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1.
Cancers (Basel) ; 14(7)2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35406564

RESUMO

Nonmetastatic castration-resistant prostate cancer (nmCRPC) represents a condition in which patients with prostate cancer show biochemical progression during treatment with androgen-deprivation therapy (ADT) without signs of radiographic progression according to conventional imaging. The SPARTAN, ARAMIS and PROSPER trials showed that apalutamide, darolutamide and enzalutamide, respectively, prolong metastasis-free survival (MFS) and overall survival (OS) of nmCRPC patients with a short PSA doubling time, and these antiandrogens have been recently introduced in clinical practice as a new standard of care. No direct comparison of these three agents has been conducted to support treatment choice. In addition, a significant proportion of nmCRPC on conventional imaging is classified as metastatic with new imaging modalities such as the prostate-specific membrane antigen positron emission tomography (PSMA-PET). Some experts posit that these "new metastatic" patients should be treated as mCRPC, resizing the impact of nmCRPC trials, whereas other authors suggest that they should be treated as nmCRPC patients, based on the design of pivotal trials. This review discusses the most convincing evidence regarding the use of novel antiandrogens in patients with nmCRPC and the implications of novel imaging techniques for treatment selection.

2.
Expert Rev Anticancer Ther ; 22(1): 115-121, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34738499

RESUMO

BACKGROUND: Cabozantinib improves survival in metastatic renal cell carcinoma (mRCC) after prior antiangiogenics. The best treatment at disease progression (PD) is unknown. Being also a AXL/MET inhibitor, involved in acquired resistance, we hypothesized a prolonged tumor growth control in patients continuing cabozantinib despite PD. RESEARCH DESIGN AND METHODS: This retrospective multicenter study enrolled patients receiving cabozantinib after the first line between 2014 and 2020. We compared patients maintaining cabozantinib after first PD due to clinical benefit and good tolerability with those who changed therapy. The postprogression survival (PPS) of both was our primary endpoint. RESULTS: We analyzed 89 patients: 45 received cabozantinib beyond PD and 44 switched therapy. 40.4%, 31.5%, and 28.1% of patients received 1, 2, or >2 prior treatment, respectively. 84.3% were intermediate-poor International Metastatic Renal Cell Carcinoma Database risk. Patients continuing cabozantinib showed a higher response rate to cabozantinib before PD (46.7% vs 25%, p = 0.03) and were more heavily pretreated. Continuing cabozantinib showed a significantly longer PPS compared with switching therapy (median PPS 16.9 vs 13.2 months, HR 0.66, 95%CI 0.48-0.92, p = 0.011). CONCLUSIONS: We observed longer PPS in patients continuing cabozantinib beyond PD, suggesting that this could be an effective option.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Anilidas/farmacologia , Anilidas/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Feminino , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Masculino , Piridinas , Estudos Retrospectivos
3.
Ther Adv Urol ; 13: 17562872211053189, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34733356

RESUMO

BACKGROUND: In recent years, new therapeutic combinations based on immunotherapy provided significant benefits as a first-line treatment for patients with advanced renal cell carcinoma (mRCC). OBJECTIVE: This work aims to address the lack of head-to-head comparisons and the uncertainty of the benefit from immunotherapy-based combinations in all the International Metastatic RCC Database Consortium (IMDC) subgroups. DESIGN SETTING AND PARTICIPANTS: A systematic review and a network meta-analysis were performed. Overall survival (OS) in the intention-to-treat (ITT) population was the primary endpoint. OS according to IMDC subgroups (favorable, intermediate, poor), PD-L1 expression, and grade ⩾3 adverse events (AEs) were secondary endpoints. A SUCRA analysis was performed. RESULTS AND LIMITATIONS: Six randomized phase III trials with 5121 patients were included. There was a high likelihood (82%) that nivolumab-cabozantinib was the preferred treatment in OS. The benefit of ICI-based combinations over sunitinib was unclear in the favorable-risk subgroup. Nivolumab-ipilimumab had the best risk/benefit ratio among all the ICI-based combinations. The limitations were the lack of individual patient data; the heterogeneity of patients' characteristics, trial designs, and follow-up times; and a limited number of studies for indirect comparisons. CONCLUSIONS: A customized approach for the first-line treatment of patients with mRCC should consider the risk/benefit profile of each treatment option, especially considering the likeliness of long-term survival finally reached in this setting.

