Abstract
Objective:
This multicenter randomized controlled trial investigated whether the mesenteric approach, which is an infracolic superior mesenteric artery (SMA)-first approach during pancreatoduodenectomy (PD), can improve survival in patients with pancreatic ductal adenocarcinoma (PDAC), compared with the Kocher-first conventional approach.
Background:
The mesenteric approach might improve surgical outcomes through a nontouch isolation technique for PDAC.
Methods:
This trial was conducted in 24 Japanese high-volume centers. Patients who were scheduled to undergo PD for resectable PDAC or borderline resectable PDAC with portal vein invasion (BR-PV PDAC) were randomly assigned (1:1) via a central web-based application to the conventional or mesenteric approach. The primary endpoint was overall survival (OS). We also analyzed circulating tumor cell (CTC) DNA in the PV blood obtained during surgery. This trial is registered with ClinicalTrials.gov. NCT03317886, and UMIN Clinical Trials UMIN000029615.
Results:
Between 2018 and 2021, 360 patients were randomly assigned to conventional (n=181) and mesenteric groups (n=179). With a median follow-up of 39.3 months, the median OS was comparable between conventional and mesenteric groups (41.7 vs. 39.3 months; HR 1.02, 95% CI: 0.76–1.37, P=0.897). CTC analysis showed that the mean change in CTC DNA copy number in PV obtained at laparotomy and just before removal of the specimen was significantly different between the conventional (10.1±2.7) and mesenteric (−7.3±2.6) groups (P<0.001).
Conclusions:
The mesenteric approach does not improve survival in patients with resectable or BR-PV PDAC, although it might prevent spread of cancer cells via vessels during surgery through the nontouch isolation procedure.
Key Words: artery-first approach, conventional approach, mesenteric approach, pancreatoduodenectomy, pancreatic ductal adenocarcinoma, superior mesenteric artery
To achieve a cure for pancreatic ductal adenocarcinoma (PDAC), curative resection (R0) is necessary; however, the most frequent R1 site is the dissected margin around the superior mesenteric artery (SMA).1–5 Pancreatoduodenectomy (PD) traditionally starts from Kocher’s maneuver, including mobilization of the pancreatic head from the retroperitoneum.6,7 In the final step of resection, the connective tissues around the SMA are dissected, including the inferior pancreatoduodenal artery (IPDA), lymph nodes, and nerve-rich lamina, which correspond to the second nerve plexuses of the pancreatic head (plPh-II), according to the Japanese General Rules for the Study of Pancreatic Cancer.8,9 The artery-first approach during PD was first reported in 2010,10 the concept of which is to start with dissection of the connective tissues around the SMA. Among them, the mesenteric approach was first reported by Nakao et al in 1993;11 it involves starting the dissection around the SMA at the infracolic mesenterium.11–13
The aims of the mesenteric approach are: (1) decrease of intraoperative blood loss by early division of the IPDA; (2) increase of R0 rates by complete dissection of the connective tissues around the SMA; and (3) to avoid the risk of cancer cells spread through the vessels secondary to manipulation of the pancreatic head by division of all arteries supplying the pancreatic head and all drainage veins for this region before handling the pancreatic head.11–13
The aim of this randomized controlled trial (RCT) was to determine whether the mesenteric approach could have oncological and surgical benefits compared with the conventional approach during PD for resectable PDAC and borderline resectable PDAC with portal vein invasion (BR-PV PDAC).14 Furthermore, we analyzed circulating tumor cell (CTC) DNA in the PV blood obtained immediately after laparotomy and just before removal of the specimen to scientifically determine whether the mesenteric approach can prevent the spread of cancer cells during PD.
METHODS
Study Design and Patients
The MAPLE-PD trial was a RCT in 24 Japanese high-volume centers, which were board-certified training institutions by the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JHPBS); the interventions were performed by board-certified instructors and expert surgeons by JHPBS to ensure the high quality of the study. The protocol was approved by the Wakayama Medical University Hospital (WMUH) Ethics Committee (Approval No. 2128). The trial protocol is registered in the protocol registration system at ClinicalTrials.gov (NCT03317886) and the University Hospital Medical Information Network Clinical Trials Registry (UMIN000029615).
Eligible for enrollment in the study were: patients who were scheduled to undergo elective PD for resectable PDAC or BR-PV PDAC defined by the National Comprehensive Cancer Network,15 and provided written informed consent. A full list of the inclusion and exclusion criteria is available in the protocol.14
Randomization
Patients were randomized in a 1:1 allocation ratio to 2 arms: conventional approach (conventional group); and mesenteric approach (mesenteric group), with random block size. Central randomization and registration system were applied using the Electronic Data Capture (EDC) system. To minimize background bias between the 2 groups, this study was stratified for resectability (resectable vs. BR-PV), neoadjuvant therapy (NAT) (yes or no), and by participating institution. We used the Pcock and Simon’s minimization method for random assignment and Mersenne Twister for random number generation.
All patients were blinded to the surgical approach; however, blinding of surgeons was not feasible due to the nature of the surgical interventions. To reduce assessment bias, outcome assessors and statisticians were blinded to the treatment allocation when evaluating postoperative outcomes.
Procedures
Control Intervention (conventional approach)
After laparotomy, following mobilization of the pancreatic head from the retroperitoneum by Kocher’s maneuver, regional lymph node dissection around the common hepatic artery (#8), the root of the left gastric artery (#7), the right side of the celiac axis (#9), and in the hepatoduodenal ligament (#12) was performed. After the stomach or duodenum, bile duct, and pancreas were divided, division of inferior and superior pancreatoduodenal veins and dissection of the connective tissues around the SMA, including lymph nodes (#14) and plPh-II, and division of the IPDA or the common trunk of the IPDA and first branch of the jejunal artery (J1 artery) were performed. After complete isolation of the pancreatic head from the SMA, the jejunum was transected and the specimen was removed. If tumor invasion of the PV and/or superior mesenteric vein (PV/SMV) was suspected, concomitant PV/SMV resection was performed. In reconstruction, pancreaticojejunostomy or pancreaticogastrostomy, choledochojejunostomy, and gastrojejunostomy or duodenojejunostomy were performed in turn.
