Monique van Prooijen

Gold Nanoparticles as Radiation Sensitizers in Cancer Therapy

Abstract Among other nanoparticle systems, gold nanoparticles have been explored as radiosensitizers. While most of the research in this area has focused on either gold nanoparticles with diameters of less than 2 nm or particles with micrometer dimensions, it has been shown that nanoparticles 50 nm in diameter have the highest cellular uptake. We present the results of in vitro studies that focus on the radiosensitization properties of nanoparticles in the size range from 14–74 nm. Radiosensitization was dependent on the number of gold nanoparticles internalized within the cells. Gold nanoparticles 50-nm in diameter showed the highest radiosensitization enhancement factor (REF) (1.43 at 220 kVp) compared to gold nanoparticles of 14 and 74 nm (1.20 and 1.26, respectively). Using 50-nm gold nanoparticles, the REF for lower- (105 kVp) and higher- (6 MVp) energy photons was 1.66 and 1.17, respectively. DNA double-strand breaks were quantified using radiation-induced foci of γ-H2AX and 53BP1, and a modest increase in the number of foci per nucleus was observed in irradiated cell populations with internalized gold nanoparticles. The outcome of this research will enable the optimization of gold nanoparticle-based sensitizers for use in therapy.

Dosimetric comparison of IMRT vs. 3D conformal radiotherapy in the treatment of cancer of the cervical esophagus

BACKGROUND AND PURPOSE Radiotherapy planning for cervical esophageal cancer is challenging. We compared IMRT and 3D conformal radiotherapy (CRT) with respect to conformality of target coverage and normal tissue sparing. MATERIALS AND METHODS We selected five patients with cervical esophagus cancer, who represented the heterogeneity of clinical cases, treated to radical dose and planned with Pinnacle v6.2. Target doses for CRT plans were 50, 60, and 70Gy (single-phase IMRT 56, 63, and 70). We compared PTV coverage by the 95% isodose (PTV(95)), conformality ratio (CR), conformation number (CN), and maximum or mean doses (D(max), D(mean)) to normal structures. RESULTS Median PTV(95) for IMRT plans for PTV70, PTV63, and PTV56 were 97%, 99%, and 98% (CRT 91%, 98%, and 85%). IMRT plans demonstrated lower D(max) to the spinal cord and brainstem (42 and 36Gy) compared to CRT (46 and 39Gy). Median left parotid D(mean) was 35Gy (IMRT) vs. 53Gy (CRT). Median right parotid D(mean) was 35Gy (IMRT) vs. 36Gy (CRT). The median CR50/56Gy was 1.4 (CRT) vs. 1.2 (IMRT), CR70Gy 1.7 (CRT) vs. 1.1 (IMRT). CN50/56 and CN70 values were 0.80 and 0.85 (IMRT) vs. 0.56 and 0.5 (CRT). CONCLUSIONS IMRT provides superior target volume coverage and conformality, with decreased dose to normal structures.

Limitation of conventional two dimensional radiation therapy planning in nasopharyngeal carcinoma.

PURPOSE To assess the adequacy of coverage of gross tumor volume (GTV) with traditional two dimensional (2D) radiation therapy (RT) planning in patients with nasopharyngeal cancer (NPC). MATERIALS AND METHODS The study comprised 94 of 179 patients treated with definitive RT between 1993 and 1997. The inclusion requirement was the availability of a digitally archived pretreatment magnetic resonance imaging. The digital images were used to record the precise location of the GTV in the sagittal plane. As a separate procedure, sagittal dose distributions for each treatment phase were created by digitizing the simulation field parameters into treatment planning software without knowledge of the GTV. The location of the GTV and dose distribution in the sagittal plane were superimposed on each other and GTV coverage by the 50, 90 and 95% isodose lines determined for each phase of treatment. RESULTS The 1997 tumour node metastasis (TNM) stage distribution was: 7 (8%) stage I, 16 (16%) stage II, 30 (32%) stage III and 41 (44%) stage IV. Median follow-up was 4.4 years. Median primary dose was 66 Gy. The actuarial 5-year overall survival, disease free survival and local relapse free rates were 88, 54 and 66%, respectively. The GTV was covered by the 50, 90 and 95% isodose lines for all phases of the multiphase plan in only 53, 20 and 9% of patients, respectively. The GTV was more likely to be undercovered in the latter phases of the plan particularly in those patients with advanced T category. CONCLUSION 2D RT planning has significant limitations in achieving adequate GTV coverage in NPC. We strongly recommend 3D planning using either conformal techniques of dose delivery or intensity modulated radiation therapy for the treatment of these patients.

Predicting nonauditory adverse radiation effects following radiosurgery for vestibular schwannoma: a volume and dosimetric analysis.

