食管鳞状细胞癌和贲门腺癌放射治疗临床靶体积的病理及临床研究
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摘要
食管癌是世界第八大常见癌症,中国是高发地区。食管癌患者就诊时绝大多数处于中晚期,已失去手术机会。而放射治疗是治疗食管癌患者的重要手段之一。但是常规外照射的5年生存率为10%左右,而食管癌放射治疗失败的主要原因为局部未控或复发。而接受手术治疗的食管癌患者,局部及区域复发仍然是失败的主要原因,为了改善食管癌术后局部和区域的控制率,将术后放疗作为手术后的辅助治疗手段之一。然而,由于靶区的遗漏造成的局部区域失败以及由于放射治疗射野的扩大造成的治疗有关的毒性反应存在于相当一部分病人中。在我国贲门癌死亡率呈上升趋势,对于不能接受手术治疗的患者,也需要进行放射治疗。因此准确地定义放射治疗靶区以改善局部控制率和降低副反应是非常必要的。传统上二维计划的外照射治疗模式,存在剂量分布的高度不确定性和正常组织损伤几率高的缺点。目前,三维适形放射治疗(3DCRT)逐渐成为放射治疗的主要治疗手段并取代常规外照射。3DCRT特别是调强适形放射治疗(IMRT)的剂量适形度对于尽可能的减少对危及器官和其他正常组织的照射进而降低毒副作用是适合的。3DCRT和IMRT在很大程度上依赖病人体位的精确固定、治疗靶区的精确勾画和精确的治疗计划。然而,目前食管癌的靶区勾画仍然根据以前的二维治疗计划模式设计,各国定义临床靶体积(CTV)范围存在一定差异。了解肿瘤扩散的自然途径,并了解采用不同CTV范围放射治疗食管癌后的失败方式及预后,对于确保包括镜下浸润的区域、定义食管癌及贲门癌合理的CTV是十分重要的。故本研究对食管癌及贲门癌放射治疗的CTV进行了病理方面的研究,并对食管癌放射治疗CTV进行了临床方面的探讨。
第一部分食管胸中、下段鳞状细胞癌及贲门腺癌放射治疗临床靶体积的病理学研究
目的:前瞻性研究食管胸中、下段鳞状细胞癌与贲门腺癌大体肿瘤外的镜下扩散长度与淋巴结转移的情况,来评价放射治疗的临床靶体积的范围。
方法:有计划地收集食管癌(34例)和贲门癌(32例)手术标本共66例。所有病例术前未接受过任何治疗如放疗和化疗。分别详细记录食管病变、所取淋巴结术中的所处位置。将大体标本均以长轴20mm、横径3mm大小取组织制作蜡块,编号,连续切片及HE染色,由有经验的病理医生在光学显微镜下观察大体肿瘤的浸润深度和大体肿瘤外的镜下浸润长度及淋巴结的转移情况。根据回缩率计算出实际的大体肿瘤(GTV)外镜下外侵长度。
结果:对于食管鳞状细胞癌,大体肿瘤外镜下浸润的平均长度为10.6±11.0 mm (0～71.0mm) ,34例患者中32例<30mm。而贲门腺癌大体肿瘤外近端镜下浸润为10.3±7.2mm ( 0～29.0 mm),可统计病例29例,均小于<30mm;远端镜下浸润的平均长度为18.3±16.3 mm (0～57.0 mm),32例中27例患者(84.4%)<30mm,93.8%(30/32)<50mm。胸中、下段食管鳞癌,淋巴结转移率为35.3%(12/34),其中发生于隆突下淋巴结4例、食管旁3例、气管旁2例、胃左5例和贲门旁3例。而贲门腺癌中,淋巴结的转移率为46.9%(15/32),其中发生于食管旁淋巴结5例、胃左14例、贲门旁14例、脾周和后纵隔各1例。
结论:1.食管鳞状细胞癌大体肿瘤的近、远侧端和贲门腺癌的近侧段从GTV外扩30mm作为CTV比较适宜,但对于贲门腺癌的远侧端,从GTV外扩50mm作为CTV比较适宜。2.准确的N分期对于放射治疗计划的靶区勾画是非常重要的,特别是对CTV的勾画。高危的淋巴结区域应该包括在CTV范围内。
第二部分不同照射技术及临床靶体积放射治疗食管胸中、下段鳞状细胞的失败方式
目的:通过分析食管癌放射治疗后初次失败的方式来评价不同的的照射技术及临床靶体积范围。
方法:收集了2004年1月至2006年6月在河北医科大学第四医院放一科以根治性目的收治的食管胸中、下段鳞状细胞癌单纯放疗或放化疗的患者共151例,并进行了较为详细的跟踪随访,对初次失败的部位及方式进行了分析。常规野组64例:在常规模拟机下定位,治疗的靶区中心参照食管造影、内镜检查及胸部CT综合而定。照射范围为食管原发灶大体肿瘤上下外扩3～5cm,周围外扩1.5cm,如果有区域淋巴结肿大,还应包全累及淋巴结区,靶区照射剂量为50～62Gy/5～6.5周。87例接受3DCRT,其中累及野组55例:GTV包括影像学可见的食管原发灶和有意义的肿大淋巴结。CTV包括原发灶上下外扩3cm、周围外扩0.8cm及肿大淋巴结累及区,PTV为CTV外上下外扩1cm,周围外扩0.5cm,PTV1为食管GTV上下外扩1.5cm、周围外扩0.8cm和淋巴累及区。扩大野组32例:GTV、PTV和PTV1勾画同累及野组,CTV食管外扩同累及野,但还要根据食管原发灶部位不同,给予邻近区域淋巴结的预防照射。PTV的处方剂量为54～62Gy/27～31次/5.5～6.5周,或PTV的处方剂量为50Gy/25次/5周,后程缩野加量PTV1为10～12 Gy。
结果:总失败率为57.0%(86/151),总的局部及区域失败率为40.4%(61/151),而单纯局部及区域复发率为36.4%(55/151),总的远处转移率为20.5%(31/151)。常规野组、累及野组、扩大野组的总失败率分别为59.4%(38/64)、61.8%(34/55)和43.8%(14/32);单纯局部及区域失败率分别为40.6%(26/64)、30.9%(17/55)和37.5%(12/32);总远处转移率分别18.8%(12/64)、30.9%(17/55)和6.3%(2/32)。前两组的总失败率高于扩大野组,无统计学差异(P=0.228),总远处转移率高于扩大野组,有统计学差异(P=0.021)。常规组和累及野组的单纯野外区域淋巴结失败发生率分别为6.3%(4/64)和7.3%(4/55),而扩大野组中未出现区域淋巴结的野外复发。单纯放疗组和放化疗组总失败率分别为60.5%(69/114)和45.9%(17/37)(P<0.05),单纯局部及区域失败率分别为40.4%(46/114)和24.3%(9/37)(P<0.05) ;总远处转移率分别为20.2%(23/114)和21.6%(8/37)(P>0.05)。从区域淋巴结复发的部位来看,食管气管旁沟淋巴结失败的比例最大,占4.6%(7/151);其次为胃左,4.0%(6/151)。野外食管失败3例,占2.0%(3/151)。
结论: 1.治疗失败的主要原因是局部/区域失败,远处转移占20%左右。而单纯野外淋巴结失败占5.3%。野外食管发生病变率为2%左右。2.扩大野有降低总失败率的趋势,可降低远处转移和野外区域淋巴结失败。3.联合放化疗可以提高局部控制、降低总失败率。4.食管GTV上下外扩3cm作为CTV对原发灶局部控制是合理的。
第三部分不同临床靶体积范围对食管胸中、下段鳞状细胞癌放射治疗预后的影响
目的:分析不同范围的CTV对食管胸中、下段鳞状细胞癌放射治疗预后的影响及副反应的发生,以指导适形放射治疗计划的合理应用。
方法:收集了2004年1月至2006年6月在放一科以根治性目的收治的食管胸中、下段鳞状细胞癌单纯放疗或放化疗的患者共151例,进行了较为详细的跟踪随访,对生存预后及副反应进行了分析。常规野组64例,87例患者接收3DCRT,其中累及野组55例,扩大野组32例。定位、治疗方式、适形放疗靶区勾划及靶区剂量同第二部分。
结果:常规野组、累及野组和扩大野组的12月和18月总生存率分别为75.1%和62.2%、69.2%和51.1%、73.4%和73.4%;局控率分别为73.7%和68.1%、66.0%和55.9%、61.3%和61.3%;无进展生存率分别为63.2%和55.9%、47.6%和29.8%、53.4%和26.7%;无转移生存率分别为87.8%和79.5%、75.1%和71.4%、93.3%和93.3%。各组间比较均无明显差异。多因素分析显示影响总生存率的独立预后因素为CT-T分期和近期疗效,放化疗有提高总生存率的趋势,而CTV范围不同对总生存率无明显影响;CT-T分期早和联合化疗有提高局控率的趋势(P接近0.05);T分期是影响无进展生存的独立预后因素(P=0.003),联合化疗有提高无进展生存的趋势,但无统计学差异(P=0.061)。常规野组、累及野组和扩大野组的放射性食管炎发生率分别为71.9%(46/64)、69.1%(38/55)和87.5%(28/32),扩大野组高于其他两组,有统计学差异(P<0.05)。扩大野组的放射性肺炎的发生率高于常规野组和累及野组。
结论:1.食管胸中、下段鳞状细胞癌扩大野适形放射治疗较常规定位放射治疗和累及野适形放射治疗在总生存率、局部控制率、无进展生存率及无转移生存率方面未显示出明显的优势。2.扩大野组较常规野组和累及野组的放射性食管炎、肺炎发生率高。3.放化疗联合治疗食管癌有提高局控率、改善生存率及无进展生存的趋势。4.CT-T分期和近期疗效是影响生存率的独立预后因素。CT-T分期是影响无进展生存的独立预后因素。
第四部分食管鳞状细胞癌根治术后预防照射临床靶体积的研究
目的:比较和分析食管癌术后预防照射临床靶体积范围对生存率的影响。
方法:对102例食管癌根治术后放疗剂量在50Gy或以上的病例进行生存分析。大野组43例,照射范围为双锁骨上区、全纵隔、吻合口及胃左区;小野组59例,临床靶体积范围根据病变部位不同而不同:胸上段食管癌为食管瘤床、双侧锁骨上区、上中纵隔;胸中段食管癌患者为食管瘤床上下各扩大5cm及纵隔淋巴结引流区(不包括胃左区);胸下段食管癌包括瘤床、隆突下淋巴结区及胃左淋巴结区。
