质子束在肝细胞肝癌治疗中的临床应用研究
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摘要
研究背景：
肝细胞肝癌(hepatocellular carcinoma, HCC)的发病率在全球呈上升趋势,其在欧美发病率较低,亚洲的发病率较高。HCC是我国的高发肿瘤之一,其恶性程度较高,死亡率亦高。早期肝细胞肝癌患者多以手术切除为主,但约有80%的肝细胞肝癌患者因发现时已处晚期或由于肝功能差及腹水等限制不适合手术治疗。近年来开展的肝移植治疗对于部分不能切除的晚期肝细胞肝癌患者提供了一个新的治疗手段,但手术创伤大、术后排异、移植后肝癌复发及可供移植的肝脏来源缺乏使肝移植手术的开展受到一定限制。经皮肝穿刺瘤内注射无水乙醇法(percutaneous ethanol injection therapy, PEIT)、肝动脉介入栓塞化疗(transarterial chemoembolization, TACE)、射频消融(radiofrequency ablation, RFA)和微波凝固治疗(microwave coagulation therapy, MCT)等方法的应用使肝细胞肝癌综合治疗的疗效有了改善,但上述治疗方法受到肿瘤的大小、数量及其与血管关系的限制。
常规放射治疗由于正常肝脏组织的耐受量较低,很难给予肿瘤根治剂量,且常会引起放射性肝功能损害甚至放射性肝病(radiation-induced liver disease, RILD)。随着放射治疗技术的发展,X线三维适形放射治疗(3-dimensional conformal radiation therapy,3D-CRT)使RILD的发生率明显降低,但正常肝脏的受照射剂量仍较高。质子束具有较好的物理学特性,其最大特征是进入人体内形成尖锐的Bragg峰。在形成峰之前的低平坦段为坪(plateau),峰后则是一个突然减弱陡直的尾。由于Bragg峰的宽度较小,所以一般都将它扩展后形成与肿瘤大小一致的扩展Bragg峰(spread out Bragg peak, SOBP)用于临床治疗。因其能量传递是以量子的形式释放,其射程具有能量依赖性,可根据肿瘤在体内的深度,使质子束精准地定位在肿瘤病灶处,以使肿瘤受到较高的照射剂量而正常组织受到较低的照射剂量,可进一步提高治疗增益比。从而得以实现在给予靶区高剂量的同时降低正常肝组织及其周围器官的并发症,以期提高肝癌的局部控制率和生存率[5-8]。
目的：
1对肝细胞肝癌患者质子束治疗(proton beam therapy, PBT)的剂量分布进行研究并与X线三维适形放射治疗(3-dimensional conformal radiation therapy,3D-CRT)及调强放射治疗(intensity-modulated radiation therapy, IMRT)计划进行剂量学分布对比研究,比较其正常肝脏组织的平均剂量(Dmean)、V10Gy、V20Gy和V30Gy(分别为正常肝脏组织受到10Gy、20Gy、30Gy以上照射剂量时的体积百分比)和危及器官(organs at risks, OARs)的照射剂量以评价三种治疗方法在靶区剂量分布和正常组织受照射剂量分布的差异。
2对质子束治疗肝细胞肝癌的临床疗效、放射引起的副反应进行评估,探讨质子束治疗肝细胞肝癌的安全性、可行性和有效性及其影响预后的因素。
材料与方法：
1 2005年4月-2008年5月间在淄博万杰质子治疗中心进行质子束治疗的拒绝手术治疗或不能手术切除的Ⅰ-ⅡA期肝细胞肝癌患者22例,其中男19例,女例3,平均年龄52岁。临床Ⅰ期肝细胞肝癌患者10例(肿瘤直径≤5cm),临床ⅡA期患者12例(肿瘤直径5.1-l0cm)。不能手术切除的原因包括肿瘤侵及血管、多发病灶、年龄大或心肺功能不全及病人拒绝手术治疗。诊断依据临床表现、实验室检查、影像学和细胞学检查,全部患者均符合2001年9月在广州召开的第八届全国肝癌学术会议上由中国抗癌协会肝癌专业委员会制定的“肝细胞肝癌的临床诊断与分期标准”。其中17例经病理证实,5例未能行穿刺活检者,其AFP≥400μg/L并经影像学检查及临床随访观察证实。治疗计划系统采用Varian公司的Eclipse Proton、Eclipse Photon和Eclipse Inverse IMRT治疗计划系统(Varian Medical System, Inc., Palo Alto, CA, USA)。体位固定及CT扫描：患者采取仰卧位,用负压垫固定。对在模拟定位机下观察呼吸动度大于lcm的患者采用腹部加压。采用8排螺旋CT进行常规扫描(GE Medical Systems Inc., Milwaukee, WI, USA),扫描层厚5.Omm。在相同固定体位进行常规CT平扫和增强扫描。以常规平扫CT图像实施剂量计算以免增强剂对阻止本领(stopping power)的校正造成影响。Ⅰ期肝细胞肝癌患者总剂量为66Gy,推量至86Gy；ⅡA期肝细胞肝癌患者总剂量为60Gy,推量至72Gy。为了便于比较,三种治疗计划采用相同的总剂量和剂量分割模式。分别设计3D-CRT、IMRT和PBT治疗计划,通过剂量—体积直方图(dose-volume histograms, DVHs)比较其正常肝脏和危及器官剂量分布的差异。为了便于比较不同照射方法的剂量分布,三种治疗计划的靶区勾画范围相同,均参考融合图像在平扫CT图像上勾画大体肿瘤体积(gross tumor volume, GTV), GTV外扩0.5cm为临床靶体积(clinical target volume, CTV)。根据呼吸动度的不同,在CTV基础上头脚方向外扩1.5～2.5cm,左右方向外扩1.0～1.5cm为计划靶体积(planning target volume, PTV)。对正常肝组织、脊髓、右肾和胃作为危及器官进行勾画并对图像进行三维重建。3D-CRT和PBT分别采用5～6个和2～3个共面照射野。对ⅡA期肝细胞肝癌患者进行了IMRT计划设计,采用静态调强,5个共面照射野。PBT治疗计划根据肿瘤形状、组织密度、肿瘤后缘形状及体表轮廓针对每个照射野需加用相应的铜挡块和聚乙烯制成的补偿器。质子束由等时回旋加速器(IBA Inc., Belgium)产生固定能量为230MeV的质子束,通过降能器得到能量范围为70-230MeV的质子束。由治疗计划系统计算所需质子束的最大能量和所需展宽的Bragg峰(spread out Bragg peak, SOBP),由射程调制器获得展宽的Bragg峰以使得高剂量分布区与靶区有较好的适形度。治疗采用双散射模式。以90%～95%等剂量线覆盖PTV。为了保证处方剂量的准确性和一致性便于比较,参照国际放射单位与测量委员会(the international commission on radiation units and measurements, ICRU)62号报告,三种治疗计划采用同一方法进行归一,使90%～95%的等剂量线覆盖PTV。PBT采用的计量单位为60Co Y射线的等效剂量(cobalt Gray equivalent, CGE),其相对生物效应(relative biological effectiveness, RBE)按1.1计算。采用DVHs图对三种计划进行评价,评价指标为(1)正常肝组织的受照射剂量：肝脏平均剂量、V10Gy、V20Gy和V30Gy;(2) OARs的受照射剂量：脊髓最大点剂量、右肾和胃的平均受照射剂量。统计学方法采用配对t检验比较三种计划剂量分布的差异。
2 2005年4月至2010年5月间在淄博万杰质子治疗中心进行质子束治疗的拒绝手术治疗或不能手术切除的肝细胞肝癌者75例,男性64例,女性11例,年龄27-91岁,中位年龄49岁。其中ⅠA-ⅡA期患者26例,ⅡB期及以上的患者49例。根据Child-Pugh肝功能分级标准,Child-Pugh肝功能A级的患者43例,Child-Pugh肝功能B级的患者32例；每次分割剂量2-6Gy,照射次数10-32次,总剂量50～78Gy,每周3-6次。
结果：
1Ⅰ期肝细胞肝癌患者3D-CRT的总剂量为66Gy时,其肝脏平均剂量(Dmean)为13.01Gy,其V10Gy、V20Gy和V30Gy分别为51.89%、36.13%和21.24%,而PBT总剂量为66Gy时,其Dmean、V10Gy、V20Gy和V30Gy则分别为6.34Gy、30.23%、17.86%和10.66%(p<0.002)。当总剂量提高至86Gy时,3D-CRT的Dmean、V10Gy、V20Gy和V30Gy分别为16.91Gy、67.51%、46.84%和27.61%；而PBT的Dmean、V10Gy、V20Gy和V30Gy则分别为8.26Gy、39.31%、23.22%和13.86% (p<0.002)。与3D-CRT总剂量为66Gy时相比,PBT在总剂量提升至86Gy时,其Dmean、V10Gy、V20Gy和V30Gy仍明显低于3D-CRT(p<0.042)。ⅡA期患者3D-CRT总剂量为60Gy时,其Dmean、V10Gy、V20Gy和V30Gy分别为29.18Gy、72.25%、58.17%和44.01%；IMRT的Dmean、V10Gy、V20Gy和V30Gy分别为24.92Gy、73.32%、56.15%和37.75%,而PBT则分别为16.28Gy、43.93%、33.54%和22.78%(p<0.002)。当总剂量提高至72Gy时,3D-CRT的Dmean、V10Gy、V20Gy和V30Gy分别为35.02Gy、86.70%、69.80%和52.81%; IMRT的Dmean、V10Gy、V20Gy和V30Gy分别为29.90Gy,87.98%,67.74%and 45.30%,而PBT的Dmean、V10Gy、V20Gy和V30Gy分别为19.54Gy、52.72%、40.25%和27.34%(p<0.002)。与3D-CRT总剂量为60Gy时相比,PBT在总剂量提升至72Gy时,其Dmean、V10Gy、V20Gy和V30Gy仍明显低于3D-CRT和IMRT(p<0.05)。22例患者采用PBT可使脊髓、右侧肾脏和胃的照射剂量较3D-CRT明显降低(p<0.002)。与IMRT相比,PBT降低了Dmean、V10Gy、V20Gy和V30Gy及右侧肾脏和胃的受照射剂量(p<0.05),脊髓的受照射剂量两者无显著性差异(p>0.05)。
2 75例肝细胞肝癌患者的完全缓解率为26.7%,部分缓解率为58.7%,总有效率为85.3%；1和3年总生存率分别为72.2%和36.4%。单因素分析显示临床分期、Child-Pugh肝功能分级、有无门静脉癌栓、肿瘤的大小、肿瘤单发或多发及靶区的生物等效剂量与生存率呈显著相关性(p<0.01)。Cox多因素回归分析显示,肿瘤分期、癌栓、肿瘤单发或多发是影响预后的因素(p<0.05)。
结论：
1与3D-CRT相比,PBT可使Ⅰ-ⅡA期肝细胞肝癌患者肝脏的平均剂量、V10Gy、V20Gy和V30Gy和OARs的照射剂量明显降低；当PBT的总剂量较3D-CRT提升20%～30.3%时,其肝脏的平均剂量及V10Gy、V20Gy和V30Gy仍较3D-CRT明显降低。与IMRT相比,PBT使ⅡA期患者的Dmean、V10Gy、V20Gy、V30Gy、右侧肾脏和胃的受照射剂量明显降低,脊髓的受量两者无显著性差异。与3D-CRT相比,IMRT降低了ⅡA期患者的脊髓受受照射剂量,其对正常肝脏、右肾和胃的照射剂量未见明显差异。
2质子束治疗是肝细胞肝癌的安全、有效的治疗手段,患者具有良好的耐受性。肿瘤分期、癌栓、肿瘤单发或多发是独立预后因子。
Background
The prevalence rates of hepatocellular carcinoma (HCC) is rising worldwide, it is one of the most frequent cause of death in China. Although surgical resection remains the most standard and reliable curative modality for the treatment of HCC, a retrospective study demonstrated only 18% of the patients were surgically resectable, more than 80% of HCC patients are inoperable at the time of diagnosis owing to advanced tumors, ascites or coexisting cirrhosis. The management of technically unresectable and medically inoperable HCC remains challenging. HCC is highly resistant to currently available chemotherapeutic drugs. Liver transplantation might be better than resection for some of the unresectable patients. However, recurrence of malignant tumor within 6 to 24 months has been the usual outcome and immunosuppressive medication seems contradicting with respect to tumor control; this option is also dependent on the availability of vital organs, which are in short supply. Several treatment modalities are currently available for patients with HCC such as PEIT(percutaneous ethanol injection therapy), TACE(transarterial chemoembolization), RFA (radiofrequency ablation) and MCT (microwave coagulation therapy), although limitations of the above techniques relate to tumor size, number and location relative to blood vessels. A less-invasive and effective treatment modality is required for patients with HCC.
