2023 pancreatic surgery treatment progress and focus outlook

Authors: Wang Ruobing, Liu Yueze, Zhang Taiping

Source: Chinese Journal of General Surgery, 2024, 39(1)

summary

Pancreatic surgery is one of the most challenging specialties in the field of general surgery. Due to the large variety of pancreatic surgical diseases, the high difficulty of surgery, and the differences in diagnosis and treatment ideas among different diseases, there are still many controversies to be resolved. This article summarizes and sorts out the cutting-edge progress of clinical and translational research in pancreatic surgery in 2023 from the aspects of surgical treatment of pancreatitis, pancreatic cystic disease, pancreatic neuroendocrine tumors, and pancreatic cancer, as well as neoadjuvant therapy, adjuvant therapy, immunotherapy, and targeted therapy, in order to further standardize the diagnosis and treatment of pancreatic surgery.

In recent years, with the innovation of surgical concepts and techniques, pancreatic surgery has made great progress, the safety of surgery has been continuously improved, the comprehensive treatment has gradually matured and standardized, and the prognosis of patients has gradually improved. However, due to the wide variety of pancreatic diseases and the large differences in the treatment of different diseases, many topics are still controversial at this stage. This article reviews the treatment progress in the field of pancreatic surgery in 2023 and looks forward to the key issues, in order to further standardize the diagnosis and treatment of pancreatic diseases.

1. Progress in the surgical treatment of pancreatic diseases

(1) Surgical treatment of pancreatitis

Acute pancreatitis is a common acute abdomen in surgery, and surgical treatment plays an important role in acute infection with necrotizing pancreatitis. In 2023, Professor Sun Bei's team summarized the surgical intervention concept of "endoscopic priority, minimally invasive surgical supplementation, and open surgical support" for acute pancreatitis, and suggested that for patients with severe and complex acute pancreatitis, individualized treatment strategies should be formulated according to the dynamic changes of the condition under the multi-disciplinary team (MDT) model [1, 2]. Although the "step-up approach" proposed by the Dutch pancreatitis research team is the mainstream mode of surgical intervention for acute pancreatitis, we also consider the application of strategies such as "step-jump", "skip-up" and "one-step" when the patient's condition is urgent.

In general, the treatment of chronic pancreatitis follows the treatment concept of non-surgical treatment, endoscopic treatment, and surgical intervention, but surgical treatment also plays a key role in the diagnosis and treatment of chronic pancreatitis, and the study published in the journal JAMA Surgery concluded that early surgical intervention is superior to endoscopic treatment in long-term pain management, improving quality of life and simplifying the treatment process [3]. However, due to the complex pathological changes of chronic pancreatitis and large individual differences, the indications for surgery should be carefully grasped. In the presence of uncontrollable pain, suspicious tumors, pseudoaneurysms, and macrovascular erosion, surgical intervention should be aggressive, while non-surgical treatment and endoscopic treatment should still be the first choice for most patients.

(2) Surgical treatment of pancreatic cystic tumors

With the development of imaging technology and the popularization of screening, the detection rate of pancreatic cystic neoplasm (PCN) is increasing year by year. Due to the wide variety of PCNs and the variety of benign and malignant indications, the indications for surgery remain controversial.

In the follow-up of patients with intraductal papillary mucinous neoplasm (IPMN) without high-risk factors, the University of Auckland School of Medicine reviewed existing guidelines and high-quality studies and recommended that the follow-up time should be determined based on the size and growth rate of the IPMN, i.e., < 15 mm and annual growthFor patients with IPMN < 2.5 mm, the recommended follow-up time is 5 years; For patients between 16~30 mm or annual growth ≥ 2.5 mm, the follow-up time was extended to 10 years. Over-monitoring of patients over 80 years of age with PCN without high-risk factors is not recommended to reduce the burden on patients and the healthcare system [4]. AT THE SAME TIME, AN INTERNATIONAL MULTICENTER STUDY PUBLISHED IN GASTROENTEROLOGY CONDUCTED LONG-TERM SURVEILLANCE OF 3 844 PATIENTS WITH SUSPECTED BRANCH DUCT IPMN (BD-IPMN), WHICH CONCLUDED THAT PATIENTS WITH BD-IPMN WITHOUT HIGH-RISK FACTORS, SUCH AS > 75 YEARS OLD WITH CYSTS < 30 MM, OR > AGEFollow-up at age 65 years with cysts ≤ 15 mm can be discontinued after five years of tumor stabilization [5]. It can be seen that for patients with IPMN with small tumor diameter and no high-risk factors, active follow-up is still the mainstay, and as a surgeon, the timing of surgical intervention should be firmly grasped and such patients should be treated with caution.

