根治性手术可使Ⅳ期胆囊癌患者获益*
2018-05-03孟强劳耿智敏姚春和王林陈晨李文智陶杰
孟强劳 耿智敏 姚春和 王林 陈晨 李文智 陶杰
(1.西安交通大学第一附属医院肝胆外科,陕西 西安 710061; 2.延安大学咸阳医院肝胆外科,陕西 咸阳 712000)
胆囊癌是胆道系统最常见的恶性肿瘤,恶性程度高,早期诊断困难[1],大多数患者初次就诊时已进展至晚期[2-4], ⅣA期患者5年生存率仅为4%,ⅣB期患者则低至2%[5]。根治性手术切除仍然是提高胆囊癌患者生存率的最主要治疗手段[6],但对于Ⅳ期患者而言,第7版AJCC分期认为不宜手术切除[5]。近年来随着扩大根治术如肝胰十二指肠切除(hepatopancreatoduodenectomy,HPD)及扩大淋巴结清扫术的普及,Ⅳ期患者获得了更多根治性手术的机会[7-10],但对于R0切除是否可改善N2淋巴结阳性患者的预后仍存在争议[11-12];有研究者表明扩大淋巴结切除并不能使此类患者获益[13-14]。此外,由于HPD手术术后并发症及死亡率较高,一些文献报道认为此类手术不应常规实施[15-16]。本文通过回顾性分析285例Ⅳ期胆囊癌患者的临床、病理特征、手术方式和术后存活时间,研究与预后相关的因素并确定可从R0切除获益的Ⅳ期胆囊癌亚人群。
1 材料与方法
1.1 病例资料 纳入2008年1月~2012年12月在西安交通大学第一附属医院及延安大学咸阳医院接受手术治疗的285例Ⅳ期胆囊癌患者。分别收集性别、年龄、症状、影像学检查(腹部B超,CT,MRI),血清肿瘤标记物(CA-125,CA19-9,CEA),手术方式及其他手术相关资料。依据2010版世界卫生组织(WHO)定义重新对患者病理和诊断进行分类整理[17]。同时根据AJCC发布的7版TNM分期系统对患者进行评估[18]。该项研究得到西安交通大学第一附属医院伦理委员会及延安大学咸阳医院伦理委员会批准。
1.2 手术方式 根据开腹探查结果、术中快速冰冻和患者意愿选择手术方式。根治性手术:对N2+患者行扩大的淋巴结清扫术;对伴有相邻器官(胆道,结肠,十二指肠,肝和胃)浸润的患者实行扩大根治术(HPD,右半肝切除术,胃大部切除术)和淋巴结清扫术;姑息性切除:对有多发转移病灶、肿瘤广泛浸润难以完整切除、全身状况较差或拒绝根治性切除治疗的患者,根据状况选择适当的姑息性手术治疗。手术后30天内或本次住院期间死亡的人数归入术后死亡人群。详细病例资料见表1。
表1 R0及R1/2切除患者的临床病理资料[n×(10-2)]Table 1 Detailed clinical and pathological data for patients with stage iv gallbladder cancer in relation to r0 or r1/2 resection
1.3 随访 术后第1、3、6和12个月分别随访,随后一年一次随访,末次随访日期为2016年9月。
2 结果
2.1 人口统计学资料 研究时间范围内IV胆囊癌患者共285例,其中男性83例,女性202例,平均年龄61.6岁(36~87岁)。
2.2 临床资料 出现黄疸的患者共91人(31.9%),161(56.5%)例合并有胆囊结石,22(7.7%)例患有糖尿病,54(18.9%)例合并高血压病。部分患者术前行血清肿瘤标志物检测,其中CA19-9阳性率为70.9%(124/175),CA-125为59.1%(91/154),CEA为43.7%(80/183)。
2.3 病理资料 有明确病理资料的病例共164份,大部分肿瘤呈浸润者型(76.2%,125/164)。主要病理类型为腺癌(82.6%,236/285),并且大多数分化程度较差,II-III级分化占96.8%(276/285)。T1、T3和T4期患者分别为1、127和157例。淋巴结状态:N0患者8人,N1+患者125人,N2+患者152人。121例出现远处转移。根据AJCC第7版TNM分期系统,ⅣA期和ⅣB期患者分别为69和216人。
