Streamlined pin-ridge-filter design for single-energy proton FLASH planning.

BACKGROUND: FLASH radiotherapy (FLASH-RT) with ultra-high dose rate has yielded promising results in reducing normal tissue toxicity while maintaining tumor control. Planning with single-energy proton beams modulated by ridge filters (RFs) has been demonstrated feasible for FLASH-RT. PURPOSE: This study explored the feasibility of a streamlined pin-shaped RF (pin-RF) design, characterized by coarse resolution and sparsely distributed ridge pins, for single-energy proton FLASH planning. METHODS: An inverse planning framework integrated within a treatment planning system was established to design streamlined pin RFs for single-energy FLASH planning. The framework involves generating a multi-energy proton beam plan using intensity-modulated proton therapy (IMPT) planning based on downstream energy modulation strategy (IMPT-DS), followed by a nested pencil-beam-direction-based (PBD-based) spot reduction process to iteratively reduce the total number of PBDs and energy layers along each PBD for the IMPT-DS plan. The IMPT-DS plan is then translated into the pin-RFs and the single-energy beam configurations for IMPT planning with pin-RFs (IMPT-RF). This framework was validated on three lung cases, quantifying the FLASH dose of the IMPT-RF plan using the FLASH effectiveness model. The FLASH dose was then compared to the reference dose of a conventional IMPT plan to measure the clinical benefit of the FLASH planning technique. RESULTS: The IMPT-RF plans closely matched the corresponding IMPT-DS plans in high dose conformity (conformity index of <1.2), with minimal changes in V7Gy and V7.4 Gy for the lung (<3%) and small increases in maximum doses (Dmax) for other normal structures (<3.4 Gy). Comparing the FLASH doses to the doses of corresponding IMPT-RF plans, drastic reductions of up to nearly 33% were observed in Dmax for the normal structures situated in the high-to-moderate-dose regions, while negligible changes were found in Dmax for normal structures in low-dose regions. Positive clinical benefits were seen in comparing the FLASH doses to the reference doses, with notable reductions of 21.4%-33.0% in Dmax for healthy tissues in the high-dose regions. However, in the moderate-to-low-dose regions, only marginal positive or even negative clinical benefit for normal tissues were observed, such as increased lung V7Gy and V7.4 Gy (up to 17.6%). CONCLUSIONS: A streamlined pin-RF design was developed and its effectiveness for single-energy proton FLASH planning was validated, revealing positive clinical benefits for the normal tissues in the high dose regions. The coarsened design of the pin-RF demonstrates potential advantages, including cost efficiency and ease of adjustability, making it a promising option for efficient production.

CBCT-Based synthetic CT image generation using conditional denoising diffusion probabilistic model.

BACKGROUND: Daily or weekly cone-beam computed tomography (CBCT) scans are commonly used for accurate patient positioning during the image-guided radiotherapy (IGRT) process, making it an ideal option for adaptive radiotherapy (ART) replanning. However, the presence of severe artifacts and inaccurate Hounsfield unit (HU) values prevent its use for quantitative applications such as organ segmentation and dose calculation. To enable the clinical practice of online ART, it is crucial to obtain CBCT scans with a quality comparable to that of a CT scan. PURPOSE: This work aims to develop a conditional diffusion model to perform image translation from the CBCT to the CT distribution for the image quality improvement of CBCT. METHODS: The proposed method is a conditional denoising diffusion probabilistic model (DDPM) that utilizes a time-embedded U-net architecture with residual and attention blocks to gradually transform the white Gaussian noise sample to the target CT distribution conditioned on the CBCT. The model was trained on deformed planning CT (dpCT) and CBCT image pairs, and its feasibility was verified in brain patient study and head-and-neck (H&N) patient study. The performance of the proposed algorithm was evaluated using mean absolute error (MAE), peak signal-to-noise ratio (PSNR) and normalized cross-correlation (NCC) metrics on generated synthetic CT (sCT) samples. The proposed method was also compared to four other diffusion model-based sCT generation methods. RESULTS: In the brain patient study, the MAE, PSNR, and NCC of the generated sCT were 25.99 HU, 30.49 dB, and 0.99, respectively, compared to 40.63 HU, 27.87 dB, and 0.98 of the CBCT images. In the H&N patient study, the metrics were 32.56 HU, 27.65 dB, 0.98 and 38.99 HU, 27.00, 0.98 for sCT and CBCT, respectively. Compared to the other four diffusion models and one Cycle generative adversarial network (Cycle GAN), the proposed method showed superior results in both visual quality and quantitative analysis. CONCLUSIONS: The proposed conditional DDPM method can generate sCT from CBCT with accurate HU numbers and reduced artifacts, enabling accurate CBCT-based organ segmentation and dose calculation for online ART.

Integration of Radiation Oncology Into the Preclinical Curriculum Through Problem-Based Learning.

