RESUMO
BACKGROUND: Although a myriad of novel treatments entered the treatment paradigm for advanced melanoma, there is lack of head-to-head evidence. We conducted a network meta-analysis (NMA) to estimate each treatment's relative effectiveness and safety. METHODS: A systematic literature review (SLR) was conducted in Embase, MEDLINE and Cochrane to identify all phase III randomised controlled trials (RCTs) with a time frame from January 1, 2010 to March 11, 2019. We retrieved evidence on treatment-related grade III/IV adverse events, progression-free survival (PFS) and overall survival (OS). Evidence was synthesised using a Bayesian fixed-effect NMA. Reference treatment was dacarbazine. In accordance with RCTs, dacarbazine was pooled with temozolomide, paclitaxel and paclitaxel plus carboplatin. To increase homogeneity of the study populations, RCTs were only included if patients were not previously treated with novel treatments. RESULTS: The SLR identified 28 phase III RCTs involving 14,376 patients. Nineteen and seventeen treatments were included in the effectiveness and safety NMA, respectively. For PFS, dabrafenib plus trametinib (hazard ratio [HR] PFS: 0.21) and vemurafenib plus cobimetinib (HR PFS: 0.22) were identified as most favourable treatments. Both had, however, less favourable safety profiles. Five other treatments closely followed (dabrafenib [HR PFS: 0.30], nivolumab plus ipilimumab [HR PFS: 0.34], vemurafenib [HR PFS: 0.38], nivolumab [HR PFS: 0.42] and pembrolizumab [HR PFS: 0.46]). In contrast, for OS, nivolumab plus ipilimumab (HR OS: 0.39), nivolumab (HR OS: 0.46) and pembrolizumab (HR OS: 0.50) were more favourable than dabrafenib plus trametinib (HR OS: 0.55) and vemurafenib plus cobimetinib (HR OS: 0.57). CONCLUSIONS: Our NMA identified the most effective treatment options for advanced melanoma and provided valuable insights into each novel treatment's relative effectiveness and safety. This information may facilitate evidence-based decision-making and may support the optimisation of treatment and outcomes in everyday clinical practice.
Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Azetidinas/administração & dosagem , Azetidinas/uso terapêutico , Benzimidazóis/administração & dosagem , Benzimidazóis/uso terapêutico , Carboplatina/administração & dosagem , Carboplatina/uso terapêutico , Dacarbazina/administração & dosagem , Dacarbazina/uso terapêutico , Humanos , Hidrazinas/administração & dosagem , Hidrazinas/uso terapêutico , Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Interleucina-2/administração & dosagem , Interleucina-2/uso terapêutico , Ipilimumab/administração & dosagem , Ipilimumab/uso terapêutico , Lenalidomida/administração & dosagem , Lenalidomida/uso terapêutico , Melanoma/imunologia , Melanoma/patologia , Metanálise em Rede , Compostos de Nitrosoureia/administração & dosagem , Compostos de Nitrosoureia/uso terapêutico , Nivolumabe/administração & dosagem , Nivolumabe/uso terapêutico , Compostos Organofosforados/administração & dosagem , Compostos Organofosforados/uso terapêutico , Oximas/administração & dosagem , Oximas/uso terapêutico , Paclitaxel/administração & dosagem , Paclitaxel/uso terapêutico , Piperidinas/administração & dosagem , Piperidinas/uso terapêutico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Piridonas/administração & dosagem , Piridonas/uso terapêutico , Pirimidinonas/administração & dosagem , Pirimidinonas/uso terapêutico , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Sorafenibe/administração & dosagem , Sorafenibe/uso terapêutico , Taxa de Sobrevida , Temozolomida/administração & dosagem , Temozolomida/uso terapêutico , Resultado do TratamentoRESUMO
