Zacariah E. Labby

Imaging in pleural mesothelioma

Imaging of malignant pleural mesothelioma (MPM) is essential to the diagnosis, assessment, and monitoring of this disease. The complex morphology and growth pattern of MPM, however, create unique challenges for image acquisition and interpretation. These challenges have captured the attention of investigators around the world, some of whom presented their work at the 2012 International Conference of the International Mesothelioma Interest Group (iMig 2012) in Boston, Massachusetts, USA, September 2012. The measurement of tumor thickness on computed tomography (CT) scans is the current standard of care in the assessment of MPM tumor response to therapy; in this context, variability among observers in the measurement task and in the tumor response classification categories derived from such measurements was reported. Alternate CT-based tumor response criteria, specifically direct measurement of tumor volume change and change in lung volume as a surrogate for tumor response, were presented. Dynamic contrast-enhanced CT has a role in other settings, but investigation into its potential use for imaging mesothelioma tumor perfusion only recently has been initiated. Magnetic resonance imaging (MRI) and positron-emission tomography (PET) are important imaging modalities in MPM and complement the information provided by CT. The pointillism sign in diffusion-weighted MRI was reported as a potential parameter for the classification of pleural lesions as benign or malignant, and PET parameters that measure tumor activity and functional tumor volume were presented as indicators of patient prognosis. Also reported was the use of PET/CT in the management of patients who undergo high-dose radiation therapy. Imaging for MPM impacts everything from initial patient diagnosis to the outcomes of clinical trials; iMig 2012 captured this broad range of imaging applications as investigators exploit technology and implement multidisciplinary approaches toward the benefit of MPM patients.

Disease volumes as a marker for patient response in malignant pleural mesothelioma

BACKGROUND The goal of this study was to create a comprehensive model for malignant pleural mesothelioma patient survival utilizing continuous, time-varying estimates of disease volume from computed tomography (CT) imaging in conjunction with clinical covariates. PATIENTS AND METHODS Serial CT scans were obtained during the course of clinically standard chemotherapy for 81 patients. The pleural disease volume was segmented for each of the 281 CT scans, and relative changes in disease volume from the baseline scan were tracked over the course of serial follow-up imaging. A prognostic model was built using time-varying disease volume measurements in conjunction with clinical covariates. RESULTS Over the course of treatment, disease volume decreased by an average of 19%, and median patient survival was 12.6 months from baseline. In a multivariate survival model, changes in disease volume were significantly associated with patient survival along with disease histology, Eastern Cooperative Oncology Group performance status, and presence of dyspnea. CONCLUSIONS Analysis of the trajectories of disease volumes during chemotherapy for patients with mesothelioma indicates that increasing disease volume was significantly and independently associated with poor patient prognosis in both univariate and multivariate survival models.

Lung Volume Measurements as a Surrogate Marker for Patient Response in Malignant Pleural Mesothelioma

Introduction: The purpose of this study was to investigate the continuous changes in three distinct response assessment methods during treatment as a marker of response for patients with mesothelioma. Linear tumor thickness measurements, disease volume measurements, and lung volume measurements (a physiological correlate of disease volumes) were investigated in this study. Methods: Serial computed tomography scans were obtained during the course of clinically standard chemotherapy for 61 patients. For each of the 216 computed tomography scans, the aerated lung volumes were segmented using a fully automated method, and the pleural disease volume was segmented using a semiautomated method. Modified Response Evaluation Criteria in Solid Tumors linear-thickness measurements were acquired clinically. Diseased (ipsilateral) lung volumes were normalized by the respective contralateral lung volumes to account for the differences in inspiration between scans for each patient. Relative changes in each metric from baseline were tracked over the course of follow-up imaging. Survival modeling was performed using Cox proportional hazards models with time-varying covariates. Results: Median survival from pretreatment baseline imaging was 12.7 months. A negative correlation was observed between measurements of lung volume and disease volume, and a positive correlation was observed between linear-thickness measurements and disease volume. As continuous numerical parameters, all three response assessment methods were significant imaging biomarkers of patient prognosis in independent survival models. Conclusions: Analysis of trajectories of linear-thickness measurements, disease volume measurements, and lung volume measurements during chemotherapy for patients with mesothelioma indicates that increasing linear thickness, increasing disease volume, and decreasing lung volume are all significantly and independently associated with poor patient prognosis.

Optimization of Response Classification Criteria for Patients with Malignant Pleural Mesothelioma

Introduction: Response-assessment metrics play an important role in clinical trials and routine patient management. For patients with malignant pleural mesothelioma (MPM), the standard for response assessment is image-based measurements of tumor thickness made according to the modified RECIST (Response Evaluation Criteria in Solid Tumors) protocol. To classify tumor response, changes in tumor thickness are compared with the standard RECIST −30% and +20% cutoffs for partial response (PR) and progressive disease (PD), respectively, which are not specific to MPM. The purpose of this work is to optimize the correlation between tumor response and patient survival by assessing the validity of existing response criteria in MPM and proposing alternative criteria. Methods: Computed tomography measurements of tumor thickness were acquired at baseline and throughout treatment for 78 patients undergoing standard-of-care chemotherapy. Overall survival was correlated with best response and first follow-up response using Harrell’s C statistic. The response criteria for PD and PR were each varied in 1% increments to obtain optimized classification criteria. The performance was cross-validated using a leave-one-out approach. Results: Median survival was 14.9 months. The performance of the standard RECIST criteria in correlating response with survival was C=0.778, whereas the optimized performance of C=0.855 was obtained with criteria of −64% for PR and +50% for PD. After cross-validation, this performance was slightly reduced to C=0.829. Conclusions: Optimized tumor-response classification criteria were obtained for patients with MPM. These criteria improve the correlation between image-based response and patient survival.