PURPOSE: Early exposure to oncology care during the preclinical years of medical school may translate to increased student interest in oncology-related fields and improved understanding of oncologic treatment modalities, including radiation oncology. Many schools incorporate problem-based learning (PBL) into the medical school curriculum; this is an opportunity to immerse students in oncologic case management. We describe the effective incorporation of one course into the medical school curriculum that may be replicated at other institutions. METHODS AND MATERIALS: A PBL case regarding pancreatic cancer was created by a radiation oncology resident and faculty member in collaboration with the gastrointestinal course director for first-year medical students at a single institution. Pancreatic cancer was chosen based on curricular needs. Learning objectives were discussed to guide the creation of the case. RESULTS: All 140 first-year medical students participated in the 1-hour small group case focused on oncologic work up, multidisciplinary care, and radiation therapy concepts. Students were provided with a case prompt and resources to review prior to the PBL session. Volunteer radiation oncology facilitators attended a 30-minute educational meeting and were provided a detailed case guide 1 week before the PBL session. During the PBL case, facilitators guided students to achieve desired learning objectives. Among the 76 (54%) medical students who completed an optional post-PBL survey, the majority reported that the case motivated them to learn more about oncology (89%) and radiation oncology (82%). There was an increase in the number of subscribers to the Oncology Interest Group (43% increase from previous year) and preclinical students shadowing in the radiation oncology department. The PBL case was continued in future years for all first-year students and extended to 2 hours to promote additional discussion in response to student and facilitator feedback. CONCLUSIONS: A cancer-specific PBL case facilitated by radiation oncology educators is an effective avenue to integrate radiation oncology into the preclinical curriculum and stimulate interest in oncology among first-year medical students.

Long-term risk of carotid stenosis and cerebrovascular disease after radiation therapy for head and neck cancer.

BACKGROUND: Recipients of radiation therapy (RT) for head and neck cancer (HNC) are at significantly increased risk for carotid artery stenosis (CAS) and cerebrovascular disease (CVD). We sought to determine (1) cumulative incidences of CAS and CVD among HNC survivors after RT and (2) whether CAS is associated with a RT dose response effect. METHODS: This single-institution retrospective cohort study examined patients with nonmetastatic HNC who completed (chemo)RT from January 2000 through October 2020 and subsequently received carotid imaging surveillance ≤2 years following RT completion and, in the absence of CAS, every 3 years thereafter. Exclusion criteria included history of known CAS/CVD. Asymptomatic CAS was defined as ≥50% reduction of luminal diameter, symptomatic CAS as stroke or transient ischemic attack, and composite CAS as asymptomatic or symptomatic CAS. RESULTS: Of 628 patients undergoing curative intent RT for HNC, median follow-up was 4.8 years (interquartile range, 2.6-8.3), with 97 patients followed ≥10 years. Median age was 61 years and 69% of patients received concurrent chemotherapy and 28% were treated postoperatively. Actuarial 10-year incidences of asymptomatic, symptomatic, and composite CAS were 29.6% (95% CI, 23.9-35.5), 10.1% (95% CI, 7.0-13.9), and 27.2% (95% CI, 22.5-32.1), respectively. Multivariable Cox models significant association between asymptomatic CAS and absolute carotid artery volume receiving ≥10 Gy (per mL: hazard ratio, 1.09; 95% CI, 1.02-1.16). CONCLUSIONS: HNC survivors are at high risk for post-RT CAS. A dose response effect was observed for asymptomatic CAS at doses as low as 10 Gy. PLAIN LANGUAGE SUMMARY: Recipients of radiation therapy for head and neck cancer are at significantly increased risk for carotid artery stenosis and cerebrovascular disease. However, carotid artery screening is not routinely performed among head and neck survivors following radiation therapy. In this single-institution retrospective cohort study, patients with head and neck cancer were initially screened for carotid artery stenosis ≤2 years following radiation therapy completion, then every 3 years thereafter. The 10-year actuarial incidence of carotid artery stenosis was >25% and stroke/transient ischemic attack >10%. Multivariable analysis demonstrated significant associations between asymptomatic carotid artery stenosis and artery volumes receiving ≥10 Gy.

Streamlined Pin-Ridge-Filter Design for Single-energy Proton FLASH Planning.

