RESUMO
Abiraterone acetate (AA) serves as a medication for managing persistent testosterone production in patients with metastatic castration-resistant prostate cancer (mCRPC). However, its efficacy varies among individuals; thus, the identification of biomarkers to predict and follow treatment response is required. In this pilot study, we explored the potential of circulating microRNAs (c-miRNAs) to stratify patients based on their responsiveness to AA. We conducted an analysis of plasma samples obtained from a cohort of 33 mCRPC patients before and after three, six, and nine months of AA treatment. Using miRNA RT-qPCR panels for candidate discovery and TaqMan RT-qPCR for validation, we identified promising miRNA signatures. Our investigation indicated that a signature based on miR-103a-3p and miR-378a-5p effectively discriminates between non-responder and responder patients, while also following the drug's efficacy over time. Additionally, through in silico analysis, we identified target genes and transcription factors of the two miRNAs, including PTEN and HOXB13, which are known to play roles in AA resistance in mCRPC. In summary, our study highlights two c-miRNAs as potential companion diagnostics of AA in mCRPC patients, offering novel insights for informed decision-making in the treatment of mCRPC.
Assuntos
Acetato de Abiraterona , Biomarcadores Tumorais , MicroRNAs , Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Acetato de Abiraterona/uso terapêutico , Projetos Piloto , Idoso , MicroRNAs/sangue , MicroRNAs/genética , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Pessoa de Meia-Idade , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , PTEN Fosfo-Hidrolase/genética , MicroRNA Circulante/sangue , Metástase Neoplásica , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/sangue , Idoso de 80 Anos ou maisRESUMO
PURPOSE: This post hoc analysis of PROSPER evaluated the relationship between depth of PSA decline and clinical outcomes in enzalutamide-treated men with nonmetastatic castration-resistant prostate cancer. MATERIALS AND METHODS: PROSPER was an international, randomized, double-blind, placebo-controlled, phase 3 trial that demonstrated significantly improved metastasis-free survival and overall survival with androgen deprivation therapy plus enzalutamide vs placebo. A total of 905 enzalutamide-treated men were included in this post hoc analysis. Metastasis-free survival (primary endpoint) and overall survival (secondary endpoint) were evaluated for 4 mutually exclusive subgroups defined by PSA decline: <50% (reference); ≥50% to <90%; ≥90%, nadir ≥0.2 ng/mL; and ≥90%, nadir <0.2 ng/mL. Medians and 95% confidence intervals were determined using a 12-month landmark analysis; hazard ratios and P values were based on an unstratified Cox proportional analysis model. RESULTS: In enzalutamide-treated men, PSA declines of <50%, ≥50% to <90%, ≥90% with nadir ≥0.2 ng/mL, and ≥90% with nadir <0.2 ng/mL were associated with median metastasis-free survival in months (95% confidence intervals) of 22.1 (14.8-not reached), 34.2 (29.4-not reached), 36.6 (33.4-not reached), and not reached, respectively, and overall survival in months (95% confidence intervals) of 40.8 (31.7-44.9), 54.4 (49.0-67.0), 64.3 (63.4-not reached), and not reached, respectively. CONCLUSIONS: There was a statistically significant correlation between greater depth of PSA decline and improved clinical outcomes, suggesting a previously underappreciated relationship between changes in PSA levels and clinical outcomes in nonmetastatic castration-resistant prostate cancer.
Assuntos
Antineoplásicos , Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Antagonistas de Androgênios/uso terapêutico , Antineoplásicos/uso terapêutico , Nitrilas/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/patologia , Resultado do TratamentoRESUMO
INTRODUCTION: Apalutamide is an oral selective androgen receptor inhibitor, approved by the FDA for the treatment of patients with non-metastatic, castration-resistant prostate cancer (M0 CRPC) at high risk of developing metastases and for patients with metastatic castration-sensitive prostate (mHSPC) in association with androgen deprivation therapy (ADT). In the registration studies, skin reactions were reported among the most common side effects and as an adverse event of special interest. CASE REPORT: Apalutamide-induced rash includes a wide spectrum of different types of skin reactions, but few cases reports and case series have described this adverse event. Here, we report an M0 CRPC patient who experienced a rare skin adverse event, a lichenoid reaction. MANAGEMENT & OUTCOME: After 4 months of therapy with apalutamide, the patient reported dorsal pricking and dry skin. Lichenoid reaction was confirmed histologically and its correlation to the drug was demonstrated after pursuing a multidisciplinary approach. DISCUSSION: To our knowledge, this is one of the first cases of Apalutamide-related lichenoid reaction and this clinical case showed the relevance of a multidisciplinary management when assessing drug-related adverse events. A broader knowledge of the spectrum of drug-related reactions would allow for a better diagnosis and therapy management by both physicians and patients.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Antagonistas de Androgênios/uso terapêutico , Tioidantoínas , Antagonistas de Receptores de Andrógenos/efeitos adversosRESUMO
