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Int. J. Radiation Oncology Biol. Phys., Vol. 65, No. 3, pp. 924 –933, 2006 Copyright © 2006 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/06/$–see front matter doi:10.1016/j.ijrobp.2006.02.035 PHYSICS CONTRIBUTION AUDIO-VISUAL BIOFEEDBACK FOR RESPIRATORY-GATED RADIOTHERAPY: IMPACT OF AUDIO INSTRUCTION AND AUDIO-VISUAL BIOFEEDBACK ON RESPIRATORY-GATED RADIOTHERAPY ROHINI GEORGE, PH.D.,*† THEODORE D. CHUNG, M.D., PH.D.,* SASTRY S. VEDAM, PH.D.,* VISWANATHAN RAMAKRISHNAN, PH.D.,‡ RADHE MOHAN, PH.D.,§ ELISABETH WEISS, M.D.,*¶ AND PAUL J. KEALL, PH.D.* Departments of *Radiation Oncology, †Biomedical Engineering, and ‡Biostatistics, Virginia Commonwealth University, Richmond, VA; §Department of Radiation Physics, The University of Texas M. D. Anderson Cancer Center, Houston, TX; and ¶Department of Radiation Oncology, Georg-August-Universität, Göttingen, Germany Purpose: Respiratory gating is a commercially available technology for reducing the deleterious effects of motion during imaging and treatment. The efficacy of gating is dependent on the reproducibility within and between respiratory cycles during imaging and treatment. The aim of this study was to determine whether audio-visual biofeedback can improve respiratory reproducibility by decreasing residual motion and therefore increasing the accuracy of gated radiotherapy. Methods and Materials: A total of 331 respiratory traces were collected from 24 lung cancer patients. The protocol consisted of five breathing training sessions spaced about a week apart. Within each session the patients initially breathed without any instruction (free breathing), with audio instructions and with audio-visual biofeedback. Residual motion was quantified by the standard deviation of the respiratory signal within the gating window. Results: Audio-visual biofeedback significantly reduced residual motion compared with free breathing and audio instruction. Displacement-based gating has lower residual motion than phase-based gating. Little reduction in residual motion was found for duty cycles less than 30%; for duty cycles above 50% there was a sharp increase in residual motion. Conclusions: The efficiency and reproducibility of gating can be improved by: incorporating audio-visual biofeedback, using a 30 –50% duty cycle, gating during exhalation, and using displacement-based gating. © 2006 Elsevier Inc. Audio-visual biofeedback, Respiratory-gated radiotherapy, Residual motion. INTRODUCTION Respiratory motion affects all tumor sites in the thorax and abdomen, although the disease of most prevalence and relevance for radiotherapy is lung cancer. Many studies have been performed to study lung-tumor motion (1–14). It can be seen from these studies that the magnitude of lung motion is highly variable: for example, observed tumor motion ranges from 0 to 5 cm for free breathing (9). Respiratory-gated radiotherapy (15–32) is a method to limit the deleterious effects of respiratory motion during computed tomography (CT) imaging (3, 12, 16, 33– 41) and radiation delivery (42– 47). Two important parameters that affect respiratory-gated treatments are (1) the part of the breathing cycle during which gating is performed and (2) duty cycle, the percentage of the beam on time to the total beam time (15, 21, 48). To acquire maximal benefit from a gated treatment, gating should preferably be performed at peak inhale or peak exhale, as mobility of internal anatomy is at its minimum at these positions. Vedam et al. (15), in a 5-patient study, have shown that gating during exhale is more reproducible than gating during inhale. As the duty cycle decreases, the radiation-treatment time increases because the beam will be turned off for a longer period of time during the respiratory cycle. This is speculated to result in an increase in patient movement from the muscular skeletal system during delivery, which will negate the effect of the gating. Longer radiation treatment time also negatively affects patient throughput. Respiratory gating reduces but does not elimi- Reprint requests to: Paul J. Keall, Ph.D., P.O. Box 980058, Richmond, VA 23298-0058. Tel: (804) 628-0980; Fax: (804) 828 6042; E-mail: [email protected] Acknowledgments—This research was supported by NCI grant RO1 CA 93626. The authors thank Ms. Devon Murphy and Dr. Michael Fix for carefully reviewing and significantly improving the clarity of this manuscript. We also thank the simulation, therapy and administrative staff at the department of Radiation Oncology, Virginia Commonwealth University, for their help in the coordination of this study. Received Sept 2, 2005, and in revised form Feb 15, 2006. Accepted for publication Feb 16, 2006. 