Promoting the Anticancer Activity with Multidentate Furan-2-Carboxamide Functionalized Aroyl Thiourea Chelation in Binuclear Half-Sandwich Ruthenium(II) Complexes.

A new set of binuclear arene ruthenium complexes [Ru2(p-cymene)2(k4-N2OS)(L1-L3)Cl2] (Ru2L1-Ru2L3) encompassing furan-2-carboxamide-based aroylthiourea derivatives (H2L1-H2L3) was synthesized and characterized by various spectral and analytical techniques. Single-crystal XRD analysis unveils the N^O and N^S mixed monobasic bidentate coordination of the ligands constructing N, S, Cl/N, O, and Cl legged piano stool octahedral geometry. DFT analysis demonstrates the predilection for the formation of stable arene ruthenium complexes. In vitro antiproliferative activity of the complexes was examined against human cervical (HeLa), breast (MCF-7), and lung (A549) cancerous and noncancerous monkey kidney epithelial (Vero) cells. All the complexes are more efficacious against HeLa and MCF-7 cells with low inhibitory doses (3.86-11.02 µM). Specifically, Ru2L3 incorporating p-cymene and -OCH3 fragments exhibits high lipophilicity, significant cytotoxicity against cancer cells, and lower toxicity on noncancerous cells. Staining analysis indicates the apoptosis-associated cell morphological changes expressively in MCF-7 cells. Mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) analyses reveal that Ru2L3 can raise ROS levels, reduce MMP, and trigger mitochondrial dysfunction-mediated apoptosis. The catalytic oxidation of glutathione (GSH) to its disulfide form (GSSG) by the complexes may simultaneously increase the ROS levels, alluding to their observed cytotoxicity and apoptosis induction. Flow cytometry determined the quantitative classification of late apoptosis and S-phase arrest in MCF-7 and HeLa cells. Western blotting analysis confirmed that the complexes promote apoptosis by upregulating Caspase-3 and Caspase-9 and downregulating BCL-2. Molecular docking studies unfolded the strong binding affinities of the complexes with VEGFR2, an angiogenic signaling receptor, and BCL2, Cyclin D1, and HER2 proteins typically overexpressed on tumor cells.

Nickel Pincer Complexes Catalyzed Sustainable Synthesis of 3,4-Dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxides via Acceptorless Dehydrogenative Coupling of Primary Alcohols.

We report the atom-economic and sustainable synthesis of biologically important 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide (DHBD) derivatives from readily available aromatic primary alcohols and 2-aminobenzenesulfonamide catalyzed by nickel(II)-N∧N∧S pincer-type complexes. The synthesized nickel complexes have been well-studied by elemental and spectroscopic (FT-IR, NMR, and HRMS) analyses. The solid-state molecular structure of complex 2 has been authenticated by a single-crystal X-ray diffraction study. Furthermore, a series of 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide derivatives have been synthesized (24 examples) utilizing a 3 mol % Ni(II) catalyst through acceptorless dehydrogenative coupling of benzyl alcohols with benzenesulfonamide. Gratifyingly, the catalytic protocol is highly selective with the yield up to 93% and produces eco-friendly water/hydrogen gas as byproducts. The control experiments and plausible mechanistic investigations indicate that the coupling of the in situ generated aldehyde with benzenesulfonamide leads to the desired product. In addition, a large-scale synthesis of one of the thiadiazine derivatives unveils the synthetic usefulness of the current methodology.

Preclinical Ultra-High Dose Rate (FLASH) Proton Radiation Therapy System for Small Animal Studies.