OBJECTIVES: The management of non-metastatic castration-resistant prostate cancer (nmCRPC) is rapidly evolving; however, little is known about the direct healthcare costs of nmCRPC. We aimed to estimate the cost-of-illness (COI) of nmCRPC from the Italian National Health Service perspective. METHODS: Structured, individual qualitative interviews were carried out with clinical experts to identify what healthcare resources are consumed in clinical practice. To collect quantitative estimates of healthcare resource consumption, a structured expert elicitation was performed with clinical experts using a modified version of a previously validated interactive Excel-based tool, EXPLICIT (EXPert eLICItation Tool). For each parameter, experts were asked to provide the lowest, highest, and most likely value. Deterministic and probabilistic sensitivity analyses (PSA) were carried out to test the robustness of the results. RESULTS: Ten clinical experts were interviewed, and six of them participated in the expert elicitation exercise. According to the most likely estimate, the yearly cost per nmCRPC patient is 4,710 (range, 2,243 to 8,243). Diagnostic imaging (i.e., number/type of PET scans performed) had the highest impact on cost. The PSA showed a 50 percent chance for the yearly cost per nmCRPC patient to be within 5,048 using a triangular distribution for parameters, and similar results were found using a beta-PERT distribution. CONCLUSIONS: This study estimated the direct healthcare costs of nmCRPC in Italy based on a mixed-methods approach. Delaying metastases may be a reasonable goal also from an economic standpoint. These findings can inform decision-making about treatments at the juncture between non-metastatic and metastatic prostate cancer disease.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/patologia , Antígeno Prostático Específico , Medicina Estatal , Custos de Cuidados de Saúde , Efeitos Psicossociais da DoençaRESUMO
BACKGROUND: We sought to assess the prognostic utility of 11C-choline positron emission tomography/computed tomography (PET/CT) in patients with metastatic castrate resistant prostate cancer (mCRPC) undergoing primary docetaxel chemotherapy. METHODS: We performed a single institution retrospective analysis of 77 mCRPC patients who were treated with 6 cycles of docetaxel chemotherapy, and who also underwent 11C-choline PET/CT scans at baseline (before chemotherapy), mid-course (after 3 cycles), and posttherapy (after 6 cycles). We evaluated treatment response based on percent change in blood pool-corrected maximum standardized uptake value (SUVmax) of the target lesion on PET/CT, as well as percent change in serum prostate specific antigen (PSA). Logistic regression analysis was used to identify factors associated with complete treatment response. Progression free survival (PFS) analysis was performed using log-rank test and shown on Kaplan-Meier plot. RESULTS: Percent change in blood pool-corrected SUVmax on mid-course scan was a significant predictor of complete response (odds ratio [OR]: 0.98, 95% confidence interval [CI]: 0.96-0.99, p = .0003), whereas percent change in PSA was not (OR: 0.99, 95% CI: 0.99-1.01, p = .6025). 57 of 77 patients (74%) achieved ≥20% reduction in blood pool-corrected SUVmax on mid-course; these patients were 3.6 times more likely to achieve complete response after full 6 cycles of docetaxel chemotherapy, compared to patients with <20% reduction in blood pool-corrected SUVmax (OR: 3.56, 95% CI: 1.04-16.52, p = .0420). Median PFS in the complete response group was 35.1 months (95% CI: 26.0-52.7 months), compared to 9.4 months (95% CI: 6.9-13.0 months) in the incomplete response group (p = .0005). CONCLUSIONS: Our study showed that mid-course and posttherapy 11C-choline PET/CT evaluation for mCRPC patients undergoing primary docetaxel chemotherapy can predict full course treatment response and PFS, respectively. 11C-choline PET/CT imaging may provide valuable prognostic information to guide treatment choices for patients with mCRPC.
