Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer with PD-L1 ≥ 1 %: A subgroup analysis from the EMPOWER-Lung 3 part 2 trial.

OBJECTIVES: EMPOWER-Lung 3 part 2 (NCT03409614), a double-blind, placebo-controlled phase 3 study, assessed cemiplimab (anti-programmed cell death protein 1) plus chemotherapy versus chemotherapy alone in patients with advanced non-small cell lung cancer (NSCLC) without EGFR, ALK, or ROS1 aberrations, regardless of histology or PD-L1 expression levels. We report results from subgroup analysis of patients with PD-L1 expression ≥ 1 %. MATERIALS AND METHODS: Patients were randomized to receive cemiplimab 350 mg or placebo with chemotherapy every 3 weeks for up to 108 weeks. Overall survival (OS), progression-free survival (PFS), overall response rates (ORRs), patient-reported outcomes (PROs), and safety were assessed. RESULTS: Of the 327 patients with PD-L1 ≥ 1 % (466 in the overall study), 217 received cemiplimab plus chemotherapy and 110 received chemotherapy alone. After median follow-up of 28.0 months, median OS for cemiplimab plus chemotherapy was 23.5 months (95 % confidence interval [CI]: 20.9-27.2) vs. 12.1 months (95 % CI: 10.1-15.7) for chemotherapy alone (hazard ratio [HR] = 0.51, 95 % CI: 0.38-0.69, P < 0.0001); median PFS was 8.3 months (95 % CI: 6.7-10.8) versus 5.5 months (95 % CI: 4.3-6.2; HR = 0.48; 95 % CI: 0.37-0.62, P < 0.0001), and ORR was 47.9 % versus 22.7 %, respectively. PRO results favored cemiplimab plus chemotherapy over chemotherapy alone. Improved efficacy over chemotherapy alone was observed in both squamous and non-squamous histology. Safety was consistent with previous reports. CONCLUSION: In this subgroup analysis from EMPOWER-Lung 3 part 2, cemiplimab plus chemotherapy demonstrated clinical benefit over chemotherapy alone in patients with advanced squamous or non-squamous NSCLC with PD-L1 ≥ 1 %.

First-line cemiplimab monotherapy and continued cemiplimab beyond progression plus chemotherapy for advanced non-small-cell lung cancer with PD-L1 50% or more (EMPOWER-Lung 1): 35-month follow-up from a mutlicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Cemiplimab provided significant survival benefit to patients with advanced non-small-cell lung cancer with PD-L1 tumour expression of at least 50% and no actionable biomarkers at 1-year follow-up. In this exploratory analysis, we provide outcomes after 35 months' follow-up and the effect of adding chemotherapy to cemiplimab at the time of disease progression. METHODS: EMPOWER-Lung 1 was a multicentre, open-label, randomised, phase 3 trial. We enrolled patients (aged ≥18 years) with histologically confirmed squamous or non-squamous advanced non-small-cell lung cancer with PD-L1 tumour expression of 50% or more. We randomly assigned (1:1) patients to intravenous cemiplimab 350 mg every 3 weeks for up to 108 weeks, or until disease progression, or investigator's choice of chemotherapy. Central randomisation scheme generated by an interactive web response system governed the randomisation process that was stratified by histology and geographical region. Primary endpoints were overall survival and progression free survival, as assessed by a blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumours version 1.1. Patients with disease progression on cemiplimab could continue cemiplimab with the addition of up to four cycles of chemotherapy. We assessed response in these patients by BICR against a new baseline, defined as the last scan before chemotherapy initiation. The primary endpoints were assessed in all randomly assigned participants (ie, intention-to-treat population) and in those with a PD-L1 expression of at least 50%. We assessed adverse events in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT03088540. FINDINGS: Between May 29, 2017, and March 4, 2020, we recruited 712 patients (607 [85%] were male and 105 [15%] were female). We randomly assigned 357 (50%) to cemiplimab and 355 (50%) to chemotherapy. 284 (50%) patients assigned to cemiplimab and 281 (50%) assigned to chemotherapy had verified PD-L1 expression of at least 50%. At 35 months' follow-up, among those with a verified PD-L1 expression of at least 50% median overall survival in the cemiplimab group was 26·1 months (95% CI 22·1-31·8; 149 [52%] of 284 died) versus 13·3 months (10·5-16·2; 188 [67%] of 281 died) in the chemotherapy group (hazard ratio [HR] 0·57, 95% CI 0·46-0·71; p<0·0001), median progression-free survival was 8·1 months (95% CI 6·2-8·8; 214 events occurred) in the cemiplimab group versus 5·3 months (4·3-6·1; 236 events occurred) in the chemotherapy group (HR 0·51, 95% CI 0·42-0·62; p<0·0001). Continued cemiplimab plus chemotherapy as second-line therapy (n=64) resulted in a median progression-free survival of 6·6 months (6·1-9·3) and overall survival of 15·1 months (11·3-18·7). The most common grade 3-4 treatment-emergent adverse events were anaemia (15 [4%] of 356 patients in the cemiplimab group vs 60 [17%] of 343 in the control group), neutropenia (three [1%] vs 35 [10%]), and pneumonia (18 [5%] vs 13 [4%]). Treatment-related deaths occurred in ten (3%) of 356 patients treated with cemiplimab (due to autoimmune myocarditis, cardiac failure, cardio-respiratory arrest, cardiopulmonary failure, septic shock, tumour hyperprogression, nephritis, respiratory failure, [n=1 each] and general disorders or unknown [n=2]) and in seven (2%) of 343 patients treated with chemotherapy (due to pneumonia and pulmonary embolism [n=2 each], and cardiac arrest, lung abscess, and myocardial infarction [n=1 each]). The safety profile of cemiplimab at 35 months, and of continued cemiplimab plus chemotherapy, was generally consistent with that previously observed for these treatments, with no new safety signals INTERPRETATION: At 35 months' follow-up, the survival benefit of cemiplimab for patients with advanced non-small-cell lung cancer was at least as pronounced as at 1 year, affirming its use as first-line monotherapy for this population. Adding chemotherapy to cemiplimab at progression might provide a new second-line treatment for patients with advanced non-small-cell lung cancer. FUNDING: Regeneron Pharmaceuticals and Sanofi.

