Pancreatectomy with lymphadenectomy remains the first-line treatment option for early- and intermediate-stage PDAC. Although laparoscopic DP have become important options for all indications including PDAC on pancreatic bodies and tails [7, 24], approaching PD laparoscopically for diseases on pancreatic heads were less frequent owing to the intricacy of the dissection and the complexity of the pancreatoenteric and biliodigestive anastomoses [5, 8]. This study suggested that TLPD for PDAC were technically feasible and safe. TLPD are longer operations for PDAC treatment than OPD but exhibit clear benefits of less blood loss and shorter hospitalization. More importantly, we found TLPD were associated with lower morbidities than open surgery for PDAC treatments. In addition, laparoscopic procedures appear to hold potential advantages in terms of R0 resections and retrieved LNs. The meta-analysis further confirmed our short-term surgical outcomes. Nevertheless, no statistically significant differences were identified between laparoscopic and open procedures for the treatment of PDAC in the long-term oncological outcomes of recurrence patterns and survival.
The prolonged operative time in TLPD is an obvious disadvantage. Our initial TLPD for PDAC lasted for nearly 600 minutes [14]. Currently, this can be completed in approximately 300–350 minutes [10]. Kendrick et al., in one of the largest single series currently available, described their initial TLPD duration to be 460 min, which improved to 320 min after approximately 50 cases [25]. Stauffer et al., reported a median operative time of 518 min, which was significantly longer than that in open surgery (140 min) [22]. The learning curve can be overcome in high volume centers, with average TLPD operative times decreasing to less than 400 min [26]. However, due to tumor biology and the aggressiveness of the disease process, TLPD for PDAC treatments are not commonly performed making it difficult to overcome the associated learning curve [5]. Although none of studies identified adverse outcomes, a recent study from the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) demonstrated that longer operative times were independently associated with worse perioperative outcomes after pancreatic resections [27]. Therefore, we believe long duration is a definite disadvantage of TLPD for PDAC treatments.
In this ITT analysis, the conversion rates were 8.2% (8/98) for all TLPD cases. We found that the conversions generally were due to hemorrhages that were difficult to control or had suspected vessel involvement, which was similar to other publications of TLPD for PDAC treatment [21, 22]. Although there was less overall blood loss, there were still 4 conversions for intraoperative uncontrollable bleeding in this TLPD group. In fact, the multicenter LEOPARD-2 trial was stopped prematurely due to safety concerns of higher mortalities in the LPD group mainly because of intraoperative bleeding [28]. We believe that part of the reason that PDAC frequently induces substantial pancreatic inflammation in the pancreatic remnant is because it is harder to resect due to pronounced adhesions to the surrounding tissues or infiltrations of the portal vein. Portomesenterical vein involvement is a common clinical finding in PDAC, but is a situation that is frequently difficult to diagnose prior to surgery [29]. The rate of venous involvement ranges from 26 to 85% in the literature [30–32]. Portomesenteric vein resection is a mean of achieving complete tumor clearance. However, researchers strongly recommend that venous resection during TLPD should only be performed by surgeons with considerable TLPD experience with TLPD and proficiency in open vascular resection [33, 34]. Therefore, approaching appropriate cases like no vessel involvement or severe adhesions laparoscopically in the learning curve would reduce conversion helping to shorten operative time and further reduce bleeding [28].
