Minimally invasive surgery for pancreatic cancer—are we there yet?—a narrative review

Introduction

Minimally invasive surgery (MIS) has gradually evolved, especially in the past two decades; and now is an integral part of management for almost all digestive diseases. In gastrointestinal (GI) cancers, MIS has shown equivalent results to the open approach for early gastric and colorectal cancers (1-3). Technological advances and the development of specific skill sets required for this approach by dedicated surgical teams led to rapid development in laparoscopic and robotic surgery for GI cancers.

The minimally invasive approach did not gain much popularity for pancreatic surgery for a long time since its first introduction in the early 1990s (4,5). Probable reasons being the anatomic disadvantages, i.e., retroperitoneal location of the organ, its intimate relations with major blood vessels and, the soft, friable, unforgiving nature of the gland. However, much progress has been made in the past decade and today MIS is widely accepted for managing benign pancreatic lesions or tumors with low malignant potential, especially in the distal pancreas.

MIPR has the potential to provide unreplaceable advantages to patients undergoing surgery for pancreatic cancer in terms of early recovery, fewer complications, reduced hospital stay, and cosmetically pleasing wounds. Several retrospective studies and a few randomized trials have demonstrated the safety and feasibility of minimally invasive pancreatic resections (MIPR), i.e., minimally invasive pancreaticoduodenectomy (MIPD), and minimally invasive distal pancreatectomy (MIDP). Although these studies reported favorable outcomes of certain parameters with MIS (lower blood loss, morbidity, and shorter hospital stay); the longer operative duration, high conversion rates, inferior oncological outcomes, and increased mortality reported in low-volume centers remain a matter of concern. Hospital volumes have a strong impact on postoperative outcomes for major pancreatic resections, even with the conventional open approach (6). With MIPR, the surgical complexity increases further, and hence it is recommended that such procedures are performed at specialized centers with a high volume of pancreatic surgery. Furthermore, the mid-term and long-term outcomes of MIPR for pancreatic ductal adenocarcinoma (PDAC) along with the issues of the indications and learning curve are controversial and need further assessment.

Also, as neoadjuvant therapy (NAT) is being more utilized for resectable and borderline resectable pancreatic ductal adenocarcinoma (PDAC), prospective evaluation of MIPR for PDAC after NAT remains the job at the fore.

In the present article, we intend to provide an overview of the progress made so far and the current position of MIPR for PDAC. We present the following article in accordance with the Narrative Review reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-21-131/rc).

Methodology

Medline, PubMed, Embase, Cochrane Library, and various international evidence-based guidelines (like Miami International Evidence-based Guidelines, International & Japanese Hepatopancreaticobiliary Association Guidelines) were searched for the current status of minimally invasive resections for pancreatic cancer/PDAC. Databases were searched using combinations of pancreatic cancer and the role of minimally invasive pancreatic resections based on both MeSH headings and text words. MeSH terms used included but were not limited to, ‘pancreatic neoplasms’, ‘pancreatic cancer treatment’, ‘minimally invasive pancreatic resections’, ‘minimally invasive pancreaticoduodenectomy’, ‘minimally invasive distal pancreatectomy’, ‘laparoscopic distal pancreatectomy’, ‘robotic pancreaticoduodenectomy’, ‘robotic pancreatico splenectomy and ‘early post-operative outcomes’, ‘oncological outcomes’, ‘long-term outcomes’, ‘cost-effectiveness’ and ‘cost-benefit. Studies published in English as peer-reviewed journal articles between January 1994 and September 2021 were considered eligible for inclusion in this review.

Discussion

Minimally invasive distal pancreatectomy (MIDP)

Left pancreatic resections are adopted more commonly for MIPR owing to a less complex and arduous nature of the surgery, requiring resection alone without any need for reconstruction, as compared to the right-sided resections i.e., pancreaticoduodenectomy (PD).

The standard surgery for resectable pancreatic body/tail adenocarcinoma requires a RAMPS (Radical Antegrade Modular Pancreatico-splenectomy) procedure. With a medial to lateral approach, this technique allows greater ability to obtain R0 resection modulating the posterior or retroperitoneal dissection plane (7,8). Also, there is some evidence to suggest that the routine excision of the upper half of Gerota’s fascia for these tumors provide additional oncological benefit (9).

