RESUMEN
Prostate cancer survivors approach 2.8 million in number and represent 1 in 5 of all cancer survivors in the United States. While guidelines exist for timely treatment and surveillance for recurrent disease, there is limited availability of guidelines that facilitate the provision of posttreatment clinical follow-up care to address the myriad of long-term and late effects that survivors may face. Based on recommendations set forth by a National Cancer Survivorship Resource Center expert panel, the American Cancer Society developed clinical follow-up care guidelines to facilitate the provision of posttreatment care by primary care clinicians. These guidelines were developed using a combined approach of evidence synthesis and expert consensus. Existing guidelines for health promotion, surveillance, and screening for second primary cancers were referenced when available. To promote comprehensive follow-up care and optimal health and quality of life for the posttreatment survivor, the guidelines address health promotion, surveillance for prostate cancer recurrence, screening for second primary cancers, long-term and late effects assessment and management, psychosocial issues, and care coordination among the oncology team, primary care clinicians, and nononcology specialists. A key challenge to the development of these guidelines was the limited availability of published evidence for management of prostate cancer survivors after treatment. Much of the evidence relies on studies with small sample sizes and retrospective analyses of facility-specific and population databases.
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Continuidad de la Atención al Paciente/normas , Atención Primaria de Salud/normas , Neoplasias de la Próstata/terapia , Sobrevivientes , American Cancer Society , Medicina Basada en la Evidencia , Promoción de la Salud/normas , Humanos , Masculino , Vigilancia de la Población , Calidad de Vida , Estados UnidosRESUMEN
BACKGROUND: Prostate cancer that progresses after enzalutamide treatment is poorly responsive to further antiandrogen therapy, and paradoxically, rapid cycling between high and low serum testosterone concentrations (bipolar androgen therapy [BAT]) in this setting might induce tumour responses. We aimed to evaluate BAT in patients with metastatic castration-resistant prostate cancer that progressed after enzalutamide. METHODS: We did this single-centre, open-label, phase 2, multicohort study in the USA. We included patients aged 18 years or older who had histologically confirmed and radiographically documented metastatic castration-resistant prostate cancer, with no more than two previous second-line hormonal therapies, and a castrate concentration of testosterone. Patients were asymptomatic, with Eastern Cooperative Oncology Group performance status of 0-2, and did not have high-risk lesions for tumour flare (eg, >5 sites of visceral disease or bone lesions with impending fracture). For the cohort reported here, we required patients to have had progression on enzalutamide with a continued prostate-specific antigen (PSA) rise after enzalutamide treatment discontinuation. Patients received BAT, which consisted of intramuscular testosterone cipionate 400 mg every 28 days until progression and continued luteinising hormone-releasing hormone agonist therapy. Upon progression after BAT, men were rechallenged with oral enzalutamide 160 mg daily. The co-primary endpoints were investigator-assessed 50% decline in PSA concentration from baseline (PSA50) for BAT (for all patients who received at least one dose) and for enzalutamide rechallenge (based on intention-to-treat analysis). These data represent the final analysis for the post-enzalutamide cohort, while two additional cohorts (post-abiraterone and newly castration-resistant prostate cancer) are ongoing. The trial is registered with ClinicalTrials.gov, number NCT02090114. FINDINGS: Between Aug 28, 2014, and May 18, 2016, we accrued 30 eligible patients and treated them with BAT. Nine (30%; 95% CI 15-49; p<0·0001) of 30 patients achieved a PSA50 to BAT. 29 patients completed BAT and 21 proceeded to enzalutamide rechallenge, of whom 15 (52%; 95% CI 33-71; p<0·0001) achieved a PSA50 response. During BAT, the only grade 3-4 adverse event occurring in more than one patient was hypertension (three [10%] patients). Other grade 3 or worse adverse events occurring during BAT in one [3%] patient each were pulmonary embolism, myocardial infarction, urinary obstruction, gallstone, and sepsis. During enzalutamide retreatment, no grade 3-4 toxicities occurred in more than one patient. No treatment-related deaths were reported during either BAT or enzalutamide retreatment. INTERPRETATION: BAT is a safe therapy that resulted in responses in asymptomatic men with metastatic castration-resistant prostate cancer and also resensitisation to enzalutamide in most patients undergoing rechallenge. Further studies with BAT are needed to define the potential clinical role for BAT in the management of metastatic castration-resistant prostate cancer and the optimal strategy for sequencing between androgen and antiandrogen therapies in metastatic castration-resistant prostate cancer to maximise therapeutic benefit to patients. FUNDING: National Institutes of Health and National Cancer Institute.