Purpose: Animal studies with ultrahigh dose-rate radiation therapy (FLASH, >40 Gy/s) preferentially spare normal tissues without sacrificing antitumor efficacy compared with conventional dose-rate radiation therapy (CONV). At the University of Washington, we developed a cyclotron-generated preclinical scattered proton beam with FLASH dose rates. We present the technical details of our FLASH radiation system and preliminary biologic results from whole pelvis radiation. Methods and Materials: A Scanditronix MC50 compact cyclotron beamline has been modified to produce a 48.7 MeV proton beam at dose rates between 0.1 and 150 Gy/s. The system produces a 6 cm diameter scattered proton beam (flat to ± 3%) at the target location. Female C57BL/6 mice 5 to 6 weeks old were used for all experiments. To study normal tissue effects in the distal colon, mice were irradiated using the entrance region of the proton beam to the whole pelvis, 18.5 Gy at different dose rates: control, CONV (0.6-1 Gy/s) and FLASH (50-80 Gy/s). Survival was monitored daily and EdU (5-ethynyl-2´-deoxyuridine) staining was performed at 24- and 96-hours postradiation. Cleaved caspase-3 staining was performed 24-hours postradiation. To study tumor control, allograft B16F10 tumors were implanted in the right flank and received 18 Gy CONV or FLASH proton radiation. Tumor growth and survival were monitored. Results: After 18.5 Gy whole pelvis radiation, survival was 100% in the control group, 0% in the CONV group, and 44% in the FLASH group (P < .01). EdU staining showed cell proliferation was significantly higher in the FLASH versus CONV group at both 24-hours and 96-hours postradiation in the distal colon, although both radiation groups showed decreased proliferation compared with controls (P < .05). Lower cleaved caspase-3 staining was seen in the FLASH versus conventional group postradiation (P < .05). Comparable flank tumor control was observed in the CONV and FLASH groups. Conclusions: We present our preclinical FLASH proton radiation system and biologic results showing improved survival after whole pelvis radiation, with equivalent tumor control.

Exploration of Antiproliferative Activity and Apoptosis Induction of New Nickel(II) Complexes Encompassing Carbazole Ligands.

To attest the effectiveness of nickel complexes as anticancer drug candidates with minimum side effects, the present investigation describes the facile synthesis and anticancer activities of nickel(II) complexes enriched with three derivatives of carbazolone-based benzhydrazone ligands(L) having a [Ni(L)2] composition. Analytical and spectral techniques were used to characterize the synthesized Ni(II) complexes. The single-crystal X-ray diffraction performed for complex 4 confirmed the square planar geometry with a [Ni(κ2-N,O-L)2] arrangement. The MTT assay was carried out for the complexes to determine in vitro cytotoxicity against cancerous human-cervical carcinoma, human-colon carcinoma, and non-cancerous L929 (fibroblast) cells. All three complexes exhibited good toxicity against the cancer cells with a low IC50 concentration. Complex 4, containing -OCH3 fragment, exhibits high lipophilicity and revealed exceptional cytotoxicity against cancer cells. AO-EB fluorescent staining indicated apoptosis-associated cell morphological changes after exposure to complex 4. The apoptosis induction was further confirmed by a HOECHST-33342 fluorescent staining technique via chromosomal condensation and nuclear fragmentation. Further, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) mechanistic studies revealed that complex 4 can raise ROS levels and reduce MMP and promote mitochondrial dysfunction-mediated apoptotic cell death. Further, stimulation of late apoptosis by complex 4 in cervical cancer cells was quantitatively differentiated through the staining of phosphatidylserine externalization by flow cytometry. Furthermore, the ELISA analysis confirmed that complex 4 induced apoptosis through caspase activation.

Improved lateral penumbra for proton ocular treatments on a general-purpose spot scanning beamline.

PURPOSE: An ocular applicator that fits a commercial proton snout with an upstream range shifter to allow for treatments with sharp lateral penumbra is described. MATERIALS AND METHODS: The validation of the ocular applicator consisted of a comparison of range, depth doses (Bragg peaks and spread out Bragg peaks), point doses, and 2-D lateral profiles. Measurements were made for three field sizes, 1.5, 2, and 3 cm, resulting in 15 beams. Distal and lateral penumbras were simulated in the treatment planning system for seven range-modulation combinations for beams typical of ocular treatments and a field size of 1.5 cm, and penumbra values were compared to published literature. RESULTS: All the range errors were within 0.5 mm. The maximum averaged local dose differences for Bragg peaks and SOBPs were 2.6% and 1.1%, respectively. All the 30 measured point doses were within +/-3% of the calculated. The measured lateral profiles, analyzed through gamma index analysis and compared to the simulated, had pass rates greater than 96% for all the planes. The lateral penumbra increased linearly with depth, from 1.4 mm at 1 cm depth to 2.5 mm at 4 cm depth. The distal penumbra ranged from 3.6 to 4.4 mm and increased linearly with the range. The treatment time for a single 10 Gy (RBE) fractional dose ranged from 30 to 120 s, depending on the shape and size of the target. CONCLUSIONS: The ocular applicator's modified design allows lateral penumbra similar to dedicated ocular beamlines while enabling planners to use modern treatment tools such as Monte Carlo and full CT-based planning with increased flexibility in beam placement.