The majority of the current evidence for MIDP is from single-center retrospective studies with surgeries performed for mixed pathologies including benign and malignant lesions. Comparable outcome measures such as operative time, postoperative morbidity, and mortality have been reported in most of these studies comparing MIDP with open distal pancreatectomy (ODP). But in addition, MIDP offered less blood loss and a shorter hospital stay although the operative time can be significantly longer for MIDP as per one of the randomized controlled trials (RCT) (10). However, as the minimally invasive approach becomes more and more common and when surgeons negotiate the learning curve, the operative time is likely to reduce. As regards the short-term oncological outcomes, the general trends have shown equivalent results for MIDP and ODP.

Laparoscopic distal pancreatectomy (LDP)

The first LDP was performed and reported by Cuschieri in 1994 (11). At present, just more than 25 years later after the first description of LDP, two RCTs have been completed together with several retrospective studies and meta-analysis of these studies evaluating LDP.

The first published RCT by de Rooij et al., LEOPARD-1 trial, was a multicenter study with 108 patients (6). Operative procedures were performed by surgeons from medium- and high-volume hospitals after going through a structured training program. Patients with pancreatic body/tail tumors (benign and malignant) without any vascular involvement, were randomized to MIDP (laparoscopic or robotic) and ODP in a 1:1 ratio, and the patients were blinded by using large abdominal bandages. The primary outcome was functional recovery time which included factors namely patient mobility, pain control, oral intake, need for intravenous fluids, and surgical site infections. The MIDP group had less intraoperative blood loss (150 vs. 400 mL; P<0.001), however; the operative time was longer (217 vs. 179 min; P=0.005). Conversion to open was observed in 8% of cases in MIDP. The perioperative morbidity, grade B/C pancreatic fistula rate, and 90-day mortality was comparable in both groups. The functional recovery time was 4 days (range, 3–6 days) after MIDP as against 6 days (range, 5–8 days) after ODP (P<0.001). Each parameter for functional recovery was reached faster with MIDP with a shorter hospital stay. The short-term quality of life was better with MIDP, while the overall cost of treatment was comparable to ODP. Although the short-term oncological outcomes i.e., the R0 resection and lymph node yield was comparable, only 23 (21%) patients had PDAC histology.

The other RCT, LAPOP, was a single-center trial with a superiority design and included 58 patients comparing LDP and ODP (12). The inclusion criteria and randomization were similar to the LEOPARD1 trial with the primary endpoint being the length of hospital stay. Blood loss was less with LDP (50 vs. 100 mL; P=0.018), and the operative time was similar to ODP. One patient was converted to open (3.4%) in the LDP group. Perioperative morbidity and mortality were comparable. The median hospital stay was 5 days (range, 4–5 days) after LDP vs. 6 days (range, 5–7 days) in the ODP group (P=0.002). Again, this study also suffered for comparison of short-term oncological outcomes as only 8 (13.7%) of the included patients were PDAC.

An individual patient data meta-analysis, combining data from both LEPORD1 and LAPOP trials (n=166) compared outcomes after MIDP and ODP (13). The primary endpoint was the rate of major (Clavien-Dindo > III) complications within 90 days in the post-operative period and was comparable after MIDP and ODP (21% vs. 35%, P=0.148).

Multiple other retrospective studies and meta-analyses have consistently reported benefits in terms of less operative blood loss and shorter hospital stay with LDP, together with comparable complication rates and mortality. In general, the short- and long-term oncological outcomes are also reported to be similar although with a smaller number of patients with PDAC (Table 1).

Robotic distal pancreatectomy (RDP)

The robotic platform is well-suited for complex abdominal surgeries due to its inherent advantages in the form of enhanced visualization, improved instrument dexterity, and surgeon ergonomics. It is being increasingly utilized for distal pancreatic resections since its first description by Melvin in 2003 (1), however is still less commonly used as compared to LDP (30). In general, studies addressing surgery specifically in malignant tumors have revealed no advantage of RDP over LDP with an equivalent rate of R0 resection, lymph node retrieval, and duration to adjuvant treatment. In studies comparing open DP, LDP, and RDP; RDP was associated with lower blood loss and lower clinically significant postoperative complications, although with a longer operative time and a higher cost (31-33).

