Radical Prostatectomy, External Beam Radiotherapy, or External Beam Radiotherapy With Brachytherapy Boost and Disease Progression and Mortality in Patients With Gleason Score 9-10 Prostate Cancer.

Importance: The optimal treatment for Gleason score 9-10 prostate cancer is unknown. Objective: To compare clinical outcomes of patients with Gleason score 9-10 prostate cancer after definitive treatment. Design, Setting, and Participants: Retrospective cohort study in 12 tertiary centers (11 in the United States, 1 in Norway), with 1809 patients treated between 2000 and 2013. Exposures: Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy, or EBRT plus brachytherapy boost (EBRT+BT) with androgen deprivation therapy. Main Outcomes and Measures: The primary outcome was prostate cancer-specific mortality; distant metastasis-free survival and overall survival were secondary outcomes. Results: Of 1809 men, 639 underwent RP, 734 EBRT, and 436 EBRT+BT. Median ages were 61, 67.7, and 67.5 years; median follow-up was 4.2, 5.1, and 6.3 years, respectively. By 10 years, 91 RP, 186 EBRT, and 90 EBRT+BT patients had died. Adjusted 5-year prostate cancer-specific mortality rates were RP, 12% (95% CI, 8%-17%); EBRT, 13% (95% CI, 8%-19%); and EBRT+BT, 3% (95% CI, 1%-5%). EBRT+BT was associated with significantly lower prostate cancer-specific mortality than either RP or EBRT (cause-specific HRs of 0.38 [95% CI, 0.21-0.68] and 0.41 [95% CI, 0.24-0.71]). Adjusted 5-year incidence rates of distant metastasis were RP, 24% (95% CI, 19%-30%); EBRT, 24% (95% CI, 20%-28%); and EBRT+BT, 8% (95% CI, 5%-11%). EBRT+BT was associated with a significantly lower rate of distant metastasis (propensity-score-adjusted cause-specific HRs of 0.27 [95% CI, 0.17-0.43] for RP and 0.30 [95% CI, 0.19-0.47] for EBRT). Adjusted 7.5-year all-cause mortality rates were RP, 17% (95% CI, 11%-23%); EBRT, 18% (95% CI, 14%-24%); and EBRT+BT, 10% (95% CI, 7%-13%). Within the first 7.5 years of follow-up, EBRT+BT was associated with significantly lower all-cause mortality (cause-specific HRs of 0.66 [95% CI, 0.46-0.96] for RP and 0.61 [95% CI, 0.45-0.84] for EBRT). After the first 7.5 years, the corresponding HRs were 1.16 (95% CI, 0.70-1.92) and 0.87 (95% CI, 0.57-1.32). No significant differences in prostate cancer-specific mortality, distant metastasis, or all-cause mortality (≤7.5 and >7.5 years) were found between men treated with EBRT or RP (cause-specific HRs of 0.92 [95% CI, 0.67-1.26], 0.90 [95% CI, 0.70-1.14], 1.07 [95% CI, 0.80-1.44], and 1.34 [95% CI, 0.85-2.11]). Conclusions and Relevance: Among patients with Gleason score 9-10 prostate cancer, treatment with EBRT+BT with androgen deprivation therapy was associated with significantly better prostate cancer-specific mortality and longer time to distant metastasis compared with EBRT with androgen deprivation therapy or with RP.

Reduced-dose radiotherapy for human papillomavirus-associated squamous-cell carcinoma of the oropharynx: a single-arm, phase 2 study.

