提高乳腺癌区域淋巴结放射治疗精确性的研究及影像引导下放射治疗技术在早期乳腺癌治疗中的运用
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摘要
第一部分乳腺癌区域淋巴结的靶区勾画
目的:对关于乳腺区域淋巴结的勾画文献作一汇总,结合可操作性和可重复性进行调整,提出我们的勾画指南,用于后续的乳腺癌全局部完整的区域三维适形照射的技术优化。
材料与方法:在结合文献回顾和调整的基础上提出了基于平扫定位CT图像上的第Ⅰ,第Ⅱ,第Ⅲ腋窝淋巴结和肌间淋巴结,锁骨上淋巴结和内乳淋巴结的勾画细则。按照该原则对10例因浸润性乳腺癌接受肿块切除+第Ⅰ、第Ⅱ站腋窝淋巴结清扫的患者进行双侧各站腋窝淋巴结和患侧锁骨上淋巴结的靶区勾画和双侧解剖结构的比较。
结果:由同一研究者勾画患侧所有淋巴结引流的中位时间50分钟(40-90)。其中第Ⅰ,第Ⅱ和第Ⅲ站腋窝淋巴结的中位体积分别为60.2mL(37.3-119.8),17.5 mL(11.4-28.3)和12.6 mL(6.0-20.0),肌间淋巴结和锁骨上淋巴结的中位体积分别为7.0 mL(4.6-18.0)和22.5mL(18.4-32.1)。双侧各站腋窝淋巴结的深度比较都没有发现统计学意义。双侧体积比较发现只有第Ⅰ站腋窝淋巴结体积的差别有统计学意义(p＜0.001)。以腋静脉为界区分为腋静脉以上部分和以下部分并分别进行双侧体积对比发现,患侧和健侧总的腋静脉以下腋窝淋巴结的体积中位数分别为48.2mL(32.9-110.1)和116.7mL(77.6-221.4),差别有统计学意义(p＜0.001)。腋静脉以上淋巴结双侧体积差别没有统计学意义。
结论:平扫治疗位CT图像上,参考腋静脉水平可以较清晰地勾画各站乳腺癌区域淋巴结。双侧淋巴结体积的差异主要存在于腋静脉以下水平,从影像上证实了腋窝淋巴结清扫上界止于腋静脉水平,说明在高危患者腋静脉以上的区域淋巴结应该是术后放疗主要的靶区。
第二部分乳房保留手术后正向调强技术进行全乳照射的腋窝淋巴结剂量学研究
目的:研究在早期乳腺癌接受保乳手术以后,采用野中野正向调强技术照射单纯乳房患者的各站腋窝淋巴结受到的实际剂量分布,并分析腋窝单纯全乳照射时腋窝淋巴结剂量的因素。
材料与方法:分析了连续的21例因浸润性乳腺癌接受乳房保留手术+第Ⅰ/第Ⅱ站腋窝淋巴结清扫或前哨淋巴结活检以及导管内癌接受单纯肿块切除的患者的剂量学资料。所有患者的放疗计划都是采用“野中野”技术照射单纯全乳靶区。在定位CT图像上勾画患侧第Ⅰ-第Ⅲ站和肌间淋巴结靶区,同时勾画腋静脉,在三维放疗计划软件上逐站分析它们接受的剂量。
结果:腋静脉深度和该层面最大前后径存在线性相关性。第Ⅰ,第Ⅱ,第Ⅲ和肌间淋巴结被95%的处方剂量所包括的体积比均数分别为35.5%,5%,0和37.7%。在全乳PTV处方剂量50Gy/25次的情况下,上述各站淋巴结平均剂量的均数分别为32.4 Gy,12.9Gy,0和28.4Gy。腋静脉以下和以上淋巴结区域被95%的处方剂量包括的体积比均数分别44.9%和0.1%,平均剂量均数分别为38.8Gy和6.6Gy。乳房照射野的上界距离肱骨头的距离是影响腋静脉以下淋巴结区域平均剂量的唯一有统计学意义的因素,上界距肱骨头的距离＞2cm和≤2cm的患者中,腋静脉以下平均剂量的均数分别为36.7Gy和40.6Gy,p=0.006。
结论:全乳正向调强野中野技术对腋静脉以下的腋窝淋巴结的实际照射剂量是不可忽略的,它们被95%等剂量曲线包括的体积平均达到44.9%,必须在分析保乳接受“单纯”乳房照射的患者腋窝淋巴结控制率的时候予以考虑。但是全乳照射野无法给予腋窝淋巴结完整的照射。
第三部分定位CT图象上乳腺区域淋巴结解剖位置个体差异的分析
目的:在定位CT图像上获得国人完整的乳腺区域淋巴结解剖个体变异的范围,以评估既往基于二维骨性标志的照射技术对淋巴引流区的覆盖的合理性,并为整体的乳房/胸壁和区域淋巴结适形照射计划的优化建立基础。
材料与方法:在连续的50例因浸润性乳腺癌接受乳房改良根治术或乳房保留手术+第Ⅰ、第Ⅱ站腋窝淋巴结清扫的患者的定位CT图像上测定第Ⅰ-Ⅲ站腋窝淋巴结,肌间淋巴结和锁骨上淋巴结在皮下的最大深度。内乳淋巴结分别从胸锁关节,第1肋间,第2肋间和第3肋间测定内乳血管的最大深度和上述各层面的内乳血管的中心点距离胸骨中线的距离。测定腋静脉深度以及腋静脉水平和锁骨上淋巴结水平的最大前后径。
结果:其中第Ⅰ至第Ⅲ站腋窝淋巴结的平均深度分别为75mm,44mm和31mm,腋静脉深度的平均值为47mm,腋静脉水平前后径的均数为146mm,锁骨上淋巴结深度的均数为35mm,锁骨上水平的前后径均数为150mm。锁骨上淋巴结和前后径存在线性相关性,两者关系可以表达为:锁骨上淋巴结深度(cm)=前后径(cm)×0.28-0.64;腋静脉深度和该水平前后径之间亦存在线性相关关系,表达为:腋静脉深度(cm)=前后径(cm)*0.48-2.23。从胸锁关节,第1肋间至第3肋间的内乳血管平均分别为31.2mm,21.2mm,17.8mm和18.3mm。它们分别同该层面的前后径存在线性相关关系。内乳血管中心处距离胸骨中线的距离从胸锁关节至第三肋间的平均值分别为31.9mm,29.7mm,24.5mm和24.6mm。
结论:本研究证实了在中国女性乳腺癌患者,各站腋窝淋巴结,锁骨上淋巴结和内乳淋巴结存在重要的个体解剖差异,同时同一患者的内乳血管不同层面之间的深度和距离胸骨中线的距离都存在较大差异。这些差异提示在三维放疗计划上对区域淋巴结照射进行个体化的计划设计的必要性。
第四部分乳腺癌术后锁骨上和第Ⅲ站腋窝淋巴结照射的技术优化
目的:三维CT定位基础上,比较传统的单纯光子线,混合射线技术和CT优化的照射技术对锁骨上和第Ⅲ站腋窝淋巴结的剂量分布,评价既往照射技术的合理性,并探讨对锁骨上野进行放疗计划优化的方法。