Predicted Inferior Outcomes for Lung SBRT With Treatment Planning Systems That Fail Independent Phantom-Based Audits.

PURPOSE: More than 15% of radiation therapy clinics fail external audits with anthropomorphic phantoms conducted by Imaging and Radiation Oncology Core-Houston (IROC-H) while passing other industry-standard quality assurance (QA) tests. We seek to evaluate the predicted effect of such failed plans on outcomes for patients treated with stereotactic body radiation therapy (SBRT) for lung tumors. METHODS AND MATERIALS: We conducted a retrospective study of 55 patients treated with SBRT for lung tumors with a prescription biologically equivalent dose (BED)10 ≥100 Gy using a treatment planning system (TPS) that passed IROC-H phantom audits. Sample linear accelerator beam models with introduced errors were commissioned by varying the multileaf collimator leaf-tip offset parameter (ie, dosimetric leaf gap) over the range ±1.0 mm relative to the validated model. These models mimic TPS that pass internal QA measures but fail IROC-H tests. Patient plans were recalculated on sample beam models. The predicted tumor control probability (TCP) and normal tissue complication probability (NTCP) were calculated based on published dose-response models. RESULTS: A leaf-tip offset value of -1.0 mm decreased the fraction of plans receiving a planning treatment volume of BED10 ≥100 Gy from 95% to 27%. This translated to a significant decrease in 2-year TCP of 4.8% (95% CI: 2.0%-5.5%) with a decrease in TCP up to 21%. Conversely, a leaf-tip offset of +1.0 mm resulted in 36% of patients exceeding previously met organs at risk (OAR) constraints, including 2 instances of spinal cord and brachial plexus overdoses and a small increase in chest wall NTCP of 0.7%, (95% CI: 0.5%-0.8%). CONCLUSIONS: Simulated treatment plans with modest MLC leaf offsets result in lung SBRT plans that significantly underdose tumor or exceed OAR constraints. These dosimetric endpoints translate to significant detriments in TCP. These simulated plans mimic planning systems that pass internal QA measures but fail independent phantom-based tests, underscoring the need for enhanced quality assurance including external audits of TPS.

Radiation and immune checkpoint inhibitor-mediated pneumonitis risk stratification in patients with locally advanced non-small cell lung cancer: role of functional lung radiomics?

