"Non-metastatic, Castration-resistant Prostate Cancer: Diagnostic and Treatment Recommendations by an Expert Panel from Brazil".

INTRODUCTION: Non-metastatic, castration-resistant prostate cancer (nmCRPC) is an important clinical stage of prostate cancer, prior to morbidity and mortality from clinical metastases. In particular, the introduction of novel androgen-receptor signaling inhibitors (ARSi) has changed the therapeutic landscape in nmCRPC. Given recent developments in this field, we update our recommendations for the management of nmCRPC. METHODS: A panel of 51 invited medical oncologists and urologists convened in May of 2021 with the aim of discussing and providing recommendations regarding the most relevant issues concerning staging methods, antineoplastic therapy, osteoclast-targeted therapy, and patient follow-up in nmCRPC. Panel members considered the available evidence and their practical experience to address the 73 multiple-choice questions presented. RESULTS: Key recommendations and findings include the reliance on prostate-specific antigen doubling time for treatment decisions, the absence of a clear preference between conventional and novel (i.e., positron-emission tomography-based) imaging techniques, the increasing role of ARSis in various settings, the general view that ARSis have similar efficacy. Panelists highlighted the slight preference for darolutamide, when safety is of greater concern, and a continued need to develop high-level evidence to guide the intensity of follow-up in this subset of prostate cancer. DISCUSSION: Despite the limitations associated with a consensus panel, the topics addressed are relevant in current practice, and the recommendations can help practicing clinicians to provide state-of-the-art treatment to patients with nmCRPC in Brazil and other countries with similar healthcare settings.

VI-RADS score system - A primer for urologists

ABSTRACT Bladder cancer (BCa) is one of the most common cancers worldwide and is also considered to be one of the most relapsing and aggressive neoplasms. About 30% of patients will present with muscle invasive disease, which is associated with a higher risk for metastatic disease. The aim of this article is to review the state of art imaging in Radiology, while providing a complete guide to urologists, with case examples, for the rationale of the development of the Vesical Imaging Reporting and Data System (VI-RADS), a scoring system emphasizing a standardized approach to multiparametric Magnetic Resonance Imaging (mpMRI) acquisition, interpretation, and reporting for BCa. Also, we examine relevant external validation studies and the consolidated literature of mpMRI for bladder cancer. In addition, this article discusses some of the potential clinical implications of this scoring system for disease management and follow-up.

Epithelial-Mesenchymal Transition Signaling and Prostate Cancer Stem Cells: Emerging Biomarkers and Opportunities for Precision Therapeutics.

Prostate cancers may reactivate a latent embryonic program called the epithelial-mesenchymal transition (EMT) during the development of metastatic disease. Through EMT, tumors can develop a mesenchymal phenotype similar to cancer stem cell traits that contributes to metastasis and variation in therapeutic responses. Some of the recurrent somatic mutations of prostate cancer affect EMT driver genes and effector transcription factors that induce the chromatin- and androgen-dependent epigenetic alterations that characterize castrate-resistant prostate cancer (CRPC). EMT regulators in prostate cancer comprise transcription factors (SNAI1/2, ZEB1, TWIST1, and ETS), tumor suppressor genes (RB1, PTEN, and TP53), and post-transcriptional regulators (miRNAs) that under the selective pressures of antiandrogen therapy can develop an androgen-independent metastatic phenotype. In prostate cancer mouse models of EMT, Slug expression, as well as WNT/ß-Catenin and notch signaling pathways, have been shown to increase stemness potential. Recent single-cell transcriptomic studies also suggest that the stemness phenotype of advanced prostate cancer may be related to EMT. Other evidence correlates EMT and stemness with immune evasion, for example, activation of the polycomb repressor complex I, promoting EMT and stemness and cytokine secretion through RB1, TP53, and PRC1. These findings are helping clinical trials in CRPC that seek to understand how drugs and biomarkers related to the acquisition of EMT can improve drug response.

The Role of Somatic Mutations on the Immune Response of the Tumor Microenvironment in Prostate Cancer.

