RESUMO
PURPOSE: Despite guidelines recommending bone-modifying agents (BMAs) to decrease skeletal-related events (SREs) in men with metastatic castration-resistant prostate cancer (mCRPC), BMAs are underutilized. In this retrospective cohort study, we report the factors associated with BMA use in a national health care delivery system. METHODS: We used the Veterans Affairs Corporate Data Warehouse to identify men with mCRPC between 2010 and 2017. BMA prescribing frequency was evaluated, and the association between patient- and disease-specific factors with BMA use was assessed using multivariable logistic regression. RESULTS: Among 3,980 men identified with mCRPC (mean age 73.5 years, 29% Black), 47% received a BMA; median time to BMA from start of mCRPC treatment was 102 days. Factors associated with BMA use included previous BMA use (adjusted odds ratio [aOR], 7.81 [95% CI, 6.48 to 9.47]), diagnosis code for bone metastases (aOR, 1.26 [95% CI, 1.08 to 1.46]), and concomitant corticosteroid use (aOR, 1.53 [95% CI, 1.29 to 1.82]). Decreased BMA use was associated with advancing age (aOR, 0.85 per 10 years [95% CI, 0.78 to 0.92]), Charlson comorbidity index ≥2 (aOR, 0.76 [95% CI, 0.63 to 0.93]), Black race (aOR, 0.83 [95% CI, 0.70 to 0.98]), and decreased estimated glomerular filtration rate (eGFR; aOR, 0.19 [95% CI, 0.11 to 0.32] for eGFR 0-29 mL/minutes; aOR, 0.76 [95% CI, 0.64 to 0.91] for 30-59 mL/minutes). CONCLUSION: Patients who are older, Black, or have more comorbidities are less likely to receive guideline concordant care to prevent SREs. These observations highlight the unique challenges of caring for patients with mCRPC and the need for future studies to increase BMA use in these populations.
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Neoplasias Ósseas , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Idoso , Criança , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/complicações , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Retrospectivos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/complicações , Neoplasias Ósseas/patologia , Atenção à SaúdeRESUMO
In patients with prostate cancer scheduled for systemic treatment, being overweight is linked to prolonged overall survival (OS), whereas sarcopenia is associated with shorter OS. We investigated fat-related and body composition parameters in patients undergoing prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) to assess their predictive value for OS. Methods: Body mass index (BMI, in kg/m2) and CT-derived body composition parameters (total, subcutaneous, visceral fat area, and psoas muscle area at the L3-L4 level) were determined for 171 patients scheduled for PSMA-directed RLT. After normalization for stature, the psoas muscle index was used to define sarcopenia. Outcome analysis was performed using Kaplan-Meier curves and Cox regression including fat-related and other clinical parameters (Gleason score, C-reactive protein [CRP], lactate dehydrogenase [LDH], hemoglobin, and prostate-specific antigen levels). The Harrell C-index was used for goodness-of-fit analysis. Results: Sixty-five patients (38%) had sarcopenia, and 98 patients (57.3%) had increased BMI. Relative to the 8-mo OS in normal-weight men (BMI < 25), overweight men (25 ≥ BMI > 30) and obese men (BMI ≥ 30) achieved a longer OS of 14 mo (hazard ratio [HR], 0.63; 95% CI, 0.40-0.99; P = 0.03) and 13 mo (HR, 0.47; 95% CI, 0.29-0.77; P = 0.004), respectively. Sarcopenia showed no impact on OS (11 vs. 12 mo; HR, 1.4; 95% CI, 0.91-2.1; P = 0.09). Most of the body composition parameters were tightly linked to OS on univariable analyses, with the highest C-index for BMI. In multivariable analysis, a higher BMI (HR, 0.91; 95% CI, 0.86-0.97; P = 0.006), lower CRP (HR, 1.09; 95% CI, 1.03-1.14; P < 0.001), lower LDH (HR, 1.08; 95% CI, 1.03-1.14; P < 0.001), and longer interval between initial diagnosis and RLT (HR, 0.95; 95% CI, 0.91-0.99; P = 0.02) were significant predictors of OS. Conclusion: Increased fat reserves assessed by BMI, CRP, LDH, and interval between initial diagnosis and RLT, but not CT-derived body composition parameters, were relevant predictors for OS. As BMI can be altered, future research should investigate whether a high-calorie diet before or during PSMA RLT may improve OS.
