Independent association of metabolic tumor response on FDG-PET with pulmonary toxicity following risk-adaptive chemoradiation for unresectable non-small cell lung cancer: Inherent radiosensitivity or immune response?

BACKGROUND: In the context of a phase II trial of risk-adaptive chemoradiation, we evaluated whether tumor metabolic response could serve as a correlate of treatment sensitivity and toxicity. METHODS: Forty-five patients with AJCCv7 stage IIB-IIIB NSCLC enrolled on the FLARE-RT phase II trial (NCT02773238). [18F]fluorodeoxyglucose (FDG) PET-CT images were acquired prior to treatment and after 24 Gy during week 3. Patients with unfavorable on-treatment tumor response received concomitant boosts to 74 Gy total over 30 fractions rather than standard 60 Gy. Metabolic tumor volume and mean standardized uptake value (SUVmean) were calculated semi-automatically. Risk factors of pulmonary toxicity included concurrent chemotherapy regimen, adjuvant anti-PDL1 immunotherapy, and lung dosimetry. Incidence of CTCAE v4 grade 2+ pneumonitis was analyzed using the Fine-Gray method with competing risks of metastasis or death. Peripheral germline DNA microarray sequencing measured predefined candidate genes from distinct pathways: 96 DNA repair, 53 immunology, 38 oncology, 27 lung biology. RESULTS: Twenty-four patients received proton therapy, 23 received ICI, 26 received carboplatin-paclitaxel, and 17 pneumonitis events were observed. Pneumonitis risk was significantly higher for patients with COPD (HR 3.78 [1.48, 9.60], p = 0.005), those treated with immunotherapy (HR 2.82 [1.03, 7.71], p = 0.043) but not with carboplatin-paclitaxel (HR 1.98 [0.71, 5.54], p = 0.19). Pneumonitis rates were similar among selected patients receiving 74 Gy radiation vs 60 Gy (p = 0.33), proton therapy vs photon (p = 0.60), or with higher lung dosimetric V20 (p = 0.30). Patients in the upper quartile decrease in SUVmean (>39.7%) were at greater risk for pneumonitis (HR 4.00 [1.54, 10.44], p = 0.005) and remained significant in multivariable analysis (HR 3.34 [1.23, 9.10], p = 0.018). Germline DNA gene alterations in immunology pathways were most frequently associated with pneumonitis. CONCLUSION: Tumor metabolic response as measured by mean SUV is associated with increased pneumonitis risk in a clinical trial cohort of NSCLC patients independent of treatment factors. This may be partially attributed to patient-specific differences in immunogenicity.

Utilizing Clinical Trial Data to Assess Timing of Surgical Treatment for Emphysema Patients.

BACKGROUND: Lung volume reduction surgery (LVRS) and medical therapy are 2 available treatment options in dealing with severe emphysema, which is a chronic lung disease. However, or there are currently limited guidelines on the timing of LVRS for patients with different characteristics. OBJECTIVE: The objective of this study is to assess the timing of receiving LVRS in terms of patient outcomes, taking into consideration a patient's characteristics. METHODS: A finite-horizon Markov decision process model for patients with severe emphysema was developed to determine the short-term (5 y) and long-term timing of emphysema treatment. Maximizing the expected life expectancy, expected quality-adjusted life-years, and total expected cost of each treatment option were applied as the objective functions of the model. To estimate parameters in the model, the data provided by the National Emphysema Treatment Trial were used. RESULTS: The results indicate that the treatment timing strategy for patients with upper-lobe predominant emphysema is to receive LVRS regardless of their specific characteristics. However, for patients with non-upper-lobe-predominant emphysema, the optimal strategy depends on the age, maximum workload level, and forced expiratory volume in 1 second level. CONCLUSION: This study demonstrates the utilization of clinical trial data to gain insights into the timing of surgical treatment for patients with emphysema, considering patient age, observable health condition, and location of emphysema. HIGHLIGHTS: Both short-term and long-term Markov decision process models were developed to assess the timing of receiving lung volume reduction surgery in patients with severe emphysema.How clinical trial data can be used to estimate the parameters and obtain short-term results from the Markov decision process model is demonstrated.The results provide insights into the timing of receiving lung volume reduction surgery as a function of a patient's characteristics, including age, emphysema location, maximum workload, and forced expiratory volume in 1 second level.