4.
Cancers (Basel) ; 13(18)2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34572748

RESUMO

The treatment landscape of advanced prostate cancer has completely changed during the last decades. Chemotherapy (docetaxel, cabazitaxel), androgen-receptor signaling inhibitors (ARSi) (abiraterone acetate, enzalutamide), and radium-223 have revolutionized the management of metastatic castration-resistant prostate cancer (mCRPC). Lutetium-177-PSMA-617 is also going to become another treatment option for these patients. In addition, docetaxel, abiraterone acetate, apalutamide, enzalutamide, and radiotherapy to primary tumor have demonstrated the ability to significantly prolong the survival of patients with metastatic hormone-sensitive prostate cancer (mHSPC). Finally, apalutamide, enzalutamide, and darolutamide have recently provided impactful data in patients with nonmetastatic castration-resistant disease (nmCRPC). However, which is the best treatment sequence for patients with advanced prostate cancer? This comprehensive review aims at discussing the available literature data to identify the optimal sequencing approaches in patients with prostate cancer at different disease stages. Our work also highlights the potential impact of predictive biomarkers in treatment sequencing and exploring the role of specific agents (i.e., olaparib, rucaparib, talazoparib, niraparib, and ipatasertib) in biomarker-selected populations of patients with prostate cancer (i.e., those harboring alterations in DNA damage and response genes or PTEN).

5.
J Transl Med ; 19(1): 328, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34344414

RESUMO

BACKGROUND: Severe immune-related Adverse Events (irAEs) develop in 10-27% of patients treated with Immune-Oncology (IO) [Powles (Lancet 391:748-757, 2018); Galsky (Lancet 395:1547-1557, 2020); Haanen (Ann Oncol 28:119-142, 2017)]. The aim of our study was to evaluate efficacy and clinical outcome of metastatic renal cell carcinoma (mRCC) patients who stopped Immune Checkpoint Inhibitors (ICIs) due to early Grade (G) 3-G4 irAEs. METHODS: We retrospectively collected data from 204 mRCC patients treated with ICIs in 6 Italian referral centers adhering to the Meet-Uro group, between February 2017 and January 2020. To properly weight the results, patients who did not report early G3-G4 toxicities have been included as control group. Primary endpoint was to evaluate 6 months Progression Free Survival (PFS) after early treatment interruption for Grade (G) 3-4 toxicities compared to the control group. Secondary endpoints were to evaluate Time to treatment failure (TTF) and overall survival (OS) in both groups. All statistical analyses were performed using SPSS software (version 19.00, SPSS, Chicago). RESULTS: 18/204 (8.8%) patients had early treatment interruption for serious (G3-G4) irAEs. Early was defined as interruption of IO after only one or two administrations. Immune related nephritis and pancreatitis were the most common irAE that lead to treatment interruption. 6/18 patients received IO-IO combination whereas 12/18 patients antiPD1. In the study group, 12/18 (66.6%) were free from progression at 6 months since IO interruption, TTF was 1.6 months (95% CI 1.6-2.1), mPFS was 7.4 months (95% CI 3.16-11.6) and mOS was 15.5 months (5.1-25.8). In the control group 111/184 (60.3%) patients were free from progression at 6 months, TTF was 4.6 months (95% CI 3.5-5.6), mPFS was 4.6 months (95% CI 3.5-5.6) and mOS was 19.6 months (95% CI 15.1-24.0). In the overall population, mPFS was 5.0 months (95% CI 4.0-5.9) and mOS was 19.6 months (95% CI 15.1-24.0). CONCLUSIONS: ICIs seem to maintain efficacy even after early interruption due to severe irAE.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Imunoterapia/efeitos adversos , Itália , Neoplasias Renais/tratamento farmacológico , Estudos Retrospectivos
8.
Biomolecules ; 11(1)2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33477996

RESUMO

BACKGROUND: Breast cancer (BC) is the most common neoplasm in women. Many clinical and preclinical studies investigated the possible relationship between host metabolism and BC. Significant differences among BC subtypes have been reported for glucose metabolism. Insulin can promote tumorigenesis through a direct effect on epithelial tissues or indirectly by affecting the levels of other modulators, such as the insulin-like growth factor (IGF) family of receptors, sex hormones, and adipokines. The potential anti-cancer activity of metformin is based on two principal effects: first, its capacity for lowering circulating insulin levels with indirect endocrine effects that may impact on tumor cell proliferation; second, its direct influence on many pro-cancer signaling pathways that are key drivers of BC aggressiveness. METHODS: In the present review, the interaction between BC, host metabolism, and patients' prognosis has been reviewed across available literature evidence. CONCLUSIONS: Obesity, metabolic syndrome, and insulin resistance are all involved in BC growth and could have a relevant impact on prognosis. All these factors act through a pro-inflammatory state, mediated by cytokines originated in fat tissue, and seem to be related to a higher risk of BC development and worse prognosis.


