high-grade glioma, low-grade glioma, medullobastoma/primitive neuroectodermal tumor (PNET), and ependymoma. Patients received carboplatin adaptively dosed to achieve a target AUC of 3.5 mg min/ml per day (7 mg.min/ml/cycle) intravenously over 15 min on 2 consecutive days and lobradimil 600 ng/kg ideal body weight/day on 2 consecutive days each 28 day cycle. RESULTS: Forty-one patients, age 2-19 years, were enrolled; 38 patients, including 1 patient ultimately determined to have atypical neurocytoma, were evaluable for response. No objective responses were observed in the brainstem glioma (n=12) and high-grade glioma (n = 9) cohorts, although two patients with high-grade glioma had prolonged disease stabilization (>6 months). The study was closed for commercial reasons prior to achieving the accrual goals for the ependymoma (n = 8), medulloblastoma/PNET (n = 6) and low-grade glioma (n = 2) cohorts, although responses were observed in 1 patient with PNET and 2 patients with ependymoma. CONCLUSION: The combination of lobradimil and carboplatin was inactive in childhood high-grade gliomas and brainstem gliomas.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bradicinina/administração & dosagem , Bradicinina/efeitos adversos , Bradicinina/análogos & derivados , Bradicinina/uso terapêutico , Neoplasias Encefálicas/metabolismo , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carboplatina/uso terapêutico , Criança , Pré-Escolar , Estudos de Coortes , Esquema de Medicação , Humanos , Infusões Intravenosas , Resultado do TratamentoRESUMO
We investigated the significance of immature elements in an otherwise benign teratoma in 28 patients with immature teratomas diagnosed and treated at the Childrens Hospital of Los Angeles from 1941 to 1986. Different characteristics, including age, sex, primary tumor site, type of surgery (complete resection vs. partial resection or biopsy), and preoperative levels of alpha-fetoprotein (AFP) were analyzed to evaluate their association with risk of subsequent local malignant recurrence. After a median follow-up of 6 years, 21 patients are alive with no recurrence of the tumor (72% event-free survival). One patient died from infection after surgery and six patients had local malignant tumor recurrence within 1 year from diagnosis. Of the 28 patients, 12 had AFP levels measured at diagnosis. Eight patients had normal levels with no further evidence of tumor recurrence, and four had elevated levels with three tumor recurrences. Our experience demonstrates that only at the time of diagnosis do AFP levels correlate with a subsequent malignant behavior of these tumors (P = .004). Those patients with immature teratomas and elevated AFP levels at diagnosis should receive adjuvant chemotherapy after the initial surgical resection.
Assuntos
Recidiva Local de Neoplasia/patologia , Teratoma/patologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Recidiva Local de Neoplasia/sangue , Prognóstico , Fatores de Risco , Teratoma/sangue , Teratoma/terapia , alfa-Fetoproteínas/análiseRESUMO
Idarubicin (4-demethoxydaunomycin) is an anthracycline analogue with striking in vitro and in vivo activity against murine leukemias. Based on activity in adults with acute lymphoblastic leukemia, the Childrens Cancer Study Group initiated studies to evaluate idarubicin in children with leukemia in second or subsequent relapses. As part of those studies, we have characterized the plasma pharmacokinetics of idarubicin and the major circulating metabolite idarubicinol in 21 patients. Idarubicin plasma elimination was described by a three-compartment open model following i.v. infusion (10-15 mg/m2) on a schedule of weekly for 3 weeks and on a schedule of daily for 3 days every 3 weeks (total dose, 30-45 mg/m2). There was substantial variability in idarubicin elimination among patients, but no indication of dose-dependent or of schedule-dependent changes in pharmacokinetic parameters. The mean terminal half-life, total body clearance, and steady state volume of distribution were 17.6 h, 679 ml/min/m2, and 562 l/m2, respectively. Idarubicinol elimination was prolonged compared to that of the parent drug with a terminal half-life of 56.8 h. This metabolite clearly accumulated in plasma during the 3 days of treatment on the schedule of daily for 3 days. Urinary recoveries (48 h) of idarubicin and idarubicinol after a single dose of idarubicin were 2.4 and 10.1%, respectively. Idarubicin was detected in 2 of 21 cerebrospinal fluid samples obtained 18-30 h after administration. In marked contrast, idarubicinol was detected in 20 of those 21 samples. Concentrations in the 20 samples varied from 0.22-1.05 ng/ml with a mean value of 0.51 ng/ml.
