Low-risk Prostate Cancer Research Articles

Short-term prognosis of low-risk prostate cancer patients is favorable despite the presence of pathological prognostic factors: a retrospective study

BackgroundProstate cancer patients with pathological prognostic factors have a poor prognosis, but it is unclear whether pathological prognostic factors are associated with prognosis limited to low-risk patients with good prognosis according to NCCN guidelines. The present study examined whether prognosis is influenced by pathological prognostic factors using radical prostatectomy (RP) specimens from low-risk patients.MethodsWe evaluated diagnostic accuracy by examining biochemical recurrence (BCR)-free survival with respect to clinical and pathological prognostic factors in 419 all-risk patients who underwent RP. Clinical prognostic factors included age, prostate-specific antigen (PSA) levels, PSA density, and risk stratification, while pathological prognostic factors included grade group, lymphovascular space invasion, extraprostatic extension, surgical margins, seminal vesicle invasion, intraductal carcinoma of the prostate (IDCP), and pT. In a subsequent analysis restricted to 104 low-risk patients, survival curves were estimated for pathological prognostic factors using the Kaplan–Meier method and compared using log-rank and generalized Wilcoxon tests.ResultsIn the overall risk analysis, the presence of pathological prognostic factors significantly shortened BCR-free survival (p < 0.05). Univariable analysis revealed that PSA density, risk categories, and pathological prognostic factors were significantly associated with BCR-free survival, although age and PSA were not. In multivariable analysis, age, risk categories, grade group, IDCP, and pT significantly predicted BCR-free survival (p < 0.05). Conversely, no statistically significant differences were found for any pathological prognostic factors in low-risk patients.ConclusionsIn low-risk patients, pathological prognostic factors did not affect BCR-free survival, which suggests that additional treatment may be unnecessary even if pathological prognostic factors are observed in low-risk patients with RP.

Effect of a Home-based Walking Intervention on Cardiopulmonary Fitness and Quality of Life Among Men with Prostate Cancer on Active Surveillance: The Active Surveillance Exercise Randomized Controlled Trial

BackgroundActive surveillance (AS) is standard care for most men with low-risk prostate cancer (PC); yet, many men on AS eventually undergo curative therapy. Interventions to lower the risk of cancer progression and fear of recurrence among men on AS for PC are needed. ObjectiveTo determine the effect of aerobic exercise on cardiorespiratory fitness, body size, and quality of life (QOL) among men on AS for PC. Design, setting, and participantsWe conducted a 1:1 randomized controlled trial among 51 men with low-risk PC who elected AS. Participants were enrolled at the University of California, San Francisco. InterventionThe 16-wk intervention included a home-based walking program with a nonlinear exercise prescription tailored to baseline fitness level, heart rate monitor, and weekly phone call with an exercise physiologist. Controls received printed materials. Outcome measurements and statistical analysisCardiorespiratory fitness was measured using VO2peak; secondary outcomes included change in body size, anxiety, and QOL. Analyses were based on intention to treat. Results and limitationsBetween 2016 and 2021, we randomized 51 men to intervention (n = 26) or control (n = 25). Follow-up was 88% (45/51), 85% (22/26) in the intervention and 92% (23/25) in the control group. At 16 wk, the intervention group had a higher mean VO2peak than the control group (31.9 ± 4.7 vs 27.2 ± 4.8 ml/kg/min; group × time effect p value: <0.001). Additionally, the intervention group reported less fear of PC recurrence and urinary obstruction/irritation, while controls reported more of these two QOL measures, from 0 to 16 wk (p = 0.04 and 0.03, respectively). Two participants discontinued the intervention, including one due to knee pain related to the study. ConclusionsA home-based walking program improved VO2peak and reduced urinary obstruction/irritation and fear of recurrence among men on AS for PC. Patient summaryModerate to vigorous aerobic exercise improves fitness and quality of life among men on active surveillance for prostate cancer.

Disease control outcomes of stereotactic body radiation therapy or moderate hypo-fractionation for prostate cancer: Real-world experience at two Canadian centers.

Advantages of using stereotactic body radiation therapy to treat prostate cancer include short treatment times, decreased costs, and limited toxicity. Randomized trial outcomes comparing 5-fraction stereotactic body radiation therapy to conventionally fractionated radiotherapy or hypo-fractionated radiation therapy are pending. We report the 10-year experience with 5-fraction stereotactic body radiation therapy and hypo-fractionated radiation therapy at two Canadian centers. Patients with low- or intermediate-risk prostate cancer treated with stereotactic body radiation therapy alone (35-40 Gy in 5 fractions) or hypo-fractionated radiation therapy alone (60-62 Gy in 20 fractions) in the period of July 2010 and June 2020. The biochemical relapse-free survival, PSA nadir, interval time to PSA nadir, time to biochemical recurrence (2 ng/ml above PSA nadir) and overall survival were reviewed. Outcomes between treatment groups were compared after propensity-matching by patient baseline characteristics. Kaplan-Meier curves were used to assess biochemical relapse-free survival and overall survival. We identified 205 and 513 patients with low or intermediate-risk prostate cancer who were treated with stereotactic body radiation therapy or hypo-fractionation, respectively. Intermediate-risk category composed 81% and 95% of the stereotactic body radiation therapy and hypo-fractionated radiation therapy cohorts, respectively. After a median follow up of 58.6 months for the stereotactic body radiation therapy cohort and 45.0 months for the hypo-fractionated cohort, biochemical relapse-free survival and overall survival were not significantly different between treatment groups. The 5-year biochemical relapse-free survival rates were 92.1% and 93.6% and overall survival rates were 96.4% and 95.0% for the stereotactic body radiation therapy and hypo-fractionated cohorts, respectively, after propensity-matching. Stereotactic body radiation therapy resulted in a significantly lower PSA nadir (0.18 ng/ml) compared to hypo-fractionated radiation therapy (0.48 ng/ml) in patients with low-risk prostate cancer. Mean time to biochemical recurrence was not different between treatment groups. Stereotactic body radiation therapy is an effective treatment option for low and intermediate-risk prostate cancer with encouraging biochemical relapse-free survival and overall survival rates comparable with hypo-fractionated radiation therapy.

