Association Between Physician- and Patient-Reported Symptoms in Patients Treated With Definitive Radiation Therapy for Locally Advanced Lung Cancer in a Statewide Consortium.

PURPOSE: Little data have been reported about the patient experience during curative radiation therapy (RT) for lung cancer in routine clinical practice or how this relates to treatment toxicity as reported by clinicians. The purpose of this study was to compare clinician-reported adverse events (AEs) with patient-reported outcomes (PROs), including both specific symptoms/side effects, as well as overall quality of life (QoL) during and after definitive RT for locally advanced lung cancer (LALC) in a large statewide cohort. METHODS AND MATERIALS: PROs were prospectively collected from patients treated with definitive RT for LALC at 24 institutions within the Michigan Radiation Oncology Quality Consortium between 2012 and 2018 using the Functional Assessment of Cancer Therapy trial outcome index. Physicians prospectively recorded AEs using the Common Terminology Criteria for Adverse Events, version 4.0. Patient-reported QoL changes from baseline were assessed during and after RT using the Functional Assessment of Cancer Therapy trial outcome index. Spearman correlation coefficients were calculated for AEs and similar PROs, and a multivariable analysis was used to assess associations with QoL. RESULTS: A total 1361 patients were included in the study, and 53% of respondents reported clinically meaningful declines in QoL at the end of RT. The correlation between clinician-reported esophagitis and patient-reported trouble swallowing was moderate (R = .67), but correlations between clinician-reported pneumonitis and patient-reported shortness of breath (R = .13) and cough (R = .09) were weak. Clinician-reported AEs were significantly associated with clinically meaningful declines in patient-reported QoL (R = - .46 for summary AE score). QoL was more strongly associated with fatigue (R = - .41) than lung-specific AEs. CONCLUSIONS: AEs are associated with clinically meaningful declines in QoL during and after RT for LALC, but associations between AEs and QoL are only modest. This highlights the importance of PRO data, and future research should assess whether earlier detection of PRO changes could allow for interventions that reduce the frequency of treatment-related clinically meaningful declines in QoL.

Use and Outcomes of SBRT for Early Stage NSCLC Without Pathologic Confirmation in the Veterans Health Care Administration.

PURPOSE: Stereotactic body radiation therapy (SBRT) use has increased among patients without pathologic confirmation (PC) of lung cancer. Empirical SBRT without PC raises concerns about variation in workup and patient selection, but national trends have not been well described. In this study, we assessed patterns of empirical SBRT use, workup, and causes of death among a large national non-small cell lung cancer (NSCLC) cohort. METHODS AND MATERIALS: We identified 2221 patients treated with SBRT for cT1-T2aN0M0 NSCLC in the Veterans Affairs health care system from 2008 to 2015. We reviewed their pretreatment workup and assessed associations between absence of PC and clinical and demographic factors. We compared causes of death between PC and non-PC groups and used Cox proportional hazards modeling to compare overall survival and lung cancer specific survival (LCSS) between these groups. RESULTS: Treatment without PC varied from 0% to 61% among Veterans Affairs medical centers, with at least 5 cases of stage I NSCLC. Overall, 14.9% of patients were treated without PC and 8.8% did not have a biopsy attempt. Ten percent of facilities were responsible for almost two-thirds (62%) of cases of treatment without PC. Of non-PC patients, 95.5% had positron emission tomography scans, 40.6% had biopsy procedures attempted, and 12.7% underwent endobronchial ultrasound. Non-PC patients were more likely to have cT1 tumors and live outside the histoplasmosis belt. Age, sex, smoking status, and Charlson comorbidity index were similar between groups. Lung cancer was the most common cause of death in both groups. Overall survival was similar between groups, whereas non-PC patients had better LCSS (hazard ratio = 0.77, P = .031). CONCLUSIONS: Empirical SBRT use varied widely among institutions and appropriate radiographic workup was consistently used in this national cohort. Future studies should investigate determinants of variation and reasons for higher LCSS among non-PC patients.

CT and FDG-PET radiologic biomarkers in p16+ oropharyngeal squamous cell carcinoma patients treated with definitive chemoradiotherapy.

