PROTRACTED HYPOFRACTIONATED RADIOTHERAPY for GRAVES' OPHTHALMOPATHY: A PILOT STUDY of CLINICAL and RADIOLOGIC RESPONSE

Purpose: To evaluate the clinical and radiologic response of patients with Graves' ophthalmopathy given low-dose orbital radiotherapy (RT) with a protracted fractionation.Methods and Materials: Eighteen patients (36 orbits) received orbital RT with a total dose of 10 Gy, fractionated in 1 Gy once a week over 10 weeks. of these, 9 patients received steroid therapy as well. Patients were evaluated clinically and radiologically at 6 months after treatment. Clinical response assessment was carried out using three criteria: by physical examination, by a modified clinical activity score, and by a verbal questionnaire considering the 10 most common signs and symptoms of the disease. Radiologic response was assessed by magnetic resonance imaging.Results: Improvement in ocular pain, palpebral edema, visual acuity, and ocular motility was observed in all patients. Significant decrease in symptoms such as tearing (p < 0.001) diplopia (p = 0.008), conjunctival hyperemia (p = 0.002), and ocular grittiness (p = 0.031) also occurred. Magnetic resonance imaging showed decrease in ocular muscle thickness and in the intensity of the T2 sequence signal in the majority of patients. Treatments were well tolerated, and to date no complications from treatment have been observed. There was no statistical difference in clinical and radiologic response between patients receiving RT alone and those receiving RT plus steroid therapy.Conclusion: RT delivered in at a low dose and in a protracted scheme should be considered as a useful therapeutic option for patients with Graves' ophthalmopathy. (C) 2012 Elsevier Inc.

Prostate Bed Motion During Post-Prostatectomy Radiotherapy

Thesis

On-board Robotic Multi-pinhole SPECT System for Region-of-interest (ROI) Imaging

On-board image guidance, such as cone-beam CT (CBCT) and kV/MV 2D imaging, is essential in many radiation therapy procedures, such as intensity modulated radiotherapy (IMRT) and stereotactic body radiation therapy (SBRT). These imaging techniques provide predominantly anatomical information for treatment planning and target localization. Recently, studies have shown that treatment planning based on functional and molecular information about the tumor and surrounding tissue could potentially improve the effectiveness of radiation therapy. However, current on-board imaging systems are limited in their functional and molecular imaging capability. Single Photon Emission Computed Tomography (SPECT) is a candidate to achieve on-board functional and molecular imaging. Traditional SPECT systems typically take 20 minutes or more for a scan, which is too long for on-board imaging. A robotic multi-pinhole SPECT system was proposed in this dissertation to provide shorter imaging time by using a robotic arm to maneuver the multi-pinhole SPECT system around the patient in position for radiation therapy.

A 49-pinhole collimated SPECT detector and its shielding were designed and simulated in this work using the computer-aided design (CAD) software. The trajectories of robotic arm about the patient, treatment table and gantry in the radiation therapy room and several detector assemblies such as parallel holes, single pinhole and 49 pinholes collimated detector were investigated. The rail mounted system was designed to enable a full range of detector positions and orientations to various crucial treatment sites including head and torso, while avoiding collision with linear accelerator (LINAC), patient table and patient.

An alignment method was developed in this work to calibrate the on-board robotic SPECT to the LINAC coordinate frame and to the coordinate frames of other on-board imaging systems such as CBCT. This alignment method utilizes line sources and one pinhole projection of these line sources. The model consists of multiple alignment parameters which maps line sources in 3-dimensional (3D) space to their 2-dimensional (2D) projections on the SPECT detector. Computer-simulation studies and experimental evaluations were performed as a function of number of line sources, Radon transform accuracy, finite line-source width, intrinsic camera resolution, Poisson noise and acquisition geometry. In computer-simulation studies, when there was no error in determining angles (α) and offsets (ρ) of the measured projections, the six alignment parameters (3 translational and 3 rotational) were estimated perfectly using three line sources. When angles (α) and offsets (ρ) were provided by Radon transform, the estimation accuracy was reduced. The estimation error was associated with rounding errors of Radon transform, finite line-source width, Poisson noise, number of line sources, intrinsic camera resolution and detector acquisition geometry. The estimation accuracy was significantly improved by using 4 line sources rather than 3 and also by using thinner line-source projections (obtained by better intrinsic detector resolution). With 5 line sources, median errors were 0.2 mm for the detector translations, 0.7 mm for the detector radius of rotation, and less than 0.5° for detector rotation, tilt and twist. In experimental evaluations, average errors relative to a different, independent registration technique were about 1.8 mm for detector translations, 1.1 mm for the detector radius of rotation (ROR), 0.5° and 0.4° for detector rotation and tilt, respectively, and 1.2° for detector twist.

