Evaluation of deformable image registration for improved 4D CT-derived ventilation for image guided radiotherapy

Recent treatment planning studies have demonstrated the use of physiologic images in radiation therapy treatment planning to identify regions for functional avoidance. This image-guided radiotherapy (IGRT) strategy may reduce the injury and/or functional loss following thoracic radiotherapy. 4D computed tomography (CT), developed for radiotherapy treatment planning, is a relatively new imaging technique that allows the acquisition of a time-varying sequence of 3D CT images of the patient's lungs through the respiratory cycle. Guerrero et al. developed a method to calculate ventilation imaging from 4D CT, which is potentially better suited and more broadly available for IGRT than the current standard imaging methods. The key to extracting function information from 4D CT is the construction of a volumetric deformation field that accurately tracks the motion of the patient's lungs during the respiratory cycle. The spatial accuracy of the displacement field directly impacts the ventilation images; higher spatial registration accuracy will result in less ventilation image artifacts and physiologic inaccuracies. Presently, a consistent methodology for spatial accuracy evaluation of the DIR transformation is lacking. Evaluation of the 4D CT-derived ventilation images will be performed to assess correlation with global measurements of lung ventilation, as well as regional correlation of the distribution of ventilation with the current clinical standard SPECT. This requires a novel framework for both the detailed assessment of an image registration algorithm's performance characteristics as well as quality assurance for spatial accuracy assessment in routine application. Finally, we hypothesize that hypo-ventilated regions, identified on 4D CT ventilation images, will correlate with hypo-perfused regions in lung cancer patients who have obstructive lesions. A prospective imaging trial of patients with locally advanced non-small-cell lung cancer will allow this hypothesis to be tested. These advances are intended to contribute to the validation and clinical implementation of CT-based ventilation imaging in prospective clinical trials, in which the impact of this imaging method on patient outcomes may be tested.

Is a 3-mm intrafractional margin sufficient for daily image-guided intensity-modulated radiation therapy of prostate cancer?

PURPOSE: To determine whether a 3-mm isotropic target margin adequately covers the prostate and seminal vesicles (SVs) during administration of an intensity-modulated radiation therapy (IMRT) treatment fraction, assuming that daily image-guided setup is performed just before each fraction. MATERIALS AND METHODS: In-room computed tomographic (CT) scans were acquired immediately before and after a daily treatment fraction in 46 patients with prostate cancer. An eight-field IMRT plan was designed using the pre-fraction CT with a 3-mm margin and subsequently recalculated on the post-fraction CT. For convenience of comparison, dose plans were scaled to full course of treatment (75.6 Gy). Dose coverage was assessed on the post-treatment CT image set. RESULTS: During one treatment fraction (21.4+/-5.5 min), there were reductions in the volumes of the prostate and SVs receiving the prescribed dose (median reduction 0.1% and 1.0%, respectively, p<0.001) and in the minimum dose to 0.1 cm(3) of their volumes (median reduction 0.5 and 1.5 Gy, p<0.001). Of the 46 patients, three patients' prostates and eight patients' SVs did not maintain dose coverage above 70 Gy. Rectal filling correlated with decreased percentage-volume of SV receiving 75.6, 70, and 60 Gy (p<0.02). CONCLUSIONS: The 3-mm intrafractional margin was adequate for prostate dose coverage. However, a significant subset of patients lost SV dose coverage. The rectal volume change significantly affected SV dose coverage. For advanced-stage prostate cancers, we recommend to use larger margins or improve organ immobilization (such as with a rectal balloon) to ensure SV coverage.

Dynamic Chemical Shift Imaging for Image-Guided Thermal Therapy

Magnetic resonance temperature imaging (MRTI) is recognized as a noninvasive means to provide temperature imaging for guidance in thermal therapies. The most common method of estimating temperature changes in the body using MR is by measuring the water proton resonant frequency (PRF) shift. Calculation of the complex phase difference (CPD) is the method of choice for measuring the PRF indirectly since it facilitates temperature mapping with high spatiotemporal resolution. Chemical shift imaging (CSI) techniques can provide the PRF directly with high sensitivity to temperature changes while minimizing artifacts commonly seen in CPD techniques. However, CSI techniques are currently limited by poor spatiotemporal resolution. This research intends to develop and validate a CSI-based MRTI technique with intentional spectral undersampling which allows relaxed parameters to improve spatiotemporal resolution. An algorithm based on autoregressive moving average (ARMA) modeling is developed and validated to help overcome limitations of Fourier-based analysis allowing highly accurate and precise PRF estimates. From the determined acquisition parameters and ARMA modeling, robust maps of temperature using the k-means algorithm are generated and validated in laser treatments in ex vivo tissue. The use of non-PRF based measurements provided by the technique is also investigated to aid in the validation of thermal damage predicted by an Arrhenius rate dose model.

