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通讯作者:

王喜艳(1961-),男,新疆人,博士生导师,主要从事胰腺肿瘤基础研究。E-mail:wxyforum@163.com

中图分类号:R-1,R453.9,R735.9

文献标识码:A

文章编号:2096-8965(2020)01-0043-07

DOI:10.12287/j.issn.2096-8965.20200107

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目录contents

    摘要

    胰腺癌手术切除率低,预后极差。近年来,随着新型药物的出现、治疗手段的多样化及多学科诊疗模式的发展,胰腺癌的新辅助治疗与转化治疗引起了广泛的关注。本文系统梳理了新辅助治疗和转化治疗在胰腺癌中的临床应用以及转化治疗后手术时机的选择,提出将可切除型胰腺癌分为低风险组和高风险组。低风险组患者推荐优先手术切除,高风险组与交界性可切除胰腺癌患者直接手术R0切除率较低,行新辅助治疗后,可明显提高R0切除率。对于不可切除胰腺癌患者应综合评估能否行转化治疗,部分转化有效患者可行根治性手术。然而,胰腺癌新辅助治疗与转化治疗方案的选择、治疗周期及术后辅助方案等问题目前尚无共识。相信伴随高级别循证医学证据的出现,新辅助治疗和转化治疗将在胰腺癌治疗中得到更广泛的应用。

    Abstract

    Pancreatic cancer has a low surgical resection rate and a very poor prognosis. In recent years, with the emergence of new drugs, the diversification of treatment methods, the development of multidisciplinary diagnosis and treatment models, neoadjuvant treatment and translational treatment of pancreatic cancer have attracted widespread attention. This article systematically sorts out the clinical application of neoadjuvant therapy and translational therapy in pancreatic cancer, as well as the timing of surgery after translational therapy, and proposes to divide resectable pancreatic cancer into low-risk groups and high-risk groups. Patients in the low-risk groups are recommended to prioritize surgical resection. The high-risk groups and patients with borderline resectable pancreatic cancer have a lower rate of R0 resection. Neoadjuvant therapy can significantly increase the rate of R0 resection. For patients with unresectable pancreatic cancer, a comprehensive assessment should be made on whether conversion therapy can be performed, and radical surgery is feasible for some effective patients. However, there is no consensus on the selection of neoadjuvant treatment and translational treatment for pancreatic cancer, the treatment cycle, and postoperative adjuvant options. It is believed that with the emergence of highlevel evidence-based medicine, neoadjuvant therapy and conversion therapy will be more widely used in the treatment of pancreatic cancer.

  • 胰腺癌高度恶性,预后极差,5年生存率仅为7%[1]。约70%~80%的患者初诊时已处于中、晚期, 失去最佳手术治疗时机,治疗方式常为姑息性化疗或对症支持治疗,中位生存期仅8.0~12.0 个月[2, 3]。 因此,提高根治性手术切除率,对改善胰腺癌患者预后极其重要。近年来,伴随外科技术的进步和肿瘤综合治疗理念的推广,胰腺癌新辅助治疗(Neoadjuvant Therapy,NT)与转化治疗(Conversion Therapy,CT) 引起了热议与广泛的关注。据统计, 对初诊时失去最佳手术时机的患者,25%~35%为交界可切除胰腺癌(Borderline Resectable Pancreatic Cancer,BRPC)和局部晚期不可切除胰腺癌(Locally Advanced Unresectable Pancreatic Cancer,LAPC)[4]。 美国国立综合癌症网络(National Comprehensive Cancer Network,NCCN) 推荐对BRPC患者首选新辅助治疗。有研究表明,对于部分LAPC患者, 行新辅助治疗后能转化为可切除胰腺癌(Resectable Pancreatic Cancer,RPC),并推荐对LAPC患者开展转化治疗,进而达到根治性手术切除的目的[5, 6],凸显了当前新辅助治疗与转化治疗在胰腺癌治疗中的重要地位。目前对于BRPC、LAPC患者的新辅助治疗和转化治疗尚无统一方案,相关疗效评价、手术时机及手术方式等研究较少,有待进一步探讨。