Cemiplimab Plus Chemotherapy Versus Chemotherapy Alone in Advanced NSCLC: 2-Year Follow-Up From the Phase 3 EMPOWER-Lung 3 Part 2 Trial.

INTRODUCTION: EMPOWER-Lung 3 part 2 (NCT03409614), a double-blind, placebo-controlled phase 3 study, investigated cemiplimab (antiprogrammed cell death protein 1) plus chemotherapy versus placebo plus chemotherapy in patients with advanced NSCLC without EGFR, ALK, or ROS1 aberrations, with either squamous or nonsquamous histology, irrespective of programmed death-ligand 1 levels. At primary analysis, after 16.4 months of follow-up, cemiplimab plus chemotherapy improved median overall survival (OS) versus chemotherapy alone (21.9 versus 13.0 mo, hazard ratio [HR] = 0.71, 95% confidence interval [CI]: 0.53-0.93, p = 0.014). Here, we report protocol-specified final OS and 2-year follow-up results. METHODS: Patients (N = 466) were randomized 2:1 to receive histology-specific platinum-doublet chemotherapy, with 350 mg cemiplimab (n = 312) or placebo (n = 154) every 3 weeks for up to 108 weeks. Primary end point was OS; secondary end points included progression-free survival and objective response rates. RESULTS: After 28.4 months of median follow-up, median OS was 21.1 months (95% CI: 15.9-23.5) for cemiplimab plus chemotherapy versus 12.9 months (95% CI: 10.6-15.7) for chemotherapy alone (HR = 0.65, 95% CI: 0.51-0.82, p = 0.0003); median progression-free survival was 8.2 months (95% CI: 6.4-9.0) versus 5.5 months (95% CI: 4.3-6.2) (HR = 0.55, 95% CI: 0.44-0.68, p < 0.0001), and objective response rates were 43.6% versus 22.1%, respectively. Safety was generally consistent with previously reported data. Incidence of treatment-emergent adverse events of grade 3 or higher was 48.7% with cemiplimab plus chemotherapy and 32.7% with chemotherapy alone. CONCLUSIONS: At protocol-specified final OS analysis with 28.4 months of follow-up, the EMPOWER-Lung 3 study continued to reveal benefit of cemiplimab plus chemotherapy versus chemotherapy alone in patients with advanced squamous or nonsquamous NSCLC, across programmed death-ligand 1 levels.

Real-World Outcomes and Prognostic Factors Among Patients with Advanced Non-Small Cell Lung Cancer and High PD-L1 Expression Treated with Immune Checkpoint Inhibitors as First-Line Therapy.

Background: Immune checkpoint inhibitors (ICIs) are standard-of-care for patients with advanced non-small cell lung cancer (aNSCLC) and programmed cell death-ligand 1 (PD-L1) expression ≥50%. Methods: A retrospective cohort study was conducted using the US de-identified electronic health record-derived Flatiron Health aNSCLC database (January 1, 2018, to July 31, 2021) among patients with PD-L1 ≥50% initiating first-line ICIs with or without chemotherapy. A clinical trial-like sub-cohort was also identified with Eastern Cooperative Oncology Group performance status 0-1, adequate organ function, and no brain metastases or other primary cancers. Kaplan-Meier methods were used to estimate time to treatment discontinuation, time to next treatment, progression-free survival and overall survival (OS) by ICI regimen (ICI+chemotherapy, ICI monotherapy) and PD-L1 expression (50-69%, 70-89%, 90-100%). Cox proportional hazard models were used to examine associations between ICI regimen, PD-L1 level, and OS, adjusting for baseline demographic and clinical variables. Results: A total of 2631 patients with aNSCLC initiating ICI+chemotherapy (n = 992) or ICI monotherapy (n = 1639) were included; median (Q1, Q3) age was 71 (63-78) years and 51.6% were male. The trial-like sub-cohort (n = 1029) generally had better outcomes vs. the overall cohort. Patients receiving ICI+chemotherapy generally had longer median OS vs. ICI monotherapy. Multivariable analyses showed no association between ICI regimen and OS among patients with PD-L1 70-89% (hazard ratio [HR]: 0.90, 95% confidence interval [CI]: 0.73-1.09) or 90-100% (HR: 0.91, 95% CI: 0.77-1.08), but patients with PD-L1 50-69% receiving ICI+chemotherapy had longer OS (HR: 0.80, 95% CI: 0.64-0.99). Conclusion: Outcomes in real-world clinical trial-like patients with aNSCLC approached those reported in pivotal ICI trials in high PD-L1 expressers. ICI monotherapy offers a potential alternative in patients with PD-L1 ≥70% while avoiding potential chemotherapy toxicity exposure; the benefits are less clear in patients with PD-L1 50-69%. Future studies should confirm these findings.

