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OBJECTIVE: To evaluate the effects of switching from prednisone (P) to dexamethasone (D) at asymptomatic prostate-specific antigen (PSA) progression in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA). MATERIALS AND METHODS: Among 93 patients treated with AA between January 2013 and April 2016 in our institution, 48 consecutive asymptomatic patients with mCRPC, who experienced biochemical progression on treatment with AA+P 10 mg/day, were included. A corticosteroid switch to AA+D 0.5 mg/day at PSA increase was administered until radiological and/or clinical progression. The primary endpoint was progression-free-survival (PFS). A prognostic score based on independent prognostic factors was defined. RESULTS: The median time to PSA progression on AA+P was 8.94 months. The median PFS on AA+D and AA+corticosteroids (P then D) was 10.35 and 20.07 months, respectively. A total of 56.25% of patients showed a decrease or stabilization in PSA levels after the switch. In univariate analysis, three markers of switch efficiency were significantly associated with a longer PFS: long hormone-sensitivity duration (≥5 years; median PFS 16.62 vs 4.17 months, hazard ratio [HR] 0.30, 90% confidence interval [CI] 0.16-0.56); low PSA level at the time of switch (<50 ng/mL; median PFS 15.21 vs 3.86 months, HR 0.33, 90% CI 0.18-0.60); and short time to PSA progression on AA+P (<6 months; median PFS 28.02 vs 6.65 months, HR 0.41 (90% CI 0.21-0.81). In multivariate analysis, hormone sensitivity duration and PSA level were independent prognostic factors. CONCLUSION: A steroid switch from P to D appears to be a safe and non-expensive way of obtaining long-term responses to AA in selected patients with mCRPC. A longer PFS has been observed in patients with previous long hormone sensitivity duration, and/or low PSA level and/or short time to PSA progression on AA+P.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Androstenos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doenças Assintomáticas , Dexametasona/administração & dosagem , Progressão da Doença , Substituição de Medicamentos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prednisona/administração & dosagem , Prognóstico , Intervalo Livre de Progressão , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos RetrospectivosRESUMO
Introduction The PI3K/Akt/mTOR pathway plays a critical role in cancer cell growth, proliferation and angiogenesis, but also in brain homeostasis and the pathophysiology of mood disorders. The impact of the mTOR inhibitor everolimus on the mood of breast cancer patients is unknown. Materials and methods Consecutive, post-menopausal metastatic breast cancer patients receiving hormone therapy +/- everolimus were prospectively followed-up using the Beck Depression Inventory (BDI) and the MADRS (Montgomery and Asberg Depression Rating Scale) questionnaires. Results Post hoc tests comparing everolimus + hormonotherapy to hormonotherapy alone demonstrated a significant effect of everolimus after 6 weeks of treatment on BDI scores (t(1,38) = -2.0716, p < 0.05), and after 3 weeks (t(1,38) = -3.9165, p < 0.001) and 6 weeks of treatment (t(1,38) = -2.0373, p < 0.05) on MADRS scores. Analysis within each treatment group showed that the effect of time since treatment initiation on BDI and MADRS scores was specifically observed in the everolimus + hormonotherapy group (F(2,34) = 11.875, p < 0.001 and F(2,34) = 7.820, p < 0.01 respectively), but not in the hormonotherapy alone group (F(2,34) = 1.671, p > 0.2 and F(2,34) = 0.830, p > 0.2 respectively). Conclusions The mTOR inhibitor everolimus induces significant mood alterations in breast cancer patients. The evaluation of psychiatric symptoms is not only mandatory in the context of phase 1, dose-finding studies of PI3K/Akt/mTOR inhibitors, but is also clinically relevant in daily practice.