  • 1 可切除、交界可切除与不可切除胰腺癌的定义

  • 胰腺癌交界性可切除与不可切除的定义是目前胰腺外科领域极具争议的热点问题,即使在全球几家权威胰腺肿瘤中心和专业组织,也未能达成共识。 MD安德森癌症中心(MD Anderson Cancer Center)、美国肝胆协会(AHPBA)、NCCN、临床研究联盟均有各自的定义标准。其均以解剖学为基础,本质为外科医师技术、观念和经验的整合评估,主观性与个体化因素较多。虽然评估标准存在部分差异,但目前均普遍被外科医师和专业组织接受。本文以2020 年NCCN发布的最新胰腺癌临床诊疗指南为标准,分别从动脉受侵和静脉受侵方面对胰腺癌可切除性进行评估,将胰腺癌分为可切除、交界可切除、不可切除3类。认为肿瘤未侵犯腹腔干(Celiac Axis,CA)、肠系膜上动脉(Superior Mesenteric Artery,SMA) 和肝总动脉(Common Hepatic Artery,CHA),且肿瘤未侵犯肠系膜上静脉(Superior Mesenteric Vein,SMV) 和门静脉(Portal Vein,PV),或侵犯但没有超过180°,静脉轮廓规则,为可切除胰腺癌。对于交界可切除胰腺癌定义为:(1) 胰头部肿瘤侵犯CHA,但未累及CA或左右肝动脉起始部,可以被完全切除并重建,或肿瘤侵犯SMA,但未超过180°;胰体尾部肿瘤侵犯CA≤180°或者肿瘤包绕CA>180°,但未侵犯腹主动脉,且胃十二指肠动脉完整未被侵犯。(2) 肿瘤包绕SMV或PV>180°,或肿瘤侵犯≤180°并伴有静脉轮廓不规则或有血栓形成,但受累血管的近端和远端允许安全和完整的静脉切除与重建;肿瘤侵及下腔静脉(Inferior Vena Cava,IVC)。关于不可切除胰腺癌可分为局部晚期胰腺癌(LAPC) 和远处转移胰腺癌,LAPC定义为:(1) 胰头部肿瘤包绕SMA或CA>180°,胰体尾部肿瘤包绕SMA或CA> 180°或肿瘤侵及CA并累及主动脉。(2) 由于肿瘤侵犯或闭塞SMV/PV导致其无法进行切除或重建(可能由于瘤栓或者血栓)。指南推荐对胰腺癌的可切除性评估应在影像学检查完善临床分期后,由外科、消化内科、影像科医师经多学科讨论综合评估并达成一致意见。

  • 2 新辅助治疗在可切除胰腺癌治疗中的应用

  • 手术是目前唯一可以治愈胰腺癌的方法,能显著改善生存率,手术切除胰腺癌最重要的目标是实现R0切除。术后病理满足距肿瘤切缘1 mm以外的组织内无肿瘤细胞残留,可认为达到R0切除,切缘阳性(R1或R2) 与胰腺癌的复发和预后不良相关[7]。临床上行根治性手术的患者80%以上多在术后2 年内出现肿瘤复发或转移[8],因此可根据术前有无高危因素将可切除胰腺癌分为低风险组和高风险组。2020 年NCCN指南推荐对于存在CA19-9 明显升高、原发肿瘤巨大、临床怀疑有淋巴结转移、 体重明显下降、疼痛明显等高危因素的患者行新辅助治疗。目前临床新辅助治疗常用FOLFIRINOX方案、白蛋白结合型紫杉醇联合吉西他滨(AG) 方案[9],卡培他滨联合铂类、替吉奥单药或联合化疗方案也较常用。

