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BACKGROUND AND OBJECTIVE: The CABASTY study showed that more frequent administration of a lower dose of cabazitaxel (CBZ) reduced toxicity in older men with metastatic castration-resistant prostate cancer (mCRPC), without compromising efficacy. Here, we investigated the impact of a biweekly CBZ schedule on patient-reported pain and health-related quality of life (HRQoL). METHODS: We randomized 196 patients from 25 centers (1:1, stratified by age and G8 score) to the biweekly CBZ16 (CBZ 16 mg/m2) experimental arm or the triweekly CBZ25 (CBZ 25 mg/m2) control arm (CABASTY study, NCT02961257). We assessed pain using the Numeric Pain Rating Scale and HRQoL using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. KEY FINDINGS AND LIMITATIONS: A total of 141 patients were available for a pain and 160 for an HRQoL analysis. Median time to pain progression (stratified hazard ratio [HR]: 1.7, confidence interval [CI]: 0.67-4.22, p = 0.3) and median time to first opiate use (stratified HR: 1.05, CI: 0.44-2.55, p = 0.9) did not differ between arms. We did not see a significant difference in median time to deterioration of FACT-P total score between treatments (stratified HR: 0.88, CI: 0.47-1.7, p = 0.7). Interestingly, the time to onset of several adverse events was significantly longer in the biweekly CBZ16 group. CONCLUSIONS AND CLINICAL IMPLICATIONS: HRQoL did not significantly differ between the biweekly CBZ16 and the standard schedule. Additionally, onset of some adverse events was delayed. These results may increase health care providers' confidence in using CBZ in older patients with mCRPC who are denied chemotherapy. PATIENT SUMMARY: Androgen receptor pathway inhibitors are often preferred to taxane chemotherapy as a treatment of second or subsequent line in older metastatic castration-resistant prostate cancer patients due to more frequent treatment-related toxicities. Here, we showed that quality of life and pain did not differ significantly with an adapted schedule of cabazitaxel (CBZ), compared with the standard regimen. This CBZ schedule could increase eligibility of older patients for chemotherapy.
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BACKGROUND: MAGNITUDE (NCT03748641) demonstrated favourable outcomes with niraparib plus abiraterone acetate plus prednisone (+AAP) versus placebo+AAP in patients with BRCA1/2-altered metastatic castration-resistant prostate cancer (mCRPC). Imbalances in prognostic variables were reported between arms, which impacts estimation of both the clinical benefit and costeffectiveness of niraparib+AAP for healthcare systems. A pre-specified multivariable analysis (MVA) demonstrated improved overall survival (OS) with niraparib+AAP. Here, we used an inverse probability of treatment weighting (IPTW) model to adjust for covariate imbalances and assess time-to-event outcomes. METHODS: IPTW analysis of time-to-event outcomes was conducted using data from patients with BRCA1/2-altered mCRPC (N = 225) in MAGNITUDE. Patients received niraparib+AAP or placebo+AAP. OS, radiographic progression-free survival, time to symptomatic progression, time to initiation of cytotoxic chemotherapy and time to prostate-specific antigen progression were assessed. Weighted Kaplan-Meier curves were generated for each endpoint, and adjusted hazard ratios (HR) were obtained from a weighted Cox model. RESULTS: Improvements in survival outcomes were estimated for niraparib+AAP versus placebo+AAP: unadjusted median OS was 30.4 months versus 28.6 months, respectively (HR: 0.79; 95 % confidence interval [CI]: 0.55, 1.12; p = 0.183). Following IPTW, median OS increased to 34.1 months with niraparib+AAP versus a decrease to 27.4 with placebo (HR: 0.65; 95 % CI: 0.46, 0.93; p = 0.017). Similar improvements were observed for other time-to-event endpoints. CONCLUSIONS: IPTW adjustment provided a more precise estimate of the clinical benefit of niraparib+AAP versus placebo+AAP in patients with BRCA1/2-altered mCRPC. Results were consistent with the pre-specified MVA, and further demonstrated the value of adjusting for baseline imbalances, particularly in smaller studies. TRIAL REGISTRATION: NCT03748641 (MAGNITUDE).