Assuntos
Daunorrubicina/análogos & derivados , Idarubicina/farmacocinética , Leucemia/metabolismo , Adolescente , Adulto , Criança , Pré-Escolar , Daunorrubicina/líquido cefalorraquidiano , Daunorrubicina/farmacocinética , Avaliação de Medicamentos , Humanos , Idarubicina/líquido cefalorraquidiano , Lactente , Leucemia/tratamento farmacológicoRESUMO
Topotecan, a water-soluble semisynthetic analogue of camptothecin, is the first topoisomerase I inhibitor to undergo evaluation in pediatric patients with refractory malignancies. A phase I and pharmacokinetic study was performed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities, the incidence and severity of other toxicities, and the pharmacokinetics of topotecan in children. Twenty-nine patients received 42 courses of i.v. topotecan administered as a 24-h continuous infusion every 21 days at doses ranging from 2.0 to 7.5 mg/m2. Dose-related hematological toxicity was the dose-limiting toxicity. Leukopenia, neutropenia, and thrombocytopenia occurred sporadically at the 3.0- to 5.5-mg/m2 dose levels, but at 7.5 mg/m2 4 of 5 patients experienced dose-limiting thrombocytopenia (grade 4) and 2 of 5 had dose-limiting neutropenia (grade 4). No other dose-limiting toxicities were observed. Nausea and vomiting were mild and occurred in < 20 and 10% of patients, respectively. Grade 2 hematuria occurred in one patient. No objective responses were observed. Pharmacokinetic studies revealed a linear relationship between the steady-state topotecan concentration and dose. The mean steady-state concentration at the MTD was 18.2 +/- 3.7 nmol/liter and the total body clearance was 28.3 +/- 6.5 liters/h/m2. Elimination was biexponential with a t1/2 alpha of 14.4 +/- 1.8 min and a t1/2 beta of 2.9 +/- 1.1 h. The recommended starting dose for phase II pediatric trials is 5.5 mg/m2. Although this dose exceeds the MTD identified in heavily pretreated adult patients receiving topotecan on the same schedule, it is less than the MTD for minimally pretreated adult patients. Therefore, dose escalation to 7.5 mg/m2 in phase II pediatric trials should be considered for patients who tolerate treatment well at the 5.5-mg/m2 dose.
Assuntos
Antineoplásicos/efeitos adversos , Camptotecina/análogos & derivados , Neoplasias/tratamento farmacológico , Adolescente , Adulto , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/farmacocinética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Infusões Intravenosas , Masculino , Neoplasias/metabolismo , Fatores de Tempo , TopotecanRESUMO
Because of the synergy seen in adult trials when 5-fluorouracil is combined with leucovorin, we initiated a Phase I trial of this combination in children's refractory cancer. Leucovorin, an equal mixture of the (6R,S)-diastereoisomers, was administered p.o. for 6 consecutive days as 4 equal doses at 0, 1, 2, and 3 h totaling 500 mg/m2/day. 5-Fluorouracil was given daily on days 2 to 6 as an i.v. bolus immediately following the last dose of leucovorin. The leucovorin dose was held constant while the 5-fluorouracil dose was escalated in cohorts of patients from 300 mg/m2/day to its maximally tolerated dose. Thirty-five patients (19 with acute leukemia and 16 with solid tumors) were evaluable for toxicity. The maximally tolerated dose of FUra was 450 mg/m2/day for 5 treatments for patients with solid tumors and 650 mg/m2/day for 5 treatments for the children with leukemia. The dose-limiting toxicities were myelosuppression and stomatitis. Other side effects included transient, mild elevations of serum transaminases, mild nausea, vomiting, and diarrhea. The pharmacokinetics of high-dose p.o. leucovorin was studied in 23 children. There was considerable interpatient variability in the plasma concentrations of total bioactive folates (TBAF), (6S)-leucovorin, and (6S)-5-methyltetrahydrofolic acid. The maximum plasma concentration (Cmax) of TBAF was 821 +/- 97 (SE) nM, occurring at a median of 8 h; the Cmax of (6S)-leucovorin was 77 +/- 11 nM, occurring at 4 h. The TBAF concentration fell to 146 +/- 42 nM by 24 h. (6S)-5-Methyltetrahydrofolic acid accounted for 90 +/- 7% of the TBAF at the Cmax. The plasma concentration of (6R)-leucovorin, the unnatural isomer, was equal to that of TBAF. Thus, p.o. leucovorin reduced the 5-fold excess of (6R)-leucovorin over TBAF seen after i.v. doses. The relative amounts of the three major plasma species were approximately the same as in adults, even though the Cmax of each compound was lower.
