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3.
Am J Hematol ; 95(6): 583-593, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32170769

RESUMO

Immunochemotherapy followed by autologous transplant (ASCT) in CALGB/Alliance 59909 achieved a median progression-free survival (PFS) in mantle cell lymphoma (MCL) of 5 years, but late recurrences occurred. We evaluated tolerability and efficacy of adding post-transplant bortezomib consolidation (BC) or maintenance (BM) to this regimen in CALGB/Alliance 50403, a randomized phase II trial. Following augmented-dose R-CHOP/ methotrexate, high-dose cytarabine-based stem cell mobilization, cyclophosphamide/carmustine/etoposide (CBV) autotransplant, and rituximab, patients were randomized to BC (1.3 mg/m2 IV days 1, 4, 8, 11 of a 3-week cycle for four cycles) or BM (1.6 mg/m2 IV once weekly × 4 every 8 weeks for 18 months) beginning day 90. The primary endpoint was PFS, measured from randomization for each arm. Proliferation signature, Ki67, and postinduction minimal residual disease (MRD) in bone marrow were assessed. Of 151 patients enrolled; 118 (80%) underwent ASCT, and 102 (68%) were randomized. Both arms met the primary endpoint, with median PFS significantly greater than 4 years (P < .001). The 8-year PFS estimates in the BC and BM arms were 54.1% (95% CI 40.9%-71.5%) and 64.4% (95% 51.8%-79.0%), respectively. Progression-free survival was significantly longer for transplanted patients on 50403 compared with those on 59909. Both the PFS and OS were significantly better for those who were MRD-negative post-induction. The high risk proliferation signature was associated with adverse outcome. Both BM and BC were efficacious and tolerable, although toxicity was significant. The comparison between studies 50403 and 59909 with long-term follow up suggests a PFS benefit from the addition of BC or BM post- transplant.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bortezomib/administração & dosagem , Quimioterapia de Consolidação , Linfoma de Célula do Manto/terapia , Quimioterapia de Manutenção , Rituximab/administração & dosagem , Adolescente , Adulto , Idoso , Autoenxertos , Bortezomib/efeitos adversos , Carmustina/administração & dosagem , Ciclofosfamida/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
4.
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
5.
Surgery ; 167(6): 969-977, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32122657

RESUMO

BACKGROUND: Neuroblastoma is the most common pediatric extracranial solid malignancy with limited effective treatment. We have shown that sustained-release, single drugs delivered locally through a silk-based biomaterial are effective in decreasing orthotopic neuroblastoma xenograft growth. We further optimized this approach and hypothesized that increasing doses of local chemotherapy or delivering 2 chemotherapeutic agents simultaneously inhibit additional tumor growth. METHODS: MYCN-amplified and non-MYCN-amplified neuroblastoma cells were treated with combinations of cisplatin, vincristine, doxorubicin, and etoposide to determine cytotoxicity and synergy. Drug-loaded silk material was created, and the amounts of drug released from the material over time were recorded. Murine orthotopic neuroblastoma xenografts were generated; tumors were implanted with single- or dual-agent chemotherapy-loaded silk. Ultrasound was used to monitor tumor growth, and tumor histology was evaluated. RESULTS: In vitro, vincristine/cisplatin combination was synergistic and significantly decreased cell viability relative to other combinations. Both drugs loaded into silk could be released effectively for over 2 weeks. Locally implanted vincristine/cisplatin silk induced increased tumor growth suppression compared with either agent alone in MYCN-amplified tumors (P < .05). The dose-dependent effect seen in MYCN-amplified tumors treated with combination therapy diminished at higher doses in non-MYCN-amplified tumors, with little benefit with doses >50 µg to 500 µg for vincristine-cisplatin, respectively. Tumor histology demonstrated tumor cell necrosis adjacent to drug-loaded silk material and presence of large cell neuroblastoma. CONCLUSION: Local delivery of sustained release chemotherapy can suppress tumor growth especially at high doses or with 2 synergistic drugs. Locally delivered dual therapy is a promising approach for future clinical testing.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cisplatino/administração & dosagem , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Neuroblastoma/tratamento farmacológico , Vincristina/administração & dosagem , Animais , Preparações de Ação Retardada , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sistemas de Liberação de Medicamentos , Humanos , Camundongos , Transplante de Neoplasias , Neuroblastoma/patologia , Seda , Células Tumorais Cultivadas
6.
Cancer Radiother ; 24(3): 206-214, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32171674

