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1.
Clin Cancer Res ; 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34615721

RESUMO

PURPOSE: The effect of high-dose imatinib (800 mg/day) on survival in the adjuvant treatment of patients with resected KIT exon 9-mutated gastrointestinal stromal tumors (GIST) is not established. Here, the association of dose and other clinicopathologic variables with survival was evaluated in a large multi-institutional European cohort. METHODS: Data from 185 patients were retrospectively collected in 23 European GIST reference centers. Propensity score matching (PSM) and inverse-probability of treatment weighting (IPTW) were used to account for confounders. Univariate and multivariate unweighted and weighted Cox proportional hazard regression models were estimated for relapse-free survival (RFS), modified-RFS (mRFS) and imatinib failure-free survival (IFFS). Univariate Cox models were estimated for overall survival. RESULTS: Of the 185 patients, 131 (70.8%) received a starting dose of 400 mg/d and the remaining 54 (29.2%) a dose of 800 mg/d. Baseline characteristics were partially unbalanced, suggesting a potential selection bias. PSM and IPTW analyses showed no advantage of imatinib 800 mg/d. In the weighted multivariate Cox models, high-dose imatinib was not associated with the survival outcomes [RFS: hazard ratio (HR), 1.24; 95% confidence interval (CI), 0.79-1.94; mRFS: HR, 1.69; 95% CI, 0.92-3.10; IFFS: HR, 1.35; 95% CI, 0.79-2.28]. The variables consistently associated with worse survival outcomes were high mitotic index and nongastric tumor location. CONCLUSIONS: In this retrospective series of patients with KIT exon 9-mutated GIST treated with adjuvant imatinib, a daily dose of 800 mg versus 400 mg did not show better results in terms of survival outcomes. Prospective evaluation of the more appropriate adjuvant treatment in this setting is warranted.

2.
Curr Treat Options Oncol ; 22(10): 87, 2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34424422

RESUMO

OPINION STATEMENT: Patients with hepatocellular carcinoma (HCC) have been traditionally deprived from highly effective systemic therapy options in the past decades. The multi-targeted tyrosine kinase inhibitor sorafenib, approved in 2008, remained the only treatment option for advanced HCC for over a decade. A number of molecularly targeted therapies such as lenvatinib, regorafenib, cabozantinib, and ramucirumab have significantly widened treatment options in patients with advanced HCC. However, emergence of resistance and long-term toxicity from treatment are barriers to long-term survivorship. Immunotherapy is at the focus of intense research efforts in HCC. Whilst targeting of programmed cell death 1 (PD-1) and cytotoxic T lymphocyte 4 (CTLA-4) is associated with radiologically measurable disease-modulating effects in HCC, monotherapies fell short of demonstrating evidence of significant survival extension in advanced disease. Atezolizumab and bevacizumab were the first immunotherapy regimen to demonstrate clear superiority in improving the survival of patients with unresectable HCC compared to sorafenib, paving the way for immunotherapy combinations. As the treatment landscape of HCC rapidly evolves, with immunotherapy integrating within early- and intermediate-stage disease treatment algorithms, lack of level 1 evidence on sequencing of therapeutic strategies and lack of head-to-head comparisons across immunotherapy combinations will affect prescribing of immunotherapy in routine practice. In the absence of predictive biomarkers, choice of immunotherapy over kinase inhibitors will continue to remain an empirical exercise, guided by balancing anti-tumour efficacy with toxicity considerations in the individual patient.

3.
Liver Int ; 2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34250737

RESUMO

BACKGROUND AND AIM: Lenvatinib is a standard of care option in first-line therapy of advanced hepatocellular carcinoma (HCC). In the present study, we aim to identify, in patients with HCC treated with lenvatinib, a possible association between occurrence and grading of adverse events (AEs) and outcome. METHODS: We performed a retrospective analysis of 606 Japanese and Italian patients treated with lenvatinib in first-line setting and investigated the possible correlation between the onset of AEs, toxicity grade (G) and outcome measures such as overall survival (OS) and progression-free survival (PFS). RESULTS: The appearance of arterial hypertension G ≥ 2 independently predicted prolonged OS [hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.46-0.93, P = .0188], whereas decreased appetite G ≥ 2 independently predicted decreased OS (HR 1.70, 95% CI 1.25-2.32, P = .0007) by multivariate analysis. Appearance of hand-foot skin reaction independently predicted prolonged PFS (HR 0.72, 95% CI 0.56-0.93, P = .0149), whereas decreased appetite G ≥ 2 predicted decreased PFS (HR 1.36, 95% CI 1.04-1.77, P = .0277). CONCLUSIONS: Our main findings are that the occurrence of arterial hypertension G ≥ 2 is a predictor of longer survival, whereas decreased appetite G ≥ 2 predicts for a poor prognosis. A careful management of AEs under lenvatinib treatment for HCC is required, to improve patients' quality of life, minimize the need for treatment discontinuation and achieve optimal outcome.