结果:全部病例的1、3、5年生存率分别为76.3%、50.5%和42.9%,中位生存期为30个月。大野组的1、3和5年生存率分别为76.5%、52.1%和41.3%,而小野组的1、3和5年生存率分别为76.2%、49.2%和44.6%,无统计学差异,P=0.884。T1和T2病例的1、3和5年生存率分别为88.1%、63.4%、57.1%,T3和T4病例的1、3和5年生存率分别为71.0%、44.6%、36.2%,两组比较P=0.0383。N0和N1病例的1、3和5年生存率分别为95.6%、72.0%、60.3%和62.5%、31.1%、28.9%(P=0.000)。无淋巴结转移病例的1、3和5年生存率分别为95.6%、72.0%和60.3%,1～2个淋巴结转移病例的1、3和5年生存率分别为67.4%、33.3%和26.8%,而3个或3个以上淋巴结转移病例的1、3和5年生存率分别为20.0%、20.0%和20.0%(P=0.000)。小于或等于5cm病例的1、3和5年生存率为81.5%、62.0%和53.9%,5cm以上病例的1、3和5年生存率分别为67.9%、37.5%和32.4%(P=0.0224)。多因素分析显示,N分期、淋巴结转移数目及病变长度是影响预后的独立因素。
结论:1.食管癌根治术后预防照射时,适当缩小照射野是可行的,不会降低生存率。2.食管鳞状细胞癌术后放射治疗的独立预后因素包括N分期、转移淋巴结的数目及食管原发灶的长度。
结论
1.病理学研究结果显示,对于食管胸中、下段鳞状细胞癌的近侧、远侧端和贲门腺癌的近侧端,大体肿瘤外扩3cm为CTV比较合适;而对于贲门腺癌的远侧端,需要外扩5cm比较合适。准确的N分期对于放射治疗计划的靶区勾画是非常重要的,特别是对CTV的勾画。
2.食管胸中、下段鳞状细胞癌放射治疗首次失败的主要原因是局部/区域失败,但远处转移仍占有20%左右。单纯野外区域淋巴结失败占5.3%。野外食管发生病变率为2%左右。
3.扩大野适形放射治疗较常规照射组和淋巴累及野组相比,可降低总失远处转移和野外区域淋巴结失败;但在改善总生存率、局部控制率、无进展生存率及无转移生存率方面未显示出明显的优势。而其放射性食管炎及肺炎较高。
4.临床研究结果显示食管GTV上下外扩3cm作为CTV对原发灶局部控制是合理的。
5.联合放化疗治疗食管鳞状细胞癌可以减少食管局部失败的几率,有改善局控率、改善生存率及无进展生存的趋势。
6.食管癌根治术后预防照射时,适当缩小照射野是可行的,不会降低生存率。食管鳞状细胞癌术后放射治疗的独立预后因素包括N分期、转移淋巴结的数目及食管原发灶的长度。
7.本研究的临床部分,随访时间短,为非随机性。目前我们正在进行前瞻性随机分组研究。
Esophageal carcinoma is a lethal disease. It was the eighth most common cancer world wide, responsible for 462,000 new cases in 2002 and sixth most common cause of death from cancer with 386,000 death. The age-standardized incidence per 100,000 was 19.7. Most patients with esophageal cancer present with locally advanced disease. Radiotherapy is crucial for tumor local control, but locoregional control rates for locally advanced esophageal cancer are less than 50%, and the 5-year overall survival rate is only about 10% when definitive radiotherapy was given. However, locoregional recurrence due to missed targets and treatment-related toxicity caused by large fields of radiation still occur in a substantial proportion of patients. The morbidity of cardiac adenocarcinoma has the tendency to increase. Some patients with cardiac adenocarcinoma need radiotherapy because of unresectable and medically inoperable reasons. More accurate radiotherapy targeting is needed to improve locoregional control and reduce toxicity. The development of new methods of image-guided radiotherapy, including three-dimensional conformal and intensity-modulated radiotherapy, has allowed radiation oncologists to target esophageal cancers more accurately and effectively while sparing surrounding normal tissue. However, target delineation for esophageal cancer still relies on previous two-dimensional treatment designs. And the definition of clinical target volume (CTV) margins is quite different among different countries. And the extent of microscopic spread of cardiac adenocarcinoma is unknown. This information is crucial for determining the CTV margin for radiotherapy for esophageal cancer and cardiac adenocarcinoma. The purpose of this study was to clarify the CTV margin needed for radiotherapy for esophageal squamous cell carcinoma and cardiac adenocarcinoma pathologically, and to evaluate the CTV for esophageal squamous cell carcinoma clinically by analyzing the patterns of failure and prognosis after radiotherapy with different radiation technique and different CTV margins.
Part 1:Pathologic analysis of clinical target volume margin for radiotherapy in patients with esophageal SCC and cardiac adenocarcinoma treated by surgical resection only
Objective: To study prospectively the extent of microscopic spread and lymph node (LN) metastasis in patients with esophageal squamous cell carcinoma (SCC) and cardiac adenocarcinoma treated by surgery only and to evaluate the clinical target volume (CTV) in radiotherapy.
Methods: Sixty-six patients (34 with esophageal SCC and 32 with cardiac adenocarcinoma) treated by definitive surgical resection were included. All LNs received were labeled anatomically. The resected specimen was completely blocked for histological examination from proximal to distal at 20 mm interval in length and 3 mm in width. All H&E slides were examined by experienced pathologists for evidence of microscopic spread along the length of esophagus proximal and esophagus/stomach distal to gross tumor, and for LN metastasis.
