Out-of-Field Dose to the Eye Lens and Cardiac Implantable Electronic Devices (CIEDs) during VMAT of the prostate

Volumetric Modulated Arc Therapy (VMAT) is a new type of Intensity Modulated Radiation Therapy (IMRT) technique as it can deliver a more accurate shape of sculpted 3D dose distribution to the targeted tumour volume in a single 360 degree gantry rotation or multiple sub-arcs. This improvement, however, has not mitigated the problem of doses to normal tissues outside the treated volume. The out-of-field dose associated risks remains high clinical and scientific interests for investigations. A re-evaluation of the eye lens radio-sensitivity by the ICRP 2011 has resulted in a significant reduction of the threshold for lens opacities from 8 Gy to 0.5 Gy. The objective of this thesis study is to investigate the out-of-field doses to critical structures such as eye lens and CIEDs (cardiac implantable electronic devices) such as pacemakers and ICDs during 6 MV VMAT treatment of the prostate

Second primary cancers after radiation for prostate cancer: a review of data from planning studies

A review of planning studies was undertaken to evaluate estimated risks of radiation induced second primary cancers (RISPC) associated with different prostate radiotherapy techniques for localised prostate cancer. A total of 83 publications were identified which employed a variety of methods to estimate RISPC risk. Of these, the 16 planning studies which specifically addressed absolute or relative second cancer risk using dose–response models were selected for inclusion within this review. There are uncertainties and limitations related to all the different methods for estimating RISPC risk. Whether or not dose models include the effects of the primary radiation beam, as well as out-of-field regions, influences estimated risks. Regarding the impact of IMRT compared to 3D-CRT, at equivalent energies, several studies suggest an increase in risk related to increased leakage contributing to out-of-field RISPC risk, although in absolute terms this increase in risk may be very small. IMRT also results in increased low dose normal tissue irradiation, but the extent to which this has been estimated to contribute to RISPC risk is variable, and may also be very small. IMRT is often delivered using 6MV photons while conventional radiotherapy often requires higher energies to achieve adequate tissue penetration, and so comparisons between IMRT and older techniques should not be restricted to equivalent energies. Proton and brachytherapy planning studies suggest very low RISPC risks associated with these techniques. Until there is sufficient clinical evidence regarding RISPC risks associated with modern irradiation techniques, the data produced from planning studies is relevant when considering which patients to irradiate, and which technique to employ

Cancer of the Uterine Endometrium

The book Cancer of the Uterine Endometrium - Advances and Controversies brings together an international collaboration of authors who share their contributions for the management of endometrial carcinoma. The scope of the text is not basic, but rather aims to provide a comprehensive and updated source of advances in the diagnosis and therapeutic strategies in this field of gynecologic cancer. Each section in the book attempts to provide the most relevant evidence-based information in the biology and genetics, modern imaging, surgery and staging, and therapies for endometrial cancer. It is hoped that future editions will bring additional authors to contribute to this endeavor. To this end, it is our patients who will benefit from this work

Novel multifunctional platinum nanodendrites as theranostic agents in cancer imaging and radiotherapy treatment

High-Z nanoparticles have been studied over the years as a potential radio-theranostic agent due to their high X-ray absorption and good pharmacokinetic properties. However, only a few platinum-based agents have been reported in the literature, despite its wide usage in chemotherapy (i.e., cisplatin). Thus, this work aims to study platinum nanoparticles, Platinum Nanodendrites (PtND), as a novel theranostic agent. The PtNDs fabricated in this work possessed a dendritic shape with a negatively charged surface. Four PtND sizes were prepared for theranostic evaluations (29 nm, 36 nm, 42 nm, and 52 nm). In-vitro biocompatibility assessment revealed that the PtNDs of all sizes were non-cytotoxic for the particle concentration of up to 0.1 mM. Furthermore, the PtNDs’ toxicity also depended on PtNDs’ size, cell type, and incubation period. The theranostic evaluation of PtNDs was separated into diagnostic and radiotherapy sections. The diagnostic evaluation was performed with the maximum available PtND concentration, 1.0 mM, to maximize their image contrast in X-ray images. The PtNDs of different sizes were compared with the commercial iodinated contrast agent in three X-ray modalities (CT, fluoroscopy, and planar X-ray). The result in all imaging systems evidenced better attenuation of PtNDs over iodinated contrast agent at equivalent concentration. The contrast enhancement is also size-dependent, where larger PtNDs exhibited higher X-ray attenuation than the smaller ones. The radiotherapy evaluation involved a study on the radiosensitization effects of PtNDs in three different types of radiotherapy: 6 MV photon radiotherapy, 6 MeV electron beam therapy, and 150 MeV proton beam therapy. HeLa cells were treated with 0.1 mM of PtNDs of different sizes and subjected to increasing radiation doses. The clonogenic assay evaluations revealed that the PtNDs successfully enhanced the radiosensitivity of HeLa cells, depending on the particle size and types of radiotherapy. The maximum radiosensitization effect was observed in the combination of 29 nm PtNDs with PhT (SER=2.54). 36 nm and 42 nm PtNDs produced the highest radiosensitization in PrT (SER=1.38) and EBT (SER=1.83), respectively. DCF assay assessment shows that the ROS induced by the PtND-radiation combinations may not be the major determining factors that catalyse the PtNDs’ radiosensitization effect. In conclusion, this work has successfully developed and characterized the theranostic potential of PtNDs. This study provides a platform for theranostic multimodal approaches in diagnostic imaging and radiotherapy to improve cancer treatment efficacy and outcomes