Design and Optimization of Four-dimensional Cone-beam Computed Tomography in Image-guided Radiation Therapy

The influence of respiratory motion on patient anatomy poses a challenge to accurate radiation therapy, especially in lung cancer treatment. Modern radiation therapy planning uses models of tumor respiratory motion to account for target motion in targeting. The tumor motion model can be verified on a per-treatment session basis with four-dimensional cone-beam computed tomography (4D-CBCT), which acquires an image set of the dynamic target throughout the respiratory cycle during the therapy session. 4D-CBCT is undersampled if the scan time is too short. However, short scan time is desirable in clinical practice to reduce patient setup time. This dissertation presents the design and optimization of 4D-CBCT to reduce the impact of undersampling artifacts with short scan times. This work measures the impact of undersampling artifacts on the accuracy of target motion measurement under different sampling conditions and for various object sizes and motions. The results provide a minimum scan time such that the target tracking error is less than a specified tolerance. This work also presents new image reconstruction algorithms for reducing undersampling artifacts in undersampled datasets by taking advantage of the assumption that the relevant motion of interest is contained within a volume-of-interest (VOI). It is shown that the VOI-based reconstruction provides more accurate image intensity than standard reconstruction. The VOI-based reconstruction produced 43% fewer least-squares error inside the VOI and 84% fewer error throughout the image in a study designed to simulate target motion. The VOI-based reconstruction approach can reduce acquisition time and improve image quality in 4D-CBCT.

Design, Synthesis and Development of Transporter Targeting Agents for Image-guided Therapy and Drug Delivery

The purpose of this study was to design, synthesize and develop novel transporter targeting agents for image-guided therapy and drug delivery. Two novel agents, N4-guanine (N4amG) and glycopeptide (GP) were synthesized for tumor cell proliferation assessment and cancer theranostic platform, respectively. N4amG and GP were synthesized and radiolabeled with 99mTc and 68Ga. The chemical and radiochemical purities as well as radiochemical stabilities of radiolabeled N4amG and GP were tested. In vitro stability assessment showed both 99mTc-N4amG and 99mTc-GP were stable up to 6 hours, whereas 68Ga-GP was stable up to 2 hours. Cell culture studies confirmed radiolabeled N4amG and GP could penetrate the cell membrane through nucleoside transporters and amino acid transporters, respectively. Up to 40% of intracellular 99mTc-N4amG and 99mTc-GP was found within cell nucleus following 2 hours of incubation. Flow cytometry analysis revealed 99mTc-N4amG was a cell cycle S phase-specific agent. There was a significant difference of the uptake of 99mTc-GP between pre- and post- paclitaxel-treated cells, which suggests that 99mTc-GP may be useful in chemotherapy treatment monitoring. Moreover, radiolabeled N4amG and GP were tested in vivo using tumor-bearing animal models. 99mTc-N4amG showed an increase in tumor-to-muscle count density ratios up to 5 at 4 hour imaging. Both 99mTc-labeled agents showed decreased tumor uptake after paclitaxel treatment. Immunohistochemistry analysis demonstrated that the uptake of 99mTc-N4amG was correlated with Ki-67 expression. Both 99mTc-N4amG and 99mTc-GP could differentiate between tumor and inflammation in animal studies. Furthermore, 68Ga-GP was compared to 18F-FDG in rabbit PET imaging studies. 68Ga-GP had lower tumor standardized uptake values (SUV), but similar uptake dynamics, and different biodistribution compared with 18F-FDG. Finally, to demonstrate that GP can be a potential drug carrier for cancer theranostics, several drugs, including doxorubicin, were selected to be conjugated to GP. Imaging studies demonstrated that tumor uptake of GP-drug conjugates was increased as a function of time. GP-doxorubicin (GP-DOX) showed a slow-release pattern in in vitro cytotoxicity assay and exhibited anti-cancer efficacy with reduced toxicity in in vivo tumor growth delay study. In conclusion, both N4amG and GP are transporter-based targeting agents. Radiolabeled N4amG can be used for tumor cell proliferation assessment. GP is a potential agent for image-guided therapy and drug delivery.