BACKGROUND: Head and neck cancers positive for human papillomavirus (HPV) are exquisitely radiosensitive. We investigated whether chemoradiotherapy with reduced-dose radiation would maintain survival outcomes while improving tolerability for patients with HPV-positive oropharyngeal carcinoma. METHODS: We did a single-arm, phase 2 trial at two academic hospitals in the USA, enrolling patients with newly diagnosed, biopsy-proven stage III or IV squamous-cell carcinoma of the oropharynx, positive for HPV by p16 testing, and with Zubrod performance status scores of 0 or 1. Patients received two cycles of induction chemotherapy with 175 mg/m2 paclitaxel and carboplatin (target area under the curve of 6) given 21 days apart, followed by intensity-modulated radiotherapy with daily image guidance plus 30 mg/m2 paclitaxel per week concomitantly. Complete or partial responders to induction chemotherapy received 54 Gy in 27 fractions, and those with less than partial or no responses received 60 Gy in 30 fractions. The primary endpoint was progression-free survival at 2 years, assessed in all eligible patients who completed protocol treatment. This study is registered with ClinicalTrials.gov, numbers NCT02048020 and NCT01716195. FINDINGS: Between Oct 4, 2012, and March 3, 2015, 45 patients were enrolled with a median age of 60 years (IQR 54-67). One patient did not receive treatment and 44 were included in the analysis. 24 (55%) patients with complete or partial responses to induction chemotherapy received 54 Gy radiation, and 20 (45%) with less than partial responses received 60 Gy. Median follow-up was 30 months (IQR 26-37). Three (7%) patients had locoregional recurrence and one (2%) had distant metastasis; 2-year progression-free survival was 92% (95% CI 77-97). 26 (39%) of 44 patients had grade 3 adverse events, but no grade 4 events were reported. The most common grade 3 events during induction chemotherapy were leucopenia (17 [39%]) and neutropenia (five [11%]), and during chemoradiotherapy were dysphagia (four [9%]) and mucositis (four [9%]). One (2%) of 44 patients was dependent on a gastrostomy tube at 3 months and none was dependent 6 months after treatment. INTERPRETATION: Chemoradiotherapy with radiation doses reduced by 15-20% was associated with high progression-free survival and an improved toxicity profile compared with historical regimens using standard doses. Radiotherapy de-escalation has the potential to improve the therapeutic ratio and long-term function for these patients. FUNDING: University of California.

Utilizing time-driven activity-based costing to understand the short- and long-term costs of treating localized, low-risk prostate cancer.

BACKGROUND: Given the costs of delivering care for men with prostate cancer remain poorly described, this article reports the results of time-driven activity-based costing (TDABC) for competing treatments of low-risk prostate cancer. METHODS: Process maps were developed for each phase of care from the initial urologic visit through 12 years of follow-up for robotic-assisted laparoscopic prostatectomy (RALP), cryotherapy, high-dose rate (HDR) and low-dose rate (LDR) brachytherapy, intensity-modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT), and active surveillance (AS). The last modality incorporated both traditional transrectal ultrasound (TRUS) biopsy and multiparametric-MRI/TRUS fusion biopsy. The costs of materials, equipment, personnel, and space were calculated per unit of time and based on the relative proportion of capacity used. TDABC for each treatment was defined as the sum of its resources. RESULTS: Substantial cost variation was observed at 5 years, with costs ranging from $7,298 for AS to $23,565 for IMRT, and they remained consistent through 12 years of follow-up. LDR brachytherapy ($8,978) was notably cheaper than HDR brachytherapy ($11,448), and SBRT ($11,665) was notably cheaper than IMRT, with the cost savings attributable to shorter procedure times and fewer visits required for treatment. Both equipment costs and an inpatient stay ($2,306) contributed to the high cost of RALP ($16,946). Cryotherapy ($11,215) was more costly than LDR brachytherapy, largely because of increased single-use equipment costs ($6,292 vs $1,921). AS reached cost equivalence with LDR brachytherapy after 7 years of follow-up. CONCLUSIONS: The use of TDABC is feasible for analyzing cancer services and provides insights into cost-reduction tactics in an era focused on emphasizing value. By detailing all steps from diagnosis and treatment through 12 years of follow-up for low-risk prostate cancer, this study has demonstrated significant cost variation between competing treatments.

Does the addition of targeted prostate biopsies to standard systemic biopsies influence treatment management for radiation oncologists?

OBJECTIVES: To study the management impact that magnetic resonance imaging (MRI)-guided targeted prostate biopsies could provide relative to using only non-targeted systematic biopsies in men with clinically localized prostate cancer (PCa). PATIENTS AND METHODS: A consecutive series of untreated men undergoing Artemis (MRI-ultrasonography fusion) biopsies between March 2010 and June 2013 was evaluated in this retrospective, institutional review board-approved study. Fusion biopsy included MRI-targeted and systematic sampling at the same session. 3-Tesla multiparametric MRI was performed at a median of 2 weeks before biopsy. Patients were included if ≥1 systematic core was found to harbour PCa. The impact of the information obtained from targeted vs systematic biopsies was studied with regard to the following: Gleason score (GS), National Comprehensive Cancer Network (NCCN) risk reclassification, cancer core length, percentage of core positive for tumour involvement, and percentage of positive biopsy cores. RESULTS: The study sample included 215 men (mean ± sd age 66 ± 8 years). The median (range) prostate-specific antigen (PSA) was 6.0 (0.7-181) ng/mL. The mean number of total biopsy samples was 18 (12 systematic and six targeted samples). Of 215 men, 34 (16%) had a higher GS on targeted vs systematic biopsy. A total of 21/183 men (12%) were stratified into a higher NCCN risk group when incorporating targeted biopsy GS results and 18/101 men (18%) were upgraded to intermediate- or high-risk from the low-risk group. Among the 34 men whose cancer severity was upgraded, increases in cancer core length, percentage of tumour involvement and percentage of cores involved were all statistically significant (P < 0.01). CONCLUSION: Targeted prostate biopsy provided information about GS, NCCN risk and tumour volume beyond that obtained in systematic biopsies, specifically increasing the proportions of men in the intermediate- and high-risk groups. Such men may be recommended for additional treatments (pelvic nodal irradiation or hormonal therapy). The appropriateness of changing treatment because of targeted biopsy results is still unclear.

