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1.
Prostate ; 82(7): 858-866, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35286730

RESUMEN

BACKGROUND: In preclinical models of prostate cancer (PC), disulfiram (DSF) reduced tumor growth only when co-administered with copper (Cu), and Cu uptake in tumors is partially regulated by androgen-receptor signaling. However, prior trials of DSF in PC used DSF as monotherapy. OBJECTIVE: To assess the safety and efficacy of concurrent administration of DSF with Cu, we conducted a phase 1b clinical trial of patients with metastatic castration-resistant prostate cancer (mCRPC) receiving Cu with DSF. DESIGN, SETTING, AND PARTICIPANTS: Patients with mCRPC were treated in two cohorts: mCRPC with nonliver/peritoneal metastases (A), and mCRPC with liver and/or peritoneal metastases (B). Baseline Cu avidity was measured by 64 CuCl2 PET scan. Intravenous (IV) CuCl2 was given weekly for three doses with oral daily DSF followed by daily oral Cu gluconate and DSF until disease progression. DSF and metabolite diethyldithiocarbamic acid methyl ester (Me-DDC) levels in plasma were measured. DSF and Me-DDC were then assessed for cytotoxicity in vitro. RESULTS: We treated nine patients with mCRPC (six on cohort A and three on cohort B). Bone and nodal metastases showed differential and heterogeneous Cu uptake on 64 CuCl2 PET scans. No confirmed PSA declines or radiographic responses were observed. Median PFS was 2.8 months and median OS was 8.3 months. Common adverse events included fatigue and psychomotor depression; no Grade 4/5 AEs were observed. Me-DDC was measurable in all samples (LOQ = 0.512 ng/ml), whereas DSF was not (LOQ = 0.032 ng/ml, LOD = 0.01 ng/ml); Me-DDC was not cytotoxic in vitro. CONCLUSIONS: Oral DSF is not an effective treatment for mCRPC due to rapid metabolism into an inactive metabolite, Me-DDC. This trial has stopped enrollment and further work is needed to identify a stable DSF formulation for treatment of mCRPC.


Asunto(s)
Neoplasias Peritoneales , Neoplasias de la Próstata Resistentes a la Castración , Cobre/uso terapéutico , Disulfiram/uso terapéutico , Humanos , Masculino , Estudios Prospectivos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico
2.
Lancet Oncol ; 22(6): 872-882, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33991512

RESUMEN

BACKGROUND: Locally advanced or metastatic urothelial carcinoma is generally incurable and has scarce treatment options, especially for cisplatin-ineligible patients previously treated with PD-1 or PD-L1 therapy. Enfortumab vedotin is an antibody-drug conjugate directed at Nectin-4, a protein highly expressed in urothelial carcinoma. We aimed to evaluate the efficacy and safety of enfortumab vedotin in the post-immunotherapy setting in cisplatin-ineligible patients. METHODS: EV-201 is a multicentre, single-arm, phase 2 study of enfortumab vedotin in patients with locally advanced or metastatic urothelial carcinoma previously treated with PD-1 or PD-L1 inhibitors. Cohort 2 included adults (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status score of 2 or less who were considered ineligible for cisplatin at enrolment and who had not received platinum-containing chemotherapy in the locally advanced or metastatic setting. Enfortumab vedotin was given intravenously at a dose of 1·25 mg/kg on days 1, 8, and 15 of every 28-day cycle. The primary endpoint was confirmed objective response rate per Response Evaluation Criteria in Solid Tumours version 1.1 assessed by blinded independent central review. Efficacy and safety were analysed in all patients who received at least one dose of enfortumab vedotin. EV-201 is an ongoing study and the primary analysis is complete. This study is registered with Clinicaltrials.gov, NCT03219333. FINDINGS: Between Oct 8, 2017, and Feb 11, 2020, 91 patients were enrolled at 40 sites globally, of whom 89 received treatment. Median follow-up was 13·4 months (IQR 11·3-18·9). At data cutoff (Sept 8, 2020), the confirmed objective response rate was 52% (46 of 89 patients; 95% CI 41-62), with 18 (20%) of 89 patients achieving a complete response and 28 (31%) achieving a partial response. 49 (55%) of 89 patients had grade 3 or worse treatment-related adverse events. The most common grade 3 or 4 treatment-related adverse events were neutropenia (eight [9%] patients), maculopapular rash (seven [8%] patients), and fatigue (six [7%] patients). Treatment-related serious adverse events occurred in 15 (17%) patients. Three (3%) patients died due to acute kidney injury, metabolic acidosis, and multiple organ dysfunction syndrome (one [1%] each) within 30 days of first dose and these deaths were considered by the investigator to be related to treatment; a fourth death from pneumonitis occurred more than 30 days after the last dose and was also considered to be related to treatment. INTERPRETATION: Treatment with enfortumab vedotin was tolerable and confirmed responses were seen in 52% of cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma who were previously treated with PD-1 or PD-L1 inhibitors. These patients have few treatment options, and enfortumab vedotin could be a promising new therapy for a patient population with a high unmet need. FUNDING: Astellas Pharma Global Development and Seagen.


