ICG-Fluorescence Imaging for Margin Assessment During Minimally Invasive Colorectal Liver Metastasis Resection.

Importance: Unintended tumor-positive resection margins occur frequently during minimally invasive surgery for colorectal liver metastases and potentially negatively influence oncologic outcomes. Objective: To assess whether indocyanine green (ICG)-fluorescence-guided surgery is associated with achieving a higher radical resection rate in minimally invasive colorectal liver metastasis surgery and to assess the accuracy of ICG fluorescence for predicting the resection margin status. Design, Setting, and Participants: The MIMIC (Minimally Invasive, Indocyanine-Guided Metastasectomy in Patients With Colorectal Liver Metastases) trial was designed as a prospective single-arm multicenter cohort study in 8 Dutch liver surgery centers. Patients were scheduled to undergo minimally invasive (laparoscopic or robot-assisted) resections of colorectal liver metastases between September 1, 2018, and June 30, 2021. Exposures: All patients received a single intravenous bolus of 10 mg of ICG 24 hours prior to surgery. During surgery, ICG-fluorescence imaging was used as an adjunct to ultrasonography and regular laparoscopy to guide and assess the resection margin in real time. The ICG-fluorescence imaging was performed during and after liver parenchymal transection to enable real-time assessment of the tumor margin. Absence of ICG fluorescence was favorable both during transection and in the tumor bed directly after resection. Main Outcomes and Measures: The primary outcome measure was the radical (R0) resection rate, defined by the percentage of colorectal liver metastases resected with at least a 1 mm distance between the tumor and resection plane. Secondary outcomes were the accuracy of ICG fluorescence in detecting margin-positive (R1; <1 mm margin) resections and the change in surgical management. Results: In total, 225 patients were enrolled, of whom 201 (116 [57.7%] male; median age, 65 [IQR, 57-72] years) with 316 histologically proven colorectal liver metastases were included in the final analysis. The overall R0 resection rate was 92.4%. Re-resection of ICG-fluorescent tissue in the resection cavity was associated with a 5.0% increase in the R0 percentage (from 87.4% to 92.4%; P < .001). The sensitivity and specificity for real-time resection margin assessment were 60% and 90%, respectively (area under the receiver operating characteristic curve, 0.751; 95% CI, 0.668-0.833), with a positive predictive value of 54% and a negative predictive value of 92%. After training and proctoring of the first procedures, participating centers that were new to the technique had a comparable false-positive rate for predicting R1 resections during the first 10 procedures (odds ratio, 1.36; 95% CI, 0.44-4.24). The ICG-fluorescence imaging was associated with changes in intraoperative surgical management in 56 (27.9%) of the patients. Conclusions and Relevance: In this multicenter prospective cohort study, ICG-fluorescence imaging was associated with an increased rate of tumor margin-negative resection and changes in surgical management in more than one-quarter of the patients. The absence of ICG fluorescence during liver parenchymal transection predicted an R0 resection with 92% accuracy. These results suggest that use of ICG fluorescence may provide real-time feedback of the tumor margin and a higher rate of complete oncologic resection.

Robot-assisted versus laparoscopic pancreatoduodenectomy: a pan-European multicenter propensity-matched study.

BACKGROUND: The use of robot-assisted and laparoscopic pancreatoduodenectomy is increasing, yet large adjusted analyses that can be generalized internationally are lacking. This study aimed to compare outcomes after robot-assisted pancreatoduodenectomy and laparoscopic pancreatoduodenectomy in a pan-European cohort. METHODS: An international multicenter retrospective study including patients after robot-assisted pancreatoduodenectomy and laparoscopic pancreatoduodenectomy from 50 centers in 12 European countries (2009-2020). Propensity score matching was performed in a 1:1 ratio. The primary outcome was major morbidity (Clavien-Dindo ≥III). RESULTS: Among 2,082 patients undergoing minimally invasive pancreatoduodenectomy, 1,006 underwent robot-assisted pancreatoduodenectomy and 1,076 laparoscopic pancreatoduodenectomy. After matching 812 versus 812 patients, the rates of major morbidity (31.9% vs 29.6%; P = .347) and 30-day/in-hospital mortality (4.3% vs 4.6%; P = .904) did not differ significantly between robot-assisted pancreatoduodenectomy and laparoscopic pancreatoduodenectomy, respectively. Robot-assisted pancreatoduodenectomy was associated with a lower conversion rate (6.7% vs 18.0%; P < .001) and higher lymph node retrieval (16 vs 14; P = .003). Laparoscopic pancreatoduodenectomy was associated with shorter operation time (446 minutes versus 400 minutes; P < .001), and lower rates of postoperative pancreatic fistula grade B/C (19.0% vs 11.7%; P < .001), delayed gastric emptying grade B/C (21.4% vs 7.4%; P < .001), and a higher R0-resection rate (73.2% vs 84.4%; P < .001). CONCLUSION: This European multicenter study found no differences in overall major morbidity and 30-day/in-hospital mortality after robot-assisted pancreatoduodenectomy compared with laparoscopic pancreatoduodenectomy. Further, laparoscopic pancreatoduodenectomy was associated with a lower rate of postoperative pancreatic fistula, delayed gastric emptying, wound infection, shorter length of stay, and a higher R0 resection rate than robot-assisted pancreatoduodenectomy. In contrast, robot-assisted pancreatoduodenectomy was associated with a lower conversion rate and a higher number of retrieved lymph nodes as compared with laparoscopic pancreatoduodenectomy.

Preoperative chemoradiotherapy but not chemotherapy is associated with reduced risk of postoperative pancreatic fistula after pancreatoduodenectomy for pancreatic ductal adenocarcinoma: a nationwide analysis.

