Racial and Ethnic Disparities in Use of Novel Hormonal Therapy Agents in Patients With Prostate Cancer.

Importance: Novel hormonal therapy (NHT) agents have been shown to prolong overall survival in numerous randomized clinical trials for patients with advanced prostate cancer (PCa). There is a paucity of data regarding the pattern of use of these agents in patients from different racial and ethnic groups. Objective: To assess racial and ethnic disparities in the use of NHT in patients with advanced PCa. Design, Setting, and Participants: This cohort study comprised all men diagnosed with de novo advanced PCa (distant metastatic [M1], regional [N1M0], and high-risk localized [N0M0] per Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy [STAMPEDE] trial criteria) with Medicare Part A, B, and D coverage between January 1, 2011, and December 31, 2017, in a Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database including prescription drug records. Data analysis took place from January through May 2023. Exposures: Race and ethnicity (Black [non-Hispanic], Hispanic, White, or other [Alaska Native, American Indian, Asian, Pacific Islander, or not otherwise specified and unknown]) abstracted from the SEER data fields. Main Outcomes and Measures: The primary outcome was receipt of an NHT agent (abiraterone, enzalutamide, apalutamide, or darolutamide) using a time-to-event approach. Results: The study included 3748 men (median age, 75 years [IQR, 70-81 years]). A total of 312 (8%) were Black; 263 (7%), Hispanic; 2923 (78%), White; and 250 (7%) other race and ethnicity. The majority of patients had M1 disease (2135 [57%]) followed by high-risk N0M0 (1095 [29%]) and N1M0 (518 [14%]) disease. Overall, 1358 patients (36%) received at least 1 administration of NHT. White patients had the highest 2-year NHT utilization rate (27%; 95% CI, 25%-28%) followed by Hispanic patients (25%; 95% CI, 20%-31%) and patients with other race or ethnicity (23%; 95% CI, 18%-29%), with Black patients having the lowest rate (20%; 95% CI, 16%-25%). Black patients had significantly lower use of NHT compared with White patients, which persisted at 5 years (37% [95% CI, 31%-43%] vs 44% [95% CI, 42%-46%]; P = .02) and beyond. However, there was no significant difference between White patients and Hispanic patients or patients with other race or ethnicity in NHT utilization (eg, 5 years: Hispanic patients, 38% [95% CI, 32%-46%]; patients with other race and ethnicity: 41% [95% CI, 35%-49%]). Trends of lower utilization among Black patients persisted in the patients with M1 disease (eg, vs White patients at 5 years: 51% [95% CI, 44%-59%] vs 55% [95% CI, 53%-58%]). After adjusting for patient, disease, and sociodemographic factors in multivariable analysis, Black patients continued to have a significantly lower likelihood of NHT initiation (adjusted subdistribution hazard ratio, 0.76; 95% CI, 0.61-0.94, P = .01). Conclusions and Relevance: In this cohort study of Medicare beneficiaries with advanced PCa, receipt of NHT agents was not uniform by race, with decreased use observed in Black patients compared with the other racial and ethnic groups, likely due to multifactorial obstacles. Future studies are needed to identify strategies to address the disparities in the use of these survival-prolonging therapies in Black patients.

Race-dependent association of clinical trial participation with improved outcomes for high-risk prostate cancer patients treated in the modern era.

It is unclear whether cancer patients enrolled in clinical trials have improved outcomes compared with non-study patients. We compared prostate cancer-specific mortality (PCSM) in patients in a real-world setting (SEER-Medicare database) versus on a trial (NRG/RTOG 0521). The 7-year freedom from PCSM was superior in trial patients (92.4% vs. 88.1%, sHR = 1.77 [95% CI 1.05-2.97], P = 0.03). Black trial patients had significantly superior freedom from PCSM than Black real-world patients (sHR 6.52, 95% CI 1.43-29.72, P = 0.02), which was not seen among non-Black patients. Trial patients may have improved outcomes, and racial disparities are accentuated in the real world.