Assuntos
Radioisótopos de Carbono/farmacologia , Docetaxel , Metástase Neoplásica , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Neoplasias de Próstata Resistentes à Castração , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Docetaxel/administração & dosagem , Docetaxel/efeitos adversos , Monitoramento de Medicamentos/métodos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/diagnóstico , Metástase Neoplásica/terapia , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Intervalo Livre de Progressão , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Compostos Radiofarmacêuticos/farmacologia , Estudos RetrospectivosRESUMO
BACKGROUND: Although prostate cancer is a very common form of malignancy in men, the clinical significance of androgen deprivation therapy (ADT) with abiraterone acetate versus the nonsteroidal antiandrogen bicalutamide has not yet been verified in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC). The present study was designed to initiate this verification in real-world Japanese clinical practice. METHODS: We retrospectively analyzed the records of 312 patients with high-risk mHSPC based on LATITUDE criteria and had received ADT with bicalutamide (n = 212) or abiraterone acetate (n = 100) between September 2015 and December 2020. Bicalutamide was given at 80 mg daily and abiraterone was given at 1000 mg daily as four 250-mg tablets plus prednisolone (5-10 mg daily). Overall survival (OS), cancer-specific survival (CSS), and time to castration-resistant prostate cancer (CRPC) were compared. The prognostic factor for time to CRPC was analyzed by Cox proportional hazard model. RESULTS: Patients in the bicalutamide group were older, and more of them had poor performance status (â§2), than in the abiraterone group. Impaired liver function was noted in 2% of the bicalutamide group and 16% of the abiraterone group (p < 0.001). Median follow-up was 22.5 months for bicalutamide and 17 months for abiraterone (p < 0.001). Two-year OS and CSS for bicalutamide versus abiraterone was 77.8% versus 79.5% (p = 0.793) and 81.1% versus 82.5% (p = 0.698), respectively. Median time to CRPC was significantly longer in the abiraterone group than in the bicalutamide group (NA vs. 13 months, p < 0.001). In multivariate analysis, Gleason score â§9, high alkaline phosphatase, high lactate dehydrogenase, liver metastasis, and bicalutamide were independent prognostic risk factors for time to CRPC. Abiraterone prolonged the time to CRPC in patients with each of these prognostic factors. CONCLUSIONS: Despite limitations regarding the time-dependent bias, ADT with abiraterone acetate significantly prolonged the time to CRPC compared to bicalutamide in patients with high-risk mHSPC. However, further study with longer follow-up is needed.
Assuntos
Acetato de Abiraterona , Anilidas , Neoplasias Hepáticas , Nitrilas , Prednisolona , Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Compostos de Tosil , Acetato de Abiraterona/administração & dosagem , Acetato de Abiraterona/efeitos adversos , Antagonistas de Androgênios/administração & dosagem , Antagonistas de Androgênios/efeitos adversos , Anilidas/administração & dosagem , Anilidas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Pesquisa Comparativa da Efetividade , Humanos , Japão/epidemiologia , Testes de Função Hepática/métodos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Nitrilas/administração & dosagem , Nitrilas/efeitos adversos , Drogas Antiandrogênicas não Esteroides/administração & dosagem , Drogas Antiandrogênicas não Esteroides/efeitos adversos , Prednisolona/administração & dosagem , Prednisolona/efeitos adversos , Prognóstico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/epidemiologia , Neoplasias de Próstata Resistentes à Castração/etiologia , Estudos Retrospectivos , Medição de Risco/métodos , Compostos de Tosil/administração & dosagem , Compostos de Tosil/efeitos adversosRESUMO
BACKGROUND: Gene expression in circulating tumor cells (CTCs) can be used as a predictive liquid biopsy test in metastatic castration-resistant prostate cancer (mCRPC). We developed a novel 6-plex reverse transcription droplet digital PCR (RT-ddPCR) assay for the absolute quantification of 4 prostate cancer biomarkers, a reference gene, and a synthetic DNA external control (DNA-EC) in CTCs isolated from mCRPC patients. METHODS: A novel 6-plex RT-ddPCR assay was developed for the simultaneous absolute quantification of AR-FL, AR-V7, PSA, and PSMA, HPRT (used as a reference gene), and a synthetic DNA-EC that was included for quality control. The assay was optimized and analytically validated using DNA synthetic standards for each transcript as positive controls. Epithelial cellular adhesion molecule (EpCAM)-positive CTC fractions isolated from 90 mCRPC patients and 11 healthy male donors were analyzed, and results were directly compared with reverse transcription quantitative PCR (RT-qPCR) for all markers in all samples. RESULTS: Linear dynamic range, limit of detection, limit of quantification, intra- and interassay precision, and analytical specificity were determined for each marker. Application of the assay in EpCAM-positive CTC showed positivity for AR-FL (71/90; 78.9%), AR-V7 (28/90; 31.1%), PSA (41/90; 45.6%), PSMA (38/90; 42.2%), and HPRT (90/90; 100%); DNA-EC concentration was constant across all samples. Direct comparison with RT-qPCR for the same markers in the same samples revealed RT-ddPCR to have superior diagnostic sensitivity. CONCLUSIONS: Our 6-plex RT-ddPCR assay was highly sensitive, specific, and reproducible, and enabled simultaneous and absolute quantification of 5 gene transcripts in minute amounts of CTC-derived cDNA. Application of this assay in clinical samples gave diagnostic sensitivity and specificity comparable to, or better than, RT-qPCR.
