Magnetic Resonance Assessment of Response to Therapy: Tumor Change Measurement,Truth Data and Error Sources

This article describes methods and issues that are specific to the assessment of change in tumor characteristics as measured using quantitative magnetic resonance (MR) techniques and how this relates to the establishment of quantitative MR imaging (MRI) biomarkers of patient response to therapy. The initial focus is on the various sources of bias and variance in the measurement of microvascular parameters and diffusion parameters as such parameters are being used relatively commonly as secondary or exploratory end points in current phase 1/2 clinical trails of conventional and targeted therapies. Several ongoing initiatives that seek to identify the magnitude of some of the sources of measurement variations are then discussed. Finally, resources being made available through the National Cancer Institute Reference Image Database to Evaluate Response (RIDER) project that might be of use in investigations of quantitative MRI biomarker change analysis are described. These resources include 1) data from phantom-based assessment of system response, including short-term (1 hour) and moderate-term (1 week) contrast response and relaxation time measurement, 2) data obtained from repeated dynamic contrast agent-enhanced MRI studies in intracranial tumors, and 3) data obtained from repeated diffusion MRI studies in both breast and brain. A concluding section briefly discusses issues that must be addressed to allow the transition of MR-based imaging biomarker measures from their current role as secondary/exploratory end points in clinical trials to primary/surrogate markers of response and, ultimately, in clinical application.     

PET/CT Assessment of Response to Therapy: Tumor Change Measurement,Truth Data,and Error

We describe methods and issues that are relevant to the measurement of change in tumor uptake of ¹⁸F-fluorodeoxyglucose (FDG) or other radiotracers, as measured from positron emission tomography/computed tomography (PET/CT) images, and how this would relate to the establishment of PET/CT tumor imaging as a biomarker of patient response to therapy. The primary focus is on the uptake of FDG by lung tumors, but the approach can be applied to diseases other than lung cancer and to tracers other than FDG. The first issue addressed is the sources of bias and variance in the measurement of tumor uptake of FDG, and where there are still gaps in our knowledge. These are discussed in the context of measurement variation and how these would relate to the early detection of response to therapy. Some of the research efforts currently underway to identify the magnitude of some of these sources of error are described. In addition, we describe resources for these investigations that are being made available through the Reference Image Database for the Evaluation of Response project. Measures derived from PET image data that might be predictive of patient response as well as the additional issues that each of these metrics may encounter are described briefly. The relationship between individual patient response to therapy and utility for multicenter trials is discussed. We conclude with a discussion of moving from assessing measurement variation to the steps necessary to establish the efficacy of PET/CT imaging as a biomarker for response.     

Quantitative Imaging to Assess Tumor Response to Therapy: Common Themes of Measurement,Truth Data,and Error Sources

RATIONALE: Early detection of tumor response to therapy is a key goal. Finding measurement algorithms capable of early detection of tumor response could individualize therapy treatment as well as reduce the cost of bringing new drugs to market. On an individual basis, the urgency arises from the desire to prevent continued treatment of the patient with a high-cost and/or high-risk regimen with no demonstrated individual benefit and rapidly switch the patient to an alternative efficacious therapy for that patient. In the context of bringing new drugs to market, such algorithms could demonstrate efficacy in much smaller populations, which would allow phase 3 trials to achieve statistically significant decisions with fewer subjects in shorter trials. MATERIALS AND METHODS: This consensus-based article describes multiple, image modality-independent means to assess the relative performance of algorithms for measuring tumor change in response to therapy. In this setting, we describe specifically the example of measurement of tumor volume change from anatomic imaging as well as provide an overview of other promising generic analytic methods that can be used to assess change in heterogeneous tumors. To support assessment of the relative performance of algorithms for measuring small tumor change, data sources of truth are required. RESULTS: Very short interval clinical imaging examinations and phantom scans provide known truth for comparative evaluation of algorithms. CONCLUSIONS: For a given category of measurement methods, the algorithm that has the smallest measurement noise and least bias on average will perform best in early detection of true tumor change.     

