Prostate-Specific Membrane Antigen PET/CT-Guided, Metastasis-Directed Radiotherapy for Oligometastatic Castration-Resistant Prostate Cancer.

Systemic treatments for metastatic castration-resistant prostate cancer (mCRPC) include androgen deprivation therapy, androgen receptor pathway inhibitors, chemotherapy, and radiopharmaceuticals, all of which have associated toxicity. Prostate-specific membrane antigen (PSMA) PET/CT allows for higher sensitivity in detecting metastatic disease than is possible with conventional imaging. We hypothesized that PSMA PET/CT-guided, metastasis-directed radiotherapy may offer durable disease control with low toxicity rates in patients with mCRPC who have a limited number of metastases. Methods: We retrospectively screened 5 prospective PSMA PET/CT studies for patients with mCRPC who had up to 5 sites of oligorecurrent or oligoprogressive disease on PSMA PET/CT and subsequently received definitive-intent, metastasis-directed radiotherapy to all new or progressing sites with concurrent androgen deprivation therapy. Progression-free survival, freedom from new lines of systemic therapy, and overall survival (OS) were calculated from the start of metastasis-directed radiotherapy using Kaplan-Meier analysis. Biochemical response was defined as at least a 50% decrease in prostate-specific antigen 6 mo after the start of treatment. Toxicity was graded using the Common Terminology Criteria for Adverse Events, version 5. Results: Twenty-four patients met the inclusion criteria with a median follow-up of 33.8 mo (interquartile range, 27.6-45.1 mo). Between October 2017 and April 2023, 11 patients (45.8%) had 1 treated site, 10 patients (41.7%) had 2, and 3 patients (12.5%) had 3. Five sites were prostate or prostate bed, 15 were nodal, 19 were osseous, and 1 was visceral. Seventeen patients (70.8%) continued their preexisting systemic therapy, whereas 7 (29.2%) started a new systemic therapy. Median progression-free survival was 16.4 mo (95% CI, 9.8-23.0 mo). The biochemical response rate was 66.7%. Median freedom from a new line of systemic therapy was 29.0 mo (95% CI, 7.6-50.4 mo). Median OS was not reached. The 2- and 4-y OS rates were 91.1% (95% CI, 79.3%-100%) and 68.8% (95% CI, 45.1%-92.5%), respectively. Grade 2 and grade 3 or higher toxicity rates were 4.2% and 0%, respectively. Conclusion: PSMA PET/CT-guided, metastasis-directed radiotherapy appears to offer durable disease control with low toxicity rates for oligometastatic castration-resistant prostate cancer. Further prospective studies are needed to compare metastasis-directed radiotherapy with systemic therapy versus systemic therapy alone and PSMA PET/CT-guided versus conventional imaging-guided radiotherapy.

Transcriptomic Profiling of Primary Prostate Cancers and Nonlocalized Disease on Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography: A Multicenter Retrospective Study.

PURPOSE: To characterize the relationship between Decipher genomic classifier scores and prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT)-based metastatic spread. MATERIALS AND METHODS: We identified patients from four institutions who underwent PSMA PET/CT scans pretreatment for primary staging or postradical prostatectomy (RP) for suspected recurrence and had Decipher transcriptomic data available from biopsy or RP specimens. PSMA PET/CT-based patterns of spread were classified as localized (miT + N0M0) or nonlocalized (miN1M0 or miM1a-c). We calculated the association between Decipher scores and the risk of nonlocalized disease on PSMA PET/CT using multivariable logistic regression for pretreatment patients and multivariable Cox regression for post-RP patients. We also compared select transcriptomic signatures between patients with localized and nonlocalized diseases. RESULTS: Five hundred eighty-six patients were included (pretreatment: n = 329; post-RP: n = 257). Higher Decipher scores were associated with nonlocalized disease on PSMA PET/CT both pretreatment (odds ratio, 1.18 [95% CI, 1.03 to 1.36] per 0.1 increase in Decipher score, P = .02) and post-RP (hazard ratio, 1.15 [95% CI, 1.05 to 1.27] per 0.1 increase in Decipher score, P = .003). In the pretreatment setting, nonlocalized disease was associated with higher rates of TP53 mutations and lower rates of PAM50 luminal A subtype compared with localized disease. In the post-RP setting, overexpression of signatures related to metabolism, DNA repair, and androgen receptor signaling were associated with higher rates of nonlocalized disease. CONCLUSION: Higher Decipher scores were associated with nonlocalized disease identified on PSMA PET/CT both pretreatment and post-RP. There were several transcriptomic differences between localized and nonlocalized diseases in both settings.