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Neoplasias da Mama/tratamento farmacológico , Everolimo/efeitos adversos , Everolimo/uso terapêutico , Transtornos do Humor/induzido quimicamente , Adulto , Idoso , Neoplasias da Mama/psicologia , Estudos de Casos e Controles , Depressão/induzido quimicamente , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: In non-small cell lung cancer patients (NSCLC), median survival from the time patients develop bone metastasis is classically described being inferior to 6 months. We investigated the subcategory of patients having an inaugural skeletal-related-event revealing NSCLC. The purpose of this study was to assess the impact of bone involvement on overall survival and to determine biological and tumoral prognosis factors on OS and PFS. An analysis of the subgroup of solitary bone metastasis patients was also performed. METHODS: In a population of 1208 lung cancer patients, 55 consecutive NSCLC patients revealed by inaugural bone metastasis and treated between 2003 and 2010, were retrospectively analysed. Survival was measured with a Kaplan-Meyer curve. Univariate and multivariate analysis were performed using the Stepwise Cox proportional hazard regression model. A p value of less than 0,05 was considered statistically significant. RESULTS: Estimated incidence of revealing bone metastasis is 4,5% among newly diagnosed lung cancer patients. Median duration of skeletal symptoms before diagnosis was 3 months and revealing bone site was located on axial skeleton in 70% of the cases. Histology was adenocarcinoma (78%), with small primary tumors Tx-T1-2 accounting for 71% of patients. Rate of second SRE is 37%.Median overall survival was 8.15 months, IQR [5-16 months], mean survival 13.4 months, and PFS was 3.5 months. In multivariate analysis, variables significantly associated with shortened survival were advanced T stage (HR=2.8; p=0.004), weight loss>10% (HR=3.1; p=0.02), inaugural spinal epidural metastasis (HR 2.5; p=0.0036), elevated C-reactive protein (HR=4.3; p=0.002) and TTF-1 status (HR=2.42; p=0.004). Inaugural spinal epidural metastasis is a very strong adverse pronostic factor in these cases, with a 3 months median survival. Single bone metastasis patients showed prolonged survival of 14.2 months versus 7.6 months, only in univariate analysis (HR=0.42; p=0.0059). CONCLUSION: Prognosis of lung cancer patients with inaugural SRE remains pejorative. Accurately estimating the survival of this population is helpful for bone surgical decision-making at diagnosis. The trend for a higher proportion of adenocarcinoma in NSCLC patients should result with an increasing number of patients with inaugural SRE at diagnosis.
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Neoplasias Ósseas/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Prognóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/secundário , Proteína C-Reativa/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos RetrospectivosRESUMO
Introduction: The aim of this study was to evaluate the impact of the thoracic robotic approach in a high-volume center regarding procedures and clinical outcomes after 1,000 procedures. Methods: In a single-center subset of the Epithor® database, a prospective cohort database of French thoracic surgery, we analyzed procedural characteristics and clinical outcomes from February 2014 to April 2023. A surgical technique for lung surgery was conducted with a four-arm closed chest with the port access approach and vascular sewing and knotting were preferred over stapling. Statistical analysis was performed using the Chi-2 test for discontinuous variables and the Mann-Whitney-Wilcoxon test for continuous variables. Tests were considered significant for a p-value <0.05. Results: Robotic thoracic surgery was used in anatomical lung resection in 85% of the cases. Over the study period, 1,067 patients underwent robotic surgery, of which 509 had lobectomies and 391 segmentectomies. In the segmentectomy group vs. lobectomy group we observed a shorter length of stay (9 ± 7 vs. 7 ± 5.6 days, p < 0.001), a shorter surgery time (99 ± 24 vs. 116 ± 38â min, p < 0.001) a lower conversion rate (n = 2 vs. n = 17, p = 0.004), and a lower complication rate (28% vs. 40%, p = 0.009, mainly Clavien-Dindo II, 18% and 28%, respectively). For cancer treatment surgery, we found more previous cancer in the segmentectomy group (48% vs. 26%, p < 0.001). We also observed a progressive change of lobectomy vs. segmentectomy from 80%/20% to 30%/70% over the 9â years. Discussion: A robotic platform is an appropriate tool to perform anatomical lung resection and especially to develop a safe and systematic approach to lung-sparing sub-lobar resection.
