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1.
Clin Cancer Res ; 26(9): 2104-2110, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31937614

RESUMO

PURPOSE: Radium-223 is approved for metastatic castration-resistant prostate cancer (mCRPC) based on improved overall survival, and delay in skeletal related events. However, it is not associated with PSA or radiographic response, which poses a challenge in real-time assessment of its efficacy. Surrogate markers of treatment outcomes may facilitate tailoring treatment duration with radium-223, by limiting the duration of therapy with radium-223 in these patients. Here, we sought to investigate the utility of bone metabolic markers (BMMs) as surrogate markers of response to radium-223 in mCRPC. PATIENTS AND METHODS: A prospective phase II trial of radium-223 plus enzalutamide (RE) versus enzalutamide alone was designed to assess surrogacy of BMMs with respect to response to radium-223. Enzalutamide was used as a comparator in lieu of placebo due to the progressive disease. Co-primary endpoints were relative change in serum BMM N-telopeptide (NTP) levels from baseline to 6 months between the two arms and safety and feasibility of the combination. RESULTS: Thirty-nine men were randomized to RE (n = 27) or enzalutamide (n = 12). Combination was safe and feasible. Primary endpoint was met. A statistically significant relative change to NTP ratios between arms (0.64, 95% confidence interval, 0.51-0.81; P = 0.00048) favored RE versus enzalutamide. Overall, BMMs decreased with the RE therapy compared with enzalutamide. Improved PSA response rate in RE versus enzalutamide (P = 0.024), correlated with decline in BMMs. CONCLUSIONS: BMMs declined significantly with combination therapy, and were associated with improved outcomes. Upon external validation, BMMs may emerge as surrogate markers to monitor treatment with radium-223 in real-time.


Assuntos
Neoplasias Ósseas/sangue , Neoplasias Ósseas/radioterapia , Colágeno Tipo I/sangue , Peptídeos/sangue , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/radioterapia , Rádio (Elemento)/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Receptores de Andrógenos/uso terapêutico , Benzamidas , Biomarcadores Tumorais/sangue , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Quimiorradioterapia , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas , Feniltioidantoína/uso terapêutico , Estudos Prospectivos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Taxa de Sobrevida
2.
Cancer Treat Res Commun ; 19: 100120, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30743187

RESUMO

BACKGROUND: Targeted therapies have shown promise for men with metastatic castration-resistant prostate cancer (mCRPC). Due to the difficulty with obtaining tumor tissue in bony metastases, liquid biopsies are a promising alternative to guide treatment selection. While concurrent tissue next-generation sequencing (tNGS) and liquid biopsy has high concordance, it is unknown whether the genomic landscape of metastatic prostate cancer (mPC) changes over time or treatment. Herein, we hypothesize that the genomic landscape of mPC evolves with new treatments and/or time between tests. PATIENTS AND METHODS: Men with mPC from the University of Utah with matched tNGS and liquid biopsy were included. Clinical data was collected retrospectively. Exonic regions from 69 genes covered by both platforms were included for analysis. Paired t tests were used to assess number of genomic alterations (GAs) between testing platforms. Number of alterations was assessed by time and number of treatments between testing by multivariate nonparametric trend tests. RESULTS: 101 men with mPC were eligible and included. In men with no new treatments and ≤ 1 year between tests, a similar number of GAs were detected in both tests (2.0 vs. 2.2). In contrast, men with ≥ 1 new treatment between tests had significantly more GAs after treatment (5.0 vs. 2.4, p = 0.005). Total number of GAs was correlated with number of new treatments between testing (p = 0.003) and not time between testing (p = 0.76). CONCLUSION: The genomic landscape of mPC evolves with subsequent therapies. This finding suggests that contemporary tumor genomic profile upon disease progression may optimize guidance towards subsequent therapy selection.


