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1.
Mol Cancer Res ; 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300540

RESUMO

The combined loss of CHD1 and MAP3K7 promotes aggressive prostate cancer by unknown mechanisms. Because both of these genes are lost genetically in prostate cancer, they cannot be directly targeted. We applied an established computational systems pharmacology approach (TRAP) to identify altered signaling pathways and associated druggable targets. We compared gene expression profiles of prostate cancer with coloss of CHD1 and MAP3K7 with prostate cancer diploid for these genes using The Cancer Genome Atlas patient samples. This analysis prioritized druggable target genes that included CDK1 and CDK2 We validated that inhibitors of these druggable target genes, including the CDK1/CDK2 inhibitor dinaciclib, had antiproliferative and cytotoxic effects selectively on mouse prostate cells with knockdown of Chd1 and Map3k7 Dinaciclib had stronger effects on prostate cells with suppression of Map3k7 independent of Chd1 and also compared with cells without loss of Map3k7 Dinaciclib treatment reduced expression of homologous recombination (HR) repair genes such as ATM, ATR, BRCA2, and RAD51, blocked BRCA1 phosphorylation, reduced RAD51 foci formation, and increased γH2AX foci selectively in prostate cells with suppression of Map3k7, thus inhibiting HR repair of chromosomal double-strand breaks. Dinaciclib-induced HR disruption was also observed in human prostate cells with knockdown of MAP3K7 Cotreatment of dinaciclib with DNA-damaging agents or PARP inhibitor resulted in a stronger cytotoxic effect on prostate cells with suppression of MAP3K7 compared with those without loss of MAP3K7, or to each single agent.Implications: These findings demonstrate that loss of MAP3K7 is a main contributing factor to drug response through disruption of HR in prostate cancer.

2.
Lancet Oncol ; 20(4): 581-590, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30827746

RESUMO

BACKGROUND: Cabozantinib is approved for patients with metastatic renal cell carcinoma on the basis of studies done in clear-cell histology. The activity of cabozantinib in patients with non-clear-cell renal cell carcinoma is poorly characterised. We sought to analyse the antitumour activity and toxicity of cabozantinib in advanced non-clear-cell renal cell carcinoma. METHODS: We did a multicentre, international, retrospective cohort study of patients with metastatic non-clear-cell renal cell carcinoma treated with oral cabozantinib during any treatment line at 22 centres: 21 in the USA and one in Belgium. Eligibility required patients with histologically confirmed non-clear-cell renal cell carcinoma who received cabozantinib for metastatic disease during any treatment line roughly between 2015 and 2018. Mixed tumours with a clear-cell histology component were excluded. No other restrictive inclusion criteria were applied. Data were obtained from retrospective chart review by investigators at each institution. Demographic, surgical, pathological, and systemic therapy data were captured with uniform database templates to ensure consistent data collection. The main objectives were to estimate the proportion of patients who achieved an objective response, time to treatment failure, and overall survival after treatment. FINDINGS: Of 112 identified patients with non-clear-cell renal cell carcinoma treated at the participating centres, 66 (59%) had papillary histology, 17 (15%) had Xp11.2 translocation histology, 15 (13%) had unclassified histology, ten (9%) had chromophobe histology, and four (4%) had collecting duct histology. The proportion of patients who achieved an objective response across all histologies was 30 (27%, 95% CI 19-36) of 112 patients. At a median follow-up of 11 months (IQR 6-18), median time to treatment failure was 6·7 months (95% CI 5·5-8·6), median progression-free survival was 7·0 months (5·7-9·0), and median overall survival was 12·0 months (9·2-17·0). The most common adverse events of any grade were fatigue (58 [52%]), and diarrhoea (38 [34%]). The most common grade 3 events were skin toxicity (rash and palmar-plantar erythrodysesthesia; five [4%]) and hypertension (four [4%]). No treatment-related deaths were observed. Across 54 patients with available next-generation sequencing data, the most frequently altered somatic genes were CDKN2A (12 [22%]) and MET (11 [20%]) with responses seen irrespective of mutational status. INTERPRETATION: While we await results from prospective studies, this real-world study provides evidence supporting the antitumour activity and safety of cabozantinib across non-clear-cell renal cell carcinomas. Continued support of international collaborations and prospective ongoing studies targeting non-clear-cell renal cell carcinoma subtypes and specific molecular alterations are warranted to improve outcomes across these rare diseases with few evidence-based treatment options. FUNDING: None.

