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1.
Lancet Haematol ; 8(1): e34-e44, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33357480

RESUMO

BACKGROUND: Fit patients with mantle cell lymphoma aged 18-65 years are usually given cytarabine and rituximab-based induction regimens followed by autologous haematopoetic stem-cell transplantation (HSCT). We investigated whether post-autologous HSCT maintenance with lenalidomide improves progression-free survival in this population. METHODS: This open-label, randomised, multicentre, phase 3 trial was done at 49 haematology and oncology units in Italy and Portugal. Eligible patients had Ann Arbor stage III or IV treatment-naive mantle cell lymphoma (or stage II plus bulky disease [≥5 cm] or B symptoms), and had evidence of cyclin D1 overexpression or the translocation t(11;14)(q13;q32). Patients were aged 18-59 years with Eastern Cooperative Oncology Group (ECOG) performance status 0-3, or aged 60-65 years with ECOG 0-2. After an optional prephase with vincristine and steroids (intravenous vincristine 1·4 mg/m2 on day 1, oral prednisone 100 mg [total dose] on days 1-5), patients were given three courses of R-CHOP (21-day cycle, intravenous rituximab 375 mg/m2 on day 1; intravenous doxorubicin 50 mg/m2, vincristine 1·4 mg/m2, and cyclophosphamide 750 mg/m2 on day 2; oral prednisone 100 mg/m2 on day 2-6). Patients then received one cycle of high-dose CTX (intravenous cyclophosphamide 4 g/m2 on day 1, intravenous rituximab 375 mg/m2 on day 4). After restaging, patients received two cycles of R-HD-cytarabine (high-dose intravenous cytarabine 2 g/m2 every 12 h on days 1-3, intravenous rituximab 375 mg/m2 on days 4 and 10). Patients with complete remission or partial remission proceeded to autologous HSCT and responding patients (complete remission or partial remission) with haematological recovery were randomly assigned (1:1) to receive 24 courses of oral lenalidomide maintenance (15 mg per day for patients with platelets >100 × 109 cells per L or 10 mg per day for platelets 60-100 × 109 cells per L, days 1-21 every 28 days) for 24 months, or observation. The primary endpoint was progression-free survival, measured in the randomised population. This study is registered with EudraCT (2009-012807-25) and ClinicalTrials.gov (NCT02354313). FINDINGS: Between May 4, 2010, and Aug 24, 2015, 303 patients were screened for inclusion and 300 patients were enrolled (median age 57 years, IQR 51-62; 235 [78%] male). 95 patients were excluded before randomisation, mostly due to disease progression, adverse events, and inadequate recovery. 104 patients were randomly assigned to the lenalidomide maintenance group and 101 patients to the observation group. 11 (11%) of 104 patients assigned to lenalidomide did not start treatment (3 withdrew, 6 adverse events or protocol breach, 2 lost to follow-up). At a median follow-up of 38 months after randomisation (IQR 24-50), 3-year progression-free survival was 80% (95% CI 70-87) in the lenalidomide group versus 64% (53-73) in the observation group (log-rank test p=0·012; hazard ratio 0·51, 95% CI 0·30-0·87). 41 (39%) of 104 patients discontinued lenalidomide for reasons including death or progression. Treatment-related deaths were recorded in two (2%) of 93 patients in the lenalidomide group (1 pneumonia, 1 thrombotic thrombocytopenic purpura), and one (1%) of 101 in the observation group (pneumonia). 59 (63%) of 93 patients in the lenalidomide group had grade 3-4 haematological adverse events versus 12 (12%) of 101 patients in the observation group (p<0·0001). 29 (31%) of 93 patients in the lenalidomide group and eight (8%) of 101 patients in the observation group had grade 3-4 non-haematological adverse events (p<0·0001), of which infections were the most common.Serious adverse events were reported in 22 (24%) of 93 patients in the lenalidomide group and five (5%) of 101 patients in the observation group. Pneumonia and other infections were the most common serious adverse events. INTERPRETATION: Despite non-negligibile toxicity, lenalidomide after autologous HSCT improved progression-free survival in patients with mantle cell lymphoma, highlighting the role of maintenance in mantle cell lymphoma. FUNDING: Fondazione Italiana Linfomi and Celgene.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Lenalidomida/administração & dosagem , Linfoma de Célula do Manto , Quimioterapia de Manutenção , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Lenalidomida/efeitos adversos , Linfoma de Célula do Manto/sangue , Linfoma de Célula do Manto/mortalidade , Linfoma de Célula do Manto/terapia , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Taxa de Sobrevida , Transplante Autólogo , Vincristina/administração & dosagem , Vincristina/efeitos adversos
2.
Acta Gastroenterol Belg ; 83(4): 660-662, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33321026

RESUMO

Acute colonic pseudo-obstruction (ACPO) or Ogilvie's syndrome is characterized by acute colonic dilatation in the absence of mechanical obstruction. It usually occurs in hospitalized patients with acute illness or following surgical procedures, but several medications such as cytotoxic chemotherapy can also induce ACPO. We report three cases of patients with Ogilvie's syndrome after induction therapy with vincristine-containing chemotherapy. Conservative management failed in all three cases. Awareness for this syndrome is necessary when administrating vincristine, because delay in diagnosis may lead to colonic ischaemia and perforation.