OBJECTIVE: This prospective, randomized, controlled and open-label clinical trial sought to evaluate the tolerability and efficacy of the FTD regimen (fotemustine, teniposide and dexamethasone) compared to HD-MA therapy (high-dose methotrexate plus cytarabine) and to elucidate some biomarkers that influence outcomes in patients with newly diagnosed primary CNS lymphoma. METHODS: Participants were stratified by IELSG risk score (low versus intermediate versus high) and randomly assigned (1:1) to receive four cycles of FTD or HD-MA regimen. Both regimens were administered every 3 weeks and were followed by whole-brain radiotherapy. The primary endpoints were overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). RESULTS: Between June 2012, and June 2015, 52 patients were enrolled, of whom 49 patients were randomly assigned and analyzed. Of the 49 eligible patients, no significant difference was observed in terms of ORR between FTD (n = 24) and HD-MA (n = 25) groups (88% versus 84%, respectively, P = 0.628). Neither the 2-year PFS nor the 3-year OS rate differed significantly between FTD and HD-MA groups (37% versus 39% for 2-year PFS, P = 0.984; 51% versus 46% for 3-year OS, P = 0.509; respectively). The HD-MA group showed more serious neutropenia (P = 0.009) than the FTD group. High Bcl-6 expression correlated with longer OS (P = 0.038). CONCLUSIONS: FTD chemotherapy appeared to be safe and effective for PCNSL patients. High Bcl-6 expression correlated with longer survival.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Linfoma/tratamento farmacológico , Adolescente , Adulto , Idoso , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores Tumorais/metabolismo , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/mortalidade , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Feminino , Humanos , Linfoma/metabolismo , Linfoma/mortalidade , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Compostos de Nitrosoureia/administração & dosagem , Compostos de Nitrosoureia/efeitos adversos , Compostos Organofosforados/administração & dosagem , Compostos Organofosforados/efeitos adversos , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Teniposídeo/administração & dosagem , Teniposídeo/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: In the NIBIT-M1 study, we reported a promising activity of ipilimumab combined with fotemustine in metastatic melanoma (MM) patients with or without brain metastases. To corroborate these initial findings, we now investigated the long-term efficacy of this combination. PATIENTS AND METHODS: This analysis captured the 3-year outcome of MM patients who received ipilimumab combined with fotemustine as first- or second-line treatment. Median overall survival (OS), 3-year survival rates, immune-related (ir) progression-free survival (irPFS), brain PFS, and ir duration of response (irDOR) for the entire population and for patients with brain metastases were assessed. Clinical results were correlated with circulating CD3(+)CD4(+)ICOS(+)CD45RO(+) or CD45RA(+) T cells, neutrophil/lymphocyte (N/L) ratios, and tumorBRAF-V600 mutational status. RESULTS: Eighty-six MM patients, including 20 with asymptomatic brain metastases that had been pre-treated with radiotherapy in 7 subjects, were enrolled in the study. With a median follow-up of 39.9 months, median OS and 3-year survival rates were 12.9 months [95% confidence interval (CI) 7.1-18.7 months] and 28.5% for the whole study population, and 12.7 months (95% CI 2.7-22.7 months) and 27.8% for patients with brain metastases, respectively. Long-term ir adverse events consisting of G1 rush and pruritus occurred in 21% of patients. The absolute increase from baseline to week 12 in 'memory' but not in 'naïve' T cells identified patients with a better survival (P = 0.002). The N/L ratio correlated with a significantly better survival at early time points. BRAF status did not correlate with clinical outcome. CONCLUSIONS: Long-term analysis of the NIBIT-M1 trial continues to demonstrate efficacy of ipilimumab combined with fotemustine in MM patients. Fotemustine does not seem to impair the immunologic activity of ipilimumab. EUDRACT NUMBER: 2010-019356-50. CINICALTRIALSGOV: NCT01654692.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Biológica/mortalidade , Neoplasias Encefálicas/tratamento farmacológico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Feminino , Seguimentos , Humanos , Ipilimumab , Masculino , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos de Nitrosoureia/administração & dosagem , Compostos Organofosforados/administração & dosagem , Prognóstico , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Taxa de SobrevidaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Melanoma/tratamento farmacológico , Neoplasias Uveais/tratamento farmacológico , Idoso , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Metástase Linfática , Masculino , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Compostos de Nitrosoureia/administração & dosagem , Compostos Organofosforados/administração & dosagem , Compostos de Fenilureia/administração & dosagem , Estudos Retrospectivos , Sorafenibe , Taxa de Sobrevida , Neoplasias Uveais/mortalidade , Neoplasias Uveais/patologiaRESUMO
