Pancreatic cancer is a digestive tumor with extremely high malignancy and poor prognosis. Its incidence is increasing year by year, and the long-term survival of patients is sobering. The National Comprehensive Cancer Network (NCCN), which consists of 21 top oncology centers in the United States, strives to provide the best clinical recommendations for oncology patients by developing and promoting clinical practice guidelines. The NCCN Clinical Practice Guidelines for Pancreatic Cancer (hereinafter referred to as “the Guidelines”) are highly authoritative and widely accepted in the pancreatic surgery community, and were formally introduced to China in 2010 and have been widely accepted by the domestic pancreatic disease community. Recently, the 2011 Guidelines (Chinese version), which is based on the English version of the 2011 Guidelines and revised with the participation of many medical institutions in China, was officially launched, with updated research results, more suitable for China’s national conditions and convenient for Chinese physicians. This article interprets the main points of the guidelines in order to further improve the diagnosis and treatment of pancreatic cancer in China.
I. Diagnosis and staging
I) Preoperative imaging examination
Radical surgical resection is an important way for pancreatic cancer patients to achieve long-term survival, however, pancreatic cancer has insidious onset, rapid progression, high malignancy, and low early diagnosis rate, and more than 80% of patients cannot be radically resected at the time of diagnosis. The concept of pancreatic CT, i.e. triphasic imaging plus pancreatic thin-section CT, has been proposed in the 2010 Guidelines (Chinese version) and is now widely used in large pancreatic cancer treatment centers in China, which can clearly show the relationship between tumor and blood vessels in combination with vascular 3D reconstruction, and the accuracy rate of predicting tumor resectability is about 80%, which is the best method for preoperative resectability assessment of pancreatic cancer [1 ]. In addition, ultrasound endoscopy, PET-CT, MRI, and laparoscopy are also important methods for preoperative examination of pancreatic cancer. 2011 Guidelines (Chinese version) added MRI for preoperative imaging evaluation compared with the previous version, and enhanced MRI can be used for patients who are allergic to CT contrast agent, and it can also be used as a complementary examination method to CT to better diagnose extra-pancreatic lesions. At the same time, the 2011 Guidelines (Chinese version) elaborated the role of PET-CT in more detail and objectively, updating the old version, “PET scan can be considered if CT results are ambiguous,” to “The role of PET-CT scan is still unclear. PET-CT is not a substitute for high-resolution enhanced CT.”
ii) Tumor markers
CA19-9 is a sialic acid Lewis-a blood group antigen that is usually expressed and shed in pancreatic and hepatobiliary system diseases as well as numerous malignancies and therefore is not tumor specific. However, its expression level in serum helps to identify chronic pancreatitis from pancreatic cancer and is also one of the indicators for postoperative monitoring of pancreatic cancer. 2011 Guidelines (Chinese version) provides a more detailed interpretation of CA19-9, emphasizing that there are false positives and false negatives for CA19-9, i.e., it can be elevated in benign biliary system obstruction and can be false negative in Lewis antigen negative individuals. It was also emphasized that preoperative CA19-9 values as a baseline must be measured in the presence of a patent biliary system and normal bilirubin to be clinically meaningful.
iii) Pathological diagnosis
Pancreatic cancer is in some cases more difficult to differentiate from chronic pancreatitis, benign lesions or pancreatic neuroendocrine tumors and the treatment options are completely different. The disadvantages of fine needle aspiration are low cell count, poor puncture location, or other factors causing false negatives. For patients with pathologically undiagnosed pancreatic cancer but with high clinical suspicion, the 2011 English version of the Guidelines still insists that patients must have a pathologic diagnosis before adjuvant therapy can be administered in order to avoid harm to non-oncologic patients. In addition, the importance of pathological diagnosis in patients with metastatic pancreatic cancer, unresectable tumors and those who are to undergo neoadjuvant therapy is further emphasized, that is, for patients diagnosed with metastatic pancreatic cancer, pathological confirmation of metastases is recommended as a priority; when radical resection is found to be impossible during surgery, the requirement of pancreatic cancer tissue biopsy is added for patients who have not undergone pathological examination before surgery; for those who plan to undergo neoadjuvant For those who plan to undergo neoadjuvant therapy, pathological diagnosis must be obtained before treatment. However, according to the current situation in China, after discussion by our experts, it was proposed in the 2011 Guidelines (Chinese version) in the form of footnotes that for patients with a clinical diagnosis or high suspicion of pancreatic cancer that cannot be pathologically confirmed by repeated biopsies, the next step of treatment can be carried out cautiously after discussion by qualified experts and multidisciplinary consultation, and after obtaining fully informed consent from the patient or family. Thus, the 2011 Guidelines (Chinese version) are closer to China’s national conditions and facilitate clinical promotion and application.