Assuntos
Células Neoplásicas Circulantes , Neoplasias de Próstata Resistentes à Castração , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , DNA Complementar , Molécula de Adesão da Célula Epitelial/genética , Humanos , Hipoxantina Fosforribosiltransferase/genética , Hipoxantina Fosforribosiltransferase/metabolismo , Masculino , Células Neoplásicas Circulantes/patologia , Reação em Cadeia da Polimerase , Próstata/metabolismo , Próstata/patologia , Antígeno Prostático Específico/genética , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Isoformas de Proteínas , Receptores Androgênicos/genética , Transcrição ReversaRESUMO
PURPOSE: Evaluate the percentage of patients with prostate cancer treated with luteinizing hormone-releasing hormone analogues (LHRHa) that develop castration resistance after a follow-up period of 3 years. The secondary objective is to evaluate the variables potentially related to the progression to castration resistant prostate cancer (CRPC). METHODS: A post-authorization, nation-wide, multicenter, prospective, observational, and longitudinal study that included 416 patients treated with LHRHa between 2012 and 2017 is presented. Patients were followed for 3 years or until development of CRPC, thus completing a per-protocol population of 350 patients. A Cox regression analysis was carried out to evaluate factors involved in progression to CRPC. RESULTS: After 3 years of treatment with LHRHa 18.2% of patients developed CRPC. In contrast, in the subgroup analysis, 39.6% of the metastatic patients developed CRPC, compared with 8.8% of the non-metastatic patients. The patients with the highest risk of developing CRPC were those with a nadir prostate-specific antigen (PSA) > 2 ng/ml (HR 21.6; 95% CI 11.7-39.8; p < 0.001) and those receiving concomitant medication, most commonly bicalutamide (HR 1.8; 95% CI 1-3.1, p = 0.0431). CONCLUSIONS: The proportion of metastatic patients developing CRPC after 3 years of treatment with LHRHa is consistent with what has been previously described in the literature. In addition, this study provides new findings on CRPC in non-metastatic patients. Concomitant medication and nadir PSA are statistically significant predictive factors for the time to diagnosis of CRPC, the nadir PSA being the strongest predictor.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Antagonistas de Androgênios/uso terapêutico , Castração , Hormônio Liberador de Gonadotropina , Humanos , Estudos Longitudinais , Masculino , Estudos Prospectivos , Antígeno Prostático Específico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológicoRESUMO
INTRODUCTION: Current therapeutic developments in prostate cancer (PCa) tend to increasingly personalize the treatment strategy, in particular as a function of tumor genomics. Recently, poly ADP-ribose polymerase (PARPi) inhibitors have shown their efficacy at the stage of castration resistance, in case of alteration of DNA repair genes in tumor tissue. MATERIAL AND METHODS: A narrative review was carried out on recent data in the literature since 2000. A consensus among the members of the Committee was obtained in order to synthesize the current data, with a particular focus on the practical considerations regarding indications and developments of molecular testing circuits concerning DNA repair genes, for theranostics purpose. RESULTS: The establishment of an efficient molecular testing network is based on the multidisciplinary organization of the various actors and the coordination of all material resources. Its goal is the routine search for somatic mutations (in tumor tissue) of BRCA1/2 genes in patients who may benefit from PARPi. The current indications are for BRCA1 or 2 mutated castration-resistant metastatic PCa after next-generation hormone therapy failure. The demand for molecular testing must be decided in the tumor board, giving priority to archived tissue less than 10 years old. In case of unsuccess, biopsies of the primary or metastases, or even analysis of circulating tumor DNA, may be necessary. Any demand for a genetic test on tumor tissue must be accompanied by detailed information for the patient on the possible familial consequences, in case of associated germline mutation. CONCLUSION: This article aims to guide the practical implementation of molecular testing circuits for DNA repair genes alterations, in order to guide the therapeutic management of patients with advanced PCa.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Urologia , Criança , Reparo do DNA/genética , Testes Genéticos , Genômica , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genéticaRESUMO
BACKGROUND: The most common site of disease in metastatic castration-resistant prostate cancer (mCRPC) is the bone. The ALSYMPCA study demonstrated that radium-223 significantly improved overall survival (OS) in mCRPC patients with symptomatic bone metastases and without visceral metastases. However, administration requires a multidisciplinary approach and an infrastructure that supports coordination of care, which may differ by practice site. We aimed to evaluate practice patterns and treatment outcomes in patients with mCRPC treated at a community practice (CP) compared with those treated at an academic center (AC). METHODS: This retrospective review included 200 adult mCRPC patients receiving radium-223 between January 2014 and June 2017. The primary endpoint, OS, was estimated from the date of radium-223 initiation. Secondary outcomes included a comparison of baseline characteristics, reasons for initiation and discontinuation of radium-223, and treatment sequencing. A subset analysis of OS based on the number of radium-223 doses and on sequencing of radium-223 either before or after chemotherapy was also conducted. RESULTS: Most patients were treated at a CP (57%). Patients treated at CP sites were significantly older (74.9 vs. 71.9 years; p = .031) and had more comorbidities (Klabunde score 1.1 vs. 0.7; p = .020) than those in an AC but initiated treatment within a shorter period of time from diagnosis of mCRPC (1.3 vs. 1.9 years; p < .001) and received a greater mean number of radium-223 doses (5.4 vs. 4.8; p = .001). There were no observed differences in OS between CPs versus ACs (21.6 vs. 20.7 months; p = .306). Overall, patients who received 5-6 doses versus 1-4 doses of radium-223 had a longer median OS (23.3 vs. 6.4 months; p < .001). The most common reason for discontinuation in patients who did not complete treatment was disease progression. Overall, 43% of patients received radium-223 monotherapy and 57% concurrently with other agents. CONCLUSIONS: Most patients received radium-223 concurrently with abiraterone acetate or enzalutamide and were able to complete 5-6 doses of radium-223. Despite differences in the populations and treatment patterns, no survival differences between patients treated in ACs versus CPs were observed. Additional real-world data are needed to validate these findings.
