The expanding role of radiation oncology across the prostate cancer continuum.

Radiotherapy is used in the treatment of prostate cancer in a variety of disease states with significant reliance on imaging to guide clinical decision-making and radiation delivery. In the definitive setting, the choice of radiotherapy treatment modality, dose, and fractionation for localized prostate cancer is determined by the patient's initial risk stratification and other clinical considerations. Radiation is also an option as salvage therapy in patients with locoregionally recurrent disease after prior definitive radiation or surgery. In recent years, the role of radiation has expanded for patients with metastatic disease, including prostate-directed radiotherapy in de novo low volume metastatic disease, metastasis-directed therapy for oligorecurrent disease, and palliative management of symptomatic metastases in the advanced setting. Here we review the expanding role of radiation in the treatment of prostate cancer in the definitive, locoregionally recurrent, and metastatic settings, as well as highlight the role of imaging in clinical reasoning, radiation planning, and treatment delivery.

Patterns of chemotherapy use with primary radiotherapy for localized bladder cancer in patients 65 or older.

Introduction: Bladder preservation with concurrent chemoradiotherapy after maximum transurethral resection of bladder tumor is an alternative to radical cystectomy in select patients with muscle invasive bladder cancer (MIBC). Concurrent administration of radio-sensitizing chemotherapy and radiation therapy (RT) has been shown to have superior disease control compared with RT alone and can often be administered with modest added toxicity. We sought to describe national patterns of chemotherapy use. Methods: The linked surveillance, epidemiology, and end results (SEER)-Medicare database was used to identify patients with cT2-4, N0/X, M0/X BC who received radiation between 2004 and 2018. Data on demographics, clinicopathologic factors, therapy and outcomes were extracted. Concurrent utilization of chemotherapy with RT was also identified (CRT). Multivariate logistic regression (MVA) models were used to explore factors associated with receipt of chemotherapy and overall survival (OS). Results: 2190 patients met inclusion criteria. Of these, 850 (38.8%) received no chemotherapy. Among those receiving chemotherapy, the most frequent regimens were single agent carboplatin, cisplatin, or gemcitabine. Factors that were independently associated with decreased likelihood of chemotherapy use were increasing age (OR 0.93, CI 0.92 - 0.95), Hispanic race (compared with White, OR 0.62, CI 0.39 - 0.99), cT3 or T4 (compared with cT2, OR 0.70, CI 0.55 - 0.90), and lower National Cancer Institute comorbidity index (OR 0.60, CI 0.51 - 0.70) (p < 0.05). Variables independently associated with increased likelihood of receipt of chemotherapy were married status (OR 1.28, CI 1.06 - 1.54), higher socioeconomic status (OR 1.31, CI 1.06 - 1.64), and later year of diagnosis (OR 1.09, CI 1.06 - 1.12). Receipt of concurrent chemotherapy with RT was associated with superior OS compared with RT alone. Conclusion: Over a third of patients >/65 years old receiving curative-intent RT for MIBC do not receive concurrent chemotherapy. Considering the improvement in oncologic outcomes with CRT over RT alone and more options, such as low dose gemcitabine which can be administered with modest toxicity, efforts are needed to identify barriers to utilization and increase the use of radio-sensitizing chemotherapy.

Prostate-specific membrane antigen-positron emission tomography (PSMA-PET) of prostate cancer: current and emerging applications.

Prostate-specific membrane antigen-positron emission tomography (PSMA-PET) is transforming the management of patients with prostate cancer. In appropriately selected patients, PSMA-PET offers superior sensitivity and specificity compared to conventional imaging (e.g., computed tomography and bone scintigraphy) as well as choline and fluciclovine PET, with the added benefit of consolidating bone and soft tissue evaluation into a single study. Despite being a newly available imaging tool, PSMA-PET has established indications, interpretation guidelines, and reporting criteria, which will be reviewed. The prostate cancer care team, from imaging specialists to those delivering treatment, should have knowledge of physiologic PSMA radiotracer uptake, patterns of disease spread, and the strengths and limitations of PSMA-PET. In this review, current and emerging applications of PSMA-PET, including appropriateness use criteria as well as image interpretation and pitfalls, will be provided with an emphasis on clinical implications.