Immunotherapy has improved patient survival in many types of cancer, but for prostate cancer, initial results with immunotherapy have been disappointing. Prostate cancer is considered an immunologically excluded or cold tumor, unable to generate an effective T-cell response against cancer cells. However, a small but significant percentage of patients do respond to immunotherapy, suggesting that some specific molecular subtypes of this tumor may have a better response to checkpoint inhibitors. Recent findings suggest that, in addition to their function as cancer genes, somatic mutations of PTEN, TP53, RB1, CDK12, and DNA repair, or specific activation of regulatory pathways, such as ETS or MYC, may also facilitate immune evasion of the host response against cancer. This review presents an update of recent discoveries about the role that the common somatic mutations can play in changing the tumor microenvironment and immune response against prostate cancer. We describe how detailed molecular genetic analyses of the tumor microenvironment of prostate cancer using mouse models and human tumors are providing new insights into the cell types and pathways mediating immune responses. These analyses are helping researchers to design drug combinations that are more likely to target the molecular and immunological pathways that underlie treatment failure.

Consensus on diagnosis and management of non-metastatic castration resistant prostate cancer in Brazil: focus on patient, selection, treatment efficacy, side effects and physician's perception according to patient comorbidities

ABSTRACT Background: Non-metastatic castration resistant prostate cancer (M0 CRPC) has seen important developments in drugs and diagnostic tools in the last two years. New hormonal agents have demonstrated improvement in metastasis free survival in M0 CRPC patients and have been approved by regulatory agencies in Brazil. Additionally, newer and more sensitive imaging tools are able to detect metastasis earlier than before, which will impact the percentage of patients staged as M0 CRPC. Based on the available international guidelines, a group of Brazilian urology and medical oncology experts developed and completed a survey on the diagnosis and treatment of M0 CRPC in Brazil. These results are reviewed and summarized and associated recommendations are provided. Objective: To present survey results on management of M0 CRPC in Brazil. Design, setting, and participants: A panel of six Brazilian prostate cancer experts determined 64 questions concerning the main areas of interest: 1) staging tools, 2) treatments, 3) side effects of systemic treatment/s, and 4) osteoclast-targeted therapy. A larger panel of 28 Brazilian prostate cancer experts answered these questions in order to create country-specific recommendations discussed in this manuscript. Outcome measurements and statistical analysis: The panel voted publicly but anonymously on the predefined questions. These answers are the panelists' opinions, not a literature review or meta-analysis. Therapies not yet approved in Brazil were excluded from answer options. Each question had five to seven relevant answers including two non-answers. Results were tabulated in real time. Conclusions: The results and recommendations presented can be used by Brazilian physicians to support the management of M0 CRPC patients. Individual clinical decision making should be supported by available data, however, for Brazil, guidelines for diagnosis and management of M0 CRPC patients have not been developed. This document will serve as a point of reference when confronting this disease stage.

Value of adding the apparent diffusion coefficient to capsular contact for the prediction of extracapsular extension in prostate cancer / Valor incremental do coeficiente de difusão aparente ao contato capsular na predição da extensão extracapsular do câncer de próstata

Abstract Objective: To determine whether evaluating the mean apparent diffusion coefficient (ADC) together with capsular contact (CC) adds value in the prediction of microscopic extracapsular extension (ECE) of prostate cancer. Materials and Methods: Between January 2012 and December 2016, 383 patients underwent multiparametric magnetic resonance imaging (mpMRI) of the prostate. A total of 67 patients were selected for inclusion. Two radiologists (observers 1 and 2), working independently, performed qualitative and quantitative analyses of ECE, macroscopic ECE, and microscopic ECE. A third radiologist assessed the correlation with the clinical data, and two experienced pathologists reviewed all histopathological findings. Results: Among the 67 patients, mpMRI showed lesions that were confined to the capsule in 44 (66.7%), had microscopic ECE in 12 (17.9%), and had macroscopic ECE in 11 (16.4%). There were no significant differences, in terms of the diagnostic accuracy, as measured by determining the area under the curve (AUC), of CC on T2-weighted images (CCT2), CC on diffusion-weighted imaging (CCDWI), and the mean ADC for the prediction of microscopic ECE, between observer 1 (AUC of 0.728, 0.691, and 0.675, respectively) and observer 2 (AUC of 0.782, 0.821, and 0.799, respectively). Combining the mean ADC with the CCT2 or CCDWI did not improve the diagnostic accuracy for either observer. There was substantial interobserver agreement for the qualitative evaluation of ECE, as demonstrated by the kappa statistic, which was 0.77 (0.66-0.87). The diagnostic accuracy (AUC) of the qualitative assessment for predicting microscopic ECE was 0.745 for observer 1 and 0.804 for observer 2, and the difference was less than significant. In a multivariate analysis, none of clinical or imaging parameters were found to be associated with ECE. Conclusion: For the detection of microscopic ECE on mpMRI, CC appears to have good diagnostic accuracy, especially if the observer has considerable experience. Adding the mean ADC to the CCT2 or CCDWI does not seem to provide any significant improvement in that diagnostic accuracy.