PURPOSE: To assess associations between imaging biomarkers from standard of care pre-treatment CT and FDG-PET scans and locoregional (LR) and distant metastatic (DM) recurrences in patients with p16+ oropharyngeal squamous cell carcinoma (OPSCC) treated with definitive chemoradiotherapy (CRT). METHODS: An institutional database from a single NCI-designated cancer center identified 266 patients with p16+ OPSCC treated with definitive CRT in our department from 2005 to 2016 with evaluable pre-treatment FDG-PET scans. Quantitative SUV metrics and qualitative imaging metrics were determined from FDG-PET and CT scans, while clinical characteristics were abstracted from the medical record. Associations between clinical/imaging features and time to LR (TTLRF) or DM (TTDMF) failure and overall survival (OS) were assessed using univariable Cox regression and penalized stepwise regression for multivariable analyses (MVA). RESULTS: There were 27 LR and 32 DM recurrences as incident failures. Imaging biomarkers were significantly associated with TTLRF, TTDMF and OS. FDG-PET metrics outperformed CT and clinical metrics for TTLRF, with metabolic tumor volume being the only significant feature selected on MVA: C-index = 0.68 (p = 0.01). Radiographic extranodal extension (rENE), positive retropharyngeal nodes (RPN+), and clinical stage were significant on MVA for TTDMF: C-index = 0.84 (p < 0.001). rENE, group stage, and RPN+ were significant on MVA for OS: C-index = 0.77 (p < 0.001). CONCLUSIONS: In the largest study to date of uniformly treated patients with CRT to evaluate both pretreatment CT and FDG-PET, radiographic biomarkers were significantly associated with TTLRF, TTDMF and OS among patients with p16+ OPSCC treated with CRT. CT metrics performed best to predict TTDMF, while FDG-PET metrics showed improved prediction for LRRFS. These metrics may help identify candidates for treatment intensification or de-escalation of therapy. STATEMENT OF TRANSLATIONAL RELEVANCE: Pre-treatment imaging features from standard-of-care PET/CT imaging show promise for predicting long-term outcomes following HPV-associated oropharynx cancer (HPV-OPC) therapy. This study comprehensively characterizes qualitative and quantitative pre-treatment imaging metrics associated with time to pattern-specific failure in a cohort of 266 patients treated uniformly with definitive chemoradiation. Multivariate analysis (MVA) for time to locoregional failure (TTLRF), time to distant metastatic failure (TTDMF), and overall survival (OS) was performed. FDG-PET metrics outperformed CT and clinical metrics for TTLRF. CT radiographic extranodal extension, positive retropharyngeal nodes, and stage strongly predicted TTDMF (combined C-index = 0.84, log rank p < 0.001). Number of smoking pack-years complemented clinical and imaging features only in patients without radiographic extranodal extension or positive retropharyngeal nodes. Time to pattern-specific failure is important for guiding treatment de-escalation strategies, which intend to reduce treatment-related toxicity in patients with relatively long expected survival times. This study suggests that PET/CT features should play a crucial role in future de-escalation trials and management of HPV-OPC patients.

Early MRI Blood Volume Changes in Constrictor Muscles Correlate With Postradiation Dysphagia.

