W D'Souza

Real-time intra-fraction-motion tracking using the treatment couch: a feasibility study

Significant differences between planned and delivered treatments may occur due to respiration-induced tumour motion, leading to underdosing of parts of the tumour and overdosing of parts of the surrounding critical structures. Existing methods proposed to counter tumour motion include breath-holds, gating and MLC-based tracking. Breath-holds and gating techniques increase treatment time considerably, whereas MLC-based tracking is limited to two dimensions. We present an alternative solution in which a robotic couch moves in real time in response to organ motion. To demonstrate proof-of-principle, we constructed a miniature adaptive couch model consisting of two movable platforms that simulate tumour motion and couch motion, respectively. These platforms were connected via an electronic feedback loop so that the bottom platform responded to the motion of the top platform. We tested our model with a seven-field step-and-shoot delivery case in which we performed three film-based experiments: (1) static geometry, (2) phantom-only motion and (3) phantom motion with simulated couch motion. Our measurements demonstrate that the miniature couch was able to compensate for phantom motion to the extent that the dose distributions were practically indistinguishable from those in static geometry. Motivated by this initial success, we investigated a real-time couch compensation system consisting of a stereoscopic infra-red camera system interfaced to a robotic couch known as the Hexapod, which responds in real time to any change in position detected by the cameras. Optical reflectors placed on a solid water phantom were used as surrogates for motion. We tested the effectiveness of couch-based motion compensation for fixed fields and a dynamic arc delivery cases. Due to hardware limitations, we performed film-based experiments (1), (2) and (3), with the robotic couch at a phantom motion period and dose rate of 16 s and 100 MU min(-1), respectively. Analysis of film measurements showed near-equivalent dose distributions (<or=2 mm agreement of corresponding isodose lines) for static geometry and motion-synchronized real-time robotic couch tracking-based radiation delivery.

Impact of prolonged fraction delivery times on tumor control: a note of caution for intensity-modulated radiation therapy (IMRT).

PURPOSE Intensity-modulated radiation therapy (IMRT) allows greater dose conformity to the tumor target. However, IMRT, especially static delivery, usually requires more time to deliver a dose fraction than conventional external beam radiotherapy (EBRT). The purpose of this work is to explore the potential impact of such prolonged fraction delivery times on treatment outcome. METHODS AND MATERIALS The generalized linear-quadratic (LQ) model, which accounts for sublethal damage repair and clonogen proliferation, was used to calculate the cell-killing efficiency of various simulated and clinical IMRT plans. LQ parameters derived from compiled clinical data for prostate cancer (alpha = 0.15 Gy(-1), alpha/beta = 3.1 Gy, and a 16-min repair half-time) were used to compute changes in the equivalent uniform dose (EUD) and tumor control probability (TCP) due to prolonged delivery time of IMRT as compared with conventional EBRT. EUD and TCP calculations were also evaluated for a wide range of radiosensitivity parameters. The effects of fraction delivery times ranging from 0 to 45 min on cell killing were studied. RESULTS Our calculations indicate that fraction delivery times in the range of 15-45 min may significantly decrease cell killing. For a prescription dose of 81 Gy in 1.8 Gy fractions, the EUD for prostate cancer decreases from 78 Gy for a conventional EBRT to 69 Gy for an IMRT with a fraction delivery time of 30 min. The values of EUD are sensitive to the alpha/beta ratio, the repair half-time, and the fraction delivery time. The instantaneous dose-rate, beam-on time, number of leaf shapes (segments), and leaf-sequencing patterns given the same overall fraction delivery time were found to have negligible effect on cell killing. CONCLUSIONS The total time to deliver a single fraction may have a significant impact on IMRT treatment outcome for tumors with a low alpha/beta ratio and a short repair half-time, such as prostate cancer. These effects, if confirmed by clinical studies, should be considered in designing IMRT treatments.