PURPOSE: This study explored the feasibility of a streamlined pin-shaped ridge filter (pin-RF) design for single-energy proton FLASH planning. METHODS: An inverse planning framework integrated within a TPS was established for FLASH planning. The framework involves generating a IMPT plan based on downstream energy modulation strategy (IMPT-DS), followed by a nested spot reduction process to iteratively reduce the total number of pencil beam directions (PBDs) and energy layers along each PBD for the IMPT-DS plan. The IMPT-DS plan is then translated into the pin-RFs for a single-energy IMPT plan (IMPT-RF). The framework was validated on three lung cases, quantifying the FLASH dose of the IMPT-RF plan using the FLASH effectiveness model and comparing it with the reference dose of a conventional IMPT plan to assess the clinical benefit of the FLASH planning technique. RESULTS: The IMPT-RF plans closely matched the corresponding IMPT-DS plans in high dose conformity, with minimal changes in V7Gy and V7.4Gy for the lung (< 5%) and small increases in Dmax for other OARs (< 3.2 Gy). Comparing the FLASH doses to the doses of corresponding IMPT-RF plans, drastic reductions of up to ~33% were observed in Dmax for OARs in the high-to-moderate-dose regions with negligible changes in Dmax for OARs in low-dose regions. Positive clinical benefits were observed with notable reductions of 18.4-33.0% in Dmax for OARs in the high-dose regions. However, in the moderate-to-low-dose regions, only marginal positive or even negative clinical benefit for OARs were observed, such as increased lung V7Gy and V7.4Gy (16.4-38.9%). CONCLUSIONS: A streamlined pin-RF design for single-energy proton FLASH planning was validated, revealing positive clinical benefits for OARs in the high dose regions. The coarsened design of the pin-RF demonstrates potential cost efficiency and efficient production.

Radiation Facility Volume and Survival for Men With Very High-Risk Prostate Cancer Treated with Radiation and Androgen Deprivation Therapy.

Importance: Very high-risk (VHR) prostate cancer is an aggressive substratum of high-risk prostate cancer, characterized by high prostate-specific antigen levels, high Gleason score, and/or advanced T category. Contemporary management paradigms involve advanced molecular imaging and multimodal treatment with intensified prostate-directed or systemic treatment-resources more readily available at high-volume centers. Objective: To examine radiation facility case volume and overall survival (OS) in men with VHR prostate cancer. Design, Setting, and Participants: A retrospective cohort study was performed from November 11, 2022, to March 4, 2023, analyzing data from US facilities reporting to the National Cancer Database. Patients included men diagnosed with nonmetastatic VHR prostate cancer by National Comprehensive Cancer Network criteria (clinical T3b-T4 category, primary Gleason pattern 5, >4 cores with grade group 4-5, and/or 2-3 high-risk features) and treated with curative-intent radiotherapy and androgen deprivation therapy between January 1, 2004, to December 31, 2016. Exposures: Treatment at high- vs low-average cumulative facility volume (ACFV), defined as the total number of prostate radiotherapy cases at an individual patient's treatment facility from 2004 until the year of their diagnosis. The nonlinear association between a continuous ACFV and OS was examined through a Martingale residual plot; an optimal ACFV cutoff was identified that maximized the separation between high vs low ACFV via a bias-adjusted log rank test. Main Outcomes and Measures: Overall survival was assessed between high vs low ACFV using Kaplan-Meier analysis with and without inverse probability score weighted adjustment and multivariable Cox proportional hazards. Results: A total of 25 219 men (median age, 71 [IQR, 64-76] years; 78.7% White) with VHR prostate cancer were identified, 6438 (25.5%) of whom were treated at high ACFV facilities. Median follow-up was 57.4 (95% CI, 56.7-58.1) months. Median OS for patients treated at high ACFV centers was 123.4 (95% CI, 116.6-127.4) months vs 109.0 (95% CI, 106.5-111.2) months at low ACFV centers (P < .001). On multivariable analysis, treatment at a high ACFV center was associated with lower risk of death (hazard ratio, 0.89; 95% CI, 0.84-0.95; P < .001). These results were also significant after inverse probability score weighted-based adjustment. Conclusions and Relevance: In this cohort study of patients with VHR prostate cancer who underwent definitive radiotherapy and androgen deprivation therapy, facility case volume was independently associated with longer OS. Further studies are needed to identify which factors unique to high-volume centers may be responsible for this benefit.

An optimized framework for cone-beam computed tomography-based online evaluation for proton therapy.