The prevalence and clinical significance of HER2 expression in prostate adenocarcinoma

AimsAbnormalities in HER2 are well-established oncogenic drivers and are approved therapeutic targets in various malignancies. Prior studies evaluating HER2 expression in prostate cancer (PCa) have yielded variable results. Most of these studies used immunohistochemistry scoring systems based on breast cancer data. The goal of this study was to determine the prevalence and clinical significance of HER2 expression using a scoring system that better reflects the HER2 staining pattern observed in PCa. MethodsWe randomly selected similar numbers of localized low risk (AJCC stage I), locally advanced (AJCC stages II & III), and metastatic (AJCC stage IV) PCa patients treated at the DC VA Medical Center between 2000 and 2022. Among them, we included patients who had sufficient PCa tissue samples and clinical information required for this analysis. Two experienced pathologists independently scored HER2 expression (Ventana Pathway anti-HER2) according to a modified gastric cancer HER2 scoring system. ResultsOut of the 231 patients included, 85 % self-identified as Black. 58.9 % of patients expressed HER2 (1+: 35.5 %; 2+: 18.2 %; 3+: 5.2 %). Validity of the results was confirmed using the HercepTest antibody. Higher HER2 expression was associated with a higher Gleason Score/Grade Group and advanced disease. ConclusionsOur findings support the adverse prognostic impact on HER2 in PCa. We propose the use of a modified scoring system to evaluate HER2 expression in PCa. The observed high prevalence of HER2 expression supports the consideration of novel HER2-targeted therapies addressing even low levels of HER2 expression in future PCa trials.

Location and Types of Treatment for Prostate Cancer After the Veterans Choice Program Implementation

The Veterans Choice Program (VCP) was implemented in 2014 to help veterans gain broader access to specialized care outside of the Veterans Health Administration (VHA) facilities by providing them with purchased community care (CC). To describe the prevalence and patterns in VCP-funded purchased CC after the implementation of the VCP among veterans with prostate cancer. This cohort study used VHA administrative data on veterans with prostate cancer diagnosed between January 1, 2015, and December 31, 2018. These veterans were regular VHA primary care users. Analyses were performed from March to July 2023. Driving distance (in miles) from residence to nearest VHA tertiary care facility. The location (VHA or purchased CC) in which treatment decisions were made was ascertained by considering 3 factors: (1) location of the diagnostic biopsy, (2) location of most of the postdiagnostic prostate-specific antigen laboratory testing, and (3) location of most of the postdiagnostic urological care encounters. The main outcome was receipt of definitive treatment and proportion of purchased CC by treatment type (radical prostatectomy [RP], radiotherapy [RT], or active surveillance) and by distance to nearest VHA tertiary care facility. Quality was evaluated based on receipt of definitive treatment for Gleason grade group 1 prostate cancer (low risk/limited treatment benefit by guidelines). The cohort included 45 029 veterans (mean [SD] age, 67.1 [6.9] years) with newly diagnosed prostate cancer; of these patients, 28 866 (64.1%) underwent definitive treatment. Overall, 56.8% of patients received definitive treatment from the purchased CC setting, representing 37.5% of all RP care and 66.7% of all RT care received during the study period. Most patients who received active surveillance management (92.5%) remained within the VHA. Receipt of definitive treatment increased over the study period (from 5830 patients in 2015 to 9304 in 2018), with increased purchased CC for patients living farthest from VHA tertiary care facilities. The likelihood of receiving definitive treatment of Gleason grade group 1 prostate cancer was higher in the purchased CC setting (adjusted relative risk ratio, 1.79; 95% CI, 1.65-1.93). This cohort study found that the percentage of veterans receiving definitive treatment in VCP-funded purchased CC settings increased significantly over the study period. Increased access, however, may come at the cost of low care quality (overtreatment) for low-risk prostate cancer.