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Andrógenos/administración & dosificación , Antineoplásicos Hormonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Testosterona/análogos & derivados , Anciano , Anciano de 80 o más Años , Andrógenos/efectos adversos , Antineoplásicos Hormonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Baltimore , Benzamidas , Progresión de la Enfermedad , Hormona Liberadora de Gonadotropina/agonistas , Hormona Liberadora de Gonadotropina/metabolismo , Humanos , Calicreínas/sangre , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Nitrilos , Feniltiohidantoína/administración & dosificación , Feniltiohidantoína/efectos adversos , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata Resistentes a la Castración/sangre , Neoplasias de la Próstata Resistentes a la Castración/patología , Testosterona/administración & dosificación , Testosterona/efectos adversos , Testosterona/sangre , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Prognostic factors associated with clinical outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with a novel androgen receptor-directed therapies (ARDT) in the second line setting has not been formally evaluated. PATIENTS AND METHODS: We retrospectively reviewed and analyzed medical records of all patients with mCRPC who received sequential treatment with ARDT. We analyzed potential clinical factors associated with post treatment endpoints including 50% decline in prostatic-specific antigen (PSA), PSA-progression-free survival (PFS), clinical or radiographic PFS and overall survival (OS). Prognostic univariate and multivariate Cox proportional hazard models were developed and assessed. RESULTS: One hundred twenty-six patients with mCRPC treated with a second-line novel ARDT were included. Overall, 50% decline in PSA was observed in 22% of patients and a median PSA-PFS of 2.9 months and a PFS of 3.6 months. After adjusting for potential confounders including prior exposure to docetaxel and number of prior antiandrogen agents, time to development of CRPC was an independent factor associated with PSA-PFS (hazard ratio [HR]: 0.99; 95% confidence interval [CI]: 0.99-1; P = 0.02) and PFS (HR: 0.99; CI: 0.98-1; P= 0.01). PSA response (50% decline) to first-line novel ARDT correlated negatively with PSA-PFS with second-line novel ARDT (HR: 1.7; 95% CI: 1.14-2.53; P = 0.009) and lower pre-treatment levels of albumin were associated with shorter PFS (HR: 0.56; 95% CI: 0.32-0.97; P = 0.03). Performance status, pre-treatment levels of albumin, extent of disease and time to development CRPC were associated with OS. CONCLUSIONS: Second-line ARDT is associated with modest outcomes in patients with mCRPC. Time to development of CRPC is the strongest predictor of PSA response, PSA-PFS and OS which suggest that intrinsic resistance to AR directed treatment is the major treatment outcome factor in these patients. Future studies in patients receiving long term ARTD should include the identification of predictive biomarkers to facilitate treatment selection.
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Antagonistas de Andrógenos/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/patología , Anciano , Progresión de la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Antígeno Prostático Específico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Receptores Androgénicos/análisis , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Sunitinib is a standard treatment for metastatic clear cell renal cell carcinoma (mccRCC). Data on its activity in the rare variant of metastatic chromophobe renal cell carcinoma (mchRCC), are limited. We aimed to analyze the activity of sunitinib in a relatively large and homogenous international cohort of mchRCC patients in terms of outcome and comparison with mccRCC. METHODS: Records from mchRCC patients treated with first-line sunitinib in 10 centers across 4 countries were retrospectively reviewed. Univariate and multivariate analyses of association between clinicopathologic factors and outcome were performed. Subsequently, mchRCC patients were individually matched to mccRCC patients. We compared the clinical benefit rate, progression-free survival (PFS), and overall survival (OS) between the groups. RESULTS: Between 2004 and 2014, 36 patients (median age, 64 years; 47% male) with mchRCC were treated with first-line sunitinib. Seventy-eight percent achieved a clinical benefit (partial response + stable disease). Median PFS and OS were 10 and 26 months, respectively. Factors associated with PFS were the Heng risk (hazard ratio [HR], 3.3; p = .03) and pretreatment neutrophil-to-lymphocyte ratio (NLR) >3 (HR, 0.63; p = .02). Factors associated with OS were the Heng risk (HR, 4.1; p = .04), liver metastases (HR, 3.8; p = .03), and pretreatment NLR <3 (HR, 0.55; p = .03). Treatment outcome was not significantly different between mchRCC patients and individually matched mccRCC patients. In mccRCC patients (p value versus mchRCC), 72% achieved a clinical benefit (p = .4) and median PFS and OS were 9 (p = .6) and 25 (p = .7) months, respectively. CONCLUSION: In metastatic chromophobe renal cell carcinoma, sunitinib therapy may be associated with similar outcome and toxicities as in metastatic clear cell renal cell carcinoma. The Heng risk and pretreatment NLR may be associated with PFS and OS. IMPLICATIONS FOR PRACTICE: Data on the activity of sunitinib in metastatic chromophobe renal cell carcinoma (mchRCC) are limited. This study analyzed the activity of sunitinib in a cohort of mchRCC patients. Of 36 patients with mchRCC who were treated with first-line sunitinib, 78% achieved a clinical benefit. Median PFS and OS were 10 and 26 months, respectively. Treatment outcome was not significantly different between mchRCC patients and individually matched metastatic clear cell RCC patients.
