"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.

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.

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.

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.

Inpatient palliative chemotherapy is associated with high mortality and aggressive end-of-life care in patients with advanced solid tumors and poor performance status.

BACKGROUND: The benefit of palliative chemotherapy (PC) in patients with advanced solid tumors and poor performance status (ECOG-PS) has not been prospectively validated, which makes treatment decision challenging. We aimed to evaluate the overall survival, factors associated with early mortality, and adoption of additional procedures in hospitalized patients with advanced cancer and poor ECOG-PS treated with PC. METHODS: We analyzed a retrospective cohort of patients with advanced cancer treated with PC during hospitalization at an academic cancer center in Brazil from 2014 to 2016. Eligibility criteria included: ECOG-PS 3-4 and start of first-line PC; or ECOG-PS ≥ 2 and start of second or subsequent lines. Primary endpoint was 30-day survival from start of PC. Kaplan-Meier method was used for survival estimates and Cox regression for factors associated with 30-day mortality. RESULTS: Two hundred twenty-eight patients were eligible. 21.9, 66.7 and 11.4% of patients had ECOG-PS 2, 3 and 4, respectively. 49.6% had gastrointestinal tumors. Median follow-up was 49 days (range 1-507). 98.2% of patients had died, 32% during the index hospitalization. The 30-day and 60-day survival rates were 55.7 and 38.5%, respectively. 30% of patients were admitted to the intensive care unit. In a multivariable analysis, ECOG-PS 3/4 (HR 2.01; P = 0.016), hypercalcemia (HR 2.19; P = 0.005), and elevated bilirubin (HR 3.17; P <  0.001) were significantly associated with 30-day mortality. CONCLUSIONS: Patients with advanced cancer and poor ECOG-PS had short survival after treatment with inpatient PC. Inpatient PC was associated with aggressive end-of-life care. Prognostic markers such as ECOG-PS, hypercalcemia and elevated bilirubin can contribute to the decision-making process for these patients.

Assessment of methyl methacrylate genotoxicity by the micronucleus test

The aim of this study was to evaluate the genotoxic potential of methyl methacrylate (MMA) vapor by simulating standard occupational exposure of 8 hours per day and using the micronucleus test. We used 32 adult male Wistar rats divided into three groups: A - 16 rats exposed to MMA for 8 hours a day, B - Eight rats receiving single subcutaneous doses of cyclophosphamide on the first day of the experiment (positive control), C - Eight rats receiving only water and food ad libitum (negative control). Eight rats from group A and all of the rats from groups B and C were sacrificed 24 hours after beginning the experiment (acute exposure in group A). The remaining animals in group A were sacrificed 5 days after the experiment began (repeated exposure assessment in group A, simulating occupational exposure 40 hours/week). Femoral bone marrow was collected from each rat at the time of sacrifice for use in the micronucleus test. Two slides were completed per animal and were stained with Giemsa staining. Two thousand polychromatic erythrocytes were counted per animal. The Kruskal-Wallis test followed by a multiple comparisons test (Dunn test) was used for statistical analysis. The median number of micronuclei was 7.00 in the group exposed to MMA for 1 day, 2.00 in the group exposed to MMA for 5 days, 9.00 in the group exposed to cyclophosphamide (positive control) and 0.756 in the negative control group (p < 0.0001). MMA was genotoxic when measured after 1 day of exposure but was not evidently genotoxic after 5 days.

Assessment of methyl methacrylate genotoxicity by the micronucleus test.

The aim of this study was to evaluate the genotoxic potential of methyl methacrylate (MMA) vapor by simulating standard occupational exposure of 8 hours per day and using the micronucleus test. We used 32 adult male Wistar rats divided into three groups: A - 16 rats exposed to MMA for 8 hours a day, B - Eight rats receiving single subcutaneous doses of cyclophosphamide on the first day of the experiment (positive control), C - Eight rats receiving only water and food ad libitum (negative control). Eight rats from group A and all of the rats from groups B and C were sacrificed 24 hours after beginning the experiment (acute exposure in group A). The remaining animals in group A were sacrificed 5 days after the experiment began (repeated exposure assessment in group A, simulating occupational exposure 40 hours/week). Femoral bone marrow was collected from each rat at the time of sacrifice for use in the micronucleus test. Two slides were completed per animal and were stained with Giemsa staining. Two thousand polychromatic erythrocytes were counted per animal. The Kruskal-Wallis test followed by a multiple comparisons test (Dunn test) was used for statistical analysis. The median number of micronuclei was 7.00 in the group exposed to MMA for 1 day, 2.00 in the group exposed to MMA for 5 days, 9.00 in the group exposed to cyclophosphamide (positive control) and 0.756 in the negative control group (p < 0.0001). MMA was genotoxic when measured after 1 day of exposure but was not evidently genotoxic after 5 days.