边界可切除胰腺癌新辅助治疗的机遇与挑战

摘 要：胰腺癌在腹部常见恶性肿瘤中预后最差,根治性手术切除是唯一可能治愈的方法。然而,越来越多的研究结果证实新辅助治疗能改善边界可切除胰腺癌（BRPC）的预后。目前,BRPC的主要治疗方式是新辅助治疗后手术切除肿瘤。全文就BRPC新辅助治疗的发展历程、理论基础、化疗方案、疗效评估及手术时机等方面进行综述。     

胰腺癌新辅助与辅助放疗进展

新辅助和辅助放疗在胰腺癌中的作用还不明确.对于可切除的胰腺癌首选手术,新辅助放疗只是手术存在困难时的补充;对于交界可切除及局部晚期的胰腺癌,基于化疗基础上联合放疗的新辅助治疗方案,可提高R0切除率并提高局控率;由于现有的临床试验的结果不一致,胰腺癌术后辅助放疗存在争议,但对于非R0切除及pN1的患者,建议在辅助化疗的基...     

可切除或交界可切除胰腺癌新辅助放化疗+手术对比直接手术疗效及安全性Meta分析

目的 系统评价可切除或交界可切除胰腺癌新辅助放化疗+手术与直接手术治疗模式有效性及安全性差异。方法 以pancreatic neoplasm、pancreatic cancer、surgery、preoperative chemoradiotherapy、neoadjuvant chemoradiotherapy及胰腺癌、新辅助放化疗、手术为检索词,检索Pubmed、Embase、Cochrane Library、Web of Science、中国生物医学文献数据库、万方、中国知网和维普数据库。检索时间为建库至 2020年2月。纳入新辅助放化疗+手术对比直接手术治疗可切除或交界可切除胰腺癌的随机对照试验(RCT)研究,由两名研究者独立筛选文献、提取数据和进行质量评价。总生存时间的评价采用HR及 95%CI表示,R0切除率、组间术后并发症发生率和治疗期间死亡率的评价采用RR及 95%CI表示,并且采用I²对纳入文献进行异质性检验。结果 最终纳入4项RCT研究,共 400例患者,其中新辅助放化疗+手术组 197例,直接手术组 203例。结果显示新辅助放化疗+手术组较直接手术组提高了总生存期(HR=0.76,95%CI为 0.60~0.97,P=0.03)以及R0切除率(RR=1.72,95%CI为 1.40~2.13,P<0.01),组间术后并发症发生率和治疗期间死亡率差异均无统计学意义(RR=1.02,95%CI为 0.73~1.43,P=0.90;RR=1.19,95%CI为 0.48~2.93,P=0.71)。结论 在可切除或交界可切除胰腺癌治疗中,新辅助放化疗+手术较直接手术可能会带来更多生存获益,且未增加术后不良反应发生率和治疗期间死亡率。新辅助放化疗+手术可作为可切除或交界可切除胰腺癌患者一种推荐治疗方式。     

对"边缘可切除"胰腺癌的新认识

随着胰腺影像学和外科手术技巧的发展,外科医生在"可切除的"胰腺癌与"局部进展的"胰腺癌之间划分出一类"边缘可切除"胰腺癌.这一大类肿瘤包括部分累及肝动脉、门静脉、肠系膜上动静脉,并且其受累的血管有切除与重建可能的胰腺癌.对"边缘可切除"胰腺癌施行根治性手术,有助于提高以往被认为是"无法切除"的胰腺癌的手术切除率,但是根据现有的资料统计,"边缘可切除"肿瘤的术后切缘阳性发生率较高,直接影响患者的预后.因此,术前应对肿瘤进行准确的分期分级,并联合新辅助治疗有可能为此类患者获得RO切除创造条件,并改善预后.     

可切除胰腺癌的围手术期治疗与全程管理

胰腺癌是恶性程度和致死率极高的消化道恶性肿瘤.可切除胰腺癌是指可以通过手术达到根治性切除的胰腺癌,临床研究表明辅助化疗能延长可切除胰腺癌患者的生存期,但总体预后仍不乐观.目前国内缺乏一套规范的可切除胰腺癌患者全程管理模式.本文通过对可切除胰腺癌近20年来辅助治疗、新辅助治疗、分子靶向治疗、靶向肿瘤微环境的治疗如免疫治疗...     