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Neoplasias de Próstata Resistentes à Castração , Sarcopenia , Masculino , Humanos , Índice de Massa Corporal , Neoplasias de Próstata Resistentes à Castração/radioterapia , Neoplasias de Próstata Resistentes à Castração/complicações , Sarcopenia/induzido quimicamente , Sarcopenia/complicações , Sarcopenia/tratamento farmacológico , Antígeno Prostático Específico/metabolismo , Sobrepeso/induzido quimicamente , Sobrepeso/complicações , Sobrepeso/tratamento farmacológico , Próstata/metabolismo , Resultado do Tratamento , Lutécio/uso terapêutico , Estudos Retrospectivos , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Dipeptídeos/uso terapêuticoRESUMO
INTRODUCTION: Sarcopenia is common in men with metastatic castrate-resistant prostate cancer (mCRPC) and has been largely assessed opportunistically through computed-tomography (CT) scans, excluding measures of muscle function. Therefore, the impact of a comprehensive assessment of sarcopenia on clinical outcomes in men with mCRPC is poorly understood. The objectives of this study were to comprehensively assess sarcopenia through CT scans and measures of muscle function and examine its impact on severe treatment toxicity, time to first emergency room (ER) visit, disease progression, and overall mortality in men initiating chemotherapy or androgen receptor-targeted axis (ARAT) therapy for mCRPC. METHODS: This was a secondary analysis of a prospective observational study of men with mCRPC at the Princess Margaret Cancer Centre between July 2015-May 2021. Participants were classified as sarcopenic if they had CT-based low muscle mass or low muscle density, a grip strength and gait speed score of <35.5kg and <0.8m/s, respectively, prior to treatment initiation. The impact of sarcopenia on severe treatment toxicity was assessed using multivariable logistic regression. Multivariable Cox regression models were used to determine the impact of sarcopenia on risk of visiting the ER, prostate-specific antigen progression, radiographic progression, and overall mortality. RESULTS: A total of 110 men (mean age: 74.6) were included in the analysis. At baseline, 30 (27.3%) were classified as sarcopenic. Sarcopenia was a significant predictor of severe toxicity (aOR = 6.26, 95%CI = 1.17-33.58, P = 0.032) and ER visits (aHR = 4.41, 95%CI = 1.26-15.43, p = 0.020) in men initiating ARAT but not in men initiating chemotherapy. Sarcopenia was also a predictor of radiographic progression (aHR = 2.39, 95%CI = 1.06-5.36, p = 0.035) and overall mortality (aHR = 2.44, 95%CI = 1.17-5.08, p = 0.018) regardless of treatment type. CONCLUSIONS: Baseline sarcopenia predicts radiographic progression and overall mortality in men with mCRPC regardless of the type of treatment and may also predict severe treatment toxicity and ER visits in men initiating ARAT.
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Neoplasias de Próstata Resistentes à Castração , Sarcopenia , Masculino , Humanos , Idoso , Sarcopenia/complicações , Neoplasias de Próstata Resistentes à Castração/complicações , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Antígeno Prostático Específico/uso terapêutico , Modelos de Riscos Proporcionais , Estudos ProspectivosRESUMO
OBJECTIVE: Prostate cancer is a common malignancy and patients may progress to castration-resistant prostate cancer (CRPC). Among patients with CRPC, fatigue is a common symptom associated with current treatments. The aim of this real-world study was to describe patient-reported fatigue in Japanese patients treated with androgen receptor-axis-targeted therapies for CRPC. METHODS: Data of this observational study were collected in a quantitative phase for the description of patient-reported fatigue, and a qualitative phase for elicitation of fatigue perception and barriers to reporting fatigue. RESULTS: In the quantitative phase (N = 22), fatigue was investigated in two formats: symptoms report and Brief Fatigue Inventory (BFI). In the report of the symptoms, 12 patients reported tiredness, and four moderate-to-severe tiredness during treatment. In the BFI, all patients reported fatigue; eight reported moderate-to-severe fatigue. The most affected BFI domain was mood: five patients reporting moderate-to-severe impact. In interviews (qualitative phase; N = 8), diverse patient experience on fatigue was observed, including apathetic feelings, affected speed and distance during the walk, negative impact on profession, housework, or driving, reduced outgoing activity, and difficulty in enjoying time with grandchildren or travel. Five out of eight patients communicated fatigue to their physicians but received diverse reactions. CONCLUSION: Patient interviews highlighted the impact of fatigue on patients' lives and difficulties in communicating fatigue to physicians. Fatigue frequency after medication may need to be monitored and its burden is considered to provide treatment that meets the needs, wishes, and circumstances of each patient. Further research is needed to elucidate how fatigue affects patients' lives, and underscore patient-physician communication difficulties.