Solid pseudopapillary neoplasm (SPN) is low-grade malignant and usually has a good prognosis. In a review of the long-term prognosis and postoperative quality of life of patients undergoing SPN surgery over the past 20 years, only 4.1% of the patients had local recurrence or metastasis after surgery, and 80% of the follow-up patients reported that their postoperative quality of life was not significantly affected [6]. It can be seen that active surgical intervention can achieve good results for patients with SPN who are clearly diagnosed.

However, the definitive diagnosis of PCN is still challenging. In a 30-year review of 1,290 patients with PCN at Massachusetts General Hospital, it was found that approximately one-tenth of patients with benign PCN were misdiagnosed as malignant and underwent unnecessary surgery [7]. Therefore, it is particularly important to further explore accurate preoperative diagnosis methods, and only when the diagnosis is clear can the treatment be targeted.

（三）胰腺神经内分泌肿瘤（pancreatic neuroendocrine neoplasm，PanNEN）的外科治疗

PanNEN is highly heterogeneous, with most of them slow-growing, low-grade malignancy, and some of them can also be highly aggressive and metastasize early.

Surgery is an important treatment for PanNED, and the prognosis is good for most patients, with a recurrence rate of less than 15 percent [8]. The specific surgical plan is usually determined according to the location and size of the tumor, and for marginal pancreatic tumors with low malignancy and small tumors, local enucleation has certain advantages. In a study at the University of Verona, Italy, in which 65 patients underwent local enucleation of PanNON, were followed up, the overall long-term prognosis was relatively high, with only about 7 percent of patients with new-onset diabetes [9]. However, patients undergoing enucleation have a relatively high risk of postoperative pancreatic fistula, and more attention should be paid to perioperative management.

The treatment of small, non-functional PanNENs has been controversial. The University of Colorado Cancer Center stratified 4 641 patients with non-metastatic non-functioning PanNENs <2 cm according to tumor size, and the results showed that surgical resection could significantly prolong the survival of patients with 1~2 cm non-functioning PanNENs, and the survival benefit of surgical treatment was more significant in patients aged < 65 years, without other comorbidities, and the tumor was located in the tail of the pancreatic body [10]. The author believes that in clinical practice, we should not only focus on the size of the tumor, but also evaluate its behavioral characteristics, and at the same time, we should also consider it comprehensively in combination with the subjective wishes of patients.

(4) Progress in surgical treatment of pancreatic cancer

Pancreatic cancer has a high degree of malignancy and a poor prognosis, with a five-year survival rate of only about 12 percent [11]. Comprehensive treatment has become the main diagnosis and treatment mode of pancreatic cancer at present, and with the continuous improvement of the surgical level of surgeons, the mortality rate related to pancreatic surgery is decreasing. In the Dutch national cohort study, the in-hospital mortality rate of pancreatic cancer patients who underwent pancreaticoduodenectomy decreased from 4.1 percent in 2014 to 2015 to 2.4 percent in 2018 and 2019 [12].

