Impact of Oral Cavity Dosimetry on Patient Reported Xerostomia and Dysgeusia in the Setting of Deintensified Chemoradiotherapy.

Purpose: To determine the relationship between mean oral cavity (OC) dose (treated as a singular organ at risk) to patient reported xerostomia and dysgeusia. In addition, we will examine the relationship between oral cavity substructure doses to patient reported xerostomia and dysgeusia. All patients were treated in the setting of deintensification (60 Gy). Methods and Materials: In the study, 184 and 177 prospectively enrolled patients for de-escalated chemoradiotherapy (CRT) for human papillomavirus (HPV)-positive oropharyngeal cancer submitted PROs at 6 and 12 months, respectively using Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events questionnaire. Patient's OC consisting of the following substructures were segmented: oral tongue, base of tongue, floor of mouth, hard and soft palate, cheek mucosa, and upper and lower lip mucosa. Ordinal logistic regression (no/mild vs moderate vs severe/very severe symptoms) was used to compare organs at risk dosimetry to patient reported xerostomia and dysgeusia at 6 and 12 months. Multivariate ordinal logistic regression models were generated. Results: Mean dose to the contralateral parotid (P = .04), OC (P = .04), and baseline patient reported xerostomia (P = .009) were significantly associated with xerostomia severity at 6 months. Only baseline xerostomia (P = .02) and mean dose to the contralateral submandibular gland (P = .0001) were significantly associated with xerostomia severity at 12 months. The only significant factor related to dysgeusia at either time point was mean dose to the OC at 12 months (P = .009). On examining substructures, the mean dose to the floor of mouth was implicated for the dose relationship to 6-month xerostomia (P = .04), and the oral tongue was found to be implicated for the relationship for 12-month dysgeusia (P = .04). Conclusions: The mean dose to the OC was found to relate to xerostomia symptoms at 6 months post-CRT and dysgeusia symptoms at 12 months post-CRT. The mean dose to the floor of mouth and oral tongue appeared to drive this relationship for xerostomia and dysgeusia symptoms, respectively. This work suggests the floor of mouth and oral tongue should be prioritized during planning over the rest of the OC. The effect of OC dose relative to other salivary structures for xerostomia appeared to depend on time post-CRT.

Prospective assessment of sparing the parotid ducts via MRI sialography for reducing patient reported xerostomia.

PURPOSE: To assess the impact of prospectively sparing the parotid ducts via MRI sialography on patient reported xerostomia for those receiving definitive radiotherapy (RT) for oropharyngeal squamous cell carcinoma. METHODS AND MATERIALS: Thirty-eight patients with oropharynx cancer to be treated with definitive RT underwent pre-treatment MRI sialograms to localize their parotid ducts. The parotid ducts were maximally spared during treatment planning. Patients reported symptoms (PRO-CTCAE and QLQ-H&N35) were collected at 6 and 12 months post-RT and compared to a historical cohort who underwent conventional parotid gland mean dose sparing. Regression models were generated using parotid and submandibular gland doses with and without incorporating the dose to the parotid ducts to determine the impact of parotid duct dose on patient reported xerostomia. RESULTS: At 6 months post-RT, 12/26 (46%) patients reported ≥moderate xerostomia when undergoing parotid ductal sparing compared to 43/61 (70%) in the historical cohort (p = 0.03). At 12 months post-RT, 8/22 (36%) patients reported ≥moderate xerostomia when undergoing parotid ductal sparing compared to 34/68(50%) in the historical cohort (p = 0.08). Using nested logistic regression models, the mean parotid duct dose was found to significantly relate to patient reported xerostomia severity at 6 months post-RT (p = 0.04) and trended towards statistical significance at 12 months post-RT (p = 0.09). At both 6 and 12 months post-RT, the addition of mean parotid duct dose significantly improved model fit (p < 0.05). CONCLUSIONS: MRI sialography guided parotid duct sparing appears to reduce the rates of patient-reported xerostomia. Further, logistic regression analysis found parotid duct dose to be significantly associated with patient reported xerostomia. A significant improvement in model fit was observed when adding mean parotid duct dose compared to models that only contain mean parotid gland dose and mean contralateral submandibular gland dose.

Clinical Use of A Priori Knowledge of Organ-At-Risk Sparing During Radiation Therapy Treatment for Oropharyngeal Cancer: Dosimetric and Patient Reported Outcome Improvements.

