Monitoring deep inspiration breath hold for left‐sided localized breast cancer radiotherapy with an in‐house developed laser distance meter system

Abstract Deep inspiration breath hold (DIBH) in left‐sided breast cancer radiotherapy is a technique to reduce cardiac and pulmonary doses while maintaining target coverage. This study aims at evaluating an in‐house developed DIBH system. Free‐breathing (FB) and DIBH plans were generated for 22 left‐sided localized breast cancer patients who had radiation therapy (RT) after breast‐conserving surgery. All patients were treated utilizing an in‐house laser distance measuring system. 50 Gy was prescribed, and parameters of interest were target coverage, left anterior descending coronary artery, (LAD) and heart doses. Portal images were acquired and the reproducibility and stability of DIBH treatment were compared to FB. The comparing result shows there is a significant reduction in all LAD and heart dose statistics for DIBH compared to FB plans without compromising the target coverage. The maximum LAD dose was reduced from 43.7 Gy to 29.0 Gy and the volume of the heart receiving >25 Gy was reduced from 3.3% to 1.0% using the in‐house system, both statistically significant. The in‐house system gave a reproducible and stable DIBH treatment where the systematic error ∑, and random error σ, were less than 2.2 mm in all directions, but were not significantly better than at FB. The system was well tolerated and all patients completed their treatment sessions with DIBH.

The pathogenesis of radiation-induced cardiovascular damage from animal studies have shown microvascular disease causing chronic ischemic heart disease, and macrovascular disease causing development of age-related atherosclerosis in the coronary arteries. 2 There is also new evidence of high-grade coronary artery stenosis in mid and distal left anterior descending artery (LAD) in hotspot areas for radiation, and a four-to seven-fold increase has been shown. 15 A recent study has found increased use of percutaneous coronary intervention in patients treated with modern radiotherapy techniques, but this risk was limited to women with previous cardiac disease. 1,16 With free-breathing (FB) radiotherapy parts of LAD might receive up to 50 Gy, and even with DIBH there can be a very high dose given to parts of the LAD for some of the patients. It is still unknown whether it is the mean dose to the heart, the high doses to the coronary arteries or the combination of both which causes an increased number of deaths from cardiac disease in left-sided breast cancer that have undergone RT.
There are several commercial systems that offer the possibility to perform DIBH. The Active Breathing Coordinator system (Elekta, Crawley, UK) uses a spirometer where the patient makes use of a mouthpiece that closes a valve to ensure a standardized air-volume into the patient's lungs. However, the spirometer technique has been reported to be less comfortable by the patients and Nissen et al.
reported that 22 of 166 patients could not tolerate this system mainly due to the mouthpiece or to psychological reasons. 9,17,18 The Real-Time Positioning Management system (Varian, Palo Alto, USA) is less invasive, and relies on a box with infrared markers that is placed on the patients xiphoid process. The position of the box is tattooed on the patient, since its placement can influence the breath hold and could increase the dose to the skin if placed within the field borders due to the build-up effect. Noninvasive systems like the Catalyst (C-RAD Positioning, Uppsala, Sweden) and GateRT (Vision RT Ltd, London, UK) have recently entered the market. [19][20][21] These systems project a light-pattern onto the patient which is scanned by one or two CCD cameras. A high-resolution 3D model of the patient can be reconstructed and used to perform gating when using these kinds of systems. The UK HeartSpare study relies on equipment-free voluntary breath hold using skin surface marks as fiducials, and the technique has been shown to be effective and reproducible. [22][23][24] We have previously published data on an in-house developed noninvasive DIBH system based upon an industrial laser distance measurer. 25 The system utilizes a laser distance measurer that tracks the motion of the sternum with high precision and frequency, Fig. 1.
The method is noninvasive, and causes no discomfort to the patient.
Anzai (Anzai Medical, Tokyo, Japan) has recently released a resembling commercial solution but there is no published data on that solution in the literature to date. 26 The aim of this study was to evaluate DIBH stability and reproducibility during left breast radiation treatments under the control of an in-house developed laser-based DIBH system for breast cancer patients. A secondary aim was to report doses to target and organs at risk (OAR).

2.A | Patient selection and training
Patients referred to Alesund Hospital for left-sided tangential radiation were eligible for the study. Twenty-four patients requiring RT to breast only were asked for written consent to participate in the Regional Ethics Committee approved protocol. Patients had to maintain a stable breath hold for at least 20 s to be eligible for DIBH, and two patients were not able to comply with the requirement and were excluded from the analysis. Patients performed two CT-scans, one in FB and one with DIBH.
The CT scanner was a 16 slice multidetector MX8000 Brilliance IDT (Philips Medical Systems, Eindhoven, Netherlands), and images were obtained with 3 mm slice thickness. Images were transferred to Oncentra Masterplan v 3.4 (Elekta, Crawley, UK) treatment planning system.