RESUMO

PURPOSE: The aim of this study was to extensively describe the epidemiological, clinical and therapeutic outcomes of adolescents and young adults (AYA) population with classical Hodgkin Lymphoma (cHL). Then, a comparison between AYAs and adults and between the subgroups of AYAs treated with the same adult protocol was accomplished to further inform on optimal therapy approach of choice for adolescent patients. MATERIAL AND METHODS: In this mono-centric, retrospective study, we reviewed the medical records. We analyzed 112 consecutive North Tunisian patients, including 66 AYAs (15 to 39 years) and 46 adults (≥40years) affected by cHL treated from 2000 to 2015 at Salah Azaiez Institute. Then, we performed a comparative analysis between AYA and 46 adult patients and a subgroup analysis between adolescents and young adults. All patients were treated according to the national protocol for HL, edited by the Tunisian Society of Hematology. The treatment included chemotherapy and involved-field radiotherapy (RT) at a dose of 20 or 30 Grays (Gy) for responders and 36Gy for non-responders. RESULTS: AYA patients presented with adverse features with nodular sclerosis subtype (p=3.88×10-02) and mediastinal mass involvement (p=9.40×10-04). At a median follow-up of 51 and 32 months for AYAs and adults, respectively, no statistical difference in terms of 3 and 5-years overall survival (OS) and event-free survival (EFS) was shown. Using the Kaplan-Meier method, in AYAs, the ABVD regimen has an impact on 3-years EFS (p=4.63×10-02). The 36Gy RT was associated with the best 3-years EFS (p=9.24×10-03). Besides, AYA patients with advanced-stage had the worst 3-years OS (76%) (p=2.41×10-02). Although the adolescents and young adults shared similar clinical presentation, we noted that the adolescent group had the worst 3-years EFS (48%), but the best 3-years OS (91%). We identified 15% of primary refractory patients and a rate of toxicity of 5.3% in AYA. CONCLUSION: The treatment approach used is well tolerated by adult patients. However, the AYA patients and particularly adolescent subgroup had more advanced disease at diagnosis and should be treated more intensively in dedicated units. RT dose<36Gy and ABVD chemotherapy were associated with lower EFS in this population.


Assuntos
Doença de Hodgkin/terapia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bleomicina/administração & dosagem , Ciclofosfamida/administração & dosagem , Dacarbazina/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Doença de Hodgkin/epidemiologia , Doença de Hodgkin/mortalidade , Doença de Hodgkin/patologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Mecloretamina/administração & dosagem , Neoplasias do Mediastino/patologia , Pessoa de Meia-Idade , Órgãos em Risco/efeitos da radiação , Prednisona/administração & dosagem , Procarbazina/administração & dosagem , Dosagem Radioterapêutica , Recidiva , Estudos Retrospectivos , Resultado do Tratamento , Tunísia/epidemiologia , Vimblastina/administração & dosagem , Vincristina/administração & dosagem , Adulto Jovem
7.
Ann Hematol ; 99(5): 1041-1048, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32130471

RESUMO

Multiple myeloma (MM) almost invariably progresses through novel therapies. Patients with quad-refractory MM (refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide) and penta-refractory MM (additional refractoriness to daratumumab) have few treatment options. Two chemotherapy regimens, bendamustine/prednisone (BP) and dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP), are often used in quad- and penta-refractory MM, but there are limited data on outcomes in this heavily pre-treated population. We conducted a single-center retrospective study to identify all patients who received DCEP and/or BP for quad- or penta-refractory MM. Disease response and refractoriness were defined by International Myeloma Working Group criteria. The primary endpoint was overall response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), and duration of response (DOR). We identified 27 patients who received BP for quad- or penta-refractory MM. The median number of prior lines of therapy was 6. The ORR for BP was 26%. The median PFS for BP was 1.4 months (95% CI 1.1-1.6) and median OS was 8.7 months (95% CI 2.3-15.0). Patients treated with cyclophosphamide had less response to BP. Thirty-one patients received DCEP for quad-refractory or penta-refractory MM. The median number of prior treatment regimens was 8. The ORR to DCEP was 35%. The median PFS was 2.7 months (95% CI 1.5-3.8) and median OS was 6.2 months (95% CI 4.4-7.8). DCEP and BP retain efficacy in quad- and penta-refractory MM. Our analysis supports prospective study of these regimens, possibly in combination or in comparison with other agents in this area of unmet need.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cloridrato de Bendamustina/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Prednisolona/administração & dosagem , Terapia de Salvação , Adulto , Idoso , Idoso de 80 Anos ou mais , Cisplatino/administração & dosagem , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Intervalo Livre de Doença , Etoposídeo/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida
8.
Ann Hematol ; 99(4): 819-828, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32025840

