RESUMO
PURPOSE: Considering the increased cancer patient survivorship, the focus is now on addressing the impacts of treatment on quality of life. In young people, altered reproductive function is a major issue and its effects in young males are largely neglected by novel research. To improve clinician awareness, we systematically reviewed side effects of chemotherapy for Hodgkin lymphoma (HL) in young males. METHODS: The review was prospectively registered (PROSPERO N. CRD42019122868). Three databases (Medline via PUBMED, SCOPUS, and Cochrane Library) were searched for studies featuring males aged 13-51-years who underwent chemotherapy for HL using ABVD (Adriamycin® (doxorubicin), bleomycin, vinblastine, and dacarbazine) or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone) regimens. These chemotherapy regimens were compared against each other using sperm characteristics, FSH, and inhibin B levels to measure fertility levels. RESULTS: Data were extracted from five studies featuring 1344 patients. 6 months post-ABVD saw marked deterioration in sperm count, further reduced by more cycles (P = 0.05). Patients treated with BEACOPP rather than ABVD were more prone to oligospermia. Receiving fewer cycles of both regimens increased the likelihood of sperm production recovering. Patients treated with 6-8 cycles of BEACOPP did not recover spermiogenesis. CONCLUSIONS: ABVD and BEACOPP regimens significantly reduce fertility function to varying effects depending on treatment duration. ABVD temporarily causes significant reductions in male fertility, whereas BEACOPP's effects are more permanent. Therefore, clinicians should discuss fertility preservation with male patients receiving infertility-inducing gonadotoxic therapy. Further high-quality studies are required to more adequality describe the risk to fertility by chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Fertilidade/efeitos dos fármacos , Doença de Hodgkin/tratamento farmacológico , Infertilidade Masculina/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bleomicina/efeitos adversos , Bleomicina/farmacologia , Bleomicina/uso terapêutico , Ciclofosfamida/efeitos adversos , Ciclofosfamida/farmacologia , Ciclofosfamida/uso terapêutico , Dacarbazina/efeitos adversos , Dacarbazina/farmacologia , Dacarbazina/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Etoposídeo/efeitos adversos , Etoposídeo/farmacologia , Etoposídeo/uso terapêutico , Humanos , Masculino , Prednisona/efeitos adversos , Prednisona/farmacologia , Prednisona/uso terapêutico , Procarbazina/efeitos adversos , Procarbazina/farmacologia , Procarbazina/uso terapêutico , Vimblastina/efeitos adversos , Vimblastina/farmacologia , Vimblastina/uso terapêutico , Vincristina/efeitos adversos , Vincristina/farmacologia , Vincristina/uso terapêuticoRESUMO
Resumo Objetivo Identificar os sinais e sintomas apresentados por pacientes com Linfoma de Hodgkin submetidos ao protocolo quimioterápico composto por Doxorrubicina, Bleomicina, Vimblastina e Dacarbazina (ABVD) por meio de aconselhamento telefônico e comparar os escores de gradação dos sinais e sintomas apresentados nos ciclos do protocolo. Métodos Descritivo, prospectivo, quantitativo. Sete pacientes receberam aconselhamento telefônico, em 24 tempos de chamadas programadas e não programadas, correspondentes a 6 ciclos de quimioterapia com protocolo ABVD. Utilizou-se o Inventário de Sintomas do M.D Anderson e o Critério Comum de Terminologia para Eventos Adversos, para a gradação dos sintomas e um protocolo de condutas. Realizou-se análise descritiva e analítica. Resultados Duzentas e oitenta e seis chamadas telefônicas geraram1.870 queixas sintomáticas. Nas chamadas programadas, as queixas com maior prevalência foram fadiga, preocupações, falta de apetite, vômitos e náuseas. Quanto a interferência nas atividades de vida diária, os itens relacionados a atividades em geral, no trabalho e dificuldade para caminhar, além de alterações no humor foram relatados em maior frequência. Nas chamadas não programadas, a falta de apetite e desregulação menstrual foram as queixas mais recorrentes. Na análise da progressão dos sintomas, observou-se aumento de náuseas e vômitos (p=0,02), diminuição da fadiga e falta de ar (p≤0,03), melhora do sono (p=0,02) e diminuição do estresse (p=0,02). Conclusão A fadiga, náusea, vômito e alteração nas atividades de trabalho foram relatados frequentemente. Houve progressão de náuseas e vômitos, mas regressão da fadiga e do estresse. O aconselhamento telefônico permitiu a comunicação e o manejo rápido de um número expressivo de sintomas.
