Symmetry, separation, and stability: Physical properties for effective dosimetric space with a stabilized hyaluronic acid spacer.

BACKGROUND: The proximity of the rectum to the prostate in radiation therapy (RT) for prostate cancer presents a significant dosimetric challenge, leading to high rectal doses and resulting in detrimental side effects. Perirectal tissue spacing reduces rectal dose and gastrointestinal toxicities by mechanically separating these organs. A variety of materials have been explored for use as rectal spacers, most recently, a stabilized hyaluronic acid (HA) gel, which can be formed into deliberate a shape, and retains the definition of that shape, while remaining flexible, unlike polyethylene glycol (PEG) hydrogels. PURPOSE: This study evaluates the dosimetric impact of the spacer, including shape symmetry, the degree of separation at different locations, and the temporal stability of the space. Our goal is to provide physics-informed guidance on the optimal use of this sculptable spacer. METHODS: A secondary analysis was performed on data from a 13-center prospective randomized trial (NCT04189913), involving 136 patients with centrally-reviewed treatment plans conducted on CT/MR simulation scans before and after receiving HA spacer implants. Patients were treated with 60 Gy in 20 fractions to the prostate. For this study, python software was utilized for automated processing of DICOM RTstruct and RTdose files, facilitating detailed analysis of the spacer's impact on anatomical displacement and dosimetric outcomes. Complete dose-volume histograms (DVHs) were reconstructed, and combined into composite population DVHs before and after implant, verified against trial-reported dose points. Patients were divided into similar groups of separation and symmetry, and differences in their composite DVHs were tested for significance. Stability of the spacer was studied by comparing serial MRI images and by computing the distance between contours at four axial planes, at simulation and 3-month follow-up, post RT. RESULTS: The introduction of the HA spacer significantly enhanced rectal sparing, as evidenced by a reduction in the mean rectal integral dose by over 6 Gy. High rates of implant symmetry (>95%) were observed, indicating nearly optimal lateral spacer placement. In superior-inferior coverage, this study like many others, saw the spacing largest at the superior extent but becoming more variable inferiorly at the level of the prostate apex. This allowed study of the apex as a specific area for dosimetric concern. Stability assessments confirmed that the spacer maintained its position and dimensions between the simulation and the 3-month post-RT, implying stable geometry during treatment, with only minimal separation changes observed. Statistical analysis using the Kruskal-Wallis test revealed significant correlations of larger separations at the inferior and apical planes with improved dosimetric outcomes, including rV30Gy. CONCLUSION: The use of a stabilized HA spacer in prostate RT effectively enhances prostate-rectum separation, leading to significant rectal sparing without undesirable dose compromises. This study underscores the role of strategic placement and shape, specifically including > 1 cm separation from the base down to the prostate apex. When combined with the treatment planning techniques used in the trial to create a steep dosimetric gradient across the spacer, these findings elucidate the dosimetric outcomes that can be expected in the clinical implementation of HA spacer. This is particularly relevant in the evolution of hypofractionated treatment regimens for prostate cancer therapy.

Evaluating the Quality-of-Life Effect of Apical Spacing with Hyaluronic Acid Prior to Hypofractionated Prostate Radiation Therapy: A Secondary Analysis.

PURPOSE: Recently, a randomized trial demonstrated that a hyaluronic acid (HA) spacer placed before prostate hypofractionated intensity modulated radiation therapy improved rectal dosimetry and reduced acute grade 2+ gastrointestinal toxicity. However, 26.5% of patients receiving the spacer experienced a minimal clinically important decline (MCID) in bowel quality-of-life (QOL). The purpose of this study is to evaluate whether certain characteristics of the rectal spacer, as determined on postimplant imaging, were associated with change in bowel QOL at 3-months. METHODS AND MATERIALS: This is a secondary analysis of the 136 patients who received the HA spacer on the randomized trial. Postimplant spacer characteristics (ie, prostate-rectum spacing at superior/midgland/inferior/apex planes, symmetry, prostate volume, spacer volume) were systematically analyzed from structure sets using custom software code. Characteristics demonstrating significant associations with rectal V30 on multivariate linear regression were identified. Linear regression models were used to analyze the associations of such characteristics with change (baseline to 3 months) in both bowel and urinary QOL. RESULTS: Apical spacing (mean 9.4 (standard deviation 4.0)) was significantly smaller than spacing measurements at more superior planes. 95.6% of patients had a symmetrical implant. Apical spacing (P < .001) and prostate volume (P = .01) were significantly associated with rectal V30 on multivariate analysis. However, only apical spacing (0.38/mm; P = .01) was associated with change in bowel QOL, even with adjustment of baseline bowel score (-0.33; P < .01). Percentages of patients with bowel MCID were 14.8% for >= 10 mm versus 36.6% for <10 mm apical spacing (P = .01). Apical spacing was not associated with change in urinary QOL (-0.09; P = .72), when adjusted for baseline urinary QOL (-0.52; P < .01). CONCLUSION: Greater apical spacing was associated with improved rectal dosimetry and smaller decline in bowel QOL at 3-months. Further prospective data are needed to fully understand the ramifications of increased apical spacing.

