RESUMEN
BACKGROUND: In metastatic castration-resistant prostate cancer (mCRPC), assessing treatment response and bone lesions with technetium-99m is limited by image resolution and subjectivity. We evaluated bone scan lesion area (BSLA), a quantitative imaging assessment of response in patients with mCRPC receiving radium-223 alone or in combination with androgen receptor pathway inhibitors (abiraterone/prednisone or enzalutamide). PATIENTS AND METHODS: This randomized, non-comparative phase IIa three-arm trial (NCT02034552) evaluated technetium-99m-based BSLA response rate (RR), safety, radiologic progression-free survival (rPFS), and time to first symptomatic skeletal event (SSE) in men with mCRPC and bone metastases receiving radium-223 with/without abiraterone/prednisone or enzalutamide. The primary endpoint was week 24 BSLA RR. RESULTS: Overall, 63 patients received treatment (abiraterone/prednisone combination, n = 22; enzalutamide combination, n = 22; radium-223 monotherapy, n = 19). Median treatment duration (first to last dose of any study treatment) was 12 months (abiraterone/prednisone combination), 10 months (enzalutamide combination), and 3 months (radium-223 monotherapy). Week 24 BSLA RR was 58% [80% confidence interval (CI) 41% to 74%; one-sided P < 0.0001; 11/19 patients] with abiraterone/prednisone combination, 50% (32% to 68%; one-sided P < 0.0001; 8/16 patients) with enzalutamide combination, and 22% (10% to 40%; one-sided P = 0.0109; 4/18 patients) with radium-223 monotherapy. Median rPFS was not evaluable for combination arms and 4 months (80% CI 4 to 12) for monotherapy. SSEs were reported in 32% of patients; median time to first SSE was not estimable. Fatigue and back pain were the most commonly reported treatment-emergent adverse events (TEAEs); more patients receiving combination therapy than monotherapy had TEAEs. Fractures were reported in 18% receiving abiraterone/prednisone, 32% receiving enzalutamide, and 11% receiving radium-223 monotherapy. Fracture rates were lower in patients taking bone health agents versus not taking bone health agents at baseline. CONCLUSIONS: Technetium-99m imaging BSLA may offer objective, quantifiable assessment of isotope uptake changes, and potentially treatment response, in patients with mCRPC and bone metastases treated with radium-223 alone or in combination with abiraterone/prednisone or enzalutamide. In this largely treatment-naive population, BSLA RR was numerically lower with radium-223 monotherapy versus combination therapy, indicating a limited role as first-line treatment. Use of radium-223 should follow evidence-based treatment guidelines and the licensed indication.
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Acetato de Abiraterona , Neoplasias de la Próstata Resistentes a la Castración , Acetato de Abiraterona/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Benzamidas , Humanos , Masculino , Nitrilos , Feniltiohidantoína , Prednisona/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/radioterapia , Radio (Elemento) , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: We have shown previously in multivariable analysis that black men had 19% lower risk of death than white men with metastatic castration-resistant prostate cancer (mCRPC) treated with a docetaxel and prednisone (DP)-based regimen. The primary goal of this analysis was to compare progression-free survival (PFS), biochemical PFS, ≥50% decline in prostate-specific antigen (PSA) from baseline and objective response rate (ORR) in white, black and Asian men with mCRPC treated with a DP-based regimen. PATIENTS AND METHODS: Individual patient data from 8820 mCRPC men randomized on nine phase III trials to a DP-containing regimen were combined. Race used in the analysis was based on self-report. End points were PFS, biochemical PSA, ≥50% decline in PSA from baseline and ORR. The proportional hazards and the logistic regression models were employed to assess the prognostic importance of race in predicting outcomes adjusting for established prognostic factors. RESULTS: Of 8820 patients, 7528 (85%) were white, 500 (6%) were black, 424 were Asian (5%) and 368 (4%) had race unspecified. Median PFS were 8.3 [95% confidence interval (CI) 8.2-8.5], 8.2 (95% CI 7.4-8.8) and 8.3 (95% CI 7.6-8.8) months in white, black and Asian men, respectively. Median PSA PFS were 9.9 (95% CI 9.7-10.4), 8.5 (95% CI 8.0-10.3) and 11.1 (95% CI 9.9-12.5) months in white, black and Asian men, respectively. CONCLUSIONS: We observed no differences in clinical outcomes by race and ethnic groups in men with mCRPC enrolled on these phase III clinical trials with DP.