Assuntos
Fluoruracila/uso terapêutico , Leucovorina/uso terapêutico , Neoplasias/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Criança , Pré-Escolar , Esquema de Medicação , Avaliação de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Fluoruracila/toxicidade , Humanos , Lactente , Leucovorina/farmacocinética , Leucovorina/toxicidade , Masculino , Neoplasias/metabolismo , Estereoisomerismo , Tetra-Hidrofolatos/metabolismo , Tetra-Hidrofolatos/toxicidadeRESUMO
Epidemiological studies of reserpine use and breast cancer have generally found only small increases in breast cancer risk, even after long-term use. Prolactin levels in short-term reserpine users have been reported to be in the range of those of lactating women, levels which rodent experiments suggest should greatly increase breast cancer incidence. We measured prolactin levels in 15 women who had been taking reserpine-containing drugs for at least 5 years and compared them to levels in 15 women taking non-reserpine-containing antihypertensives and 15 women taking no antihypertensive medicines. Although reserpine users had significantly elevated levels of prolactin, their mean level was only approximately 50% greater than the mean level of the combined results from the two control groups. Based on a statistical model of breast cancer incidence, we calculate that such increases in prolactin in the postmenopausal period would be likely to cause only small increases in breast cancer risk, as have been observed in epidemiological studies.
Assuntos
Neoplasias da Mama/epidemiologia , Prolactina/sangue , Reserpina/uso terapêutico , Idoso , Anti-Hipertensivos/uso terapêutico , California , Feminino , Humanos , Menopausa , Reserpina/toxicidade , Risco , Inquéritos e Questionários , Fatores de TempoRESUMO
Fludarabine phosphate is a nucleotide analogue of adenine arabinoside with antitumor activity in murine and human lymphoid malignancies; it has occasional, unpredictable neurotoxicity after high dose bolus injections in adults. To avoid this toxicity, we studied a loading dose plus 5-day continuous infusion in 47 evaluable pediatric patients. Dose limiting myelosuppression was seen in children with solid tumors after a loading dose of 8 mg/m2 followed by 23.5 mg/m2/day for 5 days. In children with leukemia, no dose limiting toxicity was seen at dose level 6, consisting of a loading dose of 10 mg/m2 and an infusion of 30.5 mg/m2/day for 5 days. One complete and 3 partial remissions were seen in 26 evaluable children with acute lymphoblastic leukemia. 9-beta-D-arabinofuranosyl-2-fluoroadenine plasma concentrations and the area under the moment curve increased linearly with dose. The terminal half-life was similar, while the total body clearance was shorter than that reported for adults receiving bolus or continuous doses. Lymphoblasts isolated from 2 patients during fludarabine phosphate (9-beta-D-arabinofuranosyl-2-fluoroadenine) treatment increased their ability to convert 1-beta-D-arabinofuranosylcytosine to 1-beta-D-arabinofuranosylcytosine 5'-triphosphate by more than 10-fold. The antileukemic activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-phosphate and its ability to alter the metabolism of 1-beta-D-arabinofuranosylcytosine indicate that timed combinations of these 2 agents should be tested.