Moderate predictive value of demographic and behavioral characteristics for a diagnosis of HPV16-positive and HPV16-negative head and neck cancer

Patients with HPV-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) are significantly different with regard to sociodemographic and behavioral characteristics that clinicians may use to assume tumor HPV status. Machine learning methods were used to evaluate the predictive value of patient characteristics and laboratory biomarkers of HPV exposure for a diagnosis of HPV16-positive HNSCC compared to in situ hybridization, the current gold-standard. Models that used a combination of demographic characteristics such as age, tobacco use, gender, and race had only moderate predictive value for tumor HPV status among all patients with HNSCC (positive predictive value [PPV]=75%, negative predictive value [NPV]=68%) or when limited to oropharynx cancer patients (PPV=55%, NPV=65%) and thus included a sizeable number of false positive and false negative predictions. Prediction was not improved by the addition of other demographic or behavioral factors (sexual behavior, income, education) or biomarkers of HPV16 exposure (L1, E6/7 antibodies or DNA in oral exfoliated cells). Patient demographic and behavioral characteristics as well as HPV biomarkers are not an accurate substitute for clinical testing of tumor HPV status.

Spatial-Temporal [18F]FDG-PET Features for Predicting Pathologic Response of Esophageal Cancer to Neoadjuvant Chemoradiation Therapy

PURPOSE To extract and study comprehensive spatial-temporal (18)F-labeled fluorodeoxyglucose ([(18)F]FDG) positron emission tomography (PET) features for the prediction of pathologic tumor response to neoadjuvant chemoradiation therapy (CRT) in esophageal cancer. METHODS AND MATERIALS Twenty patients with esophageal cancer were treated with trimodal therapy (CRT plus surgery) and underwent [(18)F]FDG-PET/CT scans both before (pre-CRT) and after (post-CRT) CRT. The 2 scans were rigidly registered. A tumor volume was semiautomatically delineated using a threshold standardized uptake value (SUV) of ≥2.5, followed by manual editing. Comprehensive features were extracted to characterize SUV intensity distribution, spatial patterns (texture), tumor geometry, and associated changes resulting from CRT. The usefulness of each feature in predicting pathologic tumor response to CRT was evaluated using the area under the receiver operating characteristic curve (AUC) value. RESULTS The best traditional response measure was decline in maximum SUV (SUVmax; AUC, 0.76). Two new intensity features, decline in mean SUV (SUVmean) and skewness, and 3 texture features (inertia, correlation, and cluster prominence) were found to be significant predictors with AUC values ≥0.76. According to these features, a tumor was more likely to be a responder when the SUVmean decline was larger, when there were relatively fewer voxels with higher SUV values pre-CRT, or when [(18)F]FDG uptake post-CRT was relatively homogeneous. All of the most accurate predictive features were extracted from the entire tumor rather than from the most active part of the tumor. For SUV intensity features and tumor size features, changes were more predictive than pre- or post-CRT assessment alone. CONCLUSION Spatial-temporal [(18)F]FDG-PET features were found to be useful predictors of pathologic tumor response to neoadjuvant CRT in esophageal cancer.

Tissue mimicking materials for a multi‐imaging modality prostate phantom

Materials that simultaneously mimic soft tissue in vivo for magnetic resonance imaging (MRI), ultrasound (US), and computed tomography (CT) for use in a prostate phantom have been developed. Prostate and muscle mimicking materials contain water, agarose, lipid particles, protein, Cu++, EDTA, glass beads, and thimerosal (preservative). Fat was mimicked with safflower oil suffusing a random mesh (network) of polyurethane. Phantom material properties were measured at 22 degrees C. (22 degrees C is a typical room temperature at which phantoms are used.) The values of material properties should match, as well as possible, the values for tissues at body temperature, 37 degrees C. For MRI, the primary properties of interest are T1 and T2 relaxations times, for US they are the attenuation coefficient, propagation speed, and backscatter, and for CT, the x-ray attenuation. Considering the large number of parameters to be mimicked, rather good agreement was found with actual tissue values obtained from the literature. Using published values for prostate parenchyma, T1 and T2 at 37 degrees C and 40 MHz are estimated to be about 1,100 and 98 ms, respectively. The CT number for in vivo prostate is estimated to be 45 HU (Hounsfield units). The prostate mimicking material has a T1 of 937 ms and a T2 of 88 ms at 22 degrees C and 40 MHz; the propagation speed and attenuation coefficient slope are 1,540 m/s and 0.36 dB/cm/MHz, respectively, and the CT number of tissue mimicking prostate is 43 HU. Tissue mimicking (TM) muscle differs from TM prostate in the amount of dry weight agarose, Cu++, EDTA, and the quality and quantity of glass beads. The 18 microm glass beads used in TM muscle increase US backscatter and US attenuation; the presence of the beads also has some effect on T1 but no effect on T2. The composition of tissue-mimicking materials developed is such that different versions can be placed in direct contact with one another in a phantom with no long term change in US, MRI, or CT properties. Thus, anthropomorphic phantoms can be constructed.

