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.

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.

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.

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.

The RECITE Study: A Canadian Prospective, Multicenter Study of the Incidence and Severity of Residual Neuromuscular Blockade.

BACKGROUND: Postoperative residual neuromuscular blockade (NMB), defined as a train-of-four (TOF) ratio of <0.9, is an established risk factor for critical postoperative respiratory events and increased morbidity. At present, little is known about the occurrence of residual NMB in Canada. The RECITE (Residual Curarization and its Incidence at Tracheal Extubation) study was a prospective observational study at 8 hospitals in Canada investigating the incidence and severity of residual NMB. METHODS: Adult patients undergoing open or laparoscopic abdominal surgery expected to last <4 hours, ASA physical status I-III, and scheduled for general anesthesia with at least 1 dose of a nondepolarizing neuromuscular blocking agent for endotracheal intubation or maintenance of neuromuscular relaxation were enrolled in the study. Neuromuscular function was assessed using acceleromyography with the TOF-Watch SX. All reported TOF ratios were normalized to the baseline values. The attending anesthesiologist and all other observers were blinded to the TOF ratio (T4/T1) results. The primary and secondary objectives were to determine the incidence and severity of residual NMB (TOF ratio <0.9) just before tracheal extubation and at arrival at the postanesthesia care unit (PACU). RESULTS: Three hundred and two participants were enrolled. Data were available for 241 patients at tracheal extubation and for 207 patients at PACU arrival. Rocuronium was the NMB agent used in 99% of cases. Neostigmine was used for reversal of NMB in 73.9% and 72.0% of patients with TE and PACU data, respectively. The incidence of residual NMB was 63.5% (95% confidence interval, 57.4%-69.6%) at tracheal extubation and 56.5% (95% confidence interval, 49.8%-63.3%) at arrival at the PACU. In an exploratory analysis, no statistically significant differences were observed in the incidence of residual NMB according to gender, age, body mass index, ASA physical status, type of surgery, or comorbidities (all P > 0.13). CONCLUSIONS: Residual paralysis is common at tracheal extubation and PACU arrival, despite qualitative neuromuscular monitoring and the use of neostigmine. More effective detection and management of NMB is needed to reduce the risks associated with residual NMB.

Feasibility of MV CBCT-based treatment planning for urgent radiation therapy: dosimetric accuracy of MV CBCT-based dose calculations.

Unlike scheduled radiotherapy treatments, treatment planning time and resources are limited for emergency treatments. Consequently, plans are often simple 2D image-based treatments that lag behind technical capabilities available for nonurgent radiotherapy. We have developed a novel integrated urgent workflow that uses onboard MV CBCT imaging for patient simulation to improve planning accuracy and reduce the total time for urgent treatments. This study evaluates both MV CBCT dose planning accuracy and novel urgent workflow feasibility for a variety of anatomic sites. We sought to limit local mean dose differences to less than 5% compared to conventional CT simulation. To improve dose calculation accuracy, we created separate Hounsfield unit-to-density calibration curves for regular and extended field-of-view (FOV) MV CBCTs. We evaluated dose calculation accuracy on phantoms and four clinical anatomical sites (brain, thorax/spine, pelvis, and extremities). Plans were created for each case and dose was calculated on both the CT and MV CBCT. All steps (simulation, planning, setup verification, QA, and dose delivery) were performed in one 30 min session using phantoms. The monitor units (MU) for each plan were compared and dose distribution agreement was evaluated using mean dose difference over the entire volume and gamma index on the central 2D axial plane. All whole-brain dose distributions gave gamma passing rates higher than 95% for 2%/2 mm criteria, and pelvic sites ranged between 90% and 98% for 3%/3 mm criteria. However, thoracic spine treatments produced gamma passing rates as low as 47% for 3%/3 mm criteria. Our novel MV CBCT-based dose planning and delivery approach was feasible and time-efficient for the majority of cases. Limited MV CBCT FOV precluded workflow use for pelvic sites of larger patients and resulted in image clearance issues when tumor position was far off midline. The agreement of calculated MU on CT and MV CBCT was acceptable for all treatment sites.

