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1.
Anticancer Res ; 41(3): 1671-1676, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33788764

RESUMO

BACKGROUND/AIM: This study aimed to investigate the efficacy of first-line gemcitabine monotherapy for metastatic breast cancer (MBC) and its effect on health-related quality of life (HRQoL) compared with treatment of physician's choice (TPC). PATIENTS AND METHODS: We enrolled 96 patients into the first-line gemcitabine group (n=47) or other treatment of physician's choice (TPC) group (n=49) from May 2010 to April 2013. HRQoL was evaluated every 4 weeks. RESULTS: There was no significant difference in the median time to treatment failure (5.3 vs. 4.6 months, hazard ratio=0.87, p=0.546) and the incidence rates of grade 3/4 haematological toxicity (10.6% vs. 8.1%, p=0.677) and grade 3/4 non-haematological toxicity (4.2% vs. 8.1%, p=0.429) between the gemcitabine and TPC groups. Changes in HRQoL from baseline to 12 weeks were not significantly different. CONCLUSION: Gemcitabine achieves similar efficacy and HRQoL benefit to other chemotherapy and can be used as first-line treatment for MBC.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Desoxicitidina/análogos & derivados , Adulto , Idoso , Neoplasias da Mama/patologia , Neoplasias da Mama/psicologia , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Médicos , Estudos Prospectivos , Qualidade de Vida , Falha de Tratamento
2.
Lancet Oncol ; 22(1): 118-131, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33387490

RESUMO

BACKGROUND: Standard chemotherapy remains inadequate in metastatic pancreatic adenocarcinoma. Combining an agonistic CD40 monoclonal antibody with chemotherapy induces T-cell-dependent tumour regression in mice and improves survival. In this study, we aimed to evaluate the safety of combining APX005M (sotigalimab) with gemcitabine plus nab-paclitaxel, with and without nivolumab, in patients with pancreatic adenocarcinoma to establish the recommended phase 2 dose. METHODS: This non-randomised, open-label, multicentre, four-cohort, phase 1b study was done at seven academic hospitals in the USA. Eligible patients were adults aged 18 years and older with untreated metastatic pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status score of 0-1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. All patients were treated with 1000 mg/m2 intravenous gemcitabine and 125 mg/m2 intravenous nab-paclitaxel. Patients received 0·1 mg/kg intravenous APX005M in cohorts B1 and C1 and 0·3 mg/kg in cohorts B2 and C2. In cohorts C1 and C2, patients also received 240 mg intravenous nivolumab. Primary endpoints comprised incidence of adverse events in all patients who received at least one dose of any study drug, incidence of dose-limiting toxicities (DLTs) in all patients who had a DLT or received at least two doses of gemcitabine plus nab-paclitaxel and one dose of APX005M during cycle 1, and establishing the recommended phase 2 dose of intravenous APX005M. Objective response rate in the DLT-evaluable population was a key secondary endpoint. This trial (PRINCE, PICI0002) is registered with ClinicalTrials.gov, NCT03214250 and is ongoing. FINDINGS: Between Aug 22, 2017, and July 10, 2018, of 42 patients screened, 30 patients were enrolled and received at least one dose of any study drug; 24 were DLT-evaluable with median follow-up 17·8 months (IQR 16·0-19·4; cohort B1 22·0 months [21·4-22·7], cohort B2 18·2 months [17·0-18·9], cohort C1 17·9 months [14·3-19·7], cohort C2 15·9 months [12·7-16·1]). Two DLTs, both febrile neutropenia, were observed, occurring in one patient each for cohorts B2 (grade 3) and C1 (grade 4). The most common grade 3-4 treatment-related adverse events were lymphocyte count decreased (20 [67%]; five in B1, seven in B2, four in C1, four in C2), anaemia (11 [37%]; two in B1, four in B2, four in C1, one in C2), and neutrophil count decreased (nine [30%]; three in B1, three in B2, one in C1, two in C2). 14 (47%) of 30 patients (four each in B1, B2, C1; two in C2) had a treatment-related serious adverse event. The most common serious adverse event was pyrexia (six [20%] of 30; one in B2, three in C1, two in C2). There were two chemotherapy-related deaths due to adverse events: one sepsis in B1 and one septic shock in C1. The recommended phase 2 dose of APX005M was 0·3 mg/kg. Responses were observed in 14 (58%) of 24 DLT-evaluable patients (four each in B1, C1, C2; two in B2). INTERPRETATION: APX005M and gemcitabine plus nab-paclitaxel, with or without nivolumab, is tolerable in metastatic pancreatic adenocarcinoma and shows clinical activity. If confirmed in later phase trials, this treatment regimen could replace chemotherapy-only standard of care in this population. FUNDING: Parker Institute for Cancer Immunotherapy, Cancer Research Institute, and Bristol Myers Squibb.