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.

Adaptive Fluorodeoxyglucose-Positron Emission Tomography Based Chemotherapy Selection for Metastatic Non-small Cell Lung Cancer.

Objectives The change in tumor fluorodeoxyglucose (FDG) uptake by positron emission tomography (PET) scan after one cycle of platinum-based chemotherapy has been shown to predict progression-free and overall survival (PFS and OS) among advanced non-small cell lung cancer (NSCLC) patients. Using early FDG-PET response to determine subsequent chemotherapy, we aim to evaluate the role that adaptive chemotherapy regimens have on later CT response, PFS, and OS in patients with advanced NSCLC. Materials and Methods Chemotherapy-naïve patients with metastatic NSCLC received carboplatin and paclitaxel (CP) on day one and repeated FDG-PET on day 18. PET-responding patients continued CP chemotherapy for a total of four cycles. PET non-responders were switched to alternate docetaxel and gemcitabine (DG) for three additional cycles. The primary outcome was the CT Response Evaluation Criteria in Solid Tumors (RECIST 1.0) response. Secondary endpoints included PFS and OS. Results  Forty-six patients initiated treatment with chemotherapy on trial and were evaluable by PET/CT. Of these, 19 (41%) met the FDG-PET criteria for the response after a single cycle of CP. Only one non-responding patient had a CT response. Despite the lack of CT response in the DG arm, no trend for worse PFS or OS was seen between the two arms. Conclusions This work demonstrates that changing chemotherapy in the event of non-response by PET did not lead to improved CT RECIST response. However, non-responding patients who switched chemotherapy had similar PFS and OS to those who responded by PET and continued the same regimen.

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.

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.

Development and testing of SPECT/CT lung phantoms made from expanding polyurethane foam.

PURPOSE: Currently, single-photon emission computed tomography (SPECT)/computed tomography (CT) lung phantoms are commonly constructed using polystyrene beads and interstitial radioactive water. However, this approach often results in a phantom with a density (typically -640 HU) that is considerably higher than that of healthy lung (-750 to -850 HU) or diseased lung (-900 to -950 HU). Furthermore, the polystyrene and water phantoms are often quite heterogeneous in both density and activity concentration, especially when reused. This work is devoted to examining methods for creating a more realistic lung phantom for quantitative SPECT/CT using 99m Tc-laced expanding polyurethane foam (EPF). METHODS: Numerous aspects of EPF utilization were studied, including stoichiometric mixing to control final foam density and the effect of water during growth. We also tested several ways of molding the foam lung phantoms. The most successful method utilized a three-part silicone mold that allowed for creation of a two-lobe phantom, with a different density and activity concentration in each lobe. RESULTS: The final phantom design allows for a more anatomically accurate geometry as well as customizable density and activity concentration in the different lobes of the lung. We demonstrated final lung phantom densities between -760 and -690 HU in the "healthy" phantom and -930 to -890 HU in the "unhealthy" phantom tissue. On average, we achieved 15% activity concentration nonuniformity and 12% density nonuniformity within a given lobe. CONCLUSIONS: Final EPF lung phantoms closely matched the densities of both health and diseased lung tissue and had sufficient uniformities in both density and activity concentration for most nuclear medicine applications. Management of component moisture content is critical for phantom reproducibility.

Comparison of regional lung perfusion response on longitudinal MAA SPECT/CT in lung cancer patients treated with and without functional tissue-avoidance radiation therapy.

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.

Voxel Forecast for Precision Oncology: Predicting Spatially Variant and Multiscale Cancer Therapy Response on Longitudinal Quantitative Molecular Imaging.