4.
Cancer Manag Res ; 13: 9379-9389, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34992463

RESUMO

Background: Lenvatinib has been approved in Italy since October 2019 as a first-line therapy for advanced hepatocellular carcinoma (HCC) and to date data on effectiveness and safety of lenvatinib are not available in our region. To fill this gap, we performed a multicentric analysis of the real-world treatment outcomes with the propensity score matching in a cohort of Italian patients with unresectable HCC who were treated with either sorafenib or lenvatinib. Aims and Methods: To evaluate the effectiveness of sorafenib and lenvatinib as primary treatment of advanced HCC in clinical practice we performed a multicentric analysis of the treatment outcomes of 288 such patients recruited in 11 centers in Italy. A propensity score was used to mitigate confounding due to referral biases in the assessment of mortality and progression-free survival. Results: Over a follow-up period of 11 months the Cox regression model showed 48% reduction of death risk for patients treated with lenvatinib (95% CI: 0.34-0.81; p = 0.0034), compared with those treated with sorafenib. The median PFS was 9.0 and 4.9 months for lenvatinib and sorafenib arm, respectively. Patients treated with lenvatinib showed a higher percentage of response rate (29.4% vs 2.8%; p < 0.00001) compared with patients treated with sorafenib. Sorafenib was shown to be correlated with more HFSR, diarrhea and fatigue, while lenvatinib with more hypertension and fatigue. Conclusion: Our study highlighted for the first time the efficacy and safety of lenvatinib in an Italian cohort of patients.

5.
Cancers (Basel) ; 14(1)2021 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-35008350

RESUMO

Systemic inflammation is a hallmark of cancer, and it has a pivotal role in hepatocellular carcinoma (HCC) development and progression. We conducted a retrospective study including 362 patients receiving immune check-point inhibitors (ICIs) across three continents, evaluating the influence of neutrophiles to lymphocytes ratio (NLR), platelets to lymphocytes ratio (PLR), and prognostic nutritional index (PNI) on overall (OS), progression free survival (PFS), and radiologic responses. In our 362 patients treated with immunotherapy, median OS and PFS were 9 and 3.5 months, respectively. Amongst tested inflammatory biomarkers, patients with NLR ≥ 5 had shorter OS (7.7 vs. 17.6 months, p < 0.0001), PFS (2.1 vs. 3.8 months, p = 0.025), and lower objective response rate (ORR) (12% vs. 22%, p = 0.034); similarly, patients with PLR ≥ 300 reported shorter OS (6.4 vs. 16.5 months, p < 0.0001) and PFS (1.8 vs. 3.7 months, p = 0.0006). NLR emerged as independent prognostic factors for OS in univariate and multivariate analysis (HR 1.95, 95%CI 1.45-2.64, p < 0.001; HR 1.73, 95%CI 1.23-2.42, p = 0.002) and PLR remained an independent prognostic factor for both OS and PFS in multivariate analysis (HR 1.60, 95%CI 1.6-2.40, p = 0.020; HR 1.99, 95%CI 1.11-3.49, p = 0.021). Systemic inflammation measured by NLR and PLR is an independent negative prognostic factor in HCC patients undergoing ICI therapy. Further studies are required to understand the biological mechanisms underlying this association and to investigate the predictive significance of circulating inflammatory biomarkers in HCC patients treated with ICIs.

