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1.
Cancer Immunol Immunother ; 73(6): 106, 2024 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-38634928

RESUMEN

BACKGROUND: Immune checkpoint inhibitors have changed previous treatment paradigm of advanced urothelial carcinoma (UC). The ARON-2 study (NCT05290038) aimed to assess the real-world effectiveness of pembrolizumab in patients recurred or progressed after platinum-based chemotherapy. PATIENTS AND METHODS: Medical records of patients with documented metastatic UC treated by pembrolizumab as second-line therapy were retrospectively collected from 88 institutions in 23 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). Cox proportional hazards models were adopted to explore the presence of prognostic factors. RESULTS: In total, 836 patients were included: 544 patients (65%) received pembrolizumab after progression to first-line platinum-based chemotherapy in the metastatic setting (cohort A) and 292 (35%) after recurring within < 12 months since the completion of adjuvant or neoadjuvant chemotherapy (cohort B). The median follow-up time was 15.3 months. The median OS and the ORR were 10.5 months and 31% in the overall study population, 9.1 months and 29% in cohort A and 14.6 months and 37% in cohort B. At multivariate analysis, ECOG-PS ≥ 2, bone metastases, liver metastases and pembrolizumab setting (cohort A vs B) proved to be significantly associated with worst OS and PFS. Stratified by the presence of 0, 1-2 or 3-4 prognostic factors, the median OS was 29.4, 12.5 and 4.1 months (p < 0.001), while the median PFS was 12.2, 6.4 and 2.8 months, respectively (p < 0.001). CONCLUSIONS: Our study confirms that pembrolizumab is effective in the advanced UC real-world context, showing outcome differences between patients recurred or progressed after platinum-based chemotherapy.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Adyuvantes Inmunológicos , Platino (Metal) , Estudios Retrospectivos
2.
BJU Int ; 133(2): 214-222, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37803523

RESUMEN

OBJECTIVE: To evaluate the predictive capability of the pre- and post-pembrolizumab Vesical Imaging-Reporting and Data System (VI-RADS) to identify ypT0N0 or ypT≤1N0 response in muscle-invasive bladder cancer (MIBC) within the PURE-01 trial (ClinicalTrials.gov identifier: NCT02736266). PATIENTS AND METHODS: Patients were staged with bladder multiparametric magnetic resonance imaging (mpMRI) before and after treatment (three cycles of pembrolizumab) prior to radical cystectomy (RC). Logistic regression models were used to analyse the pre- and post- pembrolizumab VI-RADS against ypT≤1N0 and ypT0N0 response. The VI-RADS scores were dichotomised between 0 and 3 (0 = no evidence of disease) and 4-5. Event-free survival (EFS) and overall survival (OS) analyses were performed. Comprehensive genomic profiling and transcriptome-wide expression profiling data were matched with the VI-RADS scores. RESULTS: In total, 110 patients underwent centrally reviewed scans (N = 220 mpMRI), treated between February 2017 and July 2020. Both pre- and post-pembrolizumab VI-RADS 0-3 scores were the only significant covariates that predicted the ypT≤1N0 endpoint in multivariable analyses, and the strongest effect was seen with post-pembrolizumab VI-RADS 0-3 predicting the ypT≤1N0 response (P < 0.001). The area under the curve for this model was 0.90. Post-pembrolizumab VI-RADS 0-3 also predicted a longer EFS (P < 0.001) and OS (P = 0.044). The scores of several gene signatures from baseline tumours differed between the pre-pembrolizumab VI-RADS 0-3 and 4-5 categories. CONCLUSION: Post-pembrolizumab VI-RADS scores are strongly associated with pathological downstaging and survival. VI-RADS scores were also characterised by distinct biomarker features. These results indicate that the VI-RADS is emerging as an important tool for designing next-generation trials for MIBC.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Neoplasias de la Vejiga Urinaria , Vejiga Urinaria , Humanos , Vejiga Urinaria/patología , Terapia Neoadyuvante , Invasividad Neoplásica/patología , Neoplasias de la Vejiga Urinaria/diagnóstico por imagen , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Músculos/patología , Imagen por Resonancia Magnética/métodos , Estudios Retrospectivos
3.
Acta Oncol ; 63: 213-219, 2024 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-38647024