Assuntos
Fosfato de Vidarabina/análogos & derivados , Antimetabólitos Antineoplásicos , Arabinofuranosilcitosina Trifosfato/metabolismo , Pré-Escolar , DNA de Neoplasias/biossíntese , Relação Dose-Resposta a Droga , Esquema de Medicação , Avaliação de Medicamentos , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Fosfato de Vidarabina/administração & dosagem , Fosfato de Vidarabina/efeitos adversos , Fosfato de Vidarabina/farmacocinéticaRESUMO
The pharmacodynamic parameters of 1-beta-D-arabinofuranosylcytosine (ara-C) in patient plasma and its active anabolite 1-beta-D-arabinofuranosylcytosine-5-triphosphate (ara-CTP) in circulating and bone marrow blast cells were studied in 20 pediatric patients with acute leukemia. ara-C (3 g/m2) was administered as a short-term infusion over 3 h every 12 h for a total of eight doses. The peak plasma concentration of ara-C ranged from 0.02 to 5.6 microM after the first dose of ara-C. The area under the concentration-time curve (AUC) of ara-C in plasma ranged from 302 to 20,298 microMh after the first dose of ara-C. The half-life of elimination (t1/2,el) of ara-C from plasma was 2.4 +/- 1.5 h in three patients with acute nonlymphoblastic leukemia (ANLL) and 4.78 +/- 4.1 h in 9 patients with acute lymphoblastic leukemia (ALL). The intracellular peak concentration of ara-CTP in circulating blast cells averaged 432.2 +/- 14.5 microM and 544.3 +/- 330 microM in patients with ANLL and ALL, respectively. The elimination kinetics of ara-CTP was monoexponential with t1/2,el of 3.30 +/- 0.8 h and 6.9 +/- 2.8 h in patients with ANLL and ALL. DNA synthetic capacity (DSC) of the blast cells was inhibited to between 24 and 64% of control after the first dose of ara-C and it declined further to between 1 and 32% after four doses of ara-C. The AUC of ara-CTP in leukemic cells ranged from 1,073 to 14,751 microMh and it was not related to the AUC of ara-C in plasma. The pharmacodynamic parameters of ara-CTP in circulating blast cells were more homogeneous in patients with ANLL than in patients with ALL. Four of six patients (67%) with ANLL and six of 14 patients (43%) with ALL achieved either complete remission or partial remission with high dose ara-C. We conclude that treatment of pediatric patients with leukemia in relapse with high dose ara-C is tolerable and moderately successful. Inhibition of DSC is positively correlated with the probability of having zero nadir peripheral blast cells. In turn there is a trend for a zero nadir peripheral blast cell count to be related to achievement of a response to therapy. This latter result is consistent with the results of larger studies in adults with leukemia.
Assuntos
Citarabina/farmacocinética , Leucemia/tratamento farmacológico , Arabinofuranosilcitosina Trifosfato/sangue , Criança , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Meia-Vida , Humanos , Leucemia/sangue , Leucemia Linfoide/sangue , Leucemia Linfoide/tratamento farmacológico , Neutropenia/induzido quimicamenteRESUMO
Ninety-four newly diagnosed patients with hematologic malignancies were monitored for compliance with oral medication and scheduled clinic appointments over a 6-month treatment period. They were assigned at entry either to a control condition or an intervention condition designed to improve compliance. Compliance with medication was assessed objectively with serial serum drug and metabolite levels, as well as with self-report indices obtained on a monthly basis. Medical records were abstracted to obtain data on the number of appointments kept, treatment given, disease characteristics, and survival. On univariate analyses using the log-rank test, five variables were found to be significantly related to survival. These included compliance with allopurinol (probably acting as a surrogate for self-medication with other chemotherapeutic agents) (P = .007), control versus educational program cohort (P less than .001), disease severity (P = .009), Karnofsky at diagnosis (P = .011), sex (P = .084), and clinic appointments kept (P = .043). In hierarchical proportional hazards models, the following variables were associated with decreased risk of death: disease severity (P less than .025), keeping over 60% of appointments (P less than .05), allopurinol/oxipurinol compliance (P less than .01), and educational program cohort (P less than .05). After controlling for all other variables, three variables were associated with increased survival: high disease severity (relative risk [RR] = 2.48), high compliance with allopurinol (RR = .45), and educational program cohort (RR = .39). We conclude that compliance with oral medication has a significant effect on patient survival. In addition, the use of special educational and supportive programs designed to improve patient compliance are associated with significant prolongation of patient survival due to, as well as independent of their effects on compliance.