An analysis of the treatment couch and control system dynamics for respiration-induced motion compensation

Sophisticated methods for real-time motion compensation include using the linear accelerator, MLC, or treatment couch. To design such a couch, the required couch and control system dynamics need to be investigated. We used an existing treatment couch known as the Hexapod to gain insight into couch dynamics and an internal model controller to simulate feedback control of respiration-induced motion. The couch dynamics, described using time constants and dead times, were investigated using step inputs. The resulting data were modeled as first and second order systems with dead time. The couch was determined to have a linear response for step inputs < or = 1 cm. Motion data from 12 patients were obtained using a skin marker placed on the abdomen of the patient and the marker data were assumed to be an exact surrogate of tumor motion. The feedback system was modeled with the couch as a second-ordersystem and the controller as a first order system. The time constants of the couch and controller and the dead times were varied starting with parameters obtained from the Hexapod couch and the performance of the feedback system was evaluated. The resulting residual motion under feedback control was generally <0.3 cm when a fast enough couch was simulated.

Deformable planning CT to cone‐beam CT image registration in head‐and‐neck cancer

PURPOSE The purpose of this work was to implement and validate a deformable CT to cone-beam computed tomography (CBCT) image registration method in head-and-neck cancer to eventually facilitate automatic target delineation on CBCT. METHODS Twelve head-and-neck cancer patients underwent a planning CT and weekly CBCT during the 5-7 week treatment period. The 12 planning CT images (moving images) of these patients were registered to their weekly CBCT images (fixed images) via the symmetric force Demons algorithm and using a multiresolution scheme. Histogram matching was used to compensate for the intensity difference between the two types of images. Using nine known anatomic points as registration targets, the accuracy of the registration was evaluated using the target registration error (TRE). In addition, region-of-interest (ROI) contours drawn on the planning CT were morphed to the CBCT images and the volume overlap index (VOI) between registered contours and manually delineated contours was evaluated. RESULTS The mean TRE value of the nine target points was less than 3.0 mm, the slice thickness of the planning CT. Of the 369 target points evaluated for registration accuracy, the average TRE value was 2.6 +/- 0.6 mm. The mean TRE for bony tissue targets was 2.4 +/- 0.2 mm, while the mean TRE for soft tissue targets was 2.8 +/- 0.2 mm. The average VOI between the registered and manually delineated ROI contours was 76.2 +/- 4.6%, which is consistent with that reported in previous studies. CONCLUSIONS The authors have implemented and validated a deformable image registration method to register planning CT images to weekly CBCT images in head-and-neck cancer cases. The accuracy of the TRE values suggests that they can be used as a promising tool for automatic target delineation on CBCT.

Selection of beam orientations in intensity-modulated radiation therapy using single-beam indices and integer programming

While the process of IMRT planning involves optimization of the dose distribution, the procedure for selecting the beam inputs for this process continues to be largely trial-and-error. We have developed an integer programming (IP) optimization method to optimize beam orientation using mean organ-at-risk (MOD) data from single-beam plans. Two test cases were selected in which one organ-at-risk (OAR) and four OARs were simulated, respectively, along with a PTV. Beam orientation space was discretized in 10 degrees increments. For each beam orientation, a single-beam plan without intensity modulation and without constraints on OAR dose was generated and normalized to yield a mean PTV dose of 2 Gy and the corresponding MOD was calculated. The degree of OAR sparing was related to the average OAR MODs resulting from the beam orientations utilized with improvements of up to 10% at some dose levels. On the other hand, OAR DVHs in the IMRT plans were insensitive to beam numbers (in the 6-9 range) for similar average single-beam MODs. These MOD data were input to an IP optimization process, which then selected specified numbers of beam angles as inputs to a treatment planning system. Our results show that sets of beam angles with lower average single-beam MODs produce IMRT plans with better OAR sparing than manually selected beam angles. To optimize beam orientations, weights were assigned to each OAR following MOD input to the IP which was subsequently solved using the branch-and-cut algorithm. Seven-beam orientations obtained from solving the IP were applied to the test case with four OARs and the resulting plan with a dose prescription of 63 Gy was compared with an equi-spaced beam plan. The IP selected beams produced dose-volume improvements of up to 40% for OARs proximal to the PTV. Further improvement in the DVH can be obtained by increasing the weights assigned to these OARs but at the expense of the remaining OARs.

