RESUMO
An 11-year-old Caucasian girl who had been cured of bilateral retinoblastoma developed non-radiation-induced osteosarcoma in multiple sites of the extremities. Investigation of the medical histories of 36 of her family members through six generations revealed that 8 relatives on the maternal side (22%) had malignant tumors, predominately genitourinary carcinomas, 2(6%) had benign tumors only, and 2(6%) had both benign and malignant neoplasms. The histologic variety of these tumors, the predominance of genitourinary carcinoma, the higher than expected frequency of tumor appearance over six generations, and the occurrence of malignant tumors in direct lineage suggest that the case of retinoblastoma followed by osteosarcoma is part of a familial cancer syndrome.
Assuntos
Neoplasias Primárias Múltiplas/genética , Osteossarcoma/genética , Retinoblastoma/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias Urogenitais/genética , Adenoma/genética , Adulto , Idoso , Neoplasias Ósseas/genética , Carcinoma de Células de Transição/genética , Criança , Pré-Escolar , Neoplasias Oculares/genética , Feminino , Humanos , Leiomioma/genética , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Neoplasias Uterinas/genéticaRESUMO
BACKGROUND: The combination of carboplatin, ifosfamide, and etoposide has shown promising activity in a variety of relapsed childhood solid tumors but has not been studied in newly diagnosed patients. PURPOSE: The tolerance for and activity of escalating targeted doses of carboplatin combined with ifosfamide and etoposide (ICE) were assessed in children with advanced germ cell tumors or other rare solid tumors for which no standard therapy exists. METHODS: Fifteen children with newly diagnosed solid tumors received ICE chemotherapy. Individualized carboplatin doses were calculated to achieve a target area under the concentration x time curve (AUC) and adjusted for the glomerular filtration rate (estimated by 99mTc-labeled diethylene-triamine pentaacetic acid clearance). Cohorts of at least three patients received carboplatin at an initial target AUC of 6 mg.min/mL, with escalations of 2 mg.min/mL in subsequent cohorts. Carboplatin was given on day 1, followed by ifosfamide at 2 g/m2 per day and etoposide at 100 mg/m2 per day on days 2 through 4. All patients received at least two courses of therapy in the absence of progressive disease, and as many as eight courses could be given. RESULTS: The 15 patients received a total of 46 assessable courses of ICE. Myelosuppression was the dominant toxicity; 30 courses (67%) resulted in hospitalization for febrile neutropenia. Neutropenia was dose limiting at the carboplatin target AUC of 12 mg.min/mL. One complete and eight partial responses were seen in the 14 assessable patients; two additional patients had at least partial responses documented at surgery or autopsy. Six patients are without evidence of disease at a median of 548 days after diagnosis. CONCLUSION: ICE chemotherapy, with the carboplatin dose based on a target AUC of 10 mg.min/mL, is tolerable and has significant activity in a variety of rare malignancies, including extragonadal germ cell tumors. IMPLICATIONS: The combination of carboplatin, etoposide, and ifosfamide holds promise in the treatment of rare pediatric malignancies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Doenças da Medula Óssea/induzido quimicamente , Carboplatina/administração & dosagem , Criança , Pré-Escolar , Etoposídeo/administração & dosagem , Feminino , Humanos , Ifosfamida/administração & dosagem , Lactente , Masculino , Neoplasias/metabolismo , Resultado do TratamentoRESUMO
Forty-one pediatric patients with advanced cancer (24 with acute leukemia and 17 with diverse solid tumors) received 74 courses of therapy with a new chemotherapeutic agent, 4'-(9-acridinylamino)methanesulfon-m-anisidide (AMSA: NSC 249992). Treatments were given by slow i.v. injection daily for five days every two to three weeks. In patients with leukemia: (a) dosages were escalated from 1.3 to 150 mg/sq m/day; (b) toxicity in the form of stomatitis, vomiting, and phlebitis occurred at dosage levels of 125 to 150 mg/sq m/day; and (c) oncolytic effects were observed in 13 of 24 patients. In patients with solid tumors: (a) dosages were escalated from 5 to 50 mg/sq m/day; (b) toxicity (stomatitis, myelosuppression, and phlebitis) occurred at the dosage level of 50 mg/sq m/day; and (c) no oncolytic responses were noted. Serum concentrations of total and free AMSA were assayed by a fluorescence technique and declined in a biphasic manner with free AMSA declining more rapidly than total AMSA. Dosages of greater than 100 mg/sq m/day were required to maintain serum concentrations of total and free AMSA greater than 0.2 microM for the entire five-day schedule. The results suggest that maximum tolerated dosages of AMSA may differ in children with leukemia and solid tumors; however, hematopoietic toxicity could not be fully evaluated in the patients with leukemia. AMSA has clear antileukemic activity that warrants future Phase II trials.