924 Audio-visual biofeedback for respiratory-gated radiotherapy nate respiratory tumor motion during radiotherapy. Large duty cycles may result in a large residual motion within the gating window. Residual motion is the remaining respiratory motion that exists during respiratory-gated radiotherapy caused by motion within the gating window for a given breathing cycle and the cycle-to-cycle variations. For this work, the magnitude of residual motion was quantified by the standard deviation. In general, residual motion will ● R. GEORGE et al. 925 increase with duty cycle as more motion within each cycle is included. Typical beam duty cycle values during gated treatments vary between 30% and 50% (21, 22, 49, 50). For respiratory gating, minimizing the variation of patient breathing within a treatment fraction and from fraction to fraction, i.e., increasing the reproducibility of patient breathing, is important. However, the respiratory-gating amplitude and period Fig. 1. Schematic diagram showing phase- and displacement-based gating and how a baseline shift affects these techniques. Phase-based gating at (a) inhale and (b) exhale. In this case, the beam is turned on when the respiratory signal is within a specified phase, even if the signal shifts trends. The beam on is shown as thicker lines in the respiratory trace. Displacement-based gating at (c) inhale and (d) exhale. In this case, the beam is turned on when the respiratory signal is within specified position limits. Because of baseline shift, after a while the beam may not be turned on at all (c) or turned on in the wrong phase (d). In the cases shown above for displacement-based gating, the respiratory signal should be retracked. 926 I. J. Radiation Oncology ● Biology ● Physics vary with time and from patient to patient because of various anatomic and physiologic factors (51–57). Respiratory gating is also affected by the technique selected to trigger the radiation beam, namely, displacementbased gating or phase-based gating (15). For regular respiratory motion, displacement-based and phase-based gating essentially give the same result for a given duty cycle. However, the differences between these two techniques are exhibited during irregular breathing and especially in the case of a baseline shift. Figure 1 shows an example of one such an irregular trace exhibiting a baseline shift. In this case, the patient’s breathing trace shifts out of the gating window, and therefore the beam is not triggered at all or is triggered at the wrong phase of the breathing cycle. In such situations, the treatment has to be stopped, and the patient’s breathing has to be retracked. However, during phase-based gating, baseline shifts do not cause the treatment or simulation to be interrupted and thus, irrespective of the position of the target, while the phase of the breathing cycle is within the gating window the beam is triggered. Biofeedback techniques are being increasingly embedded in the behavioral treatment of patients with lung disease such as chronic obstructive pulmonary disease, asthma, and cystic fibrosis (58 – 65). For respiratory gating, several studies suggest that verbal prompts improve respiration reproducibility (21, 28, 44, 49, 50). Kini et al. (28) concluded that audio prompts improves the stability of respiration frequency of the patient but does not maintain the range of respiratory motion, whereas visual prompts control only the regularity of the displacement and the frequency is not reproducible. Based on the results of Kini et al., combined audio-visual biofeedback was devised to improve the reproducibility of audio-visual biofeedback. Recently Neicu et al. (66) described results of audio and visual prompting and demonstrated improvement in the efficacy of so-called synchronized moving aperture radiation therapy, using respiratory traces from single-patient and volunteer sessions. The aim of this study was to determine the reproducibility of patient breathing with (a) no feedback, called free breath- Volume 65, Number 3, 2006 ing, (b) audio instruction, and (c) audio-visual biofeedback as a function of two variables used in respiratory gating: the duty cycle and the gating technique, i.e., displacementbased or phase-based gating. METHODS AND MATERIALS Data collection A total of 331 4-min breathing traces of patient-respiratory motion using various types of feedback were collected for 24 lung cancer patients enrolled in an Institutional