Assuntos
Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Genoma Humano , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias da Próstata/genética , DNA Tumoral Circulante/análise , Estudos de Coortes , Terapia Combinada , DNA de Neoplasias/genética , Seguimentos , Humanos , Biópsia Líquida , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Fatores de Tempo
3.
Oncologist ; 23(12): 1413-e151, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30575560

RESUMO

LESSONS LEARNED: Pazopanib was not effective in altering the premetastatic niche in the neoadjuvant setting.Pazopanib was safe and well tolerated without any new safety signals. BACKGROUND: Vascular endothelial growth factor receptor 1 (VEGFR1) expressing myeloid-derived suppressor cells (VEGFR1+ MDSCs) potentially foster metastases by establishing a premetastatic niche. In a preclinical study, VEGFR1+ clustering in lymph nodes (LNs) independently predicted time to biochemical recurrence (TTBR) in localized prostate cancer [1]. The hypothesis was that neoadjuvant pazopanib therapy will decrease VEGFR1+ clusters in pelvic lymph nodes and improve outcomes. METHODS: This is a phase II trial (NCT01832259) of neoadjuvant pazopanib 800 mg versus placebo daily for 4 weeks in high-risk localized prostate cancer. The primary endpoint was a decrease in VEGFR1+ MDSC clustering assessed by immunohistochemistry (IHC) analysis. Secondary endpoints were safety, feasibility, and TTBR. RESULTS: Thirty patients were randomized to pazopanib versus placebo, with 15 patients randomized to each arm. Demographic and disease characteristics were similar in both arms. There was no difference in the VEGFR1+ clustering between the treatment arms (p = .345). Neoadjuvant therapy with pazopanib was well tolerated, and surgical complications were similar in both arms. CONCLUSION: Neoadjuvant pazopanib therapy did not alter the premetastatic niche; however, treatment targeting vascular endothelial growth factor (VEGF) in the preoperative period was safe and feasible, which may open up the avenue to investigate novel combinatorial regimens, including a VEGF inhibitor in combination with immune checkpoint inhibitor in this setting.


Assuntos
Prostatectomia/métodos , Neoplasias da Próstata/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/metabolismo , Humanos , Indazóis , Masculino , Neoplasias da Próstata/patologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Sulfonamidas/farmacologia
4.
J Oncol Pharm Pract ; 24(3): 190-197, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28436250

RESUMO

Purpose Hand-foot syndrome is a common dose limiting toxicity of vascular endothelial growth factor receptor tyrosine kinase inhibitors used for treatment of patients with metastatic renal cell carcinoma. The effect of treatment dose reductions, in the context of hand-foot syndrome, on survival outcomes is reported. Methods This was a retrospective case series of patients receiving vascular endothelial growth factor receptor tyrosine kinase inhibitors from 1 January 2004 to 31 October 2013. The main outcomes were progression-free and overall survival in these patients experiencing hand-foot syndrome and undergoing treatment dose reductions. Univariate and multivariate analyses were conducted utilizing Kaplan-Meier method and COX Proportional Hazard model with landmark analyses at 2 months. Results Of the 120 patients evaluated, treatment dose reductions for any reason were required in 68 (56.7%) patients. The most common reasons for treatment dose reductions were mucositis, hand-foot syndrome, and fatigue. The median progression-free survival and overall survival were significantly longer in patients with hand-foot syndrome with or without treatment dose reductions as compared to those without hand-foot syndrome. Conclusions An improvement in survival outcomes was observed in metastatic renal cell carcinoma patients with treatment-associated hand-foot syndrome despite treatment dose reductions. These data need validation in a larger cohort to confirm the hypothesis that treatment dose reductions in the setting of hand-foot syndrome do not negatively impatient survival.


Assuntos
Carcinoma de Células Renais/mortalidade , Síndrome Mão-Pé/mortalidade , Neoplasias Renais/mortalidade , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/tratamento farmacológico , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Neoplasias Renais/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Resultado do Tratamento
5.
Clin Genitourin Cancer ; 15(4): e599-e602, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28131750