RESUMEN

BACKGROUND: Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in various cancers. ICI treatment is associated with the incidence of immune-related adverse events (irAEs) which can affect any organ. Data on irAEs occurrence in relation to sex- differentiation and their association with gender-specific factors are limited. AIMS: The primary objective of the G-DEFINER study is to compare the irAEs incidence in female and male patients who undergo ICI treatment. Secondary objectives are: to compare the irAEs incidence in pre- and postmenopausal female patients; to compare the irAEs incidence in female and male patients according to different clinical and gender-related factors (lifestyle, psychosocial, and behavioral factors). Exploratory objectives of the study are to compare and contrast hormonal, gene-expression, SNPs, cytokines, and gut microbiota profiles in relation to irAEs incidence in female and male patients. METHODS AND RESULTS: The patients are recruited from Fondazione IRCCS Istituto Nazionale dei Tumori, Italy, St Vincent's University Hospital, Ireland, Oslo University Hospital, Norway, and Karolinska Insitutet/Karolinska University Hospital, Sweden. The inclusion of patients was delayed due to the Covid pandemic, leading to a total of 250 patients recruited versus a planned number of 400 patients. Clinical and translational data will be analyzed. INTERPRETATION: The expected outcomes are to improve the management of cancer patients treated with ICIs, leading to more personalized clinical approaches that consider potential toxicity profiles. The real world nature of the trial makes it highly applicable for timely irAEs diagnosis.


Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Neoplasias , Humanos , Femenino , Masculino , Neoplasias/tratamiento farmacológico , Estudios Prospectivos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Factores Sexuales , Incidencia , Inmunoterapia/efectos adversos , Inmunoterapia/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Estudios Observacionales como Asunto
4.
Cancer Immunol Immunother ; 72(9): 2961-2970, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37248424

RESUMEN

BACKGROUND: The advent of immune-checkpoint inhibitors has challenged previous treatment paradigms for advanced urothelial carcinoma (UC) in the post-platinum setting as well as in the first-line setting for cisplatin-ineligible patients. In this study, we investigated the effectiveness of pembrolizumab as first-line treatment for cisplatin-ineligible UC. METHODS: Data from patients aged ≥ 18 years with cisplatin-ineligible UC and receiving first-line pembrolizumab from January 1st 2017 to September 1st 2022 were collected. Cisplatin ineligibility was defined according to the Galsky criteria. Thirty-three Institutions from 18 countries were involved in the ARON-2 study. RESULTS: Our analysis included 162 patients. The median follow-up time was 18.9 months (95%CI 15.3-76.9). In the overall study population, the median OS was 15.8 months (95%CI 11.3-32.4). The median OS was significantly longer in males versus females while no statistically significant differences were observed between patients aged < 65y versus ≥ 65y and between smokers and non-smokers. According to Recist 1.1 criteria, 26 patients (16%) experienced CR, 32 (20%) PR, 39 (24%) SD and 55 (34%) PD. CONCLUSIONS: Our data confirm the role of pembrolizumab as first-line therapy for cisplatin-unfit patients. Further studies investigating the biological and immunological characteristics of UC patients are warranted in order to optimize the outcome of patients receiving immunotherapy in this setting.


Asunto(s)
Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Masculino , Femenino , Humanos , Carcinoma de Células Transicionales/patología , Cisplatino/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Anticuerpos Monoclonales Humanizados/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica
5.
Cancer Immunol Immunother ; 72(11): 3665-3682, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37676282

RESUMEN

BACKGROUND: Concomitant medications may potentially affect the outcome of cancer patients. In this sub-analysis of the ARON-2 real-world study (NCT05290038), we aimed to assess the impact of concomitant use of proton pump inhibitors (PPI), statins, or metformin on outcome of patients with metastatic urothelial cancer (mUC) receiving second-line pembrolizumab. METHODS: We collected data from the hospital medical records of patients with mUC treated with pembrolizumab as second-line therapy at 87 institutions from 22 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate. We carried out a survival analysis by a Cox regression model. RESULTS: A total of 802 patients were eligible for this retrospective study; the median follow-up time was 15.3 months. PPI users compared to non-users showed inferior PFS (4.5 vs. 7.2 months, p = 0.002) and OS (8.7 vs. 14.1 months, p < 0.001). Concomitant PPI use remained a significant predictor of PFS and OS after multivariate Cox analysis. The use of statins or metformin was not associated with response or survival. CONCLUSIONS: Our study results suggest a significant prognostic impact of concomitant PPI use in mUC patients receiving pembrolizumab in the real-world context. The mechanism of this interaction warrants further elucidation.