Since multiple myeloma (MM) is still not-curable, the management of relapse remains challenging. Given the known efficacy of alkylating agents in MM, we conducted a phase I/II study to test a new three drug combination in which Fotemustine (Muphoran), an alkylating agent of nitrosurea family, was added to bortezomib + dexamethasone backbone (B-MuD) for the treatment of MM relapsed patients. Fotemustine was administered at two dose levels (80-100 mg/m² i.v.) on day 1. The original 21-day schedule was early amended for extra-hematological toxicity and a 35-day schedule was adopted (Bortezomib 1.3 mg/m² i.v. on days 1, 8, 15, and 22, Dexamethasone 20 mg i.v. on days 1, 8, 15, and 22) for a total of six courses. Twenty-four patients were enrolled. The maximum tolerated dose of Fotemustine was 100 mg/m². The overall response rate was of 62% (CR 8%, VGPR 33%, and PR 21%). The median OS was 28.5 months, the median progression-free survival (PFS) was 19.1 months. B-MuD resulted effective in patients previous exposed to bortezomib without difference of response (P = 0.25) and PFS (P = 0.87) when compared to bortezomib-naive patients. Thrombocytopenia was the most common AE overall. In conclusion, B-MuD is an effective and well tolerated combination in relapsed MM patients even in advanced disease phase.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ácidos Borônicos/uso terapêutico , Dexametasona/uso terapêutico , Mieloma Múltiplo/prevenção & controle , Compostos de Nitrosoureia/uso terapêutico , Compostos Organofosforados/uso terapêutico , Pirazinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/efeitos adversos , Bortezomib , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Estadiamento de Neoplasias , Compostos de Nitrosoureia/administração & dosagem , Compostos de Nitrosoureia/efeitos adversos , Compostos Organofosforados/administração & dosagem , Compostos Organofosforados/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/fisiopatologia , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Prevenção Secundária , Índice de Gravidade de Doença , Análise de Sobrevida , Trombocitopenia/induzido quimicamente , Trombocitopenia/fisiopatologiaRESUMO
A 23-year-old man presented with the right upper monoparesis. The right little finger paresis was apparent at first, and ring finger two weeks later, and middle, index, thumb were simultaneously four weeks later. Then the monoparesis gradually progressed to the proximal upper limb. Magnetic resonance imaging showed a small lesion at the knob of the left precentral gyrus. The lesion was low-intensity on T1-, and high-intensity on T2-weighted images, and clearly detected on high-intensity on FLAIR images, but showed no enhancement by gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA). Angiography and thallium scintigraphy showed no remarkable findings. Proton MR spectroscopy demonstrated lower N-acetylaspartate (NAA) and higher choline (Cho) level compared to the contralateral cortico-subcortical area. Diffusion weighted images demonstrated low apparent diffusion coefficient (ADC) value and high intensity on b = 1,000. To clarify the diagnosis of the lesion, we performed open biopsy by using the neuronavigation system to detect the lesion accurately and minimize the biopsy. Histological examination revealed an high grade astrocytoma with high MlIB-1 index over 30%. The progressive symptoms were due to highly infiltrative and proliferative nature of the tumor arising in the focal hand area of the primary motor cortex, according to the homunculus. We discuss herein the neuroimagings of the case that was considered to be in the initial stage of a malignant tumor.