Assuntos
Adenocarcinoma/tratamento farmacológico , Albuminas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígenos CD40/antagonistas & inibidores , Desoxicitidina/análogos & derivados , Nivolumabe/administração & dosagem , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/imunologia , Adenocarcinoma/secundário , Idoso , Albuminas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígenos CD40/imunologia , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Paclitaxel/efeitos adversos , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
3.
PLoS One ; 15(12): e0244487, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33373398

RESUMO

BACKGROUND: In pancreatic cancer, toxicities associated with current chemotherapeutic regimens remain concerning. A modified combination of gemcitabine, S-1, and leucovorin (GSL) was used as the first-line treatment for newly diagnosed locally advanced or metastatic pancreatic adenocarcinoma patients. METHODS: GSL was administered every 2 weeks-intravenous gemcitabine 800 mg/m2 at a fixed-dose rate of 10 mg/m2/min on day 1 and oral S-1 (80-120 mg/day) plus leucovorin 30 mg twice daily on days 1-7. We retrospectively analyzed the feasibility of GSL and patient outcomes in three medical centers in Taiwan. RESULTS: Overall, 49 patients received GSL with a median follow-up of 24.9 months from May 2015 to March 2019. The median patient age was 68 years (range, 47-83 years), with a marginally higher number of females (57.1%). Among the 44 patients who underwent image evaluation, 13 demonstrated a partial response (29.5%) and 17 presented with stable disease (38.6%). The partial response rate and stable disease rate was 26.5% and 34.7%, respectively, in the intent-to-treat analysis. The median time-to-treatment failure was 5.79 months (95% C.I., 2.63-8.94), progression-free survival was 6.94 months (95% C.I., 5.55-8.33), and overall survival time was 11.53 months (95% C.I., 9.94-13.13). For GSL treatment, the most common grade 3 or worse toxicities were anemia (18.3%), neutropenia (6.1%), nausea (4.1%), and mucositis (4.1%). Treatment discontinuation was mostly due to disease progression (65.3%). CONCLUSIONS: The modified GSL therapy can be a promising and affordable treatment for patients with advanced and metastatic pancreatic cancer in Taiwan. A prospective trial of modified GSL for elderly patients is currently ongoing in Taiwan.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Progressão da Doença , Combinação de Medicamentos , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Análise de Intenção de Tratamento , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Ácido Oxônico/administração & dosagem , Ácido Oxônico/efeitos adversos , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/secundário , Intervalo Livre de Progressão , Estudos Retrospectivos , Taiwan/epidemiologia , Tegafur/administração & dosagem , Tegafur/efeitos adversos , Falha de Tratamento
4.
Anticancer Res ; 40(11): 6399-6406, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109578

RESUMO

BACKGROUND/AIM: The aim of this study was to investigate the timing of severe toxicity in lung cancer patients receiving chemotherapy. PATIENTS AND METHODS: Patients with advanced non-small cell lung cancer or limited disease small cell lung cancer included in two randomized controlled trials were analysed. Severe toxicity was defined as grade 3-5 toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. RESULTS: We analysed 569 patients and 433 (76.1%) experienced severe toxicity. Of these, 249 (57.5%) experienced the first episode of severe toxicity after the first, 109 (25.2%) after the second, 54 (12.5%) after the third and 18 (4.2%) after the fourth course of chemotherapy. Performance status (PS 2 vs. 0-1; p=0.046) and treatment arm were independent predictive factors for severe toxicity. CONCLUSION: Severe toxicity was most frequent after the first chemotherapy course, but some patients did not experience severe toxicity until after the fourth course. Accounting for timing might be important when studying factors predicting severe toxicity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Desoxicitidina/efeitos adversos , Neoplasias Pulmonares/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Fatores de Tempo
5.
Anticancer Res ; 40(7): 3995-4000, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620643

RESUMO

We present here the case of a 39-year-old man with metastatic pancreatic carcinoma receiving chemotherapy with the combination of gemcitabine and nab-paclitaxel as part of a clinical trial. Despite an impressive response to therapy, he ultimately developed profound anasarca, renal insufficiency, progressive cytopenias, and malignant hypertension 6 months into his treatment course. The diagnosis of gemcitabine-associated thrombotic microangiopathy (G-TMA) was made based on renal biopsy, and receipt of the anti-C5 monoclonal antibody eculizumab proved successful at reversing his deteriorating clinical course and improving his laboratory parameters. This case illustrates the importance of recognizing this rare but serious complication, and highlights one potential therapeutic option that can be used in the appropriate clinical context.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antimetabólitos Antineoplásicos/efeitos adversos , Inativadores do Complemento/uso terapêutico , Desoxicitidina/análogos & derivados , Microangiopatias Trombóticas/tratamento farmacológico , Adulto , Albuminas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/efeitos adversos , Evolução Fatal , Humanos , Masculino , Paclitaxel/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Microangiopatias Trombóticas/induzido quimicamente
6.
Anticancer Res ; 40(7): 4011-4015, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620645

RESUMO

BACKGROUND/AIM: The aim of this monocentric study was to evaluate the efficacy and tolerability of a polychemotherapy regimen based on gemcitabine, docetaxel, capecitabine, cisplatin (PDGX) as second-line for advanced pancreatic cancer after FOLFIRINOX. PATIENTS AND METHODS: Patients received FOLFIRINOX as first-line regimen were retrospectively identified between January 2016 and January 2019. After disease progression or unacceptable toxicity, patients eligible for second-line therapy were treated in our center by PDGX. RESULTS: During this period, 18 patients received PDGX regimen as second-line therapy. Main grade 3 toxicities were hematologic, which required dose adaptation in 14/18 patients. No toxic death was observed. Median second-line progression-free survival (PFS) and overall survival (OS) were 2,91 and 5,3 months, respectively. Total OS from the initiation of first-line was and 11,9 months. CONCLUSION: Second-line PDGX regimen after FOLFIRINOX failure is feasible, with notable toxicity profile and is associated with poor clinical outcomes.