BACKGROUND: Postoperative pancreatic fistula remains the leading cause of significant morbidity after pancreatoduodenectomy for pancreatic ductal adenocarcinoma. Preoperative chemoradiotherapy has been described to reduce the risk of postoperative pancreatic fistula, but randomized trials on neoadjuvant treatment in pancreatic ductal adenocarcinoma focus increasingly on preoperative chemotherapy rather than preoperative chemoradiotherapy. This study aimed to investigate the impact of preoperative chemotherapy and preoperative chemoradiotherapy on postoperative pancreatic fistula and other pancreatic-specific surgery related complications on a nationwide level. METHODS: All patients after pancreatoduodenectomy for pancreatic ductal adenocarcinoma were included in the mandatory nationwide prospective Dutch Pancreatic Cancer Audit (2014-2020). Baseline and treatment characteristics were compared between immediate surgery, preoperative chemotherapy, and preoperative chemoradiotherapy. The relationship between preoperative chemotherapy, chemoradiotherapy, and clinically relevant postoperative pancreatic fistula (International Study Group of Pancreatic Surgery grade B/C) was investigated using multivariable logistic regression analyses. RESULTS: Overall, 2,019 patients after pancreatoduodenectomy for pancreatic ductal adenocarcinoma were included, of whom 1,678 underwent immediate surgery (83.1%), 192 (9.5%) received preoperative chemotherapy, and 149 (7.4%) received preoperative chemoradiotherapy. Postoperative pancreatic fistula occurred in 8.3% of patients after immediate surgery, 4.2% after preoperative chemotherapy, and 2.0% after preoperative chemoradiotherapy (P = .004). In multivariable analysis, the use of preoperative chemoradiotherapy was associated with reduced risk of postoperative pancreatic fistula (odds ratio, 0.21; 95% confidence interval, 0.03-0.69; P = .033) compared with immediate surgery, whereas preoperative chemotherapy was not (odds ratio, 0.59; 95% confidence interval, 0.25-1.25; P = .199). Intraoperatively hard, or fibrotic pancreatic texture was most frequently observed after preoperative chemoradiotherapy (53% immediate surgery, 62% preoperative chemotherapy, 77% preoperative chemoradiotherapy, P < .001). CONCLUSION: This nationwide analysis demonstrated that in patients undergoing pancreatoduodenectomy for pancreatic ductal adenocarcinoma, only preoperative chemoradiotherapy, but not preoperative chemotherapy, was associated with a reduced risk of postoperative pancreatic fistula.

Prophylactic abdominal drainage after distal pancreatectomy (PANDORINA): an international, multicentre, open-label, randomised controlled, non-inferiority trial.

BACKGROUND: Prophylactic passive abdominal drainage is standard practice after distal pancreatectomy. This approach aims to mitigate the consequences of postoperative pancreatic fistula (POPF) but its added value, especially in patients at low risk of POPF, is currently being debated. We aimed to assess the non-inferiority of a no-drain policy in patients after distal pancreatectomy. METHODS: In this international, multicentre, open-label, randomised controlled, non-inferiority trial, we recruited patients aged 18 years or older undergoing open or minimally invasive elective distal pancreatectomy for all indications in 12 centres in the Netherlands and Italy. We excluded patients with an American Society of Anesthesiology (ASA) physical status of 4-5 or WHO performance status of 3-4, added by amendment following the death of a patient with ASA 4 due to a pre-existing cardiac condition. Patients were randomly assigned (1:1) intraoperatively by permuted blocks (size four to eight) to either no drain or prophylactic passive drain placement, stratified by annual centre volume (<40 or ≥40 distal pancreatectomies) and low risk or high risk of grade B or C POPF. High-risk was defined as a pancreatic duct of more than 3 mm in diameter, a pancreatic thickness at the neck of more than 19 mm, or both, based on the Distal Pancreatectomy Fistula Risk Score. Other patients were considered low-risk. The primary outcome was the rate of major morbidity (Clavien-Dindo score ≥III), and the most relevant secondary outcome was grade B or C POPF, grading per the International Study Group for Pancreatic Surgery. Outcomes were assessed up to 90 days postoperatively and analysed in the intention-to-treat population and per-protocol population, which only included patients who received the allocated treatment. A prespecified non-inferiority margin of 8% was compared with the upper limit of the two-sided 95% CI (Wald) of unadjusted risk difference to assess non-inferiority. This trial is closed and registered in the Netherlands Trial Registry, NL9116. FINDINGS: Between Oct 3, 2020, and April 28, 2023, 376 patients were screened for eligibility and 282 patients were randomly assigned to the no-drain group (n=138; 75 [54%] women and 63 [46%] men) or the drain group (n=144; 73 [51%] women and 71 [49%] men). Seven patients in the no-drain group received a drain intraoperatively; consequently, the per-protocol population included 131 patients in the no-drain group and 144 patients in the drain group. The rate of major morbidity was non-inferior in the no-drain group compared with the drain group in the intention-to-treat analysis (21 [15%] vs 29 [20%]; risk difference -4·9 percentage points [95% CI -13·8 to 4·0]; pnon-inferiority=0·0022) and the per-protocol analysis (21 [16%] vs 29 [20%]; risk difference -4·1 percentage points [-13·2 to 5·0]; pnon-inferiority=0·0045). Grade B or C POPF was observed in 16 (12%) patients in the no-drain group and in 39 (27%) patients in the drain group (risk difference -15·5 percentage points [95% CI -24·5 to -6·5]; pnon-inferiority<0·0001) in the intention-to-treat analysis. Three patients in the no-drain group died within 90 days; the cause of death in two was not considered related to the trial. The third death was a patient with an ASA score of 4 who died after sepsis and a watershed cerebral infarction at second admission, leading to multiple organ failure. No patients in the drain group died within 90 days. INTERPRETATION: A no-drain policy is safe in terms of major morbidity and reduced the detection of grade B or C POPF, and should be the new standard approach in eligible patients undergoing distal pancreatectomy. FUNDING: Ethicon UK (Johnson & Johnson Medical, Edinburgh, UK).