Assuntos
Insulina/metabolismo , Somatomedinas/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco
9.
Tumori ; 107(6): 542-549, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33153416

RESUMO

BACKGROUND: Cabozantinib strongly inhibits osteoclast differentiation and bone resorption in vitro. We aimed to evaluate its effect on bone turnover markers (BTMs) in metastatic renal cell carcinoma. METHODS: This is a monocentric prospective study on patients with mRCC treated with cabozantinib between October 2016 and July 2018. We collected blood samples at baseline and after 3 and 6 months of treatment. We compared sets of data obtained from plasma samples in the whole population with unpaired 2-tailed Student t tests and data for a subset of patients for which all timepoints were available with paired 2-tailed Student t tests. We used the Kaplan-Meier method for survival analyses and the log-rank test to compare the curves. RESULTS: Our analysis included 39 patients. At month 3, the mean C-terminal cross-linked telopeptides of type I collagen (CTx) and the mean N-terminal propeptide of type 1 collagen (PINP) levels were significantly decreased in the whole population (p = 0.013 and p < 0.0001, respectively), as well as at paired analysis (p = 0.015 and p = 0.045, respectively). No differences were observed between baseline and 6 months (p = 0.053 and p = 0.087, respectively). After 3 months, the mean parathyroid hormone (PTH) levels significantly increased in the whole population (p = 0.004), as well as at paired analysis; the mean PTH levels increased significantly at 3 and 6 months, respectively (p = 0.019 and p = 0.041, respectively). Changes in BTM levels were not associated with outcome. CONCLUSIONS: Cabozantinib significantly reduced bone resorption as demonstrated by the decrease of CTx and showed a transient secondary increase of PTH.


Assuntos
Anilidas/farmacologia , Antineoplásicos/farmacologia , Biomarcadores , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Carcinoma de Células Renais/metabolismo , Neoplasias Renais/metabolismo , Piridinas/farmacologia , Anilidas/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/patologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Gerenciamento Clínico , Feminino , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Masculino , Estudos Prospectivos , Piridinas/uso terapêutico
10.
Immunotargets Ther ; 9: 273-288, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33224904

RESUMO

Over the last 20 years, different therapies have been considered as the mainstay for the treatment of patients with metastatic renal cell carcinoma (mRCC). Since angiogenesis is a key mechanism in the pathogenesis of renal carcinoma, research is still focusing on the inhibition of new vessel growth through the development of novel and potent tyrosine kinase inhibitors (TKIs), such as cabozantinib. On the other hand, a new therapeutic scenario has opened up in the forefront with immunotherapy. Immune checkpoint inhibitors (ICIs), which already represent a standard treatment option in pretreated mRCC patients, are revolutionizing the frontline therapeutic armamentarium of mRCC. Upfront combination immunotherapy as well as combinations of immunotherapy with targeted agents showed to significantly improved outcomes of mRCC patients compared to single-agent TKIs. ICIs are associated with long-lasting responses. Nonetheless, several unmet needs remain, as a small proportion of patients shows primary refractoriness to immunotherapy. Multiple treatment strategies combining different mechanisms of action or targeting immune escape pathways are emerging with the aim to improve response rates and survival outcomes. This review summarizes current immunotherapeutic targets and therapies approved for mRCC, while examining mechanisms of resistance and future directions, with the aim to address novel treatment strategies and help in improving the management of this tumor.