Treatment intensification strategies for men undergoing definitive radiotherapy for high-risk prostate cancer.

PURPOSE: Treatment intensification of external beam radiotherapy (EBRT) plays a crucial role in the treatment of high-risk prostate cancer. METHODS: We performed a critical narrative review of the relevant literature and present new developments in evidence-based treatment intensification strategies. RESULTS: For men with high-risk prostate cancer, there is strong evidence to support prolonging androgen deprivation therapy (ADT) to 18-36 months and escalating the dose to the prostate using a brachytherapy boost. A potentially less toxic alternative to a brachytherapy boost is delivering a focal boost to dominant intraprostatic lesions using EBRT. In patients who meet STAMPEDE high-risk criteria, there is evidence to support adding a second-generation anti-androgen agent, such as abiraterone acetate, to long-term ADT. Elective pelvic lymph node irradiation may be beneficial in select patients, though more prospective data is needed to elucidate the group of patients who may benefit the most. Tumor genomic classifier (GC) testing and advanced molecular imaging will likely play a role in improving patient selection for treatment intensification as well as contribute to the evolution of treatment intensification strategies for future patients. CONCLUSION: Treatment intensification using a combination of EBRT, advanced hormonal therapies, and brachytherapy may improve patient outcomes and survival in men with high-risk prostate cancer. Shared decision-making between patients and multidisciplinary teams of radiation oncologists, urologists, and medical oncologists is essential for personalizing care in this setting and deciding which strategies make sense for individual patients.

Systemic and Tumor-directed Therapy for Oligorecurrent Metastatic Prostate Cancer (SATURN): Primary Endpoint Results from a Phase 2 Clinical Trial.

Nearly all men with metastatic hormone-sensitive prostate cancer treated with intermittent androgen deprivation therapy (ADT) experience recurrence within 6 mo of testosterone recovery. We conducted a single-arm phase 2 trial to evaluate whether addition of dual androgen receptor pathway inhibitors (ARPIs) and metastasis-directed stereotactic body radiotherapy (SBRT) to intermittent ADT improves recurrence rates for men with between one and five nonvisceral, extrapelvic metastases on prostate-specific membrane antigen positron emission tomography/computed tomography after prior radical prostatectomy. Patients received 6 mo of androgen annihilation therapy (AAT; leuprolide, abiraterone acetate plus prednisone, and apalutamide) and metastasis-directed SBRT. The primary endpoint was the percentage of patients with prostate-specific antigen (PSA) <0.05 ng/ml 6 mo after testosterone recovery (≥150 ng/dl), with the study powered to detect an improvement from 1% to 12%. We enrolled 28 men between March 2021 and June 2022. Median follow-up was 20 mo (interquartile range 16-22). Twenty-six patients (93%) completed SBRT with 6 mo of hormone therapy, of whom six discontinued at least one ARPI; two patients withdrew prematurely. At 6 mo after testosterone recovery, PSA was maintained at <0.05 ng/ml in 13/26 patients (50%, 95% confidence interval 32-67%). Rates of grade 2 and 3 AAT toxicity were 21% and 21%. The results confirm that addition of metastasis-directed SBRT to highly potent systemic therapy can maintain low PSA after testosterone recovery, although further studies are needed to clarify the optimal systemic therapy regimen. PATIENT SUMMARY: We tested a combination of intensified hormone therapy (called androgen annihilation therapy) and radiotherapy targeted at metastases in men with recurrence of metastatic prostate cancer. We found that half of patients were recurrence-free 6 months after their testosterone level recovered, and that less than a quarter of patients experienced a severe drug-related side effect. Overall, this appears to be an effective therapy with acceptable side effects. This trial is registered on ClinicalTrials.gov as NCT03902951.

