Publications by authors named "David A Jaffray"

187 Publications

Curative-intent Metastasis-directed Therapies for Molecularly-defined Oligorecurrent Prostate Cancer: A Prospective Phase II Trial Testing the Oligometastasis Hypothesis.

Eur Urol 2021 Mar 5. Epub 2021 Mar 5.

University of Toronto, Department of Radiation Oncology, 149 College Street, Unit 504, Toronto, Ontario, M5T 1P5, Canada; Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, 700 University Avenue, 7th floor, Toronto, Ontario, M5G 1Z5, Canada; TECHNA Institute, University Health Network, University of Toronto, 200 Elizabeth Street, Toronto, Ontario, M5G 2C4, Canada. Electronic address:

Background: The hypothesis of a curable oligometastatic prostate cancer (PCa) state remains to be clinically-proven. Conventional imaging often fails to localize early recurrences, hampering the potential for radical approaches.

Objective: We hypothesize that prostate-specific membrane antigen (PSMA)-targeted PET-MR/CT allows for earlier detection and localization of oligorecurrent-PCa, unveiling a molecularly-defined state amenable to curative-intent metastasis-directed treatment (MDT).

Design/setting/participants: Single-institution single-arm phase-two study. Patients with rising PSA (0.4-3.0 ng/mL) after maximal local therapy (radical prostatectomy and post-operative radiotherapy), negative conventional staging, and no prior salvage hormonal therapy (HT) were eligible.

Interventions: All patients underwent [F]DCFPyL PET-MR/CT. Patients with molecularly-defined oligorecurrent-PCa had MDT (stereotactic ablative body radiotherapy [SABR] or surgery) without HT.

Outcome Measurements/statistical Analysis: Primary endpoint was biochemical response (complete, i.e. biochemical 'no evidence of disease' [bNED], or partial response [100% or ≥50% PSA decline from baseline, respectively]) after MDT. Simon's two-stage design was employed (null and alternate hypotheses <5% and >20% response rate, respectively), with α and β of 0.1.

Results: Seventy-two patients were enrolled (May/2017-July/2019). Thirty-eight (53%) had PSMA-detected oligorecurrent-PCa amenable for MDT. Thirty-seven (51%) agreed to MDT: 10 and 27 underwent surgery and SABR, respectively. Median follow-up was 15.9 months (IQR 9.8-19.1). Of patients receiving MDT, the overall response rate was 60%, including 22% rendered bNED. One (2.7%) grade 3 toxicity (intra-operative ureteric injury) was observed.

Conclusions: PSMA-defined oligorecurrent-PCa can be rendered bNED, a necessary step towards cure, in 1 of 5 patients receiving MDT alone. Randomized trials are justified to determine if MDT +/- systemic agents can expand the curative therapeutic armamentarium for PCa.

Patient Summary: We studied men treated for prostate cancer with rising PSA. We found PSMA imaging detected recurrent cancer in three-quarters of patients, and targeted treatment to these areas significantly decreased PSA in half of patients.
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http://dx.doi.org/10.1016/j.eururo.2021.02.031DOI Listing
March 2021

In the Era of Deep Learning, Why Reconstruct an Image at All?

J Am Coll Radiol 2021 Jan;18(1 Pt B):170-173

Chief Technology and Digital Officer, The University of Texas MD Anderson Cancer Center, Houston, Texas.

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http://dx.doi.org/10.1016/j.jacr.2020.09.050DOI Listing
January 2021

Assessment of a liposomal CT/optical contrast agent for image-guided head and neck surgery.

Nanomedicine 2020 Nov 19;32:102327. Epub 2020 Nov 19.

Princess Margaret Cancer Centre and University Health Network, TECHNA Institute, Guided Therapeutic (GTx) Program, Toronto, ON, Canada.; Department of Otolaryngology-Head and Neck Surgery-Surgical Oncology, Princess Margaret Cancer Centre/University Health Network, University of Toronto, Toronto, ON, Canada.. Electronic address:

This study evaluates a long-acting liposomal fluorescence / CT dual-modality contrast agent (CF800) in head and neck cancer to enhance intraoperative tumor demarcation with fluorescence imaging and cone-beam computed tomography (CBCT). CF800 was administered to 12 buccal cancer-bearing rabbits. Imaging was acquired at regular time points to quantify time-dependent contrast enhancement. Surgery was performed 5-7 days after, with intraoperative near-infrared fluorescence endoscopy and CBCT, followed by histological and ex-vivo fluorescence assessment. Tumor enhancement on CT was significant at 24, 96 and 120 hours. Volumetric analysis of tumor segmentation showed high correlation between CBCT and micro-CT. Fluorescence signal was apparent in both ex-vivo and in-vivo imaging. Histological correlation showed [100%] specificity for primary tumor. Sensitivity and specificity of CF800 in detecting nodal involvement require further investigation.CF800 is long acting and has dual function for CT and fluorescence contrast, making it an excellent candidate for image-guided surgery.
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http://dx.doi.org/10.1016/j.nano.2020.102327DOI Listing
November 2020

Vision 2020: looking back and thinking forward on The Lancet Oncology Commissions.

Lancet Oncol 2020 09;21(9):1144-1146

Institute for Advanced Study of the Americas, and Sylvester Comprehensive Cancer Center, University of Miami, Coral Gables, FL, USA; Tómatelo a Pecho, Mexico City, Mexico; Mexican Health Foundation, Mexico City, Mexico.

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http://dx.doi.org/10.1016/S1470-2045(20)30481-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462593PMC
September 2020

Cost-function testing methodology for image-based registration of endoscopy to CT images in the head and neck.

Phys Med Biol 2020 Jul 23. Epub 2020 Jul 23.

Radiation Medicine Program, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, CANADA.

One of the largest geometric uncertainties in designing radiotherapy treatment plans for squamous cell cancers of the head and neck is contouring the gross tumour volume. We have previously described a method of projecting mucosal disease contours, visible on endoscopy, to volumetrically reconstructed planning CT datasets, using electromagnetic (EM) tracking of a flexible endoscope, enabling rigid registration between endoscopic and CT images. However, to achieve better accuracy for radiotherapy planning, we propose refining this initial registration with image-based registration methods. In this paper, several types of cost functions are evaluated based on accuracy and robustness. Three phantoms and eight clinical cases are used to test each cost function, with initial registration of endoscopy to CT provided by the pose of the flexible endoscope recovered from EM tracking. Cost function classes include: cross correlation, mutual information and gradient methods. For each test case, a ground truth virtual camera pose was first defined by manual registration of anatomical features visible in both real and virtual endoscope images. A new set of evenly spaced fiducial points and a sample contour were created and projected onto the CT image to be used in assessing image registration quality. A new set of 5000 displaced poses was generated by random sampling displacements along each translational and rotational dimension. At each pose, fiducial and contour points in the real image were again projected on the CT image. The cost function, fiducial registration error and contouring error values were then calculated. While all cost functions performed well in select cases, only the normalized gradient field function consistently had registration errors less than 2 mm, which is the accuracy needed if this application of registering mucosal disease identified on optical image to CT images is to be used in the clinical practice of radiation treatment planning. (Registration: ClinicalTrials.gov NCT02704169).
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http://dx.doi.org/10.1088/1361-6560/aba8b3DOI Listing
July 2020

[F]DCFPyL PET-MRI/CT for unveiling a molecularly defined oligorecurrent prostate cancer state amenable for curative-intent ablative therapy: study protocol for a phase II trial.