Resumen Objetivo Identificar los signos y síntomas presentados por pacientes con linfoma de Hodgkin sometidos al protocolo quimioterápico compuesto por doxorrubicina, bleomicina, vinblastina y dacarbazina (ABVD) mediante consulta telefónica, y comparar los puntajes de graduación de los signos y síntomas presentados en los ciclos del protocolo. Métodos Descriptivo, prospectivo, cuantitativo. Siete pacientes recibieron asesoramiento telefónico en 24 momentos de llamadas programadas y no programadas, correspondientes a 6 ciclos de quimioterapia con protocolo ABVD. Se utilizó el Inventario de Síntomas de M. D. Anderson y el Criterio de Terminología Común para Efectos Adversos, para la puntuación de lis síntomas, y un protocolo de conductas. Se realizó análisis descriptivo y analítico. Resultados Doscientas ochenta y seis llamadas telefónicas determinaron 1.870 quejas sintomáticas. En las llamadas programadas, las quejas más prevalentes fueron: fatiga, preocupaciones, falta de apetito, vómitos y náuseas. Respecto a interferencia en actividades cotidianas, los ítems relacionados con actividad en general, laboral y dificultad para caminar, además de cambios del humor, fueron informados con mayor frecuencia. En llamadas no programadas, la falta de apetito y la irregularidad menstrual resultaron las quejas más habituales. En el análisis de progresión de los síntomas se observó aumento de náuseas y vómitos (p=0,02), disminución de fatiga y falta de aire (p≤0,03), mejora del sueño (p=0,02) y disminución del estrés (p=0,02). Conclusión Hubo informe frecuente de fatiga, náuseas, vómitos y cambios en actividades laborales. Existió progresión de náuseas y vómitos, y regresión de fatiga y estrés. La consulta telefónica permitió comunicación y rápido manejo de una expresiva cantidad de síntomas.
Abstract Objective To identify through telephone counselling the signs and symptoms presented by patients with Hodgkin's Lymphoma undergoing chemotherapy with the protocol composed by doxorubicin, bleomycin, vinblastine and dacarbazine and to compare severity scores of the signs and symptoms presented in the cycles of the protocol. Methods Descriptive, prospective, quantitative study. Seven patients received telephone counselling in 24 scheduled and unscheduled calls, corresponding to 6 ABVD chemotherapy cycle. The MD Anderson Symptom Inventory and the Common Terminology Criteria for Adverse Events were used for scoring the symptoms, along with a conduct protocol. A descriptive and analytical analysis was conducted. Results Two hundred and eighty-six telephone calls generated 1,870 symptomatic complaints. In scheduled calls, the most prevalent complaints were fatigue, distress, lack of appetite, vomiting and nausea. As for the interference in daily life activities, the items related to general activities, work, difficulty walking, and mood changes were reported more frequently. In unscheduled calls, lack of appetite and irregular menstruation were the most recurring complaints. The analysis of the progression of symptoms showed an increase in nausea and vomiting (p=0.02), decrease in fatigue and shortness of breath (p≤0.03), improvement in sleep (p=0.02) and decrease of stress (p=0.02). Conclusion Fatigue, nausea, vomiting and alterations in work activities were frequently reported. There was progression of nausea and vomiting but regression of fatigue and stress. Telephone consultation allowed a rapid communication and management of an expressive number of symptoms.
Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto , Telefone , Doença de Hodgkin/tratamento farmacológico , Educação em Saúde , Antineoplásicos Alquilantes/efeitos adversos , Aconselhamento a Distância , Antibióticos Antineoplásicos/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos Fitogênicos/efeitos adversos , Vimblastina/efeitos adversos , Bleomicina/efeitos adversos , Doxorrubicina/efeitos adversos , Epidemiologia Descritiva , Estudos Prospectivos , Dacarbazina/efeitos adversos , Estudos de Avaliação como AssuntoRESUMO
Hodgkin's lymphoma (HL) is a lymphoid malignancy representing 5% of all cancers in children, 16% in adolescents, and 30-40% of all malignant lymphomas and has a survival rate of ~95% at 10 years. One of the most common treatment schemes uses a cocktail of genotoxic agents including adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) with or without radiotherapy. We investigated the occurrence of chromosomal damage in peripheral blood lymphocytes from five patients diagnosed with HL who provided samples before (BT), during chemotherapy (DT) and ~1 year after ABVD chemotherapy/radiotherapy (AT). Five healthy subjects served as controls. Chromosomal abnormalities were evaluated by multicolor fluorescence in situ hybridization. The average frequencies of structural chromosomal aberrations in HL samples were 0.11, 0.22, and 0.96 per cell in BT, DT, and AT samples, respectively. These frequencies were significantly different (P < 0.0001) with respect to control subjects (0.02 per cell). Interestingly, the highest frequency of structural damage, including genomic chaos and nonclonal abnormalities, was observed in the AT samples indicating that new aberrations were continuously produced. Rejoined structural chromosomal aberrations were the most common type of aberrations, although aneuploidies were also significantly increased. Finally, we found several chromosomal abnormalities linked to cancer secondary to treatment in all five HL patients. Our results show that ABVD chemotherapy plus radiotherapy is inducing genomic chaos in vivo; moreover, the persistence of genomic instability in the hematopoietic stem cells from HL patients may play a role in the occurrence of secondary cancer that is observed in 5-20% of HL patients. Environ. Mol. Mutagen. 59:755-768, 2018. © 2018 Wiley Periodicals, Inc.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimiorradioterapia/efeitos adversos , Aberrações Cromossômicas/induzido quimicamente , Dano ao DNA/efeitos dos fármacos , Doença de Hodgkin/terapia , Linfócitos/citologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bleomicina/efeitos adversos , Bleomicina/uso terapêutico , Dano ao DNA/genética , Dacarbazina/efeitos adversos , Dacarbazina/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Feminino , Doença de Hodgkin/genética , Humanos , Masculino , Células Tumorais Cultivadas , Vimblastina/efeitos adversos , Vimblastina/uso terapêutico , Adulto JovemRESUMO
OBJECTIVE: Prospective analysis of clinical characteristics and long-term treatment results of a pediatric cohort with Hodgkin lymphoma (HL) treated in a single institution with ABVD and restricted radiotherapy (RT). PATIENTS AND METHODS: Between September 2000 and December 2015, 165 new consecutive assessable patients with HL were registered at our institution. Lymphocyte predominant nodular HL was excluded. Low risk (LR) patients were stage I and IIA (no bulky disease, <4 involved ganglionar areas and no lung hilar nodes), high risk (HR) was assigned to stage IV and any other stage with bulky mediastinum. The rest of the cohort was treated as intermediate risk (IR). Chemotherapy for LR and IR patients was 4 and 6 courses of ABVD regimen, respectively. These subsets received Low-dose involved field radiotherapy only in case of partial remission at the end of chemotherapy (21 Gy in initially involved areas, plus 14 Gy boost on residual disease). The HR group was treated with 6 courses of ABVD followed always with 21 Gy involved field radiotherapy if complete remission (CR) was achieved. A boost of 14 Gy was added to residual disease in case of partial remission. RESULTS: Median age was 10.6 years (range, 2.7 to 17 y). Males: 117 (71%); females: 48 (29%). Eighteen (11%) patients were stage I, 76 (46%) stage II, 35 (21%) stage III, and 35 (21%) stage IV. Forty-nine (30%) patients were assigned to LR, 49 (30%) to IR, and 67 (40%) to HR. Forty-three patients (26%) had "bulky" mediastinum involvement. One hundred thirty (79%) patients achieved CR after chemotherapy and 161 (98%) after RT. Four patients (all HR), did not respond to initial therapy and died of disease. One patient died in first CR due to adenovirus infection on previously therapy-related damaged lungs. Seventeen (10%) patients relapsed and 13 of them remained in second CR after further therapy. Seventy-six (46%) patients could be spared from RT and cured of disease (88% of LR patients and 67% of IR patients). With a median follow-up of 5 years, event free and overall survival were 0.84 (SE: 0.03) and 0.95 (SE: 0.02), respectively. Overall survival according to risk group was 1 for LR, 0.93 for IR, and 0.85 for HR. Acute toxicity and late effects due to therapy were not significant. CONCLUSIONS: The strategy of avoiding RT for LR and IR patients that responded completely to ABVD chemotherapy achieved very good results. For the HR group, the combination of 6 cycles of ABVD and Low-dose involved field radiotherapy was efficacious with similar good results. Nearly half of the patients could be cured without RT.