材料与方法:对连续20例因浸润性乳腺癌接受乳房改良根治术或乳房保留手术+第Ⅰ/第Ⅱ站腋窝淋巴结清扫的患者在定位CT图像上勾画患侧第Ⅲ站腋窝淋巴结和锁骨上淋巴结区域,并进行4种不同放疗计划的剂量学比较。计划1:单纯6MVX线源皮距照射。计划2:简单混合射线技术,即6MVX线和9-12MEV电子束照射混合照射,计划1和2的剂量参考点均位于皮下3cm。计划3:CT优化的6MVX线“野中野”适形照射技术(field in field conformal technique,FIF),要求目标函数:100%的PTV接受90%的处方剂量,同时靶区内低于93%和高于110%处方剂量的区域不超过PTV的2%。计划4:CT优化的6MVX线野中野适形照射合并电子束(field in field conformal technique with electron,FIF+E),即在计划3技术基础上加入15%-20%权重的电子束。
结果:单纯6MVX线,FIF技术及野中野配合电子束技术FIF+E技术的PTV被95%处方剂量包括的体积比都达到了95%以上,而简单混合射线只有86.6%,P值＜0.001。两种CT优化技术显著降低了被110%等剂量线包括的体积比,p=0.003。单纯混合射线技术出现了最大的剂量冷点范围,PTV内低于93%处方剂量的体积比平均值达10%,FIF技术达到了最低的冷点体积比,为0.38%,p＜0.001。4种照射技术间的同侧肺V20,V10和V5都没有显著性差别。和FIF技术相比,加入电子束增加了105%和107%的体积比,没有显示出剂量学优势。
结论:常规设定参考点深度的单纯光子或混合射线技术无法对锁骨上和第Ⅲ站腋窝淋巴结提供满意的剂量覆盖且带来过大范围的高剂量区域。采用野中野技术的CT优化适形技术可以显著提高靶区被95%的处方剂量覆盖的体积比,降低处方剂量110%及以上的热点范围和93%处方剂量以下的冷点范围。建议在乳腺癌术后放疗的三维治疗计划中将锁骨上照射野整合到胸壁/乳房的照射中。
第五部分早期乳腺癌乳房保留术后部分乳腺加速照射的临床Ⅰ/Ⅱ期试验及影像引导下放射治疗的初步探索
目的:观察在低危的早期乳腺癌接受乳房保留治疗的患者中采用部分乳腺照射替代全乳照射的可行性和乳房的急性皮肤反应,并进行图像引导下的放射治疗(image guided radiation therapy,IGRT)技术在乳腺癌放射治疗中运用的初步探索。
材料与方法:入组条件包括年龄≥18岁-＜70岁,T1N0M0,接受乳房保留手术并达到阴性切缘(＞2mm),并获得知情同意的除外小叶癌的浸润性导管癌或导管内癌患者。在2008年6月至9月共入组患者6例。临床肿瘤靶区(CTV)指由金属标记范围加上1-1.5cm的边界;在此基础上再加上1cm边界为计划靶区(PTV)。放疗计划采用三维适形外照射,或以缩小的切线野为基础的正向调强技术,处方剂量为肿瘤量38.5Gy/10次,3.85Gy/次,一天照射2次,两次放疗间隔6小时以上。每次治疗前先按患者皮肤标识进行摆位,然后采集其锥形束CT(cone beam CT,CBCT)影像,进行在线配准及位置校准。配准方式包括骨配准,灰度配准和手动配准,实际治疗以手动配准结果进行校准。灰度配准后获得配准系数。
结果:全组病例部分乳腺照射PTV体积占全乳PTV的20%-40%,平均29.3%。5例患者采用单纯的6MV光子线照射,中位照射野3个(3-6个)。1例患者因肿瘤浅表混合使用了6MeV电子束。6例患者在治疗结束后都发生Ⅱ度皮肤反应,出现的中位时间是17天(15-20),没有Ⅲ度皮肤反应出现。4例患者的配准系数平均为-0.71,-0.71,-0.75和-0.86。每例患者在每次CBCT扫描后以3种不同配准方式各获得X,Y和Z轴方向的校准数值1组,汇总各个轴向以同一配准方式获得的10次校准均数,发现除了在Y轴方向有1例患者骨骼配准后校准距离超过0.8cm以外,其余所有患者各个轴向每一种配准方法的校准平均值都不超过0.6cm。
结论:三维适形外照射技术在早期乳腺癌乳房保留治疗以后的短程加速部分乳腺照射在剂量学和短期随访中证实了可行性。影像引导的放射治疗在加速部分乳腺照射技术中的运用证实在头脚,左右和上下六个方向分次照射之间的摆位误差平均数均没有超过0.8cm,说明从CTV到PTV的1cm边界是安全的。如何选择最佳的在线配准方式以及将配准系数与剂量的关系量化有待于进一步的研究。
Part I: Delineation of the regional lymph nodes in the treatment position for breast cancer patients receiving radiotherapy.
Purpose: To review the literature about the definition of the regional lymph nodes for breast cancer in CT images and to establish a practical guideline of lymph nodes delineation as to apply to the total local-regional treatment planning of radiotherapy.
Material and methods: A practical guideline based on plain CT scan in the treatment position was established regarding the delineation of level I, II, III, interpectoral nodes, supraclavicular nodes and internal mammary nodes. A total of 10 patients with infiltrative breast cancer treated with lumpectomy and level I and II axillary dissection were then delineated with this guideline and anatomical comparison was made with regard to the bilateral axillary nodes was made.