Asunto(s)
Carcinoma de Células Transicionales , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Metformina , Neoplasias de la Vejiga Urinaria , Humanos , Inhibidores de la Bomba de Protones , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Metformina/uso terapéutico , Estudios Retrospectivos
6.
Curr Oncol Rep ; 25(6): 671-677, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37000341

RESUMEN

PURPOSE OF REVIEW: In this review, we analyze the current state of research in development of new biomarkers that may be useful in managing metastatic renal cell carcinoma (mRCC) setting. RECENT FINDINGS: Combining tumor-based biomarkers (gene expression profile) and blood-based biomarkers (ctDNA, cytokines) would be helpful in acquiring information regarding RCC and might be significant in the decision-making process. Renal cell carcinoma (RCC) is the sixth most frequently diagnosed neoplasm in men and tithe in women, making it responsible for 5% and 3% of all diagnosed cancers respectively. Metastatic stage represents a non-negligible percentage at diagnosis and is characterized by poor prognosis. Despite clinical features and prognostic score could guide clinicians in therapeutic approach of this disease, biomarkers predictive of response to treatment remain an unmet need.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Masculino , Humanos , Femenino , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/patología , Pronóstico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Transcriptoma
7.
Oncologist ; 27(11): e912-e915, 2022 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-36166584

RESUMEN

BACKGROUND: Primary mediastinal nonseminoma germ cell tumors (PMNSGCT) are a subgroup of nonseminoma germ cell tumors (GCT) with poor prognosis. In this study, PMNSGCT-specific genomic landscape was analyzed and correlated with clinical outcomes. METHODS: DNA was extracted and sequenced from 28 archival tumor tissue of patients with mediastinal GCT (3 seminoma and 25 nonseminoma). Overall survival (OS) and association with gene alterations were estimated using the Kaplan-Meier and univariate Cox regression methods. RESULTS: Three patients (11%) had a karyotype XXY, 17/28 (61%) tumor samples presented chromosome 12p amplification. Somatic mutations were detected in 19/28 (68%) samples. The most frequently mutated genes were: TP53 (13/28; 46%), KIT (5/28; 18%), and KRAS (5/28; 18%). Deleterious TP53 alterations were associated with significantly reduced overall survival (HR: 7.16; P = .012). CONCLUSIONS: TP53 alterations are common in PMNSGCT and are associated with reduced overall survival, potentially underlying the poor sensitivity to chemotherapy observed in these patients.


Asunto(s)
Neoplasias del Mediastino , Neoplasias de Células Germinales y Embrionarias , Seminoma , Neoplasias Testiculares , Masculino , Humanos , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias Testiculares/genética , Neoplasias Testiculares/patología , Seminoma/patología , Neoplasias del Mediastino/genética , Neoplasias del Mediastino/patología , Pronóstico , Proteína p53 Supresora de Tumor/genética
8.
Future Oncol ; 18(19): 2455-2464, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35387485

RESUMEN

FGFR inhibitors represent a new and promising therapeutic approach to urothelial cancer (UC). Erdafitinib (Balversa©) was the first FGFR inhibitor approved for the treatment of metastatic UC, showing proper pharmacological activity and a consistent safety profile in a population with limited or no therapeutic alternatives. While results from comparative phase II and III trials are needed to assess the efficacy of erdafitinib in different clinical settings, there are still questions unsolved regarding a typical class effect of FGFR inhibitors, hyperphosporemia. In this review, the authors focus on the state-of-art administration of erdatifinib in advanced UC, pointing out the more recent evidence, pitfalls and possible future research. Insight on the management of hyperphosporemia in patients undergoing treatment with FGFR inhibitors is also provided.


Asunto(s)
Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/genética , Carcinoma de Células Transicionales/patología , Humanos , Inhibidores de Proteínas Quinasas/efectos adversos , Pirazoles/efectos adversos , Quinoxalinas/efectos adversos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/genética
9.
World J Urol ; 39(9): 3407-3414, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-33683412

RESUMEN

PURPOSE: The prognostic significance of lactate dehydrogenase (LDH) in patients with metastatic seminoma is not defined. We investigated the prognostic impact of LDH levels prior to first-line systemic treatment and other clinical characteristics in this subset of patients. METHODS: Files from two registry studies and one single-institution database were analyzed retrospectively. Uni- and multivariate analyses were conducted to identify patient characteristics associated with recurrence free survival (RFS), overall survival (OS), and complete response rate (CRR). RESULTS: The dataset included 351 metastatic seminoma patients with a median follow-up of 5.36 years. Five-year RFS, OS and CRR were 82%, 89% and 52%, respectively. Explorative analysis revealed a cut-off LDH level of < 2.5 upper limit of normal (ULN) (n = 228) vs. ≥ 2.5 ULN (n = 123) to be associated with a significant difference concerning OS associated with 5-years OS rates of 93% vs. 83% (p = 0.001) which was confirmed in multivariate analysis (HR 2.87; p = 0.004). Furthermore, the cut-off LDH < 2.5 ULN vs. ≥ 2.5 ULN correlated with RFS and CRR associated with a 5-years RFS rate and CRR of 76% vs. 86% (p = 0.012) and 32% vs. 59% (p ≤ 0.001), respectively. CONCLUSIONS: LDH levels correlate with treatment response and survival in metastatic seminoma patients and should be considered for their prognostic stratification.