2.4 手术治疗 行手术治疗的患者中,44例达到R0切除,包括1例T1N2M0,26例T3N2M0,2例T4N0M0, 7例T4N1M0,3例T4N2M0,1例T3N0M1,2例T3N1M1,T3N2M1和T4N0M1各1例。5例M1患者中,1例为右腹壁孤立转移灶,4例为右半肝孤立转移灶。44例R0切除中包括12例HPD手术,4例右半肝切除,3例胃大部分切除,25例胆囊切除、肝4b+5段切除和扩大淋巴结清扫术(图1)。其余的241例患者实施姑息性手术治疗,包括姑息性胆囊切除58例,胆囊切除+胆道外引流术126例,胆囊切除+胆肠吻合术6例,经皮穿刺胆道引流术19例,剖腹探查术19例,胃肠吻合术9例和胆道外引流4例,见表1。
图1 R0切除的IV期胆囊癌患者Figure 1 R0 resection for patients with stage IV gallbladder carcinoma注:A.T4N1M0患者行肝胰十二指肠切除;B.T3N2M0患者行扩大区域淋巴结清扫
2.5 生存分析 229例患者(80.4%)得到有效随访,中位随访时间6.0个月(1~48个月)。30天死亡率为4.6%。死亡原因为肝功能衰竭4例,腹腔积血2例,败血症3例,急性心肌梗死1例,急性肺栓塞1例和重症肺炎2例。总体1、2和3年总生存率分别为7.9%,2.2%和0.8%,中位生存时间(mean survival time,MST)3.0个月。单因素分析显示对行手术切除的IV期患者,年龄,病理学分级,有无远处转移和手术切缘对患者的生存有明显影响,多因素分析确定年龄>65岁,远处转移,切缘R1/2或R0是胆囊癌预后的独立危险因素(表2)。
达到R0切缘的IV期患者1、2和3年总生存率分别为22.9%、11、4%和7.6%,MST为6.0个月。生存率高于切缘为R1/2的患者(5.2%、0.5%和0.5%,MST:2.7个月)(P<0.001)(图2),而30天死亡率和手术并发症比较差异无统计学意义(表1)。
图2 R0和R1/2切缘患者总的生存曲线Figure 2 Overall survival curve of stage IV GBC patients
项目单因素分析多因素分析平均生存时间(月)1年生存率(×10-2)2年生存率(×10-2)3年生存率(×10-2)P相对危险度(RR)P95%CI黄疸 无37525190962 有3881515病理分化 高500000171 中4843216162602260740~3574 低2791616218400510997~4785性别 男3582900875 女3881919年龄(岁) <50486341700111 50⁃6531022424110605340805~1519 >6523000175000071169~2619T分期 T1未及100未及未及0071 T357210NR T426762315N分期 N082861431430056 N13102100 N227482424M分期 M0431173929<00011 M12030001855<00011402~2455手术 R0622911476<00011 R1/227520505179500041200~2687病理类型 腺癌38016080316 非腺癌3714848CA19⁃9 阳性267810未及0453 阴性31194824CA12⁃5 阳性37525未及0651 阴性2310400CEA 阳性27981200896 阴性278829未及
44例手术切缘为R0的患者中包括5例M1患者,1例为右腹壁孤立转移灶,4例为右肝孤立转移灶;其余为M0患者,包括1例T1N2M0,26例T3N2M0,2例T4N0M0,7例T4N1M0,和3例T4N2M0;其中胰十二指肠后淋巴结阳性患者18例,腹腔动脉淋巴结阳性21例和腹主动脉旁淋巴结阳性2例。在ⅣA期患者中,R0切除可明显改善预后(R0切除患者1、2和3年总生存率分别为37.5%,12.5%和0%;R1/2切缘1、2和3年生存率分别为13.3%,2.2%和2.2%;R0切缘MST为11.0个月,R1切缘MST为4个月,P=0.038);同时在无远处转移的ⅣB期患者中R0切除组预后同样显著高于R1/2切除组(R0切除组1、2和3年生存率分别为21.7%,13.0%和13.0%,R1/2切除组1、2和3年生存率分别为1.9%,0%和0%;R0切缘组MST为6.0个月,R1/2切缘组为3.0个月,P=0.004)(图3)。