Assuntos
Adenocarcinoma/tratamento farmacológico , Capecitabina/uso terapêutico , Cisplatino/uso terapêutico , Desoxicitidina/análogos & derivados , Docetaxel/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/mortalidade , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/efeitos adversos , Cisplatino/efeitos adversos , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Docetaxel/efeitos adversos , Feminino , Fluoruracila/uso terapêutico , Humanos , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Oxaliplatina/uso terapêutico , Neoplasias Pancreáticas/mortalidade , Resultado do Tratamento
7.
Oncology ; 98(9): 612-620, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32485713

RESUMO

INTRODUCTION: Conventional first-line chemotherapy for patients with metastatic urothelial carcinoma (UC) is gemcitabine and cisplatin (GC). However, cisplatin can cause renal failure, necessitating abundant fluid replacement and hospitalization during treatment. Recent evidence exists for short hydration methods in cisplatin-based chemotherapy. OBJECTIVE: This study aims to analyze the efficacy of newly established modified short hydration GC (m-shGC) therapy in patients with UC. METHODS: From May 2017 to March 2019, 48 patients with UC who received m-shGC therapy were treated with 1,000 mg/m2 gemcitabine on days 1, 8, and 15, and 70 mg/m2 cisplatin and 2,000 mL fluid replacement on day 1, in each 28-day cycle. We retrospectively evaluated renal function, serum electrolyte abnormalities, and adverse events (AEs) following treatment, and retrospectively compared patients under m-shGC therapy with those under conventional GC (c-GC) therapy from 2015 to 2017. In addition, from April 2019 to August 2019 in a prospective analysis, 15 patients were newly enrolled, and AE profiles and physical activity during m-shGC therapy were quantified using a wearable tracker. RESULTS: In a retrospective analysis of 101 patients (53 c-GC and 48 m-shGC), patient characteristics were not statistically significant between the two groups. Myelosuppression, including predominant neutropenia and decreased platelets, fatigue, nausea, and constipation were the main common AEs. However, renal function and serum sodium levels in the m-shGC group remained unchanged. Grade 3-4 AEs were not more severe in the m-shGC compared with the c-GC group. Furthermore, in a prospective analysis using a wearable tracker, the amount of walking by patients on day 1 significantly declined. However, immediate recovery occurred reflecting the short hydration. CONCLUSION: Our m-shGC therapy has an acceptable AE profile compared with conventional therapy, with UC patients showing good physical activity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Hidratação/métodos , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Neoplasias Urológicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Estudos de Coortes , Creatinina/sangue , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Feminino , Humanos , Hiponatremia/sangue , Hiponatremia/induzido quimicamente , Nefropatias/sangue , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sódio/sangue , Neoplasias da Bexiga Urinária/sangue , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias Urológicas/sangue
8.
Cancer Chemother Pharmacol ; 85(5): 979-993, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32314030

RESUMO

PURPOSE: Following promising responses to the DNA methyltransferase (DNMT) inhibitor 5-fluoro-2'-deoxycytidine (FdCyd) combined with tetrahydrouridine (THU) in phase 1 testing, we initiated a non-randomized phase 2 study to assess response to this combination in patients with advanced solid tumor types for which tumor suppressor gene methylation is potentially prognostic. To obtain pharmacodynamic evidence for DNMT inhibition by FdCyd, we developed a novel method for detecting expression of tumor suppressor protein p16/INK4A in circulating tumor cells (CTCs). METHODS: Patients in histology-specific strata (breast, head and neck [H&N], or non-small cell lung cancers [NSCLC] or urothelial transitional cell carcinoma) were administered FdCyd (100 mg/m2) and THU (350 mg/m2) intravenously 5 days/week for 2 weeks, in 28-day cycles, and progression-free survival (PFS) rate and objective response rate (ORR) were evaluated. Blood specimens were collected for CTC analysis. RESULTS: Ninety-three eligible patients were enrolled (29 breast, 21 H&N, 25 NSCLC, and 18 urothelial). There were three partial responses. All strata were terminated early due to insufficient responses (H&N, NSCLC) or slow accrual (breast, urothelial). However, the preliminary 4-month PFS rate (42%) in the urothelial stratum exceeded the predefined goal-though the ORR (5.6%) did not. An increase in the proportion of p16-expressing cytokeratin-positive CTCs was detected in 69% of patients evaluable for clinical and CTC response, but was not significantly associated with clinical response. CONCLUSION: Further study of FdCyd + THU is potentially warranted in urothelial carcinoma but not NSCLC or breast or H&N cancer. Increase in the proportion of p16-expressing cytokeratin-positive CTCs is a pharmacodynamic marker of FdCyd target engagement.


