RESUMEN
BACKGROUND: Androgen-deprivation therapy (ADT) historically represented the milestone for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC). Recently, combining androgen receptor-targeted agents (ARTA) or docetaxel with ADT significantly improved clinical outcomes in this setting. The efficacy of the combined use of an ARTA with docetaxel and ADT (triplet), however, was unknown, and often conflicting data derived from subgroup analysis of randomized phase III trials. In order to better define the benefits and risks of the triplet in mHSPC, we carried out a systematic review and meta-analysis of available clinical trials. METHODS: A literature search with no data restriction using Medline/PubMed, the Cochrane Library, and American Society of Clinical Oncology/European Society for Medical Oncology (ASCO/ESMO) Meeting abstracts was carried out up to April 2022. The meta-analysis was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statements. Overall survival (OS) was the primary endpoint; progression-free survival (PFS) and safety were secondary endpoints. For OS and PFS, summary hazard ratios (HRs) were calculated; for safety, risk ratio (RR) was assessed. Random- or fixed-effects models were used, depending on studies heterogeneity. RESULTS: Five randomized clinical trials fulfilled the prespecified inclusion criteria. The triplet significantly improved OS (fixed-effect, HR = 0.74; P < 0.00001) and PFS (fixed-effect; HR = 0.50 for clinical PFS, HR = 0.49 for radiological PFS; P < 0.0001) compared with docetaxel plus ADT. We did not show heterogeneity between treatment efficacy and the disease burden, metachronous versus synchronous presentation, concomitant versus sequential strategy. Compared with docetaxel + ADT, the triplet did not increase the risk of adverse events (AEs) (RR = 1.00, P = 0.27 for any-grade AEs; RR = 1.13, P = 0.14 for severe AEs), except for severe hypertension (RR = 1.73, P = 0.001). CONCLUSIONS: Emerging evidence supports the combination of an ARTA plus docetaxel and ADT in mHSPC patients. Given the availability of several strategies in this setting, clinical characteristics and drug safety profile may help clinicians select the appropriate treatment for mHSPC patients who are more likely to benefit from treatment intensification.
Asunto(s)
Antineoplásicos , Neoplasias de la Próstata , Masculino , Humanos , Docetaxel/farmacología , Docetaxel/uso terapéutico , Antagonistas de Andrógenos/efectos adversos , Neoplasias de la Próstata/tratamiento farmacológico , Andrógenos/uso terapéutico , Receptores Androgénicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antineoplásicos/efectos adversosRESUMEN
In localized prostate cancer (PCa), Grade Group (GG) and Gleason Score (GS) have a well-established prognostic role. In metastatic castration resistant prostate cancer (mCRPC), the prognostic role of GS and GG is less defined. In first-line treatment of mCRPC, androgen receptor (AR)-directed drugs (abiraterone acetate, enzalutamide) and docetaxel represent the referring options. There is no evidence that the GS/GG systems can add information to guide the choice between AR-directed drugs and docetaxel in the first-line setting of mCRPC. Nowadays there are no validated biomarkers, which define patients who may benefit or not from hormonal treatments or chemotherapy. Androgen receptor (AR) copy number variations (CNV) are predictive factors of poor response to abiraterone and enzalutamide. There are no available data about the association between AR CNV and GG. In this retrospective study, we analysed the association of the highest GG score with AR CNV and their impact on the clinical outcome of AR-directed drugs and docetaxel as first-line therapy for mCRPC patients. Patients benefit from docetaxel, abiraterone or enzalutamide regardless the GG. However, the presence of GG5 and AR CNV gain identifies a subgroup of patients with poor prognosis, which could benefit from front-line docetaxel instead of AR-directed drugs.
Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Variaciones en el Número de Copia de ADN , Docetaxel/uso terapéutico , Humanos , Masculino , Nitrilos/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/genética , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: First-line sunitinib is recommended in metastatic renal cell carcinoma (mRCC), but it is frequently associated with relevant toxicities and subsequent dose reductions. Alternative schedules, such as 2-week-on treatment and 1-week-off (2/1 schedule), might improve tolerability. We evaluated the safety and outcomes of this schedule in a large multicenter analysis. PATIENTS AND METHODS: Retrospective, multicenter analysis of mRCC patients treated with first-line sunitinib on a 2/1 schedule. Data of 249 patients were reviewed: 208 cases who started sunitinib on the 4/2 schedule (full dosage: 188/208, 90.4%) and thereafter switched to the 2/1 schedule for toxicity (group 4/2 â 2/1) and 41 patients who started first-line sunitinib with the 2/1 schedule because of suboptimal clinical conditions (group 2/1). A total of 211 consecutive patients treated with the 4/2 schedule in another institution served as external controls. Safety was the primary end point. Treatment duration (TD), progression-free survival (PFS) and overall survival (OS) were also analyzed. RESULTS: In group 4/2 â 2/1, the overall incidence of grade ≥ 3 toxicities was significantly reduced (from 45.7% to 8.2%, P < 0.001) after the switch to 2/1 schedule. This advantage was maintained also in the 106/188 cases (56.4%) who maintained the full dosage. Fatigue, hypertension, hand-foot syndrome and thrombocytopenia were less frequent. The incidence of grade ≥ 3 adverse events in the negatively selected group 2/1 (only 73.2% starting at full dose) was 26.8%, similar to what observed in the external control group (29.4%). Median TD was 28.2 months in the 4/2 â 2/1 group (total time spent with both schedules), 7.8 months in the 2/1 group and 9.7 months in external controls. Median PFS was 30.2, 10.4 and 9.7 months, respectively. Median OS was not reached, 23.2 and 27.8 months, respectively. CONCLUSIONS: mRCC patients who moved to a modified 2/1 schedule of sunitinib experience an improved safety profile compared with that observed during the initial 4/2 schedule.
Asunto(s)
Neoplasias Óseas/tratamiento farmacológico , Carcinoma Papilar/tratamiento farmacológico , Carcinoma de Células Renales/tratamiento farmacológico , Indoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Pirroles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Neoplasias Óseas/mortalidad , Neoplasias Óseas/secundario , Carcinoma Papilar/mortalidad , Carcinoma Papilar/patología , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/secundario , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Sunitinib , Tasa de SupervivenciaRESUMEN
BACKGROUND: Abiraterone is a CYP17A1 inhibitor that improves survival in castration-resistant prostate cancer (CRPC). Abiraterone is licensed in combination with prednisone 5 mg twice daily to prevent a syndrome of secondary mineralocorticoid excess. We hypothesised that a 'steroid switch' from prednisone to dexamethasone would induce secondary responses in patients progressing on abiraterone and prednisone 5 mg b.i.d. METHODS: We performed a 'steroid switch' in patients with CRPC at PSA progression on abiraterone and prednisolone. Patients were monitored for secondary declines in PSA, radiological tumour regression and toxicity. RESULTS: A retrospective analysis of 30 CRPC patients who underwent a steroid switch from prednisolone to dexamethasone while on abiraterone was performed. A total of six patients (20%) had a ⩾50% PSA decline that was confirmed by a second PSA level at least 3 weeks later. In all, 11 patients (39.2%) had a confirmed ⩾30% PSA decline. Median time to PSA progression on abiraterone and dexamethasone was 11.7 weeks (95% CI: 8.6-14.8 weeks) in the whole cohort and 27.6 weeks (95% CI: 14.5-40.7 weeks) in patients who achieved a confirmed 50% PSA decline. Nine patients had RECIST evaluable disease: two of these patients had RECIST partial response, six patients had stable disease and one patient had progressive disease at the first imaging assessment. Treatment was well tolerated, with no grade 3 and grade 4 adverse events. One patient had to be reverted to prednisolone because of grade 2 hypotension. CONCLUSIONS: Durable PSA responses occur in up to 40% of patients following a 'steroid switch' for PSA progression on abiraterone and prednisone. Studies are ongoing to elucidate the mechanisms underlying this response.
Asunto(s)
Androstenos/uso terapéutico , Antiinflamatorios/uso terapéutico , Dexametasona/uso terapéutico , Prednisona/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata Resistentes a la Castración/patología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Metastatic involvement of the viscera in men with advanced castration-resistant prostate cancer (CRPC) has been poorly characterised to date. In 359 CRPC patients treated between June 2003 and December 2011, the frequency of radiologically detected visceral metastases before death was 32%. Of the 92 patients with computed tomography performed within 3 mo of death, 49% had visceral metastases. Visceral metastases most commonly involved the liver (20%) and lung (13%). Median survival from diagnosis of visceral disease was 7.1 mo (95% confidence interval, 5.9-8.3). Survival was affected by the degree of bone involvement at detection of visceral disease, varying from 6.1 mo in men with more than six bone metastases to 18.2 mo in men with no bone metastases (p=0.001). Heterogeneity was noted in clinical phenotypes and prostate-specific antigen trends at development of visceral metastases. Visceral metastases are now more commonly detected in men with CRPC, likely due to the introduction of novel survival-prolonging treatments.