Patient and Context Factors in the Adoption of Active Surveillance for Low-Risk Prostate Cancer

Although active surveillance for patients with low-risk prostate cancer (LRPC) has been recommended for years, its adoption at the population level is often limited. To make active surveillance available for patients with LRPC using a research framework and to compare patient characteristics and clinical outcomes between those who receive active surveillance vs radical treatments at diagnosis. This population-based, prospective cohort study was designed by a large multidisciplinary group of specialists and patients' representatives. The study was conducted within all 18 urology centers and 7 radiation oncology centers in the Piemonte and Valle d'Aosta Regional Oncology Network in Northwest Italy (approximate population, 4.5 million). Participants included patients with a new diagnosis of LRPC from June 2015 to December 2021. Data were analyzed from January to May 2023. At diagnosis, all patients were informed of the available treatment options by the urologist and received an information leaflet describing the benefits and risks of active surveillance compared with active treatments, either radical prostatectomy (RP) or radiation treatment (RT). Patients choosing active surveillance were actively monitored with regular prostate-specific antigen testing, clinical examinations, and a rebiopsy at 12 months. Outcomes of interest were proportion of patients choosing active surveillance or radical treatments, overall survival, and, for patients in active surveillance, treatment-free survival. Comparisons were analyzed with multivariable logistic or Cox models, considering centers as clusters. A total of 852 male patients (median [IQR] age, 70 [64-74] years) were included, and 706 patients (82.9%) chose active surveillance, with an increasing trend over time; 109 patients (12.8%) chose RP, and 37 patients (4.3%) chose RT. Median (IQR) follow-up was 57 (41-76) months. Worse prostate cancer prognostic factors were negatively associated with choosing active surveillance (eg, stage T2a vs T1c: odds ratio [OR], 0.51; 95% CI, 0.28-0.93), while patients who were older (eg, age ≥75 vs <65 years: OR, 4.27; 95% CI, 1.98-9.22), had higher comorbidity (Charlson Comorbidity Index ≥2 vs 0: OR, 1.98; 95% CI, 1.02-3.85), underwent an independent revision of the first prostate biopsy (OR, 2.35; 95% CI, 1.26-4.38) or underwent a multidisciplinary assessment (OR, 2.65; 95% CI, 1.38-5.11) were more likely to choose active surveillance vs active treatment. After adjustment, center at which a patient was treated continued to be an important factor in the choice of treatment (intraclass correlation coefficient, 18.6%). No differences were detected in overall survival between active treatment and active surveillance. Treatment-free survival in the active surveillance cohort was 59.0% (95% CI, 54.8%-62.9%) at 24 months, 54.5% (95% CI, 50.2%-58.6%) at 36 months, and 47.0% (95% CI, 42.2%-51.7%) at 48 months. In this population-based cohort study of patients with LRPC, a research framework at system level as well as favorable prognostic factors, a multidisciplinary approach, and an independent review of the first prostate biopsy at patient-level were positively associated with high uptake of active surveillance, a practice largely underused before this study.

Analysis of active surveillance uptake for localized prostate cancer in Quebec in 2016: A Canadian bicentric study and comparison with 2010 data

IntroductionActive surveillance (AS) has emerged as a primary management strategy for low-risk prostate cancer (PC) patients. We aimed to assess AS uptake over a 1-year snapshot throughout Quebec and to compare it to 2010 multicentric Canadian data. MethodsA retrospective chart review and data collection was performed in 1 academic and 2 non-academic community centres from Quebec, among men identified in 2016 with localized T1c-T2c PC on biopsy, fulfilling NCCN criteria of low-risk (LR)-PC, including very-low-risk (VLR) and non-VLR-PC, and favourable-intermediate risk (FIR)-PC. AS adherence was defined when chosen as initial strategy, without any radical treatment within 6 months. ResultsOverall, 259 patients fulfilled the inclusion criteria with 50.2% of VLR-PC patients. At 6 months, 81% patients in the LR group and 65% in the FIR group were considered as adherent to AS, in both centres, but with an increased use of AS in the community centres compared to 2010 data. The rates of AS maintenance decreased at 12 months to respectively 69% and 58%. Among the VLR group, the rate of initiation was 98% and decreased to 85% at 12 months. ConclusionOur data suggest that the majority of low-risk PC patients indeed initiated an AS in 2016, with even a greater proportion of VLR-PC patients compared to 2010. This ideal strategy should be encouraged and improved at 12 months, and assessed with recent data and longer follow-up. Level of evidence4

Clinical stage and grade migration of localized prostate cancer at diagnosis during the past decade

ObjectivesEarly 2010s data suggest a reverse stage and grade migration towards more aggressive prostate cancer (PCa) at diagnosis, accelerated by the 2012 US Preventive Services Task Force recommendation against PSA screening. Using the National Cancer Database, we investigated the impact of the 2018 USPSTF recommendation and the COVID-19 outbreak on this shift. We hypothesized that the COVID-19 outbreak would further contribute to a stage and grade migration towards more aggressive disease. Material and methodsWe identified men with localized PCa diagnosed between 2010 and 2020. We analyzed the shift in the proportion of PCa stratified according to D'Amico risk classification. We used multivariable logistic regression models to assess the association between year of diagnosis and dichotomous variables related to clinical stage and grade of PCa. Predicted probabilities with 95% CI were computed through marginal effect analyses. ResultsWe identified 910,898 men with localized PCa. The proportion of low-risk PCa almost halved from 34.9% in 2010 to 17.7% in 2020 (P < 0.001). Compared to 2010, we found in each year increased odds of: PSA≥10 ng/dL starting from 2012 (aOR2012 1.05; 95% CI, 1.02–1.08); cT3–T4 starting from 2015 (aOR2015 1.10; 95% CI, 1.03–1.17); ISUP GG 3–5 starting from 2011 (aOR2011 1.06; 95% CI, 1.03–1.08); and consequently, D'Amico intermediate/high-risk class starting from 2011 (aOR2011 1.03; 95% CI, 1.01–1.05). Fluctuations in the probabilities of PSA≥10 ng/dL and cT3–T4 at diagnosis were observed over time (all P < 0.001). The probability of PSA≥10 ng/dL peaked at 29.0% (95% CI, 28.0%–29.0%) in 2018, while the probability of cT3–T4 peaked at 3.7% (95% CI, 3.6%–3.8%) in 2020. All other outcome variables demonstrated a consistent upward shift (all P < 0.001), with the highest probabilities in 2020 for ISUP GG 3–5 (42.3%, 95% CI, 41.9%–42.6%) and D'Amico intermediate/high-risk (81.3%, 95% CI, 81.0%–81.6%). ConclusionsOur study confirms an enduring shift towards a higher proportion of aggressive PCa at diagnosis, likely influenced by the COVID-19 pandemic. The impact of the 2018 USPSTF PCa screening recommendation on the proportion of aggressive PCa seems restricted and likely affected by the pandemic outbreak. Future investigations should evaluate the long-term effects of the 2018 USPSTF recommendations in the postpandemic setting.