IV) Tumor Staging
The accurate staging of tumor is significant for guiding treatment. With the development of imaging and the increase of biopsy rate of laparoscopic exploration of suspicious metastases in recent years, the diagnosis rate of metastatic pancreatic cancer has increased year by year. Therefore, the 2011 Guidelines (Chinese version) adopted the American Joint Committee on Cancer (AJCC) TNM Staging of Pancreatic Cancer (2010) criteria. Compared with the AJCC TNM staging criteria for pancreatic cancer (2002) adopted in the 2010 Guidelines (Chinese version), the new TMN staging removes the “MX: uncertainty of metastasis” from the original M staging, thus improving the tumor staging.
V) Multidisciplinary assessment
Since pancreatic cancer is highly malignant, rapidly progressing, and the effect of single treatment is not good, it is very important to optimize the diagnosis and treatment process of pancreatic cancer and establish a green treatment channel for pancreatic cancer. 2011 Guidelines (Chinese version) added “multidisciplinary assessment” and added the footnote “Ideally, multidisciplinary assessment should include Ideally, multidisciplinary evaluation should include surgery, imaging, medical oncology, radiology oncology and pathology.” The aim is to make a comprehensive and rapid assessment for the patient and to develop a comprehensive treatment plan including surgery.
II. Surgical treatment
I) Resectability assessment and neoadjuvant treatment
Based on the preoperative assessment of the relationship between the tumor and adjacent blood vessels and the presence of distant metastases, pancreatic cancer can be classified into the following three categories: (1) resectable; (2) potentially resectable (tumor involves surrounding structures and the risk of obtaining R0 resection is high); and (3) unresectable (locally advanced or distant metastases). The purpose of preoperative resectability assessment is to better select patients for radical surgery and increase the R0 resection rate. Patients with potentially resectable pancreatic cancer are at greater risk of surgically obtaining R0 resection. Studies have demonstrated that neoadjuvant therapy is safe and effective [2-3], and the 2011 Guidelines (Chinese version) added a new footnote to the neoadjuvant treatment program: “In centers with a large surgical volume, most NCCN institutions prefer neoadjuvant therapy for patients with potentially resectable pancreatic cancer”, increasing the recommendation for neoadjuvant therapy. The recommendation for neoadjuvant therapy has been increased. It also added pancreatic CT to the reassessment tests after neoadjuvant therapy to more accurately determine the efficacy, and explicitly recommended the acquisition of pathological diagnosis by ultrasound endoscopy-guided fine-needle aspiration (EUS-FNA) before neoadjuvant therapy, with a view to reducing peritoneal implant metastases due to other percutaneous biopsies.
II) About preoperative yellowing reduction
About 70% of patients with pancreatic head cancer have obstructive jaundice as the first symptom [4]. At present, preoperative reduction of yellowness is mainly performed by percutaneous hepatic puncture choledochotomy (PTCD) and endoscopic retrograde cholangiopancreatography (ERCP) stent implantation in clinical practice. The former is mainly used to relieve jaundice in proximal bile duct obstruction or severe biliary obstruction, while the latter is mainly used to relieve middle and distal bile duct obstruction; however, complications such as bile leakage, bleeding, infection, and reobstruction can occur in both methods. The need for preoperative reduction has been debated, with proponents arguing that preoperative reduction improves liver function and thus reduces the incidence of surgical complications, and opponents arguing that preoperative reduction delays surgery and may increase the incidence of complications and prolong the patient’s hospital stay. After weighing all the evidence, the 2011 Guidelines (Chinese version) still recommend preoperative biliary drainage in patients with biliary ductitis, fever, or potentially resectable pancreatic cancer receiving neoadjuvant therapy.
III) Surgical modality and scope
1. whether to preserve the pylorus: compared with the traditional Whipple procedure, pylorus-preserving pancreaticoduodenectomy (PPPD) preserves the pylorus and proximal duodenum. pppd reduces surgical trauma, and it has been reported that pppd can reduce complications such as postoperative dumping syndrome, steatorrhea, anastomotic ulceration, and does not increase the incidence of postoperative gastric emptying disorder. However, it should be pointed out that ensuring R0 resection of tumor is the prerequisite for choosing the surgical method, so the indications for PPPD surgery should be strictly controlled, and Whipple surgery should be chosen instead of PPPD when the tumor has invaded the duodenum or group 5 or 6 lymph nodes.