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Médicos , Neoplasias de Próstata Resistentes à Castração , Comunicação , Fadiga/epidemiologia , Fadiga/etiologia , Humanos , Japão , Masculino , Neoplasias de Próstata Resistentes à Castração/complicações , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológicoRESUMO
Cancer is a risk factor for venous thromboembolism (VTE). Plasma tumor DNA (ptDNA) is an independent predictor of outcome in metastatic castration-resistant prostate cancer (mCRPC). We aimed to investigate the association between ptDNA and VTE in mCRPC. This prospective biomarker study included 180 mCRPC patients treated with abiraterone and enzalutamide from April 2013 to December 2018. We excluded patients with a previous VTE history and/or ongoing anticoagulation therapy. Targeted next-generation sequencing was performed to determine ptDNA fraction from pretreatment plasma samples. VTE risk based on survival analysis was performed using cumulative incidence function and estimating sub-distributional hazard ratio (SHR). At a median follow-up of 58 months (range 0.5-111.0), we observed 21 patients who experienced VTE with a cumulative incidence at 12 months of 17.1% (95% confidence interval [CI] 10.3-23.9). Elevated ptDNA, visceral metastasis, prior chemotherapy and lactate dehydrogenase (LDH) were significantly associated with higher VTE incidence compared to patients with no thrombosis (12-month estimate, 18.6% vs 3.5%, P = .0003; 44.4% vs 14.8%, P = .015; 24.7% vs 4.5%, P = .006; and 30.0% vs 13.5%, P = .05, respectively). In the multivariate analysis including ptDNA level, visceral metastases, number of lesions and serum LDH, high ptDNA fraction was the only independent factor associated with the risk of thrombosis (HR 5.78, 95% CI 1.63-20.44, P = .006). These results first suggest that baseline ptDNA fraction in mCRPC patients treated with abiraterone or enzalutamide may be associated with increased VTE risk. These patients may be followed-up more closely for the VTE risk, and the need for a primary thromboprophylaxis should be taken into account in mCRPC with elevated ptDNA.
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DNA de Neoplasias/sangue , Neoplasias de Próstata Resistentes à Castração/complicações , Tromboembolia Venosa/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , L-Lactato Desidrogenase/sangue , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Prospectivos , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/patologia , RiscoRESUMO
BACKGROUND: Fatigue is a multifactorial symptom commonly reported by patients with prostate cancer as a result of disease and treatment. This study assesses the impact enzalutamide has on patient-reported fatigue ("fatigue") by using patient-reported outcomes from four pivotal, placebo-controlled trials of enzalutamide (ARCHES (NCT02677896), PROSPER (NCT02003924), PREVAIL (NCT01212991), and AFFIRM (NCT00974311)). METHODS: Fatigue was assessed in the individual studies using the Functional Assessment of Cancer Therapy-Prostate item GP1 at baseline, weeks 13 or 17, and every 12 weeks until disease progression. Longitudinal changes were assessed using mean scores and mixed-model repeated measures. RESULTS: The fatigue rates at baseline were higher in patients with later-stage disease (metastatic and/or castration-resistant prostate cancer (CRPC)) and among patients who had already received prior treatment lines; rates ranged between 58% in PROSPER (nonmetastatic CRPC) and 86% in AFFIRM (post-docetaxel metastatic CRPC). Irrespective of disease state, initiation of enzalutamide or placebo resulted in an early increase of fatigue (by weeks 13 or 17), with fatigue levels stabilizing thereafter. At last assessment, ≥55% of patients reported fatigue improvement or stabilization in all trials compared to baseline. More patients reported fatigue worsening by ≥1 or ≥2 units with enzalutamide plus androgen deprivation therapy (ADT) than with placebo plus ADT in ARCHES, PROSPER, and PREVAIL, but the between-group difference was <10% in all trials. CONCLUSIONS: The levels of fatigue were greater in mCRPC and lower in earlier states of disease. In all trials, patients reported a small increase in fatigue for the first 13-17 weeks after starting enzalutamide or placebo, with slightly greater fatigue with enzalutamide in all studies except AFFIRM, but fatigue stabilized or improved thereafter. This suggests a role for clinical management of fatigue to help patients cope early in treatment.
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Neoplasias de Próstata Resistentes à Castração , Antagonistas de Androgênios/uso terapêutico , Benzamidas , Fadiga/tratamento farmacológico , Fadiga/etiologia , Humanos , Masculino , Nitrilas/uso terapêutico , Medidas de Resultados Relatados pelo Paciente , Feniltioidantoína , Neoplasias de Próstata Resistentes à Castração/complicações , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Resultado do TratamentoRESUMO
INTRODUCTION: Asian prostate cancer (PC) patients are particularly susceptible to docetaxel-related febrile neutropenia (FN). We evaluated primary granulocyte colony-stimulating factor (GCSF) for preventing FN in Chinese patients with metastatic hormone-sensitive PC (mHSPC) and castration-resistant PC (mCRPC). PATIENTS AND METHODS: Data from two cohorts of 377 Chinese patients with mHSPC (100; 26.5%) and mCRPC (277; 73.5%) treated with docetaxel at six public oncology centres were analysed with multivariate regression. Primary GCSF prophylaxis was defined as administration within 5 days of starting docetaxel. The primary outcome was FN within 21 days of the first docetaxel cycle (1st FN). RESULTS: Primary GCSF was given to 71 (18.8%) patients. FN occurred in 61 patients (16.2%) including 37 (9.8%) during the first cycle. Among patients who developed 1st cycle FN (n = 37) or not (n = 340), 2 and 69 received primary GCSF (5.4 vs. 20.3%, P = .03). Primary GCSF was associated with an overall reduced risk of 1st cycle FN (odds ratio [OR] = 0.22; 95% confidence interval [CI]: 0.05-0.96, P = .04), and similar trends were observed in the mHSPC (OR = 0.36, P = .35) and mCRPC (OR = 0.16, P = .08) subgroups. Poor Eastern Cooperative Oncology Group performance status (>1) was associated with an increased risk of 1st FN (OR = 3.90; 95% CI: 1.66-9.13, P = .002). CONCLUSIONS: To alleviate the risk of docetaxel-related FN, primary GCSF prophylaxis is suggested for Asian mCRPC and mHSPC patients, particularly those with poor performance status.