PURPOSE: Prediction of spatially variant response to cancer therapies can inform risk-adaptive management within precision oncology. We developed the "Voxel Forecast" multiscale regression framework for predicting spatially variant tumor response to chemoradiotherapy on fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging. EXPERIMENTAL DESIGN: Twenty-five patients with locally advanced non-small cell lung cancer, enrolled on the FLARE-RT phase II trial (NCT02773238), underwent FDG PET/CT imaging prior to (PETpre) and during week 3 (PETmid) of concurrent chemoradiotherapy. Voxel Forecast was designed to predict tumor voxel standardized uptake value (SUV) on PETmid from baseline patient-level and voxel-level covariates using a custom generalized least squares (GLS) algorithm. Matérn covariance matrices were fit to patient- specific empirical variograms of distance-dependent intervoxel correlation. Regression coefficients from variogram-based weights and corresponding standard errors were estimated using the jackknife technique. The framework was validated using statistical simulations of known spatially variant tumor response. Mean absolute prediction errors (MAEs) of Voxel Forecast models were calculated under leave-one-patient-out cross-validation. RESULTS: Patient-level forecasts resulted in tumor voxel SUV MAE on PETmid of 1.5 g/mL while combined patient- and voxel-level forecasts achieved lower MAE of 1.0 g/mL (P < 0.0001). PETpre voxel SUV was the most important predictor of PETmid voxel SUV. Patients with a greater percentage of under-responding tumor voxels were classified as PETmid nonresponders (P = 0.030) with worse overall survival prognosis (P < 0.001). CONCLUSIONS: Voxel Forecast multiscale regression provides a statistical framework to predict voxel-wise response patterns during therapy. Voxel Forecast can be extended to predict spatially variant response on multimodal quantitative imaging and may eventually guide optimized spatial-temporal dose distributions for precision cancer therapy.

Long term follow-up of neoadjuvant chemotherapy for non-small cell lung cancer (NSCLC) investigating early positron emission tomography (PET) scan as a predictor of outcome.

BACKGROUND: Neoadjuvant chemotherapy is effective in improving survival of resectable NSCLC. Based on findings in the adjuvant and metastatic setting, FDG positron emission tomography (PET) scans may offer early prognostic or predictive value after one cycle of induction chemotherapy. METHODS: In this phase II non-randomized trial, patients with AJCC version 6 stage IB to IIIB operable NSCLC were treated with 3 cycles of cisplatin and pemetrexed neoadjuvant chemotherapy. Patients underwent FDG-PET scanning prior to and 18 to 21 days after the first cycle of chemotherapy. Investigators caring for patients were blinded to results, unless the scans showed evidence of disease progression. FDG-PET response was defined prospectively as a ≥ 20% decrease in the SUV of the primary lesion. RESULTS: Between October 2005 and February 2010, 25 patients enrolled. Fifty two percent were female, 88% white, and median age was 62 years. Histology was divided into adenocarcinoma 66%, not otherwise specified (NOS) 16%, squamous cell 12%, and large cell 4%. Stage distribution was: 16% IB, 4% IIB, and 79% IIIA. Treatment was well tolerated and only one patient had a grade 4 toxicity. The median follow up was 95 months. The 5 year progression free survival (PFS) and overall survival (OS) for the entire population were 54 and 67%, respectively. Eighteen patients had a baseline FDG-PET scan and a repeat scan at day 18-21 available for comparison. Ten patients (56%) were considered metabolic responders on the day 18-21 FDG-PET scan. Responders had a 5 year PFS and OS of 60 and 70%, respectively, while the percentage for non-responders was 63 and 75% (p = 0.96 and 0.85). CONCLUSIONS: This phase II trial did not demonstrate that a PET scan after one cycle of chemotherapy can predict survival outcomes of patients with NSCLC treated with neoadjuvant chemotherapy. TRIAL REGISTRATION: NCT00227539 registered September 28th, 2005.