PURPOSE: This study aimed to prospectively assess dosimetric and clinical effects of treatment planners having a priori knowledge of the maximum achievable dose sparing for organs at risk (OARs) for patients with oropharynx cancer receiving intensity modulated radiation therapy (RT). METHODS AND MATERIALS: We examined patients with oropharynx cancer who were treated in prospective clinical trials between February 2012 and April 2019 at our institution. A tool generating estimates of maximum achievable dose sparing for OARs (feasibility dose-volume histogram [FDVH]) was used clinically starting July 2016. Patients were divided into 2 cohorts: Before (ie, baseline) and after (ie, FDVH-guided) FDVH. Doses received by various OARs were compared with those estimated to be achievable per FDVH, and that difference was defined as the excess of feasible dose (EFD). Patient-reported outcome (PRO) questionnaires were completed at 3, 6, and 12 months after treatment. The baseline and FDVH-guided cohorts were compared in terms of EFD, plan quality metrics, and post-RT PRO assessments. RESULTS: A total of 139 patients were included in the analysis (60 in the baseline cohort, 79 in the FDVH-guided cohort). The FDVH-guided cohort had lower EFD to the contralateral parotid by 4.1 Gy, the ipsilateral parotid by 10.6 Gy, the larynx by 4.3 Gy, the oral cavity by 1.5 Gy, and the contralateral submandibular gland by 0.4 Gy. Plan quality metrics were similar between the cohorts. Less variation of EFD was seen in the FDVH-guided cohort for the parotid glands and contralateral submandibular gland (P < .05). The average post-RT PROs were better in the FVHD cohort versus baseline (particularly at the 6-month timepoint for dry mouth frequency, sticky saliva, meal enjoyment, severity of pain, and Eating Assessment Tool 10 composite [swallowing]; P < .05). CONCLUSIONS: Use of FDVH was associated with improved and less variable OAR sparing for clinically delivered plans. FDVH-guided patients had improved PROs compared with baseline with a variety of outcomes significantly improved at 6 months after treatment.

Prognostic value of combining a quantitative image feature from positron emission tomography with clinical factors in oligometastatic non-small cell lung cancer.

BACKGROUND AND PURPOSE: Oligometastatic non-small cell lung cancer (NSCLC) is a heterogeneous condition with few known risk stratification factors. A quantitative imaging feature (QIF) on positron emission tomography (PET), gray-level co-occurrence matrix energy, has been linked with outcome of nonmetastatic NSCLC. We hypothesized that GLCM energy would enhance the ability of models comprising standard clinical prognostic factors (CPFs) to stratify oligometastatic patients based on overall survival (OS). MATERIALS AND METHODS: We assessed 79 patients with oligometastatic NSCLC (≤3 metastases) diagnosed in 2007-2015. The primary and largest metastases at diagnosis were delineated on pretreatment scans with GLCM energy extracted using imaging biomarker explorer (IBEX) software. Iterative stepwise elimination feature selection based on the Akaike information criterion identified the optimal model comprising CPFs for predicting OS in a multivariate Cox proportional hazards model. GLCM energy was tested for improving prediction accuracy. RESULTS: Energy was a significant predictor of OS (P = 0.028) in addition to the selected CPFs. The c-indexes for the CPF-only and CPF + Energy models were 0.720 and 0.739. CONCLUSIONS: Incorporating Energy strengthened a CPF model for predicting OS. These findings support further exploration of QIFs, including markers of the primary tumor vs. those of the metastatic sites.

Imaging Radiation-Induced Normal Tissue Injury to Quantify Regional Dose Response.

Noninvasive imaging has and will continue to play a pivotal role in the assessment of radiation-induced normal tissue toxicity. In this review, we will examine key literature regarding the use of anatomic and physiological imaging in relation to radiation-induced normal tissue toxicity. Additionally, this review contains a novel methodology for potentially incorporating dose-response data into treatment planning and normal tissue toxicity modeling.

Assessment of PlanIQ Feasibility DVH for head and neck treatment planning.