At present, laparoscopic and robotic minimally invasive techniques have been widely used in pancreatic surgery in major medical institutions. The safety and feasibility of minimally invasive surgery in the treatment of pancreatic cancer have been demonstrated in several studies [13, 14, 15]. In terms of the choice of minimally invasive surgical methods, a study in the United States conducted a retrospective analysis of the case data of laparoscopic pancreaticoduodenectomy (LPD) and robotic pancreaticoduodenectomy (RPD) from 2014 to 2019, and found that the proportion of RPD in the United States has increased from 2.4% in 2014 to 8.9% in 2019; At the same time, the incidence of postoperative complications and the rate of conversion to laparotomy are lower than those of LPD [16]. Robotic minimally invasive technology has become a new trend in pancreatic surgical treatment, but the choice of surgical method still needs to be based on the actual situation of each center, taking into account health economics to improve the benefits of patients. It is believed that with the innovation of technology research and development, RPD will become an important minimally invasive surgical method after breaking through the technical cost barrier. Several randomized controlled trials (RCTs) have taken a negative view of whether extended lymph node dissection should be performed for pancreatic cancer, and studies have shown that patients with extended lymph node dissection do not have long-term survival benefits, and although lymph node dissection can help with accurate staging of tumors, the trauma associated with extended lymph dissection reduces short-term survival [17, 18].

Surgery for pancreatic cancer with vascular invasion often requires combined angioresection and reconstruction, which is difficult to routinely carry out in most centers due to technical difficulties and high surgical risks. For locally advanced caudal pancreatic cancer that invades the celiac artery, distal pancreatectomy with en-bloc celiac axis resection (DP-CAR) is usually used. In a retrospective analysis of 626 cases of DP-CAR surgery in Japan, DP-CAR was a safe and feasible procedure for patients with locally advanced pancreatic caudal cancer, but there was no clear oncological benefit for resectable tumors close to splenic artery branches [19]. Another single-center retrospective study from the University of Heidelberg School of Medicine in Germany also demonstrated that DP-CAR is safe and effective, with acceptable perioperative morbidity and mortality, and that some patients have a good oncological prognosis after combined venous and multivisceral resection, but this is also accompanied by increased mortality [20]. Professor Tingbo Liang's team retrospectively analyzed the clinical data of 36 patients with pancreatic cancer involved in superior mesenteric artery (SMA) who underwent radical pancreatic cancer resection combined with autologous small bowel transplantation after receiving modified FOLFIRINOX, and the median overall survival (OS) after surgery was 14.5 months, and 2 of them died within 30 days after surgery. Twelve patients experienced serious postoperative adverse events (diarrhea, gastric paralysis, and abdominal infection) [21]. This provides a new treatment direction for patients with locally advanced pancreatic cancer (LAPC) with arterial invasion, but the number of surgeries in this study is small, and the actual effect still needs to be confirmed by large-sample studies. In a multicenter study in the Netherlands, pancreatic resection in combination with SMA was challenging, with a poor prognosis, and the oncological benefits of borderline resectable pancreatic cancer (BRPC) and LACC need to be further investigated [22]. For cases requiring revascularization and reconstruction, the patient needs to be carefully evaluated and selected preoperatively, and neoadjuvant therapy should still be preferred in cases where R0 resection is difficult to achieve surgically.

2. Application of neoadjuvant therapy in the treatment of pancreatic cancer

At present, neoadjuvant therapy has become a hot spot in the treatment of pancreatic cancer, and a number of high-quality studies have shown that neoadjuvant therapy can reduce tumor burden and improve the surgical resection rate, which also allows many patients with advanced pancreatic cancer to obtain surgical treatment opportunities and achieve clear survival benefits.

Neoadjuvant therapy for patients with resectable pancreatic cancer (RPC) remains controversial. In a meta-analysis of large RCTs based on the SWOG 1505 study in the United States, the Perp-02/JSAP05 study in Japan, the PREPANC-1 study in the Netherlands, the PACT-15 study in Italy, and the NEONAX study in Germany, neoadjuvant therapy did not significantly improve OS and disease-free survival (DFS) in patients with RPC, but it increased the rate of R0 resection by about 20 percent [23, 24]. It can be seen that for patients with RPC, neoadjuvant therapy cannot replace the radical effect achieved by surgery, and surgery is still the preferred option.

In the neoadjuvant treatment of BRPC patients, the results of the multicenter, open-label, randomized controlled phase II clinical trial ESPAC5 conducted at 16 pancreatic centers in the United Kingdom and Germany showed that 8 weeks of short-term neoadjuvant therapy had a significant survival benefit for BRPC patients compared with direct surgery, and the one-year survival rates of preoperative neoadjuvant gemcitabine plus capecitabine and FOLFIRINOX were 78 and 84 percent, respectively, which were significantly higher than those of direct surgery (39 percent) [25].

