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INTRODUCTION
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers with a low 5-year survival rate of less than 10% [1]. While surgical resection offers the only chance of long-term survival, a mere 25%–30% of PDAC patients are candidates for upfront resection at the time of diagnosis [2]. However, surgical application is expanding as neoadjuvant treatment (NAT) has shown to improve oncological outcomes for more advanced stages such as borderline resectable pancreatic cancer (BRPC) [345] or to be considered as a therapeutic option even in resectable or locally advanced disease [67].
The complex resection and reconstruction process and the high morbidity of pancreatic surgery have slowed the implementation of minimally invasive surgery in PDAC; laparoscopic pancreaticoduodenectomy (PD) was introduced in 1994 [8], and robotic PD (RPD) in 2003 [9], and even then was performed mostly at limited specialized high-volume centers. Recently, several reports have demonstrated the short-term benefits of minimally invasive surgery for pancreatic resection [1011]. Despite laparoscopic PD achieving comparable clinical outcomes to open PD (OPD), there remain numerous limitations, notably ergonomic challenges hindering the precision of pancreatic anastomosis—a critical aspect of PD. Consequently, many medical centers have increasingly embraced robot-assisted PD (RAPD) as a mean to surmount the shortcomings of laparoscopic surgery, which has led to promising outcomes [121314].
Overall, studies show a positive trend in favor of minimally invasive approaches for periampullary cancer including PDAC [131516]. However, there are very limited studies focusing on pancreatic cancer with vessel invasion while providing evidence for the equivalence or superiority of robotic platforms for PD [1617].
With an increasing number of patients undergoing NAT, there is a growing demand for RPD, even in cases of advanced pancreatic cancer involving major vessels. Generally, many centers consider OPD as the standard choice of operation for conversion surgery after NAT, due to technical difficulties increased by preoperative treatment-related inflammation and fibrosis. Meanwhile, centers with sufficient expertise have slowly been increasing their experience in performing robotic surgery for conversion surgery after NAT and other complex advanced PDAC cases. At this point, there is a need to confirm the clinical safety of performing RPD in such patients. Hence, this study aims to explore the feasibility of adopting robotic platforms in PD in the context of advanced pancreatic cancer after NAT by comparing the clinical outcomes observed at our institution.
METHODS
Ethics statement
This study was approved by the Institutional Review Board of Seoul National University Hospital (No. H2403-060-1518), and the requirement for informed consent was waived.
Design and patient selection
This study was a single-center, retrospective analysis of prospectively collected clinicopathological data from Seoul National University Hospital's electronic medical records. A total of 223 patients who received PD or pylorus-preserving PD between 2015 and 2023 after NAT for PDAC with radiologic evidence of vessel contact or invasion of the major vessels included in the National Comprehensive Cancer Network (NCCN) guideline defining resectability status [18] were enrolled. Patients were categorized according to the method of surgery: OPD or RAPD. The decision to perform RAPD was made by the surgeon based on the feasibility of complete laparoscopic transection and robotic anastomosis without compromising patient safety, oncological outcomes, or increasing the risk of serious complications. After NAT, reassessment of vessel involvement, tumor size change, and the extent of inflammation influencing the difficulty of surgery were considered. Table 1 demonstrates the clinical characteristics of patients selected for RAPD.
Robot-assisted pancreaticoduodenectomy procedure
Our procedures, as described in previous reports [19], include laparoscopic partial omentectomy, laparoscopic transections of the duodenum, common bile duct, jejunum, and pancreas, laparoscopic cholecystectomy, and robotic pancreaticojejunal and hepaticojejunal anastomosis. The duodenojejunal anastomosis is carried out extracorporeally using the handsewn method.
Neoadjuvant treatment
The administered chemotherapy regimens were gemcitabine-based or FOLFIRINOX (folinic acid [leucovorin], fluorouracil, irinotecan, and oxaliplatin). Since the introduction of FOLFIRINOX for pancreatic cancer at our institution in 2011, the main regimen shifted from gemcitabine-based to FOLFIRINOX. Gemcitabine was administered weekly for 6 weeks at a dosage of 400 mg/m2, accounting for the body surface area. The FOLFIRINOX regimen was administered every 2 weeks. Oxaliplatin at a dosage of 85 mg/m2, then leucovorin at a dosage of 400 mg/m2 was administered intravenously for 2 hours. After a 30-minute interval, an infusion of 180 mg/m2 irinotecan was carried out for 90 minutes. This was followed by an intravenous bolus (400 mg/m2) and continuous infusion (2,400 mg/m2) of 5-fluorouracil for a 46-hour period. The number of cycles administered was individualized for each patient and ranged from 2 to 14 cycles.