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ácido Aspártico/análogos & derivados , Astrocitoma/diagnóstico , Neoplasias Encefálicas/diagnóstico , Córtex Motor/patologia , Adulto , Ácido Aspártico/metabolismo , Astrocitoma/tratamento farmacológico , Astrocitoma/patologia , Astrocitoma/radioterapia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Terapia Combinada , Imagem de Difusão por Ressonância Magnética , Esquema de Medicação , Gadolínio DTPA , Humanos , Interferon beta/administração & dosagem , Espectroscopia de Ressonância Magnética , Masculino , Compostos de Nitrosoureia/administração & dosagem , Vincristina/administração & dosagemRESUMO
Chemotherapy trials were run with mice bearing transplants of carcinomas originally induced from fetal mouse lung cells by asbestos. After treatments with a nitrosourea (PCNU), mice bearing transplants of a large-cell carcinoma (ASB XIV) had complete remissions (CR) in 13 of 20 animals on a 15 mg/kg regimen, in 6 of 20 on an 8 mg/kg regimen, and in none of 10 on a 4 mg/kg regimen. With comparable total doses, treatment was most effective when PCNU was given in a few large doses. In groups where CRs occurred, continued PCNU treatment of animals without CRs prolonged survival but yielded no additional CRs. No CRs of ASB XIV occurred in 80 mice treated with eight other anticancer agents or in 50 controls injected with 0.9% NaCl solution. In mice bearing transplants of a squamous cell carcinoma (ASB XIII), treatments with PCNU were followed by CRs in 3 of 38 animals on 15 mg/kg regimens and in 3 of 28 animals on 8 mg/kg regimens. In groups of 6 mice fed a retinoid (Ro 10-9359) and treated with PCNU, CRs of ASB XIII occurred in 3 animals in each of two trials and in none in a third trial. Ro 10-9359 inhibited growth of transplants of squamous cell carcinoma LC 12 that had been induced from fetal mouse lung cells by a polycyclic hydrocarbon. In trials of four other anticancer agents vs. ASB XIII, CRs occurred only with cyclophosphamide (CPA). There were 7 CRs among 8 mice treated with CPA 100 mg/kg x 3, no CRs in 10 after 100 mg/kg x 2, one CR in 8 after 50 mg/kg x 3, and no CRs in 6 after 50 mg/kg x 4. With the 50 mg/kg x 4 regimen of CPA and 7.5 mg/kg PCNU on the same days, there were 5 CRs in 8 mice. As a single agent, aziridinylbenzoquinone (AZQ) increased life span but gave no CRs. There were CRs of ASB XIII in all of 8 mice after toxic combined therapy with PCNU and AZQ. There were no CRs in 66 control mice bearing ASB XIII.
Assuntos
Antineoplásicos/uso terapêutico , Asbestos Serpentinas/toxicidade , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Compostos de Nitrosoureia/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Aziridinas/administração & dosagem , Aziridinas/uso terapêutico , Benzoquinonas/administração & dosagem , Benzoquinonas/uso terapêutico , Carcinoma de Células Escamosas/induzido quimicamente , Carcinoma de Células Escamosas/mortalidade , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Dianidrogalactitol/administração & dosagem , Dianidrogalactitol/uso terapêutico , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/mortalidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mitoxantrona/administração & dosagem , Mitoxantrona/uso terapêutico , Modelos Animais , Compostos de Nitrosoureia/administração & dosagem , Pentostatina/administração & dosagem , Pentostatina/uso terapêutico , Indução de Remissão , Análise de Sobrevida , Triazinas/administração & dosagem , Triazinas/uso terapêuticoRESUMO
We report here a 20-year-old man presenting with primary nasal NK/T-cell lymphoma which showed an aggressive clinical course spreading to the spleen and skin despite various treatments. Eight months after high dose chemotherapy followed by autologous peripheral blood stem cell transplantation, acute appendicitis with perforation occurred and the patient underwent appendectomy. The histopathological diagnosis was NK/T-cell lymphoma of the appendix. Lymphoma of the appendix is extremely rare and the majority of appendiceal lymphomas are of B-cell origin. This is the first report of involvement of appendix by nasal NK/T-cell lymphoma.