Accelerated Hypofractionated Chemoradiation Followed by Stereotactic Ablative Radiotherapy Boost for Locally Advanced, Unresectable Non-Small Cell Lung Cancer: A Nonrandomized Controlled Trial.

Importance: Intrathoracic progression remains the predominant pattern of failure in patients treated with concurrent chemoradiation followed by a consolidation immune checkpoint inhibitor for locally advanced, unresectable non-small cell lung cancer (NSCLC). Objective: To determine the maximum tolerated dose (MTD) and use of hypofractionated concurrent chemoradiation with an adaptive stereotactic ablative radiotherapy (SABR) boost. Design, Setting, and Participants: This was an early-phase, single-institution, radiation dose-escalation nonrandomized controlled trial with concurrent chemotherapy among patients with clinical stage II (inoperable/patient refusal of surgery) or III NSCLC (American Joint Committee on Cancer Staging Manual, seventh edition). Patients were enrolled and treated from May 2011 to May 2018, with a median patient follow-up of 18.2 months. Patients advanced to a higher SABR boost dose if dose-limiting toxic effects (any grade 3 or higher pulmonary, gastrointestinal, or cardiac toxic effects, or any nonhematologic grade 4 or higher toxic effects) occurred in fewer than 33% of the boost cohort within 90 days of follow-up. The current analyses were conducted from January to September 2023. Intervention: All patients first received 4 Gy × 10 fractions followed by an adaptive SABR boost to residual metabolically active disease, consisting of an additional 25 Gy (low, 5 Gy × 5 fractions), 30 Gy (intermediate, 6 Gy × 5 fractions), or 35 Gy (high, 7 Gy × 5 fractions) with concurrent weekly carboplatin/paclitaxel. Main Outcome and Measure: The primary outcome was to determine the MTD. Results: Data from 28 patients (median [range] age, 70 [51-88] years; 16 [57%] male; 24 [86%] with stage III disease) enrolled across the low- (n = 10), intermediate- (n = 9), and high- (n = 9) dose cohorts were evaluated. The protocol-specified MTD was not exceeded. The incidences of nonhematologic acute and late (>90 days) grade 3 or higher toxic effects were 11% and 7%, respectively. No grade 3 toxic effects were observed in the intermediate-dose boost cohort. Two deaths occurred in the high-dose cohort. Two-year local control was 74.1%, 85.7%, and 100.0% for the low-, intermediate-, and high-dose cohorts, respectively. Two-year overall survival was 30.0%, 76.2%, and 55.6% for the low-, intermediate-, and high-dose cohorts, respectively. Conclusions and Relevance: This early-phase, dose-escalation nonrandomized controlled trial showed that concurrent chemoradiation with an adaptive SABR boost to 70 Gy in 15 fractions with concurrent chemotherapy is a safe and effective regimen for patients with locally advanced, unresectable NSCLC. Trial Registration: ClinicalTrials.gov Identifier: NCT01345851.

Radiation Therapy for Prostate Cancer Using HYpofractionation Directed by UltraSound (RAPHYDUS): A Brazilian Public Health Care System Study.

PURPOSE: This study evaluated the toxicity associated with a short course dose-escalated hypofractionated radiation therapy (HFRT) using image guided RT with or without androgen suppression therapy in patients with prostate cancer. METHODS AND MATERIALS: This single-center prospective observational study included 132 patients with prostate cancer from 2016 to 2020. Patients received HFRT using image guided RT (84%) with 3-dimensional (91%) or intensity modulated RT (9%). Total prescribed doses were 66 Gy (63%), 63 Gy (12%), and 60 Gy (24%) in 22, 21, or 20 daily fractions depending on organ-at-risk dose constraints. Acute toxicity was scored using Radiation Therapy Oncology Group criteria and the international prostate symptom index. The expanded prostate cancer index composite questionnaire was used to collect quality of life data (ranging from 0-100). RESULTS: The study population consisted of 111 patients who completed RT during a period of 3 years. The risk groups were as follows: low risk (12%), intermediate (32%), and high (56%). None of the patients had suspicious lymph nodes. Ninety percent received androgen suppression therapy. Maximum acute genitourinary and gastrointestinal toxicity peaked at grade 3 in 4 of 111 evaluated patients (4%) and at grade 2 in 7 of 111 evaluated patients (8%), respectively. The average international prostate symptom score increased from 4.8 at pretreatment to 14.0 during week 4 and normalized (5.7) 3 months after treatment completion. CONCLUSIONS: The current HFRT dose-escalation trial has demonstrated the feasibility of administering 66 Gy in 22 fractions with low acute gastrointestinal and genitourinary toxicities. Further follow-up will report late toxicities and outcomes.