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INTRODUCTION: We describe the development of a molecular assay from publicly available tumor tissue mRNA databases using machine learning and present preliminary evidence of functionality as a diagnostic and monitoring tool for prostate cancer (PCa) in whole blood. MATERIALS AND METHODS: We assessed 1055 PCas (public microarray data sets) to identify putative mRNA biomarkers. Specificity was confirmed against 32 different solid and hematological cancers from The Cancer Genome Atlas (n = 10,990). This defined a 27-gene panel which was validated by qPCR in 50 histologically confirmed PCa surgical specimens and matched blood. An ensemble classifier (Random Forest, Support Vector Machines, XGBoost) was trained in age-matched PCas (n = 294), and in 72 controls and 64 BPH. Classifier performance was validated in two independent sets (n = 263 PCas; n = 99 controls). We assessed the panel as a postoperative disease monitor in a radical prostatectomy cohort (RPC: n = 47). RESULTS: A PCa-specific 27-gene panel was identified. Matched blood and tumor gene expression levels were concordant (r = 0.72, p < 0.0001). The ensemble classifier ("PROSTest") was scaled 0%-100% and the industry-standard operating point of ≥50% used to define a PCa. Using this, the PROSTest exhibited an 85% sensitivity and 95% specificity for PCa versus controls. In two independent sets, the metrics were 92%-95% sensitivity and 100% specificity. In the RPCs (n = 47), PROSTest scores decreased from 72% ± 7% to 33% ± 16% (p < 0.0001, Mann-Whitney test). PROSTest was 26% ± 8% in 37 with normal postoperative PSA levels (<0.1 ng/mL). In 10 with elevated postoperative PSA, PROSTest was 60% ± 4%. CONCLUSION: A 27-gene whole blood signature for PCa is concordant with tissue mRNA levels. Measuring blood expression provides a minimally invasive genomic tool that may facilitate prostate cancer management.
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Biomarcadores Tumorais , Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Biópsia Líquida/métodos , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Idoso , Pessoa de Meia-Idade , Aprendizado de Máquina , RNA Mensageiro/sangue , RNA Mensageiro/genética , Prostatectomia , Sensibilidade e EspecificidadeRESUMO
Prostate cancer pathology plays a crucial role in clinical management but is time-consuming. Artificial intelligence (AI) shows promise in detecting prostate cancer and grading patterns. We tested an AI-based digital twin of a pathologist, vPatho, on 2603 histological images of prostate tissue stained with hematoxylin and eosin. We analyzed various factors influencing tumor grade discordance between the vPatho system and six human pathologists. Our results demonstrated that vPatho achieved comparable performance in prostate cancer detection and tumor volume estimation, as reported in the literature. The concordance levels between vPatho and human pathologists were examined. Notably, moderate to substantial agreement was observed in identifying complementary histological features such as ductal, cribriform, nerve, blood vessel, and lymphocyte infiltration. However, concordance in tumor grading decreased when applied to prostatectomy specimens (κ = 0.44) compared to biopsy cores (κ = 0.70). Adjusting the decision threshold for the secondary Gleason pattern from 5 to 10% improved the concordance level between pathologists and vPatho for tumor grading on prostatectomy specimens (κ from 0.44 to 0.64). Potential causes of grade discordance included the vertical extent of tumors toward the prostate boundary and the proportions of slides with prostate cancer. Gleason pattern 4 was particularly associated with this population. Notably, the grade according to vPatho was not specific to any of the six pathologists involved in routine clinical grading. In conclusion, our study highlights the potential utility of AI in developing a digital twin for a pathologist. This approach can help uncover limitations in AI adoption and the practical application of the current grading system for prostate cancer pathology.
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Inteligência Artificial , Neoplasias da Próstata , Humanos , Masculino , Patologistas , Próstata , BiópsiaAssuntos
Medicina Nuclear , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/radioterapia , Compostos Radiofarmacêuticos/uso terapêutico , Dipeptídeos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Antígeno Prostático Específico , Lutécio/uso terapêutico , Resultado do Tratamento , Estudos RetrospectivosRESUMO
In metastatic or locally advanced urothelial carcinoma (UC), therapeutic options have been limited to chemotherapy and immune checkpoint inhibitors. Novel targets and drugs such as antibody drug conjugates have been developed, and enfortumab vedotin targeting nectin-4 and sacituzumab govitecan (SG) targeting trophoblast cell surface antigen 2 (TROP-2), the protein product of the TACSTD2 gene, have been approved. The expression of TROP-2 was investigated within UC and other types of carcinomas, and within the tissue of different healthy organs to understand treatment responses and toxicities. The expression of TROP-2 in the tissues of 42 patients with UC, 13 patients with other types of cancer and in the normal tissues of 11 patients was retrospectively analyzed. Immunohistochemical staining of the TROP-2 protein was performed on a BenchMark ULTRA IHC/ISH System (Roche Tissue Diagnostics; Roche Diagnostics, Ltd.) according to accredited staining protocols in a routine immunohistochemistry accredited and certified facility of the laboratory of immunohistochemistry at the Institute of Pathology (Gerhard-Domagk Institute)- University Hospital Muenster (UKM)-Muenster-Germany]. Different expression levels of TROP-2 were observed, and the highest expression rate of TROP-2 was observed in UC, independent of the tumor stage. However, normal urothelial cells had similar expression levels. Except for ductal carcinoma in situ, the expression of TROP-2 was reduced in other types of cancer and in the healthy tissues from other organs, including pancreas, gall bladder, colon and prostate. Given the treatment response based on the expression level of TROP-2, SG would be effective in almost all cases of UC. However, it would also have an effect on the normal urothelium.