Asunto(s)
L-Lactato Deshidrogenasa/sangre , Seminoma/sangre , Seminoma/mortalidad , Neoplasias Testiculares/sangre , Neoplasias Testiculares/mortalidad , Adolescente , Adulto , Anciano , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Seminoma/patología , Tasa de Supervivencia , Neoplasias Testiculares/patología , Adulto Joven
10.
J Urol ; 199(3): 741-747, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-28964782

RESUMEN

PURPOSE: The prognosis of stage I nonseminomatous germ cell tumor of the testis is favorable. Early and late side effects of treatment may affect quality of life and survival. We determined the tolerability, safety and efficacy of laparoscopic retroperitoneal lymph node dissection in patients with stage I nonseminomatous germ cell tumor of the testis at a high volume center. MATERIALS AND METHODS: Unilateral laparoscopic retroperitoneal lymph node dissection was prospectively recorded in 225 patients from 2000 to 2014. Since 2007, patients have been treated at a multidisciplinary clinic and were proposed surgery as an alternative to surveillance or adjuvant chemotherapy. The indication for adjuvant chemotherapy changed during the study period. Descriptive statistics and regression analyses were used to evaluate the domains of safety and oncologic outcomes. RESULTS: A total of 221 patients were evaluable. Median operative time was 200 minutes. Conversion to open surgery was done in 20 cases (9%). A median of 14 nodes (IQR 11-20) was retrieved. Grade greater than 2 complications in 8 cases (3.6%) increased as the number of retrieved nodes increased. Antegrade ejaculation was maintained in 98.6% of patients. Nodal metastases were found in 29 patients (13%), of whom 7 underwent adjuvant chemotherapy. There were 14 recurrences (6.3%), including 8 of 192 (4.2%) associated with no nodal metastases and 6 of 22 (27.3%) associated with nodal metastases in patients not undergoing adjuvant chemotherapy. At regression analyses lymph node ratio was the only significant factor predictive of recurrence and of the administration of any chemotherapy (each p <0.001). Operative time, the number of retrieved nodes and conversions improved with time. CONCLUSIONS: In the context of a high volume center laparoscopic retroperitoneal lymph node dissection was safe and its oncologic efficacy was comparable to that of open surgery. Select patients with stage I nonseminomatous germ cell tumor could be offered laparoscopic retroperitoneal lymph node dissection as an alternative to other options.


Asunto(s)
Hospitales de Alto Volumen/estadística & datos numéricos , Laparoscopía/métodos , Escisión del Ganglio Linfático/métodos , Ganglios Linfáticos/patología , Estadificación de Neoplasias , Neoplasias de Células Germinales y Embrionarias/secundario , Neoplasias Testiculares/secundario , Adulto , Animales , Biopsia , Terapia Combinada , Estudios de Seguimiento , Humanos , Ganglios Linfáticos/cirugía , Metástasis Linfática , Masculino , Neoplasias de Células Germinales y Embrionarias/diagnóstico , Neoplasias de Células Germinales y Embrionarias/terapia , Pronóstico , Estudios Prospectivos , Espacio Retroperitoneal , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/terapia , Resultado del Tratamiento
11.
J Urol ; 200(6): 1207-1214, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30012366

RESUMEN

PURPOSE: We evaluated the impact of the number of cycles of platinum based, first line chemotherapy (fewer than 6 cycles vs the conventional 6 cycles or more) on the survival of patients with metastatic urothelial carcinoma. MATERIALS AND METHODS: We used the RISC (Retrospective International Study of Invasive/Advanced Cancer of the Urothelium) database. The association of the number of cycles of chemotherapy with overall survival was investigated by Cox multiple regression analysis after controlling for recognized prognostic factors. We excluded patients who received fewer than 3 or more than 9 platinum chemotherapy cycles to reduce confounding factors. The primary analysis was a comparison of overall survival for 3 to 5 vs 6 to 9 cycles using 6-month landmark analysis when 281 death events were observed. RESULTS: Of the 1,020 patients in the RISC 472 received cisplatin or carboplatin, of whom 338 and 134, respectively, were evaluable. A total of 157 patients received 3 to 5 cycles (median 4) and 315 received 6 to 9 cycles (median 6). There was no significant difference in overall survival between 3 to 5 and 6 to 9 cycles (HR 1.02, 95% CI 0.78-1.33, p = 0.91). No significant interactions were observed for the type of platinum (p = 0.09) and completed planned chemotherapy (p = 0.56). The limitations of a hypothesis generating, retrospective analysis applied. CONCLUSIONS: Four cycles of platinum based, first line chemotherapy appeared adequate and did not significantly compromise the survival of patients with advanced urothelial carcinoma. The omission of excessive cycles may avoid unnecessary cumulative toxicity and facilitate a better transition to second line therapy and investigational switch maintenance therapy strategies. These results require prospective validation but they may impact practice in select patients.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Células Transicionales/tratamiento farmacológico , Compuestos de Platino/administración & dosificación , Neoplasias Urológicas/tratamiento farmacológico , Anciano , Carcinoma de Células Transicionales/mortalidad , Carcinoma de Células Transicionales/patología , Esquema de Medicación , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Retrospectivos , Resultado del Tratamiento , Neoplasias Urológicas/mortalidad , Neoplasias Urológicas/patología
12.
BJU Int ; 121(3): 348-356, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-28921872