Asunto(s)
Neoplasias Óseas/secundario , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/secundario , Neoplasias de la Próstata Resistentes a la Castración/patología , Antineoplásicos/uso terapéutico , Neoplasias Óseas/sangre , Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/mortalidad , Humanos , Calicreínas/sangre , Estimación de Kaplan-Meier , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/mortalidad , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Masculino , Fenotipo , Modelos de Riesgos Proporcionales , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata Resistentes a la Castración/sangre , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico por imagen , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Factores de Riesgo , Factores de Tiempo , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
The non-competitive N-methyl-D-aspartate receptor antagonist ketamine leads to transient psychosis-like symptoms and impairments in oculomotor performance in healthy volunteers. This study examined whether the adverse effects of ketamine on oculomotor performance can be reversed by the atypical antipsychotic risperidone. In this randomized double-blind, placebo-controlled study, 72 healthy participants performed smooth pursuit eye movements (SPEM), prosaccades (PS) and antisaccades (AS) while being randomly assigned to one of four drug groups (intravenous 100 ng ml(-1) ketamine, 2 mg oral risperidone, 100 ng ml(-1) ketamine plus 2 mg oral risperidone, placebo). Drug administration did not lead to harmful adverse events. Ketamine increased saccadic frequency and decreased velocity gain of SPEM (all P < 0.01) but had no significant effects on PS or AS (all P > or = 0.07). An effect of risperidone was observed for amplitude gain and peak velocity of PS and AS, indicating hypometric gain and slower velocities compared with placebo (both P < or = 0.04). No ketamine by risperidone interactions were found (all P > or = 0.26). The results confirm that the administration of ketamine produces oculomotor performance deficits similar in part to those seen in schizophrenia. The atypical antipsychotic risperidone did not reverse ketamine-induced deteriorations. These findings do not support the cognitive enhancing potential of risperidone on oculomotor biomarkers in this model system of schizophrenia and point towards the importance of developing alternative performance-enhancing compounds to optimise pharmacological treatment of schizophrenia.
Asunto(s)
Antipsicóticos/uso terapéutico , Antagonistas de Aminoácidos Excitadores/efectos adversos , Ketamina/efectos adversos , Trastornos de la Motilidad Ocular/tratamiento farmacológico , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Risperidona/uso terapéutico , Adolescente , Adulto , Antipsicóticos/farmacología , Método Doble Ciego , Antagonistas de Aminoácidos Excitadores/farmacología , Medidas del Movimiento Ocular , Movimientos Oculares/efectos de los fármacos , Femenino , Voluntarios Sanos , Humanos , Ketamina/farmacología , Masculino , Trastornos de la Motilidad Ocular/inducido químicamente , Seguimiento Ocular Uniforme/efectos de los fármacos , Risperidona/farmacología , Movimientos Sacádicos/efectos de los fármacos , Esquizofrenia , Adulto JovenRESUMEN
BACKGROUND: About 20% of patients with prostate cancer have an ECOG performance status (PS) î¶2 at diagnosis. We investigate if current treatment options for castration-resistant prostate cancer (CRPC) may decrease the risk of death even in patients with ECOG PS of 2. METHODS: PubMed was reviewed for phase III randomized trials in patients with CRPC progressed after docetaxel chemotherapy. Characteristics of each study and the relative hazard ratio (HR) for overall survival and 95% confidence interval (CI) were collected. Summary HR was calculated using random- or fixed-effects models depending on the heterogeneity of included studies. RESULTS: A total of 3,149 patients was available for meta-analysis. In the overall population, the experimental treatments decrease the risk of death by 31% (HR=0.69; 95% CI: 0.63-0.76; P<0.001). The activity of experimental treatments was similar in 2,859 patients with ECOG-PS=0 or 1 with a reduced risk of death of 31% (HR=0.69; 95% CI: 0.62-0.76). A total of 290 patients (9.2%) had ECOG-PS=2 and experimental treatments decreased the risk of death by 26% (HR=0.74; 95% CI: 0.56-0.98; P=0.035) compared with the controls even in this sub-group. When patients were stratified by type of treatment, the reduction of the risk of death was confirmed for hormonal therapies: abiraterone and enzalutamide (HR=0.72; 95% CI: 0.52-0.99; P=0.046), but not for chemotherapy (HR=0.81; 95% CI: 0.48-1.37; P=0.43). CONCLUSIONS: We believe this is the first study reporting a benefit in second-line setting for CRPC patients previously treated with docetaxel and poor PS.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/mortalidad , Taxoides/uso terapéutico , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos Clínicos Fase III como Asunto , Docetaxel , Humanos , Masculino , Orquiectomía , Modelos de Riesgos Proporcionales , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Sesgo de Publicación , Taxoides/administración & dosificación , Resultado del TratamientoRESUMEN
AIM: To evaluate the impact of the new European paediatric regulatory framework on the activities of Ethics Committees operating in Europe and to assess their involvement and interest in paediatric research. METHODS: Task-force in Europe for Drug Development for the Young Network of Excellence and Relating Expectations and Needs to the Participation and Empowerment of Children in Clinical Trials project set up an inventory of Ethics Committees existing in Europe and conducted a survey on their approach to paediatric trials. RESULTS: Ethics Committees operating in 22 European Countries participated in this survey. Results showed a high lack of knowledge, understanding and awareness of the current European paediatric regulatory framework and a lack of involvement of Ethics Committees in paediatric research, especially in terms of training and education, demonstrated also by the decreasing number of Ethics Committees answering exhaustively to the whole questionnaire. The majority of participating Ethics Committees expressed interest in future initiatives related to paediatric research. CONCLUSIONS: Despite a limited knowledge and understanding of the current paediatric regulatory framework, a significant number of Ethics Committees operating in Europe show interest in initiatives related to paediatric research. Networking may be an essential tool to be used to enhance Ethics Committees role in supporting paediatric research. Any initiative should be undertaken at European level in collaboration with European Union Institutions.