RESUMO

BACKGROUND: Abiraterone acetate has been approved for metastatic castration-resistant prostate cancer (mCRPC). Coadministration with prednisone has been recommended to prevent the toxicity from secondary mineralocorticoid excess, such as hypertension, hypokalemia, and edema. However, the use of prednisone is often not desired by patients because of the potential for detrimental effects of long-term therapy with corticosteroids, especially in those with comorbidities such as diabetes or who have received previous immunotherapeutic agents. Eplerenone is a nonsteroidal mineralocorticoid antagonist demonstrated to abrogate mineralocorticoid excess. In the present retrospective study, we report our real-world experience with the use of eplerenone with abiraterone in men with mCRPC who wished to avoid concomitant prednisone therapy. PATIENTS AND METHODS: The incidence and grade (Common Terminology Criteria for Adverse Events, version 4) of mineralocorticoid excess toxicities, baseline demographics, disease characteristics, and progression-free survival (PFS) were collected retrospectively. The patient population included men with mCRPC treated with abiraterone, who were not willing to receive corticosteroids, and thus received eplerenone. Their data were compared with the data from those treated with abiraterone and prednisone during the same period. Continuous variables were assessed using the Wilcoxon rank sum test or Student t test, and categorical variables were assessed using Fischer's exact test or χ2 test, as appropriate. PFS was compared using the Kaplan-Meier method. RESULTS: Of the 106 men treated with abiraterone, 40 received eplerenone and 66 received prednisone. The baseline and disease characteristics, incidence and grade of adverse events related to the syndrome of mineralocorticoid excess, and the median PFS were similar in both cohorts. CONCLUSION: In a real-world population of men with mCRPC treated with abiraterone, corticosteroids can be avoided by concomitant treatment with eplerenone. These data require further validation.


Assuntos
Acetato de Abiraterona/administração & dosagem , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Prednisona/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/dietoterapia , Espironolactona/análogos & derivados , Acetato de Abiraterona/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Eplerenona , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Metástase Neoplásica , Prednisona/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Estudos Retrospectivos , Espironolactona/administração & dosagem , Espironolactona/uso terapêutico , Análise de Sobrevida , Resultado do Tratamento
6.
Cancer Chemother Pharmacol ; 78(5): 1059-1071, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27744565

RESUMO

PURPOSE: Belinostat is an inhibitor of histone deacetylase enzymes, resulting in DNA repair inhibition and apoptosis. Present data are lacking to provide dosing recommendations in renal insufficiency. The purpose of this trial was to assess the pharmacokinetics (PK) of belinostat and belinostat metabolites in plasma and urine. METHODS: This was a phase I, single-center, open-label, two-part study. In Part I, patients received single-agent belinostat 1000 mg/m2. Blood and urine samples were collected at pre-specified time points to determine PK of belinostat and metabolites and their elimination in urine. In Part II, patients were permitted to continue belinostat in 21-day cycles on Days 1 through 5 until disease progression, unacceptable toxicity, or according to patient preference. RESULTS: A total of nine patients with advanced solid tumors were treated. Median t max for belinostat was observed 10 min after the start of infusion. Concentrations of belinostat rapidly declined with a t 1/2 of 2.9 h. The mean fraction of belinostat excreted unchanged in urine was 0.926 %. The metabolites belinostat glucuronide and 3-ASBA represented the largest fractions of belinostat dose excreted in urine (30.5 and 4.61 %, respectively), while renal excretion appeared to be a minor route of elimination for the parent belinostat (<1 %). The most common adverse events were nausea, fatigue, and diarrhea. One Grade 3 adverse event (constipation) was thought to be treatment related. CONCLUSIONS: Urinary elimination of parent belinostat was minimal, although a combined 36.7 % of belinostat metabolites were excreted in urine. Since these metabolites are primarily inactive, belinostat may not require dosage adjustment in renal dysfunction.


Assuntos
Inibidores de Histona Desacetilases/farmacocinética , Ácidos Hidroxâmicos/farmacocinética , Neoplasias/metabolismo , Sulfonamidas/farmacocinética , Adulto , Idoso , Área Sob a Curva , Biotransformação , Progressão da Doença , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Inibidores de Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/metabolismo , Ácidos Hidroxâmicos/uso terapêutico , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Sulfonamidas/metabolismo , Sulfonamidas/uso terapêutico , Resultado do Tratamento
7.
Clin Genitourin Cancer ; 13(3): e131-7, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25497584