Addressing gaps in healthcare provider knowledge regarding germline testing for prostate cancer through development and testing of a virtual genetics board.

BACKGROUND: Germline testing is important in prostate cancer and evaluation can be complex. METHODS: We instituted a monthly multi-disciplinary virtual genetics tumor board (7/2021-3/2022). Participants and panelists were surveyed on usefulness and acceptability. RESULTS: 101 participants attended a session, and 77 follow-up surveys were completed. Over 90% participants and 100% panelists endorsed usefulness of the case discussions and usability of the technology. The majority felt it provided new information they will use. CONCLUSIONS: A multidisciplinary genetics board was successfully developed to address complexity in prostate cancer genetics. The virtual platform may enhance dissemination of expertise where there are regional gaps.

Framework for Radiation Oncology Department-wide Evaluation and Implementation of Commercial Artificial Intelligence Autocontouring.

PURPOSE: Artificial intelligence (AI)-based autocontouring in radiation oncology has potential benefits such as standardization and time savings. However, commercial AI solutions require careful evaluation before clinical integration. We developed a multidimensional evaluation method to test pretrained AI-based automated contouring solutions across a network of clinics. METHODS AND MATERIALS: Curated data included 121 patient planning computed tomography (CT) scans with a total of 859 clinically approved contours used for treatment from 4 clinics. Regions of interest (ROIs) were generated with 3 commercial AI-based automated contouring software solutions (AI1, AI2, AI3) spanning the following disease sites: brain, head and neck (H&N), thorax, abdomen, and pelvis. Quantitative agreement between AI-generated and clinical contours was measured by Dice similarity coefficient (DSC) and Hausdorff distance (HD). Qualitative assessment was performed by multiple experts scoring blinded AI-contours using a Likert scale. Workflow and usability surveying was also conducted. RESULTS: AI1, AI2, and AI3 contours had high quantitative agreement in 27.8%, 32.8%, and 34.1% of cases (DSC >0.9), performing well in pelvis (median DSC = 0.86/0.88/0.91) and thorax (median DSC = 0.91/0.89/0.91). All 3 solutions had low quantitative agreement in 7.4%, 8.8%, and 6.1% of cases (DSC <0.5), performing worse in brain (median DSC = 0.65/0.78/0.75) and H&N (median DSC = 0.76/0.80/0.81). Qualitatively, AI1 and AI2 contours were acceptable (rated 1-2) with at most minor edits in 70.7% and 74.6% of ROIs (2906 ratings), higher for abdomen (AI1: 79.2%) and thorax (AI2: 90.2%), and lower for H&N (29.0/35.6%). An end-user survey showed strong user preference for full automation and mixed preferences for accuracy versus total number of structures generated. CONCLUSIONS: Our evaluation method provided a comprehensive analysis of both quantitative and qualitative measures of commercially available pretrained AI autocontouring algorithms. The evaluation framework served as a roadmap for clinical integration that aligned with user workflow preference.

The Judicious Use of Stereotactic Ablative Radiotherapy in the Primary Management of Localized Renal Cell Carcinoma.

Localized renal cell carcinoma is primarily managed surgically, but this disease commonly presents in highly comorbid patients who are poor operative candidates. Less invasive techniques, such as cryoablation and radiofrequency ablation, are effective, but require percutaneous or laparoscopic access, while generally being limited to cT1a tumors without proximity to the renal pelvis or ureter. Active surveillance is another management option for small renal masses, but many patients desire treatment or are poor candidates for active surveillance. For poor surgical candidates, a growing body of evidence supports stereotactic ablative radiotherapy (SABR) as a safe and effective non-invasive treatment modality. For example, a recent multi-institution individual patient data meta-analysis of 190 patients managed with SABR estimated a 5.5% five-year cumulative incidence of local failure with one patient experiencing grade 4 toxicity, and no other grade ≥3 toxic events. Here, we discuss the recent developments in SABR for the management of localized renal cell carcinoma, highlighting key concepts of appropriate patient selection, treatment design, treatment delivery, and response assessment.

Radiomic Analysis to Predict Histopathologically Confirmed Pseudoprogression in Glioblastoma Patients.