Trial Intervention (mesenteric approach)
After laparotomy, the mesenterium was incised at the line between the Treitz ligament and the inferior duodenal flexure to identify the SMA and the SMV. The lymph node dissection around the SMA proceeded to the origin of the SMA in a longitudinal direction, and the IPDA or common trunk of the IPDA and J1 artery was divided at the root. The mesenteric approach was completed when circumferential dissection of the connective tissues around the SMA and the SMV, including the lymph nodes (#14), plPh-II, the IPDA, and inferior and superior pancreatoduodenal veins was performed.10,11 Regional lymph node dissection around the same areas as those of the conventional approach (#7, #8, #9, and #12) was performed, and the stomach or duodenum, bile duct, pancreas, and jejunum were divided. Finally, the pancreatic head was mobilized from the retroperitoneum, and the tumor with en bloc dissected tissues was removed. Then the same reconstruction as that of the conventional approach was performed.
In both the conventional and mesenteric approach groups, the celiac axis plexus and the SMA plexus were circumferentially preserved. Lymph node dissection around the celiac axis was performed on the right semicircle, whereas that around the SMA was carried out circumferentially. We held 3 consensus meetings to determine operative techniques and perioperative management by discussing and observing several operative videos to ensure standardization of the interventions in all institutions, as described in a previous protocol paper.14
Follow-up
After surgery, the patients were followed up by measuring tumor markers (CEA, CA19-9, and DUPAN-II) and computed tomography scan or magnetic resonance imaging every 3 months to evaluate postoperative recurrence, or more often if the patient’s situation requires, such as elevated tumor markers. Overall survival (OS) was defined as the time from operation to the last follow-up or death. Recurrence-free survival (RFS) was defined as the time from operation to the time of finding any recurrence, or death. An independent data monitoring committee (Clinical Study Support Center, WMUH) monitored the safety of the trial subjects by qualitative analyses of feasibility, accrual rate, and adverse events, and drop-outs during the study. Data were collected via a case report form using the EDC system and paper, and stored and managed securely by the data monitoring committee.
Study Endpoints
The primary endpoint was OS. Secondary endpoints were operative time, intraoperative blood loss volume, and transfusion. Further secondary endpoints included incidence of postoperative complications within 90 days after surgery, the rate of R0 resection, number of harvested lymph nodes, RFS, and site of initial recurrence. Postoperative pancreatic fistula (POPF),16 delayed gastric emptying (DGE),17 and intra-abdominal hemorrhage18 were defined and graded according to the International Study Group of Pancreatic Surgery. Other complications were graded by the Clavien-Dindo classification.19 Postoperative diarrhea was graded by Common Terminology Criteria for Adverse Events version 4. R0 resection was defined as no microscopic evidence of cancer cells along all margins of the resected specimen according to the Japanese General Rules for the Study of Pancreatic Cancer 7th ed.9
CTC Analysis
The analysis of CTCs was conducted by isolating mononuclear cells from the PV and measuring the quantity of KRAS mutations within the DNA of these mononuclear cells. Blood sample collection was performed at 2 points: immediately after laparotomy by tubing the round ligament of the liver and just before removal of the specimen by directly puncturing the PV using a 21G needle. Blood samples (8 mL) were obtained in the BD Vacutainer CPTTM Mononuclear Cell Separation Blood Collection Tube. After isolating mononuclear cells by density gradient centrifugation, mononuclear cell DNA was extracted using the DNeasy Blood & Tissue Kit (Qiagen, Hilden, Germany). Samples were eluted in 100 μL elution buffer and DNA was frozen at −80°C until analysis. To guarantee the quality of CTC DNA, we decided to collect these DNA samples from only institutions where the researchers can isolated DNA in their own institutions; therefore, we received DNA from the attending institutions that could extract DNA in their own institutions (WMUH; n=55, Nagoya University; n=31, Tokyo Medical University; n=12, Gunma University; n=4, Nara Medical University; n=2, Chiba University; n=2, Toyama University; n=1).
The analysis of DNA mutations was performed using digital droplet PCR (ddPCR). The QX200 Droplet Digital PCR system (Bio-Rad, Hercules, CA) and ddPCR KRAS multiplex assays (Bio-Rad) were used. A reaction volume of 20 µL, including 8 µL of 100x diluted DNA, was used as a template for each PCR. Droplets were generated using the QX200 droplet generator (Bio-Rad), and the PCR reaction was performed in the C1000 Touch Thermo Cycler (Bio-Rad). Data analysis was performed using the Quantasoft software version 1.7.4 (Bio-Rad). The absolute quantification of KRAS mutation copy numbers was performed, and the difference in copy numbers between just before removal of the specimen and postlaparotomy was analyzed. Subsequently, thorough data scrutiny was conducted collaboratively with co-authors to ensure the most accurate values are detected.
Statistical Analyses
On the basis of the previous study, the expected hazard ratio (HR) between the mesenteric and conventional approaches was 0.70.20 To obtain a power of 80% or higher when using the log-rank test at a significance level of 0.05, 354 patients (177 patients in each group) were necessary, considering the proportion of 10% dropping out for each group, as described in the protocol paper previously published.14
The primary population for efficacy analysis was the intention-to-treat (ITT) population, defined as all randomized patients. Survival analysis was conducted using the Kaplan-Meier method and the 2 randomization groups were compared using log-rank test. The HR and 95% CI were estimated by the Cox proportional hazards model. Categorical outcomes were summarized using frequency and percentage and will be compared using the Fisher exact method. Continuous outcomes used the median and interquartile range (IQR) and were compared using the Wilcoxon rank-sum test. P <0.05 was considered statistically significant. Statistical analyses were carried out using R version 4.2.2.
RESULTS
Between January 2018 and February 2021, 360 patients with resectable or BR-PV PDAC were randomly assigned to the conventional group and mesenteric group and were included in the ITT population (Fig. 1). The per-protocol analyses included 164 patients in the conventional group and 151 patients in the mesenteric group after the exclusion of 45 patients: 17 patients because of intraoperative confirmation of peritoneal dissemination or liver metastasis (n=8: conventional group and n=9: mesenteric group), 1 patient because of R2 resection in the mesenteric group, 8 patients because of change to the other procedure (total pancreatectomy because of positive pancreatic cut margin in 1 patient in the conventional group and in 6 patients in the mesenteric group and distal pancreatectomy because of tumor location in mesenteric group), and 19 patients with pathologic other diagnose than PDAC (n=8: conventional group and n=11: mesenteric group) (Fig. 1). Baseline characteristics were well balanced between the 2 groups (Table 1).