Les grands principes des traitements du cancer de prostate localisé

Prostate cancer (PCa) was in 2020 the second most common cancer in men after lung cancer, and the 5th leading cause of cancer death worldwide. Eighty percent of patients with PCa are diagnosed at a localized stage. The therapeutic approach depends on the risk classification. Active surveillance is one of the standard treatments for low-risk PCa, and can be proposed for selected patients with intermediate-risk PCa. Radical approaches are mainly represented by surgery or radiotherapy (alone or combined with androgen deprivation therapy). Focal therapies provide the advantage of a better sparing of adjacent healthy tissue, with encouraging early results from an oncological point of view, but their interpretation remains limited by a relatively short follow-up period. On a systemic level, androgen deprivation therapyis the key treatment in combination with radiotherapy for unfavorable intermediate or high-risk PCa. Second-generation hormone therapies have a new and growing place in the management of very high-risk (or locally advanced) localized prostate cancer. The aim of this review is to detail the various local and systemic treatments that can be offered to patients diagnosed with localized CaP.

Prostate Advanced Radiation Technologies Investigating Quality of Life (PARTIQoL): A Phase III Randomized Clinical Trial of Proton Therapy vs. IMRT for Low or Intermediate Risk Prostate Cancer.

Prostate cancer is the most common non-cutaneous cancer diagnosed among men in the United States, and the majority of patients are diagnosed with localized disease. Men with localized prostate cancer have several treatment options including external beam radiotherapy with either photons or protons. Proton beam therapy (PBT) has certain dosimetric advantages and the potential to reduce treatment-associated morbidity and improve oncologic outcomes, but current PBT is significantly more costly than intensity-modulated radiotherapy (IMRT). The PARTIQoL trial (NCT01617161) is the first multicenter phase 3 randomized trial comparing protons to photons in the treatment of localized prostate cancer. Patients with low or intermediate risk prostate cancer (Stage T1c-T2c, PSA < 20, Gleason score ≤ 7) are randomized to receive either PBT or IMRT, with targeted recruitment efforts for minority populations. A companion registry study has concurrently enrolled patients who declined randomization or whose insurance denied coverage for PBT. Patients are stratified by clinical site, age, use of rectal spacer, and fractionation schedule (conventional fractionation: 79.2 Gy in 44 fractions vs moderate hypofractionation: 70.0 Gy in 28 fractions). Participants are followed longitudinally to assess patient-reported outcomes (PROs) of bowel, urinary, and erectile function for 60 months after completion of radiotherapy (with an option for additional follow up through 10 years). Participants may also participate in correlative studies, including serial CT imaging during treatment and analyses of biopsy tissue, blood and urine specimens. The primary objective is to compare PROs of bowel function using the EPIC score at 24 months following completion of radiation. Secondary objectives are to assess treatment-related differences in urinary and erectile functions, adverse events, efficacy endpoints (biochemical control, metastasis-free survival, disease-specific survival, and overall survival), health state utilities, perceptions of care, late effects, cost-effectiveness, association between radiotherapy dose distribution and PROs, and to identify biomarkers of radiation response and toxicity. The randomized trial has completed accrual, with 450 patients enrolled at 27 sites between June 2012 and November 2021. 20.3% of patients enrolled are non-white. Accrual on the companion registry is active, with 354 patients enrolled as of February 2023. Follow-up for the primary endpoint on the randomized trial will be reached in 2024. The PARTIQoL randomized clinical trial will rigorously assess the clinical benefits of PBT relative to IMRT and results will inform decision making by patients, providers, policymakers, and payers.

Clinical Application of the Prostate Cancer Radiological Estimation of Change in Sequential Evaluation Score for Reporting Magnetic Resonance Imaging in Men on Active Surveillance for Prostate Cancer.

The Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) score has been developed to standardise prostate magnetic resonance imaging (MRI) reporting in men on active surveillance (AS) for prostate cancer (PCa). To evaluate the feasibility of PRECISE scoring and assess its diagnostic accuracy. All PCa patients on AS with a baseline MRI and at least one follow-up MRI scan between January 2008 and September 2022 at a single tertiary referral centre were included in a database. The follow-up protocol of the Prostate Cancer International Active Surveillance (PRIAS) study was used. All scans were retrospectively re-reported by a dedicated uroradiologist and appointed a Prostate Imaging Reporting and Data System (version 2.1) and PRECISE score. Clinically significant progression was defined by histopathological upgrading (on biopsy or radical prostatectomy) to grade group ≥3 and/or evolution to T3 stage. A survival analysis was performed to assess differential progression-free survival (PFS) according to the PRECISE score. A total of 188 patients were included for an analysis with a total of 358 repeat MRI scans and 144 repeat biopsies. The median follow-up was 46 mo (interquartile range 21-74). Radiological progression (PRECISE 4-5) had sensitivity, specificity, negative predictive value, and positive predictive value of, respectively, 78%, 70%, 90%, and 49% for clinically significant progression. Four-year PFS was 91% for PRECISE 1-3 versus 66% for PRECISE 4-5 (p<0.001). In total, 137 patients underwent a confirmation MRI scan within 18 mo after diagnosis. Four-year PFS in this group was 81% for PRECISE 1-3 versus 43% for PRECISE 4-5 (p<0.001). Limitations include retrospective design and no strict adherence to AS protocol. Implementation of PRECISE scoring for PCa patients on AS is feasible and offers a prognostic value. Patients with PRECISE score 4-5 on confirmation MRI within 18 mo after diagnosis have a three-fold higher risk of clinically significant progression after 4 yr. Patients with low-risk prostate cancer can be followed up carefully. In this study, we evaluate the standardised reporting of repeat magnetic resonance imaging scans (using the Prostate Cancer Radiological Estimation of Change in Sequential Evaluation [PRECISE] recommendations). PRECISE scoring is feasible and helps identify patients in need of further treatment.

A randomized phase II trial of MR-guided prostate stereotactic body radiotherapy administered in 5 or 2 fractions for localized prostate cancer (FORT)

BackgroundUltra-hypofractionated regimens for definitive prostate cancer (PCa) radiotherapy are increasingly utilized due in part to promising safety and efficacy data complemented by greater patient convenience from a treatment course requiring fewer sessions. As such, stereotactic body radiation therapy (SBRT) is rapidly emerging as a standard definitive treatment option for patients with localized PCa. The commercially available magnetic resonance linear accelerator (MR-LINAC) integrates MR imaging with radiation delivery, providing several theoretical advantages compared to computed tomography (CT)-guided radiotherapy. MR-LINAC technology facilitates improved visualization of the prostate, real-time intrafraction tracking of prostate and organs-at-risk (OAR), and online adaptive planning to account for target movement and anatomical changes. These features enable reduced treatment volume margins and improved sparing of surrounding OAR. The theoretical advantages of MR-guided radiotherapy (MRgRT) have recently been shown to significantly reduce rates of acute grade ≥ 2 GU toxicities as reported in the prospective randomized phase III MIRAGE trial, which compared MR-LINAC vs CT-based 5 fraction SBRT in patients with localized PCa (Kishan et al. JAMA Oncol 9:365-373, 2023). Thus, MR-LINAC SBRT–utilizing potentially fewer treatments–is warranted and clinically relevant for men with low or intermediate risk PCa electing for radiotherapy as definitive treatment.Methods/DesignA total of 136 men with treatment naïve low or intermediate risk PCa will be randomized in a 1:1 ratio to 5 or 2 fractions of MR-guided SBRT using permuted block randomization. Randomization is stratified by baseline Expanded PCa Index Composite (EPIC) bowel and urinary domain scores. Patients undergoing 5 fractions will receive 37.5 Gy to the prostate over 10–14 days and patients undergoing 2 fractions will receive 25 Gy to the prostate over 7–10 days. The co-primary endpoints are GI and GU toxicities as measured by change scores in the bowel and urinary EPIC domains, respectively. The change scores will be calculated as pre-treatment (baseline) score subtracted from the 2-year score.DiscussionFORT is an international, multi-institutional prospective randomized phase II trial evaluating whether MR-guided SBRT delivered in 2 fractions versus 5 fractions is non-inferior from a gastrointestinal (GI) and genitourinary (GU) toxicity standpoint at 2 years post-treatment in men with low or intermediate risk PCa.Trial registrationClinicaltrials.gov identifier: NCT04984343. Date of registration: July 30, 2021.Protocol version: 4.0, Nov 8, 2022.

Increasing Use of Conservative Management of Low-Risk Prostate Cancer in the Veterans Affairs System from 2012 to 2021

