RESUMEN
PURPOSE: Cabozantinib and nivolumab (CaboNivo) alone or with ipilimumab (CaboNivoIpi) have shown promising efficacy and safety in patients with metastatic urothelial carcinoma (mUC), metastatic renal cell carcinoma (mRCC), and rare genitourinary (GU) tumors in a dose-escalation phase I study. We report the final data analysis of the safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the phase I patients and seven expansion cohorts. METHODS: This is an investigator-initiated, multicenter, phase I trial. CaboNivo doublet expansion cohorts included (1) mUC, (2) mRCC, and (3) adenocarcinoma of the bladder/urachal; CaboNivoIpi triplet expansion cohorts included (1) mUC, (2) mRCC, (3) penile cancer, and (4) squamous cell carcinoma of the bladder and other rare GU tumors (ClinicalTrials.gov identifier: NCT02496208). RESULTS: The study enrolled 120 patients treated with CaboNivo (n = 64) or CaboNivoIpi (n = 56), with a median follow-up of 49.2 months. In 108 evaluable patients (CaboNivo n = 59; CaboNivoIpi n = 49), the ORR was 38% (complete response rate 11%) and the median duration of response was 20 months. The ORR was 42.4% for mUC, 62.5% for mRCC (n = 16), 85.7% for squamous cell carcinoma of the bladder (n = 7), 44.4% for penile cancer (n = 9), and 50.0% for renal medullary carcinoma (n = 2). Grade ≥ 3 treatment-related adverse events occurred in 84% of CaboNivo patients and 80% of CaboNivoIpi patients. CONCLUSION: CaboNivo and CaboNivoIpi demonstrated clinical activity and safety in patients with multiple GU malignancies, especially clear cell RCC, urothelial carcinoma, and rare GU tumors such as squamous cell carcinoma of the bladder, small cell carcinoma of the bladder, adenocarcinoma of the bladder, renal medullary carcinoma, and penile cancer.
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Anilidas , Protocolos de Quimioterapia Combinada Antineoplásica , Ipilimumab , Nivolumab , Piridinas , Neoplasias Urogenitales , Humanos , Masculino , Anilidas/uso terapéutico , Anilidas/efectos adversos , Ipilimumab/uso terapéutico , Ipilimumab/efectos adversos , Ipilimumab/administración & dosificación , Nivolumab/uso terapéutico , Nivolumab/efectos adversos , Piridinas/uso terapéutico , Piridinas/efectos adversos , Persona de Mediana Edad , Anciano , Femenino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adulto , Neoplasias Urogenitales/tratamiento farmacológico , Neoplasias Urogenitales/patología , Anciano de 80 o más Años , Supervivencia sin ProgresiónRESUMEN
Urothelial cancer (UC) is the most common histology seen in bladder tumors. The 2022 WHO classification of urinary tract tumors includes a list of less common subtypes (formerly known as variants) for invasive UC which are considered high-grade tumors. This review summarizes the most recent advances in the management of selected nonurothelial subtypes of bladder cancer: squamous cell carcinoma, small cell carcinoma, sarcomatoid urothelial carcinoma, micropapillary carcinoma, plasmacytoid carcinoma, adenocarcinoma, and urachal carcinoma. The role of neoadjuvant and adjuvant chemotherapy has not been well characterized for most of these histologies, and prospective data are extremely limited. Participation in clinical trials is recommended in advanced disease.
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Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/terapia , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/clasificación , Manejo de la Enfermedad , Terapia Combinada , Terapia Neoadyuvante/métodosRESUMEN
The EV-302 study1 marks a pivotal leap in the management of advanced urothelial carcinoma, setting a new benchmark for frontline therapy. Enfortumab vedotin plus pembrolizumab is the first combination therapy that has ever outperformed standard chemotherapy. The degree of benefit and the reported safety profile should make this combination a first-choice option for most patients with advanced-stage urothelial carcinoma.