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Docetaxel/efeitos adversos , Neutropenia Febril/induzido quimicamente , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , China , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Estudos RetrospectivosRESUMO
OBJECTIVES: Prostate cancer and cardiovascular (CV) disease share several risk factors, with the incidence of both rising with increasing age. Systemic prostate cancer therapies may increase CV risk. For example, gonadotropic releasing hormone agonists have been associated with increased development of CV risk factors, and potentially with CV disease. For men with non-metastatic castration-resistant prostate cancer (nmCRPC), the opportunity to mitigate CV risk by appropriate selection of therapy (i.e., use of newer agents such as androgen receptor inhibitors) may be possible. The phase 3 PROSPER, SPARTAN, and ARAMIS trials for enzalutamide, apalutamide, and darolutamide, the 3 approved androgen receptor inhibitors for men with nmCRPC, were all associated with increased metastasis-free survival in patients with metastatic castration-resistant prostate cancer (mCRPC). Our objective in writing this review is to improve awareness of the relationship between long-term androgen deprivation and increased risk for CV disease and inform treatment decision making for patients with mCRPC who also have CV comorbidities. METHODS: The PubMed database was searched from 2010 to November 5, 2019 for articles pertaining to androgen receptor inhibitors, androgen inhibition, apalutamide, darolutamide, enzalutamide, CV, and CaP. RESULTS: We found literature describing the relationship between androgen inhibition and CV disease and risks. Given the increased risk of CV disease due to exposure to gonadotropic releasing hormone agonist therapy alone, understanding the potential for additional CV risks is important for patients with CV comorbidities when an androgen receptor inhibitor is added to their treatment. Another important consideration is the possibility of drug-drug interactions with comedications. CONCLUSION: Management strategies for patients with mCRPC also treated for comorbidities including CV disease require appropriate selection of therapy, diet, and exercise to meet the needs of the individual patient profile.
Assuntos
Antagonistas de Androgênios/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Antagonistas de Androgênios/uso terapêutico , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/epidemiologia , Interações Medicamentosas , Humanos , Masculino , Metástase Neoplásica , Neoplasias de Próstata Resistentes à Castração/complicações , Neoplasias de Próstata Resistentes à Castração/epidemiologia , Medição de Risco , Fatores de RiscoRESUMO
BACKGROUND: Optimal dosing of bone-targeted agents (BTAs), in patients with bone metastases remains an important clinical question. This trial compared 4-weekly versus 12-weekly therapy. PATIENTS AND METHODS: Patients with bone metastases from breast or castration-resistant prostate cancer (CRPC), who were going to start or already on BTAs, were randomised 1:1 to 4-weekly or 12-weekly BTA treatment for one year. Primary end point was change in health-related quality of life (HRQoL)-physical function European Organisation for Research and Treatment of Cancer (EORTC)-QLQ-C30). Secondary end points included pain (EORTC-QLQ-BM22), global health status (EORTC-QLQ-C30), symptomatic skeletal events (SSEs) rates and time to SSEs. Primary analysis was per protocol and a non-inferiority margin of 5 points was used. RESULTS: Of 263 patients (160 breast cancer, 103 CRPC), 133 (50.6%) and 130 (49.4%) were randomised to the 4- and 12-weekly groups, respectively. BTAs included denosumab (56.3%), zoledronate (24.0%) and pamidronate (19.8%). Using repeated-measures analysis, across all time points, patients in the 4-weekly arm had a mean HRQL-physical subdomain score which was 1.2 (95% confidence interval: -1.6 to 4.0) higher than the 12-weekly arm. The study met the definition of non-inferiority for our primary outcome. Secondary outcomes showed no significant difference in scores for pain, global health status, SSE rates and SSE-free survival between arms. Subgroup analyses for cancer type, prior BTA use or BTA type showed no significant difference between arms. CONCLUSION: These results in addition to those previously reported for de-escalating zoledronate and systematic reviews in both breast and prostate cancers, would support that de-escalation of commonly used BTAs is a reasonable treatment option.
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Conservadores da Densidade Óssea/uso terapêutico , Neoplasias Ósseas/secundário , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/complicações , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Conservadores da Densidade Óssea/farmacologia , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
A 78-year-old man had a medical history of hypertension, atrial fibrillation, chronic kidney disease, and metastatic castration-resistant prostate cancer (CRPC). He had progressed to first-line therapy for CRPC with abiraterone plus androgen-deprivation therapy (ADT) and as second-line therapy he was being treated with docetaxel, with biochemical progression in his last prostate specific antigen measurement. He was admitted to the hospital on April 2020, in the middle of the coronavirus disease 2019 (COVID-19) pandemic, because of painful bone lesions and deterioration of renal function.