Assuntos
Neoplasias do Apêndice/secundário , Linfoma de Células T/patologia , Neoplasias Nasais/patologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apendicectomia , Neoplasias do Apêndice/complicações , Neoplasias do Apêndice/cirurgia , Apendicite/etiologia , Bleomicina/administração & dosagem , Cisplatino/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Doxorrubicina/administração & dosagem , Infecções por Vírus Epstein-Barr , Etoposídeo/administração & dosagem , Humanos , Perfuração Intestinal/etiologia , Células Matadoras Naturais/patologia , Leucovorina/administração & dosagem , Linfoma de Células T/complicações , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/radioterapia , Masculino , Metotrexato/administração & dosagem , Metilprednisolona/administração & dosagem , Compostos de Nitrosoureia/administração & dosagem , Neoplasias Nasais/tratamento farmacológico , Prednisona/administração & dosagem , Neoplasias Cutâneas/secundário , Neoplasias Esplênicas/secundário , Infecções Tumorais por Vírus , Vincristina/administração & dosagemRESUMO
The mixed lineage leukemia (MLL) gene located at chromosome band 11q23 is frequently rearranged in patients with therapy-related acute monocytic leukemia who received topoisomerase II inhibitors. We have identified a novel fusion partner of MLL (FAB M5b) in a patient who developed t-AML 9 years after treatment for acute lymphoblastic leukemia (ALL). The leukemic cells had a sole karyotypic abnormality of t(3;11) (p21;q23). Screening of a genomic DNA library, prepared from leukemic cell DNA, identified rearranged clones composed of MLL and a novel gene on chromosome 3p21 (AF3p21). The AF3p21 gene encodes a protein of 722 amino acids, which contains an Src homology 3 (SH3) domain, a proline-rich domain, and a bipartite nuclear localizing signal (NLS). RNA analysis demonstrated that exon 6 of the MLL gene fused to exon 2 of the AF3p21 gene. The resulting chimeric protein consists of AT-hooks, methyltransferase, and transcription repressor domains of MLL in addition to the AF3p21 proline-rich domain and NLS but not the AF3p21 SH3 domain.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Leucemia Monocítica Aguda/genética , Proteínas Musculares , Segunda Neoplasia Primária/genética , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Domínios de Homologia de src/genética , Adolescente , Sequência de Aminoácidos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sequência de Bases , Transplante de Medula Óssea , Terapia Combinada , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , DNA Complementar/genética , Daunorrubicina/administração & dosagem , Daunorrubicina/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Humanos , Leucemia Monocítica Aguda/induzido quimicamente , Leucemia Monocítica Aguda/tratamento farmacológico , Leucemia Monocítica Aguda/terapia , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Dados de Sequência Molecular , Proteína de Leucina Linfoide-Mieloide , Segunda Neoplasia Primária/induzido quimicamente , Segunda Neoplasia Primária/tratamento farmacológico , Segunda Neoplasia Primária/terapia , Compostos de Nitrosoureia/administração & dosagem , Compostos de Nitrosoureia/efeitos adversos , Alinhamento de Sequência , Homologia de Sequência do Ácido NucleicoRESUMO
Cystemustine is a new nitrosourea with high anti-tumor activity and a short plasma half-life in mice. The influence of circadian dosing time upon its toxicities was first investigated in a total of 368 synchronized male B6D2F1 mice. Late survival rate varied from 4% in mice receiving a single dose of cystemustine (conventional lethal dose 50%) at 7 hours after light onset (HALO) up to 88% in mice treated at 15 or at 19 HALO. Target organ toxicities (bone marrow, circulating blood cells, spleen, colon and duodenum) were studied following a single slightly lower dose of cystemustine. Leukopenia was the major hematologic effect encountered. Leukocyte count nadir occurred 7 days after injection and was lowest following cystemustine at 7 HALO as compared to 13 or 19 HALO. Recovery was faster after cystemustine at 19 HALO as compared to other dosing times. Bone-marrow necrotic lesions were more pronounced 1 day after cystemustine at 7 HALO than after cystemustine at 19 HALO. Thus, a large-amplitude circadian rhythm characterized the toxicity of this nitrosourea in mice. The lowest cystemustine toxicity was found near the middle of the active span of the rest-activity circadian cycle of mice.