Assuntos
Centros Médicos Acadêmicos/métodos , Neoplasias Ósseas/radioterapia , Serviços de Saúde Comunitária/métodos , Gerenciamento Clínico , Neoplasias de Próstata Resistentes à Castração/radioterapia , Rádio (Elemento)/uso terapêutico , Centros Médicos Acadêmicos/tendências , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/secundário , Serviços de Saúde Comunitária/tendências , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Resultado do TratamentoRESUMO
PURPOSE: Radiation refractory prostate cancer (RRPCa) is common and salvage cryotherapy for RRPCa is emerging as a viable local treatment option. However, there is a paucity of long-term data. The purpose of this study is to determine long-term outcomes following salvage cryotherapy for RRPca. MATERIALS AND METHODS: Patients undergoing salvage cryotherapy for biopsy-proven, localized RRPCa from 1992 through 2004 were prospectively accrued at two centers. Preoperative characteristics, perioperative morbidity and postoperative data were reviewed from our database. The primary outcomes were overall survival (OS) and disease-specific survival (DSS). The secondary outcomes were freedom from castration-resistant prostate cancer (CRPC) and freedom from androgen deprivation therapy (ADT). RESULTS: A total of 268 patients were identified with a median followup of 10.3 years. A total of 223 complication events were recorded; of them, 168 were Clavien I-II events and 55 Clavien III events. At 10 years, 69% had freedom from ADT and 76% had freedom from CRPC. The 10-year DSS rate was 81%, and the 10-year OS rate was 77%. A pre-salvage prostate specific antigen level of >10 ng/ml was associated with an increased risk of developing CRPC and initiation of ADT but was not associated with DSS or OS. The use of neoadjuvant ADT was associated with improved OS and DSS but did not affect freedom from CRPC or adjuvant ADT. CONCLUSIONS: Salvage cryotherapy for RRPCa provides excellent long-term freedom from ADT, CRPC and DSS with acceptable morbidity. OS at 10 years was 77%. Prospective trials are required for validation.
Assuntos
Criocirurgia/efeitos adversos , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/terapia , Complicações Pós-Operatórias/epidemiologia , Neoplasias de Próstata Resistentes à Castração/terapia , Terapia de Salvação/efeitos adversos , Idoso , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Quimioterapia Adjuvante/estatística & dados numéricos , Seguimentos , Humanos , Calicreínas/sangue , Masculino , Terapia Neoadjuvante/estatística & dados numéricos , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/mortalidade , Complicações Pós-Operatórias/etiologia , Estudos Prospectivos , Próstata/patologia , Próstata/efeitos da radiação , Próstata/cirurgia , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/mortalidade , Tolerância a Radiação , Radioterapia Adjuvante/estatística & dados numéricos , Estudos Retrospectivos , Terapia de Salvação/métodos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: The summary presented herein represents Part II of the two-part series dedicated to Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline discussing prognostic and treatment recommendations for patients with castration-resistant disease. Please refer to Part I for discussion of the management of patients with biochemical recurrence without metastatic disease after exhaustion of local treatment options as well as those with metastatic hormone-sensitive prostate cancer. RESULTS: The Advanced Prostate Cancer Panel created evidence- and consensus-based guideline statements to aid clinicians in the management of patients with advanced prostate cancer. Such statements are summarized in figure 1[Figure: see text] and detailed herein. MATERIALS AND METHODS: The systematic review utilized to inform this guideline was conducted by an independent methodological consultant. A research librarian conducted searches in Ovid MEDLINE (1998 to January Week 5 2019), Cochrane Central Register of Controlled Trials (through December 2018), and Cochrane Database of Systematic Reviews (2005 through February 6, 2019). An updated search was conducted prior to publication through January 20, 2020. The methodology team supplemented searches of electronic databases with the studies included in the prior AUA review and by reviewing reference lists of relevant articles. CONCLUSIONS: This guideline attempts to improve a clinician's ability to treat patients diagnosed with advanced prostate cancer. Continued research and publication of high-quality evidence from future trials will be essential to improve the level of care for these patients.