RESUMEN

OBJECTIVE: To harness the frontline therapy in advanced penile squamous cell carcinoma (PSCC), for which chemotherapy exerts moderate activity but poor efficacy. Dacomitinib is an irreversible, pan-epidermal growth factor receptor (HER) inhibitor. PATIENTS AND METHODS: In a phase 2 study (NCT01728233), patients received dacomitinib 45 mg/day, orally, continuously. Inclusion criteria were SCC histology, clinical stage N2-3 or M1 (Tumour-Node-Metastasis classification system 2009), and no prior chemotherapy administration. The primary endpoint was the objective response rate (ORR, according to the Response Evaluation Criteria in Solid Tumors, version 1.1). Stopping rules based on the Bayesian posterior probability (PP) to demonstrate that the ORR exceeded 20% were set. RESULTS: From June 2013 to October 2016, 28 patients were treated. Eight (28.6%) had visceral metastases, 14 (50%) had pelvic and 17 (60.7%) clinically involved bilateral lymph nodes. One complete and eight partial responses were obtained (ORR 32.1%, 80% credibility interval 21.0-43.0%). The median (interquartile range [IQR]) follow-up duration was 19.8 (6.3-25.7) months; 12-month progression-free survival was 26.2% (95% confidence interval [CI] 13.2-51.9); 12-month overall survival (OS) was 54.9% (95% CI 36.4-82.8). The median (IQR) OS of locally advanced patients was 20 (11.1-not reached) months. The Bayesian PP of exceeding the 20% ORR target was 92.3%. Grade 3 adverse events (skin rash) were seen in three patients (10.7%). Tissue samples from 25 patients were analysed. Only two patients had high-risk human papillomavirus-positive tumours. Epidermal growth factor receptor (EGFR) amplification was found in four patients (equally responders and non-responders) and it was confirmed in all post-dacomitinib samples. Telomerase reverse transcriptase (TERT) mutations were found in responders only (60%), and phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway gene mutations were found in 42.9% of responders vs 8.3% of non-responders. CONCLUSION: Dacomitinib was active and well tolerated in patients with advanced PSCC and may represent an option when combined chemotherapy cannot be administered. Mutations in downstream effectors of EGFR signalling in relation to dacomitinib activity deserve further studies.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias del Pene/tratamiento farmacológico , Quinazolinonas/uso terapéutico , Administración Oral , Anciano , Antineoplásicos/administración & dosificación , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/secundario , Supervivencia sin Enfermedad , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Amplificación de Genes , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Mutación , Estadificación de Neoplasias , Neoplasias del Pene/genética , Neoplasias del Pene/patología , Fosfatidilinositol 3-Quinasa/metabolismo , Quinazolinonas/administración & dosificación , Criterios de Evaluación de Respuesta en Tumores Sólidos , Transducción de Señal/genética , Tasa de Supervivencia , Serina-Treonina Quinasas TOR/metabolismo , Telomerasa/genética
13.
Curr Opin Urol ; 28(1): 1-7, 2018 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-29028766