Review Board–approved breathing feedback protocol. All lung cancer patients to be treated with radiotherapy were approached for inclusion in this study. No attempt was made to preselect patients for this study other than by the inclusion criteria. These criteria were that the patient: (1) was !18 years of age; (2) would undergo external beam radiation at the Virginia Commonwealth University; (3) had any form of lung cancer, with or without surgery, and with or without chemotherapy; (4) was not oxygen dependent; (5) did not experience pain while in the supine position; and (6) had given signed informed consent. The patients’ respiratory traces were recorded using the Real Time Position Management (RPM) system (Varian Medical Systems, Palo Alto, CA). A typical set-up is shown in Fig. 2. The protocol consisted of five respiratory training sessions spaced about 1 week apart. Within each session, the patients recruited for the protocol were initially asked to breathe normally without any instruction or feedback (called a free-breathing session). Based on the breathing frequency recorded from the freebreathing session, the audio-instruction rate was determined. Breathe-in/breathe-out instructions were given, and breathing was recorded again for 4 min with audio instructions (referred to as an audio-instruction session). Once the audio-instruction session was completed, the patients were shown their respiratory trace on a LCD monitor, which facilitates visual biofeedback. The visual biofeedback showed the patients’ real-time respiratory motion with the range of motion limits set as determined from the audioinstruction session. In addition to this visual biofeedback, the patients were given audio instructions (referred to as an audiovisual biofeedback session). The breathing trace during this audiovisual biofeedback session was recorded for 4 min. If patients were Fig. 2. Set-up for audio and audio-visual biofeedback showing a subject viewing the visual biofeedback on a liquid crystal display screen. The respiratory signal obtained is the anterior–posterior motion of the marker block placed on the abdomen of the subject between the umbilicus and the xyphoid. The television screen has a built-in speaker used during the audio instructions and the audio-visual biofeedback. Audio-visual biofeedback for respiratory-gated radiotherapy uncomfortable with the set values for audio instruction or audiovisual biofeedback, the values were adjusted to comfort level on the first day. These audio and audio-visual settings determined during the first session were kept constant for the four subsequent sessions. The order of the respiratory data acquisition for each session (free-breathing, audio, and audio-visual) was the same for all sessions. This sequence of data acquisition could lead to potential bias: an increase in reproducibility during each session as patients relaxed and their breathing was less forced, and conversely a decrease in respiratory reproducibility with time as a result of fatigue. However, it was believed that the least biased way to acquire free breathing was without the influence of breathing training, i.e., before the breathing training. The training methods (audio then audio-visual) were ordered such that the simple training came before the more complex training, again to reduce the bias of the complex training on the simple training method. The respiratory-motion data file obtained contains information about the position of the patient’s breathing, the phase of the breathing cycle (0 –2") at that particular position and the time (0 –240 s) for the particular feedback technique sampled at a rate of 30 Hz. For an abdominal breather, anterior motion of the abdomen corresponds to inhalation, and posterior motion of the abdomen corresponds to exhalation. Patients positioned with their arms extended above their head (typical for lung treatments) predominantly use their abdomen for breathing. Examples of breathing traces 30 s in length and for all three breathing feedback types are shown in Fig. 3. Analysis of residual motion as a function of duty cycle Although respiratory gating reduces the effects of patient breathing variations within a treatment fraction and from fraction to fraction, there is some amount of residual motion within the gating window. For small duty cycles, however, the potential advantage of small residual motion is mitigated by the increase in treatment time leading to patient throughput issues and potential errors resulting from musculoskeletally induced patient movement. Large duty cycles may lead to errors caused