Results: Median delineation time for total regional nodes of ipsilateral side was 50 minutes(40-90). The median volume of ipsilateral level I, II and III axillary nodes was 60.2mL (37.3-119.8), 17.5 mL (11.4-28.3) and 12.6 mL (6.0-20.0) respectively. The median volume of interpectoral nodes and supraclavicular nodes was 7.0 mL (4.6-18.0 )and 22.5mL( 18.4-32.1)respectively. No statistically significant difference was found between the depths of different levels of axillary nodes in both sides. Only on level I of axillary nodes a statistical significant difference in volume was found between the dissected and undissected side(p<0.001). The median total volume of axillary nodes below the level of axillary vein was 48.2mL (32.9-110.1) on the dissected side and 116.7mL (77.6-221.4) on the contralateral side, (p<0.001). No statistically significant difference between both sides was found in the volume of axillary nodes above the level axillary vein.
Conclusion: Delineation of regional lymph nodes after breast cancer surgery on plain CT in treatment position is feasible. The significant difference of volume between the dissected and undissed sides was found below the level of axillary vein, which confirms the limit of axillary dissection. Regional nodes above axillary vein should be the primary target of post-operative radiotherapy in high-risk patients.
Part II Axillary lymph nodes dose for three-dimensional conformal radiotherapy with field in field technique of the whole breast.
Purpose: To evaluate the dose distribution of axillary lymph nodes with a field in field technique for whole breast in patients with breast cancer treated with breast conservative surgery, and to analysis the factors influencing the dose to the axillary nodes.
Material and methods: Twenty-one consecutive patients receiving breast conservative surgery with level I and II axillary dissection or sentinel node biopsy and lumpectomy only were evaluated. All patients underwent CT-based three-dimensional treatment planning with a field in field technique designed to treat the whole breast without regional lymph nodes. Delineation of level I-III and interpectoral lymph nodes was made on CT images, and a dosimetric analysis was made.
Results: A linear correlation between the maximum depth of axillary vein and anterior/posterior(A/P)diameter was found. At least ninety percent of the breast PTV received dose of 50Gy/25F. The 95% isodose line of the prescribed dose encompass an average the volume of level I, II, III and interpectoral nodes by 35.5%, 5%, 0 and 37.7% respectively. The mean dose to the level I, II, III and interpectoral nodes were 32.4 Gy, 12.9Gy, 0 and 28.4Gy respectively. The average percent of the lymph nodes encompassed by 95% isodose line below and above the axillary lymph nodes was 44.9% and 0.1% respectively, with average mean dose of 38.8Gy and 6.6Gy respectively. The distance between the upper limit of the radiation field and the humeral head was the only statistically significant factor influencing mean dose of axillary nodes below the level of axillary vein, with the average mean dose of 36.7Gy and 40.6Gy respectively in patients with distance >2cm and with distance≤2cm, (p=0.006).
Conclusion: Actual dose received by axillary lymph nodes below the level of axillary vein should not be neglected, an average of 44% of the volume received dose of 95% of the prescribed dose, and should be taken into consideration when local control of the axilla is analyzed after "breast only" irradiation. However, radiation field designed to treat the breast cannot deliver complete irradiation of the axilla.
Part III: Anatomical variability of regional lymph nodes of the breast on CT images in treatment position in patients with breast cancer receiving radiotherapy.
Purpose: To analyze the individual variability of regional lymph nodes of the breast in Chinese patients with breast cancer receiving radiotherapy and to explore the dosimetric consequence with traditional two-dimensional radiotherapeutic technique based on bony structure.
Material and methods: In consecutive 50 infiltrative breast cancer patients treated with breast conservative surgery with level I and II dissection or modified mastectomy, anatomical structure of the regional lymph nodes was measured on CT images in treatment position, including the maximum depth of level I, II, III, interpectoral nodes and supraclavicular nodes. The maximum depth of internal mammary vessel(IMV) and the distance between the center of the IMV to the mid-sternum was measured at the levels of sterno-clavicular articulation, first, second and third intercostals spaces. The maximum depth of the axillary vein and A/P diameter at the level of axillary vein and supraclavilar node was also measured.
Results: The average results of the maximum depth of the level I to III axillary lymph nodes were 75mm, 44mm and 31mm respectively. The average depth of the axillary vein was 47mm, and average A/P diameter at this level was 146mm. The average results of the maximum depth of the supraclavicular depth was 35mm, and average A/P diameter at this level was 150mm. A linear correlation between supraclavicular nodes and A/P diameter was found with approximation of depth of supraclavicular=0.28*A/P diameter-0.64(cm); also linear correlation between depth of axillary vein and A/P diameter was found which can be expressed as depth of axillary vein = 0.48*A/P diameter-2.23(cm). The maximum depth of IMV at the level of sterno-clavicular articulation, first, second and third intercostals space were 1.2mm, 21.2mm, 17.8mm and 18.3mm respectively. The distance between center of IMV to the mid-sternum at these levels were 31.9mm, 29.7mm, 24.5mm and 24.6mm respectively.
Conclusion: Our data confirmed important individual variability of the different levels of axillary nodes, supraclavicular nodes and internal mammary vessels exists in Chinese patients with breast cancer. Variability also exists with regard of the depth and distance to the mid-sternum of the internal mammary vessels at different levels. Individual treatment planning for regional nodal irradiation is necessary.
Part IV: Treatment optimization of the supraclavicular irradiation based on CT-delineated supraclavicular and level III of the axillary nodes.
Purpose: To compare the dose distribution of the supraclavicular irradiation on three-dimensional treatment planning using conventional photon or photon mixed with electron and CT-based optimization, as to explore the dosimetric outcome of target coverage between conventional and optimized planning.
Material and methods: Planning target volume of the supraclavicular and level III axillary lymph nodes was delineated on three-dimensional treatment planning CT in 20 patients treated with breast conservative surgery with axillary dissection or modified mastectomy. Dosimetric comparison was generated with 4 different treatment plans. Plan 1: 6MV photon prescribed to 3cm depth; plan 2: 6MV photon mixed with electron prescribed to 3cm depth; plan3: CT optimized field in field conformal technique, FIF with 6MV photon; plan 4: CT optimized FIF technique with 15-20% weight of electron, FIF+E. The optimization should reach 100% PTV received 90% or above of the prescribed dose, with no more than 2% of the PTV received dose inferior to 93% or superior to 110% of the prescribed dose.
