Pancreatic cancer is the fourth leading cause of cancer death in Europe and is expected to rank second in cancer mortality by 2030 [1]. The only potentially curative treatment option is surgical resection, which still achieves a 5-year survival rate of only 10% [2]. The aggressive tumor biology has led to the introduction of new, more effective chemotherapeutic regimens over the past 10 years, both adjuvant and neoadjuvant, resulting in the establishment of multimodal therapy concepts.
Indication for Surgery
On the initiative of the German Society for General and Visceral Surgery (DGAV), evidence-based recommendations for the indication for surgery of pancreatic cancer have been defined, whereby the indication should be made by a tumor board of experienced pancreatic surgeons in accordance with guidelines, taking into account individual patient characteristics [3]. According to the recommendations, which are based on a systematic analysis of 58 original papers and 10 guidelines, there is an indication for surgery in the case of histologically confirmed pancreatic cancer as well as in cases of high suspicion of resectable pancreatic cancer [3, 4].
Resectability
The greatest probability of survival exists with resection in healthy tissue, the R0 resection [5, 6]. Current guidelines now divide the R0 classification into "R0 narrow" (≤ 1 mm) and "R0 wide" (> 1 mm), depending on whether the carcinoma is less than or more than one millimeter from the resection margin [7]. In addition to anatomical resectability (relationship between tumor and major visceral vessels), tumor biology and the general condition of the patient have been considered as co-determining resectability criteria since 2017 and have been included in the current S3 guidelines as the ABC consensus classification of resectability [8].
ABC Criteria of Resectability According to the International Association of Pancreatology (IAP) Consensus
(Click to enlarge)
Source: Isaji S et al (2018) International consensus on definition and criteria of borderline resectable pancreatic ductal adenocarcinoma 2017. Pancreatology18(1):2–11.
To assess anatomical resectability, the S3 guidelines recommend contrast-enhanced 2-phase computed tomography [7]. Based on anatomical resectability criteria, a tumor can be classified as primarily resectable, borderline resectable, or non-resectable/local advanced [7].
The assessment of biological resectability is most often based on the tumor marker CA 19-9. The threshold value is defined as > 500 IU/ml, as above this value, resectability is present in only less than 70% of cases, and survival of less than 20 months is expected [8, 9].
Another criterion is the ECOG Performance Status as conditional resectability, with patients having a status ≥ 2 having a poor prognosis [8].
Mesopancreas
The mesopancreas, the connective tissue region around the major vessels of the pancreatic region, which is densely traversed by blood and lymph vessels as well as nerve plexuses, has been discussed for several years [10]. Meta-analyses suggest that total mesopancreatic resection allows for better oncological outcomes [11]. In pancreatic head resection, the complete removal of mesopancreatic tissue between the portal vein, hepatic artery, base of the celiac trunk, and superior mesenteric artery (Triangle Operation [12, 13]) is performed, while in left pancreatic resections (body, tail carcinomas), radical antegrade modular pancreatosplenectomy (RAMPS [14]) is performed.
[RAMPS: Depending on the extent of the tumor, an anterior is distinguished from a posterior RAMPS procedure, in which resection is essentially more radical dorsally. In anterior RAMPS, resection is performed with the inclusion of Gerota's fascia and perirenal fat on the left side. In contrast, in posterior RAMPS, in addition to Gerota's fascia and perirenal fat, the left adrenal gland is also resected.]
Vascular Resection
In centers, venous resections have minimally increased morbidity and mortality, and adequate overall survival is achieved [15, 16]. According to current S3 guidelines, vascular resection of the portal vein can be performed in cases of tumor infiltration ≤ 180° or in complex situations such as cavernous transformation with reconstruction [17]. Arterial resections, on the other hand, are very risky, often complex, and frequently require simultaneous venous reconstructions. Patients often do not benefit oncologically from extensive procedures and often show worse survival data than patients without vascular resection [18]. Therefore, arterial resections should be avoided outside of centers.