Minimally invasive robot-assisted and laparoscopic distal pancreatectomy in a pan-European registry a retrospective cohort study.

BACKGROUND: International guidelines recommend monitoring of the use and outcome of minimally invasive pancreatic surgery (MIPS). However, data from prospective international audits on minimally invasive distal pancreatectomy (MIDP) are lacking. This study examined the use and outcome of robot-assisted (RDP) and laparoscopic (LDP) distal pancreatectomy in the E-MIPS registry. MATERIALS AND METHODS: Post-hoc analysis in a prospective audit on MIPS, including consecutive patients undergoing MIDP in 83 centers from 19 European countries (01-01-2019/31-12-2021). Primary outcomes included intraoperative events (grade 1: excessive blood loss, grade 2: conversion/change in operation, grade 3: intraoperative death), major morbidity, and in-hospital/30-day mortality. Multivariable logistic regression analyses identified high-risk groups for intraoperative events. RDP and LDP were compared in the total cohort and in high-risk groups. RESULTS: Overall, 1672 patients undergoing MIDP were included; 606 (36.2%) RDP and 1066 (63.8%) LDP. The annual use of RDP increased from 30.5% to 42.6% (P<0.001). RDP was associated with fewer grade 2 intraoperative events compared to LDP (9.6% vs. 16.8%, P<0.001), with longer operating time (238 vs. 201 minutes,P<0.001). No significant differences were observed between RDP and LDP regarding major morbidity (23.4% vs. 25.9%, P=0.264) and in-hospital/30-day mortality (0.3% vs. 0.8%, P=0.344). Three high-risk groups were identified; BMI>25 kg/m2, previous abdominal surgery, and vascular involvement. In each group, RDP was associated with fewer conversions and longer operative times. CONCLUSION: This European registry-based study demonstrated favorable outcomes for MIDP, with mortality rates below 1%. LDP remains the predominant approach, whereas the use of RDP is increasing. RDP was associated with less conversions and longer operative time, including in high-risk subgroups. Future randomized trials should confirm these findings and assess cost differences.

Early experience with robotic pancreatoduodenectomy versus open pancreatoduodenectomy: nationwide propensity-score-matched analysis.

BACKGROUND: Although robotic pancreatoduodenectomy has shown promising outcomes in experienced high-volume centres, it is unclear whether implementation on a nationwide scale is safe and beneficial. The aim of this study was to compare the outcomes of the early experience with robotic pancreatoduodenectomy versus open pancreatoduodenectomy in the Netherlands. METHODS: This was a nationwide retrospective cohort study of all consecutive patients who underwent robotic pancreatoduodenectomy or open pancreatoduodenectomy who were registered in the mandatory Dutch Pancreatic Cancer Audit (18 centres, 2014-2021), starting from the first robotic pancreatoduodenectomy procedure per centre. The main endpoints were major complications (Clavien-Dindo grade greater than or equal to III) and in-hospital/30-day mortality. Propensity-score matching (1 : 1) was used to minimize selection bias. RESULTS: Overall, 701 patients who underwent robotic pancreatoduodenectomy and 4447 patients who underwent open pancreatoduodenectomy were included. Among the eight centres that performed robotic pancreatoduodenectomy, the median robotic pancreatoduodenectomy experience was 86 (range 48-149), with a 7.3% conversion rate. After matching (698 robotic pancreatoduodenectomy patients versus 698 open pancreatoduodenectomy control patients), no significant differences were found in major complications (40.3% versus 36.2% respectively; P = 0.186), in-hospital/30-day mortality (4.0% versus 3.1% respectively; P = 0.326), and postoperative pancreatic fistula grade B/C (24.9% versus 23.5% respectively; P = 0.578). Robotic pancreatoduodenectomy was associated with a longer operating time (359 min versus 301 min; P < 0.001), less intraoperative blood loss (200 ml versus 500 ml; P < 0.001), fewer wound infections (7.4% versus 12.2%; P = 0.008), and a shorter hospital stay (11 days versus 12 days; P < 0.001). Centres performing greater than or equal to 20 robotic pancreatoduodenectomies annually had a lower mortality rate (2.9% versus 7.3%; P = 0.009) and a lower conversion rate (6.3% versus 11.2%; P = 0.032). CONCLUSION: This study indicates that robotic pancreatoduodenectomy was safely implemented nationwide, without significant differences in major morbidity and mortality compared with matched open pancreatoduodenectomy patients. Randomized trials should be carried out to verify these findings and confirm the observed benefits of robotic pancreatoduodenectomy versus open pancreatoduodenectomy.

Implementation and outcome of minimally invasive pancreatoduodenectomy in Europe: a registry-based retrospective study - a critical appraisal of the first 3 years of the E-MIPS registry.