Simulation studies were performed to investigate the improvement of imaging sensitivity and accuracy of hot sphere localization for breast imaging of patients in prone position. A 3D XCAT phantom was simulated in the prone position with nine hot spheres of 10 mm diameter added in the left breast. A no-treatment-table case and two commercial prone breast boards, 7 and 24 cm thick, were simulated. Different pinhole focal lengths were assessed for root-mean-square-error (RMSE). The pinhole focal lengths resulting in the lowest RMSE values were 12 cm, 18 cm and 21 cm for no table, thin board, and thick board, respectively. In both no table and thin board cases, all 9 hot spheres were easily visualized above background with 4-minute scans utilizing the 49-pinhole SPECT system while seven of nine hot spheres were visible with the thick board. In comparison with parallel-hole system, our 49-pinhole system shows reduction in noise and bias under these simulation cases. These results correspond to smaller radii of rotation for no-table case and thinner prone board. Similarly, localization accuracy with the 49-pinhole system was significantly better than with the parallel-hole system for both the thin and thick prone boards. Median localization errors for the 49-pinhole system with the thin board were less than 3 mm for 5 of 9 hot spheres, and less than 6 mm for the other 4 hot spheres. Median localization errors of 49-pinhole system with the thick board were less than 4 mm for 5 of 9 hot spheres, and less than 8 mm for the other 4 hot spheres.

Besides prone breast imaging, respiratory-gated region-of-interest (ROI) imaging of lung tumor was also investigated. A simulation study was conducted on the potential of multi-pinhole, region-of-interest (ROI) SPECT to alleviate noise effects associated with respiratory-gated SPECT imaging of the thorax. Two 4D XCAT digital phantoms were constructed, with either a 10 mm or 20 mm diameter tumor added in the right lung. The maximum diaphragm motion was 2 cm (for 10 mm tumor) or 4 cm (for 20 mm tumor) in superior-inferior direction and 1.2 cm in anterior-posterior direction. Projections were simulated with a 4-minute acquisition time (40 seconds per each of 6 gates) using either the ROI SPECT system (49-pinhole) or reference single and dual conventional broad cross-section, parallel-hole collimated SPECT. The SPECT images were reconstructed using OSEM with up to 6 iterations. Images were evaluated as a function of gate by profiles, noise versus bias curves, and a numerical observer performing a forced-choice localization task. Even for the 20 mm tumor, the 49-pinhole imaging ROI was found sufficient to encompass fully usual clinical ranges of diaphragm motion. Averaged over the 6 gates, noise at iteration 6 of 49-pinhole ROI imaging (10.9 µCi/ml) was approximately comparable to noise at iteration 2 of the two dual and single parallel-hole, broad cross-section systems (12.4 µCi/ml and 13.8 µCi/ml, respectively). Corresponding biases were much lower for the 49-pinhole ROI system (3.8 µCi/ml), versus 6.2 µCi/ml and 6.5 µCi/ml for the dual and single parallel-hole systems, respectively. Median localization errors averaged over 6 gates, for the 10 mm and 20 mm tumors respectively, were 1.6 mm and 0.5 mm using the ROI imaging system and 6.6 mm and 2.3 mm using the dual parallel-hole, broad cross-section system. The results demonstrate substantially improved imaging via ROI methods. One important application may be gated imaging of patients in position for radiation therapy.