FIGURE 1.
CONSORT flow diagram. PDAC: Pancreatic ductal adenocarcinoma.
TABLE 1.
Baseline Characteristics of the Intention-to-treat and Per-protocol Population
| Intention-to-treat analysis | Per-protocol analysis Conventional (n=181) | Mesenteric (n=179) | Conventional (n=164) | Mesenteric (n=151) |
|---|---|---|---|---|
| Age, (IQR) years | 71 (66–76) | 72 (67–77) | 71 (67–76) | 72 (67–77) |
| Sex: male/female, (%) | 100 (55)/81 (45) | 105 (59)/74 (41) | 88 (54)/76 (46) | 82 (54)/69 (46) |
| ECOG performance status: 0/1, (%) | 153 (85)/28 (16) | 153 (86)/26 (15) | 138 (84)/26 (16) | 131 (87)/20 (13) |
| Body mass index, kg/m2 | 22 (20–24) | 22 (20–24) | 22 (20–24) | 22 (20–24) |
| Tumor marker | ||||
| CEA, ng/mL | 3 (2–4) | 3 (2–5) | 3 (2–5) | 3 (2–5) |
| CA19-9, U/mL | 55 (18–185) | 50 (15–180) | 55 (17-171) | 51 (17–178) |
| DUPAN-II, U/mL | 74 (25–240) | 77 (25–463) | 74 (25–252) | 72 (25–457) |
| Neoadjuvant therapy, (%) | 96 (53) | 92 (51) | 88 (54) | 83 (55) |
| Chemotherapy, (%) | 71 (74) | 75 (82) | 65 (74) | 67 (81) |
| Chemoradiation therapy, (%) | 25 (26) | 17 (18) | 23 (26) | 16 (19) |
| Regimen of chemotherapy | ||||
| Gemcitabine plus S-1, (%) | 49 (51) | 44 (48) | 45 (51) | 37 (45) |
| Gemcitabine plus nab-paclitaxel, (%) | 23 (24) | 30 (33) | 21 (24) | 28 (34) |
| Gemcitabine, (%) | 18 (19) | 11 (12) | 17 (19) | 11 (13) |
| Gemcitabine, nab-paclitaxel, plus S-1, (%) | 5 (5) | 3 (3) | 4 (5) | 3 (4) |
| Modified FOLFIRINOX, (%) | 1 (1) | 2 (2) | 1 (1) | 2 (2) |
| S-1, (%) | 0 (0) | 2 (2) | 0 (0) | 2 (2) |
| Resectability: resectable/BR-PV, (%) | 150 (83)/31 (17) | 148 (83)/31 (17) | 135 (82)/29 (18) | 123 (82)/28 (19) |
| Location of tumor | ||||
| Uncinate process, (%) | 81 (45) | 74 (41) | 75 (46) | 64 (42) |
| Dorsal pancreas, (%) | 69 (38) | 72 (40) | 60 (37) | 66 (44) |
| Neck, (%) | 31 (17) | 33 (18) | 29 (18) | 21 (14) |
| Operative procedure | ||||
| PD, (%) | 10 (6) | 8 (5) | 10 (6) | 7 (5) |
| Pylorus-resecting PD, (%) | 137 (76) | 131 (73) | 131 (80) | 120 (80) |
| Pylorus-preserving PD, (%) | 25 (14) | 24 (13) | 23 (14) | 24 (16) |
| Total pancreatectomy, (%) | 1 (1) | 6 (3) | 0 (0) | 0 (0) |
| Distal pancreatectomy, (%) | 0 (0) | 1 (1) | 0 (0) | 0 (0) |
| Explorative laparotomy, (%) | 5 (3) | 8 (5) | 0 (0) | 0 (0) |
| Other procedures, (%) | 3 (2) | 1 (1) | 0 (0) | 0 (0) |
| Portal vein resection, (%) | 65 (36) | 60 (34) | 63 (38) | 58 (38) |
| Pancreatic anastomosis | ||||
| Pancreaticojejunostomy, (%) | 150/172 (87) | 140/163 (86) | 143 (87) | 131 (87) |
| Pancreaticogastrostomy, (%) | 22/172 (13) | 23/163 (14) | 21 (13) | 20 (13) |
Data are the median [interquartile range (IQR)] or n (%).
BR-PV indicates borderline resectable pancreatic ductal adenocarcinoma with portal vein invasion; CA, carbohydrate antigen; CEA, carcinoembryonic antigen; DUPAN, Duke pancreatic antigen; ECOG, Eastern Cooperative Oncology Group; PD, pancreatoduodenectomy.
Primary Outcome
During a median follow-up time of 39.3 months (IQR: 18.1 to not evaluable), 177 (49.2%) of 360 patients died: 91 (50.3%) of 181 patients in the conventional group and 86 (48.0%) of 179 patients in the mesenteric group. The primary endpoint of median OS (41.7 vs. 39.3 months) with a 1-year survival rate of 86.1% and 82.3% and a 2-year survival rate of 70.8% and 66.6% was comparable in the conventional and mesenteric groups (HR: 1.02, 95% CI: 0.76–1.37; P=0.897) when analyzed by ITT analysis (Fig. 2A). The per-protocol analysis showed that median OS (38.8 vs. 41.4 months) with a 1-year survival rate of 87.1% and 84.7% and 2-year survival rate of 72.1% and 70.4% was comparable in the conventional and mesenteric groups (HR: 0.93, 95% CI: 0.67–1.27; P=0.635) (Fig. 2B).
FIGURE 2.
Overall survival and recurrence-free survival in the intention-to-treat population and per-protocol population. Overall survival (OS) in the intention-to-treat population (A), and in the per-protocol population (B) for the conventional group (black) and mesenteric approach (red). Recurrence-free survival (RFS) in the intention-to-treat population (C), and in the per-protocol population (D) for the conventional group (black) and mesenteric approach (red).
Secondary Outcomes
Table 2 provides information regarding surgical outcomes. The median operative time was longer in the mesenteric group than in the conventional group in ITT (419 vs. 379 minutes; P=0.002) and per-protocol analyses (424 vs. 380 minutes; P=0.001). Intraoperative blood loss in the mesenteric group was higher than that in the conventional group in ITT analysis (472 vs. 430 mL; P=0.033); however, that was comparable between groups in per-protocol analysis (480 vs. 454 mL; P=0.071). The rate of postoperative complications ≥ grade III was comparable in the conventional and mesenteric groups, both in ITT and per-protocol analyses. There was no statistically significant difference in the incidence of diarrhea (Table 2).