  • 国内外学者对此推荐存在较多争议,Youngwirth等[10] 分析美国国家癌症数据库收集的1998-2011 年18 243 例Ⅰ期和Ⅱ期胰腺癌患者资料,结果显示:接受新辅助治疗的患者较直接手术更易获得阴性切缘(77.8%∶85.5%,P<0.001),淋巴结转移率更低(42.9%∶59.3%,P<0.001),术后30 d病死率更低(2.0%∶4.6%,P<0.001),再住院率更低(7.4%∶9.5%,P=0.02)。Versteijne E等[11] 分析了38 项临床研究,发现新辅助治疗能改善RPC患者术后生存,比直接手术更具有生存优势,但也有相关研究发现新辅助治疗未能使患者获益[12]。有学者认为对于高危组RPC患者行新辅助治疗可导致部分患者延误手术治疗时机,甚至失去手术机会,而支持者认为术前行新辅助治疗有助于筛选出肿瘤生物学行为较差的患者,肿瘤对一线化疗方案的抵抗提示预后不良,此类患者并不能从手术切除中获益,新辅助化疗在高危组可切除胰腺癌患者中的有效性仍需进一步探究,新辅助化疗有望成为高危组可切除胰腺癌患者标准治疗的组成部分。

  • 3 新辅助治疗在交界可切除胰腺癌治疗中的应用

  • NCCN指南推荐对于BRPC患者若无化疗禁忌,可优先行新辅助治疗,多数的研究[10, 13] 结果提示BRPC患者行新辅助治疗有效,耐受性好,可提高总体生存率,支持BRPC患者开展新辅助治疗。 此外,在新辅助治疗期间,可识别病情快速进展病例,这些患者因肿瘤生物学行为较差往往无法在手术切除中获益。Jang等[14] 研究发现新辅助治疗联合手术组患者的2年生存率、中位生存时间和R0切除率明显优于直接手术组(40.7%∶26.1%,21 个月∶12个月,R0切除率51.8%∶26.1%,P=0.004); Laurence等[15] 研究显示,新辅助治疗联合手术切除的BRPC患者的1 年生存率可达到可切除组水平。 Versteijne等[11] 研究发现对于BRPC,新辅助治疗与直接手术的中位生存时间分别是19.2个月、12.8个月,R0 切除率分别为88.6%、63.9%。目前对于BRPC患者的新辅助化疗,临床常用FOLFIRINOX方案与AG方案,近几年的报道中多项研究结果显示AG方案与FOLFIRINOX方案疗效相当[16]

  • BRPC外科治疗的主要挑战是重建血管段的切缘阳性率高,导致局部和全身复发的风险高,当BRPC患者存在动脉或静脉血管受侵时,应将二者区别开来,因静脉在解剖位置上更加靠近肿瘤,术前影像学检查怀疑有静脉受侵的患者大多并非肿瘤浸润,而是肿瘤周围炎症及肿瘤压迫或接触所致[17],因而有研究认为当BRPC患者存在静脉受侵但可以实现R0切除时,可以行根治性手术加静脉切除重建;而对于存在动脉受侵的BRPC患者,是否行根治性手术尚存在争议,有研究表明[18],当存在动脉受侵患者行新辅助治疗后,可提高R0切除率,延长总生存时间。

  • 关于BRPC患者新辅助治疗后的手术时机选择仍存争议,对于初诊患者,增强CT是评估能否手术的主要指标,但BRPC患者行新辅助治疗后,因无法区别化疗引起的粘连与肿瘤组织浸润,无法仅靠影像学检查来评估,目前多数学者将新辅助治疗的疗效以肿瘤标记物CA19-9明显降低来进行判断, 而并非是肿瘤大小,行新辅助治疗后4-8周手术较为安全。对于部分患者,虽然影像学未见明显变化,但仍存在手术切除的可能,行新辅助治疗后联合手术切除的患者中位生存时间明显延长[19]。对于新辅助治疗失败,病情出现明显进展的患者,不能继续行手术治疗,可考虑吉西他滨联合替吉奥等二线方案化疗。