Assuntos
Antineoplásicos/administração & dosagem , Cronoterapia , Compostos de Nitrosoureia/administração & dosagem , Animais , Antineoplásicos/toxicidade , Masculino , Camundongos , Compostos de Nitrosoureia/toxicidadeRESUMO
Over the past 25 years, we have treated 17 patients with chiasmo-hypothalamic astrocytomas. Before 1988, the initial treatments consisted of surgery and/or radiotherapy, while since 1989, 4 children (1 male, 3 females, aged 3-8 years) were treated primarily with chemotherapy. None of them was associated with neurofibromatosis. After a biopsy of the tumor, the intravenous administration of ranimustine (MCNU; 30-86 mg/m2) and/or nimustine (ACNU; 30.3-64.1 mg/m2) was given without radiation therapy. Chemotherapy was usually given as an out-patient, with a total of 5-13 courses. The total doses of MCNU and ACNU administered ranged from 150 to 570 mg and from 64.8 mg to 100 mg, respectively. After chemotherapy 2 patients showed clinical improvement and tumor regression on neuro-imaging, while one patient showed clinical improvement and tumor size stabilization on neuro-imaging. The remaining one child, however, showed a clinical worsening and tumor progression on neuro-imaging studies. He was thus treated with a second chemotherapy regimen with carboplatin and etoposide, which brought about tumor regression. The acute and subacute toxicity of chemotherapy was mild. All patients are now leading almost normal lives with a median of 43 months after diagnosis. Although a longer and more careful clinical observation is required, the authors conclude that chemotherapy with MCNU and/or ACNU may benefit patients with unresectable pilocytic astrocytoma requiring treatment. The advantages of this therapy include its mild side effects and the lack of any hospitalization in most patients. It may also delay the need for radiation therapy, which can have a deleterious effect on the young developing brain.
Assuntos
Antineoplásicos/uso terapêutico , Astrocitoma/tratamento farmacológico , Neoplasias Encefálicas/tratamento farmacológico , Carboplatina/uso terapêutico , Quimioterapia Adjuvante , Etoposídeo/uso terapêutico , Hipotálamo/patologia , Nimustina/uso terapêutico , Compostos de Nitrosoureia/uso terapêutico , Quiasma Óptico/patologia , Antineoplásicos/administração & dosagem , Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Carboplatina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Nimustina/administração & dosagem , Compostos de Nitrosoureia/administração & dosagemAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/terapia , Neoplasias Hepáticas/terapia , Neoplasias Pulmonares/cirurgia , Adulto , Quimioterapia Adjuvante , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Feminino , Fluoruracila/administração & dosagem , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Compostos de Nitrosoureia/administração & dosagem , Taurina/administração & dosagem , Taurina/análogos & derivadosRESUMO
Tumour uptake of a radiolabelled anticancer drug, tauromustine ([14C]TCNU), was investigated, using two different routes of administration in rats with colon adenocarcinomas implanted in the liver. Intra-arterial administration produced higher concentrations of the drug and/or its metabolites in tumour tissue and lower concentrations in normal tissue compared to intravenous administration. The investigation of co-injection of [14C]TCNU intra-arterially with degradable starch microspheres (DSM) indicated that a high dose of DSM (30 mg/kg) resulted in a high concentration of radioactivity in normal liver tissue, and in adjacent organs. This unfavourable pattern was not observed with the low dose of DSM (12.5 mg/kg), which produced a significant increase in tumour uptake. The results demonstrate the efficacy of partial vascular blockade, as elicited by the low dose of DSM. This regime caused [14C]TCNU to be preferentially retained in the active peripheral regions of the tumour.
Assuntos
Adenocarcinoma/metabolismo , Antineoplásicos/farmacocinética , Neoplasias do Colo/metabolismo , Compostos de Nitrosoureia/farmacocinética , Taurina/análogos & derivados , Animais , Antineoplásicos/administração & dosagem , Radioisótopos de Carbono , Injeções Intra-Arteriais , Injeções Intravenosas , Masculino , Microesferas , Transplante de Neoplasias , Compostos de Nitrosoureia/administração & dosagem , Ratos , Ratos Wistar , Taurina/administração & dosagem , Taurina/farmacocinética , Fatores de Tempo , Distribuição TecidualRESUMO
We have developed a localized hyperthermia system using computed tomography-stereotactic surgery as malignant brain tumor therapy. In an experimental study, the temperature in the area of the cat brain within 20 mm from a radiofrequency electrode reached more than 43.7 degrees C. Intravenous administration of MCNU during hyperthermia caused a significant increase of MCNU content in the heated brain as compared with a control brain. In the clinical study, localized radiofrequent hyperthermia using stereotactic surgery was performed on 7 malignant deep-seated gliomas and 21 metastatic brain tumors. Especially, combination therapy of stereotactic hyperthermia and chemotherapy was effective treatment for gliomas less than 30 mm deep in the brain.