PURPOSE: Predicting individual patient sensitivity to radiation therapy (RT) for tumor control or normal tissue toxicity is necessary to individualize treatment planning. In head and neck cancer, radiation doses are limited by many nearby critical structures, including structures involved in swallowing. Previous efforts showed that imaging parameters correlate with RT dose; here, we investigate the role of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) blood volume (BV) changes in predicting dysphagia. METHODS AND MATERIALS: This study included 32 patients with locally advanced oropharyngeal squamous cell carcinoma treated with definitive chemoradiation on an institutional protocol incorporating baseline and early midtreatment DCE-MRI. BV maps of the pharyngeal constrictor muscles (PCM) were created, and BV increases midtreatment were correlated with the following parameters at 3 and 12 months post-RT: RT dose, Dynamic Imaging Grade of Swallowing Toxicity swallow score, aspiration frequency, European Organisation for Research and Treatment of Cancer HN35 patient-reported outcomes, physician-reported dysphagia, and feeding tube (FT) dependence. RESULTS: The mean BV to the PCMs increased from baseline to fraction 10, which was significant for the superior PCM (P = .006) and middle PCM (P < .001), with a trend in the inferior PCM where lower mean doses were seen (P = .077). The factors associated with FT dependence at 3 months included BV increases in the total PCM (correlation, 0.48; P = .006) and middle PCM (correlation, 0.50; P = .004). A post-RT increase in aspiration was associated with a BV increase in the superior PCM (correlation, 0.44; P = .013),and the increase in the total PCMs was marginally significant (correlation, 0.34; P = .06). The best-performing models of FT dependence (area under the receiver operating curve [AUC] = 0.84) and aspiration increases (AUC = 0.78) included BV increases as well as a mean RT dose to middle PCM. CONCLUSIONS: Our results suggest that midtreatment BV increases derived from DCE-MRI are an early predictor of dysphagia. Further investigation of these promising imaging markers to assess individual patient sensitivity to treatment and the patient's subsequent risk of toxicities is warranted to improve personalization of RT planning.

Characterization of very late dysphagia after chemoradiation for oropharyngeal squamous cell carcinoma.

OBJECTIVES: Improved prognosis for p16+ oropharyngeal squamous cell carcinoma (OPSCC) has led to efforts to mitigate long-term complications of treatment, which remains poorly defined in late survivors. Here we characterize very late dysphagia in OPSCC. MATERIALS AND METHODS: Long-term review of 93 p16+ OPSCC patients treated with chemoradiation was performed. We scored videofluoroscopic swallow studies (VFSS) according to the Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) scale. Very late dysphagia was defined >2.5 years from end of treatment. Fine-Gray regression models were used to assess dysphagia with competing risk of death. RESULTS: Median follow up was 10.5 years. 402 total VFSS were assessed (median 4 per patient, range 0-8). 15.1% of patients had a DIGEST score ≥2 very late after treatment. Very late DIGEST score ≥2 correlated with T-stage (HR 1.7, p = 0.049), second cancer (HR 6.5, p = 0.004), superior pharyngeal constrictor dose (HR 1.11, p = 0.050), total tongue dose (HR 1.07, p = 0.045), but not hypoglossal nerve dose (p > 0.2). Seven patients (7.5%) had late progressive dysphagia, defined as DIGEST score that increased by ≥2 beyond one year after treatment, and this correlated with higher ipsilateral hypoglossal nerve D1cc dose (75 vs 72 Gy, p = 0.037). CONCLUSION: In p16+ OPSCC patients treated with definitive chemoradiation, at least 7.5% developed late progressive dysphagia, and 15.1% experienced moderate dysphagia >2.5 years from treatment. Our study suggests that dose to tongue musculature may be associated with very late dysphagia, and hypoglossal nerve dose may be associated with late progressive dysphagia. More intensive long-term dysphagia survivorship monitoring is suggested.

Predicting late radiation-induced xerostomia with parotid gland PET biomarkers and dose metrics.

PURPOSE: To assess associations between parotid gland PET biomarkers and late radiation-induced xerostomia, and to validate improvement of xerostomia predictive models by adding pre-treatment PET features to models based on dose and pre-treatment xerostomia. MATERIALS AND METHODS: Intensity PET features from 47 patients treated on institutional prospective clinical trials for HPV-associated oropharyngeal squamous cell carcinoma with uniform chemoRT were analyzed. Associations between 90th percentile of the parotid gland standardized uptake values (P90) from pre-treatment and post-treatment PET scans, mean parotid gland doses, and late xerostomia defined by the Xerostomia Questionnaire (XQ) and salivary flow rates were quantified. Multivariable analysis was applied for dose and PET features using penalized logistic regression for feature selection and generation of predictive models using the LASSO technique, and optimism bias was estimated by bootstrap resampling. RESULTS: Significant associations between late xerostomia and both mean parotid gland dose and P90 were demonstrated, and were generally stronger for post-treatment PET scans. The addition of P90 from pre-treatment PET scans improved the prediction model for late moderate or severe xerostomia compared to the base model, from AUC = 0.74 to 0.78 (p-value <0.001) for XQ summary score and from 0.77 to 0.84 (p-value <0.001) for the single eating-related XQ item with the largest inter-patient variability; however, only the latter remained significant on cross validation (AUC = 0.69 to 0.70 and 0.73 to 0.80, respectively). CONCLUSIONS: The addition of pre-treatment parotid gland PET biomarkers improved a predictive model for late patient-reported xerostomia over dose and pre-treatment xerostomia.

