Measurements of intrafraction motion and interfraction and intrafraction rotation of prostate by three-dimensional analysis of daily portal imaging with radiopaque markers

PURPOSE: To measure the interfraction and intrafraction motion of the prostate during the course of external beam radiotherapy using a video electronic portal imaging device and three-dimensional analysis. METHODS AND MATERIALS: Eighteen patients underwent implantation with two or three gold markers in the prostate before five-angle/11-field conformal radiotherapy. Using CT data as the positional reference, multiple daily sets of portal images, and a three-dimensional reconstruction algorithm, intrafraction translations, as well as interfraction and intrafraction rotations, were analyzed along the three principal axes (left-right [LR], superoinferior [SI], and AP). The overall mean values and standard deviations (SDs), along with random and systematic SDs, were computed for these translations and rotations. RESULTS: For 282 intrafraction translational displacements, the random SD was 0.8 mm (systematic SD, 0.2) in the LR, 1.0 mm (systematic SD, 0.4) in the SI, and 1.4 mm (systematic SD, 0.7) in the AP axes. The analysis of 348 interfraction rotations revealed random SDs of 6.1 degrees (systematic SD, 5.6 degrees ) around the LR axis, 2.8 degrees (systematic SD, 2.4 degrees ) around the SI axis, and 2.0 degrees (systematic SD, 2.2 degrees ) around the AP axis. The intrafraction rotational motion observed during 44 fractions had a random SD of 1.8 degrees (systematic SD, 1.0 degrees ) around the LR, 1.1 degrees (systematic SD, 0.8 degrees ) around the SI, and 0.6 degrees (systematic SD, 0.3 degrees ) around the AP axis. CONCLUSION: The interfraction rotations observed were more important than those reported in previous studies. Intrafraction motion was generally smaller in magnitude than interfraction motion. However, the intrafraction rotations and translations of the prostate should be taken into account when designing planning target volume margins because their magnitudes are not negligible.     

电子射野影像装置对盆腔肿瘤放疗摆位误差的测定

目的利用Elekta iView GT量化测定盆腔肿瘤放疗摆位中的系统误差及随机误差,为放疗计划PTV的设定提供初步的参考依据。方法对12例接受盆腔放疗的病例进行摆位误差量化测定,共获取244组图像数据。所有入组病例均为CT模拟定位及适形放疗。将每日前后野和两侧野的电子射野影像装置(EPID),采用盆腔骨性标志与数字重建图像(DRR)比较,记录在左右、头脚、前后方向上的移动,从得到的数据计算系统和随机误差。结果每日摆位误差的最大值在左右、头脚、前后方向上分别为9.9、14.0、21.1 mm,摆位的系统误差分别为0.5、0.2、2.3 mm。12例病例数据显示,在左右、头脚、前后方向上移动幅度5～10 mm和>10mm的发生频率分别为8%、9%、21%和0%、1%、3%。结论应用EPID测定盆腔肿瘤放疗的摆位误差,为放疗计划PTV的设定提供初步的参考依据。在PTV设定时,考虑由摆位误差而引起的边界(SM)至少需5 mm,但前后方向以扩大到10 mm为好,以达到97%的靶区包绕率,且需注意个体差异。     

Set-up variation of patients treated with radiotherapy to the prostate measured with an electronic portal imaging device

The set-up variation of 11 patients treated supine with radical radiotherapy for carcinoma of the prostate was measured with an electronic portal imaging device to determine the adequacy of set-up techniques and current margins, as well as the need for immobilization. During the treatments 172 images of the anterior fields and 159 images of the left-lateral fields were taken and the errors in treatment placement were measured by template matching. The variation in the superior-inferior direction was small, 1.4-1.6 mm (1 SD), while the medio-lateral variation was 2.8 mm (1 SD). The anterior-posterior variation was largest, 4.6 mm (1 SD) with an offset of 3.3 mm anterior. This anterior offset and large anterior-posterior variation suggests that set-up techniques were not optimal for this direction. The 1 cm margin used was adequate for set-up variation except in a small number of cases, which was mainly due to the anterior trend. Random (treatment-to-treatment) variations were small (1.1-2.3 mm; 1 SD), indicating that immobilization would result in only modest improvement in reproducibility for these supine patients.     