Assuntos
Carcinoma de Células de Transição , Inibidor p16 de Quinase Dependente de Ciclina/análise , DNA (Citosina-5-)-Metiltransferase 1/antagonistas & inibidores , Desoxicitidina/análogos & derivados , Células Neoplásicas Circulantes/patologia , Neoplasias Urológicas , Administração Intravenosa , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Carcinoma de Células de Transição/metabolismo , Carcinoma de Células de Transição/patologia , Contagem de Células/métodos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/farmacocinética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Farmacogenética , Tetra-Hidrouridina/administração & dosagem , Tetra-Hidrouridina/efeitos adversos , Tetra-Hidrouridina/farmacocinética , Neoplasias Urológicas/metabolismo , Neoplasias Urológicas/patologia
9.
Cancer Sci ; 111(6): 1933-1942, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32277531

RESUMO

Combination antiprogrammed death 1/programmed death-ligand 1 Ab and platinum-based chemotherapy is standard first-line treatment for advanced non-small-cell lung cancer without targetable oncogene alterations. We describe the long-term safety and efficacy data from a previously reported phase Ib study of nivolumab and chemotherapy. Japanese patients with non-small-cell lung cancer were assigned to a treatment arm based on histology and treatment history. Nivolumab (10 mg/kg, i.v.) and chemotherapy (4 arms) were given every 3 weeks: arm A, 4 cycles of cisplatin and gemcitabine (first-line); arm B, 4 cycles of cisplatin and pemetrexed followed by pemetrexed maintenance therapy (first-line); arm C, 4-6 cycles of carboplatin, paclitaxel, and bevacizumab followed by bevacizumab (first-line); and arm D, docetaxel (second- or third-line). Study treatments were continued every 3 weeks as maintenance therapy until disease progression. Minimum follow-up period was 57.9 months. Median progression-free survival (median [range, plus sign indicates censored data]) was 6.3 (0.7+-47.8), 11.8 (1.4-65.1+), 40.7 (5.3-60.8+), and 3.2 (1.9-10.9) months, and 5-year progression-free survival was observed in 0/6, 1/6, 1/6, and 0/6 patients in arms A, B, C, and D, respectively. Median overall survival was 13.2 (11.0-55.4), 28.5 (14.6-66.2+), not reached (24.2-67.4+), and 12.5 (9.8-16.9) months; the number of patients surviving 5 years were 0/6, 1/6, 4/6, and 0/6 in arms A, B, C, and D, respectively. No unexpected severe adverse events or treatment-related deaths occurred. Nivolumab and platinum-based chemotherapy combinations showed long-term tolerability. A moderate proportion of patients in arm C showed 5-year progression-free and overall survival.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/uso terapêutico , Adulto , Idoso , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Docetaxel/administração & dosagem , Docetaxel/efeitos adversos , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Pemetrexede/administração & dosagem , Pemetrexede/efeitos adversos , Intervalo Livre de Progressão , Resultado do Tratamento
10.
Cancer Chemother Pharmacol ; 85(5): 941-947, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32279102

RESUMO

PURPOSE: The aim of this study was to investigate the association between changes in the levels of vascular endothelial growth factors (VEGFs) after treatment with bevacizumab and gemcitabine (Bev-Gem) and the clinical outcome. METHODS: Platinum-resistant ovarian cancer patients treated with Bev-Gem therapy at our hospital between 2014 and 2018 were identified. Serum VEGF levels at the first and second treatment cycle were measured by ELISA. All patients were categorized into two groups-patients with > 50% decrease in serum VEGF-A levels (Group A) and patients with < 50% decrease serum VEGF-A levels (Group B). The association between clinical outcome and serum VEGF levels was investigated between the two groups. RESULTS: Among 18 patients, 10 were in Group A and 8 in Group B. Group A exhibited a lower response rate (0% vs.75% p < 0.01) and clinical benefit rate (60% vs.100% p = 0.02) than Group B. The median serum VEGF-A level of Group A before the first cycle of Bev-Gem therapy was higher than that in Group B (61.2 vs. 3.7 pg/mL, p < 0.01). Group A exhibited worse PFS (7 vs., 10 months, p < 0.01) and OS (17 vs. 26 months, p = 0.04) than Group B. There were more patients with > 10% increase in serum VEGF-B levels in Group A than in Group B (p < 0.01). CONCLUSION: The rapid decrease in VEGF-A levels and the resultant increase in serum VEGF-B levels might be associated with an unfavorable clinical outcome. Large-scale studies are needed to further examine these results.


Assuntos
Bevacizumab , Cisplatino/farmacologia , Desoxicitidina/análogos & derivados , Recidiva Local de Neoplasia , Neoplasias Ovarianas , Fator A de Crescimento do Endotélio Vascular/sangue , Fator B de Crescimento do Endotélio Vascular/sangue , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Bevacizumab/farmacocinética , Biomarcadores Farmacológicos/sangue , Biomarcadores Tumorais/sangue , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/farmacocinética , Progressão da Doença , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Valor Preditivo dos Testes , Prognóstico
11.
Oncol Rep ; 43(4): 1331-1337, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32020226

RESUMO

Patients with urothelial carcinoma frequently fail to respond to first­line chemotherapy using cisplatin and gemcitabine due to development of resistant tumor cells. The aim of the present study was to investigate whether an alternative treatment with tumor necrosis factor­related apoptosis­inducing ligand (TRAIL) that induces tumor cell death via the extrinsic apoptotic pathway may be effective against chemotherapy­resistant urothelial cancer cell lines. The viability of the urothelial cancer cell line RT112 and its chemotherapy­adapted sublines was investigated by MTT assay. The expression of anti­apoptotic proteins was determined by western blotting and the individual roles of cellular inhibitor of apoptosis protein (cIAP)1, cIAP2, x­linked inhibitor of apoptosis protein (XIAP) and induced myeloid leukemia cell differentiation protein (Mcl­1) were investigated by siRNA­mediated depletion. In particular, the bladder cancer sublines that were resistant to gemcitabine and cisplatin were cross­resistant to TRAIL. Resistant cells displayed upregulation of anti­apoptotic molecules compared with the parental cell line. Treatment with the second mitochondrial activator of caspases (SMAC) mimetic LCL­161 that antagonizes cIAP1, cIAP2 and XIAP resensitized chemoresistant cells to TRAIL. The resensitization of tumor cells to TRAIL was confirmed by depletion of antiapoptotic proteins with siRNA. Collectively, the findings of the present study demonstrated that SMAC mimetic LCL­161 increased the sensitivity of the parental cell line RT112 and chemotherapy­resistant sublines to TRAIL, suggesting that inhibiting anti­apoptotic molecules renders TRAIL therapy highly effective for chemotherapy­sensitive and ­resistant urothelial cancer cells.