Assuntos
Oncologia/normas , Osteoporose/prevenção & controle , Fraturas por Osteoporose/prevenção & controle , Neoplasias de Próstata Resistentes à Castração/terapia , Urologia/normas , Técnicas de Ablação/métodos , Técnicas de Ablação/normas , Antagonistas de Androgênios/administração & dosagem , Antagonistas de Androgênios/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Quimioterapia Adjuvante/normas , Consenso , Medicina Baseada em Evidências/métodos , Medicina Baseada em Evidências/normas , Humanos , Masculino , Oncologia/métodos , Gradação de Tumores , Estadiamento de Neoplasias , Osteoporose/diagnóstico , Osteoporose/etiologia , Fraturas por Osteoporose/etiologia , Prognóstico , Prostatectomia/normas , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Radioterapia Adjuvante/efeitos adversos , Radioterapia Adjuvante/métodos , Radioterapia Adjuvante/normas , Sociedades Médicas/normas , Resultado do Tratamento , Estados Unidos/epidemiologia , Urologia/métodosRESUMO
BACKGROUND: The neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and circulating tumor cells (CTCs) have been associated with survival in castration-resistant prostate cancer (CRPC). However, no study has examined the prognostic value of NLR and PLR in the context of CTCs. METHODS: Baseline CTCs from mCRPC patients were enumerated using the CellSearch System. Baseline NLR and PLR values were calculated using the data from routine complete blood counts. The associations of CTC, NLR, and PLR values, individually and jointly, with progression-free survival (PFS) and overall survival (OS), were evaluated using Kaplan-Meier analysis, as well as univariate and multivariate Cox models. RESULTS: CTCs were detected in 37 (58.7%) of 63 mCRPC patients, and among them, 16 (25.4%) had ≥5 CTCs. The presence of CTCs was significantly associated with a 4.02-fold increased risk for progression and a 3.72-fold increased risk of death during a median follow-up of 17.6 months. OS was shorter among patients with high levels of NLR or PLR than those with low levels (log-rank P = 0.023 and 0.077). Neither NLR nor PLR was individually associated with PFS. Among the 37 patients with detectable CTCs, those with a high NLR had significantly shorter OS (log-rank P = 0.024); however, among the 26 patients without CTCs, the OS difference between high- and low-NLR groups was not statistically significant. Compared to the patients with CTCs and low NLR, those with CTCs and high levels of NLR had a 3.79-fold risk of death (P = 0.036). This association remained significant after adjusting for covariates (P = 0.031). Combination analyses of CTC and PLR did not yield significant results. CONCLUSION: Among patients with detectable CTCs, the use of NLR could further classify patients into different risk groups, suggesting a complementary role for NLR in CTC-based prognostic stratification in mCRPC.
Assuntos
Linfócitos/imunologia , Células Neoplásicas Circulantes/patologia , Neutrófilos/imunologia , Neoplasias de Próstata Resistentes à Castração/mortalidade , Idoso , Idoso de 80 Anos ou mais , Plaquetas , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Prognóstico , Intervalo Livre de Progressão , Estudos Prospectivos , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Retrospectivos , Medição de Risco/estatística & dados numéricosRESUMO
BACKGROUND: The purpose of this retrospective study was to evaluate the survival outcomes of pembrolizumab (PEM) plus enzalutamide (ENZ) versus PEM alone in selected populations of men with previously untreated metastatic castration-resistant prostate cancer (mCRPC) harbouring programmed cell death ligand-1 (PD-L1) staining. METHODS: Consecutive men with previously untreated mCRPC harbouring PD-L1 staining who underwent treatment with PEM plus ENZ (PE) or PEM alone (PA) at our medical centre from January 1, 2017, to January 31, 2021, were retrospectively identified. Follow-up was conducted monthly during the first year and then every 1 month thereafter. The primary outcomes of the study were overall survival (OS) and progression-free survival (PFS). Secondary outcomes were the frequency of key adverse events (AEs). RESULTS: In total, 302 men were retrospectively reviewed, 96 of whom were deemed to be ineligible per the exclusion criteria, leaving 206 men (PE: n = 100, median age 64 years [range, 43-85] and PA: n = 106, 65 years [range, 45-82]) who were eligible for the study. The median follow-up for both groups was 34 months (range, 2-42). At the final follow-up, the median OS was 25.1 months (95% confidence interval [CI], 22.3-27.6) in the PE group versus 18.3 months (95% CI, 16.5-20.9) in the PA group (hazard ratio [HR] 0.56; 95% CI, 0.39-0.80; p = 0.001). A marked distinction was also observed in the median PFS (6.1 months [95% CI, 4.7-7.8] for PE vs. 4.9 months for PA (95% CI, 3.2-6.4) for PA; HR 0.55, 95% CI, 0.41-0.75; p = 0.001). There were noteworthy differences in the rate of the key AEs between the two groups (72.0% for PE vs. 45.3% for PA, p < 0.001). Noteworthy differences were also detected for fatigue events (7.0% in the PE group vs. 0.9% in the PA group, p = 0.025) and musculoskeletal events (9.0% for PE vs. 0.9% for PA, p = 0.007), but these events tended to be manageable. CONCLUSIONS: Among selected populations of men with previously untreated mCRPC harbouring PD-L1 staining, PEM added to ENZ treatment may significantly increase the survival benefits compared with PEM treatment alone regardless of tumor mutation status. The safety profile for PE plus ENZ tends to be manageable.