Dynamic Tracking of Moving Tumors in Stereotactic

CHAPTER

6

Dynamic Tracking of Moving Tumors in Stereotactic Radiosurgery

Sonja Dieterich

Abstract

Introduction

In recent years, technologies for real-time tracking of moving tumors in stereotactic radiosurgery (SRS) have been developed. After an introduction to 4D-IMRT and robotic dynamic SRS, we give an overview of motion patterns and amplitudes for lung, pancreas, prostate and liver. Imaging techniques used in radiation therapy treatment planning for these moving organs include free breathing and breath-hold CT, 4D-CT and 4D-MR. The application of internal respiratory motion information in treatment planning and dosimetry is discussed. Limits of the available technology need to be considered. Recent developments to improve continuous internal target tracking, such as electromagnetic tracking, will be available in the near future. The complex technology of dynamic SRS systems requires regular calibration and quality assurance (QA) of all components to ensure treatment safety and efficacy.

Until recent years, radiation treatment devices were not able to actively track and compensate for respiratory motion. Presently coverage of moving lesions is achieved through the use of large treatment margins around the gross target volume (GTV) to establish the planning target volume (PTV). Immobilizing devices, compressing the abdominal wall to restrict breathing motion, lead to smaller margins and more healthy tissue sparing.1 Alternatively, patients were instructed to take shallow breaths during simulation, image acquisition and treatment. From there, it was only a small step to breath-hold techniques for imaging and treatment.2–4 Patients are instructed to hold their breath at full inspiration for 0–20 seconds, during which time the treatment beam is switched on. This creates a quasi-stationary situation, but also prolongs treatment time and requires patient cooperation. An

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PA RT I I : Physics & Radiobiology

advancement of this basic breath-hold technology is active breathing control, (ABC).5 Beam-gating techniques6 monitor patient breathing and switch the beam on during a pre-specified interval in the respiratory phase, usually during exhale. This achieves the same effect as restricting respiration. That is, smaller tumor motions during beam-on time. At the same time, it is less invasive than restricting respiration. Dynamic SRS technologies can track respiratory motion in real-time and under free breathing conditions. The patient’s breathing is continually monitored either by optic markers on the abdomen, a strain gauge, or other external surrogate respiratory markers. The extent of the tumor motion is established at simulation using various imaging techniques, (e.g., fluoroscopy or 4D-CT). Another method uses the correlation between respiration and internal motion, taking X-rays of the tumor position throughout the treatment and continuously updating the correlation model.7 Treatment sites for dynamic SRS include all organs that move with respiration. Lung cancer will constitute a large fraction of all treated cases, since it is one of the most prevalent cancers and has a small five-year survival probability. Pancreatic cancer is relatively rare, but has poor prognosis and conventional treatment options carry high risks of complications. The liver, positioned just inferior to the diaphragm, is probably the most mobile organ in the abdominal cavity; it will deform significantly during respiration, and therefore requires larger PTV margins until the changes in tumor shapes can be more easily determined and compensated for during the imaging and treatment planning process. The prostate will also move with respiration, although with much smaller amplitudes than other organs. Available imaging technologies will influence the imaging tool used for treatment planning purposes. Recent advances in CT technology, namely 4D-CT,

will become more available to radiation oncology in the near future. Careful consideration has to be given to the question of treatment margins. Advances in dosimetry will improve the accuracy of dose calculations. New, electromagnetic tracking techniques will enable direct tumor tracking. The complexity of the new technology, combined with the risks of high-dose, conformal hypofractionated dynamic SRS, make a good physics QA program essential.