RESUMO

Autologous stem cell transplant (ASCT) is an effective treatment for non-Hodgkin lymphoma (NHL). However, recent supply issues and toxicity of carmustine have necessitated a new conditioning regimen. We conducted a multicenter, phase II study of BEB (busulfan, etoposide, and bendamustine) conditioning regimen for ASCT in patients with NHL. Thirty-one patients were enrolled and underwent ASCT with the BEB conditioning regimen. The most common subtype was diffuse large B-cell lymphoma (n = 23, 74.2%). Nine patients (29.0%) had a history of relapse, and 18 patients (58.1%) received more than 2 lines of chemotherapy before ASCT. A median number of 6.05 × 106/kg CD34 cells were infused, and all patients engrafted after a median period of 11 days. Thirteen patients (41.9%) experienced neutropenic fever, and 16 patients (51.6%) had grade 3 or 4 toxicities during ASCT. No one had a documented infection, veno-occlusive disease, or treatment-related death. Three-month complete remission rate was 81.8%. Median follow-up period of 15 months showed 6 patients (19.4%) relapsed or progressed and 3 patients died. The estimated 2-year progression-free survival and overall survival rate were 73.0% and 89.8%, respectively. Our results show that BEB conditioning regimens for ASCT are feasible with tolerable toxicity in patients with NHL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Linfoma não Hodgkin/tratamento farmacológico , Condicionamento Pré-Transplante/métodos , Adulto , Antifúngicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Bendamustina/administração & dosagem , Cloridrato de Bendamustina/efeitos adversos , Bussulfano/administração & dosagem , Bussulfano/efeitos adversos , Terapia Combinada , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Neutropenia Febril/induzido quimicamente , Feminino , Seguimentos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Estimativa de Kaplan-Meier , Linfoma não Hodgkin/diagnóstico por imagem , Linfoma não Hodgkin/terapia , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Pré-Medicação , Intervalo Livre de Progressão , Estudos Prospectivos , Indução de Remissão , Condicionamento Pré-Transplante/efeitos adversos , Transplante Autólogo , Adulto Jovem
9.
Crit Rev Oncol Hematol ; 148: 102897, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32109715

RESUMO

Advanced classical Hodgkin lymphoma (cHL) is a rare lymphoid disease characterized by the presence of Hodgkin and Reed-Sternberg (HRS) cells. Each year, cHL accounts for 0.5% of all new cancer diagnoses and about 80% are diagnosed with advanced stage disease. Given the significant improvement in cure rates, the focus of treatment has shifted towards minimization of acute and long-term toxicities. PET-adapted strategies have largely been adopted as standard of care in the United States in an attempt to balance toxicities with adequate lymphoma control. However, the appropriate upfront chemotherapy regimen (ABVD versus eBEACOPP) remains controversial.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Doença de Hodgkin/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bleomicina/administração & dosagem , Ciclofosfamida/administração & dosagem , Dacarbazina/administração & dosagem , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/patologia , Humanos , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons , Valor Preditivo dos Testes , Prednisona/administração & dosagem , Procarbazina/administração & dosagem , Resultado do Tratamento , Vimblastina/administração & dosagem , Vincristina/administração & dosagem
10.
Ann Hematol ; 99(2): 255-264, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31897676