Functional Liver Imaging and Dosimetry to Predict Hepatotoxicity Risk in Cirrhotic Patients With Primary Liver Cancer.

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 <23 GyEQD2, liver-GTV V20 <36%, FLV V20 <36%, liver-GTV F20 <36%, FLV <32% (350 cc), L/Smean >0.75, TLF >0.60, tumor volume <40 cm3, and CP score A5-6 versus B7-C10. A narrower therapeutic window was observed in CP-B/C patients. The discriminatory power for RILD-SS within CP-B/C classes was improved with the addition of a functional dosimetric constraint, resulting in low- and high-risk subgroups (P = 3 × 10-6). CONCLUSIONS: Functional liver metrics and dosimetric parameters derived from pretreatment SC SPECT/CT scans were complementary predictors of hepatotoxicity and may provide useful clinical decision support in the management of cirrhotic patients with primary liver cancer.

Correlation of Functional Lung Heterogeneity and Dosimetry to Radiation Pneumonitis using Perfusion SPECT/CT and FDG PET/CT Imaging.

PURPOSE: To apply a previously designed framework for predicting radiation pneumonitis by using pretreatment lung function heterogeneity metrics, anatomic dosimetry, and functional lung dosimetry derived from 2 imaging modalities within the same cohort. METHODS AND MATERIALS: Treatment planning computed tomography (CT) scans were co-registered with pretreatment [99mTc] macro-aggregated albumin perfusion single-photon positron emission tomography (SPECT)/CT scans and [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT scans of 28 patients who underwent definitive thoracic radiation. Clinical radiation pneumonitis was defined as grade ≥2 (Common Terminology Criteria for Adverse Events, v. 4). Anatomic dosimetric parameters (mean lung dose [MLD], volume receiving ≥20 Gy [V20]) were collected from treatment planning scans. Baseline functional lung heterogeneity parameters and functional lung dose-volume parameters were calculated from pretreatment SPECT/CT and FDG PET/CT scans. Functional heterogeneity parameters calculated over the tumor-subtracted lung included skewness, kurtosis, and coefficient of variation from perfusion SPECT and FDG PET and the global lung parenchymal glycolysis and mean standardized uptake value from FDG PET. Functional dose-volume parameters calculated in regions of highly functional lung, defined on perfusion (p) or SUV (s) images, included mean lung dose (pMLD, sMLD) and V20 (pV20, sV20). Fraction of integral lung function receiving ≥20 Gy (pF20, sF20) was also calculated. Equivalent doses in 2 Gy per fraction (EQD2) were calculated to account for differences in treatment regimens and dose fractionation (EQD2Lung). RESULTS: Two anatomic dosimetric parameters (MLD, V20) and 4 functional dosimetric parameters (pMLD, pV20, pF20, sF20) were significant predictors of grade ≥2 pneumonitis (area under the curve >0.84; P < .05). Dose-independent functional lung heterogeneity metrics were not associated with pneumonitis incidence. At thresholds of 100% sensitivity and 65% to 91% specificity, corresponding to maximum prediction accuracy for pneumonitis, these parameters had the following cutoff values: MLD = 13.6 Gy EQD2Lung, V20 = 25%, pMLD = 13.2 Gy EQD2Lung, pV20 = 15%, pF20 = 17%, and sF20 = 25%. Significant parameters MLD, V20, pF20, and sF20 were not cross-correlated to significant parameters pMLD and pV20, indicating that they may offer independently predictive information (Spearman ρ < 0.7). CONCLUSIONS: We reported differences in anatomic and functional lung dosimetry between patients with and without pneumonitis in this limited patient cohort. Adding selected independent functional lung parameters may risk stratify patients for pneumonitis. Validation studies are ongoing in a prospective functional lung avoidance trial at our institution.

MDP-SPECT Versus Hybrid MDP-SPECT/CT in the Evaluation of Suspected Pars Interarticularis Fracture in Young Athletes.