In a systematic review by Zhao et al., RDP was associated with less blood transfusion, fewer lymph nodes harvested, lower complications and shorter hospital stay as compared to ODP (34). The rate of spleen preservation, positive margin, pancreatic fistula, and mortality were comparable. Another systematic review and meta-analysis by Niu et al. observed longer operative time, shorter hospital length of stay, and a higher rate of spleen preservation with RDP, in comparison with LDP (35). Also, hospital stay and overall complications were lower with RDP compared to ODP.

Data on long-term oncological outcomes for PDAC after RDP are limited. In a recent retrospective study from a national cohort, Nassour et al. compared oncological outcomes between RDP and ODP for PDAC alone (36). Lymph node retrieval, as well as overall survival (33.3 vs. 24.9 months, P=0.001), was better with RDP. The perioperative mortality was also lower in the RDP group. However, the authors acknowledged a potential for surgeon bias in selecting smaller tumors with no vascular or concomitant organ involvement for minimally invasive surgery while reserving challenging cases at risk of postoperative complications for the open approach, which could have been reflected in the analysis.

Learning curve (LC)

Regarding the LC analysis for MIDP, the evidence is heterogeneous. The Dutch Pancreatic Cancer Group has shown a seven-fold increase in LDP with a decrease in conversion rates and hospital stay via implementation of the Longitudinal Assessment and Realization of Laparoscopic Pancreatic Surgery program (LAELAPS)-1 (37). This highlights that standardization of the technique for MIPR may contribute to the optimal surgeon and patient outcomes. In studies where operative time and estimated blood loss were used to assess the LC, 10–20 cases have been proposed to reach proficiency (38). In a recent systematic review, LC for LDP was comparable to RDP. MIPD had significantly longer LC as compared to RDP and LDP. The study also highlighted the impact of institutional LC being smaller as compared to individual surgeon LC (39).

For optimizing the perioperative outcomes depending on the surgeon’s or institution’s LC phase, appropriate case selection remains extremely important. For this purpose, scoring systems have been proposed to anticipate challenges during the intra- and post-operative periods for MIDP. The original Difficulty Scoring System (DSS) for LDP by Osaka et al., later modified by Italian study includes the following parameters to grade difficulty based on the type of operation, presence of malignancy, neoadjuvant treatment, the proximity of the pancreatic transection line to the portal vein, tumor proximity to major vessels, tumor extension to peripancreatic tissues, left-sided portal hypertension and splenomegaly (40). Using these parameters, LDP was graded into low, intermediate, and high difficulty levels. Operative time, blood loss, and the conversion rate were considered as surrogate markers of difficulty. The DSS may allow for surgical stratification, better patient counseling, and graded surgical teaching while implementing a structured MIDP program (41).

Oncological outcomes (Table 1)

Thus far, no RCT has evaluated equivalence or superiority of MIDP with open surgery for pancreatic ductal adenocarcinoma (PDAC). The radicalness of surgery requires a completely different approach and training for performing MIDP in PDAC, i.e., RAMPS procedure as compared to that for benign or low-grade malignant tumors. The clearance of entire lymph node stations including 14a, 16a1 & 16a2, dissecting along the left border of SMA and celiac axis is an established standard of care for DP for PDAC, also possibly with excision of the upper part of Gerota’s fascia. Although technically this clearance is possible with MIDP, a dedicated approach by high-volume centers is required for consistent implementation of this procedure.