Identifying the Best Candidates for Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography as the Primary Staging Approach Among Men with High-risk Prostate Cancer and Negative Conventional Imaging.

Prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) is an emerging imaging modality with greater sensitivity and specificity over conventional imaging for prostate cancer (PCa) staging. Using data from two prospective trials (NCT03368547 and NCT04050215), we explored predictors of overall upstaging (nodal and metastatic) by PSMA PET/CT among patients with cN0M0 National Comprehensive Cancer Network high-risk PCa on conventional imaging (n = 213). Overall, 21.1%, 8.9%, and 23.9% of patients experienced nodal, metastatic, and overall upstaging, respectively, without histologic confirmation. On multivariable analysis, Gleason grade group (GG) and percent positive core (PPC) on systematic biopsy significantly predict overall upstaging (odds ratio [OR] 2.15, 95% confidence interval [CI] 1.33-3.45; p = 0.002; and OR 1.03, 95% CI 1.01-1.04; p < 0.001). Overall upstaging was significantly more frequent among men with GG 5 disease (33.0% vs. 17.6%; p = 0.0097) and PPC ≥50% (33.0% vs 15.0%; p = 0.0020). We constructed a nomogram that predicts overall upstaging using initial prostate-specific antigen, PPC, GG, and cT stage, with coefficients estimated from a standard logistic regression model (using maximum likelihood estimation). It is internally validated with a tenfold cross-validated area under the receiver operating characteristic curve estimated at 0.74 (95% CI 0.67-0.82). In our cohort, 90% of patients who had a nomogram-estimated risk below the cutoff of 22% for overall upstaging could have been spared PSMA PET/CT as our model correctly predicted no upstaging. In other words, the predictive model only missed 10% of patients who would otherwise have benefitted from PSMA PET/CT. PATIENT SUMMARY: We analyzed predictors of overall upstaging (lymph node or/and metastasis) by prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) from conventional imaging in men with high-risk prostate cancer undergoing initial staging deemed free of disease in the lymph nodes and distant metastasis by conventional imaging techniques. We found that the pathologic grade and disease burden in a prostate biopsy are associated with upstaging. We also developed a tool that predicts the probability of upstaging according to an individual patient's characteristics. Our study may help in defining patient groups who are most likely to benefit from the addition of a PSMA PET/CT scan.

Interplay Between Duration of Androgen Deprivation Therapy and External Beam Radiotherapy With or Without a Brachytherapy Boost for Optimal Treatment of High-risk Prostate Cancer: A Patient-Level Data Analysis of 3 Cohorts.