Gadoxetate for direct tumor therapy and tracking with real-time MRI-guided stereotactic body radiation therapy of the liver.

SBRT is increasingly utilized in liver tumor treatment. MRI-guided RT allows for real-time MRI tracking during therapy. Liver tumors are often poorly visualized and most contrast agents are transient. Gadoxetate may allow for sustained tumor visualization. Here, we report on the first use of gadoxetate during real-time MRI-guided SBRT.

Variability of tumor area measurements for response assessment in malignant pleural mesothelioma

PURPOSE The measurement of malignant pleural mesothelioma is critical to the assessment of tumor response to therapy. Current response assessment standards utilize summed linear measurements acquired on three computed tomography (CT) sections. The purpose of this study was to evaluate manual area measurements as an alternate response assessment metric, specifically through the study of measurement interobserver variability. METHODS Two CT scans from each of 31 patients were collected. Using a computer interface, five observers contoured tumor on three selected CT sections from each baseline scan. Four observers also constructed matched follow-up scan tumor contours for the same 31 patients. Area measurements extracted from these contours were compared using a random effects analysis of variance model to assess relative interobserver variability. The sums of section area measurements were also analyzed, since these area sums are more clinically relevant for response assessment. RESULTS When each observers measurements were compared with those of the other four observers, strong correlation was observed. The 95% confidence interval for relative interobserver variability of baseline scan summed area measurements was [-71%, +240%], spanning 311%. For the follow-up scan summed area measurements, the 95% confidence interval for relative interobserver variability was [-41%, +70%], spanning 111%. At both baseline and follow-up, the variability among observers was a significant component of the total variability in both per-section and summed area measurements (p<0.0001). CONCLUSIONS Despite the ability of tumor area measurements to capture tumor burden with greater fidelity than linear tumor thickness measurements, manual area measurements may not be a robust means of response assessment in mesothelioma patients.

Dosimetric Comparison of Real-Time MRI-Guided Tri-Cobalt-60 Versus Linear Accelerator-Based Stereotactic Body Radiation Therapy Lung Cancer Plans

Purpose: Magnetic resonance imaging–guided radiation therapy has entered clinical practice at several major treatment centers. Treatment of early-stage non-small cell lung cancer with stereotactic body radiation therapy is one potential application of this modality, as some form of respiratory motion management is important to address. We hypothesize that magnetic resonance imaging–guided tri-cobalt-60 radiation therapy can be used to generate clinically acceptable stereotactic body radiation therapy treatment plans. Here, we report on a dosimetric comparison between magnetic resonance imaging–guided radiation therapy plans and internal target volume–based plans utilizing volumetric-modulated arc therapy. Materials and Methods: Ten patients with early-stage non-small cell lung cancer who underwent radiation therapy planning and treatment were studied. Following 4-dimensional computed tomography, patient images were used to generate clinically deliverable plans. For volumetric-modulated arc therapy plans, the planning tumor volume was defined as an internal target volume + 0.5 cm. For magnetic resonance imaging–guided plans, a single mid-inspiratory cycle was used to define a gross tumor volume, then expanded 0.3 cm to the planning tumor volume. Treatment plan parameters were compared. Results: Planning tumor volumes trended larger for volumetric-modulated arc therapy–based plans, with a mean planning tumor volume of 47.4 mL versus 24.8 mL for magnetic resonance imaging–guided plans (P = .08). Clinically acceptable plans were achievable via both methods, with bilateral lung V20, 3.9% versus 4.8% (P = .62). The volume of chest wall receiving greater than 30 Gy was also similar, 22.1 versus 19.8 mL (P = .78), as were all other parameters commonly used for lung stereotactic body radiation therapy. The ratio of the 50% isodose volume to planning tumor volume was lower in volumetric-modulated arc therapy plans, 4.19 versus 10.0 (P < .001). Heterogeneity index was comparable between plans, 1.25 versus 1.25 (P = .98). Conclusion: Magnetic resonance imaging–guided tri-cobalt-60 radiation therapy is capable of delivering lung high-quality stereotactic body radiation therapy plans that are clinically acceptable as compared to volumetric-modulated arc therapy–based plans. Real-time magnetic resonance imaging provides the unique capacity to directly observe tumor motion during treatment for purposes of motion management.