A dual resonance, image -guided, volume localization technique for magnetic resonance spectroscopy

An interleaved, dual resonance, volume localization technique for $\sp1$H/$\sp{31}$P magnetic resonance spectroscopy has been designed, implemented on a 2 T imager/spectrometer, and verified with phantom studies.^ Localization techniques, including several single voxel techniques and spectroscopic imaging, were implemented, and studies were performed to compare the efficiency of each sequence of $\sp1$H/$\sp{31}$P spectral acquisitions. The sequence chosen was a hybrid of the stimulated echo single voxel technique and the spectroscopic imaging technique.^ Water suppression during the $\sp1$H spectral acquisitions was accomplished by the use of three narrow bandwidth RF saturation pulses in combination with three spoiler gradients. The spoiler gradient amplitudes were selected on the basis of a numerical solution of the Bloch equations. A post-acquisition water suppression algorithm was used to minimize any residual water signal.^ For interleaved $\sp1$H/$\sp{31}$P acquisitions, a dual resonance RF coil was constructed and interfaced to the existing RF detection system via a custom-designed dual resonance transcoupler and switching system. Programmable attenuators were incorporated to allow for changes in receiver and transmitter attenuation "on the fly".^ To provide the rapidly switched gradient fields required for the $\sp1$H/$\sp{31}$P acquisitions, an actively screened gradient coil system was designed and implemented. With this system, gradient field rise times on the order of 100 $\mu$s were obtained. These rapid switching times were necessary for minimizing intrasequence delays and for improving localization quality and water suppression efficiency.^ The interleaved $\sp1$H/$\sp{31}$P volume localization technique was tested using a two-compartment phantom. Analysis of the data showed that the spectral contamination was less than three percent. One-to-one spatial correspondence of the $\sp1$H and $\sp{31}$P spectra was verified and allowed for direct correlation of the spectral data with a standard magnetic resonance image. ^

RANGE ADAPTIVE PROTON THERAPY FOR PROSTATE CANCER

Purpose: The rapid distal falloff of a proton beam allows for sparing of normal tissues distal to the target. However proton beams that aim directly towards critical structures are avoided due to concerns of range uncertainties, such as CT number conversion and anatomy variations. We propose to eliminate range uncertainty and enable prostate treatment with a single anterior beam by detecting the proton’s range at the prostate-rectal interface and adaptively adjusting the range in vivo and in real-time. Materials and Methods: A prototype device, consisting of an endorectal liquid scintillation detector and dual-inverted Lucite wedges for range compensation, was designed to test the feasibility and accuracy of the technique. Liquid scintillation filled volume was fitted with optical fiber and placed inside the rectum of an anthropomorphic pelvic phantom. Photodiode-generated current signal was generated as a function of proton beam distal depth, and the spatial resolution of this technique was calculated by relating the variance in detecting proton spills to its maximum penetration depth. The relative water-equivalent thickness of the wedges was measured in a water phantom and prospectively tested to determine the accuracy of range corrections. Treatment simulation studies were performed to test the potential dosimetric benefit in sparing the rectum. Results: The spatial resolution of the detector in phantom measurement was 0.5 mm. The precision of the range correction was 0.04 mm. The residual margin to ensure CTV coverage was 1.1 mm. The composite distal margin for 95% treatment confidence was 2.4 mm. Planning studies based on a previously estimated 2mm margin (90% treatment confidence) for 27 patients showed a rectal sparing up to 51% at 70 Gy and 57% at 40 Gy relative to IMRT and bilateral proton treatment. Conclusion: We demonstrated the feasibility of our design. Use of this technique allows for proton treatment using a single anterior beam, significantly reducing the rectal dose.

AN IMPLANTABLE MOSFET DOSIMETER MODIFIED TO ACT AS A FIDUCIAL MARKER

In external beam radiation therapy, it is imperative that the prescribed dose is administered to the correct location and in the correct amount. Though several ex vivo methods of quality assurance are currently employed to achieve this goal, verifying that the correct dose is received within the patient in situ is impossible without the capability of measuring dose inside the patient. Recently, a method of measuring dose delivered within the patient has been developed, an implantable MOSFET dosimeter. This dosimeter is implanted within the patient and records the dose received. Since the dosimeter is implanted in the patient, it could serve a dual function as a fiducial marker for image guided radiation therapy (IGRT) treatment if it could be modified to be visible on x-rays. In this study, modifications to the MOSFET dosimeter were made to increase its visibility for IGRT treatment. To test whether the modifications hindered the dosimeter’s ability to accurately measure and transmit dose information, the energy dependence, angular dependence and wireless read range of the modified dosimeter were measured and compared to unmodified dosimeters. It was found that the modified dosimeter performed as well as the unmodified dosimeter while also being suitable for use as a fiducial marker for IGRT treatment.