Biodegradable and gas barrier polylactic acid/star-shaped polycaprolactone blend films functionalized with a bio-sourced polyelectrolyte coating.

This work aims at improving and disclosing new properties of films based on polylactic acid (PLA) and a star-shaped polycaprolactone (PCL). Indeed, previous works demonstrated that the presence of ad-hoc synthesized PCL, characterized by low molecular weight and carboxyl end groups (coded as PCL-COOH), improves the elongation at break of the films compared to that of neat PLA and increases their functionality. To further improve the properties of the system, alternating layers of chitosan (CH) and DNA were deposited on the surface applying a Layer-by-Layer (LbL) technique. This method was chosen because it allows the properties of the system to be modified without affecting the specific features of the bulk. In addition, the LbL technique is easily scalable and environmentally friendly because it is based on the use of an aqueous solution of two biomaterials, namely DNA and CH, which are not only derived from renewable sources but are also biocompatible and biodegradable. IR measurements on model silicon substrates subjected to the same treatment as the films, pointed out a linear growth of the proposed LbL assembly. Indeed, FE-SEM measurements highlighted the deposition of a uniform coating. The presence of the CH/DNA assembly reduced the oxygen permeability under both dry and humid (50% R.H.) conditions when compared to the uncoated film. In addition, the coating had no relevant effect on the hydrolytic and enzymatic degradation of the system, so that the biodegradability of the film was maintained.

Impact of PSMA PET on Prostate Cancer Management.

OPINION STATEMENT: PSMA-PET has been a practice-changing imaging biomarker for the management of men with PCa. Research suggests improved accuracy over conventional imaging and other PET radiotracers in many contexts. With multiple approved PSMA-targeting radiotracers, PSMA PET will become even more available in clinical practice. Its increased use requires an understanding of the prospective data available and caution when extrapolating from prior trial data that utilized other imaging modalities. Future trials leveraging PSMA PET for treatment optimization and management decision-making will ultimately drive its clinical utility.

The Use of Magnetic Resonance Imaging in Radiation Therapy Treatment Simulation and Planning.

Ever since its introduction as a diagnostic imaging tool the potential of magnetic resonance imaging (MRI) in radiation therapy (RT) treatment simulation and planning has been recognized. Recent technical advances have addressed many of the impediments to use of this technology and as a result have resulted in rapid and growing adoption of MRI in RT. The purpose of this article is to provide a broad review of the multiple uses of MR in the RT treatment simulation and planning process, identify several of the most used clinical scenarios in which MR is integral to the simulation and planning process, highlight existing limitations and provide multiple unmet needs thereby highlighting opportunities for the diagnostic MR imaging community to contribute and collaborate with our oncology colleagues. EVIDENCE LEVEL: 5 TECHNICAL EFFICACY: Stage 5.

A systematic review of endometrial cancer clinical research in Africa.