Assuntos
Pseudo-Obstrução do Colo , Pseudo-Obstrução do Colo/induzido quimicamente , Pseudo-Obstrução do Colo/diagnóstico , Tratamento Conservador , Humanos , Projetos de Pesquisa , Síndrome , Vincristina/efeitos adversos
3.
PLoS One ; 15(12): e0242218, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33370316

RESUMO

Improvements in survival rates with gonad-sparing protocols for childhood and adolescence cancer have increased the optimism of survivors to become parents after treatment. Findings in rodents indicate that chromosomal aberrations can be induced in male germ cells by genotoxic exposures and transmitted to offspring and future generations with effects on development, fertility and health. Thus, there is a need for effective technologies to identify human sperm carrying chromosomal aberrations to assess the germ-line risks, especially for cancer survivors who have received genotoxic therapies. The time-dependent changes in the burden of sperm carrying structural chromosomal aberrations were assessed for the first time in a cancer setting, using the AM8 sperm FISH protocol which simultaneously detects abnormalities in chromosomal structure and number in sperm. Nine Hodgkin lymphoma (HL) patients provided 20 semen samples before, during, and after NOVP therapy (Novantrone, Oncovin, Velban and Prednisone) and radiation therapy that produced scattered gonadal doses from <0.05 to 0.6 Gy. Late meiosis was found to be the most sensitive to NOVP treatment for the production of sperm with chromosomal abnormalities, both in structure and number. Earlier stages of spermatogenesis were less sensitive and there was no evidence that therapy-exposed stem cells resulted in increased frequencies of sperm with abnormalities in chromosomal structure or number. This indicates that NOVP therapy may increase the risks for paternal transmission of chromosomal structural aberrations for sperm produced 32 to 45 days after a treatment with these drugs and implies that there are no excess risks for pregnancies conceived more than 6 months after this therapy. This clinical evaluation of the AM8 sperm FISH protocol indicates that it is a promising tool for assessing an individual's burden of sperm carrying chromosomal structural aberrations as well as aneuploidies after cancer therapy, with broad applications in other clinical and environmental situations that may pose aneugenic or clastogenic risks to human spermatogenesis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Aberrações Cromossômicas/efeitos dos fármacos , Doença de Hodgkin/terapia , Meiose/efeitos dos fármacos , Análise do Sêmen/métodos , Espermatozoides/efeitos dos fármacos , Adulto , Células-Tronco Germinativas Adultas/efeitos dos fármacos , Células-Tronco Germinativas Adultas/efeitos da radiação , Sobreviventes de Câncer , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Aberrações Cromossômicas/efeitos da radiação , Estudos de Coortes , Preservação da Fertilidade , Humanos , Hibridização in Situ Fluorescente/métodos , Masculino , Meiose/efeitos da radiação , Mitoxantrona/efeitos adversos , Mutagênese/efeitos dos fármacos , Mutagênese/efeitos da radiação , Tratamentos com Preservação do Órgão/efeitos adversos , Tratamentos com Preservação do Órgão/métodos , Órgãos em Risco/efeitos da radiação , Prednisona/efeitos adversos , Dosagem Radioterapêutica , Espermatogênese/efeitos dos fármacos , Espermatogênese/efeitos da radiação , Espermatozoides/fisiologia , Espermatozoides/efeitos da radiação , Testículo/efeitos dos fármacos , Testículo/efeitos da radiação , Fatores de Tempo , Vimblastina/efeitos adversos , Vincristina/efeitos adversos
4.
Anticancer Res ; 40(9): 5237-5243, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878812