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Anticoagulantes/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Infecções por Coronavirus/terapia , Cuidados Paliativos , Pneumonia Viral/terapia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Insuficiência Respiratória/terapia , Idoso , Antagonistas de Androgênios/uso terapêutico , Androstenos/uso terapêutico , Antineoplásicos/uso terapêutico , Betacoronavirus , Conservadores da Densidade Óssea/uso terapêutico , Neoplasias Ósseas/complicações , Neoplasias Ósseas/secundário , COVID-19 , Dor do Câncer/complicações , Dor do Câncer/terapia , Infecções por Coronavirus/complicações , Progressão da Doença , Docetaxel/uso terapêutico , Combinação de Medicamentos , Definição da Elegibilidade , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Unidades de Terapia Intensiva/provisão & distribuição , Lopinavir/uso terapêutico , Masculino , Oxigenoterapia , Pandemias , Pneumonia Viral/complicações , Neoplasias de Próstata Resistentes à Castração/complicações , Neoplasias de Próstata Resistentes à Castração/patologia , Insuficiência Renal , Insuficiência Respiratória/etiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ritonavir/uso terapêutico , SARS-CoV-2 , Índice de Gravidade de Doença , Ácido Zoledrônico/uso terapêuticoRESUMO
BACKGROUND: The authors previously found that obesity was linked with prostate cancer (PC)-specific mortality (PCSM) among men who underwent radical prostatectomy (RP). Herein, in a larger RP cohort, the authors investigated whether the association between obesity and long-term PC outcomes, including PCSM, differed by race. METHODS: Data from 5929 patients who underwent RP and were in the Shared Equal Access Regional Cancer Hospital (SEARCH) database were analyzed. Prior to RP, body mass index (BMI) was measured and recorded in the medical records. BMI was categorized as normal weight (<25 kg/m2 ), overweight (25-29.9 kg/m2 ), and obese (≥30 kg/m2 ). The authors assessed the association between BMI and biochemical disease recurrence (BCR), castration-resistant prostate cancer (CRPC), metastasis, and PCSM, accounting for confounders. RESULTS: Of the 5929 patients, 1983 (33%) were black, 1321 (22%) were of normal weight, 2605 (44%) were overweight, and 2003 (34%) were obese. Compared with white men, black men were younger; had higher prostate-specific antigen levels; and were more likely to have a BMI ≥30 kg/m2 , seminal vesicle invasion, and positive surgical margins (all P ≤ .032). During a median follow-up of 7.4 years, a total of 1891 patients (32%) developed BCR, 181 patients (3%) developed CRPC, 259 patients (4%) had metastasis, and 135 patients (2%) had died of PC. On multivariable analysis, obesity was found to be associated with an increased risk of PCSM (hazard ratio, 1.78; 95% confidence interval, 1.04-3.04 [P = .035]). No interaction was found between BMI and race in predicting PCSM (P ≥ .88), BCR (P ≥ .81), CRPC (P ≥ .88), or metastasis (P ≥ .60). Neither overweight nor obesity was associated with risk of BCR, CRPC, or metastasis (all P ≥ .18). CONCLUSIONS: Obese men undergoing RP at several Veterans Affairs hospitals were found to be at an increased risk of PCSM, regardless of race.
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Recidiva Local de Neoplasia/epidemiologia , Obesidade/epidemiologia , Neoplasias de Próstata Resistentes à Castração/epidemiologia , Neoplasias da Próstata/epidemiologia , Negro ou Afro-Americano/genética , Idoso , Índice de Massa Corporal , Gerenciamento de Dados , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/genética , Obesidade/sangue , Obesidade/complicações , Obesidade/genética , Próstata/patologia , Próstata/cirurgia , Antígeno Prostático Específico/sangue , Prostatectomia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/complicações , Neoplasias da Próstata/genética , Neoplasias de Próstata Resistentes à Castração/complicações , Neoplasias de Próstata Resistentes à Castração/genética , Fatores de RiscoRESUMO
Bone is the most common site of metastasis in metastatic castration-resistant prostate cancer (mCRPC), which is associated with pain and skeletal events. Radium-223 dichloride (Xofigo) is an alpha-emitting radioactive isotope that can specifically target bone lesions. Herein, we report the results of a retrospective analysis that documents our experience in the use of radium-223. Data from 63 patients (pts) with mCRPC who underwent radium-223 treatment from December 2015 to September 2017 were collected. Radium-223 (55 kBq/kg) was administered every 4 weeks for up to 6 cycles. The primary endpoint was OS. Radium-223 was administered as first line therapy in 11 pts, as second line in 19 pts, as third line in 16 pts and in successive lines in 17 pts; 42 pts out of 63 (67%) completed all six cycles. Within one month after the end of 6 cycles of radium-223, 15 pts out of 42 (35.7%) had achieved PR, 11 pts out of 42 (26.2%) had SD and 14 pts out of 42 (33.3%) had PD. Levels of pain decreased with progressive cycles of radium-223. After a minimum follow-up of 2 months and a maximum of 43 months, median OS was 15 months and median PFS was 8 months. The most frequent radium-223 related toxicity was low grade haematologic toxicity, predominantly G1-G2, that occurred halfway through treatment in about 75% of pts. The favourable results reported herein confirm that radium-223 can be considered well tolerated and effective in mCRPC, and is associated with significant decreases in pain.