BMJ Open 2020 04 22;10(4):e035959. Epub 2020 Apr 22.

Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada

Introduction: The oligometastatic (OM) disease hypothesis of an intermediate metastatic state with limited distant disease deposits amenable for curative therapies remains debatable. Over a third of prostate cancer (PCa) patients treated with radical prostatectomy and postoperative radiotherapy experience disease recurrence; these patients are considered incurable by current standards. Often the recurrence cannot be localised by conventional imaging (CT and bone scan). Combined anatomical imaging with CT and/or MR with positron emission tomography (PET) using a novel second-generation prostate-specific membrane antigen (PSMA) probe, [F]DCFPyL, is a promising imaging modality to unveil disease deposits in these patients. A new and earlier molecularly defined oligorecurrent (OR) state may be amenable to focal-targeted ablative curative-intent therapies, such as stereotactic ablative radiotherapy (SABR) or surgery, thereby significantly delaying or completely avoiding the need for palliative therapies in men with recurrent PCa after maximal local treatments.

Methods And Analysis: This ongoing single-institution phase II study will enrol up to 75 patients total, to include up to 37 patients with response-evaluable disease, who have rising prostate-specific antigen (range 0.4-3.0 ng/mL) following maximal local therapies with no evidence of disease on conventional imaging. These patients will undergo [F]DCFPyL PET-MR/CT imaging to detect disease deposits, which will then be treated with SABR or surgery. The primary endpoints are performance of [F]DCFPyL PET-MR/CT, and treatment response rates following SABR or surgery. Demographics and disease characteristics will be summarised and analysed descriptively. Response rates will be described with waterfall plots and proportions.

Ethics And Dissemination: Ethics approval was obtained from the institutional Research Ethics Board. All patients will provide written informed consent. [F]DCFPyL has approval from Health Canada. The results of the study will be disseminated by the principal investigator. Patients will not be identifiable as individuals in any publication or presentation of this study.

Trial Registration Numbers: NCT03160794.
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http://dx.doi.org/10.1136/bmjopen-2019-035959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204865PMC
April 2020

User-controlled pipelines for feature integration and head and neck radiation therapy outcome predictions.

Phys Med 2020 Feb 2;70:145-152. Epub 2020 Feb 2.

Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada; IBBME, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; The Techna Institute for the Advancement of Technology for Health, Toronto, Ontario, Canada.

Purpose: Precision cancer medicine is dependent on accurate prediction of disease and treatment outcome, requiring integration of clinical, imaging and interventional knowledge. User controlled pipelines are capable of feature integration with varied levels of human interaction. In this work we present two pipelines designed to combine clinical, radiomic (quantified imaging), and RTx-omic (quantified radiation therapy (RT) plan) information for prediction of locoregional failure (LRF) in head and neck cancer (H&N).

Methods: Pipelines were designed to extract information and model patient outcomes based on clinical features, computed tomography (CT) imaging, and planned RT dose volumes. We predict H&N LRF using: 1) a highly user-driven pipeline that leverages modular design and machine learning for feature extraction and model development; and 2) a pipeline with minimal user input that utilizes deep learning convolutional neural networks to extract and combine CT imaging, RT dose and clinical features for model development.

Results: Clinical features with logistic regression in our highly user-driven pipeline had the highest precision recall area under the curve (PR-AUC) of 0.66 (0.33-0.93), where a PR-AUC = 0.11 is considered random.

Conclusions: Our work demonstrates the potential to aggregate features from multiple specialties for conditional-outcome predictions using pipelines with varied levels of human interaction. Most importantly, our results provide insights into the importance of data curation and quality, as well as user, data and methodology bias awareness as it pertains to result interpretation in user controlled pipelines.
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http://dx.doi.org/10.1016/j.ejmp.2020.01.027DOI Listing
February 2020

Quantifying Reoxygenation in Pancreatic Cancer During Stereotactic Body Radiotherapy.

Sci Rep 2020 01 31;10(1):1638. Epub 2020 Jan 31.

Ontario Cancer Institute, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada.

Hypoxia, the state of low oxygenation that often arises in solid tumours due to their high metabolism and irregular vasculature, is a major contributor to the resistance of tumours to radiation therapy (RT) and other treatments. Conventional RT extends treatment over several weeks or more, and nominally allows time for oxygen levels to increase ("reoxygenation") as cancer cells are killed by RT, mitigating the impact of hypoxia. Recent advances in RT have led to an increase in the use stereotactic body radiotherapy (SBRT), which delivers high doses in five or fewer fractions. For cancers such as pancreatic adenocarcinoma for which hypoxia varies significantly between patients, SBRT might not be optimal, depending on the extent to which reoxygenation occurs during its short duration. We used fluoro-5-deoxy-α-D-arabinofuranosyl)-2-nitroimidazole positron-emission tomography (FAZA-PET) imaging to quantify hypoxia before and after 5-fraction SBRT delivered to patient-derived pancreatic cancer xenografts orthotopically implanted in mice. An imaging technique using only the pre-treatment FAZA-PET scan and repeat dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scans throughout treatment was able to predict the change in hypoxia. Our results support the further testing of this technique for imaging of reoxygenation in the clinic.
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http://dx.doi.org/10.1038/s41598-019-57364-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994660PMC
January 2020

Feasibility study of navigated endoscopy for the placement of high dose rate brachytherapy applicators in the esophagus and lung.

Med Phys 2020 Mar 28;47(3):917-926. Epub 2020 Jan 28.

Department of Radiation Oncology, University of Toronto, Toronto, M5T 1P5, Canada.

Purpose: To evaluate the electromagnetic (EM) tracking of endoscopes and applicators as a method of positioning a high dose rate (HDR) luminal applicator.

Method: An anatomical phantom consisting of a rigid trachea and flexible esophagus was used to compare applicator placement measurements using EM tracking vs the traditional method using two-dimensional (2D) fluoroscopy and surface skin markers. The phantom included a tumor in the esophagus and several pairs of optically visible points inside the lumen that were used to simulate proximal and distal ends of tumors of varying lengths. The esophagus tumor and lung points were visible on a computed tomography (CT) image of the phantom, which was used as ground truth for the measurements. The EM tracking system was registered to the CT image using fiducial markers. A flexible endoscope was tracked using the EM system and the locations of the proximal and distal ends of the tumor identified and this position recorded. An EM-tracked applicator was then inserted and positioned relative to the tumor markings. The applicator path was mapped using the EM tracking. The gross tumor length (GTL) and the distance between the first dwell position and distal edge of tumor (offset) were measured using the EM tracking and 2D fluoroscopy methods and compared to the same measurements on the CT image.