Techniques Linear Accelerator-Based Dynamic SRS Linear accelerator-based dynamic SRS appears in the literature as motion adaptive X-ray therapy, (MAX-T),8 or synchronized moving aperture radiation therapy (SMART).9 The underlying technology is similar: namely, adapting the MLC leaf motion synchronously to the internal tumor motion. This can be summarized as 4D-IMRT. Based on the leaf sequence of a standard static IMRT treatment, the multileaf sequence is modified by a time-dependent motion component to adjust leaf positions for target motion. Since the multileaf collimator motion can only adapt in the plane perpendicular to the beam’s eye view (BEV), the tumor motion is tracked and corrected for only in the two dimensions orthogonal to the BEV axis. In both methods, MAX-T and SMART, it is assumed that the whole patient, including the tumor, moves as a rigid body. With SMART, the internal tumor motion is determined by two pairs of orthogonal imagers, which take X-rays of the tumor marked with a fiducial at the frequency of 30 Hz. The image acquisition interval is about 50 seconds. The breathing patterns are analyzed for regularity. Threshold values for period, amplitude and mean position are determined on an individual patient basis. If the observed breathing

C H A P T E R 6 : Dynamic Tracking of Moving Tumors in Stereotactic Radiosurgery

patterns during treatment deviate from the average pattern by more than the predetermined margins, the treatment is stopped, and resumed when the breathing has returned to ‘normal’. 4D-IMRT has the advantage of margin and artifact reduction and, unlike gating the treatment, is continuous. It was found that in general, SMART treatments would not be much more efficient than gating, due to breathing pattern irregularities under free breathing conditions.9

Robotic Dynamic SRS Synchrony™ 7 is at this time the only FDA-cleared dynamic SRS device in the USA . Its technology is based on the CyberKnife® SRS technology.10–12 The CyberKnife SRS system consists of an X-band linear accelerator mounted on a robotic arm (KUKA, Augsburg, Germany). The patient is placed on a treatment couch. Images from two orthogonal X-ray cameras are compared to digitally reconstructed radiographs (DRRs) from the treatment planning CT. Internal gold fiducial markers or bony landmarks can be used for registration. During the treatment, images can be produced before every treatment beam. The robot will correct for patient motions of up to 0 mm in each translational direction,  degree of roll and pitch rotation, and 3 degrees of yaw. If the patient movements are outside these limits, the system will automatically pause the treatment. The patient position can be readjusted remotely using the fully automated patient couch. The relevant clinical accuracy combines the robot pointing accuracy, camera-image tracking system and target localization accuracy. It will strongly depend on the CT slice thickness chosen during treatment planning (or simulation), since this determines the resolution of the fiducial markers. For fiducial tracking and CT slice thickness between 0.625 mm and

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.25 mm, the system accuracy has been shown to be 0.7 ± 0.3 mm.13 For Synchrony treatments, Figure , the patient wears a tight-fitting elastic harness. Three beacons emitting visible red light pulsed with 30 Hz are placed on the patient. The beacon positions are monitored by a flashpoint camera mounted on an adjustable arm at the foot end of the patient couch. The time-stamps of the beacon data (as captured by the flashpoint camera) and the location data of the internal fiducials (as determined by the X-ray cameras) are synchronized. After the initial patient alignment, two X-ray images of the internal fiducials are taken with the patient breathing freely. These images should be timed so that they are close to maximum inspiration and expiration. At the same instance, the position of the beacons is recorded. The linear correlation model between the internal and external positions is established. A third image is taken to confirm the correlation model, and the treatment will then be started. With each X-ray image, the correlation model is updated until the limit of 0 model correlation points is reached, Figure 2. From then on, the model points are updated in a ‘first-in & first-out’ fashion. During the treatment, the robot will correct for tumor motion in real time in 3D. The Synchrony system has an inherent motion lag time of about 250 ms between information on the tumor position as predicted by the beacons and the robot motion. To correct for this, the tumor location is predicted 250 ms ahead with a Kalman filter using the respiratory motion information from the beacons. Before every treatment beam, an X-ray image can be taken to check the validity of the correlation model. The user can set software limits, (e.g., maximum permissible correlation error). A typical treatment takes only about 20% longer than a comparable body SRS case with fiducials.

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Linear accelerator

Figure . Synchrony patient set-up in the CyberKnife suite.