Assuntos
Antineoplásicos , Neoplasias Encefálicas/terapia , Hipertermia Induzida/instrumentação , Compostos de Nitrosoureia/administração & dosagem , Técnicas Estereotáxicas/instrumentação , Tomografia Computadorizada por Raios X/instrumentação , Adolescente , Adulto , Idoso , Animais , Astrocitoma/tratamento farmacológico , Astrocitoma/terapia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Gatos , Terapia Combinada , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/terapia , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-IdadeRESUMO
In order to evaluate the efficacy of surgical adjuvant chemotherapy in patients undergoing gross curative resection for colorectal cancer (excluding m and sm cancer), a randomized controlled study was conducted from January, 1982 to October, 1983. Four hundred and ninety-one institutions participated in this study. The schedules for drug administration differed according to each district. In the Hokkaido and Shikoku districts, the patients were divided into the following two groups, one was a combination of ACNU and Futraful (FT) and the other was FT only. In the Chubu and Kinki districts, three groups were studied, namely those receiving a combination of ACNU and FT, those receiving FT only and those given no adjuvant chemotherapy. In the Tohoku and Kanto districts, a combination of MMC and FT and administration of FT only were studied. In the Chugoku and Kyushu districts, the patients were divided into a combination of ADM and FT, and FT only group. Among the 3,926 registered cases, 3,421 cases were valid for the study. As to the background factors, there were no significant differences among the groups in each district. There were no significant differences in one-year survival rates and one-year disease-free rates. No serious adverse effects were observed in any of the groups.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias Retais/tratamento farmacológico , Alopecia/induzido quimicamente , Neoplasias do Colo/mortalidade , Neoplasias do Colo/cirurgia , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Leucopenia/induzido quimicamente , Mitomicina , Mitomicinas/administração & dosagem , Nimustina , Compostos de Nitrosoureia/administração & dosagem , Compostos de Nitrosoureia/efeitos adversos , Período Pós-Operatório , Prognóstico , Distribuição Aleatória , Neoplasias Retais/mortalidade , Neoplasias Retais/cirurgiaRESUMO
The prognosis of patients with unresectable intracerebral primary and metastatic tumours that recur following cranial irradiation is poor. Chemotherapy agents have been of limited value. PCNU--a new nitrosourea, has been shown to have the optimum log P for treatment of murine intracerebral tumours. We conducted a preclinical toxicological study of intracarotid injection of PCNU in dogs. Our results show that there was no major neurological or retinal toxicity from the drug, suggesting that PCNU may be less toxic than the presently available BCNU.
Assuntos
Alquilantes/toxicidade , Antineoplásicos/toxicidade , Compostos de Nitrosoureia/toxicidade , Alquilantes/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Artérias Carótidas , Cães , Avaliação Pré-Clínica de Medicamentos , Feminino , Infusões Intra-Arteriais , Masculino , Compostos de Nitrosoureia/administração & dosagemRESUMO
The effects of heat and antitumor drugs on malignant brain tumor cell lines were studied. A human glioblastoma cell line (SKMG1) and rat malignant brain tumor cell lines (T9, EB 679 and TR 481) were used in this experiment. Five different modalities of treatment with heat and drugs were used as follows: (Group 1) exposure to heat alone at 42 degrees C for one hour; (Group 2) exposure to antitumor drug alone for one hour (ACNU 2.5 or 5 micrograms/ml, ACR 0.02 micrograms/ml and CDDP 1 microgram/ml); (Group 3) simultaneous exposure to heat at 42 degrees C and drug for one hour; (Group 4) heat at 42 degrees C given first for one hour, followed by one hour exposure to drug one hour later ("preheating"); (Group 5) drug given first for one hour, followed by one hour exposure to heat at 42 degrees C one hour later ("postheating"). After each treatment, the inhibition rate at 4 days was evaluated and compared for each group. A synergistic effect was observed in Group 3. For example, when T9 cells were exposed to ACNU and to heat at 42 degrees C at the same time for one hour, inhibition rate was 78%, while the rates for Group 1 and Group 2 were 7% and 21%, respectively. The cytotoxicity of simultaneous treatment with antitumor drugs (ACNU, ACR and CDDP) and hyperthermia at 42 degrees C was apparently superior to that of other treatment modalities.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/terapia , Glioma/terapia , Hipertermia Induzida , Aclarubicina , Animais , Antibióticos Antineoplásicos , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular , Cisplatino/administração & dosagem , Terapia Combinada , Glioma/tratamento farmacológico , Humanos , Naftacenos/administração & dosagem , Nimustina , Compostos de Nitrosoureia/administração & dosagem , RatosRESUMO