Conventional radiotherapy has usually been considered to be of limited value for patients with HCC because the tolerance dose is 30Gy in 3 weeks when the entire organ is irradiated, which is considered lower than that necessary for tumor control Proton beams allow a rapidly increasing dose at the end of the beam range (Bragg peak) with which excellent dose localization to the target is obtained. Theoretically this should minimize the current limitation of normal liver tissue tolerance as the dose-limiting factor in radiation therapy in the treatment of HCC. That is, the absorption and distribution characteristics of proton beam therapy should allow much higher doses to be given to a tumor volume than conventional radiotherapy, while at the same time keeping doses to adjacent normal structures below tolerance levels. Advances in diagnosing imaging have allowed the boundaries of a tumor and areas of potential regions spread to be more precisely defined. Proton beam therapy enables the radiation oncologist to utilize this precision by being able to design and deliver treatments to define 3-dimensional volumes. A preliminary trial with proton beam therapy has been conducted with promising results at Wanjie Proton Therapy Center.
Objectives
1 A comparative dose distribution study has been undertaken between proton beam therapy(PBT),3-dimensional conformal radiation therapy(3D-CRT) and intensity-modulated radiation therapy(IMRT) in the treatment of hepatocellular carcinoma, so as to assess the dose distribution differences of normal liver tissues, V10Gy V20Gy and V30Gy (percentage volume of normal liver with radiation dose more than 10Gy,20Gy,30Gy) and organs at risk among PBT,3D-CRT and IMRT.2 To evaluate the feasibility, security, toxicity, effectiveness and prognostic factors of hepatocellular carcinoma treated by proton beam therapy.
Materials and Methods
1 Twenty two patients who refused being treated with surgery or unresectable patients with stage I-IIA HCC treated at Wanjie Proton Therapy Center during April 2005 to May 2008 were studied. Seventeen patients were diagnosed based on cytology. Five patients who refused accepting biopsy were based clinically upon CT/MRI imaging and elevated AFP value of 400μg/L or higher. The treatment planning system were Eclipse Proton, Eclipse Photon and inverse IMRT from Varian Medical System, Inc.,Palo Alto, CA, USA. Immobilization and simulation:the patient was in supine position and immobilized with a custom-made vacuum frame. Routine CT scan was done with and without enhancement with a 8-slice helical CT from GE Medical Systems Inc., Milwaukee, WI, USA. A CT slice thickness of 5 mm was used. Pre-contrast CT images were used for stopping power correction instead of enhancement CT images in case of affection of the contrast agent. The criteria for HCC diagnosing and staging made by Chinese Society of Liver Cancer at Guangzhou in 2001 was used. Dose-volume histograms(DVHs) were compared between PBT and 3D-CRT or IMRT planning at a total dose of 66Gy and 86Gy in stage I patients (n=10, diameter≤5cm),60Gy and 72Gy in stage IIA patients (n=12, diameter=5.1-10cm). The same target contouring method was use for comparison of the dose distribution of the three treatment techniques. GTV was defined from the fused images (precontrast and contrast CT images), CTV was defined as GTV plus a 0.5cm margin. PTV was defined as CTV plus a 1.5 to 2.5cm margin (head-foot direction) and a 1.0 to 1.5cm margin (left-right direction) account for ventilatory motion, determined using flouroscopy. Normal liver tissues and organs at risks (spinal cord, right kidney and stomach) were also defined.2 to 3 beams and 3 to 5 beams were used for PBT and 3D-CRT respectively. For patients in stage IIA, IMRT planning were performed with step and shoot technique,5 coplanar beams were used. An aperture block was designed to project outside of the target by a distance determined from the user input parameter aperture margin for each proton beam. To make better lateral conforming and minimize the lateral scattering, a compensator was designed to shape the distal edge upon different shape of the tumor and body surface and different density of the tissues for each proton beam. Proton beam was generated with a 230MeV fixed energy cyclotron (IBA Inc., Belgium) and 70 to 230MeV proton beam could be produced through a degrader. The maximum energy of the proton beam used for the treatment and the SOPB (spread out Bragg peak) could be given through the treatment planning system(TPS). A range modulator was used to get the SOBP to have a better coverage of the PTV. Double scattering mode was used in this study. Our goal was to have 90%-95% PTV coverage and±3% homogeneity in the final DVHs analysis. The same criterion was used for the three techniques upon report ICRU 62(the international commission on radiation units and measurements). A relative biologic effectiveness (RBE) factor for protons of 1.1 (relative to 60Cobalt) was employed, and proton dose was expressed in terms of cobalt Gray equivalent (CGE,1 proton Gray=1.1CGE). DVHs were used for comparison. Evaluation parameters included(1) mean dose, V10Gy,V20Gy and V30Gy dose to the normal liver tissues;(2) dose to the OARs—maximum dose to the spinal cord and mean dose to right kidney and stomach. Paired t test was used for comparisons (SPSS software; SPSS Inc., Chicago, IL, USA). A two-tailed p<0.05 was accepted as statistically significance.2 Between April 2004 and May 2010, seventy five patients with HCC received PBT at Wanjie Proton Therapy Center. The patients were grouped based on the criterion made by Chinese Society of Liver Cancer (CSLC) in Sep.,1999 at Guangzhou, there were 26 patients with I-IIA HCC and 49 patients with IIB-IIIA.43 patients had Child-Pugh Grade A cirrhosis and 32 patients had Child-Pugh Grade B cirrhosis. All patients received a total dose of 50-78Gy,2-6Gy per fraction and 3-6 fractions per week.