BACKGROUND: Patients undergoing chemoradiation and immune checkpoint inhibitor (ICI) therapy for locally advanced non-small cell lung cancer (NSCLC) experience pulmonary toxicity at higher rates than historical reports. Identifying biomarkers beyond conventional clinical factors and radiation dosimetry is especially relevant in the modern cancer immunotherapy era. We investigated the role of novel functional lung radiomics, relative to functional lung dosimetry and clinical characteristics, for pneumonitis risk stratification in locally advanced NSCLC. METHODS: Patients with locally advanced NSCLC were prospectively enrolled on the FLARE-RT trial (NCT02773238). All received concurrent chemoradiation using functional lung avoidance planning, while approximately half received consolidation durvalumab ICI. Within tumour-subtracted lung regions, 110 radiomics features (size, shape, intensity, texture) were extracted on pre-treatment [99mTc]MAA SPECT/CT perfusion images using fixed-bin-width discretization. The performance of functional lung radiomics for pneumonitis (CTCAE v4 grade 2 or higher) risk stratification was benchmarked against previously reported lung dosimetric parameters and clinical risk factors. Multivariate least absolute shrinkage and selection operator Cox models of time-varying pneumonitis risk were constructed, and prediction performance was evaluated using optimism-adjusted concordance index (c-index) with 95% confidence interval reporting throughout. RESULTS: Thirty-nine patients were included in the study and pneumonitis occurred in 16/39 (41%) patients. Among clinical characteristics and anatomic/functional lung dosimetry variables, only the presence of baseline chronic obstructive pulmonary disease (COPD) was significantly associated with the development of pneumonitis (HR 4.59 [1.69-12.49]) and served as the primary prediction benchmark model (c-index 0.69 [0.59-0.80]). Discrimination of time-varying pneumonitis risk was numerically higher when combining COPD with perfused lung radiomics size (c-index 0.77 [0.65-0.88]) or shape feature classes (c-index 0.79 [0.66-0.91]) but did not reach statistical significance compared to benchmark models (p > 0.26). COPD was associated with perfused lung radiomics size features, including patients with larger lung volumes (AUC 0.75 [0.59-0.91]). Perfused lung radiomic texture features were correlated with lung volume (adj R2 = 0.84-1.00), representing surrogates rather than independent predictors of pneumonitis risk. CONCLUSIONS: In patients undergoing chemoradiation with functional lung avoidance therapy and optional consolidative immune checkpoint inhibitor therapy for locally advanced NSCLC, the strongest predictor of pneumonitis was the presence of baseline chronic obstructive pulmonary disease. Results from this novel functional lung radiomics exploratory study can inform future validation studies to refine pneumonitis risk models following combinations of radiation and immunotherapy. Our results support functional lung radiomics as surrogates of COPD for non-invasive monitoring during and after treatment. Further study of clinical, dosimetric, and radiomic feature combinations for radiation and immune-mediated pneumonitis risk stratification in a larger patient population is warranted.

Prognostic Value of Early Fluorodeoxyglucose-Positron Emission Tomography Response Imaging and Peripheral Immunologic Biomarkers: Substudy of a Phase II Trial of Risk-Adaptive Chemoradiation for Unresectable Non-Small Cell Lung Cancer.

Purpose: We sought to examine the prognostic value of fluorodeoxyglucose-positron emission tomography (PET) imaging during chemoradiation for unresectable non-small cell lung cancer for survival and hypothesized that tumor PET response is correlated with peripheral T-cell function. Methods and Materials: Forty-five patients with American Joint Committee on Cancer version 7 stage IIB-IIIB non-small cell lung cancer enrolled in a phase II trial and received platinum-doublet chemotherapy concurrent with 6 weeks of radiation (NCT02773238). Fluorodeoxyglucose-PET was performed before treatment start and after 24 Gy of radiation (week 3). PET response status was prospectively defined by multifactorial radiologic interpretation. PET responders received 60 Gy in 30 fractions, while nonresponders received concomitant boosts to 74 Gy in 30 fractions. Peripheral blood was drawn synchronously with PET imaging, from which germline DNA sequencing, T-cell receptor sequencing, and plasma cytokine analysis were performed. Results: Median follow-up was 18.8 months, 1-year overall survival (OS) 82%, 1-year progression-free survival 53%, and 1-year locoregional control 88%. Higher midtreatment PET total lesion glycolysis was detrimental to OS (1 year 87% vs 63%, P < .001), progression-free survival (1 year 60% vs 26%, P = .044), and locoregional control (1 year 94% vs 65%, P = .012), even after adjustment for clinical/treatment factors. Twenty-nine of 45 patients (64%) were classified as PET responders based on a priori definition. Higher tumor programmed death-ligand 1 expression was correlated with response on PET (P = .017). Higher T-cell receptor richness and clone distribution slope were associated with improved OS (P = .018-0.035); clone distribution slope was correlated with PET response (P = .031). Conclusions: Midchemoradiation PET imaging is prognostic for survival; PET response may be linked to tumor and peripheral T-cell biomarkers.

Treatment of ocular tumors through a novel applicator on a conventional proton pencil beam scanning beamline.