Inter-Fraction Tumor Volume Response during Lung Stereotactic Body Radiation Therapy Correlated to Patient Variables

PurposeAnalyze inter-fraction volumetric changes of lung tumors treated with stereotactic body radiation therapy (SBRT) and determine if the volume changes during treatment can be predicted and thus considered in treatment planning.ResultsAll tumors studied experienced volume change during treatment. Tumor increased in volume by an average of 15% and regressed by an average of 11%. The overall volume increase during treatment is contained within the planning target volume (PTV) for all tumors. Larger tumors increased in volume more than smaller tumors during treatment (q = 0.0029). The volume increase on CBCT was correlated to the treatment planning gross target volume (GTV) as well as internal target volumes (ITV) (q = 0.0085 and q = 0.0039 respectively) and could be predicted for tumors with a GTV less than 22 mL. The volume increase was correlated to the integral dose (ID) in the ITV at every fraction (q = 0.0049). The peak inter-fraction volume occurred at an earlier fraction in younger patients (q = 0.0122).ConclusionsWe introduced a new analysis method to follow inter-fraction tumor volume changes and determined that the observed changes during lung SBRT treatment are correlated to the initial tumor volume, integral dose (ID), and patient age. Furthermore, the volume increase during treatment of tumors less than 22mL can be predicted during treatment planning. The volume increase remained significantly less than the overall PTV expansion, and radiation re-planning was therefore not required for the purpose of tumor control. The presence of the studied correlations suggests that the observed volumetric changes may reflect some underlying biologic process rather than random fluctuations.     

Comparison of Aortic Annulus Diameter Measurement between Multi-Detector Computed Tomography and Echocardiography: A Meta-Analysis

Background and Purpose

Accurate measurement of aortic annulus diameter is crucial for choosing suitable prosthetic size for transcatheter aortic valve implantation (TAVI). Several imaging methods are available for the measurement, but significant variability between different modalities has been observed. The purpose of this study was to systematically compare the measurements of aortic annulus diameter between multi-detector computed tomography (MDCT), transthoracic echocardiography (TTE), and transesophegeal echocardiography (TEE).

Methods

PubMed and EMBASE databases between January 2000 and January 2012 were searched. We extracted data from eligible studies evaluating the aortic annulus diameter by MDCT and echocardiography (TTE, TEE, or both). We performed a random-effects meta-analysis to calculate the weighted mean differences of aortic annulus diameter measurement between MDCT, TTE, and TEE.

Results

A total of 10 eligible studies involving 581 subjects with aortic valve stenosis were included. Aortic annulus diameter measured on coronal view by MDCT (25.3±0.52 mm) was respectively larger than that measured on sagittal view by MDCT (22.7±0.37 mm), TTE (22.6±0.28 mm), and TEE (23.1±0.32 mm). The weighted mean difference of aortic annulus diameter between coronal view by MDCT and TTE these two methods was 2.97 mm, followed by the weighted mean difference of 2.53 mm between coronal view and sagittal view by MDCT, and the mean difference of 1.74 mm between coronal view on MDCT and TEE (P<0.0001 for all). The weighted mean difference of aortic annulus diameter measurement between TEE and TTE was significant but somewhat small (0.45 mm, P = 0.007).

Conclusion

Aortic annulus diameter measured on coronal view by MDCT was robustly and significantly larger than that obtained on sagittal view by MDCT, TTE, or TEE. Such variability of aortic annulus diameter measurement by different imaging modalities cannot be ignored when developing optimal strategies for selection of prosthetic valve size in TAVI.     

Measurement of Mandibular Growth Using Cone-Beam Computed Tomography: A Miniature Pig Model Study

The purpose of this study was to measure the long-term growth of the mandible in miniature pigs using 3D Cone-Beam Computerized Tomography (CBCT). The mandibles of the pigs were scanned monthly over 12 months using CBCT and the 3D mandibular models were reconstructed from the data. Seventeen anatomical landmarks were identified and classified into four groups of line segments, namely anteroposterior, superoinferior, mediolateral and anteroinferior. The inter-marker distances, inter-segmental angles, volume, monthly distance changes and percentage of changes were calculated to describe mandibular growth. The total changes of inter-marker distances were normalized to the initial values. All inter-marker distances increased over time, with the greatest mean normalized total changes in the superoinferior and anteroposterior groups (p<0.05). Monthly distance changes were greatest during the first four months and then reduced over time. Percentages of inter-marker distance changes were similar among the groups, reaching half of the overall growth around the 4^th month. The mandibular volume growth increased non-linearly with time, accelerating during the first five months and slowing during the remaining months. The growth of the mandible was found to be anisotropic and non-homogeneous within the bone and non-linear over time, with faster growth in the ramus than in the body. These growth patterns appeared to be related to the development of the dentition, providing necessary space for the teeth to grow upward for occlusion and for the posterior teeth to erupt.     