Results: The mean microscopic spread beyond gross tumor was 10.6±11.0 mm (range 0-71 mm, 32 of 34 cases <30mm) for esophageal SCC and 10.3±7.2 mm (range 0-29.0 mm, 29 of 29 cases <30mm) proximally and 18.3±16.3mm (range 0-57.0 mm, 27 of 32 cases <30mm) distally for cardiac adenocarcinoma. The length of microscopic spread within esophagus is less than 30 mm in 94.1% of esophageal squamous cell cancer cases. The proximal microscopic spread of cardiac adenocarcinoma is less than 30mm in all cases. While only in about 84.4% of cardiac adenocarcinomas, the distal microscopic spread is less than 30mm, and it is less than 50mm in 93.8% of cases in cardiac adenocarcinomas. The extent of microscopic spread of cancer was significantly associated with pathologic T stage (P=0.012). For patients with middle and lower esophageal SCC, LN metastases were observed in 35.3% (12/34 cases, subcarinal LN in 4 cases, paraesophageal LN in 3 case, paratracheal LN in 2 cases, left gastric LN in 5 cases, and paracardiac LN in 3 cases). For patients with cardiac adenocarcinoma, LN metastases were found in 46.9% (15 of 32) of cases (5 in paraesophageal LN, 14 in left gastric LN, 13 in paracardiac LN, 1 in peri-spleen LN and posterior mediastinal LN respectively).
Conclusion: (1) A 3-cm longitudinal margin from gross target volume to CTV appeared to be adequate for most cases of esophageal squamous cell carcinoma within esophagus and for the proximal extent of microscopic spread of cardiac adenocarcinoma. And for distal microscopic spread in cardiac adenocarcinoma, 5cm was needed to cover about 94% of cases. (2) Accurate stage of LN is very important for radiation treatment target design. High-risk lymph node regions need to be covered by CTV.
Part 2:The patterns of primary failure after radiotherapy with different radiation technique and clinical target volume margins for patients with squamous cell carcinoma of middle and lower third thoracic esophagus
Objective: To evaluate the different radiation technique and clinical target volume margins by analyzing the patterns of primary failure after radiotherapy for patients with esophageal squamous cell carcinoma (SCC).
Methods: From January 2004 to June 2006, 151 patients with middle or lower third thoracic esophageal SCC receiving definitive radiotherapy or chemoradiotherapy were accrued and were followed up. The patterns of the primary failure were analyzed. There were 64 patients in the conventional radiotherapy group. In this group, the portal was outlined on the skin under the conventional simulator. The target center was defined according to the presentation on barium meal, endoscopy and CT. Three to 5 cm proximal and distal margins and 1.5 cm lateral margin from the border of GTV were included in the CTV. The involved regional lymphatics were also included in the CTV when the lymph node was considered abnormal. The prescribed dose was 50 to 62 Gy in 5 to 6.5 weeks. 87 patients were given 3DCRT, of which there were 55 patients in the involved nodal irradiation group. The GTV was defined as any visible tumor on the image. The CTV was defined as the GTV plus a 3-cm margin superior and inferior to the primary tumor and a 0.8-1.0 cm radial margin. The PTV was defined as the CTV plus a 1.0- cm longitudinal margin and a 0.5-cm radial margin. The involved lymphatic region was also included in the CTV. The PTV1 was defined as GTV plus a 1.5cm margin superior and inferior to the primary tumor and a 0.8-1.0 cm radial margin, and also the involved lymphatic region. And 32 patients were included in the elective nodal irradiation group. The GTV, PTV and PTV1 were defined the same as that in the involved nodal irradiation group. Besides the same margins outside the primary tumor as that in the involved nodal irradiation group, the adjacent regional lymphatics was included in the CTV according to the different location of the primary tumor. The prescribed dose to PTV was 54 to 62Gy in 5.5 to 6.5 weeks or 50 Gy in 5 weeks followed by 10 to 12Gy to PTV1.
Results: The total failure rate, locoregional failure rate, locoregional failure alone and total distant metastatic rate were 57.0% (86/151), 40.4% (61/151), 36.4%(55/151) and 20.5%(31/151) respectively for all patients in this study. The total failure rate was 59.4%(38/64), 61.8%(34/55) and 43.8%(14/32) respectively in the conventional radiotherapy group, the involved nodal irradiation group and the elective nodal irradiation group, which showed that it was higher in the former two groups than in the latter group, but no statistical difference was observed (P=0.228). Locoregional failure alone was 40.6% (26/64), 30.9% (17/55) and 37.5%(12/32) respectively for the three groups. And the total distant metastatic rate was 18.8% (12/64), 30.9% (17/55) and 6.3%(2/32) respectively for the three groups, which was higher in the former two groups than that in the latter group (P=0.021). The relapse rate of elective node outside CTV was 6.3%(4/64) and 7.3%(4/55) in the conventional radiotherapy group and the involved nodal irradiation group respectively. No relapse outside CTV was found in the elective nodal irradiation group. The total failure rate and locoregional failure alone rate were 60.5%(69/114)and 45.9%(17/37), 40.4%(46/114)and 24.3%(9/37)respectively in the radiotherapy alone group and chemoradiotherapy group, P<0.05.There was no significant difference in total distant metastatic rate between the radiotherapy group and chemoradiotherapy group, 20.2%(23/114) vs. 21.6%(8/37) with P>0.05. By analyzing the anatomical sites of regional failure, the probability of paraesophagotracheal lymph node metastasis was the highest (4.6%), with left gastric lymph node metastasis followed (4.0%). Only 2% (3/151) were found with esophageal disease outside CTV.
Conclusion: (1) The main reason for the failure of esophageal SCC after radiotherapy was locoregional relapse. About 20% of esophageal SCC relapsed duo to distant metastasis. Regional relapse alone outside CTV was 5.3% and esophageal disease outside CTV was about 2%. (2) The elective nodal irradiation could decrease the total distant metastasis rate and elective node relapse rate outside the CTV. (3) Chemoradiotherapy may improve the local control. (4) The CTV defined as GTV plus a 3-cm margin superior and inferior to the primary tumor was considered as reasonable for the controlling esophageal primary tumor.
Part 3: Comparison of efficacy and toxicities of different clinical target volumes in definitive radiotherapy for squamous cell carcinoma of middle and lower third thoracic esophagus
Objective: To evaluate the different radiation technique and clinical target volume (CTV) margins by analyzing the prognosis and toxicities after radiotherapy for patients with esophageal squamous cell carcinoma (SCC) and to suggest a reasonable CTV for 3DCRT.
Methods: From January 2004 to June 2006, 151 patients with middle or lower third thoracic esophageal SCC receiving definitive radiotherapy or chemoradiotherapy were accrued and were followed up. The overall survival rate, locoregional control rate, progression-free survival, distant metastasis-free survival and toxicities were analyzed and compared. The simulating method, delineation of target volumes for 3DCRT and the prescribed dose to the target were the same as that in Part 2. There were 64 patients in the conventional radiotherapy group, 55 patients in the involved nodal irradiation group and 32 patients in the elective nodal irradiation group.
Results: The 12-month and 18-month overall survival rates were 75.1% and 62.2%, 69.2% and 51.1%, 73.4% and 73.4% respectively in the conventional radiotherapy group, the involved nodal irradiation group and the elective nodal irradiation group. The 12-month and 18-month locoregional control rates were 73.7% and 68.1%, 66.1% and 55.9%, 61.3% and 61.3% respectively in the three groups. The 12-month and 18-month progression-free survival rates were 63.2% and 55.9%, 47.6% and 29.8%, 53.4% and 26.7% respectively. The 12-month and 18-month distant metastasis-free survival rates were 87.8%% and 79.5%, 75.1% and 71.4%, 93.3% and 93.3% respectively. No statistical difference was found among the three groups, all with P>0.05. In Cox multivariate analysis, T stage and tumor response after radiotherapy were the independent factors for overall survival. T stage had the tendency to improve the local control and was the independent factor for progression-free survival rate. And chemoradiotherapy had the tendency to improve the overall survival, local control and progression-free survival. The CTV had no effect on the overall survival, local control, progression-free survival and metastasis-free survival. The radiation esophagitis was 71.9%(46/64), 69.1%(38/55) and 87.5% (28/32) respectively in the conventional radiotherapy group, the involved nodal irradiation group and the elective nodal irradiation group. The latter was higher than that of the former two groups, P<0.05.The symptomatic radiation pneumonitis was higher than that of the conventional radiotherapy group and the involved nodal irradiation group.