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Neoplasias de la Próstata Resistentes a la Castración , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Supervivencia sin Enfermedad , Docetaxel/uso terapéutico , Etnicidad , Humanos , Masculino , Prednisona/uso terapéutico , Antígeno Prostático Específico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Background: Prognostic models are needed that reflect contemporary practice for men with metastatic castration-resistant prostate cancer (mCRPC). We sought to identify predictive and prognostic variables for overall survival (OS) in chemotherapy-naïve men with mCRPC treated with enzalutamide. Patients and methods: Patients from the PREVAIL trial database (enzalutamide versus placebo) were randomly split 2 : 1 into training (n = 1159) and testing (n = 550) sets. Using the training set, 23 predefined variables were analyzed and a multivariable model predicting OS was developed and validated in an independent testing set. Results: Patient characteristics and outcomes were well balanced between training and testing sets; median OS was 32.7 months in each. The final validated multivariable model included 11 independent prognostic variables. Median OS for low-, intermediate-, and high-risk groups (testing set) defined by prognostic risk tertiles were not yet reached (NYR) (95% CI NYR-NYR), 34.2 months (31.5-NYR), and 21.1 months (17.5-25.0), respectively. Hazard ratios (95% CI) for OS in the low- and intermediate-risk groups versus high-risk group were 0.20 (0.14-0.29) and 0.40 (0.30-0.53), respectively. Secondary outcomes of response and progression differed widely in model-defined risk groups. Enzalutamide improved outcomes in all prognostic risk groups. Conclusions: Our validated prognostic model incorporates variables routinely collected in chemotherapy-naïve men with mCRPC treated with enzalutamide, identifying subsets of patients with widely differing survival outcomes that provide useful information for external validation, patient care, and clinical trial design. Trial registration: ClinicalTrials.gov: NCT01212991.
Asunto(s)
Antagonistas de Andrógenos/uso terapéutico , Antineoplásicos/uso terapéutico , Modelos Biológicos , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas , Biomarcadores de Tumor/sangre , Progresión de la Enfermedad , Humanos , Masculino , Nitrilos , Feniltiohidantoína/uso terapéutico , Pronóstico , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Neoplasias de la Próstata Resistentes a la Castración/sangre , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/patologíaRESUMEN
OBJECTIVE: Androgen deprivation therapy (ADT) is a common treatment option for men with biochemical relapse from prostate cancer. ADT is associated with changes in mood, cognition, and quality of life, and most recently with increased risk for Alzheimer's disease (AD). This study examined changes in brain metabolism using positron emission tomography (PET) in men undergoing intermittent ADT. METHODS: Nine men with prostate cancer and a rising PSA (biochemical recurrence) without evidence of metastases were treated with intermittent ADT consisting of 9 months of complete androgen blockade achieved with combined leuprolide acetate and flutamide. Patients underwent resting [Fuorine-18] fluorodeoxyglucose PET (18F-FDGPET) at baseline (before treatment) and again after 9 months of ADT. RESULTS: Whole-brain mapping analysis after 9 months of androgen deprivation compared to pretreatment baseline revealed decreased regional cerebral glucose metabolism in the cerebellum, posterior cingulate, and medial thalamus bilaterally. Associations of brain metabolism with measurements of cognition and mood while on androgen deprivation revealed positive correlations between the posterior cingulate, left inferior parietal lobule (BA40), and left mid temporal gyrus (BA39) and spatial reasoning and a negative correlation between left inferior parietal lobule and verbal memory. Several mood indices were negatively correlated with hypothalamus and brainstem. CONCLUSION: These findings suggest that complete androgen deprivation may result in changes in regional brain metabolism associated with variation in mood, verbal memory, and spatial performance. Brain regions that were impacted from ADT are similar and overlap with brain regions with metabolic decline found in early AD and diabetes, suggesting possible common mechanisms.
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Antagonistas de Andrógenos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Encéfalo/efectos de los fármacos , Neoplasias de la Próstata/tratamiento farmacológico , Calidad de Vida , Afecto/efectos de los fármacos , Anciano , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Cognición/efectos de los fármacos , Flutamida/efectos adversos , Humanos , Calicreínas/sangre , Leuprolida/efectos adversos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/patologíaRESUMEN
BACKGROUND: Mutations in the androgen receptor (AR) ligand-binding domain (LBD), such as F877L and T878A, have been associated with resistance to next-generation AR-directed therapies. ARN-509-001 was a phase I/II study that evaluated apalutamide activity in castration-resistant prostate cancer (CRPC). Here, we evaluated the type and frequency of 11 relevant AR-LBD mutations in apalutamide-treated CRPC patients. PATIENTS AND METHODS: Blood samples from men with nonmetastatic CRPC (nmCRPC) and metastatic CRPC (mCRPC) pre- or post-abiraterone acetate and prednisone (AAP) treatment (≥6 months' exposure) were evaluated at baseline and disease progression in trial ARN-509-001. Mutations were detected in circulating tumor DNA using a digital polymerase chain reaction-based method known as BEAMing (beads, emulsification, amplification and magnetics) (Sysmex Inostics' GmbH). RESULTS: Of the 97 total patients, 51 had nmCRPC, 25 had AAP-naïve mCRPC, and 21 had post-AAP mCRPC. Ninety-three were assessable for the mutation analysis at baseline and 82 of the 93 at progression. The overall frequency of detected AR mutations at baseline was 7/93 (7.5%) and at progression was 6/82 (7.3%). Three of the 82 (3.7%) mCRPC patients (2 AAP-naïve and 1 post-AAP) acquired AR F877L during apalutamide treatment. At baseline, 3 of the 93 (3.2%) post-AAP patients had detectable AR T878A, which was lost after apalutamide treatment in 1 patient who continued apalutamide treatment for 12 months. CONCLUSIONS: The overall frequency of detected mutations at baseline (7.5%) and progression (7.3%) using the sensitive BEAMing assay was low, suggesting that, based on this assay, AR-LBD mutations such as F877L and T878A are not common contributors to de novo or acquired resistance to apalutamide. CLINICALTRIALS.GOV IDENTIFIER: NCT01171898.