Machine learning models for identifying predictors of clinical outcomes with first-line immune checkpoint inhibitor therapy in advanced non-small cell lung cancer.

Immune checkpoint inhibitors (ICIs) are standard-of-care as first-line (1L) therapy for advanced non-small cell lung cancer (aNSCLC) without actionable oncogenic driver mutations. While clinical trials demonstrated benefits of ICIs over chemotherapy, variation in outcomes across patients has been observed and trial populations may not be representative of clinical practice. Predictive models can help understand heterogeneity of treatment effects, identify predictors of meaningful clinical outcomes, and may inform treatment decisions. We applied machine learning (ML)-based survival models to a real-world cohort of patients with aNSCLC who received 1L ICI therapy extracted from a US-based electronic health record database. Model performance was evaluated using metrics including concordance index (c-index), and we used explainability techniques to identify significant predictors of overall survival (OS) and progression-free survival (PFS). The ML model achieved c-indices of 0.672 and 0.612 for OS and PFS, respectively, and Kaplan-Meier survival curves showed significant differences between low- and high-risk groups for OS and PFS (both log-rank test p < 0.0001). Identified predictors were mostly consistent with the published literature and/or clinical expectations and largely overlapped for OS and PFS; Eastern Cooperative Oncology Group performance status, programmed cell death-ligand 1 expression levels, and serum albumin were among the top 5 predictors for both outcomes. Prospective and independent data set evaluation is required to confirm these results.

Characterizing the Shifting Real-World Treatment Landscape by PD-L1 Testing Status and Expression Level in Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Contemporary real-world data on advanced non-small cell lung cancer (aNSCLC) treatment patterns across programmed cell death-ligand 1 (PD-L1) expression levels and testing status are limited. METHODS: A retrospective cohort was selected of adults newly diagnosed with aNSCLC between January 1, 2018, and July 31, 2021, who initiated first-line treatments, which were described by PD-L1 status and expression levels (≥ 50%, 1-49%, < 1%). Treatment received before and after PD-L1 test results were described for patients initiating first-line treatment before PD-L1 results. For patients who initiated chemotherapy alone before PD-L1 results, the probability of receiving immune checkpoint inhibitors (ICIs) after PD-L1 results was estimated by PD-L1 level and associated factors were explored. RESULTS: Among 12,202 patients with aNSCLC initiating first-line treatment [54.7% male, mean (standard deviation) age 69.2 (9.4) years], the most common therapies were ICI-based regimens across PD-L1 levels, and chemotherapy alone among PD-L1-untested patients. Use of chemotherapy alone decreased between 2018 and 2019 and stabilized thereafter, accounting for 21-29% of first-line treatments across PD-L1 levels and 48% of untested patients in 2021. Of 1468 patients initiating first-line treatment before PD-L1 results, treatments remained unchanged in most patients after PD-L1 results. Among patients initiating chemotherapy alone before PD-L1 results, the probability of receiving ICIs within 45 days after test results was 40.5% [95% confidence interval (CI) 31.6-48.3%], 28.6% (95% CI 20.3-36.0%), and 22.9% (95% CI 16.9-28.4%) at PD-L1 ≥ 50%, 1-49%, and < 1%, respectively. CONCLUSION: While ICI-based regimens accounted for most first-line treatments across PD-L1 levels, chemotherapy alone was initiated in > 20% of patients tested for PD-L1 and 48% of untested patients in 2021. Patients who initiated chemotherapy alone had a low probability of receiving ICIs after PD-L1 test results. These results highlight the need for understanding the role and timing of PD-L1 test results for informing treatment decisions for patients with aNSCLC.

Network meta-analysis of immune-oncology monotherapy as first-line treatment for advanced non-small-cell lung cancer in patients with PD-L1 expression ⩾50.