RESUMO

We assessed the efficacy and toxicity of etoposide, methylprednisolone, high-dose cytarabine, and oxaliplatin (ESHAOx) combination chemotherapy in patients with refractory or relapsed Hodgkin's lymphoma (HL). This was an open-label, non-randomized, multi-center phase II study. The ESHAOx regimen consisted of intravenous (i.v.) etoposide 40 mg/m2 on days 1 to 4, i.v. methylprednisolone 500 mg on days 1 to 5, i.v. cytarabine 2 g/m2 on day 5, and i.v. oxaliplatin 130 mg/m2 on day 1. Cycles (up to six) were repeated every 3 weeks. In an effort to identify prognostic markers, the serum levels of cytokines including tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), and vascular endothelial growth factor (VEGF) were measured at the time of study entry. A total of 37 patients were enrolled, and 36 were available for evaluation of tumor response. The overall response rate was 72.2% (26/36) (complete response, 33.3% [12/36]; partial response, 38.9% [14/36]). The median time to progression was 34.9 months (95% confidence interval, 23.1-46.7 months). The most common grade 3 or 4 hematological adverse events were neutropenia (16/37, 43.2%), followed by thrombocytopenia (10/37, 27.0%). Grade 3 or 4 non-hematological adverse events were nausea (3/37, 8.1%), anorexia (2/37, 5.4%), mucositis (1/37, 2.7%), and skin rash (1/37, 2.7%). There were no treatment-related deaths. High levels of TNF-α and CRP were significantly associated with poorer overall survival (p = 0.00005 for TNF-α, p = 0.0004 for CRP, respectively). The ESHAOx regimen exhibited antitumor activity and an acceptable safety profile in patients with refractory or relapsed HL. Trial Registration: ClinicalTrials.gov. Registered February 21, 2011, https://clinicaltrials.gov/ct2/show/NCT01300156.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Doença de Hodgkin , Proteínas de Neoplasias/sangue , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Proteína C-Reativa/metabolismo , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Intervalo Livre de Doença , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Doença de Hodgkin/sangue , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/mortalidade , Humanos , Masculino , Metilprednisolona/administração & dosagem , Metilprednisolona/efeitos adversos , Pessoa de Meia-Idade , Oxaliplatina/administração & dosagem , Oxaliplatina/efeitos adversos , Recidiva , Taxa de Sobrevida , Fatores de Tempo , Fator de Necrose Tumoral alfa/sangue , Fator A de Crescimento do Endotélio Vascular/sangue
11.
Lancet Haematol ; 7(2): e146-e156, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31948928

RESUMO

BACKGROUND: Several strategies are available for the initial treatment of advanced-stage Hodgkin lymphoma, but the optimal strategy in terms of cost-effectiveness is unclear. The aim of this study was to compare the quality-adjusted effectiveness and costs of five modern treatment options for transplantation-eligible patients with newly diagnosed advanced-stage Hodgkin lymphoma. METHODS: A Markov decision-analytic model was developed using a 20-year time horizon. Five of the most common treatment approaches were selected based on clinical experience and expert opinion: (1) six cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD), including data from the HD2000 trial, Viviani and colleagues, and EORTC trial; (2) six cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP; from the HD15 trial or PET-adapted as in the HD18 trial, two initial cycles of BEACOPP followed by four additional cycles for patients with a positive PET and either two or four additional cycles of BEACOPP for patients with a negative PET); (3) PET-adapted escalation (as in the RATHL trial, two cycles of standard ABVD chemotherapy followed by an additional four cycles of ABVD or AVD in PET-negative patients and four cycles of BEACOPP in PET-positive patients); (4) six cycles of brentuximab vedotin, doxorubicin, vinblastine, dacarbazine (A-AVD) or ABVD as in the Echelon-1 trial; and (5) PET-adapted de-escalation (as in the AHL2011 trial, two cycles of BEACOPP followed by PET2 scan; PET-positive patients received two additional BEACOPP cycles and PET-negative patients received two cycles of ABVD; at PET4, PET-negative patients completed two further cycles of either ABVD or BEACOPP depending on what they received after PET2, and PET-positive patients received salvage therapy). Note that all uses of BEACOPP in these strategies were BEACOPPescalated. The randomised groups of interest from these studies comprised 4255 patients enrolled between April, 2000, and January, 2016. Baseline probability estimates and utilities were derived from the included trials in addition to a systematic review of published studies. A Canadian public health payer's perspective was considered (CAN$1=US$0·74) and adjusted for inflation for 2018. All costs and benefits were discounted by 1·5% per year because life-years now are more valuable than future potential life-years. FINDINGS: Probabilistic analyses (10 000 simulations) showed that, for a willingness-to-pay threshold of CAN$50 000, a PET-adapted de-escalation strategy based on AHL2011 was more cost-effective 87% of the time. This strategy had the highest number of life-years (14·6 years [95% CI 13·7-15·1]) and quality-adjusted life years (13·2 years [95% CI 10·2-14·4]), and the lowest direct costs ($53 129 [95% CI 31 914-94 446]) compared with the other treatment regimens. Sensitivity analyses showed that the model was robust to key variables, including probability of treatment-related mortality, relapse, frequency of secondary malignancy, death from secondary malignancy, and probability of infertility after BEACOPP. INTERPRETATION: Our results suggest that, when considering cost, effectiveness, and short and long-term toxicities, the preferred treatment strategy for patients with newly diagnosed advanced-stage Hodgkin lymphoma is the PET-adapted de-escalation regimen starting with BEACOPP and de-escalating to ABVD as appropriate. Although our findings do not provide an absolute best treatment approach for clinicians to follow for all patients, they can contribute to shared decision making between patients and treating physicians. FUNDING: None.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Doença de Hodgkin , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Bleomicina/administração & dosagem , Bleomicina/economia , Canadá , Análise Custo-Benefício , Ciclofosfamida/administração & dosagem , Ciclofosfamida/economia , Dacarbazina/administração & dosagem , Dacarbazina/economia , Doxorrubicina/administração & dosagem , Doxorrubicina/economia , Etoposídeo/administração & dosagem , Etoposídeo/economia , Feminino , Seguimentos , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/economia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons , Prednisona/administração & dosagem , Prednisona/economia , Procarbazina/administração & dosagem , Procarbazina/economia , Vimblastina/administração & dosagem , Vimblastina/economia , Vincristina/administração & dosagem , Vincristina/economia
12.
Int J Clin Oncol ; 25(1): 203-209, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31520175