11.
J Immunother Cancer ; 8(2)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33060148

RESUMO

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has overwhelmed the health systems worldwide. Data regarding the impact of COVID-19 on cancer patients (CPs) undergoing or candidate for immune checkpoint inhibitors (ICIs) are lacking. We depicted the practice and adaptations in the management of patients with solid tumors eligible or receiving ICIs during the COVID-19 pandemic, with a special focus on Campania region. METHODS: This survey (25 questions), promoted by the young section of SCITO (Società Campana di ImmunoTerapia Oncologica) Group, was circulated among Italian young oncologists practicing in regions variously affected by the pandemic: high (group 1), medium (group 2) and low (group 3) prevalence of SARS-CoV-2-positive patients. For Campania region, the physician responders were split into those working in cancer centers (CC), university hospitals (UH) and general hospitals (GH). Percentages of agreement, among High (H) versus Medium (M) and versus Low (L) group for Italy and among CC, UH and GH for Campania region, were compared by using Fisher's exact tests for dichotomous answers and χ2 test for trends relative to the questions with 3 or more options. RESULTS: This is the first Italian study to investigate the COVID-19 impact on cancer immunotherapy, unique in its type and very clear in the results. The COVID-19 pandemic seemed not to affect the standard practice in the prescription and delivery of ICIs in Italy. Telemedicine was widely used. There was high consensus to interrupt immunotherapy in SARS-CoV-2-positive patients and to adopt ICIs with longer schedule interval. The majority of the responders tended not to delay the start of ICIs; there were no changes in supportive treatments, but some of the physicians opted for delaying surgeries (if part of patients' planned treatment approach). The results from responders in Campania did not differ significantly from the national ones. CONCLUSION: Our study highlights the efforts of Italian oncologists to maintain high standards of care for CPs treated with ICIs, regardless the regional prevalence of COVID-19, suggesting the adoption of similar solutions. Research on patients treated with ICIs and experiencing COVID-19 will clarify the safety profile to continue the treatments, thus informing on the most appropriate clinical conducts.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Betacoronavirus/imunologia , Infecções por Coronavirus/epidemiologia , Oncologia/estatística & dados numéricos , Neoplasias/tratamento farmacológico , Pneumonia Viral/epidemiologia , Adulto , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Betacoronavirus/patogenicidade , COVID-19 , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/transmissão , Prescrições de Medicamentos/estatística & dados numéricos , Feminino , Geografia , Humanos , Controle de Infecções/normas , Itália/epidemiologia , Masculino , Oncologia/normas , Neoplasias/imunologia , Oncologistas/estatística & dados numéricos , Pandemias/prevenção & controle , Pneumonia Viral/imunologia , Pneumonia Viral/prevenção & controle , Pneumonia Viral/transmissão , Padrões de Prática Médica/normas , Padrões de Prática Médica/estatística & dados numéricos , Prevalência , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , SARS-CoV-2 , Inquéritos e Questionários/estatística & dados numéricos , Tempo para o Tratamento
12.
Am J Clin Oncol ; 43(9): 621-627, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32889831

RESUMO

OBJECTIVES: Despite the initial clinical benefit, resistance to antiangiogenic therapies develops through the activation of alternative pathways. We measured plasma levels of circulating angiogenic factors to explore their predictive role in metastatic renal cell carcinoma (mRCC) patients treated with pazopanib. MATERIALS AND METHODS: mRCC patients receiving first-line pazopanib were prospectively enrolled. The levels of circulating interleuchine (IL)-6, IL-8, stromal derived factor-1, vascular endothelial growth factor-A, hepatocyte growth factor (HGF), osteopontin, and E-selectin were quantified at baseline and every 4 weeks until disease progression (PD). Patients were dichotomized into "low" and "high" subgroups by a cutoff point defined by the respective median circulating angiogenic factor (CAF) value at baseline. Then, association with the objective response was determined. Changes in CAF levels between baseline and PD were also compared. RESULTS: Among 25 patients included in the final data set, 6 patients were still on treatment. As best response, 12 patients presented a partial response (48%), 9 showed stable disease, and 4 showed PD. The median follow-up was 31.9 months. The median progression-free survival was 14.8 months. Low baseline levels of IL-6, IL-8, HGF, and osteopontin were found to be significantly associated with objective response. In addition, patients with low baseline levels of HGF showed longer progression-free survival and overall survival, whereas patients with low baseline levels of IL-8 showed longer overall survival. Among patients experiencing PD, the median plasma levels of stromal derived factor-1 and vascular endothelial growth factor-A were significantly higher compared with the baseline (P=0.01; P=0.011). Conversely, the median levels of E-selectin were significantly lower compared with the baseline (P=0.017). CONCLUSION: Changes in levels of selected CAFs were associated with response/resistance to pazopanib in mRCC patients.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Renais/tratamento farmacológico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Idoso , Inibidores da Angiogênese/uso terapêutico , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/secundário , Quimiocina CXCL12/sangue , Progressão da Doença , Selectina E/sangue , Feminino , Fator de Crescimento de Hepatócito/sangue , Humanos , Indazóis , Interleucina-6/sangue , Interleucina-8/sangue , Neoplasias Renais/sangue , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Osteopontina/sangue , Intervalo Livre de Progressão , Estudos Prospectivos , Critérios de Avaliação de Resposta em Tumores Sólidos , Taxa de Sobrevida , Fator A de Crescimento do Endotélio Vascular/sangue
13.
Front Oncol ; 10: 1644, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32903369