Measurement and Analysis of the Tracheobronchial Tree in Chinese Population Using Computed Tomography

Objective

To ascertain accurate measurements of, and the relationships between, the normative parameters of the tracheobronchial trees in the Chinese population using multi-slice spiral computed tomography (CT) and multi-planar reconstruction (MPR).

Materials and Methods

Measurements were performed on 2107 patients who underwent thoracic CT scans in the PLA General Hospital. The lengths of the trachea and the main stem bronchi, and the sizes of the subcarinal angle were obtained through CT or MPR imaging. Multi-variance analyses were performed to detect potential correlations between obtained parameters.

Results

The mean length of the trachea was 104.9 ± 13.4 mm (107.8 ± 13.2 mm for men and 101.4 ± 12.8 mm for women). The mean lengths of the right and left main stem bronchi were 13.6 ± 4.3 and 48.3 ± 6.5 mm, respectively. The right bronchus angle and the left bronchus angle were 34.9 and 42.5 degrees, respectively. Significant gender differences were found in all the parameters measured except for the angle of the right upper lobe bronchus. There are no statistically significant correlations among these parameters.

Conclusions

The normal reference values and the likely ranges of distribution of the tracheobronchial trees in the Chinese population have been established. Significant gender differences exist in the dimensions of the trachea, with the exception of the Right upper bronchial angle (RUA).     

Quantitative Multi-Parametric Magnetic Resonance Imaging of Tumor Response to Photodynamic Therapy

ObjectiveThe aim of this study was to characterize response to photodynamic therapy (PDT) in a mouse cancer model using a multi-parametric quantitative MRI protocol and to identify MR parameters as potential biomarkers for early assessment of treatment outcome.MethodsCT26.WT colon carcinoma tumors were grown subcutaneously in the hind limb of BALB/c mice. Therapy consisted of intravenous injection of the photosensitizer Bremachlorin, followed by 10 min laser illumination (200 mW/cm²) of the tumor 6 h post injection. MRI at 7 T was performed at baseline, directly after PDT, as well as at 24 h, and 72 h. Tumor relaxation time constants (T₁ and T₂) and apparent diffusion coefficient (ADC) were quantified at each time point. Additionally, Gd-DOTA dynamic contrast-enhanced (DCE) MRI was performed to estimate transfer constants (K^trans) and volume fractions of the extravascular extracellular space (v_e) using standard Tofts-Kermode tracer kinetic modeling. At the end of the experiment, tumor viability was characterized by histology using NADH-diaphorase staining.ResultsThe therapy induced extensive cell death in the tumor and resulted in significant reduction in tumor growth, as compared to untreated controls. Tumor T₁ and T₂ relaxation times remained unchanged up to 24 h, but decreased at 72 h after treatment. Tumor ADC values significantly increased at 24 h and 72 h. DCE-MRI derived tracer kinetic parameters displayed an early response to the treatment. Directly after PDT complete vascular shutdown was observed in large parts of the tumors and reduced uptake (decreased K^trans) in remaining tumor tissue. At 24 h, contrast uptake in most tumors was essentially absent. Out of 5 animals that were monitored for 2 weeks after treatment, 3 had tumor recurrence, in locations that showed strong contrast uptake at 72 h.ConclusionDCE-MRI is an effective tool for visualization of vascular effects directly after PDT. Endogenous contrast parameters T₁, T₂, and ADC, measured at 24 to 72 h after PDT, are also potential biomarkers for evaluation of therapy outcome.     

Renal Cell Carcinoma Metastatic to the Liver: Early Response Assessment after Intraarterial Therapy Using 3D Quantitative Tumor Enhancement Analysis