Results: The errors in GTL using EM tracking were on average -0.5 ± 1.7 mm and 0.7 ± 3.6 mm for esophagus and lung measurements, similar to errors measured using the 2D fluoroscopy method of -0.9 ± 1.2 mm and 3.4 ± 4.4 mm. Offset measurements were slightly larger while using EM tracking relative to the fluoroscopy method but these were not statistically significant.

Conclusions: Electromagnetic tracking for placement of lumen applicators is feasible and accurate. Tracking of the endoscope that is used to identify the proximal and distal ends of the tumor and of the applicator during insertion generates accurate three-dimensional measurements of the applicator path, GTL and offset. Guiding the placement of intraluminal applicators using EM navigation is potentially attractive for cases with complex insertions, such as those with nonlinear paths or multiple applicator insertions.
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http://dx.doi.org/10.1002/mp.13997DOI Listing
March 2020

External validation and transfer learning of convolutional neural networks for computed tomography dental artifact classification.

Phys Med Biol 2020 02 5;65(3):035017. Epub 2020 Feb 5.

Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. The Techna Institute for the Advancement of Technology for Health, Toronto, Ontario, Canada. Author to whom any correspondence should be addressed.

Quality assurance of data prior to use in automated pipelines and image analysis would assist in safeguarding against biases and incorrect interpretation of results. Automation of quality assurance steps would further improve robustness and efficiency of these methods, motivating widespread adoption of techniques. Previous work by our group demonstrated the ability of convolutional neural networks (CNN) to efficiently classify head and neck (H&N) computed-tomography (CT) images for the presence of dental artifacts (DA) that obscure visualization of structures and the accuracy of Hounsfield units. In this work we demonstrate the generalizability of our previous methodology by validating CNNs on six external datasets, and the potential benefits of transfer learning with fine-tuning on CNN performance. 2112 H&N CT images from seven institutions were scored as DA positive or negative. 1538 images from a single institution were used to train three CNNs with resampling grid sizes of 64, 128 and 256. The remaining six external datasets were used in five-fold cross-validation with a data split of 20% training/fine-tuning and 80% validation. The three pre-trained models were each validated using the five-folds of the six external datasets. The pre-trained models also underwent transfer learning with fine-tuning using the 20% training/fine-tuning data, and validated using the corresponding validation datasets. The highest micro-averaged AUC for our pre-trained models across all external datasets occurred with a resampling grid of 256 (AUC  =  0.91  ±  0.01). Transfer learning with fine-tuning improved generalizability when utilizing a resampling grid of 256 to a micro-averaged AUC of 0.92  ±  0.01. Despite these promising results, transfer learning did not improve AUC when utilizing small resampling grids or small datasets. Our work demonstrates the potential of our previously developed automated quality assurance methods to generalize to external datasets. Additionally, we showed that transfer learning with fine-tuning using small portions of external datasets can be used to fine-tune models for improved performance when large variations in images are present.
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http://dx.doi.org/10.1088/1361-6560/ab63baDOI Listing
February 2020

Automatic classification of dental artifact status for efficient image veracity checks: effects of image resolution and convolutional neural network depth.

Phys Med Biol 2020 01 10;65(1):015005. Epub 2020 Jan 10.

Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. The Techna Institute for the Advancement of Technology for Health, Toronto, Ontario, Canada. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

Enabling automated pipelines, image analysis and big data methodology in cancer clinics requires thorough understanding of the data. Automated quality assurance steps could improve the efficiency and robustness of these methods by verifying possible data biases. In particular, in head and neck (H&N) computed-tomography (CT) images, dental artifacts (DA) obscure visualization of structures and the accuracy of Hounsfield units; a challenge for image analysis tasks, including radiomics, where poor image quality can lead to systemic biases. In this work we analyze the performance of three-dimensional convolutional neural networks (CNN) trained to classify DA statuses. 1538 patient images were scored by a single observer as DA positive or negative. Stratified five-fold cross validation was performed to train and test CNNs using various isotropic resampling grids (64, 128 and 256), with CNN depths designed to produce 32, 16, and 8 machine generated features. These parameters were selected to determine if more computationally efficient CNNs could be utilized to achieve the same performance. The area under the precision recall curve (PR-AUC) was used to assess CNN performance. The highest PR-AUC (0.92  ±  0.03) was achieved with a CNN depth  =  5, resampling grid  =  256. The CNN performance with 256 resampling grid size is not significantly better than 64 and 128 after 20 epochs, which had PR-AUC  =  0.89  ±  0.03 (p -value  =  0.28) and 0.91  ±  0.02 (p -value  =  0.93) at depths of 3 and 4, respectively. Our experiments demonstrate the potential to automate specific quality assurance tasks required for unbiased and robust automated pipeline and image analysis research. Additionally, we determined that there is an opportunity to simplify CNNs with smaller resampling grids to make the process more amenable to very large datasets that will be available in the future.
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http://dx.doi.org/10.1088/1361-6560/ab5427DOI Listing
January 2020

The transformation of radiation oncology using real-time magnetic resonance guidance: A review.

Eur J Cancer 2019 11 12;122:42-52. Epub 2019 Oct 12.

Medical College of Wisconsin, Department of Radiation Oncology, USA.

Radiation therapy (RT) is an essential component of effective cancer care and is used across nearly all cancer types. The delivery of RT is becoming more precise through rapid advances in both computing and imaging. The direct integration of magnetic resonance imaging (MRI) with linear accelerators represents an exciting development with the potential to dramatically impact cancer research and treatment. These impacts extend beyond improved imaging and dose deposition. Real-time MRI-guided RT is actively transforming the work flows and capabilities of virtually every aspect of RT. It has the opportunity to change entirely the delivery methods and response assessments of numerous malignancies. This review intends to approach the topic of MRI-based RT guidance from a vendor neutral and international perspective. It also aims to provide an introduction to this topic targeted towards oncologists without a speciality focus in RT. Speciality implications, areas for physician education and research opportunities are identified as they are associated with MRI-guided RT. The uniquely disruptive implications of MRI-guided RT are discussed and placed in context. We further aim to describe and outline important future changes to the speciality of radiation oncology that will occur with MRI-guided RT. The impacts on RT caused by MRI guidance include target identification, RT planning, quality assurance, treatment delivery, training, clinical workflow, tumour response assessment and treatment scheduling. In addition, entirely novel research areas that may be enabled by MRI guidance are identified for future investigation.
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http://dx.doi.org/10.1016/j.ejca.2019.07.021DOI Listing
November 2019

The image-guided operating room-Utility and impact on surgeon's performance in the head and neck surgery.