RESUMO

INTRODUCTION: In the last decades, the therapeutic decision-making approach to metastatic renal cell cancer (mRCC) has dramatically changed thanks to the introduction in the treatment scenario of, first, anti-angiogenic agents and, afterward, immune-checkpoint inhibitors (ICIs). Immunotherapy is now the standard of care in pretreated mRCC patients and has recently entered even the first line setting. Nevertheless, in mRCC as well as in other tumor settings, a durable and clinically meaningful benefit from treatment with ICIs is not obtained for all patients treated. Therefore, the necessity to identify and validate predictive biomarkers of response to immunotherapy has emerged, in order to design the optimal treatment strategy for mRCC patients. DISCUSSION: In this review, we present and discuss the most promising predictive biomarkers of response to ICIs in mRCC with the recent data available. In details, the first marker that was investigated is the immunohistochemical expression of programmed death receptor ligand 1 (PD-L1), showing a negative prognostic role in mRCC, but the debate about its potential predictive value is still open. Additionally, the high heterogeneity in PD-L1 determination methods adds complexity to this issue. Second, the tumor mutational or neoantigen burden is an emerging biomarker of increased response to immunotherapy, hypothesizing that the higher the TMB, the higher is the production of neoantigens, and thus the stimulation of anti-tumor immune response, even though controversial results have been obtained. Third, the tumor microenvironment, namely the different populations of the immune infiltrate, plays a key role in tumor progression and in the response to immunotherapy. Finally, several studies have collected evidence on the potential association of the occurrence of immune-related adverse events (irAEs) with the benefit from ICIs, first in non-small cell lung cancer (NSCLC) and melanoma, and recently even in mRCC. CONCLUSION: Several promising biomarkers of response to immunotherapy with ICIs have been identified, though without conclusive results upon their potential predictive value in mRCC. Therefore, the results of the exploratory analyses of the recently presented first-line trials and hopefully of future prospective, biomarker-driven studies could provide useful tools to be applied in the everyday clinical practice.

14.
Expert Rev Anticancer Ther ; 20(8): 715-726, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32758032

RESUMO

INTRODUCTION: In prostate cancer , there has recently been an emerging interest in mutations in genes belonging to the homologous recombination repair (HRR) pathway and in the inhibition of poly (ADP-ribose) polymerase (PARP) proteins. AREAS COVERED: Mutations in the HRR genes, including BRCA1, BRCA2, and Ataxia-Telangiesctasia mutated (ATM), have been reported in prostate cancer, with different incidence in the localized and advanced settings. The PARP enzyme complex is involved in repair of DNA damage and its inhibition causes the accumulation of DNA mutations in HRR deficient cells. Several PARP inhibitors (PARPi) are under development, such as olaparib, talazoparib, niraparib, rucaparib, and veliparib. In metastatic castration resistant prostate cancer (mCRPC), olaparib has been the most studied and its clinical efficacy has been validated in a phase III clinical trial. Rucaparib and niraparib have also shown promising results in the preliminary analyzes of two phase II trials, while talazoparib is currently under development. EXPERT OPINION: PARPi have become part of the treatment of mCRPC. Early results of combination therapy with PARPi and new hormonal therapy are promising and are supported by a strong biological rationale. Current results need to be validated in randomized phase III-controlled trials in order to translate the use of PARPi into real world practice.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Animais , Reparo do DNA/genética , Desenvolvimento de Medicamentos , Humanos , Masculino , Mutação , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia
15.
Cancer Treat Rev ; 88: 102057, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32574991