Background: For patients with advanced non-small-cell lung cancer (NSCLC) and high (⩾50%) programmed cell death-ligand 1 (PD-L1) expression, effective first-line immune-oncology monotherapies with significant survival benefits are approved, cemiplimab being the most recent. In a phase III trial, cemiplimab demonstrated significantly improved overall survival (OS) and progression-free survival (PFS) versus chemotherapy in patients with advanced NSCLC and PD-L1 ⩾50%. A systematic literature review and network meta-analysis (NMA) was conducted to identify/compare the efficacy/safety of cemiplimab versus pembrolizumab or other immune-oncology monotherapies from randomized-controlled trials (RCTs) published in November 2010-2020. Methods: Relevant RCTs were identified by searching databases and conference proceedings as per ISPOR, NICE, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. NMA with time-varying hazard ratios (HRs) was performed for OS and PFS. Analyses were conducted for objective response rate (ORR) and safety/tolerability. Fixed-effect models were used due to limited evidence. Various sensitivity analyses were conducted to validate the base case analyses. Results: The feasibility assessment determined that EMPOWER-Lung 1, KEYNOTE-024, and KEYNOTE-042 trials were eligible. IMpower110 was excluded because an incompatible PD-L1 assay (SP142) was used for patient selection. For first-line advanced NSCLC with PD-L1 ⩾50%, cemiplimab was associated with statistically significant improvements in PFS [HR (95% credible interval [CrI]): 0.65 (0.50-0.86), 1-12 months] and ORR [odds ratio (OR) (95% CrI): 1.64 (1.04-2.62)], and comparable OS [HR (95% CrI): 0.77 (0.54-1.10), 1-12 months] versus pembrolizumab. There was no evidence of differences between cemiplimab and pembrolizumab for Grade 3-5 adverse events (AEs) [OR (95% CrI): 1.47 (0.83-2.60)], immune-mediated AEs [1.75 (0.33-7.49)], and all-cause discontinuation due to AEs [1.21 (0.58-2.61)]. Conclusions: Considering the limitations of indirect treatment comparisons, in patients with advanced NSCLC and PD-L1 ⩾50%, cemiplimab monotherapy demonstrated significant improvements in PFS and ORR, comparable OS, and no evidence of differences in safety/tolerability versus pembrolizumab.

Impact of the treatment crossover design on comparative efficacy in EMPOWER-Lung 1: Cemiplimab monotherapy as first-line treatment of advanced non-small cell lung cancer.

Objectives: In randomized-controlled crossover design trials, overall survival (OS) treatment effect estimates are often confounded by the control group benefiting from treatment received post-progression. We estimated the adjusted OS treatment effect in EMPOWER-Lung 1 (NCT03088540) by accounting for the potential impact of crossover to cemiplimab among controls and continued cemiplimab treatment post-progression. Methods: Patients were randomly assigned 1:1 to cemiplimab 350 mg every 3 weeks (Q3W) or platinum-doublet chemotherapy. Patients with disease progression while on or after chemotherapy could receive cemiplimab 350 mg Q3W for ≤108 weeks. Those who experienced progression on cemiplimab could continue cemiplimab at 350 mg Q3W for ≤108 additional weeks with four chemotherapy cycles added. Three adjustment methods accounted for crossover and/or continued treatment: simplified two-stage correction (with or without recensoring), inverse probability of censoring weighting (IPCW), and rank-preserving structural failure time model (RPSFT; with or without recensoring). Results: In the programmed cell death-ligand 1 ≥50% population (N=563; median 10.8-month follow-up), 38.2% (n=107/280) crossed over from chemotherapy to cemiplimab (71.3%, n=107/150, among those with confirmed progression) and 16.3% (n=46/283) received cemiplimab treatment after progression with the addition of histology-specific chemotherapy (38.7%, n=46/119, among those with confirmed progression). The unadjusted OS hazard ratio (HR) with cemiplimab versus chemotherapy was 0.566 (95% confidence interval [CI]: 0.418, 0.767). Simplified two-stage correction-the most suitable method based on published guidelines and trial characteristics-produced an OS HR of 0.490 (95% CI: 0.365, 0.654) without recensoring and 0.493 (95% CI: 0.361, 0.674) with recensoring. The IPCW and RPSFT methods produced estimates generally consistent with simplified two-stage correction. Conclusions: After adjusting for treatment crossover and continued cemiplimab treatment after progression with the addition of histology-specific chemotherapy observed in EMPOWER-Lung 1, cemiplimab continued to demonstrate a clinically important and statistically significant OS benefit versus chemotherapy, consistent with the primary analysis.

Trends in real-world biomarker testing and overall survival in US patients with advanced non-small-cell lung cancer.

Background: Trends/outcomes associated with National Comprehensive Cancer Network (NCCN)-recommended biomarker testing to guide advanced non-small-cell lung cancer (aNSCLC) treatment were assessed. Methods: Patients initiating first-line aNSCLC treatment were included using a nationwide electronic health record-derived database (1/1/2015-10/31/2021). Trends in pre-first-line biomarker testing (PD-L1, major genomic aberrations), factors associated with testing and associations between testing and outcomes were assessed. Results: PD-L1/genomic aberration testing rates increased from 33% (2016) to 81% (2018), then plateaued. Certain clinical and demographic factors were associated with a greater likelihood of PD-L1 testing. Patients tested for PD-L1 or genomic aberrations had longer overall survival (OS). Conclusion: Biomarker testing may be associated with improved OS in aNSCLC, though not all patients had equal access to testing.