Flashpoint camera

Robot Vest with beacons

Couch

Silicon X-ray detectors Beacons

Treatment Sites Introduction Most organs in the abdominal cavity move with respiration. The closer the organ is to the diaphragm, the larger will be the motion amplitude. Respiratory motion has several components. The tumor motion has translation, rotation, and deformation components. If we assume the tumor is a rigid body, six independent, generalized coordinates can describe its motion in space. The translational motion can be either in phase or out of phase, in which case the tumor could describe for example, an elliptical

motion. One or more point markers usually monitor the skin motion, which reduces the skin motion to a purely translational motion. The skin motion can also have an out-of-phase component. The correlation between tumor and skin motion may be very complicated, but can be approximated by a linear model. The literature on organ motion is abundant and at times contradictory. Within the scope of this chapter, only a short summary of results for major treatment sites can be presented. The reader may refer to the overview article by Langen & Jones 14 and references therein.

Lung Good tumor control with only minor clinical symptoms from healthy tissue damage has been observed for SRS treatments of stage I lung cancer.15 Stereotactic radiation therapy may be the treatment of choice for stage I and/or very advanced, inoperable lung cancers. Numerous authors have studied motion of tumors


in the lung.16–18 Results are sometimes contradictory, and the number of cases studied in each paper is small. Until very recently, studies were performed under fluoroscopy, using radio-opaque markers in the tumor itself. To ensure that the radiation dose was kept low, study lengths were 3–5 breaths (~ 90s) and limited to patients who would undergo external beam radiation therapy. Recently, research groups in Germany and the US have developed a 4D-MR protocol,19–21 which enabled them to compare healthy and cancerous lung motions over an extended time period. Generally, motion amplitudes and shapes in the lower lung close to the diaphragm were found to be larger and more complicated than in the upper lung, although some studies suggest that tumor location in the lung alone cannot predict tumor mobility.22 Breathing patterns are highly subject-dependent and may show intra-fractional and inter-fractional changes.23 Respiratory motion patterns and amplitudes

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cannot be predicted by subject age, gender, weight, height, or other conditions.17 The skin motion was shown to be well correlated (correlation coefficients > 0.6) to the tumor motion in 88% of patients in one study.24 Figure 3 shows trajectories of 2 lung tumors in the sagittal and coronal plane.

Pancreas Cancers of the pancreas are often unresectable, since life-supporting arteries and veins are in the immediate vicinity. Critical organs surrounding the pancreas, such as the small bowel, are radiation-sensitive. The lack of aggressive treatment options makes pancreas cancers good candidates for dynamic SRS. The extent of pancreatic motion has been studied under fluoroscopy by tracking surgical clips.25 For the seven patients studied, the tumor motion was mostly in the sagittal plane. The observed tumor motion in the left-right direction was a maximal 2 mm. The average cranio-caudal motion amplitude was 7.4 mm, and

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Figure 2. Correlation model between internal and

external motion. Two X-ray images at different phases of breathing are taken. The position of the skin marker (beacon) versus internal fiducial is plotted. Up to 0 model points may be used in the correlation plot and are fitted using the least-squares method.

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Figure 3. Orthogonal projections

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of the 3D trajectories of the 2

tumors on the coronal and the sagittal plane. The tumors are

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displayed at their approximate positions. Tumors that were attached to bony structures are colored red; lower-lobe tumors are colored light blue. Figure with permission from reference.17

for anterior-posterior was 3.8 mm, with large variations up to 47% between the maximum and average excursion amplitudes due to variation in breathing. The correlation between the anterior-posterior and cranio-caudal motion was presented for only one patient, in whom the correlation was very linear. These motion amplitudes were slightly smaller than in other studies reported in the literature.26–29 While not many studies on the extent of respiratory motion of the pancreas have been published, there is more extensive data for the liver.

Liver The location of the liver, abutting the diaphragm, leads to considerable motion. The liver will also show deformation as a function of the respiratory phase. The heartbeat may cause measurable motion for fiducials placed close to a major vessel. Tumor motions have been observed of about –2 mm left-right, 2–9 mm cranio-caudally and 2–2 mm in the anterior-posterior.30 Hysteresis was observed in 20% of the patients studied.

Prostate The proximity of the prostate to the bladder and rectal wall requires careful dose shaping to avoid radiationinduced complications. Inter-fraction prostate motion due to bowel and bladder has been studied extensively and is summarized by Langen & Jones.14 For patients immobilized in thermoplastic shells in the prone position, mean displacements of 3.3 mm ± 0.8 mm were observed under fluoroscopy.31 A total of 23% of displacements were 4 mm and greater. The intra-fraction prostate motion was significantly reduced when the thermoplastic shells were removed.

