Advances on Clinical Application of Adaptive Radiotherapy in Treatment of Nasopharyngeal Carcinoma / 肿瘤防治研究

Radiotherapy is the first treatment choice for nasopharyngeal carcinoma. With the rapid development of image-guided radiotherapy, adaptive radiotherapy (ART) has become widely available in clinical practice. ART may be implemented to monitor the anatomical or physiological variations of patients using dynamic imaging technology and feedback information during the treatment course, including geometric changes (size, shape, and position) of tumor and normal organs. ART also allows the modification of the treatment plan to accurately deliver the maximize dose to target and minimize normal tissue explosion. This review discusses the physics basis of ART and its state-of-art application and potential pitfalls.

Clinical implementation of iterative cone-beam computed tomography guided online adaptive radiotherapy for the pelvic malignancies / 中华放射肿瘤学杂志

Objective:To evaluate the clinical application of online adaptive radiotherapy based on iterative cone-beam computed tomography (iCBCT) for the pelvic malignancies.Methods:This was a prospective clinical trial of iCBCT guided online adaptive radiotherapy for pelvic malignancies in Department of Radiation Oncology, Peking Union Medical College Hospital. Clinical data of 13 patients with pelvic malignancies who received online adaptive radiotherapy from August to November, 2022 were preliminarily analyzed (2 cases of cervical cancer, 4 postoperative cervical cancer, 3 postoperative endometrial cancer, 3 bladder cancer and 1 prostate cancer). The feasibility of online adaptive radiotherapy, adaptive radiotherapy time, the frequency and magnitude of edits for organs at risk and target volume, target volume coverage and organs at risk doses were analyzed. Statistical analysis was performed by SPSS software. Data conforming to normal distribution were described by Mean±SD, and data with non-normal distribution were expressed by M ( Q1, Q3). Data with homogeneous variances were analyzed by t-test, and data with non-normal distribution or heterogeneous variances were analyzed by nonparametric test. Results:The average adaptive time was 15 min and 38 s (from acceptance of acquired CBCT scan to completion of the final plan selection). 85.4% (830/972 fractions) of influencer structures (system-defined organs adjacent to and with high impact on the generation of clinical target volume and planning target volume, primarily bladder, rectum and small intestine in pelvic neoplasms) automatically generated by artificial intelligence required no edits or minor editors, and 89.8% (491/547 fractions) of clinical target volume automatically generated by artificial intelligence required no edits or minor editors. The adapted plan was adopted in 98.5% (319/324 fractions) of radiotherapy fractions. Compared with the scheduled plan, the adapted plan showed better target volume coverage and reduced the dose of organs at risk.Conclusions:iCBCT guided online adaptive radiotherapy for the pelvic malignancies can be achieved within clinically acceptable timeslots. In addtion, better dose coverage of target volume shows the advantages of online adaptive radiotherapy.

Application of MR-guided radiotherapy for brain metastases / 中华放射肿瘤学杂志

Radiotherapy (RT) is the primary local treatment modality for brain metastases, which are common secondary malignancies. Image-guidance system such as cone beam computed tomography (CBCT) may be not applicable to adaptive radiotherapy (ART), as well as hypofractionated RT in brain metastases, because it cannot clearly show the shrinkage and deformation of intracranial tumors, and the peritumoral edema changes in a real-time manner. Magnetic resonance (MR) image has high spatial resolution and soft tissue contrast and no radiation dose burden compared with CBCT. MR-guided adaptive radiotherapy (MR-gART) allows real-time tracking of deformation and position changes of the intracranial tumors, and enables online planning reconstruction during the treatment process. MR-gART could deliver high dose irradiation to the tumors while reducing the radiation dose of important organs at risk around, which contributes to achieving precision RT. In this work, the application of MR-gART in brain metastases was reviewed.

