Session S16: Focus Session: General Techniques and Radiation Therapies in Biological Physics

The Evolution of External Beam Radiation Therapy (EBRT) from a Technological Perspective.

Since the discovery of x-rays by Roentgen in 1895 ionizing radiations have been used as a treatment for cancer. Such treatments have been based on either implantation of radioactive materials at the site of disease or by aiming external radiation beams at the diseased site. This later method is referred to as \textit{teletherapy} because the beams originate from a location outside of the body distant from the disease site itself. A brief review of the basic radiation biology will be given to illustrate the rationale for therapeutic use of ionizing radiations and the effects of beam energy and beam type- particulate or photon. The remainder of the presentation will focus on the technological \textit{teletherapy} developments supported by the required physical properties of the beams and their associated characteristics that make them suitable for patient treatments. Chronological highlights will include the following sources or devices: superficial x-rays, orthovaltage x-rays, megavoltage x-rays and Cobalt 60 photons, electron beams, neutron beams, negative pi mesons, protons, and heavy ions. The presentation will illustrate how the physical beam properties have been incorporated into modern radiation treatment devices, many of which are equipped with radiation imaging capability. Such devices include: linacs equipped with multileaf collimators for beam shaping and intensity modulation, the Gamma Knife for precise and accurate irradiation of brain tumors or arterial-venous malformations (AVM), the robotic arm based Cyber Knife, and the Helical Tomotherapy unit.   

State-of-the-Art External Beam Radiation Therapy: Challenges and Opportunities

Intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT) allow delivery of highly conformal non-convex dose distributions. However, these treatment modalities require precise knowledge of multimodality imaging, internal organ motion, tumor control probabilities, normal tissue complication probabilities, three-dimensional dose calculation and optimization, dynamic beam delivery of non-uniform beam intensities, and most importantly the knowledge of uncertainties in the radiation therapy planning and delivery process. These uncertainties arise from a variety of sources throughout the whole process that consists of three distinct steps: imaging, planning, and delivery. In the imaging step, 3D patient information is obtained for treatment planning. Any problem in the acquisition, transfer, conversion, registration, or use of imaging data can lead to increased geometrical uncertainties. Dose calculation algorithms have inherent errors, because they are based on approximate solutions to a complex physical situation. The assumptions of a RTP system in modeling a treatment machine significantly impact dose calculation accuracy. The accuracy of the beam geometry depends on the tolerance of each machine parameter and the magnitude of setup errors. Therefore, one must clearly identify and account for all sources of error in imaging, treatment planning, and delivery process to understand the uncertainty in dose delivered to a patient with IMRT/IGRT. It is necessary to properly account for these uncertainties in radiation therapy to improve the accuracy of the dose delivered to patients. This presentation will provide the framework and guidance to safely implement these technologies in the clinic.   

Technological Advances in Proton Therapy

Proton therapy has interested radiation oncologists since the 1946 paper by Robert R. Wilson describing the energy deposition of proton beams and suggesting it would be more suitable for radiation treatments than beams of x-rays. For all its proposed benefits, only 25,000 or so cancer patients worldwide have been treated with high-energy proton beams over the last fifty years. However, during the past decade that number has started to rapidly increase. In the United States alone the number of dedicated facilities has grown from two to five in the last three years and will likely double again by the end of the current decade. We will soon be treating as many patients in one year as was treated during the first fifty years of proton therapy. Surprisingly, the reason is because of what has been happening in x-ray radiotherapy. Conventional radiotherapy underwent a dramatic change during the past decade with the introduction of multiple advances in imaging technology and beam delivery methods. The imaging advances include both imaging for treatment planning (multislice CT systems, high resolution MRI, and increasing use of PET) and imaging of the target location in the treatment room. The treatment delivery advances, dominated by methods that permit intensity modulated beam delivery, were made possible by increased computational power and more computer control of the treatment delivery. These imaging and beam delivery advances should benefit proton therapy treatments even more than x-ray treatments because of the better conformation of dose to the target that one can achieve with proton beams. However, because of the small size of the proton therapy community it has had difficulty implementing some of the advances made in x-ray therapy. The treatment planning imaging is also used by proton therapy but the on-treatment imaging and the intensity modulation often must be specially developed for each proton therapy system. This talk will present the developments in these areas that are expected to be implemented in the next few years.   

The active catheter: a novel approach for in-situ dose measurements in brachytherapy

Radiation therapy is the primary mean to combat cancerous tissues. However, although efficient, it still lacks from having a tool that could enable accurate measurement of the dose delivered to the tissue in-situ. The active catheter concept was taken from a common approach used in nuclear/high energy physics where the target is sometimes constructed so as to provide additional information on the scattering process (i.e., active target). By making the catheters used to transport radioactive sources during brachytherapy treatments becoming sensitive to radiation, one is able to extract dose information in-vivo with minimal to no modification during the treatment process. The technique relies on the use of thin (few 1o0s microns) scintillating fibers embedded within the brachytherapy device. We will report on two applications of such active catheters pertaining to breast and prostate cancer. The former was applied to the MammoSite{\textregistered} balloon from Cytyc, the accelerated partial breast irradiation technique that is becoming the preferred mode of radiation in breast brachytherapy. Results from water phantom data will be presented and discussed. For the latter, gel phantom tests were performed simulating prostate brachytherapy treatments. Comparison with a treatment planning to these data will be also presented and discussed.   