INTRODUCTION: Designing a radiation plan that optimally delivers both target coverage and normal tissue sparing is challenging. There are limited tools to determine what is dosimetrically achievable and frequently the experience of the planner/physician is relied upon to make these determinations. PlanIQ software provides a tool that uses target and organ at risk (OAR) geometry to indicate the difficulty of achieving different points for organ dose-volume histograms (DVH). We hypothesized that PlanIQ Feasibility DVH may aid planners in reducing dose to OARs. METHODS AND MATERIALS: Clinically delivered head and neck treatments (clinical plan) were re-planned (re-plan) putting high emphasis on maximally sparing the contralateral parotid gland, contralateral submandibular gland, and larynx while maintaining routine clinical dosimetric objectives. The planner was blinded to the results of the clinically delivered plan as well as the Feasibility DVHs from PlanIQ. The re-plan treatments were designed using 3-arc VMAT in Raystation (RaySearch Laboratories, Sweden). The planner was then given the results from the PlanIQ Feasibility DVH analysis and developed an additional plan incorporating this information using 4-arc VMAT (IQ plan). The DVHs across the three treatment plans were compared with what was deemed "impossible" by PlanIQ's Feasibility DVH (Impossible DVH). The impossible DVH (red) is defined as the DVH generated using the minimal dose that any voxel outside the targets must receive given 100% target coverage. RESULTS: The re-plans performed blinded to PlanIQ Feasibilty DVH achieved superior sparing of aforementioned OARs compared to the clinically delivered plans and resulted in discrepancies from the impossible DVHs by an average of 200-700 cGy. Using the PlanIQ Feasibility DVH led to additionalOAR sparing compared to both the re-plans and clinical plans and reduced the discrepancies from the impossible DVHs to an average of approximately 100 cGy. The dose reduction from clinical to re-plan and re-plan to IQ plan were significantly different even when taking into account multiple hypothesis testing for both the contralateral parotid and the larynx (P < 0.004 for all comparisons). No significant differences were observed between the three plans for the contralateral parotid when considering multiple hypothesis testing. CONCLUSIONS: Clinical treatment plans and blinded re-plans were found to suboptimally spare OARs. PlanIQ could aid planners in generating treatment plans that push the limits of OAR sparing while maintaining routine clinical target coverage goals.

Estimating the excess lifetime risk of radiation induced secondary malignancy (SMN) in pediatric patients treated with craniospinal irradiation (CSI): Conventional radiation therapy versus helical intensity modulated radiation therapy.

PURPOSE: To quantify the risk of radiation-induced second malignancies (SMN) in pediatric patients receiving craniospinal irradiation (CSI) either with 3-dimensional conformal radiation therapy (Conv CSI) or tomotherapy helical intensity modulated radiation therapy (Tomo CSI). METHODS AND MATERIALS: A novel predictive model that accounts for short- and long-term carcinogenesis was incorporated into our institutional treatment planning system to quantify the lifetime risk of SMN in incidentally irradiated organs. Five pediatric patients previously treated with CSI were studied. For each case, Conv CSI and Tomo CSI plans were computed. The excess absolute number of SMN was computed for each plan for each patient. For female patients, age was varied to assess its impact. RESULTS: Tomo CSI has a much higher risk than Conv CSI for breast cancer. Tomo has a slightly increased risk for the lung, and conventional has a slightly higher risk for the thyroid. Both techniques have intermediate risks to the pancreas and stomach, and lesser risks to the bladder and rectum. For the breast, the magnitude of the absolute risks varied with age: 14.2% versus 7.4% (Tomo vs Conv) age 5; 16.9% versus 7.6% age 10, and 18.6% versus 8.0% age 15. CONCLUSIONS: Tomo has a higher risk for inducing breast and lung second cancers, and when using Tomo-based intensity modulated radiation therapy, care should be taken to avoid incidental radiation to the breast. When planning CSI, one needs to balance these cancer risks against other normal tissue effects.

The value of 18F-FDG PET before and after induction chemotherapy for the early prediction of a poor pathologic response to subsequent preoperative chemoradiotherapy in oesophageal adenocarcinoma.