Purpose: Pseudoprogression mimicking recurrent glioblastoma remains a diagnostic challenge that may adversely confound or delay appropriate treatment or clinical trial enrollment. We sought to build a radiomic classifier to predict pseudoprogression in patients with primary isocitrate dehydrogenase wild type glioblastoma. Methods and Materials: We retrospectively examined a training cohort of 74 patients with isocitrate dehydrogenase wild type glioblastomas with brain magnetic resonance imaging including dynamic contrast enhanced T1 perfusion before resection of an enhancing lesion indeterminate for recurrent tumor or pseudoprogression. A recursive feature elimination random forest classifier was built using nested cross-validation without and with O6-methylguanine-DNA methyltransferase status to predict pseudoprogression. Results: A classifier constructed with cross-validation on the training cohort achieved an area under the receiver operating curve of 81% for predicting pseudoprogression. This was further improved to 89% with the addition of O6-methylguanine-DNA methyltransferase status into the classifier. Conclusions: Our results suggest that radiomic analysis of contrast T1-weighted images and magnetic resonance imaging perfusion images can assist the prompt diagnosis of pseudoprogression. Validation on external and independent data sets is necessary to verify these advanced analyses, which can be performed on routinely acquired clinical images and may help inform clinical treatment decisions.

Prostate and metastasis-directed focal therapy in prostate cancer: hype or hope?

INTRODUCTION: The paradigm of focal therapy's role in metastatic patients is being challenged by evolving attitudes and emerging data. At the current time, specifically regarding prostate cancer, does the evidence indicate this is more hype or hope? AREAS COVERED: We searched the literature via PubMed, MEDLINE, and Embase for studies from 2014 to the present addressing focal therapy with non-palliative intent in metastatic prostate cancer patients, emphasizing prospective trials when available. We sought to address all common clinical scenarios: de novo synchronous diagnosis, oligorecurrence, oligoprogression, and mCRPC disease. EXPERT OPINION: Current evidence is strongest, and in our opinion practice-changing, for prostate-directed RT in de novo metastatic patients with low metastatic burden. Metastasis-directed therapy with SBRT is consistently shown to have low rates of toxicity, and promising rates of ADT-free survival and progression-free survival. These can be utilized on a patient-by-patient basis with these endpoints in mind, but do not yet show sufficient benefit to be standard of care. This is a rich area of ongoing research, and many trials should publish in the coming years to shed light on many unanswered questions, including the role of cytoreductive prostatectomy, systemic therapy combined with MDT, and the integration of modern PET imaging.

A Prospective Study of a Resorbable Intravesical Fiducial Marker for Bladder Cancer Radiation Therapy.

Purpose: We conducted a prospective pilot study to evaluate safety and feasibility of TraceIT, a resorbable radiopaque hydrogel, to improve image guidance for bladder cancer radiation therapy (RT). Methods and Materials: Patients with muscle invasive bladder cancer receiving definitive RT were eligible. TraceIT was injected intravesically around the tumor bed during maximal transurethral resection of bladder tumor. The primary endpoint was the difference between radiation treatment planning margin on daily cone beam computed tomography based on alignment to TraceIT versus standard-of-care pelvic bone anatomy. The Van Herk margin formula was used to determine the optimal planning target volume margin. TraceIT visibility, recurrence rates, and survival were estimated by Kaplan-Meier method. Toxicity was measured by Common Terminology Criteria for Adverse Events version 4.03. Results: The trial was fully accrued and 15 patients were analyzed. TraceIT was injected in 4 sites/patient (range, 4-6). Overall, 94% (95% confidence interval [CI], 90%-98%) of injection sites were radiographically visible at RT initiation versus 71% (95% CI, 62%-81%) at RT completion. The median duration of radiographic visibility for injection sites was 106 days (95% CI, 104-113). Most patients were treated with a standard split-course approach with initial pelvic radiation fields, then midcourse repeat transurethral resection of bladder tumor followed by bladder tumor bed boost fields, and 14/15 received concurrent chemotherapy. Alignment to fiducials could allow for reduced planning target volume margins (0.67 vs 1.56 cm) for the initial phase of RT, but not for the boost (1.01 vs 0.96 cm). This allowed for improved target coverage (D95% 80%-83% to 91%-94%) for 2 patients retrospectively planned with both volumetric-modulated arc therapy and 3-dimensional conformal RT. At median follow-up of 22 months, no acute or late complications attributable to TraceIT placement occurred. No patients required salvage cystectomy. Conclusions: TraceIT intravesical fiducial placement is safe and feasible and may facilitate tumor bed delineation and targeting in patients undergoing RT for localized muscle invasive bladder cancer. Improved image guided treatment may facilitate strategies to improve local control and minimize toxicity.