by large residual ● R. GEORGE et al. 927 motion within the gating window. Thus, reducing treatment time and increasing accuracy are competing goals. The residual-motion data sets were tested for normality using the Kolmogorov-Smirnov (67) test. After examining the D-values from the Kolmogorov-Smirnov test and observing the probability plots, D-values !0.08 were classified as approximately normal. Although the 10% and 20% data sets had relatively high ("0.1) D-values for the Kolmogorov-Smirnov test, the 30% to 100% (with D-values ranging from "0.08 to 0.04 respectively) data sets could be considered approximately normal, and thus the standard deviation is appropriate to describe fully the distribution of the residual motion. For each breathing feedback type, the data of all patients for all of the sessions were concatenated for analysis. To facilitate concatenating respiratory traces from different sessions and patients, the respiratory traces were normalized such that the average of the first three breathing cycles were set to 0. This normalization was performed to be consistent with clinical gating treatments, as tracking (learning the breathing cycle) is typically performed for approximately 15 s (approximately three cycles) before the gated treatment is initiated. Thus the assumption is that set-up accuracy is maintained at gated position for each session at the start of the session. Gating techniques The impact of breathing feedback on residual motion as a function of duty cycle was investigated for phase- and displacement-based gating. For each training type (i.e., free breathing, audio instruction, audio-visual biofeedback), each patient, and each session, the respiratory trace was analyzed. For each respiratory trace, complete cycles were used to perform the phase- and displacement-based analysis. If the respiratory signal was irregular during simulation and treatment, the Real Time Position Management system did not initiate the CT simulator or the linear accelerator. Thus we excluded irregular respiratory motion by using the phase values to determine complete cycles, which were included in subsequent analyses. The two criteria for a complete cycle were that (1) consecutive phase values were monotonically increasing, and (2) the cycle started with phase values between the values 0 and 0.2 and ended with phase values between 6.1 and 6.28. The rationale for the second criterion is that a regular breathing cycle has approximately 120 points (4-s period at 30-Hz acquisition). As the phase values were acquired discretely, the criteria of starting at zero was approximated by ensuring that at least 1 data point had phase !0.2. (For a 30-Hz signal acquisition, 3 or 4 points are expected.) Similarly the end criterion of phase 6.1 assumes that at least 1 point exists between 6.1 and 6.28. Phase-based gating In phase-based gating analysis, for both inhale and exhale for each duty cycle interval, the standard deviations of the points recorded in the gating thresholds were recorded. The percentage of the duty cycle was increased from 10% to 100% in intervals of 10%, where 100% duty cycle indicated that no gating is performed. The breathing trace that was within this duty cycle range was the residual motion and was grouped for all patients for all sessions for each breathing type. The standard deviation is calculated from the data points within the phase-based gating window. Fig. 3. Example of a respiratory trace for free breathing, audio instruction, and audio-visual biofeedback. A constant y-offset value has been added to the displacement values of each these traces to improve the clarity of the figure. Displacement-based gating For displacement-based gating, the algorithm implemented to calculate the duty cycle emulates the procedure followed in the 928 I. J. Radiation Oncology ● Biology ● Physics clinic while treating a patient using displacement-based gating. Unlike phase-based gating, during displacement-based gating the beam is often turned off because of baseline shift, and the motion is retracked to complete the treatment. Figure 1 shows a comparison of what happens in displacement-based gating as opposed to phase-based gating in the presence of a baseline shift. At the point at which the beam is not being triggered at all or is being triggered at the wrong portion of the respiratory signal, the therapist turns off the beam and the respiratory trace is retracked. For inhale and exhale for each duty cycle the gating threshold was set depending on the value for the initial 3 cycles. This value was kept constant for each complete