Background
Limited real‐world data exist on treatment patterns and outcomes in patients with metastatic castration‐sensitive prostate cancer (mCSPC).
Methods
A retrospective cohort study was ...conducted, using the Veterans Health Administration claims database (April 2013–March 2018). Among 369,734 prostate cancer patients, we selected all men who developed metastases within 90 days before or after medical/surgical castration and who received androgen deprivation therapy (ADT). Patients were categorized into four cohorts: ADT‐only (± <90‐day nonsteroidal anti‐androgen NSAA use), ADT + NSAA, ADT + docetaxel, and ADT + abiraterone. Main outcomes were treatment patterns, time‐to‐progression to metastatic castration‐resistant disease, and overall survival. Multivariable analysis and sensitivity analysis were conducted.
Results
Of 1395 patients, 874 (63%) received ADT‐only, 338 (24%) received ADT + NSAA, 108 (8%) received ADT + docetaxel, and 75 (5%) received ADT + abiraterone. Proportions on ADT‐only and ADT + NSAA declined (from 66% to 60% and from 31% to 17%, respectively) over the study period, while proportions prescribed ADT + docetaxel or abiraterone increased from 3% to 9% and from 1% to 15%, respectively. Patients treated with ADT + NSAA had similar risks of castration‐resistant disease (hazard ratio HR 1.05; 95% confidence interval CI: 0.87, 1.26) and overall mortality (HR 1.22; 95% CI: 0.97, 1.54) as ADT‐only.
Conclusions
Most patients with mCSPC initiating ADT received ADT‐only or ADT + NSAA, despite the emergence of docetaxel and novel hormonal therapies. Even in the most recent period (2017 to early 2018), only 24% of men received intensified therapy with agents known to prolong survival versus ADT‐only. These data in real‐world clinical practice suggest substantial room for improved outcomes in patients with mCSPC.
A retrospective cohort study of 1395 men with metastatic castration‐sensitive prostate cancer initiating androgen deprivation therapy (ADT) found that the vast majority received ADT alone or with a first‐generation anti‐androgen. Despite the emergence of life‐prolonging treatments such as docetaxel and novel hormonal therapies, only a small proportion of patients received these treatments, indicating substantial room for improved outcomes in this population.
Prostate-specific membrane antigen (PSMA) imaging has been suggested as highly sensitive modality for detection of metastases in patients with biochemically recurrent or advanced prostate cancer ...(PCa). PSMA expression is associated with grade and stage and has a relationship with androgen receptor signaling. The aim of this study was to evaluate the prognostic utility of radiographic PSMA expression in men with metastatic castration-resistant prostate cancer (mCRPC).
Patients with mCRPC and available baseline PSMA imaging were studied. Images by planar/single-photon emission computed tomography (SPECT) or positron emission tomography (PET)/CT were reviewed. Planar/SPECT images were scored semi-quantitatively and PET/CT scored quantitatively with comparison of tumor uptake to liver uptake on a scale of 0-4 in order to determine an imaging score (IS). The IS (high: 2-4 versus low: 0-1), subsequent receipt of life-prolonging systemic therapies (taxane chemotherapy, potent androgen receptor pathway inhibitors, sipuleucel-T, and radium-223), and the CALGB prognostic risk stratification of patients were analyzed according to overall survival (OS) in univariate and multivariate Cox's proportional hazards models.
High PSMA expression (IS 2-4) was found in 179 (75.21%) patients, and 59 (24.79%) patients had low PSMA uptake. The median OS of the entire cohort was 16.8 (95%CI: 14.9-19.3) months. Patients with a high IS had a significantly shorter OS of 15.8 (95%CI 13.0-18.1) months compared to those with low expression 22.7 (95%CI: 17.7-30.7) months, p = 0.002. After accounting for use of life-prolonging therapies (p<0.001) and CALGB prognostic groups (p = 0.001), high PSMA IS emerged as an independent prognostic factor for OS HR(95%CI): 1.7 (1.2-2.2); p = 0.003.
Presence of high radiographic PSMA expression on SPECT or PET/CT may portend a poor prognosis in patients with mCRPC treated with standard systemic therapies. This provides implications for therapeutic targeting of PSMA-avid disease as a means to improve outcomes.
