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Background Clinical medical physics duties include routine tasks, special procedures, and development projects. It can be challenging to distribute the effort equitably across all team members, especially in large clinics or systems where physicists cover multiple sites. The purpose of this work is to study an equitable workload distribution system in radiotherapy physics that addresses the complex and dynamic nature of effort assignment. Methods We formed a working group that defined all relevant clinical tasks and estimated the total time spent per task. Estimates used data from the oncology information system, a survey of physicists, and group consensus. We introduced a quantitative workload unit, “equivalent workday” (eWD), as a common unit for effort. The sum of all eWD values adjusted for each physicist's clinical full‐time equivalent yields a “normalized total effort” (nTE) metric for each physicist, that is, the fraction of the total effort assigned to that physicist. We implemented this system in clinical operation. During a trial period of 9 months, we made adjustments to include tasks previously unaccounted for and refined the system. The workload distribution of eight physicists over 12 months was compared before and after implementation of the nTE system. Results Prior to implementation, differences in workload of up to 50% existed between individual physicists (nTE range of 10.0%–15.0%). During the trial period, additional categories were added to account for leave and clinical projects that had previously been assigned informally. In the 1‐year period after implementation, the individual workload differences were within 5% (nTE range of 12.3%–12.8%). Conclusion We developed a system to equitably distribute workload and demonstrated improvements in the equity of workload. A quantitative approach to workload distribution improves both transparency and accountability. While the system was motivated by the complexities within an academic medical center, it may be generally applicable for other clinics.

The best survival for patients with unresectable, locally advanced NSCLC is currently achieved through concurrent chemoradiation followed by durvalumab for a year. Despite the best standard of care treatment, the majority of patients still develop disease recurrence, which could be distant and/or local. Trials continue to try and improve outcomes for patients with unresectable NSCLC, typically through treatment intensification, with the addition of more systemic agents, or more radiation dose to the tumor. Although RTOG 0617 showed that uniform dose escalation across an unselected population of patients undergoing chemoradiation is not beneficial, efforts continue to select patients and tumor subsets that are likely to benefit from dose escalation. This review describes some of the ongoing therapeutic trials in unresectable NSCLC, with an emphasis on quantitative imaging and precision radiation dose escalation.

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.

Purpose: Pencil beam (PB) analytical algorithms have been the standard of care for proton therapy dose calculations. The introduction of Monte Carlo (MC) algorithms may provide more robust and accurate planning and can improve therapeutic benefit. We conducted a dosimetric analysis to quantify the differences between MC and PB algorithms in the clinical setting of dose-painted nasopharyngeal cancer intensity-modulated proton radiotherapy. Patients and Methods: Plans of 14 patients treated with PB analytical algorithm optimized and calculated (PBPB) were retrospectively analyzed. The PBPB plans were recalculated using MC to generate PBMC plans and, finally, reoptimized and recalculated with MC to generate MCMC plans. The plans were compared across several dosimetric endpoints and correlated with documented toxicity. Robustness of the planning scenarios (PBPB, PBMC, MCMC) in the presence of setup and range uncertainties was compared. Results: A median decrease of up to 5 Gy (P < .05) was observed in coverage of planning target volume high-risk, intermediate-risk, and low-risk volumes when PB plans were recalculated using the MC algorithm. This loss in coverage was regained by reoptimizing with MC, albeit with a slightly higher dose to normal tissues but within the standard tolerance limits. The robustness of both PB and MC plans remained similar in the presence of setup and range uncertainties. The MC-calculated mean dose to the oral avoidance structure, along with changes in global maximum dose between PB and MC dosimetry, may be associated with acute toxicity-related events. Conclusion: Retrospective analyses of plan dosimetry quantified a loss of coverage with PB that could be recovered under MC optimization. MC optimization should be performed for the complex dosimetry in patients with nasopharyngeal carcinoma before plan acceptance and should also be used in correlative studies of proton dosimetry with clinical endpoints.

PURPOSE/OBJECTIVE(S) We hypothesized that FDG PET imaging during chemoradiation for unresectable non-small cell lung cancer (NSCLC) is prognostic for survival, and that PET response is correlated with systemic immune response to treatment, as characterized by peripheral immunologic correlates and tumor PD-L1 status. A prognostic test that could predict patient outcome would help better select patients who need additional therapies, and spare toxicity in patients who do not. MATERIALS/METHODS A total of 45 patients with AJCCv7 stage IIB-IIIB NSCLC enrolled on the phase II FLARE-RT trial and received platinum-doublet chemotherapy concurrent with 6 weeks of radiation (NCT02773238). FDG PET imaging was performed prior to treatment start and after 24 Gy of radiation (week 3). PET response status was prospectively defined by multifactor radiomics. PET responders received 60 Gy in 30 fractions, while non-responders received concomitant boosts to 74 Gy in 30 fractions. 22/45 patients received durvalumab post-chemoradiation. Peripheral blood was drawn synchronously with PET imaging, from which germline DNA sequencing, T-cell receptor (TCR) sequencing, and plasma cytokines analysis were performed. Overall survival (OS), progression-free survival (PFS), and locoregional control (LRC) were estimated by Kaplan-Meier. Unsupervised learning of germline DNA sequencing SNP genotypes was performed with hierarchical clustering and summarized with cumulative frequency distributions of rank ordered SNPs. Genotype associations to OS, PFS, and PET response status were characterized by logistic regression with Firth penalization for estimating odds ratios (OR). TCR diversity metric trends were estimated by Spearman rank correlation and pairwise changes by Wilcoxon signed rank testing. TCR diversity metric associations to OS and PFS were assessed by Permutation testing of Harrell's c-index. RESULTS Median follow-up was 18.8 months, 1-year OS 82%, 1-year PFS 53%, and 1-year LRC 88%. Higher mid-treatment PET total lesion glycolysis was detrimental to OS (1-yr 87% vs. 63%, P 50%) classified as PET responders and 4/5 patients with negative PD-L1 TPS (< 1%) classified as PET non-responders. Germline DNA alterations in immunologic pathways had an outsized effect on OS and PET response; of the top 30 SNPs ranked by association with PET response status (P < 0.016), a plurality (13/30) came from immunologic pathways. Higher TCR richness, higher clone distribution slope, and smaller decline in clone distribution slope was associated with improved OS (P = 0.018-0.05); clone distribution slope was correlated with PET response (P = 0.031). CONCLUSION Mid-chemoradiation PET imaging is prognostic for survival; PET response may be linked to tumor and peripheral immunologic biomarkers.