Assuntos
Aminacrina/uso terapêutico , Aminoacridinas/uso terapêutico , Sulfanilamidas/uso terapêutico , Adolescente , Adulto , Aminacrina/efeitos adversos , Aminacrina/análogos & derivados , Aminacrina/farmacologia , Criança , Pré-Escolar , Avaliação de Medicamentos , Histiocitoma Fibroso Benigno/tratamento farmacológico , Humanos , Lactente , Cinética , Leucemia/tratamento farmacológico , Taxa de Depuração Metabólica , Neuroblastoma/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Rabdomiossarcoma/tratamento farmacológico , Sulfanilamidas/efeitos adversos , Sulfanilamidas/farmacologiaRESUMO
We investigated the relationship between prior therapy and three distinct forms of toxicity that developed during ifosfamide administration (1.6 g/m2/day for 5 days) in 36 children with malignant solid tumors. Of ten therapies that were studied by multiple regression techniques, only the number of doses of cisplatin that patients had received was significantly related to neurotoxicity, hematotoxicity, and tubular nephrotoxicity, with the more severe cases occurring after three or more doses (P less than 0.05). Increased urinary concentrations of the renal tubular enzyme N-acetyl-beta-D-glucosaminidase, measured before each course of ifosfamide, were predictive of neurotoxicity (P = 0.02) and hematotoxicity (P = 0.01). We suggest that cisplatin-induced renal tubular damage, leading to the impaired clearance of ifosfamide metabolites, may account for this added toxicity.
Assuntos
Sangue/efeitos dos fármacos , Cisplatino/efeitos adversos , Ifosfamida/efeitos adversos , Túbulos Renais/efeitos dos fármacos , Sistema Nervoso/efeitos dos fármacos , Acetilglucosaminidase/urina , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Sinergismo Farmacológico , Feminino , Humanos , Ifosfamida/metabolismo , Masculino , Neoplasias/tratamento farmacológicoRESUMO
To characterize the excretion of 2-mercaptoethanesulfonate sodium (mesna) administered by intermittent infusion, urinary concentrations of mesna and its corresponding inactive disulfide were measured during 50 courses of ifosfamide (1.6 g/m2 for 5 days) and mesna (400 mg/m2 at 0.25, 4, and 6 h after each ifosfamide dose) administered i.v. to 19 patients. Some patients had previously received nephrotoxic therapy that might influence the excretion of mesna and its associated uroprotective effects. The median urinary free thiol concentration increased to 3 mM by 1 h after mesna infusion, declining to background levels by 4 h. The rate of mesna excretion correlated with the creatinine clearance rate in a subset of six patients. The proportion of mesna recovered in urine within 4 h after infusion was lower (P less than 0.05) in children who had evidence of preexisting renal tubular damage. Ifosfamide-induced tubular proteinuria was associated with lower urinary mesna recovery. Low urinary mesna concentrations indicated potentially subtherapeutic renal tubular levels. However, ifosfamide nephrotoxicity was subclinical and is not necessarily linked to differences in mesna excretion.
Assuntos
Ifosfamida/efeitos adversos , Nefropatias/induzido quimicamente , Mesna/urina , Adolescente , Adulto , Criança , Pré-Escolar , Creatinina/urina , Feminino , Humanos , Ifosfamida/uso terapêutico , Masculino , Mercaptoetanol , Neoplasias/tratamento farmacológico , Neoplasias/urina , Proteinúria/induzido quimicamenteRESUMO
Lumbar punctures (n = 115) and bone marrow aspirations (n = 114) were performed as part of the routine initial diagnostic evaluation of 115 children with retinoblastoma. Three spinal fluid examinations were positive for tumor cells, and bone marrow smears of three children demonstrated clumps of tumor cells. Five of the six positive studies were in patients with stage IV (extraglobar) disease. These results show that demonstrable CSF or bone marrow involvement is so infrequent an event at diagnosis in patients without symptoms, signs, or histologic evidence of tumor dissemination (stages I-II) as to support a recommendation that these studies need not be performed routinely in such patients. If, after enucleation, there is evidence of extraglobar extension, or if patients have symptoms or signs of CNS or systemic spread (stages III or IV), both procedures should be performed to accurately stage disease and provide baseline measurements of tumor involvement for monitoring of response to chemotherapy and/or irradiation. These results have importance in terms of justification of invasive work-up of most (greater than 85%) affected children, and cost containment.
