Principal Investigator/Program Director (Last, first, middle): Jiang, Steve Bin
RESEARCH PLAN
A. Specific Aims
Respiratory gated radiotherapy holds promise to reduce the incidence and severity of normal tissue complications and perhaps provide a means for increased local control by dose escalation for the management of mobile tumors in thorax and abdomen. Precise target localization in real time is particularly important for gated radiotherapy due to the reduced clinical tumor volume to planning target volume (CTV-to-PTV) margin and/or escalated dose. Our overall hypothesis is that, with precise target localization using image guidance techniques, gated radiotherapy will enable improvements in radiotherapy outcome for mobile tumors in thorax and abdomen.
Direct localization of the tumor mass in real time is often difficult, if not impossible. Various surrogates are then used to derive the tumor position during the treatment. Currently there are two forms of gated radiotherapy based on the surrogates used: internal gating and external gating. Internal gating utilizes internal tumor motion surrogates such as the implanted fiducial markers while external gating uses external respiratory surrogates such as markers placed on the surface of the patient’s abdomen. Each method has its own pros and cons. By using external markers, external gating is easy, noninvasive, and does not require radiation dose for imaging. The weakness of external gating is related to the uncertainty in correlation between external surrogates and internal target position. One can then say that external gating is “cheap” however often inaccurate. For internal gating, with the fluoroscopically tracking of implanted markers, the precision of target localization is often satisfactory, since in most cases fiducial markers implanted inside or near the tumor are good surrogates for tumor position. However, fluoroscopically tracking requires radiation dose for imaging and the marker implantation procedure is invasive. With many treatment fractions or long treatment time of a single fraction, the imaging dose can be more than what is clinically acceptable. The invasiveness of the marker implantation procedure might be clinically acceptable for abdominal tumors such as liver, but not for thoracic tumors such as lung, due to the risk of pneumothorax that could be caused by percutaneous marker insertion. Therefore, internal gating can be described as accurate but “expensive” or even impractical for some tumor sites.
The existence of various problems with the current state-of-art techniques for gated radiotherapy has prevented this new treatment modality from being widely implemented in clinical routine. These problems mainly are: 1) external gating is non-invasive but inaccurate, therefore should not be used alone; 2) abdominal tumors can be treated with internal gating by fluoroscopically tracking the implanted markers but imaging dose is a concern; and 3) for thoracic tumors internal gating does not work even if one ignores the imaging dose issue, due to the difficulty in target localization without implanted fiducial markers. These problems have to be solved before gated radiotherapy can be safely implemented in many clinics.
The project proposed here will try to solve the above mentioned problems by developing necessary tools and software infrastructure, using an in-house on-board x-ray imaging system and a commercial respiratory gating system as hardware platforms. We plan to develop two sets of tools. One will allow direct lung tumor mass localization without implanted fiducial markers. The other will allow an optimal combination of external gating with internal gating. The combined gating scheme can be called hybrid gating. Hybrid gating is the solution to both imaging dose problem for internal gating and accuracy problem for external gating. By combining external gating surrogates with internal surrogates, the imaging frequency thus the imaging dose can be greatly reduced. By frequently re-calibrating the external/internal correlation during the treatment, target localization accuracy should be greatly improved. A software infrastructure will also be developed to facilitate the use of the developed tools in a streamlined clinical gating procedure. Correspondingly, there are three specific aims of this proposal.
SA1. To develop tools for gated treatment of lung cancer without implanted fiducial markers.
Patient’s 4D CT images will be acquired using developed techniques. Target volume will be segmented either manually or automatically (using tools developed for other projects) at each breathing phase of the 4D CT scan. Tools will be developed to generate digitally reconstructed fluoroscopy (DRF) images from the 4D CT scan. Before each fraction of the treatment, two simultaneous anterior-posterior (AP) and lateral fluoroscopic images for about 15 seconds long will be acquired using the on-board x-ray imaging system. Tools will be developed to register these fluoroscopic images with corresponding DRF images 1) to identify the target contour in the fluoroscopic images and 2) to align the patient. During the treatment delivery, two simultaneous orthogonal sets of fluoroscopic images will be acquired. Tools will be developed to localize the target in every frame of these images to generate gating signals, by using the DRF images of the corresponding imaging angle.