RESUMO

BACKGROUND/AIM: Adult T-cell leukemia/lymphoma (ATLL) is a relatively refractory CD4-positive peripheral T-cell lymphoma. VCAP-AMP-VECP (mLSG15) is one of the standard chemotherapeutic regimens for patients with aggressive ATLL. Mogamulizumab (moga), a monoclonal antibody for C-C chemokine receptor 4 antigen expressed on the cell surface, has recently been poised for use as monotherapy and in combination with chemotherapy. However, to date, a significant survival benefit has not been obtained with the combination of moga + mLSG15 therapy. PATIENTS AND METHODS: We retrospectively analyzed 77 patients diagnosed with aggressive ATLL. Of them, 22 were treated with moga + a chemotherapy regimen comprised of etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisolone (EPOCH), 16 with moga + mLSG15, and 39 with chemotherapy alone. RESULTS: A risk reduction of approximately 30% was obtained with moga + EPOCH compared with moga + mLSG15. CONCLUSION: The addition of moga to chemotherapy did not result in a survival benefit compared with chemotherapy alone. However, a statistically significant overall survival benefit was observed in patients with moga-induced skin disorders.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma de Células T do Adulto/diagnóstico , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Esquema de Medicação , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Feminino , Humanos , Leucemia-Linfoma de Células T do Adulto/mortalidade , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Prognóstico , Modelos de Riscos Proporcionais , Retratamento , Estudos Retrospectivos , Resultado do Tratamento , Vincristina/efeitos adversos , Vincristina/uso terapêutico
5.
Int J Hematol ; 112(6): 807-816, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32880824

RESUMO

CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) -/+ rituximab (R) is the standard chemotherapeutic regimen for aggressive lymphoma, but is insufficient for aggressive lymphoma with adverse prognostic factors. Dose-adjusted (DA)-EPOCH (etoposide, doxorubicin, cyclophosphamide, vincristine, and prednisolone) -/+ R demonstrates excellent efficacy against some aggressive lymphoma. Thus, we conducted a retrospective study to evaluate the feasibility and efficacy of this therapy in clinical practice. We enrolled 149 patients from 17 institutions diagnosed between 2007 and 2015. The median follow-up period for survivors was 27 months (range 0.2-123). The complete response (CR) rate of newly diagnosed patients was 79% (95% CI 68-87%). All patients were hospitalized to receive this therapy and 94% of patients also received granulocyte-colony-stimulating factor support. There were no treatment-related deaths. Febrile neutropenia (FN) and grade 3 or 4 infection occurred in 55% and 28% of patients, respectively. There were no significant differences in FN or infection between young (≤ 65 years) and elderly patients (> 65 years). In newly diagnosed diffuse large B-cell lymphoma-not otherwise specified patients (n = 46), the CR rate was 80% (95% CI 64-91%) and the 2-year OS rate was 81% (95% CI 66-90%). In the present study, DA-EPOCH -/+ R exhibited excellent efficacy and feasibility for aggressive lymphoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma/tratamento farmacológico , Rituximab/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doenças Transmissíveis/epidemiologia , Doenças Transmissíveis/etiologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Estudos de Viabilidade , Neutropenia Febril/epidemiologia , Neutropenia Febril/etiologia , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Adulto Jovem
6.
Medicine (Baltimore) ; 99(38): e22238, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32957367

RESUMO

BACKGROUND: Systematic evaluation of the effectiveness and safety of combined procarbazine, lomustine, and vincristine for treating recurrent high-grade glioma. METHODS: Electronic databases including PubMed, MEDLINE, EMBASE, Cochrane Library Central Register of Controlled Trials, WanFang, and China National Knowledge Infrastructure (CNKI) were used to search for studies related to the utilization of combined procarbazine, lomustine, and vincristine as a therapeutic method for recurrent high-grade glioma. Literature screening, extraction of data, and evaluation of high standard studies were conducted by 2 independent researchers. The robustness and strength of the effectiveness and safety of combined procarbazine, lomustine, and vincristine as a therapeutic methodology for recurrent high-grade glioma was assessed based on the odds ratio (OR), mean differences (MDs), and 95% confidence interval (CI). RevMan 5.3 software was used for carrying out the statistical analysis. RESULTS: These results obtained in this study will be published in a peer-reviewed journal. CONCLUSION: Evidently, the conclusion of this study will provide an assessment on whether combined procarbazine, lomustine, and vincristine provides an effective and safe form of treatment for recurrent high-grade glioma. SYSTEMATIC REVIEW REGISTRATION NUMBER: INPLASY202080078.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Metanálise como Assunto , Recidiva Local de Neoplasia/tratamento farmacológico , Revisões Sistemáticas como Assunto , Adolescente , Adulto , Neoplasias Encefálicas/patologia , Glioma/patologia , Humanos , Lomustina/efeitos adversos , Lomustina/uso terapêutico , Gradação de Tumores , Recidiva Local de Neoplasia/patologia , Procarbazina/efeitos adversos , Procarbazina/uso terapêutico , Vincristina/efeitos adversos , Vincristina/uso terapêutico , Adulto Jovem
7.
Ann Hematol ; 99(8): 1771-1778, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32601796