RESUMO

OBJECTIVE: This study aimed to evaluate the efficacy and toxicity of 4-day chemotherapy with methotrexate, etoposide, and actinomycin D (MEA) for patients who were diagnosed with choriocarcinoma and high-risk gestational trophoblastic neoplasia (GTN). METHODS: Between January 1999 and December 2015, 29 patients were treated with 4-day MEA after being diagnosed with choriocarcinoma or high-risk GTN. Complete remission to 4-day MEA and adverse effects were retrospectively evaluated. RESULTS: The complete remission rates were 79.3% (23/29) and 87.5% (21/24) in all patients and in those who received 4-day MEA as first-line therapy, respectively. Of six patients who developed drug resistance to 4-day MEA, three patients showed complete remission by other treatments, while the other three patients died of the disease. The major adverse effects were leukocytopenia, anemia, and nausea. Of 23 patients who were cured with 4-day MEA, treatment was changed to the etoposide and actinomycin D (EA) regimen in 14 patients, because of leukocytopenia, hepatotoxicity, and stomatitis. Among 20 patients who required hormonal therapy, 15 patients showed normal menstrual cycles after therapy. Five patients had nine conceptions (seven term live births and two spontaneous abortions). No babies were premature or had low birth weight nor did they have congenital anomalies. CONCLUSION: The results suggest that the efficacy and the adverse effects of 4-day MEA for choriocarcinoma and high-risk GTN may be the same level as EMA/CO. However, further study will be needed for determining the criteria of changing the treatment regimen from 4-day MEA to the EA regimen.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Coriocarcinoma/tratamento farmacológico , Doença Trofoblástica Gestacional/tratamento farmacológico , Neoplasias Uterinas/tratamento farmacológico , Adolescente , Adulto , Idoso , Anemia/induzido quimicamente , Dactinomicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Leucopenia/induzido quimicamente , Ciclo Menstrual/efeitos dos fármacos , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Gravidez , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
14.
Am J Hematol ; 95(3): 245-250, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31804723

RESUMO

Most patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) do not benefit from current re-induction or approved targeted therapies. In the absence of targetable genetic mutations, there is minimal guidance on optimal treatment selection particularly in the R/R setting highlighting an unmet need for clinically useful functional biomarkers. Blood and bone marrow samples from patients treated on two clinical trials were used to test the combination of lenalidomide (LEN) and MEC (mitoxantrone, etoposide, and cytarabine) chemotherapy in R/R AML patients. The bone marrow samples were available to test the clinical utility of the mitochondrial apoptotic BH3 and dynamic BH3 profiling (DBP) assays in predicting response, as there was no clear genetic biomarker identifying responders. To test whether LEN-induced mitochondrial priming predicted clinical response to LEN-MEC therapy, we performed DBP on patient myeloblasts. We found that short-term ex vivo treatment with lenalidomide discriminated clinical responders from non-responders based on drug-induced change in priming (delta priming). Using paired patient samples collected before and after clinical LEN treatment (prior to MEC dosing), we confirmed LEN-induced increased apoptotic priming in vivo, suggesting LEN enhanced vulnerability of myeloblasts to cytotoxic MEC chemotherapy. This is the first study demonstrating the potential role of DBP in predicting clinical response to a combination regimen. Our findings demonstrate that functional properties of relapsed AML can identify active therapies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Apoptose/efeitos dos fármacos , Quimioterapia de Indução , Leucemia Mieloide Aguda , Mitocôndrias/metabolismo , Adulto , Idoso , Citarabina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Lenalidomida/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Mitocôndrias/patologia , Mitoxantrona/administração & dosagem
16.
Pediatr Blood Cancer ; 67(4): e28134, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31876107