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/radioterapia , Radioterapia Adjuvante , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bleomicina/efeitos adversos , Bleomicina/uso terapêutico , Quimiorradioterapia , Criança , Pré-Escolar , Dacarbazina/efeitos adversos , Dacarbazina/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Feminino , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/mortalidade , Humanos , Masculino , Imagem Multimodal , Estadiamento de Neoplasias , Análise de Sobrevida , Resultado do Tratamento , Vimblastina/efeitos adversos , Vimblastina/uso terapêuticoRESUMO
BACKGROUND: Temozolomide is an antineoplastic agent of proven efficacy against high-grade gliomas. PURPOSE: The objective of this crossover, single-dose, bioequivalence study was to compare the rate and extent of absorption of oral temozolomide after administration of the study product (Dralitem®, Monte Verde Sociedad Anónima) and the reference product (Temodal®, originator product manufactured by Schering Plough Laboratories) in patients with primary central nervous system (CNS) tumors under fasting conditions. METHODS: Sixteen male and female subjects with primary CNS tumors (excluding CNS lymphoma) were recruited, and were administered temozolomide 200 mg/m2 (Dralitem®) on days 1, 2 and 5 of a 5-day treatment. On days 3 and 4, subjects received the same dose of the test product (Dralitem®), or the reference product (Temodal®) on alternate days. The single dose of 200 mg/m2 was reached with three different temozolomide capsule strengths: 20, 100 and 250 mg. On days 3 and 4, blood samples were obtained for pharmacokinetic (PK) evaluation after drug administration. RESULTS: Bioequivalence assessment was made for the 90% confidence interval (CI) for the ratio of log-transformed means (µT/µR) of the area under the concentration-time curve (AUC from time zero to the final quantifiable sample [AUCt] and AUC from time zero to infinity [AUC∞]) and maximum concentration (C max) of both the test (Dralitem®) and reference (Temodal®) products. The point estimate and 90% CI of the ratios of C max, AUCt and AUC∞ values were 94.37 (82.69-107.69), 100.99 (97.81-104.28) and 101.53 (98.60-104.54), respectively. The ratio met the predefined bioequivalence criteria (i.e. 90% CI between 80.00 and 125.00) for C max and AUC. The most commonly reported adverse events (AE) on this study were vomiting, abdominal pain, asthenia and weakness. One subject experienced expressive aphasia, possibly unrelated to the study drug and with no significant sequelae upon recovery. No serious AEs or unexpected AEs were reported. CONCLUSIONS: Temozolomide Dralitem® capsules, 20, 100 and 250 mg, were bioequivalent to Temodal® capsules under fasting conditions in patients with CNS primary tumors, supporting that they are therapeutic equivalents. ClinicalTrials.gov Identifier: NCT02343081.
Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Dacarbazina/análogos & derivados , Adulto , Idoso , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/farmacocinética , Área Sob a Curva , Cápsulas , Estudos Cross-Over , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Dacarbazina/farmacocinética , Relação Dose-Resposta a Droga , Jejum , Feminino , Glioma/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Temozolomida , Equivalência Terapêutica , Adulto JovemRESUMO
Low-grade gliomas (LGG) comprise nearly 15-20 % of all central nervous system glial tumors. Several factors have been recognized as playing role in LGG malignant transformation (MT). A breakthrough analysis of a multidisciplinary group pointed that temozolomide may play a role in MT of LGGs. We analyzed the prevalence of MT in LGG patients submitted to adjuvant therapy (AT). We analyzed the medical charts of 43 patients with LGG submitted to surgery or biopsy and attending at Hospital do Servidor Público Estadual de São Paulo (São Paulo, Brazil), consecutively diagnosed from 1995 to 2013. 43 patients (24 women and 19 men) were evaluated, with mean age of 45.3 years. According to histology, 30 were astrocytomas (70 %), 12 (27 %) were oligodendrogliomas, and 1 (3 %) were mixed glioma. Mean follow-up time was 4.2 years with the standard deviation of 2.1. Twenty-eight patients did not receive adjuvant therapy and 15 received adjuvant therapy. From 43 patients with complete follow-up, 21 (48 %) experienced malignant transformation. Among such patients, nine were users of AT. Forty-eight percent of patients presented MT, being 60 % in the AT group and 42.8 % without AT. Our analysis revealed a high prevalence of MT in patients undergoing AT, higher than in patients without AT.