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Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Indoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Pirroles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estudios Retrospectivos , Sunitinib , Resultado del TratamientoRESUMEN
BACKGROUND: Abiraterone, a potent CYP 17 inhibitor, is standard treatment in docetaxel refractory, metastatic castrate resistant prostate cancer (mCRPC). However, in countries where abiraterone has not been approved yet, or for patients who cannot afford it, ketoconazole is used as an alternative CYP 17 inhibitor. Although preclinical data suggests that ketoconazole is a less potent inhibitor of CYP 17, there are limited clinical data comparing both agents. We aimed to compare the clinical effectiveness of abiraterone versus ketoconazole in docetaxel refractory mCRPC. METHODS: Records from mCRPC patients treated with ketoconazole (international multicenter database, n = 162) were reviewed retrospectively. Twenty-six patients treated post docetaxel were individually matched by clinicopathologic factors to patients treated with abiraterone (national multicenter database, n = 140). We compared the PSA response, biochemical and radiological progression free survival (PFS), and overall survival (OS) between the groups. PFS and OS were determined by Cox regression. RESULTS: The groups were matched by Gleason score, pre-treatment disease extent, ECOG PS, pre-treatment risk category (Keizman, Oncologist 2012). Furthermore, they were balanced regarding other known confounding risk factors. In the groups of abiraterone versus ketoconazole, PSA response was 46% versus 19% (OR 4.3, P = 0.04), median biochemical PFS 7 versus 2 months (HR 1.54, P = 0.02), median radiological PFS 8 versus 2.5 months (HR 1.8, P = 0.043), median OS 19 versus 11 months (HR 0.53, P = 0.79), and treatment interruption d/t severe adverse events 8% (n = 2) versus 31% (n = 8) (0R 0.6, P = 0.023). CONCLUSIONS: In docetaxel refractory mCRPC, the outcome of abiraterone treatment may be superior to ketoconazole.
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Androstadienos/uso terapéutico , Antineoplásicos/uso terapéutico , Cetoconazol/uso terapéutico , Orquiectomía , Neoplasias de la Próstata/tratamiento farmacológico , Taxoides/uso terapéutico , Acetato de Abiraterona , Anciano , Anciano de 80 o más Años , Terapia Combinada , Bases de Datos Factuales , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Docetaxel , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/cirugía , Retratamiento , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Obesity, smoking, hypertension, and diabetes are risk factors for renal cell carcinoma development. Their presence has been associated with a worse outcome in various cancers. We sought to determine their association with outcome of sunitinib treatment in metastatic renal cell carcinoma (mRCC). METHODS: An international multicenter retrospective study of sunitinib-treated mRCC patients was performed. Multivariate analyses were performed to determine the association between outcome and the pretreatment status of smoking, body mass index, hypertension, diabetes, and other known prognostic factors. RESULTS: Between 2004 and 2013, 278 mRCC patients were treated with sunitinib: 59 were active smokers, 67 were obese, 73 were diabetic, and 165 had pretreatment hypertension. Median progression-free survival (PFS) was 9 months, and overall survival (OS) was 22 months. Factors associated with PFS were smoking status (past and active smokers: hazard ratio [HR]: 1.17, p = .39; never smokers: HR: 2.94, p < .0001), non-clear cell histology (HR: 1.62, p = .011), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 3.51, p < .0001), use of angiotensin system inhibitors (HR: 0.63, p = .01), sunitinib dose reduction or treatment interruption (HR: 0.72, p = .045), and Heng risk (good and intermediate risk: HR: 1.07, p = .77; poor risk: HR: 1.87, p = .046). Factors associated with OS were smoking status (past and active smokers: HR: 1.25, p = .29; never smokers: HR: 2.7, p < .0001), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 2.95, p < .0001), and sunitinib-induced hypertension (HR: 0.57, p = .002). CONCLUSION: Active smoking may negatively affect the PFS and OS of sunitinib-treated mRCC. Clinicians should consider advising patients to quit smoking at initiation of sunitinib treatment for mRCC.
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Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Indoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Pirroles/uso terapéutico , Fumar/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/patología , Femenino , Humanos , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Análisis Multivariante , Metástasis de la Neoplasia , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Factores de Riesgo , Sunitinib , Resultado del Tratamiento , Adulto JovenRESUMEN
Cyclic high-dose testosterone administration, known as bipolar androgen therapy (BAT), is a treatment strategy for patients with metastatic castration-resistant prostate cancer (mCRPC). Here, we report the results of a multicenter, single arm Phase 2 study (NCT03554317) enrolling 45 patients with heavily pretreated mCRPC who received BAT (testosterone cypionate, 400 mg intramuscularly every 28 days) with the addition of nivolumab (480 mg intravenously every 28 days) following three cycles of BAT monotherapy. The primary endpoint of a confirmed PSA50 response rate was met and estimated at 40% (N = 18/45, 95% CI: 25.7-55.7%, P = 0.02 one-sided against the 25% null hypothesis). Sixteen of the PSA50 responses were achieved before the addition of nivolumab. Secondary endpoints included objective response rate (ORR), median PSA progression-free survival, radiographic progression-free survival (rPFS), overall survival (OS), and safety/tolerability. The ORR was 24% (N = 10/42). Three of the objective responses occurred following the addition of nivolumab. After a median follow-up of 17.9 months, the median rPFS was 5.6 (95% CI: 5.4-6.8) months, and median OS was 24.4 (95% CI: 17.6-31.1) months. BAT/nivolumab was well tolerated, resulting in only five (11%) drug related, grade-3 adverse events. In a predefined exploratory analysis, clinical response rates correlated with increased baseline levels of intratumoral PD-1 + T cells. In paired metastatic tumor biopsies, BAT induced pro-inflammatory gene expression changes that were restricted to patients achieving a clinical response. These data suggest that BAT may augment antitumor immune responses that are further potentiated by immune checkpoint blockade.