关于电子荧光类射野影像系统作为出射剂量仪使用的研究

目的研究利用射野影像系统进行出射剂量测量的可能性。以便能进一步把该类系统发展为剂量仪系统。材料与方法使用荧光型电子射野影像系统，探头由金属板—荧光屏和Ｐｌｕｍｂｉｃｏｎ照像机组成。通过与电离室及射野证实片所测结果的比较，建立一套与像素位置对应的灰度校正矩阵。并在多种射野面积和体模厚度下验证，所用射线为６ＭＶ－Ｘ线。结果通过对该系统的各种性能测试，如灰度的稳定性、探头的均匀性、剂量响应曲线、灰度的射野依赖性及对体模厚度的依赖性，发现短期稳定性好于１％，有较明显的灰度饱和性，但需作灰度饱和校正。作为相对剂量仪使用时，只要建立一个探头非均匀性校正矩阵，就能与证实片的剂量结果保持一致，误差小于±５％。结论研究证明，电子射野影像系统完全可以成为一套剂量仪系统。在对靶区的位置进行实时监测的同时，还能通过对影像灰度的计算，得出出射野的剂量分布     

Image-guided total-body irradiation with a movable electronic portal imaging device for bone marrow transplant conditioning

IntroductionTo prevent radiation pneumonitis following total body irradiation (TBI) clinicians usually use lung shield blocks. The correct position of these shields relative to the patient's lungs is usually verified via mega-voltage imaging and computed radiographic (CR) films. In order to improve this time-consuming procedure, we developed in our department a dedicated, movable, real-time imaging system for image-guided TBI.Material & MethodsThe system consists of an electronic portal imaging device (EPID) mounted on a dedicated support whose motion along a rail can be controlled from the linac console outside the bunker room. Images are acquired online using a stand-alone console. To test the system efficacy we retrospectively analyzed data of lung blocks positioning from two groups of 10 patients imaged with EPID or CR-films, respectively.ResultsThe median number of portal images per fraction was 2 (range 1-5) and 1 (range 1-2) for the EPID and the CR-film system, respectively. The minimum time required for an EPID image acquisition, without interpretation and no need of patient position correction in the bunker, was 20 seconds against 214 seconds for the CR-film. Lung shielding positioning in the right-left and superior-inferior directions was improved using the EPID system (p< 0.01).ConclusionsCompared to CR-films, our movable real-time imaging EPID system is a simple technical solution able to reduce the minimum imaging time for lung shielding by a factor of 10. With the increased possibility to acquire more images as compared to CR-film system the EPID system has the potential to improve patient alignment, as well as patient's comfort and overall setup time.     

Shielding of the contralateral breast during tangential irradiation

The purpose of this study was to investigate both optimal and practical contralateral breast shielding during tangential irradiation in young patients. A shaped sheet of variable thickness of lead was tested on a phantom with rubber breasts, and an optimized shield was created. Testing on 18 consecutive patients 50 years or younger showed shielding consistently reduced contralateral breast dose to at least half, with small additional reduction after removal of the medial wedge. For younger patients in whom radiation exposure is of considerable concern, a simple shield of 2 mm lead thickness proved practical and effective.     

利用电子射野影像装置测量放疗摆位误差的初步研究

目的 利用电子射野影像装置(EPID)对不同部位肿瘤放疗中的摆位误差进行量化分析,了解不同部位的摆位误差,不同医生对摆位误差的接受程度有无差异。方法 2006年1月—2007年12月接受放射治疗的患者中按头颈、胸部、腹盆腔不同部位,及不同医生治疗组随机抽出58例,按部位分别为头及头颈部20例,胸部19例,腹盆部19例。所有病例采用Philips公司AcQ-Sim大孔径CT和/或Nucletron公司Simulix-HQ X线模拟机模拟定位,治疗计划为ADCC公司Pinnacle3 7.4,用Elekta公司的Precise加速器实施放疗,利用Elekta的iViewGT采集图像,采用双曝光法拍摄照射野验证片。参考图像为CT定位后的DRR或X线模拟机定位图像,图像比较采用骨性结构为标志,勾画出参考图像上的骨性结构,与EPID进行最大程度重合后得出在水平、垂直方向上的摆位误差数据并进行分析。结果 得到102组数据,其中EPID为拍摄角度为0° 38组,90° 21组,其他角度43组。摆位误差水平方向为1.02mm±1.15mm(0mm~5mm),垂直方向为1.11mm±1.20mm(0mm~6mm)。90%以上摆位误差小于3mm。头部或头颈部固定摆位误差最小,水平方向和垂直方向分别为0.64mm±0.65mm和0.91mm±0.98mm。不同医生组之间摆位误差有所不同。结论 绝大多数摆位误差在容许范围。需提高EPID在胸、腹盆部的解剖识别率,以减少其对摆位误差的影响。实施治疗前,先行X线模拟机摆位不失为一种缩小摆位误差的有效办法。     