RESUMEN

PURPOSE OF REVIEW: The treatment paradigm of urothelial carcinoma has been revolutionized by the advent of multiple anti-programmed-cell death-1/ligand-1 (PD-1/PD-L1) antibodies. Significant improvements have been obtained in the locally advanced or metastatic stage, which was lacking of therapeutic standards. This review reports key findings from completed and ongoing clinical trials that highlight the potential of PD-1/PD-L1 blockade in this disease. RECENT FINDINGS: Anti-PD-1/PD-L1 monoclonal antibodies have shown efficacy and safety in patients with urothelial carcinoma, regardless of their prognostic features. Efficacy was similar across different compounds, with objective responses that approximate 20%, with some differences favoring PD-L1-expressing patients. Typically, responding patients have good chances of achieving durable response, but biomarkers predictive of therapeutic effect are lacking. To date, evidences from randomized studies are limited to the second-line, postplatinum therapy. SUMMARY: Despite the activity of PD-1/PD-L1 inhibitors is well established in metastatic urothelial carcinoma, multiple gray zones still exist regarding their optimal use in clinical practice. These uncertainties are related to patient and treatment-related criteria, to the optimal duration of treatment, including combination or sequence with standard chemotherapy. Special issues are represented by pseudoprogression or hyperprogression. Generally, enhanced predictive tools are needed and a myriad of further investigations are underway.


Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Inmunoterapia/métodos , Neoplasias Urológicas/tratamiento farmacológico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Carcinoma de Células Transicionales/inmunología , Carcinoma de Células Transicionales/mortalidad , Carcinoma de Células Transicionales/patología , Humanos , Inmunoterapia/tendencias , Estadificación de Neoplasias , Pronóstico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Terapia Recuperativa/métodos , Terapia Recuperativa/tendencias , Resultado del Tratamiento , Neoplasias Urológicas/inmunología , Neoplasias Urológicas/mortalidad , Neoplasias Urológicas/patología
14.
Future Oncol ; 14(26): 2683-2690, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-29927336

RESUMEN

Nivolumab is a fully human monoclonal antibody blocking PD-1 with demonstrated effectiveness against metastatic urothelial carcinoma. In this review, we describe the pharmacological properties of nivolumab and the treatment of metastatic urothelial carcinoma with this checkpoint inhibitor after the failure of first-line platinum-based chemotherapy. Cancer immunotherapy by checkpoint inhibition offers potential to prolong patient survival with well manageable toxicity although serious immune-related adverse events may occur. The overall response rate to nivolumab after first-line chemotherapy is about 20%. Patients unfit for cisplatin may benefit from first-line cancer immunotherapy. It remains unclear which patient will respond and PD-1/PD-L1 expression alone is not a sufficiently reliable predictive biomarker.


Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Nivolumab/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Antineoplásicos Inmunológicos/farmacología , Biomarcadores de Tumor/genética , Carcinoma de Células Transicionales/genética , Carcinoma de Células Transicionales/cirugía , Quimioterapia Adyuvante/métodos , Ensayos Clínicos como Asunto , Cistectomía , Humanos , Terapia Neoadyuvante/métodos , Nivolumab/farmacología , Medicina de Precisión/métodos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/cirugía
16.
Invest New Drugs ; 35(4): 524-528, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28155045

RESUMEN

Background and purpose Salvage therapies for urothelial carcinoma are needed. A single-arm trial in patients with advanced or metastatic urothelial carcinoma refractive to other therapies found that alisertib, a selective inhibitor of aurora kinase A, maintained stable disease in a few cases, despite a low objective response rate. To better understand why some patients benefited from alisertib, we genotyped the 22 patients of this pilot trial for two single nucleotide polymorphisms (rs2273535 and rs1047972) in AURKA, the gene encoding aurora kinase A, and looked for associations with survival and treatment response. Results Carrier status for the minor allele of rs2273535 (T91A, p. F31I) was a favorable prognostic factor for progression-free survival (HR = 0.18; 95% CI, 0.039-0.81; P = 0.026) but not for overall survival (HR = 0.88; 95% CI, 0.26-2.9; P = 0.83). These results were confirmed in multivariable analyses, adjusting for sex, age and hemoglobin, for both progression-free survival (HR = 0.11; 95% CI, 0.018-0.69; P = 0.018) and overall survival. No association was found between rs1047972 and survival. Moreover, neither SNP was associated with treatment response. Conclusion In patients who received alisertib for advanced or metastatic urothelial carcinoma, longer progression-free survival was observed in carriers of the minor allele A of rs2273535 in AURKA than in patients who were homozygous for the major allele T. This finding, based on a small pilot trial, warrants further investigation.