The administration of neoadjuvant radiation therapy (RT) and the selection of its type were determined by a multidisciplinary team. As neoadjuvant RT has been reported to have benefits in locoregional failure and R0 resection rates [520], our institution currently incorporates subsequent RT following neoadjuvant chemotherapy for pancreatic cancer patients with vascular contact. As a result, most patients in this study also underwent a short-course stereotactic body RT consisting of 50 Gy in 5 fractions.
Outcome measure
Patient demographics, clinical characteristics, and outcomes were compared between the OPD and RAPD groups. Variables compared included age, sex, body mass index, American Society of Anesthesiologists physical status classification, neoadjuvant and adjuvant treatments, operation type, estimated blood loss, operative time, complications, survival duration, and postoperative staging according to the 8th edition of the American Joint Committee on Cancer manual [21]. Resectability was determined by a multidisciplinary team according to version 2.2021 of the NCCN Guidelines [18]. Postoperative pancreatic fistula (POPF) grading was classified according to the International Study Group of Pancreatic Surgery classification [22]. Resection margin status was characterized using the 0 mm rule. Overall survival (OS) was defined as the time between the date of diagnosis of PDAC and the date of death, and disease-free survival (DFS) was defined as the time between the date of operation and the date of diagnosis of recurrence.
Statistical analysis
Propensity score matching (PSM) was performed to reduce potential treatment allocation bias and confounding factors due to the retrospective nature of our study. Matching was based on patients' age, sex, and TNM staging and performed in a 1:3 ratio. Non-normally distributed continuous data are presented as medians with interquartile ranges and were compared using the Mann-Whitney U-test. Categorical data are presented as frequencies with percentages and were compared using the chi-square or Fisher exact test, as appropriate. The Kaplan-Meier method was used to estimate OS rates and DFS rates, and the log-rank test was used to determine differences in survival between the OPD and RAPD groups. All statistical analysis used IBM SPSS Statistics ver. 27.0 for Windows (IBM Corp.).
RESULTS
Demographics and clinicopathological findings
Among the 223 patients, 119 (53.4%) were male and 104 (46.6%) were female, with a mean age of 62.3 years. In the preoperative initial assessment, 44 (19.7%), 128 (57.4%), and 41 (18.4%) were categorized into resectable (with ≤180° portal vein/superior mesenteric vein contact, according to the NCCN resectability criteria), BRPC, and locally advanced pancreatic cancer (LAPC), respectively (Table 2).
After PSM, 42 patients who underwent OPD (27 males [64.3%] with mean age of 64.7 years) were compared with 14 patients who underwent RAPD (7 males [50.0%] with mean age of 63.0 years). According to clinical stage, 30 (71.4%) and 7 patients (50.0%) were diagnosed with BRPC, and 4 (9.5%) and 4 patients (28.6%) were diagnosed with LAPC in the OPD and RAPD groups, respectively. All patients received neoadjuvant chemotherapy, with the FOLFIRINOX regimen administered in 38 patients (90.5%) in the OPD group and 13 (92.9%) in the RAPD group. As for neoadjuvant RT, all RAPD patients received neoadjuvant RT while more than half of the OPD patients received neoadjuvant RT (26 patients [61.9%], P = 0.006) (Table 2).
A majority (33 OPD patients [78.6%] and 11 [78.6%] RAPD patients) were diagnosed with stage I pancreatic cancer. There was no significant difference in the number of harvested lymph nodes, with 20.7 ± 8.6 and 19.6 ± 8.6 harvested lymph nodes in the OPD and RAPD groups, respectively (P = 0.669). Resection status was also comparable with R0 resection achieved in 40 OPD patients and 13 RAPD patients (95.2% vs. 92.9%, P = 0.732) (Table 3).
Comparison of the perioperative outcomes
Vessel resection was carried out more in the OPD group, although the difference was not statistically significant (OPD, 40.5% vs. RAPD, 28.6%, P = 0.426). While there was a trend for less intraoperative blood loss in the RAPD group, this did not reach statistical significance (OPD, 793 mL vs. RAPD, 537 mL; P = 0.178). Operation time was comparable between the two groups, with a mean duration of 286.9 ± 56 minutes for OPD and 278.2 ± 60 minutes for RAPD (Table 4).