Combined effects of ACNU and 5-Fu on rat glioma clone-6 cells grown exponentially as monolayers and in multicell spheroids (500-600 micron in diameter) were analyzed by the colony-forming assay. Cells in spheroids with central necroses were more sensitive to ACNU than cells in monolayer, although a large fraction of the cells in these spheroids was resistant to 5-Fu. The effect of ACNU was enhanced by the combined treatment with 5-Fu for cells in both spheroids and monolayers, and was more remarkable when 5-Fu was administered 24 hr prior to ACNU treatment. The enhancement was mainly due to a decrease in the number of spheroid-cells resistant to 5-Fu. Isobologram analysis indicated that the enhancement was supra-additive when a low concentration of 5-Fu was combined with a high concentration of ACNU. It is suggested that a low dose of 5-Fu combined with a high dose of ACNU may preferentially kill more cells in solid tumors.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Fluoruracila/administração & dosagem , Glioma/tratamento farmacológico , Compostos de Nitrosoureia/administração & dosagem , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Glioma/patologia , Nimustina , RatosRESUMO
Hyperthermic treatment using ACNU combined with a thermosensitizing drug, methylglyoxal-bis-guanylhydrazone (MGBG), was studied in human gastric cancer xenotransplanted into nude mice. In order to increase the intra-cellular MGBG content, intraperitoneal injection of alpha-difluoromethylornithine(DFMO) 1000 mg/kg was performed twice with an interval of 6 hours and 50 mg/kg of MGBG was given at the time of the second administration of DFMO. After 6 hours of MGBG administration, ACNU 20 mg/kg was given intraperitoneally and, subsequently a 23-minute hyperthermia was carried out in a water bath at 43.5 degrees C. After 48 hours a second hyperthermia was performed by the same method. Tumor weight was estimated using Battelle's Columbus Institute protocol and the inoculated tumors, which were extirpated 60 minutes after 3H-thymidine injection at a prescribed interval after cessation of hyperthermia, were assayed biochemically for the determination of DNA biosynthesis. In mice given ACNU, DFMO, MGBG plus heat, considerably superior results were obtained. Although the DFMO plus MGBG group was inferior in antitumor activity to the ACNU only or heat only group, the DFMO, MGBG plus heat group showed much the same antitumor effects, compared to the ACNU plus heat group. These data suggest that the thermosensitizing efficacy of MGBG may be applicable for clinical use.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Hipertermia Induzida , Neoplasias Gástricas/terapia , Animais , Replicação do DNA/efeitos dos fármacos , Eflornitina , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Mitoguazona/administração & dosagem , Transplante de Neoplasias , Nimustina , Compostos de Nitrosoureia/administração & dosagem , Ornitina/administração & dosagem , Ornitina/análogos & derivadosRESUMO
Combinations of retinol palmitate (RP) and six different anticancer agents were examined to determine their effects on the life-span of mice bearing ascites sarcoma 180 or P388 leukemia. With ascites sarcoma 180, administration of a fixed dose of RP (3.3 mg/kg) considerably enhanced the antitumor effects of 5-fluorouracil (5-FU) (5 mg/kg, or 20 mg/kg), methotrexate (MTX) (0.5 mg/kg, or 1 mg/kg) and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) (12.5 mg/kg), when given by intraperitoneal injection. However RP failed to potentiate the antitumor effects of adriamycin (ADM) and 6-mercaptopurine (6-MP) against sarcoma 180. With P388 leukemia, RP (167 mg/kg, or 333 mg/kg) enhanced the antitumor effects of 6-MP (25 mg/kg, or 50 mg/kg), MTX (1 mg/kg, or 2 mg/kg), ADM (0.2 mg/kg), ACNU (5 mg/kg) and cis-dichlorodiammine-platinum (CDDP) (1 mg/kg) to a considerable extent, but it did not potentiate the antitumor effect of 5-FU. The combination of RP with ACNU or CDDP was particularly effective against P388 leukemia.