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Gemcitabine has shown clinical activity against angiosarcoma in small series, alone, or combined with taxanes. We aimed to evaluate its activity as a single-agent in a larger series of patients with advanced angiosarcoma. We retrospectively reviewed the electronic medical records of consecutive adult patients with advanced angiosarcoma treated with single-agent gemcitabine at our institutions from January 2010 to January 2021. Response was evaluated according to RECIST 1.1, and toxicity was graded according to NCI-CTC v5.0. 42 patients were identified. 38 patients (90%) had received prior anthracyclines and weekly paclitaxel, and 9 (21%) had received pazopanib. The best tumor response was partial response (PR) in 16 patients (38%), or stable disease (10 patients, 24%). All 8 patients with cardiac angiosarcoma experienced a PR. Median PFS was 5.4 months (95%CI: 3.1-6.5), and median OS was 9.9 months (95%CI: 6.6-13.4). Single-agent gemcitabine has clinically meaningful activity in advanced, heavily pre-treated angiosarcoma.
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Gencitabina , Hemangiossarcoma , Adulto , Humanos , Hemangiossarcoma/etiologia , Estudos Retrospectivos , Desoxicitidina/uso terapêutico , Taxoides/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: Sorafenib displays major interpatient pharmacokinetic variability. It is unknown whether the pharmacokinetics of sorafenib influence its toxicity. METHODS: We analyzed the severity and kinetics of sorafenib-induced toxicities in unselected consecutive patients with cancer, as well as their relationship with biological, clinical, and pharmacokinetic parameters. Toxicity was recorded bimonthly. Sorafenib plasma concentrations were assessed by liquid chromatography. RESULTS: For 83 patients (median age, 62 years; range, 21-84 years), median sorafenib 12-hour area under the curve (AUC(0-12)) was 52.8 mg · h/L (range: 11.8-199.6). A total of 51 patients (61%) experienced grade 3-4 toxicities, including hand-foot skin reactions (23%), asthenia (18%), and diarrhea (11%). Sorafenib AUC(0-12) preceding grade 3-4 toxicities was significantly higher than that observed in the remaining population (61.9 mg · h/L vs. 53 mg · h/L). In 25 patients treated with fixed doses of sorafenib for the first 4 months, median dose-normalized AUC(0-12) on day 120 was significantly lower than on day 15 (63 vs. 102 mg · h/L). The incidence of hypertension and hand-foot skin reactions significantly decreased over time. CONCLUSION: Sorafenib AUC(0-12) decreases over time, similarly to the incidence of hypertension and hand-foot skin reactions. Monitoring of sorafenib plasma concentrations may help to prevent acute severe toxicities and detect patients with suboptimal exposure at disease progression.
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Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Benzenossulfonatos/efeitos adversos , Benzenossulfonatos/farmacocinética , Relação Dose-Resposta a Droga , Piridinas/efeitos adversos , Piridinas/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/sangue , Área Sob a Curva , Benzenossulfonatos/sangue , Cromatografia Líquida , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/sangue , Estudos Retrospectivos , Sorafenibe , Testes de Toxicidade/métodos , Resultado do Tratamento , Adulto JovemRESUMO
A close relationship between tumor angiogenesis, growth, and carcinomatosis has been observed. Netrin-4 (NT-4) has been shown to regulate angiogenic responses. We aimed to examine the effects of NT-4 on colon tumor angiogenesis, growth, and carcinomatosis. We showed that NT-4 was expressed in human colon cancer cells (LS174). A 20-fold increase in NT-4 expression was stably induced by NT-4 pcDNA in LS174 cells. In vivo, a Matrigel angiogenesis assay showed that NT-4 overexpression altered vascular endothelial growth factor (VEGF)/basic fibroblast growth factor-induced angiogenesis. In nude mice with LS174 xenografts, NT-4 overexpression inhibited tumor angiogenesis and growth. In addition, these NT-4-involved inhibitory effects were associated with decreased tumor cell proliferation and increased tumor cell apoptosis. Using an orthotopic peritoneal carcinomatosis model, we demonstrated that NT-4 overexpression decreased colorectal cancer carcinomatosis. Moreover, carcinomatosis-related ascites formation was significantly decreased in mice transplanted with NT-4 LS174 cells versus control LS174 cells. The antiangiogenic activity of NT-4 was probably mediated by binding to its receptor neogenin. Netrin-4 had a direct effect on neither in vitro apoptosis and proliferation of cultured LS174 cells nor the VEGF-induced acute increase in vascular permeability in vivo. We propose that NT-4 overexpression decreases tumor growth and carcinomatosis, probably via an antiangiogenic effect, underlying the potential therapeutic interest in NT-4 in the treatment of colorectal cancer growth and carcinomatosis.