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Importance: Many patients 65 years or older with metastatic castration-resistant prostate cancer (mCRPC) are denied taxane chemotherapy because this treatment is considered unsuitable. Objective: To determine whether biweekly cabazitaxel (CBZ), 16 mg/m2 (biweekly CBZ16), plus prophylactic granulocyte colony-stimulating factor (G-CSF) at each cycle reduces the risk of grade 3 or higher neutropenia and/or neutropenic complications (eg, febrile neutropenia, neutropenic infection, or sepsis) compared with triweekly CBZ, 25 mg/m2 (triweekly CBZ25), plus G-CSF (standard regimen). Design, Setting, and Participants: A total of 196 patients 65 years or older with progressive mCRPC were enrolled in this prospective phase 3 randomized clinical trial conducted in France (18 centers) and Germany (7 centers) between May 5, 2017, and January 7, 2021. All patients had received docetaxel and at least 1 novel androgen receptor-targeted agent. Interventions: Patients were randomly assigned 1:1 to receive biweekly CBZ16 plus G-CSF and daily prednisolone (experimental group) or triweekly CBZ25 plus G-CSF and daily prednisolone (control group). Main Outcome and Measures: The primary end point was the occurrence of grade 3 or higher neutropenia measured at nadir and/or neutropenic complications. Results: Among 196 patients (97 in the triweekly CBZ25 group and 99 in the biweekly CBZ16 group), the median (IQR) age was 74.6 (70.4-79.3) years, and 181 (92.3%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. The median (IQR) follow-up duration was 31.3 (22.5-37.5) months. Relative dose intensities were comparable between groups (median [IQR], 92.7% [83.7%-98.9%] in the triweekly CBZ25 group vs 92.8% [87.0%-98.9%] in the biweekly CBZ16 group). The rate of grade 3 or higher neutropenia and/or neutropenic complications was significantly higher with triweekly CBZ25 vs biweekly CBZ16 (60 of 96 [62.5%] vs 5 of 98 [5.1%]; odds ratio, 0.03; 95% CI, 0.01-0.08; P < .001). Grade 3 or higher adverse events were more common with triweekly CBZ25 (70 of 96 [72.9%]) vs biweekly CBZ16 (55 of 98 [56.1%]). One patient (triweekly CBZ25 group) died of a neutropenic complication. Conclusions and Relevance: In this randomized clinical trial, compared with the standard regimen, biweekly CBZ16 plus G-CSF significantly reduced by 12-fold the occurrence of grade 3 or higher neutropenia and/or neutropenic complications, with comparable clinical outcomes. The findings suggest that biweekly CBZ16 regimen should be offered to patients 65 years or older with mCRPC for whom the standard regimen is unsuitable. Trial Registration: ClinicalTrials.gov Identifier: NCT02961257.
