BACKGROUND:The expansion of treatment options for prostate cancer (PC) has improved disease-specific and overall survival outcomes but has also raised questions about the optimal level of treatment needed for patients based on their individual prognosis and accounting for potential toxicity, incorporating quality of life considerations. METHODS:A panel of experts met to discuss current controversies in the care of patients with PC across the disease continuum. Multidisciplinary experts review advances and persistent uncertainties in biomarker-guided assessment, imaging, and systemic therapy for prostate cancer. The discussion outlines priority gaps in evidence that must be addressed to optimize individualized patient care. RESULTS:Workshop topics included use of genomic biomarkers and artificial intelligence-guided tools to identify and manage high-risk and very-high risk localized disease, management of biochemical recurrence, identification of patients with metastatic hormone-sensitive PC who warrant treatment escalation, radiopharmaceutical therapy for metastatic castration-resistant PC including optimal sequencing of approved therapies, role of imaging in identification and management of extraprostatic disease, and lifestyle interventions to optimize survivorship. CONCLUSIONS:Many questions remain about management of PC related to biomarker-based risk stratification to guide treatment selection, use of prostate-specific membrane antigen-positron emission tomography, and balancing the risk for PC-related death with risks for treatment-related toxicity. Ongoing research efforts are needed to optimize risk-based treatment, sequence of therapies throughout the disease continuum, and survivorship care.

Imaging with prostate-specific membrane antigen (PSMA) PET has significantly improved prostate cancer staging with superior diagnostic performance compared to conventional methods. Although it is increasingly adopted in clinical practice, several barriers hinder its full integration into routine workflows. This review highlights the existing knowledge gaps, infrastructure limitations, and inconsistencies in interpretation that affect the utility of PSMA PET across healthcare settings. We examine the potential reasons behind variability in scan performance, including scanner design, detector technology, sensitivity, and resolution, as well as the accreditation status of the facilities and reader expertise. We also highlight the inconsistent understanding of PSMA PET ordering practices, particularly among urologists, and the influence of ownership-driven utilization, both of which contribute to underuse and overuse. Radiology reporting that lacks sufficient detail and a shortage of trained nuclear medicine specialists may present additional challenges to effective treatment planning, although diagnostic radiologists also contribute to PET scan interpretation. This review highlights the potential role of standardized reporting protocols, accreditation, expanded education, and integration of AI tools in enhancing diagnostic accuracy and consistency. Additionally, we examine the impact of PSMA PET on clinical decision-making in unfavorable intermediate-, high risk-, and biochemically recurrent prostate cancer, as well as the emerging role of PSMA PET-derived metrics in staging, biopsy guidance, and treatment planning. While PSMA PET has shown value in modifying management strategies, its clinical benefit requires validation through future, prospective, outcome-driven studies. In addition, emerging applications of PSMA PET in non-prostate malignancies hold the potential to transform diagnostic and therapeutic approaches beyond prostate cancer.

NRG Oncology's Developmental Therapeutics and Radiation Therapy Subcommittee assembled an interdisciplinary group of investigators to address barriers to successful early phase clinical trials of novel combination therapies involving radiation. This Policy Review elucidates some of the many challenges associated with study design for early phase trials combining radiotherapy with novel systemic agents, which are distinct from drug-drug combination development and are often overlooked. We also advocate for potential solutions that could mitigate or eliminate some of these barriers, providing examples of specific clinical trial designs that could help facilitate efficient and effective evaluation of novel drug-radiotherapy combinations.