Conclusion: (1) Conformal radiotherapy with elective nodal irradiation for middle and lower third thoracic esophageal SCC showed no significant advantage over the conformal radiotherapy with the involved nodal irradiation and the conventional radiotherapy in overall survival, local control, progression-free survival and distant metastasis-free survival. (2) Conformal radiotherapy with elective nodal irradiation conferred a higher radiation esophagitis and pneumonitis rate compared to the conventional radiotherapy and conformal radiotherapy with involved nodal irradiation. (3) Combined chemoradiotherapy showed a tendency to improve the overall survival, local control and progression-free survival. (4) CT-T stage and tumor response were the independent factors for overall survival. CT-T stage was the independent factor for the progression-free survival.
Part 4: Comparison of efficacy and toxicity of regional and extensive clinical target volumes in postoperative radiotherapy for esophageal squamous cell carcinoma
Objective: To compare and analyze the effect of different clinical target volumes (CTVs) on survival rate after postoperative radiotherapy (RT) for esophageal squamous cell carcinoma (SCC).
Methods: We studied 102 patients who underwent postoperative RT after radical resection for esophageal SCC (T3/4 or N1). The radiation dose was at least 50 Gy. In the extensive portal group (E group, 43 patients), the CTV encompassed the bilateral supraclavicular region, all mediastinal lymph nodes, the anastomosis site, and the left gastric and paracardiac lymphatics. In the regional portal group (R group, 59 patients), the CTV was confined to the lymph nodes in the immediate region of the primary lesion. The 1-, 3-, and 5-year survival rates were compared between the groups and multivariate/univariate analysis for factors predicting survival was studied.
Results: The 1-, 3- and 5- survival rates were 76.3%, 50.53% and 42.87% respectively, with a median survival of 30 months. The 1-, 3-and 5-year survival rates were 76.5%, 52.1% and 41.3% in the extensive portal group and 76.2%, 49.2%, and 44.6% in the regional portal group respectively, with no statistical difference between the two groups, P=0.884。The 1-, 3-, and 5-year survival rates were 88.1%, 63.4%, and 57.1%, respectively, for patients with T1 or T2 disease and 71.0%, 44.6 %, and 36.2%, respectively, for those with T3 or T4 disease. Patients with T1 or T2 disease had significantly better survival rates than did those with T3 or T4 disease (P=0.0383). The 1-, 3-, and 5-year survival rates were 95.6%, 72.0%, and 60.3%, respectively, for patients with N0 disease and 62.5%, 31.1%, and 28.9%, respectively, for patients with N1 disease (P=0.000). The 1-, 3-, and 5-year survival rates were 95.6%, 72.0%, and 60.3%, respectively, in patients with no metastatic lymph nodes (group 1); 67.4%, 33.3%, and 26.8%, respectively, in patients with 1-2 metastatic lymph nodes (group 2); and 20%, 20%, and 20% in patients with 3 or more metastatic lymph nodes (group 3) (P=0.000). The 1-, 3-, and 5-year survival rates were 81.5%, 62.0%, and 53.9%, respectively, for patients with tumors≤5 cm long and 67.9%, 37.5%, and 32.4%, respectively, for patients with tumors >5 cm long (P=0.0224). According to the multivariate analysis, N stage, number of metastatic lymph nodes and tumor length were the independent factors in survival.
Conclusion: Using a regional CTV for postoperative RT in patients with esophageal SCC is feasible, and it does not compromise survival rates. Factors predicting survival time in patients with esophageal SCC are N stage, number of lymph nodes with metastatic disease, and tumor length.
Conclusion
1. The pathological analysis showed that a 3-cm longitudinal margin from gross target volume to CTV appeared to be adequate for most cases of esophageal squamous cell carcinoma within esophagus and for the proximal extent of microscopic spread of cardiac adenocarcinoma. And for distal microscopic spread in cardiac adenocarcinoma, 5cm was needed to cover about 94% of cases. Accurate stage of LN is very important for radiation treatment target design. High-risk lymph node regions need to be covered by CTV.
2. The main reason for the primary failure of esophageal SCC after radiotherapy was locoregional relapse. About 20% of esophageal SCC relapsed duo to distant metastasis. Regional nodal relapse alone outside CTV was 5.3% and esophageal disease outside CTV was about 2%.
3. Conformal radiotherapy with elective node portal for middle and lower third thoracic esophageal SCC could decrease total distant metastasis rate and elective nodal relapse rate outside the CTV. But it showed no significant advantage over the conformal radiotherapy with involved node portal and the conventional radiotherapy in overall survival, local control, progression-free survival and distant metastasis-free survival. And higher morbidities of radiation esophagitis and pneumonitis were observed in the elective node portal group.
4. The clinical analysis showed that the CTV defined as GTV plus a 3-cm margin superior and inferior to the primary tumor was considered as reasonable for controlling the esophageal primary tumor.
5. Chemoradiotherapy may reduce the local failure and showed a tendency to improve the overall survival, local control and progression-free survival.
6. Using a regional CTV for postoperative RT in patients with esophageal SCC is feasible, and it does not compromise survival rates. Factors predicting survival time in patients with esophageal SCC are N stage, number of lymph nodes with metastatic disease, and tumor length.
7. The clinical study was non-randomized and the follow-up time was not longer enough. A randomized study is being done about the different CTVs on the prognosis of esophageal SCC.