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Antagonistas de Andrógenos/uso terapéutico , Mutación Puntual , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Receptores Androgénicos/genética , Tiohidantoínas/uso terapéutico , Anciano , Anciano de 80 o más Años , ADN Tumoral Circulante/genética , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Advanced prostate cancer is a phenotypically diverse disease that evolves through multiple clinical courses. PSA level is the most widely used parameter for disease monitoring, but it has well-recognized limitations. Unlike in clinical trials, in practice, clinicians may rely on PSA monitoring alone to determine disease status on therapy. This approach has not been adequately tested. METHODS: Chemotherapy-naive asymptomatic or mildly symptomatic men (n=872) with metastatic castration-resistant prostate cancer (mCRPC) who were treated with the androgen receptor inhibitor enzalutamide in the PREVAIL study were analyzed post hoc for rising versus nonrising PSA (empirically defined as >1.05 vs ⩽1.05 times the PSA level from 3 months earlier) at the time of radiographic progression. Clinical characteristics and disease outcomes were compared between the rising and nonrising PSA groups. RESULTS: Of 265 PREVAIL patients with radiographic progression and evaluable PSA levels on the enzalutamide arm, nearly one-quarter had a nonrising PSA. Median progression-free survival in this cohort was 8.3 months versus 11.1 months in the rising PSA cohort (hazard ratio 1.68; 95% confidence interval 1.26-2.23); overall survival was similar between the two groups, although less than half of patients in either group were still at risk at 24 months. Baseline clinical characteristics of the two groups were similar. CONCLUSIONS: Non-rising PSA at radiographic progression is a common phenomenon in mCRPC patients treated with enzalutamide. As restaging in advanced prostate cancer patients is often guided by increases in PSA levels, our results demonstrate that disease progression on enzalutamide can occur without rising PSA levels. Therefore, a disease monitoring strategy that includes imaging not entirely reliant on serial serum PSA measurement may more accurately identify disease progression.
Asunto(s)
Feniltiohidantoína/análogos & derivados , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata Resistentes a la Castración/sangre , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Anciano , Antineoplásicos/administración & dosificación , Benzamidas , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Nitrilos , Feniltiohidantoína/administración & dosificación , Modelos de Riesgos Proporcionales , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico por imagen , Neoplasias de la Próstata Resistentes a la Castración/patología , Resultado del TratamientoRESUMEN
BACKGROUND: Heat shock protein 27 (Hsp27) is a chaperone protein that regulates cell survival via androgen receptor and other signaling pathways, thereby mediating cancer progression. Apatorsen (OGX-427) is a 2'-methoxyethyl-modified antisense oligonucleotide that inhibits Hsp27 expression. This study evaluated the safety profile and recommended phase II dosing of apatorsen in patients with advanced cancer. PATIENTS AND METHODS: Patients with castration-resistant prostate (CRPC), breast, ovary, lung, or bladder cancer were enrolled to this phase I dose-escalation study. Apatorsen was administered i.v. weekly in 21-day cycles following 3 loading doses and over 5 dose levels (200-1000 mg). Apatorsen plasma concentrations, circulating tumor cells (CTCs) and CTC Hsp27 expression, and serum Hsp27 levels were evaluated. RESULTS: Forty-two patients were accrued, of which 52% had CRPC. Patients were heavily pretreated, with 57% having had ≥3 prior chemotherapy regimens. During the loading dose/cycle 1 and overall study period, 93% and 100% of patients (N = 42) experienced treatment-related adverse events, respectively; most were grade 1-2 and included chills, pruritus, flushing, prolonged aPTT, lymphopenia, and anemia. One patient experienced a dose-limiting toxicity at the 600 mg dose level (intracranial hemorrhage in a previously undiagnosed brain metastasis). A maximum tolerated dose was not defined. Apatorsen Cmax increased proportionally with dose. Decreases in tumor markers and declines in CTCs were observed, with a prostate-specific antigen decline >%50% occurring in 10% of patients with CRPC; 29/39 assessable patients (74%) had reductions from ≥5 CTC/7.5 ml at baseline to <5 CTC/7.5 ml post-treatment. Twelve patients had stable measurable disease as best response. CONCLUSIONS: Apatorsen was tolerated at the highest dose evaluated (1000 mg). Single-agent activity was suggested by changes in tumor markers, CTC, and stable measurable disease. Phase II studies evaluating apatorsen are underway. CLINICALTRIALSGOV ID: NCT00487786.