Background Ultra-hypofractionated image-guided stereotactic body radiotherapy (SBRT) is increasingly used for definitive treatment of localized prostate cancer. Magnetic resonance imaging-guided ...radiotherapy (MRgRT) facilitates improved visualization, real-time tracking of targets and/or organs-at-risk (OAR), and capacity for adaptive planning which may translate to improved targeting and reduced toxicity to surrounding tissues. Given promising results from NRG-GU003 comparing conventional and moderate hypofractionation in the post-operative setting, there is growing interest in exploring ultra-hypofractionated post-operative regimens. It remains unclear whether this can be done safely and whether MRgRT may help mitigate potential toxicity. SHORTER (NCT04422132) is a phase II randomized trial prospectively evaluating whether salvage MRgRT delivered in 5 fractions versus 20 fractions is non-inferior with respect to gastrointestinal (GI) and genitourinary (GU) toxicities at 2-years post-treatment. Methods A total of 136 patients will be randomized in a 1:1 ratio to salvage MRgRT in 5 fractions or 20 fractions using permuted block randomization. Patients will be stratified according to baseline Expanded Prostate Cancer Index Composite (EPIC) bowel and urinary domain scores as well as nodal treatment and androgen deprivation therapy (ADT). Patients undergoing 5 fractions will receive a total of 32.5 Gy over 2 weeks and patients undergoing 20 fractions will receive a total of 55 Gy over 4 weeks, with or without nodal coverage (25.5 Gy over 2 weeks and 42 Gy over 4 weeks) and ADT as per the investigator's discretion. The co-primary endpoints are change scores in the bowel and the urinary domains of the EPIC. The change scores will reflect the 2-year score minus the pre-treatment (baseline) score. The secondary endpoints include safety endpoints, including change in GI and GU symptoms at 3, 6, 12 and 60 months from completion of treatment, and efficacy endpoints, including time to progression, prostate cancer specific survival and overall survival. Discussion The SHORTER trial is the first randomized phase II trial comparing toxicity of ultra-hypofractionated and hypofractionated MRgRT in the salvage setting. The primary hypothesis is that salvage MRgRT delivered in 5 fractions will not significantly increase GI and GU toxicities when compared to salvage MRgRT delivered in 20 fractions. Trial registration ClinicalTrials.gov Identifier: NCT04422132. Date of registration: June 9, 2020. Keywords: Prostate cancer, Salvage radiotherapy, Stereotactic body radiotherapy (SBRT), MR-Linac, MRI-guided radiotherapy (MRgRT), Genitourinary, Hypofractionation, Ultra-hypofractionated, Toxicity
The year 2020 will be remembered for a number of different events, both good and bad. For the journal Urologic Oncology, Seminars and Original Investigations, this year represents the 25th ...anniversary of its inception and 1st publication. Under the encouragement of Editor-in-Chief Dr. Michael Droller, the collective editorial board has put together a reflection of the progresses made among the spectrum of genitourinary cancers across the entirety of therapeutic disciplines. In this review, we discuss the advances achieved in our knowledge and understanding of testicular germ cell tumors since 1995, and the challenges that lie ahead.
Evaluation of the comparative effectiveness of enzalutamide and abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) is limited to meta-analyses of randomized trials ...that exclude patients with significant comorbidities. We evaluated overall survival (OS) in patients with chemotherapy-naive mCRPC treated with enzalutamide or abiraterone acetate (abiraterone) in a real-world single payer setting.
A retrospective analysis (4/1/2014-3/31/2018) of the Veterans Health Administration (VHA) database was conducted. Patients with mCRPC had ≥1 pharmacy claim for enzalutamide or abiraterone (first claim date = index date) following disease progression on surgical/medical castration, without chemotherapy <12 months prior to index date. Patients had continuous VHA enrollment for ≥12 months pre-index date and were followed until death, disenrollment, or end of study. Kaplan-Meier analysis and multivariable Cox proportional hazards regression models examined the OS treatment effect.
Patients with chemotherapy-naive mCRPC (N = 3174; enzalutamide, n = 1229; abiraterone, n = 1945) had mean ages of 74 and 73 years, respectively. Median follow-up was 18.27 and 19.07 months with enzalutamide and abiraterone, respectively. Enzalutamide-treated patients had longer median treatment duration than abiraterone-treated patients (9.93 vs 8.47 months, respectively, p = 0.0008). After baseline comorbidity adjustment, enzalutamide-treated patients had a 16% reduced risk of death (hazard ratio HR = 0.84; 95% CI, 0.76-0.94; p = 0.0012). For patients who remained on first line-therapy only, enzalutamide-treated patients had improved OS versus abiraterone-treated patients (HR = 0.71; 95% CI, 0.62-0.82). Enzalutamide-treated patients who crossed over to abiraterone had a comparable risk of death versus abiraterone-treated patients who crossed over to enzalutamide (HR = 1.10; 95% CI, 0.89-1.35). These results were confirmed by sensitivity analysis, which considered prognostic variables.