PURPOSE To define clinical and dosimetric predictors of nonauditory adverse radiation effects after radiosurgery for vestibular schwannoma treated with a 12 Gy prescription dose. METHODS We retrospectively reviewed our experience of vestibular schwannoma patients treated between September 2005 and December 2009. Two hundred patients were treated at a 12 Gy prescription dose; 80 had complete clinical and radiological follow-up for at least 24 months (median, 28.5 months). All treatment plans were reviewed for target volume and dosimetry characteristics; gradient index; homogeneity index, defined as the maximum dose in the treatment volume divided by the prescription dose; conformity index; brainstem; and trigeminal nerve dose. All adverse radiation effects (ARE) were recorded. Because the intent of our study was to focus on the nonauditory adverse effects, hearing outcome was not evaluated in this study. RESULTS Twenty-seven (33.8%) patients developed ARE, 5 (6%) developed hydrocephalus, 10 (12.5%) reported new ataxia, 17 (21%) developed trigeminal dysfunction, 3 (3.75%) had facial weakness, and 1 patient developed hemifacial spasm. The development of edema within the pons was significantly associated with ARE (p = 0.001). On multivariate analysis, only target volume is a significant predictor of ARE (p = 0.001). There is a target volume threshold of 5 cm3, above which ARE are more likely. The treatment plan dosimetric characteristics are not associated with ARE, although the maximum dose to the 5th nerve is a significant predictor of trigeminal dysfunction, with a threshold of 9 Gy. The overall 2-year tumor control rate was 96%. CONCLUSIONS Target volume is the most important predictor of adverse radiation effects, and we identified the significant treatment volume threshold to be 5 cm3. We also established through our series that the maximum tolerable dose to the 5th nerve is 9 Gy.

Assessment and management of radiotherapy beam intersections with the treatment couch

The impact of the treatment couch on a radiotherapy plan is rarely fully assessed during the treatment planning process. Incorporating a couch model into the treatment planning system (TPS) enables the planner to avoid or dosimetrically evaluate beam‐couch intersections. In this work, we demonstrate how existing TPS tools can be used to establish this capability and assess the accuracy and effectiveness of the system through dose measurements and planning studies. Such capabilities may be particularly relevant for the planning of arc therapies. Treatment couch top models were introduced into a TPS by fusing their CT image sets with the patient CT dataset. Regions of interest characterizing couch elements were then imported and assigned appropriate densities in the TPS. Measurements in phantom agreed with TPS calculations to within 2% dose and 1° gantry rotation. To clinically validate the model, a retrospective study was performed on patient plans that posed difficulties in beam‐couch intersection during setup. Beam‐couch intersection caused up to a 3% reduction in PTV coverage, defined by the 95% of the prescribed dose, and up to a 1% reduction in mean CTV coverage. Dose compensation strategies for IMRT treatments with beams passing through couch elements were investigated using a four‐field IMRT plan with three beams passing through couch elements. In this study, ignoring couch effects resulted in point dose reductions of 8±3%. A methodology for incorporating detailed couch characteristics into a TPS has been established and explored. The method can be used to predict beam‐couch intersections during planning, potentially eliminating the need for pretreatment appointments. Alternatively, if a beam‐couch intersection problem arises, the impact of the couch can be assessed on a case‐by‐case basis and a clinical decision made based on full dosimetric information. PACS numbers: 87.53.Bn;87.55.Gh;87.55.de;87.56.nk

Pretreatment Predictors of Adverse Radiation Effects After Radiosurgery for Arteriovenous Malformation

PURPOSE To identify vascular and dosimetric predictors of symptomatic T2 signal change and adverse radiation effects after radiosurgery for arteriovenous malformation, in order to define and validate preexisting risk models. METHODS AND MATERIALS A total of 125 patients with arteriovenous malformations (AVM) were treated at our institution between 2005 and 2009. Eighty-five patients have at least 12 months of clinical and radiological follow-up. Any new-onset headaches, new or worsening seizures, or neurological deficit were considered adverse events. Follow-up magnetic resonance images were assessed for new onset T2 signal change and the volume calculated. Pretreatment characteristics and dosimetric variables were analyzed to identify predictors of adverse radiation effects. RESULTS There were 19 children and 66 adults in the study cohort, with a mean age of 34 (range 6-74). Twenty-three (27%) patients suffered adverse radiation effects (ARE), 9 patients with permanent neurological deficit (10.6%). Of these, 5 developed fixed visual field deficits. Target volume and 12 Gy volume were the most significant predictors of adverse radiation effects on univariate analysis (p < 0.001). Location and cortical eloquence were not significantly associated with the development of adverse events (p = 0.12). No additional vascular parameters were identified as predictive of ARE. There was a significant target volume threshold of 4 cm(3), above which the rate of ARE increased dramatically. Multivariate analysis target volume and the absence of prior hemorrhage are the only significant predictors of ARE. The volume of T2 signal change correlates to ARE, but only target volume is predictive of a higher volume of T2 signal change. CONCLUSIONS Target volume and the absence of prior hemorrhage is the most accurate predictor of adverse radiation effects and complications after radiosurgery for AVMs. A high percentage of permanent visual field defects in this series suggest the optic radiation is a critical radiosensitive structure.