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Neutropenia , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Idoso , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Prospectivos , Resultado do Tratamento , Taxoides/administração & dosagem , Neutropenia/induzido quimicamente , Prednisolona/administração & dosagem , Prednisolona/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/efeitos adversosRESUMO
PURPOSE: There is ongoing controversy about the recommended dose of cabazitaxel in patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: This multicenter phase II open-label, randomized, parallel-group study compared 3-weekly cabazitaxel at 25 mg/m2 (conventional arm A) with cabazitaxel therapeutic drug monitoring (experimental arm B) in mCRPC. The primary objective was to improve the clinical feasibility rate (CFR), defined as the absence of grade 4 neutropenia or thrombocytopenia, any thrombocytopenia with bleeding, febrile neutropenia, severe nonhematologic toxicity, withdrawal for cabazitaxel-related toxicity, or death. A total of 60 patients had to be randomized to detect a difference in CFR of 35% (power 80%, two-sided alpha 10%). RESULTS: A total of 40 patients were randomized to arm A and 33 patients to arm B. CFR was 69.4% in arm A and 64.3% in arm B (P = 0.79). Week-12 PSA response was 38.5% in both arms. A radiological response by RECIST v.1.1 was seen in 3 (9.7%) patients in arm A versus 6 (23.1%) patients in arm B (P = 0.28), disease progression was higher in arm A compared with arm B (61.3% vs. 30.8%, P = 0.05). Median progression-free survival was longer in arm B compared with arm A (9.5 vs. 4.4 months; HR = 0.46; P = 0.005). Median overall survival was higher in arm B compared with arm A (16.2 vs. 7.3 months; HR = 0.33; P < 0.0001). CONCLUSIONS: Pharmacokinetic-guided dosing of cabazitaxel in patients with mCRPC is feasible and improves clinical outcome due to individual dose escalations in 55% of patients.
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Neutropenia , Neoplasias de Próstata Resistentes à Castração , Trombocitopenia , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/patologia , Resultado do Tratamento , Neutropenia/induzido quimicamente , Neutropenia/prevenção & controle , Antígeno Prostático EspecíficoRESUMO
BACKGROUND: From 1941 to 2014, metastatic hormone-sensitive prostate cancer (mHSPC) was solely treated by surgery or medical castration (androgen deprivation therapy [ADT]). In 2014, the addition of docetaxel chemotherapy (CTX) was shown to significantly improve overall survival. However, CTX is not ideal for all patients. Some are too old, too sick, or oppose to treatment with CTX. Therefore, alternatives with low toxicity and equal efficacy were explored. Abiraterone (Abi), apalutamide (Apa), and enzalutamide (Enza) are new antihormonal therapies (NHT) which meet these requirements. OBJECTIVES: To review the role of NHTsâ¯+ ADT in mHSPC. MATERIALS AND METHODS: Prerequisites and challenges are summarized and key data on combination therapy with NHTsâ¯+ ADT in mHSPC are reviewed. RESULTS: Treatment of mHSPC with Abi, Apa, or Enza represents a big step forward. Especially for patients who do not qualify for CTX or oppose CTX, NHTs are a valid alternative. The use of Abi is more challenging than the use of Apa and Enza due to more complex conditions that need to be fulfilled for its use. Thus, the time for the patient in the mHSPC stage will be longer with more intensive androgen deprivation, which may lead to increased risk of cardiovascular disease and osteoporosis. When choosing a treatment with NHTs in this setting, possible follow-up treatment needs to be considered. CONCLUSIONS: Treatment of mHSPC using NHTsâ¯+ ADT is an important new standard. Almost every patient can be treated with one of the NHTs with relatively low risk of toxicity. Therefore, these treatments are widely used. In the future, the addition of new therapeutics could further strengthen the relevance of NHTs in the mHSPC setting.
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Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/tratamento farmacológico , Antagonistas de Androgênios/efeitos adversos , Androgênios/uso terapêutico , Resultado do Tratamento , DocetaxelRESUMO
BACKGROUND: Prognostication is essential to determine the risk profile of patients with urologic cancers. METHODS: We utilized the SEER national cancer registry database with approximately 2 million patients diagnosed with urologic cancers (penile, testicular, prostate, bladder, ureter, and kidney). The cohort was randomly divided into the development set (90%) and the out-held test set (10%). Modeling algorithms and clinically relevant parameters were utilized for cancer-specific mortality prognosis. The model fitness for the survival estimation was assessed using the differences between the predicted and observed Kaplan-Meier estimates on the out-held test set. The overall concordance index (c-index) score estimated the discriminative accuracy of the survival model on the test set. A simulation study assessed the estimated minimum follow-up duration and time points with the risk stability. RESULTS: We achieved a well-calibrated prognostic model with an overall c-index score of 0.800 (95% CI: 0.795-0.805) on the representative out-held test set. The simulation study revealed that the suggestions for the follow-up duration covered the minimum duration and differed by the tumor dissemination stages and affected organs. Time points with a high likelihood for risk stability were identifiable. CONCLUSIONS: A personalized temporal survival estimation is feasible using artificial intelligence and has potential application in clinical settings, including surveillance management.