RESUMO

Mantle cell lymphoma has a dismal prognosis at relapse or in the refractory setting. Among therapies, mTor pathway targeting by temsirolimus has been the first strategy approved for relapse in Europe. While its efficacy in monotherapy has long been demonstrated, its use remains limited. In the T3 phase Ib clinical trial, we investigated the recommended dose of temsirolimus in association with R-CHOP (R-CHOP-T), or high-dose cytarabine plus rituximab (R-DHA-T), or fludarabine, cyclophosphamide plus rituximab (R-FC-T). From November 11, 2011 to February 26, 2015, forty-one patients were enrolled. Patients presented with high MIPI (47.5%) at relapse and a median number of treatments of 1 (1-3). Patients were treated by R-CHOP-T (n = 10), R-FC-T (n = 14), or R-DHA-T (n = 17) according to the choice of local investigators. The maximum tolerated dose (MTD) was 15 mg in the R-CHOP-T arm and has not been determined in other treatment arms because of toxicities. All patients experienced ≥ Grade 3 adverse events, mainly thrombocytopenia (76%). Twenty-six patients discontinued prematurely the treatment, mostly for toxicity (n = 12) and progression of the disease (n = 8). Of note, 6 patients of the R-DHA-T arm reached complete remission (35%). Temsirolimus with immuno-chemotherapy is associated with a high rate of toxicities. Determination of MTD could only be achieved for R-CHOP-T arm. Associations between temsirolimus and other targeted therapies may be warranted for R/R MCL patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Imunoterapia , Linfoma de Célula do Manto/terapia , Sirolimo/análogos & derivados , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Linfoma de Célula do Manto/mortalidade , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Taxa de Sobrevida , Trombocitopenia/induzido quimicamente , Trombocitopenia/mortalidade , Vincristina/administração & dosagem , Vincristina/efeitos adversos
8.
Int J Hematol ; 112(3): 369-376, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32529585

RESUMO

Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) is one of the standard regimens for indolent B-cell non-Hodgkin's lymphoma (NHL). It is unclear whether the prednisolone (PSL) dosage affects the therapeutic effect or the adverse event profile. We retrospectively examined 48 patients with indolent B-cell NHL who were treated with R-CHOP (PSL 50 mg/m2/day for 5 days) at our institute between 2006 and 2016. We compared them with 149 patients with indolent B-cell lymphoma who were treated with R-CHOP (PSL 100 mg for 5 days) in the JCOG 0203 trial. The proportions of patients with bulky disease, extranodal involvement, and increased nodal sites were higher at our institute. Nevertheless, there was no difference in the CR rate, PFS, OS or the frequency of adverse events, except for peripheral neuropathy, between the two treatment groups. In our institute, there was no difference in the CR rate, PFS, OS or adverse event profile between patients who received PSL at 60-80 mg/day and at 81-100 mg/day. Patients who received PSL at 60-80 mg/day included many female and light-weight patients. In conclusion, the PSL dose adjusted based on body surface area appeared to be appropriate in terms of efficacy and safety.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Prednisolona/administração & dosagem , Rituximab/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Superfície Corporal , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Linfoma Folicular/mortalidade , Linfoma não Hodgkin/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prednisolona/efeitos adversos , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Indução de Remissão , Estudos Retrospectivos , Rituximab/efeitos adversos , Rituximab/uso terapêutico , Resultado do Tratamento , Vincristina/efeitos adversos , Vincristina/uso terapêutico
10.
Intern Med ; 59(13): 1643-1647, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32238719

RESUMO

Varicella-zoster virus (VZV) encephalitis in the absence of vasculopathy may rarely occur in association with herpes zoster. We herein report the case of a 67-year-old woman with non-Hodgkin's lymphoma undergoing chemotherapy who presented with an acute alteration in consciousness. Magnetic resonance imaging of the brain revealed multiple and nonspecific lesions of hyperintensity with mild edema in the cortex and subcortex. She was treated with intravenous acyclovir. However, two days after admission, the patient died and was diagnosed with VZV encephalitis. This case highlights the risk of VZV reactivation with severe neurological complications in patients undergoing immunosuppressive therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Encefalite por Varicela Zoster/etiologia , Linfoma não Hodgkin/tratamento farmacológico , Aciclovir/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antivirais/uso terapêutico , Autopsia , Encéfalo/patologia , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Encefalite por Varicela Zoster/tratamento farmacológico , Feminino , Herpesvirus Humano 3 , Humanos , Imagem por Ressonância Magnética/efeitos adversos , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Rituximab/efeitos adversos , Rituximab/uso terapêutico , Vincristina/efeitos adversos , Vincristina/uso terapêutico
11.
Intern Med ; 59(14): 1745-1748, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32296003