A large pan-European retrospective study (DIPLOMA) provides important data comparing MIDP and ODP including patients with PDAC alone (29). The primary aim of this study was to compare oncological outcomes. Consecutive patients undergoing distal pancreatic resection among 34 participating centers with laparoscopic, robotic, or open approaches were analyzed. In the total cohort of 1,212 cases, after propensity matching, 340 MIDPs were compared to 340 ODPs. The majority of MIDPs were LDPs, with only 16 patients undergoing robotic distal pancreatectomy (RDP). A higher conversion rate of 19% was observed with MIDP, probably related to the difference in the learning curve in the participating centers. Short-term clinical advantages of MIDP were observed in the comparison. The median intraoperative blood loss was less with MIDP (200 vs. 300 mL, P=0.001) and the median hospital stay was also shorter (8 vs. 9 days, P=0.001). R0 resection rate was higher with MIDP (67%) as compared to OPD (58%, P=0.019), however; the OPD group had a significantly higher number of patients with node-positive disease, lymphovascular emboli, and peri-neural invasion. The lymph node retrieval was significantly less in the MIDP group (14 vs. 22, P<0.001), as well as in patients with the adrenal gland and Gerota’s fascia resection. Although the overall median survival was comparable in both groups (29 months in MIDP and 31 months in ODP), with the opposing differences in R0 resection rate, resection of Gerota’s fascia, and lymph node retrieval, the authors concluded that the oncological safety of MIDP remains uncertain.

A systematic review comparing MIDP with ODP for PDAC showed a significant heterogeneity indicating treatment allocation bias towards MIDP. Patients undergoing MIDP had smaller tumors with less perineural and lymphovascular invasion (42). Table 1 highlights the oncological and perioperative outcomes of minimally invasive distal pancreatectomy and open distal pancreatectomy for pancreatic cancer. Hence, the long-term oncological outcomes with this procedure, purely for left-sided PDAC, need to be evaluated before wide adoption of MIDP for PDAC (14-28).

In this background, the following three important ongoing RCTs would provide valuable information as regards the real oncological safety of MIDP for PDAC (Table 2).

The DIPLOMA multicenter trial is recruiting 258 PDAC patients from 11 countries undergoing MIDP (LDP/RDP) and ODP, with the primary endpoint being R0 resection status (microscopic margins), and secondary endpoint of overall survival.

A multicentric Korean RCT with a non-inferiority design plans to include 244 resectable body/tail PDAC patients. LDP and ODP will be compared with a primary endpoint of 2-year survival.

Another RCT from China is also comparing LDP and OPD for patients with pancreatic body/tail malignant tumors and will include 306 patients with a primary endpoint of 2-year disease-free survival.

Minimally invasive pancreaticoduodenectomy (MIPD)

MIPD remains a highly complex and demanding procedure, as the resection involves more meticulous and difficult dissection along the superior mesenteric artery (SMA) and portal vein (PV) followed by an extremely challenging reconstruction procedure, specially pancreaticojejunostomy (PJ). The challenge of achieving R0 resection is even more for PDAC, as compared to other malignancies in the periampullary region. R0 resection rate for pancreatic head cancers has been traditionally reported to be lower (43). In this context, SMA first approaches have become a standard routine for all open PD’s (OPD) for pancreatic head cancers (44,45). The different artery first approaches can be utilized during MIPD, however, requires significant training with a long LC.

The majority of the current evidence for MIPD is from single-center retrospective studies, systematic reviews, and meta-analyses with only four published RCTs.

Laparoscopic pancreaticoduodenectomy (LPD)

At present, the evidence is conflicting as regards the safety and reproducibility of LPD. The majority of retrospective studies and three of the published RCTs have reported equivalent short-term outcomes with LPD as compared to the OPD.

The first published RCT, PLOT (Randomized Clinical Trial of Laparoscopic Versus Open Pancreaticoduodenectomy for Periampullary Tumors); was a single-center, non-blinded RCT from India. The trial included 64 patients with periampullary tumors, randomized in a 1:1 ratio to LPD or OPD, with the primary outcome variable being the length of hospital stay. LPD was associated with longer operative time but reduced intraoperative blood loss. Hospital stay was shorter with LPD (7 vs. 13 days; P=0.001) as compared with OPD. Short-term perioperative outcomes, including major morbidity, mortality, rates of postoperative pancreatic fistula, delayed gastric emptying, postoperative hemorrhage was comparable. Also, parity was observed in the short-term oncological outcomes, i.e., lymph node yield, and R0 resection, between both groups (46).

