Acute hospitalizations after proton therapy versus intensity-modulated radiotherapy for locally advanced non-small cell lung cancer in the durvalumab era.

INTRODUCTION: It was hypothesized that use of proton beam therapy (PBT) in patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiation and consolidative immune checkpoint inhibition is associated with fewer unplanned hospitalizations compared with intensity-modulated radiotherapy (IMRT). METHODS: Patients with locally advanced non-small cell lung cancer treated between October 2017 and December 2021 with concurrent chemoradiation with either IMRT or PBT ± consolidative immune checkpoint inhibition were retrospectively identified. Logistic regression was used to assess the association of radiation therapy technique with 90-day hospitalization and grade 3 (G3+) lymphopenia. Competing risk regression was used to compare G3+ pneumonitis, G3+ esophagitis, and G3+ cardiac events. Kaplan-Meier method was used for progression-free survival and overall survival. Inverse probability treatment weighting was applied to adjust for differences in PBT and IMRT groups. RESULTS: Of 316 patients, 117 (37%) received PBT and 199 (63%) received IMRT. The PBT group was older (p < .001) and had higher Charlson Comorbidity Index scores (p = .02). The PBT group received a lower mean heart dose (p < .0001), left anterior descending artery V15 Gy (p = .001), mean lung dose (p = .008), and effective dose to immune circulating cells (p < .001). On inverse probability treatment weighting analysis, PBT was associated with fewer unplanned hospitalizations (adjusted odds ratio, 0.55; 95% CI, 0.38-0.81; p = .002) and less G3+ lymphopenia (adjusted odds ratio, 0.55; 95% CI, 0.37-0.81; p = .003). There was no difference in other G3+ toxicities, progression-free survival, or overall survival. CONCLUSIONS: PBT is associated with fewer unplanned hospitalizations, lower effective dose to immune circulating cells and less G3+ lymphopenia compared with IMRT. Minimizing dose to lymphocytes may be warranted, but prospective data are needed.

Pneumonitis Rates Before and After Adoption of Immunotherapy Consolidation in Patients With Locally Advanced Non-Small Cell Lung Cancer Treated With Concurrent Chemoradiation.

PURPOSE: We hypothesized that after adoption of immune checkpoint inhibitor (ICI) consolidation for patients with locally advanced non-small cell lung cancer (LA-NSCLC) receiving concurrent chemoradiation therapy (cCRT), rates of symptomatic pneumonitis would increase, thereby supporting efforts to reduce lung radiation dose. METHODS AND MATERIALS: This single institution, multisite retrospective study included 783 patients with LA-NSCLC treated with definitive cCRT either before introduction of ICI consolidation (pre-ICI era cohort [January 2011-September 2017]; N = 448) or afterward (ICI era cohort [October 2017-December 2021]; N = 335). Primary endpoint was grade ≥2 pneumonitis (G2P) and secondary endpoint was grade ≥3 pneumonitis (G3P), per Common Terminology Criteria for Adverse Events v5.0. Pneumonitis was compared between pre-ICI era and ICI era cohorts using the cumulative incidence function and Gray's test. Inverse probability of treatment weighting (IPTW)-adjusted Fine-Gray models were generated. Logistic models were developed to predict the 1-year probability of G2P as a function of lung dosimetry. RESULTS: G2P was higher in the ICI era than in the pre-ICI era (1-year cumulative incidence 31.4% vs 20.1%; P < .001; IPTW-adjusted multivariable subdistribution hazard ratio, 2.03; 95% confidence interval, 1.53-2.70; P < .001). There was no significant interaction between ICI era treatment and either lung volume receiving ≥20 Gy (V20) or mean lung dose in Fine-Gray regression for G2P; however, the predicted probability of G2P was higher in the ICI era at clinically relevant values of lung V20 (≥24%) and mean lung dose (≥14 Gy). Cut-point analysis revealed a lung V20 threshold of 28% in the ICI era (1-year G2P rate 46.0% above vs 19.8% below; P < .001). Among patients receiving ICI consolidation, lung V5 was not associated with G2P. G3P was not higher in the ICI era (1-year cumulative incidence 7.5% vs 6.0%; P = .39; IPTW-adjusted multivariable subdistribution hazard ratio, 1.12; 95% confidence interval, 0.63-2.01; P = .70). CONCLUSIONS: In patients with LA-NSCLC treated with cCRT, the adoption of ICI consolidation was associated with an increase in G2P but not G3P. With ICI consolidation, stricter lung dose constraints may be warranted.

Phase 2 Trial of Consolidation Pembrolizumab After Proton Reirradiation for Thoracic Recurrences of Non-Small Cell Lung Cancer.