TABLE 2.
Operative Outcomes and Pathologic Findings of the Intention-to-treat and Per-protocol Population
| Intention-to-treat analysis Conventional (n=181) | Mesenteric(n=179) | P | Per-protocol analysis Conventional (n=164) | Mesenteric (n=151) | P | |
|---|---|---|---|---|---|---|
| Operative time, (IQR) min | 379 (324–464) | 419 (353–507) | 0.002 | 380 (327–466) | 424 (359–515) | 0.001 |
| Intraoperative blood loss, mL | 430 (187–713) | 472 (268–883) | 0.033 | 454 (208–740) | 480 (292–891) | 0.071 |
| Postoperative complications*, ≥grade III, (%) | 13 (7) | 11 (6) | 0.833 | 13 (8) | 11 (7) | >0.999 |
| Pancreatic fistula, (%)† | 12 (7) | 11 (6) | >0.999 | 12 (7) | 9 (6) | 0.659 |
| Delayed gastric emptying, (%)† | 17 (9) | 12 (7) | 0.493 | 16 (10) | 11 (7) | 0.547 |
| Intra-abdominal hemorrhage, (%)† | 7 (4) | 4 (2) | 0.543 | 7 (4) | 3 (2) | 0.340 |
| Diarrhea‡, grade 3–4, (%) | 3 (2) | 9 (5) | 0.086 | 3 (2) | 9 (6) | 0.076 |
| Mortality, (%) | 1 (1) | 0 (0) | >0.999 | 1 (1) | 0 (0) | >0.999 |
| Pathologic findings | ||||||
| Marginal status, R0, (%) | 156 (86) | 151 (84) | 0.657 | 148 (90) | 136 (90) | >0.999 |
| Harvested lymph nodes, (%) | 26 (19–34) | 33 (23–40) | <0.001 | 27 (20–35) | 32 (24–40) | <0.001 |
| Lymph node metastasis, (%) | 96 (53) | 97 (54) | 0.833 | 96 (59) | 92 (61) | 0.730 |
| UICC-TNM stage, 8th edition | 0.902 | 0.935 | ||||
| 0/IA/IB, (%) | 1 (1)/36 (21)/25 (15) | 0 (0)/28 (17)/27 (16) | 1 (1)/35 (21)/25 (15) | 0 (0)/28 (19)/26 (17) | ||
| /IIA/IIB/III, (%) | /5 (3)/77 (45)/17 (10) | /4 (2)/75 (45)/21 (13) | /5 (3)/77 (47)/17 (10) | 3 (2)/71 (47)/19 (13) | ||
| /IV, (%) | /12 (7) | /13 (8) | /3 (2) | 4 (3) | ||
| Missing data | n=8 | n=11 | n=1 (complete response) | n=0 | ||
| Introduction of adjuvant therapy, (%) | 150 (83) | 147 (82) | 0.671 | 145 (88) | 132 (87) | 0.863 |
| Regimen of adjuvant therapy | 0.684 | 0.457 | ||||
| S-1, (%) | 126 (84) | 126 (86) | 121 (83) | 115 (87) | ||
| 5-FU HAI plus gemcitabine, (%) | 11 (7) | 7 (5) | 11 (8) | 7 (5) | ||
| Gemcitabine plus S-1, (%) | 5 (3) | 7 (5) | 5 (3) | 6 (5) | ||
| Gemcitabine plus nab-paclitaxel, (%) | 5 (3) | 6 (4) | 5 (3) | 4 (3) | ||
| Gemcitabine, (%) | 3 (2) | 1 (1) | 3 (2) | 0 (0) | ||
| Time to adjuvant therapy, day | 45 (34–57) | 44 (33–55) | 0.544 | 47 (36–57) | 43 (31–55) | 0.193 |
| Completion of adjuvant therapy, (%) | 101 (56) | 92 (51) | 0.387 | 96 (59) | 83 (55) | 0.524 |
| Postoperative recurrence, (%) | 110 (61) | 99 (55) | 0.293 | 106 (65) | 94 (62) | 0.661 |
| Pattern of postoperative recurrence | 0.753 | 0.953 | ||||
| Local/remnant pancreas only, (%) | 32 (18) | 29 (16) | 32 (20) | 29 (19) | ||
| Systemic only, (%) | 65 (36) | 57 (32) | 61 (37) | 52 (34) | ||
| Local and systemic, (%) | 13 (7) | 13 (7) | 13 (8) | 13 (9) | ||
| Sites of postoperative recurrence | ||||||
| Local recurrence, (%) | 40 (22) | 38 (21) | 0.841 | 40 (24) | 38 (25) | 0.873 |
| Liver, (%) | 38 (21) | 30 (17) | 0.305 | 36 (22) | 27 (18) | 0.367 |
| Lung, (%) | 20 (11) | 18 (10) | 0.759 | 20 (12) | 17 (11) | 0.796 |
| Peritoneum, (%) | 17 (9) | 17 (10) | 0.973 | 15 (9) | 16 (11) | 0.666 |
| Distant lymph node, (%) | 12 (7) | 12 (7) | 0.978 | 12 (7) | 12 (8) | 0.833 |
| Remnant pancreas, (%) | 5 (3) | 4 (2) | >0.999 | 5 (3) | 4 (3) | >0.999 |
| Bone, (%) | 5 (3) | 1 (1) | 0.215 | 5 (3) | 1 (1) | 0.217 |
Data are the median [interquartile range (IQR)] or n (%).
Postoperative complications were graded by Clavien-Dindo classification.
Pancreatic fistula, delayed gastric emptying, and intra-abdominal hemorrhage were defined and graded according to the International Study Group of Pancreatic Surgery.
Postoperative diarrhea was graded by Common Terminology Criteria for Adverse Events version 4.
AT indicates adjuvant therapy; HAI, hepatic arterial infusion; TNM, tumor-node-metastasis; UICC, International Union for Cancer Control.
The rate of R0 resection was comparable in the conventional and mesenteric groups by ITT analysis (86.2% vs. 84.4%; P=0.657) and per-protocol analysis (90.2% vs. 90.1%; P>0.999) (Table 2). The number of harvested lymph nodes was higher in the mesenteric group than in the conventional group both by ITT and per-protocol analyses (33 vs. 26; P<0.001, and 32 vs. 27; P<0.001), although the number of metastatic lymph nodes was comparable (Table 2).