第一部分食管胸中、下段鳞状细胞癌及贲门腺癌放射治疗临床靶体积的病理学研究
目的:前瞻性研究食管胸中、下段鳞状细胞癌与贲门腺癌大体肿瘤外的镜下扩散长度与淋巴结转移的情况,来评价放射治疗的临床靶体积的范围。
方法:有计划地收集食管癌(34例)和贲门癌(32例)手术标本共66例。所有病例术前未接受过任何治疗如放疗和化疗。分别详细记录食管病变、所取淋巴结术中的所处位置。将大体标本均以长轴20mm、横径3mm大小取组织制作蜡块,编号,连续切片及HE染色,由有经验的病理医生在光学显微镜下观察大体肿瘤的浸润深度和大体肿瘤外的镜下浸润长度及淋巴结的转移情况。根据回缩率计算出实际的大体肿瘤(GTV)外镜下外侵长度。
结果:对于食管鳞状细胞癌,大体肿瘤外镜下浸润的平均长度为10.6±11.0 mm (0～71.0mm) ,34例患者中32例<30mm。而贲门腺癌大体肿瘤外近端镜下浸润为10.3±7.2mm ( 0～29.0 mm),可统计病例29例,均小于<30mm;远端镜下浸润的平均长度为18.3±16.3 mm (0～57.0 mm),32例中27例患者(84.4%)<30mm,93.8%(30/32)<50mm。胸中、下段食管鳞癌,淋巴结转移率为35.3%(12/34),其中发生于隆突下淋巴结4例、食管旁3例、气管旁2例、胃左5例和贲门旁3例。而贲门腺癌中,淋巴结的转移率为46.9%(15/32),其中发生于食管旁淋巴结5例、胃左14例、贲门旁14例、脾周和后纵隔各1例。
结论:1.食管鳞状细胞癌大体肿瘤的近、远侧端和贲门腺癌的近侧段从GTV外扩30mm作为CTV比较适宜,但对于贲门腺癌的远侧端,从GTV外扩50mm作为CTV比较适宜。2.准确的N分期对于放射治疗计划的靶区勾画是非常重要的,特别是对CTV的勾画。高危的淋巴结区域应该包括在CTV范围内。
第二部分不同照射技术及临床靶体积放射治疗食管胸中、下段鳞状细胞的失败方式
目的:通过分析食管癌放射治疗后初次失败的方式来评价不同的的照射技术及临床靶体积范围。
方法:收集了2004年1月至2006年6月在河北医科大学第四医院放一科以根治性目的收治的食管胸中、下段鳞状细胞癌单纯放疗或放化疗的患者共151例,并进行了较为详细的跟踪随访,对初次失败的部位及方式进行了分析。常规野组64例:在常规模拟机下定位,治疗的靶区中心参照食管造影、内镜检查及胸部CT综合而定。照射范围为食管原发灶大体肿瘤上下外扩3～5cm,周围外扩1.5cm,如果有区域淋巴结肿大,还应包全累及淋巴结区,靶区照射剂量为50～62Gy/5～6.5周。87例接受3DCRT,其中累及野组55例:GTV包括影像学可见的食管原发灶和有意义的肿大淋巴结。CTV包括原发灶上下外扩3cm、周围外扩0.8cm及肿大淋巴结累及区,PTV为CTV外上下外扩1cm,周围外扩0.5cm,PTV1为食管GTV上下外扩1.5cm、周围外扩0.8cm和淋巴累及区。扩大野组32例:GTV、PTV和PTV1勾画同累及野组,CTV食管外扩同累及野,但还要根据食管原发灶部位不同,给予邻近区域淋巴结的预防照射。PTV的处方剂量为54～62Gy/27～31次/5.5～6.5周,或PTV的处方剂量为50Gy/25次/5周,后程缩野加量PTV1为10～12 Gy。
结果:总失败率为57.0%(86/151),总的局部及区域失败率为40.4%(61/151),而单纯局部及区域复发率为36.4%(55/151),总的远处转移率为20.5%(31/151)。常规野组、累及野组、扩大野组的总失败率分别为59.4%(38/64)、61.8%(34/55)和43.8%(14/32);单纯局部及区域失败率分别为40.6%(26/64)、30.9%(17/55)和37.5%(12/32);总远处转移率分别18.8%(12/64)、30.9%(17/55)和6.3%(2/32)。前两组的总失败率高于扩大野组,无统计学差异(P=0.228),总远处转移率高于扩大野组,有统计学差异(P=0.021)。常规组和累及野组的单纯野外区域淋巴结失败发生率分别为6.3%(4/64)和7.3%(4/55),而扩大野组中未出现区域淋巴结的野外复发。单纯放疗组和放化疗组总失败率分别为60.5%(69/114)和45.9%(17/37)(P<0.05),单纯局部及区域失败率分别为40.4%(46/114)和24.3%(9/37)(P<0.05) ;总远处转移率分别为20.2%(23/114)和21.6%(8/37)(P>0.05)。从区域淋巴结复发的部位来看,食管气管旁沟淋巴结失败的比例最大,占4.6%(7/151);其次为胃左,4.0%(6/151)。野外食管失败3例,占2.0%(3/151)。
结论: 1.治疗失败的主要原因是局部/区域失败,远处转移占20%左右。而单纯野外淋巴结失败占5.3%。野外食管发生病变率为2%左右。2.扩大野有降低总失败率的趋势,可降低远处转移和野外区域淋巴结失败。3.联合放化疗可以提高局部控制、降低总失败率。4.食管GTV上下外扩3cm作为CTV对原发灶局部控制是合理的。
第三部分不同临床靶体积范围对食管胸中、下段鳞状细胞癌放射治疗预后的影响
目的:分析不同范围的CTV对食管胸中、下段鳞状细胞癌放射治疗预后的影响及副反应的发生,以指导适形放射治疗计划的合理应用。
方法:收集了2004年1月至2006年6月在放一科以根治性目的收治的食管胸中、下段鳞状细胞癌单纯放疗或放化疗的患者共151例,进行了较为详细的跟踪随访,对生存预后及副反应进行了分析。常规野组64例,87例患者接收3DCRT,其中累及野组55例,扩大野组32例。定位、治疗方式、适形放疗靶区勾划及靶区剂量同第二部分。
结果:常规野组、累及野组和扩大野组的12月和18月总生存率分别为75.1%和62.2%、69.2%和51.1%、73.4%和73.4%;局控率分别为73.7%和68.1%、66.0%和55.9%、61.3%和61.3%;无进展生存率分别为63.2%和55.9%、47.6%和29.8%、53.4%和26.7%;无转移生存率分别为87.8%和79.5%、75.1%和71.4%、93.3%和93.3%。各组间比较均无明显差异。多因素分析显示影响总生存率的独立预后因素为CT-T分期和近期疗效,放化疗有提高总生存率的趋势,而CTV范围不同对总生存率无明显影响;CT-T分期早和联合化疗有提高局控率的趋势(P接近0.05);T分期是影响无进展生存的独立预后因素(P=0.003),联合化疗有提高无进展生存的趋势,但无统计学差异(P=0.061)。常规野组、累及野组和扩大野组的放射性食管炎发生率分别为71.9%(46/64)、69.1%(38/55)和87.5%(28/32),扩大野组高于其他两组,有统计学差异(P<0.05)。扩大野组的放射性肺炎的发生率高于常规野组和累及野组。
结论:1.食管胸中、下段鳞状细胞癌扩大野适形放射治疗较常规定位放射治疗和累及野适形放射治疗在总生存率、局部控制率、无进展生存率及无转移生存率方面未显示出明显的优势。2.扩大野组较常规野组和累及野组的放射性食管炎、肺炎发生率高。3.放化疗联合治疗食管癌有提高局控率、改善生存率及无进展生存的趋势。4.CT-T分期和近期疗效是影响生存率的独立预后因素。CT-T分期是影响无进展生存的独立预后因素。
第四部分食管鳞状细胞癌根治术后预防照射临床靶体积的研究
目的:比较和分析食管癌术后预防照射临床靶体积范围对生存率的影响。
方法:对102例食管癌根治术后放疗剂量在50Gy或以上的病例进行生存分析。大野组43例,照射范围为双锁骨上区、全纵隔、吻合口及胃左区;小野组59例,临床靶体积范围根据病变部位不同而不同:胸上段食管癌为食管瘤床、双侧锁骨上区、上中纵隔;胸中段食管癌患者为食管瘤床上下各扩大5cm及纵隔淋巴结引流区(不包括胃左区);胸下段食管癌包括瘤床、隆突下淋巴结区及胃左淋巴结区。
结果:全部病例的1、3、5年生存率分别为76.3%、50.5%和42.9%,中位生存期为30个月。大野组的1、3和5年生存率分别为76.5%、52.1%和41.3%,而小野组的1、3和5年生存率分别为76.2%、49.2%和44.6%,无统计学差异,P=0.884。T1和T2病例的1、3和5年生存率分别为88.1%、63.4%、57.1%,T3和T4病例的1、3和5年生存率分别为71.0%、44.6%、36.2%,两组比较P=0.0383。N0和N1病例的1、3和5年生存率分别为95.6%、72.0%、60.3%和62.5%、31.1%、28.9%(P=0.000)。无淋巴结转移病例的1、3和5年生存率分别为95.6%、72.0%和60.3%,1～2个淋巴结转移病例的1、3和5年生存率分别为67.4%、33.3%和26.8%,而3个或3个以上淋巴结转移病例的1、3和5年生存率分别为20.0%、20.0%和20.0%(P=0.000)。小于或等于5cm病例的1、3和5年生存率为81.5%、62.0%和53.9%,5cm以上病例的1、3和5年生存率分别为67.9%、37.5%和32.4%(P=0.0224)。多因素分析显示,N分期、淋巴结转移数目及病变长度是影响预后的独立因素。
结论:1.食管癌根治术后预防照射时,适当缩小照射野是可行的,不会降低生存率。2.食管鳞状细胞癌术后放射治疗的独立预后因素包括N分期、转移淋巴结的数目及食管原发灶的长度。
结论
1.病理学研究结果显示,对于食管胸中、下段鳞状细胞癌的近侧、远侧端和贲门腺癌的近侧端,大体肿瘤外扩3cm为CTV比较合适;而对于贲门腺癌的远侧端,需要外扩5cm比较合适。准确的N分期对于放射治疗计划的靶区勾画是非常重要的,特别是对CTV的勾画。
2.食管胸中、下段鳞状细胞癌放射治疗首次失败的主要原因是局部/区域失败,但远处转移仍占有20%左右。单纯野外区域淋巴结失败占5.3%。野外食管发生病变率为2%左右。
3.扩大野适形放射治疗较常规照射组和淋巴累及野组相比,可降低总失远处转移和野外区域淋巴结失败;但在改善总生存率、局部控制率、无进展生存率及无转移生存率方面未显示出明显的优势。而其放射性食管炎及肺炎较高。
4.临床研究结果显示食管GTV上下外扩3cm作为CTV对原发灶局部控制是合理的。
5.联合放化疗治疗食管鳞状细胞癌可以减少食管局部失败的几率,有改善局控率、改善生存率及无进展生存的趋势。
6.食管癌根治术后预防照射时,适当缩小照射野是可行的,不会降低生存率。食管鳞状细胞癌术后放射治疗的独立预后因素包括N分期、转移淋巴结的数目及食管原发灶的长度。
7.本研究的临床部分,随访时间短,为非随机性。目前我们正在进行前瞻性随机分组研究。
Esophageal carcinoma is a lethal disease. It was the eighth most common cancer world wide, responsible for 462,000 new cases in 2002 and sixth most common cause of death from cancer with 386,000 death. The age-standardized incidence per 100,000 was 19.7. Most patients with esophageal cancer present with locally advanced disease. Radiotherapy is crucial for tumor local control, but locoregional control rates for locally advanced esophageal cancer are less than 50%, and the 5-year overall survival rate is only about 10% when definitive radiotherapy was given. However, locoregional recurrence due to missed targets and treatment-related toxicity caused by large fields of radiation still occur in a substantial proportion of patients. The morbidity of cardiac adenocarcinoma has the tendency to increase. Some patients with cardiac adenocarcinoma need radiotherapy because of unresectable and medically inoperable reasons. More accurate radiotherapy targeting is needed to improve locoregional control and reduce toxicity. The development of new methods of image-guided radiotherapy, including three-dimensional conformal and intensity-modulated radiotherapy, has allowed radiation oncologists to target esophageal cancers more accurately and effectively while sparing surrounding normal tissue. However, target delineation for esophageal cancer still relies on previous two-dimensional treatment designs. And the definition of clinical target volume (CTV) margins is quite different among different countries. And the extent of microscopic spread of cardiac adenocarcinoma is unknown. This information is crucial for determining the CTV margin for radiotherapy for esophageal cancer and cardiac adenocarcinoma. The purpose of this study was to clarify the CTV margin needed for radiotherapy for esophageal squamous cell carcinoma and cardiac adenocarcinoma pathologically, and to evaluate the CTV for esophageal squamous cell carcinoma clinically by analyzing the patterns of failure and prognosis after radiotherapy with different radiation technique and different CTV margins.