Purpose: We conducted a prospective pilot study to evaluate safety and feasibility of TraceIT, a resorbable radiopaque hydrogel, to improve image guidance for bladder cancer radiation therapy (RT). Methods and Materials: Patients with muscle invasive bladder cancer receiving definitive RT were eligible. TraceIT was injected intravesically around the tumor bed during maximal transurethral resection of bladder tumor. The primary endpoint was the difference between radiation treatment planning margin on daily cone beam computed tomography based on alignment to TraceIT versus standard-of-care pelvic bone anatomy. The Van Herk margin formula was used to determine the optimal planning target volume margin. TraceIT visibility, recurrence rates, and survival were estimated by Kaplan-Meier method. Toxicity was measured by Common Terminology Criteria for Adverse Events version 4.03. Results: The trial was fully accrued and 15 patients were analyzed. TraceIT was injected in 4 sites/patient (range, 4-6). Overall, 94% (95% confidence interval [CI], 90%-98%) of injection sites were radiographically visible at RT initiation versus 71% (95% CI, 62%-81%) at RT completion. The median duration of radiographic visibility for injection sites was 106 days (95% CI, 104-113). Most patients were treated with a standard split-course approach with initial pelvic radiation fields, then midcourse repeat transurethral resection of bladder tumor followed by bladder tumor bed boost fields, and 14/15 received concurrent chemotherapy. Alignment to fiducials could allow for reduced planning target volume margins (0.67 vs 1.56 cm) for the initial phase of RT, but not for the boost (1.01 vs 0.96 cm). This allowed for improved target coverage (D95% 80%-83% to 91%-94%) for 2 patients retrospectively planned with both volumetric-modulated arc therapy and 3-dimensional conformal RT. At median follow-up of 22 months, no acute or late complications attributable to TraceIT placement occurred. No patients required salvage cystectomy. Conclusions: TraceIT intravesical fiducial placement is safe and feasible and may facilitate tumor bed delineation and targeting in patients undergoing RT for localized muscle invasive bladder cancer. Improved image guided treatment may facilitate strategies to improve local control and minimize toxicity.

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.

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.

Purpose This study aims to investigate the use of machine learning models for delivery error prediction in proton pencil beam scanning (PBS) delivery. Methods A dataset of planned and delivered PBS spot parameters was generated from a set of 20 prostate patient treatments. Planned spot parameters (spot position, MU and energy) were extracted from the treatment planning system (TPS) for each beam. Delivered spot parameters were extracted from irradiation log-files for each beam delivery following treatment. The dataset was used as a training dataset for three machine learning models which were trained to predict delivered spot parameters based on planned parameters. K-fold cross validation was employed for hyper-parameter tuning and model selection where the mean absolute error (MAE) was used as the model evaluation metric. The model with lowest MAE was then selected to generate a predicted dose distribution for a test prostate patient within a commercial TPS. Results Analysis of the spot position delivery error between planned and delivered values resulted in standard deviations of 0.39 mm and 0.44 mm for x and y spot positions respectively. Prediction error standard deviation values of spot positions using the selected model were 0.22 mm and 0.11 mm for x and y spot positions respectively. Finally, a three-way comparison of dose distributions and DVH values for select OARs indicates that the random-forest-predicted dose distribution within the test prostate patient was in closer agreement to the delivered dose distribution than the planned distribution. Conclusions PBS delivery error can be accurately predicted using machine learning techniques.

PURPOSE Mitigating radiation-induced liver disease (RILD) is an ongoing need in patients with hepatocellular carcinoma. We hypothesize that [99mTc]-sulfur colloid (SC) single photon emission computed tomography (SPECT)/computed tomography (CT) scans can provide global functional liver metrics and functional liver dosimetric parameters that are predictive of hepatotoxicity risk in patients with primary liver cancer with cirrhosis. MATERIALS AND METHODS We retrospectively reviewed 47 patients (n = 26 proton, n = 21 stereotactic body radiation therapy) with Child-Pugh (CP)-A (62%) or CP-B (38%) cirrhosis who underwent SC SPECT/CT scans for radiation therapy planning. SC SPECT scans were mined for image intensity threshold-based functional liver volumes (FLV), mean liver-spleen uptake ratio (L/Smean), and total liver function (TLF = FLV*L/Smean). Radiation therapy doses were voxel-wise converted to the biologically equivalent dose (EQD2a/b=3) and relative biological effectiveness (GyRBE). Normal liver (liver minus gross tumor volume [GTV]) and FLV mean doses, absolute and relative dose-volumes (VGy[cc], VGy[%]), and relative dose-function histogram quantiles in 10 GyEQD2 increments were calculated. Logistic regression was performed for correlation to CP score increase of 2 or higher (CP+2). Cox regression was performed for correlation to RILD-specific survival (RILD-SS) and overall survival. RESULTS The strongest predictors of RILD-SS were FLV V20 and liver-GTV F20. FLV mean dose, but not CT-derived anatomic mean dose, was predictive of RILD-SS. TLF and L/Smean were the only parameters that were associated with CP+2 after adjusting for baseline CP score. Optimal cutoffs to mitigate risk RILD-SS were identified: FLV mean dose 0.75, TLF >0.60, tumor volume

Charged particle therapy with proton beam therapy (PBT) and carbon ion radiotherapy (CIRT) has emerged as a promising radiation modality to minimize radiation hepatotoxicity while maintaining high rates of tumor local control. Both PBT and CIRT deposit the majority of their dose at the Bragg peak with little to no exit dose, resulting in superior sparing of normal liver tissue. CIRT has an additional biological advantage of increased relative biological effectiveness, which may allow for increased hypofractionation regimens. Retrospective and prospective studies have demonstrated encouragingly high rates of local control and overall survival and low rates of hepatotoxicity with PBT and CIRT. Ongoing randomized trials will evaluate the value of PBT over photons and other standard liver-directed therapies and future randomized trials are needed to assess the value of CIRT over PBT.