Neuromuscular disuse and atrophy: {\it In vivo\/} magnetic resonance studies of intramuscular lipid metabolism and fluid shift changes

We postulated that neuromuscular disuse results in deleteriously affected tissue-vascular fluid exchange processes and subsequently damages the important oxidative bioenergetic process of intramuscular lipid metabolism. The in-depth research reported in the literature is somewhat limited by the ex vivo nature and sporadic time-course characterization of disuse atrophy and recovery. Thus, an in vivo controlled, localized animal model of disuse atrophy was developed in one of the hindlimbs of laboratory rabbits (employing surgically implanted tetrodotoxin (TTX)-filled mini-osmotic pump-sciatic nerve superfusion system) and tested repeatedly with magnetic resonance (MR) throughout the 2-week period of temporarily induced disuse and during the recovery period (following explantation of the TTX-filled pump) for a period of 3 weeks. Controls consisted of saline/"sham"-implanted rabbit hindlimbs. The validity of this model was established with repeated electrophysiologic nerve conduction testing using a clinically appropriate protocol and percutaneously inserted small needle stimulating and recording electrodes. Evoked responses recorded from proximal (P) and distal (D) sites to the sciatic nerve cuff in the TTX-implanted group revealed significantly decreased (p $<$ 0.001) proximal-to-distal (P/D) amplitude ratios (as much as 50-70% below Baseline/pre-implanted and sham-implanted group values) and significantly increased (p $<$ 0.01) differential latency (PL-DL) values (as much as 1.5 times the pre- and sham-implanted groups). By Day 21 of recovery, observed P/D and PL-DL levels matched Baseline/sham-implemented levels. MRI-determined cross-sectional area (CSA) values of Baseline/pre-implanted, sham- or TTX-implanted, and recovering/explanted and the corresponding contralateral hindlimb tibialis anterior (TA) muscles normalized to tibial bone (TB) CSA (in TA/TB ratios) revealed that there was a significant decline (indicative of atrophic response) from pre- and sham-implanted controls by as much as 20% (p $<$ 0.01) at Day 7 and 50-55% (p $<$ 0.001) at Day 13 of TTX-implantation. In the non-implanted contralaterals, a significant increase (indicative of hypertrophic response) by as much as 10% (p $<$ 0.025) at Day 7 and 27% (p $<$ 0.001) at Day 13 + TTX was found. The induced atrophic/hypertrophic TA muscles were observed to be fully recovered by Day 21 post-explantation as evidenced by image TA/TB ratios. End-point biopsy results from a small group of rabbits revealed comprehensive atrophy of both Type I and Type II fibers, although the heterogeneity of the response supports the use of image-guided, volume-localized proton magnetic resonance spectroscopy (MRS) to noninvasively assess tissue-level metabolic changes. MRS-determined results of a 0.25cc volume of tissue within implanted limb TA muscles under resting/pre-ischemic, ischemic-stressed, and post-ischemic conditions at timepoints during and following disuse atrophy/recovery revealed significantly increased intramuscular spectral lipid levels, as much as 2-3 times (p $<$ 0.01) the Baseline/pre-implanted values at Day 7 and 6-7 times (p $<$ 0.001) at Day 13 + TTX, which approached normal levels (compared to pre- and sham-implanted groups) by Day 21 of post-explanation recovery. (Abstract shortened by UMI.) ^

Reduction of setup uncertainties and tumor motion in the radiation therapy of lung tumors