BACKGROUND AND PURPOSE: To assess benefits of hybrid (single photon emission computerized tomography [SPECT]/computed tomography [CT]) imaging over SPECT imaging only in the management of young athletes with low back pain (LBP) due to suspected pars interarticularis fracture. METHODS: Retrospectively reviewed medical records of 163 consecutive patients who had radionuclide SPECT imaging for evaluation of LBP between January 1, 2010 and December 30, 2015. All enrolled patients were divided into two groups (group 1: patients with radionuclide SPECT imaging only and group 2: patients with radionuclide hybrid imaging). Radiation dose, cost benefits, and mean duration of delay in complete diagnosis were assessed and compared using Fisher's exact test. RESULTS: A total of 91 patients were enrolled after applying inclusion and exclusion criteria. The volume CT dose index and dose length product (DLP) estimated for a scan length of 10 cm (DLP 10) were significantly lower for patients in group II (CTDIvol ) (P  =  .001 and P  =  .001). Although, there was no significant difference in actual DLP (P  =  .52). There was a median delay of 7 days (interquartile range 2-10 days) for complete diagnosis in group I patients. Least expensive imaging for early definitive diagnosis required for the treatment decisions was in patients who had a radionuclide Technetium-99m methylene diphosphonate bone scan with limited lumbar spine planar and SPECT imaging followed by a thin slice, limited CT performed only when SPECT imaging was positive for an active pars interarticularis fracture. No significant difference in the management of patients between the groups (P  =  .47). CONCLUSION: Hybrid imaging should be preferred over SPECT only imaging for initial evaluation of suspected pars interarticularis fracture in young athletes with LBP.

Regional Radiation Dose-Response Modeling of Functional Liver in Hepatocellular Carcinoma Patients With Longitudinal Sulfur Colloid SPECT/CT: A Proof of Concept.

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 <5 GyEQD2, were calculated in each binned dose region. Dose-response data were parameterized by sigmoid functions (double exponential) consisting of maximum reduction (%ΔSCmax), dose midpoint (Dmid), and dose-response slope (αmid) parameters. RESULTS: Individual patient sigmoid dose-response curves had high goodness-of-fit (median R2 = 0.96, range 0.76-0.99). Large interpatient variability was observed, with median (range) in %ΔSCmax of 44% (20%-75%), Dmid of 13 Gy (4-27 GyEQD2), and αmid of 0.11 GyEQD2-1 (0.04-0.29 GyEQD2-1), respectively. Eight of 15 patients had %ΔSCmax of 20% to 45%, whereas 7 of 15 had %ΔSCmax of 60% to 75%, with subgroups made up of variable baseline liver function status and radiation treatment modality. Fatal hepatotoxicity occurred in patients (2 of 15) with low total liver funcation (<0.12) and low Dmid (<7 GyEQD2). CONCLUSIONS: Longitudinal SC SPECT/CT imaging revealed patient-specific variations in dose-response and may identify patients with poor baseline liver function and increased sensitivity to radiation therapy. Validation of this regional liver dose-response modeling concept as a surrogate for patient-specific radiosensitivity has potential to guide HCC therapy regimen selection and planning constraints.

Hepatopulmonary shunting on Tc99m-MAA liver mapping: correlation with dynamic cross-sectional imaging and description of different shunting patterns.