Head Neck 2019 09 9;41(9):3372-3382. Epub 2019 Jul 9.

Department of Otolaryngology-Head and Neck Surgery, University of Toronto, Toronto, Ontario, Canada.

Background: The image-guided operating room (OR) is an emerging standard for dealing with complex cases in many surgical disciplines including neurosurgery, thoracic surgery, maxillofacial trauma, and orthopedic surgery. Its use in head and neck oncological surgery is not well established. The primary aim of this study was to assess the image quality of cone-beam CT (CBCT) under real clinical conditions. The secondary aim was to assess the effect on surgical performance and decision making.

Methods: Intraoperative 3D imaging was performed using a CBCT capable C-Arm mounted on a multi-axis robot (Siemens Zeego) in the image-guided OR. All patients had immediate preoperative imaging taken with further intraoperative imaging performed as required. Ten initial patients, comprising 28 intraoperative scans, were used for questionnaire-based image reviews conducted with experienced head and neck clinicians. Scans were assessed for aspects of both image quality and clinical utility, on separate 5-point Likert scales (1-5).

Results: The median rating for bony detail was 4 out of 5. Vascular detail was increased (P < 10 ) from 1 to 3 with the use of IV contrast (region of interest CT# was 284 HU [SD, 47 HU]). Images were rated as 4 for freedom from artifact. Soft tissue definition was 2, with no significant improvement (P = .2) with the addition of IV iodinated contrast. Surgeons rated the greatest clinical utility (4) for the CBCT when assessing postreconstruction imaging of a complex case.

Conclusions: The image quality of CBCT in the image-guided OR is good for bony detail and complex oncological reconstructions in the head and neck setting but probably has limited benefit for intraoperative soft tissue delineation. Future studies must also focus on clinical outcomes to help demonstrate the value of the image-guided OR.
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http://dx.doi.org/10.1002/hed.25864DOI Listing
September 2019

Scale-up of radiotherapy for cervical cancer in the era of human papillomavirus vaccination in low-income and middle-income countries: a model-based analysis of need and economic impact.

Lancet Oncol 2019 07 28;20(7):915-923. Epub 2019 May 28.

Radiation Medicine Program, Princess Margaret Cancer Centre Toronto, Toronto, ON, Canada; Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada.

Background: Radiotherapy is standard of care for cervical cancer, but major global gaps in access exist, particularly in low-income and middle-income countries. We modelled the health and economic benefits of a 20-year radiotherapy scale-up to estimate the long-term demand for treatment in the context of human papillomavirus (HPV) vaccination.

Methods: We applied the Global Task Force on Radiotherapy for Cancer Control investment framework to model the health and economic benefits of scaling up external-beam radiotherapy and brachytherapy for cervical cancer in upper-middle-income, lower-middle-income, and low-income countries between 2015 and 2035. We estimated the unique costs of external-beam radiotherapy and brachytherapy and included a specific valuation of women's caregiving contributions. Model outcomes life-years gained and the human capital and full income net present value of investment. We estimated the effects of stage at diagnosis, radiotherapy delivery system, and simultaneous HPV vaccination (75% coverage) up to a time horizon set at 2072.

Findings: For the period from 2015 to 2035, we estimated that 9·4 million women in low-income and middle-income countries required treatment with external-beam radiotherapy, of which 7·0 million also required treatment with brachytherapy. Incremental scale-up of radiotherapy in these countries from 2015 to meet optimal radiotherapy demand by 2035 yielded 11·4 million life-years gained, $59·3 billion in human capital net present value (-$1·5 billion in low-income, $19·9 billion in lower-middle-income, and $40·9 billion in upper-middle-income countries), and $151·5 billion in full income net present value ($1·5 billion in low-income countries, $53·6 billion in lower-middle-income countries, and $96·4 billion in upper-middle-income countries). Benefits increased with advanced stage of cervical cancer and more efficient scale up of radiotherapy. Bivalent HPV vaccination of 12-year-old girls resulted in a 3·9% reduction in incident cases from 2015-2035. By 2072, when the first vaccinated cohort of girls reaches 70 years of age, vaccination yielded a 22·9% reduction in cervical cancer incidence, with 38·4 million requiring external-beam radiotherapy and 28·8 million requiring brachytherapy.

Interpretation: Effective cervical cancer control requires a comprehensive strategy. Even with HPV vaccination, radiotherapy treatment scale-up remains essential and produces large health benefits and a strong return on investment to countries at different levels of development.

Funding: None.
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http://dx.doi.org/10.1016/S1470-2045(19)30308-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055962PMC
July 2019

Editorial. Leksell Gamma Knife Society and radiosurgery: a legacy and a vision for the future.

J Neurosurg 2018 12;129(Suppl1):2-4

7Departments of Radiation Oncology and Medical Biophysics, University of Toronto, and Department of Medical Physics, Radiation Medicine Program, Princess Margaret Cancer Centre/University Health Network, Toronto, Canada.

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http://dx.doi.org/10.3171/2018.7.GKS181992DOI Listing
December 2018

Vulnerabilities of radiomic signature development: The need for safeguards.

Radiother Oncol 2019 01 8;130:2-9. Epub 2018 Nov 8.

Department of Medical Biophysics, University of Toronto, Canada; Department of Radiation Oncology, University of Toronto, Canada; IBBME, University of Toronto, Canada; Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada; The Techna Institute for the Advancement of Technology for Health, Toronto, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. Electronic address:

Purpose: Refinement of radiomic results and methodologies is required to ensure progression of the field. In this work, we establish a set of safeguards designed to improve and support current radiomic methodologies through detailed analysis of a radiomic signature.

Methods: A radiomic model (MW2018) was fitted and externally validated using features extracted from previously reported lung and head and neck (H&N) cancer datasets using gross-tumour-volume contours, as well as from images with randomly permuted voxel index values; i.e. images without meaningful texture. To determine MW2018's added benefit, the prognostic accuracy of tumour volume alone was calculated as a baseline.

Results: MW2018 had an external validation concordance index (c-index) of 0.64. However, a similar performance was achieved using features extracted from images with randomized signal intensities (c-index = 0.64 and 0.60 for H&N and lung, respectively). Tumour volume had a c-index = 0.64 and correlated strongly with three of the four model features. It was determined that the signature was a surrogate for tumour volume and that intensity and texture values were not pertinent for prognostication.

Conclusion: Our experiments reveal vulnerabilities in radiomic signature development processes and suggest safeguards that can be used to refine methodologies, and ensure productive radiomic development using objective and independent features.
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http://dx.doi.org/10.1016/j.radonc.2018.10.027DOI Listing
January 2019

Intraoperative Near-Infrared Fluorescence-Guided Peripheral Lung Tumor Localization in Rabbit Models.

Ann Thorac Surg 2019 01 6;107(1):248-256. Epub 2018 Oct 6.