Definitions of disease burden across the spectrum of metastatic castration-sensitive prostate cancer: comparison by disease outcomes and genomics.

BACKGROUND: Several definitions have attempted to stratify metastatic castrate-sensitive prostate cancer (mCSPC) into low and high-volume states. However, at this time, comparison of these definitions is limited. Here we aim to compare definitions of metastatic volume in mCSPC with respect to clinical outcomes and mutational profiles. METHODS: We performed a retrospective review of patients with biochemically recurrent or mCSPC whose tumors underwent somatic targeted sequencing. 294 patients were included with median follow-up of 58.3 months. Patients were classified into low and high-volume disease per CHAARTED, STAMPEDE, and two numeric (≤3 and ≤5) definitions. Endpoints including radiographic progression-free survival (rPFS), time to development of castration resistance (tdCRPC), and overall survival (OS) were evaluated with Kaplan-Meier survival curves and log-rank test. The incidence of driver mutations between definitions were compared. RESULTS: Median OS and tdCRPC were shorter for high-volume than low-volume disease for all four definitions. In the majority of patients (84.7%) metastatic volume classification did not change across all four definitions. High volume disease was significantly associated with worse OS for all four definitions (CHAARTED: HR 2.89; p < 0.01, STAMPEDE: HR 3.82; p < 0.01, numeric ≤3: HR 4.67; p < 0.01, numeric ≤5: HR 3.76; p < 0.01) however, were similar for high (p = 0.95) and low volume (p = 0.79) disease across all four definitions. Those with discordant classification tended to have more aggressive clinical behavior and mutational profiles. Patients with low-volume disease and TP53 mutation experienced a more aggressive course with rPFS more closely mirroring high-volume disease. CONCLUSIONS: The spectrum of mCSPC was confirmed across four different metastatic definitions for clinical endpoints and genetics. All definitions were generally similar in classification of patients, outcomes, and genetic makeup. Given these findings, the simplicity of numerical definitions might be preferred, especially when integrating metastasis directed therapy. Incorporation of tumor genetics may allow further refinement of current metastatic definitions.

Time-Driven Activity-Based Costing of CT-Guided vs MR-Guided Prostate SBRT.

BACKGROUND AND PURPOSE: Stereotactic body radiation therapy (SBRT) has become a standard-of-care option for localized prostate cancer. While prostate SBRT has traditionally been delivered using computed-tomography-guided radiation therapy (CTgRT), MR-imaging-guided radiation therapy (MRgRT) is now available. MRgRT offers real-time soft-tissue visualization and ease of adaptive planning, obviating the need for fiducial markers, and potentially allowing for smaller planning target volume (PTV) margins. Although prior studies have focused on evaluating the cost-effectiveness of MRgRT vs CTgRT from a payor perspective, the difference in provider costs to deliver such treatments remains unknown. This study thus used time-driven activity-based costing (TDABC) to determine the difference in provider resources consumed by delivering prostate SBRT via MRgRT vs CTgRT. METHODS: Data was collected from a single academic institution where prostate SBRT is routinely performed using both CTgRT and MRgRT. Five-fraction SBRT (40 Gy total dose) was assumed to be delivered through volumetric-modulated arc therapy for CTgRT patients, and through step-and-shoot, fixed-gantry intensity-modulated radiation therapy for MRgRT patients. Process maps were constructed for each portion of the radiation delivery process via interviews/surveys with departmental personnel and by measuring CTgRT and MRgRT treatment times. Prior to simulation, only CTgRT patients underwent placement of three gold fiducial markers. Personnel capacity cost rates were calculated by dividing total personnel costs by the annual minutes worked by a given personnel. Equipment costs included both an annualized purchase price and annual maintenance costs. Ultimately, the total costs of care encompassing personnel, space/equipment, and materials were aggregated across the entire chain of care for both CTgRT and MRgRT patients in a base case. RESULTS: Direct costs associated with delivering a 5-fraction course of prostate SBRT were $1,497 higher with MRgRT than with CTgRT - comprised of personnel costs ($210 higher with MRgRT), space/equipment ($1,542 higher with MRgRT), and materials ($255 higher with CTgRT). Only CTgRT patients underwent fiducial placement, which accounted for $591. MRgRT patients were assumed to undergo both CT simulation (for electron density calculation) and MRI simulation, with the former accounting for $168. Mean time spent by patients in the treatment vault per fraction was 20 minutes (range 15-26 minutes) for CTgRT, and 31 minutes (range 30-34 minutes) for MRgRT. Patient time spent during fiducial placement (CTgRT only) was 60 minutes. Modifying the number of fractions treated would result in the cost difference of $1,497 (5 fractions) changing to $441 (1 fraction) or to $2,025 (7 fractions). CONCLUSION: This study provides an approximate comparison of the direct resources required for a radiation oncology provider to deliver prostate SBRT with CTgRT vs MRgRT. We await findings from the currently accruing phase III MIRAGE trial, which is comparing these modalities, and will subsequently measure acute and late genitourinary/gastrointestinal (GU/GI) toxicities, temporal change in quality-of-life outcomes, and 5-year biochemical, recurrence-free survival. Results from studies comparing the efficacy and safety of MRgRT vs CTgRT will ultimately allow us to put this cost difference into context.