A deep learning method for generating pseudo-CT by cone beam CT in radiotherapy / 中华放射肿瘤学杂志

Objective:To investigate the pseudo-CT generation from cone beam CT (CBCT) by a deep learning method for the clinical need of adaptive radiotherapy.Methods:CBCT data from 74 prostate cancer patients collected by Varian On-Board Imager and their simulated positioning CT images were used for this study. The deformable registration was implemented by MIM software. And the data were randomly divided into the training set ( n=59) and test set ( n=15). U-net, Pix2PixGAN and CycleGAN were employed to learn the mapping from CBCT to simulated positioning CT. The evaluation indexes included mean absolute error (MAE), structural similarity index (SSIM) and peak signal to noise ratio (PSNR), with the deformed CT chosen as the reference. In addition, the quality of image was analyzed separately, including soft tissue resolution, image noise and artifacts, etc. Results:The MAE of images generated by U-net, Pix2PixGAN and CycleGAN were (29.4±16.1) HU, (37.1±14.4) HU and (34.3±17.3) HU, respectively. In terms of image quality, the images generated by U-net and Pix2PixGAN had excessive blur, resulting in image distortion; while the images generated by CycleGAN retained the CBCT image structure and improved the image quality.Conclusion:CycleGAN is able to effectively improve the quality of CBCT images, and has potential to be used in adaptive radiotherapy.

Research progress of adaptive radiotherapy in radiotherapy of nasopharyngeal carcinoma / 国际生物医学工程杂志

Intensity-modulated radiation therapy(IMRT) is currently the main treatment method for nasopharyngeal carcinoma. During radiotherapy for nasopharyngeal carcinoma, factors such as body mass reduction, tumor regression, and organ displacement at risk can affect the precise implementation of radiation therapy. Applying adaptive radiotherapy (ART) technology to optimize the treatment plan at the appropriate timing can reduce the adverse effects caused by the above factors and enhance the accuracy of radiotherapy. There are no uniform standards for the necessity, timing, and case selection of ART. In this review, the research progress of ART in the radiotherapy of nasopharyngeal carcinoma in recent years was reviewed to provide a reference for further clinical application of ART in nasopharyngeal carcinoma.

Statistical analysis of duration of each phase of Unity MR-linac in clinical application / 中华放射肿瘤学杂志

Objective:To analyze the duration of each phase of Unity MR-linac in clinical application, aiming to provide reference for clinical optimization of the process time.Methods:Clinical data of 55 patients treated with Unity MR-linac were retrospectively analyzed. All patients were divided into the adapt to position (ATP) and adapt to shape (ATS) groups according to the planning method. The duration of each phase in the treatment process, the name and the time of each sequence, the number of beams, segments and total monitor units (MUs) were recorded and compared between two groups. In addition, the set-up time was counted according to different treatment sites. The time of each sequence and set-up time were expressed as the median M (Q 1, Q 3), and the number of beams, segments and total MUs of each plan were described as the mean±SD. Results:42 patients underwent ATP with a total of 305 treatment sessions: setup time was 3(2, 5) min, MR scanning time was 5(4, 7) min, registration time was 3(3, 4) min, adaptive planning time was 8(4, 12) min, beam on time was 8(6, 11) min, and the total time was 30(25, 36) min. 13 patients received ATS with a total of 65 treatment sessions: setup time was 2(2, 3) min, MR scanning time was 7(5, 8) min, registration time was 4(3, 5) min, time of delineation of target and organs at risk was 12(9, 16) min, adaptive planning time was 11(10, 14) min, beam on time was 10(9, 11) min and the total time was 55(49, 61) min. The set-up time according to treatment sites was 4(2, 4) min in the head and neck, 2(2, 4) min in the chest, and 3(2, 5) min in the abdomen. The number of fields, segments and total MUs during ATP were 8.1±1.7, 49.9±31.2, 846.75±363.44 in the head and neck, 8.0±2.0, 60.7±13.3, 790.21±279.00 in the chest, and 9.7±2.0, 81.2±22.3, 2007.32±1053.81 in the abdomen, respectively. The number of fields, segments and total MUs during ATS in head and neck of one case were 13, 39, 993.07, and 9.5±1.5, 65.5±6.3, 2763.26±835.41 in the abdomen.Conclusions:MR-guided radiotherapy yields huge potential in clinical application. However, there is still much room for the improvement of shortening the process duration.

Application and basic application process of MR accelerator in lung cancer / 中华放射肿瘤学杂志

Radiotherapy is one of the most important components of cancer treatment. Image-guided radiotherapy (IGRT) is the mainstream tool in the precision radiation oncology. Magnetic resonance (MR) accelerator can perform MRI for tumors during radiotherapy, deliver real-time tracing and monitoring of tumors and thus realize the MRI-guided adaptive radiotherapy. Here, the latest research status and clinical application of MR accelerator in lung cancer were reviewed.