BACKGROUND: Women in Africa are experiencing a rising burden of endometrial cancer. Research and investment to improve treatment and outcomes are critically needed. We systematically reviewed and characterized endometrial cancer-related research within a clinically relevant context to help organize and assess existing endometrial cancer research in Africa. METHODS: According to PRISMA guidelines, we searched online databases for published endometrial cancer articles from African countries from January 1, 2011, to July 20, 2021. Based on our inclusion and exclusion criteria, independent reviewers documented the study design, country/region, human development index, focus of research, type of interventions performed, and histologic and molecular type to illustrate the breadth of research coverage in each region. RESULTS: A total of 18 research articles were included. With an average Human Development Index (HDI) in Africa of 0.536, the average HDI of the represented countries in this study was 0.709. The majority (88.9%) of prospective endometrial cancer research articles in Africa were from North Africa, with Egypt encompassing 83.3% of the papers. Most of these studies focused on endometrial cancer diagnosis. Research on the treatment of endometrial cancer is still emerging (33% of papers). Of all included articles, only 11.1% represented Sub-Saharan Africa, where the majority population of black Africans reside. CONCLUSIONS: Endometrial cancer research in Africa is extremely limited, with the majority being concentrated in African countries with higher HDIs. As the incidence of endometrial cancer rises in Sub-Saharan Africa, there is a pressing need for more prospective clinical research to tackle the growing disease burden and improve outcomes.

Impact of Interfractional Bladder and Trigone Displacement and Deformation on Radiation Exposure and Subsequent Acute Genitourinary Toxicity: A Post Hoc Analysis of Patients Treated with Magnetic Resonance Imaging-Guided Prostate Stereotactic Body Radiation Therapy in a Phase 3 Randomized Trial.

PURPOSE: Emerging data suggest that trigone dosimetry may be more associated with poststereotactic body radiation therapy (SBRT) urinary toxicity than whole bladder dosimetry. We quantify the dosimetric effect of interfractional displacement and deformation of the whole bladder and trigone during prostate SBRT using on-board, pretreatment 0.35T magnetic resonance images (MRI). METHODS AND MATERIALS: Seventy-seven patients treated with MRI-guided prostate SBRT (40 Gy/5 fractions) on the MRI arm of a phase 3 single-center randomized trial were included. Bladder and trigone structures were contoured on images obtained from a 0.35T simulation MRI and 5 on-board pretreatment MRIs. Dice similarity coefficient (DSC) scores and changes in volume between simulation and daily treatments were calculated. Dosimetric parameters including Dmax, D0.03 cc, Dmean, V40 Gy, V39 Gy, V38 Gy, and V20 Gy for the bladder and trigone for the simulation and daily treatments were collected. Both physician-scored (Common Terminology Criteria for Adverse Events, version 4.03 scale) as well as patient-reported (International Prostate Symptom Scores and the Expanded Prostate Cancer Index Composite-26 scores) acute genitourinary (GU) toxicity outcomes were collected and analyzed. RESULTS: The average treatment bladder volume was about 30% smaller than the simulation bladder volume; however, the trigone volume remained fairly consistent despite being positively correlated with total bladder volume. Overall, the trigone accounted for <2% of the bladder volume. Median DSC for the bladder was 0.79, whereas the median DSC of the trigone was only 0.33. No statistically significant associations between our selected bladder and trigonal dosimetric parameters and grade ≥2 GU toxicity were identified, although numerically, patients with GU toxicity (grade ≥2) had higher intermediate doses to the bladder (V20 Gy and Dmean) and larger volumes exposed to higher doses in the trigone (V40 Gy, V39 Gy, and V38 Gy). CONCLUSIONS: The trigone exhibits little volume change, but considerable interfractional displacement/deformation. As a result, the relative volume of the trigone receiving high doses during prostate SBRT varies substantially between fractions, which could influence GU toxicity and may not be predicted by radiation planning dosimetry.

Prostate-Specific Antigen Response to Androgen Deprivation Therapy in the Neoadjuvant Setting for High-Risk Prostate Adenocarcinoma (PIRANHA): Pooled Analysis of Two Randomized Clinical Trials.