Treatment of ocular tumors on dedicated scattering-based proton therapy systems is standard afforded due to sharp lateral and distal penumbras. However, most newer proton therapy centers provide pencil beam scanning treatments. In this paper, we present a pencil beam scanning (PBS)-based ocular treatment solution. The design, commissioning, and validation of an applicator mount for a conventional PBS snout to allow for ocular treatments are given. In contrast to scattering techniques, PBS-based ocular therapy allows for inverse planning, providing planners with additional flexibility to shape the radiation field, potentially sparing healthy tissues. PBS enables the use of commercial Monte Carlo algorithms resulting in accurate dose calculations in the presence of heterogeneities and fiducials. The validation consisted of small field dosimetry measurements of point doses, depth doses, and lateral profiles relevant to ocular therapy. A comparison of beam properties achieved through the applicator against published literature is presented. We successfully showed the feasibility of PBS-based ocular treatments.

Clinical Outcomes After Proton Beam Therapy for Locally Advanced Non-Small Cell Lung Cancer: Analysis of a Multi-institutional Prospective Registry.

PURPOSE: For most disease sites, level 1 evidence is lacking for proton beam therapy (PBT). By identifying target populations that would benefit most from PBT, prospective registries could overcome many of the challenges in clinical trial enrollment. Herein, we report clinical outcomes of patients treated with PBT for locally advanced non-small cell lung cancer (LA-NSCLC). METHODS AND MATERIALS: Data were obtained from the multi-institutional prospective database of the Proton Collaborative Group (PCG). Inclusion criteria of our study were stage III de novo or recurrent LA-NSCLC, use of PBT, and availability of follow-up data. Overall survival (OS) time was calculated from the start of treatment until death or last follow-up. Kaplan-Meier curves were generated for groups of interest and compared with log-rank tests. Cox regression modeling was used to evaluate the multivariate association between selected covariates and OS. RESULTS: A total of 195 patients were included in the analysis. PBT was given with a median equivalent dose in 2 Gy fractions (EQD2) of 63.8 Gy (relative biological effectiveness). Pencil beam scanning was used in 20% of treatments. Treatment-related grade 3 adverse events were rare: 1 pneumonitis, 2 dermatitis, and 3 esophagitis. No grade 4 events were reported. Two cardiac-related grade 5 events occurred in patients with multiple risk factors. The median follow-up time for living patients was 37.1 months and the median OS was 19.0 months. On multivariate analysis, good performance status (hazard ratio, 0.27; [95% confidence interval, 0.15-0.46]; P < .0001), pencil beam scanning use (0.55; [0.31-0.97]; P = .04), and increased EQD2 (0.80; [0.71-0.90] - per 10 Gy increase; P = .0002) were associated with decreased mortality. CONCLUSIONS: PBT appears to yield low rates of adverse events with an OS similar to other retrospective studies on PBT for LA-NSCLC. PBS use and increased EQD2 can potentially improve OS.

The Impact of COVID-19 on US Radiation Oncology Residents.

The purpose of our study is to assess the impact of COVID-19 on the clinical responsibilities, training, and wellness of US radiation oncology residents. An anonymous cross-sectional survey was sent to all 91 radiation oncology residency programs in the USA. The survey included questions related to demographics, changes in clinical duties and training, job prospects, and wellness indicators. Univariate and multivariate logistic regression analyses were used to evaluate factors associated with residents endorsing high satisfaction with their departments' response to COVID-19. A total of 96 residents completed the survey from 67 US radiation oncology programs. In the multivariate logistic regression model, remote contouring (OR: 3.91 (95% CI: 1.11, 13.80), p = 0.03) and belief that one will be adequately trained to independently practice after completing residency (OR: 4.68 (1.12, 19.47), p = 0.03) were significantly associated with high resident satisfaction with their department's response to COVID-19. Most residents indicated that hypofractionation was encouraged to a greater extent (n = 79, 82.3%), patients were triaged by disease risk (n = 67, 69.8%), and most agreed/strongly agreed that they have been provided with adequate personal protective equipment (PPE) (n = 85, 88.5%). The COVID-19 pandemic has affected the training and wellness of radiation oncology residents. Our analysis suggests that radiation oncology programs might increase resident satisfaction with their department's response to COVID-19 by enabling remote contouring and working with residents to identity and remedy possible concerns regarding their ability to independently practice post residency.