Asunto(s)
Ensayos Clínicos como Asunto/ética , Comités de Ética , Pediatría/legislación & jurisprudencia , Discusiones Bioéticas , Niño , Unión Europea , HumanosRESUMEN
A case of bizarre parosteal osteochondromatous proliferation (BPOP) arising in the head of the fibula of a young man following injury on the lateral aspect of the knee is reported. Microscopically, four zones could be recognized proceeding from the periphery to the deep portion: 1) an outer thick fibrous cap showing an abundant cellular component, composed of thin spindled elements of fibroblastic appearance, haphazardly arranged and exhibiting intense and diffuse immunohistochemical expression of S100 protein (a previously unreported observation); 2) an irregular and atypical cartilaginous cap beneath the fibrous cap; 3) a layer of blue bone in which islands of atypical chondrocytes are still present but gradually decreasing, moving towards the deeper areas; 4) a layer of mature bone, pink bone, which is implanted in the skeletal segment (the deep margin is devoid of periosteum). The intratrabecular spaces of blue or pink bone did not contain haematopoietic marrow, but rather a loose myxoid stroma. This case confirms the fact that BPOP can occur in skeletal segments other than those indicated in the original report of Nora, and that trauma, even if minor, is an important factor in the development of the lesion. The latter begins at the periosteal level, where fibroblasts may acquire a chondroformative function (becoming chondrofibroblasts), as witnessed by the strong and widespread expression of P S100, first documented in this report.
Asunto(s)
Neoplasias Óseas/patología , Peroné/patología , Neoplasias Postraumáticas/patología , Osteocondroma/patología , Periostio/patología , Adolescente , Biomarcadores de Tumor/metabolismo , Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/cirugía , Cartílago Articular/metabolismo , Cartílago Articular/patología , Fibroblastos/metabolismo , Fibroblastos/patología , Peroné/diagnóstico por imagen , Peroné/cirugía , Humanos , Masculino , Neoplasias Postraumáticas/diagnóstico por imagen , Neoplasias Postraumáticas/cirugía , Osteocondroma/diagnóstico por imagen , Osteocondroma/cirugía , Periostio/diagnóstico por imagen , Periostio/cirugía , Radiografía , Proteínas S100/metabolismoRESUMEN
Besides the undeniable need to respect parental autonomy, providing information is a legal and moral obligation, to be informed a basic right. The act of informing should be considered as an exchange and necessarily begins by listening to the other. According to the jurisprudence of the Court of Cassation that draws on Article 35 of the Deontological Code, information has to be clear (implying an educational effort, availability and to check that the information has been well understood), appropriate (adapted to each situation and person) and honest (which supposes a moral contract between parents and physicians). Loyalty implies a consideration of the uncertainty underlying medical practice, and of the limitations in arriving at a prognosis. Indeed, caution needs to be exercised in conveying information, taking into account the risk of its becoming self-fulfilling, which could modify the way in which parents take care of their child. The information given has to be coherent, both within the spatial dimension (coherence of information between the different maternity services in the perinatal network) and the temporal dimension (coherence of information between pre- and postnatal stages). It must be acknowledged that information is essentially subjective. There is a fundamental difference between coherence and uniformity, and as regards information, uniformity is neither possible nor desirable. In each situation, priority must be given to oral information delivered in an appropriate material context. The principle of establishing, in the medical file, a written trace of the information given at various stages is one way to guarantee its coherence.