The rate of administration of postoperative adjuvant therapy was similar in the conventional and mesenteric groups by ITT (82.9% vs. 82.1%; P=0.671) and per-protocol (88.4% vs. 87.4%; P=0.863) analyses (Table 2). The median time until start of adjuvant therapy from surgery was also comparable in the conventional and mesenteric groups by ITT (45 vs. 44 days; P=0.544) and per-protocol (47 vs. 43 days; P=0.193) analyses (Table 2). Furthermore, the rate of completion of postoperative adjuvant therapy with 24 weeks was comparable in the conventional and mesenteric groups by ITT (55.8% vs. 51.4%; P=0.387) and per-protocol (58.5% vs. 55.0%; P=0.524) analyses (Table 2).
Recurrence or disease progression occurred in 110 patients (60.8%) in the conventional group and 99 patients (55.3%) in the mesenteric group after a median follow-up of 17.5 months (IQR: 8.1–59.6), and there was no significant difference in RFS between the 2 groups when analyzed by ITT analysis (HR: 1.08, 95% CI: 0.84–1.39; P=0.566) (Fig. 2C). Per-protocol analysis also showed no difference in RFS between the conventional and mesenteric groups (HR: 1.04, 95% CI: 0.79–1.36; P=0.785) (Fig. 2D), and the rates of local and/or systemic recurrence were similar in both groups (Table 2).
CTC Analysis
A total of 107 cases in which PV blood could be collected were included in the CTC analysis, with 52 cases (44 resectable and 8 BR-PV PDAC) in the conventional group and 55 cases (49 resectable and 6 BR-PV PDAC) in the mesenteric group. There were no significant differences in baseline characteristics or pathologic diagnoses between conventional and mesenteric groups (supplemental Table 1, Supplemental Digital Content 1, http://links.lww.com/SLA/F594). The mean DNA copy number immediately after laparotomy was 16.0±16.2 copies in the conventional group and 23.7±28.9 copies in the mesenteric group. The mean DNA copy number just before removal of the specimen was 26.1±29.3 copies in the conventional group and 16.3±17.8 copies in the mesenteric group. When calculating the difference in values at laparotomy and just before removal of the specimen for each case, the mean change was 10.1±2.6 copies in conventional group (Fig. 3A) and −7.3±2.6 copies in the mesenteric group (Fig. 3B). A significant difference was observed between the 2 groups in the analysis of changes before and after the procedure (P<0.0001; Fig. 3C). There was no significant difference in OS between conventional and mesenteric groups (HR: 0.67, 95% CI: 0.39–1.13; P=0.127) (supplemental Fig. 1A, Supplemental Digital Content 1, http://links.lww.com/SLA/F594). Similarly, no significant difference in OS was observed between patients with increased (n=63) and decreased (n=44) CTC DNA copy numbers before resection from at laparotomy (HR: 0.77, 95% CI: 0.45–1.31; P=0.331) (supplemental Fig. 1B, Supplemental Digital Content 1, http://links.lww.com/SLA/F594).
FIGURE 3.
Analysis of CTC DNA copy in portal venous blood obtained during surgery. CTC DNA copies immediately after laparotomy and just before removal of the specimen in the conventional group (A), and mesenteric group (B). (C) The mean change in CTC copies between at laparotomy and just before removal of the specimen.
Subgroup Analysis
For patients with resectable PDAC, there were no significant differences in both OS and RFS between the conventional and mesenteric groups by ITT analysis (HR: 1.17, 95% CI: 0.84–1.63, P=0.351; Fig. 4A, and HR: 1.21, 95% CI: 0.91–1.61, P=0.183; Fig. 4B) and per-protocol analysis (HR: 1.03, 95% CI: 0.72–1.48, P=0.860; Fig. 4C and HR: 1.16, 95% CI: 0.86–1.56, P=0.346; Fig. 4D). In BR-PV PDAC, we also found no significant differences in both OS and RFS between the conventional and mesenteric groups by ITT analysis (HR: 0.61, 95% CI: 0.32–1.17, P=0.129; Fig. 5A, and HR: 0.60, 95% CI: 0.34–1.07, P=0.083; Fig. 5B) and per-protocol analysis (HR: 0.64, 95% CI: 0.32–1.28, P=0.198; Fig. 5C and HR: 0.62, 95% CI: 0.34–1.13, P=0.117; Fig. 5D).
FIGURE 4.
Overall survival and recurrence-free survival of resectable and borderline resectable PDAC in the intention-to-treat population and per-protocol population. (A) Overall survival (OS) and (B) recurrence-free survival (RFS) of resectable PDAC in the intention-to-treat population, and (C) OS and (D) RFS in the per-protocol population for the conventional group (black) and mesenteric approach (red). (E) OS and (F) RFS of border resectable PDAC with portal vein invasion (BR-PV PDAC) in the intention-to-treat population, and (G) OS and (H) RFS in the per-protocol population for the conventional group (black) and mesenteric approach (red).
FIGURE 5.
Overall survival and recurrence-free survival of patients who received neoadjuvant therapy for PDAC and those who did not in the intention-to-treat population and per-protocol population. (A) OS and (B) RFS of patients who received neoadjuvant therapy (NAT) for PDAC in the intention-to-treat population, and (C) OS and (D) RFS in the per-protocol population for the conventional group (black) and mesenteric approach (red). (E) OS and (F) RFS of patients who did not receive NAT for PDAC in the intention-to-treat population, and (G) OS and (H) RFS in the per-protocol population for the conventional group (black) and mesenteric approach (red).
As for the association between NAT and survival outcomes, no significant differences in OS or RFS were observed between the conventional and mesenteric groups among patients who received NAT for PDAC by ITT analysis (HR: 1.18, 95% CI: 0.77–1.81, P=0.457; Fig. 5A, and HR: 1.14, 95% CI: 0.80–1.63, P=0.483; Fig. 5B) and per-protocol analysis (HR: 1.23, 95% CI: 0.78–1.95, P=0.379; Fig. 4C and HR: 1.17, 95% CI: 0.81–1.71, P=0.401; Fig. 4D). Similarly, among patients who did not receive NAT, there were no significant differences in OS or RFS between the conventional and mesenteric groups by ITT analysis (HR: 0.90, 95% CI: 0.60–1.34, P=0.590; Fig. 5E, and HR: 1.02, 95% CI: 0.71–1.46, P=0.925; Fig. 5F) and per-protocol analysis (HR: 0.72, 95% CI: 0.46–1.11, P=0.138; Fig. 5G and HR: 0.91, 95% CI: 0.62–1.34, P=0.639; Fig. 5H).