PURPOSELiver metastases from renal cell carcinoma (RCC) are not uncommon in the course of disease. However, data about tumor response to intraarterial therapy (IAT) are scarce. This study assessed whether changes of enhancing tumor volume using quantitative European Association for the Study of the Liver (qEASL) on magnetic resonance imaging (MRI) and computed tomography (CT) can evaluate tumor response and predict overall survival (OS) early after therapy.RESULTSMean qEASL (cm³) decreased from 93.5 to 67.2 cm³ (P= .004) and mean qEASL (%) from 63.1% to 35.6% (P= .001). No significant changes were observed using other response criteria. qEASL was the only significant predictor of OS when used to stratify patients into responders and nonresponders with median OS of 31.9 versus 11.1 months (hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.19-0.97; P= .042) for qEASL (cm³) and 29.9 versus 10.2 months (HR, 0.09; 95% CI, 0.01-0.74; P= .025) for qEASL (%).CONCLUSIONThree-dimensional (3D) quantitative tumor analysis is a reliable predictor of OS when assessing treatment response after IAT in patients with RCC metastatic to the liver. qEASL outperforms conventional non-3D methods and can be used as a surrogate marker for OS early after therapy.     

Establishing Intracranial Brain Tumor Xenografts With Subsequent Analysis of Tumor Growth and Response to Therapy using Bioluminescence Imaging

Transplantation models using human brain tumor cells have served an essential function in neuro-oncology research for many years. In the past, the most commonly used procedure for human tumor xenograft establishment consisted of the collection of cells from culture flasks, followed by the subcutaneous injection of the collected cells in immunocompromised mice. Whereas this approach still sees frequent use in many laboratories, there has been a significant shift in emphasis over the past decade towards orthotopic xenograft establishment, which, in the instance of brain tumors, requires tumor cell injection into appropriate neuroanatomical structures. Because intracranial xenograft establishment eliminates the ability to monitor tumor growth through direct measurement, such as by use of calipers, the shift in emphasis towards orthotopic brain tumor xenograft models has necessitated the utilization of non-invasive imaging for assessing tumor burden in host animals. Of the currently available imaging methods, bioluminescence monitoring is generally considered to offer the best combination of sensitivity, expediency, and cost. Here, we will demonstrate procedures for orthotopic brain tumor establishment, and for monitoring tumor growth and response to treatment when testing experimental therapies.     

The Detection of Preoperative Parathyroid Lesions: The Success of Ultrasonography,Technetium-99m Methoxyisobutylisonitrile Parathyroid Scintigraphy,and Single-Photon Emission Computed Tomography–Computed Tomography

ObjectiveWe aimed to find and compare the efficacy of ultrasonography (US), technetium-99m methoxyisobutylisonitrile parathyroid scintigraphy (MIBI-S), and single-photon emission computed tomography–computed tomography (SPECT-CT) in detecting the localization of parathyroid adenomas in patients with primary hyperparathyroidism.MethodsIn total, 348 patients were included in this study. Preoperative parathyroid imaging with US, MIBI-S, and SPECT-CT was evaluated and compared with operative findings. The results of the imaging methods were compared with pathology and operation reports.ResultsIn 318 patients (91.3%), one of the imaging methods was able to localize the lesion correctly. US detected the localization of the parathyroid lesions correctly in 268 patients (77%), whereas SPECT-CT and MIBI-S were correct in 254 (73%) and 209 (60%) patients, respectively. There was a statistically significant relationship between the parathyroid hormone (PTH) level and 3 imaging methods’ success rates (P < .05). The PTH cut-off value, which best determined the correct localization, was 152.5 pg/mL for US, 143 pg/mL for MIBI-S, and 143 pg/mL for SPECT-CT. It was observed that the correct localization rate for parathyroid lesions increased with higher PTH levels.ConclusionIn our study population, US was more successful, in most cases, than other imaging methods in localizing parathyroid lesions but SPECT-CT was more accurate in localizing mediastinal lesions. In addition, it was found that preoperative PTH levels affect the accuracy of imaging methods.     

Intra and Interobserver Reliability and Agreement of Semiquantitative Vertebral Fracture Assessment on Chest Computed Tomography

Objectives

To evaluate the reliability of semiquantitative Vertebral Fracture Assessment (VFA) on chest Computed Tomography (CT).

Methods

Four observers performed VFA twice upon sagittal reconstructions of 50 routine clinical chest CTs. Intra- and interobserver agreement (absolute agreement or 95% Limits of Agreement) and reliability (Cohen''s kappa or intraclass correlation coefficient(ICC)) were calculated for the visual VFA measures (fracture present, worst fracture grade, cumulative fracture grade on patient level) and for percentage height loss of each fractured vertebra compared to the adjacent vertebrae.