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Nivolumab , Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Nivolumab/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/patología , Andrógenos , Antígeno Prostático Específico , Supervivencia sin Progresión , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR), an inflammation marker, is prognostic in several cancers. We assessed the association between the pretreatment NLR and outcome of patients with metastatic castration-resistant prostate cancer (mCRPC) treated with the CYP17 inhibitor ketoconazole. METHODS: This was an international, retrospective study of 156 mCRPC patients treated with ketoconazole. The independent effect of the pretreatment NLR and factors associated with treatment outcome were determined by multivariate analysis. RESULTS: Seventy-eight patients (50%) had a ≥50% decline in prostate-specific antigen (PSA). The median progression-free survival (PFS) time was 8 months. Excluded from the analysis were 23 patients without available data on their NLR and those with a recent health event or treatment associated with a blood count change. Sixty-two patients (47%) had a pretreatment NLR >3. Risk factors associated with the PFS outcome were a pretreatment NLR >3 and PSA doubling time (PSADT) <3 months and a prior response to a gonadotropin-releasing hormone agonist of <24 months or to an antiandrogen of <6 months. The number of risk factors was used to form a predictive nomogram by patient categorization into favorable (zero or one factor), intermediate (two factors), and poor (three or four factors) risk groups. CONCLUSIONS: In mCRPC patients treated with ketoconazole, the pretreatment NLR and PSADT, and prior response to androgen-deprivation therapy, may be associated with the PFS time and used to form a risk stratification predictive nomogram.
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Cetoconazol/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/cirugía , Anciano , Anciano de 80 o más Años , Antagonistas de Andrógenos/uso terapéutico , Supervivencia sin Enfermedad , Hormona Liberadora de Gonadotropina/agonistas , Humanos , Modelos Logísticos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Neutrófilos/citología , Nomogramas , Modelos de Riesgos Proporcionales , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/patología , Estudios Retrospectivos , Factores de Riesgo , Esteroide 17-alfa-Hidroxilasa/antagonistas & inhibidores , Resultado del TratamientoRESUMEN
BACKGROUND: We sought to determine the change of PSA doubling time (PSADT) and its association with disease progression during intermittent androgen deprivation (IAD) therapy for prostate cancer. METHODS: Data were retrospectively analyzed in 96 patients with biochemically relapsed prostate cancer (BRPC) treated with IAD since 1995. IAD consisted of LHRH-agonists ± antiandrogen given usually at PSA threshold (ng/ml) of 10-20, for 6-9 months. Cycles were repeated until the development of castration resistance. Mixed effects model was used to study PSADT change over cycles. Multivariate cox regression model was used to identify outcome-associated variables. RESULTS: Patients received a mean of 2.8 treatment cycles over a mean follow-up time of 71 months. Fifty-seven (59%) remain on treatment and 39 (41%) developed PSA refractoriness (n = 8) or positive scans (n = 31). First off treatment interval PSADT (median 2.3 months) was significantly shorter than the baseline (median 7.34) but remained stable in subsequent cycles. Off treatment interval PSADT adjusted for testosterone recovery (median 3.7) was significantly longer than that based on all PSA determinations (median 2). Factors associated with disease progression were pre-treatment PSADT (≥6 vs. <6), first off treatment interval PSADT (≥3 vs. <3), and PSA nadir during the first treatment interval (<0.1 vs. ≥0.1). CONCLUSIONS: During IAD for BRPC, PSADT becomes shorter, and is associated with testosterone recovery. PSADT before treatment and during the first off treatment interval is associated with disease progression. If prospectively validated these data may guide treatment with IAD and clinical trial design.