Molecular diagnostics play a critical role in precision medicine. Treatment guidelines from the National Comprehensive Cancer Network (NCCN) recommend that patients newly diagnosed with advanced non-small-cell lung cancer (aNSCLC) undergo molecular testing for PD-L1 and genomic aberrations to guide treatment choices. Based on the results of such biomarker testing, physicians can select optimal treatments for individual patients. The aim of this study was to describe the latest trends and disparities in real-world biomarker testing with a focus on PD-L1 and to explore the impact of biomarker testing on outcomes in first-line treatment of aNSCLC in the United States. Patients initiating first-line aNSCLC treatment were identified in the Flatiron Health database (1/1/2015­10/31/2021; N = 30,631). Annual trends in pre-first-line biomarker testing (PD-L1, major genomic aberrations), demographic and clinical factors associated with PD-L1 testing, and associations between PD-L1 and/or ≥1 genomic aberration testing and outcomes (e.g., overall survival [OS], time-to-next treatment [TTNT]) were assessed. Biomarker testing in patients receiving first-line treatment for aNSCLC increased between 2015 and 2017 and plateaued between 2018 and 2021. By 2021, approximately 20% of patients did not receive PD-L1 testing before first-line treatment and not all patients had equal access to testing. Both PD-L1 and genomic aberration testing were associated with improved OS and TTNT. This is likely due to enhanced treatment decisions leading to optimal treatment selection. Future research is warranted to understand interventions to improve biomarker testing and reduce disparities between different patient populations to improve treatment outcomes.

Evaluating the impact of extended field-of-view CT reconstructions on CT values and dosimetric accuracy for radiation therapy.

PURPOSE: Wide bore CT scanners use extended field-of-view (eFOV) reconstruction algorithms to attempt to recreate tissue truncated due to large patient habitus. Radiation therapy planning systems rely on accurate CT numbers in order to correctly plan and calculate radiation dose. This study looks at the impact of eFOV reconstructions on CT numbers and radiation dose calculations in real patient geometries. METHODS: A large modular phantom based on real patient geometries was created to surround a CIRS Model 062M phantom. The modular sections included a smooth patient surface, a skin fold in the patient surface, and the addition of arms for simulation of the patient in arms up or arms down position. This phantom was used to evaluate the accuracy of CT numbers for three extended FOV algorithms implemented on Siemens CT scanners: eFOV, HDFOV, and HDProFOV. Six different configurations of the phantoms were scanned and images were reconstructed for the three different extended FOV algorithms. The CIRS phantom inserts and overall phantom geometry were contoured in each image, and the Hounsfield units (HU) numbers were compared to an image of the phantom within the standard scan FOV (sFOV) without the modular sections. To evaluate the effect on dose calculations, six radiotherapy patients previously treated at our institution (three head and neck and three chest/pelvis) whose body circumferences extended past the 50 cm sFOV in the treatment planning CT were used. Images acquired on a Siemens Sensation Open scanner were reconstructed using sFOV, eFOV and HDFOV algorithms. A physician and dosimetrist identified the radiation target, critical organs, and external patient contour. A benchmark CT was created for each patient, consisting of an average of the 3 CT reconstructions with a density override applied to regions containing truncation artifacts. The benchmark CT was used to create an optimal radiation treatment plan. The plan was copied onto each CT reconstruction without density override and dose was recalculated. RESULTS: Tissue extending past the sFOV impacts the HU numbers for tissues inside and outside the sFOV when using extended FOV reconstructions. On average, the HU for all CIRS density inserts in the arms up (arms down) position varied by 43 HU (67 HU), 39 HU (73 HU), and 18 HU (51 HU) for the eFOV, HDFOV, and HDProFOV scans, respectively. In the patient dose calculations, patients with a smooth patient contour had the least deviation from the benchmark in the HDFOV (0.1-0.5%) compared to eFOV (0.4-1.8%) reconstructions. In cases with large amounts of tissue and irregular skin folds, the eFOV deviated the least from the benchmark (range 0.2-0.6% dose difference) compared to HDFOV (range 1.3-1.8% dose difference). CONCLUSIONS: All reconstruction algorithms demonstrated good CT number accuracy in the center of the image. Larger artifacts are seen near and extending outside the scan FOV, however, dose calculations performed using typical beam arrangements using the extended FOV reconstructions were still mostly within 2.5% of best estimated reference values.

Phase I study of dose escalation to dominant intraprostatic lesions using high-dose-rate brachytherapy.