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BACKGROUND: In patients with bone metastatic castration-resistant prostate cancer (bmCRPC) on systemic treatment, it is difficult to differentiate between continuous rise of prostate specific antigen (PSA) representing progression, and PSA-surge, which is followed by clinical response or stable disease. The purpose of this study was to evaluate the prognostic value of dynamic changes of alkaline phosphatase (ALP) and lactic acid dehydrogenase (LDH) levels as a predictor of clinical efficacy or therapeutic resistance of patients who do not show a sufficient initial PSA decline of ≥50% from baseline during early therapy with Enzalutamide. METHODS: Forty-eight men with bmCRPC on Enzalutamide 07/2010-09/2019 with initially rising PSA were analyzed. We monitored PSA, LDH and ALP at week 0, 2, 4, and every 4 weeks thereafter and analyzed the correlation between ALP rising at 12 weeks with or without LDH-normalization and the association with survival. For this we used Kaplan Meier analysis and uni- and multivariate cox-regression models. RESULTS: In Kaplan-Meier analysis, ALP rising at 12 weeks with or without LDH-normalization was associated with significantly worse median progression-free survival (PFS) of 3 months vs. 5 months (Log rank P = 0.02) and 3 months vs. 5 months (P = 0.01), respectively and overall survival (OS) with 8 months vs. 15 months (P = 0.02) and 8 months vs. 17 months (P < 0.01). In univariate analysis of PFS, ALP rising at 12 weeks alone, ALP rising at 12 weeks without LDH-normalization and application of Enzalutamide after chemotherapy showed a statistically significant association towards shorter PFS (hazard ratio (HR): 0.51, P = 0.04; HR: 0.48, P = 0.03; HR: 0.48, P = 0.03). Worse OS was significantly associated with ALP rising at 12 weeks alone, ALP rising at 12 weeks without LDH-normalization, and application of Enzalutamide after chemotherapy (HR: 0.47, P = 0.02; HR: 0.36, P < 0.01; HR: 0.31, P < 0.01). In multivariate analysis only the application of Enzalutamide after chemotherapy remained an independent prognostic factor for worse OS (HR: 0.36, P = 0.01). CONCLUSIONS: Dynamic changes of ALP (non-rise) and LDH (normalization) under therapy with Enzalutamide may be associated with clinical benefit, better PFS, and OS in patients with bmCRPC who do not show a PSA decline.
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Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração , Fosfatase Alcalina , Benzamidas , Humanos , L-Lactato Desidrogenase , Ácido Láctico , Masculino , Nitrilas/uso terapêutico , Feniltioidantoína , Prognóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Resultado do TratamentoRESUMO
INTRODUCTION: Fibroblast activation protein (FAP) has been recently presented as new imaging target for malignant diseases and offers high contrast to surrounding normal tissue. FAP tracer uptake has been reported in various tumor entities. The aim of this study was to compare FAP and Prostate-specific membrane antigen (PSMA) expression in primary prostate cancer employing histological analyses and PET imaging in two small patient collectives. METHODS: Two independent small patient collectives were included in this study. For cohort A, data of 5 prostate cancer patients and 3 patients with benign prostate hyperplasia were included. Patients with prostate cancer were initially referred for PSMA PET staging. Radical prostatectomy was performed in all patients and prostate specimen of patients and biopsies of healthy controls were available for further evaluation. Histological workup included HE and immunohistochemistry using PSMA Ab, FAP Ab. Cohort B consists of 6 Patients with diagnosed mCRPC and available PSMA as well as FAP PET. RESULTS: Patients with proven prostate cancer infiltration exhibited strong positivity for PSMA in both primary tumors and lymph node metastases while stainings for FAP were found positive in some cases, but not all (2/5). Controls with BPH presented moderate PSMA staining and in one case also with a positive FAP staining (1/3). PET imaging with FAP seemed to result in more precise results in case of low PSMA expression than PSMA-PET. CONCLUSIONS: While PSMA staining intensity is a valid indicator of prostate cancer in both primary tumor and lymph node metastases, the expression of FAP seems to be heterogeneous but not necessarily linked to cancer-associated fibroblasts. It is also present in inflammation-associated myofibroblasts. Therefore, its ultimate role in prostate cancer diagnosis remains a subject of discussion.
