Pancreatic cancer remains one of the most stubborn bastions of medicine, and epidemiological findings in recent years have shown that the incidence and mortality rates of pancreatic cancer worldwide are increasing year by year, with a trend toward rejuvenation. According to the latest statistics from the American Cancer Society, the number of new cases of pancreatic cancer in the United States in 2014 is expected to be 46,420 and the number of deaths is 39,590, ranking 4th in the rate of death from malignant tumors, with a 5-year survival rate of less than 60%. Pancreatic cancer has become an important disease that poses a serious threat to human health and poses a great challenge to clinical medicine.
So far, radical surgical resection is still the only way to cure pancreatic cancer. Although China has made some progress in the diagnosis and treatment of pancreatic cancer, the reality that more than 80% of patients are at advanced stages when they are diagnosed has not changed significantly, and the overall treatment outcome of pancreatic cancer is still not optimistic. In addition to the nature of the tumor itself, there are still some problems in the diagnosis and treatment of pancreatic cancer in China that are worthy of reflection and have not been given sufficient attention, which are summarized below in order to further improve the level of comprehensive treatment of pancreatic cancer in China and gradually improve the prognosis of patients.
I. Early diagnosis of pancreatic cancer – emphasis on screening of high-risk groups and establishment of green channel for diagnosis and treatment.
Pancreatic cancer has an insidious onset and lacks specific clinical manifestations in the early stage, and most patients have already experienced local invasion and distant metastasis by the time they are diagnosed, thus losing the time for radical surgery and eventually surviving less than 6 months. The results of several studies have shown that early diagnosis and radical surgery are independent factors affecting the prognosis of patients. Therefore, it is significant to screen the high-risk group and establish a green channel for diagnosis and treatment.
The industry standard for pancreatic cancer diagnosis (WS333) issued by the former Ministry of Health in 2011 defines the high-risk group of pancreatic cancer in China, however, there is still no consensus on the specific screening protocols among domestic and foreign scholars. Serum tumor marker screening is a more recognized ideal means of early screening, and although a lot of research has been conducted in this area at home and abroad, no significant breakthrough has been achieved so far.
Endoscopic ultrasonography (EUS) is more sensitive in detecting microscopic (about 1 cm) pancreatic lesions and is widely used for early screening. A recent prospective multicenter pancreatic cancer screening (CAPS) trial showed that the accuracy of EUS, MRI and CT in detecting abnormal lesions was 42%, 33% and 11%, respectively. Accordingly, at the recent International Pancreatic Cancer Screening Summit, multidisciplinary experts unanimously recommended EUS and/or MRI/MRCP as primary screening for people at high risk for pancreatic cancer, but there are still major differences in the age of initiation of screening, interval and management of early lesions, and more evidence-based medical evidence is needed to support this recommendation.
Because EUS technology is not yet widespread in China and the results are easily influenced by operator experience, screening and management of high-risk populations should be done by experienced physicians in large medical centers and included in clinical studies to assess its long-term efficacy.
Second, preoperative assessment promotes advanced assessment systems and strengthens multidisciplinary teamwork.
Accurate preoperative evaluation is important for rational selection of treatment, improving surgical resection rate, reducing surgical mortality and improving patient’s survival quality. The preoperative evaluation of pancreatic cancer should include TNM staging and clinical staging. At present, the widely used staging system at home and abroad is the 7th edition of TNM staging system for pancreatic cancer developed by AJCC, and on the basis of which the clinical staging criteria are further optimized, the latter of which emphasizes the resectability of the tumor and is therefore more suitable for clinical work.
The likelihood of obtaining a negative margin (i.e., RO resection) is a key factor to consider when assessing a patient’s suitability for surgical resection. Only patients in stages I and II of the TNM staging system for pancreatic cancer are suitable for direct surgical treatment, while most scholars in China and abroad prefer to re-evaluate resectability after neoadjuvant therapy for patients with a high likelihood of positive surgical margins (i.e., possible resection) in stage III.
High-quality preoperative imaging plays a key role in determining the accurate staging. Pancreatic CT, i.e., three-phase imaging plus pancreatic thin-layer scan CT, has been widely used in large pancreatic cancer centers in China, which can clearly show the relationship between the tumor and surrounding blood vessels in combination with three-dimensional vascular reconstruction, and can detect tiny metastases of 3-5 mm in size. A retrospective study found that 56% of cases were re-evaluated by pancreatic CT in a large pancreatic surgery center, resulting in different staging and treatment decisions.
EUS is also an important reference in preoperative evaluation, and most international experts believe that EUS is superior in assessing tumor invasion of certain veins (e.g., portal vein), but less accurate in determining the extent of involvement of the superior mesenteric artery. In addition, ERCP and PET-CT are also important methods for preoperative staging of pancreatic cancer, but they are not routinely recommended at present; similarly, laparoscopic staging is of great importance for patients with high preoperative suspicion of distant metastases without strong evidence to support them, and can be used to detect occult metastases on the peritoneal and hepatic surfaces to avoid unnecessary dissection.
Due to the complexity of pancreatic cancer diagnosis and management, although there are clear criteria for potentially resectable pancreatic cancer both at home and abroad, there is more flexibility in actual clinical practice and it is easily influenced by various factors such as the accuracy of imaging and operator experience, therefore, the pancreatic cancer diagnosis and management guidelines issued by NCCN over the years clearly suggest that diagnostic treatment and determination of tumor resectability should be decided by the MDT of a large medical center. In addition, the extent of the tumor should be evaluated with reference to appropriate high-quality imaging.