DISCUSSION
This multicenter RCT showed no differences in OS between the conventional and mesenteric approaches during PD for PDAC.
One aim of the mesenteric approach during PD is to reduce congestion of the pancreatic head by early dividing of the IPDA, which results in reduced intraoperative blood loss.11–13,20 However, in this trial, intraoperative blood loss volume was higher in the mesenteric group than in the conventional group in ITT analysis. The possible reason might include that some institutions had higher blood loss during the learning curve of the mesenteric approach, which might have some influence on other outcomes, including OS, although only high-volume centers were included in this trial. Furthermore, the mesenteric group had a longer operative time than the conventional group. Thus, the results of this trial did not demonstrate surgical benefits from the mesenteric approach compared with the conventional approach.
There was no difference in the postoperative complication rate between the conventional and mesenteric groups, including the incidence of severe diarrhea. In this trial, PDAC with SMA abutment was not included as a subject; therefore, the SMA plexus was preserved circumferentially, which, in theory, should decrease the incidence of diarrhea. The frequency of diarrhea in the mesenteric group decreased at 6 months (3% vs. 1%; P=0.198), 1 year (2% vs. 0%; P=0.1), and 2 years (0% vs. 1%; P=0.999) postoperatively, showing no difference from the conventional group. Furthermore, there was no difference between the conventional and mesenteric groups regarding the introduction and completion rates of postoperative adjuvant therapy, indicating that the mesenteric approach might have a similar oncological issue compared the conventional approach.
The other aim of the mesenteric approach is to increase R0 rates by complete clearance of the connective tissues around the SMA, the most frequent positive margin sites for PDAC.1–5,21 In this trial, the number of harvested lymph nodes was higher in the mesenteric group than in the conventional group, which might indicate that the mesenteric approach provides more thorough lymph node dissection around the SMA, particularly on its left and caudal sides within the mesentery. However, there was no difference in R0 rate as well as postoperative local recurrence rate between the 2 groups in this RCT. In previous studies comparing the artery-first approach and conventional approach during PD for PDAC retrospectively,7,8,20 almost all patients did not receive NAT. In this study, NAT was performed in more than half of the cases, which may have led to an increase in the R0 resection rate, and as a result, there may have been no significant difference between the conventional and mesenteric groups. In addition, to prevent local recurrence after surgery for PDAC, not only an R0 resection but also complete clearance of the TRIANGLE area—bounded by the celiac axis, SMA, and PV/SMV—as described by Hackert et al22 might be important.
One advantage of the mesenteric approach is that the spread of cancer cells through vessels is avoided during surgery based on the concept of the nontouch isolation procedure, which may help prevent distant recurrence after the operation.11,12,23 The change in CTC DNA copy number in PV collected at laparotomy and just before removal of the specimen was significantly lower in the mesenteric group than in the conventional group (−7.7 vs. 10.6 copies; P<0.001). This result could prove scientifically that the mesenteric approach prevents the spread of cancer cells during surgery through the nontouch isolation procedure compared with the conventional approach. However, we found no significant difference in not only distant metastasis after surgery (34.8% vs. 26.7%; P=0.276), including liver metastasis (22.0% vs. 17.9%; P=0.367), but also RFS between the conventional and mesenteric approaches. This suggests that in PDAC with a poor prognosis, preventing intraoperative tumor cell spillage alone is not sufficient to prevent postoperative recurrence and improve survival, and that multimodal treatments including adjuvant therapies are crucial.
In the analysis of survival based on resectable and BR-PV PDAC, the mesenteric group tended to show better survival in BR-PV PDAC compared with the conventional group; however, this difference was not statistically significant. Therefore, in this trial, the oncological benefit of the mesenteric approach could not be demonstrated for either resectable or BR-PV PDAC.
This trial had several limitations that should be considered. This study was a multicenter RCT conducted in Japan and not an international study. In this study, according to the Japanese General Rules for the Study of Pancreatic Cancer 7th ed, R0 resection was defined as no microscopic evidence of cancer cells along all margins of the resected specimen.8,9 However, in various other studies, R0 resection is defined as tumor cells 1 mm away from any margin.24,25 Therefore, it is difficult to compare the R0 resection rates of this trial with other studies. At the time of protocol development for this study, there was limited evidence regarding the impact of NAT for PDAC on survival; therefore, this study did not impose restrictions on whether NAT was administered. However, considering the possibility that NAT could affect survival,26–30 patients were stratified based on whether they received NAT during the randomization of this RCT. As a result, the rate of NAT administration was balanced between the conventional group (53%) and mesenteric group (51%), and there were no significant differences in survival outcomes between patients who received NAT and those who did not in either group. In this study, postoperative adjuvant chemotherapy was administered for 24 weeks as a general principle;31 however, the regimen was not standardized. This decision was made to prioritize the best interests of enrolled patients, as the postoperative adjuvant therapy regimens vary across institutions, and new evidence for more effective regimens might emerge during the study period.32–35 In this RCT, cases were stratified by participating institutions, minimizing bias in background factors, including adjuvant therapy regimens.
In conclusion, the mesenteric approach did not improve survival in patients with resectable or BR-PV PDAC in this RCT. However, the mesenteric approach has the potential to prevent the spread of cancer cells through vessels during PD by the nontouch isolation technique, compared with the conventional approach. Therefore, combining the mesenteric approach with more effective multimodal therapies may lead to improved survival outcomes in PDAC.
Supplementary Material
ACKNOWLEDGMENTS
The authors thank all patients involved in the study and their families. The authors also thank Ms. Mayu Hiraishi for data management in the Clinical Study Support Center, Wakayama Medical University.