Part 1:Pathologic analysis of clinical target volume margin for radiotherapy in patients with esophageal SCC and cardiac adenocarcinoma treated by surgical resection only
Objective: To study prospectively the extent of microscopic spread and lymph node (LN) metastasis in patients with esophageal squamous cell carcinoma (SCC) and cardiac adenocarcinoma treated by surgery only and to evaluate the clinical target volume (CTV) in radiotherapy.
Methods: Sixty-six patients (34 with esophageal SCC and 32 with cardiac adenocarcinoma) treated by definitive surgical resection were included. All LNs received were labeled anatomically. The resected specimen was completely blocked for histological examination from proximal to distal at 20 mm interval in length and 3 mm in width. All H&E slides were examined by experienced pathologists for evidence of microscopic spread along the length of esophagus proximal and esophagus/stomach distal to gross tumor, and for LN metastasis.
Results: The mean microscopic spread beyond gross tumor was 10.6±11.0 mm (range 0-71 mm, 32 of 34 cases <30mm) for esophageal SCC and 10.3±7.2 mm (range 0-29.0 mm, 29 of 29 cases <30mm) proximally and 18.3±16.3mm (range 0-57.0 mm, 27 of 32 cases <30mm) distally for cardiac adenocarcinoma. The length of microscopic spread within esophagus is less than 30 mm in 94.1% of esophageal squamous cell cancer cases. The proximal microscopic spread of cardiac adenocarcinoma is less than 30mm in all cases. While only in about 84.4% of cardiac adenocarcinomas, the distal microscopic spread is less than 30mm, and it is less than 50mm in 93.8% of cases in cardiac adenocarcinomas. The extent of microscopic spread of cancer was significantly associated with pathologic T stage (P=0.012). For patients with middle and lower esophageal SCC, LN metastases were observed in 35.3% (12/34 cases, subcarinal LN in 4 cases, paraesophageal LN in 3 case, paratracheal LN in 2 cases, left gastric LN in 5 cases, and paracardiac LN in 3 cases). For patients with cardiac adenocarcinoma, LN metastases were found in 46.9% (15 of 32) of cases (5 in paraesophageal LN, 14 in left gastric LN, 13 in paracardiac LN, 1 in peri-spleen LN and posterior mediastinal LN respectively).
Conclusion: (1) A 3-cm longitudinal margin from gross target volume to CTV appeared to be adequate for most cases of esophageal squamous cell carcinoma within esophagus and for the proximal extent of microscopic spread of cardiac adenocarcinoma. And for distal microscopic spread in cardiac adenocarcinoma, 5cm was needed to cover about 94% of cases. (2) Accurate stage of LN is very important for radiation treatment target design. High-risk lymph node regions need to be covered by CTV.
Part 2:The patterns of primary failure after radiotherapy with different radiation technique and clinical target volume margins for patients with squamous cell carcinoma of middle and lower third thoracic esophagus
Objective: To evaluate the different radiation technique and clinical target volume margins by analyzing the patterns of primary failure after radiotherapy for patients with esophageal squamous cell carcinoma (SCC).
Methods: From January 2004 to June 2006, 151 patients with middle or lower third thoracic esophageal SCC receiving definitive radiotherapy or chemoradiotherapy were accrued and were followed up. The patterns of the primary failure were analyzed. There were 64 patients in the conventional radiotherapy group. In this group, the portal was outlined on the skin under the conventional simulator. The target center was defined according to the presentation on barium meal, endoscopy and CT. Three to 5 cm proximal and distal margins and 1.5 cm lateral margin from the border of GTV were included in the CTV. The involved regional lymphatics were also included in the CTV when the lymph node was considered abnormal. The prescribed dose was 50 to 62 Gy in 5 to 6.5 weeks. 87 patients were given 3DCRT, of which there were 55 patients in the involved nodal irradiation group. The GTV was defined as any visible tumor on the image. The CTV was defined as the GTV plus a 3-cm margin superior and inferior to the primary tumor and a 0.8-1.0 cm radial margin. The PTV was defined as the CTV plus a 1.0- cm longitudinal margin and a 0.5-cm radial margin. The involved lymphatic region was also included in the CTV. The PTV1 was defined as GTV plus a 1.5cm margin superior and inferior to the primary tumor and a 0.8-1.0 cm radial margin, and also the involved lymphatic region. And 32 patients were included in the elective nodal irradiation group. The GTV, PTV and PTV1 were defined the same as that in the involved nodal irradiation group. Besides the same margins outside the primary tumor as that in the involved nodal irradiation group, the adjacent regional lymphatics was included in the CTV according to the different location of the primary tumor. The prescribed dose to PTV was 54 to 62Gy in 5.5 to 6.5 weeks or 50 Gy in 5 weeks followed by 10 to 12Gy to PTV1.