Hemibody irradiation (HBI) is a radiation therapy technique that involves treating one-half of the patient's skeletal system in a single radiation field. It is mostly given as upper hemibody irradiation (UHBI), lower hemibody irradiation (LHBI), or sequential UHBI and LHBI. It is used to treat extensive bone metastases from solid tumors. It was primarily utilized in the 1980s and 1990s and has since fallen out of favor. However, it is a potentially cost-effective treatment for widespread bone metastases. To determine its efficacy, we performed a meta-analysis of all available published articles on the efficacy of HBI to relieve pain from bone metastases. Twenty-seven articles involving 1318 patients were identified and analyzed. Our findings show that 80% of the patients had complete or partial pain relief and 29% had complete pain relief. The trials were of poor quality, but the results showed minimal heterogeneity in the response rates. These response rates are consistent with those seen with focal irradiation of bone metastases and for radionuclide treatment of bone metastases. The toxicity of the treatments decreased when delivered with modern treatment techniques. In light of this, we propose that this technique warrants re-evaluation with modern treatment methods.

Derivation of the mathematical model and additional simulations.

Purpose: The advent of new imaging agents offers enhanced sensitivity and specificity in the detection and staging of prostate cancer. A growing array of treatment options and ongoing advancements in imaging technologies allow earlier and more extensive detection of metastatic disease and shifting the boundaries between disease states previously defined by conventional imaging. This review seeks to synthesize existing data and expert opinion to better guide patient management in the new era of targeted precision imaging (TPI). Materials and Methods: The Radiographic Assessments for Detection of Advanced Recurrence VI Group gathered to develop pathways/recommendations regarding how TPI could best be deployed, given approvals of key radiotracers including 18 F-fluciclovine, 68 Ga-PSMA, and 18 F-DCFPyL positron emission tomography/CT. Results: Radiographic Assessments for Detection of Advanced Recurrence VI Group members developed consensus pathways/suggestions based on the best available evidence for use of TPI in prostate cancer. Conclusions: Patients with prostate cancer have the potential to benefit from judicious use of TPI. However, additional research is needed to ensure that TPI is used appropriately and provides actionable findings that inform treatment decisions for these patients.

Purpose: Adjuvant radiation therapy (RT) for breast cancer improves outcomes, but prior studies have documented substantive cardiac dose and cardiac risk. We assessed the mean heart dose (MHD) of RT and estimated the risk of RT-associated cardiac toxicity in women undergoing adjuvant RT for breast cancer in contemporary (predominantly) community practice. Methods and materials: We identified women with left-sided breast cancer receiving adjuvant RT between 2012 and 2014 from 94 centers across 16 states. We used bivariate analyses and multivariable linear regression to assess associations between RT techniques and MHD. Excess RT-related cardiac risk by age 80 was estimated for women diagnosed at age 60 using the previously reported relationship between MHD and cardiac risk. Results: Among 1161 women, 77.3% were treated in community practice and with breast conservation (77.8%). The most common techniques were free-breathing (92.2%), supine (94.8%), and fixed gantry intensity modulated RT (FG-IMRT; 46.9%). The median MHD was 2.76 Gy (interquartile range, 1.47-5.03). In multivariable analyses, the predicted median MHD with deep inspiration breath hold was 2.41 Gy compared with 3.86 Gy with free-breathing (P <.001). Three-dimensional conformal RT (3D-CRT) was associated with a lower predicted median MHD (2.78 Gy) than FG-IMRT (4.02 Gy) or rotational IMRT, 6.60 Gy, P <.001). For 60-year-old women with the median MHD of the study population (2.76 Gy) and no cardiovascular risk factors, the 20-year predicted excess risk of death from ischemic heart disease attributable to radiation was 3.5 excess events/1000 patients, in contrast to estimates of 8 events/1000 from prior analyses. The predicted risk of cardiac events varied based on radiation technique, with 4 excess events/1000 with 3D-CRT, 5 excess events/1000 with FG-IMRT, and 8 excess events/1000 with rotational IMRT. Conclusions: MHD varies substantially across patients and is influenced by technique in predominantly community settings. Overall risk of cardiac toxicity is modest. (C) 2017 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