Purpose Normal liver-sparing with proton beam therapy (PBT) allows for dose escalation in the treatment of liver malignancies, but it may result in high doses to the chest wall (CW). CW toxicity (CWT) data after PBT for liver malignancies are limited, with most published reports describing toxicity after a combination of hypofractionated proton and photon radiation therapy. We examined the incidence and associated factors for CWT after hypofractionated PBT for liver malignancies. Methods and materials We retrospectively reviewed the charts of 37 consecutive patients with liver malignancies (30 hepatocellular carcinoma, 6 intrahepatic cholangiocarcinoma, and 1 metastasis) treated with hypofractionated PBT. CWT was scored using Common Terminology Criteria for Adverse Events, version 4. Receiver-operating characteristic curves were used to identify patient and dosimetric factors associated with CWT and to determine optimal dose-volume histogram parameters/cutoffs. Cox regression univariate analysis was used to associate factors to time-dependent onset of CWT. Results Thirty-nine liver lesions were treated with a median dose of 60 GyE (range, 35-67.5) in 15 fractions (range, 13-20). Median follow-up was 11 months (range, 2-44). Grade ≥2 and 3 CW pain occurred in 7 (19%) and 4 (11%) patients, respectively. Median time to onset of pain was 6 months (range, 1-14). No patients had radiographic rib fracture. On univariate analysis, CW equivalent 2 Gy dose with an α/β = 3 Gy (EQD2 α/β=3 ), V57 >20 cm 3 (hazard ratio [HR], 2.7; P = .004), V63 >17 cm 3 (HR, 2.7; P = .003), and V78 >8 cm 3 (HR, 2.6; P = .003) had the strongest association with grade ≥2 CW pain, as did tumor dose of >75 Gy EQD2 α/β=10 (HR, 8.7; P = .03). No other patient factors were associated with CWT. Conclusions CWT after hypofractionated PBT for liver malignancies is clinically relevant. For a 15-fraction regimen, V47 >20 cm 3 , V50 >17 cm 3 , and V58 >8 cm 3 were associated with higher rates of CWT. Further investigation of PBT techniques to reduce CW dose are warranted.

Background Our purpose was to define the most clinically relevant "nonclassic" radiation-induced liver disease (RILD) endpoints in cirrhotic patients receiving stereotactic body radiation therapy or proton beam therapy for primary liver cancer. Methods and materials We retrospectively collected pretreatment, detailed toxicity (≤6 months posttreatment), and outcomes data from 48 patients. Deaths were examined for association with RILD. Univariate and multivariate Cox models defined significant predictors of overall survival (OS)/RILD-specific survival (RILD-SS). Results With median follow-up of 13 months, 23 patients (48%) had an increase in Child-Pugh (CP) score (≥2, 25%) and 3 (6%) had ≥G3 transaminase elevation. Of 18 deaths, 6 were potentially ascribed to RILD. Univariate analysis showed that CP score increases of ≥1 and ≥2 and CP class change predicted OS, as did ≥G3 aspartate transaminase (AST) elevation and ≥1 Common Terminology Criteria for Adverse Events (CTCAE) AST toxicity grade change. On multivariate analysis, CP score increase of ≥2 and ≥1 CTCAE AST toxicity grade change were the strongest independent nonclassic RILD predictors of OS. For RILD-SS, CP score increases of ≥2, ≥grade 3 CTCAE alanine transaminase, and ≥grade 2 bilirubin elevations were predictive. Conclusions Increased CP score ≥2 strongly predicts for both OS and RILD-SS and should be reported in future studies along with transaminase elevations, which are also predictive of outcomes.

Background Robust approaches to quantify tumor heterogeneity are needed to provide early decision support for precise individualized therapy. Purpose To conduct a technical exploration of longitudinal changes in tumor heterogeneity patterns on dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI) and FDG positron emission tomography / computed tomography (PET/CT), and their association to radiation therapy (RT) response in cervical cancer. Study Type Prospective observational study with longitudinal MRI and PET/CT pre-RT, early-RT (2 weeks), and mid-RT (5 weeks). Population Twenty-one FIGO IB2-IVA cervical cancer patients receiving definitive external beam RT and brachytherapy. Field Strength/Sequence 1.5T, precontrast axial T1-weighted, axial and sagittal T2-weighted, sagittal DWI (multi-b values), sagittal DCE MRI (

RaySearch Americas Inc. (NY) has introduced a commercial Monte Carlo dose algorithm (RS-MC) for routine clinical use in proton spot scanning. In this report, we provide a validation of this algorithm against phantom measurements and simulations in the GATE software package. We also compared the performance of the RayStation analytical algorithm (RS-PBA) against the RS-MC algorithm. A beam model (G-MC) for a spot scanning gantry at our proton center was implemented in the GATE software package. The model was validated against measurements in a water phantom and was used for benchmarking the RS-MC. Validation of the RS-MC was performed in a water phantom by measuring depth doses and profiles for three spread-out Bragg peak (SOBP) beams with normal incidence, an SOBP with oblique incidence, and an SOBP with a range shifter and large air gap. The RS-MC was also validated against measurements and simulations in heterogeneous phantoms created by placing lung or bone slabs in a water phantom. Lateral dose profiles near the distal end of the beam were measured with a microDiamond detector and compared to the G-MC simulations, RS-MC and RS-PBA. Finally, the RS-MC and RS-PBA were validated against measured dose distributions in an Alderson-Rando (AR) phantom. Measurements were made using Gafchromic film in the AR phantom and compared to doses using the RS-PBA and RS-MC algorithms. For SOBP depth doses in a water phantom, all three algorithms matched the measurements to within ±3% at all points and a range within 1 mm. The RS-PBA algorithm showed up to a 10% difference in dose at the entrance for the beam with a range shifter and >30 cm air gap, while the RS-MC and G-MC were always within 3% of the measurement. For an oblique beam incident at 45°, the RS-PBA algorithm showed up to 6% local dose differences and broadening of distal fall-off by 5 mm. Both the RS-MC and G-MC accurately predicted the depth dose to within ±3% and distal fall-off to within 2 mm. In an anthropomorphic phantom, the gamma index (dose tolerance = 3%, distance-to-agreement = 3 mm) was greater than 90% for six out of seven planes using the RS-MC, and three out seven for the RS-PBA. The RS-MC algorithm demonstrated improved dosimetric accuracy over the RS-PBA in the presence of homogenous, heterogeneous and anthropomorphic phantoms. The computation performance of the RS-MC was similar to the RS-PBA algorithm. For complex disease sites like breast, head and neck, and lung cancer, the RS-MC algorithm will provide significantly more accurate treatment planning.

Purpose: The results from Radiation Therapy Oncology Group (RTOG) 0617, a dose escalation trial that compared treatment with 60 Gy versus 74 Gy for patients with stage III non-small cell lung cancer (NSCLC), suggested that in these patients, the heart dose from radiation therapy correlates with survival. In particular, the study noted that patients with a high heart V5 and V30 had a poorer overall survival; however, the exact cause of this correlation is not known. We hypothesize that heart dose may be a surrogate for mediastinal nodal involvement, which has prognostic value in NSCLC. This study evaluates the relationship between heart dose and involvement of mediastinal lymph nodes in patients with stage III NSCLC treated with radiation therapy. Methods and materials: A total of 56 patients were identified and treated with definitive radiation therapy from 2007 to 2014. The heart was recontoured for every patient by a single physician, per the RTOG 1106 contouring atlas. We assessed lymph node station involvement using pretreatment data, and nodal coverage was confirmed on plan review. Results: Mean heart dose was found to be significantly higher in patients with multinodal station and level 7 involvement. On Spearman's rank correlation, level 7 was significantly associated with all heart parameters tested (P < .001). Patients who had 2 or more lymph node stations involved were found to have significantly higher heart doses for all parameters tested when compared with those who had only one station involved or no nodal involvement. Conclusions: Our findings suggest that heart dose may be a surrogate for other prognostic factors in stage III NSCLC rather than an independent predictor of outcome.