Clinical assessment of geometric distortion for a 0.35T MR-guided radiotherapy system.

PURPOSE: To estimate the overall spatial distortion on clinical patient images for a 0.35 T MR-guided radiotherapy system. METHODS: Ten patients with head-and-neck cancer underwent CT and MR simulations with identical immobilization. The MR images underwent the standard systematic distortion correction post-processing. The images were rigidly registered and landmark-based analysis was performed by an anatomical expert. Distortion was quantified using Euclidean distance between each landmark pair and tagged by tissue interface: bone-tissue, soft tissue, or air-tissue. For baseline comparisons, an anthropomorphic phantom was imaged and analyzed. RESULTS: The average spatial discrepancy between CT and MR landmarks was 1.15 ± 1.14 mm for the phantom and 1.46 ± 1.78 mm for patients. The error histogram peaked at 0-1 mm. 66% of the discrepancies were <2 mm and 51% <1 mm. In the patient data, statistically significant differences (p-values < 0.0001) were found between the different tissue interfaces with averages of 0.88 ± 1.24 mm, 2.01 ± 2.20 mm, and 1.41 ± 1.56 mm for the air/tissue, bone/tissue, and soft tissue, respectively. The distortion generally correlated with the in-plane radial distance from the image center along the longitudinal axis of the MR. CONCLUSION: Spatial distortion remains in the MR images after systematic distortion corrections. Although the average errors were relatively small, large distortions observed at bone/tissue interfaces emphasize the need for quantitative methods for assessing and correcting patient-specific spatial distortions.

Underutilization of Androgen Deprivation Therapy with External Beam Radiotherapy in Men with High-grade Prostate Cancer.

Multiple randomized trials have shown a survival benefit to long durations of androgen deprivation therapy (ADT) in patients with Gleason grade group (GG) 4-5 (ie, Gleason score 8-10) prostate cancer (PCa) undergoing definitive external beam radiotherapy (EBRT). We conducted a population-based retrospective study utilizing the complete Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database from 2008 to 2011, extracting PCa patients of non-Hispanic white (NHW) and African-American (AA) race diagnosed with GG 4-5PCa who received EBRT with or without concomitant ADT. Of 961 patients receiving definitive EBRT, 225 (23.4%) received no ADT, 297 (30.9%) received 1-6mo of ADT, 313 (32.6) received 7-23mo of ADT, and 126 (13.1%) received ≥24mo of ADT. On multinomial logistic regression after inverse probability treatment weighting to balance for differences in other covariates, AA men still had significantly lower odds of receiving 1-6mo of ADT versus no ADT compared with NHW men (odds ratios 0.519 [95% confidence interval, 0.384-0.700]). In conclusion, long-duration ADT is underutilized, with nearly 90% of patients with GG 4-5PCa receiving <24mo of concomitant ADT, and AA men are less likely to receive ADT than NHW men. PATIENT SUMMARY: In this report, we examined the utilization of concomitant androgen deprivation therapy (ADT) among men with high-grade prostate cancer undergoing definitive external beam radiotherapy. We found that long-duration ADT was underutilized overall; moreover, African-American men were less likely to receive concomitant ADT than non-Hispanic white men.