Use of TrueBeam developer mode for imaging QA.

The purpose of this study was to automate regular Imaging QA procedures to become more efficient and accurate. Daily and monthly imaging QA for SRS and SBRT protocols were fully automated on a Varian linac. A three-step paradigm where the data are automatically acquired, processed, and analyzed was defined. XML scripts were written and used in developer mode in a TrueBeam linac to automatically acquire data. MATLAB R013B was used to develop an interface that could allow the data to be processed and analyzed. Hardware was developed that allowed the localization of several phantoms simultaneously on the couch. 14 KV CBCTs from the Emma phantom were obtained using a TrueBeam onboard imager as example of data acquisition and analysis. The images were acquired during two months. Artifacts were artificially introduced in the images during the reconstruction process using iTool reconstructor. Support vector machine algorithms to automatically identify each artifact were written using the Machine Learning MATLAB R2011 Toolbox. A daily imaging QA test could be performed by an experienced medical physicist in 14.3 ± 2.4 min. The same test, if automated using our paradigm, could be performed in 4.2 ± 0.7 min. In the same manner, a monthly imaging QA could be performed by a physicist in 70.7 ± 8.0 min and, if fully automated, in 21.8 ± 0.6 min. Additionally, quantitative data analysis could be automatically performed by Machine Learning Algorithms that could remove the subjectivity of data interpretation in the QA process. For instance, support vector machine algorithms could correctly identify beam hardening, rings and scatter artifacts. Traditional metrics, as well as metrics that describe texture, are needed for the classification. Modern linear accelerators are equipped with advanced 2D and 3D imaging capabilities that are used for patient alignment, substantially improving IGRT treatment accuracy. However, this extra complexity exponentially increases the number of QA tests needed. Using the new paradigm described above, not only the bare minimum ­ but also best practice ­ QA programs could be implemented with the same manpower.

Investigating the clinical advantages of a robotic linac equipped with a multileaf collimator in the treatment of brain and prostate cancer patients.

The purpose of this study was to evaluate the performance of a commercially avail-able CyberKnife system with a multileaf collimator (CK-MLC) for stereotactic body radiotherapy (SBRT) and standard fractionated intensity-modulated radiotherapy (IMRT) applications. Ten prostate and ten intracranial cases were planned for the CK-MLC. Half of these cases were compared with clinically approved SBRT plans generated for the CyberKnife with circular collimators, and the other half were compared with clinically approved standard fractionated IMRT plans generated for conventional linacs. The plans were compared on target coverage, conformity, homogeneity, dose to organs at risk (OAR), low dose to the surrounding tissue, total monitor units (MU), and treatment time. CK-MLC plans generated for the SBRT cases achieved more homogeneous dose to the target than the CK plans with the circular collimators, for equivalent coverage, conformity, and dose to OARs. Total monitor units were reduced by 40% to 70% and treatment time was reduced by half. The CK-MLC plans generated for the standard fractionated cases achieved prescription isodose lines between 86% and 93%, which was 2%-3% below the plans generated for conventional linacs. Compared to standard IMRT plans, the total MU were up to three times greater for the prostate (whole pelvis) plans and up to 1.4 times greater for the intracranial plans. Average treatment time was 25min for the whole pelvis plans and 19 min for the intracranial cases. The CK-MLC system provides significant improvements in treatment time and target homogeneity compared to the CK system with circular collimators, while main-taining high conformity and dose sparing to critical organs. Standard fractionated plans for large target volumes (> 100 cm3) were generated that achieved high prescription isodose levels. The CK-MLC system provides more efficient SRS and SBRT treatments and, in select clinical cases, might be a potential alternative for standard fractionated treatments.

Evaluation of PC-ISO for customized, 3D Printed, gynecologic 192-Ir HDR brachytherapy applicators.