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas , Biomarcadores Tumorais , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Estadiamento de Neoplasias , Nitrilas , Feniltioidantoína/administração & dosagem , Feniltioidantoína/análogos & derivados , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/mortalidade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: To assess the efficacies and potential predictors of a corticosteroid switch in metastatic castration-resistant prostate cancer (mCRPC) patients with biochemical progression on abiraterone acetate plus prednisone (A + P). METHODS: Patients with mCRPC treated between April 2016 and August 2020, who experienced biochemical progression on A + P and then switched to A plus dexamethasone (D), were retrospectively identified. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were PSA response, overall survival (OS), and safety. RESULTS: One hundred and thirty consecutive cases were enrolled. The median PFS and OS on A + D were 5.0 and 18.7 months, respectively. The best PSA decline of ≥50% (PSA50) and ≥ 30% (PSA30) were observed in 29.2 and 46.2% patients, respectively. Lower PSA at corticosteroid switch (≤ 20 ng/mL; median PFS, HR 0.63, p = 0.019; median OS, HR 0.38, p = 0.001) and longer mCRPC-free survival (≥ 18 months; median PFS, HR 0.61, p = 0.013; median OS, HR 0.51, p = 0.015) were identified as independent prognostic predictors associated with longer PFS and OS. A risk stratification tool was developed to select candidates for corticosteroid switch based on the independent prognostic predictors of PFS and OS. CONCLUSIONS: A corticosteroid switch from prednisone to dexamethasone is effective for mCRPC which progressed on A + P treatment. Patients with lower PSA at corticosteroid switch and/or longer mCRPC-free survival may gain more benefits by the corticosteroid switch.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Acetato de Abiraterona/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores , Dexametasona/administração & dosagem , Progressão da Doença , Substituição de Medicamentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prognóstico , Modelos de Riscos Proporcionais , Antígeno Prostático Específico/metabolismo , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Resultado do TratamentoRESUMO
Prostate cancer (PCa) is one of the most common cancer types among men and also acommon cause of death globally. With an increasing incidence, there is aneed for low-cost, reliable biomarkers present in samples, which could be provided non-invasively (without a need to perform prostate biopsy). Glycosylation changes of free-PSA (fPSA) are considered cancer-specific, while the level of different PSA forms can increase under other than cancerous conditions. In the present study, we investigated the role ofN,N-diacetyllactosamine (LacdiNAc) epitope of fPSA (i.e. glycoprofile of fPSA or gPSA) in combination with total-PSA (tPSA), prostate volume, and tPSA density (tPSA level divided by prostate volume i.e. PSAd) as biomarkers for monitoring of PCa development and progression in 105 men. Furthermore, we applied an genetic (evolutionary) algorithm to identify any suspicious individuals in abenign cohort having benign prostatic hyperplasia (BPH). We identified 3 suspicious men originally diagnosed with BPH using gPSA analysis. In thefollow-up we found out that two men should not be considered as BPH patients since multiparametric magnetic resonance imaging (mpMRI) identified one man with clinically significant PCa via Prostate Imaging - Reporting and Data System (PI RADS v2 = 4) and the second man was with High-gradeprostatic intraepithelial neoplasia (HG PIN), commonly described as apre-cancerous stage. Moreover, in the study we described for the first time that changed LacdiNAc on PSA can be applied to identify prostatitis patients and most importantly this is the first study suggesting that changed glycosylation on PSA can be applied to identify castration-resistant prostate cancer (CRPCa) patients.
Assuntos
Biomarcadores Tumorais/sangue , Lactose/análogos & derivados , Antígeno Prostático Específico/sangue , Hiperplasia Prostática/diagnóstico , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Idoso , Estudos de Coortes , Diagnóstico Diferencial , Detecção Precoce de Câncer , Ensaio de Imunoadsorção Enzimática , Humanos , Lactose/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
Aim: This qualitative study aimed to reveal symptoms and impacts among bone metastatic castration-resistant prostate cancer (or mCRPC) Japanese patients, prior to Radium-223 (Ra-223) treatment. Materials & Methods: Twenty-three mCRPC patients designated to receive Ra-223 and three treating physicians (Ra-223 prescribers) in Japan, were interviewed. All interview data were assessed for concept frequency, themes and saturation. Results: Forty-five percent of the patients (mean age: 75.8 years) were symptomatic at the time of enrollment. Interviews with all patients revealed 47 mCRPC symptoms, including back pain and bone-specific pain, and 45 life impacts, including worry about disease progression and the impact on daily, physical activities. Conclusion: The symptoms and impacts of living with mCRPC and the associated burden of bone metastasis and skeletal-related symptoms are varied and are important considerations for treatment.