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Antagonistas de Andrógenos/administración & dosificación , Hormona Liberadora de Gonadotropina/agonistas , Neoplasias Hormono-Dependientes/sangre , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Neoplasias Hormono-Dependientes/patología , Modelos de Riesgos Proporcionales , Neoplasias de la Próstata/patología , Estudios Retrospectivos , Testosterona/sangre , Factores de TiempoRESUMEN
BACKGROUND: Cyclic high-dose testosterone injections, also known as bipolar androgen therapy (BAT), is a novel treatment strategy for patients with metastatic castration-resistant prostate cancer (mCRPC). BAT has shown clinical activity in prior studies enrolling men with mCRPC and may potentially restore sensitivity to prior androgen receptor (AR)-targeted agents. OBJECTIVE: To evaluate the clinical activity of BAT in patients progressing on AR-targeted therapy as well as responses to abiraterone or enzalutamide upon rechallenge after BAT. DESIGN, SETTING, AND PARTICIPANTS: RESTORE is a multicohort phase II study enrolling asymptomatic mCRPC patients after abiraterone or enzalutamide at Johns Hopkins Hospital (NCT02090114). Participants (29 after abiraterone and 30 after enzalutamide) received 400 mg testosterone cypionate intramuscularly every 28 days, with ongoing luteinizing hormone-releasing hormone agonist/antagonist treatment (ie, BAT). Following progression on BAT, patients were rechallenged with their most recent AR-targeted therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Coprimary endpoints were >50% decline in PSA from baseline (PSA50) responses to BAT and following AR-targeted therapy rechallenge. Outcomes in the post-abiraterone cohort are presented, as well as updated results from the post-enzalutamide cohort and an exploratory AR-V7 analysis. RESULTS AND LIMITATIONS: No statistically significant difference in PSA50 response rates to BAT was observed (30% [post-enzalutamide cohort] vs 17% [post-abiraterone cohort], p = 0.4). However, PSA50 responses to AR-targeted therapy rechallenge were higher in the post-enzalutamide cohort (68% vs 16%, p = 0.001). The median time from enrollment to progression following rechallenge with AR-targeted therapy (ie, progression-free survival 2; PFS2) was longer in the post-enzalutamide versus post-abiraterone patients (12.8 vs 8.1 mo, p = 0.04). Outcomes were worse in patients with detectable AR-V7 in circulating tumor cells (median PFS2: 10.3 vs 7.1 mo, p = 0.005). CONCLUSIONS: BAT shows clinical activity in mCRPC patients and may be more effective at resensitizing to enzalutamide versus abiraterone. PATIENT SUMMARY: BAT is well tolerated in metastatic castration-resistant prostate cancer patients. The type of prior AR-targeted therapy might affect response to BAT as well as AR-therapy rechallenge. BAT followed by AR-targeted therapy rechallenge did not improve outcomes in AR-V7-positive patients.
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Neoplasias de la Próstata Resistentes a la Castración , Testosterona/uso terapéutico , Andrógenos , Androstenos/uso terapéutico , Benzamidas/uso terapéutico , Humanos , Masculino , Nitrilos/uso terapéutico , Feniltiohidantoína/uso terapéutico , Antígeno Prostático Específico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Receptores Androgénicos , Testosterona/administración & dosificaciónRESUMEN
BACKGROUND: Cyclical, high-dose testosterone administration, termed bipolar androgen therapy (BAT), can induce clinical responses and restore sensitivity to androgen signalling inhibition in patients with previously treated castration-resistant prostate cancer (PCa) (CRPC). This trial evaluated whether BAT is a safe and effective first-line hormonal therapy for patients with CRPC. PATIENTS AND METHODS: In cohort C of this single-centre, open-label, phase II, multi-cohort trial (RE-sensitizing with Supraphysiologic Testosterone to Overcome REsistance study), 29 patients with CRPC received first-line hormonal therapy with 400 mg of testosterone cypionate intramuscularly every 28 days concurrent with a luteinising hormone-releasing hormone agonist/antagonist. The primary end-point of the study was the PSA50 response rate to BAT treatment. RESULTS: After treatment with BAT, four of 29 patients (14%; 95% confidence interval [CI]: 4-32%) experienced a PSA50 response. The median radiographic progression-free survival to BAT was 8.5 months (95% CI: 6.9-15.1) for patients with metastatic CRPC. After progression on BAT, 17 of 18 patients (94%; 95% CI: 73-100%) achieved a PSA50 response and 15 of 18 patients (83%; 95% CI: 59-96) achieved a PSA90 response on abiraterone or enzalutamide. Twelve of 15 patients (80%; 95% CI: 52-96) with metastatic CRPC remain on abiraterone or enzalutamide with a median duration of follow-up of 11.2 months. CONCLUSION: As first-line hormonal treatment for CRPC, BAT was well tolerated and resulted in prolonged disease stabilisation. After progression on BAT, patients had favourable responses to second-generation androgen receptor-targeted therapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT02090114.
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Andrógenos/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Receptores Androgénicos/química , Testosterona/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Tasa de SupervivenciaRESUMEN
The challenges of managing the toxicities associated with the current armamentarium to combat kidney cancer continue to grow. It is therefore paramount for providers to not only have knowledge of the disease, but to also have an understanding of the potential adverse effects associated with the various treatments. In addition, it is important to incorporate palliative care strategies to help manage symptoms, improve quality of life, and support patients and their families throughout the continuum of the disease. This article will discuss the general toxicities and symptomatic issues encountered in patients with kidney cancer who are receiving targeted therapies and immunotherapies. It will also define the components of palliative care and its benefits. The recommendations in this article are from source documentation noted in various guidelines of the Oncology Nursing Society, ASCO, the National Comprehensive Cancer Network, and the Society for Immunotherapy of Cancer. We feel it is appropriate to modify and individualize management as deemed necessary to provide the best outcome for patients and their families.