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Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , Neovascularização Patológica , Fatores de Crescimento Neural/fisiologia , Inibidores da Angiogênese/farmacologia , Animais , Carcinoma/patologia , Linhagem Celular Tumoral , Colágeno/química , Progressão da Doença , Combinação de Medicamentos , Feminino , Perfilação da Expressão Gênica , Humanos , Laminina/química , Camundongos , Camundongos Nus , Transplante de Neoplasias , Fatores de Crescimento Neural/biossíntese , Netrinas , Proteoglicanas/químicaRESUMO
PURPOSE: The only drug that improves survival in hepatocellular carcinoma is sorafenib. FOLFOX-4 regimen is safe and widely used in patients with colorectal cancer, yielding interesting results with little toxicity. We conducted a retrospective study to evaluate the safety and the effectiveness of FOLFOX-4 in cirrhotic or liver transplanted patients with hepatocellular carcinoma ineligible for sorafenib. METHODS: Thirty seven patients were enrolled in the study. The medical record of either cirrhotic patients or liver transplanted patients with advanced hepatocellular carcinoma receiving FOLFOX-4 regimen between November 1999 and March 2006 were retrospectively analyzed. Patients received oxaliplatin 85 mg/m(2) as a 2-hour infusion on day one, and leucovorin 200 mg/m(2) as a 2-hour infusion followed by bolus 5-fluorouracil 400 mg/m(2) and a 48-hours infusion of 5-fluorouracil 2400 mg/m(2). Treatment was repeated every 2 weeks until disease progression or unacceptable adverse effects occurred. RESULTS: Patients had a Child-Pugh class A (n = 16), class B cirrhosis (n = 10) or a liver transplant (n = 11) and received 2 to 37 cycles of chemotherapy (total of 310 cycles). Two (5.4%) cirrhotic patients developed neutropenic sepsis and one (2.7%) toxic death occurred. At first assessment, five patients from Child-Pugh class A (33%) and two from Child-Pugh class B group (20%) achieved a radiological response and/or alpha foeto-protein decrease, and no patient achieved a complete response. CONCLUSIONS: In conclusion, with a manageable toxicity profile in cirrhotic Child-Pugh class A-B or liver transplanted patients, the FOLFOX-4 regimen appears to be a feasible treatment option for patients with advanced hepatocellular carcinoma unfit for sorafenib. These data need to be confirmed in a prospective study.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/cirurgia , Cirrose Hepática/complicações , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Transplante de Fígado , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Esquema de Medicação , Estudos de Viabilidade , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Cirrose Hepática/mortalidade , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Transplante de Fígado/efeitos adversos , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Paris , Estudos Retrospectivos , Análise de Sobrevida , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Bevacizumab is a humanized IgG1 monoclonal antibody against VEGF. Because infusion-related hypersensitivity reactions (HSRs) are a concern with monoclonal antibodies, initial phase 1 trials used a 90-, 60-, then 30-min initial infusion sequence. We evaluated the impact of a shortened bevacizumab infusion (10 min) on toxicity in nonsmall cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Consecutive patients with stage IV NSCLC eligible for anti-VEGF therapy received a platinum doublet plus bevacizumab 7.5 mg/kg infused over 10 min, every 3 weeks, in the outpatient setting. Blood pressure was monitored at home twice daily, and other toxicities (HSRs and proteinuria) were monitored at each treatment administration. RESULTS: Bevacizumab was given as a 10 min infusion in 55 patients (group A), and using the standard sequence in another 36 patients (group B). Hypertension (grade ≥ 2) was observed in 18/55 (32.7%) patients in group A and 13/36 (38.9%) patients in group B (p = 0.77). Similarly, no difference was seen regarding the incidence of grade ≥ 2 proteinuria (12.7% vs. 19.4%, p = 0.39), arterial thrombo-embolic events (0 in each group) or venous thromboembolic events (1.8% vs. 8.3%, p = 0.29). CONCLUSIONS: Our data suggest that bevacizumab 7.5 mg/kg can be safely infused over 10 min in unselected NSCLC patients despite their cardio-vascular and respiratory comorbidities, saving time for both patients and caregivers.