Asunto(s)
Antígeno B7-H1/genética , Carcinoma/tratamiento farmacológico , Moléculas de Adhesión Celular/genética , Receptor de Muerte Celular Programada 1/genética , Neoplasias Urológicas/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígeno B7-H1/antagonistas & inhibidores , Carcinoma/genética , Carcinoma/patología , Cisplatino/efectos adversos , Supervivencia sin Enfermedad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Criterios de Evaluación de Respuesta en Tumores Sólidos , Neoplasias Urológicas/genética , Neoplasias Urológicas/patología , Urotelio/efectos de los fármacos , Urotelio/patología
3.
Cancer ; 127(13): 2204-2212, 2021 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-33765337

RESUMEN

BACKGROUND: Systemic therapy (ST) can be deferred in patients who have metastatic renal cell carcinoma (mRCC) and slow-growing metastases. Currently, this subset of patients managed with active surveillance (AS) is not well described in the literature. METHODS: This was a prospective observational study of patients with mRCC across 46 US community and academic centers. The objective was to describe baseline characteristics and demographics of patients with mRCC initially managed by AS, reasons for AS, and patient outcomes. Descriptive statistics were used to characterize demographics, baseline characteristics, and patient-related outcomes. Wilcoxon 2-sample rank-sum tests and χ2 tests were used to assess differences between ST and AS cohorts in continuous and categorical variables, respectively. Kaplan-Meier survival curves were used to assess survival. RESULTS: Of 504 patients, mRCC was initially managed by AS (n = 143) or ST (n = 305); 56 patients were excluded from the analysis. Disease was present in 69% of patients who received AS, whereas the remaining 31% had no evidence of disease. At data cutoff, 72 of 143 patients (50%) in the AS cohort had not received ST. The median overall survival was not reached (95% CI, 122 months to not estimable) in patients who received AS versus 30 months (95% CI, 25-44 months) in those who received ST. Quality of life at baseline was significantly better in patients who were managed with AS versus ST. CONCLUSIONS: AS occurs frequently (32%) in real-world clinical practice and appears to be a safe and appropriate alternative to immediate ST in selected patients.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Carcinoma de Células Renales/patología , Humanos , Neoplasias Renales/patología , Calidad de Vida , Estudios Retrospectivos , Resultado del Tratamiento , Espera Vigilante
4.
Cancer ; 127(16): 2954-2965, 2021 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-33951180

RESUMEN

BACKGROUND: Retrospective analyses of randomized trials suggest that Black men with metastatic castration-resistant prostate cancer (mCRPC) have longer survival than White men. The authors conducted a prospective study of abiraterone acetate plus prednisone to explore outcomes by race. METHODS: This race-stratified, multicenter study estimated radiographic progression-free survival (rPFS) in Black and White men with mCRPC. Secondary end points included prostate-specific antigen (PSA) kinetics, overall survival (OS), and safety. Exploratory analysis included genome-wide genotyping to identify single nucleotide polymorphisms associated with progression in a model incorporating genetic ancestry. One hundred patients self-identified as White (n = 50) or Black (n = 50) were enrolled. Eligibility criteria were modified to facilitate the enrollment of individual Black patients. RESULTS: The median rPFS for Black and White patients was 16.6 and 16.8 months, respectively; their times to PSA progression (TTP) were 16.6 and 11.5 months, respectively; and their OS was 35.9 and 35.7 months, respectively. Estimated rates of PSA decline by ≥50% in Black and White patients were 74% and 66%, respectively; and PSA declines to <0.2 ng/mL were 26% and 10%, respectively. Rates of grade 3 and 4 hypertension, hypokalemia, and hyperglycemia were higher in Black men. CONCLUSIONS: Multicenter prospective studies by race are feasible in men with mCRPC but require less restrictive eligibility. Despite higher comorbidity rates, Black patients demonstrated rPFS and OS similar to those of White patients and trended toward greater TTP and PSA declines, consistent with retrospective reports. Importantly, Black men may have higher side-effect rates than White men. This exploratory genome-wide analysis of TTP identified a possible candidate marker of ancestry-dependent treatment outcomes.