To design and apply a framework for predicting symptomatic radiation pneumonitis in patients undergoing thoracic radiation, using both pretreatment anatomic and perfused lung dose–volume parameters. Radiation treatment planning CT scans were coregistered with pretreatment [99mTc]MAA perfusion SPECT/CT scans of 20 patients who underwent definitive thoracic radiation. Clinical radiation pneumonitis was defined as grade ≥ 2 (CTCAE v4 grading system). Anatomic lung dose–volume parameters were collected from the treatment planning scans. Perfusion dose–volume parameters were calculated from pretreatment SPECT/CT scans. Equivalent doses in 2 Gy per fraction were calculated in the lung to account for differences in treatment regimens and spatial variations in lung dose (EQD2lung). Anatomic lung dosimetric parameters (MLD) and functional lung dosimetric parameters (pMLD70%) were identified as candidate predictors of grade ≥ 2 radiation pneumonitis (AUC > 0.93, p 13.6 GyEQD2lung, 19.3 Gy for patients receiving 60 Gy in 30 fractions) developed radiation pneumonitis, but all individuals who also had high mean dose to perfused lung (pMLD70% > 13.3 GyEQD2) developed radiation pneumonitis. The preliminary application of this framework revealed differences between anatomic and perfused lung dosimetry in this limited patient cohort. The addition of perfused lung parameters may help risk stratify patients for radiation pneumonitis, especially in treatment plans with high anatomic mean lung dose. Further investigations are warranted.

OBJECTIVE. In this article, we describe the concepts of ventilation-perfusion planar, SPECT, and SPECT/CT and outline the advantages of integrated ventilation-perfusion SPECT/CT over planar imaging. We present an overview of the traditional and new applications of ventilation-perfusion scintigraphy. CONCLUSION. SPECT/CT has improved the diagnostic accuracy of ventilation-perfusion imaging and opened the door for a new spectrum of applications.

Objective: The effect of functional lung avoidance planning on radiation dose-dependent changes in regional lung perfusion is unknown. We characterized dose-perfusion response on longitudinal perfusion single photon emission computed tomography (SPECT)/CT in two cohorts of lung cancer patients treated with and without functional lung avoidance techniques. Methods: The study included 28 primary lung cancer patients: 20 from interventional (NCT02773238) (FLARE-RT) and eight from observational (NCT01982123) (LUNG-RT) clinical trials. FLARE-RT treatment plans included perfused lung dose constraints while LUNG-RT plans adhered to clinical standards. Pre- and 3 month post-treatment macro-aggregated albumin (MAA) SPECT/CT scans were rigidly co-registered to planning four-dimensional CT scans. Tumour-subtracted lung dose was converted to EQD2 and sorted into 5 Gy bins. Mean dose and percent change between pre/post-RT MAA-SPECT uptake (%ΔPERF), normalized to total tumour-subtracted lung uptake, were calculated in each binned dose region. Perfusion frequency histograms of pre/post-RT MAA-SPECT were analyzed. Dose–response data were parameterized by sigmoid logistic functions to estimate maximum perfusion increase (%ΔPERFmaxincrease), maximum perfusion decrease (%ΔPERFmaxdecrease), dose midpoint (Dmid), and dose-response slope (k). Results: Differences in MAA perfusion frequency distribution shape between time points were observed in 11/20 (55%) FLARE-RT and 2/8 (25%) LUNG-RT patients (p < 0.05). FLARE-RT dose response was characterized by >10% perfusion increase in the 0–5 Gy dose bin for 8/20 patients (%ΔPERFmaxincrease = 10–40%), which was not observed in any LUNG-RT patients (p = 0.03). The dose midpoint Dmid at which relative perfusion declined by 50% trended higher in FLARE-RT compared to LUNG-RT cohorts (35 GyEQD2 vs 21 GyEQD2, p = 0.09), while the dose-response slope k was similar between FLARE-RT and LUNG-RT cohorts (3.1–3.2, p = 0.86). Conclusion: Functional lung avoidance planning may promote increased post-treatment perfusion in low dose regions for select patients, though inter-patient variability remains high in unbalanced cohorts. These preliminary findings form testable hypotheses that warrant subsequent validation in larger cohorts within randomized or case-matched control investigations. Advances in knowledge: This novel preliminary study reports differences in dose-response relationships between patients receiving functional lung avoidance radiation therapy (FLARE-RT) and those receiving conventionally planned radiation therapy (LUNG-RT). Following further validation and testing of these effects in larger patient populations, individualized estimation of regional lung perfusion dose-response may help refine future risk-adaptive strategies to minimize lung function deficits and toxicity incidence.

Rationale and Objectives To explore the diagnostic value of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) intensity histogram metrics, relative to time intensity curve (TIC)-derived metrics, in patients with suspected lung cancer. Materials and Methods This retrospective study enrolled 49 patients with suspected lung cancer on routine CT imaging who underwent DCE-MRI scans and had final histopathologic diagnosis. Three TIC-derived metrics (maximum enhancement ratio, peak time [Tmax] and slope) and eight intensity histogram metrics (volume, integral, maximum, minimum, median, coefficient of variation [CoV], skewness, and kurtosis) were extracted from DCE-MRI images. TIC-derived and intensity histogram metrics were compared between benignity versus malignancy using the Wilcoxon rank-sum test. Associations between imaging metrics and malignancy risk were assessed by univariate and multivariate logistic regression odds ratios (ORs). Results There were 33 malignant lesions and 16 benign lesions based on histopathology. Lower CoV (OR = 0.2 per 1-SD increase, p = 0.0006), lower Tmax (OR = 0.4 per 1-SD increase, p = 0.005), and steeper slope (OR = 2.4 per 1-SD increase, p = 0.010) were significantly associated with increased risk of malignancy. Under multivariate analysis, CoV was significantly independently associated with malignancy likelihood after accounting for either Tmax (OR = 0.3 per 1-SD increase, p = 0.007) or slope (OR = 0.3 per 1-SD increase, p = 0.011). Conclusion This initial study found that DCE-MRI CoV was independently associated with malignancy in patients with suspected lung cancer. CoV has the potential to help diagnose indeterminate pulmonary lesions and may complement TIC-derived DCE-MRI metrics. Further studies are warranted to validate the diagnostic value of DCE-MRI intensity histogram analysis.