RESUMO

A 67-year-old woman received induction chemotherapy comprising vincristine, daunorubicin, cyclophosphamide, L-asparaginase and prednisolone for acute lymphoblastic leukemia with a common B-cell phenotype. The administration of L-asparaginase at 3,000 U/m2 for 6 days was planned. Before the fourth administration on day 16, left parotid swelling was identified along with increased serum amylase (991 U/L; 94% derived from salivary glands). An enlarged left parotid gland was apparent on computed tomography. The symptoms resolved after cessation of L-asparaginase, with serum amylase normalizing by day 20. This rare adverse event should be recognized as improving within a week after ceasing L-asparaginase.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Asparaginase/efeitos adversos , Asparaginase/uso terapêutico , Parotidite/induzido quimicamente , Parotidite/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Idoso , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Daunorrubicina/efeitos adversos , Daunorrubicina/uso terapêutico , Feminino , Humanos , Prednisolona/efeitos adversos , Prednisolona/uso terapêutico , Resultado do Tratamento , Vincristina/efeitos adversos , Vincristina/uso terapêutico
12.
Cancer Chemother Pharmacol ; 85(5): 831-842, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32222808

RESUMO

PURPOSE: The phase Ib/II open-label study (NCT01992653) evaluated the antibody-drug conjugate polatuzumab vedotin (pola) plus rituximab/obinutuzumab, cyclophosphamide, doxorubicin, and prednisone (R/G-CHP) as first-line therapy for B-cell non-Hodgkin lymphoma (B-NHL). We report the pharmacokinetics (PK) and drug-drug interaction (DDI) for pola. METHODS: Six or eight cycles of pola 1.0-1.8 mg/kg were administered intravenously every 3 weeks (q3w) with R/G-CHP. Exposures of pola [including antibody-conjugated monomethyl auristatin E (acMMAE) and unconjugated MMAE] and R/G-CHP were assessed by non-compartmental analysis and/or descriptive statistics with cross-cycle comparisons to cycle 1 and/or after multiple cycles. Pola was evaluated as a potential victim and perpetrator of a PK drug-drug interaction with R/G-CHP. Population PK (popPK) analysis assessed the impact of prior treatment status (naïve vs. relapsed/refractory) on pola PK. RESULTS: Pola PK was similar between treatment arms and independent of line of therapy. Pola PK was dose proportional from 1.0 to 1.8 mg/kg with R/G-CHP. Geometric mean volume of distribution and clearance of acMMAE ranged from 57.3 to 95.6 mL/kg and 12.7 to 18.2 mL/kg/day, respectively. acMMAE exhibited multi-exponential decay (elimination half-life ~ 1 week). Unconjugated MMAE exhibited formation rate-limited kinetics. Exposures of pola with R/G-CHP were similar to those in the absence of CHP; exposures of R/G-CHP in the presence of pola were comparable to those in the absence of pola. CONCLUSIONS: Pola PK was well characterized with no clinically meaningful DDIs with R/G-CHP. Findings are consistent with previous studies of pola + R/G, and support pola + R/G-CHP use in previously untreated diffuse large B-cell lymphoma.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais , Imunoconjugados , Linfoma de Células B , Rituximab , Administração Intravenosa , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/farmacocinética , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacocinética , Esquema de Medicação , Interações Medicamentosas , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Imunoconjugados/farmacocinética , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/patologia , Masculino , Dose Máxima Tolerável , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prednisona/farmacocinética , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Rituximab/farmacocinética , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Vincristina/farmacocinética
13.
Lancet ; 395(10231): 1195-1207, 2020 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-32145827