Results
1 For patients with stage I, the mean liver dose(Dmean), V10Gy,V20Gy and V30Gy were 13.01Gy,51.89%,36.13% and 21.24% for 3D-CRT, whereas they were 6.34Gy, 30.23%,17.86% and 10.66%, respectively, for PBT(p<0.002). With dose escalation to 86Gy, the Dmean,V10Gy,V20Gy and V30Gy were 16.91Gy,67.51%,46.84% and 27.61% for 3D-CRT, whereas they were 8.26Gy,39.31%,23.22% and 13.86%, respectively, for PBT(p<0.002). Compared with 3D-CRT with dose of 66Gy, PBT reduced the Dmean, V10Gy,V20Gy and V30Gy even with dose escalation to 86Gy(p< 0.042). For patients with stage IIA, the Dmean,,V10Gy,V2oGy and V30Gy were 29.18Gy, 72.25%,58.17%,44.01% and 24.92Gy,73.32%,56.15%,37.75% for 3D-CRT and IMRT, respectively, with dose of 60Gy, whereas they were 16.28Gy,43.93%,33.54% and 22.78%, respectively, for PBT(p<0.002). With dose escalation to 72Gy, the Dmean, V10Gy,V20Gy,V30Gy were 35.02Gy,86.70%,69.80%,52.81% and 29.90Gy, 87.98%,67.74% and 45.30% for 3D-CRT and IMRT, respectively, whereas they were 19.54Gy,52.72%,40.25% and 27.34%, respectively, for PBT (p<0.002). Compared with 3D-CRT and IMRT with total dose of 60Gy, PBT reduced the Dmean, V10Gy,V20Gy and V30Gy even with dose escalation to 72Gy(p<0.05). In all of the 22 cases, compared with 3D-CRT, PBT reduced the doses to the organs at risks (OARs) including spinal cord, right kidney and stomach(p<0.002). Compared with IMRT, PBT also reduced the dose to the right kidney and stomach significantly(p<0.05), while no significant difference was found with respect to the dose to spinal cord (p> 0.05).2 The complete response (CR) and partial response (PR) was 26.7% and 58.7% respectively. The total response rate was 85.3%. The overall 1 year and 3 years survival rates were 72.2% and 36.4% respectively. The clinical staging, Child-Pugh class, portal vein thrombosis, size and number of the tumors and BED were significantly correlated with the prognosis by individual analysis. A multivariate analysis showed that clinical staging, portal vein thrombosis and number of the tumors were associated with prognosis.
Conclusions
1 Compared with 3D-CRT, PBT reduced the dose to the normal liver tissues and OARs significantly, even with 20%-30.3% of dose escalation. Compared with IMRT, PBT reduced the dose to the normal liver tissues significantly; PBT reduced the dose to the right kidney and stomach significantly; no significant difference was observed with respect to the dose to spinal cord.2 PBT is a non-invasive technique highly suitable for HCC with tolerable side-effect. Clinical staging, portal vein thrombosis and number of the tumors are individual prognostic factors.
肝细胞肝癌(hepatocellular carcinoma, HCC)的发病率在全球呈上升趋势,其在欧美发病率较低,亚洲的发病率较高。HCC是我国的高发肿瘤之一,其恶性程度较高,死亡率亦高。早期肝细胞肝癌患者多以手术切除为主,但约有80%的肝细胞肝癌患者因发现时已处晚期或由于肝功能差及腹水等限制不适合手术治疗。近年来开展的肝移植治疗对于部分不能切除的晚期肝细胞肝癌患者提供了一个新的治疗手段,但手术创伤大、术后排异、移植后肝癌复发及可供移植的肝脏来源缺乏使肝移植手术的开展受到一定限制。经皮肝穿刺瘤内注射无水乙醇法(percutaneous ethanol injection therapy, PEIT)、肝动脉介入栓塞化疗(transarterial chemoembolization, TACE)、射频消融(radiofrequency ablation, RFA)和微波凝固治疗(microwave coagulation therapy, MCT)等方法的应用使肝细胞肝癌综合治疗的疗效有了改善,但上述治疗方法受到肿瘤的大小、数量及其与血管关系的限制。
常规放射治疗由于正常肝脏组织的耐受量较低,很难给予肿瘤根治剂量,且常会引起放射性肝功能损害甚至放射性肝病(radiation-induced liver disease, RILD)。随着放射治疗技术的发展,X线三维适形放射治疗(3-dimensional conformal radiation therapy,3D-CRT)使RILD的发生率明显降低,但正常肝脏的受照射剂量仍较高。质子束具有较好的物理学特性,其最大特征是进入人体内形成尖锐的Bragg峰。在形成峰之前的低平坦段为坪(plateau),峰后则是一个突然减弱陡直的尾。由于Bragg峰的宽度较小,所以一般都将它扩展后形成与肿瘤大小一致的扩展Bragg峰(spread out Bragg peak, SOBP)用于临床治疗。因其能量传递是以量子的形式释放,其射程具有能量依赖性,可根据肿瘤在体内的深度,使质子束精准地定位在肿瘤病灶处,以使肿瘤受到较高的照射剂量而正常组织受到较低的照射剂量,可进一步提高治疗增益比。从而得以实现在给予靶区高剂量的同时降低正常肝组织及其周围器官的并发症,以期提高肝癌的局部控制率和生存率[5-8]。
目的：
1对肝细胞肝癌患者质子束治疗(proton beam therapy, PBT)的剂量分布进行研究并与X线三维适形放射治疗(3-dimensional conformal radiation therapy,3D-CRT)及调强放射治疗(intensity-modulated radiation therapy, IMRT)计划进行剂量学分布对比研究,比较其正常肝脏组织的平均剂量(Dmean)、V10Gy、V20Gy和V30Gy(分别为正常肝脏组织受到10Gy、20Gy、30Gy以上照射剂量时的体积百分比)和危及器官(organs at risks, OARs)的照射剂量以评价三种治疗方法在靶区剂量分布和正常组织受照射剂量分布的差异。
2对质子束治疗肝细胞肝癌的临床疗效、放射引起的副反应进行评估,探讨质子束治疗肝细胞肝癌的安全性、可行性和有效性及其影响预后的因素。
材料与方法：
1 2005年4月-2008年5月间在淄博万杰质子治疗中心进行质子束治疗的拒绝手术治疗或不能手术切除的Ⅰ-ⅡA期肝细胞肝癌患者22例,其中男19例,女例3,平均年龄52岁。临床Ⅰ期肝细胞肝癌患者10例(肿瘤直径≤5cm),临床ⅡA期患者12例(肿瘤直径5.1-l0cm)。不能手术切除的原因包括肿瘤侵及血管、多发病灶、年龄大或心肺功能不全及病人拒绝手术治疗。诊断依据临床表现、实验室检查、影像学和细胞学检查,全部患者均符合2001年9月在广州召开的第八届全国肝癌学术会议上由中国抗癌协会肝癌专业委员会制定的“肝细胞肝癌的临床诊断与分期标准”。其中17例经病理证实,5例未能行穿刺活检者,其AFP≥400μg/L并经影像学检查及临床随访观察证实。治疗计划系统采用Varian公司的Eclipse Proton、Eclipse Photon和Eclipse Inverse IMRT治疗计划系统(Varian Medical System, Inc., Palo Alto, CA, USA)。体位固定及CT扫描：患者采取仰卧位,用负压垫固定。对在模拟定位机下观察呼吸动度大于lcm的患者采用腹部加压。采用8排螺旋CT进行常规扫描(GE Medical Systems Inc., Milwaukee, WI, USA),扫描层厚5.Omm。在相同固定体位进行常规CT平扫和增强扫描。以常规平扫CT图像实施剂量计算以免增强剂对阻止本领(stopping power)的校正造成影响。Ⅰ期肝细胞肝癌患者总剂量为66Gy,推量至86Gy；ⅡA期肝细胞肝癌患者总剂量为60Gy,推量至72Gy。为了便于比较,三种治疗计划采用相同的总剂量和剂量分割模式。分别设计3D-CRT、IMRT和PBT治疗计划,通过剂量—体积直方图(dose-volume histograms, DVHs)比较其正常肝脏和危及器官剂量分布的差异。为了便于比较不同照射方法的剂量分布,三种治疗计划的靶区勾画范围相同,均参考融合图像在平扫CT图像上勾画大体肿瘤体积(gross tumor volume, GTV), GTV外扩0.5cm为临床靶体积(clinical target volume, CTV)。根据呼吸动度的不同,在CTV基础上头脚方向外扩1.5～2.5cm,左右方向外扩1.0～1.5cm为计划靶体积(planning target volume, PTV)。对正常肝组织、脊髓、右肾和胃作为危及器官进行勾画并对图像进行三维重建。3D-CRT和PBT分别采用5～6个和2～3个共面照射野。对ⅡA期肝细胞肝癌患者进行了IMRT计划设计,采用静态调强,5个共面照射野。PBT治疗计划根据肿瘤形状、组织密度、肿瘤后缘形状及体表轮廓针对每个照射野需加用相应的铜挡块和聚乙烯制成的补偿器。质子束由等时回旋加速器(IBA Inc., Belgium)产生固定能量为230MeV的质子束,通过降能器得到能量范围为70-230MeV的质子束。由治疗计划系统计算所需质子束的最大能量和所需展宽的Bragg峰(spread out Bragg peak, SOBP),由射程调制器获得展宽的Bragg峰以使得高剂量分布区与靶区有较好的适形度。治疗采用双散射模式。以90%～95%等剂量线覆盖PTV。为了保证处方剂量的准确性和一致性便于比较,参照国际放射单位与测量委员会(the international commission on radiation units and measurements, ICRU)62号报告,三种治疗计划采用同一方法进行归一,使90%～95%的等剂量线覆盖PTV。PBT采用的计量单位为60Co Y射线的等效剂量(cobalt Gray equivalent, CGE),其相对生物效应(relative biological effectiveness, RBE)按1.1计算。采用DVHs图对三种计划进行评价,评价指标为(1)正常肝组织的受照射剂量：肝脏平均剂量、V10Gy、V20Gy和V30Gy;(2) OARs的受照射剂量：脊髓最大点剂量、右肾和胃的平均受照射剂量。统计学方法采用配对t检验比较三种计划剂量分布的差异。