Results: The total failure rate, locoregional failure rate, locoregional failure alone and total distant metastatic rate were 57.0% (86/151), 40.4% (61/151), 36.4%(55/151) and 20.5%(31/151) respectively for all patients in this study. The total failure rate was 59.4%(38/64), 61.8%(34/55) and 43.8%(14/32) respectively in the conventional radiotherapy group, the involved nodal irradiation group and the elective nodal irradiation group, which showed that it was higher in the former two groups than in the latter group, but no statistical difference was observed (P=0.228). Locoregional failure alone was 40.6% (26/64), 30.9% (17/55) and 37.5%(12/32) respectively for the three groups. And the total distant metastatic rate was 18.8% (12/64), 30.9% (17/55) and 6.3%(2/32) respectively for the three groups, which was higher in the former two groups than that in the latter group (P=0.021). The relapse rate of elective node outside CTV was 6.3%(4/64) and 7.3%(4/55) in the conventional radiotherapy group and the involved nodal irradiation group respectively. No relapse outside CTV was found in the elective nodal irradiation group. The total failure rate and locoregional failure alone rate were 60.5%(69/114)and 45.9%(17/37), 40.4%(46/114)and 24.3%(9/37)respectively in the radiotherapy alone group and chemoradiotherapy group, P<0.05.There was no significant difference in total distant metastatic rate between the radiotherapy group and chemoradiotherapy group, 20.2%(23/114) vs. 21.6%(8/37) with P>0.05. By analyzing the anatomical sites of regional failure, the probability of paraesophagotracheal lymph node metastasis was the highest (4.6%), with left gastric lymph node metastasis followed (4.0%). Only 2% (3/151) were found with esophageal disease outside CTV.
Conclusion: (1) The main reason for the failure of esophageal SCC after radiotherapy was locoregional relapse. About 20% of esophageal SCC relapsed duo to distant metastasis. Regional relapse alone outside CTV was 5.3% and esophageal disease outside CTV was about 2%. (2) The elective nodal irradiation could decrease the total distant metastasis rate and elective node relapse rate outside the CTV. (3) Chemoradiotherapy may improve the local control. (4) The CTV defined as GTV plus a 3-cm margin superior and inferior to the primary tumor was considered as reasonable for the controlling esophageal primary tumor.
Part 3: Comparison of efficacy and toxicities of different clinical target volumes in definitive radiotherapy for squamous cell carcinoma of middle and lower third thoracic esophagus
Objective: To evaluate the different radiation technique and clinical target volume (CTV) margins by analyzing the prognosis and toxicities after radiotherapy for patients with esophageal squamous cell carcinoma (SCC) and to suggest a reasonable CTV for 3DCRT.
Methods: From January 2004 to June 2006, 151 patients with middle or lower third thoracic esophageal SCC receiving definitive radiotherapy or chemoradiotherapy were accrued and were followed up. The overall survival rate, locoregional control rate, progression-free survival, distant metastasis-free survival and toxicities were analyzed and compared. The simulating method, delineation of target volumes for 3DCRT and the prescribed dose to the target were the same as that in Part 2. There were 64 patients in the conventional radiotherapy group, 55 patients in the involved nodal irradiation group and 32 patients in the elective nodal irradiation group.
Results: The 12-month and 18-month overall survival rates were 75.1% and 62.2%, 69.2% and 51.1%, 73.4% and 73.4% respectively in the conventional radiotherapy group, the involved nodal irradiation group and the elective nodal irradiation group. The 12-month and 18-month locoregional control rates were 73.7% and 68.1%, 66.1% and 55.9%, 61.3% and 61.3% respectively in the three groups. The 12-month and 18-month progression-free survival rates were 63.2% and 55.9%, 47.6% and 29.8%, 53.4% and 26.7% respectively. The 12-month and 18-month distant metastasis-free survival rates were 87.8%% and 79.5%, 75.1% and 71.4%, 93.3% and 93.3% respectively. No statistical difference was found among the three groups, all with P>0.05. In Cox multivariate analysis, T stage and tumor response after radiotherapy were the independent factors for overall survival. T stage had the tendency to improve the local control and was the independent factor for progression-free survival rate. And chemoradiotherapy had the tendency to improve the overall survival, local control and progression-free survival. The CTV had no effect on the overall survival, local control, progression-free survival and metastasis-free survival. The radiation esophagitis was 71.9%(46/64), 69.1%(38/55) and 87.5% (28/32) respectively in the conventional radiotherapy group, the involved nodal irradiation group and the elective nodal irradiation group. The latter was higher than that of the former two groups, P<0.05.The symptomatic radiation pneumonitis was higher than that of the conventional radiotherapy group and the involved nodal irradiation group.
Conclusion: (1) Conformal radiotherapy with elective nodal irradiation for middle and lower third thoracic esophageal SCC showed no significant advantage over the conformal radiotherapy with the involved nodal irradiation and the conventional radiotherapy in overall survival, local control, progression-free survival and distant metastasis-free survival. (2) Conformal radiotherapy with elective nodal irradiation conferred a higher radiation esophagitis and pneumonitis rate compared to the conventional radiotherapy and conformal radiotherapy with involved nodal irradiation. (3) Combined chemoradiotherapy showed a tendency to improve the overall survival, local control and progression-free survival. (4) CT-T stage and tumor response were the independent factors for overall survival. CT-T stage was the independent factor for the progression-free survival.
Part 4: Comparison of efficacy and toxicity of regional and extensive clinical target volumes in postoperative radiotherapy for esophageal squamous cell carcinoma
Objective: To compare and analyze the effect of different clinical target volumes (CTVs) on survival rate after postoperative radiotherapy (RT) for esophageal squamous cell carcinoma (SCC).
Methods: We studied 102 patients who underwent postoperative RT after radical resection for esophageal SCC (T3/4 or N1). The radiation dose was at least 50 Gy. In the extensive portal group (E group, 43 patients), the CTV encompassed the bilateral supraclavicular region, all mediastinal lymph nodes, the anastomosis site, and the left gastric and paracardiac lymphatics. In the regional portal group (R group, 59 patients), the CTV was confined to the lymph nodes in the immediate region of the primary lesion. The 1-, 3-, and 5-year survival rates were compared between the groups and multivariate/univariate analysis for factors predicting survival was studied.
Results: The 1-, 3- and 5- survival rates were 76.3%, 50.53% and 42.87% respectively, with a median survival of 30 months. The 1-, 3-and 5-year survival rates were 76.5%, 52.1% and 41.3% in the extensive portal group and 76.2%, 49.2%, and 44.6% in the regional portal group respectively, with no statistical difference between the two groups, P=0.884。The 1-, 3-, and 5-year survival rates were 88.1%, 63.4%, and 57.1%, respectively, for patients with T1 or T2 disease and 71.0%, 44.6 %, and 36.2%, respectively, for those with T3 or T4 disease. Patients with T1 or T2 disease had significantly better survival rates than did those with T3 or T4 disease (P=0.0383). The 1-, 3-, and 5-year survival rates were 95.6%, 72.0%, and 60.3%, respectively, for patients with N0 disease and 62.5%, 31.1%, and 28.9%, respectively, for patients with N1 disease (P=0.000). The 1-, 3-, and 5-year survival rates were 95.6%, 72.0%, and 60.3%, respectively, in patients with no metastatic lymph nodes (group 1); 67.4%, 33.3%, and 26.8%, respectively, in patients with 1-2 metastatic lymph nodes (group 2); and 20%, 20%, and 20% in patients with 3 or more metastatic lymph nodes (group 3) (P=0.000). The 1-, 3-, and 5-year survival rates were 81.5%, 62.0%, and 53.9%, respectively, for patients with tumors≤5 cm long and 67.9%, 37.5%, and 32.4%, respectively, for patients with tumors >5 cm long (P=0.0224). According to the multivariate analysis, N stage, number of metastatic lymph nodes and tumor length were the independent factors in survival.
Conclusion: Using a regional CTV for postoperative RT in patients with esophageal SCC is feasible, and it does not compromise survival rates. Factors predicting survival time in patients with esophageal SCC are N stage, number of lymph nodes with metastatic disease, and tumor length.
Conclusion
1. The pathological analysis showed that a 3-cm longitudinal margin from gross target volume to CTV appeared to be adequate for most cases of esophageal squamous cell carcinoma within esophagus and for the proximal extent of microscopic spread of cardiac adenocarcinoma. And for distal microscopic spread in cardiac adenocarcinoma, 5cm was needed to cover about 94% of cases. Accurate stage of LN is very important for radiation treatment target design. High-risk lymph node regions need to be covered by CTV.