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Diazepam/administración & dosificación , Proteínas de Choque Térmico HSP27/antagonistas & inhibidores , Oligonucleótidos Antisentido/administración & dosificación , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Diazepam/efectos adversos , Diazepam/farmacocinética , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteínas de Choque Térmico HSP27/genética , Proteínas de Choque Térmico , Humanos , Masculino , Persona de Mediana Edad , Chaperonas Moleculares , Células Neoplásicas Circulantes/efectos de los fármacos , Células Neoplásicas Circulantes/patología , Oligonucleótidos Antisentido/efectos adversos , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patologíaRESUMEN
BACKGROUND: Prostate cancer disproportionately affects older men. Because age affects treatment decisions, it is important to understand the efficacy and tolerability of therapies for advanced prostate cancer in elderly men. This analysis describes efficacy and safety outcomes in men aged ≥75 years who received enzalutamide, an androgen receptor inhibitor, in the phase III PREVAIL trial. PATIENTS AND METHODS: PREVAIL was a randomised, double-blind, multinational study of oral enzalutamide 160 mg/day (N = 872) versus placebo (N = 845) in chemotherapy-naive men with metastatic castration-resistant prostate cancer. Overall survival (OS) and radiographic progression-free survival (rPFS) were coprimary end points. Subgroup analysis of men aged ≥75 years (elderly) and men aged <75 years was pre-specified for the coprimary end points and adverse events (AEs). RESULTS: Among 609 elderly patients (35%) who participated in PREVAIL, median treatment duration was 16.6 and 5.0 months in the enzalutamide and placebo arms, respectively. In the elderly subgroup, OS was greater with enzalutamide than with placebo [32.4 months (95% confidence interval (CI) 27.7-not yet reached] versus 25.1 months (95% CI 22.6-28.0); hazard ratio (HR) = 0.61 (95% CI 0.47-0.79); P = 0.0001], as was rPFS [not yet reached (95% CI 12.3-not yet reached) versus 3.7 months (95% CI 3.6-5.3); HR = 0.17 (95% CI 0.12-0.24); P < 0.0001]. Irrespective of treatment assignment, incidence of AEs was similar between the two age groups, except for an overall higher incidence of falls among elderly patients than younger patients [84/609 (13.8%) versus 62/1106 (5.6%)] and among elderly patients receiving enzalutamide than those receiving placebo [61/317 (19.2%) versus 23/292 (7.9%)]. CONCLUSIONS: Elderly men benefited from treatment with enzalutamide in terms of OS and rPFS. Enzalutamide was well tolerated in the elderly subgroup and those aged <75 years. Age and enzalutamide treatment were associated with a higher incidence of falls. CLINICAL TRIAL IDENTIFIER: NCT01212991, ClinicalTrials.gov.
Asunto(s)
Antagonistas de Receptores Androgénicos/uso terapéutico , Antineoplásicos/uso terapéutico , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Accidentes por Caídas/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Antagonistas de Receptores Androgénicos/efectos adversos , Antineoplásicos/efectos adversos , Benzamidas , Supervivencia sin Enfermedad , Método Doble Ciego , Humanos , Masculino , Persona de Mediana Edad , Nitrilos , Feniltiohidantoína/efectos adversos , Feniltiohidantoína/uso terapéutico , Placebos , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/patologíaRESUMEN
BACKGROUND: Type 1 insulin-like growth factor receptor (IGF-IR) signaling is often dysregulated in cancer. Cixutumumab, a fully human IgG1 monoclonal antibody, blocks IGF-IR and inhibits downstream signaling. The current study determined the recommended dose, safety, and pharmacokinetic (PK) profile of weekly or every-2-week dosing of cixutumumab. PATIENTS AND METHODS: Two open-label, multicenter phase I studies evaluated weekly (3-15 mg/kg) or every-2-weeks (6-15 mg/kg) dosing of cixutumumab in patients with advanced solid tumors. Serial blood samples for PK were collected up to 168-336 h (day 8-15) following the first administration of cixutumumab. Efficacy was evaluated as best overall tumor response. RESULTS: A total of 24 and 16 patients were enrolled in the weekly and every-2-week dosing studies, respectively. Treatment-emergent adverse events (≥10%) included hyperglycemia, fatigue, anemia, nausea, and vomiting. Severe adverse events (AE) were infrequent; one serious AE (grade 3 electrocardiogram QT prolongation) was deemed possibly cixutumumab-related (10 mg/kg every-2-weeks). One death occurred due to disease progression (6 mg/kg weekly cohort). Maximum serum concentrations increased with dose. A maximum tolerated dose was not identified; pre-determined target serum minimum concentrations (60 µg/mL) were achieved with ≥6 mg/kg weekly and ≥10 mg/kg every-2-week dosing. Cixutumumab terminal elimination half-life is approximately a week (individual range, t1/2 = 4.58-9.33 days based upon 10 mg/kg every 2 weeks). Overall, stable disease was achieved in 25% of all patients. CONCLUSIONS: Cixutumumab was associated with favorable safety and PK profiles. A dosing regimen of 10 mg/kg every 2 weeks was recommended for subsequent disease-focused clinical trials.