First clinical experience with a newly developed electronic portal imaging device

In our institute an electronic portal imaging device (PID) has been developed and it recently became available for routine clinical practice. Images are available within 3 to 6 seconds after the start of irradiation; they are displayed on a video monitor next to the control console of the accelerator. The image quality is similar to the quality of images obtained with films. Because of its cassette-like shape and its low weight, the PID can easily be handled by technicians. An important advantage of the PID over conventional films is its pseudo-real time viewing facility. Typically, 5 to 10 images of each field can be made during one treatment session. In case a high accuracy in setup is demanded, the field edges of the first image, obtained with about 10% of the fraction dose, can be studied for acceptability before the rest of the dose is delivered. Using two prototype PID's first clinical experience has been obtained with patients treated for malignant tumors at various sites. Intra-treatment motion as a result of breathing, swallowing, or patient motion in a cast was seen. Motion of high contrast objects, for example, a field edge during irradiation, can be followed. This feature is important for future applications in computer controlled radiotherapy. Another advantage of the PID over film is that the image is digitally available. Therefore it can be further processed for quality improvement and quantitative analysis. Simple processing is done within seconds on the PID unit. A local network for the transfer of images from the accelerators to the evaluation room, where a detailed analysis of the field placement is performed, is under installation. Simulator film images are digitized in this room and are sent to the PID at the accelerator for a quick comparison with portal images during irradiation. We conclude that our device can replace the conventional film detector for portal imaging, that useful images are obtained within seconds during irradiation, and that the position of the field outline relative to the patient anatomy can be followed during dose delivery.     

A randomized comparison of interfraction and intrafraction prostate motion with and without abdominal compression

BACKGROUND AND PURPOSE: To quantify inter- and intrafraction prostate motion in a standard VacLok (VL) immobilization device or in the BodyFix (BF) system incorporating a compression element which may reduce abdominal movement. MATERIALS AND METHODS: Thirty-two patients were randomly assigned to VL or BF. Interfraction prostate motion >3 mm was corrected pre-treatment. EPIs were taken daily at the start and end of the first and last treatment beams. Interfraction and intrafraction prostate motion were measured for centre of mass (COM) and individual markers. RESULTS: There were no significant differences in interfraction (p0.002) or intrafraction (p0.16) prostate motion with or without abdominal compression. Median intrafraction motion was slightly smaller than interfraction motion in the AP (7.0 mm vs. 7.6 mm) and SI direction (3.2 mm vs. 4.7 mm). The final image captured the maximal intrafraction displacement in only 40% of fractions. Our PTV incorporated >95% of total prostate motion. CONCLUSIONS: Intrafraction motion became the major source of error during radiotherapy after online correction of interfraction prostate motion. The addition of 120 mbar abdominal compression to custom pelvic immobilization influenced neither interfraction nor intrafraction prostate motion.     

Accuracy in tangential breast treatment set-up: a portal imaging study.

To test the accuracy and reproducibility of the tangential breast treatment set-up used in The Netherlands Cancer Institute, a portal imaging study was performed in 12 patients treated for early stage breast cancer. With an on-line electronic portal imaging device (EPID) images were obtained of each patient in several fractions and compared with simulator films and with each other. In five patients, multiple images (on the average 7) per fraction were obtained to evaluate set-up variations due to respiratory movement. The central lung distance (CLD) and other set-up parameters varied within one fraction about 1 mm (1 SD). The average variation of these parameters between various fractions was about 2 mm (1 SD). The differences between simulator and treatment set-up over all patients and all fractions was on the average 2-3 mm for the central beam edge to skin distance and the central lung distance. It can be concluded that the tangential breast treatment set-up is very stable and reproducible and that respiration does not have a significant influence on treatment volume. The EPID appears to be an adequate tool for studies of treatment set-up accuracy like this.     