3.
Integr Cancer Ther ; 17(4): 1103-1108, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30289005

RESUMO

BACKGROUND: Plant derivatives have been studied as therapies for prostate cancer based on their purported anti-inflammatory and antioxidant properties and low toxicities. The acai berry is an example of a plant rich in phytochemicals, which may slow the growth of prostate cancer. METHODS: This was a phase II, Simon 2-stage clinical trial in patients with biochemically recurrent prostate cancer with a primary endpoint of prostate-specific antigen (PSA) response. Patients were asymptomatic, with a rising PSA of at least 0.2 ng/mL, and were treated with twice daily intake of Acai Juice Product until PSA progression, with a primary endpoint of PSA response. RESULTS: Twenty-one patients were enrolled in the first stage of the trial. One of those patients had a PSA response within the study time period. The PSA doubling time was lengthened in 71% of patients (95% confidence interval = 48% to 89%) on the trial, and in a small number of responders, this was sustained over an extended time. CONCLUSIONS: This study did not meet its primary endpoint of 50% PSA response. Nevertheless, the overall tolerability and effects on PSA stabilization warrant further exploration in a biochemically recurrent population.

4.
F1000Res ; 7: 307, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29568504

RESUMO

Over the past decade, our understanding of the biology and pathophysiology of renal cell carcinoma (RCC) has improved significantly. Insight into the disease process has helped us in developing newer therapeutic approaches toward RCC. In this article, we review the various genetic and immune-related mechanisms involved in the pathogenesis and development of this cancer and how that knowledge is being used to develop therapeutic targeted drugs for the treatment of RCC. The main emphasis of this review article is on the most common genetic alterations found in clear cell RCC and how various drugs are currently targeting such pathways. This article also looks at the role of the immune system in allowing the growth of RCC and how the immune system can be manipulated to reactivate cytotoxic immunity against RCC.

5.
J Clin Oncol ; 36(9): 867-874, 2018 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-29257710

RESUMO

Purpose The von Hippel-Lindau tumor suppressor is inactivated in the majority of clear cell renal cell carcinomas (ccRCCs), leading to inappropriate stabilization of hypoxia-inducible factor-2α (HIF-2α). PT2385 is a first-in-class HIF-2α antagonist. Objectives of this first-in-human study were to characterize the safety, pharmacokinetics, pharmacodynamics, and efficacy, and to identify the recommended phase II dose (RP2D) of PT2385. Patients and Methods Eligible patients had locally advanced or metastatic ccRCC that had progressed during one or more prior regimens that included a vascular endothelial growth factor inhibitor. PT2385 was administered orally at twice-per-day doses of 100 to 1,800 mg, according to a 3 + 3 dose-escalation design, followed by an expansion phase at the RP2D. Results The dose-escalation and expansion phases enrolled 26 and 25 patients, respectively. Patients were heavily pretreated, with a median of four (range, one to seven) prior therapies. No dose-limiting toxicity was observed at any dose. On the basis of safety, pharmacokinetic, and pharmacodynamic profiling, the RP2D was defined as 800 mg twice per day. PT2385 was well tolerated, with anemia (grade 1 to 2, 35%; grade 3, 10%), peripheral edema (grade 1 to 2, 37%; grade 3, 2%), and fatigue (grade 1 to 2, 37%; no grade 3 or 4) being the most common treatment-emergent adverse events. No patients discontinued treatment because of adverse events. Complete response, partial response, and stable disease as best response were achieved by 2%, 12%, and 52% of patients, respectively. At data cutoff, eight patients remained in the study, with 13 patients in the study for ≥ 1 year. Conclusion PT2385 has a favorable safety profile and is active in patients with heavily pretreated ccRCC, validating direct HIF-2α antagonism for the treatment of patients with ccRCC.