Retrospective analysis of the VHA database indicated that chemotherapy-naive patients with mCRPC initiating therapy with enzalutamide had improved survival versus abiraterone.
Squamous cell carcinoma of the penis (SCCP) is uncommon in some countries (including the U.S.), but is an important malignancy elsewhere. As a rare disease, progress has been slow compared to more ...common tumor types discussed in this anniversary issue and most often limited to single-center or retrospective datasets. In this section we describe developments leading to the current standard approach with current research questions
Prostate-specific membrane antigen (PSMA) is a well-established target for developing radiopharmaceuticals for imaging and therapy of prostate cancer (PCa). We have recently reported that novel ...(99m)Tc-labeled small-molecule PSMA inhibitors bind with high affinity to PSMA-positive tumor cells in vitro and localize in PCa xenografts. This study reports the first, to our knowledge, human data in men with metastatic PCa and in healthy male subjects.
Under an exploratory investigational new drug, using a cross-over design, we compared the pharmacokinetics, biodistribution, and tumor uptake of (99m)Tc-MIP-1404 and (99m)Tc-MIP-1405 in 6 healthy men and 6 men with radiographic evidence of metastatic PCa. Whole-body images were obtained at 10 min and 1, 2, 4, and 24 h. SPECT was performed between 3 and 4 h after injection.
Both agents cleared the blood rapidly, with MIP-1404 demonstrating significantly lower urinary activity (7%) than MIP-1405 (26%). Both agents showed persistent uptake in the salivary, lacrimal, and parotid glands. Uptake in the liver and kidney was acceptable for imaging at 1-2 h. In men with PCa, both agents rapidly localized in bone and lymph node lesions as early as 1 h. SPECT demonstrated excellent lesion contrast. Good correlation was seen with bone scanning; however, more lesions were demonstrated with (99m)Tc-MIP-1404 and (99m)Tc-MIP-1405. The high-contrast images exhibited tumor-to-background ratios from 3:1 to 9:1 at 4 and 20 h.
Compared with the standard-of-care bone scanning, (99m)Tc-MIP-1404 and (99m)Tc-MIP-1405 identified most bone metastatic lesions and rapidly detected soft-tissue PCa lesions including subcentimeter lymph nodes. Because (99m)Tc-MIP-1404 has minimal activity in the bladder, further work is planned to correlate imaging findings with histopathology in patients with high-risk metastatic PCa.
The combination of gemcitabine and cisplatin (GC) is a standard therapy for metastatic urothelial carcinoma. Based on data that angiogenesis plays a role in urothelial carcinoma growth and ...progression, a randomized placebo-controlled trial was performed with the primary objective of testing whether patients treated with GC and bevacizumab (GCB) have superior overall survival (OS) than patients treated with GC and placebo (GCP).
Between July 2009 and December 2014, 506 patients with metastatic urothelial carcinoma without prior chemotherapy for metastatic disease and no neoadjuvant or adjuvant chemotherapy within 12 months were randomly assigned to receive either GCB or GCP. The primary end point was OS, with secondary end points of progression-free survival, objective response, and toxicity.
With a median follow-up of 76.3 months among alive patients, the median OS was 14.5 months for patients treated with GCB and 14.3 months for patients treated with GCP (hazard ratio for death = 0.87; 95% CI, 0.72 to 1.05; two-sided stratified log-rank
= .14). The median progression-free survival was 8.0 months for GCB and 6.7 months for GCP (hazard ratio = 0.77; 95% CI, 0.63 to 0.95;
= .016). The proportion of patients with grade 3 or greater adverse events did not differ significantly between both arms, although increased bevacizumab-related toxicities such as hypertension and proteinuria occurred in the bevacizumab-treated arm.
The addition of bevacizumab to GC did not result in improved OS. The observed median OS of about 14 months is consistent with prior phase III trials of cisplatin-based chemotherapy.