6.
Chemotherapy ; 2021 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-34974449

RESUMO

BACKGROUND: Sarcopenia is almost constantly observed in patients with cirrhosis and hepatocellular carcinoma. SUMMARY: Chronic liver disease represents a unique pathophysiological scenario in which sarcopenia develops and all factors involved in the pathogenesis should be taken into account for an appropriate management of the disease. No properly designed intervention studies on this topic are available and, thus, no effective strategies have been developed for clinical practice. Apart from any targeted intervention, treatment and optimization of liver disease is crucial. Key Messages: In patients with cirrhosis and hepatocellular carcinoma, nutritional support to maintain and restore nutrition status, a targeted use of branched-chain amino acids and a guided physical exercise, should all be an integral part of the multidimensional assessment and tailored interventions.

7.
Curr Drug Metab ; 21(11): 866-884, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32957880

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is among the world's most common cancers. For over ten years, the only medical treatment for it has been the multikinase inhibitor Sorafenib. Currently, however, other first or second-line therapeutic options have also shown efficacy against HCC, such as multikinase inhibitors (Regorafenib, Lenvatinib, and Cabozantinib), a monoclonal antibody against the vascular endothelial growth factor receptor 2 (Ramucirumab), and immune-checkpoint inhibitors (Nivolumab, Pembrolizumab, Ipilimumab). AIM: The aim of this paper is to review the metabolic pathways of drugs that have been tested for the treatment of HCC and the potential influence of liver failure over those pathways. METHODS: The Food and Drug Administration (FDA)'s and European Medicines Agency (EMA)'s datasheets, results from clinical trials and observational studies have been reviewed. RESULTS: This review summarizes the current knowledge regarding targets, metabolic pathways, drug interactions, and adverse events of medical treatments for HCC in cirrhotic patients. CONCLUSION: The new scenario of systemic HCC therapy includes more active drugs with different metabolic pathways and different liver adverse events. Clinical and pharmacological studies providing more data on the safety of these molecules are urgently needed.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Inibidores de Checkpoint Imunológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Inibidores de Proteínas Quinases , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/farmacocinética , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do Tratamento
8.
Cancers (Basel) ; 12(8)2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32752153

RESUMO

The desmoid tumor is a locally aggressive proliferative disease within the family of soft-tissue sarcomas. Despite its relatively good prognosis, the clinical management of desmoid tumors requires constant multidisciplinary evaluation due to its highly variable clinical behavior. Recently, active surveillance has being regarded as the appropriate strategy at diagnosis, as indolent persistence or spontaneous regressions are not uncommon. Here, we review the most recent advances in desmoid tumor therapy, including low-dose chemotherapy and treatment with tyrosine kinase inhibitors. We also explore the recent improvements in our knowledge of the molecular biology of this disease, which are leading to clinical trials with targeted agents.

9.
Clin Cancer Res ; 26(17): 4485-4493, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32371540

RESUMO

PURPOSE: After 10 years of clinical practice and research studies, there are still no validated prognostic or predictive factors of response to sorafenib for hepatocellular carcinoma (HCC). On the basis of the results of our two retrospective studies, we designed the multicenter INNOVATE study with the aim to validate the role of nitric oxide synthase 3 (NOS3) and ANGPT2 polymorphisms in patients with HCC treated with sorafenib [NCT02786342]. PATIENTS AND METHODS: This prospective multicenter study was conducted at 10 centers in Italy. All eligible patients received a continuous oral treatment with 400 mg of sorafenib twice daily. Genotyping analysis was performed for NOS3 (rs2070744) and ANGPT2 SNPs (rs55633437). The primary outcome was progression-free survival (PFS), whereas secondary outcomes included overall survival (OS) and disease-control rate. RESULTS: A total of 165 patients were enrolled between March 2016 and June 2018. NOS3 rs2070744 CC/CT genotypes were significantly associated with a higher median PFS (5.9 months vs. 2.4 months; HR = 0.43; P = 0.0007) and OS (15.7 months vs. 8.6 months; HR = 0.38; P < 0.0001) compared with TT genotype. There was no statistically significant association between ANGPT2 rs55633437 TT/GT genotypes and PFS (2.4 months vs. 5.7 months; HR = 1.93; P = 0.0833) and OS (15.1 months vs. 13.0 months; HR = 2.68; P = 0.55) when compared with the other genotype. Following adjustment for clinical covariates, multivariate analysis confirmed NOS3 as an independent prognostic factor for PFS (HR = 0.50; P = 0.0128) and OS (HR = 0.29; P = 0.0041). CONCLUSIONS: The INNOVATE study met the primary endpoint, confirming that patients with advanced HCC with NOS3 rs2070744 CC/CT genotypes had a better prognosis with respect to TT genotype patients.