临界可切除胰腺癌新辅助治疗研究进展

临界可切除胰腺导管腺癌（BR-PDAC）约占初诊胰腺癌患者的20%,介于可切除与不可切除之间,具有高度的解剖学、生物学、身体条件等方面的异质性。侵袭性的生物学行为决定这部分患者应优先考虑新辅助治疗而不是直接手术,从而达到R0切除避免术后的早期复发。然而,这一治疗模式仍然存在争议。根据这一主题的最新研究,本文从BR-PDAC的定义、新辅助治疗选择与评估、新辅助治疗后手术结果、新辅助治疗后辅助治疗的疗效等方面进行综述。     

新辅助治疗与前期手术在可切除胰腺癌比较的Meta分析

[目的]比较新辅助治疗(neoadjuvant therapy,NAT)和前期手术在可切除胰腺癌(resectable pancreatic cancer,RPC)中的临床差异。[方法]计算机检索Pubmed、Embase、Web of Science和Cochrane数据库,纳入未进行新辅助治疗直接进行手术切除(前期手术组)和接受新辅助治疗后进行手术切除(NAT组)的可切除胰腺癌患者。根据异质性选择随机效应模型或固定效应模型计算文献合并的比值比(odds ratio,OR)与危险比(hazard ratio,HR)及其95%可信区间(95%confidence interval,95%Cl)。在没有提供HR的文献中,从文中提供的生存曲线提取HR及其95%CI,同时使用漏斗图与Egger’s检验的方法评估发表偏倚。[结果]共纳入11项研究,9386例患者。在所纳入的患者中,有2508例(26.7%)接受了NAT治疗。与前期手术相比,NAT可提高RPC患者的R0切除率(OR=1.89,95%CI:1.26~2.83),同时降低淋巴结阳性率(OR=0.34,95%CI:0.31~0.37)。但接受NAT的RPC患者的总生存(overall survival,OS)时间未显著增加(HR=0.93,95%CI:0.83~1.04)。[结论]在RPC患者中,NAT组的R0切除率和淋巴结阳性率均优于前期手术患者。     

胰腺癌新辅助治疗的研究现状

胰腺癌是消化系统恶性程度最高的肿瘤。近年来胰腺癌的发病率呈逐年上升趋势,预计在未来10年胰腺癌将成为发达国家癌症死亡的第二大原因。由于诊断时分期较晚,治疗选择有限,胰腺癌的预后极差,只有手术是治愈的唯一方法。为了提高手术切除率并改善预后,新辅助治疗已悄然成为目前胰腺癌治疗的热点问题。但现在胰腺癌的新辅助治疗还未有标准化的治疗方案,本文主要探讨胰腺癌新辅助治疗的研究现状。     

可切除食管鳞癌新辅助同步放化疗加手术对比单纯手术的疗效及安全性Meta分析

目的 系统评价可切除食管鳞癌新辅助同步放化疗+手术与单纯手术模式的有效性及安全性差异。方法 计算机检索Embase、Pubmed、Web of Science、Cochrane library、万方、中国知网、中国生物医学文献数据库等,查找辅助同步放化疗联合手术对比单纯手术治疗可切除食管鳞癌的临床随机对照研究文献。使用Revman 5.3统计软件对生存资料、R0切除率、术后并发症发生率及治疗期间死亡率进行Meta分析。结果 最终纳入11个临床随机对照研究文献,共计1450例患者。结果显示新辅助同步放化疗+手术组有更高的2、5年总生存率(RR=1.14,95%CI为1.05~1.23,P=0.00)和2、5年无进展生存率(RR=1.56,95%CI为1.05~2.32,P=0.03);提高了R0切除率(RR=1.10,95%CI为1.05~1.14,P=0.00),术后心律失常发生率也较高(RR=2.45,95%CI为1.37~4.38,P=0.00)。两组术后并发症总发生率和治疗期间死亡率均相近(RR=1.12,95%CI为0.79~1.59,P=0.51和RR=1.78,95%CI为0.90~3.52,P=0.10)。结论 可切除食管鳞癌新辅助同步放化疗+手术较单纯手术带来更多生存获益,并未明显增加不良反应发生率,是治疗可切除食管鳞癌的一种可选方案。     