Postoperative hospital stay was a mean of 3 days shorter in the RAPD group (OPD, 12.8 days vs. RAPD, 9.7 days), but the statistical significance was lost after PSM. Severe complications, defined by Clavien-Dindo classification III or higher, were more frequent in the OPD group (OPD, 9 [21.4%] vs. RAPD, 1 [7.1%]; P = 0.227), but to no statistical significance. Among the complications, 9 cases (4.3%) of grade B POPF occurred in the OPD group, and none was observed in the RAPD group. A majority of patients received adjuvant chemotherapy in both groups (36 out of 42 for the OPD group and 12 out of 14 for the RAPD group) (Table 4)
Analysis of prognostic factors
Prognostic factors for OS among the 223 patients were evaluated by uni- and multivariable analyses (Table 5). Univariate analysis identified T stage, N stage, resection margin, and neoadjuvant RT as statistically significant prognostic factors. Multivariate analysis showed R1 resection (R1 vs. R0: hazard ratio, 1.871; 95% confidence interval, 1.011–3.462; P = 0.046) to be an independent risk factor.
DISCUSSION
The robotic platform's enhanced motion detail and 3-dimensional visualization offer a promising approach to addressing the complexities of PD. Since its introduction, robotic surgery has predominantly been used in cases of borderline malignancies, such as intraductal papillary mucinous neoplasms and in early-stage periampullary cancer with the presence of duct dilatation and minimal peripancreatic inflammation [23].
Despite increased operability and a rise in surgeries for advanced pancreatic cancer due to NAT, open surgery remains the preferred method over minimally invasive approaches. Challenges in performing minimally invasive PD include vessel resection due to vessel involvement, as well as inflammation and peripancreatic fibrosis resulting from ductal obstruction, previous stent insertion, or RT. Previous studies and a recent meta-analysis of 16 studies involving 1,949 patients have demonstrated the non-inferiority of minimally invasive PD in terms of short-term morbidity and mortality compared to OPD [151624]. However, evidence is still lacking regarding the long-term and oncologic outcomes of RAPD for advanced PDAC in the context of NAT.
In this retrospective propensity score-matched cohort study, both short-term and long-term clinical outcomes of RAPD were equivalent to that of OPD in advanced pancreatic cancer patients who had undergone NAT. Postoperative hospital stay was shorter with less severe complications in the RAPD group. The rate of POPF, reoperation, and 30-day mortality were similar in both groups. In terms of oncological significance, lymph node yield, lymph node positivity, and R0 resection rate did not differ between the 2 groups.
When assessing the short-term outcomes of our study, postoperative hospital stay was shorter in the RAPD group, although the statistical significance was lost after PSM analysis (OPD, 11.4 days vs. RAPD, 9.8 days; P = 0.218) and severe complications were observed less in the RAPD group (OPD, 21.4% vs. RAPD, 7.1%; P = 0.227). Shorter hospital stay is consistently observed in other studies, and in the 2020 study which also analyzed RPD in NAT-administered patient population, the mean length was 8 days in the RPD group and 10 days in the OPD group (P < 0.001) [2526]. Though our study did not show significant differences in the postoperative complication rates and adjuvant chemotherapy administration between the RAPD and OPD groups, other studies report lower delayed gastric emptying rates (OPD, 32% vs. RPD, 3%; P = 0.0009) [26] and larger populations receiving adjuvant chemotherapy (OPD, 34% vs. RPD, 56%; P < 0.001) [25]. As shorter hospital stays and reduced postoperative complications are factors that influence the timely initiation and completion of adjuvant therapy and ultimately survival, further large-scale investigation of the correlation of minimally invasive procedures to long-term outcomes is needed.
A study analyzing 155 patients with stage I–III PDAC who underwent RPD reported comparable survival outcomes, with a median OS of 25.6 months in the RPD and 27.5 months in the OPD group [25]. Although there are few studies comparing the survival outcomes of RPD in advanced PDAC patients, a systematic review of 8 studies on RPD with vascular resection in PDAC found no significant differences in survival outcomes [27]. Our analysis similarly demonstrated that long-term oncologic outcomes are comparable between RAPD and OPD for patients who underwent NAT, with 5-year OS rates of 55.7% vs. 72.7% (P = 0.264) for OPD, and 2-year DFS rates of 54.4% vs. 58.4% (P = 0.759) for RAPD.