6.
Mol Cancer Ther ; 17(1): 215-221, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29054986

RESUMO

This phase I study evaluates the safety, MTD, pharmacokinetics (PK), pharmacodynamics, and preliminary anticancer activity of enavatuzumab, a humanized IgG1 antibody to the TWEAK receptor, in patients with advanced solid malignancies. Patients received escalating doses of enavatuzumab given intravenously over 60 minutes every 2 weeks. Blood was obtained for PK and biomarker assessment. Three patients were enrolled per dose level in a standard 3+3 design with response assessment by RECIST version 1.0, every 8 weeks. Thirty patients were enrolled at 6 dose levels ranging from 0.1 to 1.5 mg/kg. Dose-limiting toxicities included grade 4 (G4) lipase, G3 bilirubin, and G4 amylase elevations. There was no apparent correlation of liver or pancreatic enzyme elevation with drug exposure or the presence of liver metastases. Enavatuzumab exhibited a two-compartment linear PK model. Estimated systemic clearance was 23 to 33 mL/h with an elimination half-life of 7 to 18 days. The predicted target efficacious peak and trough concentrations occurred at 1.0 mg/kg following the second dose. There were no objective responses; 4 patients had stable disease. The MTD of enavatuzumab is 1.0 mg/kg i.v. every 2 weeks. Higher doses were not tolerated due to hepatopancreatic lab abnormalities. Further evaluation of the mechanisms of the liver and pancreatic enzyme toxicities is needed before embarking on further single-agent or combination strategies. Mol Cancer Ther; 17(1); 215-21. ©2017 AACR.

7.
J Natl Compr Canc Netw ; 15(6): 804-834, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28596261

RESUMO

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non-clear cell renal carcinoma. These guidelines are developed by a multidisciplinary panel of leading experts from NCCN Member Institutions consisting of medical oncologists, hematologists and hematologic oncologists, radiation oncologists, urologists, and pathologists. The NCCN Guidelines are in continuous evolution and are updated annually or sometimes more often, if new high-quality clinical data become available in the interim.


Assuntos
Neoplasias Renais/diagnóstico , Neoplasias Renais/terapia , Terapia Combinada , Gerenciamento Clínico , Humanos , Neoplasias Renais/mortalidade , Estadiamento de Neoplasias , Prognóstico , Recidiva , Retratamento
8.
Urol Oncol ; 35(6): 438-446, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28214281

RESUMO

PURPOSE: To evaluate usage trends and identify factors associated with proton beam therapy (PBT) compared to alternative forms of external beam radiation therapy (RT) (EBRT) for localized prostate cancer. PATIENTS AND METHODS: The National Cancer Database was queried for men with localized (N0, M0) prostate cancer diagnosed between 2004 and 2013, treated with EBRT, with available data on EBRT modality (photon vs. PBT). Binary multiple logistic regression identified variables associated with EBRT modality. RESULTS: In total, 143,702 patients were evaluated with relatively few men receiving PBT (5,709 [4.0%]). Significant differences in patient and clinical characteristics were identified between those men treated with PBT compared to those treated with photon (odds ratio [OR]; 95% CI). Patients treated with PBT were generally younger (OR = 0.73; CI: 0.67-0.82), National Comprehensive Cancer Network low-risk compared to intermediate (0.71; 0.65-0.78) or high (0.44; 0.38-0.5) risk, white vs. black race (0.66; 0.58-0.77), with less comorbidity (Charlson-Deyo 0 vs. 2+; 0.70; 0.50-0.98), live in higher income counties (1.55; 1.36-1.78), and live in metropolitan areas compared to urban (0.21; 0.18-0.23) or rural (0.14; 0.10-0.19) areas. Most patients treated with PBT travelled more than 100 miles to the treatment facility. Annual PBT utilization significantly increased in both total number and percentage of EBRT over time (2.7%-5.6%; P<0.001). PBT utilization increased mostly in men classified as National Comprehensive Cancer Network low-risk (4%-10.2%). CONCLUSION: PBT for men with localized prostate cancer significantly increased in the United States from 2004 to 2013. Significant demographic and prognostic differences between those men treated with photons and protons were identified.