SA2. To develop tools for combining internal surrogates with external surrogates.
The correlation between internal tumor position and external marker position will be investigated using some existing measured data. Emphasis will be given to the intra- and inter-fraction variation of the internal/external correlation. We will find out, if we use external marker position to derive the internal tumor position, how frequent we need to re-calibrate the internal/external correlation by acquiring the x-ray images. Four schemes of combining external signal with internal information will be investigated and the corresponding tools will be developed. The first approach is called external gating with internal verification. The external marker position will be used for gating, while x-ray images will be taken during the external gating window to verify the internal marker/tumor position. Tools will also be developed for the therapists to visualize the detected tumor/marker position and to monitor the treatment. If the tumor/marker position differs from the reference position by a pre-set tolerance value, the therapists will interrupt the treatment and resume the treatment after re-aligning the patient. The second approach is called double gating. The gating signal generated from the external surrogate will be used to gate the on-board imaging system. Then based on the x-ray images the target will be localized and the linac will be gated. The third and four approaches are both called hybrid gating, i.e., the target position will be derived and the gating signal will be generated by using the external and internal signals together. For the third approach, called hybrid gating with minimal imaging, the x-ray imaging takes place at a uniform rate but the rate will be minimized with the help of external signal. For the fourth approach, called hybrid gating with adaptive imaging, the x-ray images are only taken whenever necessary (so images are taken at a non-uniform rate). These four approaches are at an order of increasing technical difficulty. We will study for various clinical scenarios (tumor sites, individual patients, etc.), the optimal way of combining external gating with internal gating by looking at the clinical practicality, target localization accuracy, and the imaging dose reduction of each of the four schemes.
SA3. To develop a software infrastructure for gated radiotherapy
We propose to develop a software infrastructure to facilitate the incorporation of the proposed tools as well as existing tools into a streamlined clinical procedure for gated radiotherapy. The infrastructure should include the following functions: 1) display 4D CT data and generate DRFs, 2) display in real time, and play back fluoroscopic images, 3) detect and display marker/tumor position in fluoroscopic images, 5) register fluoroscopic images with the DRFs with/without implanted markers, 6) display reference marker/tumor position and generate warning sign when the detected marker/tumor position is outside the tolerance zone around the reference position, 7) input external surrogate signal and generate corresponding external gating signal, 8) input internal surrogate signal (detected marker/tumor position) and generate corresponding internal gating signal, 9) estimate marker/tumor position from the combined external/internal surrogate signals, 10) estimate the optimal time to image using the external surrogate signal, 11) gate the on-board imaging system, and 12) gate the linear accelerator. For each function, a corresponding software module will be developed. Proposed tools and existing tools will be tested and implemented into corresponding modules.
By developing the above mentioned tools, we believe we can treat tumors in thorax and abdomen with gated radiotherapy in a safe and clinically practical way.
B. Background and Significance
B.1. Problems with Respiratory Tumor Motion in Radiotherapy
Radiation therapy is a treatment modality directed towards local control of cancer. The primary goal is to precisely deliver a lethal dose to the tumor while minimizing the dose to surrounding healthy tissues and critical structures. Recent technological advances in radiation therapy, such as intensity-modulated radiation therapy (IMRT), provide the capability of delivering a highly conformal radiation dose distribution to a complex static target volume. However, treatment errors related to internal organ motion may greatly degrade the effectiveness of conformal radiotherapy for the management of thoracic and abdominal lesions, especially when the treatment is done in a hypo-fraction or single fraction manner [1-8]. This has become a pressing issue in the emerging era of image-guided radiation therapy (IGRT).
Intra-fraction organ motion is mainly caused by patient respiration, sometimes also by skeletal muscular, cardiac, or gastrointestinal systems. Respiration induced organ motion has been studied by directly tracking the movement of the tumor [2, 9-12], the host organ [13, 14], radio-opaque markers implanted at the tumor site [4, 15-19], radioactive tracer targeting the tumor [20, 21], and surrogate structures such as diaphragm and chest wall [22-24]. Various imaging modalities have been used for organ motion studies, including ultrasound [13, 14], CT [9, 10, 22, 25], MR [26], and fluoroscopy [2, 4, 11, 15-19, 23, 24, 27-31]. It has been shown that the motion magnitude can be clinically significant (e.g., of the order of 2 - 3 cm), depending on tumor sites and individual patients.