Resumo Objetivo: Avaliar se o coeficiente de difusão aparente (apparent diffusion coefficient - ADC) médio tem valor incremental ao contato capsular (CC) na predição da extensão extracapsular (EEC) do câncer de próstata. Materiais e Métodos: De janeiro de 2012 a dezembro de 2016, 383 pacientes realizaram ressonância magnética multiparamétrica de próstata. Após os critérios de inclusão e exclusão, 67 pacientes foram selecionados para avaliação qualitativa e quantitativa, por dois radiologistas independentes, da EEC, EEC grosseira e EEC microscópica. Um terceiro observador coletou dados clínicos e dois patologistas experientes revisaram os achados histopatológicos. Resultados: Dos 67 pacientes selecionados, 44 apresentaram lesões restritas à cápsula (66,7%), 12 com EEC microscópica (17,9%) e 11 com EEC grosseira (16,4%). Não houve diferença significativa entre a acurácia diagnóstica, medida pela área sob a curva, entre o CC na ponderação T2 (CCT2), CC-difusão e ADC para predição da EEC microscópica para ambos os observadores (0,728, 0,691 e 0,675, respectivamente, para o observador 1, e 0,782, 0,821 e 0,799, respectivamente, para o observador 2). A associação dos valores médios do ADC ao CCT2 e ao CC-difusão não promoveu melhora da acurácia diagnóstica. A concordância interobservador para a avaliação qualitativa da EEC mostrou coeficiente kappa de 0,77 (0,66-0,87), inferindo concordância substancial. A acurácia da avaliação qualitativa para EEC microscópica foi de 0,745 e 0,804 para os observadores 1 e 2, respectivamente, diferença não significativa. Na análise multivariada, nenhum parâmetro clínico ou de imagem foi associado a EEC. Conclusão: O CC mostrou boa acurácia diagnóstica para a detecção de EEC microscópica, especialmente para o observador mais experiente. A inclusão dos valores médios de ADC não melhorou a acurácia do CC para predição de EEC microscópica.

Prostate Cancer in Latin America: Challenges and Recommendations.

Prostate cancer (PCa) is the most frequent tumor among Latin American (LATAM) men. The incidence of de novo metastatic PCa is higher in LATAM than other parts of the world, and demographic changes in the region have increased disease burden. However, region-specific information regarding prevalence, progression, and treatment effectiveness is not currently available for nonmetastatic, castration-resistant PCa (nmCRPC). Nonmetastatic, castration-resistant PCa is a heterogeneous disease with varying potential to develop metastasis with limited treatments available, until recently. New clinical trials with promising results have allowed second-generation antiandrogen drugs to be used as first-line treatments, rendering guidelines outdated. As a result, this panel of experts reviewed the current status and challenges and developed recommendations for nmCRPC diagnosis and management in LATAM. The Americas Health Foundation (AHF) conducted a literature review and identified LATAM scientists and clinicians who have published in the field of PCa since 2012. The AHF convened a panel of 7 chosen experts urologists and medical oncologists from the region. The AHF developed specific questions relating to nmCRPC, which were answered by the experts prior to the multiday meeting. Each narrative was discussed and edited by the panel, through numerous rounds of discussion until a consensus was reached in a final manuscript. The panel proposes specific and realistic recommendations for improving access to diagnosis and management of PCa in LATAM. No treatment has yet shown improvement in overall survival; however, when including metastasis-free survival as an end point, second-generation antiandrogen drugs have emerged as effective treatment options and are currently included as first-line treatment. Although nmCRPC is a specific disease that represents a small percentage of patients with PCa, effective diagnostic and treatment strategies can contribute toward increasing quality of life and survival rates of patients with PCa in LATAM.

Prostate cancer screening among elderly men in Brazil: should we diagnose or not?