The purpose of this study was to evaluate the radiation attenuation properties of PC-ISO, a commercially available, biocompatible, sterilizable 3D printing material, and its suitability for customized, single-use gynecologic (GYN) brachytherapy applicators that have the potential for accurate guiding of seeds through linear and curved internal channels. A custom radiochromic film dosimetry apparatus was 3D-printed in PC-ISO with a single catheter channel and a slit to hold a film segment. The apparatus was designed specifically to test geometry pertinent for use of this material in a clinical setting. A brachytherapy dose plan was computed to deliver a cylindrical dose distribution to the film. The dose plan used an 192Ir source and was normalized to 1500 cGy at 1 cm from the channel. The material was evaluated by comparing the film exposure to an identical test done in water. The Hounsfield unit (HU) distributions were computed from a CT scan of the apparatus and compared to the HU distribution of water and the HU distribution of a commercial GYN cylinder applicator. The dose depth curve of PC-ISO as measured by the radiochromic film was within 1% of water between 1 cm and 6 cm from the channel. The mean HU was -10 for PC-ISO and -1 for water. As expected, the honeycombed structure of the PC-ISO 3D printing process created a moderate spread of HU values, but the mean was comparable to water. PC-ISO is sufficiently water-equivalent to be compatible with our HDR brachytherapy planning system and clinical workflow and, therefore, it is suitable for creating custom GYN brachytherapy applicators. Our current clinical practice includes the use of custom GYN applicators made of commercially available PC-ISO when doing so can improve the patient's treatment. 

Phase II study of targeted therapy with temozolomide in acute myeloid leukaemia and high-risk myelodysplastic syndrome patients pre-screened for low O(6) -methylguanine DNA methyltransferase expression.

Resistance to temozolomide is largely mediated by the DNA repair enzyme O(6) -methylguanine DNA methyltransferase (MGMT). We conducted a prospective multicentre study of patients with previously untreated acute myeloid leukaemia (AML) or high-risk myelodysplastic syndrome (MDS) who were not candidates for intensive therapy. Patient selection was based on MGMT expression by Western blot. Patients with MGMT:ACTB (ß-actin) ratio <0·2 were eligible to receive temozolomide 200 mg/m(2) /d ×7 d. Patients achieving a complete response (CR) could receive up to 12 monthly cycles of temozolomide ×5/28 d. Of 166 patients screened, 81 (49%) demonstrated low MGMT expression; 45 of these were treated with temozolomide. The overall response rate was 53%; 36% achieved complete clearance of blasts, with 27% achieving a CR/CR with incomplete platelet recovery (CRp). Factors associated with a trend toward a higher response rate included MDS, methylated MGMT promoter and standard cytogenetic risk group. Induction and post-remission cycles were well-tolerated and most patients were treated on an outpatient basis. Patient who achieved CR/CRp had a superior overall survival compared to partial or non-responders. In conclusion, targeted therapy based on pre-selection for low MGMT expression was associated with a higher response rate to temozolomide compared to previous reports of unselected patients.

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 %.

Improving plan quality and consistency by standardization of dose constraints in prostate cancer patients treated with CyberKnife.

Treatment plans for prostate cancer patients undergoing stereotactic body radiation therapy (SBRT) are often challenging due to the proximity of organs at risk. Today, there are no objective criteria to determine whether an optimal treatment plan has been achieved, and physicians rely on their personal experience to evaluate the plan's quality. In this study, we propose a method for determining rectal and bladder dose constraints achievable for a given patient's anatomy. We expect that this method will improve the overall plan quality and consistency, and facilitate comparison of clinical outcomes across different institutions. The 3D proximity of the organs at risk to the target is quantified by means of the expansion-intersection volume (EIV), which is defined as the intersection volume between the target and the organ at risk expanded by 5 mm. We determine a relationship between EIV and relevant dosimetric parameters, such as the volume of bladder and rectum receiving 75% of the prescription dose (V75%). This relationship can be used to establish institution-specific criteria to guide the treatment planning and evaluation process. A database of 25 prostate patients treated with CyberKnife SBRT is used to validate this approach. There is a linear correlation between EIV and V75% of bladder and rectum, confirming that the dose delivered to rectum and bladder increases with increasing extension and proximity of these organs to the target. This information can be used during the planning stage to facilitate the plan optimization process, and to standardize plan quality and consistency. We have developed a method for determining customized dose constraints for prostate patients treated with robotic SBRT. Although the results are technology specific and based on the experience of a single institution, we expect that the application of this method by other institutions will result in improved standardization of clinical practice.