The second single-center RCT, PADULAP (Comparison of Perioperative Outcomes Between Laparoscopic and Open Approach for Pancreaticoduodenectomy) from Spain, included 66 patients with benign, premalignant, or malignant pancreatic tumors with a 1:1 randomization to LPD and OPD. The primary endpoint of this trial too was the length of hospital stay. Like the PLOT trial, longer operative time and shorter hospital stay were observed in the LPD arm (13.5 vs. 17 days; P=0.024). Fewer Clavien-Dindo grade III or higher complications were reported in the LPD Group, however; pancreas-specific complications were comparable between both groups. The lymph node yield and R0 resection rates were similar (47).

The third RCT, LEOPARD-2 (Laparoscopic Versus Open Pancreaticoduodenectomy for Pancreatic or Periampullary Tumours), evaluates LPD versus OPD, was a large scale multicenter, patient-blinded RCT (phase II/III). The included four centers performed 20 or more PDs annually and 20 LPDs before trial participation. The estimated sample size was 136 patients. The primary outcome of the phase II study was safety i.e., perioperative complications and mortality, and that for the phase III study was time to functional recovery. The study was prematurely terminated by the data and safety monitoring board because of a difference in 90-day complication-related mortality. The mortality in the LPD group was 10% (n=5/50) as compared to 2% (n=1/49) in the OPD group. Causes of mortality included bowel ischemia from intraoperative vascular damage, post-pancreatectomy haemorrhage, and POPF. The authors concluded that these safety concerns were unexpected and worrisome, especially in the setting of trained surgeons working in centers performing 20 or more PDs annually. Experience, learning curve, and annual volume might have influenced the outcomes; and future research should focus on these issues (48).

The fourth and the most recent multicenter, open-label RCT by the MITG-P-CPAM group from China is the largest trial published to date. Eligible patients (n=656) were randomly assigned (1:1) to undergo either LPD (n=328) or OPD (n=328). PD was performed for benign, premalignant, or malignant indications. The data collectors, outcome assessors, and data analysts were blinded regarding the study arm, whereas patients and surgeons were unblinded. LPD and OPD were performed by experienced surgeons who had already done at least 104 LPD procedures individually. The primary endpoint was the length of hospital stay. All analyses were performed on a modified intention-to-treat basis. After excluding patients with major deviations while including those with crossover (between the LPD and OPD arms), 297 patients in each arm were compared. The postoperative length of stay was significantly shorter for patients in the LPD group (median 15 vs. 16 days; P=0.02) and 90-day mortality was similar in both groups (2%). The authors concluded that LPD offers equal perioperative safety with the reduction in the length of hospital stay in experienced hands. However, the clinical benefit of LPD over OPD was marginal, despite extensive procedural expertise and future research should focus to identify patient groups who would benefit most from LPD (49).

Apart from the above RCTs, several other retrospective studies have evaluated outcomes of MIPD. A propensity-matched analysis by Nassour et al., with a larger number of patients (OPD, n=1,002; MIPD, n=334) demonstrated longer operative time and a lower rate of prolonged length of stay (>14 days) with MIPD. However, readmission rate was higher with MIPD (19.2% vs. 14.3%; P=0.04). The rate of 30-day mortality (MIPD 1.8% vs. OPD 1.3%; P=0.51), overall complications, POPF, and delayed gastric emptying were comparable (50).

An international, pan-European propensity-matched study included 14 centers (7 countries) performing ≥10 MIPDs annually vs. OPD in 53 German/Dutch centers performing ≥10 OPDs annually. The primary outcome measure was 30-day major morbidity. Of the total 4,220 patients, 729 MIPDs were compared with 729 OPDs. The MIPD group included patients with LPD, RPD, and hybrid procedures. No differences were observed in 30-day major morbidity, mortality, and length of stay between MIPD and OPD. However, MIPD was associated with a 10% higher rate of grade B/C POPF. Even after sensitivity analysis, adding pancreatic duct diameter, histopathological diagnosis, and T-stage as propensity score matching variables, the association of higher POPF remained with MIPD. This finding has not been reported in the other larger studies or systematic reviews and warrants prospective evaluation in RCT. Since the etiology of POPF is complex and is known to vary according to the fistula risk score, surgeon experience, and annual case volumes, the impact of minimally invasive technique needs to be compared separately with the open technique (51). With three of the four published RCTs having hospital stay as the primary outcome measure and the rest of the larger systematic reviews and meta-analyses with other short-term measures such as mortality or major morbidity but not POPF as the primary measure, insufficient balance between groups at baseline (residual confounding) could likely have resulted in lack of detection of any difference in POPF between MIPD and OPD in these studies.