Purpose There are limited clinical data on scanning-beam proton therapy (SPT) in treating locally advanced lung cancer, as most published studies have used passive-scatter technology. There is increasing interest in whether the dosimetric advantages of SPT compared with photon therapy can translate into superior clinical outcomes. We present our experience of SPT and photon intensity modulated radiation therapy (IMRT) with clinical dosimetry and outcomes in patients with stage III lung cancer. Methods and Materials Patients with stage III lung cancer treated at our center between 2013 and May 2018 were identified in compliance with our institutional review board (64 patients = 34 SPT + 30 IMRT). Most proton patients were treated with pencil beam scanning (28 of 34), and 6 of 34 were treated with uniform scanning. Fisher exact test, χ2 test, and Mann-Whitney test were used to compare groups. All tests were 2-sided. Results Patient characteristics were similar between the IMRT and SPT patients, except for worse lung function in the IMRT group. Mean dose to lung, heart, and esophagus was lower in the SPT group, with most benefit in the low-dose region (lungs, 9.7 Gy vs 15.7 Gy for SPT vs IMRT, respectively [P = .004]; heart, 7 Gy vs 14 Gy [P = .001]; esophagus, 28.2 Gy vs 30.9 Gy [P = .023]). Esophagitis and dermatitis grades were not different between the 2 groups. Grade 2+ pneumonitis was 21% in the SPT group and 40% in the IMRT group (P = .107). Changes in blood counts were not different between the 2 groups. Overall survival and progression-free survival were not different between SPT and IMRT (median overall survival, 41.6 vs 30.7 months, respectively [P = .52]; median progression-free survival, 19.5 vs 14.6 months [P = .50]). Conclusions We report our experience with SPT and IMRT in stage III lung cancer. Our cohort of patients treated with SPT had lower doses to normal organs (lungs, heart, esophagus) than our IMRT cohort. There was no statistically significant difference in toxicity rates or survival, although there may have been a trend toward lower rates of pneumonitis.

PURPOSE: In this report, we present the commissioning and validation results for a commercial proton pencil beam scanning RayStation treatment planning system. MATERIALS AND METHODS: The commissioning data requirements are (1) integrated depth dose curves, (2) spot profiles, (3) absolute dose/monitor unit calibration, and (4) virtual source position. An 8-cm parallel plate chamber was used to measure the integrated depth dose curves by scanning a beam composed of a single spot in a water phantom. The spot profiles were measured at 5 different planes using a 2-dimensional scintillation detector. The absolute dose/monitor unit calibration was based on dose measurements in single-layer fields of size 10 × 10 cm(2). The virtual-source position was calculated from the change in spot spacing with the distance from the isocenter. The beam model validation consisted of a comparison against commissioning data as well as a new set of verification measurements. For end-to-end testing, a series of phantom plans were created. These plans were measured at 1 to 3 depths using a 2-dimensional ion chamber array and evaluated for gamma index using the 3% and 3 mm criteria. RESULTS: The maximum deviation for spot sigma measured versus calculated was −0.2 mm. The point-dose measurements for single-layer beams were within ± 3%, except for the largest field size (29 × 29 cm(2)) and the highest energy (226 MeV). The point doses in the spread-out Bragg peak plans showed a trend in which differences > 3% were seen for ranges > 30 cm, field sizes > 15 × 15 cm(2), and depths > 25 cm. For end-to-end testing, 34 planes corresponding to 13 beams were analyzed for gamma index with a minimum pass rate of 92.8%. CONCLUSION: The acceptable verification results and successful end-to-end testing ensured that all components of the treatment planning system were functional and the system was ready for clinical use.

Purpose The aim of this study was to review institutional outcomes for advanced thyroid cancers treated with fast neutron radiation therapy (FNRT) and photon radiation therapy (RT). Methods and materials In all, 62 consecutive patients were analyzed. Fifty-nine had stage IV disease. Twenty-three were treated with FNRT and 39 with photon RT. Median follow-up was 14 months. The primary endpoint was overall survival (OS). Results There was no significant difference in median OS between FNRT and photon RT (26 vs 16 months; P = .49). Patients with well-differentiated histologies had superior median OS with photon RT (17 vs 69 months; P = .04). There was a nonsignificant trend toward improved OS with FNRT for medullary and anaplastic histologies. Conclusions Outcomes in this study are in line with historical results. There is an apparent detriment in OS with FNRT for well-differentiated histologies and a trend toward improved OS with medullary and anaplastic histologies that warrants further investigation.

Background We report prospectively captured clinical toxicity and patient reported outcomes in a single institutional cohort of patients treated for prostate cancer with proton beam therapy (PBT). This is the largest reported series of patients treated mostly with pencil beam scanning PBT. Methods We reviewed 231 patients treated on an IRB approved institutional registry from 2013 to 2016; final analysis included 192 patients with > 1-year of follow-up. Toxicity incidence was prospectively captured and scored using CTCAE v4.0. International Prostate Symptoms Score (IPSS), Sexual Health Inventory for Men (SHIM) score, and Expanded Prostate Cancer Index Composite (EPIC) bowel domain questionnaires were collected at each visit. Univariate Cox regression was used to explore associations of grade 2+ toxicity with clinical, treatment, and dosimetric variables. Results Median follow-up was 1.7 years. Grade 3 toxicity was seen in 5/192 patients. No grade 4 or 5 toxicity was seen. Patient reported quality-of-life showed no change in urinary function post-radiation by IPSS scores. Median SHIM scores declined by 3.7 points at 1-year post-treatment without further decrease beyond year 1. On univariate analysis, only younger age (HR = 0.61, p = 0.022) was associated with decreased sexual toxicity. EPIC bowel domain scores declined from 96 at baseline (median) by an average of 5.4 points at 1-year post-treatment (95% CI: 2.5–8.2 points, p