BACKGROUND: Clinical evidence has demonstrated that proton therapy can achieve comparable tumor control probabilities compared to conventional photon therapy but with the added benefit of sparing healthy tissues. However, proton therapy is sensitive to inter-fractional anatomy changes. Online pre-fraction evaluation can effectively verify proton dose before delivery to patients, but there is a lack of guidelines for implementing this workflow. PURPOSE: The purpose of this study is to develop a cone-beam CT-based (CBCT) online evaluation framework for proton therapy that enables knowledge transparency and evaluates the efficiency and accuracy of each essential component. METHODS: Twenty-three patients with various lesion sites were included to conduct a retrospective study of implementing the proposed CBCT evaluation framework for the clinic. The framework was implemented on the RayStation 11B Research platform. Two synthetic CT (sCT) methods, corrected CBCT (cCBCT), and virtual CT (vCT), were used, and the ground truth images were acquired from the same-day deformed quality assurance CT (dQACT) for the comparisons. The evaluation metrics for the framework include time efficiency, dose-difference distributions (gamma passing rates), and water equivalent thickness (WET) distributions. RESULTS: The mean online CBCT evaluation times were 1.6 ± 0.3 min and 1.9 ± 0.4 min using cCBCT and vCT, respectively. The dose calculation and deformable image registration dominated the evaluation efficiency, and accounted for 33% and 30% of the total evaluation time, respectively. The sCT generation took another 19% of the total time. Gamma passing rates were greater than 91% and 97% using 1%/1 mm and 2%/2 mm criteria, respectively. When the appropriate sCT was chosen, the target mean WET difference from the reference were less than 0.5 mm. The appropriate sCT method choice determined the uncertainty for the framework, with the cCBCT being superior for head-and-neck patient evaluation and vCT being better for lung patient evaluation. CONCLUSIONS: An online CBCT evaluation framework was proposed to identify the use of the optimal sCT algorithm regarding efficiency and dosimetry accuracy. The framework is extendable to adopt advanced imaging methods and has the potential to support online adaptive radiotherapy to enhance patient benefits. It could be implemented into clinical use in the future.

Factors Affecting Clinical Outcomes Among Patients Infected With HIV and Anal Cancer Treated With Modern Definitive Chemotherapy and Radiation Therapy.

Purpose: Anal cancer affects a disproportionate percentage of persons infected with human immunodeficiency virus (HIV). We analyzed a cohort of patients with HIV and anal cancer who received modern radiation therapy (RT) and concurrent chemotherapy to assess whether certain factors are associated with poor oncologic outcomes. Patients and Methods: We performed a retrospective chart review of 75 consecutive patients with HIV infection and anal cancer who received definitive chemotherapy and RT from 2008 to 2018 at a single academic institution. Local recurrence, overall survival, changes in CD4 counts, and toxicities were investigated. Results: Most patients were male (92%) with large representation from Black patients (77%). The median pretreatment CD4 count was 280 cells/mm3, which was persistently lower at 6 and 12 months' posttreatment, 87 cells/mm3 and 182 cells/mm3, respectively (P < .001). Most (92%) patients received intensity modulated RT; median dose was 54 Gy (Range, 46.8-59.4 Gy). At a median follow-up 5.4 years (Range, 4.37-6.21 years), 20 (27%) patients had disease recurrence and 10 (13%) had isolated local failures. Nine patients died due to progressive disease. In multivariable analysis, clinically node negative involvement was significantly associated with better overall survival (hazard ratio, 0.39; 95% confidence interval, 0.16-1.00, P = .049). Acute grade 2 and 3 skin toxicities were common, at 83% and 19%, respectively. Acute grade 2 and 3 gastrointestinal toxicities were 9% and 3%, respectively. Acute grade 3 hematologic toxicity was 20%, and one grade 5 toxicity was reported. Several late grade 3 toxicities persisted: gastrointestinal (24%), skin (17%), and hematologic (6%). Two late grade 5 toxicities were noted. Conclusions: Most patients with HIV and anal cancer did not experience local recurrence; however, acute and late toxicities were common. CD4 counts at 6 and 12 months' posttreatment remained lower than pretreatment CD4 counts. Further attention to treatment of the HIV-infected population is needed.

Impact of 18 F-Fluciclovine PET/CT Findings on Failure-Free Survival in Biochemical Recurrence of Prostate Cancer Following Salvage Radiation Therapy.

PURPOSE: We aimed to evaluate the impact of 18 F-fluciclovine PET/CT imaging on failure-free survival (FFS) post-salvage radiotherapy (SRT) for prostate cancer (PCa) recurrence. METHODS: Seventy-nine patients were recruited in a phase 2/3 clinical trial to undergo 18 F-fluciclovine PET/CT before SRT for PCa. Four patients with extrapelvic disease were excluded. All patients were followed up at regular intervals up to 48 months. Treatment failure was defined as a serum prostate-specific antigen level of ≥0.2 ng/mL above the nadir after SRT, confirmed with an additional measurement, requiring systemic treatment or clinical progression. Failure-free survival was computed and compared between patients grouped according to 18 F-fluciclovine PET/CT imaging findings. RESULTS: Eighty percent (60/75) of patients had a positive finding on 18 F-fluciclovine PET/CT, of which 56.7% (34/60) had prostate bed-only uptake, whereas 43.3% (26/60) had pelvic nodal ± bed uptake. Following SRT, disease failure was detected in 36% (27/75) of patients. There was a significant difference in FFS between patients who had a positive versus negative scan (62.3% vs 92.9% [ P < 0.001] at 36 months and 59.4% vs 92.9% [ P < 0.001] at 48 months). Similarly, there was a significant difference in FFS between patients with uptake in pelvic nodes ± bed versus prostate bed only at 36 months (49.8% vs 70.7%; P = 0.003) and at 48 months (49.8% vs 65.6%; P = 0.040). Failure-free survival was also significantly higher in patients with either negative PET/CT or prostate bed-only disease versus those with pelvic nodal ± prostate bed disease at 36 (78% vs 49.8%, P < 0.001) and 48 months (74.4% vs 49.8%, P < 0.001). CONCLUSIONS: Findings on pre-SRT 18 F-fluciclovine PET/CT imaging, even when acted upon to optimize the treatment decisions and treatment planning, are predictive of post-SRT FFS in men who experience PCa recurrence after radical prostatectomy. A negative 18 F-fluciclovine PET/CT is most predictive of a lower risk of failure, whereas the presence of pelvic nodal recurrence portends a higher risk of SRT failure.