PURPOSE: The purpose of our study was to determine the value of 18F-FDG PET before and after induction chemotherapy in patients with oesophageal adenocarcinoma for the early prediction of a poor pathologic response to subsequent preoperative chemoradiotherapy (CRT). METHODS: In 70 consecutive patients receiving a three-step treatment strategy of induction chemotherapy and preoperative chemoradiotherapy for oesophageal adenocarcinoma, 18F-FDG PET scans were performed before and after induction chemotherapy (before preoperative CRT). SUVmax, SUVmean, metabolic tumour volume (MTV), and total lesion glycolysis (TLG) were determined at these two time points. The predictive potential of (the change in) these parameters for a poor pathologic response, progression-free survival (PFS) and overall survival (OS) was assessed. RESULTS: A poor pathologic response after induction chemotherapy and preoperative CRT was found in 27 patients (39 %). Patients with a poor pathologic response experienced less of a reduction in TLG after induction chemotherapy (p < 0.01). The change in TLG was predictive for a poor pathologic response at a threshold of -26 % (sensitivity 67 %, specificity 84 %, accuracy 77 %, PPV 72 %, NPV 80 %), yielding an area-under-the-curve of 0.74 in ROC analysis. Also, patients with a decrease in TLG lower than 26 % had a significantly worse PFS (p = 0.02), but not OS (p = 0.18). CONCLUSIONS: 18F-FDG PET appears useful to predict a poor pathologic response as well as PFS early after induction chemotherapy in patients with oesophageal adenocarcinoma undergoing a three-step treatment strategy. As such, the early 18F-FDG PET response after induction chemotherapy could aid in individualizing treatment by modification or withdrawal of subsequent preoperative CRT in poor responders.

Potential Use of (18)F-fluorodeoxyglucose Positron Emission Tomography-Based Quantitative Imaging Features for Guiding Dose Escalation in Stage III Non-Small Cell Lung Cancer.

PURPOSE: To determine whether previously identified quantitative image features (QIFs) based on (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) (co-occurrence matrix energy and solidity) are able to isolate subgroups of patients who would receive a benefit or detriment from dose escalation in terms of overall survival (OS) or progression-free survival (PFS). METHODS AND MATERIALS: Subgroups of a previously analyzed 225 patient cohort were generated with the use of 5-percentile increment cutoff values of disease solidity and primary tumor co-occurrence matrix energy. The subgroups were analyzed with a log-rank test to determine whether there was a difference in OS and PFS between patients treated with 60 to 70 Gy and those receiving 74 Gy. RESULTS: In the entire patient cohort, there was no statistical difference in terms of OS or PFS between patients receiving 74 Gy and those receiving 60 to 70 Gy. It was qualitatively observed that as disease solidity and primary co-occurrence matrix energy increased, patients receiving 74 Gy had an improved OS and PFS compared with those receiving 60 to 70 Gy. The opposite trend (detriment of receiving 74 Gy) was also observed regarding low values of disease solidity and primary co-occurrence matrix energy. CONCLUSIONS: FDG-PET-based QIFs were found to be capable of isolating subgroups of patients who received a benefit or detriment from dose escalation.

The Incremental Value of Subjective and Quantitative Assessment of 18F-FDG PET for the Prediction of Pathologic Complete Response to Preoperative Chemoradiotherapy in Esophageal Cancer.

UNLABELLED: A reliable prediction of a pathologic complete response (pathCR) to chemoradiotherapy before surgery for esophageal cancer would enable investigators to study the feasibility and outcome of an organ-preserving strategy after chemoradiotherapy. So far no clinical parameters or diagnostic studies are able to accurately predict which patients will achieve a pathCR. The aim of this study was to determine whether subjective and quantitative assessment of baseline and postchemoradiation (18)F-FDG PET can improve the accuracy of predicting pathCR to preoperative chemoradiotherapy in esophageal cancer beyond clinical predictors. METHODS: This retrospective study was approved by the institutional review board, and the need for written informed consent was waived. Clinical parameters along with subjective and quantitative parameters from baseline and postchemoradiation (18)F-FDG PET were derived from 217 esophageal adenocarcinoma patients who underwent chemoradiotherapy followed by surgery. The associations between these parameters and pathCR were studied in univariable and multivariable logistic regression analysis. Four prediction models were constructed and internally validated using bootstrapping to study the incremental predictive values of subjective assessment of (18)F-FDG PET, conventional quantitative metabolic features, and comprehensive (18)F-FDG PET texture/geometry features, respectively. The clinical benefit of (18)F-FDG PET was determined using decision-curve analysis. RESULTS: A pathCR was found in 59 (27%) patients. A clinical prediction model (corrected c-index, 0.67) was improved by adding (18)F-FDG PET-based subjective assessment of response (corrected c-index, 0.72). This latter model was slightly improved by the addition of 1 conventional quantitative metabolic feature only (i.e., postchemoradiation total lesion glycolysis; corrected c-index, 0.73), and even more by subsequently adding 4 comprehensive (18)F-FDG PET texture/geometry features (corrected c-index, 0.77). However, at a decision threshold of 0.9 or higher, representing a clinically relevant predictive value for pathCR at which one may be willing to omit surgery, there was no clear incremental value. CONCLUSION: Subjective and quantitative assessment of (18)F-FDG PET provides statistical incremental value for predicting pathCR after preoperative chemoradiotherapy in esophageal cancer. However, the discriminatory improvement beyond clinical predictors does not translate into a clinically relevant benefit that could change decision making.