2 2005年4月至2010年5月间在淄博万杰质子治疗中心进行质子束治疗的拒绝手术治疗或不能手术切除的肝细胞肝癌者75例,男性64例,女性11例,年龄27-91岁,中位年龄49岁。其中ⅠA-ⅡA期患者26例,ⅡB期及以上的患者49例。根据Child-Pugh肝功能分级标准,Child-Pugh肝功能A级的患者43例,Child-Pugh肝功能B级的患者32例；每次分割剂量2-6Gy,照射次数10-32次,总剂量50～78Gy,每周3-6次。
结果：
1Ⅰ期肝细胞肝癌患者3D-CRT的总剂量为66Gy时,其肝脏平均剂量(Dmean)为13.01Gy,其V10Gy、V20Gy和V30Gy分别为51.89%、36.13%和21.24%,而PBT总剂量为66Gy时,其Dmean、V10Gy、V20Gy和V30Gy则分别为6.34Gy、30.23%、17.86%和10.66%(p<0.002)。当总剂量提高至86Gy时,3D-CRT的Dmean、V10Gy、V20Gy和V30Gy分别为16.91Gy、67.51%、46.84%和27.61%；而PBT的Dmean、V10Gy、V20Gy和V30Gy则分别为8.26Gy、39.31%、23.22%和13.86% (p<0.002)。与3D-CRT总剂量为66Gy时相比,PBT在总剂量提升至86Gy时,其Dmean、V10Gy、V20Gy和V30Gy仍明显低于3D-CRT(p<0.042)。ⅡA期患者3D-CRT总剂量为60Gy时,其Dmean、V10Gy、V20Gy和V30Gy分别为29.18Gy、72.25%、58.17%和44.01%；IMRT的Dmean、V10Gy、V20Gy和V30Gy分别为24.92Gy、73.32%、56.15%和37.75%,而PBT则分别为16.28Gy、43.93%、33.54%和22.78%(p<0.002)。当总剂量提高至72Gy时,3D-CRT的Dmean、V10Gy、V20Gy和V30Gy分别为35.02Gy、86.70%、69.80%和52.81%; IMRT的Dmean、V10Gy、V20Gy和V30Gy分别为29.90Gy,87.98%,67.74%and 45.30%,而PBT的Dmean、V10Gy、V20Gy和V30Gy分别为19.54Gy、52.72%、40.25%和27.34%(p<0.002)。与3D-CRT总剂量为60Gy时相比,PBT在总剂量提升至72Gy时,其Dmean、V10Gy、V20Gy和V30Gy仍明显低于3D-CRT和IMRT(p<0.05)。22例患者采用PBT可使脊髓、右侧肾脏和胃的照射剂量较3D-CRT明显降低(p<0.002)。与IMRT相比,PBT降低了Dmean、V10Gy、V20Gy和V30Gy及右侧肾脏和胃的受照射剂量(p<0.05),脊髓的受照射剂量两者无显著性差异(p>0.05)。
2 75例肝细胞肝癌患者的完全缓解率为26.7%,部分缓解率为58.7%,总有效率为85.3%；1和3年总生存率分别为72.2%和36.4%。单因素分析显示临床分期、Child-Pugh肝功能分级、有无门静脉癌栓、肿瘤的大小、肿瘤单发或多发及靶区的生物等效剂量与生存率呈显著相关性(p<0.01)。Cox多因素回归分析显示,肿瘤分期、癌栓、肿瘤单发或多发是影响预后的因素(p<0.05)。
结论：
1与3D-CRT相比,PBT可使Ⅰ-ⅡA期肝细胞肝癌患者肝脏的平均剂量、V10Gy、V20Gy和V30Gy和OARs的照射剂量明显降低；当PBT的总剂量较3D-CRT提升20%～30.3%时,其肝脏的平均剂量及V10Gy、V20Gy和V30Gy仍较3D-CRT明显降低。与IMRT相比,PBT使ⅡA期患者的Dmean、V10Gy、V20Gy、V30Gy、右侧肾脏和胃的受照射剂量明显降低,脊髓的受量两者无显著性差异。与3D-CRT相比,IMRT降低了ⅡA期患者的脊髓受受照射剂量,其对正常肝脏、右肾和胃的照射剂量未见明显差异。
2质子束治疗是肝细胞肝癌的安全、有效的治疗手段,患者具有良好的耐受性。肿瘤分期、癌栓、肿瘤单发或多发是独立预后因子。
Background
The prevalence rates of hepatocellular carcinoma (HCC) is rising worldwide, it is one of the most frequent cause of death in China. Although surgical resection remains the most standard and reliable curative modality for the treatment of HCC, a retrospective study demonstrated only 18% of the patients were surgically resectable, more than 80% of HCC patients are inoperable at the time of diagnosis owing to advanced tumors, ascites or coexisting cirrhosis. The management of technically unresectable and medically inoperable HCC remains challenging. HCC is highly resistant to currently available chemotherapeutic drugs. Liver transplantation might be better than resection for some of the unresectable patients. However, recurrence of malignant tumor within 6 to 24 months has been the usual outcome and immunosuppressive medication seems contradicting with respect to tumor control; this option is also dependent on the availability of vital organs, which are in short supply. Several treatment modalities are currently available for patients with HCC such as PEIT(percutaneous ethanol injection therapy), TACE(transarterial chemoembolization), RFA (radiofrequency ablation) and MCT (microwave coagulation therapy), although limitations of the above techniques relate to tumor size, number and location relative to blood vessels. A less-invasive and effective treatment modality is required for patients with HCC.
Conventional radiotherapy has usually been considered to be of limited value for patients with HCC because the tolerance dose is 30Gy in 3 weeks when the entire organ is irradiated, which is considered lower than that necessary for tumor control Proton beams allow a rapidly increasing dose at the end of the beam range (Bragg peak) with which excellent dose localization to the target is obtained. Theoretically this should minimize the current limitation of normal liver tissue tolerance as the dose-limiting factor in radiation therapy in the treatment of HCC. That is, the absorption and distribution characteristics of proton beam therapy should allow much higher doses to be given to a tumor volume than conventional radiotherapy, while at the same time keeping doses to adjacent normal structures below tolerance levels. Advances in diagnosing imaging have allowed the boundaries of a tumor and areas of potential regions spread to be more precisely defined. Proton beam therapy enables the radiation oncologist to utilize this precision by being able to design and deliver treatments to define 3-dimensional volumes. A preliminary trial with proton beam therapy has been conducted with promising results at Wanjie Proton Therapy Center.
Objectives
1 A comparative dose distribution study has been undertaken between proton beam therapy(PBT),3-dimensional conformal radiation therapy(3D-CRT) and intensity-modulated radiation therapy(IMRT) in the treatment of hepatocellular carcinoma, so as to assess the dose distribution differences of normal liver tissues, V10Gy V20Gy and V30Gy (percentage volume of normal liver with radiation dose more than 10Gy,20Gy,30Gy) and organs at risk among PBT,3D-CRT and IMRT.2 To evaluate the feasibility, security, toxicity, effectiveness and prognostic factors of hepatocellular carcinoma treated by proton beam therapy.