cycle, and the displacement within each duty cycle was recorded. For each cycle, the number of points within the duty cycle was checked, and if it exceeded #20% of the initial duty cycle, the displacement parameter was acquired and set again on the basis of the average of the next 3 cycles. The value of #20% was chosen based on clinical experience in which the gated treatment was stopped and retracked if the signal shifted by approximately this amount. The standard deviation was calculated from the data points recorded within the displacement-based gating window. Types of comparisons In accordance with the aims of this paper, two types of comparisons were made. First, free breathing, audio instruction and audio-visual biofeedback were compared for each technique, i.e., separately for phase- and displacement-based gating. Second, a comparison of the two techniques was made for free breathing, audio instruction and audio-visual biofeedback; that is, the standard deviation of the residual motion for free breathing of phasebased gating was compared with the standard deviation of the residual motion for free breathing of displacement-based gating. For comparison, the percentage of the duty cycle was the same for phase- and displacement-gated radiotherapy. An F test was used to calculate the statistical significance of the comparisons. RESULTS Typical observations about patient breathing caused by various types of training The characteristics of the patients enrolled in this study are given in Table 1 and Table 2. These tables show the diverse nature of the patient population. Patients were not Volume 65, Number 3, 2006 Table 2. Distribution of the discrete variables recorded Variable Distribution Sex Ethnicity Disease stage Surgery status Chemotherapy status Inhaler use Female, 11; male, 13 White, 17; African American, 6; Asian, 1 NSCLC, 18; other, 6 With, 2; without, 22 With, 14; without, 10 Yes, 5; no, 19 preselected based on potentially favorable characteristics such as young age, high Karnofsky performance status (KPS), or high forced expiratory volume in 1 s (FEV1). In general, patient tolerance of audio instructions and audiovisual biofeedback was good. Of the patients who enrolled in the study only 1 patient withdrew before completing a session. Furthermore, of the 24 patients who completed at least one session, only 3 patients did not complete the five sessions. One of the patients died half way through the treatment, and the other two patients did not continue because of pre-existing back pain when supine. The audio instructions tended to cause the amplitude to increase as compared with the effects of the other two training types. With the discrete audio instructions it was observed, in some cases, that the transition of patient respiratory motion from inhale to exhale was abrupt rather than smooth. With the audio-visual biofeedback the breathing cycles obtained for some patients tended to be saw-toothed, as the patients did not have feedback of their breathing phase between the upper (inhale) and lower (exhale) limits set in the visual program. Limits did not need to be changed once patients were comfortable. Although this training was conducted on the day of treatment, it was not performed on a linac, and so psy- Table 1. Characteristics of the patients enrolled in the breathing training study Variable Mean Range Age (y) Height (cm) Weight (kg) Gross tumor volume (cm3) Total dose (Gy) Number of fractions Smoking status (packs/year) Fractional lung volume V20 (%) FEV1 value (L) Karnofsky performance status (%) 62 164 70 175 53 27 91 22 1.6 80 36–83 139–188 44–98 0.5–1920 20–70 5–37 25–700 2–38 0.5–3.3 40–90 FEV1 $ forced expiratory volume in 1 s. Variables are continuous. Fig. 4. Residual motion standard deviation for each duty cycle value for phase-based gating comparing all three breathing types. A $ audio instruction; AV $ audio-visual biofeedback; FB $ free breathing. Audio-visual biofeedback for respiratory-gated radiotherapy Fig. 5. Residual motion standard deviation for each duty cycle value for displacement-based gating comparing all three breathing types. A $ audio instruction; AV $ audio-visual biofeedback; FB $ free breathing. chological factors such as patient anxiety could affect the training during treatment. Comparison of the three breathing types by phase-based gating The results of duty cycle versus the standard deviation of residual motion are shown in Fig. 4. All comparisons made below are statistically significant based on the F test. The standard deviation values of the residual motion for gating at