Robotic pancreaticoduodenectomy (RPD)

Due to the inherent advantages of the robotic platforms over laparoscopy, RPD became increasingly popular since its first description in 2003 (52). In general, the available retrospective data thus far shows comparable perioperative and short-term oncological outcomes with RPD, LPD, and OPD.

A large, nonrandomized, multi-institutional study by Zureikat et al. compared 211 RPDs with 817 OPDs for perioperative outcomes (53). The study demonstrated that post-learning curve, RPD, and OPD are comparable in safety and short-term oncologic efficacy. However, OPD patients had a higher percentage of PDAC cases and a greater proportion of non-dilated (<3 mm) pancreatic ducts. RPD was associated with longer operative times, reduced blood loss, and a smaller number of major complications.

Another large cohort study using US nationwide database, with more than 22,000 operated patients with predominant PDAC histology, compared OPD with MIPD (LPD/RPD) for short and long-term outcomes over 5 years (2010–2015) (54). Several important observations were noted in this study. The utilization of MIPD was in 17% of patients in the US, across the low and high-volume centers. The 90-day mortality and unplanned 30-day readmissions were equivalent between MIPD and OPD. Mortality, despite being comparable in the groups, was high (6.7% in OPD and 5% in the LPD). A high annual hospital volume of PD and high hospital volume of MIPD was independently associated with a significant decrease in 90-day mortality. With the intention to treat design, all MIPD patients who underwent conversion to open surgery were also included. A high conversion rate of 15% with RPD and 25% with LPD was noted. RPD cases that required conversion had a significantly increased odds of 90-day mortality (OR, 3.99; 95% CI: 1.27–12.51) as compared to the completed RPD cases. LPD cases that required conversion to open did not show any higher odds for mortality. Of concern, 38.6% of OPDs and 35.6% of MIPDs were performed at low-volume centers, despite a known inverse PD hospital volume and mortality association, which was also confirmed in this study. R0 resection, lymph nodes yield, and receipt of adjuvant chemotherapy were equivalent between the groups.

A recent network meta-analysis by Kabir et al., compared outcomes after LPD, RPD, and OPD. Four RCTs and 23 propensity-score matched (PSM) studies including a total of 4,945 patients were analyzed. OPD was associated with significantly reduced operative time as compared to LPD and RPD. Four RCTs and 22 PSM studies found that patients who underwent LPD had significantly shorter hospital stays compared with OPD (OR 0.43, 95% CI: 0.28–0.95). Hospital stay was not different after RPD vs. LPD, and RPD vs. OPD (55). Intraoperative blood loss and postoperative delayed gastric emptying were reduced after LPD and RPD as compared to OPD. RPD was associated with fewer rates of wound infection compared to OPD. The other perioperative outcomes were comparable and the R0 resection rate and lymph node yield were also similar in the three approaches. The authors concluded that when LPD and RPD are performed in high-volume centers, short-term perioperative and oncologic outcomes are largely comparable with traditional OPD, at the expense of longer operating times.

Learning curve (LC)

As discussed previously, MIPD requires significant learning and a dedicated approach. A recent systemic review, that included pooled analysis of 32 studies concluded that overall LC of LPD was comparable to RPD (34 vs. 36 cases) (39). The study also highlighted that single surgeon LC of LPD was significantly higher (49 vs. 28 cases), whereas institutional LC was higher for RPD as compared to LPD (43 vs. 21 cases). Some studies have highlighted relatively shorter LC of RPD, attributable to ergonomic advantages and depth perception of the robotic systems. However, in the studies evaluating LC of RPD a large proportion of surgeons had prior familiarity with laparoscopic surgery and these studies were performed in second decade of the 21^st century that corresponds to the period of near stability on the IDEAL paradigm of surgical innovation. Although most of the studies highlight operative time and estimated blood loss as surrogate markers of LC, optimal intraoperative and postoperative outcomes may be equally important markers to study the LC for MIPD.