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Anticuerpos Monoclonales/farmacocinética , Antineoplásicos/farmacocinética , Neoplasias/tratamiento farmacológico , Receptor IGF Tipo 1/antagonistas & inhibidores , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Área Bajo la Curva , Femenino , Semivida , Humanos , Masculino , Dosis Máxima Tolerada , Tasa de Depuración Metabólica , Persona de Mediana EdadRESUMEN
BACKGROUND: Sipuleucel-T has demonstrated improved overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC). This analysis examined the effect of sipuleucel-T on time to disease-related pain (TDRP) and time to first use of opioid analgesics (TFOA) in mCRPC using data pooled from three randomized phase III studies in men with asymptomatic or minimally symptomatic mCRPC (D9901 (NCT00005947), D9902A (NCT01133704), D9902B (IMPACT; NCT00065442)). METHODS: Four-hundred and twenty-eight asymptomatic patients were analyzed for TDRP; 737 patients were analyzed for TFOA. Pain status was collected using logs adjudicated by blinded, independent reviewers. Opioid use for cancer-related pain was identified from medically reviewed reports of concomitant medication. Disease-related pain was defined as pain post enrollment. TDRP and TFOA were analyzed using the Kaplan-Meier method and Cox regression. RESULTS: Treatment with sipuleucel-T was not associated with a significant difference in TDRP (hazard ratio (HR)=0.819; 95% confidence interval (CI): 0.616-1.089; P=0.170; median TDRP 5.6 months for sipuleucel-T and 5.3 months for control, respectively), although 39.3% of sipuleucel-T-treated patients and 18.9% of control patients were pain-free at 12 months. However, there was a significant delay in TFOA with sipuleucel-T (HR=0.755; 95% CI: 0.579-0.985; P=0.038). Median TFOA for sipuleucel-T was 12.6, and 9.7 months for control, with 50.6% and 43.1% opioid-free at 12 months, respectively. Kaplan-Meier curves for both end points began to diverge at 6 months. CONCLUSIONS: Sipuleucel-T was associated with longer TFOA but not significantly longer TDRP. Both end points demonstrated evidence of a delayed treatment effect, consistent with an active immunotherapy.
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Analgésicos Opioides/uso terapéutico , Antineoplásicos/uso terapéutico , Dolor/tratamiento farmacológico , Dolor/etiología , Neoplasias de la Próstata Resistentes a la Castración/complicaciones , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Extractos de Tejidos/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Ensayos Clínicos Fase III como Asunto , Progresión de la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Metástasis de la Neoplasia , Dolor/diagnóstico , Neoplasias de la Próstata Resistentes a la Castración/patología , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de TiempoRESUMEN
AIMS: The second most frequently reported post-treatment symptom in cancer survivors are concerns about impaired cognition. Despite numerous studies demonstrating significant impairments in a portion of survivors, information on effective treatments remains an emerging area of research. This study examined the effectiveness of a group-based cognitive rehabilitation intervention in cancer survivors. MAIN METHODS: This study was a randomized, controlled study of a 7-week cognitive rehabilitation intervention delivered in group format. Participants were evaluated with subjective symptom questionnaires and objective neurocognitive tests prior to and following treatment. KEY FINDINGS: Twenty-eight participants (mean age 58 years) with a median of 3 years (± 6 years) post-primary/adjuvant treatment and various cancer sites (breast, bladder, prostate, colon, uterine) completed the study. Compared to baseline, the treatment group demonstrated improvements in symptoms of perceived cognitive impairments (p<.01), cognitive abilities (p<.01) and overall quality of life with regard to cognitive symptoms (p<.01) as measured by the FACT-Cog. The treatment group also improved on objective measures of attention (p<.05) and a trend toward improvement on verbal memory. Significant improvement was not observed on all cognitive tests. SIGNIFICANCE: A group based cognitive rehabilitation intervention in cancer survivors was effective for improving attention abilities and overall quality of life related to cognition. Results suggest that group based cognitive rehabilitation may be an effective intervention for treating cognitive dysfunction in cancer patients and should be further studied in a larger trial with an active control condition.