Assuntos
Proteína 3 com Repetições IAP de Baculovírus/genética , Proteínas Inibidoras de Apoptose/genética , Ligante Indutor de Apoptose Relacionado a TNF/genética , Neoplasias da Bexiga Urinária/tratamento farmacológico , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Apoptose/efeitos dos fármacos , Proteína 3 com Repetições IAP de Baculovírus/antagonistas & inibidores , Caspase 3/efeitos dos fármacos , Inibidores de Caspase/farmacologia , Linhagem Celular Tumoral , Cisplatino/efeitos adversos , Cisplatino/farmacologia , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Ligante Indutor de Apoptose Relacionado a TNF/antagonistas & inibidores , Tiazóis/farmacologia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Urotélio/efeitos dos fármacos , Urotélio/metabolismo , Urotélio/patologia , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/antagonistas & inibidores
12.
Lancet Gastroenterol Hepatol ; 5(3): 285-294, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31953079

RESUMO

BACKGROUND: Treatment options for patients with unresectable locally advanced pancreatic cancer are scarce. Results from a subanalysis of the phase 3 MPACT trial in metastatic pancreatic cancer suggested potential activity of nab-paclitaxel plus gemcitabine against locally advanced pancreatic cancer. The objective of this phase 2 trial was to evaluate safety and efficacy of nab-paclitaxel plus gemcitabine in previously untreated locally advanced pancreatic cancer. METHODS: This international, open-label, multicentre, phase 2 trial (LAPACT) took place at 35 sites in five countries (USA, France, Spain, Canada, and Italy). Patients with Eastern Cooperative Oncology Group performance status of up to 1 underwent six cycles of induction with nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 (days 1, 8, and 15 of each 28-day cycle). After induction, patients without progressive disease or unacceptable adverse events were eligible to receive continued therapy per investigator's choice: continued nab-paclitaxel plus gemcitabine, chemoradiation, or surgery. The primary endpoint was time to treatment failure; secondary endpoints were disease control rate, overall response rate, progression-free survival, overall survival, safety, and quality of life. The reported efficacy outcomes were analysed in the intention-to-treat population, and safety outcomes were analysed in the treated population. This trial is registered with ClinicalTrials.gov, NCT02301143, and EudraCT, 2014-001408-23 and is complete. FINDINGS: Between April 21, 2015, and April 26, 2018, 107 patients were enrolled in the study. 106 received the study treatment; one patient enrolled but did not receive treatment. 44 (41%) of 107 enrolled patients discontinued induction; the most common reason for discontinuing induction was adverse events (22 [21%] patients). 62 (58%) of 107 enrolled patients completed induction treatment and 47 (44%) patients subsequently received continued treatment per investigator's choice: 12 (11%) continued nab-paclitaxel plus gemcitabine, 18 (17%) received chemoradiation, and 17 (16%) underwent surgery (seven had R0 resection status, nine had R1). 15 (14%) patients completed induction treatment but did not receive continued treatment. Median time to treatment failure was 9·0 months (90% CI 7·3-10·1); median progression-free survival was 10·9 months (90% CI 9·3-11·6), and median overall survival was 18·8 months (90% CI 15·0-24·0). During induction, 83 patients achieved disease control and the disease control rate was 77·6% (90% CI 70·3-83·5). 36 patients had a best response of partial response; the overall response rate during induction was 33·6% (90% CI 26·6-41·5). The most common treatment-emergent adverse events that were grade 3 or higher in the treated population during induction were neutropenia (35 [33%] of 106 patients), anaemia (12 [11%]), and fatigue (11 [10%]). The most common treatment-emergent serious adverse events during induction were pneumonia (five [5%] patients), pyrexia (five [5%]), and febrile neutropenia (three [3%]). No deaths were caused by treatment-related adverse events during the induction phase, and global quality of life was maintained in most patients. INTERPRETATION: The data from this trial support the tolerability and activity of nab-paclitaxel plus gemcitabine for locally advanced pancreatic cancer, and a potential to convert unresectable, locally advanced disease to surgically resectable disease. The safety profile was generally consistent with previous findings. FUNDING: Celgene.