BACKGROUND: International multicenter audit-based studies focusing on the outcome of minimally invasive pancreatoduodenectomy (MIPD) are lacking. The European Registry for Minimally Invasive Pancreatic Surgery (E-MIPS) is the E-AHPBA endorsed registry aimed to monitor and safeguard the introduction of MIPD in Europe. MATERIALS AND METHODS: A planned analysis of outcomes among consecutive patients after MIPD from 45 centers in 14 European countries in the E-MIPS registry (2019-2021). The main outcomes of interest were major morbidity (Clavien-Dindo grade ≥3) and 30-day/in-hospital mortality. RESULTS: Overall, 1336 patients after MIPD were included [835 robot-assisted (R-MIPD) and 501 laparoscopic MIPD (L-MIPD)]. Overall, 20 centers performed R-MIPD, 15 centers L-MIPD, and 10 centers both. Between 2019 and 2021, the rate of centers performing L-MIPD decreased from 46.9 to 25%, whereas for R-MIPD this increased from 46.9 to 65.6%. Overall, the rate of major morbidity was 41.2%, 30-day/in-hospital mortality 4.5%, conversion rate 9.7%, postoperative pancreatic fistula grade B/C 22.7%, and postpancreatectomy hemorrhage grade B/C 10.8%. Median length of hospital stay was 12 days (IQR 8-21). A lower rate of major morbidity, postoperative pancreatic fistula grade B/C, postpancreatectomy hemorrhage grade B/C, delayed gastric emptying grade B/C, percutaneous drainage, and readmission was found after L-MIPD. The number of centers meeting the Miami Guidelines volume cut-off of ≥20 MIPDs annually increased from 9 (28.1%) in 2019 to 12 (37.5%) in 2021 ( P =0.424). Rates of conversion (7.4 vs. 14.8% P <0.001) and reoperation (8.9 vs. 15.1% P <0.001) were lower in centers, which fulfilled the Miami volume cut-off. CONCLUSION: During the first 3 years of the pan-European E-MIPS registry, morbidity and mortality rates after MIPD were acceptable. A shift is ongoing from L-MIPD to R-MIPD. Variations in outcomes between the two minimally invasive approaches and the impact of the volume cut-off should be further evaluated over a longer time period.

Nationwide use and Outcome of Minimally Invasive Distal Pancreatectomy in IDEAL Stage IV following a Training Program and Randomized Trial.

OBJECTIVE: To assess the nationwide long-term uptake and outcomes of minimally invasive distal pancreatectomy (MIDP) after a nationwide training program and randomized trial. BACKGROUND: Two randomized trials demonstrated the superiority of MIDP over open distal pancreatectomy (ODP) in terms of functional recovery and hospital stay. Data on implementation of MIDP on a nationwide level are lacking. METHODS: Nationwide audit-based study including consecutive patients after MIDP and ODP in 16 centers in the Dutch Pancreatic Cancer Audit (2014 to 2021). The cohort was divided into three periods: early implementation, during the LEOPARD randomized trial, and late implementation. Primary endpoints were MIDP implementation rate and textbook outcome. RESULTS: Overall, 1496 patients were included with 848 MIDP (56.5%) and 648 ODP (43.5%). From the early to the late implementation period, the use of MIDP increased from 48.6% to 63.0% and of robotic MIDP from 5.5% to 29.7% ( P <0.001). The overall use of MIDP (45% to 75%) and robotic MIDP (1% to 84%) varied widely between centers ( P <0.001). In the late implementation period, 5/16 centers performed >75% of procedures as MIDP. After MIDP, in-hospital mortality and textbook outcome remained stable over time. In the late implementation period, ODP was more often performed in ASA score III-IV (24.9% vs. 35.7%, P =0.001), pancreatic cancer (24.2% vs. 45.9%, P <0.001), vascular involvement (4.6% vs. 21.9%, P <0.001), and multivisceral involvement (10.5% vs. 25.3%, P <0.001). After MIDP, shorter hospital stay (median 7 vs. 8 d, P <0.001) and less blood loss (median 150 vs. 500 mL, P <0.001), but more grade B/C postoperative pancreatic fistula (24.4% vs. 17.2%, P =0.008) occurred as compared to ODP. CONCLUSION: A sustained nationwide implementation of MIDP after a successful training program and randomized trial was obtained with satisfactory outcomes. Future studies should assess the considerable variation in the use of MIDP between centers and, especially, robotic MIDP.

MRI in addition to CT in patients scheduled for local therapy of colorectal liver metastases (CAMINO): an international, multicentre, prospective, diagnostic accuracy trial.

BACKGROUND: Guidelines are inconclusive on whether contrast-enhanced MRI using gadoxetic acid and diffusion-weighted imaging should be added routinely to CT in the investigation of patients with colorectal liver metastases who are scheduled for curative liver resection or thermal ablation, or both. Although contrast-enhanced MRI is reportedly superior than contrast-enhanced CT in the detection and characterisation of colorectal liver metastases, its effect on clinical patient management is unknown. We aimed to assess the clinical effect of an additional liver contrast-enhanced MRI on local treatment plan in patients with colorectal liver metastases amenable to local treatment, based on contrast-enhanced CT. METHODS: We did an international, multicentre, prospective, incremental diagnostic accuracy trial in 14 liver surgery centres in the Netherlands, Belgium, Norway, and Italy. Participants were aged 18 years or older with histological proof of colorectal cancer, a WHO performance status score of 0-4, and primary or recurrent colorectal liver metastases, who were scheduled for local therapy based on contrast-enhanced CT. All patients had contrast-enhanced CT and liver contrast-enhanced MRI including diffusion-weighted imaging and gadoxetic acid as a contrast agent before undergoing local therapy. The primary outcome was change in the local clinical treatment plan (decided by the individual clinics) on the basis of liver contrast-enhanced MRI findings, analysed in the intention-to-image population. The minimal clinically important difference in the proportion of patients who would have change in their local treatment plan due to an additional liver contrast-enhanced MRI was 10%. This study is closed and registered in the Netherlands Trial Register, NL8039. FINDINGS: Between Dec 17, 2019, and July 31, 2021, 325 patients with colorectal liver metastases were assessed for eligibility. 298 patients were enrolled and included in the intention-to-treat population, including 177 males (59%) and 121 females (41%) with planned local therapy based on contrast-enhanced CT. A change in the local treatment plan based on liver contrast-enhanced MRI findings was observed in 92 (31%; 95% CI 26-36) of 298 patients. Changes were made for 40 patients (13%) requiring more extensive local therapy, 11 patients (4%) requiring less extensive local therapy, and 34 patients (11%) in whom the indication for curative-intent local therapy was revoked, including 26 patients (9%) with too extensive disease and eight patients (3%) with benign lesions on liver contrast-enhanced MRI (confirmed by a median follow-up of 21·0 months [IQR 17·5-24·0]). INTERPRETATION: Liver contrast-enhanced MRI should be considered in all patients scheduled for local treatment for colorectal liver metastases on the basis of contrast-enhanced CT imaging. FUNDING: The Dutch Cancer Society and Bayer AG - Pharmaceuticals.