Assuntos
Leucemia/tratamento farmacológico , Cooperação do Paciente , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Agendamento de Consultas , Terapia Comportamental , Estudos de Coortes , Feminino , Humanos , Leucemia/mortalidade , Masculino , Pessoa de Meia-Idade , Educação de Pacientes como Assunto , Modelos de Riscos Proporcionais , Estudos Prospectivos , Taxa de SobrevidaRESUMO
Metoclopramide is an effective antiemetic for cisplatin-induced vomiting when given in parenteral high-dose regimens but not oral low-dose regimens. Metoclopramide was compared to haloperidol, also given in a high-dose parenteral regimen. Patients received two cycles of cisplatin at a dose greater than or equal to 70 mg/m2. Metoclopramide (2 mg/kg intravenous) was given every two hours for five doses beginning one half hour before cisplatin. Haloperidol (3 mg intravenous) was given on the same schedule. A randomized double-blind crossover design was used to control subjective bias and to compare the same patient's experiences. Twenty-eight patients completed both study arms. Excellent control of vomiting was achieved with both drugs. Metoclopramide resulted in 1.92 vomiting episodes (range, 0-5) with 36% having no vomiting. Haloperidol resulted in 3.04 vomiting episodes (range, 0-8) with 20% having no vomiting. Significantly fewer vomiting episodes were noted with metoclopramide rho = .006, paired sign test). However, responses to the two drugs were well correlated (Spearman's rho = .39, P = .03). Metoclopramide and haloperidol are both excellent antiemetics when given in sufficient dosage by an effective route. Metoclopramide does show a mild advantage. However, the positive correlation in response to these agents suggests a common mechanism of action. The ability to identify related antiemetics will be useful in the design of rational combination antiemetic therapy.
Assuntos
Haloperidol/administração & dosagem , Metoclopramida/administração & dosagem , Vômito/prevenção & controle , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/efeitos adversos , Método Duplo-Cego , Avaliação de Medicamentos , Feminino , Haloperidol/uso terapêutico , Humanos , Injeções Intravenosas , Masculino , Metoclopramida/uso terapêutico , Neoplasias/tratamento farmacológico , Distribuição Aleatória , Vômito/induzido quimicamenteRESUMO
PURPOSE: We analyzed data on 31 children with primary unresectable or metastatic hepatoblastoma (HB) to investigate possible prognostic correlations between the serum level of alpha-fetoprotein (AFP), its changes during treatment, and outcome. PATIENTS AND METHODS: Patients were treated according to the Children's Cancer Group (CCG) protocol 823F, which included an initial surgery before eight courses of chemotherapy that consisted of cisplatin immediately followed by a continuous infusion of doxorubicin. Four courses were given before and four after the second surgery. AFP levels were measured before treatment, before and after second surgery, and at the end of treatment. RESULTS: Twenty-four of 31 patients showed a decline of > or = 1 log in AFP levels before second surgery (early responders). By the end of treatment, there were 16 patients, all early responders, without clinical or radiographic evidence of tumor and with normal AFP levels. Fifteen of those 16 had a decline of > or = 2 logs in AFP before second surgery (large early response). Of the 15 patients who failed to respond to treatment, 10 died, among whom only one patient had a large early response. A large early response was the strongest independent predictor of outcome in a univariate and multivariate Cox regression model, and patients with such a response had the best survival (P < .0001). CONCLUSION: For children with unresectable or metastatic HB, early changes in AFP levels are a reliable predictor of outcome and can be used for identification of poor responders to treatment, ie, patients whose AFP level fails to decrease 2 logs before second surgery should be considered for alternative treatment.