图3 IV期患者亚组分析Figure 3 Survival curves for subgroups patients注:A.T4N1M0从R0切缘中获益(P=0.040);B.T1-4N2M0患者R0切除同样可改善预后(P=0.016)
3 讨论
胆囊癌侵袭性强,预后极差[19]。TNM分期是胆囊癌术后患者最重要的预后因素[20]。一般认为Ⅳ期患者已无法行手术切除[5],但已有许多临床研究支持对晚期胆囊癌患者进行更为激进的外科手术治疗[21-22]。Kang等[22]的研究指出,对Ⅳ期胆囊癌患者行根治性手术治疗可延长患者生存时间;Christina等[23]进一步证实了这一结论,认为只要病变在局部并且可以达到R0切缘,就可以在Ⅳ患者中实行根治性手术。来自日本的研究也认为如果肿瘤相对较局限,并经过严格筛选,即使病灶较大并已侵及到相邻脏器的情况下,Ⅳ期患者行根治手术切除后仍有望获得长期生存[14-21]。然而手术并发症和死亡率的增加阻碍了这些激进的手术方式作为标准的胆囊癌治疗方法[24];同样源自日本的大宗数据研究则不支持在Ⅳ期患者中行激进的手术切除[25],甚至有研究指出,对于Ⅳ期患者,根治性手术并能改善预后[26]。而我们的研究结果显示,切缘为R0的患者1、3和5年生存率明显高于切缘为R1/2的(P<0.001),且两组患者在手术并发症发生率和死亡率上比较差异并无统计学意义。
根据第7版AJCC指南,T4期患者通常认为无法手术切除而应该进行姑息性治疗[27],Groot等[28]声称T4期胆囊癌患者从手术切除中获益的可能性不大。然而,目前对于进展期胆囊癌不可切除的因素尚未有共识[29],近期相关报道已经表明在进展期胆囊癌中行根治性手术切除加动脉切除重建术,或扩大的右三叶切除术和HPD可以改善患者的预后[16-29]。在手术切缘能够达到R0的情况下,对T4期患者进行根治性手术切除正被逐渐接受[30]。Nishio等[31]的研究结果认为,侵犯到肝外胆管的胆囊癌同样具有根治性切除的价值;Anil等[32]指出胆囊癌即使出现十二指肠浸润并不表示无法手术切除。在我们的研究中,IVA期患者中R0切除可改善患者预后,证实了无远处和第二站淋巴结转移的T4期患者,即使在肿瘤已侵犯临近器官,同样适合实施更为激进的手术治疗。
胆囊癌淋巴结转移率极高,在T4期肿瘤患者中可高达80%[33-37],而淋巴结转移一直是胆囊癌患者最重要的生存预测因素[37-40]。Birnbaum等[30]认为N分期而并非是T分期可作为进展期胆囊癌的独立预后危险因素。根据7版AJCC胆囊癌TNM分期系统,淋巴结分为肝门部淋巴结(N1)和其他区域淋巴结(N2),有N2转移的患者被归于IVB期[41]。在本研究中,IV期患者96.8%有淋巴结转移,53.3%出现N2转移。有研究称出现肝、肺、骨、腹膜和远处淋巴结转移(主动脉旁或腹外的淋巴结)的晚期胆囊癌患者通常认为不适宜进行激进的根治性手术治疗[42-44],同样伴有N2转移的患者人从手术切除中受益的可能性亦不大[19,43,45],扩大的淋巴结清扫未让这些患者生存得到明显改善,伴有N2转移而无远处转移患者的术后生存率和出现远处转移的患者一样差,因此不提倡对N2常规进行扩大的淋巴结清扫[13-14,28,47-48]。然而,目前仍没有关于N2+胆囊癌手术切除治疗指征的共识。一些研究表明手术切除能够提高N2+胆囊癌患者预后[49-50]。对伴有腹主动脉旁淋巴结转移的胆囊癌患者进行根治性切除可延长术后生存时间[49]。在我们的研究中,31例出现N2+的IVB期患者达到R0切除,较R1/2切除此类患者预后明显改善,其中大部分患者N2+淋巴结多局限在胰十二指肠后淋巴结和腹腔动脉淋巴结,表明在N2受侵的患者中也可以考虑行R0切除,至少在部分经过严格筛选的患者中可以实施。
4 结论
本研究结果显示,经手术治疗的Ⅳ期胆囊癌患者年龄>65岁,远处转移,切缘R1/2为影响胆囊癌预后的独立危险因素。在ⅣA期及无远处转移的IVB期患者中R0切除可明确改善患者预后,证实N2转移并不妨碍实施根治性手术切除,在严格术前评估后,Ⅳ期胆囊癌患者可以考虑行根治性切除以改善患者预后。
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