Results: Coverage of the PTV by 95% of the prescribed dose was reached by all the three plans except for plan 2, which resulted in 86.6% only, p<0.001. Both CT optimized plans lowered the percent of the volume received by 110% of the isodose, p=0.003. Plan 2 showed the maximum "cold area", with an average of 10% of the PTV received dose below 93% of the prescribed dose, while FIF technique got the minimal "cold percent" of 0.38%, p<0.001. No difference of the ipsilateral lung V20, V10 and V5. Compared with FIF, FIF+E increased the volume received by isodose 105% and 107% and showed no dosimetric advantage.
Conclusion: Conventional field with photon or photon mixed with electron with fixed dose reference point resulted in inadequate coverage of the supraclavicular and level III axillary lymph nodes and an excess region of high dose. CT-based field in field technique can significantly improve the PTV coverage by 95% isodose, lower the percent of volume received above 110% or below 93% of the prescribed dose. Supraclavicular irradiation should be integrated into the treatment planning with breast/chest wall.
Part V A phase I/II clinical trial of accelerated partial breast irradiation in early-stage breast cancer patients treated with breast conservative surgery with initial experience of image-guided-radiation therapy
Purpose: This trial aims to evaluate the feasibility and acute skin toxicity of accelerated partial breast irradiation(APBI) in place of the whole breast irradiation in low-risk early-stage breast cancer patients treated with breast conservative surgery, and to explore the initial experience of image-guided radiation therapy(IGRT) in breast cancer irradiation.
Material and methods: Inclusion criteria included age≥18 years-old-<70 years-old, T1N0, infiltrative carcinoma or ductal carcinoma in situ(DCIS) except for lobular carcinoma, treated with breast conservative surgery with negative margin(>2mm), and informed consent. Six patients were enrolled between June 2008 and September 2008. Clinical target volume(CTV) is defined by surgical clips plus 1-1.5 cm, another 1cm is added to form the planning target volume(PTV). Three-dimensional treatment planning or field in field technique based on modified tangential fields were generated with prescribed dose of 38.5Gy/10F, with 3.85Gy/F, twice daily with interval above 6 hours. After set-up according to skin marker , an online cone beam CT (CBCT) image was acquired prior to each fraction in 5 patients. Online image registration and correction of the position was conducted. Three different types of registration was used: bony anatomy, grey and manual. Actual treatment delivery was corrected by manual registration. Registration index, cost value was acquired after each grey registration.
Conclusion: The ratio of APBI PTV/whole breast PTV was 20%-40% (median 29.3%). 6MV photon treatment with median fields of 3(3-6) was used in 5 patients, mixed electron of 6 MeV was applied in one patient. Grade II skin toxicity was found in all the 6 patients after 15-20(median 17) days of treatment. The average Cost value obtained in 4 patients were -0.71, -0.71, -0.75 and -0.86 respectively. A group of correction distance in the X, Y and Z axis with 3 different types of registration was obtained after each CBCT scan. An analysis of the average correction distance in each axis with each different type of registration showed no average correction distance exceed 0.6cm was found except for one patient with 0.8cm after bony registration in Y axis.
Conclusion: Accelerated partial breast irradiation with three-conformal external beam is feasible on dosimetric outcome and initial follow-up. The correction distance with image-guided radiation therapy showed the set-up error does not exceed 0.8cm in either X, Y or Z axis. This resulted confirmed the safety of 1 cm margin from CTV to PTV. Optimized online registration type and the quantification of dose distribution with Cost value await further investigation.
目的:对关于乳腺区域淋巴结的勾画文献作一汇总,结合可操作性和可重复性进行调整,提出我们的勾画指南,用于后续的乳腺癌全局部完整的区域三维适形照射的技术优化。
材料与方法:在结合文献回顾和调整的基础上提出了基于平扫定位CT图像上的第Ⅰ,第Ⅱ,第Ⅲ腋窝淋巴结和肌间淋巴结,锁骨上淋巴结和内乳淋巴结的勾画细则。按照该原则对10例因浸润性乳腺癌接受肿块切除+第Ⅰ、第Ⅱ站腋窝淋巴结清扫的患者进行双侧各站腋窝淋巴结和患侧锁骨上淋巴结的靶区勾画和双侧解剖结构的比较。