PURPOSE: Reirradiation (reRT) with proton beam therapy (PBT) may offer a chance of cure while minimizing toxicity for patients with isolated intrathoracic recurrences of non-small cell lung cancer (NSCLC). However, distant failure remains common, necessitating strategies to integrate more effective systemic therapy. METHODS AND MATERIALS: This was a phase 2, single-arm trial (NCT03087760) of consolidation pembrolizumab after PBT reRT for locoregional recurrences of NSCLC. Four to 12 weeks after completion of 60 to 70 Gy PBT reRT, patients without progressive disease received pembrolizumab for up to 12 months. Primary endpoint was progression-free survival (PFS), measured from the start of reRT. Secondary endpoints were overall survival (OS) and National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 toxicity. RESULTS: Between 2017 and 2021, 22 patients received PBT reRT. Median interval from prior radiation end to reRT start was 20 months. Most recurrences (91%) were centrally located. Most patients received concurrent chemotherapy (95%) and pencil beam scanning PBT (77%), and 36% had received prior durvalumab. Fifteen patients (68%) initiated consolidation pembrolizumab on trial and received a median of 3 cycles (range, 2-17). Pembrolizumab was discontinued most commonly due to toxicity (n = 5; 2 were pembrolizumab-related), disease progression (n = 4), and completion of 1 year (n = 3). Median follow-up was 38.7 months. Median PFS and OS were 8.8 months (95% CI, 4.2-23.7) and 22.8 months (95% CI, 6.9-not reached), respectively. There was only one isolated in-field failure after reRT. Grade ≥3 toxicities occurred in 10 patients (45%); 2 were pembrolizumab-related. There were 2 grade 5 toxicities, an aorto-esophageal fistula at 6.9 months and hemoptysis at 46.8 months, both probably from reRT. The trial closed early due to widespread adoption of immunotherapy off-protocol. CONCLUSIONS: In the first-ever prospective trial combining PBT reRT with consolidation immunotherapy, PFS was acceptable and OS favorable. Late grade 5 toxicity occurred in 2 of 22 patients. This approach may be considered in selected patients with isolated thoracic recurrences of NSCLC.

Death without progression as an endpoint to describe cardiac radiation effects in locally advanced non-small cell lung cancer.

Background and purpose: Prior studies have examined associations of cardiovascular substructure dose with overall survival (OS) or cardiac events after chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC). Herein, we investigate an alternative endpoint, death without cancer progression (DWP), which is potentially more specific than OS and more sensitive than cardiac events for understanding CRT toxicity. Materials and methods: We retrospectively reviewed records of 187 patients with locally advanced or oligometastatic NSCLC treated with definitive CRT from 2008 to 2016 at a single institution. Dosimetric parameters to the heart, lung, and ten cardiovascular substructures were extracted. Charlson Comorbidity Index (CCI), excluding NSCLC diagnosis, was used to stratify patients into CCI low (0-2; n = 66), CCI intermediate (3-4; n = 78), and CCI high (≥5; n = 43) groups. Primary endpoint was DWP, modeled with competing risk regression. Secondary endpoints included OS. An external cohort consisted of 140 patients from another institution. Results: Median follow-up was 7.3 years for survivors. Death occurred in 143 patients (76.5 %), including death after progression in 118 (63.1 %) and DWP in 25 (13.4 %). On multivariable analysis, increasing CCI stratum and mean heart dose were associated with DWP. For mean heart dose ≥ 10 Gy vs < 10 Gy, DWP was higher (5-year rate, 16.9 % vs 6.7 %, p = 0.04) and OS worse (median, 22.9 vs 34.1 months, p < 0.001). Ventricle (left, right, and bilateral) and pericardial but not atrial substructure dose were associated with DWP, whereas all three were inversely associated with OS. Cutpoint analysis identified right ventricle mean dose ≥ 5.5 Gy as a predictor of DWP. In the external cohort, we confirmed an association of ventricle, but not atrial, dose with DWP. Conclusion: Cardiovascular substructure dose showed distinct associations with DWP. Future cardiotoxicity studies in NSCLC could consider DWP as an endpoint.

Fetal dose from proton pencil beam scanning craniospinal irradiation during pregnancy: a Monte Carlo study.

Objective. We conducted a Monte Carlo study to comprehensively investigate the fetal dose resulting from proton pencil beam scanning (PBS) craniospinal irradiation (CSI) during pregnancy.Approach. The gestational-age dependent pregnant phantom series developed at the University of Florida (UF) were converted into DICOM-RT format (CT images and structures) and imported into a treatment planning system (TPS) (Eclipse v15.6) commissioned to a IBA PBS nozzle. A proton PBS CSI plan (prescribed dose: 36 Gy) was created on the phantoms. The TOPAS MC code was used to simulate the proton PBS CSI on the phantoms, for which MC beam properties at the nozzle exit (spot size, spot divergence, mean energy, and energy spread) were matched to IBA PBS nozzle beam measurement data. We calculated mean absorbed doses for 28 organs and tissues and whole body of the fetus at eight gestational ages (8, 10, 15, 20, 25, 30, 35, and 38 weeks). For contextual purposes, the fetal organ/tissue doses from the treatment planning CT scan of the mother's head and torso were estimated using the National Cancer Institute dosimetry system for CT (NCICT, Version 3) considering a low-dose CT protocol (CTDIvol: 8.97 mGy).Main results. The majority of the fetal organ/tissue doses from the proton PBS CSI treatment fell within a range of 3-6 mGy. The fetal organ/tissue doses for the 38 week phantom showed the largest variation with the doses ranging from 2.9 mGy (adrenals) to 8.2 mGy (eye lenses) while the smallest variation ranging from 3.2 mGy (oesophagus) to 4.4 mGy (brain) was observed for the doses for the 20 week phantom. The fetal whole-body dose ranged from 3.7 mGy (25 weeks) to 5.8 mGy (8 weeks). Most of the fetal doses from the planning CT scan fell within a range of 7-13 mGy, approximately 2-to-9 times lower than the fetal dose equivalents of the proton PBS CSI treatment (assuming a quality factor of 7).Significance. The fetal organ/tissue doses observed in the present work will be useful for one of the first clinically informative predictions on the magnitude of fetal dose during proton PBS CSI during pregnancy.