Asunto(s)
Acetato de Abiraterona , Neoplasias de la Próstata Resistentes a la Castración , Acetato de Abiraterona/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica , Supervivencia sin Enfermedad , Humanos , Masculino , Prednisona/efectos adversos , Estudios Prospectivos , Antígeno Prostático Específico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Estudios Retrospectivos , Resultado del Tratamiento
5.
Cancer ; 126(20): 4485-4497, 2020 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-32757302

RESUMEN

BACKGROUND: Inhibition of the programmed cell death protein 1 (PD-1) pathway has demonstrated clinical benefit in metastatic urothelial cancer (mUC); however, response rates of 15% to 26% highlight the need for more effective therapies. Bruton tyrosine kinase (BTK) inhibition may suppress myeloid-derived suppressor cells (MDSCs) and improve T-cell activation. METHODS: The Randomized Phase 2 Trial of Acalabrutinib and Pembrolizumab Immunotherapy Dual Checkpoint Inhibition in Platinum-Resistant Metastatic Urothelial Carcinoma (RAPID CHECK; also known as ACE-ST-005) was a randomized phase 2 trial evaluating the PD-1 inhibitor pembrolizumab with or without the BTK inhibitor acalabrutinib for patients with platinum-refractory mUC. The primary objectives were safety and objective response rates (ORRs) according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Immune profiling was performed to analyze circulating monocytic MDSCs and T cells. RESULTS: Seventy-five patients were treated with pembrolizumab (n = 35) or pembrolizumab plus acalabrutinib (n = 40). The ORR was 26% with pembrolizumab (9% with a complete response [CR]) and 20% with pembrolizumab plus acalabrutinib (10% with a CR). The grade 3/4 adverse events (AEs) that occurred in ≥15% of the patients were anemia (20%) with pembrolizumab and fatigue (23%), increased alanine aminotransferase (23%), urinary tract infections (18%), and anemia (18%) with pembrolizumab plus acalabrutinib. One patient treated with pembrolizumab plus acalabrutinib had high MDSCs at the baseline, which significantly decreased at week 7. Overall, MDSCs were not correlated with a clinical response, but some subsets of CD8+ T cells did increase during the combination treatment. CONCLUSIONS: Both treatments were generally well tolerated, although serious AE rates were higher with the combination. Acalabrutinib plus pembrolizumab did not improve the ORR, PFS, or OS in comparison with pembrolizumab alone in mUC. Baseline and on-treatment peripheral monocytic MDSCs were not different in the treatment cohorts. Proliferating CD8+ T-cell subsets increased during treatment, particularly in the combination cohort. Ongoing studies are correlating these peripheral immunome findings with tissue-based immune cell infiltration.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzamidas/uso terapéutico , Pirazinas/uso terapéutico , Neoplasias Urológicas/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales Humanizados/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Benzamidas/farmacología , Femenino , Humanos , Inmunoterapia , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Pirazinas/farmacología
6.
J Oncol Pharm Pract ; 26(2): 330-337, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31081469