  • 4 转化治疗在局部晚期胰腺癌治疗中的应用

  • 局部晚期不可切除胰腺癌(LAPC) 的患者预后极差,中位生存时间仅为8.0-12.0个月[20]。近年来,伴随化疗、放疗、靶向治疗、免疫治疗等转化治疗的发展,使部分患者的肿瘤缩小或降期,甚至使不可切除转化为可切除,提高了R0切除率,改善了患者的预后[21]

  • 4.1 转化治疗中放化疗的应用

  • 目前,国内外对于转化治疗中放化疗方案的使用仍存差异,其中常用的化疗方案主要为吉西他滨单药或联合化疗方案,包括FOLFIRINOX方案、 AG方案、卡培他滨联合铂类等,替吉奥单药也较为常用。FOLFIRINOX方案作为晚期胰腺癌的一线治疗方案,可使局部晚期胰腺癌转化治疗的患者平均生存期达到24.2个月[22],使22.5%的不可切除患者实现R0切除[23]。Suker等[22] 纳入13 项研究共计689 例LAPC患者,发现FOLFIRINOX方案的手术转化率为26%,中位OS(Overall Survival)达24个月,接近直接手术的RPC患者。AG方案相对于FOLFIRINOX方案的毒性较小。部分研究表明[21], 对于LAPC患者的治疗,AG方案与FOLFIRINOX方案疗效相当,但Hackert等[19] 对575例LAPC患者分别行FOLFIRINOX方案和吉西他滨辅助治疗后发现,行FOLFIRINOX方案转化治疗后手术切除率为60.8%, 吉西他滨辅助治疗组手术切除率为48.0%,有统计学差异,术后患者中位生存期分别为16.0 个月和16.5 个月,无统计学差异。对于体能状态较差者,可选择吉西他滨单药或替吉奥单药方案。

  • 近年来,随着放疗技术的进步,三维适形调强放射治疗技术、立体定向放疗技术、术中125I粒子植入治疗及术中精准定位局部放疗的不断成熟,肿瘤周围的正常器官可以获得更好的保护,在一定程度上增加了肿瘤的照射剂量,有助于提高肿瘤局部控制率。FOLFIRINOX方案毒副作用较大,可导致患者重度骨髓抑制、神经病变等[24],多项研究尝试采用改良FOLFIRINOX方案联合放化疗以降低毒性反应。Nanda等[25] 对29 例LAPC患者使用改良FOLFIRINOX方案联合放化疗后,34.5%的患者实现R0切除,1年生存率为65.5%,效果与FOLFIRINOX方案相当;Khushman等[26] 对27 例LAPC患者行FOLFIRINOX方案联合放化疗后,患者中位生存时间为35.4个月,10例患者行R0切除,3年生存率达67.0%,明显高于非R0 切除的21.0%。FOLFIRINOX方案及其改良方案联合放化疗在LAPC患者治疗中取得了理想的效果,值得临床进一步研究及改进;术中125I粒子植入治疗因其安全有效而得到广泛应用,125I持续低能辐射肿瘤组织是其最大的治疗优势。Wang等[27] 报道,对28 例不可切除型胰腺癌患者行术中超声引导下行125I粒子植入治疗, 术后7例行体外放疗,10例行吉西他滨或紫杉醇联合化疗,结果显示肿瘤局部控制率为85.7%,中位生存时间为10.1个月,1年、2年及3年生存率分别为30%、11%和4%,16例癌性疼痛患者得到明显缓解。

  • Herman等[28] 报道了一项Ⅱ期临床试验,应用吉西他滨联合放疗治疗49例LAPC患者,结果显示全组中位生存期为13.9 个月,CA19-9 显著下降, 治疗后有4例患者行手术切除,切缘均阴性,其中l例病理完全缓解。Moningi等[29] 分析了88例行放疗的胰腺癌患者,其中有74例LAPC患者,结果显示全组中位生存时间为18.4 个月,放疗后19 例患者行手术治疗,16例切缘阴性,3例术后病理完全缓解,术后中位生存期达20.2个月。对于LAPC患者, 放化疗结合的治疗方式逐渐成为主流,能更好的提高局部肿瘤控制率,减少远处转移,使更多的LAPC患者获得手术治疗的机会,延长生存时间。