Uncertainty analysis of quantitative imaging features extracted from contrast-enhanced CT in lung tumors.

PURPOSE: To assess the uncertainty of quantitative imaging features extracted from contrast-enhanced computed tomography (CT) scans of lung cancer patients in terms of the dependency on the time after contrast injection and the feature reproducibility between scans. METHODS: Eight patients underwent contrast-enhanced CT scans of lung tumors on two sessions 2-7 days apart. Each session included 6 CT scans of the same anatomy taken every 15s, starting 50s after contrast injection. Image features based on intensity histogram, co-occurrence matrix, neighborhood gray-tone difference matrix, run-length matrix, and geometric shape were extracted from the tumor for each scan. Spearman's correlation was used to examine the dependency of features on the time after contrast injection, with values over 0.50 considered time-dependent. Concordance correlation coefficients were calculated to examine the reproducibility of each feature between times of scans after contrast injection and between scanning sessions, with values greater than 0.90 considered reproducible. RESULTS: The features were found to have little dependency on the time between the contrast injection and the CT scan. Most features were reproducible between times of scans after contrast injection and between scanning sessions. Some features were more reproducible when they were extracted from a CT scan performed at a longer time after contrast injection. CONCLUSION: The quantitative imaging features tested here are mostly reproducible and show little dependency on the time after contrast injection.

Stage III Non-Small Cell Lung Cancer: Prognostic Value of FDG PET Quantitative Imaging Features Combined with Clinical Prognostic Factors.

PURPOSE: To determine whether quantitative imaging features from pretreatment positron emission tomography (PET) can enhance patient overall survival risk stratification beyond what can be achieved with conventional prognostic factors in patients with stage III non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: The institutional review board approved this retrospective chart review study and waived the requirement to obtain informed consent. The authors retrospectively identified 195 patients with stage III NSCLC treated definitively with radiation therapy between January 2008 and January 2013. All patients underwent pretreatment PET/computed tomography before treatment. Conventional PET metrics, along with histogram, shape and volume, and co-occurrence matrix features, were extracted. Linear predictors of overall survival were developed from leave-one-out cross-validation. Predictive Kaplan-Meier curves were used to compare the linear predictors with both quantitative imaging features and conventional prognostic factors to those generated with conventional prognostic factors alone. The Harrell concordance index was used to quantify the discriminatory power of the linear predictors for survival differences of at least 0, 6, 12, 18, and 24 months. Models were generated with features present in more than 50% of the cross-validation folds. RESULTS: Linear predictors of overall survival generated with both quantitative imaging features and conventional prognostic factors demonstrated improved risk stratification compared with those generated with conventional prognostic factors alone in terms of log-rank statistic (P = .18 vs P = .0001, respectively) and concordance index (0.62 vs 0.58, respectively). The use of quantitative imaging features selected during cross-validation improved the model using conventional prognostic factors alone (P = .007). Disease solidity and primary tumor energy from the co-occurrence matrix were found to be selected in all folds of cross-validation. CONCLUSION: Pretreatment PET features were associated with overall survival when adjusting for conventional prognostic factors in patients with stage III NSCLC.

The emerging field of radiomics in esophageal cancer: current evidence and future potential.

'Radiomics' is the name given to the emerging field of extracting additional information from standard medical images using advanced feature analysis. This innovative form of quantitative image analysis appears to have future potential for clinical practice in patients with esophageal cancer by providing an additional layer of information to the standard imaging assessment. There is a growing body of evidence suggesting that radiomics may provide incremental value for staging, predicting treatment response, and predicting survival in esophageal cancer, for which the current work-up has substantial limitations. This review outlines the available evidence and future potential for the application of radiomics in the management of patients with esophageal cancer. In addition, an overview of the current evidence on the importance of reproducibility of image features and the substantial influence of varying smoothing scales, quantization levels, and segmentation methods is provided.