exhale for all three breathing types are lower than the corresponding values for gating at inhale. For phase-based gating at inhale it is evident that audio instruction has, on average, no reduction in motion compared with free breathing. Audio-visual biofeedback has an average of 15% lower standard deviation of residual motion ● R. GEORGE et al. 929 compared with free breathing up to 90% duty cycle and 20% lower standard deviation of residual motion compared with audio instruction for all duty cycles. At exhale, audio-visual biofeedback has an average of a 15% lower standard deviation of residual motion compared with free breathing up to an 80% duty cycle and an average of a 10% lower standard deviation of residual motion compared with audio instruction. Audio instruction has an average of 5% lower standard deviation of residual motion compared with free breathing up to a 60% duty cycle. However, with a duty cycle %60%, the audio instruction has a greater standard deviation of residual motion compared with that of free breathing. For all curves in Fig. 4, with the possible exception of the inhale audio-visual biofeedback curve (also in Fig. 5, described below), there is very little reduction in residual motion with a duty cycle !30%, indicating that of these low duty cycles the residual motion is dominated by cycle– cycle variations rather than intracycle motion. Table 3 contains values of 1 standard deviation of the residual motion for the duty cycles of 30% to 50%, which is the typical gating duty cycle used the clinical setting (21, 22, 49, 50). For this range, audio-visual biofeedback has on average a 25% lower standard deviation of residual motion compared with free breathing and on average a 25% lower standard deviation of residual motion compared with audio instruction at inhale. In this range for inhale, audio instruction shows no improvement over free breathing in terms of lower residual motion. At exhale, in the 30% to 50% range, audio-visual biofeedback has an average of a 15% lower standard deviation of residual motion compared with free breathing and an average of a 10% lower standard deviation of residual motion compared with audio instruction. Audio instruction has a lower standard deviation of residual motion of 5% compared with free breathing at exhale for this range. Table 3. Population average residual motion standard deviation (1 #) and minimal and maximal individual patient values for phase-based gating and displacement based gating from the 30% to 50% duty cycle range typically used clinically for respiratory-gated treatments Average residual motion (range) Gating type Phase-based gating Inhale/exhale Training type 30% duty cycle (cm) 40% duty cycle (cm) 50% duty cycle (cm) Inhale FB A AV FB A AV FB A AV FB A AV 0.45 (0.14–0.73) 0.45 (0.20–0.65) 0.32 (0.12–0.66) 0.31 (0.11–0.57) 0.29 (0.12–0.51) 0.25 (0.12–0.46) 0.39 (0.13–0.62) 0.42 (0.16–0.61) 0.26 (0.10–0.45) 0.25 (0.07–0.50) 0.25 (0.06–0.46) 0.18 (0.09–0.32) 0.47 (0.15–0.76) 0.47 (0.21–0.66) 0.36 (0.13–0.68) 0.32 (0.12–0.58) 0.31 (0.14–0.51) 0.27 (0.13–0.48) 0.42 (0.15–0.64) 0.44 (0.19–0.62) 0.31 (0.10–0.49) 0.27 (0.11–0.51) 0.27 (0.10–0.50) 0.21 (0.08–0.34) 0.49 (0.18–0.80) 0.50 (0.21–0.68) 0.41 (0.15–0.69) 0.35 (0.13–0.59) 0.33 (0.16–0.50) 0.30 (0.14–0.49) 0.45 (0.17–0.67) 0.48 (0.19–0.67) 0.36 (0.11–0.60) 0.30 (0.13–0.54) 0.30 (0.10–0.49) 0.26 (0.09–0.37) Exhale Displacement-based gating Inhale Exhale Abbreviations: A $ audio instruction; AV $ audio-visual biofeedback; FB $ free breathing. 930 I. J. Radiation Oncology ● Biology ● Physics Comparison of the three breathing types by displacement-based gating The results of duty cycle versus the standard deviation of residual motion are shown in Fig. 5. It can be seen that the trends for displacement-based gating are the same as those for phase-based gating. The number of baseline shifts observed was lowest for audio-visual biofeedback and ranged on average between one and four occurrences per 4-min session for duty cycles from 30% to 50%. Our study shows that displacement-based gating has a significantly lower standard deviation compared with phasebased gating. For free breathing, displacement-based gating has an average of a 20% lower standard deviation of residual motion compared with phase-based gating for both inhale and exhale. For inhale and exhale curves with audio instruction, displacement-based gating has an average of 20% and 30% lower standard deviation of residual motion, respectively, as compared with phase-based gating. Audiovisual biofeedback for displacement-based gating has very little