Superior Mesenteric Artery First Versus Standard Approach in Pancreaticoduodenectomy

Overview

"Pancreatic cancer, especially pancreatic ductal adenocarcinoma, is one of the most serious and deadly cancers. Its outlook is very poor, with fewer than 10% of patients surviving five years after diagnosis. This is largely because the disease is often discovered at a late stage and because it frequently comes back even after surgery. When the tumor is located in the head of the pancreas, the only treatment that can potentially cure the disease is a major operation called a pancreaticoduodenectomy, also known as the Whipple procedure. This surgery is now safely performed in specialized hospitals, but it remains complex and carries a high risk of complications. Importantly, even after surgery, cancer cells often remain, leading to a high rate of local recurrence. A newer surgical technique, known as the "artery-first" approach, changes the order of the operation. By carefully exposing a major blood vessel near the pancreas at the beginning of the surgery, surgeons can better assess whether the tumor can be completely removed and can improve the precision of the operation. This research protocol aims to compare this artery-first technique with the standard surgical approach. The goal is to determine whether starting the operation by addressing the artery allows for more complete tumor removal and reduces the risk of cancer coming back in patients with pancreatic cancer of the head of the pancreas."

Detailed description

"Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer death in the United States and Europe by 2030. It remains the worst prognostic gastrointestinal cancer, with a 7-9% five-year overall survival (OS) rate. The majority of patients are diagnosed at an advanced stage, i.e., locally advanced (30%) or metastatic (50%), and more than 60% of the operated patients relapse within 3 years after surgery.

Pancreaticoduodenectomy: standard approach Pancreaticoduodenectomy (PD) is the only potentially curative technique for PDAC of the pancreatic head. The procedure, commonly named the Whipple procedure, was described in 1935 when O.Whipple reported the previously modified technique by A.Codinivillan and W.Keusch. In its current form, the Whipple procedure owes its evolution to many physicians and surgeons' groundbreaking and innovative work. The procedure is now performed with an acceptable mortality rate of \< 4% in expert centers and and nevertheless 30% morbidity.

Pancreaticoduodenectomy: SMA first approach, peri-adventitial dissection Whipple procedure with mesenteric first approach is a technique described and validated in surgery for pancreatic adenocarcinoma. This technique, which involves dissecting the peri-adventitial tissues of the superior mesenteric artery, has been reported mainly in borderline or locally advanced tumors of the head of the pancreas, to control the artery and improve the quality of the resection. This technique allows exposure of the right hemicircumference of the artery and clearance of the origin of the celiac trunk before sectioning the key elements of the duodenopancreatectomy cephalic.

Six surgical approaches that can be considered as "artery first" have been reported by Sanjay et al. Two approaches to avoid technical biases in SMA dissection and arterial margins will be considered: the right posterior approach and the anterior approach.

Although PD is mature, the low R0 resection rate remains a major issue, and most patients will develop a local recurrence, as demonstrated by autopsy studies.

The investigators hypothesise that the SMA first approach (SMA-PD) improves R0 resection margins compared to the standard procedure (ST-PD) during PD in patients with pancreatic head adenocarcinoma."

Interventions

• Procedure SMA-first pancreaticoduodenectomy using either right posterior or anterior approach. SMA identified and isolated with peri-adventitial dissection before any irreversible section.
  Before any irreversible gesture, the surgeon identifies and isolates the superior mesenteric artery and dissects nerve plexus and nodes on the right side up to the SMA origin (right posterior or anterior approach).
• Procedure Conventional pancreaticoduodenectomy without prior isolation of the SMA; antero-posterior approach of the uncinate process after pancreatic section.
  Conventional pancreaticoduodenectomy without prior isolation of the SMA; antero-posterior approach of the uncinate process after pancreatic section.

Primary outcome measures

• R0 resection rate (clear margin > 1 mm) [Time frame: day of surgery]

Secondary outcome measures (7)

• Disease-free survival (DFS) [Time frame: Up to 48 months after randomization]
• Overall survival (OS) [Time frame: Up to 48 months after randomization]
• Operative Blood Loss [Time frame: During surgery]
• Operative Time [Time frame: During surgery]
• Postoperative Complications [Time frame: Up to 3 months after surgery]
• Postoperative Morbidity [Time frame: Up to 3 months after surgery]
• Health related quality of Life [Time frame: At inclusion and 6 months after surgery]

Eligibility criteria

Inclusion criteria

• Primary resectable or borderline with isolated veinous contact pancreatic adenocarcinoma (according to the NCCN classification and international consensual definition of Isaji 2018): resectability is evaluated on arterial-phase and portal-phase IV contrast-enhanced multislice CT scan of the pancreas (slice thickness: 2.5 mm), and assessed in a multidisciplinary staff meeting including at least one radiologist and one expert surgeon.
• CT-scan of the thorax and abdomen confirming non-metastatic PAC at least 45 days before inclusion
• MRI of the liver without metastasis performed maximum one month before inclusion
• CA 19.9 (carbohydrate antigen) level ≤ 500 U/mL at the time of inclusion (in absence of cholestasis or biliary drainage)
• Age 18 or over
• Grade 0 or 1 Performans Status (ECOG)
• Normal renal and liver function at the time of inclusion (According to Cockroft and Gault's equation Glomerular Function Rate > 50ml/min/m2; Prothrombin Time > 70%)
• Absolute neutrophil count > 1,500/mm3, platelet count > 100,000/mm3, haemoglobin level > 10 g/dl (transfusions are authorized) at time of inclusion
• Adequate contraception on fertile women
• "Women of childbearing potential (defined as under 50 years of age and without a history of hysterectomy or tubal ligation) must not self-report being pregnant on the day of inclusion."
• Patient who provides a signed written informed consent form
• Patient having the rights to French social insurance