Assuntos
Neoplasias da Próstata/radioterapia , Terapia com Prótons/tendências , Idoso , Humanos , Masculino , National Cancer Institute (U.S.) , Neoplasias da Próstata/mortalidade , Terapia com Prótons/estatística & dados numéricos , Estados Unidos/epidemiologia
9.
Cancer Med ; 5(12): 3386-3393, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27758076

RESUMO

Increases in the mean corpuscular volume (MCV) have been observed in patients with metastatic renal cell carcinoma (mRCC) on tyrosine kinase inhibitor (TKI) treatment; however, its association with progression-free-survival (PFS) is unknown. We aimed to characterize TKI-associated macrocytosis in mRCC and its relationship with PFS. Retrospective review of data on macrocytosis and thyroid dysfunction on mRCC patients treated with sunitinib and/or sorafenib. These results are evaluated in the context of our previous report on the association of hypothyroidism in this setting. We assessed PFS as clinically defined by the treating physician. Seventy-four patients, 29 of whom received both drugs, were included. A treatment period was defined as time from initiation to discontinuation of either sunitinib or sorafenib; 103 treatment periods [sorafenib (47), sunitinib (56)] were analyzed. Macrocytosis was found in 55 and 8% of sunitinib- and sorafenib-treated patients, respectively, P < 0.001. The median time to developing macrocytosis was 3 months (m, range 1-7). Median PFS in sunitinib-treated patients was 11 m (95% CI: 6-19). Median PFS was higher among those with macrocytosis compared to normocytosis (21 m [95% CI: 11-25] vs. 4 m [95% CI: 3-8] P = 0.0001). Macrocytosis and hypothyroidism were two significant predictors of PFS. The greatest difference in PFS among all patients was observed in patients with both macrocytosis and hypothyroidism (25 m), compared to the normocytic and euthyroid patients (5 m) (P < 0.0001). Sunitinib-related macrocytosis was associated with prolonged PFS, and concurrent development of hypothyroidism and macrocytosis further prolonged PFS. Increased MCV may have a role as a predictive biomarker for sunitinib. Prospective studies accounting for other known prognostic factors are needed to confirm this finding.


Assuntos
Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/complicações , Eritrócitos Anormais , Doenças Hematológicas/diagnóstico , Doenças Hematológicas/etiologia , Indóis/efeitos adversos , Neoplasias Renais/complicações , Pirróis/efeitos adversos , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Índices de Eritrócitos , Feminino , Doenças Hematológicas/mortalidade , Humanos , Indóis/uso terapêutico , Estimativa de Kaplan-Meier , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Metástase Neoplásica , Estadiamento de Neoplasias , Niacinamida/efeitos adversos , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/uso terapêutico , Pirróis/uso terapêutico , Sorafenibe , Sunitinibe , Resultado do Tratamento
10.
Urology ; 87: 114-9, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26505834