Reliability of Quantitative 18F-FDG PET/CT Imaging Biomarkers for Classifying Early Response to Chemoradiotherapy in Patients With Locally Advanced Non-Small Cell Lung Cancer.

PURPOSE OF THE REPORT: We evaluated the reliability of 18F-FDG PET imaging biomarkers to classify early response status across observers, scanners, and reconstruction algorithms in support of biologically adaptive radiation therapy for locally advanced non-small cell lung cancer. PATIENTS AND METHODS: Thirty-one patients with unresectable locally advanced non-small cell lung cancer were prospectively enrolled on a phase 2 trial (NCT02773238) and underwent 18F-FDG PET on GE Discovery STE (DSTE) or GE Discovery MI (DMI) PET/CT systems at baseline and during the third week external beam radiation therapy regimens. All PET scans were reconstructed using OSEM; GE-DMI scans were also reconstructed with BSREM-TOF (block sequential regularized expectation maximization reconstruction algorithm incorporating time of flight). Primary tumors were contoured by 3 observers using semiautomatic gradient-based segmentation. SUVmax, SUVmean, SUVpeak, MTV (metabolic tumor volume), and total lesion glycolysis were correlated with midtherapy multidisciplinary clinical response assessment. Dice similarity of contours and response classification areas under the curve were evaluated across observers, scanners, and reconstruction algorithms. LASSO logistic regression models were trained on DSTE PET patient data and independently tested on DMI PET patient data. RESULTS: Interobserver variability of PET contours was low for both OSEM and BSREM-TOF reconstructions; intraobserver variability between reconstructions was slightly higher. ΔSUVpeak was the most robust response predictor across observers and image reconstructions. LASSO models consistently selected ΔSUVpeak and ΔMTV as response predictors. Response classification models achieved high cross-validated performance on the DSTE cohort and more variable testing performance on the DMI cohort. CONCLUSIONS: The variability FDG PET lesion contours and imaging biomarkers was relatively low across observers, scanners, and reconstructions. Objective midtreatment PET response assessment may lead to improved precision of biologically adaptive radiation therapy.

Phase II Trial of Flaxseed to Prevent Acute Complications After Chemoradiation for Lung Cancer.

Background: Thoracic radiotherapy is complicated by acute radiation-induced adverse events such as radiation pneumonitis (RP) and radiation esophagitis (RE). Based on preclinical work and a randomized pilot trial from our laboratory, this single-arm phase II trial investigated administering flaxseed as a radioprotector in patients receiving definitive chemoradiation for nonsmall cell lung cancer (NSCLC). Methods: Between June 2015 and February 2018, 33 patients with locally advanced or metastatic NSCLC with planned definitive chemoradiation were enrolled. Finely-ground Linum usitatissimum L. (Linaceae; flaxseed or linseed) in 40-g packets were provided for daily consumption in any patient-desired formulation 1 week before radiotherapy and throughout radiotherapy as tolerated. The primary outcomes were overall adverse events, with particular focus on Grade ≥3 RP, and flaxseed tolerability. Adverse events were graded according to CTCAE v4.0. Results: Of the 33 patients enrolled, 5 patients (15%) did not receive chemoradiation, 4 (12%) withdrew promptly after enrollment, 4 (12%) did not return a flaxseed consumption log, and 1 patient had irritable bowel syndrome (3%). The remaining 19 patients (57%) had chemoradiation and flaxseed ingestion with a mean completion and standard deviation of the intended flaxseed course of 62% ± 8.3%. Nine (50%) of these 19 patients reported difficulties with flaxseed consumption, citing nausea, constipation, odynophagia, or poor taste or texture. One patient (5%), with unverifiable flaxseed consumption, developed Grade 3 RP. There were no cases of Grade 2 RP. Six patients (32%) developed Grade 2 RE, but no patients developed Grade ≥3 RE. Median overall and progression-free survival were 31 and 12 months, respectively. Conclusions: Despite the low incidence of acute radiation-induced complications reported, significant treatment-related gastrointestinal toxicities and subsequently low flaxseed tolerability inhibit accurate determination of flaxseed effect in patients receiving concurrent thoracic chemoradiation. Thus, further investigations should focus on optimizing flaxseed formulation for improved tolerability and evaluation. ClinicalTrials.gov ID: NCT02475330.