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Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Bevacizumab , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND: Hypertension is a common toxicity of anti-VEGF agents, but its optimal treatment remains to define. This study aimed to describe the efficacy and tolerability of amlodipine, a calcium channel blocker, in patients with metastatic malignancies treated with bevacizumab, a humanized monoclonal antibody to VEGF. PATIENTS AND METHODS: One hundred and eighty-seven patients with advanced or metastatic NSCLC, colorectal or ovarian cancer receiving bevacizumab (5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks) and chemotherapy were eligible for this analysis. Blood pressure was measured at home twice daily according to international guidelines. Patients received amlodipine 5 mg daily for grade ≥ 2 bevacizumab-induced hypertension. RESULTS: Twenty-six patients received amlodipine 5 mg daily for de novo hypertension (group A), and another 10 patients received amlodipine for exacerbation of previously existing hypertension (group B). Hypertension was controlled within 7 days under amlodipine in 23/26 (88.5%, 95%CI: 76.2-100) patients in group A, and 8/10 (80%, 95%CI: 55.2-100) patients in group B, with a favourable toxicity profile. CONCLUSIONS: Amlodipine 5 mg daily appears safe and efficient for the treatment of hypertension in patients receiving bevacizumab at a dose-intensity of 2.5 mg/kg/week. Further prospective studies are warranted to confirm these results.
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Anlodipino/uso terapêutico , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Anti-Hipertensivos/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Hipertensão/tratamento farmacológico , Neoplasias/tratamento farmacológico , Vasodilatadores/uso terapêutico , Adulto , Idoso , Anlodipino/administração & dosagem , Anlodipino/efeitos adversos , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Bevacizumab , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/secundário , Distribuição de Qui-Quadrado , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Esquema de Medicação , Feminino , Humanos , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Paris , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo , Vasodilatadores/administração & dosagem , Vasodilatadores/efeitos adversosRESUMO
BACKGROUND: Intra-patient variability in sorafenib pharmacokinetics has been poorly investigated to date. We hypothesized that sorafenib clearance could decrease over time, as seen with imatinib. PATIENTS AND METHODS: Sorafenib plasma concentrations were determined by liquid chromatography, every 2 weeks, in consecutive hepatocellular carcinoma patients treated with sorafenib. Sorafenib dose-normalized area under the concentration-time curve (AUC) was determined from a population pharmacokinetics model, and its kinetics was analyzed in order to identify possible alterations of exposure over time. RESULTS: Fifteen hepatocellular carcinoma patients with Child-Pugh A cirrhosis, in whom sorafenib dosing remained unchanged from initiation of treatment to disease progression, were eligible for this analysis. Sorafenib AUC significantly decreased over time: the median AUC during the third month of treatment was lower than that observed after one month of treatment (43.0 vs. 60.3 mg/L.h, p = 0.008). Most importantly, median sorafenib AUC at the time of progression was almost two-fold lower than that observed after one month of therapy (33.2 vs. 60.3 mg/L.h, p = 0.007). These findings suggest an induction of expression of efflux transporters in the gut wall, or an induction of sorafenib metabolism. CONCLUSIONS: In patients with progressive disease in whom exposure markedly decreased from baseline, sorafenib dose escalation could be considered, aiming to restore an adequate drug exposure and possibly anti-tumor activity.