Assuntos
Albuminas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Paclitaxel/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Idoso , Albuminas/administração & dosagem , Albuminas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Canadá/epidemiologia , Quimiorradioterapia Adjuvante/métodos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Feminino , França/epidemiologia , Humanos , Infusões Intravenosas , Análise de Intenção de Tratamento/métodos , Itália/epidemiologia , Avaliação de Estado de Karnofsky/normas , Avaliação de Estado de Karnofsky/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/cirurgia , Intervalo Livre de Progressão , Qualidade de Vida , Segurança , Espanha/epidemiologia , Procedimentos Cirúrgicos Operatórios/métodos , Resultado do Tratamento , Estados Unidos/epidemiologia
13.
Am J Clin Oncol ; 43(3): 173-179, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31985516

RESUMO

PURPOSE: NRG/RTOG 0848 was designed to determine whether adjuvant radiation with fluoropyrimidine sensitization improved survival following gemcitabine-based adjuvant chemotherapy for patients with resected pancreatic head adenocarcinoma. In step 1 of this protocol, patients were randomized to adjuvant gemcitabine versus the combination of gemcitabine and erlotinib. This manuscript reports the final analysis of these step 1 data. METHODS: Eligibility-within 10 weeks of curative intent pancreaticoduodenectomy with postoperative CA19-9<180. Gemcitabine arm-6 cycles of gemcitabine. Gemcitabine+erlotinib arm-gemcitabine and erlotinib 100 mg/d. Two hundred deaths provided 90% power (1-sided α=0.15) to detect the hypothesized OS signal (hazard ratio=0.72) in favor of the arm 2. RESULTS: From November 17, 2009 to February 28, 2014, 163 patients were randomized and evaluable for arm 1 and 159 for arm 2. Median age was 63 (39 to 86) years. CA19-9 ≤90 in 93%. Arm 1: 32 patients (20%) grade 4 and 2 (1%) grade 5 adverse events; arm 2, 27 (17%) grade 4 and 3 (2%) grade 5. GI adverse events, arm 1: 22% grade ≥3 and arm 2: 28%, (P=0.22). The median follow-up (surviving patients) was 42.5 months (min-max: <1 to 75). With 203 deaths, the median and 3-year OS (95% confidence interval) are 29.9 months (21.7, 33.4) and 39% (30, 45) for arm 1 and 28.1 months (20.7, 30.9) and 39% (31, 47) for arm 2 (log-rank P=0.62). Hazard ratio (95% confidence interval) comparing OS of arm 2 to arm 1 is 1.04 (0.79, 1.38). CONCLUSIONS: The addition of adjuvant erlotinib to gemcitabine did not provide a signal for increased OS in this trial.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante/métodos , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante/mortalidade , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Cloridrato de Erlotinib/administração & dosagem , Cloridrato de Erlotinib/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/mortalidade
14.
BMC Cancer ; 20(1): 38, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941506

RESUMO

BACKGROUND: Pancreatic adenosquamous carcinoma has a poor prognosis, with limited prospective trial data to guide optimal treatment. The potential impact of drug metabolism on the treatment response of patients with pancreatic adenosquamous carcinoma is largely unknown. CASE PRESENTATION: We describe the case of a 51 year old woman with pancreatic adenosquamous carcinoma who, following surgical resection, experienced early disease relapse during adjuvant gemcitabine therapy. Paradoxically, this was followed by an exceptional response to capecitabine therapy lasting 34.6 months. Strong expression of cytidine deaminase was detected within the tumour. CONCLUSIONS: This case study demonstrates that early relapse during adjuvant chemotherapy for pancreatic adenosquamous carcinoma may be compatible with a subsequent exceptional response to second line chemotherapy, an important observation given the poor overall prognosis of patients with adenosquamous carcinoma. Cytidine deaminase is predicted to inactivate gemcitabine and, conversely, catalyze capecitabine activation. We discuss strong intra-tumoural expression of cytidine deaminase as a potential mechanism to explain this patient's disparate responses to gemcitabine and capecitabine therapy, and highlight the benefit that may be gained from considering similar determinants of response to chemotherapy in clinical practice.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Carcinoma Adenoescamoso/tratamento farmacológico , Carcinoma Adenoescamoso/genética , Citidina Desaminase/genética , Desoxicitidina/análogos & derivados , Expressão Gênica , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Carcinoma Adenoescamoso/diagnóstico , Quimioterapia Adjuvante , Citidina Desaminase/metabolismo , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Feminino , Humanos , Imuno-Histoquímica , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/mortalidade , Recidiva , Retratamento , Tomografia Computadorizada por Raios X , Resultado do Tratamento
15.
Eur J Cancer ; 126: 21-32, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31896519