Conservative management (CM), including either active surveillance or watchful waiting, is the preferred management strategy for men with low-risk prostate cancer. We sought to describe contemporary trends in CM among men with localized prostate cancer across the equal-access Veterans Affairs (VA) system. Using VA tumor registry data, we identified all men with a new diagnosis of biopsy-proven, clinically node-negative, non-metastatic prostatic adenocarcinoma from 2012 to 2021, excluding men with missing National Comprehensive Cancer Network risk group. We quantified the yearly proportion of patients with low and favorable intermediate-risk (FIR) prostate cancer undergoing conservative management and examined age-specific rates. Multivariable logistic regression was used to identify independent clinical predictors of CM among men with low-risk and FIR disease. The cohort included 86,415 patients with localized prostate cancer, of whom 20,290 (23.5%) had low risk and 25,447 (29.5%) had FIR disease. The proportion of men diagnosed with low-risk disease decreased from 27.7% in 2012 to 20.1% in 2021. The proportion of men with localized prostate cancer who were 70 years or older at diagnosis increased from 19.5% in 2012 to 46.4% in 2021, with similar increases seen across risk groups. The proportion of men with low-risk disease undergoing CM increased from 63.1% in 2012 to 86.6% in 2021. CM rates in 2021 among low-risk patients were largely consistent across age groups (50-59: 85.1%; 60-69: 87.4%; 70+: 86.3%). For FIR patients, CM rates increased among the subset with Gleason 6 disease (49.5% in 2012 to 80.7% in 2021). In multivariable models, independent predictors of CM in low-risk patients included older age, more recent year, lower PSA at diagnosis, North Atlantic or Pacific region, and presence of another cancer at diagnosis; similar predictors were found in FIR patients. Self-reported race (Black, White, or Other) was not associated with CM. While there was wide geographic variation in CM rates among low-risk patients early in the study period (2012-2014: 56.1% in Southeast region vs 74.1% in Pacific), these disparities resolved in recent years (2019-2021: 83.2% in Southeast vs 83.8% in Pacific). Rates of conservative management for localized prostate cancer increased dramatically over time in the VA, with over 85% of low-risk patients managed conservatively in 2021. Recent years showed no differences in CM rates by self-reported race, geographic region, or age group. Despite this progress, we observed a concomitant increase in the proportion of men 70 years or older diagnosed with localized prostate cancer, including low risk disease. This raises a need to consider strategies to reduce the diagnosis of low-risk disease in elderly Veterans.

Long-Term Follow-Up Analysis of NRG Oncology RTOG 0415: A Randomized Phase III Non-Inferiority Study Comparing Two Fractionation Schedules in Patients with Favorable-Risk Prostate Cancer

To assess whether the efficacy of a hypofractionated (H) schedule is no worse than a conventional (C) schedule in men with low-risk prostate cancer. Accrual began April 2006 and ended in December 2009. 1115 men with favorable-risk prostate cancer were randomly assigned 1:1 to a conventional (C) schedule (73.8 Gy in 41 fractions over 8.2 weeks) or to a hypofractionated (H) schedule (70 Gy in 28 fractions over 5.6 weeks). The trial was designed to establish with 90% power and alpha = 0.05 that (H) results in 5-year disease-free survival (DFS) that is not lower than (C) by more than 7% (hazard ratio (HR) < 1.52). Protocol specified secondary endpoints evaluated for noninferiority include: biochemical recurrence (BR), local progression, disease-specific survival, and overall survival. One thousand ninety-two protocol eligible men were analyzed: 542 to C and 550 to H. Median follow-up is 12.75 years. Baseline characteristics were not different according to treatment arm. The estimated 12-year DFS is 56.1% (95% CI 51.5, 60.5) in the C arm and 61.8% (57.2, 66.0) in the H arm. The DFS hazard ratio (H/C) is 0.85 (0.71-1.03), confirming non-inferiority (p<0.001). Twelve-year cumulative incidence of biochemical recurrence (BR) was 17.0% (CI 13.8, 20.5) in the C-RT and 9.9% (CI 7.5, 12.6) in the H-RT arm; (HR = 0.56, (0.40-0.78) suggesting improved efficacy with H. Additional pre-specified secondary endpoints were non-inferior Late Grade ≥ 3 GI toxicity is 3.2% (C) vs. 4.4% (H), Relative risk (RR) for H vs. C 1.39 (CI 0.75, 2.55) Late Grade ≥ 3 GU toxicity is 3.4% (C) vs. 4.2% (H), RR = 1.26 (CI 0.69, 2.30). In men with favorable-risk prostate cancer, long-term disease-free survival is non-inferior with 70 Gy in 28 fractions compared to 73.8 Gy in 41 fractions. The risk of BR is reduced with moderate hypofractionation. No differences in late Grade ≥3 GI/GU toxicity were observed between the arms. (ClinicalTrials.gov identifier: NCT00331773).

Randomized Trial of Five or Two MRI-guided Adaptive Radiotherapy Treatments for Prostate Cancer (FORT)