Application of next-generation imaging in biochemically recurrent prostate cancer.

BACKGROUND: Biochemical recurrence (BCR) following primary interventional treatment occurs in approximately one-third of patients with prostate cancer (PCa). Next-generation imaging (NGI) can identify local and metastatic recurrence with greater sensitivity than conventional imaging, potentially allowing for more effective interventions. This narrative review examines the current clinical evidence on the utility of NGI for patients with BCR. METHODS: A search of PubMed was conducted to identify relevant publications on NGI applied to BCR. Given other relevant recent reviews on the topic, this review focused on papers published between January 2018 to May 2023. RESULTS: NGI technologies, including positron emission tomography (PET) radiotracers and multiparametric magnetic resonance imaging, have demonstrated increased sensitivity and selectivity for diagnosing BCR at prostate-specific antigen (PSA) concentrations <2.0 ng/ml. Detection rates range between 46% and 50%, with decreasing PSA levels for choline (1-3 ng/ml), fluciclovine (0.5-1 ng/ml), and prostate-specific membrane antigen (0.2-0.49 ng/ml) PET radiotracers. Expert working groups and European and US medical societies recommend NGI for patients with BCR. CONCLUSIONS: Available data support the improved detection performance and selectivity of NGI modalities versus conventional imaging techniques; however, limited clinical evidence exists demonstrating the application of NGI to treatment decision-making and its impact on patient outcomes. The emergence of NGI and displacement of conventional imaging may require a reexamination of the current definitions of BCR, altering our understanding of early recurrence. Redefining the BCR disease state by formalizing the role of NGI in patient management decisions will facilitate greater alignment across research efforts and better reflect the published literature.

Biochemical recurrence in patients with prostate cancer after primary definitive therapy: treatment based on risk stratification.

BACKGROUND: Nearly one-third of patients with prostate cancer (PCa) experience biochemical recurrence (BCR) after primary definitive treatment. BCR increases the risk of distant metastasis and mortality in patients with prognostically unfavorable features. These patients are best managed with a tailored treatment strategy incorporating risk stratification using clinicopathological factors, next-generation imaging, and genomic testing. OBJECTIVE: This narrative review examines the utility of risk stratification for the management of patients with BCR in the context of clinical trial data, referencing the latest recommendations by European and US medical societies. METHODS: PubMed was searched for relevant studies published through May 21 2023 on treatment of patients with BCR after radical prostatectomy (RP) or external beam radiotherapy (EBRT). RESULTS: European and US guidelines support the risk-stratified management of BCR. Post-RP, salvage EBRT (with or without androgen deprivation therapy [ADT]) is an accepted treatment option for patients with BCR. Post-EBRT, local salvage therapies (RP, cryotherapy, high-intensity focused ultrasound, stereotactic body radiotherapy, and low-dose-rate and high-dose-rate brachytherapy) have demonstrated comparable relapse-free survival rates but differing adverse event profiles, short and long term. Local salvage therapies should be used for local-only relapses while ADT should be considered for regional or distant relapses. In practice, patients often receive ADT, with varying guidance for intermittent ADT vs. continuous ADT, due to consideration of quality-of-life effects. CONCLUSIONS: Despite a lack of consensus for BCR treatment among guideline associations and medical societies, risk stratification of patients is essential for personalized treatment approaches, as it allows for an informed selection of therapeutic strategies and estimation of adverse events. In lower-risk disease, observation is recommended while in higher-risk disease, after failed repeat local therapy, ADT and/or clinical trial enrollment may be appropriate. Results from ongoing clinical studies of patients with BCR should provide consensus for management.

Observer preference of artificial intelligence-generated versus clinical prostate contours for ultrasound-based high dose rate brachytherapy.