RESUMEN

BACKGROUND: Neoadjuvant cisplatin-based combination chemotherapy for muscle-invasive bladder cancer (MIBC) improves overall and disease-free survival. However, there is much debate over the optimal neoadjuvant regimen. Gemcitabine plus cisplatin (GC) has been the neoadjuvant regimen of choice for many institutions for patients with MIBC based on data extrapolated from the metastatic setting. Based on recent data, many institutions are transitioning to variations of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) as the neoadjuvant regimen of choice. OBJECTIVE: To assess the effectiveness and safety of neoadjuvant chemotherapy with gemcitabine plus cisplatin in patients with muscle-invasive bladder cancer prior to cystectomy. METHODS: This is a single-center, retrospective, cohort study at Duke University Hospital (DUH). Patients included had MIBC and received gemcitabine plus cisplatin chemotherapy prior to a cystectomy. The primary endpoint was to assess the pathologic complete response (pCR) rate in MIBC after treatment with gemcitabine and cisplatin. Patients were split into two groups, those who received their chemotherapy at DUH, and those who received their chemotherapy at an outside facility. RESULTS: Overall pCR rate for all patients (n = 36) was 14%. The pCR rates for patients in the Duke Chemotherapy Group (n = 17) and in the Community Chemotherapy Group (n = 19) were 24% and 5%, respectively. GC was overall well tolerated in most patients with few adverse events ≥ grade 3. CONCLUSIONS: This retrospective study demonstrates a consistent pCR rate (24% in Duke Chemotherapy Group) for neoadjuvant GC in MIBC compared with other literature. The overall pCR rate for all patients was 14%.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Cisplatino/administración & dosificación , Desoxicitidina/análogos & derivados , Neoplasias de los Músculos/tratamiento farmacológico , Terapia Neoadyuvante/métodos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/administración & dosificación , Antineoplásicos/administración & dosificación , Estudios de Cohortes , Desoxicitidina/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de los Músculos/diagnóstico , Neoplasias de los Músculos/secundario , Invasividad Neoplásica/diagnóstico , Estudios Retrospectivos , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/diagnóstico , Gemcitabina
7.
Lancet Oncol ; 20(10): 1370-1385, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31427204

RESUMEN

BACKGROUND: In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting. METHODS: In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment. FINDINGS: Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32·4 months [IQR 13·4-36·3]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35·6-not estimable] vs 26·6 months [22·1-33·4]; hazard ratio [HR] 0·66 [95% CI 0·54-0·80], p<0·0001), progression-free survival (median 8·2 months [95% CI 6·9-10·0] vs 8·3 months [7·0-8·8]; HR 0·77 [95% CI 0·65-0·90], p=0·0014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0·0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37·9 months [32·2-not estimable]; HR 0·71 [95% CI 0·59-0·86], p=0·0003), progression-free survival (median 9·7 months [95% CI 8·1-11·1] vs 9·7 months [8·3-11·1]; HR 0·85 [95% CI 0·73-0·98], p=0·027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0·015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related. INTERPRETATION: The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories. FUNDING: Bristol-Myers Squibb and ONO Pharmaceutical.


Asunto(s)
Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Sunitinib/uso terapéutico , Alanina Transaminasa/sangre , Amilasas/sangre , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Fatiga/inducido químicamente , Estudios de Seguimiento , Humanos , Hipertensión/inducido químicamente , Análisis de Intención de Tratar , Ipilimumab/administración & dosificación , Lipasa/sangre , Nivolumab/administración & dosificación , Parestesia/inducido químicamente , Supervivencia sin Progresión , Sunitinib/efectos adversos , Tasa de Supervivencia
8.
Lancet Oncol ; 20(4): 581-590, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30827746

RESUMEN

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.


Asunto(s)
Anilidas/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Anciano , Carcinoma de Células Renales/patología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Humanos , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Estudios Retrospectivos
9.
Prostate ; 79(15): 1752-1761, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31497882

RESUMEN

BACKGROUND: Docetaxel prednisone is a standard of care for men with metastatic castration-resistant prostate cancer (mCRPC), and plasma vascular endothelial growth factor (VEGF) levels are a poor prognostic factor in this population; therefore, we evaluated the combination of docetaxel prednisone with pazopanib, an oral VEGF receptor inhibitor, for safety and preliminary efficacy. METHODS: This is a two-site phase 1b Department of Defense Prostate Cancer Clinical Trials Consortium trial of docetaxel, prednisone, and pazopanib once daily and ongoing androgen deprivation therapy and prophylactic pegfilgrastim in men with mCRPC. The primary endpoint was safety and the determination of a maximum tolerated dose (MTD) through a dose-escalation and expansion design; secondary endpoints included progression-free and overall survival (OS), prostate specific antigen (PSA) declines, radiographic responses, and pharmacokinetic and plasma angiokine biomarker analyses. RESULTS: Twenty-five men were treated over six dose levels. Pegfilgrastim was added to the regimen after myelosuppression limited dose escalation. With pegfilgrastim, our target MTD of docetaxel 75 mg/m2 q3 weeks; prednisone 10 mg daily; and pazopanib 800 mg daily was reached. Eleven additional patients were accrued at this dose level for a total of 36 patients. Dose-limiting toxicities included neutropenia, syncope, and hypertension. Three deaths attributed to study treatment occurred. The objective response rate was 31%; median PFS was 14.1 months (95% confidence interval [CI]: 7.1 and 22.2); and OS was 18.6 months (95% CI: 11.8 and 22.2). CONCLUSIONS: The combination of docetaxel, prednisone, and pazopanib (with pegfilgrastim) was tolerable at full doses and demonstrated promising efficacy in a relatively poor risk patients with mCRPC. Further development of predictive biomarkers may enrich for patients who receive clinical benefit from this regimen.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Docetaxel/uso terapéutico , Prednisona/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Pirimidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Docetaxel/administración & dosificación , Docetaxel/efectos adversos , Humanos , Indazoles , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Prednisona/administración & dosificación , Prednisona/efectos adversos , Supervivencia sin Progresión , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/patología , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Tasa de Supervivencia , Resultado del Tratamiento
10.
J Natl Compr Canc Netw ; 17(11): 1278-1285, 2019 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-31693980