RESUMO

BACKGROUND/PURPOSE: To determine the maximum tolerated dose, toxicities, and response of sirolimus combined with oral metronomic therapy in pediatric patients with recurrent and refractory solid and brain tumors. PROCEDURE: Patients younger than 30 years of age with recurrent, refractory, or high-risk solid and brain tumors were eligible. Patients received six-week cycles of sirolimus with twice daily celecoxib, and alternating etoposide and cyclophosphamide every three weeks, with Bayesian dose escalation over four dose levels (NCT01331135). RESULTS: Eighteen patients were enrolled: four on dose level (DL) 1, four on DL2, eight on DL3, and two on DL4. Diagnoses included solid tumors (Ewing sarcoma, osteosarcoma, malignant peripheral nerve sheath tumor, rhabdoid tumor, retinoblastoma) and brain tumors (glioblastoma multiforme [GBM], diffuse intrinsic pontine glioma, high-grade glioma [HGG], medulloblastoma, ependymoma, anaplastic astrocytoma, low-grade infiltrative astrocytoma, primitive neuroectodermal tumor, nongerminomatous germ cell tumor]. One dose-limiting toxicity (DLT; grade 4 neutropenia) was observed on DL2, two DLTs (grade 3 abdominal pain and grade 3 mucositis) on DL3, and two DLTs (grade 3 dehydration and grade 3 mucositis) on DL4. The recommended phase II dose of sirolimus was 2 mg/m2 (DL3). Best response was stable disease (SD) in eight patients, and partial response (PR) in one patient with GBM. A patient with HGG was removed from the study with SD and developed PR without further therapy. Western blot analysis showed inhibition of phospho-S6 kinase in all patients during the first cycle of therapy. CONCLUSION: The combination of sirolimus with metronomic chemotherapy is well tolerated in children. A phase II trial of this combination is ongoing.


Assuntos
Administração Metronômica , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias/tratamento farmacológico , Sirolimo/administração & dosagem , Adolescente , Neoplasias Encefálicas/tratamento farmacológico , Celecoxib/administração & dosagem , Criança , Pré-Escolar , Ciclofosfamida/administração & dosagem , Relação Dose-Resposta a Droga , Etoposídeo/administração & dosagem , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Adulto Jovem
17.
Pediatr Blood Cancer ; 67(1): e28012, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31544362

RESUMO

BACKGROUND: Most childhood medulloblastoma (MB) cases are curable using multimodal treatment, including craniospinal irradiation (CSI). However, late effects are a serious problem for survivors. This prospective registry study evaluated Japanese patients to determine whether a reduced radiation dose was feasible. PATIENTS AND METHODS: Patients with MB were classified as an infant group (<3 years old) and a high-risk (HR) group (≥3 years old with metastasis). The HR group received intrathecal methotrexate (IT-MTX) and high-dose chemotherapy (HDC) using thiotepa and melphalan, as well as concomitant radiotherapy with a recommended CSI dose of 18 Gy and a total local dose of 50 Gy. Radiotherapy was only considered for infants if residual tumors were present after the HDC. RESULTS: Between 1997 and 2006, we identified 28 HR patients (M1: 9, M2/3: 19) and 17 infant patients (M0: 11, M1: 3, M2/3: 3). During the median follow-up of 9.4 years for the entire HR group, the 5-year progression-free survival (PFS) rate was 82.1 ± 7.2% and the 5-year overall survival (OS) rate was 85.7 ± 6.6%. Subanalyses of the patients who received the recommended treatment revealed that the 5-year PFS and OS rates were both 90.5 ± 6.4%. In the infant group, the 5-year PFS rate was 52.9 ± 12.1% and the 5-year OS rate was 51.8 ± 12.4%. There were no serious adverse events associated with the IT-MTX and HDC treatments. CONCLUSION: Intensified chemotherapy using HDC and IT-MTX might allow for a reduced prophylactic radiation dose in patients with MB with metastases. Further studies are needed to validate these findings.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Cerebelares/tratamento farmacológico , Meduloblastoma/tratamento farmacológico , Sistema de Registros/estatística & dados numéricos , Adolescente , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/radioterapia , Criança , Pré-Escolar , Cisplatino/administração & dosagem , Terapia Combinada , Irradiação Craniana , Ciclofosfamida/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Humanos , Injeções Espinhais , Masculino , Meduloblastoma/patologia , Meduloblastoma/radioterapia , Melfalan/administração & dosagem , Metotrexato/administração & dosagem , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida
18.
Eur J Haematol ; 104(1): 59-66, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31606909