RESUMO

OBJECTIVE: To evaluate the viability of glomeruli in the peritumor parenchyma of partial nephrectomy specimens removed for renal cell carcinoma (RCC) and relate it to kidney function, to better understand the contribution of peritumor parenchyma to renal function. MATERIALS AND METHODS: A retrospective analysis of 53 partial nephrectomies containing RCC was performed. Glomeruli within 0.25-cm increments from the tumor were quantified and histologically assessed for viability. Tumor size, minimum and maximum margin size, and pre- and postoperative estimated glomerular filtration rate (eGFR) were obtained. RESULTS: Glomerular viability positively correlated with distance from tumor with mean viable glomeruli in successive 0.25-cm increments of 0-0.25 cm, 58%; 0.25-0.5 cm, 80%; 0.5-0.75 cm, 90%; and 0.75-1.0 cm, 92%. Glomerular viability near the tumor did not correlate with preoperative eGFR, whereas decreased viability further from the tumor did correlate with worse preoperative eGFR. Tumor size showed a nonstatistically significant positive trend with minimum (median 0.15 cm) and maximum margin (median 0.7 cm) sizes. Percent change of glomerular filtration rate did not correlate with margin size (P = .190). CONCLUSION: Renal parenchyma immediately adjacent to RCC contains fewer viable glomeruli compared with the parenchyma further from the tumor. Based on this information, attempts to preserve all non-neoplastic renal parenchyma via a surgical margin approaching zero may not necessarily result in clinically relevant differences in the amount of viable glomeruli remaining or the renal function preserved.


Assuntos
Carcinoma de Células Renais/cirurgia , Taxa de Filtração Glomerular/fisiologia , Glomérulos Renais/patologia , Neoplasias Renais/cirurgia , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/fisiopatologia , Sobrevivência Celular , Humanos , Testes de Função Renal , Neoplasias Renais/diagnóstico , Neoplasias Renais/fisiopatologia , Nefrectomia , Tamanho do Órgão , Período Pós-Operatório , Estudos Retrospectivos
11.
Oncology (Williston Park) ; 29(12): 956-62, 2015 12.
Artigo em Inglês | MEDLINE | ID: mdl-26676900

RESUMO

Traditionally, androgen deprivation therapy (ADT) has been the standard initial treatment for metastatic hormone-sensitive prostate cancer (mHSPC), with chemotherapy utilized in the castration-resistant setting. Data reported from three recent clinical trials shed new light on the role of upfront docetaxel in advanced or mHSPC. Two of these studies-CHAARTED and STAMPEDE-showed significant improvement in overall survival, while the third study, GETUG-AFU 15, showed no statistical difference. The CHAARTED study showed a 13.6-month survival improvement and the STAMPEDE study showed a 10-month survival improvement with ADT plus docetaxel, compared with ADT alone, in the hormone-sensitive setting. These numbers are remarkable when compared with the 2.9-month survival benefit from docetaxel in the metastatic castration-resistant setting, which has been the standard setting for the use of docetaxel in advanced prostate cancer. In this review, we describe the historical data for chemotherapy in the perioperative and metastatic prostate cancer settings, and the recent trials that are changing the paradigm in support of docetaxel in the upfront setting.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Ensaios Clínicos como Assunto , Humanos , Masculino
13.
Radiat Oncol ; 10: 218, 2015 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-26510665

RESUMO

BACKGROUND AND PURPOSE: We report the radiographic response rate of SBRT compared to conventional fractionated radiotherapy (CF-EBRT) for thoracic, abdominal, skin and soft tissue RCC lesions treated at our institution. MATERIAL AND METHODS: Fifty three lesions where included in the study (36 SBRT, 17 CF-EBRT), treated from 2004 to 2014 at our institution. We included patients that had thoracic, skin & soft tissue (SST), and abdominal metastases of histologically confirmed RCC. The most common SBRT fractionation was 50 Gy in 5 fractions. RESULTS: The median time of follow-up was 16 months (range 3-97 months). Median BED was 216.67 (range 66.67-460.0) for SBRT, and 60 (range 46.67-100.83) for CF-EBRT. Median radiographic local control rates at 12, 24, and 36 months were 100, 93.41, and 93.41 % for lesions treated with SBRT versus 62.02, 35.27 and 35.27 % for those treated with CF-EBRT (p < 0.001). Predictive factors for radiographic local control under univariate analysis included BED ≥ 100 Gy (HR, 0.048; 95 % CI, 0.006-0.382; p = 0.005), dose per fraction ≥ 9 Gy (HR, 0.631; 95 % CI, 0.429-0.931; p = 0.021), and gender (HR, 0.254; 95 % CI, 0.066-0.978; p = 0.048). Under multivariate analysis, there were no significant predictors for local control. Toxicity rates were low and equivalent in both groups, with no grade 4 or 5 side effects reported. CONCLUSIONS: SBRT is safe and effective for the treatment of RCC metastases to thoracic, abdominal and integumentary soft tissues. Radiographic response rates were greater and more durable using SBRT compared to CF-EBRT. Further prospective trials are needed to evaluate efficacy and safety of SBRT for RCC metastases.