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Próstata , Neoplasias da Próstata , Fibroblastos/metabolismo , Fibroblastos/patologia , Radioisótopos de Gálio , Humanos , Imuno-Histoquímica , Masculino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tomografia por Emissão de Pósitrons , Dados Preliminares , Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologiaRESUMO
BACKGROUND: A recent meta-analysis showed that penile cancer (PeC) is associated with the human papilloma virus (HPV) in 50â% of patients in Europe. It is unknown whether urologists are aware of the impact of viral carcinogenesis. METHODS: A (German-language) survey comprising 14 items was created and sent to urologists of 45 clinical centres in Germany (nâ=â34), Austria (nâ=â8), Switzerland (nâ=â2) and Italy/South Tyrol (nâ=â1) once in Q3/2018. According to a predefined quality standard, a total of 557 surveys were eligible for final data analysis (response rate: 85.7â%). Among other questions, urologists were asked to state the frequency of HPV-associated PeC in Europe. 4 potential answers were provided: (A)-"<â25â%", (B)-"25â-â50â%", (C)-">â50â-â75â%", (D)-"level of association unknown". For the final calculation, a tolerance of ±â50â% was considered acceptable, so B and C were deemed correct answers. Based on a bootstrap-adjusted multivariate logistic regression model, criteria independently predicting a correct answer were identified. RESULTS: Categories A-D were selected in 19.2â% (nâ=â107), 48.8â% (nâ=â272), 12.9â% (nâ=â72) and 19â% (nâ=â106), respectively, representing a rate of 61.8â% of urologists (nâ=â344) reaching the endpoint (Bâ+âC). Autonomous performance of chemotherapy for PeC by urologists within the given centre (OR 1.55, p[Bootstrap]â=â0.036) and the centre's number of urological beds (OR 1.02, p[Bootstrap]â=â0.025) were the only parameters showing a significant independent impact on the endpoint. In contrast, the status of a university centre (pâ=â0.143), a leading position of the responding urologist (pâ=â0.375) and the number of PeC patients treated per year and centre (pâ=â0.571) did not significantly predict a correct answer. CONCLUSIONS: Our results demonstrate insufficient knowledge on the association of PeC and HPV among German-speaking urologists.
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Alphapapillomavirus , Infecções por Papillomavirus , Neoplasias Penianas , Humanos , Idioma , Masculino , Papillomaviridae , Infecções por Papillomavirus/complicações , Neoplasias Penianas/epidemiologia , Estudos Prospectivos , Inquéritos e Questionários , UrologistasRESUMO
BACKGROUND: In bone metastatic castration-resistant prostate cancer (bmCRPC) treated with Enzalutamide commonly used prostate-specific antigen (PSA) can be misleading since initial PSA-flares may occur. In other therapies, bouncing of alkaline phosphatase (ALP-bouncing) was shown to be a promising surrogate for survival outcome. Low lactate dehydrogenase (LDH) is usually associated with better outcome. We evaluated the prognostic ability of ALP-bouncing, LDH, PSA, and the combination of these markers after initiation of Enzalutamide. METHODS: Eighty-nine patients with bmCRPC and dynamic changes of PSA, LDH and ALP were analyzed. ALP-bouncing, an increase after therapy start followed by a decline below baseline during the first 8 weeks, LDH-normalization and PSA-decline were analyzed regarding their association with survival using Kaplan-Meier analyses and uni- and multivariate (UV and MV) Cox-regression models. RESULTS: In Kaplan-Meier analysis a PSA-decline >50%, LDH-normalization and ALP-bouncing were associated with longer median progression-free survival (PFS) with 7 [95% confidence interval (CI): 4.2-9.8] vs. 3 (2.3-3.7) months for PSA-decline (log-rank P<0.01), 6 (4.1-8) vs. 2 (1.2-2.8) for LDH-normalization (P<0.01) and 8 (0-16.3) vs. 3 (1.9-4.1) for ALP-bouncing (P=0.01). Analysis of overall survival (OS) showed similar, not for all parameters significant, results with 17 (11.7-22.3) vs. 12 (7.0-17.1) months for PSA (P=0.35), 17 (13.2-20.8) vs. 7 (5.8-8.2) for LDH-normalization (P<0.01) and 19 (7.9-30.1) vs. 12 (7.7-16.3) for ALP-bouncing (P=0.32). In UV analysis, ALP-bouncing [hazard ratio (HR): 0.5 (0.3-1.0); P=0.02], PSA-decline >50% [HR: 0.5 (0.3-0.7); P<0.01] and LDH-normalization [HR: 0.4 (0.2-0.6); P<0.01] were significantly associated with longer PFS. For OS, LDH-normalization significantly prognosticated longer survival [HR: 0.4 (0.2-0.6); P<0.01]. In MV analysis, LDH-normalization was associated with a trend towards better OS [HR: 0.5 (0.2-1.1); P=0.09]. Comparing ALP-bouncing, LDH-normalization and PSA-decline with a PSA-decline alone, Kaplan-Meier analysis showed significantly longer PFS [11 (0.2-21.8) vs. 4 (0-8.6); P=0.01] and OS [20 (17.7-22.3) vs. 8 (0.3-15.7); P=0.02] in favor of the group presenting with the beneficial dynamics of all three markers. In UV analysis, the presence of favorable changes in the three markers was significantly associated with longer PFS [HR: 0.2 (0.1-0.7); P<0.01] and OS [HR: 0.3 (0.1-0.8); P=0.02]. CONCLUSIONS: ALP-bouncing and LDH-normalization may add to identification of bmCRPC-patients with favorable prognosis under Enzalutamide.