Exclusion criteria

• Pancreatic adenocarcinoma defined as "borderline" with arterial contact, locally advanced, non-resectable, or metastatic.
• Surgical or anesthesiologic contra-indications:

Non-controlled congestive heart failure - non-treated angina - recent myocardial infarction (in the previous year) - non-controlled AHT (SBP >160 mm or DBP > 100 mm, despite optimal drug treatment), long QT

• Major non-controlled infection
• Major comorbidity that may preclude the surgery
• Severe liver failure
• Any medical, psychological, or social situation that (in the investigator's opinion) could limit (i) the patient's compliance with the protocol or (ii) the ability to obtain or interpret data
• Pregnant or breastfeeding women and women of childbearing age not using effective means of contraception
• Curatorship or guardianship or patient placed under judicial protection
• Participation in other interventional research type 1, clinical investigation or clinical trial during the study

Secondary exclusion criterion (during surgery):

• Evaluation of abdominal cavity, presenting infra-radiologic metastasis
• Positive tumoral invasion at frozen section after picking on the inter-aortic lymph nodes performed before any irrevocable organ section.
• Anasthaesiologic complication (induction allergy or unprevisible heart disease at induction)
• For fertile women: serological pregnancy test positive before surgery

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

France · 23 centers

• CHU Amiens — Amiens
• CHU Angers — Angers
• CHU Besançon — Besançon
• Hôpital Haut Lévêque — Bordeaux
• Hôpital Estaing — Clermont-Ferrand
• Hôpital François Mitterrand — Dijon
• CHU Lille - Hôpital Claude Huriez — Lille
• Hôpital Claude Huriez — Lille
• … and 15 more centers

Publications

• 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 Aug;240(2):205-13. doi: 10.1097/01.sla.0000133083.54934.ae. PMID 15273542
• Slankamenac K, Graf R, Barkun J, Puhan MA, Clavien PA. The comprehensive complication index: a novel continuous scale to measure surgical morbidity. Ann Surg. 2013 Jul;258(1):1-7. doi: 10.1097/SLA.0b013e318296c732. PMID 23728278
• Tempero MA, Malafa MP, Al-Hawary M, Behrman SW, Benson AB, Cardin DB, Chiorean EG, Chung V, Czito B, Del Chiaro M, Dillhoff M, Donahue TR, Dotan E, Ferrone CR, Fountzilas C, Hardacre J, Hawkins WG, Klute K, Ko AH, Kunstman JW, LoConte N, Lowy AM, Moravek C, Nakakura EK, Narang AK, Obando J, Polanco PM, Reddy S, Reyngold M, Scaife C, Shen J, Vollmer C, Wolff RA, Wolpin BM, Lynn B, George GV. Pancre PMID 33845462
• Jiang X, Yu Z, Ma Z, Deng H, Ren W, Shi W, Jiao Z. Superior mesenteric artery first approach can improve the clinical outcomes of pancreaticoduodenectomy: A meta-analysis. Int J Surg. 2020 Jan;73:14-24. doi: 10.1016/j.ijsu.2019.11.007. Epub 2019 Nov 18. PMID 31751791
• Kim SY, Choi M, Hwang HK, Rho SY, Lee WJ, Kang CM. Intraoperative Transfusion is Independently Associated with a Worse Prognosis in Resected Pancreatic Cancer-a Retrospective Cohort Analysis. J Clin Med. 2020 Mar 4;9(3):689. doi: 10.3390/jcm9030689. PMID 32143434
• Kneuertz PJ, Patel SH, Chu CK, Maithel SK, Sarmiento JM, Delman KA, Staley CA 3rd, Kooby DA. Effects of perioperative red blood cell transfusion on disease recurrence and survival after pancreaticoduodenectomy for ductal adenocarcinoma. Ann Surg Oncol. 2011 May;18(5):1327-34. doi: 10.1245/s10434-010-1476-3. Epub 2011 Jan 8. PMID 21369744
• Ejaz A, Spolverato G, Kim Y, Margonis GA, Gupta R, Amini N, Frank SM, Pawlik TM. Impact of blood transfusions and transfusion practices on long-term outcome following hepatopancreaticobiliary surgery. J Gastrointest Surg. 2015 May;19(5):887-96. doi: 10.1007/s11605-015-2776-5. Epub 2015 Feb 24. PMID 25707813
• Mavros MN, Xu L, Maqsood H, Gani F, Ejaz A, Spolverato G, Al-Refaie WB, Frank SM, Pawlik TM. Perioperative Blood Transfusion and the Prognosis of Pancreatic Cancer Surgery: Systematic Review and Meta-analysis. Ann Surg Oncol. 2015 Dec;22(13):4382-91. doi: 10.1245/s10434-015-4823-6. Epub 2015 Aug 21. PMID 26293837

Identifiers

NCT: NCT07547033 · APHP220920 · 2024-A02711-46

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