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Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/patología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patología , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversosRESUMEN
Despite recent advances, advanced-stage urothelial carcinoma (aUC) remains incurable, with 5-year survival rates of approximately 10%. Platinum-based chemotherapy has a major role as first-line therapy for most patients with aUC. The approval of the anti-PD-L1 antibody avelumab as maintenance therapy for patients without initial disease progression on platinum-based chemotherapy is an important development that has improved the survival outcomes of patients with this disease. Otherwise, the use of first-line immune-checkpoint inhibitors (ICIs) targeting PD-1 or PD-L1 has been restricted to patients who are ineligible for platinum-containing chemotherapy regimens. Other important developments include the FDA-accelerated approval of first-line enfortumab vedotin plus pembrolizumab for patients ineligible to receive cisplatin and the availability of FGFR inhibitors, enfortumab vedotin and sacituzumab govitecan for subsequent lines of therapy. Several research questions remain unaddressed including the lack of adequate biomarkers, how to assign priority to the different treatment options for individual patients and which agents can be effective as monotherapies. The future is promising with the emergence of modalities such as antibody-drug conjugate-like drugs, next-generation ICIs, bispecific antibodies and cellular therapies. In this Review, we summarize the evolution of systemic therapy for patients with aUC and provide insights into the unmet needs.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/patología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Cisplatino , BiomarcadoresRESUMEN
Non-muscle-invasive bladder cancer is one of the most common malignancies. Patients with intermediate-risk or high-risk disease can be treated with intravesical Bacillus Calmette-Guerin, a vaccine against tuberculosis. However, many of these patients will experience tumor recurrence, despite appropriate treatment. 1 The standard of care in these patients is radical cystectomy (RC) with urinary diversion. 2 Patients diagnosed with muscle-invasive bladder cancer (MIBC) have traditionally faced 2 main treatment options: RC and urinary diversion, as in Bacillus Calmette-Guerin-unresponsive Non-muscle-invasive bladder cancer, or alternatively, trimodal therapy comprising maximal transurethral resection of bladder tumor plus chemoradiation. 3 For patients with MIBC and clinical (c)T2-T4a, neoadjuvant chemotherapy (NAC) preceding RC is supported by Level 1 evidence with a modest 5-year overall survival benefit of 5% with cisplatin-based regimens. 4-9 A number of factors preclude MIBC patients from standard treatment options. For example, patients with serious comorbidities might be unable to tolerate general anesthesia, while others might be unwilling to adapt to the lifestyle changes after RC. 10-12 Likewise, patients with extensive carcinoma in situ or poor bladder function might not be optimal candidates for trimodal therapy or be prepared for the ongoing risk that salvage RC might be ultimately required. Reasons for the underuse of NAC range from the fear of delaying potentially curative surgery in nonresponders to patient ineligibility to cisplatin-based NAC. 13,14 Despite best efforts, in both surgical and bladder-sparing approaches, the 5-year overall survival in treated patients with MIBC is only 35% to 50%. 3,15 Strategies to improve overall prognosis as well as to reduce the indications of RC are desperately needed. Trial results have demonstrated the unprecedented ability of immune-checkpoint inhibitors to induce durable remissions in some patients with metastatic urothelial carcinoma. 16-20 Furthermore, immune-checkpoint inhibitors have shown to be better tolerated than traditional chemotherapy. 16 These successful results have spearheaded the research on these agents in earlier curative settings, with the shared goal of improving overall outcomes, and potentially avoid surgery in patients who show complete response (pT0). Strategies to enhance the immune response by combining immunotherapy with immune sensitizers such as chemotherapy, immunotherapy, targeted therapy or radiation are on the rise.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Carcinoma de Células Transicionales/patología , Cisplatino/uso terapéutico , Vacuna BCG/uso terapéutico , Inhibidores de Puntos de Control Inmunológico , Recurrencia Local de Neoplasia/cirugía , Cistectomía/métodos , Terapia Neoadyuvante , Inmunoterapia , Invasividad NeoplásicaRESUMEN