Differences in Failure-Free Survival After Salvage Radiotherapy Guided by Conventional Imaging Versus 18F-Fluciclovine PET/CT in Postprostatectomy Patients: A Post Hoc Substratification Analysis of the EMPIRE-1 Trial.

The EMPIRE-1 (Emory Molecular Prostate Imaging for Radiotherapy Enhancement 1) trial reported a survival advantage in recurrent prostate cancer salvage radiotherapy (SRT) guided by 18F-fluciclovine PET/CT versus conventional imaging. We performed a post hoc analysis of the EMPIRE-1 cohort stratified by protocol-specified criteria, comparing failure-free survival (FFS) between study arms. Methods: EMPIRE-1 randomized patients to SRT planning via either conventional imaging only (bone scanning plus abdominopelvic CT or MRI) (arm A) or conventional imaging plus 18F-fluciclovine PET/CT (arm B). Randomization was stratified by prostate-specific antigen (PSA) level (<2.0 vs. ≥ 2.0 ng/mL), adverse pathology, and androgen-deprivation therapy (ADT) intent. We subdivided patients in each arm using the randomization stratification criteria and compared FFS between patient subgroups across study arms. Results: Eighty-one and 76 patients received per-protocol SRT in study arms A and B, respectively. The median follow-up was 3.5 y (95% CI, 3.0-4.0). FFS was 63.0% and 51.2% at 36 and 48 mo, respectively, in arm A and 75.5% at both 36 and 48 mo in arm B. Among patients with a PSA of less than 2 ng/mL (mean, 0.42 ± 0.42 ng/mL), significantly higher FFS was seen in arm B than arm A at 36 mo (83.2% [95% CI, 70.0-91.0] vs. 66.5% [95% CI, 51.6-77.8], P < 0.001) and 48 mo (83.2% [95% CI, 70.0-91.0] vs. 56.2% [95% CI, 40.5-69.2], P < 0.001). No significant difference in FFS between study arms in patients with a PSA of at least 2 ng/mL was observed. Among patients with adverse pathology, significantly higher FFS was seen in arm B than arm A at 48 mo (68.9% [95% CI, 52.1-80.8] vs. 42.8% [95% CI, 26.2-58.3], P < 0.001) though not at the 36-mo follow-up. FFS was higher in patients without adverse pathology in arm B versus arm A (90.2% [95% CI, 65.9-97.5] vs. 73.1% [95% CI, 42.9-89.0], P = 0.006) at both 36 and 48 mo. Patients in whom ADT was intended in arm B had higher FFS than those in arm A, with the difference reaching statistical significance at 48 mo (65.2% [95% CI, 40.3-81.7] vs. 29.1 [95% CI, 6.5-57.2], P < 0.001). Patients without ADT intent in arm B had significantly higher FFS than patients in arm A at 36 mo (80.7% [95% CI, 64.9-90.0] vs. 68.0% [95% CI, 51.1-80.2]) and 48 mo (80.7% [95% CI, 64.9-90.0] vs. 58.6% [95% CI, 41.0-72.6]). Conclusion: The survival advantage due to the addition of 18F-fluciclovine PET/CT to SRT planning is maintained regardless of the presence of adverse pathology or ADT intent. Including 18F-fluciclovine PET/CT to SRT leads to survival benefits in patients with a PSA of less than 2 ng/mL but not in patients with a PSA of 2 ng/mL or higher.

Incidence and predictors of toxicity in the management of vulvar squamous cell carcinoma treated with radiation therapy.