MAPLE-PD TRIAL INVESTIGATORS
Itaru Endo, Department of Gastroenterological Surgery, Yokohama City University School of Medicine. 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Keiichi Okano, Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan. Hidetoshi Eguchi, Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Ken Shirabe, Department of General Surgical Science, Division of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Gunma University, 3-39-15 Showa, Maebashi, Gunma 371-8511. Keiichi Akahoshi, Department of Hepatobiliary and Pancreatic Surgery, Institute of Science Tokyo, 1-5-45 Yushima, Bunkuo-ku, Tokyo 113-8519, Japan. Masayuki Ohtsuka, Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. Susumu Eguchi, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. Shuji Suzuki, Department of Gastroenterological Surgery, Ibaraki Medical Center, Tokyo Medical University, 3-20-1 Chuo, Ami, Inashiro-gun, Ibaraki 300-0395, Japan. Masaji Tani, Department of Surgery, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan. Tatsuya Oda, Department of GI & HBP Surgery, University of Tsukuba, Tenmondai, Tsukuba, Ibaraki 305-8575, Japan. Tomohisa Yamamoto, Department of Pancreatobiliary Surgery, Kansai Medical University, 2-5-10, Shin-machi, Hirakata, Osaka 573-1010, Japan. Takahiro Akahori. Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan. Suguru Yamada, Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8560, Japan. Ippei Matsumoto, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511, Japan. Tsutomu Fujii, Department of Surgery and Science, Faculty of Medicine, Academic Assembly, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan, Takashi Kishi. Department of Digestive and General Surgery, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan.
Footnotes
This study was funded by the Japan Surgical Society Clinical Investigation Project Award.
This manuscript was previously published as a preprint via The Lancet Preprints (SSRN): https://ssrn.com/abstract=5070287.
S.H., S.S., M.S., T.S., A.N., and H.Y. conceived and designed the study. All authors contributed to the enrollment of patients and the acquisition of data. Y.K. and H.M. conducted the circulating tumor cell analysis. K.W. and T.S. contributed to the data analysis. S.H., Y.K., K.W., and H.Y. wrote the first draft of the manuscript. All authors contributed to the critical review and revision of the manuscript, and approved the final version to be submitted. All authors had access to the data, final responsibility to submit for publication, and vouch for the accuracy and completeness of the data and confirm that the trial was performed according to the protocol.
The study was founded by Japan Surgical Society Clinical Investigation Project Award.
The authors report no conflicts of interest.
Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal's website, www.annalsofsurgery.com.
Contributor Information
Seiko Hirono, Email: se-hirono@hyo-med.ac.jp.
Yuji Kitahata, Email: yuji-kh@wakayama-med.ac.jp.
Hideki Motobayashi, Email: h-moto@wakayama-med.ac.jp.
Sohei Satoi, Email: satoi@hirakata.kmu.ac.jp.
Masayuki Sho, Email: m-sho@naramed-u.ac.jp.
Hideki Takami, Email: takamihideki@med.nagoya-u.ac.jp.
Keiko Kamei, Email: keiko-kamei@med.kindai.ac.jp.
Kazuto Shibuya, Email: shibuyak@med.u-toyama.ac.jp.
Masaaki Hidaka, Email: mahidaka@med.shimane-u.ac.jp.
Kenichiro Uemura, Email: umk@hiroshima-u.ac.jp.
Kenjiro Kimura, Email: v21873r@omu.ac.jp.
Yuko Mataki, Email: mataki@m.kufm.kagoshima-u.ac.jp.
Yuichi Nagakawa, Email: naga@tokyo-med.ac.jp.
Hiromitsu Hayashi, Email: hhayasi@kumamoto-u.ac.jp.
Ryo Morimura, Email: morimura@koto.kpu-m.ac.jp.
Masafumi Nakamura, Email: mnaka@surg1.med.kyushu-u.ac.jp.
Ke Wan, Email: wane19911017@gmail.com.
Toshio Shimokawa, Email: shimokaw@wakayama-med.ac.jp.
Akimasa Nakao, Email: akimasa.nakao@jr-central.co.jp.
Hiroki Yamaue, Email: pancreas56yama@gmail.com.
REFERENCES
- 1. Strobel O, Hank T, Hinz U, et al. Pancreatic cancer surgery: the new R-status counts. Ann Surg. 2017;265:565–73. [DOI] [PubMed] [Google Scholar]
- 2. Nitschke P, Volk A, Welsch T, et al. Impact of intraoperative re-resection to achieve R0 status on survival in patients with pancreatic cancer. A single-center experience with 483 patients. Ann Surg. 2017;265:1219–1225. [DOI] [PubMed] [Google Scholar]
- 3. Delpero JR, Jeune F, Bachellier P, et al. Prognostic value of resection margin involvement after pancreaticoduodenectomy for ductal adenocarcinoma. Updates from a French prospective multicenter study. Ann Surg. 2017;266:787–796. [DOI] [PubMed] [Google Scholar]
- 4. Demir IE, Jager C, Schlitter AM, et al. R0 versus R1 resection matters after pancreaticoduodenectomy, and less after distal or total pancreatectomy for pancreatic cancer. Ann Surg. 2018;268:1058–1068. [DOI] [PubMed] [Google Scholar]
- 5. Büchler MW, Werner J, Weitz J. R0 in pancreatic cancer surgery: surgery, pathology, biology, or definition matters? Ann Surg. 2010;251:1011–1012. [DOI] [PubMed] [Google Scholar]
- 6. Sanjay P, Takaori K, Govil S, et al. ‘Artery-first’ approaches to pancreatoduodenectomy. Br J Surg. 2012;99:1027–1035. [DOI] [PubMed] [Google Scholar]
- 7. Ironside N, Barreto SG, Loveday B, et al. Meta-analysis of an artery-first approach versus standard pancreatoduodenectomy on perioperative outcomes and survival. Br J Surg. 2018;105:628–36. [DOI] [PubMed] [Google Scholar]
- 8. Ishida M, Fujii T, Kishiwada M, et al. Japanese classification of pancreatic carcinoma by the Japan Pancreas Society: Eighth edition. J Hepatobiliary Pancreat Sci. 2024;31:755–768. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Japanese Pancreas Society . General Rules for the Study of Pancreatic Cancer. 7th ed. Kanahara; 2016. [Google Scholar]
- 10. Weitz J, Rahbari N, Koch M, et al. The “artery-first” approach for resection of pancreatic head cancer. J Am Coll Surg. 2010;210:e1–e4. [DOI] [PubMed] [Google Scholar]