Materials and Methods
1 Twenty two patients who refused being treated with surgery or unresectable patients with stage I-IIA HCC treated at Wanjie Proton Therapy Center during April 2005 to May 2008 were studied. Seventeen patients were diagnosed based on cytology. Five patients who refused accepting biopsy were based clinically upon CT/MRI imaging and elevated AFP value of 400μg/L or higher. The treatment planning system were Eclipse Proton, Eclipse Photon and inverse IMRT from Varian Medical System, Inc.,Palo Alto, CA, USA. Immobilization and simulation:the patient was in supine position and immobilized with a custom-made vacuum frame. Routine CT scan was done with and without enhancement with a 8-slice helical CT from GE Medical Systems Inc., Milwaukee, WI, USA. A CT slice thickness of 5 mm was used. Pre-contrast CT images were used for stopping power correction instead of enhancement CT images in case of affection of the contrast agent. The criteria for HCC diagnosing and staging made by Chinese Society of Liver Cancer at Guangzhou in 2001 was used. Dose-volume histograms(DVHs) were compared between PBT and 3D-CRT or IMRT planning at a total dose of 66Gy and 86Gy in stage I patients (n=10, diameter≤5cm),60Gy and 72Gy in stage IIA patients (n=12, diameter=5.1-10cm). The same target contouring method was use for comparison of the dose distribution of the three treatment techniques. GTV was defined from the fused images (precontrast and contrast CT images), CTV was defined as GTV plus a 0.5cm margin. PTV was defined as CTV plus a 1.5 to 2.5cm margin (head-foot direction) and a 1.0 to 1.5cm margin (left-right direction) account for ventilatory motion, determined using flouroscopy. Normal liver tissues and organs at risks (spinal cord, right kidney and stomach) were also defined.2 to 3 beams and 3 to 5 beams were used for PBT and 3D-CRT respectively. For patients in stage IIA, IMRT planning were performed with step and shoot technique,5 coplanar beams were used. An aperture block was designed to project outside of the target by a distance determined from the user input parameter aperture margin for each proton beam. To make better lateral conforming and minimize the lateral scattering, a compensator was designed to shape the distal edge upon different shape of the tumor and body surface and different density of the tissues for each proton beam. Proton beam was generated with a 230MeV fixed energy cyclotron (IBA Inc., Belgium) and 70 to 230MeV proton beam could be produced through a degrader. The maximum energy of the proton beam used for the treatment and the SOPB (spread out Bragg peak) could be given through the treatment planning system(TPS). A range modulator was used to get the SOBP to have a better coverage of the PTV. Double scattering mode was used in this study. Our goal was to have 90%-95% PTV coverage and±3% homogeneity in the final DVHs analysis. The same criterion was used for the three techniques upon report ICRU 62(the international commission on radiation units and measurements). A relative biologic effectiveness (RBE) factor for protons of 1.1 (relative to 60Cobalt) was employed, and proton dose was expressed in terms of cobalt Gray equivalent (CGE,1 proton Gray=1.1CGE). DVHs were used for comparison. Evaluation parameters included(1) mean dose, V10Gy,V20Gy and V30Gy dose to the normal liver tissues;(2) dose to the OARs—maximum dose to the spinal cord and mean dose to right kidney and stomach. Paired t test was used for comparisons (SPSS software; SPSS Inc., Chicago, IL, USA). A two-tailed p<0.05 was accepted as statistically significance.2 Between April 2004 and May 2010, seventy five patients with HCC received PBT at Wanjie Proton Therapy Center. The patients were grouped based on the criterion made by Chinese Society of Liver Cancer (CSLC) in Sep.,1999 at Guangzhou, there were 26 patients with I-IIA HCC and 49 patients with IIB-IIIA.43 patients had Child-Pugh Grade A cirrhosis and 32 patients had Child-Pugh Grade B cirrhosis. All patients received a total dose of 50-78Gy,2-6Gy per fraction and 3-6 fractions per week.
Results
1 For patients with stage I, the mean liver dose(Dmean), V10Gy,V20Gy and V30Gy were 13.01Gy,51.89%,36.13% and 21.24% for 3D-CRT, whereas they were 6.34Gy, 30.23%,17.86% and 10.66%, respectively, for PBT(p<0.002). With dose escalation to 86Gy, the Dmean,V10Gy,V20Gy and V30Gy were 16.91Gy,67.51%,46.84% and 27.61% for 3D-CRT, whereas they were 8.26Gy,39.31%,23.22% and 13.86%, respectively, for PBT(p<0.002). Compared with 3D-CRT with dose of 66Gy, PBT reduced the Dmean, V10Gy,V20Gy and V30Gy even with dose escalation to 86Gy(p< 0.042). For patients with stage IIA, the Dmean,,V10Gy,V2oGy and V30Gy were 29.18Gy, 72.25%,58.17%,44.01% and 24.92Gy,73.32%,56.15%,37.75% for 3D-CRT and IMRT, respectively, with dose of 60Gy, whereas they were 16.28Gy,43.93%,33.54% and 22.78%, respectively, for PBT(p<0.002). With dose escalation to 72Gy, the Dmean, V10Gy,V20Gy,V30Gy were 35.02Gy,86.70%,69.80%,52.81% and 29.90Gy, 87.98%,67.74% and 45.30% for 3D-CRT and IMRT, respectively, whereas they were 19.54Gy,52.72%,40.25% and 27.34%, respectively, for PBT (p<0.002). Compared with 3D-CRT and IMRT with total dose of 60Gy, PBT reduced the Dmean, V10Gy,V20Gy and V30Gy even with dose escalation to 72Gy(p<0.05). In all of the 22 cases, compared with 3D-CRT, PBT reduced the doses to the organs at risks (OARs) including spinal cord, right kidney and stomach(p<0.002). Compared with IMRT, PBT also reduced the dose to the right kidney and stomach significantly(p<0.05), while no significant difference was found with respect to the dose to spinal cord (p> 0.05).2 The complete response (CR) and partial response (PR) was 26.7% and 58.7% respectively. The total response rate was 85.3%. The overall 1 year and 3 years survival rates were 72.2% and 36.4% respectively. The clinical staging, Child-Pugh class, portal vein thrombosis, size and number of the tumors and BED were significantly correlated with the prognosis by individual analysis. A multivariate analysis showed that clinical staging, portal vein thrombosis and number of the tumors were associated with prognosis.
Conclusions
1 Compared with 3D-CRT, PBT reduced the dose to the normal liver tissues and OARs significantly, even with 20%-30.3% of dose escalation. Compared with IMRT, PBT reduced the dose to the normal liver tissues significantly; PBT reduced the dose to the right kidney and stomach significantly; no significant difference was observed with respect to the dose to spinal cord.2 PBT is a non-invasive technique highly suitable for HCC with tolerable side-effect. Clinical staging, portal vein thrombosis and number of the tumors are individual prognostic factors.
引文
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11 Int J Radiat Oncol Biol Phys,1995,31(5):1237-1248. Hepatic toxicity resulting from cancer treatment. Lawrance TS, Robertson JM, Anscher MS, et al.
12 Int J Radiat Oncol Biol Phys,2008,71 (2):462-467. Proton Beam Therapy for Hepatocellular Carcinoma Adjacent to the Porta Hepatis. Mizumoto M, Tokuuye K, Sugahara S, et al.
13 Int J Radiat Oncol Biol Phys,2007,69(3):805-812. Proton beam therapy for aged patients with hepatocellular carcinoma. Hata M, Tokuuye K, Sugahara S, et al.
14 国外医学肿瘤学分册,2005,32(9)：716-719.质子放射治疗与儿童肿瘤.李家敏,刘素文,于金明,等.
15 Int J Radiat Oncol Biol Phys,2006,65(1):196-202. Repeated proton beam therapy for hepatocellular carcinoma. Hashimoto T, Tokuuye k, Fukumitsu N, et al.
16 Int J Radiat Oncol Biol Phys,2002,53(2):407-421. Relative biological effectiveness (RBE) values for proton beam therapy. Paganetti H, Niemierko A, Ancukiewicz M, et al.
17 Clinical Cancer Research,2005,11(10):3799-3805. Proton Beam Therapy for Hepatocellular Carcinoma:A Retrospective Review of 162 Patients. Chiba T, Tokuuye K, Matsuzaki Y, et al.
18 Int J Radiat Oncol Biol Phys,2003,56(1):229-234. Dosimetric analysis and comparison of three-dimensional conformal radiotherapy and intensity-modulated radiation therapy for patients with hepatocellular carcinoma and radiation-induced liver disease. Cheng JC, Wu JK, Huang CM, et al.
19 中华医学杂志,2005,85(33)：2322-2326.172例肝癌射频消融治疗预后因素分析.严昆,王艳滨,陈敏华,等.
20.中华医学杂志,2005,85(2)：80-83.经皮射频消融与手术切除治疗小肝癌的疗效比较.陈敏山,李锦清,梁惠宏,等.
21 Cancer,1991,68(10):2150-2154. Effect of repeated transcatheter arterial embolization on the survival time in patients with hepatocellular carcinoma. Ikeda K, Kumada H,Saitoh S,et al.
22 Am J Clin Oncol,1992,15(4):304-307. Combination chemotherapy and radiation for palliation of hepatocellular carcinoma. Dhir V, Swaroop V,Mohandas K, et al.
23 Crit Rev Oncol Hemato,2008,67(2):113-123. Conformal radiotherapy for hepatocellular carcinoma. Tes RV, Guha C, Dawson LA.
24 Acta Oncol,2003,42(8):800-808. Proton beams to replace photon beams in radical dose treatments. Suit H, Goldberg S, Niemierko A, et al.
25 Int J Radiat Oncol Biol Phys,2008,71 (4):979-986. Proton radiotherapy for childhood ependymoma:initial clinical outcomes and dose comparisons. MacDonald SM, Safai S, Trofimov A, et al.
26 中华肿瘤杂志,2001,23(1)：7-10.质子治疗肿瘤的现状与发展趋势.唐劲天,左焕琮.