advantage over phase-based gating for inhale curves. However, for exhale curves with audio-visual biofeedback, displacement-based gating has an average of 40% lower standard deviation of residual motion compared with phasebased gating. An analysis of the variables in Table 1 and Table 2 that had a significant correlation with residual motion were disease type (SCLC vs. NSCLC) and dose per fraction for both inhale- and exhale-based gating. Variables found to be significant at inhale only were training type (both audio and audio-visual), visual training displacement, and KPS. DISCUSSION Respiratory signal amplitude and period vary with time and from patient to patient because of various factors (51– 57). This study acquired 331 4-min respiratory traces from 24 lung cancer patients to investigate the improvement in the efficacy of respiratory gating using audio instruction and audio-visual biofeedback. Although audio instructions have been used previously for respiratory-gated radiotherapy, this is the first investigation of the benefits of audio-visual biofeedback for respiratory gating. Previous studies on comparison between the phase- and displacement-based respiratory gating techniques consisted of small patient sets compared with the 24-patient data set used in this study. Audio instruction and audio-visual biofeedback From the results, it is clear that audio-visual biofeedback reduces the residual motion standard deviation and thereby increases the advantages of using respiratory gating for radiotherapy imaging and treatment. Audio instruction, compared with free breathing, can benefit respiratory gating at exhale up to a certain duty cycle. However, it is observed that audio instruction increases overall respiratory magnitude. Increasing the magnitude of the respiration or, in this case, the amplitude of respiratory motion clinically means hyperventilation, which can potentially lead to fainting. Volume 65, Number 3, 2006 A question arising from our investigations was whether breathing training would increase the accuracy of treatments without respiratory gating, corresponding to the 100% duty cycle results shown in Fig. 5. The audio instructions alone increased the magnitude of the respiratory motion and thus would decrease the treatment accuracy. Audio-visual biofeedback had a similar magnitude to that of free breathing at the 100% duty cycle value, so no benefit would be obtained using the method described here. However, our study was not designed to minimize overall respiratory motion but rather to improve respiratory reproducibility. Therefore audio-visual biofeedback designed to reduce respiratory motion may be effective and useful for treatments in centers that do not have access to technology for the explicit sake of managing respiratory motion. Phase- and displacement-based gating Our results show that displacement-based gating has a lower residual motion standard deviation compared with phase-based gating, a finding contradictory to that observed in a smaller patient study by Vedam et al. (15). However, displacement-based gating can be sensitive to sudden movement of the marker block, such as abrupt couch motion for prospective gated CT scanning. Thus displacement-based gating should be used with careful monitoring to ensure accuracy of CT imaging. During CT imaging and treatment delivery the respiratory trace needs to be monitored for baseline shift if displacement-based gating is used. For both phase- and displacement-based gating used with free breathing, audio instruction, and audio-visual biofeedback, it is seen that the residual motion standard deviations are lower for exhale compared with the respective inhale values. This supports the common notion that the exhale position is more reproducible and that the patient spends more time at exhale than at inhale (13, 15, 68). Clinically, the premise of respiratory gating relies on correlation between the respiratory signal (in this case an external respiratory signal) and the tumor motion. If a good correlation exists, then it follows that reduction in respiratory marker motion variation will result in a reduction in apparent tumor motion during respiratory-gated radiation therapy. Because respiration motion contributes to both systematic errors (during imaging) and random errors (during treatment), a reduction in the effective respiration motion will affect both of these contributors. Range of duty cycle We observed little reduction of residual motion for duty cycles !30%, independent of the breathing type or inhale/ exhale. For phase-based exhale gating, residual