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Trastornos del Conocimiento/psicología , Trastornos del Conocimiento/rehabilitación , Terapia Cognitivo-Conductual , Neoplasias/psicología , Neoplasias/rehabilitación , Sobrevivientes/psicología , Afecto , Ansiedad/complicaciones , Ansiedad/psicología , Atención , Trastornos del Conocimiento/complicaciones , Femenino , Humanos , Masculino , Memoria , Persona de Mediana Edad , Neoplasias/complicaciones , Pruebas Neuropsicológicas , Satisfacción del Paciente , Psicoterapia de Grupo , Calidad de Vida/psicologíaRESUMEN
BACKGROUND: This phase I/II study in patients with metastatic castration-resistant prostate cancer (mCRPC) explored ipilimumab as monotherapy and in combination with radiotherapy, based on the preclinical evidence of synergistic antitumor activity between anti-CTLA-4 antibody and radiotherapy. PATIENTS AND METHODS: In dose escalation, 33 patients (≥6/cohort) received ipilimumab every 3 weeks × 4 doses at 3, 5, or 10 mg/kg or at 3 or 10 mg/kg + radiotherapy (8 Gy/lesion). The 10-mg/kg cohorts were expanded to 50 patients (ipilimumab monotherapy, 16; ipilimumab + radiotherapy, 34). Evaluations included adverse events (AEs), prostate-specific antigen (PSA) decline, and tumor response. RESULTS: Common immune-related AEs (irAEs) among the 50 patients receiving 10 mg/kg ± radiotherapy were diarrhea (54%), colitis (22%), rash (32%), and pruritus (20%); grade 3/4 irAEs included colitis (16%) and hepatitis (10%). One treatment-related death (5 mg/kg group) occurred. Among patients receiving 10 mg/kg ± radiotherapy, eight had PSA declines of ≥50% (duration: 3-13+ months), one had complete response (duration: 11.3+ months), and six had stable disease (duration: 2.8-6.1 months). CONCLUSIONS: In mCRPC patients, ipilimumab 10 mg/kg ± radiotherapy suggested clinical antitumor activity with disease control and manageable AEs. Two phase III trials in mCRPC patients evaluating ipilimumab 10 mg/kg ± radiotherapy are ongoing. ClinicalTrials.gov identifier: NCT00323882.
Asunto(s)
Adenocarcinoma/terapia , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias de la Próstata/terapia , Adenocarcinoma/sangre , Adenocarcinoma/mortalidad , Anciano , Anciano de 80 o más Años , Quimioradioterapia , Humanos , Inmunoterapia , Ipilimumab , Estimación de Kaplan-Meier , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/mortalidad , Resultado del TratamientoRESUMEN
BACKGROUND: Standard treatment options are limited for the management of non-metastatic castration-resistant prostate cancer (CRPC). This study, part of the ENTHUSE (EndoTHelin A USE) phase III programme, evaluated the efficacy and safety of the oral specific endothelin (ET)A receptor antagonist zibotentan vs placebo in patients with non-metastatic CRPC (non-mCRPC). METHODS: This was a multicentre, randomized, double-blind, phase III study. Patients (n=1421) with non-mCRPC and biochemical progression (determined by rising serum PSA levels) were randomized to receive zibotentan 10 mg or placebo once daily. Based on the lack of efficacy signal in another ENTHUSE phase III study, an interim analysis was performed to determine whether the study was likely to achieve the co-primary objectives of improved overall survival (OS) and progression-free survival (PFS). RESULTS: Criteria for continuation of this study were not met. A total of 79 deaths and 293 progression events were recorded at final data cutoff. Zibotentan-treated patients did not significantly differ from placebo-treated patients for OS (hazard ratio (HR): 1.13; 95% confidence interval (CI): 0.73-1.76, P=0.589) or PFS (HR: 0.89; 95% CI: 0.71-1.12, P=0.330). The most commonly reported adverse events in zibotentan-treated patients were peripheral oedema (37.7%), headache (26.2%) and nasal congestion (24.9%); each occurred with >15% higher incidence than in the placebo group. CONCLUSIONS: This trial was terminated early because of failure at interim analysis of the efficacy data to meet the defined criteria for continuation. Owing to the absence of demonstrable survival benefits in the ENTHUSE clinical studies, zibotentan is no longer under investigation as a potential treatment for prostate cancer.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/administración & dosificación , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Pirrolidinas/administración & dosificación , Adenocarcinoma/mortalidad , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Método Doble Ciego , Esquema de Medicación , Edema/inducido químicamente , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Pirrolidinas/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Histone deacetylase blockade can promote heat shock protein 90 (HSP90) acetylation, abrogating androgen receptor signaling. A phase II trial of the histone deacetylase inhibitor (HDACi) romidepsin was conducted in patients with progressing, metastatic, castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: A dose of 13 mg/m(2) was administered i.v. over 4 h on days 1, 8 and 15 every 28 days. The primary end point was rate of disease control defined as no evidence of radiological progression at 6 months. A sample size of 16 assessable patients in stage 1 and nine assessable patients in stage 2 was selected; progression to stage 2 required one or more patients with disease control in stage 1 (H(o) = 0.10, H(a) = 0.30; alpha and beta = 0.10). RESULTS: Thirty-five patients were enrolled. Two patients achieved a confirmed radiological partial response (RECIST) lasting > or = 6 months, along with a confirmed prostate-specific antigen decline of > or = 50%. Eleven patients experienced toxicity necessitating early discontinuation. The commonest adverse events were nausea (30 patients; 85.7%), fatigue (28 patients; 80.0%), vomiting (23 patients; 65.7%) and anorexia (20 patients; 57.1%). There was no significant cardiac toxicity. CONCLUSIONS: At the dose and schedule selected, romidepsin demonstrated minimal antitumor activity in chemonaive patients with CRPC. Further studies of improved HDACi, alone and in combination with other therapies, should nevertheless be investigated.