PURPOSE: A suboptimal prostate-specific antigen (PSA) response to neoadjuvant androgen deprivation therapy (ADT) among men who go on to receive definitive radiation therapy for prostate cancer might suggest the existence of castration-resistant disease or altered androgen receptor signaling. This in turn may portend worse long-term clinical outcomes, especially in men with high-risk disease. We set out to evaluate the prognostic impact of poor PSA response to neoadjuvant ADT in men with high-risk prostate cancer. METHODS AND MATERIALS: This was a post hoc analysis of the multicenter TROG 03.04 RADAR and PCS IV randomized clinical trials. Inclusion criteria for this analysis were patients with high-risk prostate cancer (defined as Gleason score ≥8, initial PSA ≥20 ng/mL, or cT3a disease or higher) who received definitive radiation therapy, at least 18 months of ADT, and had a preradiation therapy PSA level drawn after at least 3 months of neoadjuvant ADT. Poor PSA response was defined as PSA >0.5 ng/mL. Cox regression and Fine-Gray models were used to test whether poor PSA response was associated with metastasis-free survival, biochemical recurrence, prostate-cancer specific mortality, and overall survival. RESULTS: Nine hundred thirty men met inclusion criteria for this analysis. Median follow-up was 130 months (interquartile range [IQR], 89-154 months). After a median of 3 months (IQR, 3-4.2 months) of neoadjuvant ADT, the median PSA was 0.60 ng/mL (IQR, 0.29-1.59). Overall, 535 men (57%) had a PSA >0.5 ng/mL. Poor PSA response was associated with significantly worse metastasis-free survival (hazard ratio [HR], 3.93; P = .02), worse biochemical recurrence (subdistribution HR, 2.39; P = .003), worse prostate-cancer specific mortality (subdistribution HR, 1.50; P = .005), and worse overall survival (HR, 4.51; P = .05). CONCLUSIONS: Patients with PSA >0.5 mg/mL after at least 3 months of neoadjuvant ADT had worse long-term clinical outcomes and should be considered for treatment intensification.

MRI-Guided Radiotherapy for Prostate Cancer: Seeing is Believing.

The advent of MRI guided radiotherapy (MRIgRT) offers enormous promise in the treatment of prostate cancer. The MR-linac offers men the opportunity to receive daily MR imaging to guide and influence their radiotherapy treatment. This review focuses on the advantages that MRIgRT potentially offers as well as any potential disadvantages to MRIgRT that may have been recognized thus far. Ongoing clinical trials evaluating this novel treatment platform for the treatment of prostate cancer are also discussed.

MRI-Guided Radiation Therapy-An Emerging and Disruptive Process of Care: Healthcare Economic and Policy Considerations.

MRI-guided radiation therapy (MRgRT) is an emerging, innovative technology that provides opportunities to transform and improve the current clinical care process in radiation oncology. As with many new technologies in radiation oncology, careful evaluation from a healthcare economic and policy perspective is required for its successful implementation. In this review article, we describe the current evidence surrounding MRgRT, framing it within the context of value within the healthcare system. Additionally, we highlight areas in which MRgRT may disrupt the current process of care, and discuss the evidence thresholds and timeline required for the widespread adoption of this promising technology.

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.

Long-Term Quality-of-Life Outcomes After Prostate Radiation Therapy With or Without High-Dose-Rate Brachytherapy Boost: Post Hoc Analysis of TROG 03.04 RADAR.