Tumor control probability in hypofractionated radiotherapy as a function of total and hypoxic tumor volumes.

Clinical studies in the hypofractionated stereotactic body radiotherapy (SBRT) have shown a reduction in the probability of local tumor control with increasing initial tumor volume. In our earlier work, we obtained and tested an analytical dependence of the tumor control probability (TCP) on the total and hypoxic tumor volumes using conventional radiotherapy model with the linear-quadratic (LQ) cell survival. In this work, this approach is further refined and tested against clinical observations for hypofractionated radiotherapy treatment schedules. Compared to radiotherapy with conventional fractionation schedules, simulations of hypofractionated radiotherapy may require different models for cell survival and the oxygen enhancement ratio (OER). Our TCP simulations in hypofractionated radiotherapy are based on the LQ model and the universal survival curve (USC) developed for the high doses used in SBRT. The predicted trends in local control as a function of the initial tumor volume were evaluated in SBRT for non-small cell lung cancer (NSCLC). Our results show that both LQ and USC based models cannot describe the TCP reduction for larger tumor volumes observed in the clinical studies if the tumor is considered completely oxygenated. The TCP calculations are in agreement with the clinical data if the subpopulation of radio-resistant hypoxic cells is considered with the volume that increases as initial tumor volume increases. There are two conclusions which follow from our simulations. First, the extent of hypoxia is likely a primary reason of the TCP reduction with increasing the initial tumor volume in SBRT for NSCLC. Second, the LQ model can be an acceptable approximation for the TCP calculations in hypofractionated radiotherapy if the tumor response is defined primarily by the hypoxic fraction. The larger value of OER in the hypofractionated radiotherapy compared to the conventional radiotherapy effectively extends the applicability of the LQ model to larger doses.

A stratified phase I dose escalation trial of hypofractionated radiotherapy followed by ipilimumab in metastatic melanoma: long-term follow-up and final outcomes.

We conducted a phase I dose-escalation trial of radiation with ipilimumab in patients with melanoma with ≥2 metastatic lesions. Here, we report the final full clinical analysis. Patients received RT (6 or 8 Gy x 2 or 3 doses) to a single lesion followed by 4 cycles of ipilimumab. The primary endpoint was maximum tolerated dose of RT, and secondary endpoint was response at non-radiated sites. Twenty-two patients with treatment-naïve (n = 11) or treatment-refractory (n = 11) Stage IV melanoma were enrolled. There were 31 treatment-related adverse events (AEs), of which 16 were deemed immune-related. Eleven patients had grade 3 AEs (no grade 4/5). There were no dose-limiting toxicities related to the radiation/ipilimumab combination. Five of 22 patients (22.7%, 95% CI 7.8-45.4%) had partial response as best response and three (13.6%) had stable disease. Median overall survival was 10.7 months (95% CI, 4.9 months to not-estimable) and median progression-free survival 3.6 months (95% CI, 2.9 months to 7.8 months). Seven patients were still alive at the time of last follow-up (median follow-up 89.2 months), most of whom received pembrolizumab after progression. Radiotherapy followed by ipilimumab was well tolerated and yielded a response rate that compares favorably to the objective response rate with ipilimumab alone. Furthermore, 32% of patients are long-term survivors, most of whom received pembrolizumab. Based on these results, the recommended dose that was used in subsequent Phase 2 trials was 8 Gy x 3 doses. Clinical Trial Registration: NCT01497808 (www.clinicaltrials.gov).

Radiation and Modulation of the Tumor Immune Microenvironment in Non-Small Cell Lung Cancer.

Immune checkpoint inhibitors are approved for a variety of indications for locally advanced and metastatic non-small cell lung cancer (NSCLC), and trials are ongoing in the early-stage setting. There is an unmet need to understand which patients may derive benefit from immunotherapies and how to harness combined modality therapies to improve overall response rates and durability. Here, we review studies from the bench-to-bedside to examine the role of radiation therapy (RT) on the tumor immune microenvironment in NSCLC with an eye toward augmenting antitumor immunity. Together, these data provide a foundation for developing future clinical trials harnessing RT to augment antitumor immunity and highlight the need for correlative translational studies to directly characterize the impact of RT on the human NSCLC tumor immune microenvironment.