The standard adapt-to-shape workflow for prostate cancer on MR-linac—Experience from National Cancer Institute/Cancer Hospital, Chinese Academy of Medical Sciences / 中华放射肿瘤学杂志

With aligned MR registration, the MR-Linac provides superior soft tissue resolution for prostate cancer. No fiducial markers or electromagnetic transponders insertion is needed to guarantee high-precision radiotherapy. The highly-recommended Adapt-To-Shape (ATS) workflow can resolve all the problems encountered during prostate cancer radiotherapy, including prostate volume changes and adjacent organs motion, both inter-fractionally and intra-fractionally. With all the above advantages, MR-Linac performs outstandingly than conventional linac in prostate cancer RT delivery, and probably helps us to reduce the CTV-PTV margin safely in the near future. Nevertheless, it is difficult to implement the ATS workflow in clinical practice. In this article, the standard ATS workflow for prostate cancer was summarized based on our own experience.

Clinical and dosimetric impact of adaptive intensity-modulated radiotherapy in locally advanced head-and-neck cancer

Background: Radiotherapy in head-and-neck cancer (HNC) is a challenging task, and the anatomical alterations occurring during the course of intensity-modulated radiotherapy (IMRT) can be compensated by adaptive radiotherapy (ART) which utilizes repeat computed tomography (CT) scans during the treatment course for replanning. In this study, the clinical and dosimetric benefits of ART were compared with the conventional IMRT. Materials and Methods: Sixty patients with locally advanced HNC were randomized into two arms to receive IMRT up to a curative dose of 70 Gy with concurrent weekly chemotherapy and were prospectively analyzed between March 2018 and March 2019. Repeat CT scan was acquired after the 3rd week of radiation. Patients in the study arm underwent replanning, whereas those in the control arm continued with the first IMRT plan. Assessment was done weekly till the end of treatment and at 1, 3, and 6 months post IMRT for disease response and toxicities. Tumor volume reduction rate (TVRR) and dose reduction to organs at risk were also recorded. Results: Complete response was observed in 90% and 96.7% patients in the control and study arms, respectively, at the end of 6 months. Insignificant differences were found between the two arms in terms of toxicities. Xerostomia was statistically significantly higher in the control arm at 6 months (P = 0.01). TVRR was found to be 31.85%. Dose to spinal cord, ipsilateral, and contralateral parotid reduced by 4.3%, 6%, and 2.2%, respectively, with ART. Conclusion: Mid-treatment adaptive replanning can help in better target coverage and minimize toxicities in HNC patients

Clinical application and research progress on dose-guided radiotherapy / 中华放射肿瘤学杂志

Dose-guided radiotherapy (DGRT) is a potentially useful adaptive radiotherapy method which dosimetrically compensates for interfractional non-rigid deformation.With the improvement of in-room imaging quality,development of the deformation registration algorithm and innovation of computer science,the wide application of DGRT might be realized.The purpose of this article is to briefly summarize the work flow,clinical application and prospect of DGRT.

Clinical application and research progress on dose-guided radiotherapy / 中华放射肿瘤学杂志

Dose-guided radiotherapy (DGRT) is a potentially useful adaptive radiotherapy method which dosimetrically compensates for interfractional non-rigid deformation. With the improvement of in-room imaging quality, development of the deformation registration algorithm and innovation of computer science, the wide application of DGRT might be realized. The purpose of this article is to briefly summarize the work flow, clinical application and prospect of DGRT.

Adaptive intensity-modulated radiotherapy in head-and-neck cancer: A volumetric and dosimetric study