Dual-Energy Computed Tomography Proton-Dose Calculation with Scripting and Modified Hounsfield Units.

PURPOSE: To describe an implementation of dual-energy computed tomography (DECT) for calculation of proton stopping-power ratios (SPRs) in a commercial treatment-planning system. The process for validation and the workflow for safe deployment of DECT is described, using single-energy computed tomography (SECT) as a safety check for DECT dose calculation. MATERIALS AND METHODS: The DECT images were acquired at 80 kVp and 140 kVp and were processed with computed tomography scanner software to derive the electron density and effective atomic number images. Reference SPRs of tissue-equivalent plugs from Gammex (Middleton, Wisconsin) and CIRS (Computerized Imaging Reference Systems, Norfolk, Virginia) electron density phantoms were used for validation and comparison of SECT versus DECT calculated through the Eclipse treatment planning system (Varian Medical Systems, Palo Alto, California) application programming interface scripting tool. An in-house software was also used to create DECT SPR computed tomography images for comparison with the script output. In the workflow, using the Eclipse system application programming interface script, clinical plans were optimized with the SECT image set and then forward-calculated with the DECT SPR for the final dose distribution. In a second workflow, the plans were optimized using DECT SPR with reduced range-uncertainty margins. RESULTS: For the Gammex phantom, the root mean square error in SPR was 1.08% for DECT versus 2.29% for SECT for 10 tissue-surrogates, excluding the lung. For the CIRS Phantom, the corresponding results were 0.74% and 2.27%. When evaluating the head and neck plan, DECT optimization with 2% range-uncertainty margins achieved a small reduction in organ-at-risk doses compared with that of SECT plans with 3.5% range-uncertainty margins. For the liver case, DECT was used to identify and correct the lipiodol SPR in the SECT plan. CONCLUSION: It is feasible to use DECT for proton-dose calculation in a commercial treatment planning system in a safe manner. The range margins can be reduced to 2% in some sites, including the head and neck.

Renal 99mTc-DMSA pharmacokinetics in pediatric patients.

99mTc-DMSA is one of the most commonly used pediatric nuclear medicine imaging agents. Nevertheless, there are no pharmacokinetic (PK) models for 99mTc-DMSA in children, and currently available pediatric dose estimates for 99mTc-DMSA use pediatric S values with PK data derived from adults. Furthermore, the adult PK data were collected in the mid-70's using quantification techniques and instrumentation available at the time. Using pediatric imaging data for DMSA, we have obtained kinetic parameters for DMSA that differ from those applicable to adults. METHODS: We obtained patient data from a retrospective re-evaluation of clinically collected pediatric SPECT images of 99mTc-DMSA in 54 pediatric patients from Boston's Children Hospital (BCH), ranging in age from 1 to 16 years old. These were supplemented by prospective data from twenty-three pediatric patients (age range: 4 months to 6 years old). RESULTS: In pediatric patients, the plateau phase in fractional kidney uptake occurs at a fractional uptake value closer to 0.3 than the value of 0.5 reported by the International Commission on Radiological Protection (ICRP) for adult patients. This leads to a 27% lower time-integrated activity coefficient in pediatric patients than in adults. Over the age range examined, no age dependency in uptake fraction at the clinical imaging time was observed. Female pediatric patients had a 17% higher fractional kidney uptake at the clinical imaging time than males (P < 0.001). CONCLUSIONS: Pediatric 99mTc-DMSA kinetics differ from those reported for adults and should be considered in pediatric patient dosimetry. Alternatively, the differences obtained in this study could reflect improved quantification methods and the need to re-examine DMSA kinetics in adults.

Predicted Secondary Malignancies following Proton versus Photon Radiation for Oropharyngeal Cancers.