RESUMEN

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non-clear cell renal cell carcinoma, and are intended to assist with clinical decision-making. These NCCN Guidelines Insights summarize the NCCN Kidney Cancer Panel discussions for the 2020 update to the guidelines regarding initial management and first-line systemic therapy options for patients with advanced clear cell renal cell carcinoma.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Neoplasias Renales/terapia , Humanos , Carcinoma de Células Renales/terapia , Toma de Decisiones Clínicas
11.
Semin Cell Dev Biol ; 58: 34-40, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27132022

RESUMEN

Enhancing the endogenous regenerative capacity of the mammalian heart is a promising strategy that can lead to potential treatment of injured cardiac tissues. Studies on heart regeneration in zebrafish and neonatal mice have shown that cardiomyocyte proliferation is essential for replenishing myocardium. We will review recent advancements that have demonstrated the importance of Neuregulin 1/ErbB2 and innervation in regulating cardiomyocyte proliferation using both adult zebrafish and neonatal mouse heart regeneration models. Emerging findings suggest that different populations of macrophages and inflammation might contribute to regenerative versus fibrotic responses. Finally, we will discuss variation in the severity of the cardiac injury and size of the wound, which may explain the range of outcomes observed in different injury models.


Asunto(s)
Corazón/fisiología , Regeneración/fisiología , Pez Cebra/fisiología , Animales , Animales Recién Nacidos , Modelos Animales de Enfermedad , Matriz Extracelular/metabolismo , Ratones
12.
Prostate ; 77(4): 385-395, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-27862097

RESUMEN

BACKGROUND: Tasquinimod is an immunomodulating and anti-antiangiogenic oral agent with anti-prostate cancer activity in preclinical studies and in clinical trials of men with metastatic castration resistant prostate cancer (mCRPC), including single agent activity and in combination with taxanes. We sought to identify the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of tasquinimod in combination with cabazitaxel and prednisone in men with chemorefractory mCRPC. METHODS: Men with mCRPC who had failed prior docetaxel chemotherapy received cabazitaxel 25 mg/m2 every 3 weeks with oral tasquinimod at 1 of 3 escalating dose levels (0.25, 0.5, and 1.0 mg once daily) with prednisone and PEG-filgastrim support, using a 3 + 3 dose escalation design. Treatment continued until progressive disease or unacceptable toxicity. RESULTS: We enrolled 25 men with chemorefractory mCRPC. The RP2D was 0.5 mg tasquinimod based on excess DLTs (two of three men) observed at dose level 3 (1.0 mg) including grade 3 sensory neuropathy and grade 3 atrial fibrillation. Dose level 2 was expanded to 14 men, where 3 DLTs were observed: grade 3 fatigue, grade 4 febrile neutropenia, and grade 3 liver function abnormalities. The proportion of men with a ≥30% PSA decline was 63% and the median composite progression-free survival (PFS) was 8.5 months (95% CI 4.2-16.4 months) based on 12 PFS events. The median number of cycles of cabazitaxel was 6 (range 1-13), with six men receiving >10 cycles. Best overall RECIST responses (CR + PR) were observed in three men (12%), with stable disease in 12 (48%). No pharmacokinetic interactions were observed. CONCLUSIONS: We determined the RP2D of tasquinimod combined with cabazitaxel to be 0.5 mg daily following a 3 week lead-in of tasquinimod 0.25 mg with growth factor support. No unexpected toxicities occurred. Prostate 77: 385-395, 2017. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Progresión de la Enfermedad , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Quinolonas/administración & dosificación , Taxoides/administración & dosificación , Anciano , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico por imagen , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Tasa de Supervivencia/tendencias , Resultado del Tratamiento
13.
Cancer Invest ; 35(5): 333-344, 2017 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-28368708