ABSTRACT Purpose: Prostate cancer screening in the elderly is controversial. The Brazilian government and the National Cancer Institute (INCA) do not recommend systematic screening. Our purpose was to assess prevalence and aggressiveness of prostate cancer in men aged 70 years and above, on the first Latin American database to date. Materials and Methods: Cross-sectional study (n=17,571) from 231 municipalities, visited by Mobile Cancer Prevention Units of a prostate-specific antigen (PSA) based opportunistic screening program, between 2004 and 2007. The criteria for biopsy were: PSA>4.0ng/ml, or PSA 2.5-4.0ng/ml with free/total PSA ratio ≤15%, or suspicious digital rectal examination findings. The screened men were stratified in two age groups (45-69 years, and ≥70 years). These groups were compared regarding prostate cancer prevalence and aggressiveness criteria (PSA, Gleason score from biopsy and TNM staging). Results: The prevalence of prostate cancer found was 3.7%. When compared to men aged 45-69 years, individuals aged 70 years and above presented cancer prevalence about three times higher (prevalence ratio 2.9, p<0.01), and greater likelihood to present PSA level above 10.0ng/ml at diagnosis (odds ratio 2.63, p<0.01). The group of elderly men also presented prevalence of histologically aggressive disease (Gleason 8-10) 3.6 times higher (p<0.01), and 5-fold greater prevalence of metastases (PR 4.95, p<0.05). Conclusions: Prostate cancer screening in men aged over 70 may be relevant in Brazil, considering the absence of systematic screening, higher prevalence and higher probability of high-risk disease found in this age range of the population studied.

Right atrium tumor extension through the inferior vena cava. considerations about nine cases operated under cardiopulmonary bypass

Abstract Introduction: Adrenocortical and renal cell carcinomas rarely invade the right atrium (RA). These neoplasms need surgical treatment, are very aggressive and have poor prognostic and surgical outcomes. Case series: We present a retrospective cohort of nine cases of RA invasion through the inferior vena cava (four adrenocortical carcinomas and five renal cell carcinomas). Over 13 years (2002-2014), nine patients were operated in collaboration with the team of urologists. Surgery was possible in all patients with different degrees of technical difficulty. All patients were operated considering the imaging examinations with the aid of CPB. In all reported cases (renal or suprarenal), the decision to use CPB with deep hypothermic circulatory arrest (DHCA) on surgical strategy was decided by the team of urological and cardiac surgeons. Conclusion: Data retrospectively collected from patients of public hospitals reaffirm: 1) Low incidence with small published series; 2) The selected cases did not represent the whole historical casuistry of the hospital, since they were selected after the adoption of electronic documentation; 3) Demographic data and references reported in the literature were presented as tables to avoid wordiness; 4) The series highlights the propensity to invade the venous system; 5) Possible surgical treatment with the aid of CPB in collaboration with the urology team; 6) CPB with DHCA is a safe and reliable option; 7) Poor prognosis with disappointing late results, even considering the adverse effects of CPB on cancer prognosis are expected but not confirmed.

Right Atrium Tumor Extension Through the Inferior Vena Cava. Considerations About Nine Cases Operated Under Cardiopulmonary Bypass.

INTRODUCTION: Adrenocortical and renal cell carcinomas rarely invade the right atrium (RA). These neoplasms need surgical treatment, are very aggressive and have poor prognostic and surgical outcomes. CASE SERIES: We present a retrospective cohort of nine cases of RA invasion through the inferior vena cava (four adrenocortical carcinomas and five renal cell carcinomas). Over 13 years (2002-2014), nine patients were operated in collaboration with the team of urologists. Surgery was possible in all patients with different degrees of technical difficulty. All patients were operated considering the imaging examinations with the aid of CPB. In all reported cases (renal or suprarenal), the decision to use CPB with deep hypothermic circulatory arrest (DHCA) on surgical strategy was decided by the team of urological and cardiac surgeons. CONCLUSION: Data retrospectively collected from patients of public hospitals reaffirm: 1) Low incidence with small published series; 2) The selected cases did not represent the whole historical casuistry of the hospital, since they were selected after the adoption of electronic documentation; 3) Demographic data and references reported in the literature were presented as tables to avoid wordiness; 4) The series highlights the propensity to invade the venous system; 5) Possible surgical treatment with the aid of CPB in collaboration with the urology team; 6) CPB with DHCA is a safe and reliable option; 7) Poor prognosis with disappointing late results, even considering the adverse effects of CPB on cancer prognosis are expected but not confirmed.