BACKGROUND: For trans-rectal ultrasound (TRUS)-based high dose rate (HDR) prostate brachytherapy, prostate contouring can be challenging due to artifacts from implanted needles, bleeding, and calcifications. PURPOSE: To evaluate the geometric accuracy and observer preference of an artificial intelligence (AI) algorithm for generating prostate contours on TRUS images with implanted needles. METHODS: We conducted a retrospective study of 150 patients, who underwent HDR brachytherapy. These patients were randomly divided into training (104), validation (26) and testing (20) sets. An AI algorithm was trained/validated utilizing the TRUS image and reference (clinical) contours. The algorithm then provided contours for the test set. For evaluation, we calculated the Dice coefficient between AI and reference prostate contours. We then presented AI and reference contours to eight clinician observers, and asked observers to select their preference. Observers were blinded to the source of contours. We calculated the percentage of cases in which observers preferred AI contours. Lastly, we evaluate whether the presence of AI contours improved the geometric accuracy of prostate contours provided by five resident observers for a 10-patient subset. RESULTS: The median Dice coefficient between AI and reference contours was 0.92 (IQR: 0.90-0.94). Observers preferred AI contours for a median of 57.5% (IQR: 47.5, 65.0) of the test cases. For resident observers, the presence of AI contours was associated with a 0.107 (95% CI: 0.086, 0.128; p < 0.001) improvement in Dice coefficient for the 10-patient subset. CONCLUSION: The AI algorithm provided high-quality prostate contours on TRUS with implanted needles. Further prospective study is needed to better understand how to incorporate AI prostate contours into the TRUS-based HDR brachytherapy workflow.

Salvage prostate brachytherapy in radiorecurrent prostate cancer: An international Delphi consensus study.

BACKGROUND AND PURPOSE: Local recurrences after previous radiotherapy (RT) are increasingly being identified in biochemically recurrent prostate cancer. Salvage prostate brachytherapy (BT) is an effective and well tolerated treatment option. We sought to generate international consensus statements on the use and preferred technical considerations for salvage prostate BT. MATERIALS AND METHODS: International experts in salvage prostate BT were invited (n = 34) to participate. A three-round modified Delphi technique was utilized, with questions focused on patient- and cancer-specific criteria, type and technique of BT, and follow-up. An a priori threshold for consensus of ≥ 75% was set, with a majority opinion being ≥ 50%. RESULTS: Thirty international experts agreed to participate. Consensus was achieved for 56% (18/32) of statements. Consensus was achieved in several areas of patient selection: 1) A minimum of 2-3 years from initial RT to salvage BT; 2) MRI and PSMA PET should be obtained; and 3) Both targeted and systematic biopsies should be performed. Several areas did not reach consensus: 1) Maximum T stage/PSA at time of salvage; 2) Utilization/duration of ADT; 3) Appropriateness of combining local salvage with SABR for oligometastatic disease and 4) Repeating a second course of salvage BT. A majority opinion preferred High Dose-Rate salvage BT, and indicated that both focal and whole gland techniques could be appropriate. There was no single preferred dose/fractionation. CONCLUSION: Areas of consensus within our Delphi study may serve as practical advice for salvage prostate BT. Future research in salvage BT should address areas of controversy identified in our study.

Hyaluronic Acid Spacer for Hypofractionated Prostate Radiation Therapy: A Randomized Clinical Trial.

Importance: Hypofractionated radiation therapy (RT) for prostate cancer has been associated with greater acute grade 2 gastrointestinal (GI) toxic effects compared with conventionally fractionated RT. Objective: To evaluate whether a hyaluronic acid rectal spacer could (1) improve rectal dosimetry and (2) affect acute grade 2 or higher GI toxic effects for hypofractionated RT. Design, Setting, and Participants: This randomized clinical trial was conducted from March 2020 to June 2021 among 12 centers within the US, Australia, and Spain, with a 6-month follow-up. Adult patients with biopsy-proven, T1 to T2 prostate cancer with a Gleason score 7 or less and prostate-specific antigen level of 20 ng/mL or less (to convert to µg/L, multiply by 1) were blinded to the treatment arms. Of the 260 consented patients, 201 patients (77.3%) were randomized (2:1) to the presence or absence of the spacer. Patients were stratified by intended 4-month androgen deprivation therapy use and erectile quality. Main Outcomes and Measures: For the primary outcome, we hypothesized that more than 70% of patients in the spacer group would achieve a 25% or greater reduction in the rectal volume receiving 54 Gy (V54). For the secondary outcome, we hypothesized that the spacer group would have noninferior acute (within 3 months) grade 2 or higher GI toxic effects compared with the control group, with a margin of 10%. Results: Of the 201 randomized patients, 8 (4.0%) were Asian, 26 (12.9%) Black, 42 (20.9%) Hispanic or Latino, and 153 (76.1%) White; the mean (SD) age for the spacer group was 68.6 (7.2) years and 68.4 (7.3) years for the control group. For the primary outcome, 131 of 133 (98.5%; 95% CI, 94.7%-99.8%) patients in the spacer group experienced a 25% or greater reduction in rectum V54, which was greater than the minimally acceptable 70% (P < .001). The mean (SD) reduction was 85.0% (20.9%). For the secondary outcome, 4 of 136 patients (2.9%) in the spacer group and 9 of 65 patients (13.8%) in the control group experienced acute grade 2 or higher GI toxic effects (difference, -10.9%; 95% 1-sided upper confidence limit, -3.5; P = .01). Conclusions and Relevance: The trial results suggest that rectal spacing with hyaluronic acid improved rectal dosimetry and reduced acute grade 2 or higher GI toxic effects. Rectal spacing should potentially be considered for minimizing the risk of acute grade 2 or higher toxic effects for hypofractionated RT. Trial Registration: ClinicalTrials.gov Identifier: NCT04189913.