Assuntos
Angiopoietina-2/genética , Carcinoma Hepatocelular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Hepáticas/genética , Óxido Nítrico Sintase Tipo III/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/mortalidade , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , Prognóstico , Intervalo Livre de Progressão , Estudos Prospectivos , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Adulto Jovem
10.
PLoS One ; 15(5): e0232449, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32379785

RESUMO

BACKGROUND AND AIMS: The present study aims to investigate the role of the prognostic nutritional index (PNI) on survival in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. METHODS: This multicentric study included a training cohort of 194 HCC patients and three external validation cohorts of 129, 76 and 265 HCC patients treated with Sorafenib, respectively. The PNI was calculated as follows: 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (per mm3). Univariate and multivariate analyses were performed to investigate the association between the covariates and the overall survival (OS). RESULTS: A PNI cut-off value of 31.3 was established using the ROC analysis. In the training cohort, the median OS was 14.8 months (95% CI 12-76.3) and 6.8 months (95% CI 2.7-24.6) for patients with a high (>31.3) and low (<31.3) PNI, respectively. At both the univariate and the multivariate analysis, low PNI value (p = 0.0004), a 1-unit increase of aspartate aminotransferase (p = 0.0001), and age > 70 years (p< 0.0038) were independent prognostic factors for OS. By performing the same multivariate analysis of the training cohort, the PNI <31.3 versus >31.3 was found to be an independent prognostic factor for predicting OS in all the three validation cohorts. CONCLUSIONS: PNI represents a prognostic tool in advanced HCC treated with first-line Sorafenib. It is readily available and low-cost, and it could be implemented in clinical practice in patients with HCC.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Avaliação Nutricional , Sorafenibe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/mortalidade , Estudos de Coortes , Feminino , Humanos , Itália/epidemiologia , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/mortalidade , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Albumina Sérica/metabolismo
11.
ESMO Open ; 5(1)2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31958289

RESUMO

INTRODUCTION: Desmoid tumour (DT) is a locally aggressive fibroblastic proliferative disease representing the most common extraintestinal manifestation of familial adenomatosis polyposis (FAP). As data on the activity of chemotherapy in these patients are limited, we examined the outcomes of patients treated with low-dose methotrexate (MTX)+vinca alkaloids (vinorelbine or vinblastine). PATIENTS AND METHODS: We retrospectively reviewed clinical and outcome data from all patients with confirmed FAP-associated DTs treated with weekly MTX+vinca alkaloids in seven European sarcoma reference centres between January 2000 and December 2018. Radiological responses were assessed using RECIST V.1.0 and V.1.1. The Kaplan-Meier method associated to the log-rank test was used to estimate and compare survival curves. RESULTS: We identified 37 patients (median age 29 years, range 7-44). According to RECIST, 20/37 (54.1%) patients achieved partial response (PR), 15/37 (40.5%) patients had stable disease and 2/37 (5.4%) had progressive disease as best response. Overall, the median progression-free survival (PFS) was 6.5 years (range, 0.3-12.1 years). In the subset of patients achieving PR as best response, the median PFS was not reached. In a subset of 11 patients with progressive disease offered MTX+vinca alkaloids rechallenge (after chemotherapy withdrawal following prolonged disease control), the disease control rate was 100%, resulting in a median PFS after rechallenge of 5.8 years. CONCLUSIONS: This is the largest series on the activity of low-dose chemotherapy in patients with FAP-related DT. In this population, MTX+vinca alkaloids is an active combination, as already reported in patients with sporadic DT.