Asunto(s)
Antibióticos Antineoplásicos/uso terapéutico , Depsipéptidos/uso terapéutico , Inhibidores de Histona Desacetilasas/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Hormonales/uso terapéutico , Castración , Resistencia a Antineoplásicos , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/patologíaRESUMEN
PURPOSE: Men with prostate-specific antigen (PSA)-only relapse of prostate cancer after primary therapy are generally fully functional and asymptomatic with a life expectancy of up to 10 or more years. Androgen deprivation therapy (ADT) is a common treatment option. This study examined mood and cognitive changes in otherwise healthy men with prostate cancer prior to, during and after ADT. EXPERIMENTAL DESIGN: Twenty hormone naïve, eugonadal prostate cancer patients without evidence of metastases and with a rising PSA were treated with intermittent ADT consisting of 9 months of complete androgen blockade (CAB) achieved with combined leuprolide and flutamide followed by an 'off treatment' period. Cognitive function tests and mood measures were administered at baseline, after 3 and 9 months of ADT and after 3 months of no treatment. Twenty healthy control patients without prostate cancer range matched for age and education were tested at the same time intervals. RESULTS: ADT patients evidenced a significant decline in spatial reasoning, spatial abilities and working memory during treatment compared with baseline. No changes were noted for measures of verbal or spatial memory, selective attention or language. Significant changes in self-rated mood such as increased depression, tension, anxiety, fatigue and irritability were evident during treatment compared with baseline for ADT patients. No significant changes in either cognitive tests or mood measures were noted for the healthy control group. CONCLUSIONS: These findings, suggest that 9 months of combined androgen blockade may result in some adverse changes in cognition and mood. However, many but not all of these changes can return to baseline after cessation of ADT.
Asunto(s)
Antagonistas de Andrógenos/uso terapéutico , Trastornos del Conocimiento/diagnóstico , Depresión/diagnóstico , Neoplasias de la Próstata/tratamiento farmacológico , Actitud Frente a la Salud , Trastornos del Conocimiento/epidemiología , Depresión/epidemiología , Depresión/psicología , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/epidemiología , Índice de Severidad de la Enfermedad , Percepción Espacial , Encuestas y CuestionariosRESUMEN
BACKGROUND: Drug resistance mechanisms can reduce response rate and duration in men with castration-resistant prostate cancer (CRPC) receiving docetaxel-based therapy. Patupilone (epothilone B), a microtubule-targeting agent, may be unaffected by some resistance mechanisms. Therefore, a phase II study assessed the patupilone safety and activity in CRPC patients with and without previous chemotherapy. METHODS: CRPC patients received patupilone 2.5 mg/m(2) weekly for 3 weeks of a 4-week cycle. Patients were required to have measurable disease or prostate-specific antigen (PSA) progression (levels>20 ng/ml). RESULTS: All 45 enrolled patients (median age, 69 years) were safety and response assessable. Sixty-four percent had previous chemotherapy (55% had previous taxane therapy). Patients received a median of three patupilone cycles. Patupilone was generally well tolerated. Ten (22%) patients experienced grade 3 diarrhea, six (13%) grade 3 fatigue, and one (2%) grade 3 neuropathy with no neutropenia or thrombocytopenia incidence. Six (13%) patients had >or= 50% decline in PSA (three had previous taxane therapy). No patient with measurable disease had a response. Median overall survival was 13.4 months. CONCLUSIONS: The safety profile of weekly patupilone in CRPC patients compares favorably with that of other microtubule inhibitors. At the dose and schedule tested, patupilone demonstrated minimal activity in CRPC.
Asunto(s)
Antineoplásicos/uso terapéutico , Epotilonas/uso terapéutico , Orquiectomía , Neoplasias de la Próstata/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Epotilonas/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/cirugíaRESUMEN
Conventional prostate adenocarcinomas consist mainly of tumour cells of luminal immunophenotype with scattered neuroendocrine (NE) cells. NE cells are defined by chromogranin A (CGA) immunoreactivity. Unlike luminal cells, NE cells lack androgen receptor (AR) and prostate specific antigen (PSA) immunoreactivity. This report describes the first case of conventional prostate adenocarcinoma expressing CGA, PSA, and AR as determined by immunohistochemistry. A 64 year old man was diagnosed with conventional prostate adenocarcinoma in 1993; he underwent cystoprostatectomy in 1994; he developed an iliac bone metastasis in 1997 and mediastinal lymph node metastases in 1999. All specimens obtained during the progression of the disease consisted primarily of luminal cells with only scattered NE cells. In contrast, in samples of non-osseous and osseous metastases obtained at necropsy in 2001, greater than 80% of tumour cells were shown to express PSA, AR, and CGA. This suggests that during tumour progression, conventional prostate adenocarcinomas may evolve into an NE cell phenotype.