自由与主动呼吸控制状态下乳腺癌调强放疗位移EPID误差比较

目的:应用电子射野影像系统测量自由呼吸状态(FB)和主动呼吸控制状态(ABC)下的相对位移,并对比其差别。方法:选择29例接受保留乳房术后调强放疗的乳腺癌患者,16例在FB下13例在ABC下接受放疗。患者在每次放疗前拍电子射野影像片(EPI),ABC的8例在每次放疗前拍2次。依据胸壁和乳腺表面轮廓将EPI和数字重建图像(DRR)进行配准,计算出每次配准时垂直和水平方向的差异。结果:FB组水平和垂直方向的平均位移分别为1.93和0.99mm,ABC组分别为1.97和1.14mm。位移>5mm的<4%。ABC组之间在水平和垂直方向的位移差异无统计学意义,P值分别为0.778和0.142。其中8例每次放疗前拍2次EPI的ABC患者,在水平和垂直方向差异无统计学意义,P值分别为0.220和0.862。结论:尽管从理论上ABC可减少呼吸运动,但在减少由摆位误差和呼吸运动造成的混合位移方面并无优势。乳腺癌放疗时从临床靶区到计划靶区外放5mm的边界是合理的。     

Transit dosimetry with an electronic portal imaging device (EPID) for 115 prostate cancer patients

Purpose: Comparison of predicted portal dose images (PDIs) with PDIs measured with an electronic portal imaging device (EPID) may be used to detect errors in the dose delivery to patients. However, these comparisons cannot reveal errors in the MU calculation of a beam, since the calculated number of MU is used both for treatment (and thus affects the PDI measurement) and for PDI prediction. In this paper a method is presented that enables “in vivo” verification of the MU calculation of the treatment beams. The method is based on comparison of the intended on-axis patient dose at 5 cm depth for each treatment beam, D₅, with D₅ as derived from the portal dose D_p measured with an EPID. The developed method has been evaluated clinically for a group of 115 prostate cancer patients.

Methods and Materials: The patient dose D₅ was derived from the portal dose measured with a fluoroscopic EPID using (i) the predicted beam transmission (i.e., the ratio of the portal dose with and without the patient in the beam) calculated with the planning CT data of the patient, and (ii) an empirical relation between portal doses D_p and patient doses D₅. For each beam separately, the derived patient dose D₅ was compared with the intended dose as determined from the relative dose distribution as calculated by the treatment planning system and the prescribed isocenter dose (2 Gy). For interpretation of observed deviating patient doses D₅, the corresponding on-axis measured portal doses D_p were also compared with predicted portal doses.

Results: For three beams, a total of 7828 images were analyzed. The mean difference between the predicted patient dose and the patient dose derived from the average measured portal dose was: 0.4 ± 3.4% (1 SD) for the anterior–posterior (AP) beam and −1.5 ± 2.4% (1 SD) for the lateral beams. For 7 patients the difference between the predicted portal dose and the average measured portal dose for the AP beam and the corresponding difference in patient dose were both greater than 5%. All these patients had relatively large gas pockets (3–3.5 cm in AP direction) in the rectum during acquisition of the planning CT, which were not present during (most) treatments.

Conclusions: An accurate method for verification of the MU calculation of an x-ray beam using EPID measurements has been developed. The method allows the discrimination of errors that are due to changes in patient anatomy related to appearance or disappearance of gas pockets in the rectum and errors due to a deviating cGy/MU-value.     