Assuntos
Polipose Adenomatosa do Colo/tratamento farmacológico , Adolescente , Adulto , Criança , Feminino , Humanos , Estudos Retrospectivos , Adulto Jovem
12.
Chemotherapy ; 64(2): 105-109, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31390619

RESUMO

BACKGROUND: Dexrazoxane (DEX) is indicated as a cardioprotective agent for breast cancer patients receiving the anthracycline doxorubicin. Two meta-analyses in metastatic breast cancer reported an apparent increase in the severity of myelosuppression when DEX was used. So far, no data in soft-tissue sarcoma (STS) patients are available. METHODS: We retrospectively analyzed hematological toxicity data from 133 consecutive STS patients who received a chemotherapy regimen containing an anthracycline and ifosfamide (AI) in the perioperative or metastatic settings between January 2006 and December 2017. Of these, 46 received off-label DEX concurrently with the AI treatment. The differences between incidence of any of the explored outcomes were assessed according to the Fisher exact test. RESULTS: Compared with the non-DEX group, DEX treatment was associated with significantly higher rates of grade 3/4 hematological toxicities: leukopenia (56.5 vs. 28.7%; p = 0.0014), neutropenia (69.6 vs. 24.1%; p = 0.0001), febrile neutropenia (52.2 vs. 20.7%; p = 0.0004), anemia (41.3 vs. 28.7%; p = 0.1758), and thrombocytopenia (54.3 vs. 32.1%; p = 0.0159). Similarly, in the DEX group dose reductions were more frequent compared to the non-DEX group (39.1 vs. 19.5%; p = 0.0221). CONCLUSION: Adding DEX to AI in STS patients leads to higher rates of bone marrow suppression in all blood components, as well as to more frequent events of febrile neutropenia and dose reductions.


Assuntos
Antraciclinas/uso terapêutico , Antibióticos Antineoplásicos/uso terapêutico , Dexrazoxano/uso terapêutico , Substâncias Protetoras/uso terapêutico , Sarcoma/tratamento farmacológico , Adulto , Idoso , Antraciclinas/efeitos adversos , Antibióticos Antineoplásicos/efeitos adversos , Feminino , Doenças Hematológicas/etiologia , Doenças Hematológicas/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/etiologia , Neutropenia/prevenção & controle , Estudos Retrospectivos , Sarcoma/patologia , Adulto Jovem
13.
BMJ Case Rep ; 12(6)2019 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-31160300

RESUMO

In this case report, we describe an older adult man affected by advanced chordoma progressing after treatment with cisplatin and imatinib. The patient was symptomatic for uncontrolled pain. We decided to treat the patient with metronomic cyclophosphamide, unexpectedly achieving long-lasting clinical and radiological benefit.


Assuntos
Cordoma/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Sacro , Administração Metronômica , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Cordoma/diagnóstico por imagem , Cordoma/patologia , Ciclofosfamida/administração & dosagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Recidiva Local de Neoplasia/diagnóstico por imagem
14.
Ther Adv Med Oncol ; 11: 1758835919841946, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31205499

RESUMO

The tyrosine kinase inhibitor (TKI) imatinib has radically changed the natural history of KIT-driven gastrointestinal stromal tumours (GISTs). Approved second-line and third-line medical therapies are represented by the TKIs sunitinib and regorafenib, respectively. While imatinib remains the cardinal drug for patients with GISTs, novel therapies are being developed and clinically tested to overcome the mechanisms of resistance after treatments with the approved TKI, or to treat subsets of GISTs driven by rarer molecular events. Here, we review the therapy of GISTs, with a particular focus on the newest drugs in advanced phases of clinical testing that might soon change the current therapeutic algorithm.

15.
Tumori ; 104(6): 476-479, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29739298

RESUMO

INTRODUCTION: Although sorafenib is the upfront standard of care for advanced hepatocellular carcinoma (HCC), molecular predictors of efficacy have not been identified yet. In the ALICE-1 study, rs2010963 of VEGF-A and VEGF-C proved to be independent predictive factors for progression-free survival (PFS) and overall survival (OS) in multivariate analysis. The ALICE-1 study results were confirmed in the ALICE-2 study, in which VEGF and VEGFR SNPs were analyzed. In the ePHAS study we analyzed the SNPs of eNOS. In univariate analysis, patients homozygous for an eNOS haplotype (HT1: T-4b at eNOS-786/eNOS VNTR) had significantly shorter median PFS and OS than those with other haplotypes. These data were confirmed in the validation set. METHODS: This nonpharmacological, interventional, prospective multicenter study aims to determine whether eNOS, HIF-1, VEGF, Ang2 and VEGFR polymorphisms play a role in predicting the objective response rate, PFS, and OS of advanced HCC patients treated with sorafenib. The study will involve 160 advanced HCC patients with Child-Pugh class A disease. The primary aim is to validate the prognostic or predictive roles of eNOS, Ang2, HIF-1, VEGF and VEGFR polymorphisms in relation to the clinical outcome (PFS) of HCC patients treated with sorafenib. CONCLUSIONS: Overall, our data may suggest that polymorphism analysis of the VEGF, VEGFR-2, HIF and eNOS genes can identify HCC patients who are more likely to benefit from sorafenib.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neovascularização Patológica/genética , Polimorfismo de Nucleotídeo Único/genética , Sorafenibe/uso terapêutico , Adolescente , Angiopoietina-2/genética , Antineoplásicos/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Fator 1 Induzível por Hipóxia/genética , Masculino , Óxido Nítrico Sintase Tipo III/genética , Estudos Prospectivos , Receptores de Fatores de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular
16.
Oncology ; 95(1): 1-7, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29510410