PURPOSE This study examines the relationship between dose to corneal substructures and incidence of corneal toxicity within 6 months of proton beam therapy (PBT) for uveal melanoma. We aim to develop clinically meaningful dose constraints that can be used to mitigate corneal toxicity. METHODS AND MATERIALS Ninety-two patients were treated with PBT between 2015 and 2017 and evaluated for grade 2+ (GR2+) intervention-requiring corneal toxicity in our prospectively maintained database. Most patients were treated with 50 Gy (relative biological effectiveness [RBE]) in 5 fractions, and all had complete six-month follow-up. Analyses included Mann-Whitney, χ2, Fisher exact, and receiver operating curve tests to identify risk factors for GR2+ toxicity. Bivariate logistic regression was used to identify independent dose-volume histogram (DVH) predictors of toxicity after adjustment for the most important clinical risk factor. RESULTS The 6-month PBT GR2+ corneal toxicity rate was 10.9%, with half of patients experiencing grade 2 toxicity and half experiencing grade 3 toxicity, with no grade 4 events. Patients with anterior chamber tumors had a higher risk (58.3%) for toxicity than those with posterior tumors (0%) or posterior tumors extending past the equator (25%, P

Purpose We characterized both physician- and patient-reported rates of gastrointestinal (GI) toxicity in patients treated with proton beam therapy (PBT) at our institution for prostate adenocarcinoma and identified factors associated with toxicity. Methods and materials We treated 192 patients with PBT between July 2013 and July 2016. Included patients had ≥1 year of follow-up. Potential preexisting clinical and treatment-related risk factors for GI toxicity were recorded. Common Terminology Criteria for Adverse Events version 4.0 was used to score toxicity. Expanded Prostate Cancer Index Composite (EPIC) bowel domain questionnaires assessed patient-reported quality of life. Associations between grade (GR) 2+ toxicity and clinical, treatment, and dosimetric factors were assessed using Cox models and corresponding hazard ratios. Results The median follow-up was 1.7 years. Most of the observed GI toxicity (>90%) was in the form of rectal bleeding (RB). GR2+ GI toxicity and RB actuarial rates specifically at 2 years were 21.3% and 20.4%, respectively. GR3 toxicity was rare, with only 1 observed RB event. No GR4/5 toxicity was seen. The EPIC bowel domain median score was 96 (range, 61-100) pretreatment, 93 (range, 41-100) at 1 year, 89 (range, 57-100) at 1.5 years, and 89 (range, 50-100) at 2 years. Anticoagulation use was the only factor selected during multivariate analysis for predicting GR2+ RB, with a resulting concordance index of 0.59 (95% confidence interval, 0.48-0.68; P = .088). Type of proton technology (pencil beam scanning vs uniform scanning) and number of fields treated per day (1 vs 2) showed no significant difference in toxicity rate. Conclusions PBT was associated with acceptable rates of GR2+ transient GI toxicity, mostly in the form of RB, which correlated with anticoagulation use. High EPIC bowel domain quality of life was maintained in the 2 years after treatment.

PURPOSE Hepatotoxicity risk in patients with hepatocellular carcinoma (HCC) is modulated by radiation dose delivered to normal liver tissue, but reported dose-response data are limited. Our prior work established baseline [99mTc]sulfur colloid (SC) single-photon emission computed tomography (SPECT)/computed tomography (CT) liver function imaging biomarkers that predict clinical outcomes. We conducted a proof-of-concept investigation with longitudinal SC SPECT/CT to characterize patient-specific radiation dose-response relationships as surrogates for liver radiosensitivity. METHODS AND MATERIALS SC SPECT/CT images of 15 patients with HCC with variable Child-Pugh (CP) status (8 CP-A, 7 CP-B/C) were acquired in treatment position before and 1 month (nominal) after stereotactic body radiation therapy (n = 6) or proton therapy (n = 9). Localized rigid registrations between pre/posttreatment CT to planning CT scans were performed, and transformations were applied to pre/posttreatment SC SPECT images. Radiation therapy doses were converted to EQD2 and Gy RBE (relative biological effectiveness) and binned in 5 GyEQD2 increments within tumor-subtracted livers. Mean dose and percent change (%ΔSC) between pre- and posttreatment SPECT uptake, normalized to regions receiving

To evaluate the feasibility of a novel planning concept that differentially redistributes RT dose away from functional liver regions as defined by (99m)Tc-sulphur colloid (SC) uptake on patient SPECT/CT images.Ten HCC patients with different Child-Turcotte-Pugh scores (A5-B9) underwent SC SPECT/CT scans in treatment position prior to RT that were registered to planning CT scans. Proton pencil beam scanning (PBS) therapy plans were optimized to deliver 37.5-60.0Gy (RBE) over 5-15 fractions using single field uniform dose technique robust to range and setup uncertainty. Photon volumetrically modulated arc therapy (VMAT) plans were optimized to the same prescribed dose and minimum target coverage. For both treatment modalities, differential hepatic avoidance RT (DHART) plans were generated to decrease dose to functional liver volumes (FLV) defined by a range of thresholds relative to maximum SC uptake (43-90%) in the tumor-subtracted liver. Radiation dose was redistributed away from regions of increased SC uptake in each FLV by linearly scaling mean dose objectives during PBS or VMAT optimization. DHART planning feasibility was assessed by a significantly negative Spearman's rank correlation (RS) between dose difference and SC uptake. Patient, tumor, and treatment planning characteristics were tested for association to DHART planning feasibility using non-parametric Kruskal-Wallis ANOVA.Compared to conventional plans, DHART plans achieved a 3% FLV dose reduction for every 10% SC uptake increase. DHART planning was feasible in the majority of patients with 60% of patients having RS-0.5 (p0.01, range -1.0 to 0.2) and was particularly effective in 30% of patients (RS-0.9). Mean dose to FLV was reduced by up to 20% in these patients. Only fractionation regimen was associated with DHART planning feasibility: 15 fraction courses were more feasible than 5-6 fraction courses (RS-0.93 vs. RS-0.60, p0.02).Differential avoidance of functional liver regions defined on sulphur colloid SPECT/CT is achievable with either photon VMAT or proton PBS therapy. Further investigation with phantom studies and in a larger cohort of patients may validate the utility of DHART planning for HCC radiotherapy.