27 Annu Rev Biophys Bioeng,1982,11:331-357. Proton beam therapy. Verhey LJ, Munzenrider JE.
28 J Clin Oncol,2000,18(11):2210-2218. Escalated focal liver radiation and concurrent hepatic artery fluorodeoxyuridine for unresectable intrahepatic malignancies. Dawson LA, McGinn CJ, Normolle D, et al.
29 Clinical Cancer Research,2005,11(10):3799-3805. Proton beam therapy for hepatocellular carcinoma:a retrospective review of 162 patients. Chibal T, Koiehi Tokuuye, Yasushi Matsuzakil, et al.
30 Gastroenterology,2004,127(5):s189-193. High-dose proton beam radiotherapy of hepatocellular carcinoma:preliminary results of a phase Ⅱ trial. Bush DA, Hillebrand DJ, Slater JM, et al.
31 Strahlenther Onkol,2009,185(12):782-788. Proton-beam therapy for hepatocellular carcinoma associated with portal vein tumor thrombosis. Sugahara S, Nakayama H, Fukuda K, et al.
32 J Clin Oncol,2005,23(9):1839-1846. Phase Ⅱ study of radiotherapy employing proton beam for hepatocellular carcinoma. Kawashima M, Furuse J, Nishio T, et al.
33 J Gastroenterol,2005,40(3):225-235. Updated treatment approach to hepatocellular carcinoma. Lover JM.
34 Radialogy,1964,47(5):487-491. Radiaological use of fast proton. Wilson RR.
35 基础医学与临床,2005,25(2)：102-111.质子治疗的物理与生物学基础.马秋峰,李文建,魏怀鹏.
36 Strahlenther Onkol,2005,181(1):49-53. Donut-shaped high-dose configuration for proton beam radiation therapy. Rutz HP, Lomax AJ.
37 Int J Radiat Oncol Biol Phys,2007,67(2):497-504. Spot-scanning proton therapy for malignant soft tissue tumors in childhood:First experiences at the Paul Scherrer Institute. Timmermann B, Schuck A, Niggli F, et al.
38 Int. J. Radiat. Biol,1995,67(3):237-259. Proton Radiobiology, Radiosurgery and Radiotherapy. Raju MR.
39 Phys Med Biol,1993,10:1371-1392. Current Developments in Proton Therapy:A Review. Bonnett DE.
40 Cancer,2005,104 (4):794-801. Proton beam therapy for hepatocellular carcinoma with portal vein tumor thrombus. Hata M, Tokuuye K, Sugahara S, et al.
41 Radiat Med,2005,23(7):513-519. A case of hepatocellular carcinoma initially treated by carbon ions, followed by protons for marginal recurrence with portal thrombus. Mayahara H, Oda Y, Kawaguchi A, et al.
42 Int J Radiat Oncol Biol Phys,2000,47(2):435-442. Local radiotherapy with or without transcathter arterial chemoembolization for patients with unresectable hepatocellular carcinoma. Cheng JC, ChuanVP, Cheng SH, et al.
43 Int J Radiat Oncol Biol Phys,2000,47(5):393-397. Local radiotherapy for unresectable hepatocellular carcinoma. Seong J, Park HC, Han KH, et al.
44 Hepatogastroenterology,1998,45(21):791-796. The usefulness of radiation therapy for hepatocellular carcinoma. Matsuura M, Nakajima N, Arai K, et al.
45 Int J Radiat Oncol Biol Phys,1993,27(1):117-123. Accelerated hyperfractionated hepatic irradiation in the management of patients with liver metastasis:results of the RTOG dose escalating protocol. Russell AH, Clyde C, Wasserman TH.
46 Technology in Cancer Research & Treatment,2005,2(5):389-399.Treatment Planning for Conformal Proton Radiation Therapy. Bussiere MR, Adams JA.
47 Bull Cancer Radiother,1996,83:s207-211. Clinical Applications of Proton Therapy. Habrand JL, Schlienger P, Schwartz L, et al.
48 Int J Radiat Oncol Biol Phys,1991,21(1):109-122. Tolerance of normal tissue to the therapeutic irradiation. Emami B, Lyman J, Brown A, et al.
49 Phys Med Biol,1983,29(5):553-566. Compensating For Heterogeneities in Proton Radiation Therapy. Urie M, Goitein M, Wagner M.
50 Int J Radiat Oncol Biol Phys,1997,38(2):367-372. Radiation tolerance of cirrhotic livers in relation to the preserved functional capacity:analysis of patients with hepatocellular carcinoma treated by focused proton beam radiotherapy. Ohara K, Okumura T, Tsuji H, et al.
51 Int J Cancer,2002,97(1):72-81. Estimates of the world-wide prevalence of cancer for 25 sites in the adult population. Pisani P, Bray F, Parkin DM.
52 World J Gastroenterol,2002,8(5):797-803. DNA-PKcs subunits in radiosensitization by hyperthermia on hepatocellular carcinoma HepG2 cell line. Zeng ZC, Jiang GL, Wang GM, et al.
53 World J Gastroenterol,2003,9(8):1697-1701. Comparison between chemoembolization combined with radiotherapy and chemoembolization alone for large hepatocellular carcinoma. Guo WJ, Yu EX, Liu LM, et al.
54 Int J Radiat Oncol Biol Phys,1992,22(2):383-389. The proton treatment center at Loma Linda University Medical Center:rationale for and description of its development. Slater JM, Archambeau JO, Miller DW, et al.
55 Nature,1958,182(4644):1222-1223. The high-energy proton beam as a neurosurgical tool. Larsson B, Leksell L, Rexed B, ea al.
56 Neurol Assc,1962,87:216-218. The Bragg peak of a proton beam in intracranial therapy of tumors. Trans Am Kjellberg RN, Sweet WH, Preston WM, et al.
57 Int J Radiat Oncol Biol Phys,2001,49(4):1053-1059, Proton radiation therapy for medium and large chridial melanoma:preservation of eye and its functionality. Fuss M, Loredo LN, Blacharski PA, et al.
58 Int J Radiat Oncol Biol Phys,2005,62(2):494-500. Proton radiation for treatment of cancer of the oropharynx:early experience at Loma Linda University Medical Center using a concomitant boost technique.Slater JD, Yonemoto LT, Mantik DW, et al.
59 Radiology,1999,213(2):489-494. Nasopharyngeal carcinoma:repeat treatment with conformal proton therapy-dose-volume histogram analysis. Lin R, Slater JD, Yonemoto LT, et al.
60 Urology,1999,53(5):978-984. Conformal proton therapy for early-stage prostate cancer. Slater JD, Rossi CJ Jr, Yonemoto LT, et al.
61 Int J Radiat Oncol Biol Phys,2004,59(2):348-352. Proton therapy for prostate cancer:the initial Loma Linda University experience.Slater JD, Rossi CJ Jr, Yonemoto LT, et al.
62 Int J Radiat Oncol Biol Phys,1997,39(2):455-460. Proton therapy for pediatric cranial tumors:preliminary report on treatment and disease-related morbidities. McAllister B, Archambeau JO, Nguyen MC, et al.
63 Int J Radiat Oncol Biol Phys,1997,39(2):455-460. Proton therapy for pediatric cranial tumors:preliminary report on treatment and disease-related morbidities. McAllister B, Archambeau JO, Nguyen MC, et al. 1 Pisani P, Parkin DM, Bray F, et al. Estimates of the world mortality from 25 cancers in 1990. Int J Cancer 1999; 18-29.
2 Chang JC, ChuanVP, Cheng SH, et al. Local radiotherapy with or without transcathter arterial chemoembolization for patients with unresectable hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2000;47:435-442.
3 Ikeda K, Kumada H, Saitoh S, et al. Effect of repeated transcatheter arterial embolization on the survival time in patients with hepatocellular carcinoma. Cancer 1991;68:2150-2154.
4 Dhir V, Swaroop V, Mohandas KM, et al. Combination chemotherapy and radiation for palliation of hepatocellular carcinoma. Am J Clin Oncol 1992; 15:304-307.
5 SeongJ, Park HC, Han KH, et al. Local radiotherapy for unresectable hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2000;47:393-397.
6 Matsuura M, Nakajima N, Arai K, et al. The usefulness of radiation therapy for hepatocellular carcinoma. Hepatogastroenterology 1998;45:791-796.
7 Russell AH, Clyde C, Wasserman TH. Accelerated hyperfractionated hepatic irradiation in the management of patients with liver metastasis:results of the RTOG dose-escalating protocol. Int J Radiat Oncol Biol Phys 1993;27:117-123.
8 Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to the therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991;21:109-122.
9 Lawrance TS, Robertson JM, Anscher MS,et al. Hepatic toxicity resulting from cancer treatment. Int J Radiat Oncol Biol Phys 1995;31:1237-1248.
10 Park W, Lim DH, Paik SW, et al. Local radiotherapy for patients with unresectable hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2005;15:1143-1150.
11 Tes RV, Guha C, Dawson LA. Conformal radiotherapy for hepatocellular carcinoma. Crit Rev Oncol Hemato 2008;67:113-123.
12 Suit H, Goldberg S, Niemierko A, et al. Proton beams to replace photon beams in radical dose treatments. Acta Oncol 2003;42:800-808.