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Neoplasias de Próstata Resistentes à Castração/terapia , Rádio (Elemento)/uso terapêutico , Idoso , Fosfatase Alcalina/metabolismo , Anemia/complicações , Neoplasias Ósseas/secundário , Estudos de Coortes , Hemoglobinas/metabolismo , Humanos , Estimativa de Kaplan-Meier , Masculino , Dor/etiologia , Antígeno Prostático Específico/metabolismo , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/complicações , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagemRESUMO
Until recently, there have been limited options for patients with bone metastatic castration-resistant prostate cancer (BmCRPC) following the failure of or development of resistance to docetaxel (DTX), which is one of the frontline treatments. Sterol regulatory element-binding protein 1 (SREBP1) is reported to regulate abnormal lipid metabolism and to promote the progression and metastasis of prostate cancer (PCa). The siRNA interferes SREBP1 may provide an efficient treatment when combined with DTX. Methods: In this study, lipoic acid (LA) and cross-linked peptide-lipoic acid micelles were cross-linked (LC) for DTX and siSREBP1 delivery (LC/D/siR). Then, cell membrane of PCa cells (Pm) and bone marrow mesenchymal stem cells (Bm) were fused for cloaking LC/D/siR (PB@LC/D/siR). Finally, the synthesized PB@LC/D/siR was evaluated in vitro and in vivo. Results: PB@LC/D/siR is internalized in PCa cells by a mechanism of lysosome escape. Tumor targeting and bone homing studies are evaluated using bone metastatic CRPC (BmCRPC) models, both in vitro and in vivo. Moreover, the enhanced anti-proliferation, anti-migration and anti-invasion capacities of DTX- and siSREBP1- loaded PB@LC (PB@LC/D/siR) were observed in vitro. Furthermore, PB@LC/D/siR was able to suppress the growth of the tumor effectively with deep tumor penetration, high safety and good protection of the bone at the tumor site. Additionally, the mRNA levels and protein levels of SREBP1 and SCD1 were able to be significantly downregulated by PB@LC/D/siR. Conclusion: This study presented a bone-cancer dual-targeting biomimetic nanodelivery system for bone metastatic CRPC.
Assuntos
Neoplasias Ósseas/secundário , Docetaxel/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , RNA Interferente Pequeno/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Animais , Biomimética/métodos , Neoplasias Ósseas/tratamento farmacológico , Docetaxel/administração & dosagem , Docetaxel/uso terapêutico , Regulação para Baixo , Sistemas de Liberação de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Micelas , Nanomedicina/métodos , Neoplasias de Próstata Resistentes à Castração/complicações , Ratos , Ratos Sprague-Dawley , Ácido Tióctico/administração & dosagem , Moduladores de Tubulina/administração & dosagem , Moduladores de Tubulina/metabolismo , Moduladores de Tubulina/uso terapêuticoRESUMO
PURPOSE OF REVIEW: The improvement in prostate cancer survival over time, even in those with advanced disease, has led to an increasing recognition of the impact of prostate cancer and its treatment on bone health. Cancer treatment-induced bone loss (CTIBL) is a well-recognized entity but greater awareness of the risks associated with CTIBL and its treatment is required. RECENT FINDINGS: The principal culprit in causing CTIBL is hormonal ablation induced by prostate cancer treatment, including several new agents which have been developed in recent years which significantly improve survival, but may cause CTIBL. This review discusses the impact of prostate cancer and its treatment on bone health, including published evidence on the underlying pathophysiology, assessment of bone health, and strategies for prevention and treatment. It is important to recognize the potential cumulative impact of systemic prostate cancer treatments on bone health.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Neoplasias Ósseas/secundário , Reabsorção Óssea/metabolismo , Glucocorticoides/uso terapêutico , Orquiectomia , Osteoporose/metabolismo , Neoplasias da Próstata/terapia , Densidade Óssea , Doenças Ósseas Metabólicas/tratamento farmacológico , Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/metabolismo , Doenças Ósseas Metabólicas/prevenção & controle , Reabsorção Óssea/etiologia , Hormônio Liberador de Gonadotropina/agonistas , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Humanos , Masculino , Osteoporose/tratamento farmacológico , Osteoporose/etiologia , Osteoporose/prevenção & controle , Fraturas por Osteoporose/etiologia , Fraturas por Osteoporose/metabolismo , Fraturas por Osteoporose/prevenção & controle , Neoplasias da Próstata/complicações , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/complicações , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológicoRESUMO
BACKGROUND: Fatigue is one of the most prevalent symptoms among cancer patients. Specifically, in metastatic castration-resistant prostate cancer (mCRPC) patients, fatigue is the most common adverse event associated with current treatments. The purpose of this study is to describe the prevalence of fatigue and its impact on quality of life (QoL) in patients with CRPC in routine clinical practice. METHODS: This was a cross-sectional, multicentre study. Male chemo-naïve adults with high-risk non-metastatic (M0) CRPC and metastatic (M1) CRPC (mCRPC) were eligible. Fatigue was measured using the Brief Fatigue Inventory (BFI) and QoL was assessed using the Functional Assessment of Cancer Therapy questionnaire for patients with prostate cancer (FACT-P) and the FACT-General (FACT-G) questionnaire. Data were analysed using Mann-Whitney or Kruskal-Wallis tests (non-parametric distribution), a T-test or an ANOVA (parametric distribution) and the Fisher or chi-squared tests (categorical variables). RESULTS: A total of 235 eligible patients were included in the study (74 [31.5%] with M0; and 161 [68.5%] with M1). Fatigue was present in 74%, with 38.5% of patients reporting moderate-to-severe fatigue. Mean FACT-G and FACT-P overall scores were 77.6 ± 16.3 and 108.7 ± 21.4, respectively, with no differences between the CRPC M0 and CRPC M1 subgroups. Fatigue intensity was associated with decreased FACT-G/P scores, with no differences between groups. Among 151 mCRPC patients with available treatment data, those treated with abiraterone-prednisone ≥3 months showed a significant reduction in fatigue intensity (p = 0.043) and interference (p = 0.04) compared to those on traditional hormone therapy (HT). Patients on abiraterone-prednisone ≥3 months showed significantly better FACT-G/P scores than patients on HT (p = 0.046 and 0.018, respectively). CONCLUSION: Our data show a high prevalence and intensity of fatigue and its impact on QoL in chemo-naïve CRPC patients. There is an association between greater fatigue and less QoL, irrespective of the presence or absence of metastasis. Chemo-naïve mCRPC patients receiving more than 3 months of abiraterone acetate plus prednisone showed an improvement of fatigue and QoL when compared to those on traditional HT. TRIAL REGISTRATION: Not applicable since it is not an interventional study.
Assuntos
Fadiga/epidemiologia , Fadiga/etiologia , Neoplasias de Próstata Resistentes à Castração/complicações , Qualidade de Vida , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Humanos , Masculino , Pessoa de Meia-Idade , PrevalênciaAssuntos
Antineoplásicos/administração & dosagem , Fadiga/diagnóstico , Preferência do Paciente/estatística & dados numéricos , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Benzamidas , Cápsulas , Deglutição , Relação Dose-Resposta a Droga , Fadiga/etiologia , Fadiga/psicologia , Voluntários Saudáveis , Humanos , Masculino , Nitrilas , Feniltioidantoína/administração & dosagem , Feniltioidantoína/efeitos adversos , Placebos/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/complicações , Neoplasias de Próstata Resistentes à Castração/psicologia , Índice de Gravidade de Doença , Inquéritos e Questionários/estatística & dados numéricos , Comprimidos , Vitaminas/administração & dosagemRESUMO
BACKGROUND: Although skeletal-related events (SREs) are linked with a reduced quality of life and worse outcomes, to the authors' knowledge the factors that predict SREs are minimally understood. The objective of the current study was to identify predictors of SREs and all-cause mortality among men with metastatic castration-resistant prostate cancer (mCRPC). METHODS: Data were collected on 837 men with bone mCRPC at 8 Veterans Affairs medical centers within the Shared Equal Access Regional Cancer Hospital (SEARCH) database from 2000 through 2017. Patients were followed to assess development of SREs (pathological fracture, radiotherapy to bone, spinal cord compression, or surgery to bone). Cox proportional hazards models were used to evaluate predictors of SREs and mortality. RESULTS: Of the 837 men with bone mCRPC, 287 developed a SRE and 740 men died (median follow-up, 26 months). Bone pain was found to be the strongest predictor of SREs (hazard ratio [HR], 2.96; 95% CI, 2.25-3.89). A shorter time from CRPC to the development of metastasis (HR, 0.92; 95% CI, 0.85-0.99), shorter progression to CRPC (HR, 0.94; 95% CI, 0.91-0.98), and visceral metastasis at the time of diagnosis of bone metastasis (HR, 1.91; 95% CI, 1.18-3.09) were associated with an increased risk of SREs. Ten or more bone metastases (HR, 2.17; 95% CI, 1.72-2.74), undergoing radical prostatectomy (HR, 0.73; 95% CI, 0.61-0.89), shorter progression to CRPC (HR, 0.97; 95% CI, 0.94-0.99), older age (HR, 1.03; 95% CI, 1.02-1.04), higher prostate-specific antigen level at the time of diagnosis of metastasis (HR, 1.21; 95% CI, 1.14-1.28), bone pain (HR, 1.44; 95% CI, 1.23-1.70), and visceral metastasis (HR, 1.72; 95% CI, 1.23-2.39) were associated with an increased mortality risk. CONCLUSIONS: Among men with bone mCRPC, bone pain was found to be the strongest predictor of SREs and the number of bone metastases was a strong predictor of mortality. If validated, these factors potentially may be used for risk stratification and for SRE prevention strategies.