Assuntos
Hepatoblastoma/sangue , Neoplasias Hepáticas/sangue , Proteínas de Neoplasias/metabolismo , alfa-Fetoproteínas/metabolismo , Criança , Pré-Escolar , Estudos de Viabilidade , Feminino , Hepatoblastoma/tratamento farmacológico , Hepatoblastoma/cirurgia , Humanos , Lactente , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Masculino , Projetos Piloto , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
Persistent, generalized lymphadenopathy (PGL) is considered part of the acquired immunodeficiency syndrome (AIDS)-related complex. The clinical course is usually benign, although some patients may evolve to AIDS. Characteristic features on lymph node biopsy have been described. Recently, large series of PGL have been reported in which many study patients have not undergone initial diagnostic biopsy. The value of such biopsy has been questioned. We report the clinical, pathologic, and laboratory findings in six homosexual men initially considered as potential candidates for study of the natural history of PGL. They were excluded by initial lymph node biopsy, which revealed small-cleaved lymphoma in two, focal Kaposi's sarcoma in two, disseminated mycobacterium tuberculosis in one, and histoplasma encapsulatum in one. The clinical and laboratory data from these six patients were compared with those from 34 patients with biopsy-proven PGL; no statistically significant difference in any prebiopsy clinical parameter was found. We conclude that initial lymph node biopsy may reveal changes other than reactive hyperplasia in homosexual men with generalized lymphadenopathy.
Assuntos
Homossexualidade , Linfonodos/patologia , Doenças Linfáticas/patologia , Síndrome da Imunodeficiência Adquirida/patologia , Adulto , Axila , Biópsia , Contagem de Células Sanguíneas , Citometria de Fluxo , Hemoglobinas/análise , Humanos , Doenças Linfáticas/sangue , Doenças Linfáticas/imunologia , Linfócitos/classificação , Masculino , Pescoço , Exame Físico , Estudos ProspectivosRESUMO
PURPOSE: Although remission can be achieved in 80% of children with acute myelogenous leukemia (AML), many patients experience relapse. Because interleukin-2 (IL-2) can induce remission in patients with overt evidence of AML, we hypothesized that IL-2 given to patients in first remission after intensive consolidation chemotherapy might prevent relapse. This study sought to determine whether such an approach was feasible. PATIENTS AND METHODS: Twenty-one patients in complete remission received IL-2 after completion of treatment on Children's Cancer Group (CCG) protocol 2941. Recombinant IL-2 9 x 10(6) IU/m2 daily by continuous intravenous infusion (c.i.v.) was given for 4 days. After 4 days rest, IL-2 1.6 x 10(6) IU/m2 daily c.i.v. was resumed for 10 days. We monitored patients for toxicity and measured absolute lymphocyte count, the absolute count of cells that express CD56 and CD3 antigen, and soluble IL-2 receptor alpha-chain (sIL-2R alpha) levels before the start of IL-2 and after completion of each of the two courses of IL-2. RESULTS: Observed toxicities included fever (57%), vascular leak (48%), hypotension (38%), tachycardia (14%), rash (29%), septicemia (5%), thrombocytopenia (29%), elevated transaminase (14%), electrolyte disturbance (29%), and hyperglycemia (10%). No patient required cardiac pressors or transfer to an intensive care unit. All patients studied developed an increase in lymphocyte count, CD56 count, CD3 count, and sIL-2R alpha levels after treatment with IL-2. CONCLUSION: This schedule of IL-2 was reasonably well tolerated by children with AML in first remission. After treatment, increased levels of sIL-2R alpha were observed. CCG is conducting a randomized prospective trial to assess the efficacy of IL-2 to prevent the relapse of AML (CCG-2961).