IBEX: an open infrastructure software platform to facilitate collaborative work in radiomics.

PURPOSE: Radiomics, which is the high-throughput extraction and analysis of quantitative image features, has been shown to have considerable potential to quantify the tumor phenotype. However, at present, a lack of software infrastructure has impeded the development of radiomics and its applications. Therefore, the authors developed the imaging biomarker explorer (IBEX), an open infrastructure software platform that flexibly supports common radiomics workflow tasks such as multimodality image data import and review, development of feature extraction algorithms, model validation, and consistent data sharing among multiple institutions. METHODS: The IBEX software package was developed using the MATLAB and c/c++ programming languages. The software architecture deploys the modern model-view-controller, unit testing, and function handle programming concepts to isolate each quantitative imaging analysis task, to validate if their relevant data and algorithms are fit for use, and to plug in new modules. On one hand, IBEX is self-contained and ready to use: it has implemented common data importers, common image filters, and common feature extraction algorithms. On the other hand, IBEX provides an integrated development environment on top of MATLAB and c/c++, so users are not limited to its built-in functions. In the IBEX developer studio, users can plug in, debug, and test new algorithms, extending IBEX's functionality. IBEX also supports quality assurance for data and feature algorithms: image data, regions of interest, and feature algorithm-related data can be reviewed, validated, and/or modified. More importantly, two key elements in collaborative workflows, the consistency of data sharing and the reproducibility of calculation result, are embedded in the IBEX workflow: image data, feature algorithms, and model validation including newly developed ones from different users can be easily and consistently shared so that results can be more easily reproduced between institutions. RESULTS: Researchers with a variety of technical skill levels, including radiation oncologists, physicists, and computer scientists, have found the IBEX software to be intuitive, powerful, and easy to use. IBEX can be run at any computer with the windows operating system and 1GB RAM. The authors fully validated the implementation of all importers, preprocessing algorithms, and feature extraction algorithms. Windows version 1.0 beta of stand-alone IBEX and IBEX's source code can be downloaded. CONCLUSIONS: The authors successfully implemented IBEX, an open infrastructure software platform that streamlines common radiomics workflow tasks. Its transparency, flexibility, and portability can greatly accelerate the pace of radiomics research and pave the way toward successful clinical translation.

Prognostic value and reproducibility of pretreatment CT texture features in stage III non-small cell lung cancer.

PURPOSE: To determine whether pretreatment CT texture features can improve patient risk stratification beyond conventional prognostic factors (CPFs) in stage III non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: We retrospectively reviewed 91 cases with stage III NSCLC treated with definitive chemoradiation therapy. All patients underwent pretreatment diagnostic contrast enhanced computed tomography (CE-CT) followed by 4-dimensional CT (4D-CT) for treatment simulation. We used the average-CT and expiratory (T50-CT) images from the 4D-CT along with the CE-CT for texture extraction. Histogram, gradient, co-occurrence, gray tone difference, and filtration-based techniques were used for texture feature extraction. Penalized Cox regression implementing cross-validation was used for covariate selection and modeling. Models incorporating texture features from the 33 image types and CPFs were compared to those with models incorporating CPFs alone for overall survival (OS), local-regional control (LRC), and freedom from distant metastases (FFDM). Predictive Kaplan-Meier curves were generated using leave-one-out cross-validation. Patients were stratified based on whether their predicted outcome was above or below the median. Reproducibility of texture features was evaluated using test-retest scans from independent patients and quantified using concordance correlation coefficients (CCC). We compared models incorporating the reproducibility seen on test-retest scans to our original models and determined the classification reproducibility. RESULTS: Models incorporating both texture features and CPFs demonstrated a significant improvement in risk stratification compared to models using CPFs alone for OS (P=.046), LRC (P=.01), and FFDM (P=.005). The average CCCs were 0.89, 0.91, and 0.67 for texture features extracted from the average-CT, T50-CT, and CE-CT, respectively. Incorporating reproducibility within our models yielded 80.4% (±3.7% SD), 78.3% (±4.0% SD), and 78.8% (±3.9% SD) classification reproducibility in terms of OS, LRC, and FFDM, respectively. CONCLUSIONS: Pretreatment tumor texture may provide prognostic information beyond that obtained from CPFs. Models incorporating feature reproducibility achieved classification rates of ∼80%. External validation would be required to establish texture as a prognostic factor.