The Radiation Therapy Committee of SWOG periodically evaluates its strategic plan in an effort to maintain a current and relevant scientific focus, and to provide a standard platform for future development of protocol concepts. Participants in the 2017 Strategic Planning Workshop included leaders in cancer basic sciences, molecular theragnostics, pharmaceutical and technology industries, clinical trial design, oncology practice, and statistical analysis. The committee discussed high-priority research areas, such as optimization of combined modality therapy, radiation oncology-specific drug design, identification of molecular profiles predictive of radiation-induced local or distant tumor responses, and methods for normal tissue-specific mitigation of radiation toxicity. The following concepts emerged as dominant questions ready for national testing: (i) what is the role of radiotherapy in the treatment of oligometastatic, oligorecurrent, and oligoprogressive disease? (ii) How can combined modality therapy be used to enhance systemic and local response? (iii) Can we validate and optimize liquid biopsy and other biomarkers (such as novel imaging) to supplement current response criteria to guide therapy and clinical trial design endpoints? (iv) How can we overcome deficiencies of randomized survival endpoint trials in an era of increasing molecular stratification factors? And (v) how can we mitigate treatment-related side effects and maximize quality of life in cancer survivors? The committee concluded that many aspects of these questions are ready for clinical evaluation and example protocol concepts are provided that could improve rates of cancer cure and quality of survival. Clin Cancer Res; 24(15); 3500-9. ©2018 AACR.

OBJECTIVE:To offer recommendations on identification of disease progression, treatment management strategies, and suggestions on timing of initiating and discontinuing specific castration-resistant prostate cancer (CRPC) treatments.MATERIALS AND METHODS:The Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence II Working Group convened to provide guidance on sequencing, combination, or layering of approved treatments for metastatic CRPC based on available data and clinical experience.RESULTS:A consensus was developed to address important questions on management of patients with metastatic CRPC.CONCLUSION:In the absence of large-scale clinical trials, the Working Group recommends that patients may best be managed with a layered approach of approved therapies with unique or complimentary mechanisms of action.

It remains unclear how localized radiotherapy for cancermetastases can occasionally elicit a systemic antitumor effect, known as the abscopal effect, but historically, it has been speculated to reflect the generation of a host immunotherapeutic response. The ability to purposefully and reliably induce abscopal effects in metastatic tumors could meet many unmet clinical needs. Here, we describe a mathematical model that incorporates physiologic information about T-cell trafficking to estimate the distribution of focal therapy–activated T cells between metastatic lesions. We integrated a dynamic model of tumor–immune interactions with systemic T-cell trafficking patterns to simulate the development of metastases. In virtual case studies, we found that the disseminationof activated T cells amongmultiplemetastatic sites is complex and not intuitively predictable. Furthermore, we show that not all metastatic sites participate in systemic immune surveillance equally, and therefore the success in triggering the abscopal effect depends, at least in part, on which metastatic site is selected for localized therapy. Moreover, simulations revealed that seeding new metastatic sites may accelerate the growth of the primary tumor, because T-cell responses are partially diverted to the developing metastases, but the removal of the primary tumor can also favor the rapid growth of preexisting metastatic lesions. Collectively, our work provides the framework to prospectively identify anatomically defined focal therapy targets that are most likely to trigger an immune-mediated abscopal response and therefore may inform personalized treatment strategies in patients with metastatic disease. Cancer Res; 76(5); 1–10. 2016 AACR.