RESUMO

BACKGROUND: Optimal treatment regimens for AIDS-associated Kaposi sarcoma, a frequent contributor to morbidity and mortality among people with HIV, have not been systematically evaluated in low-income and middle-income countries, where the disease is most common. In this study, we aimed to investigate optimal treatment strategies for advanced stage disease in areas of high prevalence and limited resources. METHODS: In this open-label, non-inferiority trial, we enrolled people with HIV and advanced stage AIDS-associated Kaposi sarcoma attending 11 AIDS Clinical Trials Group sites in Brazil, Kenya, Malawi, South Africa, Uganda, and Zimbabwe. Eligible participants were randomly assigned (1:1:1) with a centralised computer system to receive either intravenous bleomycin and vincristine or oral etoposide (the investigational arms), or intravenous paclitaxel (the control arm), together with antiretroviral therapy (ART; combined efavirenz, tenofovir disoproxil fumarate, and emtricitabine). The primary outcome was progression-free survival (PFS) at week 48, using a 15% non-inferiority margin to compare the investigational groups against the active control group. Safety was assessed in all eligible treated study participants. The study was registered with ClinicalTrials.gov, NCT01435018. FINDINGS: 334 participants were enrolled between Oct 1, 2013, and March 8, 2018, when the study was closed early due to inferiority of the bleomycin and vincristine plus ART arm, as per the recommendations of the Data and Safety Monitoring Board (DSMB). The etoposide plus ART arm also closed due to inferiority in March, 2016, following a DSMB recommendation. Week-48 PFS rates were higher in the paclitaxel plus ART arm than in both investigational arms. The absolute differences in PFS were -30% (95% CI -52 to -8) for the comparison of paclitaxel plus ART (week 48 PFS 50%, 32 to 67; n=59) and etoposide plus ART (20%, 6 to 33; n=59), and -20% (-33% to -7%) for the comparison of paclitaxel plus ART (64%, 55 to 73; n=138) and bleomycin and vincristine plus ART (44%, 35 to 53; n=132). Both CIs overlapped the non-inferiority margin. The most common adverse events, in 329 eligible participants who began treatment, were neutropenia (48 [15%]), low serum albumin (33 [10%]), weight loss (29 [9%]), and anaemia (28 [9%]), occurring at similar frequency across treatment arms. INTERPRETATION: Non-inferiority of either investigational intervention was not shown, with paclitaxel plus ART showing superiority to both oral etoposide plus ART and bleomycin and vincristine plus ART, supporting its use in treating advanced AIDS-associated Kaposi sarcoma in resource-limited settings. FUNDING: US National Institute of Allergy and Infectious Diseases and National Cancer Institute, National Institutes of Health.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Antibióticos Antineoplásicos/efeitos adversos , Antineoplásicos Fitogênicos/efeitos adversos , Bleomicina/efeitos adversos , Sarcoma de Kaposi/tratamento farmacológico , Vincristina/efeitos adversos , Infecções Oportunistas Relacionadas com a AIDS/mortalidade , Adulto , África , Fármacos Anti-HIV/administração & dosagem , Antibióticos Antineoplásicos/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica , Terapia Antirretroviral de Alta Atividade/métodos , Bleomicina/administração & dosagem , Países em Desenvolvimento , Quimioterapia Combinada , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Humanos , Masculino , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Intervalo Livre de Progressão , Sarcoma de Kaposi/mortalidade , Vincristina/administração & dosagem
14.
Lancet Haematol ; 7(4): e295-e308, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32135128

RESUMO

BACKGROUND: Patients treated for non-Hodgkin lymphoma are at risk of cardiovascular adverse events, with the risk of heart failure being particularly high. A regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone, with (R-CHOP) or without (CHOP) rituximab is the standard first-line treatment for aggressive non-Hodgkin lymphoma, and doxorubicin and cyclophosphamide are both associated with left ventricular dysfunction. The aim of this systematic review and meta-analysis was to evaluate the cardiovascular toxicity of this regimen. METHODS: We systematically searched PubMed, EMBASE, and the Cochrane Library from database inception to June 3, 2019, for clinical trials and observational studies in adult patients with non-Hodgkin lymphoma (diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma, and non-Hodgkin lymphoma not otherwise specified) that received first-line treatment with R-CHOP or CHOP. Studies reporting on cardiovascular adverse events and treatment-related cardiovascular mortality were included. Abstracts and articles not written in English were excluded. The main outcomes were the proportion of patients with grade 3-4 cardiovascular adverse events and heart failure. Meta-analyses of one-sample proportions were done in all patients receiving CHOP or R-CHOP. Subgroup analyses on summary estimates were done to determine the effect of number of CHOP or R-CHOP cycles, cycle interval, age, and sex. FINDINGS: Of 2314 identified entries, 137 studies (21 211 patients) published between April, 1984, and June, 2019 were eligible (9541 patients treated with CHOP, 11 293 patients treated with R-CHOP, 377 both regimens used in the study; median follow-up 39·0 months [IQR 25·5-52·8]). From the included studies, 85 subgroups were treated with CHOP, 76 with R-CHOP, and in four studies both CHOP and R-CHOP were used without a subdivision in separate groups. The pooled proportion for grade 3-4 cardiovascular adverse events, based on 77 studies (n=14 351 patients), was 2·35% (95% CI 1·81-2·93; heterogeneity test Q=326·21; τ2=0·0042; I2=71·40%; p<0·0001). For heart failure, the pooled proportion, based on 38 studies (n=5936 patients), was 4·62% (2·25-7·65; heterogeneity test Q=527·33; τ2=0·0384; I2=95·05%; p<0·0001), with a significant increase in reported heart failure from 1·64% (95% CI 0·82-2·65) to 11·72% (3·00-24·53) when cardiac function was evaluated post-chemotherapy (p=0·017). 53 (39%) of 137 studies were rated as having high risk of bias for incomplete outcome data and 54 (39%) for selective reporting. INTERPRETATION: The considerable increase of reported heart failures with cardiac monitoring, indicates that this complication often remains undiagnosed in patients with non-Hodgkin lymphoma who received first-line R-CHOP or CHOP. Our findings are of importance to raise awareness of this complication among clinicians treating patients with non-Hodgkin lymphoma and stresses the need for cardiac monitoring during and after chemotherapy. Prompt initiation of treatment for heart failure in the presymptomatic phase can mitigate the progression to more advanced heart failure stages. FUNDING: None.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doenças Cardiovasculares/etiologia , Linfoma não Hodgkin/tratamento farmacológico , Rituximab/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doenças Cardiovasculares/patologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Humanos , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Rituximab/efeitos adversos , Índice de Gravidade de Doença , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Vincristina/uso terapêutico
15.
Br J Haematol ; 189(1): 97-105, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32068243