Late Morbidity (Dysphagia) in Head and Neck Cancer after Radiotherapy using various Treatment Techniques

Oropharyngeal Cancer (Chapter 2) Good tumor control but late-side effects occur e.g. dysphagia. Quality of Life: Dysphagia (Chapters 3-6) Dose-effects relationships in base of tongue, tonsillar fossa and nasopharyngeal cancer are found for swallowing problems. Quality of Lfe: Trismus (Chapter 7) Dose-effects relationships in base of tongue and tonsillar fossa are found for trismus problems. Brachytherapy (Chapters 8-10) Patient treated by brachyhterapy have better local control, disease-free survival and overal survival than those treated with EBRT. Also BT patients were found to have fewer swallowing problems compared with the non-BT group of patients. Hyperbaric Oxygen (Chapter 11) A great benefit for the quality of life of patients was seen in patients who were randomized for hyperbaric oxygen after radiotherapy. A significant difference of different aspects of quality of life was seen for H&N35 ‘swallowing problems’, H&N35 ‘sticky saliva’, H&N35 ‘dry mouth’, visual analogue scale (VAS) ‘Dry mouth’, PSS ‘eating in public’ and VAS ‘pain in mouth’ in favor of the hyperbaric oxygen group. Non-Rigid Registration / Atlas-Based Auto-Segmentation (Chapters 12-14) Non-rigid registration method is a powerful tool to accurately assess local shape and position changes in HNC patients. When using ABAS, edited auto-contours were somewhat more in concordance with the corresponding levels of this atlas as opposed to the originally contoured levels

Improving total body irradiation with a dedicated couch and 3D-printed patient-specific lung blocks: A feasibility study

Introduction: Total body irradiation (TBI) is an important component of the conditioning regimen in patients undergoing hematopoietic stem cell transplants. TBI is used in very few patients and therefore it is generally delivered with standard linear accelerators (LINACs) and not with dedicated devices. Severe pulmonary toxicity is the most common adverse effect after TBI, and patient-specific lead blocks are used to reduce mean lung dose. In this context, online treatment setup is crucial to achieve precise positioning of the lung blocks. Therefore, in this study we aim to report our experience at generating 3D-printed patient-specific lung blocks and coupling a dedicated couch (with an integrated onboard image device) with a modern LINAC for TBI treatment. Material and methods: TBI was planned and delivered (2Gy/fraction given twice a day, over 3 days) to 15 patients. Online images, to be compared with planned digitally reconstructed radiographies, were acquired with the couch-dedicated Electronic Portal Imaging Device (EPID) panel and imported in the iView software using a homemade Graphical User Interface (GUI). In vivo dosimetry, using Metal-Oxide Field-Effect Transistors (MOSFETs), was used to assess the setup reproducibility in both supine and prone positions. Results: 3D printing of lung blocks was feasible for all planned patients using a stereolithography 3D printer with a build volume of 14.5×14.5×17.5 cm3. The number of required pre-TBI EPID-images generally decreases after the first fraction. In patient-specific quality assurance, the difference between measured and calculated dose was generally<2%. The MOSFET measurements reproducibility along each treatment and patient was 2.7%, in average. Conclusion: The TBI technique was successfully implemented, demonstrating that our approach is feasible, flexible, and cost-effective. The use of 3D-printed patient-specific lung blocks have the potential to personalize TBI treatment and to refine the shape of the blocks before delivery, making them extremely versatile