IMPORTANCE: Radiotherapy combined with androgen deprivation therapy (ADT) is a standard of care for high-risk prostate cancer. However, the interplay between radiotherapy dose and the required minimum duration of ADT is uncertain. OBJECTIVE: To determine the specific ADT duration threshold that provides a distant metastasis-free survival (DMFS) benefit in patients with high-risk prostate cancer receiving external beam radiotherapy (EBRT) or EBRT with a brachytherapy boost (EBRT+BT). DESIGN, SETTINGS, AND PARTICIPANTS: This was a cohort study of 3 cohorts assembled from a multicenter retrospective study (2000-2013); a post hoc analysis of the Randomized Androgen Deprivation and Radiotherapy 03/04 (RADAR; 2003-2007) randomized clinical trial (RCT); and a cross-trial comparison of the RADAR vs the Deprivación Androgénica y Radio Terapía (Androgen Deprivation and Radiation Therapy; DART) 01/05 RCT (2005-2010). In all, the study analyzed 1827 patients treated with EBRT and 1108 patients treated with EBRT+BT from the retrospective cohort; 181 treated with EBRT and 203 with EBRT+BT from RADAR; and 91 patients treated with EBRT from DART. The study was conducted from October 15, 2020, to July 1, 2021, and the data analyses, from January 5 to June 15, 2021. EXPOSURES: High-dose EBRT or EBRT+BT for an ADT duration determined by patient-physician choice (retrospective) or by randomization (RCTs). MAIN OUTCOMES AND MEASURES: The primary outcome was DMFS; secondary outcome was overall survival (OS). Natural cubic spline analysis identified minimum thresholds (months). RESULTS: This cohort study of 3 studies totaling 3410 men (mean age [SD], 68 [62-74] years; race and ethnicity not collected) with high-risk prostate cancer found a significant interaction between the treatment type (EBRT vs EBRT+BT) and ADT duration (binned to <6, 6 to <18, and ≥18 months). Natural cubic spline analysis identified minimum duration thresholds of 26.3 months (95% CI, 25.4-36.0 months) for EBRT and 12 months (95% CI, 4.9-36.0 months) for EBRT+BT for optimal effect on DMFS. In RADAR, the prolongation of ADT for patients receiving only EBRT was not associated with significant improvements in DMFS (hazard ratio [HR], 1.01; 95% CI, 0.65-1.57); however, for patients receiving EBRT+BT, a longer duration was associated with improved DMFS (DMFS HR, 0.56; 95% CI, 0.36-0.87; P = .01). For patients receiving EBRT alone (DART), 28 months of ADT was associated with improved DMFS compared with 18 months (RADAR HR, 0.37; 95% CI, 0.17-0.80; P = .01). CONCLUSIONS AND RELEVANCE: These cohort study findings suggest that the optimal minimum ADT duration for treatment with high-dose EBRT alone is more than 18 months; and for EBRT+BT, it is 18 months or possibly less. Additional studies are needed to determine more precise minimum durations.

Expanding the use of real-time electromagnetic tracking in radiation oncology.

In the past 10 years, techniques to improve radiotherapy delivery, such as intensity-modulated radiation therapy (IMRT), image-guided radiation therapy (IGRT) for both inter- and intrafraction tumor localization, and hypofractionated delivery techniques such as stereotactic body radiation therapy (SBRT), have evolved tremendously. This review article focuses on only one part of that evolution, electromagnetic tracking in radiation therapy. Electromagnetic tracking is still a growing technology in radiation oncology and, as such, the clinical applications are limited, the expense is high, and the reimbursement is insufficient to cover these costs. At the same time, current experience with electromagnetic tracking applied to various clinical tumor sites indicates that the potential benefits of electromagnetic tracking could be significant for patients receiving radiation therapy. Daily use of these tracking systems is minimally invasive and delivers no additional ionizing radiation to the patient, and these systems can provide explicit tumor motion data. Although there are a number of technical and fiscal issues that need to be addressed, electromagnetic tracking systems are expected to play a continued role in improving the precision of radiation delivery.

Visualization of 3D volumetric lung dynamics for real-time external beam lung radiotherapy.

This paper reports on the usage of physics-based 3D volumetric lung dynamic models for visualizing and monitoring the radiation dose deposited on the lung of a human subject during lung radiotherapy. The dynamic model of each subject is computed from a 4D Computed Tomography (4DCT) imaging acquired before the treatment. The 3D lung deformation and the radiation dose deposited are computed using Graphics Processing Units (GPU). Additionally, using the dynamic lung model, the airflow inside the lungs during the treatment is also investigated. Results show the radiation dose deposited on the lung tumor as well as the surrounding tissues, the combination of which is patient-specific and varies from one treatment fraction to another.

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.

Stereotactic Body Radiotherapy for High-Risk Localized Carcinoma of the Prostate (SHARP) Consortium: Analysis of 344 Prospectively Treated Patients.

PURPOSE: To explore the efficacy and toxicity of stereotactic body radiation therapy (SBRT) in high-risk prostate cancer (HRPCa) in a consortium of 7 institutional phase 2 trials and prospective registries. METHODS AND MATERIALS: Individual patient data were pooled for 344 patients with a minimum follow-up of 24 months. Biochemical recurrence-free survival (BCRFS) and distant metastasis-free survival (DMFS) were estimated using a Kaplan-Meier framework. Fine and Gray competing risk and Cox proportional hazards regression models were developed to assess the association between time to BCR and time to distant metastasis and prespecified variables of interest. Logistic regression models were developed to evaluate associations between acute and late grade ≥2 genitourinary and gastrointestinal and the following a priori-specified variables: age, dose per fraction, ADT use, and nodal radiation therapy. RESULTS: Median follow-up was 49.5 months. Seventy-two percent of patients received ADT, with a median duration of 9 months, and 19% received elective nodal radiation therapy. Estimated 4-year BCRFS and DMFS rates were 81.7% (95% CI, 77.2%-86.5%) and 89.1% (95% CI, 85.3%-93.1%). The crude incidences of late grade ≥3 genitourinary and gastrointestinal toxicity were 2.3% and 0.9%. CONCLUSIONS: These data support a favorable toxicity and efficacy profile for SBRT for HRPCa. Further prospective studies are needed to evaluate the optimal dose and target volume in the context of SBRT for HRPCa.