PURPOSE: Adding high-dose-rate brachytherapy (BT) boost to external beam radiation therapy (EBRT) improves biochemical control but may affect patient-reported quality of life (QOL). We sought to determine long-term QOL outcomes for EBRT+BT versus EBRT alone. METHODS AND MATERIALS: This was a post hoc analysis of the Trans-Tasman Radiation Oncology Group 03.04 Randomized Androgen Deprivation and Radiotherapy (TROG 03.04 RADAR) trial. Only patients who received 74 Gy conventionally fractionated EBRT (n = 260) or 46 Gy conventionally fractionated EBRT plus 19.5 Gy in 3 fractions high-dose-rate BT boost (n = 237) were included in this analysis. The primary endpoint was patient-reported QOL measured using the European Organisation for Research and Treatment of Cancer QOL (EORTC QLQ-C30) and prostate-specific QOL module (EORTC QLQ-PR25) questionnaires. We evaluated temporal changes in QOL scores, rates of symptom resolution, and the proportion of men who had decrements from baseline of >2 × the threshold for minimal clinically important change (2 × MCIC) for each domain. RESULTS: At 5, 17, and 29 months after radiation therapy, the EBRT+BT group had 2.5 times (95% confidence interval [CI], 1.4-4.2; P < .001), 2.9 times (95% CI, 1.7-4.9; P < .001), and 2.6 times (95% CI, 1.4-4.6; P = .002) greater odds of reporting 2 × MCIC in urinary QOL score compared with EBRT. There were no differences beyond 29 months. EBRT+BT led to a slower rate of urinary QOL symptom score resolution up to 17 months after radiation therapy compared with EBRT (P < .001) but not at later intervals. In contrast, at the end of the radiation therapy period and at 53 months after radiation therapy, the EBRT+BT group had 0.65 times (95% CI, 0.44-0.96; P = .03) and 0.51 times (95% CI, 0.32-0.79; P = .003) the odds of reporting 2 × MCIC in bowel QOL symptom scores compared with EBRT. There were no significant differences in the rate of bowel QOL score resolution. There were no significant differences in global health status or sexual activity scores between the 2 groups. CONCLUSIONS: There were no persistent differences in patient-reported QOL measures between EBRT alone and EBRT+BT. BT boost does not appear to negatively affect long-term, patient-reported QOL.

MRI-Guided Radiation Therapy for Prostate Cancer: The Next Frontier in Ultrahypofractionation.

Technological advances in MRI-guided radiation therapy (MRIgRT) have improved real-time visualization of the prostate and its surrounding structures over CT-guided radiation therapy. Seminal studies have demonstrated safe dose escalation achieved through ultrahypofractionation with MRIgRT due to planning target volume (PTV) margin reduction and treatment gating. On-table adaptation with MRI-based technologies can also incorporate real-time changes in target shape and volume and can reduce high doses of radiation to sensitive surrounding structures that may move into the treatment field. Ongoing clinical trials seek to refine ultrahypofractionated radiotherapy treatments for prostate cancer using MRIgRT. Though these studies have the potential to demonstrate improved biochemical control and reduced side effects, limitations concerning patient treatment times and operational workflows may preclude wide adoption of this technology outside of centers of excellence. In this review, we discuss the advantages and limitations of MRIgRT for prostate cancer, as well as clinical trials testing the efficacy and toxicity of ultrafractionation in patients with localized or post-prostatectomy recurrent prostate cancer.

Selecting the optimal radiation modality in prostate cancer.

There are numerous radiation modalities for the definitive treatment of localized prostate cancer. Classic clinical trials have established the basic tenets of treatment approaches, and emerging data have generated new potential avenues of treatment that optimize the therapeutic ratio by increasing prostate cancer tumor control while minimizing treatment-related toxicity. In the definitive setting, the selection of the optimal radiation therapy approach depends largely on the appropriate up-front risk stratification of men with prostate cancer, with greater intensification of treatment and greater integration of multimodality therapies for men with higher-risk disease. Hormonal therapy should be selectively deployed based on prognostic information derived from the National Comprehensive Cancer Network risk group and biologic tumor aggressiveness informed by genomic classifiers. Moreover, treatment intensification and target volume delineation are increasingly informed by molecular imaging and multiparametric magnetic resonance imaging. Herein, we perform a critical appraisal of the literature focusing on the optimal selection of radiation therapy modality for localized prostate cancer. Collaboration among medical oncologists, surgeons, and radiation oncologists will be critical for coordinating evidence-based radiation therapies when clearly indicated and for supporting shared decision-making when the evidence is incomplete.

Biochemical Recurrence Surrogacy for Clinical Outcomes After Radiotherapy for Adenocarcinoma of the Prostate.

PURPOSE: The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods. MATERIALS AND METHODS: Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the R2). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed. RESULTS: Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The R2 values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively. CONCLUSION: BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events.