结果:由同一研究者勾画患侧所有淋巴结引流的中位时间50分钟(40-90)。其中第Ⅰ,第Ⅱ和第Ⅲ站腋窝淋巴结的中位体积分别为60.2mL(37.3-119.8),17.5 mL(11.4-28.3)和12.6 mL(6.0-20.0),肌间淋巴结和锁骨上淋巴结的中位体积分别为7.0 mL(4.6-18.0)和22.5mL(18.4-32.1)。双侧各站腋窝淋巴结的深度比较都没有发现统计学意义。双侧体积比较发现只有第Ⅰ站腋窝淋巴结体积的差别有统计学意义(p＜0.001)。以腋静脉为界区分为腋静脉以上部分和以下部分并分别进行双侧体积对比发现,患侧和健侧总的腋静脉以下腋窝淋巴结的体积中位数分别为48.2mL(32.9-110.1)和116.7mL(77.6-221.4),差别有统计学意义(p＜0.001)。腋静脉以上淋巴结双侧体积差别没有统计学意义。
结论:平扫治疗位CT图像上,参考腋静脉水平可以较清晰地勾画各站乳腺癌区域淋巴结。双侧淋巴结体积的差异主要存在于腋静脉以下水平,从影像上证实了腋窝淋巴结清扫上界止于腋静脉水平,说明在高危患者腋静脉以上的区域淋巴结应该是术后放疗主要的靶区。
第二部分乳房保留手术后正向调强技术进行全乳照射的腋窝淋巴结剂量学研究
目的:研究在早期乳腺癌接受保乳手术以后,采用野中野正向调强技术照射单纯乳房患者的各站腋窝淋巴结受到的实际剂量分布,并分析腋窝单纯全乳照射时腋窝淋巴结剂量的因素。
材料与方法:分析了连续的21例因浸润性乳腺癌接受乳房保留手术+第Ⅰ/第Ⅱ站腋窝淋巴结清扫或前哨淋巴结活检以及导管内癌接受单纯肿块切除的患者的剂量学资料。所有患者的放疗计划都是采用“野中野”技术照射单纯全乳靶区。在定位CT图像上勾画患侧第Ⅰ-第Ⅲ站和肌间淋巴结靶区,同时勾画腋静脉,在三维放疗计划软件上逐站分析它们接受的剂量。
结果:腋静脉深度和该层面最大前后径存在线性相关性。第Ⅰ,第Ⅱ,第Ⅲ和肌间淋巴结被95%的处方剂量所包括的体积比均数分别为35.5%,5%,0和37.7%。在全乳PTV处方剂量50Gy/25次的情况下,上述各站淋巴结平均剂量的均数分别为32.4 Gy,12.9Gy,0和28.4Gy。腋静脉以下和以上淋巴结区域被95%的处方剂量包括的体积比均数分别44.9%和0.1%,平均剂量均数分别为38.8Gy和6.6Gy。乳房照射野的上界距离肱骨头的距离是影响腋静脉以下淋巴结区域平均剂量的唯一有统计学意义的因素,上界距肱骨头的距离＞2cm和≤2cm的患者中,腋静脉以下平均剂量的均数分别为36.7Gy和40.6Gy,p=0.006。
结论:全乳正向调强野中野技术对腋静脉以下的腋窝淋巴结的实际照射剂量是不可忽略的,它们被95%等剂量曲线包括的体积平均达到44.9%,必须在分析保乳接受“单纯”乳房照射的患者腋窝淋巴结控制率的时候予以考虑。但是全乳照射野无法给予腋窝淋巴结完整的照射。
第三部分定位CT图象上乳腺区域淋巴结解剖位置个体差异的分析
目的:在定位CT图像上获得国人完整的乳腺区域淋巴结解剖个体变异的范围,以评估既往基于二维骨性标志的照射技术对淋巴引流区的覆盖的合理性,并为整体的乳房/胸壁和区域淋巴结适形照射计划的优化建立基础。
材料与方法:在连续的50例因浸润性乳腺癌接受乳房改良根治术或乳房保留手术+第Ⅰ、第Ⅱ站腋窝淋巴结清扫的患者的定位CT图像上测定第Ⅰ-Ⅲ站腋窝淋巴结,肌间淋巴结和锁骨上淋巴结在皮下的最大深度。内乳淋巴结分别从胸锁关节,第1肋间,第2肋间和第3肋间测定内乳血管的最大深度和上述各层面的内乳血管的中心点距离胸骨中线的距离。测定腋静脉深度以及腋静脉水平和锁骨上淋巴结水平的最大前后径。
结果:其中第Ⅰ至第Ⅲ站腋窝淋巴结的平均深度分别为75mm,44mm和31mm,腋静脉深度的平均值为47mm,腋静脉水平前后径的均数为146mm,锁骨上淋巴结深度的均数为35mm,锁骨上水平的前后径均数为150mm。锁骨上淋巴结和前后径存在线性相关性,两者关系可以表达为:锁骨上淋巴结深度(cm)=前后径(cm)×0.28-0.64;腋静脉深度和该水平前后径之间亦存在线性相关关系,表达为:腋静脉深度(cm)=前后径(cm)*0.48-2.23。从胸锁关节,第1肋间至第3肋间的内乳血管平均分别为31.2mm,21.2mm,17.8mm和18.3mm。它们分别同该层面的前后径存在线性相关关系。内乳血管中心处距离胸骨中线的距离从胸锁关节至第三肋间的平均值分别为31.9mm,29.7mm,24.5mm和24.6mm。
结论:本研究证实了在中国女性乳腺癌患者,各站腋窝淋巴结,锁骨上淋巴结和内乳淋巴结存在重要的个体解剖差异,同时同一患者的内乳血管不同层面之间的深度和距离胸骨中线的距离都存在较大差异。这些差异提示在三维放疗计划上对区域淋巴结照射进行个体化的计划设计的必要性。
第四部分乳腺癌术后锁骨上和第Ⅲ站腋窝淋巴结照射的技术优化
目的:三维CT定位基础上,比较传统的单纯光子线,混合射线技术和CT优化的照射技术对锁骨上和第Ⅲ站腋窝淋巴结的剂量分布,评价既往照射技术的合理性,并探讨对锁骨上野进行放疗计划优化的方法。
材料与方法:对连续20例因浸润性乳腺癌接受乳房改良根治术或乳房保留手术+第Ⅰ/第Ⅱ站腋窝淋巴结清扫的患者在定位CT图像上勾画患侧第Ⅲ站腋窝淋巴结和锁骨上淋巴结区域,并进行4种不同放疗计划的剂量学比较。计划1:单纯6MVX线源皮距照射。计划2:简单混合射线技术,即6MVX线和9-12MEV电子束照射混合照射,计划1和2的剂量参考点均位于皮下3cm。计划3:CT优化的6MVX线“野中野”适形照射技术(field in field conformal technique,FIF),要求目标函数:100%的PTV接受90%的处方剂量,同时靶区内低于93%和高于110%处方剂量的区域不超过PTV的2%。计划4:CT优化的6MVX线野中野适形照射合并电子束(field in field conformal technique with electron,FIF+E),即在计划3技术基础上加入15%-20%权重的电子束。
结果:单纯6MVX线,FIF技术及野中野配合电子束技术FIF+E技术的PTV被95%处方剂量包括的体积比都达到了95%以上,而简单混合射线只有86.6%,P值＜0.001。两种CT优化技术显著降低了被110%等剂量线包括的体积比,p=0.003。单纯混合射线技术出现了最大的剂量冷点范围,PTV内低于93%处方剂量的体积比平均值达10%,FIF技术达到了最低的冷点体积比,为0.38%,p＜0.001。4种照射技术间的同侧肺V20,V10和V5都没有显著性差别。和FIF技术相比,加入电子束增加了105%和107%的体积比,没有显示出剂量学优势。
结论:常规设定参考点深度的单纯光子或混合射线技术无法对锁骨上和第Ⅲ站腋窝淋巴结提供满意的剂量覆盖且带来过大范围的高剂量区域。采用野中野技术的CT优化适形技术可以显著提高靶区被95%的处方剂量覆盖的体积比,降低处方剂量110%及以上的热点范围和93%处方剂量以下的冷点范围。建议在乳腺癌术后放疗的三维治疗计划中将锁骨上照射野整合到胸壁/乳房的照射中。
第五部分早期乳腺癌乳房保留术后部分乳腺加速照射的临床Ⅰ/Ⅱ期试验及影像引导下放射治疗的初步探索
目的:观察在低危的早期乳腺癌接受乳房保留治疗的患者中采用部分乳腺照射替代全乳照射的可行性和乳房的急性皮肤反应,并进行图像引导下的放射治疗(image guided radiation therapy,IGRT)技术在乳腺癌放射治疗中运用的初步探索。
材料与方法:入组条件包括年龄≥18岁-＜70岁,T1N0M0,接受乳房保留手术并达到阴性切缘(＞2mm),并获得知情同意的除外小叶癌的浸润性导管癌或导管内癌患者。在2008年6月至9月共入组患者6例。临床肿瘤靶区(CTV)指由金属标记范围加上1-1.5cm的边界;在此基础上再加上1cm边界为计划靶区(PTV)。放疗计划采用三维适形外照射,或以缩小的切线野为基础的正向调强技术,处方剂量为肿瘤量38.5Gy/10次,3.85Gy/次,一天照射2次,两次放疗间隔6小时以上。每次治疗前先按患者皮肤标识进行摆位,然后采集其锥形束CT(cone beam CT,CBCT)影像,进行在线配准及位置校准。配准方式包括骨配准,灰度配准和手动配准,实际治疗以手动配准结果进行校准。灰度配准后获得配准系数。
结果:全组病例部分乳腺照射PTV体积占全乳PTV的20%-40%,平均29.3%。5例患者采用单纯的6MV光子线照射,中位照射野3个(3-6个)。1例患者因肿瘤浅表混合使用了6MeV电子束。6例患者在治疗结束后都发生Ⅱ度皮肤反应,出现的中位时间是17天(15-20),没有Ⅲ度皮肤反应出现。4例患者的配准系数平均为-0.71,-0.71,-0.75和-0.86。每例患者在每次CBCT扫描后以3种不同配准方式各获得X,Y和Z轴方向的校准数值1组,汇总各个轴向以同一配准方式获得的10次校准均数,发现除了在Y轴方向有1例患者骨骼配准后校准距离超过0.8cm以外,其余所有患者各个轴向每一种配准方法的校准平均值都不超过0.6cm。
结论:三维适形外照射技术在早期乳腺癌乳房保留治疗以后的短程加速部分乳腺照射在剂量学和短期随访中证实了可行性。影像引导的放射治疗在加速部分乳腺照射技术中的运用证实在头脚,左右和上下六个方向分次照射之间的摆位误差平均数均没有超过0.8cm,说明从CTV到PTV的1cm边界是安全的。如何选择最佳的在线配准方式以及将配准系数与剂量的关系量化有待于进一步的研究。
Part I: Delineation of the regional lymph nodes in the treatment position for breast cancer patients receiving radiotherapy.