PURPOSE: This study investigated the efficacy and tolerability of cabozantinib plus nivolumab (CaboNivo) in patients with metastatic urothelial carcinoma (mUC) that progressed on checkpoint inhibition (CPI). PATIENTS AND METHODS: A phase I expansion cohort of patients with mUC who received prior CPI was treated with cabozantinib 40 mg/day and nivolumab 3 mg/kg every 2 weeks until disease progression/unacceptable toxicity. The primary goal was objective response rate (ORR) per RECIST v.1.1. Secondary objectives included progression-free survival (PFS), duration of response (DoR), overall survival (OS), safety, and tolerability. RESULTS: Twenty-nine out of 30 patients enrolled were evaluable for efficacy. Median follow-up was 22.2 months. Most patients (86.7%) received prior chemotherapy and all patients received prior CPI (median seven cycles). ORR was 16.0%, with one complete response and three partial responses (PR). Among 4 responders, 2 were primary refractory, 1 had a PR, and 1 had stable disease on prior CPI. Median DoR was 33.5 months [95% confidence interval (CI), 3.7-33.5], median PFS was 3.6 months (95% CI, 2.1-5.5), and median OS was 10.4 months (95% CI, 5.8-19.5). CaboNivo decreased immunosuppressive subsets such as regulatory T cells (Tregs) and increased potential antitumor immune subsets such as nonclassical monocytes and effector T cells. A lower percentage of monocytic myeloid-derived suppressor cells (M-MDSC) and polymorphonuclear MDSCs, lower CTLA-4 and TIM-3 expression on Tregs, and higher effector CD4+ T cells at baseline were associated with better PFS and/or OS. CONCLUSIONS: CaboNivo was clinically active, well tolerated, and favorably modulated peripheral blood immune subsets in patients with mUC refractory to CPI.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Anilidas , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Transicionales/tratamiento farmacológico , Humanos , Inhibidores de Puntos de Control Inmunológico , Nivolumab , Piridinas , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
Urothelial carcinoma (UC) is a highly lethal malignancy in the metastatic state. Platinum-based chemotherapy regimens have been the backbone treatment for patients with advanced UC in the first-line setting. However, a large subset of patients are suboptimal candidates for these combinations owing to poor renal function and/or other comorbidities. Patients who are unable to tolerate or who progress after frontline platinum chemotherapy face a poor outcome. Recent insights into UC biology and immunology are being translated into new therapies for metastatic UC (mUC) including immune checkpoint inhibitors (ICIs), erdafitinib, a FGFR inhibitor, and antibody drug conjugates (ADC) such enfortumab vedotin.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Carcinoma de Células Transicionales/tratamiento farmacológico , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoconjugados/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
BACKGROUND: Evidence is scarce on how to promote health and decrease cumulative inequalities for disadvantaged older people. Downstream complex interventions focusing on intermediate factors (self-management, health literacy and social capital) may have the potential to mitigate the inequitable impacts of social determinants in health. The aim of the AEQUALIS study was to assess the effectiveness of a group-based intervention to improve self-perceived health as indicator of health inequality. METHODS: Pragmatic randomised clinical trial addressed to older adults (≥ 60 years) living in urban disadvantaged areas with low self-perceived health. The intervention was delivered in primary care settings and community assets between 2015 and 2017 and consisted in 12 weekly sessions. The primary outcome was self-perceived health assessed in two ways: with the first item of the SF-12 questionnaire, and with the EQ-5D visual analog scale. Secondary outcomes were health-related quality of life, social capital, self-management, mental health and use of health services. Outcomes were assessed at baseline, post intervention and follow-up at 9 months after the end of the intervention. RESULTS: 390 people were allocated to the intervention group (IG) or the control group (CG) and 194 participants and 164 were included in the data analysis, respectively. Self perceived health as primary outcome assessed with SF-12-1 was not specifically affected by the intervention, but with the EQ-5D visual analog scale showed a significant increase at one-year follow-up only in the IG (MD=4.80, 95%CI [1.09, 8.52]). IG group improved health literacy in terms of a better understanding of medical information (- 0.62 [- 1.10, - 0.13]). The mental component of SF-12 improved (3.77 [1.82, 5.73]), and depressive symptoms decreased at post-intervention (- 1.26 [- 1.90, - 0.63]), and at follow-up (- 0.95 [- 1.62, - 0.27]). The use of antidepressants increased in CG at the follow-up (1.59 [0.33, 2.86]), while it remained stable in the IG. CONCLUSIONS: This study indicates that a group intervention with a strong social component, conducted in primary health care and community assets, shows promising effects on mental health and can be used as a strategy for health promotion among older adults in urban disadvantaged areas. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02733523 . Registered 11 April 2016 - Retrospectively registered.