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Antineoplásicos/farmacocinética , Carcinoma Hepatocelular/metabolismo , Niacinamida/análogos & derivados , Compostos de Fenilureia/farmacocinética , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Área Sob a Curva , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/tratamento farmacológico , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Niacinamida/administração & dosagem , Niacinamida/sangue , Niacinamida/farmacocinética , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/sangue , SorafenibeRESUMO
Sorafenib is an oral tyrosine kinase inhibitor approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma. By using a population approach, this study aimed to characterise its pharmacokinetics. Plasma concentration-time data (n = 372) from 71 patients under sorafenib were analysed using nonlinear mixed-effect modelling to estimate population pharmacokinetic parameters, as well as relationships between these parameters and different covariates (demographic, biological). Simulations were done to compare different daily dosing regimens in a context of dose-escalation. A 1-compartment model with saturated absorption, first-order intestinal loss and elimination best described the pharmacokinetics of sorafenib. Absolute bioavailability significantly dropped with increasing daily doses of sorafenib. AUC increased less than proportionally with increasing doses [47.3 (41.3-63.3), 60.3 (56.3-64.4), 71.4 (51.3-99.1), 75.9 (45.5-100.9) mg/L.h for 400, 800, 1,200 and 1,600 mg/day, respectively]. According to the simulations, dividing the daily dose in three or four doses for daily dose >800 mg would significantly increase AUC compared with a twice daily dosing regimen (101.7 vs 81.6 mg/L.h for 400 mg q8h and 600 mg q12h respectively; 131.6 vs 91.5 mg/L.h for 400 mg q6h and 800 mg q12h, respectively). Thrice daily regimen may be most suitable in a context of dose-escalation (>800 mg/day) in non-responders to standard-dosing regimen.
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Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Absorção , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Niacinamida/administração & dosagem , Niacinamida/farmacocinética , Sorafenibe , Adulto JovemRESUMO
The use of gemcitabine and oxaliplatin is well documented in selected patients with advanced biliary tract carcinoma (BTC), but little is known on the feasibility of systemic treatments in patients with a performance status (PS) of 2. We retrospectively examined the medical records of consecutive BTC patients with a PS of 2 receiving gemcitabine 1000 mg/m(2) plus oxaliplatin 100 mg/m(2) every 2 weeks from January 2003 to December 2011 in our institution. Body composition was analysed by computed tomography scan to detect sarcopenia. The primary evaluation criterion was safety. The secondary evaluation criteria were the response rate, progression-free survival (PFS) and overall survival (OS). Twenty-eight patients (median age: 63 years, range 41-83) received a total of 175 cycles (median per patient: 6, range 2-12). Ten patients (35.7%) had sarcopenia on the pretreatment computed tomography scan. The most frequent toxicities were thrombocytopenia (grades 2-4: n=4, 14.3%), peripheral neuropathy (grades 2-3: n=9, 32.1%) and cholangitis (n=4, 14.3%). The best response was a partial response in 10.7% of patients [95% confidence interval (CI): 0-22.2] and stable disease in 42.9% of patients. The median PFS and OS were 4.6 (95% CI: 2.5-6.3) and 7.5 (95% CI: 5.2-9.5) months, respectively. The median PFS and OS were significantly longer in patients without sarcopenia: 7.0 months (95% CI: 4.4-8.0) vs. 2.2 months (95% CI: 2.0-2.5), P less than 0.01, and 10.4 months (95% CI: 7.5-11.6) vs. 4.9 months (95% CI: 3.7-5.2), P less than 0.01, respectively. In our experience, gemcitabine-oxaliplatin was feasible and induced effective palliation in PS2 patients with advanced BTC. Further studies are warranted to confirm these findings.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Carcinoma/tratamento farmacológico , Cuidados Paliativos/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Colangite/induzido quimicamente , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Estudos Retrospectivos , Sarcopenia , Índice de Gravidade de Doença , Trombocitopenia/induzido quimicamente , Resultado do Tratamento , GencitabinaRESUMO
BACKGROUND: Previous reports suggested that selective serotonin reuptake inhibitors (SSRI) could decrease the activity of 5-hydroxytryptamine type 3 (5-HT3) antagonists against acute chemotherapy-induced nausea and vomiting (CINV), possibly through serotonin accumulation for 5-HT3 receptors. PATIENTS AND METHODS: Chemonaive cancer patients receiving SSRI and antiemetic agents, including the 5-HT3 antagonist ondansetron and the neurokinin 1 (NK1) antagonist aprepitant for highly emetogenic chemotherapy (etoposide-platinum), were matched to control patients for the following variables: age, gender, primary tumor, past history of gestational emesis, chronic intake of benzodiazepines and/or corticosteroids, chronic alcohol intake, and aprepitant use. The primary evaluation criterion was the occurrence of acute vomiting during the first two cycles of treatment. RESULTS: Forty-four patients were eligible for this analysis. The proportion of patients, who experienced at least one episode of grade ≥ 1 acute vomiting in patients receiving SSRI, compared to patients who did not, was significantly higher (59.1 vs. 22.7%, respectively, p = 0.03, odds ratio 4.72, 95% confidence interval 1.13-22.88). Grade ≥ 2 acute vomiting was also significantly more frequent in patients receiving SSRI, even after the implementation of aprepitant to antiemetic prophylaxis (41.2 vs. 5.9%, p = 0.04). CONCLUSIONS: Our findings reinforce the hypothesis that SSRI decrease the antiemetic activity of the 5-HT3 serotonin antagonist ondansetron, resulting in higher rates of acute vomiting in cancer patients despite adequate antiemetic prophylaxis. Adding the NK1 antagonist aprepitant do not counterbalance the deleterious effect of SSRI, probably due to the synergistic effects of SSRI and NK1 antagonists on serotonin transmission.