The objective of this randomized clinical trial is to demonstrate that 2 treatments of real-time MRI-guided radiotherapy (RT) does not significantly increase patient-reported GI and GU symptoms compared to 5 treatments of RT 2 years after treatment completion (24 months). Key Eligibility Criteria: Inclusion Criteria 1. Men aged > 18 with histologically confirmed low or intermediate risk prostate cancer per NCCN guidelines. 2. ECOG 0 - 1 3. IPSS < 18 4. Ability to receive MRI-guided radiotherapy. 5. Ability to complete the Expanded Prostate Cancer Index Composite (EPIC) questionnaire. Exclusion Criteria 1. Prior history of receiving pelvic RT. 2. Patient with history of IBD. 3. Hip replacements. 4. History of bladder neck or urethral stricture. 5. TURP < 8 weeks prior to RT 6. Metastatic (pelvic nodal or distant) disease on CT, Bone, and/or PSMA PET scan. Study Design/Endpoints: This is a randomized phase II non-inferiority trial comparing 2 fractions of ultrahypofractionated RT (25 Gy total with optional PSMA/MRI boost to 28 Gy) versus 5 fractions of ultra-hypofractionated RT (37.5 Gy total with optional PSMA/MRI boost to 45 Gy) in the definitive setting for prostate cancer. Subjects will be stratified based on pre-specified stratification factors and randomized 1:1 to receive 2 or 5 fractions using permuted block randomization. The primary endpoint is the change in patient-reported GI and GU symptoms as measured by EPIC at 2 years from end of treatment. Secondary endpoints will include both the safety endpoints including change in GI and GU symptoms at 3, 6, 12 and 60 months from end of treatment, and multiple efficacy endpoints including time to progression, prostate cancer specific survival and overall survival. The sample size is calculated based on a non-inferiority design. The non-inferiority margins are set to be a change score of 6 points for the GI symptoms and 5 points for the GU symptoms. The standard deviations of the change scores are assumed to be 13.2 for the GI symptoms and 10.5 for the GU symptoms based on estimates generated in RTOG 0415 trial. This level of change in scores are deemed as clinically meaningful. For example, 6 points of change score for GI symptoms corresponds to two symptoms worsening by 1 level (i.e., loose stools and frequency of bowel movements change from "no problem" to "very small problem") or one of the symptoms worsening by 2 levels (i.e., loose stool change from "no problem" to "small problem"). A sample size of 122 with 61 in each arm will ensure 80% power for GI endpoint and 83% power for GU endpoint to detect non-inferiority using a one-sided two-sample t-test at the significance level of 0.05. Adjusting for a projected 10% EPIC/non-compliance rate, 136 patients (68 per arm) will be randomized. Stratification Factors: Patients will be stratified according to baseline EPIC bowel and urinary domain scores and country of treatment. Enrollment: Twenty patients. To be determined. To be determined.

Utilization of Radical Prostatectomy vs. Radiation Therapy for Gleason Grade Group 5 Prostate Cancer before and after USPSTF Grade D Recommendation against Prostate-Specific Antigen Screening in 2012

The 2012 United States Preventive Services Task Force (USPSTF) Grade D recommendation against prostate-specific antigen (PSA) screening has resulted in a shift to higher-stage prostate cancer (PC) at diagnosis. While incidence of low-risk prostate cancer has declined, more men are diagnosed with high-risk disease, and multimodal treatment is often required. The impact of this epidemiologic shift on practice patterns, specifically radical prostatectomy (RP) versus definitive radiation therapy (RT), for men with localized PC at high risk of recurrence is unknown. Herein, we evaluate the utilization of RP versus RT in the United States for Gleason grade group 5 (GG5) prostate cancer before and after 2012. We identified 34,011 men with localized GG5 PC treated with (1) RP or (2) RT plus androgen deprivation therapy (ADT) between 2004 and 2017 in the National Cancer Database. We excluded those who were clinically node-positive, had metastatic disease, or received chemotherapy or palliative-intent treatment. Chi-square was used to compare the relative use of RP and RT before versus after January 1, 2012, corresponding to the year of USPSTF recommendation against PSA screening. Annual use of RP versus RT from 2004 to 2017 was compared in academic and non-academic centers using Cochran-Armitage test for trend. Joinpoint regression assessed if 2012 was significant for inflection of crude rates of RP. Finally, we modeled the effect of treatment year (i.e., 2012-2017 versus 2004-2011) on use of RP using multivariable logistic regression. Sensitivity analysis tested an interaction term for facility type (i.e., academic versus community). Tests were two-sided with a 0.05 level of significance. Of the eligible men, 10,745 (31.6%) had T3-T4 disease. Between 2004 and 2011, 36.5% (n = 5,483) underwent RP; between 2012 and 2017, 42.3% (n = 8,034) underwent RP (p = .02). Across all centers, use of RP increased from 31% to 41% (p for trend <.001). In academic centers, use of RP increased from 32% to 44% (p for trend <.001); in community centers, use of RP increased from 30% to 39% (p for trend <.001). 2012 was associated with significant inflection for increase in RP use in all centers. On multivariable analysis, there was an increased odds of receiving RP after 2012 (adjusted OR 1.34, 95% CI 1.28-1.40, p<.001). No differential effect by facility type was observed (p = .15). Utilization of RP for GG5 PC has significantly increased in the United States over the past decade, particularly after the USPSTF Grade D recommendation against PSA screening in 2012. It remains unknown whether oncologic or functional outcomes may be compromised in this group of high-risk men, many of whom require post-prostatectomy RT and/or ADT. While historically rare, prospective comparison of RP versus RT+ADT for GG5 PC may be helpful given the evolving epidemiology of localized PC.

Barriers and enablers of active surveillance for prostate cancer: a qualitive study of clinicians.

To identify and explore barriers to, and enablers of, active surveillance (AS) in men with low-risk prostate cancer (LRPCa), as perceived by PCa clinicians. Urologists and radiation oncologists in Australia and New Zealand were purposively sampled for a cross-section on gender and practice setting (metropolitan/regional; public/private). Using a grounded theory approach, semi-structed interviews were conducted with participants. Interviews were coded independently by two researchers using open, axial, and selective coding. A constant comparative approach was used to analyse data as it was collected. Thematic saturation was reached after 18 interviews, and a detailed model of barriers to, and enablers of, AS for LRPCa, as perceived by clinicians was developed. A model explaining what affects clinician decision making regarding AS in LRPCa emerged. It was underpinned by three broad themes: (i) clinician perception of patients' barriers and enablers; (ii) clinician perception of their own barriers and enablers; and (iii) engagement with healthcare team and resource availability. Clinicians unanimously agree that AS is an evidence-based approach for managing LRPCa. Despite this many men do not undergo AS for LRPCa, which is due to the interplay of patient and clinician factors, and their interaction with the wider healthcare system. This study identifies strategies to mitigate barriers and enhance enablers, which could increase access to AS by patients with LRPCa.