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Alfabetización en Salud , Automanejo , Capital Social , Anciano , Anciano de 80 o más Años , Disparidades en el Estado de Salud , Humanos , Calidad de VidaRESUMEN
No consensus currently exist on the optimal treatment of patients with high-risk nonmuscle invasive (HGT1) micropapillary variant of bladder cancer (MPBC). Transcripsome analysis may allow stratification of MPBC-HGT1 enabling prediction of recurrence and guide therapeutic management for individual patients. Whole transcriptome RNA-Sequencing of tumors from 23 patients with MPBC-HGT1 and 64 conventional urothelial carcinomas (cUC) (reference set) was performed. Differentially expressed genes between MPBC-HGT1 and cUC-HGT1 were explored. Cox proportional hazard models and Kapplan-Meier methods were used to assess the relation between time to progression (TTP) and individual gene expression adjusting for clinical covariates. Over 3000 genes were differentially expressed in MPBC-HGT1 as compared with cUC-HGT1 and a 26-gene signature is characteristic of MPBC within HGT1. A set of three genes; CD36, FAPB3 and RAETE1; were significantly associated with TTP. High expression of FABP3 and CD36 were associated with shorter TTP (p = 0.045 and p = 0.08) as was low expression of RAET1E (p = 0.01). Our study suggest that a 26-gene signature can define MPBC-HGT1 within conventional urothelial carcinomas. A prognostic risk index of three genes (FABP3, CD36 and RAET1E) was found to be associated with shorter TTP and may help classify a group of patients with MPBC-HGT1 with high-risk of early progression. These observations might have implications in terms of radical cystectomy recommendation in MPBC patients.
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Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Antígenos CD36/genética , Proteínas Portadoras/genética , Proteína 3 de Unión a Ácidos Grasos/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Estimación de Kaplan-Meier , Masculino , Proteínas de la Membrana/genética , Estadificación de Neoplasias , Análisis de Secuencia de ARN , Neoplasias de la Vejiga Urinaria/mortalidadRESUMEN
Anti-androgen therapy with Enzalutamide (Enz) has been used as a therapy for castration resistant prostate cancer (CRPC) patients after development of resistance to chemotherapy with Docetaxel (Doc). The potential impacts of Doc-chemotherapy on the subsequent Enz treatment, however, remain unclear. Here we found the overall survival rate of patients that received Enz was significantly less in patients that received prior Doc-chemotherapy than those who had not. In vitro studies from 3 established Doc resistant CRPC (DocRPC) cell lines are consistent with the clinical findings showing DocRPC patients had decreased Enz-sensitivity as well as accelerated development of Enz-resistance via enhanced androgen receptor (AR) splicing variant 7 (ARv7) expression. Mechanism dissection found that Doc treatment might increase the generation of ARv7 via altering the MALAT1-SF2 RNA splicing complex. Preclinical studies using in vivo mouse models and in vitro cell lines proved that targeting the MALAT1/SF2/ARv7 axis with small molecules, including siMALAT1, shSF2, and shARv7 or ARv7 degradation enhancers: Cisplatin or ASC-J9®, can restore/increase the Enz sensitivity to further suppress DocRPC cell growth. Therefore, combined therapy of Doc-chemotherapy with anti-ARv7 therapy, including Cisplatin or ASC-J9®, may be developed to increase the efficacy of Enz to further suppress DocRPC in patients.