Catheter reconstruction and dosimetric verification of MRI-only treatment planning (MRTP) for interstitial HDR brachytherapy using PETRA sequence.

Objective. The feasibility of MRI-only treatment planning (MRTP) for interstitial high-dose rate (HDR) brachytherapy (BT) was investigated for patients diagnosed with gynecologic cancer.Approach. A clinical MRTP workflow utilizing a 'pointwise encoding time reduction with radial acquisition (PETRA)' sequence was proposed. This is a clinically available MRI sequence optimized to improve interstitial catheter-tissue contrast. Interstitial needles outside the obturator region were reconstructed using MR images only. For catheters penetrating through the obturator, a library-based reconstruction was proposed. In this work, dwell coordinates from the clinical CT-based reconstruction were used as the surrogate for the library-based approach. For MR-only plan, dwell times were activated and assigned as in the clinical plans. The catheter reconstruction was assessed by comparing dwell position coordinates. The dosimetric comparisons between a clinical plan and MR-only plan were assessed for physical and EQD2 dose and volume parameters forD90,D50andD98for clinical target volume (CTV) andD2cc,D0.1ccandD5ccfor OARs.Main results. Catheter reconstruction was possible using the optimized PETRA sequence on MR images. An overall reconstruction difference of 1.7 ± 0.5 mm, attributed to registration-based errors, was found compared to the CT-based reconstruction. The MRTP workflow has the potential to generate a treatment plan with an equivalent dosimetric quality compared to the conventional CT/MRI-based approach. For CTVD90, physical and EQD2 dose and volume parameter differences were 1.5 ± 1.9% and 0.7 ± 1.0 Gy, respectively. ForD2ccOARs, DVH (EQD2) differences were -0.4 ± 1.1% (-0.2 ± 0.5 Gy), 0.5 ± 2.8% (0.2 ± 1.3 Gy) and -0.5 ± 1.4% (-0.2 ± 0.5 Gy) for rectum, bladder, and sigmoid, respectively.Significance. With the proposed MRTP approach, CT imaging may no longer be needed in HDR BT for interstitial gynecologic treatment. A proof-of-concept study was conducted to demonstrated that MRTP using PETRA is feasible, with comparable dosimetric results to the conventional CT/MRI-based approach.

Magnetic Resonance-Guided Prostate Stereotactic Body Radiation Therapy With Daily Online Plan Adaptation: Results of a Prospective Phase 1 Trial and Supplemental Cohort.