RESUMO

Chemotherapy objective response rates (ORRs) in metastatic soft tissue sarcoma (STS) are typically 20-40% with median progression-free survival (PFS) less than 6 months. Lurbinectedin is a new anticancer agent under investigation. The primary objective of this three-arm, phase II study was to determine the disease control rate (DCR = ORR + stable disease [SD]) at 24 weeks of lurbinectedin alone or with chemotherapy in STS. Eligible patients included adults with ≤2 prior cytotoxic therapies. Study cohorts were: stratum A (StrA; anthracycline-naive), lurbinectedin/doxorubicin; stratum B (StrB; prior anthracycline), lurbinectedin/gemcitabine; stratum C (StrC; prior anthracycline/gemcitabine) lurbinectedin monotherapy. Each stratum was analysed separately by Simon two-stage design. Forty-two patients were accrued (StrA = 20, StrB = 10, StrC = 12) including leiomyosarcoma [LMS] (n = 20), synovial sarcoma [SS](n = 4), malignant peripheral nerve sheath tumour (n = 3) and other STS histologies (n = 15). For StrA there were seven partial responses (PR) plus one stable disease (SD) at 24 weeks. For StrB, two patients met the 24-week DCR including one PR (leiomyosarcoma) and one SD (desmoplastic small round cell tumour [DSRCT]). StrB did not continue to the second stage. In StrC, no patients met the primary end-point. Median progression-free survival (PFS) was: StrA = 4.2 months (90% CI 1.4-7.8), StrB = 1.7 months (90% confidence interval (CI) 1.0-7.4), and StrC = 1.3 months (90% CI 1.1-3.0). Lurbinectedin as a single agent or with chemotherapy was well tolerated with haematologic adverse events (AE's) as the most common toxicity. There were no treatment-related deaths. The combination of lurbinectedin/doxorubicin reached the DCR end-point with seven PR and one patient with SD (ORR 35.0%, 24-week DCR 40.0%). Evidence of drug benefit was seen in leiomyosarcoma, dedifferentiated liposarcoma (DDLS), myxoid liposarcoma (MLS), synovial sarcoma (SS), and desmoplastic small round cell tumour (DSRCT). TRIAL REGISTRATION: clinicaltrials.gov; NCT02448537.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carbolinas/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Sarcoma/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carbolinas/administração & dosagem , Carbolinas/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Leucopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neutropenia/induzido quimicamente , Projetos de Pesquisa , Sarcoma/classificação , Sarcoma/patologia
16.
Ann Hematol ; 99(1): 105-112, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31776726

RESUMO

Outcome of patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) remains poor, highlighting the need for novel treatment approaches. The multicentre randomised phase II LEGEND trial evaluated lenalidomide in combination with rituximab, methylprednisolone and gemcitabine (R-GEM-L) vs. standard R-GEM-P as second-line treatment of DLBCL. The study closed early to recruitment after the planned interim analysis failed to demonstrate a complete response (CR) rate of ≥ 40% in either arm. Among 34 evaluable patients, 7/18 (38.9%) achieved CR with R-GEM-L and 3/16 (18.8%) with R-GEM-P. Median event-free and overall survival was 3.5/3.8 months and 10.8/8.3 months for R-GEM-L and R-GEM-P, respectively. The incidence of grade ≥ 3 toxicities was 52% in R-GEM-L and 83% in R-GEM-P. Efficacy and tolerability of R-GEM-L seem comparable with R-GEM-P and other standard salvage therapies, but a stringent design led to early trial closure. Combination of lenalidomide with gemcitabine-based regimens should be further evaluated in r/r DLBCL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Metilprednisolona/administração & dosagem , Metilprednisolona/efeitos adversos , Pessoa de Meia-Idade , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Taxa de Sobrevida
17.
Br J Cancer ; 122(4): 498-505, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31857726

RESUMO

BACKGROUND: The Hedgehog (Hh) signalling pathway is overexpressed in pancreatic ductal adenocarcinoma (PDA). Preclinical studies have shown that Hh inhibitors reduce pancreatic cancer stem cells (pCSC), stroma and Hh signalling. METHODS: Patients with previously untreated metastatic PDA were treated with gemcitabine and nab-paclitaxel. Vismodegib was added starting on the second cycle. The primary endpoint was progression-free survival (PFS) as compared with historical controls. Tumour biopsies to assess pCSC, stroma and Hh signalling were obtained before treatment and after cycle 1 (gemcitabine and nab-paclitaxel) or after cycle 2 (gemcitabine and nab-paclitaxel plus vismodegib). RESULTS: Seventy-one patients were enrolled. Median PFS and overall survival (OS) were 5.42 months (95% confidence interval [CI]: 4.37-6.97) and 9.79 months (95% CI: 7.85-10.97), respectively. Of the 67 patients evaluable for response, 27 (40%) had a response: 26 (38.8%) partial responses and 1 complete response. In the tumour samples, there were no significant changes in ALDH + pCSC following treatment. CONCLUSIONS: Adding vismodegib to chemotherapy did not improve efficacy as compared with historical rates observed with chemotherapy alone in patients with newly diagnosed metastatic pancreatic cancer. This study does not support the further evaluation of Hh inhibitors in this patient population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01088815.


Assuntos
Anilidas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Piridinas/administração & dosagem , Idoso , Albuminas/administração & dosagem , Albuminas/efeitos adversos , Anilidas/efeitos adversos , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/secundário , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Neoplasias Pancreáticas/mortalidade , Intervalo Livre de Progressão , Piridinas/efeitos adversos , Resultado do Tratamento
18.
Cancer ; 126(6): 1235-1242, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31821549

RESUMO

BACKGROUND: Both gemcitabine and bendamustine have been evaluated in patients with recurrent/refractory Hodgkin lymphoma but to the authors' knowledge not as a doublet. The authors completed a phase 1/2 trial to identify the optimal dose and frequency of administration and to assess the efficacy of this combination in patients with recurrent/refractory Hodgkin lymphoma. METHODS: Patients were treated up to a maximum dose of gemcitabine (1000 mg/m2 on day 1) and bendamustine (120 mg/m2 on days 1 and 2), which was determined to be the recommended phase 2 dose, administered every 21 days for up to 6 cycles. Patients could discontinue study therapy after 2 cycles to proceed with autologous or allogeneic stem cell transplantation. RESULTS: No dose-limiting toxicities were identified, but 4 patients experienced grade 3 to 5 pulmonary adverse events (toxicity was graded according to Common Terminology Criteria for Adverse Events [version 4]). A total of 26 patients were enrolled having completed a median of 4 prior lines of therapy (range, 1-7 lines), including 13 patients at the recommended phase 2 dose, in whom the overall response rate was 69% and the complete response rate was 46%. The median progression-free survival for the phase 2 patients was 11 months (95% CI, 3 months to not reached), and the median overall survival for this group had not been reached at the time of last follow-up (95% CI, 4 months to not reached). CONCLUSIONS: This doublet was found to be tolerable and effective, but patients must be monitored closely for pulmonary toxicity. The authors currently are evaluating this doublet in combination with nivolumab.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cloridrato de Bendamustina/administração & dosagem , Desoxicitidina/análogos & derivados , Doença de Hodgkin/tratamento farmacológico , Terapia de Salvação/métodos , Adulto , Idoso , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Bendamustina/efeitos adversos , Bleomicina/administração & dosagem , Bleomicina/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Recidiva , Adulto Jovem
19.
Eur J Cancer ; 124: 91-101, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760314