Introduction and Objective: Anatomic and volumetric changes occur in head-and-neck cancer during fractionated radiotherapy (RT), and the actual dose received by patient is considerably different from the original plan. The purpose of this study is to evaluate volumetric and dosimetric changes occurring during radiation therapy. Patients and Methods: Ten patients of locally advanced head-and-neck cancer, 6 oropharynx, 3 larynx, and 1 hypopharynx underwent computed tomography (CT) simulation before treatment and after 4 weeks during RT treatment. Original plan (OPLAN) was generated based on initial CT scan for the entire course of treatment. The initial plan is implemented on the second planning CT scan, and the dose distribution is recalculated. Beam configuration of OPLAN was applied onto the second CT scan and then hybrid plan (HPLAN30) was generated. RPLAN30 is the intensity-modulated RT replan generated on the second CT scan for the remaining 30 Gy. Dose and volume parameters between OPLAN30 (based on the first CT scan for the remaining 30 Gy), HPLAN30, and RPLAN30 were compared. Results: The volume reduction of planning target volume (PTV), ipsilateral and contralateral parotid after 4 weeks of RT, was statistically significant (P < 0.05). D2% and V > 107% of PTV were higher in HPLAN than that of RPLAN (P < 0.05). Hybrid plans showed increase in delivered dose to spinal cord. Mid treatment replanning reduced doses to spinal cord (Dmax and D1%), which is statistically significant (P < 0.05). Mean doses to ipsilateral and contralateral parotid of RPLAN (21.4 Gy and 16.74 Gy, respectively) were reduced when compared to that of HPLAN (22.99 Gy and 22 Gy, respectively). Conclusion: Interim CT scanning and replanning (adaptive) improves target volume coverage and normal tissue sparing

Evaluation of the auto-segmentation based on self-registration and Atlas in adaptive radiotherapy for cervical cancer / 中华放射肿瘤学杂志

Objective To evaluate the accuracy and validate the feasibility of auto-segmentation based on self-registration and Atlas in adaptive radiotherapy for cervical cancer using MIM-Maestro software.Methods The CT scan images and delineation results of 60 cervical cancer patients were obtained to establish the Atlas template database.The planning CT (pCT) and replanning CT (rCT) images were randomly selected from 15 patients for the contouring of clinical target volume (CTV) and organs at risk (OAR) by an experienced radiation oncologist.The rCT images of 15 patients were auto-contoured using Atlas-based auto-segmentation (Atlas group),and mapping contours from the pCT to the rCT images was performed by rigid and deformable image registration (rigid group and deformable group).The time for the three methods of auto-segmentation was also recorded.The similarity of the auto-contours and reference contours was assessed using dice similarity coefficient (DSC),overlap index (OI),the average hausdorff distance (AHD) and the deviation of centroid (DC),and the results were statistically compared among three groups by using one-way analysis of variance.Results The mean time was 89.2 s,22.4 s and 42.6 s in the Atlas,rigid and deformable groups respectively.The DSC,OI and AHD for the CTV and rectum in the rigid and deformable groups significantly differed from those in the Atlas group (all P＜0.001).In the rigid and deformable groups,the OI for the intestine significantly differed from that in the Atlas group.The mean DSC for CTV was 0.89 in the rigid and deformable groups,and 0.76 in the Atlas group.The optimal delineation of the bladder,pelvis and femoral heads was obtained in the deformable group.Conclusions AIl three methods of auto-segmentation can automatically and rapidly contour the CTV and OARs.The performance in the deformable group is better than that in the rigid and Atlas groups.

Application of deformable image registration in adaptive radiotherapy for lung cancer / 中华放射肿瘤学杂志

Objective To evaluate the effect of different methods of deformable image registration on the dose evaluation in adaptive radiotherapy for lung cancer. Methods By using Raystation Ver4. 5 treatment planning system platform, two algorithms ( Hybrid-and Biomechanics-based deformable image registration) and two orders (CT images before and during radiotherapy as reference images) were adopted. Four deformable image registration methods were utilized to calculate the accumulative dose. Eleven patients of lung cancer received adaptive radiotherapy for 35. 0-61. 6 Gy were recruited. The mean doses of lung,heart and GTV and the D98 and D2 of GTV were statistically compared using four methods. Results With the four deformable image registration methods, the standard deviation of the mean lung dose of 11 lung cancer patients was ranged from 0. 07 to 0. 70 Gy,0. 01 to 0. 79 Gy for the mean heart dose,0. 01 to 2. 23 Gy for the mean GTV dose,0. 02 to 6. 51 Gy for the D98 of GTV and 0. 01 to 0. 97 Gy for the D2 of GTV,respectively. Conclusion The selection of deformable image registration method causes uncertainty to the calculation of accumulative dose during adaptive radiotherapy for lung cancer.