Imaging In conventional radiation therapy, the treatment planning CT is acquired using slow image acquisition times under free breathing conditions. The tumor motion artifacts from the respiration will cover most of the potential tumor locations. A PTV margin is applied to the GTV to account for additional set-up and motion uncertainties.


Target motion amplitudes, deformations, rotational and out-of-phase motion patterns during breathing are very important in treatment planning for dynamic SRS. If we assume the lesion is a rigid body and moves only linearly, breath-hold imaging studies may be sufficient for treatment planning. To assess the target shape and position at the extremes of motion, two breath-hold CT sets at full inspiration and full expiration can be acquired. With modern multi-slice CT scanners, the added image acquisition time and radiation dose is outweighed by the benefit of more information for treatment planning. Recently, various groups have studied tumor motion with 4D-CT image acquisition, Figure 4. While the individual techniques vary with equipment,32–34 the underlying principle is similar. An external marker placed on the abdomen, usually halfway between xyphoid and umbilicus, is used to record the patient’s

respiratory motion. The external marker information is synchronized with the CT image acquisition. Several image sets of the target volume at one couch position are acquired under free breathing. The couch is then shifted and the image acquisition is repeated (one or more times) until the desired patient volume is covered. The individual CT images are time-stamped. After the examination is finished, the individual CT slices at each table position are sorted into time bins with respect to the respiratory phase. The result is a snapshot of the tumor at several positions throughout the respiratory cycle. These image sets can be linked to a 4D -CT ‘movie’ to visualize target motion. While 4D -CT will become a more widely available imaging technique in the near future, there are some important considerations. First, the imaging time and radiation dose increase proportionally to

Figure 4. Principle

CT examination FE

ME

MI

MI

MI

ME

ME

FI

FE

FI

of 4D-CT. Images are FI: full inhale MI: mid inhale ME: mid exhale FE: full exhale

one couch position. The couch position is then acquisition repeated. After the examination

Couch position

is completed, the

Sort images

images are processed

After examination FI

FI

MI

FE

acquired repeatedly at

shifted and the image

FE

FI

ME

57

FI

MI ME FE

Full inhale CT set

and ordered into their respective respiratory

MI

phases. A full CT of the

ME

patient at a specific

FE

Full exhale CT set Couch position

phase is achieved by grouping together all images from one phase.

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the number of bins the breath cycle is separated into, as will the required storage space and transfer time. In addition, a 4D -CT is acquired over several breath cycles; the resulting image set will represent an ‘average’ respiratory motion. A recently published paper23 has challenged the belief that an individual internal motion will not change relative to external markers between fractions, or between the CT acquisition and the radiation treatment.

Treatment Planning & Dosimetry Information about target motion is only useful when it is applied in a meaningful way. Tools to analyze the wealth of information contained in 4D -CT have to be developed. Few radiation therapy treatment planning software packages are capable of processing 4D -CT at this time. Segmenting tools to delineate tumors on diagnostic images based on tissue density are still under development. Even when tissue densities are high, for example for lung tumors, manual adjustments to the automatic segmentation are still necessary. If contouring segmentation tools are not available in the treatment planning software, manual delineation of the tumor in several image sets will require additional physician time. Once a tumor’s position and extent is known, the information can be used in the treatment planning process. Underberg et al 35 delineate the GTV in each of the 4D -CT image sets and develop the PTV as the sum of the contours plus set-up margin. In SRS, this method may lead to too much healthy tissue coverage. Careful consideration has to be given to the question of treatment margins.36 What constitutes the GTV may be dependent on the imaging technique used. Determining how much CTV expansion is needed to cover microscopic disease lies within the responsibility of the treating physician. If the CTV