Time-Driven Activity-Based Costing Analysis of Telemedicine Services in Radiation Oncology.

PURPOSE: Health systems have increased telemedicine use during the SARS-CoV-2 outbreak to limit in-person contact. We used time-driven activity-based costing to evaluate the change in resource use associated with transitioning to telemedicine in a radiation oncology department. METHODS AND MATERIALS: Using a patient undergoing 28-fraction treatment as an example, process maps for traditional in-person and telemedicine-based workflows consisting of discrete steps were created. Physicians/physicists/dosimetrists and nurses were assumed to work remotely 3 days and 1 day per week, respectively. Mapping was informed by interviews and surveys of personnel, with cost estimates obtained from the department's financial officer. RESULTS: Transitioning to telemedicine reduced provider costs by $586 compared with traditional workflow: $47 at consultation, $280 during treatment planning, $237 during on-treatment visits, and $22 during the follow-up visit. Overall, cost savings were $347 for space/equipment and $239 for personnel. From an employee perspective, the total amount saved each year by not commuting was $36,718 for physicians (7243 minutes), $19,380 for physicists (7243 minutes), $17,286 for dosimetrists (7210 minutes), and $5599 for nurses (2249 minutes). Patients saved $170 per treatment course. CONCLUSIONS: A modified workflow incorporating telemedicine visits and work-from-home capability conferred savings to a department as well as significant time and costs to health care workers and patients alike.

Cost-Effectiveness of Metastasis-Directed Therapy in Oligorecurrent Hormone-Sensitive Prostate Cancer.

PURPOSE: Oligorecurrent prostate cancer has historically been treated with indefinite androgen deprivation therapy (ADT), although many patients and providers opt to defer this treatment at the time of recurrence given quality-of-life and/or comorbidity considerations. Recently, metastasis-directed therapy (MDT) has emerged as a potential intermediary between surveillance and immediate continuous ADT. Simultaneously, advanced systemic therapy in addition to ADT has also been shown to improve survival in metastatic hormone-sensitive disease. This study aimed to compare the cost-effectiveness of treating oligorecurrent patients with upfront MDT before standard-of-care systemic therapy. METHODS AND MATERIALS: A Markov-based cost-effectiveness analysis was constructed comparing 3 strategies: (1) upfront MDT → salvage abiraterone acetate plus prednisone (AAP) + ADT → salvage docetaxel + ADT; (2) upfront AAP + ADT → salvage docetaxel + ADT; and (3) upfront docetaxel + ADT → salvage AAP + ADT. Transition probabilities and utilities were derived from the literature. Using a 10-year time horizon and willingness-to-pay threshold of $100,000/quality-adjusted life year (QALY), net monetary benefit values were subsequently calculated for each treatment strategy. RESULTS: At 10 years, the base case revealed a total cost of $141,148, $166,807, and $136,154 with QALYs of 4.63, 4.89, and 4.00, respectively, reflecting a net monetary benefit of $322,240, $322,018, and $263,407 for upfront MDT, upfront AAP + ADT, and upfront docetaxel + ADT, respectively. In the probabilistic sensitivity analysis using a Monte Carlo simulation (1,000,000 simulations), upfront MDT was the cost-effective strategy in 53.6% of simulations. The probabilistic sensitivity analysis revealed 95% confidence intervals for cost ($75,914-$179,862, $124,431-$223,892, and $103,298-$180,617) and utility in QALYs (3.85-6.12, 3.91-5.86, and 3.02-5.22) for upfront MDT, upfront AAP + ADT, and upfront docetaxel + ADT, respectively. CONCLUSIONS: At 10 years, upfront MDT followed by salvage AAP + ADT, is comparably cost-effective compared with upfront standard-of-care systemic therapy and may be considered a viable treatment strategy, especially in patients wishing to defer systemic therapy for quality-of-life or comorbidity concerns. Additional studies are needed to determine whether MDT causes a sustained meaningful delay in disease natural history and whether any benefit exists in combining MDT with upfront advanced systemic therapy.