Results

Observers classified 24–38% patients as having at least one vertebral fracture, giving rise to kappa''s of 0.73–0.84 (intraobserver) and 0.56–0.81 (interobserver). For worst fracture grade we found good intraobserver (76–88%) and interobserver (74–88%) agreement, and excellent reliability with square-weighted kappa''s of 0.84–0.90 (intraobserver) and 0.84–0.94 (interobserver). For cumulative fracture grade the 95% Limits of Agreement were maximally ±1,99 (intraobserver) and ±2,69 (interobserver) and the reliability (ICC) varied from 0.84–0.94 (intraobserver) and 0.74–0.94 (interobserver). For percentage height-loss on a vertebral level the 95% Limits of Agreement were maximally ±11,75% (intraobserver) and ±12,53% (interobserver). The ICC was 0.59–0.90 (intraobserver) and 0.53–0–82 (interobserver). Further investigation is needed to evaluate the prognostic value of this approach.

Conclusion

In conclusion, these results demonstrate acceptable reproducibility of VFA on CT.     

Challenges and Approaches to Quantitative Therapy Response Assessment in Glioblastoma Multiforme Using the Novel Apoptosis Positron Emission Tomography Tracer F-18 ML-10

Evaluation of cancer-therapy efficacy at early time points is necessary for realizing the goal of delivering maximally effective treatment. Molecular imaging with carefully selected tracers and methodologies can provide the means for realizing this ability. Many therapies are aimed at inducing apoptosis in malignant tissue; thus, the ability to quantify apoptosis in vivo may be a fruitful approach. Apoptosis rate changes occur on a fast time scale, potentially allowing correspondingly rapid decisions regarding therapy value. However, quantification of tissue status based on apoptosis imaging is complicated by this time scale and by the spatial heterogeneity of the process. Using the positron emission tomography (PET) tracer 2-(5-fluoro-pentyl)-2-methyl-malonic acid (F-18 ML-10), we present methods of voxelwise analysis yielding quantitative measures of apoptosis changes, parametric apoptosis change images, and graphical representation of apoptotic features. A method of deformable registration to account for anatomic changes between scan time points is also demonstrated. Overall apoptotic rates deduced from imaging depend on tumor density and the specific rate of apoptosis, a situation resulting in an ambiguity in the source of observed image-based changes. The ambiguity may be resolved through multimodality imaging. An example of intracellular sodium magnetic resonance imaging coupled with F-18 ML-10 PET is provided.     

Real-Time Measurement of Functional Tumor Volume by MRI to Assess Treatment Response in Breast Cancer Neoadjuvant Clinical Trials: Validation of the Aegis SER Software Platform

PURPOSE: To evaluate the Aegis software implementation for real-time calculation of functional tumor volume (FTV) in the neoadjuvant breast cancer treatment trial setting. METHODS: The validation data set consisted of 689 contrast-enhanced magnetic resonance imaging (MRI) examinations from the multicenter American College of Radiology Imaging Network 6657 study. Subjects had stage III tumors ≥3 cm in diameter and underwent MRI before, during, after receiving anthracycline-cyclophosphamide chemotherapy. Studies were previously analyzed by the University of California San Francisco core laboratory using the three-timepoint signal enhancement ratio (SER) FTV algorithm; FTV measurement was subsequently implemented on the Hologic (formerly Sentinelle Medical Inc) Aegis platform. All cases were processed using predefined volumes of interest with no user interaction. Spearman rank correlation was evaluated for all study sites and visits. Cox proportional hazards analysis was used to compare predictive performance of the platforms for recurrence-free survival (RFS) time. RESULTS: Overall agreement between platforms was good; ρ varied from 0.96 to 0.98 for different study visits. Site-by-site analysis showed considerable variation, from ρ = 0.54 to near perfect agreement (ρ = 1.000) for several sites. Mean absolute difference between platforms ranged from 1.67 cm³ pretreatment to 0.2 cm³ posttreatment. The two platforms showed essentially identical performance for predicting RFS using pretreatment or posttreatment FTV. CONCLUSION: Implementation of the SER FTV algorithm on a commercial platform for real-time MRI volume assessments showed very good agreement with the reference core laboratory system, but variations by site and outlier analysis point out sensitivities to implementation-specific differences.     

用度量误差模型方法编制相容的生长过程表和材积表

指出了按照常规方法建立的生长模型和材积模型不相容的原因、利用两阶段度量误差模型方法估计生长模型和材积模型的参数,进而编制相容的生长过程表和材积表．