were chosen too small, the generous PTV margin applied in conformal 3D -RT would compensate for it. With the technological advances in dynamic SRS, there is a temptation to reduce the PTV margin too much and exclude part of the CTV from the treatment field. The decision of how much margin to apply has to be made on an individual basis, taking into consideration the pathology, available technology and patient respiration pattern, as well as the available technical and human resources. Changes in lung tissue density during the breathing cycle are not implemented in any treatment planning software. It is assumed the tumor is a rigid body and will not rotate. If the treatment planning image sets suggest that deformations and rotations take place, the physician will have to set PTV margins accordingly. In linear accelerator-based adaptive SRS, the change in tumor shape has to be assessed as a function of the BEV. The multileaf collimator could be driven not only to compensate for respiratory motion, but also the respective tumor shape projection as it changes throughout the respiratory cycle. The effect of SSD change will be strongly dependent on the beam directions and would have to be assessed per patient. For Synchrony, the robot will adapt to linear tumor motions and keep the source-to-tumor distance constant. Stereotactic treatments use significantly more treatment fields than conventional external beam treatments. Surface dosimeters e.g., diodes or MOSFET detectors are not sufficient to verify the accuracy of delivered dose. In vivo dosimetry using implantable, wireless MOSFET detectors (Sicel Technologies Inc., Morrisville, NC) have been tested at clinical X-ray energies in the range 4–8 MV.37, 38 In the range 5– 500 cGy the response was linear and did not change for dose rates in the range 00–600 MU/min. The


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CyberKnife

Figure 5. Experimental set-up of

the Aurora tracking system in the CyberKnife suite. The needle with sensor coil was positioned using a needle driver

Robot

Aurora

robot. The CyberKnife was positioned at about 80 cm source-to-needle distance.

Needle with sensor coil

directional dependence observed is ± 2% and the overall dose accuracy is reported to be ± 5%. To fully simulate the external abdominal motion and internal tumor motion, two independent, programmable 3D simulator stages are necessary. Such a motion simulator has been built and successfully used by our group at Georgetown University Hospital.39 An alternative to a motion simulator is to calculate dosimetric changes of a moving tumor relative to conventional IMRT or 3D -RT treatments.40 The effective fluence incident on a moving target can be calculated if the multileaf and target positions are known as a function of time. This method could be expanded to account for either a linear accelerator-based or robot-based moving treatment delivery device.

Tumor Tracking Currently, external substitute markers are used to predict internal tumor motion. For Synchrony, X-ray images during the treatment verify the accuracy of

the correlation model between external and internal motion. Ideally, the tumor motion would be directly tracked continuously throughout the treatment. However, because of the long treatment times, non-ionizing radiation is the only feasible imaging option. One method (Aurora, Northern Digital Inc., Ontario, Canada) uses an electromagnetic field generator in a tetrahedron shape to track miniaturized induction coils, which can be placed in the tips of biopsy needles.41 An AC current excites the six differential coils in the field generator during a measurement cycle. During each cycle, the six induction voltages in the sensor coil are measured and analyzed to determine the position and orientation of the sensor coil. The author tested the system in the CyberKnife suite under treatment conditions, Figure 5. The beam was switched on and pointed in the direction of the sensor coil; the SSD was about 80 cm. The average error was .–.2 mm, with a standard deviation of 0.8 mm. There appeared to be no significant

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effect on the tracking accuracy from turning the CyberKnife beam on. A disadvantage of the current Aurora system is that the sensor coils need to be connected to the readout electronics by a twisted pair of fine wires. While this may be acceptable for singlefraction treatments in the liver, pancreas or prostate, it is too invasive for fractionated treatments. For lung tumors, the risk of pneumothorax would be too high. The benefits of continuous electromagnetic tracking may not outweigh the risks, especially since non-invasive alternatives using a combination of internal and external surrogate markers are available.7 How well implanted fiducials track the tumor motion is a question that has yet to be investigated. It is well known that fiducials can migrate after being placed in soft tissue. At Georgetown University, a wait time of about seven days between fiducial placement and CT is usually enough for fibrosis to develop and localize the fiducials. Since dynamic SRS treatments last only a few days, further migration is minimal. If more than one fiducial is implanted, potential migration between the CT and successive treatments can be detected by change of distance between the fiducial markers, since it is unlikely that all fiducial markers would migrate the exact same distance in the exact same direction. If the center of mass of several fiducial markers is used for tracking, a statistically distributed migration will keep the center of the dose distribution fairly constant. Extreme caution must be used if only one marker is used for tracking. A drift in this marker’s position relative to the target volume will cause an offset in the dose distribution. For tracking technologies that assume no rotation of the tumor during respiration, the PTV margins have to be expanded to compensate for potential rotations around the translational motion path. Tumors and surrounding tissue may swell or shrink during the course of the treatment. These

tumor close deformations may change the shape of the target relative to the implanted fiducial configuration, or change the fiducial configuration itself.

