CHERENKOV IMAGING AND BIOCHEMICAL SENSING IN VIVO DURING RADIATION THERAPY A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Physics and Astronomy by RONGXIAO ZHANG DARTMOUTH COLLEGE Hanover, New Hampshire 05/12/2015 Examining Committee: Chairman_______________________ Brian W. Pogue Member________________________ Miles P. Blencowe Member________________________ David J. Gladstone Member________________________ James W. LaBelle Member________________________ Timothy C. Zhu ___________________ F. Jon Kull Dean of Graduate Studies THIS PAGE IS INTENTIONALLY LEFT BLANK, UNCOUNTED AND UNNUMBERED Abstract While Cherenkov emission was discovered more than eighty years ago, the potential applications of imaging this during radiation therapy have just recently been explored. With approximately half of all cancer patients being treated by radiation at some point during their cancer management, there is a constant challenge to ensure optimal treatment efficiency is achieved with maximal tumor to normal tissue therapeutic ratio. To achieve this, the treatment process as well as biological information affecting the treatment should ideally be effective and directly derived from the delivery of radiation to the patient. The value of Cherenkov emission imaging was examined here, primarily for visualization of treatment monitoring and then secondarily for Cherenkov-excited luminescence for tissue biochemical sensing within tissue. Through synchronized gating to the short radiation pulses of a linear accelerator (200Hz & 3 µs pulses), and applying a gated intensified camera for imaging, the Cherenkov radiation can be captured near video frame rates (30 frame per sec) with dim ambient room lighting. This procedure, sometimes termed Cherenkoscopy, is readily visualized without affecting the normal process of external beam radiation therapy. With simulation, phantoms and clinical trial data, each application of Cherenkoscopy was examined: i) for treatment monitoring, ii) for patient position monitoring and motion tracking, and iii) for superficial dose imaging. The temporal dynamics of delivered radiation fields can easily be directly imaged on the patient’s surface. Image registration and edge detection of Cherenkov images were used to verify patient positioning during treatment. Inter-fraction setup accuracy and intra-fraction patient motion was detectable to better than 1 mm accuracy. ii Cherenkov emission in tissue opens up a new field of biochemical sensing within the tissue environment, using luminescent agents which can be activated by this light. In the first study of its kind with external beam irradiation, a dendritic platinum-based phosphor (PtG4) was used at micro-molar concentrations (~5 µM) to generate Cherenkov- induced luminescent signals, which are sensitive to the partial pressure of oxygen. Both tomographic reconstruction methods and linear scanned imaging were investigated here to examine the limits of detection. Recovery of optical molecular distributions was shown in tissue phantoms and small animals, with high accuracy (~1 µM), high spatial resolution (~0.2 mm) and deep-tissue detectability (~2 cm for Cherenkov luminescence scanned imaging (CELSI)), indicating potentials for in vivo and clinical use. In summary, many of the physical and technological details of Cherenkov imaging and Cherenkov-excited emission imaging were specified in this study. iii Preface My graduate study has been a journey filled with pleasure, curiosity, hesitation, wonder and sometimes pain. Close to the end of it, I feel much more bounded to it. The past five years I spent at Dartmouth has made it feel very real and truly unforgettable. Here I would like to thank all the people helped me going through it. I still clearly remember the first time I met Prof. Brian Pogue, who later became my graduate study advisor, in front his office as Dean of Graduate Studie s. From that moment on, he helped me in every aspect and step of my graduate study with great patience. His door was never closed for helping me solving problems encountered in research and coursework. He tirelessly revised my writing in such great detail that the manuscripts ended up being improved to a completely different level. His enthusiasm and insight about the Cherenkov research project guided me through obstacles which seemed to be impossible to overcome by myself. I feel fortunate to have Brian as my advisor and cannot appreciate enough the immeasurable amount of work he has done for me. I would not be able to make it through my graduate study without the tremendous help and guidance from Prof. David Gladstone. It is his sharp insight that guided my research to the correct directions, especially when I got lost. The access to the clinical linear accelerators and treatment planning system provided by Prof. Gladstone was essential for my research project. The research support I got from Dr. Lesley Jarvis on the clinical side has also been an essential part of my PhD work. I also want to thank Prof. Pogue, Prof. Gladstone and Dr. Jarvis for their support in helping me prepare for my next step. It was fortunate for me iv to work with my colleague, Dr. Adam Glaser, and I thank him for a lot of productive collaborations and discussions. I express my gratitude to Prof. Timothy Zhu, Prof. David Gladstone, Prof. Miles Blencowe and Prof. James LaBelle for serving on my committee. Finally, I appreciate the spiritual supports from my parents and my wife. Without them, the rest of the world would mean nothing to me. v Table of Contents Abstract ............................................................................................................................... ii Preface ................................................................................................................................ iv Table of Contents ............................................................................................................... vi List of Tables .................................................................................................................... xii List of Figures .................................................................................................................. xiii List of abbreviations ...................................................................................................... xviii Chapter 1: Introduction ....................................................................................................... 1 1.1 External Beam Radiation Therapy (EBRT) ........................................................................... 1 1.1.1 The Medical LINAC ....................................................................................................... 2 1.1.2 Delivery of Radiation Dose............................................................................................. 4 1.2 Cherenkov Radiation ............................................................................................................. 6 1.2.1 Simple Physical Picture .................................................................................................. 7 1.2.2 Review of Classical Theory ............................................................................................ 9 1.2.3 The Relationship between Cherenkov Emission and Radiation Dose .......................... 14 1.2.4 Transport in Biological Medium ................................................................................... 15 1.3 Biomedical Applications of Cherenkov Radiation .............................................................. 21 1.3.1 Cherenkov Luminescence Imaging (CLI) ..................................................................... 21 1.3.2 Cherenkov Imaging Based Quality Assurance ............................................................. 22 1.3.3 Real-Time Cherenkov Imaging During Radiation Therapy (Cherenkoscopy) ............. 23 1.3.4 Cherenkov-Excited Optical Molecular Imaging from Radiation Therapy .................... 24 vi 1.4 Summary .............................................................................................................................. 25 Chapter 2: Surface-Emitted Cherenkov Radiation for Superficial Dose Imaging: Tissue Phantom Imaging & Monte Carlo Studies ........................................................................ 26 2.1 Superficial Dosimetry Imaging of Cherenkov Emission for Electron Beams ..................... 26 2.1.1 Introduction ................................................................................................................... 26 2.1.2 Materials and Methods .................................................................................................. 29 2.1.3 Results ........................................................................................................................... 34 2.1.4 Discussions ................................................................................................................... 41 2.2 Superficial Dosimetry Imaging Based on Cherenkov Emission for Megavoltage X-ray Beam .......................................................................................................................................... 51 2.2.1 Introduction ................................................................................................................... 51 2.2.2 Materials and Methods .................................................................................................