Asunto(s)
Aurora Quinasa A/genética , Azepinas/uso terapéutico , Carcinoma de Células Transicionales , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Neoplasias Urológicas , Adulto , Anciano , Alelos , Aurora Quinasa A/antagonistas & inhibidores , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/genética , Supervivencia sin Enfermedad , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Modelos de Riesgos Proporcionales , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/genética
17.
J Urol ; 196(1): 95-100, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-26748165

RESUMEN

PURPOSE: We assessed prognostic factors, treatments and outcomes in patients with teratoma with malignant transformation, a rare occurrence among germ cell tumors. MATERIALS AND METHODS: Data on patients diagnosed with teratoma with malignant transformation between June 1981 and August 2014 were collected across 5 referral centers. Chemotherapy was dichotomized as based on germ cell tumor or teratoma with malignant transformation. Cox analyses were done to evaluate prognostic factors of overall survival, the primary end point. Each factor was evaluated in a univariable model. Forward stepwise selection was used to construct an optimal model. RESULTS: Among 320 patients the tumor primary site was gonadal in 287 (89.7%), retroperitoneal in 17 (5.3%) and mediastinal in 16 (5%). Teratoma with malignant transformation and germ cell tumor were diagnosed concurrently in 130 patients (40.6%). A total of 49 patients (16.8%) initially presented with clinical stage I. The remaining patients were at good (123 or 42.3%), intermediate (42 or 14.4%) and poor (77 or 26.5%) risk for metastasis according to IGCCCG (International Germ Cell Cancer Collaborative Group). First line chemotherapy was given for germ cell tumor in 159 patients (49.7%), chemotherapy for teratoma with malignant transformation was performed in 14 (4.4%) and only surgery was done in 147 (45.9%). Median followup was 25.1 months (IQR 5.4-63.8). Five-year overall survival was 83.4% (95% CI 61.3 to 93.5) in patients with clinical stage I and it was also worse than expected in those with metastasis. On multivariable analyses nonprimitive neuroectodermal tumor histology (overall p = 0.004), gonadal primary tumor (p = 0.005) and fewer prior chemotherapy regimens (p <0.001) were independent predictors of better overall survival. Chemotherapy was not independently prognostic. CONCLUSIONS: Less heavily pretreated teratoma with malignant transformation with a gonadal primary tumor and nonprimitive neuroectodermal tumor histology appears to be associated with longer overall survival. Generally, teratoma with malignant transformation had a worse prognosis than germ cell tumor. Uncertainties persist regarding optimal chemotherapy.


Asunto(s)
Transformación Celular Neoplásica , Neoplasias de los Genitales Masculinos/terapia , Neoplasias del Mediastino/terapia , Neoplasias Retroperitoneales/terapia , Teratoma/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Quimioterapia Adyuvante , Estudios de Seguimiento , Neoplasias de los Genitales Masculinos/diagnóstico , Neoplasias de los Genitales Masculinos/mortalidad , Neoplasias de los Genitales Masculinos/patología , Humanos , Masculino , Neoplasias del Mediastino/diagnóstico , Neoplasias del Mediastino/mortalidad , Neoplasias del Mediastino/patología , Persona de Mediana Edad , Pronóstico , Neoplasias Retroperitoneales/diagnóstico , Neoplasias Retroperitoneales/mortalidad , Neoplasias Retroperitoneales/patología , Estudios Retrospectivos , Análisis de Supervivencia , Teratoma/diagnóstico , Teratoma/mortalidad , Teratoma/patología , Adulto Joven
18.
Invest New Drugs ; 34(2): 236-42, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26873642

RESUMEN

BACKGROUND: Progress in developing effective salvage therapies for UC is warranted. Alisertib is an orally available, selective inhibitor of the aurora kinase A. METHODS: A single-group, phase 2 trial was conducted with alisertib 50 mg orally BID for 7 days, with 14d rest until disease progression (PD) (NCT02109328). The primary endpoint (EP) was RECIST 1.1 objective response-rate (ORR, H0 ≤ 5%, H1 ≥ 20%, α = 10% and ß = 20%). Eligibility included failure of at least one platinum-based regimen. RESULTS: From 10/2014 to 04/2015, 22 patients were enrolled (20 evaluable for response), 8 (36.4%) in second-line and 14 (63.6 %) beyond the second-line. Eight (36.4%) had an ECOG-performance status 1-2. Two partial responses (PR, ORR: 9.1%), 7 stable disease (SD) and 11 PD were obtained. Median follow-up was 8.3 months (IQR: 7-10.3), 6-month progression-free survival (PFS) was 13.6% (95%CI: 4.8-39.0). Two SD are still receiving treatment after 11.5 and 6.3 months. Median overall survival (OS) was not reached (6-month OS: 59.1%, 95%CI: 41.7-83.7). Hb < 10 g/dl was significantly associated with shorter PFS and OS multivariably (p = 0.031 and p = 0.033). Tissue of the case with 11.5 month SD harbored a missense mutation of mTOR (E1813D), the nonsense mutation Q527STOP of TSC1, HER3 and TAF1L missense mutations. Grade 3-4 adverse events (AE) were: 40.9% mucositis, 36.4% fatigue, 18.2% neutropenia (13.6% febrile neutropenia). There were 2 treatment-related deaths. CONCLUSIONS: The study did not meet the primary EP, yet sustained disease control was obtained in about 14% of patients. The incidence of AE and the issue of patient selection are two major concerns.