Assuntos
Interleucina-2/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Complexo CD3/análise , Antígeno CD56/análise , Criança , Pré-Escolar , Estudos de Viabilidade , Feminino , Citometria de Fluxo , Humanos , Lactente , Interleucina-2/efeitos adversos , Leucemia Mieloide Aguda/imunologia , Masculino , Receptores de Interleucina-2/sangue , Proteínas Recombinantes/uso terapêutico , Indução de RemissãoRESUMO
PURPOSE: Ganglioside G(D2) is strongly expressed on the surface of human neuroblastoma cells. It has been shown that the chimeric human/murine anti-G(D2) monoclonal antibody (ch14.18) can induce lysis of neuroblastoma cells by antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. The purposes of the study were (1) to determine the maximum-tolerated dose (MTD) of ch14.18 in combination with standard dose granulocyte-macrophage colony-stimulating factor (GM-CSF) for patients with neuroblastoma who recently completed hematopoietic stem-cell transplantation (HSCT), and (2) to determine the toxicities of ch14.18 with GM-CSF in this setting. PATIENTS AND METHODS: Patients became eligible when the total absolute phagocyte count (APC) was greater than 1, 000/microL after HSCT. ch14.18 was infused intravenously over 5 hours daily for 4 consecutive days. Patients received GM-CSF 250 microg/m(2)/d starting at least 3 days before ch14.18 and continued for 3 days after the completion of ch14.18. The ch14.18 dose levels were 20, 30, 40, and 50 mg/m(2)/d. In the absence of progressive disease, patients were allowed to receive up to six 4-day courses of ch14.18 therapy with GM-CSF. Nineteen patients with neuroblastoma were treated. RESULTS: A total of 79 courses were administered. No toxic deaths occurred. The main toxicities were severe neuropathic pain, fever, nausea/vomiting, urticaria, hypotension, mild to moderate capillary leak syndrome, and neurotoxicity. Three dose-limiting toxicities were observed among six patients at 50 mg/m(2)/d: intractable neuropathic pain, grade 3 recurrent urticaria, and grade 4 vomiting. Human antichimeric antibody developed in 28% of patients. CONCLUSION: ch14.18 can be administered with GM-CSF after HSCT in patients with neuroblastoma with manageable toxicities. The MTD is 40 mg/m(2)/d for 4 days when given in this schedule with GM-CSF.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Gangliosídeos/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Neuroblastoma/terapia , Adolescente , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/imunologia , Formação de Anticorpos/imunologia , Citotoxicidade Celular Dependente de Anticorpos , Criança , Pré-Escolar , Terapia Combinada , Progressão da Doença , Relação Dose-Resposta Imunológica , Esquema de Medicação , Feminino , Seguimentos , Humanos , Masculino , Camundongos , Neuroblastoma/imunologia , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/imunologiaRESUMO
PURPOSE: Patients with lymphoblastic non-Hodgkin's lymphoma (LB NHL) were randomized to treatment with either modified LSA2L2 or ADCOMP, which added daunorubicin (DAUN) and asparaginase (L-ASP) to the methotrexate (MTX), cyclophosphamide (CYT), vincristine (VCR), and prednisone (PRED) (COMP) regimen, in a clinical trial to determine the relative effectiveness and toxicity of the two regimens. PATIENTS AND METHODS: Patients with LB NHL were eligible for this randomized study if they were less than 22 years of age at diagnosis and had < or = 25% blasts in the bone marrow. Of 307 patients registered, 281 were fully eligible and assessable. Patients were stratified by extent of disease at diagnosis. RESULTS: The 5-year event-free survival (EFS) rate for patients with localized disease was 84%, and for patients with disseminated disease, 67%. There were four relapses in 28 patients with localized disease. Two hundred six patients had mediastinal primary tumors and despite local radiation, 34 of 63 failures in these patients involved the primary tumor site with or without other involvement. After adjusting for extent of disease at diagnosis, the regimens did not differ significantly with respect to risk for adverse events. The acute toxicity was primarily neutropenia and thrombocytopenia, with greater initial toxicity in patients on the LSA2L2 regimen. Three patients developed acute myelogenous leukemia. CONCLUSION: Long-term EFS in children with LB NHL can be achieved in the majority of patients. Disease progression, which includes recurrence at the primary tumor site, is a major cause of treatment failure in patients with mediastinal presentations. Addition of DAUN and L-ASP to the COMP regimen does not produce a more effective treatment than LSA2L2.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Asparaginase/administração & dosagem , Asparaginase/efeitos adversos , Causas de Morte , Criança , Pré-Escolar , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Lactente , Linfoma não Hodgkin/mortalidade , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Recidiva , Tioguanina/administração & dosagem , Tioguanina/efeitos adversos , Falha de Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