Purpose: Stereotactic magnetic resonance (MR)-guided adaptive radiation therapy (SMART) for prostate cancer allows for MR-based contouring, real-time MR motion management, and daily plan adaptation. The clinical and dosimetric benefits associated with prostate SMART remain largely unknown. Methods and Materials: A phase 1 trial of prostate SMART was conducted with primary endpoints of safety and feasibility. An additional cohort of patients similarly treated with prostate SMART were included in the analysis. SMART was delivered to 36.25 Gy in 5 fractions to the prostate ± seminal vesicles using the MRIdian linear accelerator system (ViewRay, Inc). Rates of urinary and gastrointestinal toxic effects and patient-reported outcome measures were assessed. Dosimetric analyses were conducted to evaluate the specific benefits of daily plan adaptation. Results: The cohort included 22 patients (n = 10 phase 1, n = 12 supplemental) treated in 110 fractions. Median follow-up was 7.9 months. Acute grade 2 urinary and gastrointestinal toxic effects were observed in 22.7% and 4.5%, respectively, and 4.5% and 0%, respectively, at last follow-up. No grade 3+ events were observed. Expanded Prostate Cancer Index-26 urinary obstructive scores decreased during SMART (mean, 9.3 points; P = .03) and returned to baseline by 3 months. No other significant changes in patient-reported outcome measures were observed. One-hundred percent of fractions required plan adaptation owing to exceeding organ-at-risk metrics (68%) or suboptimal target coverage (33%) resulting from anatomic changes. Minimum acceptable planning target volume, rectal, bladder, and urethra/bladder neck metrics were violated in 24%, 20%, 24%, and 33% of predicted plans, respectively; 0% of reoptimized plans violated metrics. Underlying causes for deficient dosimetry before reoptimization included changes in bladder filling, seminal vesicle position, prostate volume (median 4.7% increase by fraction 3; range, 0%-56%), and hotspots shifting into urethra/bladder neck. Conclusions: Prostate SMART results in low risk of acute toxic effects with improvements in target and organ-at-risk dosimetry. The clinical benefits resulting from daily plan adaptation, including urethra/bladder neck protection, warrant further investigation.

First pointwise encoding time reduction with radial acquisition (PETRA) implementation for catheter detection in interstitial high-dose-rate (HDR) brachytherapy.

PURPOSE: A pointwise encoding time reduction with radial acquisition (PETRA) sequence was optimized to detect empty catheters in interstitial (HDR) brachytherapy with clinically acceptable spatial accuracy for the first time. Image quality and catheter detectability were assessed in phantoms, and the feasibility of PETRA's clinical implementation was assessed on a gynecological cancer patient. METHODS AND RESULTS: Empty catheters embedded in a gelatin phantom displayed positive signal on PETRA and more accurate cross-sections than on clinically employed T2-weighted sequences, differing by 0.4 mm on average from their nominal 2 mm diameter. PETRA presented minimal susceptibility differences and a symmetric metal artifact, contrary to the clinical sequences. The PETRA-CT catheter tip position differences assessed by a treatment planning system (TPS) were < 1 mm. PETRA also detected an interstitial template with empty catheters penetrating a poultry phantom and fused very well with CT. Interstitial catheter positional difference between PETRA and CT images was < 1 mm on average, increasing with distance from isocenter. All interstitial catheters and the employed interstitial template were detected on PETRA images of an endometrial adenocarcinoma patient. Empty needles were traceable using a TPS, with higher spatial resolution and more favorable contrast than on T2-weighted images used for contouring. A treatment plan could be produced by combining information from PETRA for catheter detection and from T2-weighted images for tumor and organs delineation. CONCLUSIONS: PETRA detected successfully and accurately interstitial catheters in phantoms. Its first clinical implementation shows a potential for MR-only treatment planning in interstitial HDR brachytherapy.

Clinical outcomes and dosimetric predictors of toxicity for re-irradiation of vaginal recurrence of endometrial cancer.

OBJECTIVE: To report clinical outcomes and dosimetric predictors of late toxicity for patients with vaginal recurrence of endometrial cancer treated with brachytherapy in the re-irradiation setting. METHODS: On retrospective review, 32 patients with vaginal recurrence of endometrial cancer received salvage brachytherapy with or without pelvic radiotherapy (RT) from 06/2003-12/2017. Prior RT modalities were vaginal brachytherapy (19, 59%), pelvic RT (7, 22%) or both (6, 19%). Image-guided brachytherapy was performed with CT- (25, 78%) or MR-guidance (7, 22%). Vaginal control, recurrence-free survival (RFS) and overall survival (OS) were estimated by Kaplan-Meier method. Late toxicity was graded by Common Toxicity Criteria for Adverse Events. RESULTS: Median time from prior RT to re-irradiation was 22 months (range, 4-140). Salvage RT modalities were pelvic RT and brachytherapy (25, 78%) or brachytherapy alone (7, 22%). With median follow-up of 47 months, 3/5-year vaginal control, RFS and OS rates were 64/56%, 47/41% and 68/42%, respectively. Six patients (19%) had no evidence of disease at 85-155 months. Late grade 2/3 GI, GU and vaginal toxicity rates were 13%/16%, 19%/13%, and 9%/16%. Cumulative D2cc rectum (sum of prior and salvage RT courses) was predictive of grade 2+ and grade 3 GI toxicity. Cumulative D2cc rectum for an estimated 10% risk of late grade 2+ and 3 GI toxicity was 86 Gy and 92 Gy, respectively. CONCLUSIONS: Salvage image-guided brachytherapy in the re-irradiation setting results in modest local control and increased late toxicity for localized recurrent endometrial cancer. With long-term disease control, cumulative D2cc rectum may be used to reduce late GI complication risk.