Unexpected arterial resections can be avoided by early exposure to check for tumor freedom of the superior mesenteric artery and celiac trunk during curative-intended pancreatic resection. The "Artery-first" strategy helps avoid futile procedures, allows better planning of vascular resections and reconstructions, and improves long-term survival for selected patients in centers with appropriate expertise [19].
Oligometastasis
The term oligometastasis appears for the first time in the current S3 guidelines and describes the presence of ≤ 3 metastases, which should only be resected within studies as part of a multimodal treatment concept [7]. No randomized studies are currently available, but resection of oligometastases seems to improve patient survival data compared to palliative chemotherapy, especially after neoadjuvant therapy [20 - 23]. In Germany, the HOLIPANC and METAPANC studies are currently addressing the issue [24].
Neoadjuvant Therapy Concepts
For patients with borderline resectable pancreatic cancer, the current guideline recommends preoperative chemotherapy or radiochemotherapy, while for resectable carcinomas, it should not be performed outside of studies [7]. The recommendations are based on data from a meta-analysis and currently published study data [25, 26]. Since after neoadjuvant therapy, resectability in initially borderline resectable and locally advanced pancreatic carcinomas is difficult to assess morphologically, the guideline recommends surgical exploration for the assessment of secondary resectability in stable disease [7, 27]. The decrease in CA 19-9 levels can also help in assessing secondary resectability [28, 29].
Laparoscopic Techniques and Robotics in Pancreatic Cancer
Pancreatic left and pancreatic head resections must be considered separately. For left resections in laparoscopic technique, the randomized controlled LEOPARD study showed faster recovery, less blood loss, and no higher complication rate compared to the open technique [30]. The combined analysis of the LEOPARD and LAPOPS studies confirmed the data [31]. Long-term quality of life remains unchanged by the laparoscopic technique [32]. A meta-analysis of existing data showed comparable results for the R0 resection rate and the rate of adjuvant chemotherapy [33]. Median overall survival was the same for laparoscopic and open pancreatic left resections, at 28 and 31 months, respectively [34].
For pancreatic head resections, the 2019 published randomized and controlled LEOPARD-2 study showed higher mortality (90-day mortality 10%) in the laparoscopic group, which showed no advantages over the open group in terms of postoperative pain, recovery, hospital stay, and quality of life [36]. A recent Chinese randomized study showed comparable mortality in laparoscopic pancreatic head resection with only slight advantages of the laparoscopic technique [37].
Robotics has also been established in pancreatic surgery over the past 10 years. In addition to the technically simpler left resection, pancreatoduodenectomy is increasingly being performed. However, a long learning curve is required [37], and a final evaluation regarding oncological outcomes is not yet possible. Observational studies on the use of robotics for malignant indications demonstrate feasibility and potential advantages of the minimally invasive technique [38, 39, 40]. According to international guidelines, a malignant indication is not a fundamental contraindication for robotics, but results from randomized controlled studies and thus high-quality results are expected in 3 to 5 years [41].
Centralization of Pancreatic Surgery
In high-volume centers for pancreatic surgery, postoperative mortality can be reduced and survival increased [42, 43, 44]. Against this background, the minimum volumes for complex pancreatic procedures in Germany will be increased from the current 10 to 20 resections per year starting in 2024 by decision of the Joint Federal Committee.
Whipple Procedure versus Pylorus-preserving Pancreatoduodenectomy (PPPD)
Two surgical procedures are considered for the resection of pancreatic head and periampullary carcinomas, the classic resection according to Kausch-Whipple and the pylorus-preserving pancreatoduodenectomy. The latter has the advantage of preserved physiological food passage and the reduction of dumping syndromes, postoperative weight loss, and reflux [45-52].
The more recent studies [49, 51, 52] showed a lower transfusion rate and hospital stay for PPPD patients compared to the Whipple group. Postoperative morbidity did not differ significantly between the two groups. The occurrence of gastric emptying disorders was comparable in both groups (Whipple 23% vs. PPPD 22%). There was also no significant difference in surgical radicality (R0-Whipple 82.6% vs. R0-PPPD 73.6%). Long-term follow-up showed comparable overall survival rates.