Twenty-two consecutive patients with high-grade, B-cell lymphomas related to the acquired immunodeficiency syndrome (AIDS) were accrued onto two sequential phase II studies, consisting of a standard regimen (M-BACOD, group no. 1, N = 13), or a novel, intensive regimen (group no. 2, N = 9), which included high-dose cytosine arabinoside (HD-Ara-C), and high-dose methotrexate (HD-MTX), in an attempt to prevent CNS relapse and improve response rates. Stage IV disease was present in 82%. Complete remission (CR) was achieved in seven of 13 patients (54%) in group no. 1, and in three of nine (33%) group no. 2 (P = NS). By multivariate analysis, the most significant factor in predicting response was a Karnofsky performance score (KPS) greater than 60 (P = .04). Three of the ten patients who achieved CR on either regimen have relapsed; in all, five of 13 patients (31%) in group no. 1 have achieved disease-free survival for more than 1 year, compared with one of nine (11%) in group no. 2. CNS progression occurred in six patients in group no. 2, and in two patients in group no. 1. Hematologic toxicity was significantly greater in group no. 2, and these patients had an increased risk of opportunistic infection (one in group no. 1 v seven in group no. 2; P less than .01). Survival was similar, with a median of 11 months in group no. 1 and 6 months in group no. 2. We conclude that the intensive regimen of combination chemotherapy described here is associated with significant risk of early death due to opportunistic infection in patients with AIDS-related lymphoma, and that progression in the CNS remains a major problem. Trials of combination chemotherapy of a less intensive nature, perhaps in combination with immunomodulators or antiretroviral agents should be explored.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma/tratamento farmacológico , Adulto , Asparaginase/administração & dosagem , Linfócitos B , Bleomicina/administração & dosagem , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Dexametasona/administração & dosagem , Doxorrubicina/administração & dosagem , Esquema de Medicação , Avaliação de Medicamentos , Feminino , Humanos , Leucovorina/administração & dosagem , Linfoma/etiologia , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Estudos Prospectivos , Vincristina/administração & dosagemRESUMO
PURPOSE: The Children's Cancer Group conducted a phase I trial of temozolomide stratified by prior craniospinal irradiation (CSI). PATIENTS AND METHODS: Children and adolescents with recurrent or progressive cancer were enrolled. Temozolomide was administered orally daily for 5 days, with subsequent courses administered every 21 to 28 days after full hematologic recovery. Dose levels tested included 100, 150, 180, 215, 245, and 260 mg/m2 daily. RESULTS: Twenty-seven patients on the non-CSI stratum were assessable for hematologic toxicity. During the first three dose levels (100, 150, and 180 mg/m2 daily), only grades 1 and 2 hematologic toxicity occurred. One patient at 215 mg/m2 daily had grade 3 hematologic toxicity. Three of eight patients (38%) treated at 245 to 260 mg/m2 daily had dose-limiting toxicity (DLT), which included both neutropenia and thrombocytopenia. Twenty-two patients on the CSI stratum were assessable for hematologic toxicity. Hematologic DLT occurred in one of six patients (17%) at 100 mg/m2 daily and in two of four patients (50%) at 215 mg/m2 daily. No nonhematologic DLT occurred; nausea and vomiting occurred in more than half of the patients. After two courses of temozolomide, 10 patients had stable disease (SD), and three patients had a partial response (PR), one of whom subsequently had a complete response (CR) that persists through 24 months of follow-up. CONCLUSION: The maximum-tolerated dose (MTD) of temozolomide for children and adolescents without prior CSI is 215 mg/m2 daily and for those with prior CSI is 180 mg/m2 daily for 5 days, with subsequent courses that begin on day 28. Temozolomide is well tolerated and should undergo phase II testing in children and adolescents.