Research progress on predictive factors and time points of adaptive re-planning in intensity-modulated radiation therapy for head and neck cancer / 中华放射肿瘤学杂志

Adaptive re-planning contributes to improve the dosimetric uncertainties induced by anatomical changes during intensity-modulated radiation therapy (IMRT) for head and neck cancer patients and can enhance the local control rate and quality of life of patients.Previous research has demonstrated that presence of relatively large lymph nodes before treatment and significant loss of body weight during treatment are pivotal predictive factors of re-planning during IMRT.At 4 weeks after IMRT,the volume of the target and peripheral organ at risk (OAR) tends to steadily decrease.One to two cycles of adaptive re-planning are recommended at 3 or 4 weeks after IMRT.

Dosimetric evaluation of four adaptive IMRT strategies for head-neck cancer / 中华放射肿瘤学杂志

Objective To investigate the effects of numerous re-planning strategies on the anatomic and dosimetric outcomes of target volume and organs at risk (OARs) in patients with head and neck cancer receiving fractionated radiotherapy.Methods From 2015 to 2016,28 patients with head and neck cancer were enrolled in this study with Shandong Cancer Hospital,consisting of 19 patients with nasopharyngeal carcinoma, 4 patients with laryngocarcinoma, and 5 patients with carcinoma of the maxillary sinus.All of them received conventionally fractionated radiotherapy.Each patient had six weekly cone-beam CT (CBCT) scans, which were performed on the first day of every week, to obtain reference images.A virtual CT image was generated by registration of planning CT and each weekly CBCT image.The four re-planning strategies were used for the reconstruction of re-planned dose, while the initial planning was used as a reference.The weekly doses calculated using virtual CT were summed together to obtain the actual dose.The actual and initial planned doses were evaluated.The nonparametric Friedman test was used to evaluate the differences between multiple groups, and the differences between any two groups were analyzed by paired t test.Results The sizes of planning target volume, clinical target volume, and left/right parotid glands (PGs) changed significantly within the six weeks (P=0.041, 0.046, 0.024, and 0.017, respectively).For these four re-planning strategies, there were significant differences between the actual dose and the initial planned dose to the PGs (all P<0.05), with average values decreased by 5.02%, 11.17%, 12.08%, and 13.19%, respectively, compared with that in the reference strategy.Conclusions Re-planning during treatment course could ensure the sparing of OARs and allow for sufficient dose to the target volume.The higher the number of re-planning strategies, the more the actual dose is close to the initial planed dose;the efficiency of two re-planning strategies is the highest.

Image-guided determination of actual dose for nasopharyngeal carcinoma patients treated with helical tomotherapy / 中国肿瘤临床

Objective:To determine the law of dose variation in nasopharyngeal carcinoma patients treated with helical tomotherapy by observing the difference between the actual and planned doses of targets and at-risk organs in these patients. Methods:Ten naso-pharyngeal carcinoma patients were treated with helical tomotherapy. Each single dose distribution and the corresponding computed tomography (CT) images were transmitted to the commercial software MIMvista 6.50, which was used to perform deformable image registration on the CT images. The sum of the actual dose was then obtained by accumulating the single doses. The image-guided actu-al dose was denoted as Plan 2, and the initial plan was called Plan 1. The dose-volume histogram of the dose distribution of targets and at-risk organs in Plans 1 and 2 were compared. Results:The D98 and D95 doses of the planning gross target volume (PGTV) in Plan 2 were significantly lower than those in Plan 1. Compared with Plan 1, the Dmean and D50 doses of double parotids in Plan 2 were higher by 42.23%and 63.82%(P<0.001, P=0.001) on average, respectively, for the left parotid, as well as by 38.64%and 66.76%(P=0.002, 0.004), respectively, for the right parotid. The D2 dose of spinal cord in Plan 2 was significantly higher than that in Plan 1. The doses were higher by 16.49%on average (P=0.026). Conclusion:To achieve precise and individually adaptive radiotherapy, correcting the error between anatomy and placement during tomotherapy for nasopharyngeal carcinoma patients is necessary.