Because the goal of radiation therapy is to deliver a lethal dose to the tumor, accurate information on the location of the tumor needs to be known. Margins are placed around the tumor to account for variations in the daily position of the tumor. If tumor motion and patient setup uncertainties can be reduced, margins that account for such uncertainties in tumor location in can be reduced allowing dose escalation, which in turn could potentially improve survival rates. ^ In the first part of this study, we monitor the location of fiducials implanted in the periphery of lung tumors to determine the extent of non-gated and gated fiducial motion, and to quantify patient setup uncertainties. In the second part we determine where the tumor is when different methods of image-guided patient setup and respiratory gating are employed. In the final part we develop, validate, and implement a technique in which patient setup uncertainties are reduced by aligning patients based upon fiducial locations in projection images. ^ Results from the first part indicate that respiratory gating reduces fiducial motion relative to motion during normal respiration and setup uncertainties when the patients were aligned each day using externally placed skin marks are large. The results from the second part indicate that current margins that account for setup uncertainty and tumor motion result in less than 2% of the tumor outside of the planning target volume (PTV) when the patient is aligned using skin marks. In addition, we found that if respiratory gating is going to be used, it is most effective if used in conjunction with image-guided patient setup. From the third part, we successfully developed, validated, and implemented on a patient a technique for aligning a moving target prior to treatment to reduce the uncertainties in tumor location. ^ In conclusion, setup uncertainties and tumor motion are a significant problem when treating tumors located within the thoracic region. Image-guided patient setup in conjunction with treatment delivery using respiratory gating reduces these uncertainties in tumor locations. In doing so, margins around the tumor used to generate the PTV can be reduced, which may allow for dose escalation to the tumor. ^

Development of automated image analysis tools for verification of radiotherapy field accuracy with an electronic portal imaging device

The successful management of cancer with radiation relies on the accurate deposition of a prescribed dose to a prescribed anatomical volume within the patient. Treatment set-up errors are inevitable because the alignment of field shaping devices with the patient must be repeated daily up to eighty times during the course of a fractionated radiotherapy treatment. With the invention of electronic portal imaging devices (EPIDs), patient's portal images can be visualized daily in real-time after only a small fraction of the radiation dose has been delivered to each treatment field. However, the accuracy of human visual evaluation of low-contrast portal images has been found to be inadequate. The goal of this research is to develop automated image analysis tools to detect both treatment field shape errors and patient anatomy placement errors with an EPID. A moments method has been developed to align treatment field images to compensate for lack of repositioning precision of the image detector. A figure of merit has also been established to verify the shape and rotation of the treatment fields. Following proper alignment of treatment field boundaries, a cross-correlation method has been developed to detect shifts of the patient's anatomy relative to the treatment field boundary. Phantom studies showed that the moments method aligned the radiation fields to within 0.5mm of translation and 0.5$\sp\circ$ of rotation and that the cross-correlation method aligned anatomical structures inside the radiation field to within 1 mm of translation and 1$\sp\circ$ of rotation. A new procedure of generating and using digitally reconstructed radiographs (DRRs) at megavoltage energies as reference images was also investigated. The procedure allowed a direct comparison between a designed treatment portal and the actual patient setup positions detected by an EPID. Phantom studies confirmed the feasibility of the methodology. Both the moments method and the cross-correlation technique were implemented within an experimental radiotherapy picture archival and communication system (RT-PACS) and were used clinically to evaluate the setup variability of two groups of cancer patients treated with and without an alpha-cradle immobilization aid. The tools developed in this project have proven to be very effective and have played an important role in detecting patient alignment errors and field-shape errors in treatment fields formed by a multileaf collimator (MLC). ^

Thoracic radiotherapy treatment planning with cine PET/CT

Purpose: Respiratory motion causes substantial uncertainty in radiotherapy treatment planning. Four-dimensional computed tomography (4D-CT) is a useful tool to image tumor motion during normal respiration. Treatment margins can be reduced by targeting the motion path of the tumor. The expense and complexity of 4D-CT, however, may be cost-prohibitive at some facilities. We developed an image processing technique to produce images from cine CT that contain significant motion information without 4D-CT. The purpose of this work was to compare cine CT and 4D-CT for the purposes of target delineation and dose calculation, and to explore the role of PET in target delineation of lung cancer. Methods: To determine whether cine CT could substitute 4D-CT for small mobile lung tumors, we compared target volumes delineated by a physician on cine CT and 4D-CT for 27 tumors with intrafractional motion greater than 1 cm. We assessed dose calculation by comparing dose distributions calculated on respiratory-averaged cine CT and respiratory-averaged 4D-CT using the gamma index. A threshold-based PET segmentation model of size, motion, and source-to-background was developed from phantom scans and validated with 24 lung tumors. Finally, feasibility of integrating cine CT and PET for contouring was assessed on a small group of larger tumors. Results: Cine CT to 4D-CT target volume ratios were (1.05±0.14) and (0.97±0.13) for high-contrast and low-contrast tumors respectively which was within intraobserver variation. Dose distributions on cine CT produced good agreement (< 2%/1 mm) with 4D-CT for 71 of 73 patients. The segmentation model fit the phantom data with R2 = 0.96 and produced PET target volumes that matched CT better than 6 published methods (-5.15%). Application of the model to more complex tumors produced mixed results and further research is necessary to adequately integrate PET and cine CT for delineation. Conclusions: Cine CT can be used for target delineation of small mobile lesions with minimal differences to 4D-CT. PET, utilizing the segmentation model, can provide additional contrast. Additional research is required to assess the efficacy of complex tumor delineation with cine CT and PET. Respiratory-averaged cine CT can substitute respiratory-averaged 4D-CT for dose calculation with negligible differences.