motion starts to increase at values %50%, and for inhale-based gating residual motion starts to increase at values %30%. For displacement-based gating, for both exhale- and inhale-based gating, residual motion starts to increase at values %30%. Audio-visual biofeedback for respiratory-gated radiotherapy ● R. GEORGE et al. 931 Exhale- versus inhale-based gating The advantage of treating at inhale as opposed to exhale is that the lung volume is larger than at exhale, and therefore the mass of lung receiving radiation is less at inhale as compared with exhale. Recently, however, a gated intensity-modulated radiation therapy (IMRT) lung cancer study showed limited benefit for treatment at regular, as opposed to deep, inspiration levels (69). Given that a good correlation is observed and remains constant during treatment, the reduction of internal motion with audio-visual biofeedback will be proportional to the ratio of the magnitude of the external motion reduction. Although this study uses external motion data to analyze audio-visual biofeedback, the benefits of using this biofeedback will also be observed if used while tracking internal motion, for example using the signal from radiopaque markers (8, 76) or electromagnetic transponders (77). External versus internal respiratory signal In this study, the external respiratory signal was analyzed. There are several studies that correlate external respiration signal to internal organ motion (70 –74, 48, 75). Vedam et al. (71) reported a good correlation between diaphragmatic motion and abdominal motion (mean correlation coefficient, 0.94). Hoisak et al. (72) showed a correlation with coefficients ranging from 0.51 to 0.98 between abdominal motion and lung-tumor motion. Ahn et al. (73) found an average correlation of 0.77 between skin and tumor movements with a range between 0.41 and 0.97. Schweikard et al. (70) have also confirmed the hypothesis that external motion is related to internal motion. Tsunashima et al. (74) have also found an evident correlation between 3D tumor motion and external respiratory motion obtained from laser displacement sensors. Mageras et al. (75; personal communication, Mageras et al., 2004) investigated the lung-tumor motion with respiratory correlated CT and found a correlation range of 0.73 to 0.96 with phase shifts !1 s. Berbeco et al. (48) examined internal marker motion and the external respiratory signal correlation in the respiratory gating context for 8 patients, observing beam-to-beam and day-to-day variations; however an overall positive correlation was found (inferred from the general reduction in residual motion with duty cycle). Thus, the external signal may potentially be used as a surrogate for lung-cancer motion, although these studies indicate that day-to-day variations in tumor position can be significant and will not be detected by the use of an external respiratory signal alone. From our results and the previous works described, we can hypothesize that a reproducible respiratory signal is a necessary (if insufficient) condition for reproducible tumor motion. From this hypothesis the increase in respiratory reproducibility observed will lead to improved tumor motion reproducibility. This hypothesis is the subject of an ongoing study. Improved audio-visual biofeedback The current audio-visual biofeedback system does not yield information to guide the position of the patient’s breathing at each instant in time but, rather, only at the inhale and exhale points. This can limit the cycle-to-cycle reproducibility. An improved audio-visual biofeedback system providing the patient with information to guide the respiratory position throughout the breathing cycle may further reduce the variability of the residual motion. CONCLUSION Respiratory gating effectively reduces motion during CT imaging and radiation treatments. However, as the residual motion increases, the gating accuracy decreases. Based on the 24-patient, multisession study described in this article, the following statistically significant conclusions can be made regarding respiratory motion: (1) Audio-visual biofeedback can significantly reduce residual motion variability for a given duty cycle, thus potentially improving the accuracy of respiratory-gating. (2) Displacement-based gating has a lower residual motion variability compared with phasebased gating. (3) Duty cycles !30% provide little benefit for respiratory gating, as there is only a slight reduction in residual motion below this value at the cost of increased treatment time. 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