Assuntos
Neoplasias Oculares/diagnóstico , Retinoblastoma/diagnóstico , Adolescente , Exame de Medula Óssea , Criança , Pré-Escolar , Neoplasias Oculares/líquido cefalorraquidiano , Neoplasias Oculares/patologia , Feminino , Humanos , Lactente , Masculino , Estadiamento de Neoplasias , Retinoblastoma/líquido cefalorraquidiano , Retinoblastoma/patologia , Punção EspinalRESUMO
PURPOSE: A phase I study was undertaken to determine the toxicity and maximum-tolerated dose (MTD) of recombinant human tumor necrosis factor (rTNF) in children. PATIENTS AND METHODS: Twenty-seven patients with recurrent or refractory solid tumors were enrolled on the study. rTNF was administered daily for 5 days by 30-minute intravenous (IV) infusion, and doses were escalated in cohorts of three to six patients. Courses were repeated after a 9-day rest period, if toxicity was tolerable. Daily doses ranged from 100 to 350 micrograms/m2. RESULTS: Most courses were associated with grade I/II fever, rigors, nausea, or vomiting. Three patients experienced moderate dyspnea that responded to supplemental oxygen. All abnormalities resolved on discontinuation of the infusion. One patient had a cardiac arrest 90 minutes after receiving the first dose of rTNF and died 10 days later of related complications. In two other patients, rTNF was discontinued due to persistent grade IV hypotension. Toxicities were not consistently related to dose and no cumulative effects were noted. The dose-limiting toxicity was transient hepatic dysfunction, which occurred in three of six patients receiving 350 micrograms/m2; this toxicity was rapidly reversed on discontinuation of the rTNF. One patient, whose non-Hodgkin's lymphoma had recurred after bone marrow transplantation, had a partial response. Disease was stabilized in two patients. CONCLUSION: We recommend that phase II testing proceed at a dose of 300 micrograms/m2/d on the schedule described.
Assuntos
Neoplasias/tratamento farmacológico , Fator de Necrose Tumoral alfa/uso terapêutico , Adolescente , Adulto , Criança , Pré-Escolar , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Masculino , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento , Fator de Necrose Tumoral alfa/administração & dosagem , Fator de Necrose Tumoral alfa/efeitos adversosRESUMO
Neurotoxicity developed in 22 of 97 children and adolescents with malignant solid tumors treated within a phase II ifosfamide protocol. The occurrence of neurotoxicity was related to previous cumulative dosages of cisplatin. One third of the patients who had received more than 600 mg/m2 of cisplatin developed this complication. The relative risk increased 3.2-fold with previous cisplatin dosages above 301 to 600 mg/m2, and 4.1-fold with dosages of 601 to 1,340 mg/m2. The increased risk of neurotoxicity in patients who had received more than 600 mg/m2 of cisplatin may be related to either a decreased clearance of ifosfamide itself or of the drug's active metabolites.