Nationwide Use and Outcome of Surgery for Locally Advanced Pancreatic Cancer Following Induction Chemotherapy.

BACKGROUND: Several international high-volume centers have reported good outcomes after resection of locally advanced pancreatic cancer (LAPC) following chemo(radio)therapy, but it is unclear how this translates to nationwide clinical practice and outcome. This study aims to assess the nationwide use and outcome of resection of LAPC following induction chemo(radio)therapy. PATIENTS AND METHODS: A multicenter retrospective study including all patients who underwent resection for LAPC following chemo(radio)therapy in all 16 Dutch pancreatic surgery centers (2014-2020), registered in the mandatory Dutch Pancreatic Cancer Audit. LAPC is defined as arterial involvement > 90° and/or portomesenteric venous > 270° involvement or occlusion. RESULTS: Overall, 142 patients underwent resection for LAPC, of whom 34.5% met the 2022 National Comprehensive Cancer Network criteria. FOLFIRINOX was the most commonly (93.7%) used chemotherapy [median 5 cycles (IQR 4-8)]. Venous and arterial resections were performed in 51.4% and 14.8% of patients. Most resections (73.9%) were performed in high-volume centers (i.e., ≥ 60 pancreatoduodenectomies/year). Overall median volume of LAPC resections/center was 4 (IQR 1-7). In-hospital/30-day major morbidity was 37.3% and 90-day mortality was 4.2%. Median OS from diagnosis was 26 months (95% CI 23-28) and 5-year OS 18%. Surgery in high-volume centers [HR = 0.542 (95% CI 0.318-0.923)], ypN1-2 [HR = 3.141 (95% CI 1.886-5.234)], and major morbidity [HR = 2.031 (95% CI 1.272-3.244)] were associated with OS. CONCLUSIONS: Resection of LAPC following chemo(radio)therapy is infrequently performed in the Netherlands, albeit with acceptable morbidity, mortality, and OS. Given these findings, a structured nationwide approach involving international centers of excellence would be needed to improve selection of patients with LAPC for surgical resection following induction therapy.

Nationwide Outcome after Pancreatoduodenectomy in Patients at very High Risk (ISGPS-D) for Postoperative Pancreatic Fistula.

OBJECTIVE: To assess nationwide surgical outcome after pancreatoduodenectomy (PD) in patients at very high risk for postoperative pancreatic fistula (POPF), categorized as ISGPS-D. SUMMARY BACKGROUND DATA: Morbidity and mortality after ISGPS-D PD is perceived so high that a recent randomized trial advocated prophylactic total pancreatectomy (TP) as alternative aiming to lower this risk. However, current outcomes of ISGPS-D PD remain unknown as large nationwide series are lacking. METHODS: Nationwide retrospective analysis including consecutive patients undergoing ISGPS-D PD (i.e., soft texture and pancreatic duct ≤3 mm), using the mandatory Dutch Pancreatic Cancer Audit (2014-2021). Primary outcome was in-hospital mortality and secondary outcomes included major morbidity (i.e., Clavien-Dindo grade ≥IIIa) and POPF (ISGPS grade B/C). The use of prophylactic TP to avoid POPF during the study period was assessed. RESULTS: Overall, 1402 patients were included. In-hospital mortality was 4.1% (n=57), which decreased to 3.7% (n=20/536) in the last 2 years. Major morbidity occurred in 642 patients (45.9%) and POPF in 410 (30.0%), which corresponded with failure to rescue in 8.9% (n=57/642). Patients with POPF had increased rates of major morbidity (88.0% vs. 28.3%; P<0.001) and mortality (6.3% vs. 3.5%; P=0.016), compared to patients without POPF. Among 190 patients undergoing TP, prophylactic TP to prevent POPF was performed in 4 (2.1%). CONCLUSION: This nationwide series found a 4.1% in-hospital mortality after ISGPS-D PD with 45.9% major morbidity, leaving little room for improvement through prophylactic TP. Nevertheless, given the outcomes in 30% of patients who develop POPF, future randomized trials should aim to prevent and mitigate POPF in this high-risk category.

Minimally invasive versus open pancreatoduodenectomy for pancreatic and peri-ampullary neoplasm (DIPLOMA-2): study protocol for an international multicenter patient-blinded randomized controlled trial.

BACKGROUND: Minimally invasive pancreatoduodenectomy (MIPD) aims to reduce the negative impact of surgery as compared to open pancreatoduodenectomy (OPD) and is increasingly becoming part of clinical practice for selected patients worldwide. However, the safety of MIPD remains a topic of debate and the potential shorter time to functional recovery needs to be confirmed. To guide safe implementation of MIPD, large-scale international randomized trials comparing MIPD and OPD in experienced high-volume centers are needed. We hypothesize that MIPD is non-inferior in terms of overall complications, but superior regarding time to functional recovery, as compared to OPD. METHODS/DESIGN: The DIPLOMA-2 trial is an international randomized controlled, patient-blinded, non-inferiority trial performed in 14 high-volume pancreatic centers in Europe with a minimum annual volume of 30 MIPD and 30 OPD. A total of 288 patients with an indication for elective pancreatoduodenectomy for pre-malignant and malignant disease, eligible for both open and minimally invasive approach, are randomly allocated for MIPD or OPD in a 2:1 ratio. Centers perform either laparoscopic or robot-assisted MIPD based on their surgical expertise. The primary outcome is the Comprehensive Complication Index (CCI®), measuring all complications graded according to the Clavien-Dindo classification up to 90 days after surgery. The sample size is calculated with the following assumptions: 2.5% one-sided significance level (α), 80% power (1-ß), expected difference of the mean CCI® score of 0 points between MIPD and OPD, and a non-inferiority margin of 7.5 points. The main secondary outcome is time to functional recovery, which will be analyzed for superiority. Other secondary outcomes include post-operative 90-day Fitbit™ measured activity, operative outcomes (e.g., blood loss, operative time, conversion to open surgery, surgeon-reported outcomes), oncological findings in case of malignancy (e.g., R0-resection rate, time to adjuvant treatment, survival), postoperative outcomes (e.g., clinically relevant complications), healthcare resource utilization (length of stay, readmissions, intensive care stay), quality of life, and costs. Postoperative follow-up is up to 36 months. DISCUSSION: The DIPLOMA-2 trial aims to establish the safety of MIPD as the new standard of care for this selected patient population undergoing pancreatoduodenectomy in high-volume centers, ultimately aiming for superior patient recovery. TRIAL REGISTRATION: ISRCTN27483786. Registered on August 2, 2023.