409 Background: Several organizations are developing clinical trials to evaluate adjuvant radiotherapy (RT) for bladder cancer patients at elevated risk of locoregional failure (LF). However, the clinical target volumes (CTVs) & organs at risk (OARs) for this treatment have not been defined in detail. Our purpose was to define multi-institutional consensus CTVs & OARs for male & female bladder cancer patients undergoing adjuvant RT in clinical trials. Methods: We convened a multi-disciplinary group of bladder cancer specialists from 9 centers in 3 countries. 5 radiation oncologists (ROs) & 7 urologists participated in the development of the proposed contours. The group proposed initial language for the CTVs & OARs and contoured them on CT scans of a male & female cystectomy patient with input from ≥ 1 urologist at each center. Using the binomial maximum-likelihood estimates method, we generated 95% level initial contours. We evaluated the contours for level of agreement using the Landis & Koch interpretation of the K statistic. Based on the initial contouring, the group updated its descriptions of the CTVs & OARs. To determine if the revised language produced consistent contours, the cystectomy bed (CB) contour was redrawn on the CT sets by an additional 5 ROs. Results: The group proposed that patients at elevated risk for LF with R0 resections should be treated to the pelvic nodes alone (internal/external iliac, distal common iliac & presacral) whereas patients with ≥ R1 resections should be treated to the pelvic nodes & CB. The group proposed the rectum, bowel space, bone marrow & urinary diversion as OARs. The level of agreement for the initial CTVs & OARs from the group varied substantially (Table). Consensus language to describe CTV & OAR structures where the initial contours varied was successfully developed. Contours & feedback from the validation group are being analyzed. Conclusions: Initial descriptions of CTVs & OARs have been successfully developed. External validation & feedback are pending. The results will be applicable to clinical trials of adjuvant RT in bladder cancer. [Table: see text]

Background and purpose: Evaluate changes in bowel, urinary and sexual patient-reported quality of life following treatment with moderately hypofractionated radiotherapy (<5 Gray/fraction) or stereotactic body radiation therapy (SBRT;5-10 Gray/fraction) for prostate cancer.Materials and methods: In a pooled multi-institutional analysis of men treated with moderate hypofrac-. tionation or SBRT, we compared minimally detectable difference in bowel, urinary and sexual quality of life at 1 and 2 years using chi-squared analysis and logistic regression.Results: 378 men received moderate hypofractionation compared to 534 men who received SBRT. After 1 year, patients receiving moderate hypofractionation were more likely to experience worsening in bowel symptoms (39.5%) compared to SBRT (32.5%; p = .06), with a larger difference at 2 years (37.4% versus 25.3%, p = .002). Similarly, patients receiving moderate fractionation had worsening urinary symptom score compared to patients who underwent SBRT at 1 and 2 years (34.7% versus 23.1%, p < .001; and 32.8% versus 14.0%, p < .001). There was no difference in sexual symptom score at 1 or 2 years. After adjusting for age and cancer characteristics, patients receiving SBRT were less likely to experience worsening urinary symptom scores at 2 years (odds ratio: 0.24[95%Cl: 0.07-0.79]).onclusions: Patients who received SBRT or moderate hypofractionation have similar patient-reported change in bowel and sexual symptoms, although there was worse change in urinary symptoms for patients receiving moderate hypofractionation. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Purpose: The new short Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP) patient-reported health-related quality of life (HRQOL) tool has removed the rectal bleeding question from the previous much longer version, EPIC-26. Herein, we assess the impact of losing the dedicated rectal bleeding question in 2 independent prospective multicenter cohorts.Methods and Materials: In a prospective multicenter test cohort (n=865), EPIC-26 patient-reported HRQOL data were collected for 2 years after treatment from patients treated with prostate radiation therapy from 2003 to 2011. A second prospective multicenter cohort (n=442) was used for independent validation. A repeated-effects model was used to predict the change from baseline in bowel summary scores from longer EPIC instruments using the change in EPIC-CP bowel summary scores with and without rectal bleeding scores.Results: Two years after radiation therapy, 91% of patients were free of bleeding, and only 2.6% reported bothersome bleeding problems. Correlations between EPIC-26 and EPIC-CP bowel scores were very high (r(2) =0.90-0.96) and were statistically improved with the addition of rectal bleeding information (r(2) =0.94-0.98). Considering all patients, only 0.2% of patients in the test cohort and 0.7% in the validation cohort reported bothersome bleeding and had clinically relevant HRQOL changes missed with EPIC-CP. However, of the 2.6% (n=17) of men with bothersome rectal bleeding in the test cohort, EPIC-CP failed to capture 1 patient (6%) as experiencing meaningful declines in bowel HRQOL.Conclusions: Modern prostate radiation therapy results in exceptionally low rates of bothersome rectal bleeding, and <1% of patients experience bothersome bleeding and are not captured by EPIC-CP as having meaningful HRQOL declines after radiation therapy. However, in the small subset of patients with bothersome rectal bleeding, the longer EPIC-26 should strongly be considered, given its superior performance in this patient subset. (C) 2016 Elsevier Inc. All rights reserved.