Lay abstract Aim: This study looked at symptoms and impacts among patients with a type of prostate cancer called metastatic castration-resistant prostate cancer. This cancer has spread to other parts of the body including patients' bones. Patients' prostate-specific antigen levels continue to rise despite surgical or medical treatment and their doctors decided the next best treatment is Radium-223 (Ra-223), a radiopharmaceutical therapy. Materials & methods: Twenty-three metastatic castration-resistant prostate cancer patients designated to receive Ra-223 and three treating physicians (Ra-223 prescribers) in Japan, were interviewed. All interview data were assessed for the number of times some words or themes are mentioned by the patients. Results: Ten of the 23 patients (average age of 76 years) had symptoms when the study started. Interviewed patients talked about symptoms including back pain and pain in their bones, and how their cancer caused them to worry about their physical activities and disease progression. Conclusion: The symptoms impact on patients' daily living and the burden of bone metastasis and bone-related symptoms are varied and are important considerations for treatment.
Assuntos
Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/radioterapia , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/radioterapia , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/psicologia , Neoplasias Ósseas/secundário , Efeitos Psicossociais da Doença , Tomada de Decisões , Humanos , Entrevistas como Assunto , Japão , Masculino , Pessoa de Meia-Idade , Médicos , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/psicologia , Pesquisa Qualitativa , Qualidade de Vida , Rádio (Elemento)/uso terapêuticoRESUMO
Aim: To assess the patterns of genetic testing for homologous recombination repair mutations in patients with metastatic castration-resistant prostate cancer (mCRPC) pre-PARP inhibitors approval. Patients & methods: mCRPC patients were selected in an oncology electronic medical records database. Patterns and predictors of testing for ATM, BRCA1/2, CDK12, PALB2 and FANCA gene alterations were assessed. Results: Of 5213 mCRPC patients, 674 (13%) had a documented genetic test. The number of tested patients increased from 1 in 2013 to 313 in 2018 (out of 3161 and 3010 clinically active patients, respectively). Receiving care in an academic oncology center (versus a community-based center) strongly predicted genetic testing (hazard ratio = 2.41). Conclusion: The use of and access to genetic testing pre-PARP inhibitor approval was suboptimal.
Lay abstract In 2017, US guidelines recommended the use of genetic testing in patients with metastatic castration-resistant prostate cancer (mCRPC). While the initial goal of genetic testing was to guide referral to genetic counselling and clinical trial enrollment, it is now also used to identify patients who could benefit from new drugs that target specific molecular defects. Using medical record data of US patients with mCRPC, we found that the rates of genetic testing and the breadth of molecular defects tested were suboptimal from 2013 to 2019. We also found lower rates of genetic testing in patients treated in community-based centers compared with those treated in academic oncology centers. These results underscore the importance of increasing the take up rate of genetic testing in patients with mCRPC to help guide treatment decisions.
Assuntos
Biomarcadores Tumorais/genética , Testes Genéticos/estatística & dados numéricos , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Padrões de Prática Médica/estatística & dados numéricos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Centros Médicos Acadêmicos , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/antagonistas & inibidores , Institutos de Câncer/estatística & dados numéricos , Tomada de Decisão Clínica/métodos , Centros Comunitários de Saúde/estatística & dados numéricos , Reparo do DNA , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Medicina de Precisão/métodos , Medicina de Precisão/estatística & dados numéricos , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologiaRESUMO
Despite recent advances, treatment options for men with metastatic castration-resistant prostate cancer (mCRPC) progressing after next-generation hormonal agents (NHAs) are limited and provide only modest survival benefit. Thus, an unmet need remains for mCRPC patients after treatment with targeted endocrine therapy or NHA therapy. Pembrolizumab, a humanized monoclonal antibody for PD-1, has been found to have activity as monotherapy in patients with mCRPC and as combination therapy in a Phase Ib/II study with docetaxel and prednisone/prednisolone for patients previously treated with enzalutamide or abiraterone acetate. The aim of the randomized, double-blind, Phase III KEYNOTE-921 study is to evaluate the efficacy and safety of pembrolizumab plus docetaxel in patients with mCRPC who were previously treated with an NHA. Clinical trial registration: NCT03834506 (ClinicalTrials.gov).
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Docetaxel/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ensaios Clínicos Fase III como Assunto , Docetaxel/efeitos adversos , Método Duplo-Cego , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Prednisolona/administração & dosagem , Prednisolona/efeitos adversos , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Intervalo Livre de Progressão , Próstata/diagnóstico por imagem , Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Background: Radium 223 (RA223) is currently administered as part of a therapeutic sequence with the other life-prolonging agents (LPAs) for metastatic castration-resistant prostate cancer (mCRPC). Patients & methods: We retrospectively reviewed the clinical records of patients who had received at least three LPAs including RA223. Results: Median overall survival (OS) from the start of first-line treatment was 39.8 months, with the patients who completed all six planned courses of RA223 having a longer OS than those who did not (53.2 vs 29.5 months; p < 0.0001). Conclusions: Our study confirms the activity of RA223 regardless of the treatment line in which it is administered and suggests that patient selection plays a central role in maximizing this activity.