Clinical Assessment of Prostate Displacement and Planning Target Volume Margins for Stereotactic Body Radiotherapy of Prostate Cancer.

Purpose: To assess the optimal planning target volume (PTV) margins for stereotactic body radiotherapy (SBRT) of prostate cancer based on inter- and intra-fractional prostate motion determined from daily image guidance. Methods and Materials: Two hundred and five patients who were enrolled on two prospective studies of SBRT (8 Gy × 5 fractions) for localized prostate cancer treated at a single institution between 2012 and 2017 had complete inter- and intra-fractional shift data available. All patients had scheduled kilovoltage planar imaging during SBRT with rigid registration to intraprostatic fiducials prior to each of four half-arcs delivered per fraction, as well as cone beam CT verification of anatomy prior to each fraction. Inter- and intra- fractional shift data were obtained to estimate the required PTV margins based on the classic van Herk formula. Inter- and intra-fractional motion were compared between patients with and without severe toxicities using the independent two-sample Wilcoxon test. Results: The margins required to account for inter-fractional motion were estimated to be 0.99, 1.52, and 1.45 cm in lateral (LR), longitudinal (SI), and vertical (AP) directions, respectively. The margins required to account for intra-fractional motion were estimated to be 0.19, 0.27, and 0.31 cm in LR, SI and AP directions, respectively. Large intra-fractional shifts were mostly observed in the SI and AP directions, with 2.0 and 5.4% of patients experiencing average intra-fractional motion >3 mm in the SI and AP directions, respectively, compared with none experiencing mean shifts >3 mm in the LR direction. Six patients experienced grade 3 gastrointestinal or genitourinary toxicity. There were no significant differences in mean inter- or intra-fractional motion in any of the cardinal directions compared to patients without severe toxicity (inter-fractional p = 0.46-0.99, intra-fractional p = 0.10-0.84). Conclusion: The inter- and intra-fractional margins estimated from this study are in line with prior reported values. Intra-fractional prostate motion was generally small with larger margins required for the SI and AP directions, notably just slightly exceeding the commonly used 3 mm posterior PTV margin even with realignment between half-arcs. Development of severe toxicity was not significantly associated with the degree of inter- or intra-fractional motion.

Clinical Indicators of Psychosocial Distress Predict for Acute Radiation-Induced Fatigue in Patients Receiving Adjuvant Radiation Therapy for Breast Cancer: An Analysis of Patient-Reported Outcomes.

PURPOSE: To assess the magnitude and predictors of patient-reported fatigue among breast cancer patients receiving radiation therapy (RT). METHODS AND MATERIALS: Patients receiving breast RT completed a survey querying fatigue at each weekly on-treatment visit. Patient-reported fatigue severity and interference was assessed on an ordinal scale of 0 to 4, using a validated scoring system. Baseline anxiety and depression scores were also obtained. The kinetics of mean fatigue scores per week and the maximum fatigue scores over the course of the entire treatment were assessed, and clinical predictors were identified by univariate and multivariate regression. RESULTS: The average fatigue severity and interference scores were 0.6 and 0.46. The average fatigue scores increased to an equivalent extent from week to week, with expected increases of 0.99 in fatigue severity and 0.85 in interference over 7 weeks. Patients treated with hypofractionated RT (HF-RT) versus conventionally fractionated RT (CF-RT) had significantly fewer maximum fatigue severity or interference scores that were >2 (ie, severe or very severe; 29% vs 10% for severity, and 26% vs 8% for interference, P<.01). Age ≤45 years, presence of psychiatric/pain-related comorbidities, and baseline sadness and anxiety severity were predictive of average and maximum fatigue scores (P<.05), but variables related to treatment intensity (eg, mastectomy vs lumpectomy, chemotherapy use, radiation target volumes) and other host factors (working, children, marital status, proximity to RT facility) were not. CONCLUSION: Patient-reported fatigue modestly increases over RT courses, with less maximum fatigue reported with HF-RT. Younger age and baseline sadness, anxiety, and psychiatric/pain-related comorbidities are powerful predictors of fatigue, whereas other factors, such as treatment intensity, are not. Future studies will investigate interventions for patients at high risk for fatigue.