Assuntos
Cisplatino/administração & dosagem , Ifosfamida/efeitos adversos , Neoplasias/tratamento farmacológico , Doenças do Sistema Nervoso/induzido quimicamente , Adolescente , Adulto , Criança , Cisplatino/uso terapêutico , Humanos , RiscoRESUMO
PURPOSE: Our aim was to evaluate the pharmacokinetics and pharmacodynamics of paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ) in children, and to determine whether paclitaxel exhibited saturable pharmacokinetics. PATIENTS AND METHODS: We evaluated the pharmacokinetics and pharmacodynamics of paclitaxel (200 to 420 mg/m2) administered as a 24-hour intravenous (i.v.) infusion in a phase 1 study of 30 pediatric patients (age, 2.3 to 22.8 years) with refractory solid tumors. Fourteen serial blood samples were obtained during and up to 48 hours after the infusion, and paclitaxel concentrations were measured by a high-performance liquid chromatography-UV (HPLC-UV) method. Four pharmacokinetic models were compared for their ability to describe the patients' data. RESULTS: Paclitaxel disposition was not consistent with a first-order, two-compartment pharmacokinetic model. Rather, the majority of data sets were best described by a two-compartment model that incorporated both saturable tissue distribution and saturable elimination; a smaller number of patient data sets were best described by models that incorporated either saturable distribution or saturable elimination. Clearance was dose-dependent, with a median clearance at the lower dosages (< 400 mg/m2) of 161 mL/min/m2, and at the highest dosages (> 400 mg/m2) of 123 mL/min/m2 (P = .044). The duration that paclitaxel plasma concentrations exceeded 0.1 mumol/L was highly variable (range, 26 to 71 hours). There was a trend toward higher median area under the concentration-versus-time curve (AUC) in those children with musculoskeletal (72 mumol/L.h; P = .054) or neurologic toxicity (54 mumol/L.h; P = .062) versus those without toxicity (30 mumol/L.h). Toxicity was not significantly correlated with dosage. CONCLUSION: We conclude that paclitaxel distribution and elimination are saturable, and that estimates of paclitaxel systemic exposure correlate better with toxicity than does dosage.
Assuntos
Neoplasias/tratamento farmacológico , Paclitaxel/farmacocinética , Adolescente , Adulto , Criança , Pré-Escolar , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Masculino , Neoplasias/metabolismo , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversosRESUMO
PURPOSE: To determine the effects of enucleation, irradiation, and age at diagnosis on bony orbital growth in long-term survivors of retinoblastoma using measurements based on computed tomographic (CT) imaging. PATIENTS AND METHODS: We used CT obtained at a median age of 13 years to measure orbital volume and configuration in 54 patients who had been treated for retinoblastoma a minimum of 5 years previously. RESULTS: Enucleation and high-dose orbital irradiation (> 35 Gy) both independently adversely affected orbital development (P = .014 and P = .022, respectively). Orbital volume differences for children treated when < or = 1 year old were no greater than those for children treated when older than 1 year of age. In children treated for bilateral retinoblastoma, the impact of enucleation on orbital development was not statistically different from that of irradiation (P = .13). Small implants (12 to 14 mm in diameter) were more commonly associated with smaller orbital volumes. Migration of orbital implants was associated with the smaller orbital sphere size in children < or = 1 year of age (P < .035). CONCLUSION: Treatment for retinoblastoma compromises orbital development. Resulting orbital asymmetry seems to be at least partially related to the size of the implant. Detailed imaging-based measurements of orbital volume and configuration may aid the planning for cosmetic and reconstructive surgery in those who develop orbital asymmetry.
Assuntos
Enucleação Ocular/efeitos adversos , Neoplasias Oculares/terapia , Órbita/crescimento & desenvolvimento , Retinoblastoma/terapia , Fatores Etários , Idade de Início , Criança , Pré-Escolar , Neoplasias Oculares/patologia , Neoplasias Oculares/radioterapia , Olho Artificial/efeitos adversos , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/radioterapia , Neoplasias Primárias Múltiplas/terapia , Órbita/diagnóstico por imagem , Órbita/efeitos da radiação , Dosagem Radioterapêutica , Retinoblastoma/patologia , Retinoblastoma/radioterapia , Sobreviventes , Tomografia Computadorizada por Raios XRESUMO
PURPOSE: Topotecan pharmacokinetics and pharmacodynamics were studied following a 72-hour continuous infusion in 20 children with cancer (median age, 8 years; range, 3.5 to 18). METHODS: Serial plasma and urine samples were collected during the infusion and for up to 6 hours following the end of infusion. Topotecan (lactone) and total (lactone plus hydroxy acid) concentrations were determined by a sensitive and specific high-performance liquid chromatography (HPLC) assay with fluorescence detection. Using maximum a posteriori-Bayesian modeling, lactone and total plasma concentrations were described separately by a two-compartment model. Hematologic toxicity was expressed as the percent decrease in absolute neutrophil count (ANC) and platelet count. The relation between systemic exposure (SE) and hematologic toxicity was modeled using a sigmoid maximum-effect model. RESULTS: Systemic clearance rates for lactone and total topotecan were (mean +/- SD) 18.5 +/- 7.0 and 6.5 +/- 2.4 L/h/m2, respectively. Urinary recovery of total topotecan was (mean +/- SD) 67.5% +/- 25.2% (n = 12 patients). SE (area under the concentration-time curve from zero to infinity [AUC] or steady-state plasma concentration [Cpss]) to either topotecan lactone or total topotecan was significantly correlated to hematologic toxicity (P < .05). Overall, patients with a higher SE to topotecan experienced greater hematologic toxicity. CONCLUSION: These data demonstrate a relation between systemic exposure to topotecan and clinical effect (myelosuppression). Moreover, these data provide the basis for development of individualized topotecan administration schedules.