13 MacDonald SM, Safai S, Trofimov A, et al. Proton radiotherapy for childhood ependymoma:initial clinical outcomes and dose comparisons. Int J Radiat Oncol Biol Phys 2008; 71:979-986.
14 H. Suit, S. Goldberg, A. Niemierko, et al. Proton beams to replace photon beams in radical dose treatments. Acta Oncologica 2003;42:800-808.
15 Mizumoto M, Tokuuye K, Sugahara S, et al. Proton beam therapy for hepatocellular carcinoma adjacent to the Porta Hepatis. Int J Radiat Oncol Biol Phys 2008;71:462-467.
16 Paganetti H, Niemierko A, Ancukiewicz M, et al. Relative biological effectiveness (RBE) values for proton beam therapy. Int J Radiat Oncol Biol Phys 2002;53:407-421.
17 Lee CT, Bilton SD, Famiglietti RM. et al. Treatment planning with protons for pediatric retinoblastoma, medulloblastoma, and pelvic sarcoma:how do protons compare with other conformal techniques? Int J Radiat Oncol Biol Phys 2005; 63:362-372.
18 Cozzi L, Fogliata A, Lomax A, et al. A treatment planning comparison of 3D conformal therapy, intensity modulated photon therapy and proton therapy for treatment of advanced head and neck tumors. Radiother Oncol 2001;61:287-297.
19 Miralbell R, Lomax A, Russo M. Potential role of proton therapy in the treatment of pediatric medulloblastoma/primitive neuron-ectodermal tumors. Int J Radiat Oncol Biol Phys 1997;38:805-811.
20 Verhev LG, Smith V, Serago CF. Comparison of radiosurgery treatment modalities based on physical dose distributions. Int J Radiat Oncol Biol Phys 1998;40:497-505.
21 Liang SX, Zhu XD, Xu ZY, et al. Radiation-induced liver disease in three-dimensional conformal radiation therapy for primary liver carcinoma:the risk factors and hepatic radiation tolerance. Int J Radiat Oncol Biol Phys 2006;65: 426-434.
22 Cheng JC, Wu JK, Huang CM, et al. Radiation-induced liver disease after three-dimensional conformal radiotherapy for patients with hepatocellular carcinoma: dosimetric analysis and implication. Int J Radiat Oncol Biol Phys 2002;54:156-162.
23 Cheng JC, Wu JK, Huang CM, et al. Dosimetric analysis and comparison of three-dimensional conformal radiotherapy and intensity-modulated radiation therapy for patients with hepatocellular carcinoma and radiation-induced liver disease.Int J
24 Park HC, Seong J, Han KH, et al. Dose-response relationship in local radiotherapy for hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2002;54:150-155.
25 St Clair WH, Adams JA, Bues M, et al. Advantage of protons compared to conventional X-ray or IMRT in the treatment of a pediatric patient with medulloblastoma. Int J Radiat Oncol Biol Phys 2004;58:727-734.
26 Ohara K, Okumura T, Tsuji H, et al. Radiation tolerance of cirrhotic livers in relation to the preserved functional capacity:analysis of patients with hepatocellular carcinoma treated by focused proton beam radiotherapy. Int J Radiat Oncol Biol Phys 1997;38:367-372.
27 Chiba T, Tokuuye K, Matsuzaki Y, et al. Proton beam therapy for hepatocellular carcinoma:a retrospective review of 162 patients. Clin Cancer Res 2005;11:3799-3805.
28 Hashimoto T, Tokuuye K, Fukumitsu N, et al. Repeated proton beam therapy for hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2006;65:196-202.
1 R. R. Wilson."Radiological Use of Fast Proton", Radiology,1946,47:487-491.
2 H. D. Suit. "Protons to Replace Photons in External Beam Radiation Therapy?", Clinical oncology,2003,15:S29-S31.
3.H. Suit, S. Goldberg, A. Niemierko, et al. "Proton Beams to Replace Photon Beams in Radical Dose Treatments". Acta Oncologica,2003,42(8):800-808.
4 M. Urie, M. Goitein, and M. Wagner. "Compensating For Heterogeneities in Proton Radiation Therapy", Phys Med Biol,1983,29(5):553-566.
5 L. J. Verhey and J. E. Munzenrider. "Proton Beam Therapy", Ann Rev Biophys
6 M. R. Raju. "Proton Radiobiology, Radiosurgery and Radiotherapy", Int J Radiat Biol,1995,67(3):237-259.
7 D E Bonnett. "Current Developments in Proton Therapy:A Review", Phys Med Biol,1993,38:1371-1392.
8 M. R. Bussiere and J. A. Adams. "Treatment Planning for Conformal Proton Radiation Therapy", Technology in Cancer Research & Treatment,2003,2(5):389-399.
9 H. Breuer and B. J. Smit. "Proton Therapy and Radiosurgery", ISBN 3-540-64100-9 Spring-Verlag Berlin Heidelberg New York.
10 J. L. Habrand, P. Schlienger, L. Schwartz, et al. "Clinical Applications of Proton Therapy", Radiat Environ Biophys,1995,34:41-44.
11 A Lomax. "Intensity Modulation Methods for Proton Radiotherapy", Phys Med Biol,1999,44:185-205.
12 L. Hong, M. Goitein, M. Bucciolini, et al. "A Pencil Beam Algorithm for Proton Dose Calculations", Phys Med Biol,1996,41:1305-1330.
13 H. Szymanowski, U.Oelfke. "Two-Dimensional Pencil Beam Scaling:An Improved Proton Dose Algorithm for Heterogeneous Media", Phys Med Biol, 2002,47:3313-3330.
14 J.O. Deasy. "A Proton Dose Calculation Algorithm for Conformal Therapy Simulations Based on Moliere's Theory of Lateral Deflections", Med Phys,1998,25 (4):476-483.
15 J. S. Li, B. Shaline, E. Fourkal, et al. "A Particle Track-repeating Algorithm for Proton Beam Dose Calculation", Phys Med Biol,2005,50:1001-1010.
16 M. Fipple. "A Monte Carlo Dose Calculation Algorithm for Proton Therapy", Med Phys,2004,31(8):2263-2273.
17 H. Paganetti, H. Jiang and A Trofimov. "4D Monte Carlo Simulation of Proton Beam Scanning Modeling of Variations in Time and Space to Study The Interplay Between Scanning Pattern and Time-dependent Patient Geometry", Phys Med Biol, 2005,50:983-990.
18 H. E. romeijn, R. K. ahuja, J. F. Dempsey, et al. "A New Linear Programming Approach to Radiation Therapy Treatment Planning Problems", Operations Research, 2006,54(2):201-216.
19 J. Lomax, T. Bohringer, A. Bolsi, et al. "Treatment Planning and Verification of Proton Therapy Using Spot Scanning:Initial Experiences", Med Phys, 2004,31(11):150-157.
20 D. G Kirsch and N. J. Tarbell. "New Technologies in Radiation Therapy for Pediatric Brain Tumors:The Rationale for Proton Radiation Therapy", Pediatr Blood Cancer,2004; 42:461-464.
21 C. Yeboah and G A. Sandison. "Optimized Treatment Planning for Prostate Cancer Comparing IMPT, VHEET and 15MV IMXT", Phys Med Biol,2002,47:2247-2261.
22 V S Khoroshkov and E I Minakova. "Proton Beams in Radiotherapy", Eur J Phys, 1998,19:523-536.
23 E. Fourkal, J. S. Li, W. Xiong, et al. "Intensity Modulated Radiation Therapy Using Laser-Accelerated Protons:A Monte Carlo Dosimetric Study", Phys Med Biol, 2003,48:3977-4000
2 Cancer,2002,95(11):2353-2360. Percutaneous radiofrequency ablation therapy for patients with hepatocellular carcinoma during occlusion of hepatic blood flow. Comparison with standard percutaneous radiofrequency ablation therapy. Yamasaki T, Kurokawa F, Shirahashi H, et al.
3 Int J Radiat Oncol Biol Phys,2003,57(1):113-119. Prospective trial of combined transcatheter arterial chemoembolization and three-dimensional eonformal radiotherapy for portal vein tumor thrombus in patients with unresectable hepatocellular carcinoma. Yamada K, Izaki K, Sugimoto K, et al.
4 Clinical oncology,2003,15(1):s29-31. Protons to Replace Photons in External Beam Radiation Therapy?. Suit. HD.
5.中华肝脏病杂志,2001,9(6)：324.原发性肝癌的临床诊断与分期标准.杨秉辉,夏景林.
6 Hepatology Research,2003,27(1):30-35. Clinical results of 3-dimensional conformal with transarterial chemoembolization for hepatocellular carcinoma in the cirrhotic patients.Seong J, Park HC, Han KH, et al.
7 Int J Radiat Oncol Biol Phys,2002,54(1):150-155. Dose-response relationship in local radiotherapy for hepatocellular carcinoma. Park HC, Seong J, Han KH, et al.
8 Int J Radiat Oncol Biol Phys,2002,54(1):156-162. Radiation-induced liver disease after three-dimensional conformal radiotherapy for patients with hepatocellular carcinoma:dosimetric analysis and implication. Cheng JC, Wu JK, Huang CM, et al.