Clinical significance of indeterminate pulmonary nodules in patients with locally advanced head and neck squamous cell carcinoma.

BACKGROUND: The purpose of this study was to determine whether indeterminate pulmonary nodules (IPNs) at staging are predictive of lung metastasis, primary lung carcinoma, or survival in patients with advanced head and neck squamous cell carcinoma (HNSCC). METHODS: One hundred ten patients with IPN at staging who had follow-up imaging and 100 patients without IPN were identified from an HNSCC database. The primary endpoints were lung progression-free survival (PFS) and overall survival (OS). RESULTS: Two-year lung PFS for the IPN and No-IPN cohorts were 66% versus 61% (p = .92) and the OS for these cohorts were 71% versus 68% (p = .77). Within the IPN cohort, level IV/V lymph node involvement (odds ratio = 4.34; p = .03), hypopharynx primary (odds ratio = 21.5; p = .005), and race (odds ratio = 9.29; p = .001) were independent predictors of developing lung malignancy. CONCLUSION: IPNs at staging in patients with HNSCC do not affect prognosis and should neither influence initial treatment planning nor the frequency of posttreatment surveillance.

Costs of care in a matched pair comparison of intensity-modulated radiation therapy (IMRT) versus conventional radiation therapy (CRT) for the treatment of head and neck cancer.

OBJECTIVES: Intensity-modulated radiation therapy (IMRT) has been rapidly adopted for the treatment of head and neck cancer. Limited comparative effectiveness data suggest that IMRT reduces the incidence of xerostomia and improves quality of life. We assess the cost of IMRT versus the older conventional radiation therapy (CRT) relative to other potential drivers of cost in patients with head and neck cancer. METHODS: We compared patients treated with definitive radiation with or without chemotherapy for squamous cell carcinoma of the head and neck treated between 2000 and 2009. IMRT-treated patients were matched to CRT-treated patients by site, stage, and smoking status. Itemized billing charges were obtained for each patient and used to estimate cost using the Medicare fee schedule. Multivariate analysis was used to assess the influence of demographic, clinical, and treatment variables on total, pretreatment, during treatment, and follow-up costs. RESULTS: Models indicate that compared with CRT, IMRT was associated with, on average, a $5881 increase in total costs (P=0.043), a $1700 decrease in pretreatment costs (P=0.014), a $4768 increase in costs during treatment (P=0.004), and no significant difference in follow-up costs. Positron emission tomography scans, cancer recurrence, and comorbidity were also associated with higher total costs in this sample. CONCLUSIONS: Use of IMRT relative to CRT was strongly correlated with higher total costs, but disease control, patient comorbidity, and use of positron emission tomography also had significant effects on overall costs. Cost-effectiveness models should be developed to assess whether the potential benefits of IMRT are worth the associated investment.

Dosimetric evaluation of an ipsilateral intensity modulated radiotherapy beam arrangement for parotid malignancies.

BACKGROUND: We conducted a dosimetric comparison of an ipsilateral beam arrangement for intensity modulated radiotherapy (IMRT) with off-axis beams. PATIENTS AND METHODS: Six patients who received post-operative radiotherapy (RT) for parotid malignancies were used in this dosimetric study. Four treatment plans were created for each CT data set (24 plans): 1) ipsilateral 4-field off-axis IMRT (4fld-OA), 2) conventional wedge pair (WP), 3) 7 field co-planar IMRT (7fld), and 4) ipsilateral co-planar 4-field quartet IMRT (4fld-CP). Dose, volume statistics for the planning target volumes (PTVs) and planning risk volumes (PRVs) were compared for the four treatment techniques. RESULTS: Wedge pair plans inadequately covered the deep aspect of the PTV. The 7-field IMRT plans delivered the largest low dose volumes to normal tissues. Mean dose to the contralateral parotid was highest for 7 field IMRT. Mean dose to the contralateral submandibular gland was highest for 7 field IMRT and WP. 7 field IMRT plans had the highest dose to the oral cavity. The mean doses to the brainstem, spinal cord, ipsilateral temporal lobe, cerrebellum and ipsilateral cochlea were similar among the four techniques. CONCLUSIONS: For postoperative treatment of the parotid bed, 4-field ipsilateral IMRT techniques provided excellent coverage while maximally sparing the contralateral parotid gland and submandibular gland.

Patterns of local failure for sinonasal malignancies.

