Spleen Preservation Versus Splenectomy in Left Pancreatectomy for Pancreatic Ductal Adenocarcinoma (SPLENDID)

Rationale: During left pancreatectomy for pancreatic ductal adenocarcinoma (PDAC), routine en-bloc splenectomy is performed to achieve complete nodal clearance of the splenic hilum. However, there is no evidence that routine splenectomy improves survival. Splenectomy has been associated with increased postoperative morbidity, lifelong vaccination requirements, and risk of overwhelming post-splenectomy infection. In addition, lymph node metastases in the splenic hilum are uncommon (\~4%), and preservation of splenic immune function is becoming increasingly important with the emergence of novel immunotherapies. Spleen-preserving left pancreatectomy (SPLP) may therefore be a safe alternative to routine splenectomy, but no randomized trials have evaluated this approach.

Objective: To compare SPLP with left pancreatectomy with splenectomy (LPS) regarding (1) overall survival over a 3-year period, assessed using restricted mean survival time (RMST), and (2) major postoperative complications within 90 days (Clavien-Dindo grade III or higher) in patients with resectable or borderline resectable PDAC.

Study design: An international randomized multicenter non-inferiority trial performed in high-volume pancreatic centers. Participating centers perform at least 15 left pancreatectomies annually, and participating surgeons have completed at least 30 SPLPs (for any indication) and 15 left pancreatectomies for PDAC. Randomization will be performed in a 1:1 ratio using a secure web-based system, stratified for receipt of neoadjuvant therapy (yes/no) and tumor location (body/neck versus tail).

Study population: Two groups of 180 patients (360 in total) with proven or suspected resectable or borderline resectable PDAC requiring left pancreatectomy.

Intervention: Spleen-preserving left pancreatectomy.

Control: Left pancreatectomy with splenectomy.

Main study parameters/endpoints: The primary endpoint is overall survival over a 3-year period, assessed using RMST. The main secondary endpoint is major postoperative morbidity within 90 days (Clavien-Dindo grade III or higher). Other secondary outcomes include quality of life, R0 resection rate, disease-free survival, time to and site of recurrence, receipt, timing and completion of adjuvant therapy, pancreas-specific and general postoperative complications, unplanned splenectomy in the SPLP group, secondary splenectomy, spleen- and asplenia-related complications, time to functional recovery, length of hospital stay, health-care resource utilization, and cost-effectiveness.

• SPLP (Procedure): Spleen-preserving Left Pancreatectomy
• LPS (Procedure): Left Pancreatectomy with Splenectomy

Primary outcomes

• Overall survival over a 3-year time period (3-year restricted mean survival time (RMST)) [Until 3-years after the day of surgery]

Secondary outcomes

• 90-day major postoperative complications [From the day of surgery until 90-days postoperative]: Clavien-Dindo classification grade ≥3