INTEGRATION OF BIOMEDICAL IMAGING AND TRANSLATIONAL APPROACHES FOR MANAGEMENT OF HEAD AND NECK CANCER

The aim of the clinical component of this work was to determine whether the currently available clinical imaging tools can be integrated with radiotherapy (RT) platforms for monitoring and adaptation of radiation dose, prediction of tumor response and disease outcomes, and characterization of patterns of failure and normal tissue toxicity in head and neck cancer (HNC) patients with potentially curable tumors. In Aim 1, we showed that the currently available clinical imaging modalities can be successfully used to adapt RT dose based-on dynamic tumor response, predict oncologic disease outcomes, characterize RT-induced toxicity, and identify the patterns of disease failure. We used anatomical MRIs for the RT dose adaptation purpose. Our findings showed that after proper standardization of the immobilization and image acquisition techniques, we can achieve high geometric accuracy. These images can then be used to monitor the shrinkage of tumors during RT and optimize the clinical target volumes accordingly. Our results also showed that this MR-guided dose adaptation technique has a dosimetric advantage over the standard of care and was associated with a reduction in normal tissue doses that translated into a reduction of the odds of long-term RT-induced toxicity. In the second aim, we used quantitative MRIs to determine its benefit for prediction of oncologic outcomes and characterization of RT-induced normal tissue toxicity. Our findings showed that delta changes of apparent diffusion coefficient parameters derived from diffusion-weighted images at mid-RT can be used to predict local recurrence and recurrence free-survival. We also showed that Ktrans and Ve vascular parameters derived from dynamic contrast-enhanced MRIs can characterize the mandibular areas of osteoradionecrosis. In the final clinical aim, we used CT images of recurrence and baseline CT planning images to develop a methodology and workflow that involves the application of deformable image registration software as a tool to standardize image co-registration in addition to granular combined geometric- and dosimetric-based failure characterization to correctly attribute sites and causes of locoregional failure. We then successfully applied this methodology to identify the patterns of failure following postoperative and definitive IMRT in HNC patients. Using this methodology, we showed that most recurrences occurred in the central high dose regions for patients treated with definitive IMRT compared with mainly non-central high dose recurrences after postoperative IMRT. We also correlated recurrences with pretreatment FDG-PET and identified that most of the central high dose recurrences originated in an area that would be covered by a 10-mm margin on the volume of 50% of the maximum FDG uptake. In the translational component of this work, we integrated radiomic features derived from pre-RT CT images with whole-genome measurements using TCGA and TCIA data. Our results demonstrated a statistically significant associations between radiomic features characterizing different tumor phenotypes and different genomic features. These findings represent a promising potential towards non-invasively tract genomic changes in the tumor during treatment and use this information to adapt treatment accordingly. In the final project of this dissertation, we developed a high-throughput approach to identify effective systemic agents against aggressive head and neck tumors with poor prognosis like anaplastic thyroid cancer. We successfully identified three candidate drugs and performed extensive in vitro and in vivo validation using orthotopic and PDX models. Among these drugs, HDAC inhibitor and LBH-589 showed the most effective tumor growth inhibition that can be used in future clinical trials

Risk of Second Malignant Neoplasms Following Proton Arc Therapy and Volumetric Modulated Arc Therapy for Prostate Cancer

The risk of second malignant neoplasms (SMNs) following prostate radiotherapy is a concern due to the large population of survivors and decreasing age at diagnosis. It is known that parallel-opposed beam proton therapy carries a lower risk than photon IMRT. However, a comparison of SMN risk following proton and photon arc therapies has not previously been reported. The purpose of this study was to predict the ratio of excess relative risk (RRR) of SMN incidence following proton arc therapy to that after volumetric modulated arc therapy (VMAT). Additionally, we investigated the impact of margin size and the effect of risk-minimized proton beam weighting on predicted RRR. Physician-approved treatment plans were created for both modalities for three patients. Therapeutic dose was obtained with differential dose-volume histograms from the treatment planning system, and stray dose was estimated from the literature or calculated with Monte Carlo simulations. Then, various risk models were applied to the total dose. Additional treatment plans were also investigated with varying margin size and risk-minimized proton beam weighting. The mean RRR ranged from 0.74 to 0.99, depending on risk model. The additional treatment plans revealed that the RRR remained approximately constant with varying margin size, and that the predicted RRR was reduced by 12% using a risk-minimized proton arc therapy planning technique. In conclusion, proton arc therapy was found to provide an advantage over VMAT in regard to predicted risk of SMN following prostate radiotherapy. This advantage was independent of margin size and was amplified with risk-optimized proton beam weighting