The intraprostatic immune environment after stereotactic body radiotherapy is dominated by myeloid cells.

BACKGROUND: Hundreds of ongoing clinical trials combine radiation therapy, mostly delivered as stereotactic body radiotherapy (SBRT), with immune checkpoint blockade. However, our understanding of the effect of radiotherapy on the intratumoral immune balance is inadequate, hindering the optimal design of trials that combine radiation therapy with immunotherapy. Our objective was to characterize the intratumoral immune balance of the malignant prostate after SBRT in patients. METHODS: Sixteen patients with high-risk, non-metastatic prostate cancer at comparable Gleason Grade disease underwent radical prostatectomy with (n = 9) or without (n = 7) neoadjuvant SBRT delivered in three fractions of 8 Gy over 5 days completed 2 weeks before surgery. Freshly resected prostate specimens were processed to obtain single-cell suspensions, and immune-phenotyped for major lymphoid and myeloid cell subsets by staining with two separate 14-antibody panels and multicolor flow cytometry analysis. RESULTS: Malignant prostates 2 weeks after SBRT had an immune infiltrate dominated by myeloid cells, whereas malignant prostates without preoperative treatment were more lymphoid-biased (myeloid CD45+ cells 48.4 ± 19.7% vs. 25.4 ± 7.0%; adjusted p-value = 0.11; and CD45+ lymphocytes 51.6 ± 19.7% vs. 74.5 ± 7.0%; p = 0.11; CD3+ T cells 35.2 ± 23.8% vs. 60.9 ± 9.7%; p = 0.12; mean ± SD). CONCLUSION: SBRT drives a significant lymphoid to myeloid shift in the prostate-tumor immune infiltrate. This may be of interest when combining SBRT with immunotherapies, particularly in prostate cancer.

Comparison of Multimodal Therapies and Outcomes Among Patients With High-Risk Prostate Cancer With Adverse Clinicopathologic Features.

Importance: The optimal management strategy for high-risk prostate cancer and additional adverse clinicopathologic features remains unknown. Objective: To compare clinical outcomes among patients with high-risk prostate cancer after definitive treatment. Design, Setting, and Participants: This retrospective cohort study included patients with high-risk prostate cancer (as defined by the National Comprehensive Cancer Network [NCCN]) and at least 1 adverse clinicopathologic feature (defined as any primary Gleason pattern 5 on biopsy, clinical T3b-4 disease, ≥50% cores with biopsy results positive for prostate cancer, or NCCN ≥2 high-risk features) treated between 2000 and 2014 at 16 tertiary centers. Data were analyzed in November 2020. Exposures: Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy (ADT), or EBRT plus brachytherapy boost (BT) with ADT. Guideline-concordant multimodal treatment was defined as RP with appropriate use of multimodal therapy (optimal RP), EBRT with at least 2 years of ADT (optimal EBRT), or EBRT with BT with at least 1 year ADT (optimal EBRT with BT). Main Outcomes and Measures: The primary outcome was prostate cancer-specific mortality; distant metastasis was a secondary outcome. Differences were evaluated using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression models. Results: A total of 6004 men (median [interquartile range] age, 66.4 [60.9-71.8] years) with high-risk prostate cancer were analyzed, including 3175 patients (52.9%) who underwent RP, 1830 patients (30.5%) who underwent EBRT alone, and 999 patients (16.6%) who underwent EBRT with BT. Compared with RP, treatment with EBRT with BT (subdistribution hazard ratio [sHR] 0.78, [95% CI, 0.63-0.97]; P = .03) or with EBRT alone (sHR, 0.70 [95% CI, 0.53-0.92]; P = .01) was associated with significantly improved prostate cancer-specific mortality; there was no difference in prostate cancer-specific mortality between EBRT with BT and EBRT alone (sHR, 0.89 [95% CI, 0.67-1.18]; P = .43). No significant differences in prostate cancer-specific mortality were found across treatment cohorts among 2940 patients who received guideline-concordant multimodality treatment (eg, optimal EBRT alone vs optimal RP: sHR, 0.76 [95% CI, 0.52-1.09]; P = .14). However, treatment with EBRT alone or EBRT with BT was consistently associated with lower rates of distant metastasis compared with treatment with RP (eg, EBRT vs RP: sHR, 0.50 [95% CI, 0.44-0.58]; P < .001). Conclusions and Relevance: These findings suggest that among patients with high-risk prostate cancer and additional unfavorable clinicopathologic features receiving guideline-concordant multimodal therapy, prostate cancer-specific mortality outcomes were equivalent among those treated with RP, EBRT, and EBRT with BT, although distant metastasis outcomes were more favorable among patients treated with EBRT and EBRT with BT. Optimal multimodality treatment is critical for improving outcomes in patients with high-risk prostate cancer.