Purpose/Objective: Given the rarity of vulvar cancer, data on the incidence of acute and late severe toxicity and patients' symptom burden from radiotherapy (RT) are lacking. Materials/Methods: This multi-center, single-institution study included patients with vulvar squamous cell carcinoma treated with curative intent RT between 2009 and 2020. Treatment-related acute and late grade ≥ 3 toxicities and late patient subjective symptoms (PSS) were recorded. Results: Forty-two patients with predominantly stage III/IV disease (n = 25, 59.5 %) were treated with either definitive (n = 25, 59.5 %) or adjuvant (n = 17, 40.5 %) external beam RT to a median dose of 64 Gy and 59.4 Gy, respectively. Five patients received a brachytherapy boost with a median total dose of 84.3 Gy in 2 Gy-equivalent dose (EQD2). Intensity-modulated RT was used in 37 (88.1 %) of patients, and 25 patients (59.5 %) received concurrent chemotherapy. Median follow-up was 27 months. Acute grade ≥ 3 toxicity occurred in 17 patients (40.5 %), including 13 (31.0 %) acute grade 3 skin events. No factors, including total RT dose (p = 0.951), were associated with acute skin toxicity. Eleven (27.5 %) patients developed late grade ≥ 3 toxicity events, including 10 (23.8 %) late grade ≥ 3 skin toxicity events. Patients with late grade ≥ 3 skin toxicity had a higher mean body-mass index (33.0 vs 28.2 kg/m2; p = 0.009). Common late PSS included vaginal pain (n = 15, 35.7 %), skin fibrosis (n = 10, 23.8 %), and requirement of long-term opiates (n = 12, 28.6 %). Conclusion: RT for vulvar cancer is associated with considerable rates of severe acute and late toxicity and PSS burden. Larger studies are needed to identify risk factors, explore toxicity mitigation strategies, and assess patient-reported outcomes.

Randomized Trial of Conventional Versus Conventional Plus Fluciclovine (18F) Positron Emission Tomography/Computed Tomography-Guided Postprostatectomy Radiation Therapy for Prostate Cancer: Volumetric and Patient-Reported Analyses of Toxic Effects.

PURPOSE: Postprostatectomy radiation therapy planning with fluciclovine (18F) positron emission tomography (PET)/computed tomography has demonstrated improved disease-free survival over conventional only (computed tomography- or magnetic resonance imaging-based) treatment planning. We hypothesized that incorporating PET would result in larger clinical target volumes (CTVs) without increasing patient-reported toxic effects. METHODS AND MATERIALS: From 2012 to 2019, 165 postprostatectomy patients with detectable prostate-specific antigen were randomized (arm 1 [no PET]: 82; arm 2 [PET]: 83). Prostate bed target volumes with (CTV1: 45.0-50.4 Gy/1.8 Gy) or without (CTV2/CTV: 64.8-70.2 Gy/1.8 Gy) pelvic nodes, as well as organ-at-risk doses, were compared pre- versus post-PET (arm 2) using the paired t test and between arms using the t test. Patient-reported outcomes used International Prostate Symptom Score and Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP). Univariate and multivariable analyses were performed and linear mixed models were fitted. RESULTS: Median follow-up of the whole cohort was 3.52 years. All patients had baseline patient-reported outcomes, 1 patient in arm 1 and 3 patients in arm 2 withdrew, and 4 arm 2 patients had extrapelvic uptake on PET with radiotherapy aborted, leaving 81 (arm 1) and 76 patients (arm 2) for analysis of toxic effects. Mean CTV1 (427.6 vs 452.2 mL; P = .462, arm 1 vs arm 2) and CTV2/CTV (137.18 vs 134.2 mL; P = .669) were similar before PET incorporation. CTV1 (454.57 vs 461.33 mL; P = .003) and CTV2/CTV (134.14 vs 135.61 mL; P < .001) were modestly larger after PET incorporation. Although V40 Gy (P = .402 and P = .522 for rectum and bladder, respectively) and V65 Gy (P = .157 and P = .182 for rectum and bladder, respectively) were not significantly different pre- versus post-PET, penile bulb dose significantly increased post-PET (P < .001 for both V40 Gy and V65 Gy). On univariate and multivariable analyses, arm was not significant for any EPIC-CP subdomain. International Prostate Symptom Score and EPIC-CP linear mixed models were not significantly different between arms. CONCLUSIONS: Despite larger CTVs after incorporation of fluciclovine (18F) PET, we found no significant difference in patient-reported toxic effects with long-term follow-up.

Impact of Metastasectomy and Aggressive Local Therapy in Newly Diagnosed Metastatic Soft Tissue Sarcoma: An Analysis of the NCDB.

BACKGROUND: The optimal management of patients with stage IV soft tissue sarcoma of the extremity (STSE) with distant metastases at diagnosis is unclear due to limited evidence and heterogeneity of current practice patterns. National guidelines have recommended surgical management of the primary site (SP) with or without radiotherapy (R), chemotherapy (C), and metastasectomy (M). METHODS: In the National Cancer Database (NCDB), patients with initially metastatic STSE who received definitive SP from 2004 to 2014 were identified. Survival distributions were estimated and compared using the Kaplan-Meier method and log-rank tests, and covariates were compared using Chi-square tests or analysis of variance (ANOVA). Propensity score analysis using inverse probability of treatment weighting was used. RESULTS: Overall, 1124 patients were included, with a median age of 55 years (range 18-90). Utilization of SP+M increased over time from 18.8% in 2004-2006, to 33.3% in 2007-2009, to 47.9% in 2010-2014 (p = 0.024). The addition of M to SP was associated with superior 5-year overall survival (OS) at 30.8% (SP+M+/-C+/-R) compared with 18.2% for those treated with non-surgical adjuvant therapies (SP+/-C+/-R) and 12.6% for SP alone (p < 0.0001). Positive surgical margins were noted in 24.1% of patients and was associated with worse OS (hazard ratio 1.44, p < 0.001) on multivariable analysis. CONCLUSIONS: This is the first known study utilizing a large database to explore practice patterns and outcomes for patients with metastatic STSE receiving definitive SP. Utilization of metastasectomy increased in the study period and was associated with longer survival compared with SP alone. These hypothesis-generating data warrant additional study.