Big data analysis of associations between patient reported outcomes, observer reported toxicities, and overall quality of life in head and neck cancer patients treated with radiation therapy.

PURPOSE: To assess associations between a variety of patient-reported outcomes (PROs), observer reported toxicities (ORTs), and patient-reported overall quality of life (QOL) for head and neck cancer patients treated with radiotherapy, in order to identify important items for inclusion in prospective patient reporting in the clinic. METHODS: 612 patients completed 27 PRO items from three questionnaires at 1273 follow-up visits, and clinicians provided ORTs according to CTCAE criteria. Using a big data approach, we measured associations among all PROs, between all PROs and ORTs, and between PROs/ORTs and QOL with Pearson (ρ) and Kendall (τ) correlation coefficients, and a novel analysis method based on receiver operating characteristic (ROC) curves used to detect thresholds in response levels demonstrating strong interactions. RESULTS: PROs most strongly associated with QOL were recreation/entertainment, activity, and fatigue, with ρ = 0.51-0.60. Several PROs assessing a common functional outcome (eg. xerostomia) were highly associated with each other (PRO-PRO), with maximum ρ = 0.84. Maximum ORT-PRO correlations were ρ = 0.61 (dysgeusia versus taste), and ρ = 0.5 for ORT-QOL (dry mouth - day). The ROC method identified response thresholds with high area under the curve (AUC) scores for many ORT-PRO associations with maximum AUCavg = 0.78. CONCLUSIONS: PRO associations identified activity, lifestyle and fatigue as items for strong consideration for inclusion in questionnaires in the clinic, and suggest that outcome information can be captured in fewer items than the 27 in this study. The ability of clinicians to assess patient toxicities is highest with more severe toxicities, underscoring the need for PRO collection in patient visits to understand and address patient symptoms.

Use of plan quality degradation to evaluate tradeoffs in delivery efficiency and clinical plan metrics arising from IMRT optimizer and sequencer compromises.

PURPOSE: Plan degradation resulting from compromises made to enhance delivery efficiency is an important consideration for intensity modulated radiation therapy (IMRT) treatment plans. IMRT optimization and/or multileaf collimator (MLC) sequencing schemes can be modified to generate more efficient treatment delivery, but the effect those modifications have on plan quality is often difficult to quantify. In this work, the authors present a method for quantitative assessment of overall plan quality degradation due to tradeoffs between delivery efficiency and treatment plan quality, illustrated using comparisons between plans developed allowing different numbers of intensity levels in IMRT optimization and/or MLC sequencing for static segmental MLC IMRT plans. METHODS: A plan quality degradation method to evaluate delivery efficiency and plan quality tradeoffs was developed and used to assess planning for 14 prostate and 12 head and neck patients treated with static IMRT. Plan quality was evaluated using a physician's predetermined "quality degradation" factors for relevant clinical plan metrics associated with the plan optimization strategy. Delivery efficiency and plan quality were assessed for a range of optimization and sequencing limitations. The "optimal" (baseline) plan for each case was derived using a clinical cost function with an unlimited number of intensity levels. These plans were sequenced with a clinical MLC leaf sequencer which uses >100 segments, assuring delivered intensities to be within 1% of the optimized intensity pattern. Each patient's optimal plan was also sequenced limiting the number of intensity levels (20, 10, and 5), and then separately optimized with these same numbers of intensity levels. Delivery time was measured for all plans, and direct evaluation of the tradeoffs between delivery time and plan degradation was performed. RESULTS: When considering tradeoffs, the optimal number of intensity levels depends on the treatment site and on the stage in the process at which the levels are limited. The cost of improved delivery efficiency, in terms of plan quality degradation, increased as the number of intensity levels in the sequencer or optimizer decreased. The degradation was more substantial for the head and neck cases relative to the prostate cases, particularly when fewer than 20 intensity levels were used. Plan quality degradation was less severe when the number of intensity levels was limited in the optimizer rather than the sequencer. CONCLUSIONS: Analysis of plan quality degradation allows for a quantitative assessment of the compromises in clinical plan quality as delivery efficiency is improved, in order to determine the optimal delivery settings. The technique is based on physician-determined quality degradation factors and can be extended to other clinical situations where investigation of various tradeoffs is warranted.