To quantitatively estimate the impact of different methods for both boost volume delineation and respiratory motion compensation of [18F] FDG PET/CT images on the fidelity of planned non-uniform 'dose painting' plans to the prescribed boost dose distribution.Six locally advanced non-small cell lung cancer (NSCLC) patients were retrospectively reviewed. To assess the impact of respiratory motion, time-averaged (3D AVG), respiratory phase-gated (4D GATED) and motion-encompassing (4D MIP) PET images were used. The boost volumes were defined using manual contour (MANUAL), fixed threshold (FIXED) and gradient search algorithm (GRADIENT). The dose painting prescription of 60 Gy base dose to the planning target volume and an integral dose of 14 Gy (total 74 Gy) was discretized into seven treatment planning substructures and linearly redistributed according to the relative SUV at every voxel in the boost volume. Fifty-four dose painting plan combinations were generated and conformity was evaluated using quality index VQ0.95-1.05, which represents the sum of planned dose voxels within 5% deviation from the prescribed dose. Trends in plan quality and magnitude of achievable dose escalation were recorded.Different segmentation techniques produced statistically significant variations in maximum planned dose (P 0.02), as well as plan quality between segmentation methods for 4D GATED and 4D MIP PET images (P 0.05). No statistically significant differences in plan quality and maximum dose were observed between motion-compensated PET-based plans (P 0.75). Low variability in plan quality was observed for FIXED threshold plans, while MANUAL and GRADIENT plans achieved higher dose with lower plan quality indices.The dose painting plans were more sensitive to segmentation of boost volumes than PET motion compensation in this study sample. Careful consideration of boost target delineation and motion compensation strategies should guide the design of NSCLC dose painting trials.

A semiquantitative assessment of hepatic reticuloendothelial system function using colloidal particles scintigraphy has been proposed previously as a surrogate for liver function evaluation. In this article, we present an updated method for the overall assessment of technetium-99m (Tc)-sulfur colloid (SC) biodistribution that combines information from planar and attenuation-corrected Tc-SC single-photon emission computed tomography (SPECT) images. The imaging protocol described here was developed as an easy-to-implement method to assess overall and regional liver function changes associated with chronic liver disease.Thirty patients with chronic liver disease and primary liver cancers underwent Tc-SC whole-body planar imaging and upper-abdomen SPECT/computed tomography (CT) imaging before external beam radiation therapy. Liver plus spleen and bone marrow counts as a fraction of whole-body total counts were calculated from SC planar imaging. Attenuation correction Tc-SC images were rigidly coregistered with treatment planning CT images that contained liver and spleen regions-of-interest. Ratios of total liver counts to total spleen counts were obtained from the aligned Tc-SC SPECT and CT images, and were subsequently used to separate liver plus spleen counts obtained on the planar images. This hybrid SPECT/CT and planar scintigraphy approach yielded an updated estimation of whole-body SC distribution. These biodistribution estimates were compared with historical data for reference. Statistical associations of Tc-SC biodistribution to liver function parameters and liver disease scoring systems (Child-Pugh) were evaluated by Spearman rank correlation.Percentages of Tc-SC uptake ranged from 19.3 to 77.3% for the liver; 3.4 to 40.7% for the spleen; and 19.0 to 56.7% for the bone marrow. Spearman's correlation coefficient showed a significant statistical association between Child-Pugh score and bone marrow uptake at 0.55 (P≤0.05), liver uptake at 0.71 (P≤0.001), spleen uptake at 0.56 (P≤0.05), and spleen plus bone marrow uptake at 0.71 (P≤0.001). There was also a good correlation of SC uptake percentages with individual quantitative liver function components such as albumin and total bilirubin, and qualitative liver function components (varices, portal hypertension, ascites). For albumin: r=0.64 (P0.001) compared with liver uptake percentage from the whole-body counts, r=0.49 (P0.001) compared with splenic uptake percentage, and r=0.45 (P≤0.05) compared with bone marrow uptake percentage.We describe a novel liver function quantitative assessment method that combines whole-body planar images and SPECT/CT attenuation-corrected images of Tc-SC distribution. Attenuation-corrected SC images provide valuable regional liver function information, which is a unique feature compared with other imaging methods available. The results of our study indicate that the Tc-SC uptake by the liver, spleen, and bone marrow correlates with liver function parameters in patients with diffuse liver disease and the correlation with liver disease severity is slightly better for liver uptake percentages than for individual values of bone marrow and spleen uptake percentages.

Background Assessment of liver function is critical in hepatocellular carcinoma (HCC) patient management. We evaluated parameters of [99mTc] sulfur colloid (SC) SPECT/CT liver uptake for association with clinical measures of liver function and outcome in HCC patients. Methods Thirty patients with HCC and variable Child-Turcotte-Pugh scores (CTP A5-C10) underwent [99mTc]SC SPECT/CT scans for radiotherapy planning. Gross tumor volume (GTV), anatomic liver volume (ALV), and spleen were contoured on CT. SC SPECT image parameters include threshold-based functional liver volumes (FLV) relative to ALV, mean liver-to-spleen uptake ratio (L/Smean), and total liver function (TLF) ratio derived from the product of FLV and L/Smean. Optimal SC uptake thresholds were determined by ROC analysis for maximizing CTP classification accuracy. Image metrics were tested for rank correlation to composite scores and clinical liver function parameters. Image parameters of liver function were tested for association to overall survival with Cox proportional hazard regression. Results Optimized thresholds on SC SPECT were 58 % of maximum uptake for FLV, 38 % for L/Smean, and 58 % for TLF. TLF produced the highest CTP classification accuracy (AUC = 0.93) at threshold of 0.35 (sensitivity = 0.88, specificity = 0.86). Higher TLF was associated with lower CTP score: TLFA = 0.6 (0.4–0.8) versus TLFB = 0.2 (0.1–0.3), p 0.63). Only TLF >0.30 was independently associated with overall survival when adjusting for CTP class (HR = 0.12, 95 % CI = 0.02–0.58, p = 0.008). Conclusions SC SPECT/CT liver uptake correlated with differential liver function. TLF was associated with improved overall survival and may aid in personalized oncologic management of HCC patients.

The aim of this study is to present the dosimetry, feasibility, and preliminary clinical results of a novel pencil beam scanning (PBS) posterior beam technique of proton treatment for esophageal cancer in the setting of trimodality therapy. From February 2014 to June 2015, 13 patients with locally advanced esophageal cancer (T3-4N0-2M0; 11 adenocarcinoma, 2 squamous cell carcinoma) were treated with trimodality therapy (neoadjuvant chemoradiation followed by esophagectomy). Eight patients were treated with uniform scanning (US) and 5 patients were treated with a single posterior–anterior (PA) beam PBS technique with volumetric rescanning for motion mitigation. Comparison planning with PBS was performed using three plans: AP/PA beam arrangement; PA plus left posterior oblique (LPO) beams, and a single PA beam. Patient outcomes, including pathologic response and toxicity, were evaluated. All 13 patients completed chemoradiation to 50.4 Gy (relative biological effectiveness, RBE) and 12 patients underwent surgery. All 12 surgical patients had an R0 resection and pathologic complete response was seen in 25 %. Compared with AP/PA plans, PA plans have a lower mean heart (14.10 vs. 24.49 Gy, P < 0.01), mean stomach (22.95 vs. 31.33 Gy, P = 0.038), and mean liver dose (3.79 vs. 5.75 Gy, P = 0.004). Compared to the PA/LPO plan, the PA plan reduced the lung dose: mean lung dose (4.96 vs. 7.15 Gy, P = 0.020) and percentage volume of lung receiving 20 Gy (V20; 10 vs. 17 %, P < 0.01). Proton therapy with a single PA beam PBS technique for preoperative treatment of esophageal cancer appears safe and feasible.