9 Int J Radiat Oncol Biol Phys,2003,55(2):329-336. Clinical results and prognostic factors in radiotherapy for unresectable hepatocellular carcinoma:a retrospective study of 158 patients. Seong J, Park HC, Han KH, et al.
10 Int J Radiat Oncol Biol Phys,2005,61(4):1143-1150. Local radiotherapy for patients with unresectable hepatocellular carcinoma. Park W, Lim DH, Paik SW, et al.
11 Int J Radiat Oncol Biol Phys,1995,31(5):1237-1248. Hepatic toxicity resulting from cancer treatment. Lawrance TS, Robertson JM, Anscher MS, et al.
12 Int J Radiat Oncol Biol Phys,2008,71 (2):462-467. Proton Beam Therapy for Hepatocellular Carcinoma Adjacent to the Porta Hepatis. Mizumoto M, Tokuuye K, Sugahara S, et al.
13 Int J Radiat Oncol Biol Phys,2007,69(3):805-812. Proton beam therapy for aged patients with hepatocellular carcinoma. Hata M, Tokuuye K, Sugahara S, et al.
14 国外医学肿瘤学分册,2005,32(9)：716-719.质子放射治疗与儿童肿瘤.李家敏,刘素文,于金明,等.
15 Int J Radiat Oncol Biol Phys,2006,65(1):196-202. Repeated proton beam therapy for hepatocellular carcinoma. Hashimoto T, Tokuuye k, Fukumitsu N, et al.
16 Int J Radiat Oncol Biol Phys,2002,53(2):407-421. Relative biological effectiveness (RBE) values for proton beam therapy. Paganetti H, Niemierko A, Ancukiewicz M, et al.
17 Clinical Cancer Research,2005,11(10):3799-3805. Proton Beam Therapy for Hepatocellular Carcinoma:A Retrospective Review of 162 Patients. Chiba T, Tokuuye K, Matsuzaki Y, et al.
18 Int J Radiat Oncol Biol Phys,2003,56(1):229-234. Dosimetric analysis and comparison of three-dimensional conformal radiotherapy and intensity-modulated radiation therapy for patients with hepatocellular carcinoma and radiation-induced liver disease. Cheng JC, Wu JK, Huang CM, et al.
19 中华医学杂志,2005,85(33)：2322-2326.172例肝癌射频消融治疗预后因素分析.严昆,王艳滨,陈敏华,等.
20.中华医学杂志,2005,85(2)：80-83.经皮射频消融与手术切除治疗小肝癌的疗效比较.陈敏山,李锦清,梁惠宏,等.
21 Cancer,1991,68(10):2150-2154. Effect of repeated transcatheter arterial embolization on the survival time in patients with hepatocellular carcinoma. Ikeda K, Kumada H,Saitoh S,et al.
22 Am J Clin Oncol,1992,15(4):304-307. Combination chemotherapy and radiation for palliation of hepatocellular carcinoma. Dhir V, Swaroop V,Mohandas K, et al.
23 Crit Rev Oncol Hemato,2008,67(2):113-123. Conformal radiotherapy for hepatocellular carcinoma. Tes RV, Guha C, Dawson LA.
24 Acta Oncol,2003,42(8):800-808. Proton beams to replace photon beams in radical dose treatments. Suit H, Goldberg S, Niemierko A, et al.
25 Int J Radiat Oncol Biol Phys,2008,71 (4):979-986. Proton radiotherapy for childhood ependymoma:initial clinical outcomes and dose comparisons. MacDonald SM, Safai S, Trofimov A, et al.
26 中华肿瘤杂志,2001,23(1)：7-10.质子治疗肿瘤的现状与发展趋势.唐劲天,左焕琮.
27 Annu Rev Biophys Bioeng,1982,11:331-357. Proton beam therapy. Verhey LJ, Munzenrider JE.
28 J Clin Oncol,2000,18(11):2210-2218. Escalated focal liver radiation and concurrent hepatic artery fluorodeoxyuridine for unresectable intrahepatic malignancies. Dawson LA, McGinn CJ, Normolle D, et al.
29 Clinical Cancer Research,2005,11(10):3799-3805. Proton beam therapy for hepatocellular carcinoma:a retrospective review of 162 patients. Chibal T, Koiehi Tokuuye, Yasushi Matsuzakil, et al.
30 Gastroenterology,2004,127(5):s189-193. High-dose proton beam radiotherapy of hepatocellular carcinoma:preliminary results of a phase Ⅱ trial. Bush DA, Hillebrand DJ, Slater JM, et al.
31 Strahlenther Onkol,2009,185(12):782-788. Proton-beam therapy for hepatocellular carcinoma associated with portal vein tumor thrombosis. Sugahara S, Nakayama H, Fukuda K, et al.
32 J Clin Oncol,2005,23(9):1839-1846. Phase Ⅱ study of radiotherapy employing proton beam for hepatocellular carcinoma. Kawashima M, Furuse J, Nishio T, et al.
33 J Gastroenterol,2005,40(3):225-235. Updated treatment approach to hepatocellular carcinoma. Lover JM.
34 Radialogy,1964,47(5):487-491. Radiaological use of fast proton. Wilson RR.
35 基础医学与临床,2005,25(2)：102-111.质子治疗的物理与生物学基础.马秋峰,李文建,魏怀鹏.
36 Strahlenther Onkol,2005,181(1):49-53. Donut-shaped high-dose configuration for proton beam radiation therapy. Rutz HP, Lomax AJ.
37 Int J Radiat Oncol Biol Phys,2007,67(2):497-504. Spot-scanning proton therapy for malignant soft tissue tumors in childhood:First experiences at the Paul Scherrer Institute. Timmermann B, Schuck A, Niggli F, et al.
38 Int. J. Radiat. Biol,1995,67(3):237-259. Proton Radiobiology, Radiosurgery and Radiotherapy. Raju MR.
39 Phys Med Biol,1993,10:1371-1392. Current Developments in Proton Therapy:A Review. Bonnett DE.
40 Cancer,2005,104 (4):794-801. Proton beam therapy for hepatocellular carcinoma with portal vein tumor thrombus. Hata M, Tokuuye K, Sugahara S, et al.
41 Radiat Med,2005,23(7):513-519. A case of hepatocellular carcinoma initially treated by carbon ions, followed by protons for marginal recurrence with portal thrombus. Mayahara H, Oda Y, Kawaguchi A, et al.
42 Int J Radiat Oncol Biol Phys,2000,47(2):435-442. Local radiotherapy with or without transcathter arterial chemoembolization for patients with unresectable hepatocellular carcinoma. Cheng JC, ChuanVP, Cheng SH, et al.
43 Int J Radiat Oncol Biol Phys,2000,47(5):393-397. Local radiotherapy for unresectable hepatocellular carcinoma. Seong J, Park HC, Han KH, et al.
44 Hepatogastroenterology,1998,45(21):791-796. The usefulness of radiation therapy for hepatocellular carcinoma. Matsuura M, Nakajima N, Arai K, et al.
45 Int J Radiat Oncol Biol Phys,1993,27(1):117-123. Accelerated hyperfractionated hepatic irradiation in the management of patients with liver metastasis:results of the RTOG dose escalating protocol. Russell AH, Clyde C, Wasserman TH.
46 Technology in Cancer Research & Treatment,2005,2(5):389-399.Treatment Planning for Conformal Proton Radiation Therapy. Bussiere MR, Adams JA.
47 Bull Cancer Radiother,1996,83:s207-211. Clinical Applications of Proton Therapy. Habrand JL, Schlienger P, Schwartz L, et al.
48 Int J Radiat Oncol Biol Phys,1991,21(1):109-122. Tolerance of normal tissue to the therapeutic irradiation. Emami B, Lyman J, Brown A, et al.
49 Phys Med Biol,1983,29(5):553-566. Compensating For Heterogeneities in Proton Radiation Therapy. Urie M, Goitein M, Wagner M.
50 Int J Radiat Oncol Biol Phys,1997,38(2):367-372. Radiation tolerance of cirrhotic livers in relation to the preserved functional capacity:analysis of patients with hepatocellular carcinoma treated by focused proton beam radiotherapy. Ohara K, Okumura T, Tsuji H, et al.
51 Int J Cancer,2002,97(1):72-81. Estimates of the world-wide prevalence of cancer for 25 sites in the adult population. Pisani P, Bray F, Parkin DM.
52 World J Gastroenterol,2002,8(5):797-803. DNA-PKcs subunits in radiosensitization by hyperthermia on hepatocellular carcinoma HepG2 cell line. Zeng ZC, Jiang GL, Wang GM, et al.
53 World J Gastroenterol,2003,9(8):1697-1701. Comparison between chemoembolization combined with radiotherapy and chemoembolization alone for large hepatocellular carcinoma. Guo WJ, Yu EX, Liu LM, et al.
54 Int J Radiat Oncol Biol Phys,1992,22(2):383-389. The proton treatment center at Loma Linda University Medical Center:rationale for and description of its development. Slater JM, Archambeau JO, Miller DW, et al.
55 Nature,1958,182(4644):1222-1223. The high-energy proton beam as a neurosurgical tool. Larsson B, Leksell L, Rexed B, ea al.
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