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In this review, we describe how clinical investigators addressed some of the challenges in prostate cancer chemotherapy trials 20 years ago, and we indicate what has evolved in the field since that time. We consider the impact that prostate-specific antigen measurement had in this setting, evolving clinical paradigms, multidisciplinary programs, and the current armamentarium of cancer treatment, including targeted molecular therapy, for patients with hormone-refractory disease.
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Protocolos Antineoplásicos , Resistencia a Antineoplásicos , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/tratamiento farmacológico , Antineoplásicos Hormonales/uso terapéutico , Humanos , Masculino , Neoplasias de la Próstata/mortalidad , Tasa de SupervivenciaRESUMEN
PURPOSE: To evaluate the safety and biological activity of three different doses of marimastat given for 6 months to patients with biochemically relapsed prostate cancer. EXPERIMENTAL DESIGN: Patients with a biochemical relapse within 2 years of primary therapy, a prostate-specific antigen (PSA) increase of at least 50% within 6 months of study entry, and no prior systemic therapy were eligible. Patients were randomized to receive marimastat at total daily doses of 5, 20, or 40 mg for 6 months unless dose-limiting toxicity or new evidence of disease occurred. RESULTS: Thirty-nine patients were treated. Grade 3-4 reversible musculoskeletal toxicity was the only dose-limiting toxicity. Increasing dose was associated with increased probability of experiencing dose-limiting toxicity (5.9%, 42.9% and 88.9% for the 5, 20, and 40 mg groups, respectively; P = 0.03). Accrual was discontinued early on the two higher dose levels due to toxicity. A significant decrease in PSA slope was shown in the 20 mg group when compared with the 5 mg group (0.117 and -0.0046, respectively; P = 0.03) The 40 mg group (versus the 5 mg group) showed a similar change (0.109) with a trend towards significance (P = 0.07). An increased serum matrix metalloproteinase 2 level at month 3 compared with the baseline correlated with a decrease in PSA slopes (Slope, 0.001; 95% confidence interval, 0.0002-0.0018; P = 0.02). CONCLUSION: These data suggest that marimastat has a biological effect and may effectively delay progression in patients with biochemical relapsed prostate cancer, as shown by the change in PSA slope; however, dose-limiting toxicity at active doses is significant. Confirmatory studies with less toxic matrix metalloproteinase inhibitors employing more conventional end points are indicated. This design is feasible and potentially efficient for screening antimetastatic agents.
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Ácidos Hidroxámicos/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Anciano , Análisis de Varianza , Artralgia/inducido químicamente , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/uso terapéutico , Humanos , Ácidos Hidroxámicos/administración & dosificación , Ácidos Hidroxámicos/efectos adversos , Masculino , Metaloendopeptidasas/antagonistas & inhibidores , Metaloendopeptidasas/metabolismo , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estudios Prospectivos , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/patología , Tiempo , Resultado del TratamientoRESUMEN
PURPOSE: Studies suggested the existence of a 'trial effect', in which for a given treatment, participation in a clinical trial is associated with a better outcome. Sunitinib is a standard treatment for metastatic renal cell carcinoma (mRCC). We aimed to study the effect of clinical trial participation on the outcome of mRCC patients treated with sunitinib, which at present, is poorly defined. MATERIALS AND METHODS: The records of mRCC patients treated with sunitinib between 2004-2013 in 7 centers across 2 countries were reviewed. We compared the response rate (RR), progression free survival (PFS), and overall survival (OS), between clinical trial participants (n=49) and a matched cohort of non-participants (n=49) who received standard therapy. Each clinical trial participant was individually matched with a non-participant by clinicopathologic factors. PFS and OS were determined by Cox regression. RESULTS: The groups were matched by age (median 64), gender (male 67%), Heng risk (favorable 25%, intermediate 59%, poor 16%), prior nephrectomy (92%), RCC histology (clear cell 86%), pre-treatment NLR (>3 in 55%, n=27), sunitinib induced hypertension (45%), and sunitinib dose reduction/treatment interruption (41%). In clinical trial participants versus non-participants, RR was partial response/stable disease 80% (n=39) versus 74% (n=36), and progressive disease 20% (n=10) versus 26% (n=13) (p=0.63, OR 1.2). The median PFS was 10 versus 11 months (HR=0.96, p=0.84), and the median OS 23 versus 24 months (HR=0.97, p=0.89). CONCLUSIONS: In mRCC patients treated with sunitinib, the outcome of clinical trial participants was similar to that of non-participants who received standard therapy.