PURPOSE: Radiation dose escalation for prostate cancer improves biochemical control but is limited by toxicity. Magnetic resonance spectroscopic imaging (MRSI) can define dominant intraprostatic lesions (DIL). This phase I study evaluated dose escalation to MRSI-defined DIL using high-dose-rate (HDR) brachytherapy. MATERIAL AND METHODS: Enrollment was closed early due to low accrual. Ten patients with prostate cancer (T2a-3b, Gleason 6-9, PSA < 20) underwent pre-treatment MRSI, and eight patients had one to three DIL identified. The eight enrolled patients received external beam radiation therapy to 45 Gy and HDR brachytherapy boost to the prostate of 19 Gy in 2 fractions. MRSI images were registered to planning CT images and DIL dose-escalated up to 150% of prescription dose while maintaining normal tissue constraints. The primary endpoint was genitourinary (GU) toxicity. RESULTS: The median total DIL volume was 1.31 ml (range, 0.67-6.33 ml). Median DIL boost was 130% of prescription dose (range, 110-150%). Median urethra V120 was 0.15 ml (range, 0-0.4 ml) and median rectum V75 was 0.74 ml (range, 0.1-1.0 ml). Three patients had acute grade 2 GU toxicity, and two patients had late grade 2 GU toxicity. No patients had grade 2 or higher gastrointestinal toxicity, and no grade 3 or higher toxicities were noted. There were no biochemical failures with median follow-up of 4.9 years (range, 2-8.5 years). CONCLUSIONS: Dose escalation to MRSI-defined DIL is feasible. Toxicity was low but incompletely assessed due to limited patients' enrollment.

EM-enhanced US-based seed detection for prostate brachytherapy.

PURPOSE: Intraoperative dosimetry in low-dose-rate (LDR) permanent prostate brachytherapy requires accurate localization of the implanted seeds with respect to the prostate anatomy. Transrectal Ultrasound (TRUS) imaging, which is the main imaging modality used during the procedure, is not sufficiently robust for accurate seed localization. We present a method for integration of electromagnetic (EM) tracking into LDR prostate brachytherapy procedure by fusing it with TRUS imaging for seed localization. METHOD: Experiments were conducted on five tissue mimicking phantoms in a controlled environment. The seeds were implanted into each phantom using an EM-tracked needle, which allowed recording of seed drop locations. After each needle, we reconstructed a 3D ultrasound (US) volume by compounding a series of 2D US images acquired during retraction of an EM-tracked TRUS probe. Then, a difference image was generated by nonrigid registration and subtraction of two consecutive US volumes. A US-only seed detection method was used to detect seed candidates in the difference volume, based on the signature of the seeds. Finally, the EM-based positions of the seeds were used to detect the false positives of the US-based seed detection method and also to estimate the positions of the missing seeds. After the conclusion of the seed implant process, we acquired a CT image. The ground truth for seed locations was obtained by localizing the seeds in the CT image and registering them to the US coordinate system. RESULTS: Compared to the ground truth, the US-only detection algorithm achieved a localization error mean of 1.7 mm with a detection rate of 85%. By contrast, the EM-only seed localization method achieved a localization error mean of 3.7 mm with a detection rate of 100%. By fusing EM-tracking information with US imaging, we achieved a localization error mean of 1.8 mm while maintaining a 100% detection rate without any false positives. CONCLUSIONS: Fusion of EM-tracking and US imaging for prostate brachytherapy can combine high localization accuracy of US-based seed detection with the robustness and high detection rate of EM-based seed localization. Our phantom experiments serve as a proof of concept to demonstrate the potential value of integrating EM-tracking into LDR prostate brachytherapy.

Direct (Hetero)arylation Polymerization: Simplicity for Conjugated Polymer Synthesis.

Direct (hetero)arylation polymerization (DHAP) has recently been established as an environmentally benign method for the preparation of conjugated polymers. This synthetic tool features the formation of C-C bonds between halogenated (hetero)arenes and simple (hetero)arenes with active C-H bonds, thereby circumventing the preparation of organometallic derivatives and decreasing the overall production cost of conjugated polymers. Since its inception, selectivity and reactivity of DHAP procedures have been improved tremendously through the careful scrutinity of polymerization outcomes and the fine-tuning of reaction conditions. A broad range of monomers, from simple arenes to complex functionalized heteroarenes, can now be readily polymerized. The successful application of DHAP now leads to nearly defect-free conjugated polymers possessing comparable, if not slightly better, characteristics than their counterparts prepared using classical cross-coupling methods. This comprehensive review describes the mechanisms involved in this process from experimental and theoretical standpoints, presents an up-to-date compendium of materials obtained by this means, and exposes its current limitations and challenges.

Non-local total-variation (NLTV) minimization combined with reweighted L1-norm for compressed sensing CT reconstruction.