Patient-reported outcomes after Low-dose-rate versus High-dose-rate brachytherapy boost in combination with external beam radiation for intermediate and high risk prostate cancer.

PURPOSE: Addition of a brachytherapy boost to external beam radiation therapy (EBRT) reduces prostate cancer (PCa) recurrence at the expense of genitourinary (GU) toxicity. Whether brachytherapy boost technique, specifically low-dose-rate (LDR-BT) versus high-dose-rate (HDR-BT), impacts treatment-related toxicity is unclear. METHODS: Between 2012-2018, 106 men with intermediate/high risk PCa underwent EBRT (37.5-45 Gy in 1.8-2.5 Gy/fraction) plus brachytherapy boost, either with LDR-BT (110 Gy I-125 or 100 Gy Pd-103; n = 51) or HDR-BT (15 Gy x1 Ir-192; n = 55). Patient-reported outcomes (PRO) were assessed by International Prostate Symptom Score (IPSS) and Expanded Prostate Cancer Index Composite (EPIC-CP) surveys at 3-6-month intervals for up to three years following treatment, with higher scores indicating more severe toxicity. Provider-reported GU and gastrointestinal (GI) toxicity was graded per CTCAE v5.0 at each follow-up. Linear mixed models comparing PROs between LDR-BT versus HDR-BT were fitted. Stepwise multivariable analysis (MVA) was performed to account for age, gland size, androgen deprivation therapy use, and alpha-blocker medication use. Incidence rates of grade 2+ GU/GI toxicity was compared using Fisher's exact test. RESULTS: Use of LDR-BT was associated with greater change in IPSS (p=0.003) and EPIC-CP urinary irritative score (p = 0.002) compared with HDR-BT, but effect size diminished over time (LDR-BT versus HDR-BT: baseline to 6-/24-month mean IPSS change, +6.4/+1.4 versus +2.7/-3.0, respectively; mean EPIC-CP irritative/obstructive change, +2.5/+0.1 versus +0.9/+0.1, respectively). Results remained significant on MVA. Post-treatment grade 2+ GU toxicity was significantly higher in the LDR-BT group (67.5% versus 42.9% for LDR-BT and HDR-BT, respectively; p <0.001). There were no differences between groups in incontinence, bowel function, and erectile function, or grade 2+ GI toxicity. CONCLUSION: Compared with LDR-BT, HDR-BT was associated with lower acute patient- and provider-reported GU toxicity.

18F-fluciclovine-PET/CT imaging versus conventional imaging alone to guide postprostatectomy salvage radiotherapy for prostate cancer (EMPIRE-1): a single centre, open-label, phase 2/3 randomised controlled trial.

BACKGROUND: Molecular imaging is increasingly used to guide treatment decisions and planning in prostate cancer. We aimed to evaluate the role of 18F-fluciclovine-PET/CT in improving cancer control compared with conventional imaging (bone scan and either CT or MRI) alone for salvage postprostatectomy radiotherapy. METHODS: In EMPIRE-1, a single-centre, open-label, phase 2/3 randomised controlled trial, patients with prostate cancer with detectable PSA after prostatectomy and negative conventional imaging (no extrapelvic or bone findings) were randomly assigned in a 1:1 ratio to radiotherapy directed by conventional imaging alone or to conventional imaging plus 18F-fluciclovine-PET/CT. Computer-generated randomisation was stratified by PSA concentration, adverse pathology indicators, and androgen deprivation therapy intent. In the 18F-fluciclovine-PET/CT group, radiotherapy decisions were rigidly determined by PET findings, which were also used for target delineation. The primary endpoint was 3 year event-free survival, with events defined as biochemical or clinical recurrence or progression, or initiation of systemic therapy, using univariate and multivariable analyses in patients who received radiotherapy. This trial is registered with ClinicalTrials.gov, NCT01666808 and is closed to new participants. FINDINGS: From Sept 18, 2012, to March 4, 2019, 165 patients were randomly assigned, with median follow-up of 3·52 years (95% CI 2·98-3·95). PET findings resulted in four patients in the 18F-fluciclovine-PET/CT group having radiotherapy aborted; these patients were excluded from survival analyses. Median survival was not reached (95% CI 35·2-not reached; 33% of 81 patients had events) in the conventional imaging group compared with not reached (95% CI not reached-not reached; 20% of 76 patients) in the 18F-fluciclovine-PET/CT group, and 3 year event-free survival was 63·0% (95% CI 49·2-74·0) in the conventional imaging group versus 75·5% (95% CI 62·5-84·6) for 18F-fluciclovine-PET/CT (difference 12·5; 95% CI 4·3-20·8; p=0·0028). In adjusted analyses, study group (hazard ratio 2·04 [95% CI 1·06-3·93], p=0·0327) was significantly associated with event-free survival. Toxicity was similar in both study groups, with the most common adverse events being late urinary frequency or urgency (37 [46%] of 81 patients in the conventional imaging group and 31 [41%] of 76 in the PET group), and acute diarrhoea (11 [14%] in the conventional imaging group and 16 [21%] in the PET group). INTERPRETATION: Inclusion of 18F-fluciclovine-PET into postprostatectomy radiotherapy decision making and planning significantly improved survival free from biochemical recurrence or persistence. Integration of novel PET radiotracers into radiotherapy decisions and planning for prostate cancer patients warrants further study. FUNDING: National Institutes of Health/National Cancer Institute, Blue Earth Diagnostics, and Winship Cancer Institute of Emory University.