PURPOSE: The purpose of the study was to correlate lung shunt fraction (LSF) calculated by intra-arterial injection of Technetium-99m (Tc-99m)-labeled macroaggregated albumin (MAA) in a hepatic artery branch with the presence of certain patterns of vascular shunts on dynamic CT or MRI of the liver. METHODS: This retrospective study was approved by the institutional review board and informed consent was waived. We reviewed 523 MAA scans in 453 patients (301 men, 152 women) performed from July 2007 to June 2015 and their correlative cross-sectional imaging. Patterns of vascular shunts on dynamic CT or MRI performed within 3 months of the MAA study and that potentially divert hepatic arterial inflow to the systemic venous return were defined as "target shunts." Dynamic CT or MRI was classified into three groups with target shunt present, absent, or indeterminate. The mean LSF was compared across the first and second groups using paired t test. RESULTS: 342 CT and MRI studies met inclusion criteria: target shunts were present in 63 studies, absent in 271 studies, and 8 studies were indeterminate. When target shunts were visualized, the mean LSF on corresponding MAA scans was 12.9 ± 10.36% (95% CI 10.29-15.15%) compared to 4.3 ± 3.17% (95% CI 3.93-4.68%) when no target shunt was visualized. The difference was statistically significant (p value < 0.001). Identified target shunts were either direct (arteriohepatic venous shunt) or indirect (arterioportal shunt combined with a portosystemic shunt). CONCLUSIONS: Visualizing certain patterns of vascular shunting on a dynamic CT or MRI scan is associated with high LSF.

Semi-quantitative metabolic values on FDG PET/CT including extracardiac sites of disease as a predictor of treatment course in patients with cardiac sarcoidosis.

BACKGROUND: Cardiac sarcoidosis is associated with major adverse cardiac events including cardiac arrest, for which anti-inflammatory treatment is indicated. Oral corticosteroid is the mainstay among treatment options; however, adverse effects are a major concern with long-term use. It would be beneficial for providers to predict treatment response and prognosis for proper management strategy of sarcoidosis, though it remains challenging. Fluorine (F)-18 fluorodeoxyglucose (FDG)-positron emission tomography(PET)/computed tomography(CT) has an advantage over anatomical imaging in providing semi-quantitative functional parameters such as standard uptake value (SUV), metabolic volume, and total lesion glycolysis (TLG), which are well-established biomarkers in oncology. However, the relationship between these parameters and treatment response has not been fully investigated in cardiac sarcoidosis. Also, the prognostic value of extracardiac active inflammation noted on FDG-PET/CT in the setting of cardiac sarcoidosis is unclear. The aim of this retrospective study was to investigate the prognostic value of semi-quantitative values of both cardiac and extracardiac disease sites derived from FDG-PET/CT in predicting treatment course in cardiac sarcoidosis. METHODS: Sixteen consecutive patients with suspected cardiac sarcoidosis, who demonstrated abnormal myocardial activity on cardiac-inflammation FDG-PET/CT encompassing the entire chest/upper abdomen and subsequently underwent corticosteroid therapy for diagnosis of active cardiac sarcoidosis, were included. Semi-quantitative values of hypermetabolic lesions were derived from all visualized organ system and were compared to daily corticosteroid dose at 6 months. RESULTS:  Of the 16 patients, 81.3% (13/16) of the patients showed extracardiac involvement. The lesion with the greatest SUV was identified in the heart in 11 patients (68.7%), in the liver in 1 patient (6.3%), and in lymph nodes in 4 patients (25%). The maximum SUV across all visualized organ systems including the heart were 8.8 ± 3.1 for the patients with corticosteroid dose ≤ 10 mg and 12.5 ± 3.3 for those with > 10 mg (P = 0.04). Metabolic volume and TLG across all visualized organ systems or any values in the heart alone showed no significant statistical difference between the two groups. CONCLUSIONS: Maximum SUV across all involved organ-systems of the chest and upper abdomen, not that of the heart alone, could be a predictor of treatment course of steroid therapy at 6 months in patients with active cardiac sarcoidosis.

Assessment of functional liver reserve: old and new in 99mTc-sulfur colloid scintigraphy.

PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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 (P<0.001) compared with liver uptake percentage from the whole-body counts, r=0.49 (P<0.001) compared with splenic uptake percentage, and r=0.45 (P≤0.05) compared with bone marrow uptake percentage. CONCLUSION: 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.

Functional lung avoidance and response-adaptive escalation (FLARE) RT: Multimodality plan dosimetry of a precision radiation oncology strategy.