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.

Chemosensitized radiosurgery for recurrent brain metastases.

Temozolomide is known to penetrate the blood-brain barrier and sensitize brain tumors to radiation and has been used clinically to sensitize fractionated external beam radiotherapy. However, there are limited prospective clinical data available on the safety of temozolomide as a chemosensitizing agent administered with stereotactic radiosurgery. This is a phase I trial of previously irradiated patients with one to four progressive brain metastases and Karnofsky performance scale score ≥60 % enrolled in three sequential cohorts: temozolomide 100, 150 or 200 mg/(m(2) day) administered for 5 days. Stereotactic radiosurgery (SRS) was administered on day 5. The SRS dose was dependent on target diameter: 15 Gy (31-40 mm), 18 Gy (21-30 mm) or 21 Gy (<20 mm). The primary endpoint was safety of increasing temozolomide doses. Secondary endpoints included local control and survival. 26 subjects were enrolled and 49 total metastatic lesions were treated. The median number of brain metastases was 1.5, with a median target diameter of 21 mm. The most common grade 1-2 adverse events irrespective of causality were vomiting (23 %), nausea (23 %), edema (12 %), seizure (8 %), psychosis (4 %) and thrombocytopenia (4 %). The frequency of nausea and vomiting did not appear to be dose-dependent. Grade 3-4 toxicities were not observed. Median overall survival was 10.2 months. Crude local control was 87.5 %, with a radiological response seen in eight of 24 evaluable patients (33.3 %), and stable disease >6 months in 13 of 24 patients (54.2 %). Temozolomide, at doses up to 200 mg/(m(2) day) × 5 days, prior to SRS is well tolerated, with no dose-limiting toxicities in patients with recurrent brain metastases. Local control of target lesions was >80 %.

Dosimetric aspects of inverse-planned modulated-arc total-body irradiation.

PURPOSE: To develop optimal beam parameters and to verify the dosimetric aspects of the recently developed modulated-arc total-body irradiation (MATBI) technique, which delivers an inverse-planned dose to the entire body using gantry rotation. METHODS: The patient is positioned prone and supine underneath the gantry at about 2 m source-to-surface distance (SSD). Then, up to 28 beams irradiate the patient from different gantry angles. Based on full-body computed-tomography (CT) images of the patient, the weight of each beam is optimized, using inverse planning, to create a uniform body dose. This study investigates how to best simulate patients and the ideal beam setup parameters, such as field size, number of beams, and beam geometry, for treatment time and dose homogeneity. In addition, three anthropomorphic water phantoms were constructed and utilized to verify the accuracy of dose delivery, with both diode array and ion chamber measurements. Furthermore, to improve the accuracy of the new technique, a beam model is created specifically for the extended-SSD positioning for MATBI. RESULTS: Low dose CT scans can be utilized for dose calculations without affecting the accuracy. The largest field size of 40 × 40 cm(2) was found to deliver the most uniform dose in the least amount of time. Moreover, a higher number of beams improves dose homogeneity. The average dose discrepancy between ion chamber measurements and extended-SSD beam model calculations was 1.2%, with the largest discrepancy being 3.2%. This average dose discrepancy was 1.4% with the standard beam model for delivery at isocenter. CONCLUSIONS: The optimum beam setup parameters, regarding dose uniformity and treatment duration, are laid out for modulated-arc TBI. In addition, the presented dose measurements show that these treatments can be delivered accurately. These measurements also indicated that a new beam model did not significantly improve the accuracy of dose calculations. The optimum beam setup parameters along with the measurements performed to ensure accurate dose delivery serve as a useful guide for the clinical implementation of MATBI.

Inverse-planned modulated-arc total-body irradiation.