RESUMO

BACKGROUND: The standard first-line treatment for primary mediastinal B-cell lymphoma (PMBCL) patients is rituximab-based immunochemotherapy; however, this is not due to the result of randomized clinical trials. AIMS: We retrospectively investigated 53 PMBCL patient outcomes treated either with R-CHOP-21 or DA-EPOCH-R-28. The primary endpoint was overall survival (OS). Secondary endpoints were complete remission (CR), overall response rate (ORR), progression-free survival (PFS), and treatment-related complications. RESULTS: Treatment with R-CHOP-21 resulted in a 92.0% ORR (60% CR), while DA-EPOCH-R yielded a 92.6% ORR (70.4% CR). There were no differences in the occurrence of grade 3-4 hematological adverse events, but grade 1-2 cardiologic complications (P = .003) were observed more frequently in the DA-EPOCH-R arm. Median PFS and OS were not achieved. The differences in estimated 12-month PFS in R-CHOP and DA-EPOCH-R group (87% vs 73.9%) and OS (100% vs 92%) were insignificant. Patients treated with R-CHOP-21 and autologous hematopoietic stem cell transplantation (auto-HSCT) had an improved OS (P = .03) but not PFS (P = .43) compared to those treated solely with R-CHOP-21. No differences in PFS or OS were observed between patients treated with R-CHOP-21/auto-HSCT and DA-EPOCH-R. CONCLUSION: The results of this study suggest that R-CHOP-21 may be an alternative to DA-EPOCH-R treatment for PMBCL patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B , Neoplasias do Mediastino , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoenxertos , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/terapia , Masculino , Neoplasias do Mediastino/mortalidade , Neoplasias do Mediastino/terapia , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Rituximab/administração & dosagem , Taxa de Sobrevida , Vincristina/administração & dosagem
19.
Theriogenology ; 142: 177-183, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31600638

RESUMO

Testicular cancer is one of the most common malignancy in young men, chemotherapy induced damage in cancerous cells as well as healthy tissue, and we decided to investigate recovery effect of zinc (Zn) on chemotherapy-induced complications in rat chromatin integrity and testicular histomorphometry. The male rats (n = 40) were treated with BEP at appropriate dose levels of BEP (0.75, 7.5, and 1.5 mg/kg) for 9 weeks, with or without Zn; testicular histology, sperm DNA methylation, ubiquitination, DNA fragmentation and protamination were further assessed through immunofluorescence. BEP treatment significantly increased ubiquitination, and DNA fragmentation, considerably reducing global DNA methylation and protamination (P < 0.001), resulting in degenerative changes in testicular structure. Zn restored normal DNA methylation, protamination and structure of male gonads, maintained spermatogonial stem cells, and significantly reduced the mean percentage of ubiquitination and sperm DNA fragmentation as compared with BEP group (P < 0.001). We found that supplementation of Zn following chemotherapy can improve chromatin integrity, testicular organization and spermatogenesis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cromatina/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Zinco/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bleomicina/administração & dosagem , Bleomicina/efeitos adversos , Cromatina/metabolismo , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Citoproteção/genética , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Preservação da Fertilidade/métodos , Instabilidade Genômica/efeitos dos fármacos , Infertilidade Masculina/induzido quimicamente , Infertilidade Masculina/prevenção & controle , Masculino , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/patologia , Protaminas/metabolismo , Ratos , Ratos Wistar , Espermatozoides/metabolismo , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/patologia , Ubiquitinação/efeitos dos fármacos , Zinco/uso terapêutico
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