Low dose rate brachytherapy for primary treatment of localized prostate cancer: A systemic review and executive summary of an evidence-based consensus statement.

PURPOSE: The purpose of this guideline is to present evidence-based consensus recommendations for low dose rate (LDR) permanent seed brachytherapy for the primary treatment of prostate cancer. METHODS AND MATERIALS: The American Brachytherapy Society convened a task force for addressing key questions concerning ultrasound-based LDR prostate brachytherapy for the primary treatment of prostate cancer. A comprehensive literature search was conducted to identify prospective and multi-institutional retrospective studies involving LDR brachytherapy as monotherapy or boost in combination with external beam radiation therapy with or without adjuvant androgen deprivation therapy. Outcomes included disease control, toxicity, and quality of life. RESULTS: LDR prostate brachytherapy monotherapy is an appropriate treatment option for low risk and favorable intermediate risk disease. LDR brachytherapy boost in combination with external beam radiation therapy is appropriate for unfavorable intermediate risk and high-risk disease. Androgen deprivation therapy is recommended in unfavorable intermediate risk and high-risk disease. Acceptable radionuclides for LDR brachytherapy include iodine-125, palladium-103, and cesium-131. Although brachytherapy monotherapy is associated with increased urinary obstructive and irritative symptoms that peak within the first 3 months after treatment, the median time toward symptom resolution is approximately 1 year for iodine-125 and 6 months for palladium-103. Such symptoms can be mitigated with short-term use of alpha blockers. Combination therapy is associated with worse urinary, bowel, and sexual symptoms than monotherapy. A prostate specific antigen <= 0.2 ng/mL at 4 years after LDR brachytherapy may be considered a biochemical definition of cure. CONCLUSIONS: LDR brachytherapy is a convenient, effective, and well-tolerated treatment for prostate cancer.

Second malignancy probabilities in prostate cancer patients treated with SBRT and other contemporary radiation techniques.

BACKGROUND: Prostate radiotherapy has been associated with an increased risk of developing a second malignancy (SM). However, relative SM probabilities following treatment with contemporary radiation techniques such as stereotactic body radiotherapy (SBRT) or moderately hypofractionated intensity modulated radiotherapy (HF-IMRT) remain unknown. METHODS: A cohort analysis was performed of men from a nationally representative database with localized prostate cancer with at least 60 months of follow-up comparing SM probability amongst men receiving either radical prostatectomy (RP), conventionally fractionated intensity-modulated radiotherapy (CF-IMRT), HF-IMRT, brachytherapy (BT), or SBRT, using multivariable logistic models, which were used to generate predicted probabilities. Additionally, propensity score-adjusted pairwise assessments of modalities were performed. RESULTS: For 303,432 patients included in the study, median follow-up was 9.08 years (IQR 7.01-11.21). Predicted rates of SM by treatment modality and adjusted odds ratios (AOR) for development of SM (referent: RP) were: 6.0% for RP (AOR n/a), 7.1% for CF-IMRT (AOR 1.20, 95%CI 1.14-1.25, P < 0.001), 7.3% for HF-IMRT (AOR 1.25, 95%CI 1.01-1.55, P = 0.045), 6.6% for BT (AOR 1.11, 95%CI 1.07-1.16, P < 0.001), and 5.7% for SBRT (AOR 0.95, 95%CI 0.81-1.12, P = 0.567). On propensity score-adjusted analysis, SBRT was associated with lower odds of SM compared to CF-IMRT (AOR 0.78, 95%CI 0.66-0.93, P = 0.005); no significant difference was found when SBRT was compared to RP (AOR 0.86, 95%CI 0.73-1.03, P = 0.102). CONCLUSIONS: Conventionally fractionated intensity-modulated radiotherapy, moderately hypofractionated intensity-modulated radiotherapy, and brachytherapy but not stereotactic body radiotherapy were associated with increased probability of a second malignancy compared to radical prostatectomy. Patients treated with SBRT may be at lower risk of second malignancy due to improved conformality, radiobiological differences or patient selection. The possibility that SBRT in select patients may minimize the probability of SM underscores the need for assessment of second malignancy risk in prospective studies of SBRT.