PURPOSE: To develop a simple and robust method for inverse-planned total-body irradiation (TBI) that is more comfortable and has better dose homogeneity than the conventional forward-planned techniques and that can be delivered in a standard-sized treatment vault. METHODS: Modulated-arc TBI (MATBI) utilizes an arc of static open-field beams to irradiate patients as they lay on a stationary couch beneath the gantry, with cerrobend blocks suspended over organs at risk to provide shielding. Prior to treatment, full-body computed tomography (CT) images are acquired of each patient and imported into the PINNACLE(3) planning system, which modulates the monitor units for the open-field beams to optimize the body dose uniformity. The volume of the body within 10% of the prescription dose, V(±10), is used as a metric to evaluate the dose uniformity. For comparison to MATBI, the dose distribution of a conventional forward-planned treatment is also calculated. Quality assurance measurements are acquired before treatment by delivering the plans to a phantom and during treatment with an ionization chamber inside a buildup block, placed between the patient's ankles. RESULTS: For MATBI, the achieved values of V(±10) were 75.8%, 90.2%, 84.6%, and 79.8% compared to 60.3%, 77.4%, 65.6%, and 68.5% for the conventional TBI technique, respectively. The pretreatment ion chamber measurements in the phantom had an average error of 1.2%. Those acquired during treatment had larger errors, with most points being within 3% of predictions. CONCLUSIONS: MATBI provides better dose uniformity and comfort than the conventional forward-planned TBI techniques. In addition, the technique can be implemented on most linacs, in standard-sized vaults, without the use of a translating couch.

NPIP: A skew line needle configuration optimization system for HDR brachytherapy.

PURPOSE: In this study, the authors introduce skew line needle configurations for high dose rate (HDR) brachytherapy and needle planning by integer program (NPIP), a computational method for generating these configurations. NPIP generates needle configurations that are specific to the anatomy of the patient, avoid critical structures near the penile bulb and other healthy structures, and avoid needle collisions inside the body. METHODS: NPIP consisted of three major components: a method for generating a set of candidate needles, a needle selection component that chose a candidate needle subset to be inserted, and a dose planner for verifying that the final needle configuration could meet dose objectives. NPIP was used to compute needle configurations for prostate cancer data sets from patients previously treated at our clinic. NPIP took two user-parameters: a number of candidate needles, and needle coverage radius, δ. The candidate needle set consisted of 5000 needles, and a range of δ values was used to compute different needle configurations for each patient. Dose plans were computed for each needle configuration. The number of needles generated and dosimetry were analyzed and compared to the physician implant. RESULTS: NPIP computed at least one needle configuration for every patient that met dose objectives, avoided healthy structures and needle collisions, and used as many or fewer needles than standard practice. These needle configurations corresponded to a narrow range of δ values, which could be used as default values if this system is used in practice. The average end-to-end runtime for this implementation of NPIP was 286 s, but there was a wide variation from case to case. CONCLUSIONS: The authors have shown that NPIP can automatically generate skew line needle configurations with the aforementioned properties, and that given the correct input parameters, NPIP can generate needle configurations which meet dose objectives and use as many or fewer needles than the current HDR brachytherapy workflow. Combined with robot assisted brachytherapy, this system has the potential to reduce side effects associated with treatment. A physical trial should be done to test the implant feasibility of NPIP needle configurations.

Quality assurance for image-guided radiation therapy utilizing CT-based technologies: a report of the AAPM TG-179.

PURPOSE: Commercial CT-based image-guided radiotherapy (IGRT) systems allow widespread management of geometric variations in patient setup and internal organ motion. This document provides consensus recommendations for quality assurance protocols that ensure patient safety and patient treatment fidelity for such systems. METHODS: The AAPM TG-179 reviews clinical implementation and quality assurance aspects for commercially available CT-based IGRT, each with their unique capabilities and underlying physics. The systems described are kilovolt and megavolt cone-beam CT, fan-beam MVCT, and CT-on-rails. A summary of the literature describing current clinical usage is also provided. RESULTS: This report proposes a generic quality assurance program for CT-based IGRT systems in an effort to provide a vendor-independent program for clinical users. Published data from long-term, repeated quality control tests form the basis of the proposed test frequencies and tolerances. CONCLUSION: A program for quality control of CT-based image-guidance systems has been produced, with focus on geometry, image quality, image dose, system operation, and safety. Agreement and clarification with respect to reports from the AAPM TG-101, TG-104, TG-142, and TG-148 has been addressed.

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.