Assuntos
Antineoplásicos/farmacocinética , Camptotecina/análogos & derivados , Adolescente , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/farmacocinética , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Infusões Intravenosas/métodos , Lactonas/farmacocinética , Contagem de Leucócitos/efeitos dos fármacos , Masculino , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neutrófilos , Contagem de Plaquetas/efeitos dos fármacos , TopotecanRESUMO
PURPOSE: To identify areas of concern regarding the conduct of phase I trials, the perceived expectations and motivations of the parents of children entered, the expectations of toxicity and benefit, and the ethical concerns of pediatric hematologists and oncologists in the United Kingdom and North America. METHODS: A survey instrument consisting of 19 open- and closed-ended questions was sent to United Kingdom Children's Cancer Study Group (UKCCSG)- and Pediatric Oncology Group (POG)-affiliated pediatricians. RESULTS: Fifty-three UKCCSG- and 78 POG-affiliated pediatricians responded. Thirty-two UKCCSG and 51 POG respondents had previously entered at least one child into a phase I study. Overall, respondents believed that parents entered their children for medical benefit, altruism, and hope of cure. Although many respondents believed that children could benefit from medical improvement, feelings of altruism, and maintenance of hope, the chance of cure or complete remission was thought to be small. Similarly, parents were thought to potentially benefit through altruism and maintenance of hope. Whereas 83% of UKCCSG respondents indicated that phase I trials were associated with ethical difficulties, this was a concern for 48% of POG respondents. The main ethical concerns of respondents were risk of toxicity, consent of the child, unrealistic hope, and coercion. CONCLUSION: The respondents in this survey expressed mainly ethical concerns regarding the conduct of phase I trials and had realistic expectations of the potential for toxicity and benefit for those children who participate in these studies.
Assuntos
Ensaios Clínicos Fase I como Assunto , Ética Médica , Oncologia , Seleção de Pacientes , Pediatria , Adulto , Atitude do Pessoal de Saúde , Criança , Feminino , Pesquisas sobre Atenção à Saúde , Humanos , Consentimento Livre e Esclarecido , Masculino , Estudos Multicêntricos como Assunto , Neoplasias/terapia , América do Norte , Médicos , Projetos de Pesquisa , Revelação da Verdade , Reino UnidoRESUMO
Three of 218 children treated with ifosfamide plus the uroprotectant mesna, in single- or combination-agent protocols, have developed Fanconi's renal syndrome, all of whom were in a subgroup of 86 children who had also received cisplatin or carboplatin therapy. Patients receiving ifosfamide who have received prior cisplatin (or carboplatin) are at significantly higher risk of developing Fanconi's syndrome than are those who have received no prior nephrotoxic therapy (P = .04). The role of prior nephrotoxic therapy, including cisplatin and its derivatives, and the total dose of ifosfamide should be considered in the assessment of this rare but serious and apparently irreversible side effect.