  • 4.2 免疫治疗及靶向治疗

  • 目前免疫治疗并没有达到预期的效果,这可能与胰腺癌的免疫逃逸有关,而免疫逃逸与其所在的肿瘤微环境关系密切[30]。程序性细胞死亡蛋白1(Programmed Cell Death Protein 1,PD-1) 表达于T细胞、B细胞等表面,与相关配体PD-L1结合后最终导致免疫逃逸,因此选择PD-1/PD-L1 抑制剂可有效阻止肿瘤细胞免疫逃逸,增强免疫T细胞杀伤肿瘤细胞的能力,但目前临床上PD-1/PD-L1 单药治疗几乎对胰腺癌无效[31],这与胰腺癌的肿瘤微环境中缺乏T细胞浸润密切相关。有研究发现[32], PD-1/PD-L1 抑制剂联合其它治疗,可有效抑制胰腺癌细胞生长,但仍需临床验证,相信随着分子免疫学的发展,免疫治疗有望在胰腺癌的治疗中取得进一步突破。

  • 在胰腺癌靶向治疗中,舒尼替尼、索拉非尼、 阿西替尼等靶向药物都没能改善胰腺癌患者生存状况,厄洛替尼为胰腺癌患者的治疗带来了一线曙光,但也仅延长2周左右的生存时间。奥拉帕利是一种口服多聚二磷酸腺苷核酸聚合酶(PARP) 抑制剂,Golan等[33] 一项随机的临床试验招募了具有种系BRCA1或BRCA2突变的LAPC患者,结果发现,与安慰剂组相比,接受奥拉帕利作为维持治疗的患者无进展生存期明显延长,中位生存期7.4 个月,客观缓解率为23.1%,1年、2年无进展生存率均为安慰剂组的2倍以上,而接受安慰剂的患者中位生存期为3.8 个月,客观缓解率为11.5%,该研究使奥拉帕利成为第一个在胰腺癌中被Ⅲ期临床试验证明有效的PARP抑制剂,同时也开启了胰腺癌基于生物标志物实施精准治疗的先河,为胰腺癌的靶向治疗提供了新的思路与方向。

  • 4.3 转化治疗后手术指征及手术时机的选择

  • 随着FOLFIRINOX方案、AG方案、免疫治疗及靶向治疗等转化治疗的广泛运用,越来越多的LAPC患者可以行R0切除(20.0%~57.0%),提高了患者的生存率,对于转化治疗的手术指征及手术时间,仍存在较大争议。目前多数学者认为肿瘤标记物CA19-9 明显下降,转化治疗超过8 个月后,经评估LAPC患者经转化治疗后降期为交界可切除或可切除时,若满足手术指征,可实现R0切除。术后辅助治疗对延长患者的生存期尤为重要,对化疗方案有良好的疗效、不良反应小也是行转化治疗后手术的重要指征。Wright等[34] 研究发现LAPC患者行手术治疗后,20%~30%的患者在术后6个月即发生肿瘤复发、转移,因此适当延长抗肿瘤时间,筛选出部分肿瘤生物学行为较差、进展较快的患者, 可避免不必要的手术带来的风险。

  • 5 转化治疗在远处转移胰腺癌治疗中的应用

  • 远处转移胰腺癌患者中位生存时间仅为4-6个月,预后极差[35]。胰腺癌最常转移的部位是肝脏, 其次是腹膜、肺、胸膜、骨骼、肾上腺等。当肿瘤发生远处脏器转移,包括非区域淋巴结转移时,无论原发灶解剖学可切除性如何,都不应直接行手术切除。关于转移性胰腺癌手术治疗的报道很少,随着转化治疗的发展,目前可以对部分基础状态较好的肝寡转移患者选择性的行根治性手术,但其有效性尚存争议。