Endoscopic ultrasonography-guided gastroenterostomy versus surgical gastrojejunostomy for palliation of malignant gastric outlet obstruction (ENDURO): study protocol for a randomized controlled trial.

BACKGROUND: Malignant gastric outlet obstruction (GOO) is a debilitating condition that frequently occurs in patients with malignancies of the distal stomach and (peri)ampullary region. The standard palliative treatment for patients with a reasonable life expectancy and adequate performance status is a laparoscopic surgical gastrojejunostomy (SGJ). Recently, endoscopic ultrasound-guided gastroenterostomy (EUS-GE) emerged as a promising alternative to the surgical approach. The present study aims to compare these treatment modalities in terms of efficacy, safety, and costs. METHODS: The ENDURO-study is a multicentre, open-label, parallel-group randomized controlled trial. In total, ninety-six patients with gastric outlet obstruction caused by an irresectable or metastasized malignancy will be 1:1 randomized to either SGJ or EUS-GE. The primary endpoint is time to tolerate at least soft solids. The co-primary endpoint is the proportion of patients with persisting or recurring symptoms of gastric outlet obstruction for which a reintervention is required. Secondary endpoints are technical and clinical success, quality of life, gastroenterostomy dysfunction, reinterventions, time to reintervention, adverse events, quality of life, time to start chemotherapy, length of hospital stay, readmissions, weight, survival, and costs. DISCUSSION: The ENDURO-study assesses whether EUS-GE, as compared to SGJ, results in a faster resumption of solid oral intake and is non-inferior regarding reinterventions for persistent or recurrent obstructive symptoms in patients with malignant GOO. This trial aims to guide future treatment strategies and to improve quality of life in a palliative setting. TRIAL REGISTRATION: International Clinical Trials Registry Platform (ICTRP): NL9592. Registered on 07 July 2021.

Minimally invasive versus open distal pancreatectomy for resectable pancreatic cancer (DIPLOMA): an international randomised non-inferiority trial.

Background: The oncological safety of minimally invasive surgery has been questioned for several abdominal cancers. Concerns also exist regarding the use of minimally invasive distal pancreatectomy (MIDP) in patients with resectable pancreatic cancer as randomised trials are lacking. Methods: In this international randomised non-inferiority trial, we recruited adults with resectable pancreatic cancer from 35 centres in 12 countries. Patients were randomly assigned to either MIDP (laparoscopic or robotic) or open distal pancreatectomy (ODP). Both patients and pathologists were blinded to the assigned approach. Primary endpoint was radical resection (R0, ≥1 mm free margin) in patients who had ultimately undergone resection. Analyses for the primary endpoint were by modified intention-to-treat, excluding patients with missing data on primary endpoint. The pre-defined non-inferiority margin of -7% was compared with the lower limit of the two-sided 90% confidence interval (CI) of absolute difference in the primary endpoint. This trial is registered with the ISRCTN registry (ISRCTN44897265). Findings: Between May 8, 2018 and May 7, 2021, 258 patients were randomly assigned to MIDP (131 patients) or ODP (127 patients). Modified intention-to-treat analysis included 114 patients in the MIDP group and 110 patients in the ODP group. An R0 resection occurred in 83 (73%) patients in the MIDP group and in 76 (69%) patients in the ODP group (difference 3.7%, 90% CI -6.2 to 13.6%; pnon-inferiority = 0.039). Median lymph node yield was comparable (22.0 [16.0-30.0] vs 23.0 [14.0-32.0] nodes, p = 0.86), as was the rate of intraperitoneal recurrence (41% vs 38%, p = 0.45). Median follow-up was 23.5 (interquartile range 17.0-30.0) months. Other postoperative outcomes were comparable, including median time to functional recovery (5 [95% CI 4.5-5.5] vs 5 [95% CI 4.7-5.3] days; p = 0.22) and overall survival (HR 0.99, 95% CI 0.67-1.46, p = 0.94). Serious adverse events were reported in 23 (18%) of 131 patients in the MIDP group vs 28 (22%) of 127 patients in the ODP group. Interpretation: This trial provides evidence on the non-inferiority of MIDP compared to ODP regarding radical resection rates in patients with resectable pancreatic cancer. The present findings support the applicability of minimally invasive surgery in patients with resectable left-sided pancreatic cancer. Funding: Medtronic Covidien AG, Johnson & Johnson Medical Limited, Dutch Gastroenterology Society.

Practice variation in venous resection during pancreatoduodenectomy for pancreatic cancer: A nationwide cohort study.