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Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Ensayos Clínicos como Asunto/psicología , Indoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Pirroles/uso terapéutico , Adulto , Anciano , Inhibidores de la Angiogénesis/uso terapéutico , Artefactos , Carcinoma de Células Renales/psicología , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Renales/psicología , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Estudios Retrospectivos , Sunitinib , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Although studies in several cancer types suggest that metformin has antitumor activity, its effect on the outcome of targeted therapies in metastatic renal cell carcinoma (mRCC) is poorly defined. We aimed to analyze the effect of metformin use on the outcome of sunitinib treatment in diabetic patients with mRCC. PATIENTS AND METHODS: We performed a retrospective study of diabetic patients with mRCC, who were treated with sunitinib in 8 centers across 2 countries. Patients were divided into metformin users and nonusers. The effect of metformin use on response rate, progression-free survival (PFS), and overall survival (OS), was tested. Furthermore, univariate and multivariate analyses of the association between clinicopathologic factors and metformin use, and outcome were performed using the entire patient cohort. RESULTS: Between 2004 and 2014, 108 diabetic patients with mRCC were treated with sunitinib. There were 52 metformin users (group 1) and 56 nonusers (group 2). The groups were balanced regarding clinicopathologic factors. Clinical benefit (partial response + stable disease) in group 1 versus 2 was 96% versus 84% (P = .054). Median PFS was 15 versus 11.5 months (P = .1). Median OS was 32 versus 21 months (P = .001). In multivariate analyses of the entire patient cohort (n = 108), factors associated with PFS were active smoking and pretreatment neutrophil to lymphocyte ratio > 3. Factors associated with OS were metformin use (hazard ratio, 0.21; P < .0001), Heng risk, active smoking, liver metastases, and pretreatment neutrophil to lymphocyte ratio > 3. CONCLUSION: Metformin might improve the OS of diabetic patients with mRCC who are treated with sunitinib.
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Carcinoma de Células Renales/tratamiento farmacológico , Diabetes Mellitus/tratamiento farmacológico , Indoles/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Metformina/administración & dosificación , Pirroles/administración & dosificación , Anciano , Anciano de 80 o más Años , Comorbilidad , Supervivencia sin Enfermedad , Femenino , Humanos , Indoles/uso terapéutico , Masculino , Metformina/uso terapéutico , Persona de Mediana Edad , Metástasis de la Neoplasia , Modelos de Riesgos Proporcionales , Pirroles/uso terapéutico , Estudios Retrospectivos , Sunitinib , Resultado del TratamientoRESUMEN
PURPOSE: Endothelin receptors, particularly the ET(A) receptor, have been shown to participate in the pathophysiology of prostate and other cancers. Atrasentan, an endothelin antagonist, binds selectively to the ET(A) receptor. This study evaluated the safety, pharmacokinetics, and maximum-tolerated dose of atrasentan in cancer patients. PATIENTS AND METHODS: Patients who were 18 years or older and had histologically confirmed adenocarcinoma refractory to therapy enrolled in this 28-day, open-label, phase I study. Enrollment was planned for cohorts of three patients at doses escalating from 10 to 140 mg/d. When any patient had dose-limiting toxicity, that cohort was expanded. The primary outcome variable was safety; secondary outcome variables were pharmacokinetics, tumor response, and pain relief. RESULTS: Thirty-one cancer patients (14 prostate) were treated at daily atrasentan doses of 10, 20, 30, 45, 60, and 75 mg (n = 3 to 8 per cohort). The most common adverse events, such as rhinitis, headache, asthenia, and peripheral edema, were reversible on drug discontinuation and responded to symptom-specific treatment. Reversible hemodilution was apparent in laboratory findings and weight gain. Clinically significant headache was the dose-limiting adverse event; the maximum-tolerated dose was 60 mg/d. Pharmacokinetics were dose-proportional across the 10- to 75-mg dose range. Atrasentan was rapidly absorbed; the time to maximum observed concentration was approximately 1.5 hours. The terminal elimination half-life was approximately 24 hours, and steady-state plasma concentrations were achieved within 7 days. Decreases in prostate-specific antigen and pain relief were noted in a patient subset. CONCLUSION: Adverse events were consistent with atrasentan's pharmacologic vasodilatory effect. Linear, dose-proportional pharmacokinetics suggest that atrasentan can be easily and consistently dosed.
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Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Antagonistas de los Receptores de Endotelina , Pirrolidinas , Adulto , Anciano , Antineoplásicos/farmacocinética , Atrasentán , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/tratamiento farmacológico , Terapia RecuperativaRESUMEN
The combination of temozolomide (TEM) and interferon-alpha (IFN-alpha) previously demonstrated a 30% response rate in metastatic melanoma. A single institution, phase II trial evaluating the efficacy of TEM/IFN in patients with advanced renal cell carcinoma (RCC) was conducted. Safety and tumor response were the main outcomes. Eligible patients received 200 mg/m(2)/day TEM orally on days 1-5 every 28 days, with IFN 2.5 million U/m(2)/day subcutaneously (s.c.) three alternate days/week for days 1-15 first cycle, then 5 million U/m(2)/day s.c. 3 alternate days/week throughout each 28-day cycle. Efficacy was evaluated every 8 weeks, and dose-limiting toxicities (DLTs) were treated with dose reductions of the culprit drug. Sixteen patients (ages 37-67) were initially enrolled. Of the 14 evaluable patients, there was one minor response. Best response was stable disease, with 7 patients remaining on study for > or =6 months. Five were alive for more than 2 years, and 2 remain alive at 45 and 50 months after enrollment. DLTs included TEM-induced myelosuppression and IFN-induced fever/chills. Other toxicities were mild to moderate (grades 1-3). The combination of TEM/IFN proved quite tolerable. This regimen appears inactive in terms of response in this population with poor prognosis, but the patients with stable disease > or =6 months remain of interest.