Asunto(s)
Adenocarcinoma/química , Cromograninas/análisis , Neoplasias de la Próstata/química , Receptores Androgénicos/análisis , Adenocarcinoma/patología , Adenocarcinoma/secundario , Biomarcadores de Tumor/análisis , Neoplasias Óseas/secundario , Cromogranina A , Resultado Fatal , Humanos , Inmunohistoquímica , Metástasis Linfática , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/patología , Antígeno Prostático Específico/análisis , Neoplasias de la Próstata/patologíaRESUMEN
PURPOSE: Men with prostate specific antigen (PSA) only relapse of prostate cancer after primary therapy are generally fully functional and asymptomatic with a life expectancy of up to 10 or more years. These patients are often treated with androgen suppression. We evaluate the effects of androgen suppression on cognitive function. MATERIALS AND METHODS: Hormone naïve patients without evidence of metastases with an increasing PSA were treated with intermittent androgen suppression consisting of 9 months of leuprolide and flutamide followed by an off treatment period determined by the increase in PSA. Cognitive function tests were administered at baseline, after 9 months of androgen suppression and after 3 months off treatment. Cognitive tests measured spatial abilities, spatial memory, verbal fluency, verbal memory and selective attention. A total of 19 patients 52 to 76 years old completed the intermittent androgen suppression study along with 15 healthy community dwelling control participants. RESULTS: Combined androgen blockade reduced PSA and testosterone in all patients compared to baseline. Patients did not significantly change on measures of verbal and spatial memory, executive functions or language. Patients declined on a measure of spatial rotation and improved on a measure of verbal memory during treatment which continued during the off treatment period. CONCLUSIONS: Although preliminary, these findings demonstrate that 9 months of combined androgen blockade resulted in a beneficial effect on verbal memory but adversely affected a measure of spatial ability. Intermittent androgen suppression for a period of 9 months in otherwise healthy men with prostate cancer may have beneficial and adverse effects on cognition that are selective.
Asunto(s)
Antagonistas de Andrógenos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Flutamida/uso terapéutico , Leuprolida/uso terapéutico , Pruebas Neuropsicológicas , Neoplasias de la Próstata/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antagonistas de Andrógenos/efectos adversos , Antineoplásicos Hormonales/efectos adversos , Atención/efectos de los fármacos , Biomarcadores de Tumor/sangre , Quimioterapia Adyuvante , Esquema de Medicación , Quimioterapia Combinada , Flutamida/efectos adversos , Humanos , Leuprolida/efectos adversos , Masculino , Recuerdo Mental/efectos de los fármacos , Persona de Mediana Edad , Estadificación de Neoplasias , Solución de Problemas/efectos de los fármacos , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/psicología , Percepción Espacial/efectos de los fármacos , Testosterona/sangreRESUMEN
Bisphosphonates (BisP) are non-metabolized compounds with high bone affinity used in bone metastasis diagnosis and treatment. Currently, BisP are used to treat hypercalcemia of malignancy as well as to prevent, minimize, or delay skeletal morbidity. These compounds have a long half-life in bone. Thus long-term BisP treatment might saturate bone and interfere with a single-dose scanning agent used for bone scintigraphy when visualizing bone metastases. In an effort to answer this question, this study evaluated the concordance of histology and Technetium99 methylene diophosphonate (Tc99 MDP) bone scintigraphy in the diagnosis of bone metastases in prostate cancer patients. We assessed the concordance of findings between bone scintigraphy and histology using 188 bone biopsies from 11 autopsied patients who died with metastatic prostate cancer, 5 of whom were treated with pamidronate for 2 to 13 months before death. Overall agreement between histology and bone scintigraphy was 84%, 86% in non-pamidronate-treated patients and 82% in pamidronate-treated patients. Scintigraphic bone metastases without histological metastasis (false negatives = 12.7%) were observed in 24 anatomic locations; half of these were in one patient who had been treated with pamidronate and had no histological bone response to the carcinoma. There were only 4 sites where a positive bone scan was not associated with histologic metastasis (false positives = 2.21%). There was no statistical difference between the treated and non-treated group for concordance, specificity, sensitivity, positive and negative predictive values of bone scintigraphy and prevalence of histological abnormality. Long-term pamidronate treatment of prostate cancer bone metastases does not generally affect the ability to detect bone metastases with Tc99 MDP bone scintigraphy.