PURPOSE: There has been a recent epidemic of human papillomavirus (HPV)-positive oropharyngeal cancer, accounting for 70% to 80% of diagnosed cases. These patients have an overall favorable prognosis and are typically treated with a combination of surgery, chemotherapy, and radiation. Because these patients live longer, they are at risk of secondary malignant neoplasms (SMNs) associated with radiation therapy. Therefore, we assessed the predicted risk of SMNs after adjuvant radiation therapy with intensity-modulated proton therapy (IMPT) compared with intensity modulated photon radiation therapy (IMRT) in patients with HPV- positive oropharyngeal cancers after complete resection. MATERIALS AND METHODS: Thirteen consecutive patients with HPV-positive oropharyngeal cancers treated with postoperative radiation alone were selected. All patients were treated with pencil beam scanning IMPT to a total dose of 60 Gy in 2 Gy fractions. The IMRT plans were generated for clinical backup and were used for comparative purposes. The SMN risk was calculated based on an organ equivalent dose model for the linear-exponential dose-response curve. RESULTS: Median age of the patient cohort was 63 years (range, 47-73 years). There was no difference in target coverage between IMPT and IMRT plans. We noted significant reductions in mean mandible, contralateral parotid, lung and skin organ equivalent doses with IMPT compared with IMRT plans (P < .001). Additionally, a significant decrease in the risk of SMNs with IMPT was observed for all the evaluated organs. Per our analysis, for patients with oropharyngeal cancers diagnosed at a national median age of 54 years with an average life expectancy of 27 years (per national Social Security data), 4 excess SMNs per 100 patients could be avoided by treating them with IMPT versus IMRT. CONCLUSIONS: Treatment with IMPT can achieve comparable target dose coverage while significantly reducing the dose to healthy organs, which can lead to fewer predicted SMNs compared with IMRT.

Robust treatment planning in whole pelvis pencil beam scanning proton therapy for prostate cancer.

Whole-pelvis pencil beam scanning (PBS) proton therapy is utilized in both the intact and post-operative settings in patients with prostate cancer. As whole pelvis prostate radiotherapy has traditionally been delivered with standard photon beams, limited evidence and technical descriptions have been reported regarding the use of proton therapy. Here we present two robust three-field treatment planning approaches utilized to maximize target coverage in the presence of anatomic and delivery uncertainties. Both techniques, conventional optimization (CO) and robust optimization (RO), create treatment plans with acceptable target coverage and sparing of organs at risk (OAR). While the RO method is less time intensive and may theoretically allow for superior OAR sparing and improved robustness, the CO method can be implemented by institutions who do not have RO capabilities.

Per-fraction positional and dosimetric performance of prone breast tangential radiotherapy on Halcyon™ linear accelerator assessed with daily rapid kilo-voltage cone beam computed tomography: a single-institution pilot study.

BACKGROUND: This study investigates daily breast geometry and delivered dose to prone-positioned patients undergoing tangential whole breast radiation therapy (WBRT) on an O-ring linear accelerator with 6X flattening filter free mode (6X-FFF), planned with electronic compensation (ECOMP) method. Most practices rely on skin marks or daily planar image matching for prone breast WBRT. This system provides low dose daily CBCT, which was used to study daily robustness of delivered dose parameters for prone-positioned WBRT. METHODS: Eight patients treated with 16-fraction prone-breast WBRT were retrospectively studied. Planning CTs were deformed to daily CBCT to generate daily synthetic CTs, on which delivered dose distributions were calculated. A total of 8 × 16 = 128 synthetic CTs were generated. Consensus ASTRO definition was used to contour Breast PTV Eval for each daily deformed CT. Breast PTV Eval coverage (V90%) and hotspot (V105% and Dmax) were monitored daily to compare prescription dose with daily delivered dose. Various predictors including patient weight, breast width diameter (BWD), and Dice similarity coefficient (DSC) were fit into an analysis of covariance model predicting V90% and V105% deviation from prescribed (ΔV90%, ΔV105%). Statistical significance is indicated with asterisks (* for p < 0.05; ** for p < 0.001). RESULTS: Daily delivered Breast PTV Eval V90% was moderately smaller than prescribed (median ΔV90% = - 0.1%*), while V105% was much larger (median ΔV105% = + 10.1%** or + 92.4 cc**). Patient's weight loss correlated with significantly increased ΔV105% (+ 4.6%/ - 1% weight, R2 = 0.4**) and moderately decreased ΔV90% (- 0.071%/ - 1% wt., R2 = 0.2**). Comprehensive ANCOVA models indicated three factors affect ΔV90% and ΔV105% the most: (1) BWD decrease (- 0.09%* and + 10%**/ - 1 cm respectively), (2) PTV Eval volume decrease (- 0.4%** and + 9%**/ - 100 cc), and for ΔV105% only, (3) the extent of breast deformation (+ 10%**/ - 0.01 DSC). Breast PTV Eval volume also decreased with time (- 2.21*cc/fx), possibly indicating seroma resolution and increase in V105% over time. CONCLUSIONS: Daily CBCT revealed key delivered dose parameters vary significantly for patients undergoing tangential prone breast WBRT planned with ECOMP using 6X-FFF. Patient weight, BWD, and breast shape deformation could be used to predict dosimetric variations from prescribed. Preliminary findings suggest an adaptive plan based on daily CBCT could reduce excessive dose to the breast.