Adjuvant Radiation Field Extent and Sites of Failure in Node Positive Endometrioid Endometrial Cancer.

PURPOSE: In patients with node-positive endometrial cancer, adjuvant radiation therapy with chemotherapy decreases local-regional recurrence compared with chemotherapy alone. However, the optimal radiation field borders and extent of nodal coverage have not been well studied. In a multi-institutional cohort, survival outcomes and sites of failure were analyzed for patients with International Federation of Gynaecology and Obstetrics (FIGO) stage IIIC endometrioid endometrial cancer treated with pelvic radiation therapy (PRT) versus extended-field radiation therapy (EFRT), which encompassed high para-aortic lymph nodes. METHODS AND MATERIALS: In a multi-institutional retrospective study, 143 patients with FIGO stage IIIC1 or IIIC2 endometrioid endometrial cancer treated with adjuvant radiation therapy from 2000 to 2016 were identified. Patient subgroups were classified by substage and radiation field extent: stage IIIC1 received EFRT, stage IIIC1 received PRT, and stage IIIC2 received EFRT. Recurrence-free survival (RFS), overall survival (OS), and out-of-field recurrence were calculated by the Kaplan-Meier method. Multivariate analysis was performed using the Cox proportional hazards model. Sites of failure were categorized as within or outside the radiation field. RESULTS: The median follow-up was 59 months; 87% of patients received chemotherapy. The 5-year RFS and OS rates were 73% and 87%, respectively. By subgroup, 5-year RFS rates were 79% for stage IIIC1 EFRT, 73% for stage IIIC1 PRT, and 69% for stage IIIC2 EFRT (P = .4). On multivariate analysis, the recurrence risk was highest for stage IIIC2 EFRT, although this result was not statistically significant (adjusted hazard ratio, 2.0; P = .4). In-field vaginal and nodal recurrences were observed in 2 patients (1%) and 4 patients (3%), respectively. Of 78 patients with stage IIIC1 cancer treated with PRT, 5 (6%) had isolated para-aortic nodal relapse outside the radiation field; 3 were long-term survivors (more than 6 years after salvage therapy). For patients with para-aortic recurrence, 86% had lymphovascular invasion, 71% had myometrial invasion of ≥50%, and 57% had grade 3 disease. CONCLUSIONS: Adjuvant chemoradiation therapy resulted in excellent survival outcomes for patients with FIGO stage IIIC endometrioid endometrial cancer. For patients with positive pelvic nodes, isolated para-aortic relapse outside the PRT field was uncommon and amenable to salvage therapy.

Association of Increased Prostate-Specific Antigen Levels After Treatment and Mortality in Men With Locally Advanced vs Localized Prostate Cancer: A Secondary Analysis of 2 Randomized Clinical Trials.

Importance: Increased prostate-specific antigen (PSA) levels after treatment (PSA failure) may have different associations with outcomes for men with locally advanced vs localized prostate cancer. Objective: To evaluate whether the association between PSA failure and death may be different in locally advanced vs localized prostate cancer. Design, Setting, and Participants: This multicenter cohort study included patients from 2 randomized clinical trials. The Dana-Farber Cancer Institute (DFCI) 95-096 trial randomized 206 men with localized prostate cancer from December 1, 1995, to April 15, 2001, whereas the European Organisation for Research and Treatment of Cancer (EORTC) 22961 trial randomized 970 men with locally advanced prostate cancer from October 30, 1997, to May 1, 2002. Data were analyzed from January 1, 2020, to October 31, 2020. Interventions: The DFCI 95-096 trial randomized men to 0 vs 6 months of androgen deprivation therapy (ADT) with external beam radiotherapy; the EORTC 22961 trial randomized men to 6 vs 36 months of ADT with external beam radiotherapy. Main Outcomes and Measures: For each trial, the PSA doubling time (time to doubling of PSA levels) associated with PSA failure was evaluated. The risk of all-cause mortality associated with PSA failure (nadir plus 2 definition) was evaluated after adjustment of baseline covariates and treatment. Results: This analysis included a total of 1173 men (206 from DFCI 95-096 and 967 with available tumor stage from EORTC 22961; median age, 70.0 [interquartile range (IQR), 65.0-74.0 years). For DFCI 95-096, 161 men died (30 [18.6%] due to prostate cancer) at a median follow-up of 18.2 (IQR, 17.3-18.8) years. Among the 108 men with PSA failure, the median PSA doubling time was 13.0 (IQR, 7.4-31.1) months. For EORTC 22961, 230 men died (75 [32.6%] due to prostate cancer) at a median follow-up of 6.4 (IQR, 6.3-6.6) years. Among 290 men who experienced PSA failure, the median PSA doubling time was 5.0 (IQR, 2.9-8.9) months. Compared with DFCI 95-096, PSA failure was associated with a higher risk of all-cause mortality in EORTC 22961 (adjusted hazard ratios, 3.98 [95% CI, 2.92-5.44]; P < .001 vs 1.51 [95% CI, 1.03-2.23]; P = .04). Conclusions and Relevance: The association of PSA failure with outcomes may differ between locally advanced and localized prostate cancer. This finding supports the study of treatment intensification with the use of novel antiandrogen agents in addition to ADT at the time of PSA failure after treatment for locally advanced disease. Trial Registration: ClinicalTrials.gov Identifiers: NCT00116220 and NCT00003026.