The results of studies have shown that the establishment of MDTs and the development of comprehensive and coordinated evaluation and treatment plans are the most effective means to improve the prognosis of patients with pancreatic cancer. However, the construction of this treatment model is still not perfected in many medical centers in China, resulting in some pancreatic cancer patients not receiving accurate staging and standardized treatment. In this regard, the MDT model for pancreatic cancer diagnosis and treatment must be established and perfected as soon as possible to improve the overall treatment outcome of pancreatic cancer in China.
The surgical operation of pancreatic cancer – continuous standardization and improvement of RO resection rate.
There are many surgical procedures for pancreatic cancer treatment, and although each procedure has its indications and contraindications, there are still many debates in the practical application. Therefore, emphasis should be placed on strictly mastering the indications for surgery, standardizing the surgical operation, and improving the RO resection rate. Regarding whether the pylorus should be preserved for surgery of pancreatic head cancer, the results of a recent meta-analysis showed that pylorus-preserving pancreaticoduodenectomy (PPPD) did not differ from the standard Whipple procedure (PD) in terms of complication rate, morbidity and mortality rate, and overall survival, but had significant advantages in terms of operative time and bleeding volume.
It should be noted, however, that ensuring RO resection of the tumor is a prerequisite for the choice of surgical approach. Therefore, the indications for PPPD must be strictly controlled, and Whipple surgery should be chosen instead of PPPD when the tumor has invaded the duodenum or the 5th or 6th group of lymph nodes, and the results of more and more studies have shown that extended regional lymph node dissection for pancreatic cancer does not prolong the survival of patients but increases the occurrence of complications, therefore, it is still not routinely recommended.
As for pancreatic cancer surgery with combined vascular resection, some studies have shown that combined resection and reconstruction of portal vein and superior mesenteric vein does not significantly increase the complication rate and mortality, but the prognosis of patients with combined arterial resection is poor in the near and long term, so combined arterial resection is not recommended for pancreatic cancer, while for patients with indications for combined venous resection, it is emphasized that it should be performed by a high level pancreatic surgery center. The results of a large number of studies have shown that in the large pancreatic cancer centers, the treatment is not recommended. The overall prognosis of pancreatic cancer patients treated in large pancreatic centers (with more than 16 pancreatic cancer surgeries per year) is significantly better than that of small medical institutions, according to numerous studies.
In addition, the use of minimally invasive techniques in pancreatic surgery has developed rapidly in recent years; however, their applicability in the treatment of pancreatic cancer has been highly controversial. Although there is a large body of literature reporting that laparoscopic pancreatic caudal resection is safe, feasible and has significant advantages over open surgery, most of these studies are retrospective and mainly focus on patients with benign and low-grade malignant tumors, and few studies have actually been applied to the treatment of pancreatic cancer, so the long-term prognosis is not conclusive. Similarly, laparoscopic pancreaticoduodenectomy is currently performed in only a few centers due to the complexity of the operation, and it is not yet popular.
Theoretically, minimally invasive surgical incisions have fewer complications, less impact on the body’s immune system, and faster postoperative recovery, which can enable more patients to receive adjuvant treatment as early as possible and have great potential to improve the prognosis of pancreatic cancer surgery. Especially in recent years, the development of robot-assisted laparoscopic technology has elevated minimally invasive technology to a higher level, which has attracted great attention from many pancreatic surgeons, but its value in the treatment of pancreatic cancer still remains to be verified by time.
Fourth, adjuvant therapy – strengthen clinical trial research for new breakthroughs.
Currently, there is more and more evidence-based medical evidence showing the importance of systemic chemotherapy in adjuvant therapy, while the conclusions of major studies on radiotherapy vary greatly and no unified opinion has been reached internationally. This shows that clinical trial studies are crucial to optimize the choice of adjuvant therapy.
The results of a multicenter phase III randomized controlled trial (RCT) in the United States showed that fluorouracil-based radiotherapy combined with gemcitabine has potential advantages in the postoperative adjuvant treatment of patients with pancreatic head cancer, and the results of another recently published multicenter phase III RCT (CONOK-O01) have more fully confirmed the value of gemcitabine in postoperative adjuvant treatment.
In addition, for patients with locally advanced and metastatic pancreatic cancer, the results of a phase III clinical trial (NCT00844649) showed that the combination of chemotherapy with nanopaclitaxel and gemcitabine significantly prolonged survival and improved response rates. With the advancement of radiotherapy equipment and technology, clinical trials using the latest modern radiotherapy with combination chemotherapy for the adjuvant treatment of pancreatic cancer are underway and hopefully will lead to a breakthrough.
In conclusion, pancreatic cancer is highly malignant and rapidly progressing, and the effect of single treatment is not good. Therefore, the diagnosis and treatment should emphasize multidisciplinary teamwork, emphasize screening of high-risk groups, standardize the diagnosis and treatment process, and conduct accurate preoperative evaluation to improve the RO resection rate and actively carry out comprehensive treatment. At present, there is a great difference in the level of pancreatic cancer diagnosis and treatment among medical units at all levels in China. Therefore, improving the overall treatment effect of pancreatic cancer in China still depends on the unremitting efforts of all pancreatic surgery colleagues, continuously exploring new diagnosis and treatment methods, strengthening communication and cooperation, and actively promoting clinical research, and we believe that the diagnosis and treatment level of pancreatic cancer in China will make remarkable progress.