Higher Dose Volumes May Be Better for Evaluating Radiation Pneumonitis in Lung Proton Therapy Patients Compared With Traditional Photon-Based Dose Constraints.

PURPOSE: The dosimetric parameters used clinically to reduce the likelihood of radiation pneumonitis (RP) for lung cancer radiation therapy have traditionally been V20Gy ≤ 30% to 35% and mean lung dose ≤ 20 to 23 Gy; however, these parameters are derived based on studies from photon therapy. The purpose of this study is to evaluate whether such dosimetric predictors for RP are applicable for locally advanced non-small cell lung cancer (LA-NSCLC) patients treated with proton therapy. METHODS AND MATERIALS: In the study, 160 (78 photon, 82 proton) patients with LA-NSCLC treated with chemoradiotherapy between 2011 and 2016 were retrospectively identified. Forty (20 photon, 20 proton) patients exhibited grade ≥2 RP after therapy. Dose volume histograms for the uninvolved lung were extracted for each patient. The percent lung volumes receiving above various dose levels were obtained in addition to V20Gy and Dmean. These dosimetric parameters and patient characteristics were evaluated with univariate and multivariate logistic regression tests. Receiver operating characteristic curves were generated to obtain the optimal dosimetric constraints through analyzing RP and non-RP sensitivity and specificity values. RESULTS: The multivariate analysis showed V40Gy and Dmean to be statistically significant for proton and photon patients, respectively. V35Gy to V50Gy were strongly correlated to V40Gy for proton patients. Based on the receiver operating characteristic curves, V35Gy to V50Gy had the highest area under the curve compared with other dose levels for proton patients. A potential dosimetric constraint for RP predictor in proton patients is V40Gy ≤ 23%. CONCLUSIONS: In addition to V20Gy and Dmean, the lung volume receiving higher doses, such as V40Gy, may be used as an additional indicator for RP in LA-NSCLC patients treated with proton therapy.

Dose to Highly Functional Ventilation Zones Improves Prediction of Radiation Pneumonitis for Proton and Photon Lung Cancer Radiation Therapy.

PURPOSE: We hypothesized that the radiation dose in high-ventilation portions of the lung better predicts radiation pneumonitis (RP) outcome for patients treated with proton radiation therapy (PR) and photon radiation therapy (PH). METHODS AND MATERIALS: Seventy-four patients (38 protons, 36 photons) with locally advanced non-small cell lung cancer treated with concurrent chemoradiation therapy were identified, of whom 24 exhibited RP (graded using Common Terminology Criteria for Adverse Events v4.0) after PR or PH, and 50 were negative controls. The inhale and exhale simulation computed tomography scans were deformed using Advanced Normalization Tools. The 3-dimensional lung ventilation maps were derived from the deformation matrix and partitioned into low- and high-ventilation zones for dosimetric analysis. Receiver operating curve analysis was used to study the power of relationship between RP and ventilation zones to determine an optimal ventilation cutoff. Univariate logistic regression was used to correlate dose in high- and low-ventilation zones with risk of RP. A nonparametric random forest process was used for multivariate importance assessment. RESULTS: The optimal high-ventilation zone definition was determined to be the higher 45% to 60% of the ventilation values. The parameter vV20Gy_high (high ventilation volume receiving ≥20 Gy) was found to be a significant indicator for RP (PH: P = .002, PR: P = .035) with improved areas under the curve compared with the traditional V20Gy for both photon and proton cohorts. The relationship of RP with dose to the low-ventilation zone of the lung was insignificant (PH: P = .123, PR: P = .661). Similar trends were observed for ventilation mean lung dose and ventilation V5Gy. Multivariate importance assessment determined that vV20Gy_high, vV5_high, and mean lung dose were the most significant parameters for the proton cohort with a combined area under the curve of 0.78. CONCLUSION: Dose to the high-ventilated regions of the lung can improve predictions of RP for both PH and PR.

Inter-fraction robustness of intensity-modulated proton therapy in the post-operative treatment of oropharyngeal and oral cavity squamous cell carcinomas.