Multiparametric magnetic resonance imaging for prostate cancer improves Gleason score assessment in favorable risk prostate cancer.

PURPOSE: Magnetic resonance imaging (MRI) guidance may improve the accuracy of Gleason score (GS) determination by directing the biopsy to regions of interest (ROI) that are likely to harbor high-grade prostate cancer (CaP). The aim of this study was to determine the frequency and predictors of GS upgrading when a subsequent MRI-guided biopsy is performed on patients with a diagnosis of GS 6 disease on the basis of conventional, transrectal ultrasound-guided biopsy. METHODS AND MATERIALS: A consecutive series of 245 men with a diagnosis of low-risk CaP (ie, cT1c, GS 6, prostate-specific antigen <10) based on transrectal ultrasound-guided biopsy was enrolled in an active surveillance protocol that used subsequent MRI-guided biopsy for confirmation of GS. ROIs were categorized on a scale of 1 to 5. The Artemis ultrasound-MRI fusion device was used to perform targeted biopsies of ROIs as well as systematic biopsies from a software-based 12-point map. Predictors of GS upgrading were analyzed using univariate and multivariate analyses. RESULTS: Fusion biopsy resulted in 26% of patients having GS upgrading (GS 3+4 in 18%, 4+3 in 5%, and 8-9 in 3%). Of the 72% of patients with ROIs appropriate for targeting, targeted cores upgraded the GS in 18%, whereas systematic cores upgraded the GS in 24%. In patients without targeted biopsy, GS upgrading was seen in 14%. On multivariate analysis, a category 5 ROI was the most significant predictor of GS upgrading with an odds ratio of 10.56 (P < .01). CONCLUSIONS: Nearly 25% of men with GS 6 CaP diagnosed by standard transrectal ultrasound biopsy may experience GS upgrading when a subsequent MRI-ultrasound fusion biopsy is performed. The most important single predictor of upgrading is a category 5 ROI on multiparametric MRI. GS upgrading may influence treatment decisions. Therefore, MRI-guided biopsy should be considered prior to formulating a management strategy in patients whose conventional biopsy reveals low-risk CaP.

Late rectal toxicity after low-dose-rate brachytherapy: incidence, predictors, and management of side effects.

As clinical outcomes for patients with clinically localized prostate cancer continue to improve, patients and physicians are increasing making treatment decisions based on concerns regarding long-term morbidity. A primary concern is late radiation proctitis, a clinical entity embodied by various signs and symptoms, ranging from diarrhea to rectal fistulas. Here, we present a comprehensive literature review examining the clinical manifestations and pathophysiology of late radiation proctitis after low-dose-rate brachytherapy (BT), as well as its incidence and predictors. The long-term risks of rectal bleeding after BT are on the order of 5-7%, whereas the risks of severe ulceration or fistula are on the order of 0.6%. The most robust predictor appears to be the volume of rectum receiving the prescription dose. In certain situations (e.g., salvage setting, for patients with increased radiosensitivity, and following aggressive biopsy after BT), the risk of these severe toxicities may be increased by up to 10-fold. A variety of excellent management options exist for rectal bleeding, with endoscopic methods being the most commonly used.