2.B | Treatment planning
The clinical target volume (CTV) and OARs were delineated by the same radiation oncologist inn all FB and DIBH scans. Radiation therapists delineated the lungs and external contour. The breast was F I G . 1. Laser measurer mounted on the ceiling in the treatment room. delineated according to national guidelines at the time of inclusion (www.nbcg.no), and the heart and LAD according to other published guidelines. 27 Planning target volume (PTV) was automatically generated, derived from CTV with 10/5/5 mm extension in the superiorinferior/anterior-posterior/left-right directions (SI/AP/LR), but always 5 mm inside the external contour.
The radiation therapists made FB and DIBH treatment plans according to national guidelines and in-house protocol. The clinical goals used in the treatment planning are listed in Table 1. 6 MV opposing tangential conformal beams with low-weight segments were used. Wedged fields were not used in the DIBH plans to minimize the length of breath hold. Since our laser system had a fixed measuring point in the room; all patients had their isocenter placed on the sternum.
Treatment plans were calculated with the Collapsed Cone algorithm, and originally transferred to the record and verify system Visir, but from December 2011 to Mosaiq (both Elekta, Crawley, UK) for treatment delivery. All patients followed an offline portal imaging protocol, where the patients were imaged on day 1-3 and then weekly. The chest wall and ribs were outlined and used to match the portal image to the digitally reconstructed radiograph from the CT scan. Displacements were analyzed in the (u,v)-plane for each patient (v-direction parallel to CC axis and u-direction perpendicular to this in AP direction). Localization offset was calculated after the 3 rd fraction and systematic errors were corrected. Weekly patient positioning errors of less than 5 mm were accepted; in case of having deviations over 5 mm new images were acquired and a new trend was calculated.

2.C | Treatment delivery
All portal images were analyzed for systematic and random errors in accordance with the formalism proposed by van Herk et al. 28 The average of the individual systematic setup error for the population (l), the standard deviation of the individual systematic setup errors for the population (∑), and the average of the individual random setup error for the population (r) was calculated.

2.D | Statistics
Statistical analysis was made using a Wilcoxon signed-rank test. The test was two tailed for each evaluated parameter and considered significant if P was <0.05. SPSS version 23 (IBM, Armonk, USA) was used in the calculations.

3.B | FB versus DIBH treatment plans
Treatment planning statistics for all included patients are reported in Table 3.

| DISCUSSION
Left-sided breast RT will to some extent irradiate the heart and increase the risk of heart disease. 29 Darby et al. reported that the rates of major coronary events increased linearly with the mean heart dose, this increase is of 7.4% per Gy and there seems to be no lower dose threshold. 30 The best approach would be to minimize any dose to the heart without compromising the dose to the target. 30 Our clinical study assessed the interfraction setup variability with an in-house developed DIBH system, and also evaluated the doses to OAR and target with the system. We found that the DIBH system gave a significant dose reduction in heart and LAD, while maintaining dose coverage to the clinical target, and typical beam's eye views can be seen in Fig. 2. The results are consistent with what others have presented previously. 6,9,10 Anzai Medical has just released a system utilizing a distance laser measurer similar to the in-house system we report clinical data on. 26 Their solution will possibly be susceptible to setup variations and also varying inclination angle. Our study is the first to report clinical data on such a DIBH-solution. other studies have reported on absolute lung volume increase in the range of 72%-84%. 6,8,9 Our study has a lower lung volume increase, and there could be a potential for optimizing the doses even more.
Vikstr€ om et al. reported the highest lung volume increase, but the study did not report on the DIBH level, and only 1 of the 17 patients went on to perform DIBH treatment.
A limitation of our study is that the results are based on an estimate of the dose at the time of the planning CT scan; patient contour and the inhaled volume can differ during the radiotherapy course and the setup variability is not accounted for. This can alter the dose to OARs, especially the heart and the LAD, and the coverage of the CTV could also be compromised. Some patients might also tend to flex their muscles during DIBH, something that leads to variations in how the patient returns to the baseline between two breath holdssee Fig. 3. This will again result in less inhaled air during the treatment session. There is a call for studies that take these changes into account. Another limitation of our study is the contouring of the OARs without using margins, which in particular may be relevant for heart and LAD due to heartbeats even during DIBH-CT LAD, and found that the use of guidelines reduced the spatial distance variation for heart and LAD delineations. 40 The heart atlas by Feng et al. was used as guideline in our study. 27 There is a decreased volume of the heart during DIBH which is probably due to increased intrathoracic pressure, and this is consistent with other studies that have found a 5%-10% reduction. 6,41 Another limitation was that the laser system had a fixed measuring point in the room; all patients had their isocenter placed on the sternum. The in-house system has since been improved and is now capable to measure a suitable region regardless of the isocenter position. 25 The FB plans in our study show large variation in minimum doses to the PTV. In most FB plans we had to shield the heart extensively and this also influenced the PTV coverage. A large variation in the minimum doses to the PTV would also indicate that these plans would generally not be as robust as DIBH plans; a DIBH plan would tolerate greater variations in patient setup without compromising the dose to the CTV. We found no reduction in doses to the left lung, even if the volume of the lungs increased with DIBH. The reason for this was that the increased therapeutic ratio DIBH offers was used to improve PTV coverage instead of lowering the doses to the lung. The national recommendation that maximum 5% of the heart should receive >25 Gy led to extensive shielding of the FB plans. We found that for some patients the heart follows the movement of the anterior wall of the thorax, and we could not easily improve the heart doses from FB to DIBH. All patients would benefit from DIBH, but with varying degree in regard to anatomy.

| CONCLUSION
We have successfully implemented an in-house developed DIBH system for left-sided breast cancer patients in our clinic, and the clinical results are promising. The system was well tolerated and all patients that complied with the requirements completed their treatment sessions with DIBH. The in-house system gave a reproducible and stable DIBH treatment verified with portal imaging. We found a significant dose reduction in heart and LAD with the DIBH system, while maintaining dose coverage to the clinical target. The most important features of our in-house system are its simplicity, its noninvasiveness and its low cost for performing DIBH.

ACKNOWLEDG MENTS
The work was supported by the Liaison Committee between the Central Norway Regional Health Authority (RHA) and the Norwegian University of Science and Technology (NTNU).