PURPOSE: This registry trial studied the long-term outcomes of women receiving accelerated partial breast irradiation (APBI) using strut-based applicators and reports on the local control, toxicity, and survival for the first 250 patients treated with this device.METHODS AND MATERIALS: Patients were treated using the strut-based brachytherapy device with conventional dose and fractionation of 34 Gy in 10 twice-daily fractions. Planning goals for the planning target volume were V-90 > 90%, V-150 < 50 cc, and V-200 < 20 cc. Toxicity was graded based on the Common Terminology Criteria for Adverse Events v3.0. Recurrence rates were also calculated.RESULTS: Median followup was 59.5 months for the 250 patients. Grade 2 or higher adverse events at any time for hyperpigmentation, induration, erythema, telangiectasia, breast pain, seroma, and fat necrosis were 0.4%, 3.0%, 3.0%, 3.0%, 3.9%, 4.8%, and 1.3%, respectively. The median V-90 was 97%, V-95 was 95.1%, V-150 was 28.7 cc, and V-200 was 14.2 cc. For those patients with a less than a 5-mm or 3-mm-skin bridge, the median skin max doses were 272 and 289 cGy, respectively. The 4-year actuarial recurrence rates for true recurrence/marginal miss and ipsilateral breast tumor recurrence were 2.3% and 3.6%, respectively. The 4-year actuarial rates for overall survival, cause-specific survival, and disease-free survival were 97%, 98%, and 92%, respectively.CONCLUSIONS: The strut-based applicator was designed to simplify APBI compared to interstitial brachytherapy. This report confirms excellent tumor control and survival with low toxicity and supports the evidence that brachytherapy has less normal tissue toxicity than APBI with external beam irradiation. (C) 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Purpose: To determine the effect of biologically effective dose (BED10) and radiation treatment schedule on overall survival (OS) in patients with early-stage non-small cell lung cancer (NSCLC) undergoing stereotactic body radiation therapy (SBRT).Methods and Materials: Using data from 65 treatment centers in the United States, we retrospectively reviewed the records of T1-2 N0 NSCLC patients undergoing SBRT alone from 2006 to 2014. Biologically relevant covariates, including dose per fraction, number of fractions, and time between fractions, were used to quantify BED10 and radiation treatment schedule. The linear-quadratic equation was used to calculate BED10 and to generate a dichotomous dose variable of <105 Gy versus >= 105 Gy BED10. The primary outcome was OS. We used the Kaplan-Meier method, the logerank test, and Cox proportional hazards regression with propensity score matching to determine whether prescription BED10 was associated with OS.Results: We identified 747 patients who met inclusion criteria. The median BED10 was 132 Gy, and 59 (7.7%) had consecutive-day fractions. Median follow-up was 41 months, and 452 patients (60.5%) had died by the conclusion of the study. The 581 patients receiving >= 105 Gy BED10 had a median survival of 28 months, whereas the 166 patients receiving <105 Gy BED10 had a median survival of 22 months (loge rank, P=.01). Radiation treatment schedule was not a significant predictor of OS on univariable analysis. After adjusting for T stage, sex, tumor histology, and Eastern Cooperative Oncology Group performance status, BED10 >= 105 Gy versus <105 Gy remained significantly associated with improved OS (hazard ratio 0.78, 95% confidence interval 0.62-0.98, P=.03). Propensity score matching on imbalanced variables within high-and low-dose cohorts confirmed a survival benefit with higher prescription dose.Conclusions: We found that dose escalation to 105 Gy BED10 and beyond may improve survival in NSCLC patients treated with SBRT. (C) 2016 Elsevier Inc. All rights reserved.