Quality Assurance In dynamic SRS, a thorough understanding of the interactions between components is necessary to assess total system accuracy. In linear accelerator-based SRS, the machine calibration should be performed according to the recommendations in the AAPM TG 51.43 For the CyberKnife, it is also possible to follow AAPM TG 21, since the difference to AAPM TG 51 would be very small.44 Several components of the SRS delivery system contribute to the overall precision of dose delivery. Information on target geometry and electron densities is provided by the treatment planning CT. The linear accelerator energy, field sizes and output have to be calibrated and made available to the treatment planning system. The treatment planning system itself has to be commissioned and verified by independent dose calculations. The pointing accuracy of the treatment delivery system has to be checked. In addition, the image-guided set-up and treatment system have to be calibrated. If the treatment delivery is truly image-guided, correct feedback from the imaging system to the treatment delivery is required. Each of these components has to be commissioned, calibrated and checked on a regular basis. A check of the complete system, an ‘end-to-end test’ (E2E) on an anthropomorphic phantom should be performed as part of the regular physics QA schedule. The phantom is ‘immobilized’, e.g., using a face mask and a CT scan with the same slice thickness as used for patients is obtained. The images are transferred to the treatment planning system. A target region is delineated, a treatment plan calculated and the phantom is then irradiated. Dose delivery accuracy is best


6

analyzed using film. After the film is developed, it is scanned and the shape of the dose distribution compared to the planned dose distribution. The AAPM TG 54 45 recommendation for SRS dose targeting precision is 2 mm for CT-and-MR based localization techniques. This part of physics QA forms the baseline for the dynamic delivery testing and QA . For dynamic SRS QA, a basic, commercially available 3D motion table with enough workload capability to carry an appropriate phantom is sufficient. The simplest mathematical functions to provide a good imitation of natural respiratory motion are sin 3 or sin4. To test the capability of the system to follow motion, the external markers are directly placed on the dosimetry phantom, achieving a direct correlation between internal and external motion. To include the correlation model in the QA, the external markers can be placed on one of the 3D stages to decouple the external marker motion from the phantom motion. The phantom is loaded with the required dosimetry equipment (3D TLD array or film) and placed on the motion table. A CT scan of the static phantom using the same slice thickness as for patients is acquired and used for treatment planning. The phantom and motion table are then brought to the treatment room and set up for treatment. Two treatment fractions should be given for comparison: a static treatment to establish the baseline and a dynamic treatment with the desired motion parameters.

can be very complicated and vary greatly among individual patients for similar lesion locations. Even for the same patient, respiratory motion has been observed to change during a treatment regimen. Modern imaging technologies for radiation therapy treatment planning provide more information about tumor motion patterns. Including this additional information in the treatment planning process will require a revision of currently applied techniques, especially when considering CTV and PTV margins. The advance of computing technology and software improvements will lead to better corrections for changes in lung tissue density, tumor deformation, changes in tumor depth and SSD during respiration. New, wireless electromagnetic tumor tracking techniques will eliminate the use of external surrogate markers and enable direct, continuous tumor tracking. The complexity of dynamic SRS requires novel approaches to commissioning and quality assurance. More medical physics time and new QA and treatment verification tools will be required to ensure the safety and efficacy of dynamic SRS. Cancer treatment trials will determine the areas where dynamic SRS is beneficial compared to current treatment protocols. Radiobiological research needs to be expanded to guide the development of new dose and fractionation schemes to make optimum use of the highly conformal, precisely targeted dose delivery available with dynamic SRS.

Conclusions

References

Dynamic SRS is a very useful addition to currently available tools in radiation medicine. Linear accelerator-based and robot-based technologies are available or being developed. Data on the correlation between external surrogate respiratory markers and tumor motion for organs that move with respiration is sparse and more research is needed. Tumor motion patterns

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