OBJECTIVE: To evaluate dosimetric consequences of inter-fraction setup variation and anatomical changes in patients receiving multifield optimised (MFO) intensity modulated proton therapy for post-operative oropharyngeal (OPC) and oral cavity (OCC) cancers. METHODS: Six patients receiving MFO for post-operative OPC and OCC were evaluated. Plans were robustly optimised to clinical target volumes (CTVs) using 3 mm setup and 3.5% range uncertainty. Weekly online cone beam CT (CBCT) were performed. Planning CT was deformed to the CBCT to create virtual CTs (vCTs) on which the planned dose was recalculated. vCT plan robustness was evaluated using a setup uncertainty of 1.5 mm and range uncertainty of 3.5%. Target coverage, D95%, and hotspots, D0.03cc, were evaluated for each uncertainty along with the vCT-calculated nominal plan. Mean dose to organs at risk (OARs) for the vCT-calculated nominal plan and relative % change in weight from baseline were evaluated. RESULTS: Robustly optimised plans in post-operative OPC and OCC patients are robust against inter-fraction setup variations and range uncertainty. D0.03cc in the vCT-calculated nominal plans were clinically acceptable across all plans. Across all patients D95% in the vCT-calculated nominal treatment plan was at least 100% of the prescribed dose. No patients lost ≥10% weight from baseline. Mean dose to the OARs and max dose to the spinal cord remained within tolerance. CONCLUSION: MFO plans in post-operative OPC and OCC patients are robust to inter-fraction uncertainties in setup and range when evaluated over multiple CT scans without compromising OAR mean dose. ADVANCES IN KNOWLEDGE: This is the first paper to evaluate inter-fraction MFO plan robustness in post-operative head and neck treatment.

Current pediatric administered activity guidelines for 99m Tc-DMSA SPECT based on patient weight do not provide the same task-based image quality.

PURPOSE: In the current clinical practice, administered activity (AA) for pediatric molecular imaging is often based on the North American expert consensus guidelines or the European Association of Nuclear Medicine dosage card, both of which were developed based on the best clinical practice. These guidelines were not formulated using a rigorous evaluation of diagnostic image quality (IQ) relative to AA. In the guidelines, AA is determined by a weight-based scaling of the adult AA, along with minimum and maximum AA constraints. In this study, we use task-based IQ assessment methods to rigorously evaluate the efficacy of weight-based scaling in equalizing IQ using a population of pediatric patients of different ages and body weights. METHODS: A previously developed projection image database was used. We measured task-based IQ, with respect to the detection of a renal functional defect at six different AA levels (AA relative to the AA obtained from the guidelines). IQ was assessed using an anthropomorphic model observer. Receiver-operating characteristics (ROC) analysis was applied; the area under the ROC curve (AUC) served as a figure-of-merit for task performance. In addition, we investigated patient girth (circumference) as a potential improved predictor of the IQ. RESULTS: The data demonstrate a monotonic and modestly saturating increase in AUC with increasing AA, indicating that defect detectability was limited by quantum noise and the effects of object variability were modest over the range of AA levels studied. The AA for a given value of the AUC increased with increasing age. The AUC vs AA plots for all the patient ages indicate that, for the current guidelines, the newborn and 10- and 15-yr phantoms had similar IQ for the same AA suggested by the North American expert consensus guidelines, but the 5- and 1-yr phantoms had lower IQ. The results also showed that girth has a stronger correlation with the needed AA to provide a constant AUC for 99m Tc-DMSA renal SPECT. CONCLUSIONS: The results suggest that (a) weight-based scaling is not sufficient to equalize task-based IQ for patients of different weights in pediatric 99m Tc-DMSA renal SPECT; and (b) patient girth should be considered instead of weight in developing new administration guidelines for pediatric patients.

Influence of intravenous contrast agent on dose calculation in proton therapy using dual energy CT.

The purpose of this study is to evaluate the effect of an intravenous (IV) contrast agent on proton therapy dose calculation using dual-energy computed tomography (DECT). Two DECT methods are considered. The first one, [Formula: see text], attempts to accurately predict the proton stopping powers relative to water (SPR) of contrast enhanced (CE) DECT images, while the second generates a virtual non-contrast (VNC) volume that can be processed as a native non-contrast (NC) one. Both methods are compared against single-energy computed tomography (SECT). The accuracy of SPR predicted for different concentrations of IV contrast diluted in water is first evaluated using simulated data. Results then are validated in an experimental set-up comparing SPR predictions for both NC and CE images to measurements made with a multi-layer ionisation chamber (MLIC). Finally, the impact of IV contrast on dose calculation using both SECT and DECT is evaluated for one liver and one head and neck patient. Using simulated data, DECT is shown to be less sensitive to the presence of IV contrast than SECT, although the performance of the [Formula: see text] method is sensitive to the level of beam hardening considered. For different concentrations of IV contrast diluted in water, experimental MLIC measurement of SPR agrees with DECT predictions within 3% while SECT introduce errors above 20%. This error in the SPR value results in a range error of up to 3.2 mm (2.6%) for proton beams calculated on SECT CE patient images. The error is reduced below 1 mm using DECT with the [Formula: see text] and VNC methods. Globally, it is observed that the influence of IV contrast on proton therapy dose calculation is mitigated using DECT over SECT. In patient anatomies, the VNC approach provides the best agreement with the reference dose distribution.

Re-evaluation of pediatric 18F-FDG dosimetry: Cristy-Eckerman versus UF/NCI hybrid computational phantoms.