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BACKGROUND: Temsirolimus is a mTOR inhibitor approved for the first-line treatment of advanced or metastatic renal cell carcinoma (a/mRCC) with poor prognosis. In treatment of a/mRCC several prognostic scoring systems are used. We assessed the prognostic value of these scores in a large temsirolimus treated cohort and compared the results with the physician's prognosis. METHODS: A German multicenter registry (STAR-TOR) for a/mRCC patients (NCT00700258) was established to evaluate the efficacy and safety of temsirolimus 25 mg weekly in a routine clinical setting. These prospective data were systematically analyzed and followed-up by an independent clinical research organization to compare established prognostic scores (MSKCC, IMDC and Hudes) with the risk assessment by treating physicians based on their medical expertise and match them with survival outcomes. RESULTS: This interim analysis included 547 patients between 02/2008 and 05/2015 in 87 centers. Either prognostic tool resulted in significant and clinically meaningful differentiation between good, intermediate and poor prognosis. However, physician's prognosis identified more patients with good prognosis (9.1% vs. 1.3%). In patients with good physician's prognosis and intermediate prognosis by MSKCC, overall survival was nearly doubled compared to consensual intermediate prognosis (26.6 vs. 13.6 months), albeit without reaching statistical significance (P=0.09). For poor prognosis assessed by the physician, MSKCC performed statistically better for differentiation between poor and intermediate prognosis with a median overall survival of 10.3 vs. 5.5 months (P<0.01). CONCLUSIONS: Physician's prognosis may be able to identify a subset of patients treated with temsirolimus with good prognosis when MSKCC-determines intermediate prognosis while the MSKCC score could identify patients which were falsely placed in the poor risk group by physicians.
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Patients suffering from metastatic castration-resistant prostate cancer (mCRPC) have a poor prognosis. As a further treatment option 177Lutetium (Lu) prostate-specific membrane antigen (PSMA) radioligand therapy gained a significant interest of many investigators. Several publications showed great response and prolonged survival with limited adverse events. However, to this point, it still remains unclear which patients benefit the most from 177Lu-PSMA therapy, and how to improve the treatment regimen to achieve best outcome while minimizing potential adverse events. The efficacy for mCRPC patients is a given fact, and with the newly published results of the VISION trial its approval is only a matter of time. Recently, investigators started to focus on treating prostate cancer patients in earlier disease stages and in combination with other compounds. This review gives a brief overview of the current state and the future perspectives of 177Lu labelled PSMA radioligand therapy.