Purpose: To review the literature about the definition of the regional lymph nodes for breast cancer in CT images and to establish a practical guideline of lymph nodes delineation as to apply to the total local-regional treatment planning of radiotherapy.
Material and methods: A practical guideline based on plain CT scan in the treatment position was established regarding the delineation of level I, II, III, interpectoral nodes, supraclavicular nodes and internal mammary nodes. A total of 10 patients with infiltrative breast cancer treated with lumpectomy and level I and II axillary dissection were then delineated with this guideline and anatomical comparison was made with regard to the bilateral axillary nodes was made.
Results: Median delineation time for total regional nodes of ipsilateral side was 50 minutes(40-90). The median volume of ipsilateral level I, II and III axillary nodes was 60.2mL (37.3-119.8), 17.5 mL (11.4-28.3) and 12.6 mL (6.0-20.0) respectively. The median volume of interpectoral nodes and supraclavicular nodes was 7.0 mL (4.6-18.0 )and 22.5mL( 18.4-32.1)respectively. No statistically significant difference was found between the depths of different levels of axillary nodes in both sides. Only on level I of axillary nodes a statistical significant difference in volume was found between the dissected and undissected side(p<0.001). The median total volume of axillary nodes below the level of axillary vein was 48.2mL (32.9-110.1) on the dissected side and 116.7mL (77.6-221.4) on the contralateral side, (p<0.001). No statistically significant difference between both sides was found in the volume of axillary nodes above the level axillary vein.
Conclusion: Delineation of regional lymph nodes after breast cancer surgery on plain CT in treatment position is feasible. The significant difference of volume between the dissected and undissed sides was found below the level of axillary vein, which confirms the limit of axillary dissection. Regional nodes above axillary vein should be the primary target of post-operative radiotherapy in high-risk patients.
Part II Axillary lymph nodes dose for three-dimensional conformal radiotherapy with field in field technique of the whole breast.
Purpose: To evaluate the dose distribution of axillary lymph nodes with a field in field technique for whole breast in patients with breast cancer treated with breast conservative surgery, and to analysis the factors influencing the dose to the axillary nodes.
Material and methods: Twenty-one consecutive patients receiving breast conservative surgery with level I and II axillary dissection or sentinel node biopsy and lumpectomy only were evaluated. All patients underwent CT-based three-dimensional treatment planning with a field in field technique designed to treat the whole breast without regional lymph nodes. Delineation of level I-III and interpectoral lymph nodes was made on CT images, and a dosimetric analysis was made.
Results: A linear correlation between the maximum depth of axillary vein and anterior/posterior(A/P)diameter was found. At least ninety percent of the breast PTV received dose of 50Gy/25F. The 95% isodose line of the prescribed dose encompass an average the volume of level I, II, III and interpectoral nodes by 35.5%, 5%, 0 and 37.7% respectively. The mean dose to the level I, II, III and interpectoral nodes were 32.4 Gy, 12.9Gy, 0 and 28.4Gy respectively. The average percent of the lymph nodes encompassed by 95% isodose line below and above the axillary lymph nodes was 44.9% and 0.1% respectively, with average mean dose of 38.8Gy and 6.6Gy respectively. The distance between the upper limit of the radiation field and the humeral head was the only statistically significant factor influencing mean dose of axillary nodes below the level of axillary vein, with the average mean dose of 36.7Gy and 40.6Gy respectively in patients with distance >2cm and with distance≤2cm, (p=0.006).
Conclusion: Actual dose received by axillary lymph nodes below the level of axillary vein should not be neglected, an average of 44% of the volume received dose of 95% of the prescribed dose, and should be taken into consideration when local control of the axilla is analyzed after "breast only" irradiation. However, radiation field designed to treat the breast cannot deliver complete irradiation of the axilla.