RESUMEN

The Metastatic Renal Cell Cancer Registry, a large, nationally representative, prospective registry of patients with metastatic renal cell carcinoma (mRCC), aims to understand real-world treatment patterns and outcomes of patients with mRCC in routine clinical practice across the United States. This observational study is designed to enroll 500 patients with previously untreated mRCC from approximately 60 academic and community treatment sites; as of December 7, 2016, 500 patients have enrolled at 54 sites. Key endpoints include real-world data on reasons for treatment initiation and discontinuation; treatment regimens; disease progression; patient-reported outcomes; and healthcare resource utilization in this patient population.


Asunto(s)
Carcinoma de Células Renales/secundario , Carcinoma de Células Renales/terapia , Servicios de Salud Comunitaria/tendencias , Neoplasias Renales/patología , Neoplasias Renales/terapia , Pautas de la Práctica en Medicina/tendencias , Sistema de Registros , Servicios de Salud Comunitaria/estadística & datos numéricos , Progresión de la Enfermedad , Recursos en Salud/estadística & datos numéricos , Recursos en Salud/tendencias , Humanos , Medición de Resultados Informados por el Paciente , Estudios Prospectivos , Calidad de Vida , Proyectos de Investigación , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos
14.
J Natl Compr Canc Netw ; 15(6): 804-834, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28596261

RESUMEN

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.


Asunto(s)
Neoplasias Renales/diagnóstico , Neoplasias Renales/terapia , Terapia Combinada , Manejo de la Enfermedad , Humanos , Neoplasias Renales/mortalidad , Estadificación de Neoplasias , Pronóstico , Recurrencia , Retratamiento
15.
Oncology (Williston Park) ; 31(4): 286-94, 2017 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-28412780

RESUMEN

Sexual and urinary morbidities resulting from treatment of pelvic malignancies are common. These treatment sequelae are significantly bothersome to patients and challenging to address. Awareness of these complications is critical in order to properly counsel patients regarding potential side effects and to facilitate prompt diagnosis and management. Addressing these issues often necessitates a coordinated multidisciplinary approach; however, the effort required often translates into improvement in patient quality of life. Herein we review the sexual and urinary side effects that may arise during or after treatment of pelvic malignancies.


Asunto(s)
Supervivientes de Cáncer/psicología , Neoplasias Pélvicas/terapia , Humanos , Neoplasias Pélvicas/mortalidad , Neoplasias Pélvicas/psicología , Calidad de Vida , Disfunciones Sexuales Psicológicas/terapia , Incontinencia Urinaria de Esfuerzo/terapia
16.
Clin Adv Hematol Oncol ; 14(6): 436-46, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-27379813

RESUMEN

The use of targeted therapies in patients with genitourinary malignancies has significantly improved outcomes. For example, androgen receptor (AR) pathway inhibitors have improved outcomes for patients with prostate cancer, and antiangiogenic agents have improved outcomes for those with kidney cancer. However, these advances have been accompanied by musculoskeletal side effects that manifest as physical dysfunction. Although the effects of androgen deprivation therapy on skeletal muscle are well-known, an additional concern is that the muscle loss associated with these newer drugs-especially AR pathway inhibitors-may result in insulin resistance and metabolic syndrome, thus increasing the risk for cardiovascular events and diabetes. Antiangiogenic agents also may cause muscle loss, although this has been poorly described in the literature. As these targeted therapies begin to be used in the earlier stages of treatment, there will be a critical need to prevent treatment-related toxicities with nonpharmacologic interventions. Over the past decade, exercise training has emerged as a novel nonpharmacologic adjunctive method to address toxicities resulting from these targeted therapies. Despite numerous studies in patients with prostate cancer, there remains a large gap in our knowledge of the true efficacy of exercise therapy, as well as the best way to prescribe exercise programs. Here, we suggest that the central role of skeletal muscle in the development of side effects of AR pathway inhibitors and antiangiogenic agents may unlock a number of unique opportunities to study how exercise prescriptions can be used more effectively. Resistance training may be a particularly important modality.