Division of Thoracic Surgery, Toronto General Hospital, University of Toronto, University Health Network, Toronto, Ontario, Canada; Guided Therapeutics, TECHNA Institute, University Health Network, Toronto, Ontario, Canada. Electronic address:

Background: A novel liposomal nanoparticle, CF800, that co-encapsulates indocyanine green for near-infrared (NIR) imaging and iohexol for computed tomography (CT) imaging has shown preferential tumor accumulation after intravenous injection by the enhanced permeability and retention effect. We hypothesized that CF800-enhanced NIR imaging would facilitate intraoperative localization of small lung nodules.

Methods: A rabbit VX2 lung tumor model was implemented. CF800 was injected intravenously, followed by sequential CT acquisitions to track the biodistribution of CF800. Eleven rabbits were used for NIR fluorescence evaluation after thoracotomy at time points until 7 days after injection by using a NIR fluorescence thoracoscope in vivo. Organs of interests were removed for ex vivo analysis by using NIR imaging. Tumor-to-background (inflated lung) ratio was calculated and compared among the time points.

Results: Both CT and NIR imaging indicated enhanced accumulation of CF800 within the VX2 tumor. NIR image analysis revealed the highest tumor-to-background ratio on days 4 and 5. High background at day 2 and low tumor signal at day 7 prevented distinct demarcation. Metastatic pulmonary small nodules (less than 2 mm in diameter) were successfully visualized by NIR imaging on day 4. However, NIR signal penetration was limited, resulting in localization failure for the few tumors deep (>0 mm) to the lung surface.

Conclusions: NIR image-guided localization of small lung nodules appears to be feasible under certain conditions. However, further refinement will be required to increase tumor signal intensity and to reduce background signal from normal lung parenchyma, which is at least in part a consequence of persistent CF800 in the vasculature.
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http://dx.doi.org/10.1016/j.athoracsur.2018.08.020DOI Listing
January 2019

Radiation and Heat Improve the Delivery and Efficacy of Nanotherapeutics by Modulating Intratumoral Fluid Dynamics.

ACS Nano 2018 08 20;12(8):7583-7600. Epub 2018 Jul 20.

Department of Medical Biophysics , University of Toronto , Toronto , ON M5G 1L7 , Canada.

Nanomedicine drug delivery systems are capable of transporting significant payloads to solid tumors. However, only a modest increase in antitumor efficacy relative to the standard of care has been observed. In this study, we demonstrate that a single dose of radiation or mild hyperthermia can substantially improve tumor uptake and distribution of nanotherapeutics, resulting in improved treatment efficacy. The delivery of nanomedicine was driven by a reduction in interstitial fluid pressure (IFP) and small perturbation of steady-state fluid flow. The transient effects on fluid dynamics in tumors with high IFP was also shown to dominate over immune cell endocytic capacity, another mechanism suspected of improving drug delivery. Furthermore, we demonstrate the specificity of this mechanism by showing that delivery of nanotherapeutics to low IFP tumors with high leukocyte infiltration does not benefit from pretreatment with radiation or heat. These results demonstrate that focusing on small perturbations to steady-state fluid dynamics, rather than large sustained effects or uncertain immune cell recruitment strategies, can impart a vulnerability to tumors with high IFP and enhance nanotherapeutic drug delivery and treatment efficacy.
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http://dx.doi.org/10.1021/acsnano.7b06301DOI Listing
August 2018

Editorial: Radiomics: The New World or Another Road to El Dorado?

J Natl Cancer Inst 2017 Jul;109(7)

Affiliations of authors: Department of Medical Biophysics (MLW, DAJ), Department of Radiation Oncology (DAJ), and IBBME (DAJ), University of Toronto, Toronto, Ontario, Canada; Techna Institute for the Advancement of Technology for Health (MLW, DAJ) and Radiation Medicine Program, Princess Margaret Cancer Centre (DAJ), University Health Network, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1093/jnci/djx116DOI Listing
July 2017

The Use of Quantitative Imaging in Radiation Oncology: A Quantitative Imaging Network (QIN) Perspective.

Int J Radiat Oncol Biol Phys 2018 11 30;102(4):1219-1235. Epub 2018 Jun 30.

Department of Radiation Oncology, University of Iowa, Iowa City, Iowa.

Modern radiation therapy is delivered with great precision, in part by relying on high-resolution multidimensional anatomic imaging to define targets in space and time. The development of quantitative imaging (QI) modalities capable of monitoring biologic parameters could provide deeper insight into tumor biology and facilitate more personalized clinical decision-making. The Quantitative Imaging Network (QIN) was established by the National Cancer Institute to advance and validate these QI modalities in the context of oncology clinical trials. In particular, the QIN has significant interest in the application of QI to widen the therapeutic window of radiation therapy. QI modalities have great promise in radiation oncology and will help address significant clinical needs, including finer prognostication, more specific target delineation, reduction of normal tissue toxicity, identification of radioresistant disease, and clearer interpretation of treatment response. Patient-specific QI is being incorporated into radiation treatment design in ways such as dose escalation and adaptive replanning, with the intent of improving outcomes while lessening treatment morbidities. This review discusses the current vision of the QIN, current areas of investigation, and how the QIN hopes to enhance the integration of QI into the practice of radiation oncology.
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http://dx.doi.org/10.1016/j.ijrobp.2018.06.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348006PMC
November 2018

Spatial frequency performance limitations of radiation dose optimization and beam positioning.

Phys Med Biol 2018 06 11;63(12):125006. Epub 2018 Jun 11.

Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada. Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

The flexibility and sophistication of modern radiotherapy treatment planning and delivery methods have advanced techniques to improve the therapeutic ratio. Contemporary dose optimization and calculation algorithms facilitate radiotherapy plans which closely conform the three-dimensional dose distribution to the target, with beam shaping devices and image guided field targeting ensuring the fidelity and accuracy of treatment delivery. Ultimately, dose distribution conformity is limited by the maximum deliverable dose gradient; shallow dose gradients challenge techniques to deliver a tumoricidal radiation dose while minimizing dose to surrounding tissue. In this work, this 'dose delivery resolution' observation is rigorously formalized for a general dose delivery model based on the superposition of dose kernel primitives. It is proven that the spatial resolution of a delivered dose is bounded by the spatial frequency content of the underlying dose kernel, which in turn defines a lower bound in the minimization of a dose optimization objective function. In addition, it is shown that this optimization is penalized by a dose deposition strategy which enforces a constant relative phase (or constant spacing) between individual radiation beams. These results are further refined to provide a direct, analytic method to estimate the dose distribution arising from the minimization of such an optimization function. The efficacy of the overall framework is demonstrated on an image guided small animal microirradiator for a set of two-dimensional hypoxia guided dose prescriptions.
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http://dx.doi.org/10.1088/1361-6560/aac501DOI Listing
June 2018

How Advances in Imaging Will Affect Precision Radiation Oncology.