Assuntos
Doenças Ósseas/epidemiologia , Doenças Ósseas/etiologia , Neoplasias de Próstata Resistentes à Castração/complicações , Neoplasias de Próstata Resistentes à Castração/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Biópsia , Doenças Ósseas/diagnóstico , Neoplasias Ósseas/complicações , Neoplasias Ósseas/epidemiologia , Neoplasias Ósseas/secundário , Causas de Morte , Suscetibilidade a Doenças , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Mortalidade , Estadiamento de Neoplasias , Prognóstico , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/terapiaRESUMO
PURPOSE: Radium 223 dichloride (radium-223) is an alpha particle-emitting bone-directed therapy that prolongs overall survival in men with bone-predominant metastatic castration-resistant prostate cancer (mCRPC). Docetaxel is an antimicrotubule cytotoxic agent that improves survival in mCRPC. We investigated whether combining these potentially cross-sensitising agents to dually target tumour and bone would be safe and effective. PATIENTS AND METHODS: Phase 1 was a dose escalation study to define a recommended phase 2 dose (RP2D) of docetaxel and radium-223. In phase 2a, patients were randomised 2:1 to the recommended combination regimen or docetaxel at a dose of 75 mg/m2 every 3 weeks (q3w). Patients with bone-predominant mCRPC were eligible. End-points were safety, efficacy and treatment-related changes in serum and imaging biomarkers. RESULTS: Twenty patients were enrolled in phase 1; 53 patients were randomised in phase 2a: 36 to combination treatment and 17 to docetaxel alone. The RP2D for the combination was radium-223 55 kBq/kg every six weeks × 5 doses, plus docetaxel 60 mg/m2 q3w × 10 doses. Febrile neutropenia was dose limiting. A higher rate of febrile neutropenia was seen in the docetaxel monotherapy arm (15% vs 0%); the safety profile of the treatment groups was otherwise similar. The combination arm had more durable suppression of prostate-specific antigen (median time to progression, 6.6 vs 4.8 months, respectively), alkaline phosphatase (9 vs 7 months) and osteoblastic bone deposition markers. CONCLUSIONS: Radium-223 in combination with docetaxel at the RP2D was well tolerated. Exploratory efficacy data suggested enhanced antitumour activity for the combination relative to docetaxel alone. Comparative studies with end-points of clinical benefit are warranted. ClinicalTrials.gov number: NCT01106352.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/secundário , Docetaxel/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Rádio (Elemento)/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Docetaxel/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias de Próstata Resistentes à Castração/complicações , Rádio (Elemento)/farmacologiaAssuntos
Anemia Mielopática/fisiopatologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Pancitopenia/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Neoplasias Ósseas/complicações , Neoplasias Ósseas/secundário , Humanos , Masculino , Pancitopenia/complicações , Pancitopenia/patologia , Prognóstico , Neoplasias de Próstata Resistentes à Castração/complicações , Neoplasias de Próstata Resistentes à Castração/patologiaRESUMO
The aim of this study was to assess the safety, tolerability, and effects on renal function as well as therapeutic efficacy of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (PRLT) using 177Lu-labeled PSMA-617 in patients with metastatic castration-resistant prostate cancer and a single functioning kidney before PRLT. Methods: Sixteen patients (aged 53-78 y; mean age, 64.7 ± 6.5 y) with a single functioning kidney received PRLT with 177Lu-PSMA-617 between March 2015 and October 2018. All parameters of renal function (serum creatinine, blood urea nitrogen, and electrolytes) were prospectively documented in a structured database and analyzed before each PRLT cycle and in follow-up. Renal function was further quantified by measuring tubular extraction rate (TER) using 99mTc-mercaptoacetyltriglycine renal scintigraphy. Treatment-related adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Kaplan-Meier analysis was performed to obtain the progression-free survival and overall survival. Results: The median administered activity was 22.1 GBq (range, 15.4-33.8 GBq). The calculated absorbed radiation dose to the kidney per cycle was 5.3 ± 2.1 Gy (0.81 ± 0.32 Gy/GBq). Renal function was already impaired at baseline in 43.7% of patients, including CTCAE grade 1 renal impairment in 25.0% and CTCAE grade 2 in 18.8%. Grade 1 and 2 renal impairment, respectively, were present in 37.5% and 6.3% of the patients after the first PRLT cycle and in 31.3% and 12.5% after the second cycle. No CTCAE grade 3 or 4 nephrotoxicity was observed during or after treatment. There was no significant change in either TER or the ratio of TER to lower-limit TER after the last cycle of treatment (P > 0.05). The median PFS was 8.1 mo based on both the criteria of the European Organization for Research and Treatment of Cancer and RECIST. The median overall survival has yet to be reached with a median follow-up time of 19.3 mo (range, 5.8-45.3 mo). Conclusion: In patients with a single functioning kidney, 177Lu-PSMA-617 PRLT is feasible, seems to be effective, and is well tolerated, without any signs of acute or subacute nephrotoxicity during a mean follow-up of nearly 2 y (and up to 45.3 mo). Further long-term follow-up of this special patient group is warranted.