Other outcomes

• Intraoperative outcomes [Day of operation]: \- Diagnostic laparoscopy performed (yes vs no);
• Complications [Day of surgery until 90-days postoperative]: * Postoperative pancreatic fistula (grade B/C); * Post-pancreatectomy hemorrhage (grade B/C); * Delayed gastric emptying (grade B/C); * Post-pancreatectomy acute pancreatitis (grade B/C); * Chyle leak (grade B/C); All reported according to the ISGPS definitions
• Pathological outcomes [When pathology report available postoperative]: \- Tumor size; mm
• Oncological outcomes [Until 5-years postoperative]: * (Neo-)adjuvant treatment; yes/no * Recurrence: yes/no * Treatment of recurrence: yes/no
• Outpatient clinic follow-up [Until 5-years postoperative]: * Metastatic disease; yes/no * Overwhelming postoperative sepsis; yes/no * Prophylactic or use of on-demand antibiotics; yes/no * Vaccinations; yes/no * Death. yes/no
• Quality of Life - EQ-5D-5L [Preoperative until 5 years postoperative]: EQ-5D-5L; Health states are converted into an index value using the prespecified value set. A value of 1 represents full health, 0 represents a health state equivalent to death, and negative values represent health states considered worse than death. Higher values indicate a better outcome. The possible minimum value is \[insert minimum for the selected value set\] and the maximum is 1.
• Quality of Life - QLQ-C30 [Preoperatively until 5 years postoperatively]: QLQ-C30; Scale and single-item scores range from 0 to 100. Higher scores on the functional scales and global health status/quality-of-life scale indicate better functioning or quality of life, whereas higher scores on the symptom scales indicate more severe symptoms and therefore a worse outcome.
• Quality of Life - PAN26 [Preoperatively until 5 years postoperative]: PAN26; Scale and single-item scores range from 0 to 100. Higher scores on symptom scales indicate more severe symptoms and therefore a worse outcome, whereas higher scores on the satisfaction with health care and sexuality functional scales indicate better functioning and therefore a better outcome.
• Intraoperative [Day of operation]: \- Type of left pancretectomy performed: Pancreatic Tail Resection (PTR), Pancreatic Body Tail Resection (PBRT), Panreatic Neck Body Tail Resection (PNBTR), Extended Pancreatic Neck Body Tail Resection (ePNBTR)
• Intraoperative [Day of surgery]: Conversion; yes/no, emergency of non emergency
• Intraoperative [Day of surgery]: Pancreatic duct size; mm
• Intraoperative [Day of surgery]: \- Pancreatic texture; Soft/normal or Hard/Fibrotic
• Intraoperative [Day of surgery]: \- Estimated intraoperative blood loss; mL
• Intraoperative [Day of surgery]: \- Intraoperative blood transfusion; Yes/no and number of units transfused
• Intraoperative [Day of surgery]: \- Total duration of the procedure; minutes
• Intraoperative [Day of surgery]: \- Vascular resection; yes/no and specified which vessels
• Intraoperative [Day of surgery]: \- Extended resection; yes/no and specify which additional organs are resected
• Intraoperative [Day of surgery]: \- Serious intraoperative complications: Satava classification
• Complications [Day of surgery until 90 days postoperative]: * Non-surgical complications (including pulmonary complications); yes/no * Surgical site infection; yes/no * Postoperative re-intervention (radiological/endoscopic/surgical): yes/no * Single- or multi organ failure; yes/no * Need for secondary splenectomy; yes/no * 30- and 90-day mortality; yes/no
• Pathological outcomes [When pathology report available postoperative]: \- Histology grading; according to the royal collega of pathologists
• Pathology outcomes [When pathology report available postoperative]: \- R0/1; according to royal college of pathologists
• Pathological outcomes [When pathology report available postoperative]: \- Total lymph nodes retrieved and number of positive lymph nodes;
• Pathological outcomes [When pathology available postoperative]: \- Lymphovascular invasion and perineural invasion; yes/no
• Pathological outcomes [When pathology report available postoperative]: \- TNM classification: Pathological tumour-node-metastasis (pTNM) stage according to the Union for International Cancer Control TNM Classification of Malignant Tumours, 8th edition. Stage groups range from stage 0 to IV, with higher stages indicating more advanced malignant disease and a worse outcome.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Age at least 18 years;
* Elective indication for left pancreatectomy for proven or suspected PDAC;
* Upfront resectable or borderline-resectable PDAC in the pancreatic neck, body or tail, according to the National Comprehensive Cancer Network® (NCCN®);

  o Patients receiving neo-adjuvant treatment can be included in the trial, if the tumor was upfront resectable or borderline-resectable before the start of neoadjuvant therapy. Patients receiving induction therapy for locally advanced pancreatic cancer (LAPC) will be excluded.
* Spleen preservation using SPLP with the Warshaw (splenic vessel-resecting) procedure including Gerota's fascia (i.e. circumferentially radical) is feasible according to the local treatment team;
* Fit to undergo left pancreatectomy according to the surgeon and anesthesiologist;
* Written informed consent.

Exclusion Criteria:

* Preoperative imaging indicating (possible) tumor involvement of the perisplenic LNs (LN station 10 and perisplenic fat);
* Distance between the left border of the tumor and the center of the splenic hilum is <3cm on preoperative imaging;
* Locally advanced PDAC according to the NCCN definition or distant metastasis;
* Previous abdominal surgery in which the short gastric and/or left gastroepiploic vessels were ligated (e.g. gastrectomy, gastric sleeve, fundoplication), resulting in the impossibility of performing a Warshaw (spleen-vessel resecting) procedure;
* Pregnancy.

• Jony van Hilst, MD, PhD, Principal investigator, Amsterdam UMC
• Marc G. Besselink, MD, PhD, Principal investigator, Amsterdam UMC
• Mohammad Abu Hilal, MD, PhD, Principal investigator, Jordan University Hospital