Asunto(s)
Aurora Quinasa A/antagonistas & inhibidores , Azepinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Urotelio/patología , Anciano , Aurora Quinasa A/metabolismo , Azepinas/efectos adversos , Azepinas/farmacología , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/efectos adversos , Pirimidinas/farmacología , Resultado del Tratamiento , Urotelio/efectos de los fármacos
19.
BJU Int ; 116(5): 727-33, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24128128

RESUMEN

OBJECTIVE: To evaluate the association between lymph node ratio (LNR) and cancer-specific survival (CSS) in a population of patients with penile cancer and lymph node metastases (LNM). PATIENTS AND METHODS: We evaluated 81 patients with pathologically determined LNM who were surgically treated at our institution between 2000 and 2012. We considered LNR both as a continuously coded and as a categorically coded variable. The minimum-P-value approach was used to determine the most significant LNR threshold. The Kaplan-Meier method was used to determine CSS rates, and univariable and multivariable Cox regression models were fitted to test the predictors of CSS. RESULTS: The median (interquartile range [IQR]) numbers of positive and removed lymph nodes were 2 (1-4) and 22 (13-30), respectively. The median (IQR) LNR was 10.3 (6.3-16.6)% and the most significant LNR threshold was 22%. The median (IQR) follow-up was 26 (16-62) months. Overall, the 5-year CSS rate was 50.5%. After stratification according to LNR, 5-year CSS rates were 65.2% vs 9.6% in patients with LNR < 22% vs LNR ≥ 22%, respectively (P < 0.001). In multivariable Cox regression models, after adjusting for several established prognostic factors, LNR was as independent predictor of CSS (P≤0.012). Finally, LNR significantly improved the accuracy of multivariable Cox regression models by 4.9-10.5%. CONCLUSIONS: Although further investigations are needed to evaluate the relationship between tumour burden and treatment intensity, LNR may represent a powerful predictor of CSS in patients with penile cancer and pathologically determined LNM.


Asunto(s)
Carcinoma de Células Escamosas/patología , Ganglios Linfáticos/patología , Neoplasias del Pene/patología , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/cirugía , Humanos , Italia , Estimación de Kaplan-Meier , Escisión del Ganglio Linfático , Metástasis Linfática , Masculino , Estadificación de Neoplasias , Neoplasias del Pene/mortalidad , Neoplasias del Pene/cirugía , Valor Predictivo de las Pruebas , Pronóstico
20.
J Urol ; 191(4): 977-82, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24262497

RESUMEN

PURPOSE: We determined predictors of pelvic lymph node metastases in patients with penile cancer. MATERIALS AND METHODS: We retrieved a total of 188 node positive inguinal groins from 142 patients treated for penile cancer. Logistic regression models were fitted to test for predictors of pelvic lymph node metastases. The minimum p value method was used to determine the most significant cutoff values of each predictor. RESULTS: Pelvic lymph node metastases were observed in 45 cases (31.7%). The 5-year cancer specific survival rate was 71.0% vs 33.2% in patients with inguinal vs pelvic lymph node metastases. The most significant cutoff values were 3 inguinal lymph node metastases and a metastasis diameter of 30 mm. According to univariable logistic regression models the number of inguinal metastases (OR 1.92, p <0.001), the diameter of the metastases (OR 1.03, p = 0.001) and extranodal extension (OR 8.01, p <0.001) were significant predictors of pelvic lymph node metastases. These variables were also independent predictors of metastases in multivariable logistic regression models (p ≤ 0.012). Patients with 3 or more inguinal lymph node metastases and those with a metastasis diameter of 30 mm or greater were at 4.77 and 2.53-fold higher risk, respectively, of harboring pelvic lymph node metastases (p ≤ 0.006). The proportion of metastases increased significantly from 0% in cases with no risk factors to 57.1% when all 3 risk factors were observed (p <0.001). CONCLUSIONS: The number and diameter of inguinal lymph node metastases as well as extranodal extension are significantly associated with pelvic lymph node metastases. These variables should be considered to determine the need for pelvic lymph node dissection. Patients with no risk factors may be spared this dissection.


Asunto(s)
Carcinoma de Células Escamosas/secundario , Neoplasias del Pene/patología , Anciano , Algoritmos , Humanos , Conducto Inguinal , Metástasis Linfática , Masculino , Persona de Mediana Edad , Pelvis , Estudios Retrospectivos
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