Daniela Thorwarth

Kinetic analysis of dynamic 18F-fluoromisonidazole PET correlates with radiation treatment outcome in head-and-neck cancer

BackgroundHypoxia compromises local control in patients with head-and-neck cancer (HNC). In order to determine the value of [18F]-fluoromisonidazole (Fmiso) with regard to tumor hypoxia, a patient study with dynamic Fmiso PET was performed. For a better understanding of tracer uptake and distribution, a kinetic model was developed to analyze dynamic Fmiso PET data.MethodsFor 15 HNC patients, dynamic Fmiso PET examinations were performed prior to radiotherapy (RT) treatment. The data was analyzed using a two compartment model, which allows the determination of characteristic hypoxia and perfusion values. For different parameters, such as patient age, tumor size and standardized uptake value, the correlation to treatment outcome was tested using the Wilcoxon-Mann-Whitney U-test. Statistical tests were also performed for hypoxia and perfusion parameters determined by the kinetic model and for two different metrics based on these parameters.ResultsThe kinetic Fmiso analysis extracts local hypoxia and perfusion characteristics of a tumor tissue. These parameters are independent quantities. In this study, different types of characteristic hypoxia-perfusion patterns in tumors could be identified.The clinical verification of the results, obtained on the basis of the kinetic analysis, showed a high correlation of hypoxia-perfusion patterns and RT treatment outcome (p = 0.001) for this initial patient group.ConclusionThe presented study established, that Fmiso PET scans may benefit from dynamic acquisition and analysis by a kinetic model. The pattern of distribution of perfusion and hypoxia in the tissue is correlated to local control in HNC.

Physical radiotherapy treatment planning based on functional PET/CT data

Positron emission tomography (PET) provides molecular information about the tumor microenvironment in addition to anatomical imaging. Hence, it seems to be highly beneficial to integrate PET data into radiotherapy (RT) treatment planning. Functional PET images can be used in RT planning following different strategies, with different orders of complexity. In a first instance, PET imaging data can be used for better target volume delineation. A second strategy, dose painting by contours (DPBC), consists of creating an additional PET-based target volume which will then be treated with a higher dose level. In contrast, dose painting by numbers (DPBN) aims for a locally varying dose prescription according to the variation of the PET signal. For both dose painting approaches, isotoxicity planning strategies should be applied in order not to compromise organs at risk compared to conventional modern RT treatment. In terms of physical dose painting treatment planning, several factors that may introduce limitations and uncertainties are of major importance. These are the PET voxel size, uncertainties due to image acquisition and reconstruction, a reproducible image registration, inherent biological uncertainties due to biological and chemical tracer characteristics, accurate dose calculation algorithms and radiation delivery techniques able to apply highly modulated dose distributions. Further research is necessary in order to investigate these factors and their influence on dose painting treatment planning and delivery thoroughly. To date, dose painting remains a theoretical concept which needs further validation. Nevertheless, molecular imaging has the potential to significantly improve target volume delineation and might also serve as a basis for treatment alteration in the future.

Implementation of hypoxia imaging into treatment planning and delivery

PURPOSE To review the current status of implementation of functional hypoxia imaging in radiotherapy (RT) planning and treatment delivery. METHODS Before biological imaging techniques such as positron emission tomography (PET) or magnetic resonance (MR) can be used for individual RT adaptation, three main requirements have to be fulfilled. First, tissue parameters have to be derived from the imaging data that correlate with individual therapy outcome. Then, the spatial and temporal stability of hypoxia PET images needs to be established. Finally, the dose painting (DP) concepts have to be practically feasible to be used as a basis for clinical trials. RESULTS A number of recent clinical studies could show the correlation of hypoxia PET imaging with different tracers and RT outcome. Most of the studies revealed a correlation between mean or maximum values and parameters assessed from the PET avid volume and treatment success, only few investigations used quantitative imaging. Multiparametric imaging seems to be very valuable. Recently, the spatial and temporal stability of hypoxia PET attracted attention. Temporal changes in the distribution of functional tumour properties were reported. Furthermore, technical feasibility of DP by contours (DPC) as well as DP by numbers (DPBN) was shown by several investigators. The challenge is now to design clinical studies in order to prove the impact of DP treatments on individual therapy success. CONCLUSION A patient-specific adaptation of RT based on functional hypoxia imaging with PET is possible and promising. Conceptual feasibility could be shown for DPBN whereas to date, only DPC seems to be plausible and feasible in a clinical context.

Simultaneous 68Ga-DOTATOC-PET/MRI for IMRT treatment planning for meningioma: first experience.