Uncovering the Changing Treatment Landscape for Low-risk Prostate Cancer in the USA from 2010 to 2020: Insights from the National Cancer Data Base

The management of prostate cancer (PCa) has evolved from a paradigm of “treat when caught early” to “treat only when necessary”. Despite inconsistency in its use, active surveillance has evolved over the past two decades into the gold standard for management of low-risk PCa. Our objective was to investigate whether the use of expectant management (active surveillance, watchful waiting, no treatment) as a first-line approach for low-risk PCa has increased over the past decade. We queried the US National Cancer Data Base for men diagnosed with localized PCa between 2010 and 2020. Two multivariable logistic regression models with different two-way interaction terms (year of diagnosis × D’Amico risk classification, and year of diagnosis × International Society of Urological Pathology [ISUP] grade group) were fitted to predict the probability of undergoing expectant management versus active treatment. The predicted probability of expectant management increased from 13.7% in 2010 to 64.4% in 2020 for men with low-risk PCa, and from 12.9% in 2010 to 61.6% in 2020 for ISUP grade group 1 PCa (both pinteraction < 0.001). The frequency of expectant management for low-risk PCa has increased dramatically during the past decade. We expect this trend to further increase owing to the growing awareness of the harms of overtreatment of indolent disease. Patient summaryWe examined the use of expectant management for prostate cancer between 2010 and 2020 in a large hospital-based registry from the USA. We found that the proportion of men receiving expectant management for low-risk prostate cancer is increasing. We conclude that growing awareness of the harms of overtreatment has profoundly affected trends for prostate cancer treatment in the USA.

Causal relationship between prostate cancer and 12 types of cancers: multivariable and bidirectional Mendelian randomization analyses.

Previous observational studies have shown an association between certain cancers and the subsequent risk of prostate cancer (PCa). However, the causal relationship between these cancers and PCa is still unclear. This study aimed to investigate the causal relationship between 12 common cancers and the risk of PCa. We employed genome-wide association studies (GWAS) to perform forward and reverse Mendelian randomization (MR) within two-sample frameworks. Furthermore, we conducted multivariable MR analyses to investigate the relationships between different types of cancer. In addition, multiple sensitivity analysis methods were employed to assess the robustness of our findings. Our univariable MR analysis showed that genetically predicted hematological cancer was associated with a reduced risk of PCa (OR: 0.911, 95% CI 0.89-0.922, P = 0.03). Furthermore, MR analysis demonstrates that genetically predicted occurrence of thyroid gland and endocrine gland cancer also raised the risk of PCa (all P < 0.05). Multivariable analysis showed that thyroid gland cancer exhibited a higher incidence of PCa (OR: 1.12, 95% CI: 1.08-1.16, P = 0.008). In the reverse MR analysis, we found no significant inverse causal associations between PCa and 12 types of cancers. In summary, this study provided insights into the causal relationships between various types of cancer and PCa. Hematological cancer was suggested to associate with a lower risk of PCa, while thyroid gland cancer and endocrine gland cancer might increase the risk. These findings contribute to the understanding of genetic factors related to PCa and its potential associations with other cancers.

Secondary Primary Cancer Risk After Radiation Therapy in Rectal Cancer: A Population-Based Cohort Study With Propensity Score Matching

BackgroundIt remains unclear whether radiation therapy (RT) has an impact on the development of secondary primary cancer (SC) in rectal cancer (RC) patients, especially within the true pelvis. AimTo examine the incidence of SC in a population-based cohort of RC after surgical treatment with or without radiation therapy (RT, NRT). Patients and MethodsThe epidemiological cohort consisting of 13,919 RC patients with primary M0 stage diagnosed between 1998 and 2019 was collected from cancer registry data of Upper Bavaria. Competing risk analyses were conducted regarding the development of SC on 11 687 first malignancies, stratified by RT/NRT. A propensity score (PS) was generated by logistic regression modeling of RT to repeat competing risk analyses on a PS-matched cohort. ResultsThe median age (interquartile range) of the epidemiological cohort was 68.9 years (60.4-76.7). About 60.8%, were men, 38.7% had UICC III, 35.8% of tumors were localized lower than 8 cm, 41.3% underwent RT. Only 17.1% of patients older than 80 years at diagnosis received RT. In general, RT patients were 5 years younger than NRT patients (65.9 years [58.0-73.0] vs. 71.3 years [62.4-79.2], P < .0001). The 20-year cumulative incidence of SC was 16.5% in RT and 17.4% in NRT patients (P = .2298). Men with RT had a lower risk of prostate cancer (HR = 0.55, 95%CI [0.34-0.91], P = .0168). In the PS-matched cohort, RT patients had a significantly higher risk of bladder cancer during follow-up (10-year cumulative incidence of 1.1% vs. 0.6% in NRT). The direction of the RT effects in men and women and different tumor sites may cancel each other. ConclusionA protective effect of RT in rectal cancer patients on developing prostate SC by half is reproduced. Further analyses studying the long-term SC risks of RT should essentially focus on stratification by sex, and focus on more recent data.