Because of the concerns associated with radiation exposure at a young age, there is an increased interest in pediatric absorbed dose estimates for imaging agents. Almost all reported pediatric absorbed dose estimates, however, have been determined using adult pharmacokinetic data with radionuclide S values that take into account the anatomical differences between adults and children based upon the older Cristy-Eckerman (C-E) stylized phantoms. In this work, we use pediatric model-derived pharmacokinetics to compare absorbed dose and effective dose estimates for 18F-FDG in pediatric patients using S values generated from two different geometries of computational phantoms. Time-integrated activity coefficients of 18F-FDG in brain, lungs, heart wall, kidneys and liver, retrospectively, calculated from 35 pediatric patients at the Boston's Children Hospital were used. The absorbed dose calculation was performed in accordance with the Medical Internal Radiation Dose method using S values generated from the University of Florida/National Cancer Institute (UF/NCI) hybrid phantoms, as well as those from C-E stylized computational phantoms. The effective dose was computed using tissue-weighting factors from ICRP Publication 60 and ICRP Publication 103 for the C-E and UF/NCI, respectively. Substantial differences in the absorbed dose estimates between UF/NCI hybrid pediatric phantoms and the C-E stylized phantoms were found for the lungs, ovaries, red bone marrow and urinary bladder wall. Large discrepancies in the calculated dose values were observed in the bone marrow; ranging between -26% to +199%. The effective doses computed by the UF/NCI hybrid phantom S values were slightly different than those seen using the C-E stylized phantoms with percent differences of -0.7%, 2.9% and 2.5% for a newborn, 1 year old and 5 year old, respectively. Differences in anatomical modeling features among computational phantoms used to perform Monte Carlo-based photon and electron transport simulations for 18F, and very likely for other radionuclides, impact internal organ dosimetry computations for pediatric nuclear medicine studies.

Automated Information Extraction on Treatment and Prognosis for Non-Small Cell Lung Cancer Radiotherapy Patients: Clinical Study.

BACKGROUND: In outcome studies of oncology patients undergoing radiation, researchers extract valuable information from medical records generated before, during, and after radiotherapy visits, such as survival data, toxicities, and complications. Clinical studies rely heavily on these data to correlate the treatment regimen with the prognosis to develop evidence-based radiation therapy paradigms. These data are available mainly in forms of narrative texts or table formats with heterogeneous vocabularies. Manual extraction of the related information from these data can be time consuming and labor intensive, which is not ideal for large studies. OBJECTIVE: The objective of this study was to adapt the interactive information extraction platform Information and Data Extraction using Adaptive Learning (IDEAL-X) to extract treatment and prognosis data for patients with locally advanced or inoperable non-small cell lung cancer (NSCLC). METHODS: We transformed patient treatment and prognosis documents into normalized structured forms using the IDEAL-X system for easy data navigation. The adaptive learning and user-customized controlled toxicity vocabularies were applied to extract categorized treatment and prognosis data, so as to generate structured output. RESULTS: In total, we extracted data from 261 treatment and prognosis documents relating to 50 patients, with overall precision and recall more than 93% and 83%, respectively. For toxicity information extractions, which are important to study patient posttreatment side effects and quality of life, the precision and recall achieved 95.7% and 94.5% respectively. CONCLUSIONS: The IDEAL-X system is capable of extracting study data regarding NSCLC chemoradiation patients with significant accuracy and effectiveness, and therefore can be used in large-scale radiotherapy clinical data studies.

A projection image database to investigate factors affecting image quality in weight-based dosing: application to pediatric renal SPECT.

Balancing the tradeoff between radiation dose, acquisition duration and diagnostic image quality is essential for medical imaging modalities involving ionizing radiation. Lower administered activities to the patient can reduce absorbed dose, but can result in reduced diagnostic image quality or require longer acquisition durations. In pediatric nuclear medicine, it is desirable to use the lowest amount of administered radiopharmaceutical activity and the shortest acquisition duration that gives sufficient image quality for clinical diagnosis. However, diagnostic image quality is a complex function of patient factors including body morphometry. In this study, we present a digital population of 90 computational anatomic phantoms that model realistic variations in body morphometry and internal anatomy. These phantoms were used to generate a large database of projection images modeling pediatric SPECT imaging using a 99mTc-DMSA tracer. We used an analytic projection code that models attenuation, spatially varying collimator-detector response, and object-dependent scatter to generate the projections. The projections for each organ were generated separately and can be subsequently scaled by parameters extracted from a pharmacokinetics model to simulate realistic tracer biodistribution, including variations in uptake, inside each relevant organ or tissue structure for a given tracer. Noise-free projection images can be obtained by summing these individual organ projections and scaling by the system sensitivity and acquisition duration. We applied this database in the context of 99mTc-DMSA renal SPECT, the most common nuclear medicine imaging procedure in pediatric patients. Organ uptake fractions based on literature values and patient studies were used. Patient SPECT images were used to verify that the sum of counts in the simulated projection images was clinically realistic. For each phantom, 384 uptake realizations, modeling random variations in the uptakes of organs of interest, were generated, producing 34 560 noise-free projection datasets (384 uptake realizations times 90 phantoms). Noisy images modeling various count levels (corresponding to different products of acquisition duration and administered activity) were generated by appropriately scaling these images and simulating Poisson noise. Acquisition duration was fixed; six count levels were simulated corresponding to projection images acquired using 25%, 50%, 75%, 100%, 125%, and 150% of the original weight-based administrated activity as computed using the North American Guidelines (Gelfand et al 2011 J. Nucl. Med. 52 318-22). Combined, a total number of 207 360 noisy projection images were generated, creating a realistic projection database for use in renal pediatric SPECT imaging research. The phantoms and projection datasets were used to calculate three surrogate indices for factors affecting image quality: renal count density, average radius of rotation, and scatter-to-primary ratio. Differences in these indices were seen across the phantoms for dosing based on current guidelines, and especially for the phantom modeling the newborn. We also performed an image quality study using an anthropomorphic model observer that demonstrates that the weight-based dose scaling does not equalize image quality as measured by the area under the receiver-operating characteristics curve. These studies suggest that a dosing procedure beyond weight-based scaling of administered activities is required to equalize image quality in pediatric renal SPECT.