RESUMO

PURPOSE: This Phase IIb (NCT02195180) open-label study evaluated erythrocyte-encapsulated asparaginase (eryaspase) in combination with chemotherapy in second-line advanced pancreatic adenocarcinoma. METHODS: Eligible patients were randomized 2:1 to either eryaspase in combination with gemcitabine or mFOLFOX6 (eryaspase arm), or to gemcitabine or mFOLFOX6 alone (control arm). Co-primary endpoints were overall survival (OS) and progression-free survival (PFS) in patients with low asparagine synthetase (ASNS) expression. Secondary endpoints included OS and PFS in the entire population. RESULTS: 141 patients were randomized (eryaspase arm, n = 95; control arm, n = 46). Median OS and PFS in patients with low ASNS expression were 6.2 months (95% CI, 5.1-8.8) in the eryaspase arm versus 4.9 months (3.1-7.1) in the control arm (HR, 0.63; 95% CI, 0.39-1.01; P = 0.056) and 2.0 months (95% CI, 1.8-3.4) in the eryaspase arm versus 1.8 months (1.4-3.8) in the control arm (HR, 0.67; 95% CI, 0.40-1.12; P = 0.127), respectively. In the entire population, median OS and PFS for the eryaspase arm versus control were 6.0 months versus 4.4 months (HR, 0.60; P = 0.008) and 2.0 months versus 1.6 months (HR, 0.56; 95% CI, 0.37-0.84; P = 0.005), respectively. The combination of eryaspase and chemotherapy was well tolerated. The most frequent Grade 3/4 adverse events in the eryaspase arm (n = 93) were gamma-glutamyltransferase increase (16 [17.2%]), neutropenia (12 [12.9%]), and physical health deterioration (12 [12.9%]). CONCLUSION: Eryaspase in combination with chemotherapy is associated with improvements in OS and PFS, irrespective of ASNS expression in second-line advanced pancreatic adenocarcinoma. A Phase III trial is underway.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Asparaginase/administração & dosagem , Neutropenia/epidemiologia , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Asparaginase/efeitos adversos , Biópsia , Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/metabolismo , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neutropenia/induzido quimicamente , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Pâncreas/patologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Intervalo Livre de Progressão , Critérios de Avaliação de Resposta em Tumores Sólidos
20.
Int J Clin Oncol ; 25(1): 158-164, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31520176

RESUMO

BACKGROUND: To evaluate the relationship between sarcopenia and myelosuppression or between sarcopenia and survival outcomes in patients with urothelial carcinoma (UC) undergoing chemotherapy with gemcitabine plus cisplatin (GC) or carboplatin (GCa). METHODS: We evaluated 80 patients with UC who underwent chemotherapy between 2013 and 2017 at our institution. In total, 53 patients had metastatic UC and were ultimately included in the study. Predictive factors for myelosuppression (neutropenia, thrombocytopenia, and anemia) in all patients and overall survival (OS) in metastatic UC patients were analyzed. Sarcopenia was assessed on computed tomography before chemotherapy. Each patient's total psoas area was measured at the lumbar vertebrae (L3) and sarcopenia was defined as median values or lower. Predictive factors for myelosuppression were assessed using logistic regression analysis and survival was evaluated using Cox regression analysis. RESULTS: The patients' mean age was 71.6 years (range 44.4-89.2 years). Of the initial 80 patients, 39 were diagnosed with sarcopenia and 26 of 53 patients with metastatic UC were diagnosed with sarcopenia. Sarcopenia was an independent predictive factor (P = 0.030; odds ratio, 3.526; 95% confidence interval [CI] 1.128-11.01) for neutropenia on multivariate analysis. Patients without sarcopenia had a significantly longer OS compared to those with sarcopenia (P = 0.013). Sarcopenia and albumin (P = 0.045, 0.023; hazard ratio (HR), 2.309, 2.652; 95% CI 1.021-5.225, 1.141-6.165, respectively) were independent predictors of OS in multivariate analysis. CONCLUSIONS: Sarcopenia was predictive for neutropenia associated with GC or GCa in UC patients and OS in metastatic UC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células de Transição/tratamento farmacológico , Neutropenia/induzido quimicamente , Sarcopenia/complicações , Neoplasias Urológicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/patologia , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Cistectomia , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sarcopenia/diagnóstico por imagem , Trombocitopenia/induzido quimicamente , Tomografia Computadorizada por Raios X , Neoplasias Urológicas/mortalidade , Neoplasias Urológicas/patologia
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