Dosimetric consequences of using a surrogate urethra to estimate urethral dose after brachytherapy for prostate cancer.

PURPOSE To assess the accuracy and dosimetric consequences of defining a surrogate urethra at the geometric center of the prostate in postimplant CT scans. METHODS AND MATERIALS Eighty postimplant CT scans were obtained with a Foley catheter in place at Day 0 and at 1 month for 40 patients who had undergone (125)I prostate brachytherapy. The percentage of urethral volume receiving at least 275% of the prescribed dose (uV(275)), uV(250), uV(200), uV(150), maximal dose received by 90% of urethral volume (uD(90)), uD(70), uD(30), and uD(1) were measured for the Foley catheter and surrogate urethra. The distance between the Foley catheter and surrogate urethra was measured at the base, middle, and apex of the prostate. RESULTS A statistically significant difference was found in all the above-listed dosimetric parameters between the Foley catheter and surrogate urethra at Day 0 (p <or= 0.001). At 1 month, the uD(90), uD(70), and uD(1) remained significantly different between the Foley catheter and surrogate urethra (p <or= 0.05). The difference in the uV(275) (p = 0.055) and uV(150) (p = 0.059) between the Foley catheter and surrogate urethra showed a trend toward statistical significance at 1 month. The uV(250), uV(200), and uD(30) were greater for the surrogate urethra than for the Foley catheter at 1 month, but were not significantly different statistically. The mean distance between the Foley catheter and the surrogate urethra was greatest at the base (1.2 cm) in the vertical axis at Day 0 and decreased substantially to 0.87 cm at 1 month (p = 0.0004). CONCLUSION Using a surrogate urethra at the geometric center of the prostate may significantly overestimate the urethral dose at Day 0 and certain dosimetric parameters at 1 month. An alternative position for a surrogate urethra accounting for the difference in the location of the Foley catheter near the base of the prostate at Day 0 and 1 month could be considered in future studies.

Modeling Pathologic Response of Esophageal Cancer to Chemoradiation Therapy Using Spatial-Temporal 18F-FDG PET Features, Clinical Parameters, and Demographics

PURPOSE To construct predictive models using comprehensive tumor features for the evaluation of tumor response to neoadjuvant chemoradiation therapy (CRT) in patients with esophageal cancer. METHODS AND MATERIALS This study included 20 patients who underwent trimodality therapy (CRT+surgery) and underwent 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) both before and after CRT. Four groups of tumor features were examined: (1) conventional PET/CT response measures (eg, standardized uptake value [SUV]max, tumor diameter); (2) clinical parameters (eg, TNM stage, histology) and demographics; (3) spatial-temporal PET features, which characterize tumor SUV intensity distribution, spatial patterns, geometry, and associated changes resulting from CRT; and (4) all features combined. An optimal feature set was identified with recursive feature selection and cross-validations. Support vector machine (SVM) and logistic regression (LR) models were constructed for prediction of pathologic tumor response to CRT, cross-validations being used to avoid model overfitting. Prediction accuracy was assessed by area under the receiver operating characteristic curve (AUC), and precision was evaluated by confidence intervals (CIs) of AUC. RESULTS When applied to the 4 groups of tumor features, the LR model achieved AUCs (95% CI) of 0.57 (0.10), 0.73 (0.07), 0.90 (0.06), and 0.90 (0.06). The SVM model achieved AUCs (95% CI) of 0.56 (0.07), 0.60 (0.06), 0.94 (0.02), and 1.00 (no misclassifications). With the use of spatial-temporal PET features combined with conventional PET/CT measures and clinical parameters, the SVM model achieved very high accuracy (AUC 1.00) and precision (no misclassifications)-results that were significantly better than when conventional PET/CT measures or clinical parameters and demographics alone were used. For groups with many tumor features (groups 3 and 4), the SVM model achieved significantly higher accuracy than did the LR model. CONCLUSIONS The SVM model that used all features including spatial-temporal PET features accurately and precisely predicted pathologic tumor response to CRT in esophageal cancer.