Assuntos
Neoplasias Encefálicas/patologia , Transformação Celular Neoplásica/efeitos dos fármacos , Quimiorradioterapia Adjuvante/efeitos adversos , Glioma/patologia , Adulto , Antineoplásicos/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Transformação Celular Neoplásica/efeitos da radiação , Quimiorradioterapia Adjuvante/métodos , Dacarbazina/efeitos adversos , Dacarbazina/análogos & derivados , Feminino , Glioma/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Radioterapia/efeitos adversos , Radioterapia/métodos , TemozolomidaRESUMO
El melanoma ha experimentado un aumento constante en su tasa de incidencia en las últimas cinco décadas a nivel mundial. El pronóstico del paciente con melanoma se relaciona con el estadio de la enfermedad al momento del diagnóstico, con una sobrevida global media de 6,2 meses en pacientes con melanoma metastásico. El avance en las investigaciones sobre la biología y el comportamiento tumoral permitió el desarrollo de nuevas terapias con distintos mecanismos de acción y mayor eficacia. En esta revisión se abordan las terapias biológicas en melanoma metastásico, su mecanismo de acción y principales resultados en ensayos clínicos. (AU)
Melanoma has experienced a consistent increase in incidence over the past five decades worldwide. The prognosis of patients with melanoma is related to the stage of disease at diagnosis, with a median overall survival of 6.2 months in metastatic melanoma. Progress in research on tumor biology allowed the development of new therapies with different mechanisms of action and greater efficiency. In this review, biologic therapies in metastatic melanoma, its mechanism of action and main results in clinical trials are discussed. (AU)
Assuntos
Humanos , Terapia Biológica , Melanoma/terapia , Metástase Neoplásica/terapia , Incidência , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Dacarbazina/efeitos adversos , Dacarbazina/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Ipilimumab/efeitos adversos , Ipilimumab/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Vemurafenib/efeitos adversos , Vemurafenib/uso terapêutico , Nivolumabe/efeitos adversos , Nivolumabe/uso terapêutico , ImunoterapiaRESUMO
PURPOSE: To evaluate the risk factors associated with lung cancer (LC) and other second neoplasms (SN) in Hodgkin lymphoma (HL) survivors. METHODS: We retrospectively analyzed the clinical characteristics and outcomes of 604 patients treated in our institution between 1968 and 2012. RESULTS: 90 out of 604 patients developed SN: 27 LC and 63 other SN. The median time elapsed until LC and other SN was 16.5 and 11.8 years, respectively (p = 0.003). In the LC group, 85.5 % of patients were male and 84.6 % smokers (HR 7, 95 % CI 2.4-20.7, p < 0.001). Radiotherapy (RT) doses applied were higher in the SN group with an increased risk of LC (HR: 4.0 95 % CI 1.1-11.6, p = 0.010) and other SN (HR: 3.3 95 % CI 1.6-6.7 p = 0.001) with doses higher than 42 Gy. No association was found between alkylating agents and development of SN. In LC, the most frequent histology was adenocarcinoma with an elapsed time after HL of 13.2 years in early stages and 21.3 in advanced (p = 0.02). Median OS after a diagnosis of LC was 12.6 months ranging from 5.9 (in cases presenting due to symptoms) to 49.1 (incidentally diagnosed cases) (p = 0.005). CONCLUSIONS: RT treatment, especially with doses higher than 42 Gy, and smoking increase the risk of SN after HL. In this series, LC patients with early stages had a shorter elapsed time from HL diagnosis and longer OS, therefore the role of LC screening in HL survivors should be prospectively evaluated and smoking cessation counseling ought to be a key aspect during follow-up.