Int J Radiat Oncol Biol Phys 2018 06 31;101(2):292-298. Epub 2018 Jan 31.

The D-Lab: Decision Support for Precision Medicine, GROW -School for Oncology, Maastricht University Medical Centre+, Maastricht, the Netherlands.

Radiation oncology is 1 of the most structured disciplines in medicine. It is of a highly technical nature with reliance on robotic systems to deliver intervention, engagement of diverse expertise, and early adoption of digital approaches to optimize and execute the application of this highly effective cancer treatment. As a localized intervention, the dependence on sensitive, specific, and accurate imaging to define the extent of disease, its heterogeneity, and adjacency to normal tissues directly affects the therapeutic ratio. Image-based in vivo temporal monitoring of the response to treatment enables adaptation and further affects the therapeutic ratio. Thus, more precise intervention will enable fractionation schedules that better interoperate with advances such as immunotherapy. In the data set-rich era that promises precision and personalized medicine, the radiation oncology field will integrate these new data into highly protocoled pathways of care that begin with multimodality prediction and enable patient-specific adaptation of therapy based on quantitative measures of the individual's dose-volume temporal trajectory and midtherapy predictions of response. In addition to advancements in computed tomography imaging, emerging technologies, such as ultra-high-field magnetic resonance and molecular imaging will bring new information to the design of treatments. Next-generation image guided radiation therapy systems will inject high specificity and sensitivity data and stimulate adaptive replanning. In addition, a myriad of pre- and peritherapeutic markers derived from advances in molecular pathology (eg, tumor genomics), automated and comprehensive imaging analytics (eg, radiomics, tumor microenvironment), and many other emerging biomarkers (eg, circulating tumor cell assays) will need to be integrated to maximize the benefit of radiation therapy for an individual patient. We present a perspective on the promise and challenges of fully exploiting imaging data in the pursuit of personalized radiation therapy, drawing from the presentations and broader discussions at the 2016 American Society of Therapeutic Radiation Oncology-National Cancer Institute workshop on Precision Medicine in Radiation Oncology (Bethesda, MD).
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http://dx.doi.org/10.1016/j.ijrobp.2018.01.047DOI Listing
June 2018

Spatiotemporal assessment of spontaneous metastasis formation using multimodal in vivo imaging in HER2+ and triple negative metastatic breast cancer xenograft models in mice.

PLoS One 2018 3;13(5):e0196892. Epub 2018 May 3.

TECHNA Institute for the Advancement of Technology for Health, University Health Network, Toronto, Ontario, Canada.

Background: Preclinical breast cancer models recapitulating the clinical course of metastatic disease are crucial for drug development. Highly metastatic cell lines forming spontaneous metastasis following orthotopic implantation were previously developed and characterized regarding their biological and histological characteristics. This study aimed to non-invasively and longitudinally characterize the spatiotemporal pattern of metastasis formation and progression in the MDA-MB-231-derived triple negative LM2-4 and HER2+ LM2-4H2N cell lines, using bioluminescence imaging (BLI), contrast enhanced computed tomography (CT), fluorescence imaging, and 2-deoxy-2-[fluorine-18]fluoro-D-glucose positron emission tomography ([18F]FDG-PET).

Material And Methods: LM2-4, LM2-4H2N, and MDA-MB-231 tumors were established in the right inguinal mammary fat pad (MFP) of female SCID mice and resected 14-16 days later. Metastasis formation was monitored using BLI. Metabolic activity of primary and metastatic lesions in mice bearing LM2-4 or LM2-4H2N was assessed by [18F]FDG-PET. Metastatic burden at study endpoint was assessed by CT and fluorescence imaging following intravenous dual-modality liposome agent administration.

Results: Comparable temporal metastasis patterns were observed using BLI for the highly metastatic cell lines LM2-4 and LM2-4H2N, while metastasis formed about 10 days later for MDA-MB-231. 21 days post primary tumor resection, metastases were detected in 86% of LM2-4, 69% of LM2-4H2N, and 60% of MDA-MB-231 inoculated mice, predominantly in the axillary region, contralateral MFP, and liver/lung. LM2-4 and LM2-4H2N tumors displayed high metabolism based on [18F]FDG-PET uptake. Lung metastases were detected as the [18F]FDG-PET uptake increased significantly between pre- and post-metastasis scan. Using a liposomal dual-modality agent, CT and fluorescence confirmed BLI detected lesions and identified additional metastatic nodules in the intraperitoneal cavity and lung.

Conclusions: The combination of complementary anatomical and functional imaging techniques can provide high sensitivity characterization of metastatic disease spread, progression and overall disease burden. The described models and imaging toolset can be implemented as an effective means for quantitative treatment response evaluation in metastatic breast cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0196892PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933713PMC
August 2018

Quality control methods for linear accelerator radiation and mechanical axes alignment.

Med Phys 2018 Jun 3;45(6):2388-2398. Epub 2018 May 3.

Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON, M5G 2M9, Canada.

Purpose: The delivery accuracy of highly conformal dose distributions generated using intensity modulation and collimator, gantry, and couch degrees of freedom is directly affected by the quality of the alignment between the radiation beam and the mechanical axes of a linear accelerator. For this purpose, quality control (QC) guidelines recommend a tolerance of ±1 mm for the coincidence of the radiation and mechanical isocenters. Traditional QC methods for assessment of radiation and mechanical axes alignment (based on pointer alignment) are time consuming and complex tasks that provide limited accuracy. In this work, an automated test suite based on an analytical model of the linear accelerator motions was developed to streamline the QC of radiation and mechanical axes alignment.

Methods: The proposed method used the automated analysis of megavoltage images of two simple task-specific phantoms acquired at different linear accelerator settings to determine the coincidence of the radiation and mechanical isocenters. The sensitivity and accuracy of the test suite were validated by introducing actual misalignments on a linear accelerator between the radiation axis and the mechanical axes using both beam steering and mechanical adjustments of the gantry and couch.

Results: The validation demonstrated that the new QC method can detect sub-millimeter misalignment between the radiation axis and the three mechanical axes of rotation. A displacement of the radiation source of 0.2 mm using beam steering parameters was easily detectable with the proposed collimator rotation axis test. Mechanical misalignments of the gantry and couch rotation axes of the same magnitude (0.2 mm) were also detectable using the new gantry and couch rotation axis tests. For the couch rotation axis, the phantom and test design allow detection of both translational and tilt misalignments with the radiation beam axis. For the collimator rotation axis, the test can isolate the misalignment between the beam radiation axis and the mechanical collimator rotation axis from the impact of field size asymmetry. The test suite can be performed in a reasonable time (30-35 min) due to simple phantom setup, prescription-based beam delivery, and automated image analysis. As well, it provides a clear description of the relationship between axes. After testing the sensitivity of the test suite to beam steering and mechanical errors, the results of the test suite were used to reduce the misalignment errors of the linac to less than 0.7-mm radius for all axes.