RESUMO

Despite advances in metastatic prostate cancer therapy, expected survival for patients in the castration-resistant phase of disease is poor. Immune-checkpoints inhibitors significantly prolonged life expectancy in some solid tumors and have been evaluated also in advanced stage prostate cancer. The majority of data available derive from preliminary phase I and II trials evaluating CTLA-4 and PD-1 as monotherapy or in combination with each other, vaccines, radiotherapy or targeted/hormonal therapy, achieving only limited benefits in terms of biochemical and radiologic responses. There are many reasons that may explain why prostate cancer responds poorly to modern immunotherapies, such as its characteristic low tumor mutational burden or immune-suppressive tumor microenvironment. The present review summarizes the results obtained treating advanced prostate cancer patients with immune-checkpoints inhibitors and analyzes potential mechanisms of both resistance and sensitivity, in order to hypothesize possible avenues of special interest for future research.


Assuntos
Imunoterapia/métodos , Neoplasias de Próstata Resistentes à Castração/terapia , Antineoplásicos Imunológicos/administração & dosagem , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Vacinas Anticâncer/administração & dosagem , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Masculino , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto
16.
J Clin Med ; 9(4)2020 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-32231117

RESUMO

The frontline treatment options for patients with metastatic renal cell carcinoma (mRCC) are evolving rapidly since the approval of combination immunotherapies by the U.S. Food and Drug Administration (USFDA) and the European Medicines Agency (EMA). In particular, in combination with vascular endothelial growth factor receptor (VEGFR) tyrosine-kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs) have significantly improved the outcome of patients with mRCC compared to TKI monotherapy. Here, we review the preclinical data supporting the combination of ICIs with VEGFR TKIs. The VEGF-signaling inhibition could ideally sustain immunotherapy through a positive modulation of the tumor microenvironment (TME). Antiangiogenetics, in fact, with their inhibitory activity on myelopoiesis that indirectly reduces myeloid-derived suppressor cells (MDSCs) and regulatory T cells' (Tregs) frequency and function, could have a role in determining an effective anti-tumor immune response. These findings are relevant for the challenges posed to clinicians concerning the clinical impact on treatment strategies for mRCC.

17.
Curr Oncol Rep ; 22(1): 9, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31989430

RESUMO

PURPOSE OF REVIEW: The aim of this review is to sum up the state of the art of urachal carcinoma (UC) in order to easily guide clinicians. RECENT FINDINGS: UC is a rare and aggressive disease with consequent few data about diagnosis and treatment. Dates are mainly based on retrospective trial and case reports with limited prospective trial. Clinical presentation is not specific, often with urinary symptoms. Diagnosis is mainly based on CT scan and MRI, useful to evaluate local invasion and nodal status and to detect the presence of distant metastases. Therefore, biopsy is needed to obtain histological confirmation. Surgery is the gold standard for localized disease, while different chemotherapy schemes have been used in metastatic setting. Novel findings based on mutational analysis of the tumor include the use of biological treatment, such as cetuximab, and immunotherapy, such as atezolizumab, with satisfactory responses, suggesting that personalized treatment could be the most suitable option for UC.


Assuntos
Adenocarcinoma/diagnóstico , Adenocarcinoma/terapia , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/terapia , Adenocarcinoma/patologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Quimioterapia Adjuvante , Cistectomia/métodos , Humanos , Imunoterapia , Terapia de Alvo Molecular , Prognóstico , Neoplasias da Bexiga Urinária/patologia
18.
Crit Rev Oncol Hematol ; 139: 53-66, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31112882

RESUMO

HER2-positive breast cancer (HER2 + BC) represents 15-20% of all BCs. In the last two decades, the introduction of monoclonal antibodies (MoAbs), tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs) directed against HER2 impressively improved patient prognosis in all disease stages. Yet, not all patients with limited-stage disease are cured, and HER2+ metastatic BC (mBC) remains an almost invariably deadly disease. Primary or acquired resistance to anti-HER2 therapies is responsible for most treatment failures. In recent years, several resistance mechanisms have been identified, such as impaired drug binding to HER2, constitutive activation of signaling pathways parallel or downstream of HER2, metabolic reprogramming or reduced immune system activation. However, only a few of them have been validated in clinical series; moreover, in the era of standard-of-care dual HER2 blockade, these mechanisms should be re-assessed and, in case, confirmed with anti-HER2 combinations. Defining the best strategies to delay or revert resistance to anti-HER2 treatments will be crucial to improve their clinical efficacy.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/uso terapêutico , Neoplasias da Mama/patologia , Feminino , Humanos , Resultado do Tratamento
19.
Clin Breast Cancer ; 19(2): e306-e318, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30635175