The compressed sensing (CS) technique has been employed to reconstruct CT/CBCT images from fewer projections as it is designed to recover a sparse signal from highly under-sampled measurements. Since the CT image itself cannot be sparse, a variety of transforms were developed to make the image sufficiently sparse. The total-variation (TV) transform with local image gradient in L1-norm was adopted in most cases. This approach, however, which utilizes very local information and penalizes the weight at a constant rate regardless of different degrees of spatial gradient, may not produce qualified reconstructed images from noise-contaminated CT projection data. This work presents a new non-local operator of total-variation (NLTV) to overcome the deficits stated above by utilizing a more global search and non-uniform weight penalization in reconstruction. To further improve the reconstructed results, a reweighted L1-norm that approximates the ideal sparse signal recovery of the L0-norm is incorporated into the NLTV reconstruction with additional iterates. This study tested the proposed reconstruction method (reweighted NLTV) from under-sampled projections of 4 objects and 5 experiments (1 digital phantom with low and high noise scenarios, 1 pelvic CT, and 2 CBCT images). We assessed its performance against the conventional TV, NLTV and reweighted TV transforms in the tissue contrast, reconstruction accuracy, and imaging resolution by comparing contrast-noise-ratio (CNR), normalized root-mean square error (nRMSE), and profiles of the reconstructed images. Relative to the conventional NLTV, combining the reweighted L1-norm with NLTV further enhanced the CNRs by 2-4 times and improved reconstruction accuracy. Overall, except for the digital phantom with low noise simulation, our proposed algorithm produced the reconstructed image with the lowest nRMSEs and the highest CNRs for each experiment.

Clinical applications of custom-made vaginal cylinders constructed using three-dimensional printing technology.

PURPOSE: Three-dimensional (3D) printing technology allows physicians to rapidly create customized devices for patients. We report our initial clinical experience using this technology to create custom applicators for vaginal brachytherapy. MATERIAL AND METHODS: Three brachytherapy patients with unique clinical needs were identified as likely to benefit from a customized vaginal applicator. Patient 1 underwent intracavitary vaginal cuff brachytherapy after hysterectomy and chemotherapy for stage IA papillary serous endometrial cancer using a custom printed 2.75 cm diameter segmented vaginal cylinder with a central channel. Patient 2 underwent interstitial brachytherapy for a vaginal cuff recurrence of endometrial cancer after prior hysterectomy, whole pelvis radiotherapy, and brachytherapy boost. We printed a 2 cm diameter vaginal cylinder with one central and six peripheral catheter channels to fit a narrow vaginal canal. Patient 3 underwent interstitial brachytherapy boost for stage IIIA vulvar cancer with vaginal extension. For more secure applicator fit within a wide vaginal canal, we printed a 3.5 cm diameter solid cylinder with one central tandem channel and ten peripheral catheter channels. The applicators were printed in a biocompatible, sterilizable thermoplastic. RESULTS: Patient 1 received 31.5 Gy to the surface in three fractions over two weeks. Patient 2 received 36 Gy to the CTV in six fractions over two implants one week apart, with interstitial hyperthermia once per implant. Patient 3 received 18 Gy in three fractions over one implant after 45 Gy external beam radiotherapy. Brachytherapy was tolerated well with no grade 3 or higher toxicity and no local recurrences. CONCLUSIONS: We established a workflow to rapidly manufacture and implement customized vaginal applicators that can be sterilized and are made of biocompatible material, resulting in high-quality brachytherapy for patients whose anatomy is not ideally suited for standard, commercially available applicators.

Performance variations among clinically available deformable image registration tools in adaptive radiotherapy - how should we evaluate and interpret the result?

The purpose of this study is to evaluate the performance variations in commercial deformable image registration (DIR) tools for adaptive radiation therapy and further to interpret the differences using clinically available terms. Three clinical examples (prostate, head and neck (HN), and cranial spinal irradiation (CSI) with L-spine boost) were evaluated in this study. Firstly, computerized deformed CT images were generated using simulation QA software with virtual deformations of bladder filling (prostate), neck flexion/bite-block repositioning/tumor shrinkage (HN), and vertebral body rotation (CSI). The corresponding transformation matrices served as a "reference" for the following comparisons. Three commercialized DIR algorithms: the free-form deformation from MIMVista 5.5 and the RegRefine from MIMMaestro 6.0, the multipass B-spline from VelocityAI v3.0.1, and the adap-tive demons from OnQ rts 2.1.15, were applied between the initial images and the deformed CT sets. The generated adaptive contours and dose distributions were compared with the "reference" and among each other. The performance in transfer-ring contours was comparable among all three tools with an average Dice similarity coefficient of 0.81 for all the organs. However, the dose warping accuracy appeared to rely on the evaluation end points and methodologies. Point-dose differences could show a difference of up to 23.3 Gy inside the PTVs and to overestimate up to 13.2 Gy for OARs, which was substantial for a 72 Gy prescription dose. Dose-volume histogram-based evaluation might not be sensitive enough to illustrate all the detailed variations, while isodose assessment on a slice-by-slice basis could be tedious. We further explored the possibility of using 3D gamma index analysis for warping dose variation assessment, and observed differences in dose warping using different DIR tools. Overall, our results demonstrated that evaluation based only on the performance of contour transformation could not guarantee the accuracy in dose warping, while dose-transferring validation strongly relied on the evaluation endpoint. As dose-transferring errors could cause misinterpretations when attempting to accumulate dose for adaptive radiation therapy and more DIR tools are available for clinical use, a standard and clinically meaningful quality assurance criterion should be established for DIR QA in the near future.

Assessment of image quality and dose calculation accuracy on kV CBCT, MV CBCT, and MV CT images for urgent palliative radiotherapy treatments.