A robotic SPECT imaging system was constructed utilizing a gamma camera detector (Digirad 2020tc) and a robot (KUKA KR150-L110 robot). An imaging study was performed with a phantom (PET CT PhantomTM), which includes 5 spheres of 10, 13, 17, 22 and 28 mm in diameter. The phantom was placed on a flat-top couch. SPECT projections were acquired with a parallel-hole collimator and a single-pinhole collimator both without background in the phantom, and with background at 1/10th the sphere activity concentration. The imaging trajectories of parallel-hole and pinhole collimated detectors spanned 180 degrees and 228 degrees respectively. The pinhole detector viewed a 14.7 cm-diameter common volume which encompassed the 28 mm and 22 mm spheres. The common volume for parallel-hole was a 20.8-cm-diameter cylinder which encompassed all five spheres in the phantom. The maneuverability of the robotic system was tested by navigating the detector to trace the flat-top table while avoiding collision with the table and maintaining the closest possible proximity to the common volume. For image reconstruction, detector trajectories were described by radius-of-rotation and detector rotation angle θ. These reconstruction parameters were obtained from the robot base and tool coordinates. The robotic SPECT system was able to maneuver the parallel-hole and pinhole collimated SPECT detectors in close proximity to the phantom, minimizing impact of the flat-top couch on detector to center-of-rotation (COR) distance. In no background case, all five spheres were visible in the reconstructed parallel-hole and pinhole images. In with background case, three spheres of 17, 22 and 28 mm diameter were readily observed with the parallel-hole imaging, and the targeted spheres (22 and 28 mm diameter) were readily observed in the pinhole ROI imaging.

In conclusion, the proposed on-board robotic SPECT can be aligned to LINAC/CBCT with a single pinhole projection of the line-source phantom. Alignment parameters can be estimated using one pinhole projection of line sources. This alignment method may be important for multi-pinhole SPECT, where relative pinhole alignment may vary during rotation. For single pinhole and multi-pinhole SPECT imaging onboard radiation therapy machines, the method could provide alignment of SPECT coordinates with those of CBCT and the LINAC. In simulation studies of prone breast imaging and respiratory-gated lung imaging, the 49-pinhole detector showed better tumor contrast recovery and localization in a 4-minute scan compared to parallel-hole detector. On-board SPECT could be achieved by a robot maneuvering a SPECT detector about patients in position for radiation therapy on a flat-top couch. The robot inherent coordinate frames could be an effective means to estimate detector pose for use in SPECT image reconstruction.

No association between TGFB1 polymorphisms and late radiotherapy toxicity: a meta-analysis.

BACKGROUND: Transforming growth factor-beta 1 (TGF-β1) protein may be multifunctional and related to the development of fibrosis, induction of apoptosis, extracellular signaling and inhibition of proliferation in response to radiation-induced DNA damage. Several studies have investigated associations between single nucleotide polymorphisms (SNPs) in the TGFB1 gene and risk of late radiation-induced injury of normal tissue, but the conclusions remain controversial. METHODS: We searched three electronic databases (i.e., MEDLINE, EMBASE and EBSCO) for eligible publications and performed a meta-analysis assessing the association of three commonly studied SNPs in TGFB1 (i.e., rs1800469, rs1800470 and rs1800471) with risk of late radiation-induced injury of normal tissue. RESULTS: We finally included 28 case-only studies from 16 publications on aforementioned SNPs in TGFB1. However, we did not find statistical evidence of any significant association with overall risk of late radiotherapy toxicity in the pooled analysis or in further stratified analysis by cancer type, endpoint, ethnicity and sample size. CONCLUSIONS: This meta-analysis did not find statistical evidence for an association between SNPs in TGFB1 and risk of late radiation-induced injury of normal tissue, but this finding needs further confirmation by a single large study.

Apoptotic variants as predictors of risk of oropharyngeal cancer recurrence after definitive radiotherapy.