Assuntos
Doença de Hodgkin/epidemiologia , Doença de Hodgkin/terapia , Neoplasias Pulmonares/epidemiologia , Neoplasias Induzidas por Radiação/epidemiologia , Segunda Neoplasia Primária/epidemiologia , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bleomicina/efeitos adversos , Dacarbazina/efeitos adversos , Doxorrubicina/efeitos adversos , Doença de Hodgkin/radioterapia , Humanos , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/patologia , Masculino , Mecloretamina/efeitos adversos , Pessoa de Meia-Idade , Neoplasias Induzidas por Radiação/patologia , Segunda Neoplasia Primária/patologia , Prednisona/efeitos adversos , Procarbazina/efeitos adversos , Dosagem Radioterapêutica , Estudos Retrospectivos , Fatores de Risco , Vimblastina/efeitos adversos , Vincristina/efeitos adversos , Adulto JovemRESUMO
Despite recent advances in the treatment of some forms of leishmaniasis, the available drugs are still far from ideal due to inefficacy, parasite resistance, toxicity and cost. The wide-spectrum antimicrobial activity of 2-nitrovinylfuran compounds has been described, as has their activity against Trichomonas vaginalis and other protozoa. Thus, the aim of this study was to test the antileishmanial activities of six 2-nitrovinylfurans in vitro and in a murine model of leishmaniasis. Minimum parasiticide concentration (MPC) and 50% inhibitory concentration (IC50) values for these compounds against the promastigotes of Leishmania amazonensis, Leishmania infantum and Leishmania braziliensis were determined, as were the efficacies of two selected compounds in an experimental model of cutaneous leishmaniasis (CL) caused by L. amazonensis in BALB/c mice. All of the compounds were active against the promastigotes of the three Leishmania species tested. IC50 and MPC values were in the ranges of 0.8-4.7 µM and 1.7-32 µM, respectively. The compounds 2-bromo-5-(2-bromo-2-nitrovinyl)-furan (furvina) and 2-bromo-5-(2-methyl-2-nitrovinyl)-furan (UC245) also reduced lesion growth in vivo at a magnitude comparable to or higher than that achieved by amphotericin B treatment. The results demonstrate the potential of this class of compounds as antileishmanial agents and support the clinical testing of Dermofural(r) (a furvina-containing antifungal ointment) for the treatment of CL.
Assuntos
Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bleomicina/efeitos adversos , Bleomicina/uso terapêutico , Terapia Combinada , Tomada de Decisões , Dacarbazina/efeitos adversos , Dacarbazina/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Doença de Hodgkin/mortalidade , Estadiamento de Neoplasias , Guias de Prática Clínica como Assunto , Medição de Risco , Resultado do Tratamento , Vimblastina/efeitos adversos , Vimblastina/uso terapêuticoRESUMO
BACKGROUND: Patients with metastatic melanoma, 50% of whose tumours harbour a BRAF mutation, have a poor prognosis. Selumetinib, a MEK1/2 inhibitor, has shown antitumour activity in patients with BRAF-mutant melanoma and in preclinical models when combined with chemotherapy. This study was designed to look for a signal of improved efficacy by comparing the combination of selumetinib and dacarbazine with dacarbazine alone. METHODS: This double-blind, randomised, placebo-controlled phase 2 study investigated selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment in patients older than 18 years with histologically or cytologically confirmed advanced BRAF-mutant cutaneous or unknown primary melanoma. Patients were randomly assigned by central interactive voice response system (1:1 ratio, block size four) to take either oral selumetinib (75 mg twice daily in a 21-day cycle) or placebo; all patients received intravenous dacarbazine (1000 mg/m(2) on day 1 of a 21-day cycle). Patients, investigators, and the study team were masked to the treatment assigned. The primary endpoint was overall survival analysed by intention to treat. This study is registered at ClinicalTrials.gov, NCT00936221. FINDINGS: Between July 20, 2009, and April 8, 2010, 91 patients were randomly assigned to receive dacarbazine in combination with selumetinib (n=45) or placebo (n=46). Overall survival did not differ significantly between groups (median 13·9 months, 80% CI 10·2-15·6, in the selumetinib plus dacarbazine group and 10·5 months, 9·6-14·7, in the placebo plus dacarbazine group; hazard ratio [HR] 0·93, 80% CI 0·67-1·28, one-sided p=0·39). However, progression-free survival was significantly improved in the selumetinib plus dacarbazine group versus the placebo plus dacarbazine group (HR 0·63, 80% CI 0·47-0·84, one-sided p=0·021), with a median of 5·6 months (80% CI 4·9-5·9) versus 3·0 months (2·8-4·6), respectively. The most frequent adverse events included nausea (28 [64%] of 44 patients on selumetinib vs 25 [56%] of 45 on placebo), acneiform dermatitis (23 [52%] vs one [2%]), diarrhoea (21 [48%] vs 13 [29%]), vomiting (21 [48%] vs 15 [33%]), and peripheral oedema (19 [43%] vs three [7%]). The most common grade 3-4 adverse event was neutropenia (six [14%] patients in the selumetinib plus dacarbazine group vs four [9%] in the placebo plus dacarbazine group). INTERPRETATION: Selumetinib plus dacarbazine showed clinical activity in patients with BRAF-mutant cutaneous or unknown primary melanoma, reflected by a significant benefit in progression-free survival compared with placebo plus dacarbazine group, although no significant change in overall survival was noted. The tolerability of this combination was generally consistent with monotherapy safety profiles. FUNDING: AstraZeneca.