Assuntos
Carcinoma de Células Renais/cirurgia , Neoplasias Renais/cirurgia , Radiocirurgia/métodos , Neoplasias de Tecidos Moles/cirurgia , Neoplasias Abdominais/mortalidade , Neoplasias Abdominais/secundário , Neoplasias Abdominais/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/secundário , Fracionamento da Dose de Radiação , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Radioterapia , Estudos Retrospectivos , Neoplasias de Tecidos Moles/mortalidade , Neoplasias de Tecidos Moles/secundário , Neoplasias Torácicas/mortalidade , Neoplasias Torácicas/secundário , Neoplasias Torácicas/cirurgia
14.
Pract Radiat Oncol ; 5(6): e589-e596, 2015 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26142027

RESUMO

PURPOSE: We report the radiographic and clinical response rate of stereotactic body radiation therapy (SBRT) compared with conventional fractionated external beam radiation therapy (CF-EBRT) for renal cell carcinoma (RCC) bone lesions treated at our institution. METHODS AND MATERIALS: Forty-six consecutive patients were included in the study, with 95 total lesions treated (50 SBRT, 45 CF-EBRT). We included patients who had histologic confirmation of primary RCC and radiographic evidence of metastatic bone lesions. The most common SBRT regimen used was 27 Gy in 3 fractions. RESULTS: Median follow-up was 10 months (range, 1-64 months). Median time to symptom control between SBRT and CF-EBRT were 2 (range, 0-6 weeks) and 4 weeks (range, 0-7 weeks), respectively. Symptom control rates with SBRT and CF-EBRT were significantly different (P = .020) with control rates at 10, 12, and 24 months of 74.9% versus 44.1%, 74.9% versus 39.9%, and 74.9% versus 35.7%, respectively. The median time to radiographic failure and unadjusted pain progression was 7 months in both groups. When controlling for gross tumor volume, dose per fraction, smoking, and the use of systemic therapy, biologically effective dose ≥80 Gy was significant for clinical response (hazard ratio [HR], 0.204; 95% confidence interval [CI], 0.043-0.963; P = .046) and radiographic (HR, 0.075; 95% CI, 0.013-0.430; P = .004). When controlling for gross tumor volume and total dose, biologically effective dose ≥80 Gy was again predictive of clinical local control (HR, 0.140; 95% CI, 0.025-0.787; P = .026). Toxicity rates were low and equivalent in both groups, with no grade 4 or 5 toxicity reported. CONCLUSIONS: SBRT is both safe and effective for treating RCC bone metastases, with rapid improvement in symptoms after treatment and more durable clinical and radiographic response rate. Future prospective trials are needed to further define efficacy and toxicity of treatment, especially in the setting of targeted agents.


Assuntos
Neoplasias Ósseas/prevenção & controle , Neoplasias Ósseas/cirurgia , Carcinoma de Células Renais/cirurgia , Neoplasias Renais/cirurgia , Tolerância a Radiação , Radiocirurgia , Adulto , Idoso , Neoplasias Ósseas/secundário , Carcinoma de Células Renais/secundário , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia de Intensidade Modulada
15.
J Natl Compr Canc Netw ; 13(6): 772-99, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26085393

RESUMO

Germ cell tumors (GCTs) account for 95% of testicular cancers. Testicular GCTs constitute the most common solid tumor in men between the ages of 20 and 34 years, and the incidence of testicular GCTs has been increasing in the past 2 decades. Testicular GCTs are classified into 2 broad groups--pure seminoma and nonseminoma--which are treated differently. Pure seminomas, unlike nonseminomas, are more likely to be localized to the testis at presentation. Nonseminoma is the more clinically aggressive tumor associated with elevated serum concentrations of alphafetoprotein (AFP). The diagnosis of a seminoma is restricted to pure seminoma histology and a normal serum concentration of AFP. When both seminoma and elements of a nonseminoma are present, management follows that for a nonseminoma. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Testicular Cancer outline the diagnosis, workup, risk assessment, treatment, and follow-up schedules for patients with both pure seminoma and nonseminoma.