可切除食管鳞癌新辅助同步放化疗加手术对比单纯手术的疗效及安全性Meta分析

目的 系统评价可切除食管鳞癌新辅助同步放化疗+手术与单纯手术模式的有效性及安全性差异。方法 计算机检索Embase、Pubmed、Web of Science、Cochrane library、万方、中国知网、中国生物医学文献数据库等,查找辅助同步放化疗联合手术对比单纯手术治疗可切除食管鳞癌的临床随机对照研究文献。使用Revman 5.3统计软件对生存资料、R0切除率、术后并发症发生率及治疗期间死亡率进行Meta分析。结果 最终纳入11个临床随机对照研究文献,共计1450例患者。结果显示新辅助同步放化疗+手术组有更高的2、5年总生存率(RR=1.14,95%CI为1.05~1.23,P=0.00)和2、5年无进展生存率(RR=1.56,95%CI为1.05~2.32,P=0.03);提高了R0切除率(RR=1.10,95%CI为1.05~1.14,P=0.00),术后心律失常发生率也较高(RR=2.45,95%CI为1.37~4.38,P=0.00)。两组术后并发症总发生率和治疗期间死亡率均相近(RR=1.12,95%CI为0.79~1.59,P=0.51和RR=1.78,95%CI为0.90~3.52,P=0.10)。结论 可切除食管鳞癌新辅助同步放化疗+手术较单纯手术带来更多生存获益,并未明显增加不良反应发生率,是治疗可切除食管鳞癌的一种可选方案。     

Current update of treatment strategies for borderline resectable pancreatic cancer: a narrative review

Background and ObjectiveBorderline resectable pancreatic cancer (BRPC) is a tumor that infiltrates into the large blood vessels, with a high probability that the tumor will remain after surgical resection. To date, there has been no confirmed treatment strategy for BRPC. However, high-level studies, such as those using the intention-to-treat analysis, have recently been published. This review aimed to update the current status of treatment strategies for BRPC.MethodsWe searched for studies, including those investigating patients with BRPC, either treated by upfront surgery or with neoadjuvant treatment and reported the R0 resection rate and overall survival using an intention-to-treat analysis.Key Content and FindingsConsequently, 22 articles were identified. Twelve were prospective studies. Six studies compared neoadjuvant therapy with upfront surgery, and both the R0 resection rate and overall survival in patients who underwent upfront surgery were significantly worse than in those who underwent neoadjuvant treatment in all studies. Six studies evaluated neoadjuvant chemotherapy, while 15 studies neoadjuvant chemoradiation. No reports showed the superiority or inferiority of the two methods, and the optimal regimen was not determined in either treatment. The high-precision radiation therapy techniques have been studied, but the optimal method and dose fractionation were unclear.ConclusionsThe current standard of care for the BRPC is neoadjuvant therapy. Although the optimal regimen of neoadjuvant therapy was not determined, several prospective trials are underway to identify the optimal neoadjuvant treatment.     

Neoadjuvant chemoradiotherapy has a potential role in pancreatic carcinoma

Pancreatic cancer has an extremely poor prognosis, only a small minority of patients undergo a resection with curative intent. Chemotherapy and/or radiochemotherapy may improve this by prolonging survival or disease-free interval and improving resectability and the proportion of microscopically complete (R0) resections. With regard to prolonging survival, both in the postoperative adjuvant setting and in locally advanced disease, chemotherapy has a positive but limited effect on survival and may be considered standard. The role of postoperative adjuvant radiochemotherapy remains debatable. For improving resectability/proportion of R0 resections, many studies suggest that the proportion of patients undergoing a resection during exploration and the proportion of R0 resections increase after neoadjuvant radiochemotherapy. This may improve the prognosis of patients with a resectable or borderline resectable pancreatic carcinoma. The effect of neoadjuvant radiochemotherapy, if any, is modest. The search for better combinations, including targeted therapy, must continue. The interpretation of single-arm studies is hampered by (selection) biases. The reporting of pathology and study endpoints should be internationally standardized. To avoid biases in studies of patients with (borderline) resectable tumours, prospective parallel registration of all patients referred for surgery would help. Ultimately, randomized controlled phase III trials should establish the role of neoadjuvant radiochemotherapy. Thus, neoadjuvant radiochemotherapy has a potential benefit in resectable and borderline resectable pancreatic cancer, but better combinations are warranted.     