Assuntos
Distúrbio Mineral e Ósseo na Doença Renal Crônica/induzido quimicamente , Síndrome de Fanconi/induzido quimicamente , Ifosfamida/efeitos adversos , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Cisplatino/efeitos adversos , Feminino , Humanos , Ifosfamida/administração & dosagem , Rim/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Masculino , Mesotelioma/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Osteossarcoma/secundário , Neoplasias Peritoneais/tratamento farmacológico , Tumor de Wilms/tratamento farmacológicoRESUMO
Ifosfamide/mesna treatment of 50 patients with pediatric malignant solid tumors was associated with the development of neurotoxic signs and symptoms in 11 of these individuals who received 29 courses of treatment. Neurologic toxicity included changes in mental status, cerebellar function, cranial nerve, and cerebellar and motor system function, including seizures. All symptoms, signs, and EEG abnormalities were transient. Some of the affected individuals failed to develop acute neurotoxic signs of symptoms when retreated with ifosfamide. A grading system for scoring these neurologic abnormalities is presented for comparison of acute neurotoxic effects of other agents. Recommendations are made regarding early termination or delay of ifosfamide/mesna treatments in the presence of significant neurotoxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doenças do Sistema Nervoso Central/induzido quimicamente , Adolescente , Adulto , Doenças do Sistema Nervoso Central/fisiopatologia , Criança , Pré-Escolar , Eletroencefalografia , Feminino , Humanos , Ifosfamida/efeitos adversos , Masculino , Mesna/efeitos adversos , Neoplasias/tratamento farmacológico , Convulsões/induzido quimicamenteRESUMO
PURPOSE AND METHODS: We reviewed the clinical records and pathologic findings of 37 children and adolescents with synovial sarcoma treated at our institution over a 30-year period to evaluate the prognostic significance of tumor size, invasiveness, histology, and other features. RESULTS: The 20 male and 17 female patients with synovial sarcoma had a median age of 13.7 years at diagnosis. Primary tumor sites were the extremities (n = 27), trunk (n = 8), and head and neck (n = 2). Disease stage (clinical group) was as follows: group I, n = 21; group II, n = 7; group III, n = 4; and group IV, n = 5. Nineteen patients had invasive (T2) lesions, 20 had tumors more than 5 cm in diameter, and 14 had histologic grade 3 lesions. The estimated 5-year survival rate (+/- SE) for patients with group I or II disease was 80% +/- 9%, compared with 17% +/- 15% for those with group III or IV tumors (P = .0003). An exact log-rank test, adjusted for clinical group, showed that tumor invasiveness and grade independently predicted overall and progression-free survival (P < .05); tumor size was significantly correlated with progression-free survival. A borderline significant relationship with overall survival was found for both tumor size and histologic subtype (P = .09). CONCLUSION: A controlled trial of adjuvant chemotherapy is merited in children with resected synovial sarcoma (clinical group I or II) who present with unfavorable clinicopathologic features such as large, invasive, or grade 3 lesions. Children with unresected or metastatic disease fare poorly despite multimodality therapy and require novel treatment approaches.
Assuntos
Sarcoma Sinovial/fisiopatologia , Adolescente , Adulto , Amputação Cirúrgica , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Terapia Combinada , Feminino , Hospitais Pediátricos , Humanos , Masculino , Invasividade Neoplásica , Recidiva Local de Neoplasia , Prognóstico , Sarcoma Sinovial/mortalidade , Sarcoma Sinovial/patologia , Sarcoma Sinovial/terapia , Análise de SobrevidaRESUMO
PURPOSE: To determine the dose-limiting toxicity and potential efficacy of topotecan in pediatric patients with refractory malignant solid tumors. PATIENTS AND METHODS: In this phase I clinical trial, 27 patients received topotecan 0.75-1.9 mg/m2 by continuous intravenous infusion daily for 3 days. Fifty-three treatment courses were given to these patients. RESULTS: Myelosuppression was the dose-limiting toxicity at levels of 1.3 to 1.9 mg/m2 for 3 days, requiring significant support with transfused packed RBCs and platelets. Myelosuppression was variable in severity at the 1.0-mg/m2 dosage level; thus, additional patients were treated with this dosage, followed by human recombinant granulocyte-colony stimulating factor (G-CSF). Other toxicities were not significant. One patient with neuroblastoma had a complete response that lasted for 8 months. Stable disease activity was recorded for other patients with neuroblastoma, rhabdomyosarcoma, and islet cell carcinoma. Pharmacokinetic studies showed that topotecan plasma concentrations ranged from 1.6 to 7.5 ng/mL during infusions of 1.0 mg/m2/d, and that there was a biphasic plasma distribution with a mean terminal half-life of 2.9 +2- 1.0 hours. CONCLUSION: Topotecan is a promising anticancer agent that deserves phase II testing in pediatric solid tumors. We recommend that pediatric phase II topotecan trials use 1.0 mg/m2/d for 3 days as a constant intravenous infusion, followed by G-CSF for 14 days, and that these treatment courses be repeated every 21 days.