Assuntos
Seminoma/terapia , Neoplasias Testiculares/terapia , Terapia Combinada , Gerenciamento Clínico , Humanos , Masculino , Estadiamento de Neoplasias , Guias de Prática Clínica como Assunto , Seminoma/diagnóstico , Neoplasias Testiculares/diagnóstico
16.
J Clin Oncol ; 33(14): 1601-8, 2015 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-25847934

RESUMO

PURPOSE: Cixutumumab, formerly IMC-A12, is a recombinant human monoclonal immunoglobulin G1 antibody that targets insulin-like growth factor I receptor (IGF-IR). Cixutumumab was synergistic with castration in a hormone-sensitive prostate cancer xenograft model. PATIENTS AND METHODS: Patients with new metastatic prostate cancer were randomly assigned within 30 days of initiating androgen deprivation (AD) to cixutumumab added to a luteinizing hormone-releasing hormone agonist with bicalutamide versus AD alone. With 180 patients and one-sided alpha of 0.10, there would be 90% power to detect an absolute 20% difference in undetectable prostate-specific antigen (PSA; ≤ 0.2 ng/mL) rate at 28 weeks (relative risk, 1.44); this end point was previously strongly correlated with survival. Secondary end points included the proportion of patients with PSA > 4.0 ng/mL, safety and tolerability, circulating tumor cell (CTC) levels, and seven plasma IGF-IR biomarkers. Fisher's exact test was used for the primary end point, and extended Mantel-Haenszel χ(2) test was used for three PSA response categories. RESULTS: The trial accrued 210 eligible patients (105 randomly assigned to each arm). Patient characteristics were similar in both arms. Undetectable PSA rate was 42 (40.0%) of 105 for cixutumumab plus AD and 34 (32.3%) of 105 for AD alone (relative risk, 1.24; one-sided P = .16). Lower baseline CTCs (0 v 1 to 4 v ≥ 5/7.5 mL whole blood) were associated with higher rate of PSA response (three categories; P = .036) in 39 evaluable patients. IGF-IR biomarkers were not correlated with PSA outcome, and cixutumumab did not significantly change these biomarker levels. CONCLUSION: Cixutumumab plus AD did not significantly increase the undetectable PSA rate in men with new metastatic hormone-sensitive prostate cancer. CTCs at baseline may carry prognostic value.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Biomarcadores Tumorais/sangue , Células Neoplásicas Circulantes , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/tratamento farmacológico , Receptor IGF Tipo 1/sangue , Idoso , Anilidas/administração & dosagem , Esquema de Medicação , Hormônio Liberador de Gonadotropina/agonistas , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nitrilos/administração & dosagem , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Compostos de Tosil/administração & dosagem , Resultado do Tratamento
17.
Invest New Drugs ; 33(3): 691-9, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25895965