PURPOSE: Nonsmall cell lung cancer (NSCLC) patient radiation therapy (RT) is planned without consideration of spatial heterogeneity in lung function or tumor response. We assessed the dosimetric and clinical feasibility of functional lung avoidance and response-adaptive escalation (FLARE) RT to reduce dose to [99m Tc]MAA-SPECT/CT perfused lung while redistributing an escalated boost dose within [18 F]FDG-PET/CT-defined biological target volumes (BTV). METHODS: Eight stage IIB-IIIB NSCLC patients underwent FDG-PET/CT and MAA-SPECT/CT treatment planning scans. Perfused lung objectives were derived from scatter/collimator/attenuation-corrected MAA-SPECT uptake relative to ITV-subtracted lung to maintain < 20 Gy mean lung dose (MLD). Prescriptions included 60 Gy to the planning target volume (PTV) and concomitant boost of 74 Gy mean to biological target volumes (BTV = GTV + PET gradient segmentation) scaled to each BTV voxel by relative FDG-PET SUV. Dose-painting-by-numbers prescriptions were integrated into commercial treatment planning systems via uptake threshold discretization. Dose constraints for lung, heart, cord, and esophagus were defined. FLARE RT plans were optimized with volumetric modulated arc therapy (VMAT), proton pencil beam scanning (PBS) with 3%-3 mm robust optimization, and combination of PBS (avoidance) plus VMAT (escalation). The high boost dose region was evaluated within a standardized SUVpeak structure. FLARE RT plans were compared to reference VMAT plans. Linear regression between radiation dose to BTV and normalized FDG PET SUV at every voxel was conducted, from which Pearson linear correlation coefficients and regression slopes were extracted. Spearman rank correlation coefficients were estimated between radiation dose to lung and normalized SPECT uptake. Dosimetric differences between treatment modalities were evaluated by Friedman nonparametric paired test with multiple sampling correction. RESULTS: No unacceptable violations of PTV and normal tissue objectives were observed in 24 FLARE RT plans. Compared to reference VMAT plans, FLARE VMAT plans achieved a higher mean dose to BTV (73.7 Gy 98195. 61.3 Gy), higher mean dose to SUVpeak (89.7 Gy vs. 60.8 Gy), and lower mean dose to highly perfused lung (7.3 Gy vs. 14.9 Gy). These dosimetric gains came at the expense of higher mean heart dose (9.4 Gy vs. 5.8 Gy) and higher maximum cord dose (50.1 Gy vs. 44.6 Gy) relative to the reference VMAT plans. Between FLARE plans, FLARE VMAT achieved higher dose to the SUVpeak ROI than FLARE PBS (89.7 Gy vs. 79.2 Gy, P = 0.01), while FLARE PBS delivered lower dose to lung than FLARE VMAT (11.9 Gy vs. 15.6 Gy, P < 0.001). Voxelwise linear dose redistribution slope between BTV dose and FDG PET uptake was higher in magnitude for FLARE PBS + VMAT (0.36 Gy per %SUVmax ) compared to FLARE VMAT (0.27 Gy per %SUVmax ) or FLARE PBS alone (0.17 Gy per %SUVmax ). CONCLUSIONS: FLARE RT is clinically feasible with VMAT and PBS. A combination of PBS for functional lung avoidance and VMAT for FDG PET dose escalation balanced target and normal tissue objective tradeoffs. These results provide a technical platform for testing of FLARE RT safety and efficacy within a precision radiation oncology trial.

Framework for radiation pneumonitis risk stratification based on anatomic and perfused lung dosimetry.

PURPOSE: 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. MATERIALS AND METHODS: 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). RESULTS: 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 < 0.01). Pairing of an anatomic and functional dosimetric parameter (e. g., MLD and pMLD70%) may further improve prediction accuracy. Not all individuals with high anatomic lung dose (MLD > 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. CONCLUSIONS: 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.