PURPOSE To evaluate intensity-modulated radiotherapy (IMRT) treatment planning based on simultaneous positron-emission tomography and magnetic resonance imaging (PET/MRI) of meningioma. METHODS AND MATERIALS A meningioma patient was examined prior to radiotherapy with dedicated planning computed tomography (CT), MRI, PET/CT with gallium-68-labeled DOTATOC (68Ga-DOTATOC), and simultaneous 68Ga-DOTATOC-PET/MRI. The first gross target volume (GTV) was defined based on a combination of separate MR and 68Ga-DOTATOC-PET/CT imaging (GTVPET/CT+MR). Then, the simultaneous PET/MR images were used to delineate a second GTV (GTVPET/MR) by following exactly the same delineation strategy. After an isotropic expansion of those volumes by a 4-mm safety margin, the resulting planning target volumes (PTVs) were compared by calculating the intersection volume and the relative complements. A cross-evaluation of IMRT plans was performed, where the treatment plan created for the PTVPET/CT+MR was applied to the PET/MR-based PTVPET/MR. RESULTS Generally, target volumes for IMRT treatment planning did not differ between MRI plus 68Ga-DOTATOC-PET/CT and simultaneous PET/MR imaging. Only in certain regions of the GTV were differences observed. The overall volume of the PET/MR-based PTV was approximately the same as that obtained from PET/CT data. A small region of infiltrative tumor growth next to the main tumor mass was better visualized with combined PET/MR due to smaller PET voxel sizes and improved recovery. An IMRT treatment plan was optimized for the PTVPET/CT+MR. The evaluation of this plan with respect to the PTVPET/MR showed parts of the target volume that would not have received the full radiation dose after delineation of the tumor, based on simultaneous PET/MR. CONCLUSION This case showed that differences in target volumes delineated on the basis of separate MR and PET/CT and simultaneous PET/MR may be observed that can have significant consequences for an effectively applied radiotherapy treatment plan.

PET/CT imaging for target volume delineation in curative intent radiotherapy of non-small cell lung cancer: IAEA consensus report 2014

This document describes best practice and evidence based recommendations for the use of FDG-PET/CT for the purposes of radiotherapy target volume delineation (TVD) for curative intent treatment of non-small cell lung cancer (NSCLC). These recommendations have been written by an expert advisory group, convened by the International Atomic Energy Agency (IAEA) to facilitate a Coordinated Research Project (CRP) aiming to improve the applications of PET based radiation treatment planning (RTP) in low and middle income countries. These guidelines can be applied in routine clinical practice of radiotherapy TVD, for NSCLC patients treated with concurrent chemoradiation or radiotherapy alone, where FDG is used, and where a calibrated PET camera system equipped for RTP patient positioning is available. Recommendations are provided for PET and CT image visualization and interpretation, and for tumor delineation using planning CT with and without breathing motion compensation.

A strategy for multimodal deformable image registration to integrate PET/MR into radiotherapy treatment planning

Abstract Background. Combined positron emission tomography (PET)/magnetic resonance imaging (MRI) is highly promising for biologically individualized radiotherapy (RT). Hence, the purpose of this work was to develop an accurate and robust registration strategy to integrate combined PET/MR data into RT treatment planning. Material and methods. Eight patient datasets consisting of an FDG PET/computed tomography (CT) and a subsequently acquired PET/MR of the head and neck (HN) region were available. Registration strategies were developed based on CT and MR data only, whereas the PET components were fused with the resulting deformation field. Following a rigid registration, deformable registration was performed with a transform parametrized by B-splines. Three different optimization metrics were investigated: global mutual information (GMI), GMI combined with a bending energy penalty (BEP) for regularization (GMI+ BEP) and localized mutual information with BEP (LMI+ BEP). Different quantitative registration quality measures were developed, including volumetric overlap and mean distance measures for structures segmented on CT and MR as well as anatomical landmark distances. Moreover, the local registration quality in the tumor region was assessed by the normalized cross correlation (NCC) of the two PET datasets. Results. LMI+ BEP yielded the most robust and accurate registration results. For GMI, GMI+ BEP and LMI+ BEP, mean landmark distances (standard deviations) were 23.9 mm (15.5 mm), 4.8 mm (4.0 mm) and 3.0 mm (1.0 mm), and mean NCC values (standard deviations) were 0.29 (0.29), 0.84 (0.14) and 0.88 (0.06), respectively. Conclusion. Accurate and robust multimodal deformable image registration of CT and MR in the HN region can be performed using a B-spline parametrized transform and LMI+ BEP as optimization metric. With this strategy, biologically individualized RT based on combined PET/MRI in terms of dose painting is possible.