Part III: Anatomical variability of regional lymph nodes of the breast on CT images in treatment position in patients with breast cancer receiving radiotherapy.
Purpose: To analyze the individual variability of regional lymph nodes of the breast in Chinese patients with breast cancer receiving radiotherapy and to explore the dosimetric consequence with traditional two-dimensional radiotherapeutic technique based on bony structure.
Material and methods: In consecutive 50 infiltrative breast cancer patients treated with breast conservative surgery with level I and II dissection or modified mastectomy, anatomical structure of the regional lymph nodes was measured on CT images in treatment position, including the maximum depth of level I, II, III, interpectoral nodes and supraclavicular nodes. The maximum depth of internal mammary vessel(IMV) and the distance between the center of the IMV to the mid-sternum was measured at the levels of sterno-clavicular articulation, first, second and third intercostals spaces. The maximum depth of the axillary vein and A/P diameter at the level of axillary vein and supraclavilar node was also measured.
Results: The average results of the maximum depth of the level I to III axillary lymph nodes were 75mm, 44mm and 31mm respectively. The average depth of the axillary vein was 47mm, and average A/P diameter at this level was 146mm. The average results of the maximum depth of the supraclavicular depth was 35mm, and average A/P diameter at this level was 150mm. A linear correlation between supraclavicular nodes and A/P diameter was found with approximation of depth of supraclavicular=0.28*A/P diameter-0.64(cm); also linear correlation between depth of axillary vein and A/P diameter was found which can be expressed as depth of axillary vein = 0.48*A/P diameter-2.23(cm). The maximum depth of IMV at the level of sterno-clavicular articulation, first, second and third intercostals space were 1.2mm, 21.2mm, 17.8mm and 18.3mm respectively. The distance between center of IMV to the mid-sternum at these levels were 31.9mm, 29.7mm, 24.5mm and 24.6mm respectively.
Conclusion: Our data confirmed important individual variability of the different levels of axillary nodes, supraclavicular nodes and internal mammary vessels exists in Chinese patients with breast cancer. Variability also exists with regard of the depth and distance to the mid-sternum of the internal mammary vessels at different levels. Individual treatment planning for regional nodal irradiation is necessary.
Part IV: Treatment optimization of the supraclavicular irradiation based on CT-delineated supraclavicular and level III of the axillary nodes.
Purpose: To compare the dose distribution of the supraclavicular irradiation on three-dimensional treatment planning using conventional photon or photon mixed with electron and CT-based optimization, as to explore the dosimetric outcome of target coverage between conventional and optimized planning.
Material and methods: Planning target volume of the supraclavicular and level III axillary lymph nodes was delineated on three-dimensional treatment planning CT in 20 patients treated with breast conservative surgery with axillary dissection or modified mastectomy. Dosimetric comparison was generated with 4 different treatment plans. Plan 1: 6MV photon prescribed to 3cm depth; plan 2: 6MV photon mixed with electron prescribed to 3cm depth; plan3: CT optimized field in field conformal technique, FIF with 6MV photon; plan 4: CT optimized FIF technique with 15-20% weight of electron, FIF+E. The optimization should reach 100% PTV received 90% or above of the prescribed dose, with no more than 2% of the PTV received dose inferior to 93% or superior to 110% of the prescribed dose.
Results: Coverage of the PTV by 95% of the prescribed dose was reached by all the three plans except for plan 2, which resulted in 86.6% only, p<0.001. Both CT optimized plans lowered the percent of the volume received by 110% of the isodose, p=0.003. Plan 2 showed the maximum "cold area", with an average of 10% of the PTV received dose below 93% of the prescribed dose, while FIF technique got the minimal "cold percent" of 0.38%, p<0.001. No difference of the ipsilateral lung V20, V10 and V5. Compared with FIF, FIF+E increased the volume received by isodose 105% and 107% and showed no dosimetric advantage.
Conclusion: Conventional field with photon or photon mixed with electron with fixed dose reference point resulted in inadequate coverage of the supraclavicular and level III axillary lymph nodes and an excess region of high dose. CT-based field in field technique can significantly improve the PTV coverage by 95% isodose, lower the percent of volume received above 110% or below 93% of the prescribed dose. Supraclavicular irradiation should be integrated into the treatment planning with breast/chest wall.
Part V A phase I/II clinical trial of accelerated partial breast irradiation in early-stage breast cancer patients treated with breast conservative surgery with initial experience of image-guided-radiation therapy
Purpose: This trial aims to evaluate the feasibility and acute skin toxicity of accelerated partial breast irradiation(APBI) in place of the whole breast irradiation in low-risk early-stage breast cancer patients treated with breast conservative surgery, and to explore the initial experience of image-guided radiation therapy(IGRT) in breast cancer irradiation.
Material and methods: Inclusion criteria included age≥18 years-old-<70 years-old, T1N0, infiltrative carcinoma or ductal carcinoma in situ(DCIS) except for lobular carcinoma, treated with breast conservative surgery with negative margin(>2mm), and informed consent. Six patients were enrolled between June 2008 and September 2008. Clinical target volume(CTV) is defined by surgical clips plus 1-1.5 cm, another 1cm is added to form the planning target volume(PTV). Three-dimensional treatment planning or field in field technique based on modified tangential fields were generated with prescribed dose of 38.5Gy/10F, with 3.85Gy/F, twice daily with interval above 6 hours. After set-up according to skin marker , an online cone beam CT (CBCT) image was acquired prior to each fraction in 5 patients. Online image registration and correction of the position was conducted. Three different types of registration was used: bony anatomy, grey and manual. Actual treatment delivery was corrected by manual registration. Registration index, cost value was acquired after each grey registration.
Conclusion: The ratio of APBI PTV/whole breast PTV was 20%-40% (median 29.3%). 6MV photon treatment with median fields of 3(3-6) was used in 5 patients, mixed electron of 6 MeV was applied in one patient. Grade II skin toxicity was found in all the 6 patients after 15-20(median 17) days of treatment. The average Cost value obtained in 4 patients were -0.71, -0.71, -0.75 and -0.86 respectively. A group of correction distance in the X, Y and Z axis with 3 different types of registration was obtained after each CBCT scan. An analysis of the average correction distance in each axis with each different type of registration showed no average correction distance exceed 0.6cm was found except for one patient with 0.8cm after bony registration in Y axis.