The proton and carbon therapy experience of the medical physics group at the Italian Southern Laboratories: Monte Carlo simulation and experiment

At the Italian Southern Laboratories (LNS) of the Italian National Institute for Nuclear Physics the first, and actually unique, Italian proton therapy center is installed and operating. Up to now, 140 patients have been treated. In this environment a big effort is devoted towards Monte Carlo simulation expeciallt with the GEANT4 Toolkit. The authors of this work belong to the Geant4 Collaboration and they use the toolkit in their research programs. They maintain a Monte Carlo application devoted to the complete simulation of a generic hadron-therapy beam line and take active part in the study of fragmentation processes. Moreover they are working in the development of a prototype of a proton Computed tomographic system. In this work we will report our results in the field of proton and carbon therapy either in the simulation as well in the experimental side of our activity.   

Real-time High Resolution Plasmonic nanosensors: pH modulated captavidin/biotin binding

The ability to observe real-time molecular binding kinetics is important for understanding the functions and interactions of biological molecules. Localized surface plasmon resonance (LSPR) nanosensors exhibit intense extinction and scattering spectra that redshift when molecules bind to their surface. Herein, we use an array of biotin functionalized silver nanoprisms to detect pH-modulated binding and dissociation of captavidin to biotin as a model system. The captavidin binds at neutral pH and dissociates at high pH. Spectral shifts are monitored in real-time at high resolution during pH-modulated binding and dissociation cycles over hours. After the first cycle, good reversibility is observed. We also observe pH modulated charging and nanoparticle etching effects which are important experimental parameters and also provide a means to control and modulate the nanoparticle spectra.   

Electrical noise gives away presence of cancer or toxins in culture

Since 1984, electric cell-substrate impedance sensing (ECIS) has been used to monitor cell behavior in culture and has proven sensitive to morphological changes and cell mobility. Several authors have associated fluctuations in the measured impedance with cellular micromotion; however we are unaware of any previous work applying statistical techniques in order to distinguish two different cell types. We have now demonstrated a method for distinguishing cancerous from non-cancerous cultures of human ovarian surface epithelial cells;\footnote{\frenchspacing D.C. Lovelady {\it et al.}, {\it Phys. Rev. E} {\bf 76}, 041908 (2007).} applying similar ideas, we have also determined the presence and concentration of the toxin cytochalisin B in cultures of 3T3 fibroblasts at levels lower than the detection thresholds of other techniques. Measures indicative of both short-time (autocorrelation) and long-time ($1/f^\alpha$ noise in the power spectrum and Hurst and detrended-fluctuation-analysis exponents) show statistically significant differences between the populations. Our measures confirm that the noise from non-cancerous cultures has a higher degree of temporal order, order which we argue must arise from greater coordination of motion between healthy cells than between cancerous ones.   

Delayed Luminescence and Biophotons from Biological Materials

There has recently been increased interest in the field of biophotonics, since it is a non-invasive technique.~ Many biological systems, such as yeast, bacteria, leaves, seeds, and algae display the unusual phenomenon of a weak, delayed luminescence on the timescale of seconds to minutes after transient illumination. It is also observed that the time decay of the biophotonic emission is not exponential, even after the delay, and that there can be oscillations in intensity with time, which depend on the duration of the illumination. Results from two types of yeast, i.e. bread yeast, and saccharomyces, as well as those from several types of algae are presented. Possible mechanisms for the source of the ultraweak photon emission are discussed.   

Dielectric Spectroscopy: noninvasive and fast method for measuring changes in the membrane potential

We present a noninvasive and fast method, dielectric spectroscopy, to measure changes in the membrane potential of live cell suspensions, in particular to E. coli. This technique can be applied virtually to any cell suspension, regardless of size or shape and is tested against the traditional one-using voltage sensitive dyes. Precise measurements of the dielectric permittivity $\varepsilon $ and conductivity $\sigma $ of live cells suspensions require prior elimination of the polarization errors. Polarization errors are caused by the ionic content of a buffer, and they affect the total impedance in the low frequency interval. We hereby present our approach of polarization removal in low frequency limit by fitting both real and imaginary experimental curves with an ideal impedance Z=d/i$\omega \varepsilon ^{\ast }$S, where $\varepsilon ^{\ast }=\varepsilon $+1/i$\omega \sigma $. Here, $\varepsilon $ and $\sigma $ represent the fitting parameters; a higher weight is given to each of them for the high frequency domain (3kHz-10kHz), where polarization effects were proven negligible. Measurements were performed in a low electric field (1V/cm) and 40Hz-10kHz frequency domain. Different buffers are measured, such as HEPES, DMEM with different KCl concentrations. Adding different KCl concentration or ionophores triggers changes in the membrane potential of E. coli. Those changes are measured using dielectric spectroscopy and voltage sensitive dyes.