Verification of source and collimator configuration for Gamma Knife Perfexion using panoramic imaging

PURPOSE The new model of stereotactic radiosurgery system, Gamma Knife Perfexion, allows automatic selection of built-in collimation, eliminating the need for the time consuming manual collimator installation required with previous models. However, the configuration of sources and collimators inside the system does not permit easy access for the verification of the selected collimation. While the conventional method of exposing a film at the isocenter is useful for obtaining composite dose information, it is difficult to interpret the data in terms of the integrity of each individual source and corresponding collimation. The primary aim of this study was to develop a method of verifying the geometric configuration of the sources and collimator modules of the Gamma Knife Perfexion. In addition, the method was extended to make dose measurements and verify the accuracy of dose distributions calculated by the mathematical formalism used in the treatment planning system, Leksell Gamma Plan. METHODS A panoramic view of all of 192 cobalt sources was simultaneously acquired by exposing a radiochromic film wrapped around the surface of a cylindrical phantom. The center of the phantom was mounted at the isocenter with its axis aligned along the longitudinal axis of the couch. The sizes and shapes of the source images projected on the phantom surface were compared to those calculated based on the manufacturers design specifications. The measured dose at various points on the film was also compared to calculations using the algorithm of the planning system. RESULTS The panoramic images allowed clear identification of each of the 192 sources, verifying source integrity and selected collimator sizes. Dose on the film surface is due to the primary beam as well as phantom scatter and leakage contributions. Therefore, the dose at a point away from the isocenter cannot be determined simply based on the proportionality of collimator output factors; the use of a dose computation algorithm is required. Scatter and leakage dose contributions from neighboring sources were calculated and found to be 6.3% (ranging from 4.5% to 7.4%), 16.7% (12.5%-19.3%), and 66.6% (38%-78%) for the 4, 8, and 16 mm collimators, respectively, at the centers of the source images. The measured average dose on films with 16 mm collimators agrees with the dose model of the treatment planning system to within 1.0%. The average doses on the film were 24.0, 60.8, and 186.2 cGy for 4, 8, and 16 mm diameter collimators, respectively, when the machine was set to deliver a reference dose of 100 Gy to the center of an 80 mm radius spherical dosimetry phantom. CONCLUSIONS A method of simultaneously capturing and analyzing the panoramic images of 192 cobalt sources has been developed to verify the source and collimator configuration of GK systems. The method was extended to verify the dose calculation model of the treatment planning system by comparing the measured doses on the panoramic film images and the corresponding calculated doses. The method presented can play a significant role in comprehensive commissioning and routine quality assurance testing of the Gamma Knife systems.

COMP report: CPQR technical quality control guidelines for Gamma Knife radiosurgery

Abstract The Canadian Organization of Medical Physicists (COMP), in close partnership with the Canadian Partnership for Quality Radiotherapy (CPQR), has developed a series of Technical Quality Control (TQC) guidelines for radiation treatment equipment. These guidelines outline the performance objectives that equipment should meet in order to ensure an acceptable level of radiation treatment quality. The TQC guidelines have been rigorously reviewed and field tested in a variety of Canadian radiation treatment facilities. The development process enables rapid review and update to keep the guidelines current with changes in technology (the most updated version of this guideline can be found on the CPQR website). This particular TQC details recommended quality control testing for Gamma Knife radiosurgery.

Poster - 30: Use of a Hazard-Risk Analysis for development of a new eye immobilization tool for treatment of choroidal melanoma

Purpose: Our treatment for choroidal melanoma utilizes the GTC frame. The patient looks at a small LED to stabilize target position. The LED is attached to a metal arm attached to the GTC frame. A camera on the arm allows therapists to monitor patient compliance. To move to mask-based immobilization we need a new LED/camera attachment mechanism. We used a Hazard-Risk Analysis (HRA) to guide the design of the new tool. Method: A pre-clinical model was built with input from therapy and machine shop personnel. It consisted of an aluminum frame placed in aluminum guide posts attached to the couch top. Further development was guided by the Department of Defense Standard Practice - System Safety hazard risk analysis technique. Results: An Orfit mask was selected because it allowed access to indexes on the couch top which assist with setup reproducibility. The first HRA table was created considering mechanical failure modes of the device. Discussions with operators and manufacturers identified other failure modes and solutions. HRA directed the design towards a safe clinical device. Conclusion: A new immobilization tool has been designed using hazard-risk analysis which resulted in an easier-to-use and safer tool compared to the initial design. The remaining risks are all low probability events and not dissimilar from those currently faced with the GTC setup. Given the gains in ease of use for therapists and patients as well as the lower costs for the hospital, we will implement this new tool.

VMAT delivery through couch tops: an illustration of loss of dose coverage for prostate plans

Introduction: Complex radiation therapy treatments are designed using computer algorithms which rely on specific dosimetric inputs. Optimization will be continued until all dosimetric criteria are met or otherwise accepted. Such optimization typically takes place on data sets that exclude the treatment couch top, yielding plans that do not reflect reality. We investigated what ignoring the couch top means dosimetrically for five full arc VMAT prostate plans.