Single nucleotide polymorphisms (SNPs) in the promoter region of FAS and FASLG may alter their transcriptional activity. Thus, we determined the associations between four FAS and FASLG promoter variants (FAS1377G>A, rs2234767; 670A>G, rs1800682; FASLG844T>C, rs763110 and 124A>G, rs5030772) and the risk of recurrence of squamous cell carcinoma of the oropharynx (SCCOP). We evaluated the associations between FAS and FASLG genetic variants and the risk of recurrence in a cohort of 1,008 patients. The log-rank test and multivariate Cox models were used to evaluate the associations. Compared with patients with common homozygous genotypes of FAS670 and FASLG844 polymorphisms, patients with variant genotypes had lower disease-free survival rates (log-rank p < 0.0001 and p < 0.0001, respectively) and an approximately threefold higher risk of SCCOP recurrence (HR, 3.2;95% CI, 2.2-4.6; and HR, 3.1; 95% CI, 2.2-4.4, respectively) after multivariate adjustment. Furthermore, among patients with HPV16-positive tumors, those with variant genotypes of these two polymorphisms had lower disease-free survival rates (log-rank, p < 0.0001 and p < 0.0001, respectively) and a higher recurrence risk than did patients with common homozygous genotypes (HR, 12.9; 95% CI, 3.8-43.6; and HR, 8.1; 95% CI, 3.6-18.6, respectively), whereas no significant associations were found for FAS1377 and FASLG124 polymorphisms. Our findings suggest that FAS670 and FASLG844 polymorphisms modulate the risk of recurrence of SCCOP, particularly in patients with HPV16-positive tumors. Larger studies are needed to validate these results.

Visual functioning and quality of life in the subfoveal radiotherapy study (SFRADS): SFRADS report 2

Aims: To determine whether or not self reported visual functioning and quality of life in patients with choroidal neovascularisation caused by age related macular degeneration (AMD) is better in those treated with 12 Gy external beam radiotherapy in comparison with untreated subjects. Methods: A multicentre single masked randomised controlled trial of 12 Gy of external beam radiation therapy (EBRT) delivered as 6x2 Gy fractions to the macula of an affected eye versus observation. Patients with AMD, aged 60 years or over, in three UK hospital units, who had subfoveal CNV and a visual acuity equal to or better than 6/60 (logMAR 1.0). Methods: Data from 199 eligible participants who were randomly assigned to 12 Gy teletherapy or observation were available for analysis. Visual function assessment, ophthalmic examination, and fundus fluorescein angiography were undertaken at baseline and at 3, 6, 12, and 24 months after study entry. To assess patient centred outcomes, subjects were asked to complete the Daily Living Tasks Dependent on Vision (DLTV) and the SF-36 questionnaires at baseline, 6, 12, and 24 months after enrolment to the study. Cross sectional and longitudinal analyses were conducted using arm of study as grouping variable. Regression analysis was employed to adjust for the effect of baseline co-variates on outcome at 12 months and 24 months. Results: Both control and treated subjects had significant losses in visual functioning as seen by a progressive decline in mean scores in the four dimensions of the DLTV. There were no statistically significant differences between treatment and control subjects in any of dimensions of the DLTV at 12 months or 24 months after study entry. Regression analysis confirmed that treatment status had no effect on the change in DLTV dimensional scores. Conclusions: The small benefits noted in clinical measures of vision in treated eyes did not translate into better self reported visual functioning in patients who received treatment when compared with the control arm. These findings have implications for the design of future clinical trials and studies.

Prediction of Scattered Dose to the Testes in Abdominopelvic Radiotherapy.

Radical abdominal radiotherapy in men runs the risk of impairing their fertility owing to scattered dose to the testes, outside of the treated volume. In patients for whom this is a concern it is important to be able to predict the dose to the testes before treatment in order to determine whether semen cryopreservation should be undertaken and testicular shielding performed during treatment. Measurements have been made on an anthropomorphic phantom to determine the magnitude of these doses for a four-field treatment consisting of an anterior-posterior parallel pair and a lateral parallel pair. A dataset is presented, which, together with a correction for patients size, allows an estimate of testicular dose to be made given only the photon energy, interfield distances and the distance from the testes to the nearest beam edge. Thermoluminescent dosimetry has been carried out in 17 patients to validate the use of the data tables. The results indicate that testicular doses may be estimated with a standard deviation corresponding to 1%-2% of the tumour dose, which is sufficient for the purpose of determining whether fertility is threatened by a planned treatment.