PURPOSE: To identify the patterns of local failure for sinonasal malignancies treated with radiation therapy (RT). METHODS AND MATERIALS: We retrospectively identified 79 patients with sinonasal malignancies treated between 2000 and 2011. The median follow-up was 34 months (7-137). Fifty patients (63%) had surgery and RT with or without chemotherapy, and 29 (37%) received definitive chemoradiation therapy. Twenty-six of 79 patients (33%) failed locally; 11 had persistent disease and 15 had local recurrence (LR). The patients with LR had at least a 3-month disease-free interval posttreatment. Imaging of the 15 LR was registered to the treatment planning computed tomography. Failures were categorized as in-field, marginal, or out-of-field if >95%, 20%-95%, or <20% of the LR was within the 95% prescription isodose line, respectively. RESULTS: Of the 15 patients with LR, 7 were in-field, 2 were marginal, and 6 were out-of-field. For 3 patients, treatment plans were not retrievable; however, it was apparent from clinical records that 2 had in-field LR and 1 had an out-of-field LR (untreated contralateral maxillary sinus). No patient with a marginal or out-of-field recurrence had more than 39% of their recurrent tumor volume within 95% of the prescribed dose. Coverage of the LR by 54 Gy and 45 Gy was suboptimal in 7/7 and 5/7 patients with LR, respectively. Marginal and out-of-field LR were predominantly above the pretreatment tumor location and at the level of or superior to the eyes. CONCLUSIONS: Sinonasal malignancies failed marginally or out-of-field in 53% (8/15) of LR and 31% (8/26) of all local failures. The anatomic location of these marginal and out-of field LR are predominately at, or superior to, the level of the eyes. This pattern of failure may be directly related to efforts to minimize RT to the optic structures and the degree of difficulty of skull base operations.

Assessing the impact of radiation-induced changes in soft tissue density ∕ thickness on the study of radiation-induced perfusion changes in the lung and heart.

PURPOSE: Abnormalities in single photon emission computed tomography (SPECT) perfusion within the lung and heart are often detected following radiation for tumors in∕around the thorax (e.g., lung cancer or left-sided breast cancer). The presence of SPECT perfusion defects is determined by comparing pre- and post-RT SPECT images. However, RT may increase the density of the soft tissue surrounding the lung∕heart (e.g., chest wall∕breast) that could possibly lead to an "apparent" SPECT perfusion defect due to increased attenuation of emitted photons. Further, increases in tissue effective depth will also increase SPECT photon attenuation and may lead to "apparent" SPECT perfusion defects. The authors herein quantitatively assess the degree of density changes and effective depth in soft tissues following radiation in a series of patients on a prospective clinical study. METHODS: Patients receiving thoracic RT were enrolled on a prospective clinical study including pre- and post-RT thoracic computed tomography (CT) scans. Using image registration, changes in tissue density and effective depth within the soft tissues were quantified (as absolute change in average CT Hounsfield units, HU, or tissue thickness, cm). Changes in HU and tissue effective depth were considered as a continuous variable. The potential impact of these tissue changes on SPECT images was estimated using simulation data from a female SPECT thorax phantom with varying tissue densities. RESULTS: Pre- and serial post-RT CT images were quantitatively studied in 23 patients (4 breast cancer, 19 lung cancer). Data were generated from soft tissue regions receiving doses of 20-50 Gy. The average increase in density of the chest was 5 HU (range 46 to -69). The average change in breast density was a decrease of -1 HU (range 13 to -13). There was no apparent dose response in neither the dichotomous nor the continuous analysis. Seventy seven soft tissue contours were created for 19 lung cancer patients. The average change in tissue effective depth was +0.2 cm (range -1.9 to 2.2 cm). The changes in HU represent a <2% average change in tissue density. Based on simulation, the small degree of density and tissue effective depth change is unlikely to yield meaningful changes in either SPECT lung or heart perfusion. CONCLUSIONS: RT doses of 20-50 Gy can cause up to a 46 HU increase in soft tissue density 6 months post-RT. Post-RT soft tissue effective depth may increase by 2.0 cm. These modest increases in soft tissue density and effective depth are unlikely to be responsible for the perfusion changes seen on post-RT SPECT lung or heart scans. Further, there was no clear dose response of the soft tissue density changes. Ultimately, the authors findings suggest that prior perfusion reports do reflect changes in the physiology of the lungs and heart.