The most important concern regarding TLPD for PDAC treatments is the patient’s safety. We found less postoperative morbidities in TLPD than in OPD (after PSM, 19.1% vs. 33.7%, p = 0.02). Furthermore, the meta-analysis indicated not only overall less morbidities in TLPD group, but major and minor complications were also less in the TLPD group when dividing overall complications into major and minor ones according to the Clavien–Dindo classification. POPF is a frequent event and the best management for the pancreatic stump is still under debate with our results revealing no significant differences between the two groups. The anastomoses performed during LPD are the main topic of concern. However, there is no consensus on the best method of anastomosis after PD (e.g., pancreaticojejunostomy or pancreaticogastrostomy, duct-to-mucosa or invagination anastomosis, etc.) [9]. The reported methods in open surgery now can be meticulously performed laparoscopically [5, 35]. No appreciable differences were noted between groups for POPFs because the true risk factors of significant POPFs have been recognized as soft pancreatic parenchyma, high-risk disease pathology, and small pancreatic duct size, rather than the anastomosis method [36, 37]. We argue that the main contributors of lower morbidity in TPLD were reduced delayed gastric emptying (DGE) (after PSM, 5.6% vs. 11.2%, p = 0.18) and pulmonary complications (after PSM, 1.1% vs. 5.6%, p = 0.11). DGE is not life threatening, but can have significant consequences such as patient discomfort, prolonged hospital stays, increased hospital costs, diminished nutritional status, and delays in initiation of adjuvant therapy [38, 39]. According to the literature, the pathogenesis of DGE is multifactorial and given the improved access and visualization of the laparoscopic approach, as well as the meticulous attention to techniques, potential reasons for this advantage include [40, 41]: 1) laparoscopic surgery has less influence on the peripheral organs and peritoneum leading to less seroperitoneum helping to alleviate of gastric dysrhythmias, 2) ameliorative pyloric or antral ischemia due to reservation of small vessels, and 3) mitigant pylorospasms secondary to denervation of the stomach and duodenum or jejunum. As one of the most complex abdominal surgeries, PD involves multiple systems and would cause more medical complications than other surgeries. It is well known that major abdominal surgery has a detrimental effect on respiratory function, and this is particularly true in upper abdominal surgeries. In general, open procedures are reported to portend a higher risk of pleural effusions, pulmonary infections, and atelectasis than do minimally invasive ones [42, 43].
Oncologic safety and efficacy should be clearly demonstrated prior to a wide application of a new surgical approach. The long-term survival outcomes of MIS for common malignancies have conflicting results [44–46], leading to a constant controversy over MIS for cancer treatments. Oncological surgery requires a radical resection, adequate lymphadenectomy, and meticulous ‘no-touch’ dissection as it may prevent seeding and tumor cell dissemination. R0 resection is frequently referred to as a crucial factor, which is deemed the only hope for cure [47]. Tactile evaluation of tissue is not possible during laparoscopy and was presumed to lead to inadequate surgical margins. Nevertheless, our study revealed that the R0 resection of TLPD are comparable to those of open surgery. In addition, our data showed the retrieved LNs of TLPD were not inferior to those of OPD, or even superior to OPD for lymphadenectomy (after PSM, 21.9 ± 6.6 vs. 18.9 ± 5.4, p < 0.01). These findings were further confirmed by the rapid meta-analysis. The advantages of high-resolution imaging, multi-dimensional vision, and meticulous manipulation help to facilitate lymphadenectomy. A single-center study conducted by Asbun and Stauffer, reported a comparable long-term survival of 1-, 2-, 3-, 4-, and 5-years for OPDs (68, 40, 24, 17, and 15%) and for TLPDs (67, 43, 43, 38, and 32%), respectively [22]. Kuesters et al., conducted a series of LAPD, also reported a comparable 5-year survival rate between LAPD (20%) and OPD (14%) for PDAC [19]. Croome et al., recorded that the progression-free survival was longer in TLPD [21]. In this analysis, we found patients' survival in the TLPD group was superior to those in the OPD group before PSM (RFS: p = 0.04, OS: p = 0.02). After PSM, in which tumor size and stage were balanced, the 3-year OS and DFS in the TLPD group were still slightly higher than in the OPD group, but the differences failed to reach statistical significance. We believe our results were credible since PSM established the oncologic equivalence of two surgical techniques. We considered there may be other reasons for such results in addition to more LNs examined in the laparoscopic groups. One hypothesis was that improved recovery after laparoscopic surgery helped to instigate multimodality therapies earlier, thus leading to survival benefits [21]. However, a retrospective analysis of the NCDB found that MIS did not improve use or initiation of adjuvant chemotherapy for patients with PDAC [48]. Moreover, the survival impact of the initiation time of adjuvant chemotherapy in patients with resected PDAC remains uncertain since studies showed conflicting results [49, 50]. In our opinion, neither procedure is technically superior, but efficiency would largely depend on the techniques of the surgeon. Thus, considering the principles of radical resection, a technically similar oncologic resection could be performed regardless of whether the an open or laparoscopic approach was used.
Limitations of this study include its retrospective design, small sample size, absence of randomization, and short follow-up period. However, given the fact that TLPD for patients with PDAC are associated with novelty and unpredictable risks, the current study enrolled a relatively large number of cases. To overcome the selection bias arising from a lack of randomization, we performed PSM analyses which was deemed as the most effective method to balance the covariates and thus reduce bias in the retrospective studies.