Pan-cancer Analysis of CDK12 Alterations Identifies a Subset of Prostate Cancers with Distinct Genomic and Clinical Characteristics.

BACKGROUND: CDK12 genomic alterations occur in several tumor types, but little is known about their oncogenic role and clinical significance. OBJECTIVE: To describe the landscape of CDK12 alterations across solid cancers and the clinical features of CDK12-altered prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: A single-center retrospective study of 26743 patients across 25 solid tumor types who underwent tumor sequencing was performed. Clinicopathologic features and outcomes were assessed in prostate cancer. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: CDK12 alterations and their association with genomic characteristics are described. For prostate cancer patients, overall survival and time to castration resistance were assessed using univariable and multivariable Cox regression analysis. RESULTS AND LIMITATIONS: CDK12 alterations were identified in 404/26743 patients (1.5%) overall, but were most frequent in prostate (100/1875, 5.3%) and ovarian cancer (43/1034, 4.2%), in which they were associated with a high prevalence of truncating variants and biallelic inactivation. CDK12 alterations defined a genomic subtype of prostate cancer with a unique copy-number alteration profile and involvement of distinct oncogenic pathway alterations, including cell-cycle pathway genes. CDK12-altered prostate cancer was associated with somewhat more aggressive clinical features and shorter overall survival (median 64.4 vs 74.9 mo; p=0.032) independent of standard clinical factors and tumor copy-number alteration burden (adjusted hazard ratio 1.80, 95% confidence interval 1.12-2.89; p=0.024). The study is limited by its retrospective nature. CONCLUSIONS: CDK12 alteration is a rare event across solid cancers but defines a clinically distinct molecular subtype of prostate cancer associated with unique genomic alterations and slightly more aggressive clinical features. PATIENT SUMMARY: CDK12 gene alterations occur rarely across tumor types, but more frequently in prostate cancer, where they are associated with genomic instability, cell-cycle pathway gene alterations, and somewhat worse clinical outcomes, warranting further investigation of therapeutic targeting of this disease subset.

Oncogenic Genomic Alterations, Clinical Phenotypes, and Outcomes in Metastatic Castration-Sensitive Prostate Cancer.

PURPOSE: The genomic underpinning of clinical phenotypes and outcomes in metastatic castration-sensitive prostate cancer is unclear. EXPERIMENTAL DESIGN: In patients with metastatic castration-sensitive prostate cancer at a tertiary referral center, clinical-grade targeted tumor sequencing was performed to quantify tumor DNA copy number alterations and alterations in predefined oncogenic signaling pathways. Disease volume was classified as high volume (≥4 bone metastases or visceral metastases) versus low volume. RESULTS: Among 424 patients (88% white), 213 (50%) had high-volume disease and 211 (50%) had low-volume disease, 275 (65%) had de novo metastatic disease, and 149 (35%) had metastatic recurrence of nonmetastatic disease. Rates of castration resistance [adjusted hazard ratio, 1.84; 95% confidence interval (CI), 1.40-2.41] and death (adjusted hazard ratio, 3.71; 95% CI, 2.28-6.02) were higher in high-volume disease. Tumors from high-volume disease had more copy number alterations. The NOTCH, cell cycle, and epigenetic modifier pathways were the highest-ranking pathways enriched in high-volume disease. De novo metastatic disease differed from metastatic recurrences in the prevalence of CDK12 alterations but had similar prognosis. Rates of castration resistance differed 1.5-fold to 5-fold according to alterations in AR, SPOP (inverse), and TP53, and the cell cycle, WNT (inverse), and MYC pathways, adjusting for disease volume and other genomic pathways. Overall survival rates differed 2-fold to 4-fold according to AR, SPOP (inverse), WNT (inverse), and cell-cycle alterations. PI3K pathway alterations were not associated with prognosis once adjusted for other factors. CONCLUSIONS: This study identified genomic features associated with prognosis in metastatic castration-sensitive disease that may aid in molecular classification and treatment selection.