BACKGROUND: Practice variation exists in venous resection during pancreatoduodenectomy, but little is known about the potential causes and consequences as large studies are lacking. This study explores the potential causes and consequences of practice variation in venous resection during pancreatoduodenectomy for pancreatic cancer in the Netherlands. METHODS: This nationwide retrospective cohort study included patients undergoing pancreatoduodenectomy for pancreatic cancer in 18 centers from 2013 through 2017. RESULTS: Among 1,311 patients undergoing pancreatoduodenectomy, 351 (27%) had a venous resection, and the overall median annual center volume of venous resection was 4. No association was found between the center volume of pancreatoduodenectomy and the rate of venous resections, nor between patient and tumor characteristics and the rate of venous resections per center. Female sex, lower body mass index, neoadjuvant therapy, venous involvement, and stenosis on imaging were predictive for venous resection. Adjusted for these factors, 3 centers performed significantly more, and 3 centers performed significantly fewer venous resections than expected. In patients with venous resection, significantly less major morbidity (22% vs 38%) and longer overall survival (median 16 vs 12 months) were observed in centers with an above-median annual volume of venous resections (>4). CONCLUSION: Patient and tumor characteristics did not explain significant practice variation between centers in the Netherlands in venous resection during pancreatoduodenectomy for pancreatic cancer. The clinical outcomes of venous resection might be related to the volume of the procedure.

Predictive value of baseline serum carbohydrate antigen 19-9 level on treatment effect of neoadjuvant chemoradiotherapy in patients with resectable and borderline resectable pancreatic cancer in two randomized trials.

BACKGROUND: Guidelines suggest that the serum carbohydrate antigen (CA19-9) level should be used when deciding on neoadjuvant treatment in patients with resectable and borderline resectable pancreatic ductal adenocarcinoma (hereafter referred to as pancreatic cancer). In patients with resectable pancreatic cancer, neoadjuvant therapy is advised when the CA19-9 level is 'markedly elevated'. This study investigated the impact of baseline CA19-9 concentration on the treatment effect of neoadjuvant chemoradiotherapy (CRT) in patients with resectable and borderline resectable pancreatic cancers. METHODS: In this post hoc analysis, data were obtained from two RCTs that compared neoadjuvant CRT with upfront surgery in patients with resectable and borderline resectable pancreatic cancers. The effect of neoadjuvant treatment on overall survival was compared between patients with a serum CA19-9 level above or below 500 units/ml using the interaction test. RESULTS: Of 296 patients, 179 were eligible for analysis, 90 in the neoadjuvant CRT group and 89 in the upfront surgery group. Neoadjuvant CRT was associated with superior overall survival (HR 0.67, 95 per cent c.i. 0.48 to 0.94; P = 0.019). Among 127 patients (70, 9 per cent) with a low CA19-9 level, median overall survival was 23.5 months with neoadjuvant CRT and 16.3 months with upfront surgery (HR 0.63, 0.42 to 0.93). For 52 patients (29 per cent) with a high CA19-9 level, median overall survival was 15.5 months with neoadjuvant CRT and 12.9 months with upfront surgery (HR 0.82, 0.45 to 1.49). The interaction test for CA19-9 level exceeding 500 units/ml on the treatment effect of neoadjuvant CRT was not significant (P = 0.501). CONCLUSION: Baseline serum CA19-9 level defined as either high or low has prognostic value, but was not associated with the treatment effect of neoadjuvant CRT in patients with resectable and borderline resectable pancreatic cancers, in contrast with current guideline advice.

Minimum and Optimal CA19-9 Response After Two Months Induction Chemotherapy in Patients with Locally Advanced Pancreatic Cancer: A Nationwide Multicenter Study.

OBJECTIVE: This nationwide multicenter study aimed to define clinically relevant thresholds of relative serum CA19-9 response after 2 months induction chemotherapy in patients with locally advanced pancreatic cancer (LAPC). SUMMARY BACKGROUND DATA: CA19-9 is seen as leading biomarker for response evaluation in patients with LAPC, but early clinically useful cut-offs are lacking. METHODS: All consecutive patients with LAPC after 4 cycles (m)FOLFIRINOX or 2 cycles gemcitabine-nab-paclitaxel induction chemotherapy (±radiotherapy) with CA19-9 ≥5 U/mL at baseline were analyzed (2015-2019). The association of CA19-9 response with median OS (mOS) was evaluated for different CA19-9 cut-off points. Minimum and optimal CA19-9 response were established via log-rank test. Predictors for OS were analyzed, using cox regression analysis. RESULTS: Overall, 212 patients were included of whom 42 (19.8%) underwent resection. Minimum CA19-9 response demonstrating a clinically significant mOS difference (12.7 vs. 19.6 mo) was seen at ≥40% CA19-9 decrease. The optimal cut-off for CA19-9 response was ≥60% decrease (21.7 vs. 14.0 mo, P=0.021). Only for patients with elevated CA19-9 levels at baseline (n=184), CA19-9 decrease ≥60% (HR=0.59, 95%CI 0.36-0.98, P=0.042) was independently associated with prolonged OS, as were SBRT (HR=0.42, 95%CI 0.25-0.70; P=0.001), and resection (HR=0.25, 95%CI 0.14-0.46, P<0.001), and duration of chemotherapy (HR=0.75, 95%CI 0.69-0.82, P<0.001). CONCLUSION: CA19-9 decrease of ≥60% following induction chemotherapy as optimal response cut-off in patients with LAPC is an independent predictor for OS when CA19-9 is increased at baseline. Furthermore, ≥40% is the minimum cut-off demonstrating survival benefit. These cut-offs may be used when discussing treatment strategies during early response evaluation.

Survival of patients with colorectal liver metastases treated with and without preoperative chemotherapy: Nationwide propensity score-matched study.