Assuntos
Antineoplásicos/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias/tratamento farmacológico , Adolescente , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Camptotecina/efeitos adversos , Camptotecina/farmacocinética , Camptotecina/uso terapêutico , Criança , Pré-Escolar , Feminino , Meia-Vida , Hematopoese/efeitos dos fármacos , Humanos , Infusões Intravenosas , Masculino , Neoplasias/metabolismo , Topotecan , Resultado do TratamentoRESUMO
PURPOSE: A phase I study was performed to describe the principal toxicities and identify the maximum-tolerated dose (MTD) of Taxol (paclitaxel; Bristol-Myers Squibb Co, Wallingford, CT) in children with therapy-resistant solid tumors. Additionally, the pharmacokinetic disposition of Taxol in children was studied, and preliminary evidence of the activity of Taxol against pediatric solid tumors was assessed. PATIENTS AND METHODS: Twenty-four-hour continuous infusions of Taxol were administered every 21 days to children (median age, 12 years; range, 2 to 22) with refractory solid tumors. Doses ranged from 200 to 420 mg/m2, there was no intrapatient dose escalation. RESULTS: A total of 62 courses of Taxol were administered to 31 patients. Two patients developed acute anaphylaxis during their second infusion of taxol at doses of 200 mg/m2 and 350 mg/m2, respectively. No other allergic reactions were documented. Myelosuppression occurred at all dose levels, but was of short duration (< or = 7 days) and did not appear to increase with consecutive courses or at higher dosage levels. A stocking-and-glove peripheral neuropathy became evident at doses > or = 290 mg/m2. Dose-limiting neurotoxicity occurred at 420 mg/m2 and comprised a significant fine-motor and peripheral neuropathy in one patient, and a tonic-clonic seizure in another. End-of-infusion plasma concentrations ranged from 0.40 to 6.4 mumol/L, and were not found to be dose-dependent over the range of doses studied. A complete response was documented in one patient, partial response in two, and minimal response in one for an overall response rate of 13%. CONCLUSION: Neurotoxicity was dose-limiting when Taxol was administered by 24-hour continuous infusion to pediatric patients with relapsed solid tumors. In this population, the recommended dose for phase II trials is 350 mg/m2/d.
Assuntos
Neoplasias/tratamento farmacológico , Paclitaxel/efeitos adversos , Paclitaxel/farmacocinética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Infusões Intravenosas , Masculino , Neoplasias/metabolismo , Paclitaxel/administração & dosagem , Resultado do TratamentoRESUMO
PURPOSE: We assessed the activity of ifosfamide plus etoposide against newly diagnosed Ewing's sarcoma of bone by administering this drug pair before standard induction therapy (the upfront window approach). PATIENTS AND METHODS: Twenty-six children and adolescents with newly diagnosed, previously untreated Ewing's sarcoma of bone were enrolled onto this pilot study (EW-87). Eighteen were at a higher risk of treatment failure, with a primary tumor size of more than 8 cm or metastases at diagnosis. Window therapy with ifosfamide (1.6 g/m2/d with mesna uroprotection) and etoposide (100 mg/m2/d) was given in three 5-day cycles at 21-day intervals. Responses were evaluated clinically and radiologically. Subsequent induction therapy comprised three cycles of cyclophosphamide and doxorubicin. Radiation therapy was the primary local control modality; surgery was limited to biopsy or resection of expendable bones. After the local control phase, alternating courses of vincristine plus dactinomycin, ifosfamide plus etoposide, and cyclophosphamide plus doxorubicin were given as maintenance therapy. RESULTS: There were four complete responses and 21 partial responses to ifosfamide/etoposide window therapy (overall response rate 96%; 95% confidence interval [CI], 80% to 99%). Disease progression was observed in four patients during the cyclophosphamide/doxorubicin phase. Chemotherapy was well tolerated; only 16% (20 of 125) of all ifosfamide/etoposide window and maintenance cycles resulted in hospitalization for fever and neutropenia. Two patients developed chemotherapy-induced cystitis. CONCLUSIONS: The combination of ifosfamide and etoposide is highly active against previously untreated Ewing's sarcoma and generally is well tolerated. The ultimate impact of these two agents on outcome will be determined in randomized multicenter studies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Sarcoma de Ewing/tratamento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ósseas/diagnóstico , Criança , Pré-Escolar , Etoposídeo/administração & dosagem , Feminino , Humanos , Ifosfamida/administração & dosagem , Masculino , Projetos Piloto , Sarcoma de Ewing/diagnóstico , Resultado do TratamentoRESUMO