To quantify associations between pre-radiotherapy and post-radiotherapy PET parameters via spatially resolved regression.Ten canine sinonasal cancer patients underwent PET/CT scans of [(18)F]FDG (FDG(pre)), [(18)F]FLT (FLT(pre)), and [(61)Cu]Cu-ATSM (Cu-ATSM(pre)). Following radiotherapy regimens of 50 Gy in 10 fractions, veterinary patients underwent FDG PET/CT scans at 3 months (FDG(post)). Regression of standardized uptake values in baseline FDG(pre), FLT(pre) and Cu-ATSM(pre) tumour voxels to those in FDG(post) images was performed for linear, log-linear, generalized-linear and mixed-fit linear models. Goodness-of-fit in regression coefficients was assessed by R(2). Hypothesis testing of coefficients over the patient population was performed.Multivariate linear model fits of FDG(pre) to FDG(post) were significantly positive over the population (FDG(post) ~ 0.17 · FDG(pre), p = 0.03), and classified slopes of RECIST non-responders and responders to be different (0.37 vs. 0.07, p = 0.01). Generalized-linear model fits related FDG(pre) to FDG(post) by a linear power law (FDG(post) ~ FDG(pre)(0.93),p0.001). Univariate mixture model fits of FDG(pre) improved R(2) from 0.17 to 0.52. Neither baseline FLT PET nor Cu-ATSM PET uptake contributed statistically significant multivariate regression coefficients.Spatially resolved regression analysis indicates that pre-treatment FDG PET uptake is most strongly associated with three-month post-treatment FDG PET uptake in this patient population, though associations are histopathology-dependent.

Item does not contain fulltext PURPOSE: Unique uptake and retention mechanisms of positron emission tomography (PET) hypoxia tracers make in vivo comparison between them challenging. Differences in imaged uptake of two common hypoxia radiotracers, [(61)Cu]Cu-ATSM and [(18)F]FMISO, were characterized via computational modeling to address these challenges. MATERIALS AND METHODS: An electrochemical formalism describing bioreductive retention mechanisms of these tracers under steady-state conditions was adopted to relate time-averaged activity concentration to tissue partial oxygen tension (PO(2)), a common metric of hypoxia. Chemical equilibrium constants of product concentration to reactant concentration ratios were determined from free energy changes and reduction potentials of pertinent reactions reported in the literature. Resulting transformation functions between tracer uptake and PO(2) were compared against measured values in preclinical models. Additionally, calculated PO(2) distributions from imaged Cu-ATSM tracer activity concentrations of 12 head and neck squamous cell carcinoma (HNSCC) patients were validated against microelectrode PO(2) measurements in 69 HNSCC patients. RESULTS: Both Cu-ASTM- and FMISO-modeled PO(2) transformation functions were in agreement with preclinical measured values within single-deviation confidence intervals. High correlation (r(2)=0.94, P

Important limitations for dose painting are due to treatment planning and delivery constraints. The purpose of this study was to develop a methodology for creating voxel-based dose painting plans that are deliverable using the clinical TomoTherapy Hi-Art II treatment planning system (TPS). Material and methods. Uptake data from a head and neck patient who underwent a [(61)Cu]Cu-ATSM (hypoxia surrogate) PET/CT scan was retrospectively extracted for planning. Non-uniform voxel-based prescriptions were converted to structured-based prescriptions for compatibility with the Hi-Art II TPS. Optimized plans were generated by varying parameters such as dose level, structure importance, prescription point normalization, DVH volume, min/max dose, and dose penalty. Delivery parameters such as pitch, jaw width and modulation factor were also varied. Isodose distributions, quality volume histograms and planning target volume percentage receiving planned dose within 5% of the prescription (Q(0.95-1.05)) were used to evaluate plan conformity. Results. In general, the conformity of treatment plans to dose prescriptions was found to be adequate for delivery of dose painting plans. The conformity was better as the dose levels increased from three to nine levels (Q(0.95-1.05): 69% to 93%), jaw decreased in width from 5.0cm to 1.05cm (Q(0.95-1.05): 81% to 93%), and modulation factor increased up to 2.0 (Q(0.95-1.05): 36% to 92%). The conformity was invariant to changes in pitch. Plan conformity decreased as the prescription DVH constraint (Q(0.95-1.05): 93% vs. 89%) or the normalization point (Q(0.95-1.05): 93% vs. 90%) deviated from the means. Conclusion. This investigation demonstrated the ability of the Hi-Art II TPS to create voxel-based dose painting plans. Results indicated that agreement in prescription dose and planned dose distributions for all plans were sensitive to physical delivery parameter changes in jaw width and modulation factors, but insensitive to changes in pitch. Tight constraints on target structures also resulted in decreased plan conformity while under a relaxed set of optimization parameters, plan conformity was increased.

Voxel-based prescriptions of deliberately non-uniform dose distributions based on molecular imaging, so-called dose painting or theragnostic radiation therapy, require specification of a transformation that maps the image data intensities to prescribed doses. However, the functional form of this transformation is currently unknown. An investigation into the sensitivity of optimized dose distributions resulting from several possible prescription functions was conducted. Transformations between the radiotracer activity concentrations from Cu-ATSM PET images, as a surrogate of tumour hypoxia, and dose prescriptions were implemented to yield weighted distributions of prescribed dose boosts in high uptake regions. Dose escalation was constrained to reflect clinically realistic whole tumour doses and constant normal tissue doses. Optimized heterogeneous dose distributions were found by minimizing a voxel-by-voxel quadratic objective function in which all tumour voxels were given equal weight. Prescriptions based on a polynomial mapping function were found to be least constraining on their optimized plans, while prescriptions based on a sigmoid mapping function were the most demanding to deliver. A prescription formalism that fixed integral dose was less sensitive to errors in the choice of the mapping function than one that boosted integral dose. Integral doses to normal tissue and critical structures were insensitive to the shape of the prescription function. Planned target dose conformity improved with smaller beamlet dimensions until the inherent spatial resolution of the functional image was matched. Clinical implementation of dose painting depends on advances in absolute quantification of functional images and improvements in delivery techniques over smaller spatial scales.