Targeted radionuclide therapy with Actinium-225-labeled prostate-specific membrane antigen agents (225Ac-PSMA) is currently being studied in clinical trials for patients with metastatic ...castration-resistant prostate cancer (mCRPC). Compared to β-emitting therapeutic radionuclides, alpha-emitters (e.g., 225Ac) have a significantly higher linear energy transfer and significantly shorter range. As a result, alpha emitters could be expected to improve efficacy and reduce bystander toxicity. This systematic literature review was conducted to evaluate the impact of sequencing of 177Lu-PSMA and 225Ac-PSMA targeted radionuclide therapy (TRT) in mCRPC.
The present systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The searches were made using relevant keywords in the PubMed, Scopus, and Web of Science databases, and articles up to August 22, 2022, were included. Publications were excluded if they were duplicate publications, wrong study or publication format, or discussing a topic out of scope. Data on efficacy, toxicity, and health-related quality of life were extracted from the individual articles. The I
index was used to measure the extent of heterogeneity amongst studies. In the studies that reported subgroup outcomes according to the prior status on 177Lu-PSMA TRT, pooled estimates of the main outcomes were generated through descriptive analysis. Quality assessment was performed using the Newark-Ottawa-scale.
The study included 12 articles; 1 series was performed prospectively. In total, data of 329 patients were analyzed. About 40.1% (n = 132) of the included men were pretreated with 177Lu-PSMA TRT. Seven studies, including data of 212 individuals, were eligible for quantitative analysis based on reporting outcomes of the subgroups according to their prior status on 177Lu-PSMA TRT. >25% PSA decline after 225Ac-PSMA TRT was lower in individuals who received prior 177Lu-PSMA TRT (pooled median 42.7%) compared to those who did not (pooled median 15.4%). The pooled medians of the reported median progression-free survival and overall survival for pretreated versus not pretreated individuals was 4.3 versus 14.3 months and 11.1 versus 9.2 months, respectively. However, the outcomes for each individual study were reported inconsistently (I
= 99.9%). None of the included studies stratified the report of adverse events or changes in health-related quality of life for the subgroups.
225Ac-PSMA TRT is an experimental treatment for men with mCRPC. There is limited data available from high-quality trials but so far PSMA-targeted TRT has demonstrated a low morbidity profile. Our review revealed that there is a possible decrease in efficacy of targeted alpha-particle therapy if individuals previously were exposed to 177Lu-PSMA TRT. However, the level of evidence is low. The underlying mechanism by which 177Lu-PSMA TRT might trigger possible radioresistance as well as randomized controlled trials are required to establish the therapeutic efficacy and safety of 225-Ac-PSMA TRT in men refractory to 177Lu-PSMA TRT.
Penile cancer is a rare disease but its incidence is increasing and there are many unmet needs to address. This collaborative guideline provides updated information on the diagnosis and treatment of ...penile cancer. The lack of controlled trials and large series means that the levels of evidence and grades of recommendation are low in comparison to those for more common diseases. Referral to centres of expertise is recommended.
Penile cancer is a rare disease but has a significant impact on quality of life. Its incidence is increasing, so it is important to include new and relevant evidence in clinical practice guidelines.
To provide a collaborative guideline that offers worldwide physician and patient guidance for the management of penile cancer.
Comprehensive literature searches were performed for each section topic. In addition, three systematic reviews were conducted. Levels of evidence were assessed, and a strength rating for each recommendation was assigned according to the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology.
Penile cancer is a rare disease but its global incidence is increasing. Human papillomavirus (HPV) is the main risk factor for penile cancer and pathology should include an assessment of HPV status. The main aim of primary tumour treatment is complete tumour eradication, which has to be balanced against optimal organ preservation without compromising oncological control. Early detection and treatment of lymph node (LN) metastasis is the main determinant of survival. Surgical LN staging with sentinel node biopsy is recommended for patients with a high-risk (≥pT1b) tumour with cN0 status. While (inguinal) LN dissection remains the standard for node-positive disease, multimodal treatment is needed in patients with advanced disease. Owing to a lack of controlled trials and large series, the levels of evidence and grades of recommendation are low in comparison to those for more common diseases.
This collaborative penile cancer guideline provides updated information on the diagnosis and treatment of penile cancer for use in clinical practice. Organ-preserving surgery should be offered for treatment of the primary tumour when feasible. Adequate and timely LN management remains a challenge, especially in advanced disease stages. Referral to centres of expertise is recommended.
Penile cancer is a rare disease that significantly impacts quality of life. While the disease can be cured in most cases without lymph node involvement, management of advanced disease remains challenging. Many unmet needs and unanswered questions remain, underlining the importance of research collaborations and centralisation of penile cancer services.
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