Consensus Statement on Proton Therapy in Mesothelioma.

PURPOSE: Radiation therapy for mesothelioma remains challenging, as normal tissue toxicity limits the amount of radiation that can be safely delivered to the pleural surfaces, especially radiation dose to the contralateral lung. The physical properties of proton therapy result in better sparing of normal tissues when treating the pleura, both in the postpneumonectomy setting and the lung-intact setting. Compared with photon radiation, there are dramatic reductions in dose to the contralateral lung, heart, liver, kidneys, and stomach. However, the tissue heterogeneity in the thorax, organ motion, and potential for changing anatomy during the treatment course all present challenges to optimal irradiation with protons. METHODS: The clinical data underlying proton therapy in mesothelioma are reviewed here, including indications, advantages, and limitations. RESULTS: The Particle Therapy Cooperative Group Thoracic Subcommittee task group provides specific guidelines for the use of proton therapy for mesothelioma. CONCLUSIONS: This consensus report can be used to guide clinical practice, insurance approval, and future research.

Sensitivity analysis of FDG PET tumor voxel cluster radiomics and dosimetry for predicting mid-chemoradiation regional response of locally advanced lung cancer.

We investigated the sensitivity of regional tumor response prediction to variability in voxel clustering techniques, imaging features, and machine learning algorithms in 25 patients with locally advanced non-small cell lung cancer (LA-NSCLC) enrolled on the FLARE-RT clinical trial. Metabolic tumor volumes (MTV) from pre-chemoradiation (PETpre) and mid-chemoradiation fluorodeoxyglucose-positron emission tomography (FDG PET) images (PETmid) were subdivided into K-means or hierarchical voxel clusters by standardized uptake values (SUV) and 3D-positions. MTV cluster separability was evaluated by CH index, and morphologic changes were captured by Dice similarity and centroid Euclidean distance. PETpre conventional features included SUVmean, MTV/MTV cluster size, and mean radiation dose. PETpre radiomics consisted of 41 intensity histogram and 3D texture features (PET Oncology Radiomics Test Suite) extracted from MTV or MTV clusters. Machine learning models (multiple linear regression, support vector regression, logistic regression, support vector machines) of conventional features or radiomic features were constructed to predict PETmid response. Leave-one-out-cross-validated root-mean-squared-error (RMSE) for continuous response regression (ΔSUVmean) and area-under-receiver-operating-characteristic-curve (AUC) for binary response classification were calculated. K-means MTV 2-clusters (MTVhi, MTVlo) achieved maximum CH index separability (Friedman p < 0.001). Between PETpre and PETmid, MTV cluster pairs overlapped (Dice 0.70-0.87) and migrated 0.6-1.1 cm. PETmid ΔSUVmean response prediction was superior in MTV and MTVlo (RMSE = 0.17-0.21) compared to MTVhi (RMSE = 0.42-0.52, Friedman p < 0.001). PETmid ΔSUVmean response class prediction performance trended higher in MTVlo (AUC = 0.83-0.88) compared to MTVhi (AUC = 0.44-0.58, Friedman p = 0.052). Models were more sensitive to MTV/MTV cluster regions (Friedman p = 0.026) than feature sets/algorithms (Wilcoxon signed-rank p = 0.36). Top-ranked radiomic features included GLZSM-LZHGE (large-zone-high-SUV), GTSDM-CP (cluster-prominence), GTSDM-CS (cluster-shade) and NGTDM-CNT (contrast). Top-ranked features were consistent between MTVhi and MTVlo cluster pairs but varied between MTVhi-MTVlo clusters, reflecting distinct regional radiomic phenotypes. Variability in tumor voxel cluster response prediction can inform robust radiomic target definition for risk-adaptive chemoradiation in patients with LA-NSCLC. FLARE-RT trial: NCT02773238.