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Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Renales/tratamiento farmacológico , Dacarbazina/análogos & derivados , Dacarbazina/uso terapéutico , Interferón-alfa/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Antineoplásicos/administración & dosificación , Dacarbazina/administración & dosificación , Femenino , Humanos , Interferón-alfa/administración & dosificación , Masculino , Persona de Mediana Edad , Temozolomida , Resultado del TratamientoRESUMEN
BACKGROUND: Bisphosphonates are used to prevent skeletal events of bone metastases, and may exhibit antitumour effects. We aimed to evaluate whether bisphosphonates can bring a response rate (RR), progression free survival (PFS) and overall survival (OS) benefit to patients with bone metastasis from renal cell carcinoma (RCC) that is treated with sunitinib. METHODS: We performed a multicentre retrospective study of patients with bone metastases from RCC that was treated with sunitinib. The effect of bisphosphonates on RR, PFS and OS was tested with adjustment for known prognostic factors using a chi-square test from contingency table and partial likelihood test from Cox regression model. RESULTS: Between 2004 and 2011, 209 patients with metastatic RCC were treated with sunitinib, 76 had bone metastases, 35 bisphosphonates users and 41 non-users. The groups of bisphosphonates users and non-users were balanced regarding known prognostic factors. Objective response was partial response/stable disease 86% (n = 30) versus 71% (n = 29), and progressive disease 14% (n = 5) versus 29% (n = 12) (p = 0.125, OR 2.48) in users versus non-users, respectively. Median PFS was 15 versus 5 months (HR = 0.55, p<0.0001), and median OS was not reached (with a median follow-up time of 45 months) versus 14 months (HR = 0.4, p = 0.029), in favour of users. In multivariate analysis of the entire patient cohort (n = 76), factors associated with PFS were bisphosphonates use (HR = 0.58, p = 0.035), and pre-treatment neutrophil to lymphocyte ratio >3 (HR = 3.5, p = 0.009). Factors associated with OS were bisphosphonates use (HR = 0.5, p = 0.008), elevated pre-treatment alkaline phosphatase (HR = 2.9, p = 0.003) and sunitinib induced HTN (HR = 0.63, p<0.0001). CONCLUSIONS: Bisphosphonates may improve the RR, PFS and OS of sunitinib treatment in RCC with bone metastases.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/secundario , Difosfonatos/administración & dosificación , Indoles/administración & dosificación , Neoplasias Renales/patología , Pirroles/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/mortalidad , Esquema de Medicación , Femenino , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/mortalidad , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sunitinib , Resultado del TratamientoRESUMEN
BACKGROUND: This study was designed to evaluate toxicity and preliminary efficacy of 2 cycles of concomitant standard dose/schedule of (153)Sm-lexidronam plus Q 3 weeks schedule escalating doses of docetaxel in metastatic castration-resistant prostate cancer (mCRPC). METHODS: mCRPC patients with progressive bone metastases were treated in 4 cohorts. Docetaxel doses were escalated from 50, 50, 0 mg/m(2) (on days 1, 22, 43, per 12-week cycle) to 75, 75, 75 mg/m(2). (153)Sm-lexidronam was administered on days 2 (Q 12 weeks) at dose of 1 mCi/kg/cycle (maximum of 2 cycles). RESULTS: Thirteen patients received an average of 3.6 doses of docetaxel (range, 2-6 doses, median 4) and 1.5 doses of (153)Sm-lexidronam (range, 1-2, median 2). Toxicity was primarily hematologic. There were total 35 episodes grade 3/4 neutropenia with a median 7 (range 7-14) days to recovery to ≤grade 1. One dose limiting grade 3 thrombocytopenia occurred on cohorts 3 and 4. Eight of 13 (62%) patients had PSA > 50% decrease as best response during the treatment. Median time to bone disease progression was 5.2 months (range 91 days-10 months+); 6/13 (46%) patients had stable/improved bone scans at 6 months and 6/6 (100%) symptomatic patients had improvement in pain. CONCLUSIONS: Concurrent 6-month administration of 4 doses (75 mg/m(2)) of standard Q 3 weeks schedule of docetaxel with 2 Q 3 months infusions of 1 mCi/Kg (153)Sm-lexidronam is feasible with reversible bone marrow suppression, and deserves further testing in mCRPC patients with extensive bone metastasis.