Patterns of Clinical Progression in Radiorecurrent High-risk Prostate Cancer.

The natural history of radiorecurrent high-risk prostate cancer (HRPCa) is not well-described. To better understand its clinical course, we evaluated rates of distant metastases (DM) and prostate cancer-specific mortality (PCSM) in a cohort of 978 men with radiorecurrent HRPCa who previously received either external beam radiation therapy (EBRT, n = 654, 67%) or EBRT + brachytherapy (EBRT + BT, n = 324, 33%) across 15 institutions from 1997 to 2015. In men who did not die, median follow-up after treatment was 8.9 yr and median follow-up after biochemical recurrence (BCR) was 3.7 yr. Local and systemic therapy salvage, respectively, were delivered to 21 and 390 men after EBRT, and eight and 103 men after EBRT + BT. Overall, 435 men developed DM, and 248 were detected within 1 yr of BCR. Measured from time of recurrence, 5-yr DM rates were 50% and 34% after EBRT and EBRT + BT, respectively. Measured from BCR, 5-yr PCSM rates were 27% and 29%, respectively. Interval to BCR was independently associated with DM (p < 0.001) and PCSM (p < 0.001). These data suggest that radiorecurrent HRPCa has an aggressive natural history and that DM is clinically evident early after BCR. These findings underscore the importance of further investigations into upfront risk assessment and prompt systemic evaluation upon recurrence in HRPCa. PATIENT SUMMARY: High-risk prostate cancer that recurs after radiation therapy is an aggressive disease entity and spreads to other parts of the body (metastases). Some 60% of metastases occur within 1 yr. Approximately 30% of these patients die from their prostate cancer.

Performance of a Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography-Derived Risk-Stratification Tool for High-risk and Very High-risk Prostate Cancer.

Importance: Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) can detect low-volume, nonlocalized (ie, regional or metastatic) prostate cancer that was occult on conventional imaging. However, the long-term clinical implications of PSMA PET/CT upstaging remain unclear. Objectives: To evaluate the prognostic significance of a nomogram that models an individual's risk of nonlocalized upstaging on PSMA PET/CT and to compare its performance with existing risk-stratification tools. Design, Setting, and Participants: This cohort study included patients diagnosed with high-risk or very high-risk prostate cancer (ie, prostate-specific antigen [PSA] level >20 ng/mL, Gleason score 8-10, and/or clinical stage T3-T4, without evidence of nodal or metastatic disease by conventional workup) from April 1995 to August 2018. This multinational study was conducted at 15 centers. Data were analyzed from December 2020 to March 2021. Exposures: Curative-intent radical prostatectomy (RP), external beam radiotherapy (EBRT), or EBRT plus brachytherapy (BT), with or without androgen deprivation therapy. Main Outcomes and Measures: PSMA upstage probability was calculated from a nomogram using the biopsy Gleason score, percentage positive systematic biopsy cores, clinical T category, and PSA level. Biochemical recurrence (BCR), distant metastasis (DM), prostate cancer-specific mortality (PCSM), and overall survival (OS) were analyzed using Fine-Gray and Cox regressions. Model performance was quantified with the concordance (C) index. Results: Of 5275 patients, the median (IQR) age was 66 (60-72) years; 2883 (55%) were treated with RP, 1669 (32%) with EBRT, and 723 (14%) with EBRT plus BT; median (IQR) PSA level was 10.5 (5.9-23.2) ng/mL; 3987 (76%) had Gleason grade 8 to 10 disease; and 750 (14%) had stage T3 to T4 disease. Median (IQR) follow-up was 5.1 (3.1-7.9) years; 1221 (23%) were followed up for at least 8 years. Overall, 1895 (36%) had BCR, 851 (16%) developed DM, and 242 (5%) died of prostate cancer. PSMA upstage probability was significantly prognostic of all clinical end points, with 8-year C indices of 0.63 (95% CI, 0.61-0.65) for BCR, 0.69 (95% CI, 0.66-0.71) for DM, 0.71 (95% CI, 0.67-0.75) for PCSM, and 0.60 (95% CI, 0.57-0.62) for PCSM (P < .001). The PSMA nomogram outperformed existing risk-stratification tools, except for similar performance to Staging Collaboration for Cancer of the Prostate (STAR-CAP) for PCSM (eg, DM: PSMA, 0.69 [95% CI, 0.66-0.71] vs STAR-CAP, 0.65 [95% CI, 0.62-0.68]; P < .001; Memorial Sloan Kettering Cancer Center nomogram, 0.57 [95% CI, 0.54-0.60]; P < .001; Cancer of the Prostate Risk Assessment groups, 0.53 [95% CI, 0.51-0.56]; P < .001). Results were validated in secondary cohorts from the Surveillance, Epidemiology, and End Results database and the National Cancer Database. Conclusions and Relevance: These findings suggest that PSMA upstage probability is associated with long-term, clinically meaningful end points. Furthermore, PSMA upstaging had superior risk discrimination compared with existing tools. Formerly occult, PSMA PET/CT-detectable nonlocalized disease may be the main driver of outcomes in high-risk patients.