Axillary lymph node dose with tangential breast irradiation

PURPOSE: The advent of sentinel lymph node mapping and biopsy in the staging of breast cancer has resulted in a significant decrease in the extent of axillary nodal surgery. As the extent of axillary surgery decreases, the radiation dose and distribution within the axilla becomes increasingly important for current therapy planning and future analysis of results. This analysis examined the radiation dose distribution delivered to the anatomically defined axillary level I and II lymph node volume and surgically placed axillary clips with conventional tangential breast fields and CT-based three-dimensional (3D) planning. METHODS AND MATERIALS: Fifty consecutive patients with early-stage breast cancer undergoing breast conservation therapy were evaluated. All patients underwent 3D CT-based planning with conventional breast tangential fields designed to encompass the entire breast parenchyma. Using CT-based 3D planning, the dose distribution of the standard tangential breast irradiation fields was examined in relationship to the axillary level I and II lymph node volumes. Axillary level I and II lymph node anatomic volumes were defined by CT and surgical clips placed during complete level I-II lymph node dissection. Axillary level I-II lymph node volume doses were examined on the basis of the prescribed breast radiation dose and 3D dose distribution. RESULTS: All defined breast volumes received > or =95% of the prescribed dose. By contrast, the 95% isodose line encompassed only an average of 55% (range, 23-87%) of the axillary level I-II lymph node anatomic volume. No patient had complete coverage of the axillary level I-II lymph node region by the 95% isodose line. The mean anatomic axillary level I-II volume was 146.3 cm(3) (range, 83.1-313.0 cm(3)). The mean anatomic axillary level I-II volume encompassed by the 95% isodose line was 84.9 cm(3) (range, 25.1-219.0 cm(3)). The mean 95% isodose coverage of the surgical clip volume was 80%, and the median value was 81% (range, 58-98%). The mean volume deficit between the axillary level I-II volume and the surgical clip volume was 41.7 cm(3) (median, 30.0 cc). CONCLUSION: In this study, standard tangential breast radiation fields failed to deliver a therapeutic dose adequately to the axillary level I-II lymph node anatomic volume. No patient received complete coverage of the axillary level I-II lymph node volume. Surgically placed axillary clips also failed to delineate the level I-II axilla adequately. Definitive irradiation of the level I and II axillary lymph node region requires significant modification of standard tangential fields, best accomplished with 3D treatment planning, with specific targeting of anatomically defined axillary lymph node volumes as described, in addition to the breast parenchymal volumes.     

SIFT: a method to verify the IMRT fluence delivered during patient treatment using an electronic portal imaging device

PURPOSE: Radiotherapy patients are increasingly treated with intensity-modulated radiotherapy (IMRT) and high tumor doses. As part of our quality control program to ensure accurate dose delivery, a new method was investigated that enables the verification of the IMRT fluence delivered during patient treatment using an electronic portal imaging device (EPID), irrespective of changes in patient geometry. METHODS AND MATERIALS: Each IMRT treatment field is split into a static field and a modulated field, which are delivered in sequence. Images are acquired for both fields using an EPID. The portal dose image obtained for the static field is used to determine changes in patient geometry between the planning CT scan and the time of treatment delivery. With knowledge of these changes, the delivered IMRT fluence can be verified using the portal dose image of the modulated field. This method, called split IMRT field technique (SIFT), was validated first for several phantom geometries, followed by clinical implementation for a number of patients treated with IMRT. RESULTS: The split IMRT field technique allows for an accurate verification of the delivered IMRT fluence (generally within 1% [standard deviation]), even if large interfraction changes in patient geometry occur. For interfraction radiological path length changes of 10 cm, deliberately introduced errors in the delivered fluence could still be detected to within 1% accuracy. Application of SIFT requires only a minor increase in treatment time relative to the standard IMRT delivery. CONCLUSIONS: A new technique to verify the delivered IMRT fluence from EPID images, which is independent of changes in the patient geometry, has been developed. SIFT has been clinically implemented for daily verification of IMRT treatment delivery.     

Commissioning and periodic quality assurance of a clinical electronic portal imaging device

PURPOSE: An electronic portal imaging device (EPID) was recently installed on our dual-energy linear accelerator. Commissioning and quality assurance techniques were developed for the EPID. METHODS AND MATERIALS: A commissioning procedure was developed consisting of five parts: (a) physical operation and safety; (b) image acquisition, resolution, and sensitivity calibration; (c) image storage, analysis, and handling; (d) reference image acquisition; and (e) clinical operations. RESULTS: The physical operation and safety tests relate to the motions of the unit, stability of the unit supports, safety interlocks, and interlock overrides. Imager contrast and spatial resolutions are monitored by imaging a contrast-detail phantom. The imager calibration procedure consists of a no-radiation image to compensate for signal offsets, as well as a "flat-field image." The flat-field image is taken with 5.0 cm of homogeneous phantom material placed at isocenter to provide some photon scatter and to approximate the presence of a patient. Daily quality assurance procedures consists of safety tests and the acquisition and inspection of images of the contrast-detail phantom. After 1 year, the frequency of the daily procedure was reduced to weekly. Quarterly QA procedures are conducted by the physicist and consist of the same procedures conducted in the weekly test. The annual QA procedure consists of a duplication of the commissioning procedure. CONCLUSION: The procedures discussed in this article were applied to an ionization-chamber device. They have been useful in identifying difficulties with the EPID operation, including the need for recalibrating and monitoring the accelerator output stability.     