Small-Cell Carcinoma of the Prostate: Report of Outcomes of Localized Disease Using the National Cancer Database.

BACKGROUND: Small-cell carcinoma of the prostate (SCCP) is a rare but aggressive prostate cancer histology. We studied the reported comparative outcomes of the efficacy of radiotherapy (RT) versus surgery for nonmetastatic SCCP. METHODS: The National Cancer Database (NCDB) was queried for nonmetastatic disease diagnosed from 2004 to 2015 as SCCP (defined as having a component of SCCP) receiving a single definitive local control modality (RT or surgery). RESULTS: A total of 243 patients were included (177 RT and 66 surgery). A total of 142 patients received chemotherapy (CHT). Mean age was 68 years. One hundred forty patients had adenocarcinoma concurrently with the SCCP while 103 patients had pure histology. For pure histology, multivariable analysis (MVA) showed nonacademic facility, stage 4 disease, and poorly differentiated grade were associated with worse survival. On MVA, receipt of CHT (hazard ratio [HR] = 0.84, P = .644) or receipt of androgen deprivation therapy (HR = 0.88, P = .715) did not affect overall survival. Receipt of RT was nonsignificant compared to surgery (HR = 0.75, P = .475). For mixed histology, MVA showed receipt of CHT and prostate-specific antigen > 20 ng/mL were associated with worse survival. Receipt of androgen deprivation therapy (HR = 1.35, P = .414) did not affect overall survival. Receipt of RT was also nonsignificant compared to surgery (HR = 1.42, P = .344). CONCLUSION: RT and surgery for nonmetastatic SCCP yield comparable options as local therapies.

Overall Survival After Treatment of Localized Prostate Cancer With Proton Beam Therapy, External-Beam Photon Therapy, or Brachytherapy.

BACKGROUND: There are few comparative outcomes data regarding the therapeutic delivery of proton beam therapy (PBT) versus the more widely used photon-based external-beam radiation (EBRT) and brachytherapy (BT). We evaluated the impact of PBT on overall survival (OS) compared to EBRT or BT on patients with localized prostate cancer. PATIENTS AND METHODS: The National Cancer Data Base (NCDB) was queried for 2004-2015. Men with clinical stage T1-3, N0, M0 prostate cancer treated with radiation, without surgery or chemotherapy, were included. OS, the primary clinical outcome, was fit by Cox proportional hazard model. Propensity score matching was implemented for covariate balance. RESULTS: There were 276,880 eligible patients with a median follow-up of 80.9 months. A total of 4900 (1.8%) received PBT, while 158,111 (57.1%) received EBRT and 113,869 (41.1%) BT. Compared to EBRT and BT, PBT patients were younger and were less likely to be in the high-risk group. On multivariable analysis, compared to PBT, men had worse OS after EBRT (adjusted hazard ratio [HR] = 1.72; 95% confidence interval [CI], 1.51-1.96) or BT (adjusted HR = 1.38; 95% CI, 1.21-1.58). After propensity score matching, the OS benefit of PBT remained significant compared to EBRT (HR = 1.64; 95% CI, 1.32-2.04) but not BT (adjusted HR = 1.18; 95% CI, 0.93-1.48). The improvement in OS with PBT was most prominent in men ≤ 65 years old with low-risk disease compared to other subgroups (interaction P < .001). CONCLUSION: In this national data set, PBT was associated with a significant OS benefit compared to EBRT, and with outcomes similar to BT. These results remain to be validated by ongoing prospective trials.