Conclusions: The proposed test suite offers sub-millimeter assessment of the coincidence of the radiation and mechanical isocenters and the test automation reduces complexity with improved efficiency. The test suite results can be used to optimize the linear accelerator's radiation to mechanical isocenter alignment by beam steering and mechanical adjustment of gantry and couch.
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http://dx.doi.org/10.1002/mp.12910DOI Listing
June 2018

Administration of Hypoxia-Activated Prodrug Evofosfamide after Conventional Adjuvant Therapy Enhances Therapeutic Outcome and Targets Cancer-Initiating Cells in Preclinical Models of Colorectal Cancer.

Clin Cancer Res 2018 05 23;24(9):2116-2127. Epub 2018 Feb 23.

Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

Cancer-initiating cells (C-IC) have been described in multiple cancer types, including colorectal cancer. C-ICs are defined by their capacity to self-renew, thereby driving tumor growth. C-ICs were initially thought to be static entities; however, recent studies have determined these cells to be dynamic and influenced by microenvironmental cues such as hypoxia. If hypoxia drives the formation of C-ICs, then therapeutic targeting of hypoxia could represent a novel means to target C-ICs. Patient-derived colorectal cancer xenografts were treated with evofosfamide, a hypoxia-activated prodrug (HAP), in combination with 5-fluorouracil (5-FU) or chemoradiotherapy (5-FU and radiation; CRT). Treatment groups included both concurrent and sequential dosing regimens. Effects on the colorectal cancer-initiating cell (CC-IC) fraction were assessed by serial passage limiting dilution assays. FAZA-PET imaging was utilized as a noninvasive method to assess intratumoral hypoxia. Hypoxia was sufficient to drive the formation of CC-ICs and colorectal cancer cells surviving conventional therapy were more hypoxic and C-IC-like. Using a novel approach to combination therapy, we show that sequential treatment with 5-FU or CRT followed by evofosfamide not only inhibits tumor growth of xenografts compared with 5-FU or CRT alone, but also significantly decreases the CC-IC fraction. Furthermore, noninvasive FAZA-PET hypoxia imaging was predictive of a tumor's response to evofosfamide. Our data demonstrate a novel means to target the CC-IC fraction by adding a HAP sequentially after conventional adjuvant therapy, as well as the use of FAZA-PET as a biomarker for hypoxia to identify tumors that will benefit most from this approach. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1715DOI Listing
May 2018

2D-3D registration for cranial radiation therapy using a 3D kV CBCT and a single limited field-of-view 2D kV radiograph.

Med Phys 2018 May 24;45(5):1794-1810. Epub 2018 Mar 24.

Radiation Medicine Program, Princess Margaret Hospital, Toronto, ON, M5G-2M9, Canada.

Purpose: We present and evaluate a fully automated 2D-3D intensity-based registration framework using a single limited field-of-view (FOV) 2D kV radiograph and a 3D kV CBCT for 3D estimation of patient setup errors during brain radiotherapy.

Methods: We evaluated two similarity measures, the Pearson correlation coefficient on image intensity values (ICC) and maximum likelihood measure with Gaussian noise (MLG), derived from the statistics of transmission images. Pose determination experiments were conducted on 2D kV radiographs in the anterior-posterior (AP) and left lateral (LL) views and 3D kV CBCTs of an anthropomorphic head phantom. In order to minimize radiation exposure and exclude nonrigid structures from the registration, limited FOV 2D kV radiographs were employed. A spatial frequency band useful for the 2D-3D registration was identified from the bone-to-no-bone spectral ratio (BNBSR) of digitally reconstructed radiographs (DRRs) computed from the 3D kV planning CT of the phantom. The images being registered were filtered accordingly prior to computation of the similarity measures. We evaluated the registration accuracy achievable with a single 2D kV radiograph and with the registration results from the AP and LL views combined. We also compared the performance of the 2D-3D registration solutions proposed to that of a commercial 3D-3D registration algorithm, which used the entire skull for the registration. The ground truth was determined from markers affixed to the phantom and visible in the CBCT images.

Results: The accuracy of the 2D-3D registration solutions, as quantified by the root mean squared value of the target registration error (TRE) calculated over a radius of 3 cm for all poses tested, was ICC : 0.56 mm, MLG : 0.74 mm, ICC : 0.57 mm, MLG : 0.54 mm, ICC (AP and LL combined): 0.19 mm, and MLG (AP and LL combined): 0.21 mm. The accuracy of the 3D-3D registration algorithm was 0.27 mm. There was no significant difference in mean TRE for the 2D-3D registration algorithms using a single 2D kV radiograph with similarity measure and image view point. There was no significant difference in mean TRE between ICC , MLG , ICC (AP and LL combined), MLG (AP and LL combined), and the 3D-3D registration algorithm despite the smaller FOV used for the 2D-3D registration. While submillimeter registration accuracy was obtained with both ICC and MLG using a single 2D kV radiograph, combining the results from the two projection views resulted in a significantly smaller (P≤0.05) mean TRE.

Conclusions: Our results indicate that it is possible to achieve submillimeter registration accuracy with both ICC and MLG using either single or dual limited FOV 2D kV radiographs of the head in the AP and LL views. The registration accuracy suggests that the 2D-3D registration solutions presented are suitable for the estimation of patient setup errors not only during conventional brain radiation therapy, but also during stereotactic procedures and proton radiation therapy where tighter setup margins are required.
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http://dx.doi.org/10.1002/mp.12823DOI Listing
May 2018

Monte Carlo analysis of beam blocking grid design parameters: Scatter estimation and the importance of electron backscatter.

Med Phys 2018 Mar 11;45(3):1059-1070. Epub 2018 Feb 11.

Techna Institute and Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.

Purpose: Beam blocking grids provide a simple and direct measurement of the scattered photon signal which degrades image quality in x-ray imaging systems, such as cone-beam CT (CBCT). This study evaluates the scatter estimation accuracy of the beam blocking method to optimize the design parameters of the grid system (e.g., grid thickness, source-to-grid distance (SGD), septa width, air interspace, and grid ratio) using Monte Carlo (MC) simulations.

Method: A MC model of a CBCT imaging system with a beam blocking grid in place is made using code based on EGSnrc, with the x-ray tube portion of the simulation including electron backscatter between the anode and cathode. The inclusion of the electron backscatter allowed a more complete model of the contamination signal to be estimated. The contamination signal consists of the off-focal radiation (OFR) and source component scatter (photon scatter in source components such as tube housing, filters, and collimators). The MC model was validated against measurements collected on a bench top imaging system with a grid in place. The MC model was used to simulate 11 different grid design configurations in addition to a case with no grid. For each design a simulated projection with and without a phantom in place was computed. The simulated projections were then used to estimate the scatter and contamination portion of the signal using the signal behind the grid septa. The estimated signals from the grid data were compared to the actual signals labeled during the MC simulation.