RESUMO

BACKGROUND: Trebananib is an anti-angiogenic peptibody under investigation in patients with advanced cancer. This study evaluated the pharmacokinetic (PK) drug-drug interaction of paclitaxel and trebananib. PATIENTS AND METHODS: Patients with advanced solid tumors received weekly 80 mg/m(2) intravenous (IV) paclitaxel (3 weeks on/1 week off) with weekly 15 mg/kg IV trebananib starting at Week 2. Blood samples for PK analysis were collected at Week 1 (paclitaxel alone), Week 6 (paclitaxel and trebananib), and Week 8 (trebananib alone). An absence of interaction was to be concluded if the 90 % confidence intervals (CI) for the differences in paclitaxel exposure fell within the 0.80-1.25 interval. RESULTS: The primary study was conducted between 7/2012 and 10/2013. Thirty-five patients were enrolled and 34 received both treatments. Most patients were white (91 %) and female (59 %); mean age was 61 years. The most common tumor types were ovarian (32 %) and bladder (27 %), 71 % of patients had stage IV disease, and all had Eastern Cooperative Oncology Group (ECOG) scores of 0 or 1. PK parameter analysis was done on patients with evaluable PK data at both assessments (with and without concomitant therapy; n = 28). The geometric least squares mean (GLSM) ratio (90 % CI) of paclitaxel AUCinf with and without trebananib was 1.17 (1.10, 1.25). The GLSM ratio (90 % CI) of trebananib AUCtau,ss with and without paclitaxel was 0.92 (0.87, 0.97). The most common adverse events were fatigue, local edema, peripheral edema, and nausea. CONCLUSIONS: This study showed no evidence of clinically meaningful PK interaction between paclitaxel and trebananib.


Assuntos
Angiopoietina-1/antagonistas & inibidores , Angiopoietina-2/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Paclitaxel/farmacocinética , Proteínas Recombinantes de Fusão/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Angiopoietina-1/metabolismo , Angiopoietina-2/metabolismo , Anticorpos Antineoplásicos/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Demografia , Interações de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/efeitos adversos , Paclitaxel/sangue , Paclitaxel/uso terapêutico , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/uso terapêutico , Resultado do Tratamento
18.
J Natl Compr Canc Netw ; 13(2): 151-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25691606

RESUMO

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non-clear cell renal carcinoma. These NCCN Guidelines Insights highlight the recent updates/changes in these guidelines, and updates include axitinib as first-line treatment option for patients with clear cell renal carcinoma, new data to support pazopanib as subsequent therapy for patients with clear cell carcinoma after first-line treatment with another tyrosine kinase inhibitor, and guidelines for follow-up of patients with renal cell carcinoma.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Axitinibe , Carcinoma de Células Renais/diagnóstico , Humanos , Imidazóis/uso terapêutico , Indazóis/uso terapêutico , Neoplasias Renais/diagnóstico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico
19.
J Immunother ; 37(7): 360-5, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25075565

RESUMO

Although tyrosine kinase inhibitors (TKI) are the most common first-line therapy for metastatic renal cell carcinoma, high-dose interleukin-2 (HD-IL2) remains the only agent that provides durable complete responses. The optimal sequence of these agents remains uncertain. This retrospective multi-institutional study examined the safety and efficacy of HD-IL2 following TKI therapy. After IRB approval at 7 HD-IL2 centers, data relating to patient, disease, and treatment characteristics among 40 consecutive patients with metastatic renal cell carcinoma who were treated with HD-IL2 after at least 1 prior TKI therapy were retrospectively collected. The most common cardiac adverse events were grade 3 hypotension and vascular leak syndrome. Six patients (15%) experienced other grade ≥3 cardiac adverse events. There were 2 treatment-related deaths due to congestive heart failure, occurring in 1 patient with short TKI to HD-IL2 interval and another patient with an abnormal baseline cardiac stress test. Best responses included 2 CRs (5%, duration 40+ and 62+ mo), 3 PRs (8%, duration 6, 11, and 24 mo), 13 SD (32%, median duration 12 mo), 20 PD (50%), and 2 not evaluable patients. Median overall survival was 22 months. Administration of HD-IL2 could be safe and effective after TKI therapy; however, careful selection of patients is critical. We recommend baseline cardiac risk factor assessment, screening with both cardiac stress test and echocardiogram, and allowing a TKI to HD-IL2 interval of at least 2 months.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Interleucina-2/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/mortalidade , Doenças Cardiovasculares/etiologia , Feminino , Humanos , Interleucina-2/efeitos adversos , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
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