Potential improvements in the therapeutic ratio of prostate cancer irradiation: dose escalation of pathologically identified tumour nodules using intensity modulated radiotherapy.

The potential of intensity modulated radiotherapy (IMRT) to improve the therapeutic ratio in prostate cancer by dose escalation of intraprostatic tumour nodules (IPTNs) was investigated using a simultaneous integrated boost technique. The prostate and organs-at-risk were outlined on CT images from six prostate cancer patients. Positions of IPTNs were transferred onto the CT images from prostate maps derived from sequential large block sections of whole prostatectomy specimens. Inverse planned IMRT dose distributions were created to irradiate the prostate to 70 Gy and all the IPTNs to 90 Gy. A second plan was produced to escalate only the dominant IPTN (DIPTN) to 90 Gy, mimicking current imaging techniques. These plans were compared with homogeneous prostate irradiation to 70 Gy using dose–volume histograms, tumour control probability (TCP) and normal tissue complication probability (NTCP) for the rectum. The mean dose to IPTNs was increased from 69.8 Gy to 89.1 Gy if all the IPTNs were dose escalated (p=0.0003). This corresponded to a mean increase in TCP of 8.7–31.2% depending on the /ß ratio of prostate cancer (p

Intensity-modulated radiotherapy reduces lung irradiation in patients with carcinoma of the oesophagus.

The 2-year survival rate after conventional radiotherapy for carcinoma of the oesophagus is around 10–20% [8]. Concomitant chemoradiation schedules have produced survival figures of 25–30% at 5 years, and this is now considered standard treatment [1]. Conformal radiotherapy techniques offer the potential to deliver higher doses of radiation to oesophageal tumours [5], and this may improve local tumour control. However, concerns regarding late normal tissue damage to the lung parenchyma and spinal cord remain a concern. Intensitymodulated radiotherapy (IMRT) allows complex dose distributions to be produced, and can reduce the dose to radiosensitive organs close to the tumour [2]. The present study was designed to investigate the impact of beam intensity modulation on treatment planning for carcinoma of the oesophagus, by comparing a standard three-dimensional conformal radiotherapy (3DCRT) technique to an IMRT technique using the same number and orientation of treatment fields.

A comparison of conformal and intensity-modulated techniques for oesophageal radiotherapy.

Background and purpose: To investigate the potential of intensity-modulated radiotherapy (IMRT) to reduce lung irradiation in the treatment of oesophageal carcinoma with radical radiotherapy.Materials and methods: A treatment planning study was performed to compare two-phase conformal radiotherapy (CFRT) with IMRT in five patients. The CFRT plans consisted of anterior, posterior and bilateral posterior oblique fields, while the IMRT plans consisted of either nine equispaced fields (9F), or four fields (4F) with orientations equal to the CFRT plans. IMRT plans with seven, five or three equispaced fields were also investigated in one patient. Treatment plans were compared using dose-volume histograms and normal tissue complication probabilities.Results: The 9F IMRT plan was unable to improve on the homogeneity of dose to the planning target volume (PTV), compared with the CFRT plan (dose range, 16.9+/-4.5 (1 SD) vs. 12.4+/-3.9%; P=0.06). Similarly, the 9F IMRT plan was unable to reduce the mean lung dose (11.7+/-3.2 vs. 11.0+/-2.9 Gy; P=0.2). Similar results were obtained for seven, five and three equispaced fields in the single patient studied. The 4F IMRT plan provided comparable PTV dose homogeneity with the CFRT plan (11.8+/-3.3 vs. 12.4+/-3.9%; P=0.6), with reduced mean lung dose (9.5+/-2.3 vs 11.0+/-2.9 Gy; P=0.001).Conclusions: IMRT using nine equispaced fields provided no improvement over CFRT. This was because the larger number of fields in the IMRT plan distributed a low dose over the entire lung. In contrast, IMRT using four fields equal to the CFRT fields offered an improvement in lung sparing. Thus, IMRT with a few carefully chosen field directions may lead to a modest reduction in pneumonitis, or allow tumour dose escalation within the currently accepted lung toxicity.