RESUMO

OBJECTIVES: Low body mass index (BMI) and/or low lean body mass have been shown to be risk factors for chemotherapy-related toxicities in a number of different cancers. However, no data are available regarding the role of BMI as a risk factor for developing toxicities related to the novel anticancer agent, trabectedin, in patients with soft-tissue sarcoma (STS). We evaluated the role of BMI as a risk factor for trabectedin-related toxicity in patients with STS. METHODS: Data from 51 patients with metastatic/advanced STS treated with trabectedin after progression on ≥1 anthracycline ± ifosfamide regimen were retrospectively reviewed. RESULTS: Eighteen patients (35.3%) were underweight, and the remainder were of normal bodyweight (45.1%) or overweight (19.6%). Neutropenia of any grade (77.8 vs. 33.3%) and grade 3-4 neutropenia (50.0 vs. 18.2%) occurred more frequently in the underweight versus normal/overweight patients (p = 0.025). Febrile neutropenia also occurred more frequently in underweight patients. Differences remained statistically significant after adjusting for other predictors of toxicity. There were no significant differences in other hematological and nonhematological toxicities between the groups. CONCLUSIONS: The data suggest for the first time that BMI should be considered a risk factor for neutropenia in patients with STS treated with trabectedin.


Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Índice de Massa Corporal , Dioxóis/efeitos adversos , Dioxóis/uso terapêutico , Neutropenia/induzido quimicamente , Sarcoma/tratamento farmacológico , Tetra-Hidroisoquinolinas/efeitos adversos , Tetra-Hidroisoquinolinas/uso terapêutico , Magreza/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antraciclinas/uso terapêutico , Antineoplásicos Alquilantes/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Ifosfamida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Sarcopenia/fisiopatologia , Trabectedina
17.
Oncotarget ; 8(39): 66699-66708, 2017 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-29029548

RESUMO

Transarterial chemoembolization (TACE) is the standard treatment for intermediate stage, although the combination of TACE with sorafenib may theoretically benefit HCC patients in intermediate stage. Owing to the significant antiangiogenic effect of sorafenib and the limitation of TACE, it is rational to combine them. Though the strategy of combining TACE and sorafenib has been increasingly used in patients with unresectable HCC but the current evidence is controversial and its clinical role has not been determined yet. In first-line therapy, patients receiving sorafenib had increased overall survival and progression free survival. Therefore several antiangiogenic agents have entered clinical studies on HCC, many with negative results. This review discusses the current drug development for patients with HCC and role of TACE plus sorafenib.