Volumetric and dosimetric comparison in adaptive radiotherapy for patients with head and neck cancer:a systematic review and Meta-analysis / 中华放射肿瘤学杂志

Objective To perform a systematic review and Meta-analysis on volumetric and dosimetric changes in target volumes and organs at risk (OARs) in adaptive radiotherapy (ART) for patients with head and neck cancer (HNC),and to investigate the role of ART in the treatment of HNC.Methods Literature retrieval was performed to include related studies,and the parameters of primary tumor,GTV-T and GTV-N,parotid volume,D95 and Dmean of target volumes,Dmean of ipsilateral and contralateral parotid volume (I-PG and C-PG),and Dmax of the spinal cord and brainstem.Results A total of 17 studies involving 336 patients were included in the meta-analysis.Primary tumor and parotid volume changed significantly.The volumes of GTV-T,GTV-N,and I-PG were significantly reduced during the 15-20th radiotherapy and after the 20th radiotherapy (P＜0.05),and the C-PG was significantly reduced after the 20th radiotherapy (P=0.004).The analysis of actual dose showed that the D95 and Dmean of primary tumor showed no significant differences,and during the 15-20th radiotherapy,the Dmax of the spinal cord was increased by 2.26 Gy (P=0.000),while the Dmax of the brainstem showed no significant changes before the 20th radiotherapy and was increased by 1.78 Gy after the 25th radiotherapy (P=0.020).In addition,the Dmean of I-PG was increased by 2 Gy during the 20-25th radiotherapy (P =0.0001),and the D of C-PG was increased before the 20th radiotherapy and showed no significant changes after the 25thradiotherapy (P=0.110).The dosimetric analysis of ART showed that the Dmax of the spinal cord and brainstem was reduced significantly (spinal cord:MD =-2.15,95％ CI-3.12 to-1.18,P=0.000;brainstem:MD =-2.20,95％ CI-3.32 to-1.09,P=0.000).The Dmean of I-PG was reduced by about 3.5 Gy,and the sensitivity analysis revealed that the results of Dmean of C-PG were unstable.Conclusions The volumes of primary tumors and parotid glands change significantly,and the actual doses of OARs (Dmax of the spinal cord and brainstem and Dmean of the parotid glands) significantly increase,while the doses of GTV-T and GTV-N show no significant changes.ART can effectively protect the OARs,and patients with locally advanced HNC who receive concurrent chemoradiotherapy can obtain good dose gains from ART plan performed during the 15-20th radiotherapy and at about the 25th radiotherapy.

Dosimetric study of adaptive radiotherapy in lung cancer / 安徽医科大学学报

Six patients with lung cancer treated with therapy were included. They were retrieved the image and re-planned by fraction 10. The volume of GTV was reduced (65. 59 ± 17. 09)% after three-stage treatments. The doses of target tumor were the same in three-stage treatments. Compared with IMRT, ART1 reduced V20 , V30 , MLD of whole lung by 2. 01%,2. 66%,241. 78 cGy(P=0. 005,0. 039,0. 026). Compared with ART1,ART2 further re-duced the indexes by 3. 21%,2. 97%,288. 64 cGy(P=0. 005,0. 013,0. 046). The doses of ipsilateral lung were reduced significantly (P<0. 05). But this was not for opposite lung. The dose V50,Dmean of heart and V55 of esopha-gus were similar to each plan. Dmean of esophagus with ART1 was smaller than with IMRT(261. 98 cGy,P=0. 002) and Dmean of esophagus with ART2 was smaller than with ART1(300. 43 cGy,P=0. 008). D2% and Dmean of spinal cord were reduced in turn significantly(P<0. 05).

Dosimetric study of adaptive radiotherapy for nasopharyngeal carcinoma / 安徽医科大学学报

Seven patients with nasopharyngeal carcinoma treated with ART were recruited . All patients were treated with SIB-IMRT regimen( named IMRT) . All patients had a second computed tomography scan after 10 fractions and a new plan based on this was initiated from fraction 11 ( ART1 ) . And a third CT scan after 21 fractions and a new plan based on this was initiated from fraction 22(ART2). When the treatment was finished,a fourth CT scan was made. Results revealed that the volumes of primary tumors and parotid glands regressed significantly after the teat-ment. The position of the parotid glands shifted medially an average of 4.5(1.6~9.2)mm during the plans. ART1 reduced mean dose to left parotid by 0. 42 Gy(1. 68%)(P=0.019) and right parotid by 0. 79 Gy (3.04%) (P=0. 013) over the IMRT alone. ART2 further reduced the mean left parotid dose by 0. 86 Gy or 3.5% ( P =0.001 ) and right parotid by 1 . 04 Gy or 4 . 13% ( P=0.035 ) .