Selection criteria for high-dose-rate surface brachytherapy and electron beam therapy in cutaneous oncology.

PURPOSE: High-dose-rate (HDR) brachytherapy is an alternative treatment to electron external beam radiation therapy (EBRT) of superficial skin lesions. The purpose of this study was to establish the selection criteria for HDR brachytherapy technique (HDR-BT) and EBRT in cutaneous oncology for various clinical scenarios. MATERIAL AND METHODS: The study consists of two parts: a) EBRT and HDR-BT treatment plans comparison analyzing clinical target volumes (CTVs) with different geometries, field sizes, and topologies, and b) development of a prediction model capable of characterization of dose distributions in HDR surface brachytherapy for various geometries of treatment sites. RESULTS: A loss of CTV coverage for the electron plans (D90, D95) was recorded up to 45%, when curvature of the applicator increased over 30°. Values for D2 cm3 for both plans were comparable, and they were in range of ±8% of prescription dose. An increase in higher doses (D0.5 cm3 and D0.1 cm3) was observed in HDR-BT plans, and it was greater for larger lesions. The average increase was 3.8% for D0.5 cm3 and 12.3% for D0.1 cm3. When CTV was approximately flat, electron plans were comparable with HDR-BT plans, having lower average D2 cm3, D0.5 cm3, and D0.1 cm3 of 7.7%. Degradation of quality of electron plans was found to be more dependent on target curvature than on CTV size. CONCLUSIONS: Both EBRT and HDR-BT could be used in treatments of superficial lesions. HDR-BT revealed superior CTV coverage when the surface was very large, complex, curvy, or rounded, and when the topology was complicated. The prediction model can be used for an approximate calculation and quick assessment of radiation dose to organs-at-risk (OARs), at a depth or at a lateral distance from CTV.

Triaging abnormal cervical cancer screening tests using p16INK4a detection by ELISA on fresh cervical samples.

PROBLEM: Cervical cancer screening strategies in the United States include cotesting (human papillomavirus (HPV) with cytology), primary HPV with genotyping and reflex cytology, and cytology alone. An ongoing challenge is the appropriate triage of patients to colposcopy to those at highest risk. We investigated whether incorporation of p16INK4a immunodetection by enzyme-linked immunosorbent assay (ELISA) on fresh cervical samples obtained at the time of screening could improve appropriate referral to colposcopy. METHOD OF STUDY: A derivation group comprised of cervical swabs collected from subjects with high-grade dysplasia or cancer (positive control) and from subjects with negative screening history (negative control). Samples collected from colposcopy were used to evaluate the existing screening strategies individually and with incorporation of p16INK4a ELISA. Histology was used as the gold standard. RESULTS: Among 163 subjects recruited, 138 were included. In the derivation group, mean p16INK4a level was 2.86 ng/mL (n = 31) and 0.58 ng/mL (n = 20) among positive and negative controls respectively (p = 0.002) with an area under the receiver operator characteristic curve of 0.79 (p < 0.001). Among colposcopy subjects, sensitivity/specificity for cotesting, primary HPV, and cytology were 94%/42%, 88%/45%, and 88%/49%, respectively. Incorporation of p16INK4a resulted in similar sensitivity and improved specificity (cotesting+p16 88%/58%, primary HPV+p16 88%/57%, cytology+p16 81%/62%; p = 0.23/p = 0.008) with decrease in colposcopy referrals by 15% to 22% (p = 0.01). CONCLUSIONS: These results demonstrate the feasibility of quantifying p16INK4a by ELISA in fresh cervical samples, and its potential as an adjunct to existing screening strategies in the identification of high grade-dysplasia while reducing the number of colposcopic referrals.