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PURPOSE: We assessed the safety and efficacy of cabozantinib and nivolumab (CaboNivo) and CaboNivo plus ipilimumab (CaboNivoIpi) in patients with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignances. PATIENTS AND METHODS: Patients received escalating doses of CaboNivo or CaboNivoIpi. The primary objective was to establish a recommended phase II dose (RP2D). Secondary objectives included objective response rate (ORR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS). RESULTS: Fifty-four patients were enrolled at eight dose levels with a median follow-up time of 44.6 months; data cutoff was January 20, 2020. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 75% and 87% of patients treated with CaboNivo and CaboNivoIpi, respectively, and included fatigue (17% and 10%, respectively), diarrhea (4% and 7%, respectively), and hypertension (21% and 10%, respectively); grade 3 or 4 immune-related AEs included hepatitis (0% and 13%, respectively) and colitis (0% and 7%, respectively). The RP2D was cabozantinib 40 mg/d plus nivolumab 3 mg/kg for CaboNivo and cabozantinib 40 mg/d, nivolumab 3 mg/kg, and ipilimumab 1 mg/kg for CaboNivoIpi. ORR was 30.6% (95% CI, 20.0% to 47.5%) for all patients and 38.5% (95% CI, 13.9% to 68.4%) for patients with mUC. Median DoR was 21.0 months (95% CI, 5.4 to 24.1 months) for all patients and not reached for patients with mUC. Median PFS was 5.1 months (95% CI, 3.5 to 6.9 months) for all patients and 12.8 months (95% CI, 1.8 to 24.1 months) for patients with mUC. Median OS was 12.6 months (95% CI, 6.9 to 18.8 months) for all patients and 25.4 months (95% CI, 5.7 to 41.6 months) for patients with mUC. CONCLUSION: CaboNivo and CaboNivoIpi demonstrated manageable toxicities with durable responses and encouraging survival in patients with mUC and other GU tumors. Multiple phase II and III trials are ongoing for these combinations.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Neoplasias Urogenitales/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anilidas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígeno B7-H1/metabolismo , Carcinoma de Células Transicionales/secundario , Colitis/inducido químicamente , Diarrea/inducido químicamente , Molécula de Adhesión Celular Epitelial/metabolismo , Fatiga/inducido químicamente , Femenino , Hepatitis/etiología , Humanos , Hipertensión/inducido químicamente , Ipilimumab/administración & dosificación , Masculino , Persona de Mediana Edad , Células Neoplásicas Circulantes/metabolismo , Nivolumab/administración & dosificación , Supervivencia sin Progresión , Proteínas Proto-Oncogénicas c-met/metabolismo , Piridinas/administración & dosificación , Receptores CXCR4/metabolismo , Criterios de Evaluación de Respuesta en Tumores Sólidos , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: Cabozantinib is a multikinase inhibitor of MET, VEGFR, AXL, and RET, which also has an effect on the tumour immune microenvironment by decreasing regulatory T cells and myeloid-derived suppressor cells. In this study, we examined the activity of cabozantinib in patients with metastatic platinum-refractory urothelial carcinoma. METHODS: This study was an open-label, single-arm, three-cohort phase 2 trial done at the National Cancer Institute (Bethesda, MD, USA). Eligible patients were 18 years or older, had histologically confirmed urothelial carcinoma or rare genitourinary tract histologies, Karnofsky performance scale index of 60% or higher, and documented disease progression after at least one previous line of platinum-based chemotherapy (platinum-refractory). Cohort one included patients with metastatic urothelial carcinoma with measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Two additional cohorts that enrolled in parallel (patients with bone-only urothelial carcinoma metastases and patients with rare histologies of the genitourinary tract) were exploratory. Patients received cabozantinib 60 mg orally once daily in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate by RECIST in cohort one. Response was assessed in all patients who met the eligibility criteria and who received at least 8 weeks of therapy. All patients who received at least one dose of cabozantinib were included in the safety analysis. This completed study is registered with ClinicalTrials.gov, NCT01688999. FINDINGS: Between Sept 28, 2012, and Oct, 20, 2015, 68 patients were enrolled on the study (49 in cohort one, six in cohort two, and 13 in cohort three). All patients received at least one dose of cabozantinib. The median follow-up was 61·2 months (IQR 53·8-70·0) for the 57 patients evaluable for response. In the 42 evaluable patients in cohort one, there was one complete response and seven partial responses (objective response rate 19%, 95% CI 9-34). The most common grade 3-4 adverse events were fatigue (six [9%] patients), hypertension (five [7%]), proteinuria (four [6%]), and hypophosphataemia (four [6%]). There were no treatment-related deaths. INTERPRETATION: Cabozantinib has single-agent clinical activity in patients with heavily pretreated, platinum-refractory metastatic urothelial carcinoma with measurable disease and bone metastases and is generally well tolerated. Cabozantinib has innate and adaptive immunomodulatory properties providing a rationale for combining cabozantinib with immunotherapeutic strategies. FUNDING: National Cancer Institute Intramural Program and the Cancer Therapy Evaluation Program.
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Anilidas/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Piridinas/uso terapéutico , Neoplasias Urológicas/tratamiento farmacológico , Adulto , Anciano , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Compuestos de Platino/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Important advances in the understanding of the biology and mechanisms of tumor progression of urothelial carcinoma (UC) have been achieved over the past decade. The treatment landscape for advanced-stage, unresectable or metastatic UC has shifted dramatically over a short period of time, with 6 new therapeutic agents available for clinical use. The use of traditional chemotherapy and new immune checkpoints inhibitors (ICIs) directed at programmed cell-death protein 1 (PD-1) or its ligand has led to unprecedented survival benefits in selected patients with metastatic UC. Data show that anti-PD-1 ICIs are not only improving long-term clinical benefit, but also quality of life for patients in the second-line setting. In the front-line setting, regulatory agencies have restricted the indications of atezolizumab and pembrolizumab (both ICIs) to patients with PD-L1positivity with advanced UC and who are platinum-ineligible. Very recently, erdafitinib, a pan-FGFR inhibitor, has been granted accelerated approval by FDA for platinum-pretreated advanced metastatic UC with susceptible FGFR3 or FGFR2 genetic alterations. Enfortumab vedotin, an antibody-drug conjugate, have been granted breakthrough designation by the FDA for the treatment of metastatic UC. Here we review the clinical trial data that have established standard-of-care treatment for advanced-stage UC. In addition, mechanisms of resistance and biomarkers of response to platinum-based chemotherapies and immunotherapies are also discussed, along with the clinical benefits and limitations of these therapies.