Results: Simulated results showed good agreeance with measured results with the importance of including electron backscatter resulting in off-focal radiation in the simulation being highlighted. When the source was free of contamination photons all grids performed with an error less than 8% when estimating just the scatter from the object. When the contamination photons were included in the simulation, the error in estimating both the scatter and contamination signal rose by a factor of 4 on average. In the case when both signals are present, increasing the grid thickness, changing the SGD, and reducing septa width and air interspace sizes all showed the ability to improve the grid-based estimates of the object scatter and contamination portion signal.

Conclusions: The inclusion of the contamination signal in MC simulations of x-ray imaging systems is important in the design, validation, and evaluation of measurement-based scatter methods. Beam blocking grids show potential not only in object scatter estimation but in the estimation of the contamination signal, but appropriate interpolation functions must be used to account for higher frequencies found in contamination signal.
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http://dx.doi.org/10.1002/mp.12756DOI Listing
March 2018

Impact of tissue transport on PET hypoxia quantification in pancreatic tumours.

EJNMMI Res 2017 Dec 22;7(1):101. Epub 2017 Dec 22.

Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.

Background: The clinical impact of hypoxia in solid tumours is indisputable and yet questions about the sensitivity of hypoxia-PET imaging have impeded its uptake into routine clinical practice. Notably, the binding rate of hypoxia-sensitive PET tracers is slow, comparable to the rate of diffusive equilibration in some tissue types, including mucinous and necrotic tissue. This means that tracer uptake on the scale of a PET imaging voxel-large enough to include such tissue and hypoxic cells-can be as much determined by tissue transport properties as it is by hypoxia. Dynamic PET imaging of 20 patients with pancreatic ductal adenocarcinoma was used to assess the impact of transport on surrogate metrics of hypoxia: the tumour-to-blood ratio [TBR(t)] at time t post-tracer injection and the trapping rate k inferred from a two-tissue compartment model. Transport quantities obtained from this model included the vascular influx and efflux rate coefficients, k and k , and the distribution volume v ≡k /(k +k ).

Results: Correlations between voxel- and whole tumour-scale k and TBR values were weak to modest: the population average of the Pearson correlation coefficients (r) between voxel-scale k and TBR (1 h) [TBR(2 h)] values was 0.10 [0.01] in the 20 patients, while the correlation between tumour-scale k and TBR(2 h) values was 0.58. Using Patlak's formula to correct uptake for the distribution volume, correlations became strong (r=0.80[0.52] and r=0.93, respectively). The distribution volume was substantially below unity for a large fraction of tumours studied, with v ranging from 0.68 to 1 (population average, 0.85). Surprisingly, k values were strongly correlated with v in all patients. A model was proposed to explain this in which k is a combination of the hypoxia-sensitive tracer binding rate k and the rate k of equilibration in slow-equilibrating regions occupying a volume fraction 1-v of the imaged tissue. This model was used to calculate the proposed hypoxia surrogate marker k .

Conclusions: Hypoxia-sensitive PET tracers are slow to reach diffusive equilibrium in a substantial fraction of pancreatic tumours, confounding quantification of hypoxia using both static (TBR) and dynamic (k ) PET imaging. TBR is reduced by distribution volume effects and k is enhanced by slow equilibration. We proposed a novel model to quantify tissue transport properties and hypoxia-sensitive tracer binding in order to improve the sensitivity of hypoxia-PET imaging.
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http://dx.doi.org/10.1186/s13550-017-0347-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741574PMC
December 2017

Serial 4DCT/4DPET imaging to predict and monitor response for locally-advanced non-small cell lung cancer chemo-radiotherapy.

Radiother Oncol 2018 02 12;126(2):347-354. Epub 2017 Dec 12.

Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada; Department of Radiation Oncology, University of Toronto, Canada; Department of Biostatistics, University Health Network, Canada; Techna Institute, Toronto, Canada.

Background And Purpose: A FDG-PET/CT image feature with optimal prognostic potential for locally-advanced non-small cell lung cancer (LA-NSCLC) patients has yet to be identified, and neither has the optimal time for FDG-PET/CT response assessment; furthermore, nodal features have been largely ignored in the literature. We propose to identify image features or imaging time point with maximal prognostic power.

Materials And Methods: Consecutive consenting patients with LA-NSCLC receiving curative intent CRT were enrolled. 4DPET/4DCT scans were acquired 0, 2, 4, and 7 weeks during IMRT treatment. Eleven image features and their rates of change were recorded for each time point and tested for each of the possible outcome 2 years post CRT using the Kaplan-Meier method.

Results: 32 consecutive patients were recruited, 27 completing all scans. Restricting analysis to 4DPET/4DCT features and rates of change with p < 0.005, several volume-based features and their rates of change reached significance. Image features involving nodal disease were the only ones associated with overall survival.

Conclusions: Several 4DPET/CT features and rates of change can reach significant association (p < 0.005) with outcomes, including overall survival, at many time points. The optimal time for adaptive CRT is therefore not constrained uniquely on imaging.
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http://dx.doi.org/10.1016/j.radonc.2017.11.023DOI Listing
February 2018

Altered brain morphology after focal radiation reveals impact of off-target effects: implications for white matter development and neurogenesis.

Neuro Oncol 2018 05;20(6):788-798

Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada.

Background: Children with brain tumors treated with cranial radiation therapy (RT) often exhibit cognitive late effects, commonly associated with reduced white matter (WM) volume and decreased neurogenesis. The impact of radiation damage in particular regions or tissues on brain development as a whole has not been elucidated.

Methods: We delivered whole-brain or focal radiation (8 Gy single dose) to infant mice. Focal treatments targeted white matter (anterior commissure), neuronal (olfactory bulbs), or neurogenic (subventricular zone) regions. High-resolution ex vivo MRI was used to assess radiation-induced volume differences. Immunohistochemistry for myelin basic protein and doublecortin was performed to assess associated cellular changes within white matter and related to neurogenesis, respectively.

Results: Both whole-brain and focal RT in infancy resulted in volume deficits in young adulthood, with whole-brain RT resulting in the largest deficits. RT of the anterior commissure, surprisingly, showed no impact on its volume or on brain development as a whole. In contrast, RT of the olfactory bulbs resulted in off-target volume reduction in the anterior commissure and decreased subventricular zone neurogenesis. RT of the subventricular zone likewise produced volume deficits in both the olfactory bulbs and the anterior commissure. Similar off-target effects were found in the corpus callosum and parietal cortex.

Conclusions: Our results demonstrate that radiation damage locally can have important off-target consequences for brain development. These data suggest that WM may be less radiosensitive than volume change alone would indicate and have implications for region-sparing radiation treatments aimed at reducing cognitive late effects.
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http://dx.doi.org/10.1093/neuonc/nox211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5961122PMC
May 2018