Dose-response with stereotactic body radiotherapy for prostate cancer: A multi-institutional analysis of prostate-specific antigen kinetics and biochemical control.

BACKGROUND AND PURPOSE: The optimal dose for prostate stereotactic body radiotherapy (SBRT) is still unknown. This study evaluated the dose-response relationships for prostate-specific antigen (PSA) decay and biochemical recurrence (BCR) among 4 SBRT dose regimens. MATERIALS AND METHODS: In 1908 men with low-risk (50.0%), favorable intermediate-risk (30.9%), and unfavorable intermediate-risk (19.1%) prostate cancer treated with prostate SBRT across 8 institutions from 2003 to 2018, we examined 4 regimens (35 Gy/5 fractions [35/5, n = 265, 13.4%], 36.25 Gy/5 fractions [36.25/5, n = 711, 37.3%], 40 Gy/5 fractions [40/5, n = 684, 35.8%], and 38 Gy/4 fractions [38/4, n = 257, 13.5%]). Between dose groups, we compared PSA decay slope, nadir PSA (nPSA), achievement of nPSA ≤0.2 and ≤0.5 ng/mL, and BCR-free survival (BCRFS). RESULTS: Median follow-up was 72.3 months. Median nPSA was 0.01 ng/mL for 38/4, and 0.17-0.20 ng/mL for 5-fraction regimens (p < 0.0001). The 38/4 cohort demonstrated the steepest PSA decay slope and greater odds of nPSA ≤0.2 ng/mL (both p < 0.0001 vs. all other regimens). BCR occurred in 6.25%, 6.75%, 3.95%, and 8.95% of men treated with 35/5, 36.25/5, 40/5, and 38/4, respectively (p = 0.12), with the highest BCRFS after 40/5 (vs. 35/5 hazard ratio [HR] 0.49, p = 0.026; vs. 36.25/5 HR 0.42, p = 0.0005; vs. 38/4 HR 0.55, p = 0.037) including the entirety of follow-up, but not for 5-year BCRFS (≥93% for all regimens, p ≥ 0.21). CONCLUSION: Dose-escalation was associated with greater prostate ablation and PSA decay. Dose-escalation to 40/5, but not beyond, was associated with improved BCRFS. Biochemical control remains excellent, and prospective studies will provide clarity on the benefit of dose-escalation.

Comparison of transabdominal ultrasound and electromagnetic transponders for prostate localization.

The aim of this study is to compare two methodologies of prostate localization in a large cohort of patients. Daily prostate localization using B-mode ultrasound has been performed at the Nebraska Medical Center since 2000. More recently, a technology using electromagnetic transponders implanted within the prostate was introduced into our clinic (Calypso(R)). With each technology, patients were localized initially using skin marks. Localization error distributions were determined from offsets between the initial setup positions and those determined by ultrasound or Calypso. Ultrasound localization data was summarized from 16619 imaging sessions spanning 7 years; Calypso localization data consists of 1524 fractions in 41 prostate patients treated in the course of a clinical trial at five institutions and 640 localizations from the first 16 patients treated with our clinical system. Ultrasound and Calypso patients treated between March and September 2007 at the Nebraska Medical Center were analyzed and compared, allowing a single institutional comparison of the two technologies. In this group of patients, the isocenter determined by ultrasound-based localization is on average 5.3 mm posterior to that determined by Calypso, while the systematic and random errors and PTV margins calculated from the ultrasound localizations were 3 - 4 times smaller than those calculated from the Calypso localizations. Our study finds that there are systematic differences between Calypso and ultrasound for prostate localization.