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Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Antineoplásicos Inmunológicos/uso terapéutico , Humanos , Terapia Molecular Dirigida , Metástasis de la Neoplasia , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/inmunología , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
OPINION STATEMENT: Muscle-invasive bladder cancer (MIBC) has high metastatic potential at diagnosis but is still often curable with aggressive management, which may give patients the best odds for a favorable clinical outcome. The standard-of-care management of MIBC includes a radical cystectomy and pelvic lymph node dissection. If the patient is cisplatin-eligible, neoadjuvant cisplatin-based combination chemotherapy should also be given. Post-surgery adjuvant treatments include observation, chemotherapy, radiation, or enrollment in a clinical trial. Several adjuvant immunotherapy trials with checkpoint inhibitors, which block the interaction between PD-1 and PD-L1, as monotherapy or in combinations with chemotherapy, radiation, or other immunotherapy agents are currently ongoing. Given the lack of level 1 evidence for the survival benefit of adjuvant therapies post-cystectomy, the standard of care remains observation with radiologic and clinical surveillance. However, in patients who did not receive neoadjuvant cisplatin-based combination chemotherapy and are cisplatin-eligible, adjuvant cisplatin-based chemotherapy should be considered and discussed. Genomic alterations and gene expression profiles may eventually help to identify patient subgroups for more effective adjuvant therapy. Genetic abnormalities in the DNA repair genes and basal intrinsic tumor subtype appear to predict response to neoadjuvant cisplatin-based chemotherapy in MIBC. In the coming years, validating these genetic markers will be key to individualizing perioperative chemotherapy.
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Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/terapia , Animales , Ensayos Clínicos como Asunto , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Manejo de la Enfermedad , Humanos , Terapia Neoadyuvante , Invasividad Neoplásica , Estadificación de Neoplasias , Proyectos de Investigación , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/mortalidadAsunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Neoplasias Urológicas/tratamiento farmacológico , Urotelio/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Humanos , Metástasis de la Neoplasia , Neoplasias Urológicas/epidemiología , Urotelio/efectos de los fármacos , RamucirumabRESUMEN
BACKGROUND: There are no validated clinical decision tools to aid optimal treatment selection in men with metastatic castration-resistant prostate cancer (mCRPC). Frequently, abiraterone and enzalutamide are used prior to chemotherapy in mCRPC, given the more favorable safety profiles. However, there is no published data on clinical outcomes regarding best sequencing of these two agents. METHODS: A retrospective analysis of consecutive mCRPC patients treated with enzalutamide and abiraterone at Johns Hopkins was conducted. Patients were treated with sequential enzalutamide and abiraterone, in either order. The combined progression-free survival (PFS: PFS1 + PFS2) of abiraterone-to-enzalutamide was compared to the reverse sequence, where PFS1 and PFS2 represented clinical/radiographic progression-free survival on the first and second agents, respectively. Overall survival (OS) from the start of the first therapy to death and PSA response rates (defined as ≥50% PSA declines at any time) were also compared between groups. Outcomes were adjusted using propensity score-weighted multivariable Cox analyses. RESULTS: Eighty-one patients who satisfied our entry criteria were identified: 65 in the abiraterone-to-enzalutamide group and 16 in the enzalutamide-to-abiraterone group. There were no significant baseline differences between groups. Multivariable analysis suggested a difference between groups favoring the abiraterone-to-enzalutamide sequence with respect to combined PFS (HR 0.37, 95%CI 0.22-0.64, P < 0.001). There was no statistical difference in OS between the groups after multivariable adjustment (HR 0.57, 95%CI 0.29-1.11, P = 0.098), although OS was numerically superior in the abiraterone-to-enzalutamide group. CONCLUSIONS: We observed differences suggesting improved outcomes favoring the abiraterone-to-enzalutamide sequence in men with mCRPC, with statistical confirmation in terms of PFS but not OS. Prospective studies are required to verify these hypothesis-generating findings. Further evaluation of biomarkers to inform optimal treatment sequencing in men with mCRPC is urgently needed. Prostate 77:33-40, 2017. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Androstenos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Benzamidas , Esquema de Medicación , Humanos , Masculino , Persona de Mediana Edad , Nitrilos , Feniltiohidantoína/administración & dosificación , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: We have previously documented a paradoxical anti-tumor effect when castration-resistant prostate cancer patients were treated with intermittent, high-dose testosterone (i.e., Bipolar Androgen Therapy; BAT). Because, an adaptive increase in androgen receptor expression following chronic androgen deprivation therapy (ADT) may underlie this effect, we tested whether men with hormone-sensitive (HS) prostate cancer (PC) would also respond to BAT if given following a 6-month ADT lead-in. METHODS: Asymptomatic HS PC patients with low metastatic burden or non-metastatic biochemically recurrent disease were enrolled. Following 6-month of ADT, those with a PSA <4 ng/ml went on to receive alternating 3-month cycles of BAT and ADT. BAT was administered as intramuscular testosterone (T) cypionate or enanthate 400 mg on Days (D) 1, 29, and 57. ADT was continued throughout the study to allow rapid cycling from near castrate to supraphysiologic range T following T injections. The primary endpoint was the percent of patients with a PSA <4 ng/ml after 18 months. Secondary endpoints included radiographic response and quality of life (QoL). RESULTS: Twenty-nine of 33 patients received BAT following the ADT lead-in. The primary endpoint was met, with 17/29 men (59%, 90% confidence interval: 42-74%) having a PSA <4 ng/ml at 18 months. Ten patients receiving BAT had RECIST evaluable disease, and eight (80%) objective responses were observed (four complete; four partial). Three patients progressed per RECIST criteria and three had unconfirmed progression on bone scan. Men treated with 6-month of ADT had improved QoL following the first cycle of BAT as measured by the SF-36, FACT-P, and IIEF surveys. CONCLUSIONS: BAT demonstrated preliminary efficacy in men with HS PC following 6-month of ADT. BAT may improve QoL in men treated with ADT. Prostate 76:1218-1226, 2016. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Antagonistas de Andrógenos/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Testosterona/uso terapéutico , Anciano , Humanos , Masculino , Persona de Mediana Edad , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/sangre , Calidad de VidaRESUMEN
PURPOSE: Current standard of care conventional imaging modalities (CIM) such as X-ray computed tomography (CT) and bone scan can be limited for detection of metastatic prostate cancer and therefore improved imaging methods are an unmet clinical need. We evaluated the utility of a novel second-generation low molecular weight radiofluorinated prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) radiotracer, [(18)F]DCFPyL, in patients with metastatic prostate cancer. PROCEDURES: Nine patients with suspected prostate cancer recurrence, eight with CIM evidence of metastatic prostate cancer and one with biochemical recurrence, were imaged with [(18)F]DCFPyL PET/CT. Eight of the patients had contemporaneous CIM for comparison. A lesion-by-lesion comparison of the detection of suspected sites of metastatic prostate cancer was carried out between PET and CIM. Statistical analysis for estimated proportions of inter-modality agreement for detection of metastatic disease was calculated accounting for intra-patient correlation using general estimating equation (GEE) intercept-only regression models. RESULTS: One hundred thirty-nine sites of PET positive [(18)F]DCFPyL uptake (138 definite, 1 equivocal) for metastatic disease were detected in the eight patients with available comparison CIM. By contrast, only 45 lesions were identified on CIM (30 definite, 15 equivocal). When lesions were negative or equivocal on CIM, it was estimated that a large portion of these lesions or 0.72 (95 % confidence interval (CI) 0.55-0.84) would be positive on [(18)F]DCFPyL PET. Conversely, of those lesions negative or equivocal on [(18)F]DCFPyL PET, it was estimated that only a very small proportion or 0.03 (95 % CI 0.01-0.07) would be positive on CIM. Delayed 2-h-post-injection time point PET yielded higher tumor radiotracer uptake and higher tumor-to-background ratios than an earlier 1-h-post-injection time point. CONCLUSIONS: A novel PSMA-targeted PET radiotracer, [(18)F]DCFPyL, was able to a large number of suspected sites of prostate cancer, many of which were occult or equivocal by CIM. This study provides strong preliminary evidence for the use of this second-generation PSMA-targeted PET radiotracer for detection of metastatic prostate cancer and lends further support for the importance of PSMA-targeted PET imaging in prostate cancer.