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Aim: Examine outcomes in sunitinib-treated patients by International Metastatic RCC Database Consortium (IMDC) or Memorial Sloan-Kettering Cancer Center (MSKCC) risk factors. Patients & methods: Patients enrolled in STAR-TOR registry (n = 327). End points included overall survival, progression-free survival and objective response rate. Results: Overall survival was similar for IMDC 0 versus 1 (p = 0.238) or 2 versus ≥3 (p = 0.156), but different for MSKCC (0 vs 1, p = 0.037; 2 vs ≥3, p = 0.001). Progression-free survival was similar for IMDC 2 versus 3 (p = 0.306), but different for MSKCC (p = 0.009). Objective response rate was different for IMDC 1 (41.9%) and 2 (29.5%) and similar for MSKCC 1 (34.4%) and 2 (31.0%). Conclusion: Outcome data varied according to IMDC or MSKCC. MSKCC model accurately stratify patients into risk groups. Clinical trial registration: NCT00700258 (ClinicalTrials.gov).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/mortalidade , Neoplasias Renais/mortalidade , Sistema de Registros/estatística & dados numéricos , Idoso , Axitinibe/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/secundário , Feminino , Seguimentos , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Masculino , Prognóstico , Estudos Prospectivos , Medição de Risco , Sirolimo/administração & dosagem , Sirolimo/análogos & derivados , Sunitinibe/administração & dosagem , Taxa de SobrevidaRESUMO
INTRODUCTION: [177Lu]Lu-PSMA-617 (Lu-PSMA) radioligand therapy is an emerging treatment option for patients with end-stage prostate cancer. However, response to Lu-PSMA therapy is only achieved in approximately half of patients. It is clinically important to identify patients at risk of poor outcome. Therefore, the aim of this study was to evaluate pretherapeutic PSMA PET derived total tumor volume and related metrics as prognosticators of overall survival in patients receiving Lu-PSMA therapy. METHODS: A total number of 110 patients form the Departments of Nuclear Medicine Münster and Essen were included in this retrospective analysis. Baseline PSMA PET-CT was available for all patients. Employing a previously published approach, all tumor lesions were semi-automatically delineated in PSMA PET-CT acquisitions. Total lesion number, total tumor volume (PSMA-TV), total lesion uptake (PSMA-TLU = PSMA-TV * SUVmean), and total lesion quotient (PSMA-TLQ = PSMA-TV / SUVmean) were quantified for each patient. Log2 transformation was used for regressions. RESULTS: Lesion number, PSMA-TV, and PSMA-TLQ were prognosticators of overall survival (HR = 1.255, p = 0.009; HR = 1.299, p = 0.005; HR = 1.326, p = 0.002). In a stepwise backward Cox regression including lesion number, PSMA-TV, PSA, LDH, and PSMA-TLQ, only the latter two remained independent and statistically significant negative prognosticators of overall survival (HR = 1.632, p = 0.011; HR = 1.239, p = 0.024). PSMA-TLQ and LDH were significant negative prognosticators in multivariate Cox regression in contrast to PSA value. CONCLUSION: PSMA-TV was a statistically significant negative prognosticator of overall survival in patients receiving Lu-PSMA therapy. PSMA-TLQ was an independent and superior prognosticator of overall survival compared with PSMA-TV.
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Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias de Próstata Resistentes à Castração , Dipeptídeos/uso terapêutico , Compostos Heterocíclicos com 1 Anel , Humanos , Masculino , Antígeno Prostático Específico , Estudos Retrospectivos , Resultado do Tratamento , Carga TumoralRESUMO
Aim: Examine the effects of baseline hypertension (HTN) and statin or proton pump inhibitor (PPI) use on sunitinib treatment outcomes in STAR-TOR, a real-world registry. Materials & methods: Presence or absence of HTN and use or nonuse of statins or PPIs were determined at registry entry. End points included overall survival (OS) and progression-free survival (PFS). Results: Data were from 557 patients. Presence or absence of HTN did not affect OS or PFS. PFS (median [95% CI]) was longer in statin users (9.4 [6.5-13.6] months) versus nonusers (6.9 [5.7-8.2] months) (p = 0.0442). OS was shorter in PPI users (20.2 [14.9-28.3] months) versus nonusers (25.7 [22.7-33.0] months) (p = 0.0212). Conclusion: Comorbidities and comedications may affect real-world sunitinib treatment outcomes. Clinical Trial Registration: NCT00700258 (ClinicalTrials.gov).
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Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Sunitinibe/uso terapêutico , Idoso , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Comorbidade , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipertensão/complicações , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Inibidores da Bomba de Prótons/uso terapêutico , Sistema de RegistrosRESUMO
The therapy of advanced (clear-cell) renal cell carcinoma (RCC) has recently experienced tremendous changes. Several new treatments have been developed, with PD-1 immune-checkpoint inhibition being the backbone of therapy. Diverse immunotherapy combinations change current first-line standards. These changes also require new approaches in subsequent lines of therapy. In an expert panel, we discussed the new treatment options and how they change clinical practice. While first-line immunotherapies introduce a new level of response rates, data on second-line therapies remains poor. This scenario poses a challenge for clinicians as guideline recommendations are based on historical patient cohorts and agents may lack the appropriate label for their in guidelines recommended use. Here, we summarize relevant clinical data and consider appropriate treatment strategies.