Temporal radiographic texture analysis in the detection of periprosthetic osteolysis.

Periprosthetic osteolysis is one of the most serious long-term problems in total hip arthroplasty. It has been primarily attributed to the body's inflammatory response to submicron polyethylene particles worn from the hip implant, and it leads to bone loss and structural deterioration in the surrounding bone. It was previously demonstrated that radiographic texture analysis (RTA) has the ability to distinguish between osteolysis and normal cases at the time of clinical detection of the disease; however, that analysis did not take into account the changes in texture over time. The goal of this preliminary analysis, however, is to assess the ability of temporal radiographic texture analysis (tRTA) to distinguish between patients who develop osteolysis and normal cases. Two tRTA methods were used in the study: the RTA feature change from baseline at various follow-up intervals and the slope of the best-fit line to the RTA data series. These tRTA methods included Fourier-based and fractal-based features calculated from digitized images of 202 total hip replacement cases, including 70 that developed osteolysis. Results show that separation between the osteolysis and normal groups increased over time for the feature difference method, as the disease progressed, with area under the curve (AUC) values from receiver operating characteristic analysis of 0.65 to 0.72 at 15 years postsurgery. Separation for the slope method was also evident, with AUC values ranging from 0.65 to 0.76 for the task of distinguishing between osteolysis and normal cases. The results suggest that tRTA methods have the ability to measure changes in trabecular structure, and may be useful in the early detection of periprosthetic osteolysis.

Radiographic texture analysis in the characterization of trabecular patterns in periprosthetic osteolysis.

RATIONALE AND OBJECTIVES: Periprosthetic osteolysis is a disease attributed to the body's reaction to fine polyethylene wear debris shed from total hip replacements. The purpose of this preliminary study was to investigate the ability of radiographic texture analysis (RTA) to characterize the trabecular texture patterns on pelvic images for osteolysis and normal total hip arthroplasty (THA) cases. MATERIALS AND METHODS: Fourier-based and fractal-based texture features were calculated for a database of digitized radiographs from 202 THA cases, 70 of which developed osteolysis. The features were calculated from regions of interest selected at two time points: less than 1 month after surgery, and at the first clinical indication of osteolysis (or randomly selected follow-up time for normal cases). Receiver operating characteristic (ROC) analysis was used to compare feature performance at baseline and follow-up for osteolysis and normal cases. RESULTS: Separation between the RTA features for osteolysis and normal cases was negligible at baseline and increased substantially for the follow-up images. The directional Fourier-based feature provided the best separation with an A(z) value from ROC analysis of 0.75 for the follow-up images, in the task of distinguishing between normal and osteolytic cases. CONCLUSIONS: The results from this preliminary analysis indicate that qualitative changes in trabecular patterns from immediately after surgery to the eventual detection of osteolysis correspond to quantitative changes in RTA features. It therefore appears that RTA provides information that could potentially be useful to aid in the detection of this disease.

Feasibility study for linac-based intensity modulated total marrow irradiation.