Quantification of prostate and seminal vesicle interfraction variation during IMRT

PURPOSE: To quantify the interfraction variability in prostate and seminal vesicle (SV) positions during a course of intensity-modulated radiotherapy (IMRT) using an integrated computed tomography (CT)-linear accelerator system and to assess the impact of rectal and bladder volume changes. METHODS AND MATERIALS: We studied 15 patients who had undergone IMRT for prostate carcinoma. Patients had one pretreatment planning CT scan followed by three in-room CT scans per week using a CT-on-rails system. The prostate, bladder, rectum, and pelvic bony anatomy were contoured in 369 CT scans. Using the planning CT scan as a reference, the volumetric and positional changes were analyzed in the subsequent CT scans. RESULTS: For all 15 patients, the mean systematic internal prostate and SV variation was 0.1 +/- 4.1 mm and 1.2 +/- 7.3 mm in the anteroposterior axis, -0.5 +/- 2.9 mm and -0.7 +/- 4.5 mm in the superoinferior axis, and 0.2 +/- 0.9 mm and -0.9 +/- 1.9 mm in the lateral axis, respectively. The mean magnitude of the three-dimensional displacement vector was 4.6 +/- 3.5 mm for the prostate and 7.6 +/- 4.7 mm for the SVs. The rectal and bladder volume changes during treatment correlated with the anterior and superior displacement of the prostate and SVs. CONCLUSION: The dominant prostate and SV variations occurred in the anteroposterior and superoinferior directions. The systematic prostate and SV variation between the treatment planning CT and daily therapy as a result of the rectal and bladder volume changes emphasizes the need for daily directed target localization and/or immobilization techniques.     

CTV to PTV margins for prostate irradiation. Three-dimensional quantitative assessment of interfraction uncertainties using portal imaging and serial CT scans

Purpose  

To determine the magnitude of setup and organ motion errors from a subset of prostate cancer patients treated with conventional conformal radiotherapy, and to estimate the CTV-PTV margin according to published margin recipes.     

Intensity-modulated tangential beam irradiation of the intact breast

Purpose: To evaluate the potential benefits of intensity modulated tangential beams in the irradiation of the intact breast.

Methods and Materials: Three-dimensional treatment planning was performed on five left and five right breasts using standard wedged and intensity modulated (IM) tangential beams. Optimal beam parameters were chosen using beams-eye-view display. For the standard plans, the optimal wedge angles were chosen based on dose distributions in the central plane calculated without inhomogeneity corrections, according to our standard protocol. Intensity-modulated plans were generated using an inverse planning algorithm and a standard set of target and critical structure optimization criteria. Plans were compared using multiple dose distributions and dose volume histograms for the planning target volume (PTV), ipsilateral lung, coronary arteries, and contralateral breast.

Results: Significant improvements in the doses to critical structures were achieved using intensity modulation. Compared with a standard-wedged plan prescribed to 46 Gy, the dose from the IM plan encompassing 20% of the coronary artery region decreased by 25% (from 36 to 27 Gy) for patients treated to the left breast; the mean dose to the contralateral breast decreased by 42% (from 1.2 to 0.7 Gy); the ipsilateral lung volume receiving more than 46 Gy decreased by 30% (from 10% to 7%); the volume of surrounding soft tissue receiving more than 46 Gy decreased by 31% (from 48% to 33%). Dose homogeneity within the target volume improved greatest in the superior and inferior regions of the breast (approximately 8%), although some decrease in the medial and lateral high-dose regions (approximately 4%) was also observed.

Conclusion: Intensity modulation with a standard tangential beam arrangement significantly reduces the dose to the coronary arteries, ipsilateral lung, contralateral breast, and surrounding soft tissues. Improvements in dose homogeneity throughout the target volume can also be achieved, particularly in the superior and inferior regions of the breast. It remains to be seen whether the dosimetric improvements achievable with IMRT will lead to significant clinical outcome improvements.