Conclusion: Accelerated partial breast irradiation with three-conformal external beam is feasible on dosimetric outcome and initial follow-up. The correction distance with image-guided radiation therapy showed the set-up error does not exceed 0.8cm in either X, Y or Z axis. This resulted confirmed the safety of 1 cm margin from CTV to PTV. Optimized online registration type and the quantification of dose distribution with Cost value await further investigation.
引文
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10 Baglan KC,Sharpe NB,Jaffray D,et al.Accelerated partial breast irradiation using 3D conformal radiation therapy(3D-CRT).Int J Radiat Oncol Biol Phys,2003:55:302-311.
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17 Ragaz J,Olivotto IA,Spinelli JJ et al.Locoregional radiation therapy in patients with high risk breast cancer receiving adjuvant chemotherapy:20-year results from the British Columbia randomized trial.J Natl Cancer Inst.2005,97:116-126
18 EBCTCG.Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer:an overview of the randomized trials.Lancet.2000,355,1757-1770
19 EBCTCG.Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival:an overview of the randomized trials.Lancet.2005,366:2087-2106
20 Giordano SH,Kuo YF,Freeman JL et al.Risk of cardiac death after adjuvant radiotherapy for breast cancer.J Natl Cancer Inst.2005.97:419-424
21 周卫兵,冯炎,陈佳艺等。 术后放疗在伴有腋窝淋巴结1～3个转移的T1～T2期乳腺癌中的作用。中华放射肿瘤学杂志2006,15(5):396-400
2 Bentel G, Marks LB, Hardenbergh PH et al. Variability of the depth of supraclavicular and axillary lymph nodes in patients with breast cancer: is a posterior axillary boost field necessary[J].Int J Radiat Oncol Biol Phys, 2000,47(3): 755-758.
3 Kirova YM, Servois V, Campana F et al. CT-scan based localization of the internal mammary chain and supra clavicular nodes for breast cancer radiation therapy planning[J]. Radiotherapy and Oncology, 2006, 79(3), 310-315.
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14 Edmundson GK, Vicini FA, Chen PY, et al. Dosimetric characteristics of the MammoSite RTS,a new breast brachytherapy applicator[J]. Int J Radiat Oncol Biol Phys, 2002, 52(4): 1132-1139.
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14 Giordano SH,Kuo YF,Freeman JL et al.Risk of cardiac death after adjuvant radiotherapy for breast cancer[J].J Natl Cancer Inst.2005,97(6):419-424.
15 Pierce LJ,Butler JB,Martel MK,et al.Postmastectomy radiotherapy of the chest wall:dosimetric comparison of common techniques[J].Int J Radiat Oncol Biol Phys,2002,52(5):1220-1230.
1 Overgaard M,Hansen PS,Overgaard J et al.Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy[J].N Engl J Med,1997,337(14):945-955.
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4 Ragaz J,Olivotto IA,Spinelli JJ et al.Locoregional radiation therapy in patients with high risk breast cancer receiving adjuvant chemotherapy:20-year results from the British Columbia randomized trial[J].J Natl Cancer Inst,2005,97(1):116-126.
5 EBCTCG.Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer:an overview of the randomized trials[J].Lancet.2000,355(9217):1757-1770.
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17 Liengsawangwong R,Yu TK,Sun T1 et al.Treatment optimization using computed tomography-delineated targets should be used for supraclavicular irradiation for breast cancer[J].Int J Radiat Oncol Biol Phys,2007,69(3):711-715.
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1 Vicini FA,Chen PY,Fraile M,et al.Low-dose rate brachytherapy as the sole radiation modality in the treatment of patients with early-stage breast cancer treated with breast-conserving therapy:preliminary results of a pilot trial.Int J Radiat Oncol Biol Phys,1997,38(2):301-310.
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8 Vicini FA,Chen PY,Fraile M,et al.Low-dose rate brachytherapy as the sole radiation modality in the treatment of patients with early-stage breast cancer treated with breast-conserving therapy:preliminary results of a pilot trial,Int J Radiat Oncol Biol Phys,1997,38:301-310.
9 Baglan KC,Martinez AA,Frazier RC,et al.The use of high-dose-rate brachytherapy alone after lumpectomy in patients with early-stage breast cancer treated with breast-conserving therapy.Int J Radiat Oncol Biol Phys,2001,50:1003-1011.
10 Baglan KC,Sharpe NB,Jaffray D,et al.Accelerated partial breast irradiation using 3D conformal radiation therapy(3D-CRT).Int J Radiat Oncol Biol Phys,2003:55:302-311.
11 Edmundson GK,Vicini FA,Chen PY,et al.Dosimetric characteristics of the MammoSite RTS,a new breast brachytherapy applicator,Int J Radiat Oncol Biol Phys,2002,52:1132-9.
12 Fyles AW,McCready DR,Manchul LA et al.Tamoxifen with or without irradiation in women 50 years of age or older with early breast cancer.N Engl J Med,2004:351(10):963-970
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14 Overgaard M,Hansen PS,Overgaard J et al.Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy.N Engl J Med 1997,337:945-955
15 Overgaard M,Jensen MB,Overgaard J et al.Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients adjuvant tamoxifen:Danish Breast Cancer Cooperative Group DBCG 82c randomized trial.Lancet.1999,353:1641-1648
16 Ragaz J,Jackson SM,Le N et al.Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer.N Engl J Med.1997,337:956-962
17 Ragaz J,Olivotto IA,Spinelli JJ et al.Locoregional radiation therapy in patients with high risk breast cancer receiving adjuvant chemotherapy:20-year results from the British Columbia randomized trial.J Natl Cancer Inst.2005,97:116-126
18 EBCTCG.Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer:an overview of the randomized trials.Lancet.2000,355,1757-1770
19 EBCTCG.Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival:an overview of the randomized trials.Lancet.2005,366:2087-2106
20 Giordano SH,Kuo YF,Freeman JL et al.Risk of cardiac death after adjuvant radiotherapy for breast cancer.J Natl Cancer Inst.2005.97:419-424
21 周卫兵,冯炎,陈佳艺等。 术后放疗在伴有腋窝淋巴结1～3个转移的T1～T2期乳腺癌中的作用。中华放射肿瘤学杂志2006,15(5):396-400
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