Asunto(s)
Trastornos Musculares Atróficos/etiología , Trastornos Musculares Atróficos/terapia , Entrenamiento de Fuerza , Neoplasias Urogenitales/complicaciones , Antagonistas de Andrógenos/efectos adversos , Antagonistas de Andrógenos/uso terapéutico , Antineoplásicos Hormonales/efectos adversos , Antineoplásicos Hormonales/uso terapéutico , Humanos , Terapia Molecular Dirigida , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Estadificación de Neoplasias , Inhibidores de Proteínas Quinasas/uso terapéutico , Resultado del Tratamiento , Neoplasias Urogenitales/diagnóstico , Neoplasias Urogenitales/tratamiento farmacológico , Neoplasias Urogenitales/mortalidad
17.
Int J Urol ; 23(12): 1038-1041, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27766686

RESUMEN

Here we present, to the best of our knowledge, the first case of a paraneoplastic Cushing's syndrome (hypercortisolism) resulting from treatment-related neuroendocrine prostate cancer - a highly aggressive and difficult disease to treat. A 51-year-old man was started on androgen deprivation therapy after presenting with metastatic prostate cancer, characterized by diffuse osseous metastasis. Shortly thereafter, he developed progressive disease with biopsy proven neuroendocrine prostate cancer as well as symptoms of increased skin pigmentation, hypokalemia, hypertension, hyperglycemia and profound weakness, consistent with ectopic Cushing's syndrome. Molecular analysis of the patient's tumor through RNA sequencing showed high expression of several genes including CHGA, ASCL1, CALCA, HES6, PCSK1, CALCB and INSM1 confirming his neuroendocrine phenotype; elevated POMC expression was found, supporting the diagnosis of ectopic Cushing's syndrome.


Asunto(s)
Síndrome de Cushing/etiología , Síndromes Paraneoplásicos , Neoplasias de la Próstata/tratamiento farmacológico , Expresión Génica , Humanos , Hiperglucemia , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias
18.
Oncology (Williston Park) ; 29(9): 680-5, 687-8, 694, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26384805

RESUMEN

A number of observational studies and clinical trials have shown that physical activity after a diagnosis of prostate cancer is associated with a decrease in disease progression and an increase in survival, and that specific exercises reduce morbidity from prostate cancer treatments. However, providers need more guidance on what types of physical activity to recommend to patients across different disease states and treatments in prostate cancer, and when and how to initiate the discussion. In addition to evaluating important studies showing benefits of physical activity in patients with prostate cancer, this review suggests some evidence-based methods for incorporating physical activity interventions into clinical practice.


Asunto(s)
Antineoplásicos/uso terapéutico , Actividad Motora , Prostatectomía , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/terapia , Antineoplásicos/efectos adversos , Progresión de la Enfermedad , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Medicina Basada en la Evidencia , Humanos , Masculino , Complicaciones Posoperatorias/prevención & control , Prostatectomía/efectos adversos , Prostatectomía/mortalidad , Neoplasias de la Próstata/mortalidad , Traumatismos por Radiación/prevención & control , Radioterapia/efectos adversos , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento
20.
Clin Adv Hematol Oncol ; 12(3): 163-71, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24927264

RESUMEN

Meaningful progress has been realized in the treatment of metastatic renal cell carcinoma with the recent approval of a number of new agents; more new agents are on the horizon. Despite the recent completion of many clinical trials that have changed or will change practice, many questions remain. In this manuscript, we highlight the most noteworthy developments in the first- and second-line treatment of metastatic renal cell carcinoma, as these are the areas of greatest change. We also emphasize ongoing trials and those areas that are most in need of study in order to move the field forward. Although more data are needed, exciting progress is being made.


Asunto(s)
Carcinoma de Células Renales/patología , Carcinoma de Células Renales/terapia , Neoplasias Renales/patología , Neoplasias Renales/terapia , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Renales/mortalidad , Ensayos Clínicos como Asunto , Humanos , Terapia Molecular Dirigida , Metástasis de la Neoplasia , Retratamiento , Nivel de Atención , Insuficiencia del Tratamiento , Resultado del Tratamiento
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