RESUMO

Post-transplant lymphoproliferative disorder (PTLD) may arise after solid organ transplantation, and the most common subtype resembles diffuse large B cell lymphoma (DLBCL). In DLBCL-type PTLD, the anti-CD20 antibody rituximab (R) may be combined with chemotherapy (R-CHOP) or use a strategy (R-primary; similar to the PTLD-1 clinical trial) consisting of induction with four weekly doses of R-alone, without any chemotherapy or sequential R-CHOP follow-up. Here we report on a multicentre retrospective cohort of solid organ transplant patients with DLBCL-type PTLD that were treated with R. In 168 adults, two-year overall survival (OS) was 63·7% [95% CI (confidence interval) 56·6-71·7%]. No difference in OS was observed, whether patients were treated with R-CHOP versus the R-primary strategy. In the 109 patients treated with R-primary, multivariate analysis found that baseline IPI score and the response to R-induction predicted OS. Patients who responded to R-induction had durable remissions without the addition of chemotherapy. Conversely, of the 46 patients who had stable or progressive disease after R-induction (R-failure), those who received R-CHOP had an only marginally improved outcome, with a two-year OS of 45% (23·1-65·3%) vs. no R-CHOP at 32% (14·7-49·8%). In real-world patients, R-failure and high IPI scores predict a poor outcome in DLBCL-type PTLD.


Assuntos
Linfoma Difuso de Grandes Células B , Transplante de Órgãos/efeitos adversos , Complicações Pós-Operatórias , Rituximab , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/etiologia , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/mortalidade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Estudos Retrospectivos , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Taxa de Sobrevida , Vincristina/administração & dosagem , Vincristina/efeitos adversos
16.
Expert Opin Pharmacother ; 21(6): 653-661, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32066288

RESUMO

INTRODUCTION: Double-hit (DHL) and triple-hit lymphomas (THL) have long been among the most clinically aggressive molecular subtypes of diffuse large B-cell lymphomas. In the 2016 revised WHO classification, they represent a new entity called high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6. Unlike most B-cell lymphomas, they have poor response to standard R-CHOP therapy, tend to quickly develop resistance to cytotoxic chemotherapies, and are associated with higher central nervous system (CNS) infiltration. This can lead to increased risk of relapse and worse prognosis. DHL/THL represent a subset of lymphomas with unmet medical need. AREA COVERED: The authors present the available data for the current treatment regimens including intensive chemotherapy regimens, hematopoietic stem-cell transplantation (HSCT), and CNS prophylaxis. They also discuss treatment for relapsed disease including targeted therapies. EXPERT OPINION: There is currently no accepted standard of care for DHL/THL. For frontline therapy, we recommend enrollment in a well-designed clinical trial if possible, otherwise DA-EPOCH-R with CNS prophylaxis is a commonly used first-line therapy. The authors recommend close surveillance for patients achieving complete response, but for those who fail to achieve a complete response, then clinical trials, more aggressive salvage chemotherapy regimens, or cellular therapies are usually considered.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-6/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Humanos , Linfoma Difuso de Grandes Células B/genética , Terapia de Alvo Molecular , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-myc/genética , Recidiva , Prevenção Secundária , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Vincristina/uso terapêutico
17.
Exp Hematol ; 82: 1-7, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32006607