2. The main reason for the primary failure of esophageal SCC after radiotherapy was locoregional relapse. About 20% of esophageal SCC relapsed duo to distant metastasis. Regional nodal relapse alone outside CTV was 5.3% and esophageal disease outside CTV was about 2%.
3. Conformal radiotherapy with elective node portal for middle and lower third thoracic esophageal SCC could decrease total distant metastasis rate and elective nodal relapse rate outside the CTV. But it showed no significant advantage over the conformal radiotherapy with involved node portal and the conventional radiotherapy in overall survival, local control, progression-free survival and distant metastasis-free survival. And higher morbidities of radiation esophagitis and pneumonitis were observed in the elective node portal group.
4. The clinical analysis showed that the CTV defined as GTV plus a 3-cm margin superior and inferior to the primary tumor was considered as reasonable for controlling the esophageal primary tumor.
5. Chemoradiotherapy may reduce the local failure and showed a tendency to improve the overall survival, local control and progression-free survival.
6. Using a regional CTV for postoperative RT in patients with esophageal SCC is feasible, and it does not compromise survival rates. Factors predicting survival time in patients with esophageal SCC are N stage, number of lymph nodes with metastatic disease, and tumor length.
7. The clinical study was non-randomized and the follow-up time was not longer enough. A randomized study is being done about the different CTVs on the prognosis of esophageal SCC.
引文
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7 食管癌三维适形放射治疗规范.第一届全国肿瘤精确放射治疗规范研究年会会刊,2006,56～57
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1 谷铣之,殷尉伯,刘泰福,等主编. 肿瘤放射治疗学. 北京医科大学中国协和医科大学联合出版社,1993,493～509
2 殷尉伯,张力军,杨宗贻,等.放射治疗食管癌 3798 例临床分析. 中华肿瘤杂志,1980,2(3):216～220
3 韩春,万钧,周道安,等.100 例食管癌后程加速放疗的研究。中华放射肿瘤学杂志,1997,6(1):16～18
4 高献书,陈坤,周志国,等. 放射治疗食管癌 CT 分期的研究. 河北医科大学学报,2003,24(3):153～154
5 食管癌三维适形放射治疗规范.第一届全国肿瘤精确放射治疗规范研究年会会刊,2006 年:56～57
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8 Matsubara T, Ueda M, Kaisaki S, et al. Localization of initial lymph node metastasis from carcinoma of the thoracic esophagus. Cancer, 2000,89(9):1869～1873
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10 安丰山,黄金球,陈少湖. 217 例胸段食管癌淋巴结转移及其对预后影响的分析.癌症,2003,22(9):974～977
11 薛恒川,吴昌荣,张振斌,等.食管癌右颈气管旁三角区域的淋巴结清扫.中华肿瘤杂志,2003,25(4):397～400
12 Sharma S, Fujita H, Yamana H, et al. Patterns of lymph node metastasis in field dissection for carcinoma in the thoracic esophagus. Surg Today, 1994,24(5):410～414
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14 Miller C.Carcinoma of the thoracic esophagus and cardia: A review of 405 cases. Br J Surg, 1962, 49(4):507～522
15 Mariette C, Castel B, Balon, et al. Extent of oesophageal resection for adenocarcinoma of the oesophagastric junction. EJSO, 2003, 29(7):588～593
16 Casson AG, Darnton SJ, Subramanian S, et al. What is the optimal distal resection margin for esophageal carcinoma? Ann Thorac Surg, 2000,69(1):205～209
17 马国伟,戎铁华,吴秋良,等. 食管癌手术适宜切除长度的研究. 中华肿瘤杂志,2003,25(5):472～474
18 Elkon D, Lee MS, Hendrickson FR. Carcinoma of the esophagus: sites of recurrence and palliative benefits after definitive radiotherapy. Int J Radiat Oncol Biol Phys, 1978,4(7-8):615～620
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3 Katayama A, Mafune KI, Tanaka Y, et al. Autopsy findings in patients after curative esophagectomy for esophageal carcinoma. J AM Coll Surg, 2003,196(6):866～873
4 肖泽芬,杨宗贻,梁军, 等. 食管癌根治术后预防性放射治疗的临床价值.中华肿瘤学杂志,2002,24(6):608～611
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1 Isono K, Onoda S, Ishikawa T, et al. Studies on the causes of deaths from esophageal carcinoma. Cancer, 1982,49(10):2173～2179
2 Nakagawa S, kanda T, Kosugi SI, et al. Recurrence pattern of squamous cell carcinoma of the thoracic esophagus after extended radical esophagectomy with three-field lymphadenectomy. J Am Coll Surg,2004,198(2):205～211
3 Katayama A, Mafune KI, Tanaka Y, et al. Autopsy findings in patients after curative esophagectomy for esophageal carcinoma. J AM Coll Surg,2003,196(6):866～873
4 肖泽芬,杨宗贻,梁军, 等. 食管癌根治术后预防性放射治疗的临床价值.中华肿瘤学杂志,2002,24(6):608～611
5 Suntharalingam M, Moughan J, Coia LR, et al. The national practice forpatients receiving radiation therapy for carcinoma of the esophagus: results of the 1996-1999 Patterns of Care Study. Int J Radiat Biol Phys, 2003,56(4): 981～987
6 Gomi K, Oguchi M,Hirokawa Y, et al. Process and preliminary outcome of a patterns-of-care study of esophageal cancer in Japan: patients treated with surgery and radiotherapy. Int J Radiat Biol Phys, 2003,56(3):813～822
7 Goodner JT. Surgical and radiation treatment of cancer of the thoracic esophagus. Am J Surg, 1969,105(3):523～528
8 Kasai M, Mori S, Watanabe T. Follow-up results after resection of thoracic esophageal carcinoma. World J Surg, 1978,2(4):543～551
9 Nishimura Y, Ono K, Imamura M, et al. Postoperative radiation therapy for esophageal cancer. Radiation Medicine,1989,7(2):88～94
10 Fok M, Sham JS, Choy D, et al. Postoperative radiotherapy for carcinoma of the esophagus: A prospective, randomized controlled study. Surgery, 1993,113(2):138～147
11 Teniere P, Hay JM, Fingerhut A, et al. Postoperative radiation therapy does not increase survival after curative resection for squamous cell carcinoma of the middle and lower esophagus as shown by multicenter controlled trial. French University Association for surgical Research. Surg Gynecol Obster,1991,173(2):123～130
12 Yamamota M, Yamashita T,Matsubara T, et al. Reevaluation of postoperative radiotherapy for thoracic esophageal carcinoma. Int J Radiat Biol Phys, 1997,37(1):75～78
13 李云英,林祥松,佘志廉,等.食管癌根治术后预防性T 型野放射治疗意义的探讨.中华放射肿瘤学杂志,1996,5(1):53～54
14 朱海文,陈国雄,王迎选,等. 食管癌术后放射治疗.中华放射肿瘤学杂志,1998,7(1):46～48
15 肖泽芬,杨宗贻,王绿化,等. 食管癌术后淋巴结转移对生存率的影响和放射治疗的意义.中华肿瘤杂志,2004,26(2):112～115
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25 Zieren HU, Muller TM, Jacobi CA, et al. Adjuvant postoperative radiation therapy after curative resection of squamous cell carcinoma of the thoracic esophagus: a prospective randomized study. World J Surg,1995,19(3):444～449
26 Bedard EL, Inculet RI, Malthaner RA, et al. The Role of Surgery and Postoperative Chemoradiation Therapy in Patients with Lymph Node Positive Esophageal Carcinoma. Cancer,2001,91(12):2423～2430
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29 Minsky BD, Pajak TF, Ginsberg RJ, et al. INT 0123 (Radiation TherapyOncology Group 94-05) Phase III trial of combined-modality therapy for esophageal cancer: High-dose versus standard-dose radiation therapy. J Clin Oncol,2002,20(5):1167～1174
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