Multidisciplinary therapy for pancreatic cancer - clinical impact for preoperative therapy and peptide vaccine therapy

Pancreatic cancer survival is poor for those with high-grade malignancy, so multidisciplinary therapy is required for pancreatic cancer patients. Borderline resectable pancreatic cancer patients, according to the National Comprehensive Cancer Net- work(NCCN), have a high incidence of R1/2 resection, which demonstrates poor survival. It is thought that not only postoperative therapy but also preoperative therapy is essential to improve the survival of advanced pancreatic cancer patients. Preoperative chemoradiotherapy leads to R0 resection, resulting in improved survival of borderline resectable pancreatic cancer patients. Metastatic disease survival might be improved by intensive chemotherapy, and super-responder chemotherapy might be performed for resection, which means the new concept of adjuvant chemotherapy. On the other hand, antigenspecific CD8-positive CTL is generated by stimulation of peptide. Three clinical trials are on-going using OCV-101, OCV-105, and OTS-102, respectively. The development of a peptide vaccine used as a medicine is anticipated.     

New approaches for pancreatic cancer in Japan

Pancreatic cancer is the fifth leading cause of cancer-related mortality in Japan, with an estimated annual incidence rate of approximately 20,000 cases. Even in patients with resectable disease, the long-term outcome remains unsatisfactory due to early recurrence after resection. However, surgical resection has offered the only curative strategy for pancreatic cancer. Currently available chemotherapeutic agents have little impact on survival, although the development of gemcitabine has renewed interest in clinical research for pancreatic cancer. To further improve the prognosis of patients with pancreatic cancer, the development of more effective nonsurgical treatment is essential. Studies to identify more effective treatments, such as chemotherapy, interventional therapy and gene therapy, are ongoing in Japan. The expanding understanding of molecular and genetic biology should facilitate research to develop novel molecular-targeted agents and to establish individualized therapy regimens for this disease.     

3rd St. Gallen EORTC Gastrointestinal Cancer Conference: Consensus recommendations on controversial issues in the primary treatment of pancreatic cancer

The primary treatment of pancreatic cancer was the topic of the 3rd St. Gallen Conference 2016. A multidisciplinary panel reviewed the current evidence and discussed controversial issues in a moderated consensus session. Here we report on the key expert recommendations.It was generally accepted that radical surgical resection followed by adjuvant chemotherapy offers the only evidence-based treatment with a chance for cure. Initial staging should classify localised tumours as resectable or unresectable (i.e. locally advanced pancreatic cancer) although there remains a large grey-zone of potentially resectable disease between these two categories which has recently been named as borderline resectable, a concept which was generally accepted by the panel members. However, the definition of these borderline-resectable (BR) tumours varies between classifications due to their focus on either (i) technical hurdles (e.g. the feasibility of vascular resection) or (ii) oncological outcome (e.g. predicting the risk of a R1 resection and/or occult metastases).The resulting expert discussion focussed on imaging standards as well as the value of pretherapeutic laparoscopy. Indications for biliary drainage were seen especially before neoadjuvant therapy. Following standard resection, the panel unanimously voted for the use of adjuvant chemotherapy after R0 resection and considered it as a reasonable standard of care after R1 resection, even though the optimal pathologic evaluation and the definition of R0/R1 was the issue of an ongoing debate.The general concept of BR tumours was considered as a good basis to select patients for preoperative therapy, albeit its current impact on the therapeutic strategy was far less clear. Main focus of the conference was to discuss the limits of surgical resection and to identify ways to standardise procedures and to improve curative outcome, including adjuvant and perioperative treatment.     

Selection of methods for diagnosis and treatment of pancreatic cancer]

The prognosis for ductal cancer of the pancreas is extremely poor. Diagnosis of pancreatic cancer in the earlier stages has become possible by taking note of early symptoms, mild abdominal pain, back pain, anorexia, diabetes and obstructive jaundice. Presently, measurements of amylase in serum and urine, serum elastase-1, serum CA 19-9 and US are usually used for screening patients with the symptoms. Furthermore, for correct diagnosis, intensive study by US, dynamic CT, ERCP, MRI, cytological examination and CEA of pancreatic juice, endoscopic pancreatoscopy and endoscopic ultrasonography are used. The results of surgical treatment for resectable pancreatic cancer are not generally favorable. Extended pancreatic resection (pancreatoduodenectomy, total pancreatectomy or distal pancreatectomy) with en bloc dissection of the lymph nodes has been performed for patients with invasive cancer. However, local recurrence and distant metastasis usually occurred after surgery. It seems difficult to cure pancreatic cancer by surgery alone. To improve the prognosis of resectable pancreatic cancer, multimodality treatment with intraoperative radiation therapy and chemotherapy is performed and a better outcome is achieved.