The evidence-based Miami International guidelines on MIPR are built on studies involving more than 8,500 patients (56). These guidelines represent a pathway for evaluation, dissemination, and propagation of MIPR. By identifying the unmet needs for MIPR, multi-institutional registries, appropriate accreditation of hospitals and institutions along with multicentre clinical trials have been suggested. The guidelines have made strong recommendations for MIDP, however have reinforced the impact of factors like age, BMI, tumor size, pancreatitis on the outcomes and have suggested multi-institutional studies to evaluate the impact of these factors. Numerous issues have also been pointed out with the lack of high-level prospective data, lack of data for MIPR with vascular resections, cost-effectiveness, quality of life, and instrumentation issues. The guidelines have also highlighted the importance of surgical rescue from the bleeding event, the need for well-designed prospective studies to support the use of MIPR in PDAC patients, and the role of MIPR post neoadjuvant treatment. These guidelines represent the highest methodological standards and address all important issues regarding implementation, controversies, and performance of MIPR in the present scenario and its propagation in the future.

Thus, MIPD is safe in experienced hands in high-volume centers and offers almost equivalent, if not better, perioperative outcomes. The short-term oncological outcomes are also similar; however, the majority of the studies lack analysis and comparison of the long-term outcomes. Although the R0 resection and lymph node yield can be considered as surrogate markers for long-term outcomes, these findings must be confirmed in larger studies including patients with PDAC alone, with overall- and disease-free survival as primary outcome measures.

Oncological outcomes (Table 3)

None of the RCTs could assess long-term oncological outcomes especially with very few included patients with PDAC. The majority of evidence for long-term outcomes is from retrospective studies, propensity-matched analysis, and systematic reviews (Table 3) (57-66). A recent large systematic review by Kamarajah et al. included 31 studies with 58,622 patients with periampullary tumors i.e., ampullary, distal bile duct, duodenal, pancreatic. MIPD was performed in 14.9% while 85.1% underwent OPD. Pooled analysis revealed similar 5-year overall survival after MIPD compared with OPD (HR 0.78, 95% CI: 0.50–1.22, P=0.2). A subset analyses for PDAC demonstrated similar 5-year overall survival after MIPD compared with OPD (HR 0.69, 95% CI: 0.32–1.50, P=0.3) (68).

A study by Girgis et al., specifically evaluated oncological outcomes of PDAC, comparing robotic and open approaches. A total of 456 Patients undergoing PD, DP, or distal pancreatectomy and celiac axis resection (DP-CAR) were included with the majority of patients being with PD (n=361). R0 margin status was similar, robotic pancreatectomy patients had a shorter length of stay and reduced wound infection rate. Overall survival for the entire cohort of patients was 24.6 months. The robotic cohort had improved median overall survival nearly reaching statistical significance (25.6 vs. 23.9 months; P=0.055) (66).

A propensity-matched analysis by Kwon et al. performed a retrospective review of patients undergoing MIPD and OPD for PDAC. A data of 1,048 patients were evaluated with 7.2% patients undergoing MIPD. After PSM, 73 patients undergoing MIPD were matched with 219 patients undergoing OPD. Adjuvant treatment rates were higher following MIPD (80.8% vs. 59.8%, P=0.002). The median overall survival and disease-free survival rates were similar between the groups (67).

With the available data, MIPD largely remains investigational and the majority of PDs are performed by conventional open technique. Presently, two ongoing RCTs aim to compare MIPD and OPD with time to functional recovery as a primary endpoint in both these trials (Table 2).

PORTAL trial, from China, is a multicenter, non-inferiority, phase III trial comparing robot-assisted versus open PD for benign and malignant lesions of the pancreatic head. Apart from the functional outcomes, the secondary outcome measures will be costs, mortality, overall complication rates, oncological outcomes, and quality of life. The calculated sample size is 244 patients and the results of this trial are expected by 2024.

The second ongoing RCT is from Johns Hopkins comparing MIPD (robot-assisted and laparoscopy) with OPD. Patients with benign, premalignant, or resectable malignant tumors are eligible for inclusion. The estimated sample size is 240 patients and this trial too is expected to be completed in 2024.