18.
PLoS One ; 10(7): e0133488, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26230853

RESUMO

BACKGROUND: The European Association for the Study of the Liver (EASL) criteria and the modified Response Evaluation Criteria in Solid Tumors (mRECIST) are currently adopted to evaluate radiological response in patients affected by HCC and treated with loco-regional procedures. Several studies explored the validity of these measurements in predicting survival but definitive data are still lacking. AIM: To conduct a systematic review of studies exploring mRECIST and EASL criteria usefulness in predictive radiological response in HCC undergoing loco-regional therapies and their validity in predicting survival. METHODS: A comprehensive search of the literature was performed in electronic databases EMBASE, MEDLINE, COCHRANE LIBRARY, ASCO conferences and EASL conferences up to June 10, 2014. Our overall search strategy included terms for HCC, mRECIST, and EASL. Loco-regional procedures included transarterial embolization (TAE), transarterial chemoembolization (TACE) and cryoablation. Inter-method agreement between EASL and mRECIST was assessed using the k coefficient. For each criteria, overall survival was described in responders vs. non-responders patients, considering all target lesions response. RESULTS: Among 18 initially found publications, 7 reports including 1357 patients were considered eligible. All studies were published as full-text articles. Proportion of responders according to mRECIST and EASL criteria was 62.4% and 61.3%, respectively. In the pooled population, 1286 agreements were observed between the two methods (kappa statistics 0.928, 95% confidence interval 0.912-0.944). HR for overall survival (responders versus non responders) according to mRECIST and EASL was 0.39 (95% confidence interval 0.26-0.61, p<0.0001) and 0.38 (95% confidence interval 0.24-0.61, p<0.0001), respectively. CONCLUSION: In this literature-based meta-analysis, mRECIST and EASL criteria showed very good concordance in HCC patients undergoing loco-regional treatments. Objective response according to both criteria confirms a strong prognostic value in terms of overall survival. This prognostic value appears to be very similar between the two criteria.


Assuntos
Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Humanos , Prognóstico , Análise de Sobrevida , Resultado do Tratamento
19.
Sci Rep ; 5: 12077, 2015 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-26235506

RESUMO

Elevation in liver transaminases is common in patients treated with the marine antitumor agent trabectedin. However, the impact of trabectedin-related transaminase elevations on treatment outcomes is unclear. This retrospective study investigated the correlation between liver tests abnormalities and treatment outcomes in patients with unresectable advanced or metastatic soft tissue sarcomas (STS) treated with trabectedin 1.5 mg/m(2) once every 3 weeks at three reference centers in Italy. The effect of grade 3/4 elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) during the first two cycles and at any time during trabectedin treatment on progression-free survival (PFS) and overall survival (OS) were analyzed. Liver tests abnormalities during the first two cycles of chemotherapy or at any time during trabectedin treatment did not significantly affect PFS or OS. Nor were survival outcomes significantly different in the subgroups of patients with or without ALT/AST increases or with ALT/AST elevations ≥ 15 × the upper limit of normal (ULN) versus those with ALT/AST elevation < 15 × ULN. Although liver tests abnormalities are common in patients treated with trabectedin, elevations in ALT and AST are usually transient, occur during the first two cycles of treatment, and do not appear to affect survival.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Dioxóis/uso terapêutico , Sarcoma/tratamento farmacológico , Sarcoma/patologia , Neoplasias de Tecidos Moles/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Adulto , Idoso , Alanina Transaminase , Aspartato Aminotransferases , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Fígado/enzimologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sarcoma/mortalidade , Neoplasias de Tecidos Moles/mortalidade , Neoplasias de Tecidos Moles/patologia , Trabectedina
20.
Expert Opin Emerg Drugs ; 20(3): 479-93, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26021342

RESUMO

INTRODUCTION: Gastric cancer (GC) is the fifth most common malignancy in the world. In the last years, for the first time in literature, the addition of a targeted therapy to standard chemotherapy has proved to prolong median overall survival. In this scenario, kinase inhibitors (KIs), smaller intracellular agents, could be an interesting and novel type of targeted treatment of metastatic GC both in first and further lines of therapy. AREAS COVERED: Several KI have been evaluated in the preclinical setting. This review will underline the most relevant targeted pathways involved in GC tumorigenesis and disease progression including EGFR, VEGFR, c-MET, mTOR, fibroblast growth factor receptor, Src and Aurora kinases. EXPERT OPINION: Despite the good results of TOGA, RAINBOW and REGARD trials about the addition of monoclonal antibodies to standard of care in GC, the addition of KI seems not to achieve comparable interesting results in management of GC. However, an improved patient selection before and during treatment according to molecular characteristics, as well as combination studies evaluating the synergistic effect of combination schedules of different KIs and standard chemotherapy, or KI plus KI or KI plus antibodies-based therapy may reveal interesting results and lead to understand mechanisms of multi-drug resistance.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Humanos , Terapia de Alvo Molecular , Metástase Neoplásica , Seleção de Pacientes , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/efeitos dos fármacos , Proteínas Quinases/metabolismo , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/patologia , Taxa de Sobrevida
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