3. Application of adjuvant therapy in the treatment of pancreatic cancer

Postoperative adjuvant therapy for pancreatic cancer can help delay tumor recurrence and improve patient prognosis. The current results of the NALIRI 3 study were presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, which showed that the three-drug chemotherapy regimen of irinotecan liposome combined with 5-fluorouracil/leucovorin and oxaliplatin (NALIRIFOX) has advantages over gemcitabine combined with nab-paclitaxel in the treatment of metastatic pancreatic cancer. Median OS (11.1 months versus 9.2 months) and median progression-free survival (PFS) (7.4 versus 5.6 months) were improved [26].

Another prospective, open-label, randomized controlled trial comparing surufatinib in combination with camrelizumab, nab-paclitaxel and S-1 (NASCA) versus nab-paclitaxel plus gemcitabine showed that NASCA improved median PFS in patients with metastatic pancreatic cancer (8.8 months versus 5.8 months) and significantly improved the objective response rate in patients with liver metastases (overall). response rate (ORR) (90 versus 20 percent) [27]. At present, adjuvant therapy is still an important treatment modality for advanced pancreatic cancer, and the above studies provide new and effective options in terms of treatment.

4. Progress of targeted and immunotherapy in the treatment of pancreatic cancer

Clinical trials of targeted and immunotherapy for pancreas are ongoing. Strickler et al. [28] treated patients with locally advanced or metastatic pancreatic cancer with KRASG12C mutations with sotorasib, and of the 38 patients, 8 (21 percent) achieved partial response, 30 (79 percent) observed tumor shrinkage, and no serious adverse events leading to treatment discontinuation. At the same time, KRASG12D small molecule inhibitors MRTX1133 have successfully inhibited tumor growth in preclinical models of pancreatic cancer, and combined with immunotherapy can inhibit pancreatic cancer recurrence, which is expected to be a potential drug for targeted therapy for pancreatic cancer [29].

In recent years, treatment methods based on personalized mRNA vaccine technology have gradually entered the public eye. Patients with pancreatic cancer were treated with atezolizumab and autogene cevumeran after treatment with modified FOLFIRINOX. Recurrence-free survival (RFS) was found to be significantly longer in patients with an immune response with T cell expansion compared with non-responsive patients [30].

In a phase II clinical study in mainland China that explored the role of stereotactic body radiotherapy (SBRT) dose with immunotherapy and targeted therapy after pancreatic cancer surgery, increased SBRT dose compared with gemcitabine improved PFS compared with gemcitabine in patients with locally recurrent pancreatic cancer (8.6 months versus 5.0 months) [31]. In terms of immunotherapy exploration, a prospective phase II clinical study evaluated the clinical efficacy and safety of chemoradiotherapy combined with PD-1 inhibitors in the preoperative treatment of patients with LAPC and BRPC, and showed that although it did not improve the survival of patients, this regimen could improve the surgical R0 resection rate [32]. The study enrolled a small number of patients, and the conclusions are still to be supported by subsequent results. Individualized treatment options based on targeted therapy and immunotherapy are still the future research directions.

V. Conclusion

Pancreatic surgery has been developed for more than 100 years, and with the continuous improvement of the level of surgeons, the safety of surgery has been significantly improved. Due to the particularity and complexity of pancreatic surgery, it is still necessary to firmly grasp the indications for surgery and aim to maximize the interests of patients. In 2023, a number of high-quality studies were published at home and abroad, which made great progress in the diagnosis and treatment of benign and malignant pancreatic diseases, and the mainland also played a key role in the advancement of the field of pancreatic surgical treatment. On the basis of surgical treatment, a combination of neoadjuvant therapy, adjuvant therapy, targeted therapy and immunotherapy should be combined to bring greater benefits to the prognosis of patients. I hope that in the near future, we can witness a new breakthrough in pancreatic cancer treatment!

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