Minimally invasive vascular resections for PDAC

A few high-volume experienced pancreatic surgery centers have adopted a minimally invasive approach for pancreatectomies with vascular resections. In a systematic review of 9 studies involving 140 patients of PD with venous resections, 50% of the resections were performed robotically (69). About 60% of these resections were lateral resections requiring primary suture closure or patch closure. In the largest series of PD with vein resections by Beane et al. (70), only 1 out of 50 patients underwent segmental vein resection, whereas in a series by Croome, 9 of 22 patients underwent laparoscopic segmental vein resections (71). Segmental vein resections may sometimes need extensive mesenteric vein mobilization and prolonged vein clamping that may result in small bowel edema obscuring laparoscopic vision. The postoperative mortality rate of 0-8% is comparable to open surgery along with comparable blood loss and operative time. The results of these studies indicate that PD with venous resections may be considered feasible in hands of highly experienced surgeons, although any advantage of this approach over open procedure remains to be determined. There are centre-specific case reports and series that mention the technical feasibility of Robotic and Laparoscopic DP-CAR, but guidelines do not recommend minimally invasive surgery in left-sided pancreatic resections with vascular resections (56).

Cost

One of the limitations associated with MIPR is a higher operative cost which has significantly hampered its widespread implementation, particularly the robotic platform. Increased operative costs are attributed to higher equipment cost and the operating room expenditure. A few European and other studies suggest an absolute increase in the cost of more than 6,000 Euros in RPD as compared to OPD (31,33,72,73). However, when the robotic assistance cost is negated, the overall post-operative cost can be significantly less. When post-operative recovery, hospital stay, and quality of life are cumulatively considered, the increase in the cost of MIPR by the robotic platform may not be inhibitory (31,33). The cost-effectiveness of MIPR has been studied in many original articles in the last decade. All these studies have consistently reported higher ‘operative’ costs and lower ‘postoperative’ costs in MIPR as compared to open resections resulting in similar cost-effectiveness. It becomes imperative to point out that most of this data is from high volume centres. In an evaluation of a national database for cost-effectiveness of laparoscopic pancreaticoduodenectomy, Tran et al. reported shorter hospital stay resulting in lower median charges in high volume centres as compared to the low volume centres. So, the current cost-effective analysis may not be applicable to the low volume centres (74). Moreover, evaluation of a new intervention should include the quality-of-life measurements along with the cost which helps to determine the ‘value’ of the intervention i.e., health outcomes per unit currency spent. Present studies are deficient in value based analysis and it is premature to conclude MIPR as a valuable intervention at the healthcare level. Although results are suggestive of cost saving trends with MIPR, rigorous value-based analysis strategies in well-designed prospective controlled trials are needed to study the real cost-effectiveness of MIPR (75,76).

Future directions and conclusions

Balancing indications and learning curve is the foremost issue for optimal utilization of MIPR in pancreatic cancer at present. Unpredictable conversions have been linked to increased mortality; therefore, strict indication assessment is needed. Learning curve needs to be optimized, for which at least 10 complex MIPR per year are recommended. Furthermore, the application of artificial intelligence may optimize mentorship and propagate training.

To conclude the development of MIPR for pancreatic cancer will continue to proceed further. Even though the feasibility and the safety of MIPR has been largely established, MIPR for PDAC remains controversial owing to a dearth of the literature evaluating long-term outcomes. Apart from that, the exact indications, appropriate patient selection, enhanced cost, and learning curve issues also need further assessment. Considering the ongoing impact of neoadjuvant treatment on pancreatic cancer surgery and a corresponding increase in vascular resections and arterial divestment procedures, the application of MIPR in these scenarios also remains to be explored. Large multi-centric RCTs by high volume pancreatic centres across the countries need to evaluate these controversial issues regarding MIPR for PDAC.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Savio George Barreto) for the series “Unresolved Issues in Pancreatic Cancer” published in Chinese Clinical Oncology. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-21-131/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-21-131/coif). The series “Unresolved Issues in Pancreatic Cancer” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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