2.Superior mesenteric-portal vein resection and reconstruction: Due to the adjacent anatomical location, pancreatic head cancer is easy to invade the portal vein system. In order to obtain R0 resection of the tumor, pancreaticoduodenectomy combined with portal vein system resection and reconstruction is gradually applied in clinical practice. In fact, not all patients with preoperative imaging suspicion of vascular invasion have vascular involvement, and some of them have inflammatory adhesions, so if resection is abandoned, this group of patients will lose the chance of radical treatment. Even if venous involvement does occur, studies from Germany and the United States have confirmed that combined angiography is safe and feasible with good results [5-6]. Therefore, the 2011 Guidelines (Chinese version) still recommend combined superior mesenteric-portal vein resection and reconstruction for appropriate patients with caution.
3. Scope of lymph node dissection: the concept of extended lymph node dissection was proposed by many medical centers in the 20th century, however, the scope is not uniform. At present, the scope of expanded lymph node dissection for pancreaticoduodenectomy is more consistent and includes: peripancreatic lymph nodes, lymph nodes between the right renal hilum and the left border of the abdominal aorta, and lymph nodes between the portal vein and the emanation site of the inferior mesenteric artery. Regarding the significance and complications of extended lymph node dissection, most studies have concluded that it does not improve the prognosis of patients, while opinions differ on whether it increases postoperative complications such as pancreatic leakage and postoperative gastric emptying disorders. Therefore, the 2011 Guidelines (Chinese version) still do not recommend routine expanded lymph node dissection.
III. Postoperative adjuvant therapy
The 2011 Guidelines (Chinese version) elevated the status of fluorouracil-based drugs (fluorouracil (5-FU), capecitabine) in the treatment of pancreatic cancer, and pointed out that if systemic chemotherapy + synchronous radiotherapy is considered after surgery, it is recommended to choose synchronous radiotherapy based on 5-FU or gemcitabine; 5-FU + calcium folinic acid (LV) or gemcitabine systemic chemotherapy is administered before or after radiotherapy; if adjuvant chemotherapy alone is administered, it is recommended to choose adjuvant chemotherapy based on 5-FU or gemcitabine. If adjuvant chemotherapy alone is administered, the recommendation to prioritize gemcitabine therapy has been removed compared to the 2010 Guidelines (Chinese version). At the same time, the 2011 Guideline (Chinese version) upgraded the recommendation of both gemcitabine and 5-FU+LV from category 2A to category 1.
IV. Chemotherapy for locally advanced and metastatic pancreatic cancer
The 2011 Guideline (Chinese version) clearly defines the concept of “good physical status”, which provides a uniform standard for clinical work. Specifically: (1) Eastern Cooperative Oncology Group (ECOG) score of 0 to 1 and good pain control; (2) biliary stent drainage; (3) adequate nutritional intake. For those with good physical status, the 2011 Guidelines (Chinese version) added the recommendation of FOLFIRINOX (class 1) [7] and capecitabine (class 2A) treatment; for patients who progress after first-line treatment but still have good physical status, they should still be treated aggressively. Since the European Study Group on Pancreatic Cancer (ESPAC)-3 trial [8] showed that for locally advanced and metastatic pancreatic cancer, gemcitabine and 5-FU can be used interchangeably as first- and second-line treatment regimens, and sequential use of these two regimens can lead to longer survival for patients. Therefore, the 2011 Guideline (Chinese version) adds the following recommendations for salvage therapy (second-line treatment) regimens: if you have received previous gemcitabine-based chemotherapy, you can choose a 5-FU-based chemotherapy regimen; if you have received previous 5-FU-based chemotherapy, you can choose a gemcitabine-based chemotherapy regimen. After failure of salvage therapy, the option to participate in clinical trials was added. Meanwhile, for patients with distant metastases after surgery and >6 months from the end of adjuvant therapy, in addition to the original regimen of systemic chemotherapy, the 2011 Guidelines (Chinese version) also added “replacement systemic chemotherapy” as a treatment option, thus enhancing the treatment of locally advanced and metastatic pancreatic cancer.
Despite the tireless efforts of our pancreatic colleagues, the surgical resection rate and 5-year survival rate of pancreatic cancer have not changed significantly in the past 20 years, despite our achievements in the diagnosis and treatment of pancreatic cancer, which is still referred to as the “stubborn bastion of 21st century medicine”. The 2011 edition of the Guidelines (Chinese version) has been updated with the latest international research findings and is more in line with China’s national conditions, providing guidance for clinical treatment of pancreatic cancer. With the promotion of the 2011 Guidelines (China Version), more patients will receive more standardized treatment and the level of pancreatic cancer diagnosis and treatment in China will be further improved. The high road of Sichuan can be a long sigh of relief, but it can also inspire the brave man’s courageous spirit. We, Chinese pancreatologists, will continue to work hard to finally overcome the “stubborn fortress of 21st century medicine” for life.