A New Era of Image Guidance with Magnetic Resonance-guided Radiation Therapy for Abdominal and Thoracic Malignancies

Magnetic resonance-guided radiation therapy (MRgRT) offers advantages for image guidance for radiotherapy treatments as compared to conventional computed tomography (CT)-based modalities. The superior soft tissue contrast of magnetic resonance (MR) enables an improved visualization of the gross tumor and adjacent normal tissues in the treatment of abdominal and thoracic malignancies. Online adaptive capabilities, coupled with advanced motion management of real-time tracking of the tumor, directly allow for high-precision inter-/intrafraction localization. The primary aim of this case series is to describe MR-based interventions for localizing targets not well-visualized with conventional image-guided technologies. The abdominal and thoracic sites of the lung, kidney, liver, and gastric targets are described to illustrate the technological advancement of MR-guidance in radiotherapy.

SU‐C‐134‐05: CT Contrast Media: Impact of Scanner Parameters On Enhancement and Detectability

PURPOSE Uptake of iodine-based CT contrast media (CM) results in an increase in Hounsfield Unit (HU) value, allowing for improved detectability in CT. Further, because the increase in HU is proportional to CM concentration, quantitative measurement of HU enhancement can aid diagnosis and can determine hemodynamic properties of tissues (i.e., perfusion CT). Imaging protocol parameters (e.g., reconstruction kernel) can alter the HU-CM relationship, potentially confounding quantitation of contrast uptake. This phantom study measures the HU-CM relationship and determines the impact of imaging protocol parameters. METHODS A solid water phantom was imaged with a Philips Big Bore CT Scanner. Eighteen custom cylinders with CM concentrations ranging from 0-50 mg of iodine/mL were placed in the phantom. Tube voltages of 90, 120, and 140kVp, current-time products of 100 and 400mAs, and reconstruction kernels of UB (smooth) and D (hi-res bone enhancing) were studied. A linear fit to the HU-CM data was calculated to evaluate HU enhancement. Contrast-to-noise ratio (CNR) was calculated to evaluate detectability. RESULTS A linear relationship existed between HU and CM for all acquisitions (R-squared > 0.99). HU-CM linear slope ranged from 16 to 34 HU/mg-I/mL. A tube voltage of 140kVp increased the slope by 81% when compared to 90kVp, whereas 120kVp increased the slope by 20%. Kernel D produced a 10-15% increase in slope. For a 400mAs acquisition, CNR was optimized using 120kVp and the UB kernel, but CNR was optimized for 100mAs using 90kVp with the UB kernel. CONCLUSION HU enhancement is linear with concentration; however, the slope is strongly impacted by reconstruction kernel and tube voltage. Knowledge of CT scanning parameter impact on contrast media signal enhancement and detectability can guide optimization of CT protocols and improve interpretation of quantitative CT data.

Dosimetric measurements of an n-butyl cyanoacrylate embolization material for arteriovenous malformations

PURPOSE The therapeutic regimen for cranial arteriovenous malformations often involves both stereotactic radiosurgery and endovascular embolization. Embolization agents may contain tantalum or other contrast agents to assist the neurointerventionalists, leading to concerns regarding the dosimetric effects of these agents. This study investigated dosimetric properties of n-butyl cyanoacrylate (n-BCA) plus lipiodol with and without tantalum powder. METHODS The embolization agents were provided cured from the manufacturer with and without added tantalum. Attenuation measurements were made for the samples and compared to the attenuation of a solid water substitute using a 6 MV photon beam. Effective linear attenuation coefficients (ELAC) were derived from attenuation measurements made using a portal imager and derived sample thickness maps projected in an identical geometry. Probable dosimetric errors for calculations in which the embolized regions are overridden with the properties of water were calculated using the ELAC values. Interface effects were investigated using a parallel plate ion chamber placed at set distances below fixed samples. Finally, Hounsfield units (HU) were measured using a stereotactic radiosurgery CT protocol, and more appropriate HU values were derived from the ELAC results and the CT scanners HU calibration curve. RESULTS The ELAC was 0.0516 ± 0.0063 cm(-1) and 0.0580 ± 0.0091 cm(-1) for n-BCA without and with tantalum, respectively, compared to 0.0487 ± 0.0009 cm(-1) for the water substitute. Dose calculations with the embolized region set to be water equivalent in the treatment planning system would result in errors of -0.29% and -0.93% per cm thickness of n-BCA without and with tantalum, respectively. Interface effects compared to water were small in magnitude and limited in distance for both embolization materials. CT values at 120 kVp were 2082 and 2358 HU for n-BCA without and with tantalum, respectively; dosimetrically appropriate HU values were estimated to be 79 and 199 HU, respectively. CONCLUSIONS The dosimetric properties of the embolization agents are very close to those of water for a 6 MV beam. Therefore, treating the entire intracranial space as uniform in composition will result in less than 1% dosimetric error for n-BCA emboli smaller than 3.4 cm without added tantalum and n-BCA emboli smaller than 1.1 cm with added tantalum. Furthermore, when effective embolization can be achieved by the neurointerventionalist using n-BCA without tantalum, the dosimetric impact of overriding material properties will be lessened. However, due to the high attenuation of embolization agents with and without added tantalum for diagnostic energies, artifacts may occur that necessitate additional imaging to accurately identify the spatial extent of the region to be treated.