INTRODUCTION: Routine treatment with preoperative systemic chemotherapy (CTx) in patients with colorectal liver metastases (CRLM) remains controversial due to lack of consistent evidence demonstrating associated survival benefits. This study aimed to determine the effect of preoperative CTx on overall survival (OS) compared to surgery alone and to assess hospital and oncological network variation in 5-year OS. METHODS: This was a population-based study of all patients who underwent liver resection for CRLM between 2014 and 2017 in the Netherlands. After 1:1 propensity score matching (PSM), OS was compared between patients treated with and without preoperative CTx. Hospital and oncological network variation in 5-year OS corrected for case-mix factors was calculated using an observed/expected ratio. RESULTS: Of 2820 patients included, 852 (30.2%) and 1968 (69.8%) patients were treated with preoperative CTx and surgery alone, respectively. After PSM, 537 patients remained in each group, median number of CRLM; 3 [IQR 2-4], median size of CRLM; 28 mm [IQR 18-44], synchronous CLRM (71.1%). Median follow-up was 80.8 months. Five-year OS rates after PSM for patients treated with and without preoperative chemotherapy were 40.2% versus 38.3% (log-rank P = 0.734). After stratification for low, medium, and high tumour burden based on the tumour burden score (TBS) OS was similar for preoperative chemotherapy vs. surgery alone (log-rank P = 0.486, P = 0.914, and P = 0.744, respectively). After correction for non-modifiable patient and tumour characteristics, no relevant hospital or oncological network variation in five-year OS was observed. CONCLUSION: In patients eligible for surgical resection, preoperative chemotherapy does not provide an overall survival benefit compared to surgery alone.

The Feasibility, Proficiency, and Mastery Learning Curves in 635 Robotic Pancreatoduodenectomies Following a Multicenter Training Program: "Standing on the Shoulders of Giants".

OBJECTIVE: To assess the feasibility, proficiency, and mastery learning curves for robotic pancreatoduodenectomy (RPD) in "second-generation" RPD centers following a multicenter training program adhering to the IDEAL framework. BACKGROUND: The long learning curves for RPD reported from "pioneering" expert centers may discourage centers interested in starting an RPD program. However, the feasibility, proficiency, and mastery learning curves may be shorter in "second-generation" centers that participated in dedicated RPD training programs, although data are lacking. We report on the learning curves for RPD in "second-generation" centers trained in a dedicated nationwide program. METHODS: Post hoc analysis of all consecutive patients undergoing RPD in 7 centers that participated in the LAELAPS-3 training program, each with a minimum annual volume of 50 pancreatoduodenectomies, using the mandatory Dutch Pancreatic Cancer Audit (March 2016-December 2021). Cumulative sum analysis determined cutoffs for the 3 learning curves: operative time for the feasibility (1) risk-adjusted major complication (Clavien-Dindo grade ≥III) for the proficiency, (2) and textbook outcome for the mastery, (3) learning curve. Outcomes before and after the cutoffs were compared for the proficiency and mastery learning curves. A survey was used to assess changes in practice and the most valued "lessons learned." RESULTS: Overall, 635 RPD were performed by 17 trained surgeons, with a conversion rate of 6.6% (n=42). The median annual volume of RPD per center was 22.5±6.8. From 2016 to 2021, the nationwide annual use of RPD increased from 0% to 23% whereas the use of laparoscopic pancreatoduodenectomy decreased from 15% to 0%. The rate of major complications was 36.9% (n=234), surgical site infection 6.3% (n=40), postoperative pancreatic fistula (grade B/C) 26.9% (n=171), and 30-day/in-hospital mortality 3.5% (n=22). Cutoffs for the feasibility, proficiency, and mastery learning curves were reached at 15, 62, and 84 RPD. Major morbidity and 30-day/in-hospital mortality did not differ significantly before and after the cutoffs for the proficiency and mastery learning curves. Previous experience in laparoscopic pancreatoduodenectomy shortened the feasibility (-12 RPDs, -44%), proficiency (-32 RPDs, -34%), and mastery phase learning curve (-34 RPDs, -23%), but did not improve clinical outcome. CONCLUSIONS: The feasibility, proficiency, and mastery learning curves for RPD at 15, 62, and 84 procedures in "second-generation" centers after a multicenter training program were considerably shorter than previously reported from "pioneering" expert centers. The learning curve cutoffs and prior laparoscopic experience did not impact major morbidity and mortality. These findings demonstrate the safety and value of a nationwide training program for RPD in centers with sufficient volume.

Use and outcome of minimally invasive pancreatic surgery in the European E-MIPS registry.

BACKGROUND: The European registry for minimally invasive pancreatic surgery (E-MIPS) collects data on laparoscopic and robotic MIPS in low- and high-volume centers across Europe. METHODS: Analysis of the first year (2019) of the E-MIPS registry, including minimally invasive distal pancreatectomy (MIDP) and minimally invasive pancreatoduodenectomy (MIPD). Primary outcome was 90-day mortality. RESULTS: Overall, 959 patients from 54 centers in 15 countries were included, 558 patients underwent MIDP and 401 patients MIPD. Median volume of MIDP was 10 (7-20) and 9 (2-20) for MIPD. Median use of MIDP was 56.0% (IQR 39.0-77.3%) and median use of MIPD 27.7% (IQR 9.7-45.3%). MIDP was mostly performed laparoscopic (401/558, 71.9%) and MIPD mostly robotic (234/401, 58.3%). MIPD was performed in 50/54 (89.3%) centers, of which 15/50 (30.0%) performed ≥20 MIPD annually. This was 30/54 (55.6%) centers and 13/30 (43%) centers for MIPD respectively. Conversion rate was 10.9% for MIDP and 8.4% for MIPD. Overall 90 day mortality was 1.1% (n = 6) for MIDP and 3.7% (n = 15) for MIPD. CONCLUSION: Within the E-MIPS registry, MIDP is performed in about half of all patients, mostly using laparoscopy. MIPD is performed in about a quarter of patients, slightly more often using the robotic approach. A minority of centers met the Miami guideline volume criteria for MIPD.