RESUMO

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Therapies for pediatric ALL have improved such that more than 80% of patients survive to 5 years post-therapy, and most survive to adulthood. These ALL patients experience long-term side effects that permanently affect their quality of life, with bone loss and reduced longitudinal growth being the most common skeletal complications. To determine the effects of the chemotherapeutic agents used in ALL induction therapy on bone density and longitudinal growth in mice, we treated juvenile mice with doxorubicin, dexamethasone, vincristine, l-asparaginase, or combination therapy. At adulthood, mice were culled and bones collected and scanned by micro-computed tomography (micro-CT). Mice that received doxorubicin and combination therapy exhibited reduced longitudinal growth and significant reductions in trabecular bone volume, trabecular thickness, and trabecular number, with increased trabecular separation. Mean cortical thickness, cortical area, marrow area, endocortical perimeter, and polar moment of inertia were significantly reduced by doxorubicin and combination therapy. Vincristine treatment significantly decreased trabecular bone volume, trabecular number, and increased trabecular separation but had no effects on cortical bone. Dexamethasone treatment increased trabecular bone separation, cortical marrow area, and cortical bone periosteal perimeter. Mice treated with l-asparaginase did not have any bone phenotypes. In conclusion, these data indicate that the majority of the chemotherapy agents used in induction therapy for pediatric ALL have long-term effects on bone in mice. A single dose of doxorubicin in juvenile mice was sufficient to cause the majority of the bone phenotypes, with combination therapy intensifying these effects.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Osso Esponjoso , Lâmina de Crescimento , Quimioterapia de Indução/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Microtomografia por Raio-X , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Asparaginase/efeitos adversos , Asparaginase/farmacologia , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/crescimento & desenvolvimento , Criança , Dexametasona/efeitos adversos , Dexametasona/farmacologia , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacologia , Lâmina de Crescimento/diagnóstico por imagem , Lâmina de Crescimento/crescimento & desenvolvimento , Humanos , Masculino , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico por imagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Vincristina/efeitos adversos , Vincristina/farmacologia
18.
Int J Hematol ; 111(5): 686-691, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31993939

RESUMO

Vincristine (VCR)-induced peripheral neuropathy (VIPN) is a common and life-long toxicity in lymphoma patients receiving current standard chemotherapy. The association between VIPN and genetic polymorphisms is largely unknown in adult lymphoma patients. To examine the possible relationship between known genetic polymorphisms in patients with pediatric acute lymphoblastic leukemia and incidence of VIPN in adult patients with B cell lymphoma, we examined CEP72 rs924607, ETAA1 rs17032980, MTNR1B rs12786200, CYP3A5 rs776746, rs7963521, and rs1045644 genetic polymorphisms in samples from 56 adult patients with B-cell lymphoma who received rituximab, cyclophosphamide, doxorubicin, VCR, and prednisone (R-CHOP) chemotherapy. Mutation analysis was performed by direct sequencing. The median age was 65 years (range 30-79). The median cumulative dose of VCR was 12 mg (range 2-16). VIPN was documented in 42 patients (75%), and 9 (16%) had grade 2-4 VIPN. Age, impaired glucose tolerance, number of cycles of R-CHOP, and VCR cumulative dose were not associated with incidence of VIPN. There was no association between the incidence of grade 2-4 or any grade VIPN and these six genetic polymorphisms. These results indicate that CEP72, MTNR1B, ETAA1, CYP3A5, rs7963521, and rs1045644 genetic polymorphisms are not associated with VIPN in patients with B-cell lymphoma who received R-CHOP.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Estudos de Associação Genética , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/genética , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Polimorfismo Genético , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Vincristina/efeitos adversos , Antígenos de Superfície/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Citocromo P-450 CYP3A/genética , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Humanos , Proteínas Associadas aos Microtúbulos/genética , Resultados Negativos , Prednisolona/administração & dosagem , Prednisolona/efeitos adversos , Receptor MT2 de Melatonina/genética , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Vincristina/administração & dosagem
20.
Pediatr Blood Cancer ; 67(5): e28174, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31994316

RESUMO

Clinical trials have tested different chemotherapy regimens to improve outcome for patients with rhabdomyosarcoma (RMS), but therapy duration has never been explicitly evaluated. North American trials evolved from longer (104 weeks) to shorter duration (24-42 weeks). In Europe, treatment duration similarly evolved from 35 to 48 to 22 weeks for lower risk patients and from 56 to 72 to 27 weeks for higher risk patients. There was no evidence that chemotherapy duration influenced outcome over time. The recent RMS2005 trial showed an improved survival with the addition of 24 weeks of low-dose chemotherapy. Treatment duration remains a question to be addressed in future trials.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Dactinomicina/administração & dosagem , Dactinomicina/efeitos adversos , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/efeitos adversos , Masculino , Taxa de Sobrevida , Fatores de Tempo , Vincristina/administração & dosagem , Vincristina/efeitos adversos
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