局部进展期胰腺癌新辅助治疗的现状与进展

Current status and progress of neoadjuvant therapy for locally advanced pancreatic cancer

胰腺癌恶性程度高,其总体5年生存率仅约11%。虽然根治性手术切除可能治愈胰腺癌,但仅约15%胰腺癌在首次确诊时为可切除性疾病。新辅助治疗使得有些原本不可切除的局部进展期胰腺癌(LAPC)获得了R0切除的机会。LAPC新辅助治疗是基于目前治疗现状的一种新的治疗模式,逐渐为临床外科医生接受。新辅助治疗方案的出现,使得20%~61%的LAPC经新辅助治疗后转化为可切除病例。奥沙利铂、伊立替康、氟尿嘧啶和亚叶酸钙(FOLFIRINOX)及吉西他滨联合白蛋白紫杉醇(AG)明显提高了LAPC的手术切除率,是LAPC首选一线新辅助治疗方案。各医疗中心关于LAPC新辅助治疗的方案选择、周期、评估指标、手术时机等方面仍存在较大差异。部分术前全身化疗不足以使肿瘤降期达到手术指征的LAPC患者,可将联合化放疗作为初始治疗。对于不能耐受系统性化疗的LAPC患者,可采用立体定向放射治疗(SBRT)控制局部肿瘤进展。胰腺癌的治疗靶点包括KRAS、EGFR、PARP及NTRK等。NCCN指南建议对所有LAPC患者进行基因检测,指导最佳药物治疗方案及参与新药的临床研究。胰腺癌免疫治疗主要包括免疫检查点抑制剂、过继性T细胞治疗及肿瘤疫苗。帕博利珠单抗是唯一获得美国食品药品管理局批准用于微卫星高度不稳定或错配修复缺陷的实体瘤(包括胰腺癌)的二线治疗方案。目前过继性T细胞治疗仅限于转移性胰腺癌。肿瘤疫苗GVAX现处于临床试验阶段。免疫治疗与某些靶向药物(如抗血管生成因子及酪氨酸激酶抑制剂)之间存在协同作用。未来的免疫治疗应旨在联合多种新型免疫治疗策略,以及联合细胞毒性药物和/或局部消融治疗,针对肿瘤诱导的免疫逃逸机制产生作用。关于联合治疗,药物选择、给药顺序及剂量将是主要挑战。选择特定的LAPC患者行新辅助治疗后实施手术是值得积极推荐的方法。通过影像学评估新辅助治疗后肿瘤的可切除性是困难的,CT无法准确区分肿瘤组织与纤维组织。18F-FDG PET判断胰腺癌R0可切除性较CT更加准确,但未来仍然需要高质量的证据进一步证实。其他对于新辅助治疗效果的评估包括肿瘤标志物血清学水平下降以及临床症状的改善。液体活检技术(包括循环肿瘤细胞、循环肿瘤DNA及外泌体检测等)在确定微转移灶及新辅助治疗疗效评估方面显现出潜在的应用前景。新辅助治疗后接受手术切除的LAPC患者长期生存率有所提高。创新技术动脉外膜鞘剥离及自体小肠移植有助于新辅助治疗后的手术切除。笔者就LAPC新辅助治疗的现状和进展等方面进行回顾和讨论。

Pancreatic cancer has a high malignancy degree,with an overall 5-year survival rate of only about 11%.Although curative surgery may cure pancreatic cancer,only about 15%of pancreatic cancers are resectable at the time of initial diagnosis.Neoadjuvant therapy provides an opportunity of R,resection for some locally advanced pancreatic cancers(LAPC)that are initially unresectable.Neoadjuvant therapy for LAPC is a new treatment modality based on the current treatment status,which is gradually being accepted by clinical surgeons.The emergence of neoadjuvant treatment regimens has led to 20%to 61%of LAPC cases being converted to resectable cases after neoadjuvant therapy.Oxaliplatin,irinotecan,fluorouracil,and calcium folinate(FOLFIRINOX)and gemcitabine combined with albumin-bound paclitaxel(AG)significantly increase the surgical resection rate of LAPC and are the preferred first-line neoadjuvant treatment regimen for LAPC.There are still significant differences in the choice of treatment plan,duration,evaluation indicators,and surgical timing for LAPC neoadjuvant therapy among medical centers.For some LAPC patients who do not meet surgical indications due to inadequate tumor reduction after preoperative systemic chemotherapy,combined chemoradiotherapy can be used as initial treatment.For LAPC patients who cannot tolerate systemic chemotherapy,stereotactic body radiation thcrapy(SBRT)can bc uscd to control local tumor progression.The treatment targets for pancreatic cancer include KRAS,EGFR,PARP,and NTRK,among others.The NCCN guidelines recommend genetic testing for all LAPC patients to guide the best drug treatment plan and participate in clinical trials of new drugs.Pancreatic cancer immunotherapy mainly includes immune checkpoint inhibitors,adoptive T-cell therapy,and tumor vaccines.Pembrolizumab is the only second-line treatment approved by the US Food and Drug Administration for microsatellite-instability-high or mismatch-repair-deficient solid tumors,including pancreatic cancer.Currently,adoptive T-cell therapy is limited to metastatic pancreatic cancer.The GVAX tumor vaccine is in the clinical trial stage.There is a synergistic effect between immunotherapy and certain targeted drugs,such as antiangiogenic factors and tyrosine kinase inhibitors.Future immunotherapy should aim to combine multiple new immunotherapy strategies,as well as cytotoxic drugs and/or local ablation therapy,to target tumor-induced immune escape mechanisms.The main challenge of combination therapy will be drug selection,administration sequence,and dosage.It is worth actively recommending the approach of selecting specific LAPC patients for neoadjuvant therapy followed by surgery.It is difficult to evaluate the resectability of tumors after neoadjuvant therapy through imaging evaluation,as CT cannot accurately distinguish between tumor tissue and fibrous tissue.18F-FDG PET is more accurate than CT in determining the Ro resectability of pancreatic cancer,but high-quality evidence is still needed to further confirm this.Other evaluations of the effectiveness of neoadjuvant therapy include a decrease in serum tumor marker levels and improvement in clinical symptoms.Liquid biopsy techniques,including the detection of circulating tumor cells,circulating tumor DNA,and exosomes,have shown potential applications in the determination of micrometastases and the evaluation of neoadjuvant therapy efficacy.Long-term survival rates of LAPC patients who underwent surgical resection after neoadjuvant therapy have been improved.