Assuntos
Antieméticos/uso terapêutico , Morfolinas/farmacologia , Neoplasias/tratamento farmacológico , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia , Vômito/induzido quimicamente , Adulto , Idoso , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/uso terapêutico , Aprepitanto , Estudos de Casos e Controles , Interações Medicamentosas , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Etoposídeo/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Náusea/tratamento farmacológico , Platina/efeitos adversos , Vômito/tratamento farmacológicoRESUMO
BACKGROUND: Hypertension is a common toxicity of bevacizumab, but the frequency of assessment of blood pressure and standardized grading remain to be defined. This study aimed to describe the incidence of bevacizumab-induced hypertension and factors associated with its development, then to retrospectively assess its relation with activity. PATIENTS AND METHODS: One hundred nineteen patients with advanced or metastatic non-small cell lung cancer, colorectal cancer, or ovarian cancer receiving bevacizumab (2.5 mg/kg per week) and chemotherapy were eligible for this analysis. Blood pressure was measured at home twice daily according to international guidelines, and graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 3.0, and the European Society of Hypertension (ESH) criteria. RESULTS: Home-based measurements detected significantly more cases of hypertension than in-clinic measurements did, according to the ESH criteria (54.6% versus 24.4%; p < .001) or the NCI-CTC (42.9% versus 22.7%; p = .0015). Very early hypertension (within 42 days, according to the ESH criteria) but not hypertension (occurring at any time during treatment period) was predictive of response (p = .0011 and p = .26, respectively). CONCLUSIONS: Our preliminary results indicate that home-based measurement and grading according to the ESH criteria represents a reliable method to detect bevacizumab-induced hypertension. Whether hypertension is a biomarker of bevacizumab activity remains to be determined in a prospective study.
Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Hipertensão/induzido quimicamente , Hipertensão/diagnóstico , Neoplasias/tratamento farmacológico , Neoplasias/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab , Determinação da Pressão Arterial , Monitorização Ambulatorial da Pressão Arterial , Feminino , Humanos , Hipertensão/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos TestesRESUMO
Patients treated with anti-VEGF agents are at increased risk for arterial thrombo-embolic events (ATEs). However, the pathophysiology of such acute vascular complications remains unclear. We report on a case of bowel infarction in a renal cancer patient treated with the anti-VEGF agent sunitinib. An abdominal CT-scan evidenced the rupture of an atherosclerotic plaque located at the emergence of the superior mesenteric artery. In view of this report, we suggest that evaluation of the risk of ATE in patients receiving anti-VEGF agents should include not only age and past history of ATE as suggested by previous studies, but also assessment of atherosclerotic lesions on CT-scan.