One category of methods to account for respiratory motion is to minimize the tumor motion, using techniques such as breath holding and forced shallow breathing (such as jet ventilation) [10, 32-39]. These techniques require patient compliance, active participation and, often, extra therapist participation. They may not be well tolerated by patients with compromised lung function which is the case for most lung cancer patients [40]. Another category of the methods accounting for respiratory motion is to allow free tumor motion while adapting the radiation beam to the tumor position by either respiratory gating or beam tracking.
Respiratory gating limits radiation exposure to the portion of the breathing cycle when the tumor is in the path of the beam [15, 23, 29, 30, 40-51]. Beam tracking technique follows the target dynamically with the radiation beam [52]. It was first implemented in a robotic radiosurgery system (CyberKnife) [53-57]. For linac-based radiotherapy, tumor motion can be compensated for using a dynamic multileaf collimator (MLC) [58-67]. Linac based beam tracking is still under development. Due to technical difficulties and quality assurance considerations, a lot of work has to be done before it can be applied to patient treatment. One the other hand, respiratory gating is technically less challenging and clinically more practical. It has been introduced in clinic practice in a limited number of cancer centers. It is believed that gated radiotherapy will be widely implemented in clinical routine for treating tumors in thorax and abdomen after some needed tools are developed. This proposal will focus on the tool development for gated radiotherapy.
B.2. Some Basic Concepts of Gated Radiotherapy
For gated radiotherapy, precise and real time tumor localization is extremely important because tighter CTV-PTV (clinical tumor volume to planning target volume) margins are often applied based on the expectation of reduced tumor motion [46]. In an idealized gated treatment, tumor position should be directly detected and the delivery of radiation is only allowed when the tumor is at the right position. However, direct detection of the tumor mass in real-time during the treatment is often difficult. Various surrogates are then used to indicate the tumor position. Based on surrogates used, we may categorize respiratory gating into internal gating and external gating. Internal gating utilizes internal tumor motion surrogates such as implanted fiducial markers while external gating relies on external respiratory surrogates such as makers placed on the patient’s abdomen.
A basic concept for the gated treatment is called gate or gating window. A gating window is a range of the surrogate signal (such as the 3D marker position in case of internal gating and the marker position in case of external gating). When the surrogate signal falls in the range (gating window), the gating signal is 1; otherwise it is 0. Therefore, the gating window converts the surrogate signal into gating signal and then the gating signal controls the linac. For internal gating, the gating window is often a small rectangular solid corresponding to the 3D position of the implanted fiducial marker. For external gating, the gating window can be either defined by two anterial-posterial (AP) positions or two phase values of the surface marker, which correspond to two types of external gating: displacement or amplitude gating, and phase gating.
Another basic concept for gated treatment is called duty cycle. Duty cycle is a measure of the treatment efficiency and defined as the ratio of beam-on time to the total treatment time. Intuitively, the larger the gating window, the higher the duty cycle. However, for the same patient, the larger the gating window, the larger the tumor residual motion. Therefore, it is always a trade-off between duty cycle and residual motion.
B.3. History and Current Status of Gated Radiotherapy
Respiratory gated radiation therapy was first developed in Japan in the late 1980s and early 1990s for linac photon beams as well as for heavy ion beams [23, 41, 68, 69]. Various external surrogates were used to monitor respiratory motion, including a combination airbag and strain gauge taped on the patient’s abdomen or back (for prone treatments) to gate a proton beam [41, 68], and position sensors placed on the patient [23, 69, 70]. A major advancement of the gated radiotherapy was the real-time tumor tracking (RTRT) system developed by Mitsubishi Electronics Co., Ltd., Tokyo, in collaboration with the Hokkaido University [29, 30, 47-51]. The RTRT system uses real-time fluoroscopic tracking of gold markers implanted in tumor.