A clinical workflow was developed for urgent palliative radiotherapy treatments that integrates patient simulation, planning, quality assurance, and treatment in one 30-minute session. This has been successfully tested and implemented clinically on a linac with MV CBCT capabilities. To make this approach available to all clin-ics equipped with common imaging systems, dose calculation accuracy based on treatment sites was assessed for other imaging units. We evaluated the feasibility of palliative treatment planning using on-board imaging with respect to image quality and technical challenges. The purpose was to test multiple systems using their commercial setup, disregarding any additional in-house development. kV CT, kV CBCT, MV CBCT, and MV CT images of water and anthropomorphic phantoms were acquired on five different imaging units (Philips MX8000 CT Scanner, and Varian TrueBeam, Elekta VersaHD, Siemens Artiste, and Accuray Tomotherapy linacs). Image quality (noise, contrast, uniformity, spatial resolution) was evaluated and compared across all machines. Using individual image value to density calibrations, dose calculation accuracies for simple treatment plans were assessed for the same phantom images. Finally, image artifacts on clinical patient images were evaluated and compared among the machines. Image contrast to visualize bony anatomy was sufficient on all machines. Despite a high noise level and low contrast, MV CT images provided the most accurate treatment plans relative to kV CT-based planning. Spatial resolution was poorest for MV CBCT, but did not limit the visualization of small anatomical structures. A comparison of treatment plans showed that monitor units calculated based on a prescription point were within 5% difference relative to kV CT-based plans for all machines and all studied treatment sites (brain, neck, and pelvis). Local dose differences > 5% were found near the phantom edges. The gamma index for 3%/3 mm criteria was ≥ 95% in most cases. Best dose calculation results were obtained when the treatment isocenter was near the image isocenter for all machines. A large field of view and immediate image export to the treatment planning system were essential for a smooth workflow and were not provided on all devices. Based on this phantom study, image quality of the studied kV CBCT, MV CBCT, and MV CT on-board imaging devices was sufficient for treatment planning in all tested cases. Treatment plans provided dose calculation accuracies within an acceptable range for simple, urgently planned palliative treatments. However, dose calculation accuracy was compromised towards the edges of an image. Feasibility for clinical implementation should be assessed separately and may be complicated by machine specific features. Image artifacts in patient images and the effect on dose calculation accuracy should be assessed in a separate, machine-specific study.

An automated deformable image registration evaluation of confidence tool.

Deformable image registration (DIR) is a powerful tool for radiation oncology, but it can produce errors. Beyond this, DIR accuracy is not a fixed quantity and varies on a case-by-case basis. The purpose of this study is to explore the possibility of an automated program to create a patient- and voxel-specific evaluation of DIR accuracy. AUTODIRECT is a software tool that was developed to perform this evaluation for the application of a clinical DIR algorithm to a set of patient images. In brief, AUTODIRECT uses algorithms to generate deformations and applies them to these images (along with processing) to generate sets of test images, with known deformations that are similar to the actual ones and with realistic noise properties. The clinical DIR algorithm is applied to these test image sets (currently 4). From these tests, AUTODIRECT generates spatial and dose uncertainty estimates for each image voxel based on a Student's t distribution. In this study, four commercially available DIR algorithms were used to deform a dose distribution associated with a virtual pelvic phantom image set, and AUTODIRECT was used to generate dose uncertainty estimates for each deformation. The virtual phantom image set has a known ground-truth deformation, so the true dose-warping errors of the DIR algorithms were also known. AUTODIRECT predicted error patterns that closely matched the actual error spatial distribution. On average AUTODIRECT overestimated the magnitude of the dose errors, but tuning the AUTODIRECT algorithms should improve agreement. This proof-of-principle test demonstrates the potential for the AUTODIRECT algorithm as an empirical method to predict DIR errors.

A method for restricting intracatheter dwell time variance in high-dose-rate brachytherapy plan optimization.

PURPOSE: To present the algorithm of a modification to the inverse planning simulated annealing (IPSA) optimization engine that allows for restriction of the intracatheter dwell time variance. METHODS AND MATERIALS: IPSA was modified to allow user control of dwell time variance within each catheter through a single parameter, the dwell time deviation constraint (DTDC). The minimum DTDC value (DTDC = 0) does not impose any restriction on dwell time variance, and the maximum value (DTDC = 1) restricts all dwell times within each catheter to take on the same value. The final optimization penalty function value was evaluated as a function of DTDC. RESULTS: The algorithm proposed fully preserves the inverse planning nature of the IPSA algorithm along with the penalty-based dose optimization workflow. Increasing DTDC creates less variance in dwell time between dwell positions in each catheter and may be used to induce a more smooth change in dwell time with dwell position in each catheter. Nonzero DTDC values always increased the optimization penalty function value. CONCLUSIONS: The DTDC was developed as an extension to IPSA to allow restriction of the difference in dwell time between adjacent dwell positions. This results in less variation between neighboring dwell positions which can be clinically desirable. However, the impact of this restriction needs to be considered for its clinical relevance on a case-by-case basis because considerable degradation in dose-volume histogram metrics can result for large DTDC values.