  • 胰腺癌肝脏寡转移是指肝脏转移灶为孤立或位于同一局部肝叶内的多发肿瘤,一般不超过5 个。 部分中心尝试对肝寡转移灶行同期切除,Gleisner等[36] 研究22 例胰腺癌肝寡转移患者发现,行同期根治性切除术的患者中位总生存期5.9 个月,并不优于接受姑息性旁路手术患者的5.6 个月,表明对胰腺癌肝寡转移患者行根治性手术是安全可行的, 但未能给患者带来生存益处。

  • 目前对于胰腺癌肝寡转移患者多主张行系统性化疗,并且不建议在未行术前治疗的情况下行根治性手术[37]。术前化疗可抑制肿瘤活动,增加R0切除率,筛选出生物学行为较差的肿瘤患者,减轻肿瘤负担,提高手术的安全性。Schneitler等[38] 研究了2例术前行FOLFIRINOX方案化疗的肝寡转移性胰腺癌患者,实现了R0切除,术后患者获得了长期生存,结果表明,尽管肝转移性胰腺癌的预后较差, 但经转化治疗后行手术治疗,可能会延长部分患者生存期,因此如何选择能在转化治疗中获益的患者成为一个难题。

  • 虽然外科治疗肝寡转移性胰腺癌争议很大,笔者综合目前报道认为:对于肝寡转移性胰腺癌患者, 若无化疗禁忌,应优先考虑行FOLFIRINOX或吉西他滨联合白蛋白紫杉醇方案化疗。Wright等[34] 回顾性分析美国两家主要机构的1 147 例Ⅳ期胰腺癌患者,经转化治疗后其切除率仅为2.0%。虽然大多数出现远处转移的患者并不适合手术,但某些情况下,手术切除可能对患者是有益的,当原发灶及肝转移灶可以实现R0切除,转化治疗经评估后有效, 患者总体状况较好,无明显合并症时可考虑行根治性手术,以改善患者长期生存率。

  • 6 小结与展望

  • 综上所述,基于胰腺癌新辅助治疗与转化治疗的手术分型设想(见图1),对可切除胰腺癌患者低风险组推荐优先手术切除,以免新辅助治疗过程中病情进展,失去根治性切除的机会。对于高风险组与交界性可切除胰腺癌患者直接行根治性切除可能性小,可优先选择新辅助治疗,患者R0切除率将明显升高,可显著获益。对于不可切除胰腺癌患者术前应进行MDT讨论,根据指南、临床经验, 结合患者个体情况评估能否行转化治疗以改善预后。然而,如何采取使患者最大获益的个体化新辅助治疗方案仍是国内外学者研究的焦点。关于开展BRPC的新辅助治疗、LAPC的转化治疗仍存在一系列问题,如对于可切除性评估的影像学检查较单一,具有一定的局限性;新辅助治疗后疗效评估、 最佳手术时机的选择和手术方式的把握尚需进一步临床研究;在新辅助治疗前为明确病理学诊断对胰腺组织的穿刺活检可能发生出血、胰瘘、种植性转移等。

  • 图1 胰腺癌新辅助治疗与转化治疗的手术分型设想

  • 本文局限性:目前对于胰腺癌的可切除性分型尚未统一,本文采用2020 年NCCN发布的最新胰腺癌临床诊疗指南中的胰腺癌的可切除性分型,不同的分型可影响新辅助治疗及手术时机的选择。目前对于交界性可切除胰腺癌与不可切除胰腺癌的新辅助治疗和转化治疗尚处于初期探索阶段,相关研究主要为单中心、小样本的报道,异质性大,缺乏统一的新辅助治疗与转化治疗方案,亟需开展更多前瞻性、多中心、大样本的随机对照研究,制定更为合理、规范、个体化的治疗方案,有效提高胰腺癌患者R0切除率,改善预后,为临床治疗提供可靠的个体化指导。

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