Identification of Patient Benefit From Proton Therapy for Advanced Head and Neck Cancer Patients Based on Individual and Subgroup Normal Tissue Complication Probability Analysis

PURPOSE The purpose of this study was to determine, by treatment plan comparison along with normal tissue complication probability (NTCP) modeling, whether a subpopulation of patients with head and neck squamous cell carcinoma (HNSCC) could be identified that would gain substantial benefit from proton therapy in terms of NTCP. METHODS AND MATERIALS For 45 HNSCC patients, intensity modulated radiation therapy (IMRT) was compared to intensity modulated proton therapy (IMPT). Physical dose distributions were evaluated as well as the resulting NTCP values, using modern models for acute mucositis, xerostomia, aspiration, dysphagia, laryngeal edema, and trismus. Patient subgroups were defined based on primary tumor location. RESULTS Generally, IMPT reduced the NTCP values while keeping similar target coverage for all patients. Subgroup analyses revealed a higher individual reduction of swallowing-related side effects by IMPT for patients with tumors in the upper head and neck area, whereas the risk reduction of acute mucositis was more pronounced in patients with tumors in the larynx region. More patients with tumors in the upper head and neck area had a reduction in NTCP of more than 10%. CONCLUSIONS Subgrouping can help to identify patients who may benefit more than others from the use of IMPT and, thus, can be a useful tool for a preselection of patients in the clinic where there are limited PT resources. Because the individual benefit differs within a subgroup, the relative merits should additionally be evaluated by individual treatment plan comparisons.

Modelling and simulation of [18F]fluoromisonidazole dynamics based on histology-derived microvessel maps

Hypoxia can be assessed non-invasively by positron emission tomography (PET) using radiotracers such as [(18)F]fluoromisonidazole (Fmiso) accumulating in poorly oxygenated cells. Typical features of dynamic Fmiso PET data are high signal variability in the first hour after tracer administration and slow formation of a consistent contrast. The purpose of this study is to investigate whether these characteristics can be explained by the current conception of the underlying microscopic processes and to identify fundamental effects. This is achieved by modelling and simulating tissue oxygenation and tracer dynamics on the microscopic scale. In simulations, vessel structures on histology-derived maps act as sources and sinks for oxygen as well as tracer molecules. Molecular distributions in the extravascular space are determined by reaction-diffusion equations, which are solved numerically using a two-dimensional finite element method. Simulated Fmiso time activity curves (TACs), though not directly comparable to PET TACs, reproduce major characteristics of clinical curves, indicating that the microscopic model and the parameter values are adequate. Evidence for dependence of the early PET signal on the vascular fraction is found. Further, possible effects leading to late contrast formation and potential implications on the quantification of Fmiso PET data are discussed.

Potential role of PET/MRI in radiotherapy treatment planning

State-of-the art radiotherapy (RT) techniques have become extremely flexible. As a consequence, highly conformal target doses in combination with optimal organ-at-risk sparing are possible. Due to this highly precise application of complex dose distributions, treatments with higher radiation doses in the tumor but without increased toxicity levels are now feasible. This offers the possibility to adapt dose distributions according to individual radiation sensitivities as measured with functional imaging modalities. Recently, combined PET/MRI has become available. This novel hybrid imaging modality offers the possibility to simultaneously image anatomical, functional and molecular characteristics of a tumor. Consequently, PET/MRI may be an optimal basis for RT individualization. This review discusses different potential applications of PET/MRI for RT treatment planning, as well as technical challenges for the integration of multi-parametric PET/MRI data into RT treatment planning.

Prospective evaluation of a hydrogel spacer for rectal separation in dose-escalated intensity-modulated radiotherapy for clinically localized prostate cancer

BackgroundAs dose-escalation in prostate cancer radiotherapy improves cure rates, a major concern is rectal toxicity. We prospectively assessed an innovative approach of hydrogel injection between prostate and rectum to reduce the radiation dose to the rectum and thus side effects in dose-escalated prostate radiotherapy.MethodsAcute toxicity and planning parameters were prospectively evaluated in patients with T1-2 N0 M0 prostate cancer receiving dose-escalated radiotherapy after injection of a hydrogel spacer. Before and after hydrogel injection, we performed MRI scans for anatomical assessment of rectal separation. Radiotherapy was planned and administered to 78 Gy in 39 fractions.ResultsFrom eleven patients scheduled for spacer injection the procedure could be performed in ten. In one patient hydrodissection of the Denonvillier space was not possible. Radiation treatment planning showed low rectal doses despite dose-escalation to the target. In accordance with this, acute rectal toxicity was mild without grade 2 events and there was complete resolution within four to twelve weeks.ConclusionsThis prospective study suggests that hydrogel injection is feasible and may prevent rectal toxicity in dose-escalated radiotherapy of prostate cancer. Further evaluation is necessary including the definition of patients who might benefit from this approach. Trial registration: German Clinical Trials Register DRKS00003273.