Depth-dependent concentrations of hematopoietic stem cells in the adult skeleton: Implications for active marrow dosimetry.

PURPOSE: The hematopoietically active (or red) bone marrow is the target tissue assigned in skeletal dosimetry models for assessment of stochastic effects (leukemia induction) as well as tissue reactions (marrow toxicity). Active marrow, however, is in reality a surrogate tissue region for specific cell populations, namely the hematopoietic stem and progenitor cells. Present models of active marrow dosimetry implicitly assume that these cells are uniformly localized throughout the marrow spaces of trabecular spongiosa. Data from Watchman et al. and Bourke et al., however, clearly indicate that there is a substantial spatial concentration gradient of these cells with the highest concentrations localized near the bone trabeculae surfaces. The purpose of the present study was thus to explore the dosimetric implications of these spatial gradients on active marrow dosimetry. METHODS: Images of several bone sites from a 45-yr female were retagged to group active marrow voxels into 50 µm increments of marrow depth, after which electron and alpha-particle depth-dependent specific absorbed fractions were computed for four source tissues - active marrow, inactive marrow, bone trabeculae volumes, and bone trabeculae surfaces. Corresponding depth-dependent S values (dose to a target tissue per decay in a source tissue) were computed and further weighted by the relative target cell concentration. These depth-weighted radionuclide S values were systematically compared to the more traditional volume-averaged radionuclide S values of the MIRD schema for both individual bones of the skeleton and their skeletal-averaged quantities. RESULTS: For both beta-emitters and alpha-emitters localized in the active and inactive marrow, depth-weighted S values were shown to differ from volume-averaged S values by only a few percent, as dose gradients across the marrow tissues are nonexistent. For bone volume and bone surface sources of alpha-emitters and lower energy beta-emitters, when marrow dose gradients are expected, explicit consideration of target cell spatial concentration gradients are shown to significantly impact marrow dosimetry. CONCLUSIONS: For medical isotopes currently utilized for treatment of skeletal metastases, namely 153 Sm and 223 Ra, accounting for hematopoietic stem and progenitor cell concentration gradients resulted in maximum percent differences to reference skeletal-averaged S values of ~21% and 55%, respectively.

Organ Doses to Airline Passengers Screened by X-Ray Backscatter Imaging Systems.

Advanced imaging technologies (AIT) are being developed for passenger airline transportation. They are designed to provide enhanced security benefits by identifying objects on passengers that would not be detected by methodologies now used for routine surveillance. X-ray backscatter imaging is one AIT system being considered. Since this technology is based on scanning passengers with ionizing radiation, concern has been raised relating to the health risks associated with these exposures. Recommendations for standards of radiation safety have been proposed by the American National Standards Institute published in ANSI/HPS N43.17-2009. A Monte Carlo based methodology for estimating organ doses received from an X-ray backscatter AIT system is presented. Radiological properties of a reference scanner including beam intensity, geometry and energy spectra were modeled based on previous studies and physical measurements. These parameters were incorporated into a Monte Carlo source subroutine and validated with comparison of simulated versus measured data. One extension of this study was to calculate organ and effective dose on a wide range of potential passengers. Computational phantoms with realistic morphologies were used including adults of 5th, 25th, 50th, 75th and 95th percentile weight, children of 5th, 50th and 95th percentile weight, and the developing fetus of 15, 25, and 38 weeks after conception. Additional sensitivity studies were performed to evaluate effects of passenger positioning within the scanner, energy spectrum and beam geometry, as well as failure mode analyses. Results for routine operations yielded a maximum effective dose to the adult and pediatric passengers of 15 and 25 nSv per screen, respectively. The developing fetus received a maximum organ dose and whole body dose of 16 nGy and 8.5 nGy per screen, respectively. The sensitivity analyses indicated that variations in positioning, energy spectra, and beam geometry yielded a range of effective doses per screen that were an order of magnitude below the ANSI recommendation.