Dose-Escalated Intensity Modulated Radiation Therapy for Prostate Cancer: 15-Year Outcomes Data.

PURPOSE: To report 15-year outcomes for dose-escalated intensity modulated radiation therapy (IMRT) for localized prostate cancer (PC) by evaluating biochemical relapse, distant metastases, cancer-specific survival, and long-term toxicity. METHODS AND MATERIALS: A database search was conducted for the first cohort of patients treated at this institution with 81 or 86.4 Gy between 1996 and 1998 using IMRT. Toxicity data were scored according to the Common Terminology Criteria for Adverse Events version 3.0. Median follow-up was 11.6 years (range, 5-21 years). RESULTS: In the study, 301 patients were treated with 81 Gy (n = 269, 89%) or 86.4 Gy (n = 32, 11%). Patients were analyzed by National Comprehensive Cancer Network risk group, with 29% low risk (LR), 49% intermediate risk (IR), and 22% high risk (HR). Late grade 3 gastrointestinal (GI) toxicity was seen in 3 patients (1.0%). No grade 4 GI toxicity events occurred. Median time from radiation therapy to late grade 3 GI toxicity was 2.9 years. One event occurred after 10 years. Late grade 3 and 4 genitourinary (GU) toxicity was seen in 6 (2.0%) and 1 (0.3%) patient, respectively. Median time to late grade 3+ GU toxicity was 5.5 years. Two events occurred after 10 years. In addition, 38 (12.6%) developed second primary malignancies (SPMs), 8 of which were in-field malignancies. Median time from radiation therapy to all SPM and in-field SPM was 10 years. The 15-year relapse-free survival was 76%, 65%, and 55% in the LR, IR, and HR groups, respectively. Distant metastases-free survival was 88%, 75%, and 63% for LR, IR, and HR patients, respectively. PC-specific mortality was 1.9%, 7.1%, and 12.2% for LR, IR, and HR patients. CONCLUSIONS: This report represents the longest follow-up data set to our knowledge of patients treated with high-dose IMRT for PC. Our findings indicate that it is well tolerated with 1.0% and 2.3% incidence of long-term grade 3+ GI and GU toxicity, respectively. The cohort had excellent PC-specific survival.

Long-term Impact of Androgen-deprivation Therapy on Cardiovascular Morbidity After Radiotherapy for Clinically Localized Prostate Cancer.

OBJECTIVE: To characterize the impact of androgen-deprivation therapy (ADT) on the incidence of cardiovascular events (CE) in prostate cancer patients treated with radiotherapy (RT). MATERIALS AND METHODS: There were 2211 patients with localized prostate cancer treated with RT from 1988 to 2008 at our institution. There were 991 patients (44.8%) who received ADT at the time of RT for a median of 6.1 months. Salvage ADT was initiated prior to CE in 365 men (16.5%) at a median of 5.5 years (range: 0.6 to 18.4 years) after RT and continued for a median of 4.3 years. A nomogram was constructed to predict the 10-year risk of CE "post-RT" (i.e., after RT). RESULTS: Patients receiving ADT at the time of RT exhibited significantly higher 10-year incidence of CE (19.6%, 95% CI 17.0%-22.6%) than those not receiving ADT (14.3%, 95% CI 12.2%-16.7%, P = .005). On multivariate analysis, both ADT at the time of RT (P = .007) and the time of salvage (P = .0004) were associated with increased CE risk, as were advanced age (P = .02), smoking (P = .0007), history of diabetes (P = .0007), and history of CE before RT (P < .0001). A nomogram using patient age, smoking status, history of pre-RT CE, history of diabetes, and ADT use at the time of RT predicted the rate of 10-year CE with a C-index of 0.81 (95% CI, 0.72-0.88). CONCLUSION: While ADT is often an essential part of prostate cancer treatment, patients should be counseled regarding increased risks of CE and prophylactic efforts should be considered to mitigate that risk.