Although to no statistical difference, the 5-year OS rate of RAPD was higher by 17% than OPD in our cohort (Fig. 1). A recent study that examined the outcomes of adding neoadjuvant RT in patients with resectable and BRPC with vascular contact, found the addition of RT following neoadjuvant chemotherapy to be associated with improved postoperative survival and enhanced local control compared to neoadjuvant chemotherapy alone [20]. Though the correlation of higher rates of neoadjuvant RT and higher 5-year OS rate in the RAPD group in our study can be considered, the R0 resection rates were comparable between the OPD and RAPD groups (OPD, 95.2% vs. RAPD, 92.9%), suggesting that the observed OS differences cannot be solely attributed to the higher utilization of neoadjuvant RT. In considering the relatively higher rates of survival observed in our studies, selective bias (in which patients retrospectively selected for our study all had to have a favorable response to NAT) must be taken into account. Future studies with larger cohorts and detailed subgroup analyses could provide greater insight into the complex relationship between neoadjuvant RT and survival benefits in this clinical setting. Meanwhile, our findings do not suggest a survival advantage of RAPD over OPD; rather, they underscore that the oncologic outcomes of the 2 approaches are comparable within the context of this study cohort.
There may be concerns regarding the interference in the resection and anastomotic procedures due to the desmoplastic reaction resulting from previous NAT. As a result, many consider vessel involvement a contraindication for minimally invasive PD [12]. Attempts to perform RPD in BRPC are increasingly being explored in many large-volume centers with promising results; our center—exceeding 700 consecutive cases of RAPD—has been expanding the indication for RPD as we have experienced positive outcomes [1928]. To investigate the feasibility of performing robotic procedures on post-NAT patients, we applied the robotic approach to well-selected patients with advanced pancreatic cancer who had received NAT. Furthermore, the need for vessel resection after NAT in patients with initial vessel involvement is under discussion. In a recent study, among patients who received NAT, there was no significant difference in the R0 resection rate and OS between cases where vessel resection was performed and those where it was not [29]. If by NAT, the need for vessel resection decreases, RPD will be more favorable to perform in advanced PDAC patients for experienced surgeons.
There were several limitations to this study. Firstly, selection bias and underreporting of postoperative outcomes such as complications are possible due to the retrospective nature of our study and despite PSM, treatment allocation bias cannot be completely excluded. For example, the operation duration for RAPD was notably shorter in our study (OPD, 286.9 ± 56.0 minutes vs. RAPD, 278.2 ± 60.2 minutes; P = 0.612) compared to other studies, which generally report shorter times for OPD [2630]. This discrepancy can be attributed to the unavoidable clinical practice of performing OPD for extremely complex cases, thereby extending the average duration. Conversely, the shorter operative time for RAPD observed in our study can be attributed to its execution by experienced surgeons who have attained the mastery phase of the learning curve, coupled with careful patient selection for RAPD. Secondly, the collected data was limited to a high-volume single center and the absolute case number of RAPD was merely 14 patients. Although our center has performed over 700 RAPD, we have only recently expanded our indication of RAPD after NAT for advanced pancreatic cancer with vessel invasion. We recognize that this could influence the applicability of our findings and the expertise of the center should be considered in the comprehension of our data. The lack of statistical significance of our findings may be due to the small population number, and we expect to see a similar trend with increased case numbers. Lastly, in interpreting our results, we emphasize that our procedure was performed using a robot-assisted method, wherein resection was conducted laparoscopically, and reconstruction was performed robotically. From an oncological perspective, the laparoscopic rather than the robotic platform may be considered a key technical factor. As previously mentioned, the primary objective of our study was to evaluate the feasibility of utilizing a robotic platform for PD in the context of advanced pancreatic cancer following NAT. Therefore, we caution against interpretations that overstate the role of the robotic platform beyond the intended scope of our study.
Minimally invasive surgery is generally considered unsuitable for advanced pancreatic cancer. However, the present study demonstrates the feasibility of RAPD compared to OPD within the context of a specialized high-volume center. There is growing evidence supporting the oncological feasibility of the robotic approach for advanced pancreatic cancer patients undergoing NAT. While caution is warranted in overstating the potential benefits of the robotic platform, it is important to note that the enhanced functional recovery associated with minimally invasive surgery can facilitate the timely initiation and higher completion rates of adjuvant therapy, which are critical for improving oncological outcomes. For instance, a recent study reported higher rates of adjuvant therapy completion in patients undergoing RPD compared to OPD, underscoring its potential oncological advantages [25]. Given the anticipated role of NAT in reducing tumor burden and managing micrometastasis before surgery, the integration of NAT with the benefits of robotic surgery may have the potential to improve outcomes in select patients with advanced pancreatic cancer. Extensive artery and vein involvement persisting even after NAT remains a contraindication for RAPD. However, with increasing experience in vessel resection using minimally invasive techniques, we expect the indication for RAPD to broaden. All in all, further research is necessary to affirm the feasibility of performing minimally invasive surgery on advanced PDAC.
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