Total body irradiation (TBI) is used as a preconditioning regimen prior to bone marrow transplant for treatment of hematologic malignancies. During TBI, large volumes of normal tissue are irradiated, and this can lead to toxicities, most significantly in the lungs. Intensity modulated total marrow irradiation (IMTMI) may be able to reduce these toxicities by directly targeting the bone marrow while minimizing the dose to critical structures. The goal of this study was to assess the feasibility of IMTMI by following the planning and delivery process for a Rando phantom. A three isocenter technique was used to provide a full body plan for treatment on a linear accelerator. Thermoluminescent detectors (TLDs) were placed at 22 positions throughout the phantom to compare the delivered doses to the planned doses. Individual intensity modulated radiation therapy verification plans were delivered to a solid water phantom for the three isocenters, and doses measured from an ion chamber and film were compared to the planned doses. The treatment plan indicated that target coverage was achieved with this IMTMI technique, and that the doses to critical structures were reduced by 29%-65% compared to conventional TBI. TLD readings demonstrated accurate dose delivery, with an average difference of 3.5% from the calculated dose. Ion chamber readings for the verification plans were all within 3% of the expected dose, and film measurements showed accurate dose distributions. Results from this study suggest that IMTMI using the three isocenter technique can be accurately delivered and may result in substantial dose reductions to critical structures.

Investigation of physical image quality indices of a bone densitometry system.

Osteoporosis is a disease characterized by a loss of bone mass and a deterioration of bone structure. Bone mineral density (BMD) measures bone mass and is currently the method used to diagnose osteoporosis, while computerized radiographic texture analysis (RTA) is being investigated as a measure of bone structure. The GE/Lunar PIXI peripheral bone densitometer (PD) system, which uses dual-energy subtraction to measure BMD, also provides a digital image of the heel or forearm. The goal of our current research was to evaluate the physical imaging properties of the PIXI system (pixel size of 0.2 mm) compared to a Fuji computed radiography (CR) system (pixel size of 0.1 mm) to determine its suitability for texture analysis from image data. Contrast was measured using a series of uniform images covering the useful clinical exposure range. Spatial resolution was characterized by the presampling modulation transfer function (MTF) determined by an edge method. Noise power spectra (NPS) for different exposures were calculated using a two-dimensional Fourier analysis method. The expectation modulation transfer function was measured and combined with the NPS data to calculate the noise-equivalent number of quanta. The slope of the characteristic curve of the peripheral densitometer (PD) system was found to be position dependent across the image, although this dependence was substantially reduced by use of the system's clinical-settings corrections. An MTF value of 0.5 was found at 0.5 cycles/mm for the densitometry system compared to the same value at 1.6 cycles/mm for the CR system. Unlike the CR system, the NPS of the densitometry system was found not to be directionally dependent and did not drop off at higher spatial frequencies.

Comparison of radiographic texture analysis from computed radiography and bone densitometry systems.

Osteoporosis is a disease that results in an increased risk of bone fracture due to a loss of bone mass and deterioration of bone structure. Bone mineral density (BMD) provides a measure of bone mass and is frequently measured by bone densitometry systems to diagnose osteoporosis. In addition, computerized radiographic texture analysis (RTA) is currently being investigated as a measure of bone structure and as an additional diagnostic predictor of osteoporosis. In this study, we assessed the ability of a peripheral bone densitometry (PD) system to yield images useful for RTA. The benefit of such a system is that it measures BMD by dual-energy x-ray absorptiometry and therefore provides high- and low-energy digital radiographic images. The bone densitometry system investigated was the GE/Lunar PIXI, which provides 512 x 512 digital images of the heel or forearm (0.2 mm pixels). We compared texture features of heel images obtained with this PD system to those obtained on a Fuji computed radiography (CR) system (0.1 mm pixels). Fourier and fractal-based texture features of images from 24 subjects who had both CR and BMD exams were calculated, and correlation between the two systems was analyzed. Fourier-based texture features characterize the magnitude, frequency content, and orientation of the trabecular bone pattern. Good correlation was found between the two modalities for the first moment (FMP) with r=0.71 (p value<0.0001) and for minimum FMP with r=0.52 (p value=0.008). Root-mean-square (RMS) did not correlate with r=0.31 (p value>0.05), while the standard deviation of the RMS did correlate with r=0.79 (p value<0.0001). Good correlation was also found between the two modalities for the fractal-based texture features with r=0.79 (p value<0.0001) for the global Minkowski dimension and r=0.63 (p value=0.0007) for the fractal dimension from a box counting method. The PD system therefore may have the potential for yielding heel images suitable for RTA.