Thoracic target volume delineation using various maximum-intensity projection computed tomography image sets for stereotactic body radiation therapy

The motion of lung tumors during respiration makes the accurate delivery of radiation therapy to the thorax difficult because it increases the uncertainty of target position. The adoption of four-dimensional computed tomography (4D-CT) has allowed us to determine how a tumor moves with respiration for each individual patient. Using information acquired during a 4D-CT scan, we can define the target, visualize motion, and calculate dose during the planning phase of the radiotherapy process. One image data set that can be created from the 4D-CT acquisition is the maximum-intensity projection (MIP). The MIP can be used as a starting point to define the volume that encompasses the motion envelope of the moving gross target volume (GTV). Because of the close relationship that exists between the MIP and the final target volume, we investigated four MIP data sets created with different methodologies (3 using various 4D-CT sorting implementations, and one using all available cine CT images) to compare target delineation. It has been observed that changing the 4D-CT sorting method will lead to the selection of a different collection of images; however, the clinical implications of changing the constituent images on the resultant MIP data set are not clear. There has not been a comprehensive study that compares target delineation based on different 4D-CT sorting methodologies in a patient population. We selected a collection of patients who had previously undergone thoracic 4D-CT scans at our institution, and who had lung tumors that moved at least 1 cm. We then generated the four MIP data sets and automatically contoured the target volumes. In doing so, we identified cases in which the MIP generated from a 4D-CT sorting process under-represented the motion envelope of the target volume by more than 10% than when measured on the MIP generated from all of the cine CT images. The 4D-CT methods suffered from duplicate image selection and might not choose maximum extent images. Based on our results, we suggest utilization of a MIP generated from the full cine CT data set to ensure a representative inclusive tumor extent, and to avoid geometric miss.

IMPROVING QUANTITATIVE TREATMENT RESPONSE MONITORING WITH DEFORMABLE IMAGE REGISTRATION

Quantitative imaging with 18F-FDG PET/CT has the potential to provide an in vivo assessment of response to radiotherapy (RT). However, comparing tissue tracer uptake in longitudinal studies is often confounded by variations in patient setup and potential treatment induced gross anatomic changes. These variations make true response monitoring for the same anatomic volume a challenge, not only for tumors, but also for normal organs-at-risk (OAR). The central hypothesis of this study is that more accurate image registration will lead to improved quantitation of tissue response to RT with 18F-FDG PET/CT. Employing an in-house developed “demons” based deformable image registration algorithm, pre-RT tumor and parotid gland volumes can be more accurately mapped to serial functional images. To test the hypothesis, specific aim 1 was designed to analyze whether deformably mapping tumor volumes rather than aligning to bony structures leads to superior tumor response assessment. We found that deformable mapping of the most metabolically avid regions improved response prediction (P<0.05). The positive predictive power for residual disease was 63% compared to 50% for contrast enhanced post-RT CT. Specific aim 2 was designed to use parotid gland standardized uptake value (SUV) as an objective imaging biomarker for salivary toxicity. We found that relative change in parotid gland SUV correlated strongly with salivary toxicity as defined by the RTOG/EORTC late effects analytic scale (Spearman’s ρ = -0.96, P<0.01). Finally, the goal of specific aim 3 was to create a phenomenological dose-SUV response model for the human parotid glands. Utilizing only baseline metabolic function and the planned dose distribution, predicting parotid SUV change or salivary toxicity, based upon specific aim 2, became possible. We found that the predicted and observed parotid SUV relative changes were significantly correlated (Spearman’s ρ = 0.94, P<0.01). The application of deformable image registration to quantitative treatment response monitoring with 18F-FDG PET/CT could have a profound impact on patient management. Accurate and early identification of residual disease may allow for more timely intervention, while the ability to quantify and predict toxicity of normal OAR might permit individualized refinement of radiation treatment plan designs.