RESUMO

BACKGROUND: Hypothyroidism is a common adverse effect of vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy in patients with metastatic renal cell carcinoma (mRCC). Some studies have shown an association with improved survival. However, hypothyroidism severity has not been correlated with survival outcomes. We report the incidence and severity of VEGFR-TKI therapy-associated hypothyroidism in correlation with the survival outcomes of patients with mRCC. PATIENTS AND METHODS: A retrospective analysis of patients with mRCC who received VEGFR-TKIs (2004 through 2013) was conducted from a single institutional database. Hypothyroidism, progression-free survival (PFS), and overall survival (OS) were assessed. Univariate and multivariate analyses were performed using the Kaplan-Meier method and Cox proportional hazard models. RESULTS: Of 125 patients with mRCC, 65 were eligible. Their median age was 59 years (range, 45-79 years), and 46 (70.8%) were male. Hypothyroidism occurred in 25 patients (38.5%), of whom 13 had a peak thyroid-stimulating hormone (TSH) level > 10 mIU/L during treatment. The median OS was significantly longer in patients with a peak TSH > 10 mIU/L than in patients with a peak TSH of ≤ 10 mIU/L (not reached vs. 21.4 months, P = .005). On multivariate analysis, risk criteria, number of previous therapies, and severe hypothyroidism (TSH > 10 mIU/L) during VEGFR-TKI therapy remained significant for improvements in PFS and OS. CONCLUSION: The severity of VEGFR-TKI therapy-associated hypothyroidism (TSH > 10 mIU/L) was associated with improved survival outcomes in patients with mRCC and should not necessitate a dose reduction or therapy discontinuation.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Hipotireoidismo/patologia , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Idoso , Carcinoma de Células Renais/patologia , Feminino , Humanos , Hipotireoidismo/induzido quimicamente , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Estudos Retrospectivos , Análise de Sobrevida
8.
Prostate Cancer ; 2013: 981684, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23819055

RESUMO

Androgen deprivation therapy (ADT) with medical or surgical castration is the mainstay of therapy in men with metastatic prostate cancer. However, despite initial responses, almost all men eventually develop castration refractory metastatic prostate cancer (CRPC) and die of their disease. Over the last decade, it has been recognized that despite the failure of ADT, most prostate cancers maintain some dependence on androgen and/or androgen receptor (AR) signaling for proliferation. Furthermore, androgen independent molecular pathways have been identified as drivers of continued progression of CRPC. Subsequently, drugs have been developed targeting these pathways, many of which have received regulatory approval. Agents such as abiraterone, enzalutamide, orteronel (TAK-700), and ARN-509 target androgen signaling. Sipuleucel-T, ipilimumab, and tasquinimod augment immune-mediated tumor killing. Agents targeting classic tumorogenesis pathways including vascular endothelial growth factor, hepatocyte growth factor, insulin like growth factor-1, tumor suppressor, and those which regulate apoptosis and cell cycles are currently being developed. This paper aims to focus on emerging molecular pathways underlying progression of CRPC, and the drugs targeting these pathways, which have recently been approved or have reached advanced stages of development in either phase II or phase III clinical trials.

9.
Am J Med Sci ; 339(6): 580-1, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20421784

RESUMO

Sunitinib is an oral tyrosine kinase inhibitor, which is indicated for the treatment of renal cell carcinoma and gastrointestinal stromal tumors. The authors report the case of a patient who underwent treatment for renal cell carcinoma and noted additional benefit by improvement in his psoriatic skin lesions. This may be attributed to the antiangiogenic activity of sunitinib by inhibition of vascular endothelial growth factor receptors.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Indóis/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Psoríase/tratamento farmacológico , Pirróis/uso terapêutico , Carcinoma de Células Renais/complicações , Carcinoma de Células Renais/secundário , Humanos , Neoplasias Renais/complicações , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Psoríase/complicações , Sunitinibe
11.
Cancer ; 113(12): 3349-54, 2008 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-18988288

RESUMO

BACKGROUND: Limited data are available on the management of glioma in pregnant women. Therefore, the aim of the current article was to describe the outcome of women with malignant gliomas who were exposed to chemotherapy early in the gestation period of their pregnancies. METHODS: The authors presented a case series of 6 women with malignant gliomas who during glioma-directed treatment were discovered to have an unplanned pregnancy. All patients elected to discontinue chemotherapy and carry their pregnancy to term. RESULTS: All women had uneventful pregnancies with no glioma-related complications. All women delivered healthy newborns without evidence of congenital malformations despite exposure to cytotoxic chemotherapy and anticonvulsant medications. CONCLUSIONS: Management of malignant glioma during pregnancy is challenging; however, normal delivery and healthy live birth is possible.


Assuntos
Antineoplásicos/uso terapêutico , Glioma/tratamento farmacológico , Complicações Neoplásicas na Gravidez , Adulto , Antineoplásicos/efeitos adversos , Feminino , Glioma/mortalidade , Humanos , Recidiva Local de Neoplasia/mortalidade , Gravidez
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