RESUMO

BACKGROUND: Single-agent gemcitabine is a moderately effective compound in metastatic breast cancer (mBC) treatment. Carboplatin is frequently used in addition to gemcitabine to improve tumor responses, but with an unclear effect on survival outcomes. In this study we evaluated the antitumor efficacy and safety profiles of gemcitabine and carboplatin-gemcitabine in mBC patients. PATIENTS AND METHODS: We retrospectively collected data on patients treated between April 2012 and February 2018 with gemcitabine 800 mg/m2or carboplatin at an area under the curve of 2 with gemcitabine 800 mg/m2, given on days 1 and 8 every 21 days. We compared progression-free survival (PFS), objective response rate (ORR), overall survival, and incidence of adverse events (AEs) in the 2 cohorts. RESULTS: Of 163 consecutive patients who met the inclusion criteria, 75 received gemcitabine and 88 carboplatin-gemcitabine. Patients in the combination cohort had received a lower number of previous chemotherapy lines (2 vs. 3), and were less likely to have received carboplatin (9 patients [10%] vs. 34 patients [45%]; P < .0001). We found no PFS differences in carboplatin-gemcitabine and gemcitabine cohorts (4.24 vs. 4.61 months; adjusted hazard ratio, 0.98; P = .92), whereas the combination was associated with a trend toward higher ORR (18 patients [20.4%] vs. 8 patients [10.6%]; P = .089) and with significantly higher incidence of Grade 3/4 neutropenia (30 patients [34%] vs. 5 patients [6.6%]; P < .0001). CONCLUSION: Using carboplatin in addition to gemcitabine is associated with more hematologic AEs but not with better PFS. Although single-agent gemcitabine remains a treatment option for heavily pretreated mBC patients, finding biomarkers of response to platinum salts might help to identify patients more likely to benefit from carboplatin-gemcitabine.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carboplatina/administração & dosagem , Desoxicitidina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Neoplasias da Mama/patologia , Carboplatina/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do Tratamento
20.
Am J Clin Oncol ; 42(1): 42-45, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30204614

RESUMO

OBJECTIVE: The activity of cabozantinib in nonclear cell histologies has not been evaluated. MATERIALS AND METHODS: Data were collected across 24 Italian hospitals. Patients were aged 18 years and older with advanced nonclear cell renal cell carcinoma (RCC), with an Eastern Cooperative Oncology Group Performance Status 0 to 2, who had relapsed after previous systemic treatments for metastatic disease. Cabozantinib was administered orally at 60 mg once a day in 28 days cycles. Dose reductions to 40 or 20 mg were made due to toxicity. Adverse events (AEs) were monitored using CTCAE version 4.0. RESULTS: Seventeen patients were enrolled. Three (18%) patients were diagnosed type I papillary RCC, 9 (53%) type II papillary, 3 (18%) chromophobe, and 2 (11%) with Bellini duct carcinoma. In total, 11 patients started with 60 mg. Six patients started a lower dose of 40 mg. Median progression-free survival was 7.83 months (0.4 to 13.4 mo), while median overall survival was not reached but 1-year overall survival was about 60%. Six patients (35%) experienced a partial response to treatment and 6 patients (35%) showed a stable disease. In the remaining 5 (30%), we observed a progressive disease. Grade 3 and 4 AEs were observed in 41% of patients. Among 20 patients, only 1 (6%) discontinued treatment due to AEs. Asthenia (41%), diarrhea (35%), aminotransferase increasing (35%), mucosal inflammation (35%), hand and foot syndrome (24%), and hypothyroidism (24%) were the most frequently AEs. CONCLUSIONS: Our data showed that, cabozantinib is a active and feasible treatment in patient with nonclear cell RCC.


Assuntos
Anilidas/efeitos adversos , Anilidas/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Administração Oral , Idoso , Anilidas/administração & dosagem , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Piridinas/administração & dosagem , Resultado do Tratamento
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