External validation of nomogram to predict inguinal lymph node metastasis in patients with penile cancer and clinically negative lymph nodes

ABSTRACT Introduction Penile cancer (PC) occurs less frequently in Europe and in the United States than in South America and parts of Africa. Lymph node (LN) involvement is the most important prognostic factor, and inguinal LN (ILN) dissection can be curative; however, ILN dissection has high morbidity. A nomogram was previously developed based on clinicopathological features of PC to predict ILN metastases. Our objective was to conduct an external validation of the previously developed nomogram based on our population. Materials and methods We included men with cN0 ILNs who underwent ILN dissection for penile carcinoma between 2000 and 2014. We performed external validation of the nomogram considering three different external validation methods: k-fold, leave-one-out, and bootstrap. We also analyzed prognostic variables. Performance was quantified in terms of calibration and discrimination (receiver operator characteristic curve). A logistic regression model for positive ILNs was developed based on clinicopathological features of PC. Results We analyzed 65 men who underwent ILN dissection (cN0). The mean age was 56.8 years. Of 65 men, 24 (36.9%) presented with positive LNs. A median 21 ILNs were removed. Considering the three different methods used, we concluded that the previously developed nomogram was not suitable for our sample. Conclusions In our study, the previously developed nomogram that was applied to our population had low accuracy and low precision for correctly identifying patients with PC who have positive ILNs.

Second brazilian consensus on the treatment of advanced prostate cancer: a SBOC-SBU-SBRT panel review

ABSTRACT Prostate cancer is the second most common cancer and the fifth leading cause of cancer deaths. In Brazil, it is likewise the second most common cancer among men, second only to non-melanoma skin cancers. The aim of this consensus is to align different opinions and interpretations of the medical literature in a practical and patient-oriented approach. The first Brazilian Consensus on the Treatment of Advanced Prostate Cancer was published in 2017, with the goal of reducing the heterogeneity of therapeutic conduct in Brazilian patients with metastatic prostate cancer. We acknowledge that in Brazil the incorporation of different technologies is a big challenge, especially in the Sistema Único de Saúde (SUS), which allows for the disparity in the options available to patients treated in different institutions. In order to update the recommendations and to make them objective and easily accessible, once more a panel of specialists was formed in order to discuss and elaborate a new Brazilian Consensus on Advanced Prostate Cancer. This Consensus was written through a joint initiative of the Brazilian Society of Clinical Oncology (SBOC) and the Brazilian Society of Urology (SBU) to support the clinical decisions of physicians and other health professionals involved in the care of patients with prostate cancer.

First brazilian consensus of advanced prostate cancer: recommendations for clinical practice

ABSTRACT Introduction Prostate cancer still represents a major cause of morbidity, and still about 20% of men with the disease are diagnosed or will progress to the advanced stage without the possibility of curative treatment. Despite the recent advances in scientific and technological knowledge and the availability of new therapies, there is still considerable heterogeneity in the therapeutic approaches for metastatic prostate cancer. Objectives This article presents a summary of the I Brazilian Consensus on Advanced Prostate Cancer, conducted by the Brazilian Society of Urology and Brazilian Society of Clinical Oncology. Materials and Methods Experts were selected by the medical societies involved. Forty issues regarding controversial issues in advanced disease were previously elaborated. The panel met for consensus, with a threshold established for 2/3 of the participants. Results and Conclusions The treatment of advanced prostate cancer is complex, due to the existence of a large number of therapies, with different response profiles and toxicities. The panel addressed recommendations on preferred choice of therapies, indicators that would justify their change, and indicated some strategies for better sequencing of treatment in order to maximize the potential for disease control with the available therapeutic arsenal. The lack of consensus on some topics clearly indicates the absence of strong evidence for some decisions.

First Brazilian Consensus of Advanced Prostate Cancer: Recommendations for Clinical Practice.

INTRODUCTION: Prostate cancer still represents a major cause of morbidity, and still about 20% of men with the disease are diagnosed or will progress to the advanced stage without the possibility of curative treatment. Despite the recent advances in scientific and technological knowledge and the availability of new therapies, there is still considerable heterogeneity in the therapeutic approaches for metastatic prostate cancer. OBJECTIVES: This article presents a summary of the I Brazilian Consensus on Advanced Prostate Cancer, conducted by the Brazilian Society of Urology and Brazilian Society of Clinical Oncology. MATERIALS AND METHODS: Experts were selected by the medical societies involved. Forty issues regarding controversial issues in advanced disease were previously elaborated. The panel met for consensus, with a threshold established for 2/3 of the participants. RESULTS AND CONCLUSIONS: The treatment of advanced prostate cancer is complex, due to the existence of a large number of therapies, with different response profiles and toxicities. The panel addressed recommendations on preferred choice of therapies, indicators that would justify their change, and indicated some strategies for better sequencing of treatment in order to maximize the potential for disease control with the available therapeutic arsenal. The lack of consensus on some topics clearly indicates the absence of strong evidence for some decisions.