PURPOSE: To determine the maximum-tolerated systemic exposure (MTSE) and exposure-limiting toxicity of continuous infusion topotecan in children with recurrent acute leukemia. PATIENTS AND METHODS: Patients received escalating levels of topotecan systemic exposure as measured by steady-state topotecan lactone concentration (Css). Samples obtained within the first 24 hours were measured by high-pressure liquid chromatography (HPLC) for topotecan. A two-compartment model was fit to the data using a Bayesian algorithm. Css was calculated for each patient; if it differed by more than 20% of target, a new dosage was begun within 6 hours. Follow-up concentrations were obtained as well as serial plasma samples postinfusion. Toxicity and evidence of activity were assessed after each course. RESULTS: Thirteen boys and five girls received 23 courses of topotecan. Target Css ranged from 1.0 to 5.3 ng/mL (topotecan doses, 0.5 to 3.3 mg/m2/d). Nineteen of 23 courses were within +/- 20% of target after adjustment (range, 77% to 139%). The MTSE was 4.0 ng/mL, and mucositis was exposure-limiting at 5.3 ng/mL. A significant relation between topotecan lactone Css and the severity of mucositis was observed. Myelosuppression was experienced but was not considered exposure-limiting. One complete response and one partial response were noted. CONCLUSION: The MTSE for continuous infusion topotecan was 4.0 ng/mL. Responses were noted at Css comparable to those producing responses in a severe combined immunodeficiency (SCID) mouse model. Further studies of topotecan are warranted.
Assuntos
Antineoplásicos/efeitos adversos , Camptotecina/análogos & derivados , Leucemia/tratamento farmacológico , Doença Aguda , Adolescente , Adulto , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Camptotecina/efeitos adversos , Camptotecina/sangue , Camptotecina/farmacocinética , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Meia-Vida , Humanos , Lactente , Infusões Intravenosas , Leucemia/metabolismo , Masculino , Taxa de Depuração Metabólica , Recidiva , TopotecanRESUMO
PURPOSE: We assessed the cumulative risk of malignancies following treatment for Hodgkin's disease in childhood and adolescence and investigated related patient and treatment characteristics. PATIENTS AND METHODS: Medical records of 499 Hodgkin's disease patients treated between 1962 and 1993 were reviewed. There were 385 adolescents (> or = 10 years of age at diagnosis) and 114 preadolescents (< 10 years). Most patients (n = 346) were treated with radiation plus multiagent chemotherapy, while 30 received only chemotherapy and 123 only radiation therapy. Radiation doses ranged from 20 to 42 Gy. RESULTS: At a median follow-up duration of 9 years (range, 0.1 to 27.4), 25 patients have had second malignancies: 19 solid tumors, four acute nonlymphoblastic leukemias (ANLLs), 1 non-Hodgkin's lymphoma (NHL), and one chronic myeloid leukemia (CML). Three patients have had a third malignancy. The estimated cumulative risk of second malignancies increased from 1.5% at 5 years to 7.7% at 15 years. All but two of the patients with second malignancies were > or = 10 years of age at initial diagnosis, which reflects the higher risk among patients treated for Hodgkin's disease as adolescents (P = .01). Second malignancies were more common among female patients (P = .0002), even when those breast cancer were excluded (P = .007), and in those treated for recurrent Hodgkin's disease (P = .02). Patients with ANLL/NHL were older at diagnosis of Hodgkin's disease than those with solid tumors, (median age, 18.3 v 13.8 years; P = .04). There was no difference between groups treated with radiation therapy alone, chemotherapy alone, or radiation plus multiagent chemotherapy. CONCLUSION: Adolescents treated for Hodgkin's disease are at greater at risk of second malignancies than younger patients. Overall, adolescent females treated for recurrent Hodgkin's disease appear to be at greatest risk, while preadolescents appear to be protected from this late complication.