Assuntos
Antineoplásicos/efeitos adversos , Indóis/efeitos adversos , Placa Aterosclerótica/patologia , Pirróis/efeitos adversos , Tromboembolia/etiologia , Idoso , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/farmacologia , Humanos , Indóis/farmacologia , Indóis/uso terapêutico , Infarto/etiologia , Intestinos/irrigação sanguínea , Masculino , Pirróis/farmacologia , Pirróis/uso terapêutico , Fatores de Risco , Sunitinibe , Tromboembolia/fisiopatologia , Tomografia Computadorizada por Raios X , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
Reactivation of tuberculosis is rare in patients receiving chemotherapy for solid tumours, and poorly documented in patients receiving molecular targeted therapy. We report on a patient with metastatic renal-cell carcinoma treated with temsirolimus, who developed respiratory symptoms and mild fever after 6 weeks of treatment. CT-scan and laboratory tests were consistent with reactivation of tuberculosis. The patient received anti-tuberculosis therapy including rifampicin, a potent CYP3A4/5 inducer. After introduction of rifampicin-based treatment, the patient experienced tumour progression, leaving questionable the potential pharmacokinetic interaction between rifampicin and temsirolimus, a substrate for CYP3A4.
Assuntos
Antineoplásicos/uso terapêutico , Rifampina/uso terapêutico , Sirolimo/análogos & derivados , Tuberculose/etiologia , Idoso de 80 Anos ou mais , Antibióticos Antituberculose/farmacologia , Antibióticos Antituberculose/uso terapêutico , Antineoplásicos/metabolismo , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Citocromo P-450 CYP3A/biossíntese , Citocromo P-450 CYP3A/efeitos dos fármacos , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas , Indução Enzimática/efeitos dos fármacos , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Masculino , Metástase Neoplásica , Rifampina/farmacologia , Sirolimo/metabolismo , Sirolimo/uso terapêutico , Tuberculose/tratamento farmacológicoRESUMO
Sorafenib, an orally active multi-kinase inhibitor approved for the treatment of hepatocellular carcinoma (HCC), is primarily metabolized both via cytochrome P450 3A4 isoform (CYP3A4) and UGT1A9. Due to the contribution of these two biotransformation pathways, sorafenib is considered to be less susceptible than other agents to CYP3A4 drug-drug interactions. This report discusses a clinically relevant pharmacokinetic CYP3A4 drug-drug interaction between sorafenib and felodipine in an 80-year-old Caucasian patient with HCC. On day 15, after the introduction of sorafenib (400 mg bid), sorafenib plasma concentration was at 3.6 mg/L. Felodipine (5 mg bid), an anti-hypertensive agent that is exclusively CYP3A4 substrate, was then introduced due to grade 2 sorafenib-related hypertension. On day 30, hypertension was well controlled. However, sorafenib plasma concentration was 3-fold greater (11.4 mg/L) and the patient experienced grade-3 anorexia. Since neither diarrhea nor cutaneous side effects were noticed at this time, sorafenib treatment was continued at the same daily dosage. On day 45, sorafenib plasma concentration was stable (10.8 mg/L) before declining on days 60 and 75 (7.0 mg/L and 7.4 mg/L, respectively), which was probably related to an occurrence of grade-2 diarrhea. This observation suggests a pharmacokinetic interaction involving CYP3A4 inhibition by felodipine. According to the Drug Interaction Probability Scale, this interaction was possible. Since hypertension is a common toxicity of sorafenib, clinicians should be aware of this possible interaction. The clinical relevance of pharmacokinetic interactions involving CYP3A4 inhibition in HCC patients receiving sorafenib is analyzed in this case report.
Assuntos
Antineoplásicos/farmacocinética , Benzenossulfonatos/farmacocinética , Inibidores do Citocromo P-450 CYP3A , Felodipino/farmacologia , Piridinas/farmacocinética , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Benzenossulfonatos/efeitos adversos , Benzenossulfonatos/uso terapêutico , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas , Felodipino/uso terapêutico , Humanos , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/efeitos adversos , Piridinas/uso terapêutico , SorafenibeRESUMO
Recently, pneumatosis intestinalis has been described in patients receiving bevacizumab, a monoclonal antibody to VEGF-A. Pneumatosis intestinalis is a condition characterized by subserosal and submucosal gas-filled cysts in the gastrointestinal tract. We report on pneumatosis intestinalis in patients receiving oral anti-VEGF agents. Patients shared the following characteristics: long-term (> 4 months) exposure to anti-VEGF agents, lack of other factors predisposing to pneumatosis intestinalis, and lack of recent surgical intervention. Taken together, these observations suggest that pneumatosis intestinalis is a probable class-effect of anti-VEGF agents.