- 11. Nakao A, Takagi H. Isolated pancreatectomy for pancreatic head carcinoma using catheter bypass of the portal vein. Hepatogastroenterology. 1993;40:426–29. [PubMed] [Google Scholar]
- 12. Nakao A. The mesenteric approach in pancreatoduodenectomy. Dig Surg. 2016;33:308–313. [DOI] [PubMed] [Google Scholar]
- 13. Hirono S, Yamaue H. Tips and tricks of the surgical technique for borderline resectable pancreatic cancer: mesenteric approach and modified distal pancreatectomy with en-bloc celiac axis resection. J Hepatobiliary Pancreat Sci. 2015;22:e4–e7. [DOI] [PubMed] [Google Scholar]
- 14. Hirono S, Kawai M, Okada KI, et al. MAPLE-PD trial (Mesenteric Approach vs. Conventional Approach for Pancreatic Cancer during Pancreaticoduodenectomy): study protocol for a multicenter randomized controlled trial of 354 patients with pancreatic ductal adenocarcinoma. Trials. 2018;19:613. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. National Comprehensive Cancer Network . NCCN practice guideline for pancreatic cancer, version 3. 2017. Accessed May 4, 2025. hwww.nccn.org/patients
- 16. Bassi C, Marchegiani G, Dervenis C, et al. The 2016 update of the International Study Group (ISGPS) definition and grading of postoperative pancreatic fistula: 11 years after. Surgery. 2017;161:584–91. [DOI] [PubMed] [Google Scholar]
- 17. Wente MN, Bassi C, Dervenis C, et al. Delayed gastric emptying (DGE) after pancreatic surgery: a suggested definition by the International Study Group of Pancreatic Surgery (ISGPS). Surgery. 2007;142:761–68. [DOI] [PubMed] [Google Scholar]
- 18. Wente MN, Veit JA, Bassi C, et al. Postpancreatectomy hemorrhage (PPH): an International Study group of Pancreatic Surgery (ISGPS) definition. Surgery. 2017;142:20–25. [DOI] [PubMed] [Google Scholar]
- 19. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240:205–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Hirono S, Kawai M, Okada K, et al. Mesenteric approach during pancreaticoduodenectomy for pancreatic ductal adenocarcinoma. Ann Gastroenterol Surg. 2017;1:208–18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Sabater L, Cugat E, Serrablo A, et al. Does the artery-first approach improve the rate of R0 resection in pancreatoduodenectomy? A multicenter, randomized, controlled trial. Ann Surg. 2019;270:738–46. [DOI] [PubMed] [Google Scholar]
- 22. Hackert T, Stroble O, Michalski CW, et al. The TRIANGLE operation – radical surgery after neoadjuvant treatment for advanced pancreatic cancer: a single arm observation study. HPB. 2017;19:1001–1007. [DOI] [PubMed] [Google Scholar]
- 23. Gall TMH, Jacob J, Frampton AE, et al. Reduced dissemination of circulating tumor cells with no-touch isolation surgical technique in patients with pancreatic cancer. JAMA Surg. 2014;149:482–85. [DOI] [PubMed] [Google Scholar]
- 24. Campbell F, Cairn A, Duthie F, et al. The Royal College of Pathologists, Dataset for histopathological reporting of carcinomas of the pancreas, ampulla of Vater and common bile duct. 2019. Accessed August 22, 2025. https://www.rcpath.org/static/34910231-c106-4629-a2de9e9ae6f87ac1/G091‑Dataset‑for‑histopathological‑reporting‑of‑carcinomas‑of‑the‑pancreas‑ampulla‑of‑Vater‑and‑common‑bile‑duct.pdf
- 25. Hank T, Hinz U, Tarantino I, et al. Validation of at least 1 mm as cut-off for resection margins for pancreatic adenocarcinoma of the body and tail. Br J Surg. 2018;105:1171–1181. [DOI] [PubMed] [Google Scholar]
- 26. Jang JY, Han Y, Lee H, et al. Oncological benefits of neoadjuvant chemoradiation with gemcitabine versus upfront surgery in patients with borderline resectable pancreatic cancer: a retrospective, randomized, open-lable, multicenter phase 2/3 trial. Ann Surg. 2018;268:215–222. [DOI] [PubMed] [Google Scholar]
- 27. Versteijne E, van Dam JL, Suker M, et al. Neoadjuvant chemoradiotherapy versus upfront surgery for resectable and borderline resectable pancreatic cancer: long-term results of the Dutch randomized PREOPANC Trial. J Clin Oncol. 2022;40:1220–1230. [DOI] [PubMed] [Google Scholar]
- 28. Servin-Rojas M, Ven Fong Z, Castillo CF, et al. Lymph node yield is associated with improved overall survival and increased time to recurrence in node-negative pancreatic ductal adenocarcinoma following neoadjuvant therapy. Ann Surg. 2024. doi: 10.1097/SLA.0000000000006432 [DOI] [PubMed] [Google Scholar]
- 29. Seufferlein T, Uhl W, Kornmann M, et al. Perioperative or only adjuvant gemcitabine plus nab-paclitaxel for resectable pancreatic cancer (NEONAX)-a randomized phase II trial of the AIO pancreatic cancer group. Ann Oncol. 2023;34:91–100. [DOI] [PubMed] [Google Scholar]
- 30. Unno M, Motoi F, Matsuyama Y, et al. Neoadjuvant chemotherapy with gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer: results of the randomized phase II/III Prep-02/JSAP05 trial. Ann Surg. 2025. doi: 10.1097/SLA.0000000000006730 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Uesaka K, Boku N, Fukutomi A, et al. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomized, non-inferiority trial (JASPAC 01). Lancet. 2016;388:248–57. [DOI] [PubMed] [Google Scholar]
- 32. Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med. 2018;379:2395–2406. [DOI] [PubMed] [Google Scholar]
- 33. Ghaneh P, Kleeff J, Halloran CM, et al. The impact of positive resection margins on survival and recurrence following resection and adjuvant chemotherapy for pancreatic ductal adenocarcinoma. Ann Surg. 2019;269:520–529. [DOI] [PubMed] [Google Scholar]
- 34. Neoptolemos JP, Palmer DH, Ghaneh P, et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017;389:1011–1024. [DOI] [PubMed] [Google Scholar]
- 35. Conroy T, Castan F, Lopez A, et al. Five-year outcomes of FOLFIRINOX vs gemcitabine as adjuvant therapy for pancreatic cancer: a randomized clinical trial. JAMA Oncol. 2022;8:1571–1578. [DOI] [PMC free article] [PubMed] [Google Scholar]